Wilson & Gisvold\'s Textbook of Organic Medicinal and Pharmaceutical Chemistry 11th ed
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Wilson and Gisvold's Textbook of
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Wilson and Gisvold's Textbook of
ORGANIC MEDICINAL AND PHARMACEUTICAL CHEMISTRY E L
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Edited by
John H. Block, Ph.D., R.Ph. Professor of Mt.:dicinul Chemistry
Department of Pharmaceutical Sciences College of Phanl1acy Oregon State Uni versity Corvallis. Oregon
John M. Beale, Jr., Ph.D. Associate Profcs!iOr of Medicinal Chenl istry al1d Director of Pham13ceul ical Sciences 51. Loui ~ College of PhamlllCY 51. Louis. Mi!osouri
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lipPINCOTT WILLIAMS & WILKINS " WoI!rn Klu ..·.,. Companv
Phil.ldelphia • 1l~lt"no..., • New York • london Bu".,os ",,~ . Hong Kong • Sydn.~y • Toky.:>
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All rip'" ",,,,, .... od. '"111, booIt .. ~ ..,. ""P)'riaht. No put of lI1i, boil)' ofTe~'Js. Dr. DcISado tru~ele(] extcnsively in Mexico and South Ameri ca to prc.'!elll IectU/"e,'lOIi pharm!II,:eulical education. Jarme Delgado's first conlributions to the T,wbook lyOrg(Uli(- "'1"/'cil1l,1 (.1/1/1 Phllmlfl«u/icll/ C~m. iJfry ... ere made as II chapter author in lho: ~\'enlh and ..i,hlh edilklnS. Much oflhe malerial he pf\:StnlC'd cam.. from his Iec,ure notes. Although he was proud of the.o;c OOOlribulions.... hich ....en: upandcd III the nrnl h and tenth edilions. he ooosidf:orod hiJ role as coedilor in lhe Iauer edilions one of the highlr ghls of hIS diSlinguished career. Jaime wa.~ II lrue gentlell1an 1100 a pleasure 10 ha\'e as II collaborulOl'. He will be greatly mi",-';cd by the edilon;. 3I11hor~. and prorc.~sional staff for the TI'.nbook,
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Wi/bllm A. Rt'mt'f$
Charles O . WilSfio
1'11 _2002
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s the ,hapler,,: for the elel'ellth edition
,,'e~ being sent to the publisher. I was llO(iflC(lthat my
oollea¥\IC and fritnd. Charles Wil~. had died '\honly aftcr Chrisnnas. He was a product of the I'ocific Northwest hal ing received all of his degrees from the Unil·~ny of WashinglOO. HIS first tcaching job was 1Il the now diSl:ontinuro ph~y school at George Wa'\hingtoo Unil'ersity and then he 11101·cd to tile Unlve,..;ity of Minnesota. Charles. alooS with (Miler medicinal chemistry faculty at the Unil·ersity of Minnesota. saw the need for tex tbooks thai prellCnted modem medicinal chemi stry. In 1949. he and Professor Ole Glsvold ediled Organic Chl'misll',), in Ph(lI'"m(IC\·. "hiCh became the first edition of the Tl'XIIHKn: of M edici,wl mill PIJUrmllUfu;cill Chtm;.flry. Conli nu 109 in this tradition. Charles and Profeso.or Taito Soinc a.~!iumtd the: aulhoJship of Hogl"·J InorganiC' Phl/muluu/kill Chl'mi!/,)". which included eight edition~ before its di.oominuanct:. Finally. Charles and l"rof!!S5Of Tony Jones staned the AnrtriC'Qn Drug /ooa series. Charles continued his publishing lK.1ivities after moving 10 the University of Texas llnd then assumed the position of Dean of On:lon St:IIC Uni\'~uy'5 School of l'hamUiCY. where he overSllw a major cx pansion of ils faculty and physical plant. Ahhoul!:h a medicinal chemist. Charles devoted considerable time to his chosen plwmacy profession. Siudents. and communily. ChIlf1e.~ " ·as an activc member of the Amelic.1ll Pharm:l\;eullcal ASSOCiation lIS well as lhc phall11:lC")l associations in exh stale ....·here he lil·ed. In addition. he was a registcrW pharmacist in eacll stale where he taugllt: Wasllington. MinllC5Ota. Te.):as. On:gon, and the Oi~trict of Columbia. Charles chllired nauonal commiuces and .seclions of !he American Pharmaceulical Association and lhe A merican Association of College5 of I"II:lrmacy. Rt'laled to these, hiS IOYllity 10 $tudcms il"lCluded organi1.ing 5tudcnl bral"lChocs o(the American j'lIannaceutical Associauon 31 Georgc Washington University. the Umvcrsity of MinllCSOlll. and the Univcn;l1y ofTuas. He "'"ali IIClilely involved in the local AmcriclU1 Red Cross blood progrum and tOOk the lead in del·eloping the lIugely success(ul .student cenlcn:d blood dtil·es at ~goo Stale Unh·~ity . In 1960. Charles llnd his ,,"Ifc. Vaughn. helped launch the AFS (American Field Service) in Corvallis. an inlemational high-!iChooi uchangc program. lIe voluIl\cen:d for Mcal ~ on Wheels (or 0~C1" 30 yCarl aftcr his rctircrnent. We cl:" lIIn ly ml~s thiS fine gentleman and leaderof phDrmacy C"dllCatlOll and the p/larm:lcy profes5ion.
John II. Bkd
PREFACE
For almost six UccHdcs. Wilsoll all/I Gijl'Old's T~Albook of Organic Medicil'ml lII.d PI)(1rmOCtiuliC(Ji Chemim)' hru; been a S1and~rd in the litcnl1un:: of med icinal c/lcmistry. Generations of sl udenlS and focully have depended on this textbook 11Q\ onl)' for undergr.lduDlc courses in medicinal chemistry but also as a supplement for graduate studies. Moreover. sUldem. in other hcalt ll scicnrofessor Emeritus PhannJtCOlogy and ToJdeology Universily or ArizOIla Tucson, ArilOna
/.
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ContribulO'S
THOMAS N. RILEY, I'H.D.
GARETH TI:IOMAS, I'H.I).
School or PhalltUlt"y Auburn Unherslly Auburn. Alabama
Associate Senior L«1urer TlJc School of Pharmacy and Biomedical Scicnces UnivcrsilY of PonslTlOUlh Portsmouth. England
.' ORR ..:sr T . SMITH. )' H.D.
T . KENT WALSH, 0 .0 .
Associale Professor {)cpattmtnt of Pharmacal Scicoce!i School of Pharmacy Auburn Univcrslty Auburn. Alabama
Direclor Nuclear Medicine Program Southern Ari:rona V.A. Health CIl«: System Tucwn. Arizona
Pmfc!uor of Medicinal Chrmistry {)cpattmcnt of l'hann Drug...... MclIKuIes Supports iWId Unk.er.; SokJIIOn-Ph.Jsf Combooatooal Ch.rm~lry I'ooIIng Sl!ateglfS Dtt«IIOrt, F'uflfocatoon•• nd An.lIysrs EntOdirrg CombroatonclillbrMIeS Hrgh-Throughput SCret'!'lmg {HTS) VlI'\lJaI (an S,1Ico) 5cret'!'l,ng ClWrliCal DNersrty and library DesIgn I\cfIM Card OIl Combroatooal Chemrstry: Has II Worted ?,
" .•..
Rtsor.-te. for Combroatonal Chemistry ConOnalooal Chemtstry Termonology .
...." 49 50
"" 53 54 55
58 60 60
KAPTl R.
MtlObolic Changts of DrIlgs and R t latt d Orgullic Compol/llds ................. . SIc, t "J C.rl.r Wtd Jolm If BJ"d Gfnefcll Pathways of Orug Metabolrsm '>rl~ of Drug BIOtransformatIOn
(hemal Deitvery Systems
"
66
144
.
1S2
IS'
CHAPTER6
Wotecl",Q!ogy alld DrIlg Discol.try
• • • • • •
160
Jolm M /k,d•. Jr
BlOte1 and Our-mon of Anesthesia 5«~ Pharmac.oIogIColI Ac.tlOll
StructurE Amon HAPTER
.......
67' 67' 68S 687 687 688
68'
'90
21
lIistamine alld AlltihisUlmilll'c Agel/ts l7Ir_
NR,",. tutd Jr>rl:
SterOId NomeodaturE. Stefecxhernrslty. and Nu mber'ng SterOId BIOSynthesis _ Chemical and Physocal Propertll!S of 5teroods Changes to Mod,fy Pharmacol(ll'-.etlC PropertIeS of Steroods SterOId Hormone RKeptors GnRH and GonacIotrOplllS Sex Hor/TlOfleS . Chermcal ConltaceptlYe Agents Androgens Adlenal Cortex Hom"IorIe$
767 768 770 770 770 773 775 789 797 803
CHA PTER24
und Gwr1l' If. C""'JU' J
20
!,1"IIp J. Prol~""
622
ArltIanqIrIolI Agents.;md V.nodilators
HA~TER
Steroids and Therapeutically Related Compounds ... . ..... ................ 767
696
INRw"~r
Htsumme ufe C.,.cIe HtsU!l"llt\l! H, Antagonl5ts (Antlhlstam,nlC Agents)
'96 '" 700
Prostaglandil/s, Leukolriettes, alld Ollrer Eicosalloi(I!.' .... ..................... 8 r8
n...-.u J. 1/01_1. Jr HIStory of D&OYefY ElCosarlOfd Biosynthesis Drug ActiOn Medlated by Eorosanoods COX·2 .,hobotors DesIgn of Eorosanood Orugs DewlOf)rTlenl of Prostacyd,n..()e(lved Products ElCosanood RKeptors EICOSCInoods Approwed for HutI'Ioln CIIflICaI U!.e Prostaglandl~ for Oph\halmtC lise Vetellnary Uses 01 Pl"ostanoicls . EKosanotds In ClinICal Development for Human Treatment
818 81B 822 822 823 823 825 827 828 828 829
(HA~TEA2S
Proteill$, EII1,J'mes, alld Peptide HormOl.es ........................... 830 Sir/Wit J.
C.'II~r
/gut/o
lipid-SOluble Vitamln~ Wilter-Soluble Vitamins MIscellaneous ComIdl>I'illlOilS
86' 885
900
(HAPTER21
All II/trodflctioll to the Medici" al Chem istry of Herbs .................. . 904
J I'MI/lp HI,....." Computer GraphICS iII1d Molecular VlSUide of traditional pilarlll~y disuibo.nion chanoel$. It is imponant rOl" the pharmaciSt and the public te undel1iland the rigor thai 15 mjuired for plt:M:ription-only and rnA -approved oonPfUCripuon productS to be approved rdat;\c 10 the nomrlldilionul prodUCts. II also is imponom for all pcuple in the health can: ricld alld the public 10 realize thai .... helhcr these nontraditional prodllClS are effective as clain1l:d or nOl. many of the altcm:llc medicillCS contain plwmacological1y aclin' ageRIS that eM potentiple or interfere with ph)'~ician -pre;.cribed lliempy. Hundrals of Ihousands of new organic chemicals an: prepared annually throughoullhc world, and many of them are entered inlo pharmacological scret'ns \0 delennine wbether they ha~ useful bimogicaJ ICti vLty. n"s 1)I"'es.~ of rundom screening has been considered inefficient. but it has m;ulted in the idcntincalion of new lead compounds who!ie structures have been optimiud 10 produce cllnlcalllgenlS . Sometintrs. a lead de\'elops by careful obseT\'alLon of the pharmacological behavior of an existing drug. "The discovcry thm am:ILLladine pnxt:CtS and IreatS early innuenza A came from a generol ~n fill" antiviral agents. The usc: of amamadmc in long·tenn can: faciliti es showed that it aJ'iO cou ld be used to treat partillSQllian di§Ofders. More recently. automated high-throughpul.\Creening systcm~ utiliJ.ing cdl culture syslem~ wi!h linked enzyme asALys and receptor molecules derived from gene cloning have greatl y iLlcreased the dficicocy of random screening. It i, now practical to!iC1ttn e~ libnuies of peptide!; and nocicic acids obtained from combinatorial chemistry procedureol. Rational design. the ~lIe approach to high· volu me screening. is also nourishing. Significant :.dvaoces in ",-ray crysallogrl.phy and noclear IIUIgnetic Te.'iOOlI11Ce have made it possible to obtain detailed representations of enl.YIlll:5 and o!hcr drug recepton.. Thc techniques of molecular gruphics and compullltional chemlSlry have provided nowl chemical su'uctures that llave led to new drugs with poklll medn:mal activities. Development of H IV prote~ inhib'l ors and all· giotcnsin-coovening enzyme (ACE) inhibllOl"$ came from an understanding of the geomelry and chemLcal character of the I'l:spective enl,Yllle's aclive site. Even if lhe recepuJI" MtuCture is not koo.... n in detail. mILonnl approaches based on the physiClXhrmical propcnic.~ of lead compounds can provide new drugs. For example. the development of cimcli · dine as an antinuclear drug involved II careful s1udy of the ch:u1ges in antagonism of Hr histaminc n:ceptOl' induced by varying the physlclll propcnics of Mrocture5 based on I
histamine. Statistical methods Ixoscd on tIM: Com:lallOlI of physicocIM:mic~1 properties with biologicpl potency arc used to CJlpl~in and opumize biological act;\';ty. As you proceed through tnc chapters. thm" or ... hat pr0blem the medicinal chcmiq i~ trying to solve, Why ...en: CC1"tain .'II.ruClUrcS selected? What l1Iodifiealion~ were mnde to
produce more focused activny or reduce a(h~ or prodUl'e better ph~nllaceutical pmpc:nics? Was t typical molecule dhcovered rrom nlJ1dom ~,. medicinal chemist !Ia\'e a structural concept or an u~andlll8 oflhediscase process tnat mUSlIll" i ruptoo "
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Physicochemical Properties in Relation to Biological Action ~H.
BLOCK
\!oJdtm drug design. romp.m:d with the pOllh-lel'J mau a change 011 (In e.flSllng
clas~lCal ap('Qm(N/IHld QI'
Siruct.. ", und ue "'hal JUlI'pt'IU-COIlI;n~we.oh·c rnpidly as an approoch to soh.. inS a drug design probknl. '"The comblllution of increasing po","cr and decn:a§1111 ro.l of dc!;ktop compuTing has had a major impact on JOlI~mll drug t1c~ign problem s. Whil e drug design incrcaslolly I' ba'lCd 011 modem computMio nal chcmical technlG~\.. II 1.1-0 U'C$ sophisticated knowlcdge of disease IIIt(l\aImms ~nd n'("Cpcor properties . A good understanding If !low the drug is tr.tnsported inlo tt..: body. di~t ributed Ihroughoutthe bod) companmcnt~.melaholicl.lly ahered by tIr Ihtr lind other organs. and Cllcn:led from ~ patlenl ~ ~u~ ~g ","ilh the struclural r;-h:lt1lCleriSlles of the 1«'pI« Acid- base chemistry i~ u~ to Iud In formul:allon IIILI btodlSirioolion. Structural allribulCllilnd substill,K'nl palIL'fll.'; ~~iblc for optimum pll:ulnarologic:al activity can IIIll'll be prtdictcd by statisticallechniqucs soch as n:gn:~slon ~I)"s", Compulcn/..cd conform:1tion:ll nnalysi~ pcmUls ~ medicinal chem"l to predici the drull'~ Ihn:c-dimcn~ional ~ ilia! i~ 1UII by the receptor. With the isol:uion lind W1IC!urtl determination of sp::c ific n"l:cpcors and the IIvailabilll)" ('()InpuTer $Oftwnre thai can estimatc the three-diraemionItl wpc of the rra-pcor. il is possiblc to dc.~ign moleC\j~!IuI will MIow an optimum fit to the n"e (free anullc) is the SpeclCS most readily cffl\~i ng tile noopolnr """mbnmes (Fig, 2-4). Ct)n~ider tile dmnging pH environ ment eJpeneoced by tl'lc drug molecule orally admin iical chemicml I.",oen), equals l~l To understand lhe COIlCCl'onuOf)' fUllIM:1 model and ... hm lIClUil UYOCCllr.J in the body iJ Ihal ,he panihoning in the fUlinei will reach an c:qui librium at which the rule of chemkallca~ing the aqucous phase and rnlenng the organ ic phase will eq ual the rale ofthechemical moving from the organic phase 10 the aquwu.~ ph.1SC.'. This ., I'lOl the physiological SI\U:il,on. Refer 10 Figure 2-1 and noo: thaI dynamic changes an: occurring 10 !hi: d rug. such as II being metllbolilcd. bound 10 SC,'nun albtJrnm, e;J.erclcd from the body. and bound to m:cplOf'lO, The CTlY IIl:m mcnt for the drug is not Sialic. Upoo a(!numstr.lllon. lhe drug will be palhtd Ihmugh the mcmbnanc:s because of lhe high concenIflIItion of drog in the extrace1!ular flU id s relali"e 10 lhe conCCTllmlioo In the inlrocellu lar compan me nlli. In an lInem pi 10 maintain «juilibrium r.uios. lhe 110w of lhe drog will be from fy~tI: l1lk circulation through the "lClnbnme~ ooto the I'f«p101'l1, As the drog is mctaboli zed and c~cr~l ed fmm the body. II will be pufl~(J back across the membral\e.~. hnd the C(JOCen\rallQll of d rug at the I'«eplo~ will decn:a"e. Because much of lhe lime the drug's !1lo,enw.-"t across membranes b a panitionin8 process. the paI1l1lOn coefficient has become tnc most COlJlmon phySioochcnllCliI propcny. The que'IICIIl lhal now must be asked is "'hal IImniSol;ibk: l'IOIIpOIar w ln'llI systcm best mimics the "'"aterllip,d memboOliok b.:uners found in the OOdy'! II i~ no . . . realil.cd Ihal the II-octaool/walcr sy~em i~ an e~cc lk: nt eitimatOl" of drug rmnluoning in biologICal syqcm~. Indeed . on.e could argue tIw II "'as fortuitous thall1-octanol WI" available In n:a~na ble purity for the early partition codfic icm dctcm .inati o ns. Tuappn:dute why Ihi , is so. one mU~1 undel"Stund ItlC che minl nalure of the lipi d membrane •. 1lIc'IC membranes are nOi cxclu~h'c l y anhydrOll~ fany or oily structure~. As II !irst appro~imJtIOIl. they can be coo,ido:rtd bilD)"\'T!; composed of lipid, oon~l,tl ng of II polar cap and large h)'drophobic !!Iii. ~f'hol:IYl-eridcs ~ major components of lipid bilayer'S. OIhcr grOlJJ') of bifunctional bpids indude the sphingQln)ehnOpropoxy at R,; mett\()\y. propoxy. and bulO~y III R1: IlIl three mtrophcnoxy substltucnt" lit R,; and thio III ~ signifiC3l1tly Influence tile biolog~al rl:Sponsc:. lbc predicted )og IffiR fIJI' lhe: COItlpound. \\here RI .. meth)'1. Rl .. propo~)'. Rl _ 4-nitrophe noxy. olld R.. ". thio. would be calcu lmed from &iuation 2-29:
TABLE 2-9 coefficienb fOl" Subsmuenb In a set of Acetylcholinesterase InhibitOR"
It\aJ1I1ll1/.e
,.
~.
R, ~ O k C,II" QCH,. OC,!! •. OC,H,. OC,CI1.11 R, _ OCI!.. OC,II" OC,II ,OClC'H,.,. OC.II.
R, _ ----eno.,,;}
"""
. IHoi
0.0
O~!
".,
t .67)
0.61 1
··0.164 0.786
TIor_off_IO _ _ IIIII .............. _ · I: . . . . . . . . '"
II - . I ....
!r«..............
Ii . . . . . . - - . .• ., of ....
•
.,
,
N
0
' I
"C -IOC-1lC fIC·'JC- IOC·IIC·1 X"
tIC· 7C-8C-'lIC-1OC·1IC 6C.1(" · ' X·IIC· tOC 7C·IIC-9C · toe ·IIC- LlC 7(". 1]("· I IC'·tOC-ull i~ thai for e\U a moderate-si/..!': molecu le tYPIcal of InOI>t drugs. Ihnc can be 50 10 100 \'lInablc.~. TIle lecrunquc i5 to devdop a Luge SCI of ~heflljca" well eh:nC1emed in terms of the biological llell ... it)' that IS going 10 be' pmllCled. nils IS kllOwn as lhe lromillj/ u r. Ideally. n Ce from the utcriDec'i(mgcn rc.emse hy org anic pho!;pha'e\.
CI
Efh.~,ynlc
sufficient for a "able rombmation. COOS«jlOC'nlly. drop atl· Ing by \ 'inuc of tocir SIRIClural specirlC!!)' will bind 10 the rfi'CplOI' sile by hydrogen bonds. ionic bollds, IOIH.llpo1e and dipole-dipole 1I1 1Cl1llClion~. and ,an der Waal s' and 11),drophobk forces . Com ldcnng !he wide variel)' of funclionaJ groups found on a drug molecule and rttephX, !here will be h "ariel)' of secondary bomJing forces. 10ni7.:lI;on at physiologic:ll pH
Ac i d
eli,
H
\ .fi' .....OipECH
o-~~CHJ S"'Qllinf
Keep in mioo lhat i1 is ~i rablc 10 ha'l: most drug effects re'"co;iblc:. For lhi~ 10 occur. relal llely .... cak fOll-'es must be ill \'olved in the drug - rcccplOr complex yel be Strong enough 1hm (>\her bmding sites will 001 cOIllp:titi\'ely depl ete the .ile of action. Com pound ~ wil h hl!!h stfuctuml specificity lila)' orient $C,"eml weakly bindillg gnltlp$ so Ihatlhe summation of their imer.ll.1ions wilh 'pcriricpJly oricmc:U comple· memary groups on the receptor pru\'ide~ a l{)Ial bood strength
would nOflllully occur wilh lhe carboxyl. su lfonarnido. and alrprnn ic ammo j;TOUPS. as ""e ll as lhe qumemary ammOl1lum group al uny I'll. These !i()Urces of poIenlial ionIC hoods are frequently found in lICll ve drugs. Diffen:l1oI."eS in eleClTOnegaIInty berwce.n carbon aod OIho!r alom!l. such lIS oxygen and nnrogen.lead 10 In asymrnelric dlStributioo of eLectron s (dipoles) th;u arc also capable of fOrTInng weak bood~ .... lIh reglOrl~ of high 01' low elee.ron density. ~lICh as 100) or 0I1ler dipoles. CartxHl)'I. ester. amide:. ether. nitrile, and related glOOps lhat corl1a;n ~lICh dipolar furoction~ :ill: frequently found in cqu lvulel1l loca lions in muctur~lly specirlC drugs, The re lal lve impo:lI1ance of lhe hFfrogrll boml in lhe for· malioll (Jf 11 drug - receptor com plex is di fficult 10 U!IO.q,'SS, M uny drugN POS~Sb groups ~uc h as cu rbonyl. hydroxyl. ammo. and imillo, wilh the structural capabilities of :!Cling us lICCC plOI'!i or donors in the formation of hydrogen bond.., Howe.er. such groups ",ed to validate a hyd rophobic- bonding "lOde!. Then: an: tl'lO problcm.~ with thi~ ro~'('pt, Firl't. the term hl"droplwbic- Implies repul~ion. The ternt for Utt racllon is hydro{Jltllidll'. Secund . rind pa_ h~p~ mun: impon~l1I. there i. no truly ..... mer-frec region 1m Ihe n:ceptor. Thi, i. true even m the area. populuted by the oonpohlt ammu acid side l·haJn$. An aheroote approach is to coo'1dc:r only the C(IflCept o f tlydrophlhclty and lipopllll1clly. 1lIc ~inallng WaIC\'cnl h po,,"cr of thedistance:. Although inuividually \\euk. the ~ummut ion of their forres proVIde. a $lgmfic3m bolldmg factor In hlj;her.,Jccular· ..·elghll"Qmpound~. For example, II is not Jl'O'sible 10 di~lIJ1 /lOITIlal allane$ ""th more Ihan 80 carbon ~lontS. heeau.... the: energy of -80 "cal/mol required to sep;ullle the: mlecull'S is a pprm.,malc1y equal to the encrg) o,:qu ircd to bi'tak a c:ubon-carbon ro\ale:n1 bonLI. flat Slruo:Wr'($. suc h baromatlc nng~. pennI! do ..... npproach of Ulllrn~. W ilh VUIl tier Waals' forces of -0.5 to 1.1l " c:a llmo l for ew.:h mom. Iboot six carbons (a benlCne ri ng) would be IlCCe.·,ary to ilWch lbe Sln::nglh of :a h)drogen OOtid. 1lIc urom :ltle ring
Regan.!I.:...." of' the ultimale IlJeCh.II1"1I1 by ... hich the drug alldl/le receptor Interact. the urug mlhtllpproach the n:cep4Uf alld fit OmeN is often hrgh cnough for their illdepcndelll CArSICIlCC and tl:OCl lOO. Dlfferencrs in rt::lC1i ... uy offullC\lollal groups or intel1lCtion "'rm bIologICal n:'I:eptOf"'l may be due to differences in sterM: requrn:mcnls of lhe ~rpt()f1. In certlun semirigid nnll ~ystcm,. conf{lrl1lationallo;on~rs silo .... significant diffcrcoces in biological activilics. MClhods for caku· Iatin8 the.'iC cne'l'Y barriers IIfC discussed in ChapoCT 28. ~n chaln~ of (IIOnl!!. ",hrcb form an Important p:1rt of m.any drug nlolecules. are IlOl equally free 10 assumr all possiblc oonformallons; some are SlCrtelLll y preferred. En· ergy barriers to frec rt)Iation of lhe cha tll~ an: present. be· cause of interactions o( ItOltbont.led IItom~ . For cxample. the atoms tend 10 position them5('l\es in spacc so IMtlhey (If. tupy staggered positloos. "'tlh rtO 1.... 0 atom.~ d'~lly facmg each Oilier (eclipsed). Noobondcd imrroctlOrls III poI~.ncthy · lenc chains ICnU 10 favor the must exleltded anti conforma· tion~. althougn SOtllC of the partially e.>;lcndcd grmcht tonfonnalioo ~ also CJ( iSI. Intramolecular bondmg bcl ... een
E-Clomlphene
Z ·CIomIphene
'"
.
Z ·OOXep!n: R,' CH,C"'~It. ~ • H E·Ooxepin: R,' It ~. CH.,cti,N(CH,1t
Figure 2- 14 •
Z-Cefprwll:
R"H;Rt·~
E-CefprozH: R, • CH,: EKampiesofEandl~
~.
H
• ",• k
•• •,,, "• ~
y
I' analo,>golls IU tile fragment approach for C'"Jlcul~tinll oct.anol/ll-mer ranillOn coclTicicnu;. lltc 'altlCs f{ll" lhe frugmenb and the IK'compan)lI1g oonn;lion faelor; an: delermined b)' cumpnring \."alcuIH\L'Il panllion coefficicnls with a large popul~lion or c.~pcrllllcnlall)" determIned panltion l'Oemcicnl'.
Three-DlnMlnslonal Quantlt.tl"e Stnldure-Activlty Relationships WIth molccul3l' modehng bcm belllg isolalcd and cloned. TIus means that it IS po!osiblc to tktennine their ",rues 1IRl> Ma;! an: protcin" ..... hlCh means detcmuning their JIlllOO acid scqucrx:c. This can be tlone clther by dcgr.iding lbt protein or by obtaining the nucleotide cveral diffcrent chemical das~s and Sub>l.HUC.'1l1 JXluerns an: represented, (Sec dl!CUSSIOli of isostcrbm in the ne)( t st(1.ioo.) TIle first Step is to colllert the trudlhonal 01" histoocal t .... o-dnTlCnstOnal molecule. inlo three-dImensional structum;; whose inlramolecular tliSlarx:c~ an: known. Keeping in mind the prott.k'nL~ of finding the "co.. ",,," oonflll'TfUlhon fOl" nC'lblc molecule, f'!.Iso:: hit. and misses might n:o;ult from the scarch. Nc~t, the dimen~!(IIl" of the active ,ite nl\l~1 be !.ktennincd. lde:llly, the receptor has been CrySI3I1l/.Ctl, and from the coor· dinille", tile intrumolecular di'larx:es bet ......:en .... hat an: 1lSsUITlCd to be ley localiOllS III\: obtaincd.lf!he recep:orcannot be cry'ilallizcd, then: an: methods rOl" csti mating the: three· dllllen)ional ~hoIpc: oosed 011 ~arching cry~tul1ogrJphic data ooscs 800 matching arnino acid sequence, .of proteins .... hose: tcrti11l)' SlruCture hn.o; been delcm.incd. Fortunately. the cry~al structures .of IItcrolly tho\lsands of prutems hale been detemuncd, and their SlIlICtures havc been MOred in the Brookhn,cll PrOlein Databank. It ,. 110..... known that proteins .... ith .imilar fuoctions have similar ammo acid 5CqUCIlCCS in vwioos n:glOn~ of the pn)lein TIlese s.equcnccs tcoo to 51MI.... the ~Ille shapes III terms of u he lix. parallel and 8ntip;lmllel ~-plclltcd forms, lurns in lhe chain. etc. U\ing thi, informauon plus molecular mcchallics JXlrmTlCtc~, lhe Wpe of the protein and the dimcn~ions .of !he acti\e site can be estimated, Fil1un: 2-18 contalllS the , igmficPnt componelllS of a hypotheucal acll"C Sile. Notice that touramioo acltl residues at posilMlliS 25, 73.102, alld 147 ha"c been identified us importalll ejtl~r for binding the lig.1nd to the sile or for the reccplOr' s intnnsic aclh'ity, Keep in nllnd that Figun: 2-18 is a t.... o-dimensioo.al n:~ntatlOll of a three-dIlTlCllsional image:. ~f~. the diSUUlCC' between amino acid rc.,iduc.~ lnuSltalc into accoum the fact that each rc.'sitluc: is ahovc Of belo .... tile planes of the other thn:c residues. For an ilnlflClal ligund to "dock:' or fit into IIw:: ~i te. six t11"'lUlCC!i must be considen:d: A., LY$- G lu: 8 . Glu - Phe: C, PIle - Set; J), Ser- Lys; E, GIII- Phe: and F. Ly~ - Phe. In reality, not all SIX distaocc~ may be important. In selCC1illg potential ligunds, c.1ndidate>l might include D Pll'il ti"cly charged residue (protooated anune). aromatic ring . hydmgell bond donor or acceptor (hydroxy. phenol, amine. ni tro). and hydrogen oond acceptor 01" a negath'ely charged residue (carb())lylate) that ..... ill inter.lCt with IIw:: partate. phcn)' lalanine, pan of a di fferenl funcllonal group. 11wl. nilro,~n i~ pan of II plaU:Ir slru~'lure in the nitro group bill furrtllo lbc IIfIl'" of. p)'f1Im.(!a1Siruciure m amrnortia alld
""'If...
' OS'CRt
"'IIl1
OIlIWIC!..
Grou~
of alom~ Ih~t impan ,imilar physical
or chemical
pruptrtic'\ tu I
molecule btxauloC uf sindlarilic, m si1.1'. dce· Il'IIIIC'ptil'lly. or Slcreochemlsuy are (lOw fM:l.jllcntly n:ferrcd (() b) tile gcr.eraJ lenl! of j£w.tt'rC'. The early n:cognit iOTl Ihal tornI9t and Ihioph('uc "'C'Il.' alike in many of lheir propcnlC':'i IN III !/Ie term ""K ~quilYll~"'£ for the 'Io)'lcne group (- -CH",CII - ) alld divalent sulfur (- S-). Thi~ conccpt b.. Ictllll ~nl of thl' sulfur YIOm in thC' phC'nothi...1fIt rin~ ,yo;tem of 1f:lI1quil lliog agen" wilh the \'i nyleoc poop !II produce the dl bcnzodlW.I'pll1C cla~" of amidc:pre' , drup 1-« O1.aptcr 14). 1l1c vinylcnc group III an aro.wac: nng ')"\Icm may be I"C'placed by other alom~ i_len c \oj 1IIlrur. loch as o~yg~'n (fu ran) Of NH (pynule): ho\\cI'cr. iII_h C,"l-.K aromalic cllarncter is 'lg.nilieam ly decreased. E.umpIr-.Fn:I.dcll~ lAG E.hlml h(lpJ/Www ... .o.»>t • .cduIenllln«nn&khc~hnnlmonle.hlmt
-COSI!
hnpJ/www.clunel.eduIBiol)C:.·I .. m.nliI~lk:ry.hlm
-i-Pr
. Cornpound~ nmy be altered by II..- S,milanty [n [>noa Oo;;,n Nf... yon.. Chap...... " H~II . 1m n.,.,I1."" J .... lIabboon. AT .• (N).1: Topol"lIocaI 11In'","" 199(> Leo. ..... I~h. C.. and IIotLrnan. O. E>.rfun ... OS",R ...... 1. Itydroplloboo. EIf,c"""ic. ond St.eric" C............ w........... lX'. ............ 0..",1...[ s...:1C1y. 1995. M&'IiIl, Y C. ~ ............ de!.ip. In GAl.......... G (N.~ Modic_ R....d •• ...,. B. /Ikw Yl. y,ho leIIy\ in 96·y,ell mitrnIliCT platt'S and even using laboratory robotic::. for pi. perunl and anaJ)·sis. 1lte bottleneck had heI.."OfllC lite "ynt!te~ of lite compounds to le,l. Chemists reahl.ed thaI symhe-.es could abo be condUCted by u,inj; n parJ Ile! npprooch. The: tmn rontbinil/(lrilll cht'mi./n y,os coined to n:fer to the paralkl,UI... wion of all po!>~lblc combinmimu of substilucnLS orrompotlCnlS in a S)nthelK: expcrimcm. Whereas !he yield from.!Ielia1synthe;is is a Si ngle compound. lhe yield from 3 combnt3torial synthesis i~ II chemica! IilJmry. Figure 3-1 Ibows 11'."0 common types of ~ltcrnical libraries-a st'orrie Wnry. based 011 • Jingle pat""l'nt or IoC •
• ChapCn" j •
poipncr. In wch c:t...:s. If the molccule~ :are 100 lightly packed 011 lhoe pol)n1cr. the cnl.yrne nlokculc~ canlKll gain ~! 10 the: 'ubtOII ,hrorrul"V"p/l).
• T.... ur(;..:1 ~II!I. PoIy.I)"'''''' III ,,10..-11 )00lIe of the phenyl trouP!! poly~htlcroc II)L'1>I (I'EG) IIroo~ ~uoche1m. ptJ"II,OIl . The free 011 groups ur !he I'EG allow the .... achlllenl 0( l":M"ptJUlKb: 10 be ,yn'''''' il.c:(i. • I'oIYK1'llJomkl., r"ITI~. U" "super .11.IIe:' Ihc. .. reSIn, " . dl beucr ,n pullU .... ' ·(nl) W>C solulion-pha.c combllla· lonal elK:llli~lry III s~n1hc~ile. fOf eU IllJlIe. N-aryl-\ulfllnamide structures. llti:: resu lt mg mh lure of PEG-bound w ifooamides can be separ~ted by use llf ehromatogmphy. Another type of SQlublc SlI]lp()11 i~ dcndrinlCl"lI. The~ are large. highly branched molecules wllh termirl.1l ammo groups Ihat can be used h~e the 011 groups of PEG for the allachmcnl of products. Finally •• cillSS o f molecules lllO\hon Str~nds of oomplt'lll(':nlJry DNA Of RNA 10 lbe SlruCtures 10 "1.lp" the Structures togelher and promote reaclion. The DNA i, then rerl1QI·e!l. yielding product Ihnt would nOl OIhcrwi~c be synthes.i,~'d. Using thl ~ mcillod makes it possible to pn:~ent reaclion o( cenuin P.~I~ of 51ruCiures 11.. well.
I,
Al
COOH
o
~
R2-NH"
... R3-{
•
H
o
'"
H
,,)l~Jy~D "
R'
-
0
/
RO
Q-NC-
-
o
N-'"
R
\
R'
N-{
,
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,. A tomb,nalOf\i1I mO(· and each can be furt~
the I f'tqure reilCted to 9'V1! a lUll" 01
redrawn from descriptIOn
hom Keating. T
'!OC)Idfl,de If! the
component coodensahoo
be ..,n",l) In lhe Ih,nt """p. Sm"c II " ,n Ihc I",n! aroup. "'t In..... I C ,n posouon 3 is IIttdffi fur 11 AAC +
POOLING STRATEGIES Although $OIne solid-pha.o;e romblnatonal chernis.,y is ('011dUCIed by use of the ooc-bt:ad onc-compoond ~Ir,uegy. chenllotie!. and IU'om;ouon. tIoc pmbIerru \/o'ere redoced, and 10(13),. probably
,,,'en
mo the ~nolCl!J firsf dc«cn ..... 20 ~lIN ago whcn comt>on:r.torul chcn".uy ,,·u MOIIled. Ike,"'''''''' Fi,llre J-3 aNi ''''''g''''' M~'''i '" .he botlom u( tIoc: fillure ....h three UOOI'" "r bead;. E.:h ~p I\;ls bc:ads tM.:u-
in,. vanc1y of compuunds. but . ,....... , .nonure 1)111)' "I'JII':tr'S in 0IIl' ,,( Ihe ,roups. SlippoliC the 1IC1",'C io/l'IIClure is ARC (w" prele.od hen: Ihcrc i. ""I)' "",,_in reihl)' lhe,.., proh;,bly
,,',11
LI9' four-
sec
HAC + CAe. ARC + BOC + CBe. mild ACC + + COC, .... e do ."" by ~l,pp'''i 1M Ialil oc. "r poohn, mo.n ,n Figure 1•.1. Nil'" .. hen we SC""'n ' he", m",uf'C$, "'C find IICHvn)' ,n 1M m,dlll" ,roup of bead5. Th~ 'ell~ u, that • 8 i~ po6""'" 2 " I'CqlnrC\l rIlf'IICH,·i l),. Tho final >lep I> '0 syn.he"", Aile. IIBe. und CDC, ~~p\n G "",on ",p.:or.ue.1Ond ...:rco:n (,..10,
•
10 find Aile :oJ the UCII\e .ioIl\lClun:. S"h' noc' h'~ d l!('o",·ulu'iun. Thi, " ",milar 1" ilC:r~th c tX\:oo.
.oluII"" bul Us/.·, rcg~1 "'j) 1J;,e. n~I1Ic1)'. ka. e 001 a (UllCllom) ,mup. and ,f ;ol ,mportant fU""KlnalllffiUl". A redUl-'W 1ibr~ry '''''''a,nml! only,""'" (unc,i,,,,,,t lI,R1uf"I i~ lhen ~pared, md the miN lICU,'c compuund" arc ido:ntirted by c"hct ,)nlhe"s Ilf' 'teno". ~ dccoo ... olulion. • IIOI:'b~OIt, ddK.iun, Th'$ bcg 'n~ ""II g~""l1Ilml aIII;I """",ninillhe e"Urc hhnlry as I single ""'lUre. If act"' ,ly i, OCIt.'lUlIOII I.'Unl4lni" , I~ rompouoili. lu IN: analYI.n1 i~ pa'M-"Il",,'er Ihruugh "" dcclrinliy c~ capiLlary. The droplc:ls 11\:01 ""~rp: frum I~ capillary bear ioIronl "k\:tric cl\:lrges !hen.....,I",,~. and Ihty hl"",lIy ··",I'INlc·' ;,,1-Ol"-n;~h l (1'01/\ LI) I. TOF). Otoue a moolhful. il .imply mo:un . Ir,c, s:"lIpl" .s embcddc:d ill ~ $Ohd m.lIri~ (c .• .• 2.~-d.h)·ilro1lbc:llI.- ~) IIIIId tbc:n rombm\bl ... ,th I I.a_. Sample mokt:ulo are , ..po.ved and ionwxl In • ··(!Cllllc·· f ...,h",,, Ih~1 ali""" '" huIc: · rooIc of the 100al). Enzymes make up the nell largcst group (28%). fol lowed by horrnoot's ( 11 'llo). unknown.~ (7%). ion channels (S~). ftl.K'lear TeCCplOA (2%). and finally DNA (2%).zs II is apcclcd lh:u the anOOllltion of the human genome ....iII add adt\iliooal UUicts. although the rote of this addition is IK)t koo"o"O, New targets must be: part of _ regulatot)' pathwa), in the: ce ll and should be: sc:nsilh'e 10 some disease: State, IK)t be: e~prc:sscd allihe time: and everywhere in the cell, llIe: nc:~t concern in HTS is the: library 10 be: screened, Throughout our discuSliion, we ha,'e perhaps offered the impression thai a gh'en library for a par1iculur project was the o nly ilCl of ~'Qf1Ipounds thai ""en: ever screened for acli vil),. In facl. much !iTS invol,·c:.~ screen ing compomlds that are part of Ihe corporate blorehouse of ~'Qmpounds S)·llIhe· si7..ed in the: past. or the)' may be: a librdry purchased from a vendor. Such libraries usuall), coosist of microtncr plates containing fmun or dried $3lllples of compound - perhaps onl)' miCl'OlllllllUi per welL The: size of such hbntnes mOl)' range from I few thousand compound> 10 rocarl)' 11 million. 111e cost of completel)' §cTCemng such a library &galnst JUSt 11 single L'\Sa)' rna)' amount to o,'cr $300.()(x). so such lutgc:sclle JCfc:ens are conducted flUhn infrequentl)'. compared with routine dII)" lo-day screens, It I1as been esum atoo that one: must screen at lea't 120.()(x) • 'quality" compounds (I.e .. di"erse dlllg·like: structu res) to disco... er a $ingle- Iead series for a therapeuticoll), sound mrgel.:-e. As disc ussed above in the S«1ion o n pooling Mralegics. one can redu~"e the SCIl.'t'ning cffon by pooling groups of structures and running asS. This also cooservd reagenlS and biological material . has smaller storage n:quireme:nlS. and requirc:s fewer jK·rsonnc:J. TlIcre an. potentiol problems ",ith poolmg. A number of fact0f5limit the number of different compounds we can te..'1 in a given ""ell. including ionization. react;'ity. alld w1ubil ity. Compounds can !'!ltc-r a screening program in a nonrandom ~. such that D Gi~en assay platc may ha,'e compoullds thaI are highly similar structurdlly . This may gh'e rise 10 folse-positive hits. False·negative hits an. less likely to orise from pooling. Another concern is thoc usc of !'CpUc atc:s--compoulld~ from the ~ame series - in a given a~say. If only one representative of a gi\"en series is pre.ent. the chance of mi~ing that stries a.~ a possible lead series is greater than if multiple members 31l.' pn:stnt. Therefore. it is common 10 inc lude: st"crnl me:mbe:f1i of each senes In a given assay when pos\ible. To be: efftrth·e. a gh'c-n compound muSt dJo;.soh·e complete ly in the assay medium. It is common 10 add a small amount ( I'll» of dimethyl su1fo~idc: (0:'C pans of the sUbsttUle nooting In the sol ution will be tOO far from the beads 10 cause any nuorcsccncc. The presence of f1lKlf"CSC1:fICC implies that the lesl compound inhibi ted the enl.}nlC. The ad .. nntage of SPA O\'er filtration is lhat no fillering of the solution is needed, so bcads can be: lidded din::ctly 10 the assay IlI.IXlure in "ells 01" lest tubes. Also. speciul Sl.." inlillalJon nuid i~ not needed. The bead!; for SPA call be: engineered 10 altllCh a varlety of Substr81e types. Oilter HTS a5!111y ad.-ances include lhe use of rrucmorga· ni sms 5UCh as bacteria and yeast. the cloning and expression of mammalian receptors in microorganisms. probing pro. tein-protein intCfllCtions. and I'ery imponanlly, DNA and proIein armys. l1tesc arc: tOO 1II,'olled to discuss here, bul excellent reviews uist.~- ~7 "The incrtasing use of HTS to 'iCTttn for . nlOi«ule·. absorpt ion. distribution. rr'lCtabolism. excn::tlon, and tOXICity (Am.lET) propel1lCS has been cov· en::d ru; well.~'
VIRTUAL (IN SILlCD) SCREENING Virtual. or in silioo. ~nmg refen 10 lhe u:soe of computers 10 predict whcth~r D compound Will !;how dc:Slred properties or ocri .. ity on the basis of its two-dimensional (20) or Ihree· dimensional (30) chemical ~ruclUn:: or 115 phySICOChemical propertie~. The lIIori vnt ion for USIIIII vi rtual screeninl arises from the nuod of ncw struclUreli coming from CQlIlbmalorial d'ICmISlry. the expense and time reqUired 10 run COfI\"Cntronal lITS. the ethical c()n(."crn~ about u~;ng amlllaltls~ue Instead of prediClil'e modd ~. and IlJt increasing failuJl: role for struc· tul'Oi cormng out of CQmbll\3lorial progllllns. In gencnl. a vinual screening proglllm attcmpts to answer ooe or both of lhe.-.c queslions:
.Ie, •
SOOsIrale(')
)-- CO S'.....-, FilTER
•
<
EN)'IIIe
co
SubIIrIIe(')
511...1.... ,
t
$ N\'IIIe(') ~
t lnI'IIbIIoI
CO S'''''lfIIla,''' s..t>wale( ' )
CG-sut..lla", - SubsI.. I&! ')
b Figure 3- 1) • Compatlson of filtrallOll and sClntlllatlOll proXImity auays • . In f,ltrallOll assay. the emyme, substrate. and mhibllor all' n'IIJIed. the un,nh,b,ted enzyme splits the radro.KlM! portIOn (. ) off the !oUhstratl'. and filtenng lhe rrulC!ule. fojlowed by measunng the radroacllv.ty of the fllle!", teHs much InhlbrllOrt has OCCUlTed b.1n SPA, the same mlXtlJre IS tr~ted with resin beads contaIning a ~ntlll3nl lhat lluoresces only In dose proJUm,ry to the radooactM! source Any ladlOaCtrlrty that won splrl off by the enzyme does not need to be ftltl'led In SPA.
now
Chllplfr J • Co...bUtmorUll C~ ...ls"Y
"" \nd, ~I'
e
i~
live
r"
: of
"'d(';lel"1iotl, J.: Uni\local ..c:lechOl1 proccdtlre-s ,hal. if fol ......·w. ",II m:llc "mon: h~cly lbul POllua"u,...,) IhaI. " 'c pocl......., and......., di..- JUbstt;; 1l1c!Cad of A. T. G. Ind C. the ba>c:
deSllrnlUOfI is JUst t or 0). Wc II.at1 by se'''''',nl random IInnlls of Is and Os 10 reprc-.cm .he seoomc Each slrina is mea~urctl for .Ile d"'c~;ty lhe mu~tul'\'.' In the Mnnl rcprc-.cnt. Th,s is ~alled lhe fillltu uf .... wing. Tht-n. "'c a;>ply .he Kenct lC per-llionI,Hn()l.Ir ""'Je ....,·'MOdin. : 1:.nood,"I techn.que or ~ library hI ....J on (he
I"tw:ax ...
"
•
of 11&1 00 • belld.
Thu~,
the >aJucoce 011001 ...... 1C'l! doe coltlponcn l ~ lo~. "'och
""".\If\'
~ I e~ ~
I.
•
-
, • ,
,,
but !)t,e" ...
chlIrJ. Iut In !Ie'~ pool$ impliel Ihal a lIven member is Il'Spott!wt !lm,lar b,oloa;..:;!) OC"'·,ly ,
l'roIr the elec.ronic !le\'ices ,hal emil radiofrcljUerK:> \'£ll'l1> upon .... mul!uioll with an eI«""OI'UI~""'k '>mctime,. "'s"'~ an: simply ">Cd 10 >ln be:Kb ~ u~d to ~pam1~ compouJllb by >lI.c Of hy the: charge on a molecule, lI"lnlbc:sis: J>reparotlon of ,ndindual "",mile", III" ~uboic" of a romblllau:",.l library. 10 follow up 00 SOnl" Pr'Ujlelly of
I""
,
,_.
,,,
,
, , ,
, ,
,
, •
An cnzy"", th~l can R" 'crse lrdn,;cribe RNA inlC "~';.iIUl'IIt. Si'a'tngfr m in : A rc.sin inlroduo:cd mlO I combina lOll.1 eXJleri IIkM 10 rcacl ""h uTKlc:os,ruble mall:nals (,,"cess ",agcnt III" wdc: prodllC1S) and remove 1hem from the eXllen"",.I1. 1t~,·1'Il>1' lnlU~r1pIMst':
J • C"",b;tlllI(m'o/ Cht"ds.ry
63
St'kdh-Ity: Measure IIf a oompound' ~ tendency to bind only to • cenain largeL =11101, Onlg molecules ,hould ha,'e high sc:i«li\',ty lIS " 'ell ~s potency. Solid s upport : Insoluble. fUJlCtionalizeli by u>e of L'Omputahorull mood. AIM) called '" ~",m U'.... M/"I/.
""""'Oft'!
REFERENCES M.mr.. k/. II II Solid pha", PCPlldo: ,)"'I1o.,,,. ! The » 'n,,,,,,,, of I to ,,," Pelt,n", """. Dnoa DeI,v. II... nJ-2!l. 1991, )4 Opa. T I. Vithool ......'" ,. "'-d d"...,,~ry: • , ..... I""nt. Mo»
dna.
"" .... ,;!1 I-62,lOO2 ()pn:1. T. I.. and (lo"rnloc 01"• .1.. . 1M..... Modrl . GrapII. 11:2f>1 -214. 1 W9.,~ . _ l&. 7...... I.. .. II "falol ..... "", " ,ce",,,, filter r"" ..,....,_. NXI 3... 4 ioohibolIm ,...I_y 1_.All""";", onaIyIoI. C\In. MftI. ~ 1:98S- 99I. 1001 )K S".lIme)'CI. D. C ... no! GmoI .......... P I) I IIccmt .... ,'c lopo .... " io """«01.. dln'"'t~ ' "",,,,,,,~00BlJ 1_ r"" .....
k10.11. M.. S ~ LInd """ Dno, Oi_.... ry Today ' ; 143_ U6. :/000.
dj""".,..,
• •
,,
•
•( d
"
n"
•"
"
~
(
H
p
A
T
E
R
...
4
Metabolic Changes of Drugs and Related Organic Compounds SITPHEN 1 CUTLER AND JOHN H. BLOCK \kuboIt'-"1 pla)'~
C~Tllral role: in the c:hnunJlion of df\Jg~ C{)fI1pound~ (.ft..,Qbit/l;N) from the body.
a
IIId OIho:r fOR'lgn A ~id underslandmg of llJ and ph/uf' II (cunjugmiOfl) rc:acIi0llS. 1. 1 Phase I. 01' fuocuooalizahon rc:actlOns. include oxi dallve. reducl i~·e. and hydrolytic bioU"lIllSformulloos (Table 4.1)! The I)U.-pose of Ihese rcaction~ IS 10 introduce a functional polar group(s) (e.g .. OH. COOH. N U ~. 511) into the xenobiotic molecule 10 produce 0 iliOn: WAter soluble COlllpoUnd. ThIs can be :.c!uC\cd by dlr..'' odoh,·~
ruc:toom.
1If'd.... ln 1I....do"~ 1INIIo:!_ f oldrb)ola """ l~1 1I~1on rtf iii ......... ..., """'P"-
_II'"
\t..'1:1~ IUI.WlO It) d....) ... M.......... lI)oln~)'li, f NOn.oo omole' U)dnlllOO Qf -
'" '" ~
,
:ld
~mo h"otOpOr!lhv,!n 110 pon ..... ... It~ " Activat.cl O'VIIII'''
HOOC
4-2 • ~mphf~ depICtIOn of the "cp»ed « tNate' deactivated aromatic rings (c .g .. tho\.c containing clcctron· withdrawi"g gTOO11S e l. ·N' R.. eOO H. S02NUR ) life gC!lenl.lly slow ()I" resiscall1 to hydrmy lation. The ~lI l'l1tin! groups (a. -N ' H =e) prescnt in tM Intihypcncnsivcclonldine (Catapt"Cs) m~y uplain why thj~ drug undergoes linle aromatic hydroJ.ylaliOfl III hurrums.)I,.)OO 1llc ufJCosuric agent probenecid (Bt:'ncmid). ",lIh its clcctron-wi thdrJ"'ing car·
XCnobIOlic~ .
7
7 "'0
lvae
Ai ... 0I0dD
-
7
"
'l
T
OH
""'"
f~igl1 CUll1potJnd_~ comainmg aromati c IllQieli~ nrc ~usttpuble to arom:l.lic oxidation. In hu mans. amm:llk h) -
1\1""1
b<
droxylauon is 3 major TOOtC of nlCtnbohsm for many drug.\ COfuai ning phenyl ,roups. Impol1untlhempoeul ie a~nts such II) proprunolol..... ~ phenobarbital ..... phenytoin ..... "ohc nyl· bullll.OOC'.SI Crious ~"('l1ular damage.'_ '" Thi ... in pan. helps nplain why benzcoe can be so tO~ IC 10 mammalian )ystcnl '.
0'Y'Y0y"(-"0
coo OH
,uoo-
e ge nvali ng cloni : little !lient
C~O~CI I'oIpCl"lbOllll1lC
H
B4lI.'I'I "' ........
~ 3 7 &-T..'id .... ·> ...
V'IH'J
a
a-
H N
"-=( H N
a
COOH
J
H
Rtcenl tnvironmental pollutant .•. such a_, polychlorin:ttci.l ~a) Is (PCB~) :uK! 2.3.7 .8-leII"llCbIQl"(xlltlCnlo-p-dioxin (TOXlJ. ha.·c .lIrnCtc:d conside ..."hle public ~m over Ibtif lO~kil)" aoo health hazanls. lhcsc: compoulKb appc;ar ~ be reslstmt to aromatic o.'idatioo because of the nunlCrOl.l~ riectroorrati"e chlorine: atoms in their aromatic rings. l1Ic ItICIabobc Mabtlity coupled to the lipophllicit y of these env ifllI'lIletUIll contaminants protmbly ~~x~ai ns their long peTSi,... w.:t III the bOOy once absorbc:d.
'-!(XS'f"l
N~a I
CH 2CH aCH 1N{CH 3)2
-
CI
Quan titatively. the most impunant detoxilicalion reaction for arcnc ollide~ is the spoIllancous n:arraogcment to Uri le_porltling arellOl ~. Often. this n:arrungcllIent is accompanied by a lIO\·cl intl1lmolecu lar hydride fdcuteride) migrat ion called the ··N IH sh ift . "~7 [t was named aft('1' the Natiooal [m:tilUtes of Health ( NIH) llIbor~tory in 8ethe~. Maryland. lI'hen: Ihis process was dio;coverOO. 11M: genenll feOlull'$ of the NIl I shift an: ilIustrnted with the miled-function aft)o matlC oxidmion of 4-deult'noanisole to ) ·i.leulcri0-4-lIyi.lroxyanisole in Figure 4-6 ..-! Aftcr il\ metabolic fommtlOn. the Hrcrle o.~ ide rillg opens in the i.lil'\:etion Ihal gcncl1lll:S the n~ n:son.:mcC-SUlbihl.Co carbocation (positive charge on C-3 carbon" resonance smbililed by the OCH J group). The f.winerionic !>pec~ (posi ti.c charge on the C -3 carbon atom and negative charge 00 tile oxygen alom ) then undel"J!Ot:s a 1.2-di:uteride 'hifl (N il I shift) 10 form the dieoonc . FinaltraosromJalIOil of the dieIIOne 10 3·deu len0--4-hydro.,yani'lOle occurs .... nh lhe preferential loss of ~ "",,on because of lhe ....ealer boni.I energy of the C- II bond (compared with the C · D bood). Thus. the deuterium b (('Iained in the molecuie by UndergOIll!! this intl'llmolccular NIH shi ft. The experi mc:ntal observatioo of an NI H Miifi for arom:uic hydroxylation of adrug or xcnobiOIk i~ taken as indirect ev;(ie nee for Ihe io,·oll ement of lin 3l"\'IIC oxide. In addition to .he N IH shift. the zwiucrionic species may undergo direct 10l>S of D' to gcoer.tle: 4· hydroxyani'\()lc:. in IIhich there is 00 rctenuon of deutcrium (Fig. 4-6).11lc ultern~t;Ve pillhway (direct loss of D ' ) may be more fa'·OT'~ble than the N IH shift III some arommk ox idation re:lC1ion s. Tht:rcforc. depetJding on the sub~titl.lent group 00 the ~ne. ~1lC IUOlltatk hyi.lro~ylaliOil reaclion~ do IlOl dl ~play .ny NIH shift. T wo cxtremely imponant cllqlOatic re~ions lllso IUd III neull1ll il ing the reactivity of urclle o};id.::s. 1bc firlil of tile.'ll: involves the hydrntioo (i.e., nucleophilic allX~ of watcr on lhe epo~ ide) of arc:1lC o~ide~ 10 yid d inactive: mlll.N l ihydrodiol n ll.'t.abolit~ ( Fi!!. 4-05). n ils reaction is cmaly-LCd by
-
R
R
Reanaol()l!tT*ll
o"
J' H
OH
H
R R OH
,
H R
•
I
,I
OH
•
R M...................... 1IICIducI CO'JiI~
boo.nd TO
M .. DNA. RNA
Of proIfti'I
M
o
Fi9ur. 4- 5 • ~ble rNdJol'l palhways tOf ar_ ~. (D tOO. because fO"II:lIioo of d.h)drodiols i~ blocked. For cumpk:, the nJUtage""f} of bcn/.olalp)'n:nc-4.5-()~Ide. ns meas ured by the: : StJlmiJlu>l/lI Il"phimurium lest sy~tcm, is potemiated : tycloht~cne oxide isaddcd. lI Dihydrodiol mctabolltes bctn ICpOIlOO In the mct~boIi sm of sc\"C:rul aromatic ~dnxillbon. (e.g., naphthalene. benw{ll]pyrene, und ocher polycyclic arorHa1,C hydrocarbons),· l A few drugs 1t.J-, p/IelI)toin,n phcnobarbital.7J glutethimide u ) also ..rlI dihydrodiol productS as minor 1rK'labolites ;n humans. Otb)drodioI products Wll susI.:epllble 10 conjugation wilh ic acid. as v.eU lIS cl17ym:uic dchydrogenanoo to o.mespoodms catechollllctabolite. iI) exemplified by the IIIttlbolism of phenytoin.71
.,;.»:
.k?,H a e- T 3
H
o
!. \ j·lndDopropMll
,'-»
A SC(;ond cnl.)'matic rea(.,ion involvcs nudeoph illc ring openi ng of the urcne: o~ide by the sulillydryl group ~""'nt m cs" 10 yield the corresponding frruu-1.2-dihydro-l·S. glul.athiooyl·2·hydro~y adduct. or GS H adduct (Fig. 4-5) ..... The reaction i~ catalYl.ed by varioos GS ~I S.tr:m,fcl'1lSU. 7J Becau'
-;~" ()ooo,
!
I
..
OH H~C.
HN-VV
DAN ....
.H
HN
OH
O""'N .... H
CN......:o MoIM)OIoe
~ed. glIcu~)
TSG ""
"".-
--
"",oQ '
jHCOCH 3
_ ... S
OH
..... ci:i;'cOOH
DIr~z1'"
was confimlCd by UlIC of rndiolabckd brnmobcnl'.clIC. "..., sewnl)' of n«rosi~ com:lated well ", lIh lhe lLmoum of covalent bindinlltO hepati c ti s~ue . Use of dicthy l maleate or large doses of bromobenzcllC in rolts ~howcd lhallhe dcpletioo of hr'palic GS U led 10 lnocc 5C'a"C liver necrosis.
'"
'"
'"
SG PoIycyclK: IImmanc hydrocarbons are ubiqullous en,iroomenial contllminants thai are fQl'Tlle(! fmlll aUlD emission. refuse bumHlg, ,ndusmaJ polX(Sses. cigarette ~mole. and
OIMr combustion pl'lJoCC:!;scs. Benlol a Jpyrene. a JIOIent carcinogenk agent. i~ perhaps the most exu:nsh-ely studied of lhe po lycycl ic arOlllulic hydrocarbons.'N Inspection of it~ structure revel,l s thai lItOn1alic hydro.l yln!ion of be n:m[ u lpyrenccan occur at II. numbct-ofpositions. Tllc ido!mificat ion of sc:ver~J dihydrodiol mctllbolites is viewed a~ indirect evidence for (he form:m oo pod inmh'enl('nt of :lrel1C oxides in the metabolism of benzot ajpyrenc. Although l'Crlain arenc ollide$ of beTv.oI ajpYr'I'ne (e.g .. 4.5-ollllk. 7.8-oxide. 9.10o~ide) 8pp:'3I' to d lspl .. y some mUUlgt'ni c aod tumorigenic activily. it doe.~ 1101 appcar that they represent tile: ul ti mate reacti ve spec ies responsible for ben!.o[ a[pyre ne' s carc inogenicity. In rece nt ycal'll. Cllilensi VI! s\tllli e., havc lell 10 tile: charactCriZlllion o f a .. pccific seq uencc of rtlctllbol ic ",octions (Fig. 4-7 ) IIw gcncnnc I highly reactivc i,IIcrmL'diate that CQ\'alcntly bind$to DNA. Mcmbohc activallon ofbenzo{alpyrellC to !he uillmatc c~inogenic speciC$ invol\'e~ an initial cpo.' lIdatioo ",action to form the 7,8-oxtde. \00 hlCh ;s then
CQI1vcrlcd by cpoxitk hydrn...e 10 (-).7{ H).8( H}-dihyUro~y, 7.II-d lhytlrobc nzola )pyrenc. 1IO Tlie two-SlCP enzymatic form~lion of thi s mm,,-u ihydrodiol is ~tcreospeei fic. Subsequcnt cpoxidatioo lit the 9.IO-dooble bond of the laller IIlCtlioolite gener.llcs predominam ly (+ }-7(H).8(S)-dihy lim, y-9( H).! 0( H}-ox)' -7 .8.9 .1 O-Ie truhydrobcn-,-01 trI p)'renc or (+)7.lkIioJ-9. IO-cpoxidc. II IS thi5 kcy elcctrophilic d.oI epoxidc IfIttabolite that realily reactS wl\h DN A to form m.my covalcntl y bound adduc\$.M' 1..1 Carefu l dcgntdatlon stud ies han' shown that the principal adduct in~olves DIIOCl of the C-2 amino group of droxygu1l/lOSinc al C-I O of lhe Iliol cpox idc. Clearly. t hc~ f'Cactions are responsible for gcnc(ic code al1crnlion ~ that .dlimmdy leoo to tnc m~ l ign.~nt tron.!! _ s,bly in humans. WI
\ I
'H Sl1'
"""""',,¥!
H2.$-01I It1C1U1J' • -2,.,M"ICIP!OC*'III (I:lOM)
j
7 \' ~'·TetrllhyO-~
77
DebflilOQ!W1
3·I.!elh'¥UlOltI1ttv_
Figure 4- a • Examples of drugs and I«!flObooIICS undergoing benzylic hydroll)'lauon Arrow Il"OdlCil les of hydrol()'latlOl'l
~te
a
a,~
OCH,
2.H)t¥lro-2·(N'~
l-trtdIOlJaIIaIuxi' 8,
H
H
I
CI
C "
~ --"
H
".,H'.,,,.
OH
Ha,Aov c 011';4= '·
: hoi
",,"
H
C
CF3CH~O/ ""CH 2
""""" CH,
-AbJd Mac"'"
e
~ S02NHCNHC.H
T
c.-,..Me. AllcmlItively. the alcohol metabolites may undergo glucuronide conjugation. Aliphatic w and "" - I l'Iyliroxylations oommooly lake place: in dlUg moI«ules with straight or branched al~yl chains. ThUs, the amitpilcptic agent vaJproic acid (1Xpa • kene) undcrgoes lxMh wand w - I oxidation to the .5.h)'droxy and 4-hydroxy metabolites. n:speclively. 101. "l Further OJ.idation of the 5-l'Iydroxy metabolite yields 2-I1-propylglularic ocid . Numerous barbituruteli and oml hypoglyt-emic sulronyl un:as also havc aliphatic side chains th aI arc susceptible 10 oxidation . Note Il'Ial the scdlltive l'IypnOlic amobarb1tlll (Amyull ) undergocs extensive w - I oxidation to the com:· sponding 3'-h)'droxylaled metabolite. ' 6j Other [)arbituroJcs. such as pentobarbil1lJ. 1' 5 ,." Il'I iamy lal. In and sccob;ubllal."l reportedly are mctabolil.cd by way of wand w - I oxidauon . TIw: l1-popyi side chain attactled 10 the oral hypoalyccmlC agcnt chklt'propamide (OiabillC!iC) undergoes e~lensivc 1» I hydmx),latlon 10 yie ld the KCOnd:uy alcohol2'-hydroxy. chlO primary aromile ImIIlC drug~ or metabolites. N--oxldation con stItutes 1liiy . minor pathway In comparison Wilh other biOlrdnsfoc· IIIlion palh ...·a~~, such as N·acetylatiOfl and aromalic hy· ",,-)·l;,tlOll. in humans. Some N--olygcrl31ed metabolites iIIIe i)r(on n:por1l-d. howevcr. For c~ample, the nnlileproiic dapwnc and its N·acetylatl-d melnbolitC' lin: mc:tabo:.II \l1I"flCalltly 10 lhelr corresponding N·bydro.ylanHIIC *"laUI e5.2z& The' N· hydroxy metabolites are further l"Onju· pIfd III Ilh glucuronic acid. ~lt!hemoglobmemia to~idly i ~ caused by :Ivl¥ 0 ..... Ide 0. .......
~
..!::J Coula
~
BordoliQ ('91« I e
IUOf'GI
, w.o '
........ XR
p..QlucutOllldB (JI .r.IQogB at C-,)
HO
,
-UDP
U"dne~'~' ~ ACid (l..IOI"Go\)
("~,,C-'I
Figure 4- 11 • Forma\lOll of UOPGA and ,8-gIucuromde (onj!.lga t~
T.cnIorOWl1 ....
.t.c.Ioi •• """'''"'
--
CH,
I
CH
.,-
'CCOH
,~.
n drua
:ohohc
a.n.o.:. toO. 1'1 _ H
/" . , lriazr*!.. !H ... ]phll , " _
coo+<
o
,.,:tul. _, CH CNHNH II l
2+
N«irW1On
j
6 --
Cytod1o orne p ..fOO
As EW.. •
Medialed
,'.UW
.• -
u.. ""'- .-- :C~ .~~.~1II Bn.:Iii "III
E
'"r
""
&'''1'1.
Mclh)1auon ~actions play an im ponanl role in the bios)'nb rI many endogcllOUS compounds (e.g.• epinephrine -.I mdIIOnin) and in !he inacti v'lion of numerous physioq.aJly IC'!iI'Cbiogenic amines (~ .. IlOrCpinephrinc, dopa. _ , semtoIIin, and histamine), Methylation. oowt'-cr. \* '11J11e1 onJy. minor p3lhway for conjugating drogs and 1CIIObIoI1CS. Methylation ~llC'rnll y does no! lead '0 poll1T or ""·~ub!c ~Ilbol jtes. CACCpl when it cltale$ II qUllter..,. JIIUIQIjum deriYlllivt. Moo methylated products uend 10 be p/IarTrIIroIosicall y ill3Clivt. althoogh there are II few
"''''' ~""'''OH 1481 • • R_H
No ' hiltarlilPlW" . R _ OH
nr romzyme in\'olved in mclhyl:uion rnclions is S-ad· ~htthtonillC' (SAM). TIM: Ir.lIIsfer of the activated MII)'I JI'OUP from Ihis coen~yme to the acceptor Subslnlle C.!;·~ '!Y;;""~by various C)'t~lasmic and micro6omal methyl. :'" (fiCA. I7)..... MClhy llrllnsr~ ofpanicu· IwIll!pOlW1CC in the meloiloli sm of foreign oompounds indrIck ClkXhoI-O-flll:tby hransfel"1lSC (COMn. phenol -O-
methyhnlllsfl!'flISC'. and non~pocific N-methyltnlllsrerJ..Op)'",m\tlo:
"""'"""" ""'"'""'" "'jIOWIIi""
"'....,..
~.,,!I.
Etbi"yl~
1':lIIw>" .... dc: l'q'l
'
,
",Ind,,,,,,,,
,,"nllllyl
' ,,",,_10
Ind,tlllvit
'""",""" ""'..-
"",I
"-K',,,,_
,
$cnr:tll""
,
,~-
1..-11t1"w.
....
CYP 1M
Trl l, . - • Alf." .... '!
Primuolt
,~loo.tI
,.,.,...
"nIillridll"n~
l'hon~lOin
lIil"llJlml'''"
'~yl
........ ,-
..-..
' -. """ t:f...tftlI
C..... ~
F..thooo.,,.,....
o.id.oob)'NI
" -"' OOt •• >tdlnc
Mdaronot
Nr,.'rlf'I'"
""~~
o...tz X,'"
.-
1'!otno1bttbiW ",""ylOOn
"""""
Ct)"lII'QIII)'OII n",,~ed ..
""",0.
n............".
1I,1'abIII", 1\1(...."..
ttdi ..., ...
Rlfr.pcnlltlt St. Jnha ·~.....,
-"',
...
t ~ ..... ,~
"'*-'"'"
..,.....
"'.""" .... ·roIe
M..;oo.'OI< Noilitllly"
N.r.dlpo.. No:.11ounn
Q,,,'"
R'ION ....
.. b ,,,,",O may cnhance the IItIabohsm of endogenous compounds. such liS ~teroidal lroo"kHld and bilirubi n. For inqance. phenobarbital clln inata1> Allhough DUmerotlS OIher examplC'i of substnne SlereQ!iC':lectivity or en:lnlioseleclivity in drug metabolism exist, the e~amples ]IIT senk"d sholli d suffice to emphasize the poinl.lIIl. H I
F
OIlier fac1~ I1lso may illOucllC.'C drug mtlabolism. Diewy facl~. such 11$ the protein-to-1 Thus. bioreduction of ketone xenobiOlies. as a gcl1t'rol rule. produces predominantly ont stereoisomeric .Icohol (on-
i)(-)"",,In-xol
1
-
C
V"'-JOH
HN
CAN'A, H
Rl + HH.·Hy(Ir~·
-~
f 34
Wi...."'" ulllj (Jil ,'Old',
T~.rl"'''1Ic
"f O,gllt/ie M~,lirilll" iIIul
/'Iu,,·mt,u~rK:al
Chl'mix/n'
-
CH, N/
CH 2
fA,
-
I
C
....... Co?' ....... CH OH
I
• ~ •
'
H
+
CHl
Q
a a a
HO
HO
Q
~
~
0 -1I)(lh)'lmion 0Ci:1I1'! ... ~dus ivcly with the phenolic hydro~)' group al C_3.~74
~
... ~
Ph.... uologlc.lly Active Meu.boIlte. The traditional nOlion thai drug mctobolites are illacli ve mid insiglliflCan! in drug themp), has changed dr.lmatically in rel:"t"Ill )·eaoo. Increasi nj,; cvidence indicales Ihal m:lII)' drugs nrc blOll"lln~fOOTltd to phatm:loCOlogicaJly act,,'e metaboli tes lhm COOtnbu le 10 lhe thern.pcutic 3.~ .... ell as 10.\1C effecls of lhe pa~nt compourld. MC1abolucs ~hown 10 rul\'e )ig mficam lhempeutic al:tiYII)' in humalls are li'l~d in Tanl e 4-4 .1. H'I 'The (XIrcn! drug from ""hich the metaboli te is dcrio'ed and lhe blOlr.lllsfonnll uon rrocess Involved al50 are gi~en. How SIgnificantly an actioe metaboille COOtribul~ to !he therapeullc or tO~IC effects :l.'oCribcd to the parellt drug deperld.~ 011 ils relali ..e acl;"Il)' and (IUamitali>'c unponanc.: (e.g .. piasilla oorn:cn t Illt ion). In adl.lilion. II helher the mcwbolile !lCCul1ll,,]ate\ after "'pealed adrnin ;\tralion (e.g .. desrneIhykilll1.cpam in genalnc patients) or in pat ienlS .... ilh rellal failure is dclcmllnant. From a clinical standpoinl. lII,'1ive melaboliles are e~pe dall)' important ill patients with decreased renal fUllClion . If renal C:Jlcn: tion is the major (XIl hway for climin:uion of the lICtive metllbolile. lhen lICCulllulallOli is liJ.c1y 10 occur in (XIlienb "" Ith rcnal fallure. Espccially wilh drugs soch as proc:unamidc. clofibr~te, and dJgIII)~ln. ~ution ,lIOU ld be exercio;ed in treating palienls wilh renal failure .l. 411 Many of the tQ~ir effecis St.~n for Ihee drugs hn~e bt.~n anributcrJ [() hij;.h plasma Ie~els Qf their :acth'e metabolites. Por exumpie. the combinalion of severe muscle ..... CIlJ.ncss and tenderIIl'!i-'I ( m)opalh ) ) l)'1lc Idd Oeslpr,m lne Phef'IObartldolrme
Mesorldnlne
N-Demethylilion N-Oemethytat ion IIef1zy1ic hydrl*)'l.tlon O-Deethylltlon ...... omatic h'fdroxylllion Ketone reduction HydrolC)'latlon wid ooodiotion to ketone N·Acetyl.tlon Aromatk hydro>l)'1l1lon Allylic hydro..y1.1Ion Sulfoxicle reduction S-wldilIIOf"I
Wlrt"'n akohok
Ket_ recluction
~~
.,...,.Uin
I'ItdNsone "'"' ib...
o-H)'dfl*)'methylmetoprolol Acetaminophen OlC)'boJtazone
Predn,soIone Pherlobarbltal N-Acety!prOUllnllmide . ·ttydrolC)'propr anolo!
IIId )·h)droxylau:d mcmbolile of dia1.epum (Vulium). and -..ialtlll: (Serenli l) is the: sul foxide meboolite of the -.pI)~ilotic agent Ihioriduinc (Mtllaril ). AlIlIllnm tIt.lllR used in lreating herpes sim plex virus. 1~1I~·WMer virus. and/or human cytomegalovirus must be lNoiIctivllro.,JI Thc:sc: include acyclovir, v:.locyclovir. )!CICII:lo>lr. famc:iclovir, and gllllCiclovir. which must be . ., !bltd on the pt't1tose-like side chai n to the triphos~ dniuta·c to Ix: cffective in inhibiting the cm;yme Dl\A poIymense. The anliviml ci dovi. is dispensed as II .K~tt and only n«ds to Ix: diphosphylated for ..... eI\IOII!O the: .... i\"e tripho .......... , .... C_epU. ..... _ ........ DC• .....,."..,.. c.'1cmocal SoccIy. Im.p I .l6. T"..,.... W f. In T...u. B (cdo..~ C_ 80ca II ....... Ft.. CIIC ........ 1996. U GucntJCri. J M . et 0'" Pouc. NOlI, lIy. II C .• et aI.'!'roc, N>jl ""'" S.
Dni,
13:132. 19711
an.. o. P
R~ et 01 . An:h. 8"",lu •. lI""",p. 197:ll~ 1919. 111. Ortiz .... M"nICJI.... ~ P R.... I i 8~_m'lIry 2 i Il! I. 1911:2, 114 8ccl.. ,. A. II . _ 1IO'O'iand. M J P!wm 1'I>arm:oool. 17;628. 111M
I ll.
IIS. IJnftc.LG~ etal
8"","""'. J.116,~ll.I970.
I II>. Mc.\l ...... It E. In 8nJd>e. 8 8 .• _GOIIm1 0 ..... 1'Nnna;QI. ThCf 17""". 197', 120. Sen_r.O D . etal_ Dno. Melob, (')0."," 1:28!.197$. 111 Ton. Sholl M.. M~' 0 .... II I .............. Eop."'" 293i2,
1
L."''''
c..
~B. 200).
122. 123. 11-1 Ill, 1lf> 121 Ill.
1:IorJ:. K. 0 .. "'01 . Ac'. Ph>m........ T, J.... 01. (1>.). 8M:>1o,INl ltt"'t... I ~Wts. New y..n.. Plenum~. 1977. p. I~ 1'1 \10 """"'" P G ... >I. CMcer It... 36: 1686. 1916, 1)6. GonitJ,", S ... >I.: In Usd,n. I!.. 1'om:>I. r (td .. ). P,,)'t~lIerape"l", DnitJ. PM 2. Nc:'Wo M~I OcUet, 1m. p. 1039. III Gm:obIaII. D J.... .d.: Oin . l'h>rmacol. The, 17: 1. 1975. ItS. Y.... Y. ft oJ.: X~a S:24S. I CI .,""" J l _ 0IId SooI~ II .: Psycbo\>lW11"""""1i1 ~:461. I%(). I~' 'hIlo, A .. oDd _..,.,. R.' An:h. 1'IIarm. (Wc:inhclml 2\l(I:1 45.
\Ie"'*"
''''
1611 0.-. L F.... II.: P
In I~
11'
I" III Ie
1",1 1Il0l
liS I'" III I~ ~
1'iO
PIwmaI>. 0.'1"'>- 3:337. 1973 Wrigll' . J." I I. 7;257. 1977 118 Gal. I .. daL Itt •. Coon"",n. Cll M Bi«l>n, J.- Ir no... III
I97S
5SS. 1972.
266 7.ehndn. K.. .. al 8,...-. 1"harma..'01 II"~. 1962 lfol "'''' .... S. 1.. DI... Nnv. Syll. .\tJ;4801. 19n 268. T~Ior. D. C ... aI. Dnoi Mtry. 1975. p. "2. 21" S Oup"", 1,322. I97J Pi. 5 _ _ • Sf.. .. aL 0..., ~Ietob . DI\pIIO. 3:1110, t'J75, 276, Mdley. to: 11 ... al.; Dnil MeIoob 6: I)l. 1971. DIodIey. K II .. .. 01. Mctoh Oi.,..,.. 2103. 197~ II p~. M, L MMl III""",,", P S Dni. ~ .... iU:y 172&.1.
o..m.
... w_.
,
Droo,
0...,.,..
'lS7 to:.....,11I.U 1I~ ""Loe.V 11 L:Ad,I'In:noc, W.II•• T .. .. '" Fed. F"n:>.: . lS.I>M. 191b. 367 ...... IIe. T .... al.: Din. 1'IwtnIcot. no... 26;167. 1m .l6Il II..,,, _ S.. .. 01 J Alii. 0...... Soc. 76'IMO. 1934 369 So"".!!. J. I. alII. 1'haormocoI. 1'316. 1973. 310. lie ........ A.. tI "'~ J Pharm. Sci. 61739, 1972. 371 R.. ",.. A..... aI.; J 1'1.",-' up. Tbcr I 149. 1971. 312. 81id", •• 1 W.. " -'. B""htrn. ' I i8,~7. 1970 37) GiIKooo. T.. ..... .. Br J Cb • . "*""-'I. 2:2)3. 1973 l74 T$U"",,1'" T . ..... I.e,,),. G J. PIwm Sci 61Il00. 1971. 375 1'Ilr1et. Co C~ .. 01 DNa Mttoob. l Ii9. 191$, l76 a.-toun.N K.... aI., Ilnoc MaaIo. Do"{U. IJ72. 19711. lTI S,w. I), S..."" ",..... h.ll. I) P J Phltmoocol. f... p. Thtt.. 1114 m.
0..,..,..
""
In. l.oiiliiuI.c. 1:572. 1971 - - .... H _..... Vcn""wt. A" Acta l'hysiol Sand ~8 ,8a, 1960. I!.. CI ".: 8iochem. ' 65 41 7. 1~7,
«I' ..,.... C aor. A. B : Bioc:I>J 1Iani.. II I!IIhoJ i"""'. Ne1O' Yorl. PIonum Pre ... 19n. p. 2«7. (')_, j. L F In Ari ... I. M . and Ja1oby. W R ,"",.) Glutolho· _ Mcyo. J D, (...b ) Glulllthionc S· T-'cmIet. .-I CIrf'i' DI .. IOUn. 1970 4M. A.......·Sqo>I .. O . l>ru., 121>9. 197b. 466. 1I~1Ob'. P.>r1 2. 11nt,... Spri"p' V.na,. 1971. r
""
469 MI7dd. S. I( In rlOhmlll. W II (td.). MeuboIiI: C"""o........ M"lboIiI: U)'droIyoi .. 001. ) New Y '" M.. Londun. T.)"" & nW":;j. 19'111. 1I.""ie. B B. """Gil"" ... I Il (ech ). C""""P" ,. a..... ha' ....""'!'born: ,4· "1)' . ..... 1. &do.. Spn V' V~ ""1 Caklw". W D. , ..... ): BooIuf:""'l fkw~iflc"h... 1'1 ..... Yon:. Andoml< ~. 191B C"akl-'dL J~ ..... 1'aItI_. G 0 (td< I' Foml~ C" •• """"", M.lliboti .... t...Id
".,,,..r
' - ''''
o.M.".... F . 0IId Locl. p~ A 1011" r 501«"1" ") ..., M,*"",,t. M _ R....... at Toili.}, London. Manni" .... 1'I!l7. 011'1'10. A , Mkholjdll. C J •• ond Yo ~'IiIIwJn. E K "1rtabuI'WII at oht,_ ...... ,.. ,"" Pfw. 01. n..r ~7 26!1. Ifl' I . I) E., . U ""i.~ _bolo,., at dono .. WId .): The ''''''''''''''' 0( nn., M...boh.m Sruu,; .... S'crted by al.O reductase enZyJnes in the
age and generulion of UllIirlOSlllicyl ie acid prior 10 ubsorplioo
gUllO sulfani lamide. the aclive species (Scheme S_ IS).
prevents lht systemic absorption of tnc agenl and helps con· centrate the active agcll! al the si le of action.
H'
QlibaRyi C.lltp •• "ds
H(
Allhough pronlosil is 00 looger u~ a_~ lin anli~tC'rial. this Iype of lin~age appears in sulfasala1.ine, which is used in the treatment of ulccr.uive 00lili5. The 111.0 linkage is broI.en in Inc &UI by the action of am r..-doctases produced by microtlon.. Thi~ relc~ the ac1ivc agent. aminosalicylic acid..... hich lias an anti-inflammatory effect on lhe rolon. and sulfllPyoomc (Scheme 5-16). The advantage of this prodrug approoch is Ihal the combination of clcavageofthe u.o link-
CH.
A number of different funt"(ionalities have been enluated as prodrug dl:rivatives of carbonyls (e.g .• akkh)dcs and l eo lones). although this approach h:H no! roond wilk clinal use. 11lese nave cenerally invol\'ed derivati ves in .... hich !he
N (C H l~
OH
,
OH ....0
OH
CONH:I
0
•
OH
•
I
H.O OH
0
f'... " aldehyde
•
HNC] P)".......
Sp l
hyt
dil.ed c nitroge !ionali!
exampl
(P""ug) 0
CJ
CO NH - CH:I
Rca lThKrch
• C H,
,:,(CH:I~
CH., OH
(Sellen unne, '
o
H,N -
0
o
0
>-. =. -
0
11
>-S- NH ,
g
'H, Prork,
11
>-S- NH , II
o
&Matt': t " (Ac:IiYe Drug)
•
•
r
• H,
'H, Ses, pho!;phoryla· lion introduces a lea,jng group. "'hkh can be di splaced by an incomin, nucleopl1de . This is secn. for curnplc. in the synthesis of DNA and RNA , in which nucleutidcs are added 10 the J' end of D growing chain of DNA or RNA (Scheme 5·21). PhosphoI)lhlion IS t"Oln)nonly required for the b,oacllva· tion of antiviml agent'!. These: agents an: commonly nucleosides, which must be convened to the nucleutides to h:we
0
I 0
0
I
ce" " "'
-"
I
(XN 'N I A
0 ,
~
I
I
'
0 T1" p.lluml,..
f'\ 0,'
,
,.... NH, OH
0,
I C( ~ " " ..., ,
. OH
ONA eo.. ~Sb ..-.d
Scheme 5- 20 • ReduttIve ClCtJ'iil-
Brut ,
bOn of Inap.lZMnIn!'
activity. Most oflen . :lJlli ~ir.. 1 ag,mls di~TUpt the synthesis or fUrlCiion of DNA or RNA. ",hlch is gl!rICrully accomplislled by oonversion 10 the lri phosphate. Since oo/'l11al cells are al-o invohcxl in Ihl." synlhe'i~ or DNA and RNA. ~>()mpollnds have bcl'n sought Ihal would be converted 10 Ihe \riphosphnlcs. the act;.c fonn , in greater an'KH.mI ~ in infecled cells
than In normal celLs. 'lllcrrfon:. nuckmilk$ lhll have higher affinil)' for the viral kinase en.,.)'nlC~ than the mammalian kUlll.'iC'S art' dt'1;ir.lble and hal e grt'aler sclooh'c lo.llt-it)'. This can be seen in the prodrug idoxlIndilll'. whICh was lhe fillil agenl \0 show clinical cffectl\CIlCSS against viruSoe$ (Scheme 5_22) ..10 11Ie nucl ~ide tnlers IllC't:XpOr.ltion Into DNA. II hlch mul1J in 1IIC00lCCt base .,.unng that dis.rupl'l the ability of DNA 10 funcllo n as a templot e foc DNA and RNA syntheSIS. In addlhOil to the SC ler of dlllg.~ to tile eNS. 'The approoch Ila-~ ~n described as a chenllcaJ dclh', cry ~)"MClll. riOt j U,1 a prodrug designed 10 pcn.ctrah: the
blood- brnin barrier. II> Th IS process i~ a 111l111iSlqJ procedure i Ilvoh inl: dd t H~ry of the drug-dihydrop)'ndH~ derivathc 10 the brain via fllCile diffusiOl1 across Ihe blood- bmin hamer. follO\\'ed by o.U(iatK)Ioida. U. M .• Sa",. N .. d aI' I. l. C_ ... \4 121~.
.or
""
lot O""y. W It Eur J M.... CIotm. 'I6oSn. ~I " ~I". V. J J M... CIotm 23 117S. 1'180. 36. 1WdW
or
a tremendous increllllt In tnc number bIOleChnoJogy-re. lated phal'TTl3iCCUlical products in tk"elopmem. and. number of important new drugs progressed Ihrough trials and mlO tile el lllie. A good n: neclion of the irnpilCl o r bioltchoology is Ihe GcnBank tialaba,. or species. AOOIhc:r I"'pew' tant distinclion IS tlklt the fragn"ICnt of DNA from cukaf)'OI11: chr0m0s0mc:5 will cootllin uom ( prolcin coding 'iCgrnt'nlJ] and introns (noocoding segments bct .. ccn nons). """reM in cDNA th.e ;nlrons are sphced out .
Res1:rktlon Endonudeases..· • 1 The restriction endonuclcase (or rcstricl ion enzymc:) is probably besl dcscnbcd as a o;('t of "m()lc:culor o;ciSSln" in tIalure. RC5triclion I'ndonuclC'aJiCS are bactcriaJ e'n:tymC$ tha. lIS the name impl ies, cica"e intemal phosphOOieSlcr bond! of a DNA moleculc . ll1C cicavage ~lIe on a segment ofOI'A lies within a specific: nllCleotode 'iCq1lC1lCC of about j;1~ to eight base pau~ . More than .50) n:strittion endonuck~'ib have becn d isco\cred. aoo thc'IC rc;lc l wnh man: than 100 d iffen:nl clcavage silCll. The chcmlC"lll ~action of the rest"" lion endoollCk:asc releases the 3' cnd of One.' base as an aJco. hoi and lhe 5' elid as a ~phale . 'The general react~ is shown in Figure 6-6. TIle n:cogniliOIl ., ites ror restriction endonuclease, !lit specific palin(/ro,nic scquctlce.~ of DNA 8J II()( more .han 8 bp long . A number ()f lhese palindro",c~ arc: lisled in Table 6-2. A palindrome is II Sl..oqucncc of lellcrs Iltal reads tM s,1 me .... ay forward and bad.""ard. for mst~: "A man.1 plan, a canal: Pananu!:' " DNA · land," " Did Hannah «< bee~1 Hannah did." Kc.ICd 10 gc nerutc .,tW~, to the heterologous domams and for other bio~uWts. SometulIcs. fusiQll prote ins are made to ... ~ Ila'OOIbllunt protein that un be {'asily identified. AI (UII!PC of tillS I!. • tectmique called tpjl(J~ t(lICSi"S, in wt.ct. ,,(II~lenlcd anlibody TttOgnilion ~i tes IlIl: kIal .. nh recombinant protcins. Thc res uHing recombinant
""1Ik'
inln
hormone reccp-
One of the QUtCOlllC$ of the progre.~s lhat has boxn made In the id(ntiflCotion and cloning of genes is that mauy proteins cncodeeS. thoc genes themselves may repreSCnt the ultimate tBrget for the treatment of a tep. t'ipttiaUy if "t".filtralion is "sed. "1ft",1 "..ri/iro/w... TIle iml,~J purir~_ of the ml:>.t""'. somc:tll1leS attOIllphMled by prl'C'pttalion of lhe proIClIII. \lsm& a ~tow. stepwise ",crease of lhe tOI1ic w'n~lh of IhI: solution (iiallmg ()III). Ammon,um sulf.te i. alyplCal_" C;lII be u~ In coklaqUfOlJ< '-OluUo..... W"" .m1Sl;ibkOlJMl' ';01"'''1' iuch Il.< tochloro:>cellc :>c,d ~nd potyclhylo:fII' II)tOI chan,c lhe dicl«trK- coostl nl 01' the IOlutlon and also dr~ pra:ipit3Uon 0( prole, ..... Inlrnn~Ii"'r "..rl/iorli"". In this -"a~. the proteins 1liiy lit (l1ll1yzcd aiMIMI ",aIel 10 I'CrrIO\'C sah~ Ihal wen: u«:tl in Ill! prn:ipttltllOO filep. 100 uc""'"te chroonMop:iphy II weollD .. rrIXI m some", h:1I crude oqw'aIlOII of the proIeln) based 01 lheir behavior in ~ pU or Slilt &rndicm on the: ,~,n. AnoJIhcr filep thlot may be taken is 5il.e 1!l\( lusion (Jot; • ~1'I1Cti,," chrom~tDiI"'.phy. and -lilt excluMoo clJro. m.ltognphy_llM: protein frael"""':u-e simply collecled "'bert they dute from the Cl')Iumn .nd ...., roncmtnlil!d and for QoCtiv i,y . Sr",ili""/",, mod J.",.... /ati(lft . This Mep I:lln be lIIXOmpli;bal by uhtafiltllllion 10 n:fOO''C PYrogcns or by he""1IJ if the ~ teln Qn ... ilhstand Ihli. ForrnubllOO milhl involve Itt. :t II lion inlO !>table 5OIuuons for adm,n islr:l1ion or delcrmminl Ill! opumum oonditiool for !>tab,t" y '-'hen summlti", for cllm
as.
•
Inal,.
Complicating facton mciude (a) proteins unfolding illlO an inactive conformation during po ocusing (il may 00l be possible to refold the protein correctly) and (h) proteasc:s tNt are commonly produced by bacterial. yeasl. and mammahM cells. which may partially degrade ,lit protein.
Chupll'r (; • RIf)In:h""logy WN1 OrMII OI.Icu,·u,.
ftlARMACWncs OF RECOMBINANT DNA _I-PRODUCED AGENTS Di~
,,.,
illCrbtJlb h.t>e fac1lilllled the production of "ery pure, ill)' u'o('ful proIeins, 10e physicochemical and ~11I.'tl J!IOPCnie8 of l!lese agen!' are [hose of pro..... h.:h mean.> that rhJ'mac:i~l~ must undeOitllnd the . . . ~ IMIl lilt chm1iS1ty of inSUlbility) of proteins 10 . ., 'pll(. dio;pense. reoonslilule. and admml~tet' thcq ,.... (i:ru~. In~labllllies amollg proIci ns may be physical • . ;aI. In lhe fonner case. lhe proIein might stick 10 __ \~I\ or Oocculllie. altering lhe dose lhat lhe patienl ~>t In the lalla casc. dICmICal reaction~ taking ,we 00 IhI: protrtn may alII." the type or slerco(:hcU)i\lf)' "1IIt;mu1lO lCid~. dmnge the position of diwlfide bollds, Ib.o I~PUJe ch.:IJl15 themsc:h~s, and "Iter the charge ofli1c proICm. Any oflhese can cause unfolding lion) of the proI~in and In,s of activity. rendering ., molecule usc-ic-)s as a drug. Chcmieal instability call be I dunnl the puriraclllion staid of a proIe;n .... hen D>b:ult mlctn be subp:led to acids or ba.~. bul in~lJI ) ~kI oceUI al the point of admini,tmtion when. for
*
.
ro:;'~ ~~'" ,,~"'
.
1l1c pharn\;!· I fl OOIICepiS of the chemical and rmulKhtyof proIcms to predici and il:mUlc potential
"
• H ...... H) ... "h mi~tul'e'I of L· and D ,11:001 confi,unllOIl> The n:tlC'loon hould he ClpeocIro. the Mab,li:y of lhe carb:on...1lIIIruI. the "lie of tho: "'''''lion. Asp, which unde'llClCS ~~.¥KIII 'III • cydoc rml(ir:: mtel IIIuco-.'try
s.:.nautrn, the first recombin:lnl prepar.uion, imroductd 1985. rontIJlIS the natural 191 -aminQ add primary.'iCpI~1 one ~_~~~oo~ yl midlK' on the N-tenninal tnd. all cootain tbe 19 t ·amil1() add :Ie' wlIh tI'Ie hGH produced by the pilu;-
••10
~~"'~'i_~;~~im~.~nSlOnal with mostcrystal of its structure nOllpolnr show, amino
~
toward the interior of the mole-
I identical wilh IIlItunl]
";,.;l,yophi. tee Typi· :.~~,~poWdercd i good. If Slorcd at 2 10 sl cell harbonng the virus (Fil . 6-13). IntcTferoru then induce a state of I',ral resIstance in cells in the immediate I·ieinity. preventing s~ad of the virus. AdoJitiooally. interferoos induce a CllScade of antivlrnl proteins from the target cell. C. 1M. onr",_
""1"""1<
R· I,if
,'lIion 17, :1$ docs the nam-e molecule, Naturaj IFN ,,B and interferon beta- I a are glyc()II~'\U:d th:u the vials be ,hnwc:d In a rdTlgCr1llOf at ~ WIf(' for Ie" than 24 !loot('ntion of sc'ere:
1upcnia. It reduces the IltCd for platclet transfu&I\rr m)do'Ml~'''e chemotherupy in patlenlS wilh ... ekIId malignancies" ho are al high risl; for severe:
...
thromboc)topema. EflicllCY h.;\l, been den)()l1Stmled m persons "hu ha"e e\pcnenccd 'it"ere thromboc)topenla (01. Io","g a pt"e\'lOU( chemotherapy cycle. Opn:h'elm cau~ many ad,'el"!il" re:llCIIClnS. Among these IU"e edema. neutropenic fe\er. headache. n:lusca and/or ,omiting. dY'PIlea. and tach) cardia. PallentS must be momlorcd clotiely. Oprcr. ekin i~ ,uppl ied 1'~ a Iyophi li/.c:d pu\\'der for reconstitution . E~eipients Include glycine hnd pho~phnlc buffer componenl'. TIle puwdc:r has a shelf life of 24 month s. It should be stotCd al 2 10 8"C. If it is frolen. thaw it before /l'CQfhtllulion.
Tumor Necrosis FKtor (RecombinanQ.'J.J· lJs
11le TNF\ (Elancrcepl. Enbrel) lire: member> of a family of cylolines that 1U"t produced pnmarily in the innal~ Immune ~y§ tem by acti,·ated mononuclear phagocytcs. Along wi th ILl. TNF is typICall y the first cytol.inc 10 be: prodocetl upon infection. and liS rcact;OOIi can be both positive :l.IId negali~e. On the one hand. TNF can cau~ cytOloxiCl ty and ;nnanU1l3 lion. nnd on lhe other h:md. II servcs as a ~ignallo the lIdapl i\'e irn rnuII~ rc~punse. The TNI'~ are ull endol:lenou~ pyro~cl1s. and Ihc) cnllSt chill s. fe,er. and nu-like ~ympt oms. There arc IWO fonn, ofTNF: TNF-a(coc/ic(;lIn) and TNFp (1ymphotol ;n ). 80th bind to the same rc:cc:plOr and cau~ (Imilar tffec1.~. Elalll.-rcept is a d,meric fllSlon proIe'n COIlS"Ung of the Cllr..ccllular ligand-b1llding portion of the hunlan 75-kOa (p75) TNF fe'('('ptor (TNFRJ hnled 10 the Fc portion of human 'SO/ ypc IgG " 11le Fc component of tlilnercept contains theCH: dom:un. the CIl, domain. and lhe htnge region. btu 001 the C H I dom.ain of IgG I. lbesc re:a;'on~ 11K rcspunst· ble for the biological effccts o( immunoglobulins. Etancrccpt is produ(:ed In rec:umbmanl C HO cullul\'~. II OO/I""ts of II peplidc cham of 934 31111110 acids and has a nlO]eO that tIM: rrucc" of regeneration can bf:,gin. Normally Ihl s process is highly localil.cd 10 the damaged reg'on. so thai
the: hc:mO/llullc rc.:e doe~ nul cauloC Ihrombi to migrate to dl~tl1lll 5l te~ or pen.I'e al:IS dil'tttly ",. catalY-li ng the cleavage of plasminogen and i niliating Ih l'Qlllbolysis.. It halo high thrombolytic pot~ncy. A compamon at nltepla!i(' and releplase IS gin'n in T able 6-9. Tenecteplas~. 'J7
Tcnect~plu.'ie
is a IPA produced b) recombinant C HO ~.... II,. The molecule is a 527-amino a.ctd glyoopl"Olci n t1cvelopcd hy inlrooocing lilt fol lowi ng modifi· cations 10 the: c DN A eonSlllK.': Thrl1>l 10 Asp. ASPIIl IO GIn, boI:h w.lhin lhe kringle-l domain. and a tctraalarulll: su~i lar ion 31 I mino ocids 296 10 299 In the: protease d0main. llx: drug is a Sterile. Iyoptuhud po ....dc:r ICCOiUmended for si ngle intmn'notIs bolas !ItIml nislralion ann ~ conSlilu rion wilh ' Ierilc water. TCrlCCtepla'iC shou ld bt administered immedl alely after n:cooMilUrion .
Factor VIII.'''
Anlihemophi lic fKlor VIII (n::cornI!Inant ). ROCOftlbinaiC. Kogen:ttc. Blot ille. Helixale... I plasma protei n Ih~1 functions in the normal b.Jood-c1oru1ll eascade by increasing the V mo, for lhe actl, arion of dotlJI'f factor X by factor IXa In lilt presence of calcium ion!,mJ negatively ch~rged phospholipids. FaclOr VIII IS used 111 tb: In:alml'm of hcmophlha A. Hcmophilia A is a COI1gt'1IIIIl disorder characteriled by bleed;n!!:. 11M: mtroduction off~· lor VIII as I drug has Improved the qualn y of life and tb: life ClIpect.ancy of Individuals .... illl thl ' disorder. Unfor1llnately. ir has been ncccssary 10 re ly 00 an unsure SOUfa (human plasma) for rhe fill-"lor. Exposure of palien", 10 alloant igens and vi ru ses hps b..'C n a conccrn. F:lCtOf VIII dcnllll from a recombl nam SOUrtt .... ill poIcnti~lIy eliminate of these problems and proVide an c:ssc:nrially unlinllled Mpply o f the: drug. F3Clor VII1 is biosynrhesiLL'd as a ~ingle-chail1 polYPI? lide of2.332 am ino acids. The protein i~ very he~\'ily ,1)\'1). s)' lalcd. Short ly ofler biosy1llhc:sis. peptide cleav age I)CC\I\ ol"ld pl asma fal:tor VIII cil\"ulatcs a~ an SO·lOa light chM associated .... irh a series of heavy chai"~ of appro~imatd? 210 kDa 111 a mellli Ion-stabih led COOlplU . FacIO!" VIII put'iCW'S 2.5 potenlial N-Itnked gl)'CQ'iy lalion suc;s and 22 c,. re~idllCS. TIll: 21().k Da ht-avy chain is further clea\ed II! protease, 10 yie ld a kinetlc ' . rll mete r
t:n..ct'IIiOc~, The molccu l:lr mass of the mole· cule i~ about 29 kDa. D~Ase I i~ an cnOOnucleao;c lhal clca,·('1; double·\lrnnded DNA (and to '>(llnC Ulcnt t!. . All opposilc SIrdlcgy ntlghL be ronsiden:!d for the lreatment Qf c.aoccr. llhereby tr~nsplumed cells ~-ould be used 10 target cancer cells. Inrn:asing loclIl cell·mediated Immune reo;porucs. 1lie trun~fer of gcnes from Ol1C organbm 10 IUlOIhcr i~ termed tnulJgrmcs•• nd an anImal lnal has r"CCe1\'ed such a IflInsgcne is referred to as a trtllugrnic flrtinllli. If the transgenc IS Incorpor-.otcd IntO the grrm cells (eggs and sprrm). il II ill be inhtriled and JXI~ on to socceMive gencrdt ioos. If the Imnsgcnc i~ Il14--orporated into other cells of lhe body (somatiC crlls}. It ....·i ll be expressed only as long as the IlCwly ~'rcatcd Ir:Uls~nic ~-.: lI s are alive. Hence. if a tcm,inally dlff~'TCnnated. poo;utulotic cell recehcs a tfllnsgenc it will 11001 undergo furthl.'r cell diVIsion. wlK-rell~ If a trnnsgellC i~ crellted III an undllTcn"ntlated ~tem cell. the prodUCI .... ,11 continuoosly be upresse;i in new cells.
,roc:
AFTERWORD C ltarly. biot~hnology has becoI'Iwe lUI inlcgr.iI part of pilar. lllaCcutical care. l>tlarm:tCisl~ need to become comfurtablt with biotechnology and II!. languOIge to delher thi ~ kind rJ care 10 lheir patient!;. 1'1tis ~haplcr has tried to preM'nt II! OH'r\I;eW Qf the major biOle..:hoologlcal arenas present i. the lear 2003. 11lc: field i~ a!hllncing rnpidly. lind elety phJn naci~1 must . ta y current with the litC'T'll1ure on biolecfo. nology.
Acknowledgments PontOns of thiS Chapter lIlcludeli matenal from lhe kntb edit iOil chap4tr by John W. Regan. The author b grnlcflll for the U'iC of Ihis conlent.
REFEREN CES I NCIIL. NUl. NlII. lI.d......... MD 20894 C·II\II,'
"'ruG'.........
ft,h ......
2. ikn...... O 3_ Gen8anl..
'OI'.lIimt ~
~
RcoaIdo ..aM... ~f.......... A ~_oation_ ,""",. MtdJ.
"'...... ,n BIOIe·~'R. Ii C T",,""'~. lle:.lth cw. ~ 1I1~ 133. t99l\ 10. SIC ..." . C F. and ~lcnu .... R A: Am I I .....r I'IIarm 46( II s."I 21:5-' -SIl. 1'189 21 Tonti. J.• O/IIJ Ih""•. R I' t~,..,."P} 16(4):527- '36. I n . Kooll_ J I/oop PIIlInn.
~ 1(8)
t7Y1--t7M. 1990.
7.ano .. S. A. CIIIT CChtjliO ' ...... I'IIalJ. w.o lIId Wallcd... p .nAlu ~.S Am Ph:wm.NSI'o(II)'_9.1'19S j.I, (jI"L, B It.. MIl I'tio1 MoIf I, B,o"ham\llCetuiQI Dru, 0.:..", ... T _ .. NI. lIu"""", PrnOI. 1999. pp 39-Ml lit> I'~U •• P L.. ~_ iii Mok....l ... 1I>01of)' Bo!.IooI. WCB M~On" Ihll . 191\11. I'P In_n~ n. RUJon.,l ul. Y.. l)oUa. S.- In w"~Pt"'I. S. 1I1)j......... ul. Y I""s.!. U"'JIhiwnUlCtul",.1 Ono, D ..... II R I..... ) 11 ,,,,«,,,,,,,,'1,) ..... I'hIm>ac) "' .... YOIt.. 1991. PI'- l2~ ·In I',""", IOId C'>mf'IU1""'" 51 1.00... MO ...."', ..... CI"..,...., ........ 2000. pp. 287,290 "'''''''''IID " "'p',.1 ")"nulary SC .... iWk ,n Moj..,,,(ao Ihol"" '>n ... I"",,,,,,,,,,,,,, ON". SI. Lou ... MO. I'''''tr. and C.lftlpan ...... 2flO2. 1'1' ~11 and ''''~ 11Ic~,n VoIioli.. O.. dal. :AnnOnrol IH' ):9~- loo.2000. IJnbr:ruIC'ft. I O. (Omc: \0 form /JluJgmyso·
ErythrOqttH .nd P~"'''
New St.m Celli
7' 1 1
"""".
A4ymmetric /
I
My.101d Br.nch
Ptur!pot. nt "" Stem C.1Is
"-
I """.h...
:--
G,.nulocylO
L _"
/
•
/
L,.....""kI
.'.Mh
"-
•\IIropnl ~
TL~H
?
?
N.tur.1 Klier Cd
Scheme 7- 1 • LIfl&lgeS of blood cell~, AJI blood cells denYe from a piur lpoleol stem cell. A vallet)' of cytok,nes direct the cells ,nto the'r specific popula\lons
S()flU's.
'The antimicrobial rompourld~ in lhe phagosome~ and
1)'!IOS()me!; kill lhe rngutred palhogen and coL)'maucally clea\'(: its ",m::nll!l into !>ITIalier pieces,
EosI_phlisS Eosinopllll~ 3'" ~yte,. but much
gr.mulocY Ie!; Ihal can function II:> pha!Oless effieientl), than IICutrophiis un. They arc: pn:scnt as 2 10 4% of blood lell~ocyle~ , Their name deri yc,s from the in tense Slaining I'l:OCll00 uf lhclr Inlmcellu· lar gnmult~ with the dyt eo,in, ~i nuphil gr.mulc) con tain IIlnRmmatoty med,atOrll such a~ hi,t~ lninc ~nd lcu ~OIricrleS. SO 11 makes sense that !hee. Clues to the funcuon\ of OCISinophilsCQIfIC from thei r behavior in certain di!>('a;.e ~t ate'. Eos inophil counts a", clevated aoo\'c IlUflIlaI In me ussuc~ In many dlffe",nt di'leases. but they are rels. Eosinopllils can physically ~urroond a large paras lie. fonmng a cell ~()Ut around the invlkler. E~inophil grllnole~ rclen., e o\idal ;"... ,ub Ibr ma,t «-II tu ". Ikcause of IlIlIbilizmg units. 1be general ~tlUClure of tlte Ig looks ';';"nllt~e a Y..... nh lite antlgen-bm(itng regions :;Itlhe Wlllnltd tOO. In Ihis area arc peptKle sequences that ore "~blc" by (he immune ~ystem to allow lhe Ig II) IIlX1pue Dlarge number of anligc n~. TJt~ment .... ith either of IWO cn/ymes. papain Of pe~in.
\ ....."""/'.
J
I~
b'_ "·"·
;I •
I
J
Fig ure 1- 4 • ClassICal (ompllmoe-rlI
palhw~
AnIigeo' B do", RegIoo. (Fab)
Fe Regioo'
V.-IabIe R""",os
Figure 1- 5 • Structure of ,mmuoogJobullll G OgGl. showong an!lgen-blnd,"'9 regoons ¥III ttey of the rnoleculr
Tlt'atmcnt of the same Ab with pepsin yicld~ the two Fab units JoillCd hy the disulfide bond. plus t\\oo of the diStal peptide chains. Thesc distal units havc been crystaJl il.ed ~nd. hence. are temll"d the R: fragmcnt (fOl" '"cryMallllable'"). The disulfide bond. thelt'fore, provides a demarcation between the two molecular rcgiOlls. The oomellClature of an Ab includes a hlgh-molccular-\\o·eight. 01" heavy. chai n on the inside and II low-molecular-weight. 01" Ioght. chain on the OtJI.Mdc.
elemen~
incorporJl.e them IntO their cytoplasm ... here the anllgens_ fragmented. The fl""JgllocnlS an: then combillCd with MHC· 11. di~played on the cell membrane of the macrophage. aDd presented 10 the immunc sy5lcm. The presented anlip interact with B cells. causing differentiation to plllsma alb and Ab 5eC1\'t1on. T-helpcr celLs also interact with the 1ft"" sented antigen and arc stimulated to cause the B cells ko proliferate and mature. Plasma cells an: monoclonal (genttocally identical) lind produce monoclonal Ab. The pn:I«N.
tMPOfITANT FEATURES Of ANTIBODY MOLECULAR STRUCTURE·' , As 'lUted above. the tip end of the Fab region bind~ ant igen. Then: an: tWO of I~ regiom. tful. puttm!! labora· tory technici:ms at n~k: and (d) the pallent may upcnellC' abnonnal and h:lnnfu l ll.'''ponsts. such ill> fe. cr. oon.-ulslOns. and death. These \"X"C"lnes t)pocaJ ly arr \'iewed Wi ··dln)·· vaccines. and .;orne. hl.e the pcnu.'i..~is \liCCine. h:l~e bc:c:n associalcd " .th probkms ~rious enough 10 ..·ltrJm their tcmpor.lty rem()\:!1 from the mart et.
Uve/Attenuated Pathogens. The word /II"mrmrd fur oo r purpose$ .~ill1ply nocun§ ·· Iow vlrulcnce:' The true palhogen i~ a he~d phcllOlypicaUy so that it cannot ill"adc the hUlllDn ho~t ulO cunliOl gel ahead of Ihe ho~"s illll1l1111C system. 1.(lw·pathogen icity 'it,..ins such as these were ongi· nally obtained by passage uf the IIIkrul:lt'~ thrvugh mallY geoer:uions of hosl anilnals. The jdc,a ...." th:lt lhe animal and the pathogen. if both "ere to su .... ive, needed to adap! 10 Iovc With cach OIher Without either panner bcmll t Illed. Poliovirus IS attenualed in this f3Shion in monkey tidney lissue. In a !i"e!aucllllmed vaccine. allhgcllIcllY is sI11I ",. qu ill.'d. as i~ i llfecti~i ty (polIO vaccine )'idds all InfeclKH1), but Inc: ho!.l·' 1I'lmllllC sy~tcm must be able IU sUly ahead of the mfeclloo. The I.ey problems are: fa) t/w:: '·ac~UIC c.nnOl be u'\ed if the paliclll is Immunocompronll~d, ha, rClCr or m~1 ign nney. or IS taking IInmuoosupprts>ive drugs: (b) IheM! vacci lll:S ~hou ld not be used duri ng preg.nancy: and ft"J the nucn uutcd o rganh m commonly ",'en s to the virulent ~t,..in. which wu~ the: reasoll for the foi lure of .;ome cll(ly polio vaccines. T oday. blologkal quality cootrol i~ 'cry slrlllgelll. and th.c.;c probl.ms ll:I"e been eliminaled. Live/Attenuated Relitled Strain. Il.'latcd ~t ralll is anugenlcally related so that" cnn provide Cf"OS5·,mmllnily to the pathogen. r-orcumple, OO>\poJx viru~ can be u~ In place o f smallpox ' irus. The '\1r~lIlS are !Illt,· gcmcally ~Imllar cnough..o thai the host's munllllC system reacts to the Il.'lalcd SlrDJn to pro,ide proIcctioo agalll,t the 00"",11 pathogen. The maill advant age is thul a true pathogen is not being u'\C:d X ' 1 ~hOI.
~ ~lOCCi""
Paeteml PIMmkI DNA
2. In a "",llIple..Jrui"g oeglfncn. se"cnJ
ReAlction EnOo"""II,.
o
3.
n
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,
Grow in batch aAllft
of oil
1 .he In,":o1 mult,pIe lirs! pIIl"'"t agc5. ..~ A .... 1... i. immunily. Also. boo!;ters ure usa! if a pallenl i, lion schrdulc
// 0 L/
Prep.JfolltlOfl
h""_
Types of Dosing.
o
V"'ONA
,th
3. .~" A pQJ>~"lJI~", VIICC" ", i, prcpartd from two or """'" tlla! Catl!oC d,ffen:m di ......••. PoIYI'I.Jem ~1'CdOlCi ore conl-en~. rrilnUlly Ml tlt3t a eMd can 1M: , .."eft nllher than ,",veral. n.. n"ll)l"'-!t!um~ - ",belia (MMItI eu>c: is 0( tIM: poIP"IIlent I) 1'1'.
Vhlt Surfaoo Protein
VlIlIIONA
,.nJ
~
. . ;• •
••
•
I!f\9lneered Ab
i~_
Of
pcaed 10) 1LI,'e mn up'en: infcct, on. Thi s phenomenon is known as pmtpolio muscle atrophy (PPM A). PPMA i~ oot a rein fection or reactivation of the virus but I~ prob;lbl y a fonn of rapid agi ng m polio su ..... hors. There are t ... o types of polio v1lC"Cmes. Inactivated Polio Vacci". (IPV). Thcreare severnl 5ynOII}'ms for the IPV "accine: IPV , e- IPV. e p-IPV. and the Sal ~ vaccine (l9~4 [I POL. Alcnus- Pastellr l). e- l rV is an enhanced potency poliov irus. ITIOf"e potent and immuoogenic than any of the previous IPV formulations. e·I PV is ,ecommended for all four infant doses because of lhe incidence of rare CIIS('S of orul pol io vlICeine (Or V)-as...ociated paralytic POhOnl)'ditis. e·l r V i~ also preferred for adults for the '>ame rea!iO!l. IPV is a tri valent (,troins I. 2. 3) voecine gro...·n in monkey kidney cu ltu re and subjected to elaborate preCllutiom; to en'illre inactivation (typicall y, f0ll11aldeil yde is used). llll' anllgen fonn is .... hoIe virus. 111e anugen type is protci n. The v1lC"CUlC is IllJCCted to CIlUse Induction of IICti ve systemic immllnity from pIio 001 does not Stop polio cafriers. "'00 shed lhe virus from lhe om! and nasal cavitie!>.
Trivalent Oral Polio Vaccine (TOPV). rol'V (Sabin I·accine. 19(0) ,s a Ih'c altcnnated whole virus vaccine (lntigen type. proIein) eoolilining polio straios I. 2. and J. The virus culture is grown o n monkey kidney t i~sue witll lise of an elabor.lle allenllatioo proIocol. Oml adminisu1I.tioo of the "acclne yields I local G I infectIOn. and the initial Immune response is via lilA (mueosal. local to the GI tract). llIe Ig A- ant igen complex undergoes tmnSCytosi~ IICrob the mllmsaJ memoone. and sy~temie immun ity is induced as IgM and IgG form . A nlajor caution with TOPV is tllat it is a li ve val."(;inc und mu st never be injcct~'d . Ind icatioll~ an: o Mas. >7IfXmauon eampail'lS to control OUtbn:w of pual}11C polio. o Cn"lICI;"inalW chi~n ... hoc) will tra~cI in k)~ th;In 4 ...·IIC~' 10 arelIII ... ""re polio ... enderruc. o Ch,ldrm of ~nts "'00 00 not aooepI tM rn:om!llC"Oded IlIImbc:r of vattmc: injecuon!. 11lesc children may ."o",·e OPV only for lhe Ihull or fourth do!io: or both. In ~uch ca§C$. the b:'ahll ~ pnwillo" .w-.ould .mun'Sier OPV only after IitSCIIS~ nll !he ri.\k of OPV_ IL'l.WJC,atl,d p;lnIl)·tlC poIiomydlll' ... ,th paretlt~ or curellJvcrs. • t- IPV it m;(Nnnoen such as ...·eltbn and loc alized oulbreaks. Ou tbreuks are vcry eom mon I! neighborhoods lind schools. One of 10 ehildR.'n contractl~ measles will de\'elop an ~ar infection Of pneumonia. Measb mlly infcct the bnun (eoccphali tis) and lead to cunvu ls.ton$. hearing I~. and Illental di5.abil ity. In the United Statb-l of every SOO to 10.000 chi ldren controcting mea.~les dies
J .,
,,'"
.x.-m: ~Klneu
and death are more COIllI1l(M1 in ".0IIId .lullli tb.:m in elellX'nlllJ}' schoolc hild ren or lten~ Maos~ bas been Jinkt'dlo multiple sc leros is. In 1917. ICme epilkmlC occurrW in tnc: United Stales. and 50,000 "0\' rtpJrIw. Only 60% of tile popu laliun was Yace;· II.
vaoxinc is romposcd or live!:luenlWW meask~ . . I) grown on chick embryo culture with an auenun·
Ino:llcatiQns are •
~,,1IIdU:'bOn of lIC't,ve munum.), IIj!lllnlll. mc~1n ~'"'~.
. 1~ ...I... MMR '~I~
i,tllt I'rdel1l'd immuomng form for _ d1aldron and o,:my aduhi. • AI_ .U chiOJllCn ~nd many !ldulls ~ui~ moll: than one M..t \LI,JR. • f'rg 10 lOItiioatMJol;lllrl~l. prnons ,u'lCel'l.lblo: 10 _n y 0( the ,. .. ,..., Poiold ~Ive tM l ingle-anl'gen ,'XC'IIC OI'.he ~ . . ."XCI..... ~.
_+
Ita,-"
• \Ii>II paM*> bam bd.n 1956 arc Iolel) 10 ~o:d ..-.II)' lind an: IlOl ronsldemi JU~p"ble • fb . . to:n afIer 19:16 0I'th!Ke ,,110 tack ~ua!e donImcn,j 1u"o,1ud the dl'C'ase 5hou ld Ix: Va0 ron: uposoJ to ~hlC ~ enpCl to """eh ·e vlricCU.·I.."lcr immune ,Iobulln (VZIG). • In eklcrly ~rson~. vlII"icell~ vactlllC: can boc:JM Immllnny to varicella·ro>ter '·I!'US and ..... y pre,·tnt or attcnuate herpes lOS""'" (~,ngb) IIIlXh.
HEPATInS VACO NES-
Hepatitis i.~ a comple:< of diseases that causes fe' cr. naw;ca, abdomillal pain. jau ndlcc. liver faillln:. and tk'ath. lben: an: fi vc clinically 1Cl;0gnized lype' (A, 8 . C, O. and E) .
of
Hepa t itis A Va«iflf!. Hepatnis A virus (HAV; IO feetious hcpaUtl~) cauSoQ an acute d, sea. _
~_o( ' '''
.. ,.'c ...' ..... 1"'....,,"";.. 00.,.. _
\,,,,,,,, ... '" be Ji ... if IW'"iowIy ' ... R«oo ... , ''II io . . , _ ....... _ _
00-
_o_ po1 /0110111'11. VI.4t No. ... 12,0eIMg 10 boost the ability lhe 10 TCSiSl the infection. In adults. dm:c doses should be .~'II O. I. and 6 months. In c llildo: n. the vacl.'iroe h give n MIt. I mlollth. and 9 lIIonths. AdPl1in istr~tiOC"nUJisls ' ·a.ccine has been hillhly l"Olltro'er.;ial in ",,"'Cnt ),eOll"S. The original ,';Jj,,,cinc con~i\tetl of killed pertussis bacil h (B. pertussis) and wa.~ ConSidered somewhal ··dirty." S ide effects such lIS fever and C()fIvuL~iOf1.'li .....e re common, and IK-alth au thorities In Lhc United 5t;lte5. Japan, and the United Kingdom decided Ihat the no;],; of the vaccine out weighed the ri sk of CQIltr.IClinll the di ~ase. In all thrtt of Ihe'\C countries. pertussis VOC"CUIC was removed from the routine imrnuni1.lition schedu les. AlnlQl.t immediatel y. penussis, which had been he ld in ehed, begun 10 occur in epidemics. In 1992. a new vaccine WIIS de"eloped thaI consists of baclerilll fraclions. combi ned wllh teUlnus and diphtheria t010ids. Thi s vaccine. ca lled Acell · lmmuoc. Of DTaP. i~ SlIfe and highly effective and hWi bc:cn added to the routillC inullumzauOll schedule. The VacclllC is adsorbed and is used fOf routine immuniwio n ... the poIY"alent preparation dlphtheria- tctanus-penussi( (DTP) (at 2. 4. 6. and I S months and It 4 to 6 yean). Pcnussis ~lICCinaliOn is recommended for nlO!il children . There i~ abo a dlphthcria-Iet:mus-pcrtu ~sis whole-cell pertussis vllcdne (DT.... P ) 00 the martel. but il Is considered to be higher in si(k effects Ihan DTaP. Lastl y. a DTapnlib vaccine prepar.ulon IS on the mw1.;et and is recollllllCnded fOf U!oC only Ib the fourth dol. E. e.. 0fId "II .... M I Setnln. Virol 4213_1~3. 19'H 38. Hl 1es1 cu ltures of Swplrylococ..us /IUIl'II$) incrcase •iIt molecular w('ighl until the 8 !I:niary. Ot-spi(e thi ~ filet, 2-prol).]rlo l (i~o I~!"'~)I alcohol) is used commercially in~lcad of lI -prop),1 7': ,b«ausc It is less e.l:pensi~c. lloOpIUpyl alcohol is y ~ acth'e (han cthyl alcohol against vegetati~'e _'Will £l'OYo lh, but both alcohols are large ly ineffective spoies. The: acti"i!), of alcohols againsl microorga· I) due to the abili!)' of alcohol, (0. denature important and carbohydrates.
IkoItoI.
Ethanol (eth) 1 1l1roho1. wine spiri t) is a • roIoticss, volatile liq uid wilh a burn ing ta~te and a
USP.
characlCrislic pka~nt odor. It is flammable, miscible lIo'Uh water in all proport ionS. and sol uble in fflO5t OI'Xalllc $01vents, CommercIal ethanol coolUins -9SSf> ethallOl by \'01· ume. Thi s concenlr,lI ion fonns an a1.C01rope w,lh I'o ;Ucr th:u wSliIls al 1S.re. Alcohol has been known for centuries as a product of fcml('ntation from gr.!in and man)' OIller carboh)drates. E!h:mo l ~ Dn also be prepared s),nthetica ll y by the sulfuric add -cDlIllYlCd hydrntion of clhylelle The commcrce in. lind uo;c of. alrollol in the Unitcd StDtes is strictly cont rolled by thc Treasury Dcp;lrtmc m, y.hlch ha.~ provided lhe folloy. Ing definit ion for "alcohol": "The Icnn a/co.hol mcans tnal substance known as ethy l alcohol. hy· drated oxide of elh) I. or spint of wine. from ,,'hatel'cr source or wl!:u e\'cr proces.~ produced.. havlIIg a proof of 160 or mon: and not inc ludmg the substances commonly t oown as whiskey, brandy, rum. or gin ," ~,,(lfur~d alcohol IS cthanolthat has been renderro unfit for usc In IIIto.Xicah ng be\'crngcs by tM add ition of othc:r subsianccs. Co",p/~/"')' '/f'nlllu rro o/",hv/ COl'lIalll~ added wood alcohol (methanol) and benune and I~ ul\$ullablc for either internal or extcrnal use. S~f'iall\' ilcllllIr"f'd alt;tJho/ i ~ cthanol trealed with one or more Sub~lanCe' !IO th~1 its usc may be perrnitled for a speda lb:ed purpose. Ex amples are iodin.c in alco.hol for lincture of iodine. I1IClhanol, unu OIlier substances in mouthwashes and aftt'r..lmve 101iuns. and nICthanol in akohol for preparing plant utracts. The: pn mary medi Cinal usc o.f alcohol is utcrnal, as an anliseptlc. prt-'iCn'a!i"e. mild coullicrirri!ant. or sol"em. Rubbing alcohol is u'lCd as an astring('nl, robefacicm , and • mild local II.fICSlhelic, lllc anesthetic effect is due 10 the eVap0r3ti"e refrig('runt aclion of alcohol "hen appl i('d 10 tIM: skin, Ethanol ha~ c\'en been mjec!ed ncar flC'nc\ and &angha 10. allev iate pain, Ii has a low narc()lic pOIency and has been used inlemall y in diluted form a.~ II mild sedallve. a ",('ak "asodil ator. and a elll1n;nut;\·e. Alcohol i~ nICluOOli7.Cd in lhe human body by a "-
toxicit) in mfants bathed ill hexachlorophene and in bum pouents deansed wnh the agenl prompled the FDA to ban its us(: in over-the-counter (OTC) anu>eptic and cosmetic prepanuions. IO HexlIChloropnene is still avai lablc by preSoCnpl ion.
Cresol. NF. !llenc
•'Crrsor' IS IICluall) a mhwre of l!tree iso-
methylplll;'llol~:
Eugenol, USP,
4-Allyl-2-llIclho~yphcnol
is obtained pnmarily from clo,'c o il. It ill a pule )'ellow liquid .... lIh I 'ItOng atOnia of cloves and II pungem taste. Eugenol I~ onI) ~hghlly '\Oluble in .... ater but i~ miscible .... ilh alcohol IlnII othet" organic !I01I·enls. Eugenol possesses both local IDC>Ihetic and antio;cptic attivity and can he directly apphed a. I piece of COitOO 10 I'l'Jieve tOO4h:1chc~. Eugenol is also uSC\l in mouth .... ashes because of i.." anusepck propcny and ~ ant tast~. 1llc phcool coeffieicnt of eugenol i~ 14-",.
OH OH
I
EogeooI
H,
The nll~ t urc OCCUr! as II yello .... to bm",msh-ydlow hquid thai has II charoctcri ~lk: OlIor of cn:Q~ote. Crc~ol i~ obIailled from cool tar or petrolnun by allaline extraction into aque0I1~ medium. lICidllicalion. and fr-.telional dlsullmion. The mixture is Dn ine\pcn~ive anliseplic and disi nfectanl . It pas~se~ a phellol cucfficiem ofZ.5. C~ IS sparingly soluble III wmer. ahboough ukohoh and OIhcr org.ln1C ~I~enl~ will soluhili/.c ii , The drn .... back to it~ U'\e as an anti septic IS its unpleasant odor.
Chlonxresol, NF.
4-Chloro-3-mclhylphenol occur! as coIorldi> cry.~IIII~, Cblorot~ i~ only IIM to gcner~'e o.\ygcn and oxygen rodicals. Other oxl~ asents.. -~
'hit: 'Ulcr
cad'~Hs
CH)(CH;,)n-
I.
N
t
Q'
C2HS
H5
AI the right roncentrntion (the critical
tion). tke molecules concentrnte Dttlle: Interface bctwttl! u.. miSCible solvents. such as water and li pid. and water-in .... or oil-in-watcr emu lsions may be formed with the ammo· mum head group in the wDter layer and the nonpolar hy~ earbon chain assoc iated wi th the oil phase. The ~)"nllnl and IU1timiuobial actions of the member.. of this clau af compouoos were first reported In 1908, but it .... as the pioneering work of Gerhard Domagl; in 1935" lhatlllte.· tion "~.IS directed to thei r u.sefulness as anuscplic~ dislnltc tanlS. and preserv:llh·cs. The cationic surfOCtDnts ucrt a bactericidal action agaillll a broad spectrum ofGrom-positl,·e and Gram-lle,atil"C t.:teria. They are also actm:~ agDin~t scveral pathogenic spme! of fungi and proi07.0II. All ~I)(m:s resist the.se agents. 'Ill! mechanism of octioo probably in\"oh·es dissolution of tIIr surfllClant in co the microbial cell membrnnc. deslabJIi7""" and subsequcnt lysis. The surfacumts may alw interferc1rG enzymes associolCd with the ce ll membralle. The cD llonic surfactants pos!leS!i .severnl OIher IMope'''''' In addition to the ir broad-spectru m antimicrobial actll"'!
not'"
ChlOroazodin Oxychlorosene Sodium. O~ych lorosenc (C lorpactin) is a complex of !he SQ(Iiul1l salt of dodecylbcnzencsul fooic acid and hypochlorous acid. The complex slowly relcases hypochlol'QUs ocill in solution. O~ychloroseneoccun; as an amorphous "t organic solvents. k" used as a preo;avativc. primarily to man! ye:ut grov.·lh. I'rqI) lparnbcn sodium i, a WaICT-M)lublc o;odium sal t of the 4·phcllOl ifOOp. ~ pI I of solutiuns of propylJXI ...Jbcn sodiam IS basic (pll - 10)_
:r· ;r-
o
I3cnl)'1 ~lcOOol (phcnylcarbmol. phcn)lmelhanol ) occurs nalumlly as lhe uneSierified form in oi l of jasmine and in esters of acetic. cinnamic. and henlOic acids in Gum bcnloin, .. tor.!.' ~~in. Peru balsmll. tolu balsam. and some volatile oi ls_ II i ~ w lubk in W'Jler and alcohol and is a cleat' liquid ... i!h an nTOIllatic odor. Scn;tyl lLlcohol is commonl y u...cd us II Pf... ~rvulhe in vial~ of injectable druGS in eonccnl ....!tlOn~ of I to 4'l> in ....ater or saltllC solution_Rcnlyl alcohol h aal admin11 is unstable wbcn heated In aqueou~ solution,
Sod/urn Benzoate, NF.
Sod ium ben100 IC is 0 while cryMallinc MJlid Illal is soluble in water and alcohol. It is u..cd as a preservati \e in acidic l iqUid prt'p.'ltatIOllS in which hcnloic acid IS released,
Sodium Propionate, USP. SodIULn propionate OC'Curs as tmo sp;t~nl colorless crysm ls that ute IIOluble in waler alJd alcohol_ II is an effectiYe allllfungal . n l thai is used as a preservalwe. Sodium propionate is mOoM effa.1h·e at low pH .
Sorbk Acid, NF. 2.4-He"adienoic acid is an effective antifungal preservative. It is sparingly soluble in water and has a pK. of 4.8. Sorbic acid is used 10 prescrve syrups. elixirs. ointments. and Il)(ioll$ con taining n". in pallents on Immunosuppressive ~ and In pm.on~ with AIDS . Oppor1unisl~ can grow in al} e.'(f)' circu m., umce in which a p:1Iienl'5 immune 5Y5' ... is romprorniSt organic solvents. 1lIe greater acidity of salicylic acid and its lower solubil ity in water compare! with p-hydroxybenl.oic liCid an-. the conseqtl('OCe of intramolecu]ar hydrogen bonding.
o ,:Y ~
"".. ••
I
.. ""..
.•
from light b«ause the CQtnpound is photoseru;iun. II ~ progin i~ a,·ailable as a solution and a cn:am. both in a 1'1 COIJC('ntnuion. Iialoprogm is probably 001 the first topICal agent that should be m:OlnllK'nded. While the eore rotcs fOf topical funglll infections are relatively high, they come as a hi gh price. TllC 1c,ion typically Wor5ClI!l bcfOfe it impr aVllilable.
•~ d
a
PHENOLS AND THEIR DERIVATiVeS
Severnl phcools and their dcrivative~ possc,s lOllieal ant ifon· 81,11 propc:rties. Some of tliese, 5"'1'11 U!l hcxyln.'SQrciool s and parncllioromctuxyleool (below) have been ... .;ed for the treat· ment of tinea infections. T wo pheool ic CQmpounds, cl ioqui· 001 and haJoprogin. ~ still official In the US P. A third agent, ciclopirox olamine . is 001 a phenol btu ha..~ propcnies like tllosc or phenols.. All of these: agell ts IIptlCaJ" to interfere WIth cell membrane integrit y and f ... octlon in s... Sttpliblc fungi .
H
Cidopirox OIClmln., USp.1S 6-Cydohcxyl. !·h)!WlIOyl ...... rnethyl.2(IIl).pyridioonc: ethanolamine salt (Lorro"o' is a broad· spectrum anlifungal agenl intended only for .... caluSt'. It is active Aiamsi derm:lIopnytcs as .... ell as petIt.Igenie yeast.'i (c. albic-mrs) thai :Ill: c;l.Usali\e allents for wpn. rlCial fongal infections.
,OH
H. loprogin, USP.
J.. lodo-2.propynyl.2.4,S.trichlorophm)l ether (Halotex) crystallizes as .... hite to pale yellow foo lib that are sparingly soluble 111 WAter and very .'IOlobl(' in ethanol. It IS lUI ethereal defh·ati,·c of a phenol. Haloprogin is o~ as A I'it; cream for the treatment of ~upt:rfK:ialtinea infections. Formulations of haloprogin shou ld be protected
Cidopirox i ~ coo)idercd all agent or ehoice tn tht lINment of eotaneous candidiasis. linea corpori s. unca ~ tinea pedis. and tinea versicolor. It is a !>eCOnd·1ine lIP lhe trenlme nt or onychomycosis (.;ng.....ol"ll1 of the Loproll is rorm\lllllcd as a cream and II 100ion. ellCh
"H
III 1'10 of the WlIIer-wluhle cthanolamille ~Jt_ Ciclopirox I btlJe,ed 10 act on cell membranes of wscepuble fungI at .... ronccntr.III011S 10 block the Ir.UlSpon o f ammo acids 11110
lie ccll~. At higher 1.:onccmtrluions.
lIIembr~1lC'
.nlegrity is
and cellular cooSiduems leal 011\.
llludeos ift Antthlngals Flucytotlne, USP.x S-Fluorucytositle. 5-FC, 4·um;noHuoro- 2( III )·pyri milli none, 2- hydrox y-4 -urn i n{)- S-n uorop)nmidinc (An.:obon). 5- F1uorocyu>sine IS an UrdU )' active
.. rungal agent with a w:ry narrow ~1)C(:trum of act;v;ty. [t II illlllcaltd only for the treatment of serious systemic infcc_;~~;u~d by sUinc t1a.~ been -::~ 10 dew] and is prescnLed ill Figure g·3. n.c dru g ~ !he fungpJ cell by acth'e IIlUlSpon 00 ATPases thai II)' lr.ln'fJOf1 pynmldines. Once inSlik the cdl. 5-l1uork)1OU1lC I~ dl:aminated in 11 reaction caullp.oo by t")105ilM.' .1Ib" to yield j·nuorooracil (j·AJ). j·Auorouracil is tit 1CI1,"e metabohte of lhe drug. 5-"'uorourucil eml.'rs inlO 11}\ of boch ribonucloolide and dcollynbonuc1eotide ~~ 1"hr; nLK)f'llli bonucleoude triphosphale5 an. incorinlO RNA. causi ng fnu lly RNA synthe~I~. This pmh· (1~~ ce ll death. In the dcollynbonucleotide !ierie.~. 5· ~yuridine monophosphate (f.·d UMP) blllds to S,1(l.mclli}lcllclctl1lhydrofol ic aci d. intemlpting tile one· cabon pool su bstrnlc thai feeds thymi dylutc sy nthesis. ht. DNA synthesi s is blockoo. Ilni\lance 10 5· r-C is \'1.'1)' COIllIIlQll. attd il occurs ~ t a
The
mecl1an i~ m
POLYENE5
A numbc!r of structurally compleJI. anlifungalltnllbiOlics ha,'e been i""laled from soli bai;:tCrla of Iht.- genus Srrtpmm)"ces. The compounds an. ~lmi1ar, in thai tlley corlliun a system of conjugated double bonds In mllCTUCydil: lactone rings. They differ from the erythromycin-Iype structures (rnacrohde\: see Ch.'\plcr 10). in thai they an: largeT and conlain the conJu· ga ted ~11t' ~yste Jll of double boods. Hencc. they nil! callet1 the /1OI)"t'II(' ulilibimiC"S. The c linica ll y useful polyellC's fnll into tWO groupings on tile basis of the si1.c of the macrolidtl ring. The 26- rnclllbcrcd ·rin g polyenes. ~uc h a! IlI1lalllycin (pima ricin). fonn one gl'Ollp .... hil e the 38·membcred macrocycle~. such lIS amphotericin B and nysto!ill. fom! the other group. Al'iO common to the polycoe.~ are (u ) a stiles
OFU", -
SFC~
-J.+.
_.
5FUDP -
5-fUTP
.
5·FdUOP ___ 5-FdUTP
\ SFC. - -- "
"'U
I 5FdUMP -
Inhibitory
CoIlfllex dUMP
OTMP
• treat-
cruri\. cnt f~'If n:1II\).
;mla; n-
5,lo-Melhytene-THF
7,B-DHF
136
Wil.oon aM Gm'Old'J Twbook
of O"6Mk MttlkirtllllPld PllamJUCtu,;rol
of hydroxyl groups 00 the acid-dcri ved portion of t/we rin~ and (b) a glycosidicaJly linked deo~yaminohe~O$C called ml'COS{lIl11nt. The: number of double boods in the macrocydk: ring dlffer1 also. Nautmyci n. lhe snuUlesl mllL'roCyck. is • pcmaene: nystatin is II. hexlIC'ne: and amphoferici n B is a hep!3C:ne. The poIyenes ha,'e no lClivity agaill5t bacteria. rict eHs ia. or viruses. oot they are highly potent. !)road-spectrum antirunga l lI.h~nUl. Thocy 00 have activity a~ainSI cenam pratowa. such as Ltishmllniu ~pp. They are effective against patbogenk yeasts. molds. and derm:uophytes. Low COfKCTl' Iflllion5 of the polyenes in Vi trO will inhibit Candida spp.. Coccidioidu immiliJ. CryP'OC/ICC" J ntojomums. Hump/llJmt' r upsufalum, Bl/J.JlomyctS dtnruJlilidis. Mucor mllCtdo, ;'spt'gi/l..s jwniglJllU, CtpMloJporium spp., and FllSorium spp.
The use of the polyeoes (or the Ul'atmetlt o ( systemic infections tS limited by the toxicities of the dru gs. their low water solubilities, and their poor chemlcaJ stabilnia;. Amphotencin B. the only polyene usefu l for the treatment of serious systemic tnfectioos.. must be: solubi lized wi th a deter· gent, The IXher polyeoes are irldi cat~'d only a.~ topical agents for superficial fungal in fections . The mechamsm of aC1ion of the polyenes has been studied in some detail. Because of their three-dimensional shape. a barrel·hte oonpolar struclLlre capped by a polar group (the sugar). they penetrate the fungal cell membr.mc. acti ng 8!l "false membnne components." and bind close ly with cr· gmterol. causing membr.11IC disruption. cessatIon of membronc enzyme actI vity. and /Q$s of cel lu larconsti tu.ents. especially potllS$iurn ions. In fact. the first observable in vi tro n:aclion upon Irl:alin¥ a fungal cu lwre with amphofericin B i~ the loss of potassiu m ions. The drug is fungi SIalic at low roncc:nrnltions and fungicidal at hi gh CQIlCentralions. This suggests that at low concenlr.uions the polycncs birld 10 a membnlne· bourld enzyme component. such 8!l an An>ase,
Amphotrridn S, U5P. 11lc isolation of IlfIlphoteridn B (Fungi;wne ) wns reponed III 1956 by Gold el al.2\I The compound WlIS purified from the ferment.,ion beer of a soil culture o f the aclinomycele S'f'+(Ii myristoyl phosphatidy l~ (3 pans) to create a suspen~ion of ri bbon-I ike Sheels; _1ipo5omaI amphotericin B (AmBi'lOlne). II small laminar ~tion consisti ng of an appro!\imately 1: 10 IliIIO 0( amphoIericin B and lipid (hydrogenated 80)' Idyl choline. cholesterol. and diSiearQ)' lphosphati~ldIoIlnc In II 10:5:4 ratio) for an aqueous suspenskll1. ~ rationale behi nd these lipid prcpanlliollS is simple: .mcln B should have II greater avidity for the lipid >dI.ckdlan for cholesterol in ce ll membrane..\. Hence. toxic· " Ihould be reduced. LiPld·associated .mphotcricin B be 1,\n....11 i!lto the mlculoeudothe lilll system. concenIn the Iymphalic ussocs. spleen. liver. and lungs. IIIIM mft:Ctiou, fungi tend \0 locate. Li pase.~ elaborated by .Id~ ~ the host ~hou ld re lease the: drug from the li pid cam. making il aVailable 10 bind crgOlilerol in fU/lBal cell ":,m~ tonr:n its fungiSialic and fungicidal Kt;"ilies. I..... lISe' of each of the: approved lipid pltl'lIT"dlions • 'IolIlIltduced renal tOAicily. UposomaJ amphotericin • brm *I'P0.-edspecirlCally for the tre8nnenl of pulmo-II) ~Ik$s ~ause of its demonSlr:lled superiority to tr ~.Lum lIco~ychol ule -sIDhi li1.cd suspension. AIIIpIIotnK:1R B IS also used topically \0 treal cutaneous -' ..:o:ut;wws m)'COSC!i caused by C. al/m:unI. 1"'h/, .., ~ wppIJed In II ,-ariety of topical forms. including a a-. I 3'1 Jouon. ~ J% omunenl. and a 1000mglmL III The {)nil suspen~ion is imended for the: treat.oforallnd ptwyn~'f'al candidiasis. The patiem should
"....,.ber
sw i ~h the su'pension In hl~ or her mouth and swallow II. The ,u_pc:n~jon has a v~ry bad tasle. anulurlQ viginal cream and tablets of 100 mg II"C Ivai lable for Yulvovagi nal candidiasi s. Ii eumnely Stable. wi th a shelf life of mon:
,
"
"...
' 0
dOlnmal.0te i§ effective against a variety of well absorbed OI1I.ll y. it i I disturba/ICcs. It is al50 ellle n, Mll("e, is noI considered optimall y CIotnmuole IS noI considered suilab-le for the oi S)"Sl~ nllc Infections.
" EcOOlUOk: is used
1% cream for the topical treatment of Joeal tinea infections and cutaneous candidiasiS,
in wal"f and nlOSt organic SQlvenl5.
a~ It
8utoconazole Nirrate, USP. 1-(4-(4-Chloropheny l)-2((2.6-]Willgly sol uble in wa ler but o;olubie in cl hanoL The !;:lit is U'ioCd in a solut ion and II cn:am in I % concentration for the trenlmcnt n f local linea ;UfCCliol1S. ~lIch as jock ilCh. Plhlele's f(Jot. and ringll. orm .
Mkonilzole N;t~te. USP. 1 -1 2-(2.4- I:>!ch lorophenyl~ 2·[2.4-dlchloroplM:-ny l IIIlI'IOOx y )clhyl I-I II-nmdmlle nlOllOnilrute (Monl!>l3t. t.h cali n) is a we3];: base '" Ilh :a pK. of 6.65 The nitric ucid '\all occu.... as while cryslals thaI an:: ~paflni~ solub lc in Wlilcr lind most organic solvents. TIle fn..oe ba.e I~ :Ivililable in an injct;l ~ble form . w lubi loud witb polyc lh y1cnc glyoo l and castor oi l. and inlcrKled fCJ: the trelltment of .'lCrious ~ySlc mic fungal i nfecl ion ~. SUCh 11\ candidiasis. coccidiOldomycnsi~. cryptI)'
_I:lI1OS1erol 14a-demclhylasc is illhibitell in mammal s as 'til as in fungi . Iligh doses hav e ulso bee n reponed to lower
oJ
1e$IOS1emne arK! conicoslerone levels. re neet;ng 111u s dcmlatophytic infections nOI re!p!Iive to topicalthl':rnpy or oral grio;eofulvin . The antifunof kclocolUllOle and Ihe polyene antibiotic ~In B are reported 10 alllagonize each mher. ~a/.oIe is also used topically in II 2% conccmntt io n •• trtam aod in a Miampoo for tlte m;1nagCl1lent of cu ta_nndidiasis and til1l:;1 infec tion s.
".mons
am-
~~") I " N==
.J
'"
#
Itra conazole.
U5P.
4-14-[ 4-14-112-(2.4- Dichloropheny l)-2-1 H- I.2.4-triazol - l-y lrncthy l)- I.J-diOllolan-4-yl )nICth-
o~ytplic n y l !- I -piper.uinyllphcny l l·2.4-dihydro-2·( ]-n"ICth
ytprupyl)·3H- I. 2.4-lriul.Ol· 3·one (Spur.mox) is II. unique membc:rofthe azo le class that contains twO triazolc moietics in its stroclUn::. a we3kly basic 1.2.4-tri:u.ole and a nonoosic 1.2.4-lriuzo1-3-one. ltraconawle is an orally active . broad-spectrum am ifunllal agent that has become an impor1;l/\t IIlternmil'e to ketoconaznk. An acidic environnICnl is required for optimum solubi lization ~nd oral !lbsorption of itracona'l.Ole. Drugs such as H 2-histamine antagonists und antacids. whi ch reduce ~tom ach acidity. n::duce its gaSlroint ..stina] absorption . Food
f)
()--{ ) H
) 1. "
I "" #
c.
greatly enhances the ab.o;orption of Itraconazole. nearly doubling its ontl bioayailability. 1llc drug is av idly bound to plaslll3 pmlCnl!i (nearly 99'10 at clinically effecth'e concentrauons) and extensively melabolil.ed in the liver. Only one of the numerous metllbolile!l. namely l-hydmxyitraron:QOle, has ~lgnifiC'ant 3.fItifungai acilyity. Virtually I1OOt' of the unchanged drug is excreted in lhe uriJIC. Thus. the dosage need not be adjusted in patientJ; wilh renal impairrnenL The tenni nal eliminadon half.life of ltrllComt"lole mnges from 24 to 40 hour!.. The primary indICations fOl" itraronv.ole are for the treatment of systemic fungal infections including blastomy,osis, hIstoplasmosis (i ndud ing patients infected with human immuoodefK: lency virus lHIVI). oonmeningeal coccidioidomycosis. par".tC(lCICidioidomyCO!iis. and sporotrichosis. It may also be effective in the lJ"Catmcnt of pergellosis. disseminated and deep organ ,andidiasis. coccidioidal meningili ~. and CryptOOOCCOSIS.
In general, lInK:onll7,olc is more effective and beneT tolerated!han is ketOCOfUl7.o1e. Unli ke ketoconarole, it is not hC'patOlo.\k and docs not cause adrenal or Ie!lticular suppression in recommended therapeutic doses. I" Nonetheless. ill1ll:ol1a:wlec:an inhibit cylochrome P-4SQ oJli-dases involved in drug lind JlenOOiOilc metabolism and is known to inc~ase phlSIIl3 level!> of the antihislaminic drugs terfenadine and lISlemizoie.
00 hepatic melllbolism and i$ txcrcted substantially un· changed in the urine. A small amount of unchanged n~ zoic (- 10'10) is txcretcd III the fcca. S ide effect!; of fl~ azole lITe largely coofincd to mlllOf gastmintc:stiR.1l symptoms. Inhibi tion of C'ytochrome P-450 oxidase! by flu· COIlaloie C'an giye nse to clinically significant IIltcnctlOM inyolying increased plasma Icvels of cyclosporine. pllen)· loin, and the oroll hypoglyct'.mic drugs (tolbulllmide, ghpi. ride, and glyburidc). Auoonawle does IlOl appear to InIn· (ere wilh cotliCO!ileroid or andillgen biosynthc.~is in dosagc$ used to treat systemic fungal in(octions. AU~'Of1D:wle is recommended for the lreatmcnt and prophyluis of disseminaled and deep organ candidiasis. It II also used 10 conlrol cwphageal and oropharyngc:al ,andidUsis. Because of its efficient penetration into CSF. nucooa:tOlt is an agent of dV>tCe fOl"lhe treatment 0{ Cl)'ptococcal mall. gilis and for ptophyla.tb against cryplococcosis in AIDS patients. Although fillC(llUlZ.Ole is generally less eff(dj\f than either ketoronawle or ill1lCona.wle against 00Il1fltllltgeal coccidioidomyc(Kis, il is preferred therapy for coccKj. oida! mcnlllgitiJ. Auronl1,oIe lends itself to one-dose Ihmpies for vaginal condidiasis. NEWER ANTIFUNGAL STRATEGIES
A new v.ole. vorironv.ole," is presently in cl inical \ri.Ib
Fluconazole, U5P. a-(2.4-Dlfluoropheny l)-a-( 1"-1.2. 4-tria:wI-I-ylmethyl)-1 H _I ,2,4-tn:u:oIe- I -ethanol or 2,4difluoro-a,a-bls( I H·I. 2,4-trialol· l -ylmethyl}bcnzyl alcohol {Diflucanj is II walet"-'\(jlublc: bis- triazole wi th broadspectrum antifungal propcnies Wt is sU IUlble for both oral and intr~yenous admin istration a.~ the free ba~ . Intt:lvenous solutions o f nucoov.ole conlain 2 mg of lhe free base in I mL of isotonic sodium chloride or 5~ deJltrose vehicle.
in the United Statcs.
,
OH
(" ,_I ,
-,
1 '"
g..
'=_====_ H!~
"
l eN,
N
/
"0"
0"
HO' Figure 8- 6 • iofl,zatlon equilibria ,n the qUlnoione ,mbbaocteflal drugs.
"
"f'i.
" '0I
I N
~I-J . A 2:1
chelate of a Mg1'
I0I'l
by c!p-
L
P"
">..
,
"~"" 1
It is recommended for the treatlMnt of unnary tracI inf((;tions t aused by strai ns of Gram -negative bacteria s.uscepdble to these .~ts. Early tlinic.aJ 5ludies indicate that the drug pos~esV$ pharmacokmetic )H opt:rues supenor to tho5e of either of its p~deces.soB. Thus. followi ng 01111 administlll don. htJher urinarycontenlrations of ciooxacin than of nali dixic acid or oxolinic acid are ochie,ed. Cinoucin appears to be more completel y absorbed and less protein bound than nalidulC acKl I-Ethyl-6-fluoro- l ,4-dihydr0-4-0xI)-7-( 1piper~l.in~ I)- 3-quinolinecarboxylic add (Noroxin) is a pale ye llow crystalline powder that is sparingly sol uble in water. Thi5 quinoline has broad-spectrum activity against Gramnegative and GrdITl-positive aerobic bacteria. The nuorine atom pruvides increased potency against Gram -posi ti ve organisms, ",hc,rellS the pipenl1jne moiety improves antipseudomonal activ it y. NoriloltllCin is indicated for the trea tment of urinary tr.ICI inf((;tions caused by E. coli. K. pneumonia,. EnruOOaclu dQiIC(le, Proll'us m;mbilis, indole-posid ve Prolelu spp. including P. I'ulgaris. Prol'ilfencill rel/geri, Morgonelfa """sami, P. MrugmO$O, S. auulU, and S. epidermidis, and group D ~treplOCOCci , It is gel1l.'r~l1y not eff((;tive against obligate anaerobIC bacteria. Noriloxacin in a single 800-ml!; Or.tl dose hil.~ also been approved forthe treatment of uncomplicated gonorrhea. The om l absorption of norfIoxacin 15 about 4O'lo. The drug IS Ij'll> protein bound and is metabolized in the liver. The 1" hi~r ... the parenlrntl dose for a given irwlicalion. PlObcnedd wgluflCantly ~lICC'S the renal dearnnce of cipronQucin. pn'SIIITI3bly by Inhibi ting its acu~e wbuillf secretion. CiproOo~acln IS widely distributed 10 vu'tually all pam; of the bCldy. Including the CSF. and is gClICrally C()Ilsldercd \0 pro"ide the beSt distribution of the current ly marketed ,!uino~. This propeny. together with the poh!OC)' and broad IIIllbactc:nal 5p«lrum of ciprofloxaci n. accoun l~ for the numerous therapeutic indica tions for the drug. Ciprol1oxacin 1110 exhibits hig.tw:r poIeoc)' agai n~1 most Grnm -negative blncri31 spedc!!. including I'. /lc rug;nI)5U, than other quino-
.....
CipronOll;ICin is an agent of choice for Ihc lre;mncn l of bIctcnaI gastmcntains caused by Gmm-negatlve bacilli ... as cnlcropal~nic E. coli. 53lmonella (inclLKImg S. nplltt SIt"t/llI spp .. Vibrio spp.. and Mromt.mlIs hvdrol'hi.. II is widely used for the treatment of respiratory tmet 1If«tions and is panicu illfly effecli ve fOf controlling brondIIus .nd pneumonia caused by Grnm·ncg':llive bacteria. C i,oRoucin IS also used for combating infectioM of the sk in. idtllrnlCS. bones, andjoinlS. BoIh UllOOlliplicated and compInled urinal)' tract infections c:wo;ed by Gram·negati ve t.;t~ria cun be m~ated e rfecri~cly with ciprofloxucin. It is ptUCularly ustful for the control of chronic infec tions char1CItri1.ro by renal tissLM! invot-·emcnt. The drug also has ~t applications in controlling vcnereal diseases. A roriltll3lion of ciprofloxacin with the cephalosponn IUltibi• cd"triUone is recommended as the treatn"ICOi of ehoice b dlS$m1.m:ned gononi"Jea. while a singlc-dose lTtatmc:nt mciproflo)adn plus doxycyc line. a tetrdCycline antlblO(ic 10). can usually tflIdicalC gonoooc o f an oral dose i ~ excreted In the unne wilhin 24 hours in the form of numerous met:ibolites as .....ell as the unchanged drug. Allhough the metabolt~m of i-.onialid is ~cry complex, the principal path of inactivation JIl. volvu IlCet)laliOll of the plimary hydra711lC mtrogcn. In additlOll to lICC1ylisoniaztd. the IwmCQfin)1 hydr.l1.ones of pyruvic and &-ketoghllaric acids, t.onkounic lICid. and isonicotinuric lICi d Iulvc been isolated a.~ me t aboli te.~ in hllmans.lJ 1lte capacity 10 lnactl\ale iSQniuid by ocetyLatlOll is an inhented characteri~tie III humans. Approll imatcly Iullf of pel"'>OIIS in the population are fa~t acet ylntOl"ll (plasma hhlftife, 45 to 80 minutes). and the remainder ~low acctylllll)l"!l (plasma half-lift, 140 to 200 mmules).
Ethionamide, USP.
2-Ethyhhioisonicotinamide (Tree· ator SC) Ot'(:Ut'S as. ~11ow cryqaltinc materia! that i, sparmily soluble in ..... atn-. This nieOllnamidl-ltas ..·cllk bac:1trK>sth tic activity in vilro but. becuuse o f it ~ !tpid :I(llubllity, is em~ctiye in vivo, In COfltnl~t III the isonilll.id 5C ric~. 2· .subule form , S)'mptoms of gastTUlnt~ nul irritation arc common wilh both lhe ocid and the iIOdlla sal t A "ariety of enlcrk.cOOled fonllS have bm used in an . 0thcI'
,
i
I
. . . Im an anion
aluminum i is 1lIc oral absorption of and it is widely d i~t ributed into ti,sues, with the e~ceptiou of the III i 1c:\·cI~. significantly lower. It is excreted primari ly in the unne_ both unchanged drug and metnbohtet. 11Ic N·~)I tl\'e is the principal metabolite.. ..... nh siglllfK:llnl Tnc glycine oonjug~te also being fOl",ed. When ..... ith isonilll.ld (which also unt.lcrgoe~ increases the level of free isoniazid. 1lIc of PAS is about :2 Iloors. The mcch:mi~m of antibactcriltl lII:'lion to tNt of the s.ulfonamidcs. Thus. n 15 the incOlpOl"~tion of p-aminobcnzOIc acid ( PABA) dihydrofolic acid molecule catalp.ed by the drofolatc: $ynthcmSl:. Structure- activity i that the amino and carboxyl group!> must other and free: thus. c:.~ten; ond umiOO mUST hydrolysis in Vi\'O to be effecti"e, The: be onlm or IMrtlto the carbollyl Is seen in the former. For mMy yeIIf'I., PAS W35 thecbcmothel1lpy of tuberculosIs and was in combination regimens with isoniazid I-Iowc:"c:r. the introduction of the more ally better tolernte. Extensi yC first· pass metabolism and signifICant bllia!) excmion of the droll occur. with about 30 and 53% of tbr ontIly administcred dose exereted.largcly as meta~itcJ. 1I the feces ~ urine:, respecti vely . The 25·0-des'lC"I) I _ 31.hydro_y metabolitcs of rifabutin have been idcntir1Cd. The pan'nl dru, i~ 85 % hound to plasma proteins in a co. cenlr.tl.ion.independem mnnnc:r. Despile its greater poIt~ against M . lu~rculo.i;s in vitro. rifabutin is considered 10ft· rio.- to rifampin for the short·term lllerapy of tubert:ulOSll becau!Oe of its significant ly lo ..... er plasma cooccntnllions. A !though rifnbu tin is believed 10 cau~ less Jw:patOioxicit) and induction of cytochromc P-4SO enzyn>es than ri fampm. thc!Oe properlics should be home in mind wilen the dlllill used prophyloctically. Rifubuti n and its metabolitC5 Iff highly colored compounds that can discolor ~k in. un~ tear'S. feces. ctc.
eH,
eH,
,
./If/j/ is IIll obligate imracellular protozoan Ihat is beSt kflOwn for cau"ng blindness in l1I.·()Ilales. To~o plasmosis. the disseminated fOl'TTl of the dl"C'ar.e in IO.ohich the Iympltatic syst('m. ~keletal muscles. heart. bn"'n. eye. and placenta may be affected. has becOlTlC illC'fCasingly P'l'\alent in a.....wciation .... lth UlV mfection. A combmallon ofche ami· folate pynJ11("\hamine (Ch3p1cI'9) and the sulfa drug wlfadiaZ111C OOflStllUlts the most eff",.."'I;\(' thempy for toxoplasmos is. Varioos fonns of Lrypallosomiasis. chronic Iropical dis· eascs caused by p.:Itho~enic mctnbtTS oflhe family Trypanosomidac:. oct"Ur both in human5 and in livestock. The pO ncip.al dise:u;.c III human~. 5k:c:-ping sickness. can be broadly clllSliifled into t.... o mam geQgl1lphlc and ellolOGIeal &'lJUp!i: Afncan sleeping siclllCs-, caut been sYllthesi 7.cd in various labllnltuncs throughoul til: world. Mctronidazole was firsc nlarketed for the topical tll:'JI' ment of TriclllHlWlIll$ ,'ugm(J/is vagimlls. 11 has since bta mown to be e.ffectin·, orally Ipmst both lhe lICute and C1ll'm stales ofchediscasc:. 1l1e drug also pos5CSS('s useful amebalIal actJvny and is. III facl. effCClI\e agalllSt boIh lIlteSlll1ll and hepatIC IInICbiaJ;is. 11 has alo;o been found of usc lIIl11r creaCllloClI1 of MlCh OIN-r proIo:wa1 disca5C:I as giardiasi, ani Metronidazole,
balanl1dl asl~.
Mort recently. melronida~oIe Ilas been foond to po$_ efficacy again'\! obligate anaerobic bacceria. but il is incff(\"· tive against facultmive anaerobes or obligate acrobo. It a paniculurly active against Gram-negnt,,'e anaerobes. SId as 80cftnmlfs and Flisr/lJocfC'nlllll spp. II is also effeai>li a.gIlJllSl Gram-poslli\'e al1iltrOblc bacilli (e.g .• CloJfridiJa spp.) and coet:i (e.g .. Pt'P//JCOCCus and Ptlllidos/rtploromtJ spp.). B«ause or ilS b:oclC'ricitbl action. metmnil.lll.ok_ become an important agent forthe lreacmcnt ofscrious 1111« tions (c.g .. SCplleemia. pneumoma. penlon;l1s. pelvic !nfC!; tions. abscc~sc~. ,nc.nin gitis) caused by mnacrobic battma. 1l1e C01111110n charoclenqic of IIHcroorgllnisms (b3CIenl and prOl07.()ll) sells;ti ve 10 nIClroniduole i~ that Che:y on: .. aerobic. It h:ls been speculDtl'tl thaL I reactivc intemlCdia formed in lhe microbial reduChon of the 5-nitro grwp II metronidazole oovalt:m ly bl11ds to the DNA of the microu gamsm. II1ggenng the lethal effect .... POIenllal reacti"e __
,
, , , ,• •
••
1IIld131e~
IlIClude the nitroxidc. nit«Jt;O. hydroxylamine, and __ The abtln)' of mctrollIdalole to act as a rlKhosensilll,Igc:I1l IS abo relau:tI !O II ~ reduction potential. I>ktronidal ol e is it pale yellow cryM:tllir.e substance that 'lpan n&ly soluble In .... ater II is stable In air but is light ll'II\ili.c. Despite its low .... aler solubility . IllCtronidazole is ;absorbed followmg oral admlmSlJllllon. It has it large:
well known. Aqueous !IOludOfl~ of ....-id saIlS of oxioe. partw;;ularly the sulfale (Olloosol , Qumosol). In COllCemr.lllons of 1:3.000 10 1: 1.000. luive bc:cn used as topicalllfltiseptics. 11Ie Cd ruullllcly for trnlcler' s di~a.
",;:':"':;~'''::. of metronidazole: base are slable for ~. . BOIh solutions should be protecll.-d from Furnmidc. or tulamidc , i~ the 2-furoI il II , I various 01.("1:lell'-I ty in vitro. are also :lCuve. and
I,. I
,
of th-e
are more potent than polar OfICS . i ';;;;;;;;;~ -,;;;; in the treatment of a-symptomalic carhi.u"/yllro . Its tlTecthtoe~s against OCUle inlts·
,
Emetin. and Dehydroem. tine. 111C alkaloid_ enlCtine. and dc-hydruelnetine lire obtained by scp;arJtion from exuacls of ipecac. "They occur as le:VOf"OIaHlI"y , hghl ·sen''',,'c white po .... l.krs Ihat IU'I: inwluble in water. The alkalo ids readily form ..... atCT-,-olubJe sall~. Solution s o fthc h)druehloride salts inlendcd for inlrnlllu.",·ulpr injectlOll should be adJUSted 10 pll 3.5 WId stored in lighl-roi \ Ulnl container;.
H1C"""-O
9"""'Y/"
jsa
N
orally only as 500-mg tablel~ and lIIay in the United States from the COC In Allanta,
H"
E"",""
••
...
...
,
V
.....CH1
H"
""
qumophcnol. or O.l'.yqulfrom \\- hich the Ilflllprotozool . The antibacterial and antl and its denvalhe~, which are be· abil ity to chelate nlCtal ions. an: O ;U IlC.
and dehydrocmc llI"Ie ex en a direct amtbl cldnl action OIl various rml11s o f E. hiJlQI) l icu. They an: protopl:llirnlC poisons that ,"h'btt proIc in s)" nthesis ,n protol.ool and mal11malian cell~ by prevcnting protein elongauon. Because th-ei r crfect in Intestinal amcbia-sis is solely s)mptomEnlClIlIC
alic IU1d lhe cure nile is only 10 10 IS.... lhey should be used only III oombir\3lion wi lh other Iscnls. 'TlIe high conccmrauons of the allalonls IIChievrd in the h"cr and OIher lissues .flcr mlramUSC'lllar injcctioo provide the basis for their high cff«uvene.~ against hepalic alxccsSClIlIlld other cllOtraintcstinnl forms of the disease:. Toxic cffects limit the usefulness of cmc1illC. It caulilt. II may [\I
I or orolly. Approd· excrcted in 11M! urinc. is facili laled by in-
,
, , ,
,
"'"
llgmflCllnl and potentially usefu l aoti·
c.-mlually led 10 disco.'cry of partK'Ular
~.;,~,. activity.
Melarsoprol.
2-p . (4.6 -Oi anll00-I - triuin- 2·)' I'IIm; no)
phenyl-4-hydm:tymc:lhyl - I.J.2-dllhia~l llle
(Mel B. ANOball is pn:pan:d by l'C'doclion of a com:sponding pentavalent arsani13te to the trivalent ~noxide followed by ",:JC1;on of the biter ..... ith 2.J-dil1'lcrcaplu.l-prop'lrIol (Bnlish anti-Le ..... islle. BAL). It hilS become the drug of choice for the treat ment of the Imer stages of both forms of African trypanosomia.~is. Mclarwprol ha.' the advantage (If exedlent pene trntion into the CNS and, therefore. is effective against meningoencephalitic fonn, of T. !:{/mbi..nstl mid T. rbWtsinu ... Trivalent IIniCnical~ tC11d to be more toxic to the host (as we ll as the par:J$i tes) than the Com:spondil18 pentavalcm compounds. TIle: boo(ilng of arsenic .... ith sulfur atoms tends to l'C'ducc host toxicity. incn:asc chemical stabllIt)' (to o~idatioo), and improl'e di stribuuoo ofthr compound to the ar5CnoXide. Mclllt1IOfII'Ol shares the toxic properties of other arsenicals. howelcr. 'iO illl usc muS! be monitored for ~igns of ar.;.enic toxic;'), .
OH
'" ,b
compounds
IS
mrunimox beT. end. the
American trypanosomiasis. In only clinically pro"cn romt~ of the di:sea..o;e.
. .~. is Idminjsl~ omll}'_ Oral biouvuilubilil y is OOIblderuble firo;,-pass metabolism occurs. The
•~:~r:'::;:':~:d';~"~ :4~;hoo;~~"~,,~The drug is poorly i
vomiting. abdom~ ~.IIIOII:J.il reponed. S),mptoms of cenlml lind nermus 5~Sl~m toxicit), also fretJu~ntl)' occur
..
I
Sodium Stibogfuconare. Sodium al1timony gluconale (P!:ntostam) is a pc:ntu\'ulent untmlOlli31 compound intendl.-d prim.:lri l)' for the treatmc:nt of various foons ofk:ishrnatlia~iJ. It IS aVllilubk: from the COC as the dl.Slxhum salt. "hlCh I~ chemicall)' slIIblc and free ly .IOluble in water. The 10% aqueOII.!I solution uscd for ellht-r intr,lInuscu lar or intra\'enoo s injeclioo has a pH of - :U:. Li~e all 311timonial drugs. thiS drug has a low therapeutic ind!:~. and patients undcrgoil1g thon) and the tn\'asl\'c phase: of lnchinOSI" , In addition 10 its usc in human JIlI:dicine. thiubendazole is widely used in \'eu:nnary practkc 10 control mtestinal helmtnths in livestock,
M*lHmd.Jzole. USP. M ('th~ 1 5· bcnloyl·2· bcllltnnduolC('arbarnale (Vernl()~) i~ II broad·.~pc'::l rum anthelmintic that is effl'l:tJ\'~ agam\1 a ~1Ine'ly of JlCnt;uodc: infestations, including ... hlp"ool1. pin\\-OITn. roundworm. and hookworn!, Mcbcndazole ilTC\'cJ~ibly brock_~ glucOloC uplake in suscepti ble helminths. thereby deplcung gl)'cogcn 51on.:d in
the parasile. lt apparmlly docs no! affect glucose metabolism III the hosL It also in/liDiu ~II divIsion in ncmalodcs. '1
"
from relell5e of I,,'c ova from worm segments danlaltd II! lhe drug.
a
0\-/",
}-~
•,,
P
I
/' -""'J'--'N
•"
• Mebcndv.ole is poorly abSOf'btd by the ond route. Adverse: reactions are UlI(ommon and usually l"OOSISI of abdommal dlscomfon. It is ler:lIogenic lD laboralory animals alld therefore. shoukl not be given during pregl1:lIlcy.
Alftrtdil:tok, USP.
MelhyIS-{propyhhio}-2.ben1JmidaJ;okcaromn.ato! (Eskuole, URIc!) is a brood-spectrum ant-
helmmtlc thaI is not currently marketed in North America. 11 is Iwailable from the manufacturer on " compassionate use treaunclll for a.l\Cari!l~is. New and Old WorlU hookworm infectioru. and trichuriasis. M uh iplc-dose therapy with aJbenda7.o1c C'.lI1 eradicw lc pinwolTlI. threadlO.orm. capli lanasis. clooon:hiasis.. and hydatid disease. The Cffec1I\'cncss of albendazok against \lIp!:wonns (ceslodes) is gellrnllily more Vllriablc and less imprt'Ssl~e.
"
"
8ithiOftoi.
2.2'·Thiobi.s(4.6-dicMorophc:nol). or bI$Il, hydroxy-],5-dichlorophcnyl)~u tfjde (Lorothidol . Bithinl,l chlorinated blsphcnol. was formerly used in :;oaps and COlmelic~ fOf its antimicrobial properties but was retOOled the market for topical use beo:ause of repofts of conflICt pm. toocmlmi;is. Bi thionol has u'>C fu l :mlhclminlic (lft!pe/1it! "nd has been uglyec:mie drug tolbutamide:. the diuretic furmcmidc:. and the diuretic chlorthalidollC. In phaml3Ccuticul chemi stry. p~ vuluc~ are 1101 used to compare compounds that 1111;: uwis ~. I ~ead. if a pK.. of an amine is given. " ref~ to its ~ah octing as the eooJugate acid. For example. aniline with a pK. of 4.6 Iders tu
fABLE 11-7 Ther.py With Sulfonamide Antlbact.rlals Dlse.HllnfKtion
Svlfon.mldes Commonl, Ihed
Tro.,IIICI1' ",ill pI'IIp/Iyl.o,i. f I'>tt..-,Jri• .... rin" P'''''''''''''" f. rn orr ..... JI""IPI)Ia".ofa:,eboal I'iM IIIIK~ ,,( IIf''''''' he! .ft~ fiwoo tIImopy' """''''K''",," 1n:1Imt... 1!bocltrial ,nl«_, ~
P)'nT" ... mi ........ lfodwJ ...
Tn"'"'hopnm· .... '~ Sil.u ..,lr:Pod,,,,i.... nd "",f~"HIc
Sod,um MllfKmtzIzoIo Combo".;o..~ WE'" quEn,OIC. odwl
C"'1.I"""'''''' IIId .. I...,.) ..."",r,."al ocular ",fn:liI>no Cl\kImqw ......... ZIl
Tri~m·."lf"".. d..........
malanal~9)
Sulf"..... ~
r.o.:.v;..... Sn=
Tn ...... hoprim'e; e, ptn",q,ft O. amP'C,111A. !If ('itivc and Gnno-negative hacleria. OIX"lInha. Clllam)"diu trflChotrttl/iS. and some proIo/.llL Some cmenc bacteria. slICh as E. col; and Klebl lt'l/lI. Sillmonfl/lu. Shillt'illI. and EnltmHxlclt'r spp. aro onhibited. Sulfon-
o
o
o
NH
O-~II--q
N~
.\
HQ"'-
dUUP
.....,..
Other 6)!arT1)lea of folata-requlrtng ona-carbon pool reaction. :
c_ _ N'" ·F~·FAl-\, N'Jr-MIIIhyIeM-FN\
N'-Formyt-FAH.
MeI ·IANA
"',O"i.
•
Fu....,.. M.. _!RNA
"
Ptllfldjne Diphospl!l:Ie
,• •, • ,••• ,•• • ,•••
SulIon.rnide. Sulforlu
:
_Add , •
~'' - a7J""
'0
,.
TABLE 1-1 pK. Values fCH" Cli n ically Useful Sulfornomldes
Sutn1lO.U>'Ole
,S..lr-"'>\Ql....
,.• "
,I pi
..
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." o
erysulluri.a and tIM pIC.. fko,pne the tremendous abil ity of sul fanila illide 10 l' ffcct CUrl'S of jXl thogenic bacteria. its benefits .... ere often offsct by the propen~ity of the drug 10 ca use C to a ~ution of \IIIfisoxawle 10 bnn& lnc p~II O aboul 7_5. It is used lIS I sail to mll~e the rJru g morc soluble in,nc physiolo~ieal pH nJ.n&C: of 6.0 to 7.5 and il used in solution for ~ystc lll ic admini5ll'l· lion of Inc drug by SlOw inmwenous. intramuscular. or wbculllneil}' '" PreI.>. 1970. 25. lliod1. lt "",,"ino. F.ndl. }1 ·1J09. 1'81. 26. I'OOIk . A.. _ s.:1IoI. Mn!. 1z.t,91t. 19116. 12. lon~",pl. R.. ~ at.: Cill. ~1IeI. 23:279. 1992. n , liven. 11. L . - ' Ikuinl. R I'n)c. P.. p. B..... MeoI. 76:'1J. I"t 34 . P.n1. ... J II ''''''.): "'.... ,i l'" I'roIozo&. 2nd cd &In ","",. A on human hi~tory is fascinating bul. fortunately, ;1 nlOid) h.storical . 1be laller three dJse~s do reappear. but the CIII:I are isolated. Plague i~ treated effcctively ... uh anuoon and there are vaeeioes for yellow fevCT and polio, The publ ic i~ aware of oclluircd ImmunodcflCieocy s,.. drome (A IDS) bccaullC:. il is a disca .... Ihal "U1I~eI5" b! human carriers IU1d has mfccled and killed pronllncnt ~ ...110 are citi1.cns in ccOllOmieally developed countritl. Nc\"enhekss, compare the 200 1 ligure~ for AIDS lIId_ laria, After appro ... im~tely 20 yeao" 40 million pcopIt l1l'i been infccted with the human immunodi:flt;errcy ,inI (UI V). of ... hom 5 million ....ere illfCC1W and J m,llIo• • in 2001 , For North America, 940,000 haye])e(."OITl( Inr~ III the past 20 years. or .... hom 45.000 ....ere ,"f«ltd" 20.000 died in 2001 . In eomr.lst. nppro ... imately l '
"J-OH 0 ,J-o-L"" L l~xykhe ~
_....... ------
(OOXP)
J H,C-""
, 1,_
H,C--o~
HO-~" I
0
II
~CH1-o-$P-OH
L
Figure 9- 13 • No!lmt\lak!nilte
" ...."
TAllE 9- ' -Co"tI,,~
... .. •
D'lIqIOOnl' ond l DO ..... profu ..... 1 PnlJuJ,i~ tulXn 6l.~
at< """""" IOId
,......",
"'I
:u "'I
,.• •14.. .. 'k"n 1-2"'Y' prior 10 *1*'''"' ond «"II.,...... rat 7 cb)''lfIcr n:t\IOlI
.. -•
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• -"'II< douJy olow 1M.......
,~betuI
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r . - TIIl.. . . . "nlkoboo
ror ~ _ _ "'oIa)"
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... dlh,
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Adult>: rI ",bk1i ... dally olow for ) _>«:\Ill", do)"
""""'1W... .,101bI I' PIt"'1""""''''';M INMII'II Ichklruqll,.-.I .... If_line--..,.nmnIIaniJoo
6 ...1.... IIl I«tJgn,;
Plop/,,.....;,. Oily t:o.v-III
1-2 doY' btf.... 1n...1 ..... (or
4.....eU.,la,,,,, .. .a. ............ -....111 .... ." ...".,...4".......
0-101 .... 2 . . P''''''Y up 10 IOO-cAloy ,....."" l00 . . ~ob'11
TtnI ...... ' of P. /ak.".,rw.
1' .....
,..."" $00
"'I CY!X'rio.. N... VIlfl. FOlT¥. SInO!i .t GO ....... 2002. 3 ~oi. f..: SOrne of the older Wltibiotics allest to the spectacular suo;cess of thi \ approach as It has bcapt'd PotU; 1"- can"'" ~ It ,~nor yer dear "'ho!rller Inhlblloon of PBI' J 'S [;:rhal to 1M
I pure compound and ex.hlbltcd varying ocli\ lIy among gm. pie!;. it was IlCCC!iSllr)' 10 evalLIIUe 1\ b)' 1I11croblQlogicai as!>lIy. 1lre IlIo.:cdure for ..~y ...as dco'eloped al Ox.ron!. England.. ~nd tllC voluc became known ali the O.iford ,mil: t Oxford L1nit is defined lIS the smallest amount of penicill in that ""1M
TABLE 10-2 Structur. of Pen icillins
o
....L.H Chemlu l Nam.
R Group
""==
• PBI'!. 4 Ihrough 6 Ire: cubo~)'lX'plr" I""",dll,n HO crcl¥rm.
1-"..... lIOfyoollltlib.
...c_)' t.en, ~ I·
r .....'..I'"
...c..m..)·l-ltUortIll,
-,~llhn
Chtop'rr 10 • Anllbucll,nal AIlI/biUlin TABLE 1~2--ernlly prescnt (ic .. 2.2.dimcthyl ~nd 3-carboxyl). A thi rd {onll. followed in this chapter. uses tril ial nomenclature to nartlC' the entire 6-carbon_ ) laminopL'lIIcd lanii: acid ponlon of the molecu lc jIl'niClllrn and thell di~lIngui.he~ compou,xh on the basl~ of the R group of lhe acyl portion of the molecule, Thu ... po:niclili n Gis IIllI1lN benlylpo:nicillin. penicillin V i, p/lo."ll()t)mcth • ylpcnicilli n. methicill in is 2.6-dimcthoxyphen)Jpcnlcl lim. and so 00. For the """t pan. tlx- laner two ')~tem .• ~I'\c "iell for nllmmg and comparing close ly similar po:n;clllin StruclUn:S. but they are 100 n:strictive to be applied to Com. pounds with unusual \lIb .... ituents ono ring- modified deriva_ tives .
SterelKhemlstry
lllllibll. In ~illu. the growth of I SUlIi" of SU!phdorot:cuJ in '4 rnl. of cullUr~ medium under specified rondiuons. Now .. pure crystalline penicillin is available. the UOl/ell Staff'S ~w (US P) defines unil a.o. the arllibiOIlC lICIivily 0I0lt 111 of US P penicillin G sodium n:fen:ncc sl!Uldani.
H.
H.
CH.
TlIr'll'clghl - uni, n:lationship o f lhe penicillins varies with ... flf')1 sub!.Ii1tlem and with the ~It fonned of the rite acid: I III of peniclllirl G sodium i~ equ ivalent 10 t .667 units. I \ll'penicillin G procaim: i~ equ iva len t 10 1,009 units. mid 1l1li of penicil lin G poca~iurn is cquivalenll o 1.530 units. The l'OI1HncrciaJ production of peuiciUi n hilS iJlCll':t.'>Cd roly ,incc ils imrodUC1ion. As production irKTea'!ed, IIrr l'05I drtl(lJled COI l espondingly. When penicillin was first bilk. 100.000 units sold fOl' $20. Currently. the same ~'P:COSI~ less IlIan I penny. F1lJ('lualions in the producrJ penicillins through the years have ~ nccted manges _lilt: m..Ule populmty of broad-spectrum ant ibiotICS and • n!llM. the development of penicill in· resiWUlt strains of ,om! pathogcns. lhe more t\"Ccnt introduclion of 5emisyn_ " . penICI llinS. the use of po:nidlhns in animal f~ocds and 1I1dmnary purposes. and the inc~a..c lht"C'(': a:nters. TItc clubon atom bcannll tlx- lICylamino group (C-6) has the .. ronfigUr.tIlOfl .... hen:as the c:.. rbon 10 ... hich the carbo~yl group is IIl1:1oChcd ha.~ the 0 confil!ur:ltion. Thus. the lIC} lamino and carbo~yl groups au frtllU to cach other .... ith the former in the a (Illd lhe lallcr In the fJ onclllahon relative to the pen:un rin!: syslem. The UlOO1S comp!)',!ng lhe: 6-am inopenicill un ic acid portIon of the SlnJCIUt'll arc denvcd biosynthcl1cally from t .... o lun itlO bcitis, I ·cysld ne (S_I. C . S. C-6. C-7. lind 6-mmno) and I.-valine (2,2-dimcthy1. C-2. Col. N4. and l-ciltboxyl). The absolute slc,,:uchc miqry of the penicillin' i, deslgnal..-d lS:S R:6R. as ~ho .... n belt.... .
,
.
~
Ct., ': ,, _ _
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-,.
,,-..( H
OJ
1
~
-
~
304
-
•
Wilson and Gisvold's Textbook of Organic Medicinal alld Pharmaceutical Chemistry
Synthesis
natural penicillins are strongly dextrorotatory. The solubilit) and other physicochemical properties of the penicillins are affected by the nature of the acyl side chain and by the cations used to make salts of the acid. Most penicillins are acids with pK. values in the range of 2.5 to 3.0, but some are amphoteric. The free acids are not suitable for oral or parenteral administration. The sodium and potassium salb of most penicillins, however, are soluble in water and readily absorbed orally or parenterally. Salts of penicillins with or· ganic bases, such as benzathine, procaine, and hydrabamine, have limited water solubility and are, therefore, useful as depot forms to provide effective blood levels over a 10n1 period in the treatment of chronic infections. Some of the crystalline salts of the penicillins are hygroscopic and mu~ be stored in sealed containers. The main cause of deterioration of penicillin is the reactiv· ity of the strained lactam ring, particularly to hydrolysis. The course of the hydrolysis and the nature of the degradatioo products are influenced by the pH of the solution. IS. 19 Thul. the ,B-lactam carbonyl group of penicillin readily undergoes nucleophilic attack by water or (especially) hydroxide ion to form the inactive penicilloic acid, which is reasonably stable in neutral to alkaline solutions but readily undergoes decarboxylation and further hydrolytic reactions in acidic solutions. Other nucleophiles, such as hydroxylamines, aI· kylamines, and alcohols, open the ,B-lactam ring to form the corresponding hydroxamic acids, amides, and esters. It has been speculated 20 that one of the causes of penicillin aller!) may be the fomlation of antigenic penicilloyl proteins iJ vivo by the reaction of nucleophilic groups (e.g., E-aminol on specific body proteins with the ,B-lactam carbonyl group. In strongly acidic solutions (pH < 3), penicillin undergoo a complex series of reactions leading to a variety of inactile degradation products (Fig. 10-3).19 The first step appeaJliO involve rearrangement to the penicillanic acid. This process is initiated by protonation of the ,B-Iactam nitrogen, followell by nucleophilic attack of the acyl oxygen atom on the ~ lactam carbonyl carbon. The subsequent opening of the ~ lactam ring destabilizes the thiazoline ring, which then aI~ suffers acid-catalyzed ring opening to fOJ III the penicillan( acid. The latter is very unstable and experiences two maj~ degradation pathways. The most easily understood path in· volves hydrolysis of the oxazolone ring to form the unstab~ penamaldic acid. Because it is an enamine, penamaldic aria easily hydrolyzes to penicillamine (a major degradaiioo
Examination of the structure of the penicillin molecule shows that it contains a fused ring system of unusual design, the ,B-lactam thiazolidine structure. The nature of the ,B-lactam ring delayed elucidation of the structure of penicillin, but its determination resulted from a collaborative research program involving groups in Great Britain and the United States during the years 1943 to 1945 14 Attempts to synthesize these compounds resulted, at best, in only trace amounts until Sheehan and Henery-Logan 15 adapted techniques developed in peptide synthesis to the synthesis of penicillin V. This procedure is not likely to replace the established fermentation processes because the last step in the reaction series develops only 10 to 12% penicillin. It is of advantage in research because it provides a means of obtaining many new amide chains hitherto not possible to achieve by biosynthetic procedures. Two other developments have provided additional means for making new penicillins. A group of British scientists, Batchelor et al.,16 reported the isolation of 6-aminopenicillanic acid from a culture of P. chrysogenum. This compound can be converted to penicillins by acylation of the 6-amino group. Sheehan and Ferris 17 provided another route to synthetic penicillins by converting a natural penicillin, such as penicillin G potassium, to an intermediate (Fig. 10-1), from which the acyl side chain has been cleaved and which then can be treated to f01l1l biologically active penicillins with a variety of new side chains. By these procedures, new penicillins, superior in activity and stability to those fOllllerly in wide use, were found, and no doubt others will be produced. The first commercial products of these research activities were phenoxyethylpenicillin (phenethicillin) (Fig. 10-2) and dimethox yphenylpenici IIi n (methicill in).
Chemical Degradation The early commercial penicillin was a yellow to brown amorphous powder that was so unstable that refrigeration was required to maintain a reasonable level of activity for a short time. Improved purification procedures provided the white crystalline material in use today. Crystalline penicillin must be protected from moisture, but when kept dry, the salts will remain stable for years without refrigeration. Many penicillins have an unpleasant taste, which must be overcome in the fOllllation of pediatric dosage forms . All of the
c (
t
f
n n r
d n
f( IT
o
•
s
•
tI,
I-I!-I-OI+I-a-r" ......2
I
1-11
W
I
cc
~
B ar •
111
th if he R
•
R
\(f
va
,u , Figure 10-1 • Conversion of natural pellic .
to synthetic penicillin.
tht tio
Cha pter III • AIIII/1a hyacidic fonn a liCe-
l'cmcilioic
:acid!-substituled penicillins, exempl ified by llI.1ociliin. 11lt:1Jocillin. arKI piperncill in. exh ibit great('1'" !lCllv"y against cenain Grom·nc:gati,·e bacilli thaJt carbenici llin. Although the aeylurcidc>penicillins are aeylated derlvatl\'elj of ampicillin. the anllbactenal ~Itum of activity or the ,roup is more like thaI of carbenicillin. 1l1e acylu",idopenictl lllls 1If!.". however. ~upcrior to carbenicillin against K/t'bsit'lla spp .. I;."IIIerobaclt'r spp .. and P. tJrru.s,·· "OM. Thi~ enhanced activity is apparently not due to ,Blar:tam:I.'-C rt:S1st:mce. in !hat both inducible and plasmidmediated ,B- Iactama.C\UI!' from I variety of sl;in arKI mucous membrdne rashes 10.., fe>'er and anaphyla~ls, COllslltote the major probkm ti-«lated ",ith the usc of this class of anublOl,icl. £'>I1II1:Itl:5 pbr the preYalence of hypcrsen~itivity to penic illin G throoglXW the world between I and 1(Xf of the poputallon. In the L'. State> pnd other indostriali"tcd COOlllne5. It is ~am ~ higher fisure. rankins peniCillin IIII!' Ol(ht commOll CIiI!t. drug·induced allergy. The penkillin' most fn:quently" Uled in allergic reactmnS are penicillin G and amp.-iF Vinua ll y 1111 commc:reially available I il . ho-.ol"a. have bcc:n reponed to cause: such en. sens it ivity among m()),t chcmkal classes ici ll anic add derivative, has been The c hemical mechanislllS by I lions becoIne antigenic dcnee !Wggcst!i that peniclllllU or their ~arron¥eH1tI' odS formed in vivo (e.g .. penic,lIcnic acilb)"'1 n:act. lysine t-amino groups of protein. 10 fonn penlC;]~! ~ lei ns, which are major untigcnic: determinnnb. u , E-'! clinical observations wi th the biosynthelic pcnicllhns (j. V ilKhcatcd a higher incidence of al~ic rcactlOllS. onpurified, amorphous prcparuliOOS than with highly fted. crystalline forms. suggesting Ih3t small 3""- ' high ly antigenIC penlcilloyl proteins present In ~mple~ were a eause. l'olymeric impurilie' in
Ctuo plfr 10 •
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1 pt'nicillina- ..... aminob are also not inacli\'llioo by dan I InhibitOl'li.
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"",
Produtb C/avu/anate Potan;um, USP.
C!a>'ul:mic acid i~ Dn!llltlbiotic isolau:d from Srr''I,mm\"Cr'J dlll"uligfri.r. Structur· all y. it i~ II I -()~opennm lacking lhe 6-llCylnmiliO side chllin of penicillins but posscs.~ing D 2-h ydro.l.ycthytide~ moiety al C-2. Cilindanic aci d e~hibilS >'cry weak antibacterial activity. t"OfllI);lr:lbk: willi tlutt of 6-A PA IllMl. lherdon:. is not UK.fula~ !Ill anlibiOlic. II i~. ho,,·ever. P pOIenl inhibitlll" of S. (IIIft'U.r ,8- lactamase and plllSlllid-met.hall'd ,8-lanamases elabonued by Gnlm-negati>'e biocilh.
,"
"~,
Th< C-2.
Fill.oo-dosc cOlllbi n:lt;ons of ampici ll in sodium aIlll ... bactam sodium. markeled under the trode name: Unas)'lIa 5teri~ powders for injection, have bet:n approved for II$t iI the Unt ted Stales. TIlC..o;e I:ombinations are recommended for the lrelilment of skin. tissue. intra-abtlornlllaJ. and I)'neel' logical infect,olu caused by P.lacl.llmase-pnxIucmg 5InIII of S. IllImlJ, £. coIj, KIr'bsir'lkl spp .. P. m;rabilis. 8. fro. and i::nlt'robuc,,., and ACtnetiJbaC"ltr spp. Tazobactam. USP. Tu.obactam is a pcnicill:lIl1( a:tI sulfone thlll IS "inlliar in struclure 10 sulbacl.am. It is._ potent P.lacIHI1I~SC: IIIhibilOT lhan sul bactal1l H and No I slightly broader spe('lrurn of activity than c1avulanic has very weak ~nt ibacterial ac. i~i.y, T a7.0bactam i~ 1l'·:IlI.tblt: in fi~td·dosc. injecl~b1c combinJtions with pi\X'l1ICl lhn.1 broa(hpcc:tru'll peni('illin consisting of an lI: I nl1 io of p!ptI. acillin sodium 10 t~.tobal.'tam sodium by wei,ht an.J .. ki.'Ied under the trude nlIHle 'losyn. lbe pharmaoo~incllO" lhe 1"0 drug~ are \'el)' Similar. BOIh halC shon half·~~ (I. - I hour). a", mimmally protein bound. ClIpcncnct" ~ lillIe metaboh~m. and excreled in acth'e fom\! urioc In high conc:c:nlr.lllons.
aod..
" Cumbinmions of
amo~ ici llin
nnd Ille potu~slum sail of elavulanic acid are available (AuXIl"ICntin) in a variety of fixoo·dose oral dosage forms intended for the I",annenl of Skill, re."PlllIt(ll")'. ellr. and urinary lract mfeelions caused by ,8-1actama.;e-producing bacterial ~t r.aln~. 1lle'lC" I:ombinalionS a", dfecU\'e agaill5t ,8-htclamilSt'-produci ng "'r:lIllS of S. uurl"u.r. £. rtlli. K. f'm!u'lUHliul". i::11Il"robtlOler, 11. injlur'n;tlr'. Moru.rr'//ll CUf/lrrllllli.r. and II. duerr',·i• .. hich lilt ttSislanl to alTlOticilhn alone. The oml bioa\'llilllbility of anlO~i dllm lind pot:lSl'iu'll clavulan~le .. ~"lIIlar, Clavutanic ~id is acid·st ab~ , It cannOl undergo pcnidllanic ocid formation beeause il locks an ~rnide side chain. 1'001I!.s ium d a\'ulanatc ~nd the e~lendoo-)pcctrurn penici llin 1karci Ilin havc been COlnb; nl-d in II fi.l.ed-dose . injectable form for the t'ootrol of seriOlIS i'lft'Clions I:llu..ed by,8- lactamase-producing bacterial s!r:lins. This rou lb; nation has been recommended fill" scptiCo.'mia, lo .. cr rcspirnt(ll")' trocl info::· !Ions. and unnary tract infeclion~ cau~d by ,8- lactamaseproducing Klr'bs;r'//a lipp.. E.. cmj, P. Ul'rox;nQSlI and other PSr'IIi1lJ11lOnm spp.. CitrobtlC"ll!f ~pp., C",uOOocurspp .. Su'mill nIllrcr'sC't'ns. and SlIlph"'(i'C(XXllf IIUrt'II.~. It ;tISQ is used III 00ne and joint infections eaused by lhe..;e organi~ms. 11le combmallon rolllams 3 g ofticlIfd lhn disodium and 100 mg of potas~i um cJa>'ulanalc in I ~'erile: powder fill" injection (Timenun). Sulbactam, USP. Sul baclam is penicil1anic acid su lfonc Ill" I, I-dioxopc:nicillanic acid. This ~yrnho:lic penicillin deri>· ali\(: ;s II potent inhibitor of S. UIITf:U.f ,8- lacuulI~sc as " 'ell a.~ many ,8-lactamases clabonllcd by Cr:lrn-neg~ti,e bal:iIli. SullxlClllm ha~ " 'C8 intrinsic ~ntibactcrial :IoC\l1 ity but potenuate~ the acli .."y of ampid1lin and curbc:nicillin agaillst ,8lactl1ll\ase·producing S. aurt'11f and mcmbcl"$ of the Emerobactcoxc;\C fam;ly. II Iloe-i nOI. howe>·n. syroergi.te with cilhet" carbenicillin or licarcilJin against P. IluuRinosli stnlillS I'!'$ismnt 10 lhese agents. Failu", of sulb.K1l1m 10 pcnctnllc the cell cnl'c!opc is a posSible explanation fill" the lack of S~llC rgy ,
are
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, n baCl(
"ro!
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b "", Ihien: "~ A.
instal
moo IlIItibi s),ste. III its
Approved i combination lum cndomctriti ~.
for lhe
"«d,,, !lvati( of lhe ~I~
by caused by ;njlu",,::pe.
CAR BAPENEMS Thienamycln. Thicnamycin is a novel ,8-1ac:larn'" OIic fi"" isolHled nnd Ident ified from femlenlne;o'l of It of Struclure WId absolute spcclroscupic~JJy und by t fealu",~ of thicnamycin a", (('phalosponn~: II fUM'd lacuun and lin other respects. panu", from the elie system con"i~'s urbapcocm containin; • bond between C-2 lind C-3 (i.e .• il is • 2-cartare-." .J1-carba\X'llCl1l. system). The double bond in lhe
drolyt
ChaIMer 10 . A",ibnc,malA""InOlin
I
.!IUo.'1urc: creates COf1sider:lblc ring strain and increa.t extensive ('linical evaluauon.f>6 lt has reOffie
SemJsynthetk Deriv.tlves To date, the more uo;efu! scmi'ymhctie modifications of the basiC 7-ACA nucleus have rt'Sulted from :toCylations of the 7 -a mino ifOUl) with diffcrcllt acids Of" nuckopbilic sub~tilu tion or redlM.!lion of the acctO~) I group. Slructure-ac"~lty relation~hips (SARs) among the ccphalosporins appear to paralkllOOsc amoogthe penidllins insofar as the acyl group is concerned. The presence of an IIl1ylie accto;\yl function in the 3 position. howe\C:J". prm'itks II react"·c ~ Ile at which various 7 ·ucyhlminoccphal~nic acid structure( can easily be varied by nucleophilic displacement reactions. ReductiOll of the 3-acrtOXYlllethylto a 3-~thyl substituent 10 pre. potrc 7-amil1Odesao:.:etylccphal~pomnic OCIU (7·AIX:A) derivativC:5 can be accomplished by catalytic hydrogenation. but the proce.ss curremly used for Ihc ~"()i1lillercial synlhesis of 7-AOCA derivati\'cs invoh'es the rcalTllllgl'l11('1l1 of the corresponding penicillin su lfOlridc.l~ Perhaps the nlOSl note\Io"Ol1hy deveJopmcnt thus far ,~ the disco\'e!")' thaI 7-phcnylglycyl derivatives of 7·ACA and especially 7-AOCA lite active orally. In tho:: prepotrntiOll of semisynthetic ccphalosponn~. the following improvements are sough!: (a) increased lICid sta· bility. (b) improved phannacokincuc properties. particularly better oral a~ ion, (c} broadened IIm,rn lcrobial 'peclrum. /d) increa...:cd aclivity against resi~tam microorllan,sm~ (a~ a result of resistance 10 enqmatic dcstruction. impro\'ed pene. tration. increased receptor affinity. etc.). ( t'} t.leed allergemci1y. and (j) Increased tolernnce ufte r JXlrellicrnl adminisIr.Ition. Structures of cephaJO/oporins cum:ntly nturiell'd ill thoc United Stales are 5hown III Table 10-4.
chemk_' Oegrada-tlon C ... phalosporins experience a \'ariety or hydrolytIC degrada lion rehctrons whose speci fic nmure depends 011 the intli~id.
TABLE 10-4 Structure of C.phalosporlns ORAL CEPHALOSPOR INS
"
" -0',
...
....."'" CefU",. in-.. .. till
00
-s-
00
5
s-
00
...
00-
Cd,...,nl
"
- 00
--CO"
c,.....
,
-ctfopo nns IS bc:lie\td to gi\'c inilially ceph:dosporoic acids (in "hlch the R' group is stable. e.g., R' - H or S helerocycle) or P'X>lbly anhyrlrodc:.'illCelylct:phalosporoic acids (for the 7'lICylamlllocephaJosporJnic acids). It has 001 been llOS,ible to i~nle either of these milial hydrolysis producl ~ in aque. OtIS sySlems. Apparenlly. both types of c.:phalo,pornnic ocid undergo fmgnloCntmion reactions that h3\'e 1101 ~n ch:II1~ teriud fully . Studie~ of the in vivo nloCtaboli~mlO of ornlly admlnlstcred cephalosporins, however, have dcmonSlrnted IIr) I:lCCtylgJ~cines und arylacemmidoethanols ... hich are be· liC\ed co be formt'd from the corresporl(hng aryl:.:etylumi · rlOOC\'laklchydcs by ml!tabolic 0~id3uon arKI reducllOn. rcqICClI\·cly. The aJdeh)dcs. oodoulM. ari)C from noocnl.ymatic hydruly5i~ of~ COITeSJlOfIdlllg cephalosporoic acitb. No cvidence for lhe intnllnolC'(.."u lar opemng of lhe P.lacUlm nng by ~ 1 'lICylamioo o~ygen 10 form ouzolooes of lhe pcmcillamc acid t)·PC: has been found in the ceph3losporins. At neutral 10 alkaline pH. howe\cr. ii1tr~lllOleculllf
aminolysis of tne P.llICtam ring by the a-amioo group in Ik 1·ADCA derivall"es cephaloglydn. cephroldme. and cdldro~il OCCUI"$. fanning dilctopipenu.ine deri\'ati\'es?~ 1Ol'bed orally, presumably beeause or ... yolysis ofthe 3-aceto~~1 group in the low pH of the SlOI1lIII1 'TOO l'l'Sulting 3·h)·dro~ yl porins are signi lkantl) le~ NeIlS;U I ethan all butthc ,B-Iactamase-re~istant penicillins to hydroly~is by the enqmc:s frolll S. tJljrtUS and Bacillus sIIb/ilis. 1lIe "pcnicillinase" resi~Ulw:e of cephalosponns appcan to be. propeny of the blcyc lic ccpllem ring ~yMem rother than of the 8C) I group. \)csplte nalUral resistance to staphylococcal p. lacuma.se. the different ccphalosporins n~hlblt considemblc variation in rates of hydrolysis by tl1c enzyme?' ThU). of several cephalo~porin, tested in vitro. cephu lOlhi n and ccroxitin life the most resistant. and ~phalondine and ccflUo lin life the least resistant . 1llc same lleyl functionaliti~ that impan ,B-luctanlBsc resistance in the pen icitlin~ un fortunately render ~'CphalO!>pori ns vinWllly inactive against S. IIUrtUS IU1d other Gram-positive bact,",ria. ,B-Lactamases elaborated by Gram·negatl\·e bacteria present an exceedi ngly complex picture. Well over 100 different enzymes from various spcci,",s ofGram-neglltive bacilli rowe been identified and charactenled,~~ differing wido:ly in s~· ificilY for vurious ,B-llICtam amibiOlics. M()rnl features confer broadly based resi~anctll .8- l llCtaflla.se~ among the ~phalosporins: (a) an alkoximHID function III the anll ll()llC)'1group and (hI a methoxy l ~bst ... ent 8t the 1 j)O"Joit'oo of the cephem nucleu~ h.a~lIIg a stmoclle mistry. The "tfllClun:s of sevcm l ,B-IlICHimase-n:sI>/at cephalosporins, including ccfuroximc:. cefotaximc. cefli./m· ime, and certriaxonc. feawn: a methoox illlino aC)"1 group. p. L.octama indicated thaI OIher factOfli. such !IS perrneabi~ lIy and intrinsic IICli ~ily. are frequently mort important. TIle L-mandeJoy l isomer is Significantly less ICII'e than !bE D isomer. Cefamandole lIafate i~ very unslable in solution and h)· drolyteS rupidly 10 release cefam:mdole and formate. Then: is no loss of potency. ho....e>cr....·heu ~UC:h soIuliom IIr stored for 24 hours at room lempIet.l a.odlWII ~.
r.lcWrin Sodium, Sterile, USP.
Ccfoxitin (Mefoxm) I Knu,)nthetic derivllt;\'e obtained by modification of ."~YClll C. n 7(\'-nletho.y -subst ilUted cephalO!'e desacelyl mtTabolile. ApproximaTely 20% of the metnbolile and 2S r:l of Inc parcnl drug are excreted in the urine. The patt"nt druB reaches the cerebrospinal n uid In suffICient concenlration 10 be effecl ive in !he Ireatment of nWo!ningilis. Solutioo.~ of ~"C:fOOlxime sodium should be ue Pro/t UJ spp .. and S. marcesctnJ. CeftilO~ifOC' is claimed 10 be mo re &clive than eefoxitin againSI D. /roSiUs. II is also ,'cry acti\"e aguinst Gram· posili>e bacteria. its octivJly agalnS! P. fltrvSUWMI is sonIC"hal variable and lower than that of either cefOiax imt or cefOfXra,~ -
""
6 '-
1-
k
~
4' o
'0
", "
"""""'. USP
Tbt ct)I)lparllthely 1000g half-life of cefixime (I. is J
.
10 4
) .lIows ilto be administered on a tWlce·a·dlIy schedn:absorption and a relatively hIgh fl'llCtlon binding (about 6S % )contnbute to the 1000g two o"IlI dosage forms: 2()()" Of 4()(). for the pn:par.uio n of an aqueous
Sodium, Sterile, USP. the fim thIrd-generation
I., It 's
(Cla-
wbe
;;;I;;:~
&ch'e moxalactum againM organisms. Many ,8- loctllmasc-producing straill5 are S('nsi tin: to cefoc.a.\lmt. including ~pp .. H . inj/'WIIWt, S, flUrtlU, no! all. PstudomoooJ SlnUns an: Enlei .......... d and U s/tna mQfioc"fORtllt~' are re~i5IfIOI'e
Ceftizoxime i ~ not melabolized in vivo. It i ~ excreTed largely unch:tJ\ged in the urine. AdeqUaTe le>'cls of The drug 1lIe ochie>'w in the cerebro&pinal nu.d for the IreUTnWo!nl of GrJIll -llCgalive or Grdm-positi>"C: bacterial meningitis. It mUSI be iIodminiSlered on a thnce4aily dosing schedule because of it s relatively s tlorT hal f-life. Ceftizoxime 50dium is >'ery stable In the dry state. SoIutiOO!l mainTain potmcy for up \0 24 hOllI"$ al room lempenllure and 10 days when refrigermed.
Ceftriiuone Disod;um, Sterile, USP.
Ceflriaxone (Roa:phin) if a ,8-1lll!l.ilmaSC-rc:$i51anl cephalosporin ..... ilh an t)ttrenWo!ly long serum half. Ii{¢. Once·daily OOsing suffices for most indlC'lltions. Two factors contribute to the prolonged
duration of :lCtlOll of ceftna:lIOne: high protein bmdlng in the pillsma and slow unnUly e)(~rerion. Ceftriaxone is eKI.:«:tcd in both the bile and the urine . Its urinary excretion is not afftaed by piobenc:cid. Despite lIS romparati\'dy low volume of disrrilmtion, it reach~s the cerebrospinal fluid in conCC"IItr1II.lORS that are effecti\e in n~ningltjs. Noo linelll" pharmacol;.metiC!l are obseo·ed. ~.
('
wres: (oj a 2-mcthylproptOflloouo\lnooeyl group !hat c0nfers ,8- lactama.o;e rt's islance and. possibly. 11lCrt'lISed pcrTMability through the porin channelS or the cell envelope. and (b;a pyndinium group at the )' pi)S.lioowa1 C()(Ifers l:WI~ ionic propenies 00 the molecule. Cefta7.idimc is administered parenterally 2 or 3 timn daily_ dependin!! 011 the Rlmt)' of the infectlOll. lUi serum hair-life is about l .tI hours. It has been used effta"'ely for the treatment of meningitis caused by H. irif1lum~ and N
or ,r ~
"
m~njngilidis.
••
".
NEWER CEPHAlOSPORIN5
CeIInuone DIE 'llun
Ceftrillone CQIltains a highly acidi c ocu:rocyclic sy~tem 01\ the 3_thiOlllethyl group. Thi ~ unu~ual dioxouiazine rinll system is bel ieved It! confer lilt! unique phannocokinclic I'lOperties of th" lI,I;ent. Ceflriaxone hII~ been associated with sonographical1y detected "sludge:' or pscudohthiasis. In the gullbladderand COn1l1l00 bile duct .9J Symptoms of chole· cystitis may occur in suIlPs, in particular ,he POP 23 (or PBP2') of MRSA.l ' The o/):,en'mioo Ih.:it cenain catechol·substi tu ted cephalosporins uhlbil marked broad-spectrum arlllbacicnai act. ~i l )' led 10 the dl" c{wcry thlll ~uch l'Ompound~ and OIher ana· lotlucs capable of chl: lating irt)fl CQI,Ild mimic MiUra! ~idero phom; (imn-chchll ing peplides) and thus be actiyely Imnsponed iruo bactcnal cdls yia lhe /onB-dependc:nl irt)fllf1lnspon syslem.97. 9f; Thi~ provides a nl('uns of auacking bacl~riaJ Strains thai ~i'l ccllular penetntlion of ccphalosporin~ .
./ AJlepin) ;\ a p.vcn1hm I ~ chenucall), II alstitliled 1.3-diumlnocycloheunt cenhi ~: in kan:Ullycin. neomycin. gent:unicin. and tobra"Jtift. It IS (\eol(ystreptam.lll'. and in streptomycin. tt is *tpIIdme. 'The aminoglycos.des are mus strongly basic llCfiOUnd$ mal exist as polyutiOlls al physiological pH. ~ lDorzalllc acid salts are vel)' soluble in Wlter. All are nlabk as sulfates. SoluliQllli of the aminoglycoside ~IIS 1ft Sllblc to outoclavlng. The high walcr solubility of the >&I)'t'Nldes no doubt conlTibulC5 to their pharmarokipo¥r1ICS. TIley distribute well Into roost body nuids .. not into the ccntral nCrl/OIlS system. bone. or folly or • • live 1l$WeS. They tend to concentrate in the kKlneys are e.lcreted by glomerular filtrauon. Ammoglycoside!; _lI'PjlOlllinked tmllSfer of the aminoglyco«odc: through the ccll_ brane then oceUI");. Divalent ca lions ~ucb as Cal. and anlagoni:t.e the I mnspc:l(l of .mi llogl)Cosode.~ mlo '*'tnI cc li s by inlerferi ng wi tllt l'letr bin!.! ing to ce ll melllbra~ pbo!p/IOl ipid). The Il'SISIance of unael obic bacteria 10 t~ Ic*I action of the aminog lyCOSldcs IS apparently due to SCI1l,."e or the. ~pirntion-drh'e" actl\'e-lransport prom.! t r:ln~ I)OI"\lng lhe an tibiotICS.
OOse""'oo
Mr
tht"
Structure-Activity Re lationships Despite the coo. plexity inherent in various am,nogl)~. 5IructUTtS . ..onle conclusioru; o n S ARs in Ih is antibl(l(ic
ANT... •
\ IiO
/
m
'"
ANT·2". APH·2"
11
NH,--AAC~
Figure 10- 7 • Ir\actIValJOn of kilflMn)'Con B by I~ l.aj enzymes.
Chaptn 10 • An"~I~"'" N"'bltlIO('s
lllve been made. Ll' StICh cOIlC!uslon~ ha"1: been fonnulaled _the bMis of comp.1n50nS of nmuraliy occurring ~minogly cwde $IfUCtIII"eS. the ll.'IIullS of selective: semisynthetic modibIoos. and the elucidation of SlIe:!> of inlll,:'lll':llloo by bac· ImII enzyrtlCS. It I~ con ~enicnt 10 di!iCUs..~ sequentially .rnnoglyCQSidc SARs in IcmlS o f SllbslilUCnlS in ringl I. 11.
_m.
331
toward light and air. It is freely soluble in .. mer. fomllng solutions that ate slightly acidic or nearly neulral. It is vC'1)' slightly soluble m alcohol and I~ insoluble III IIlOSI ochtf organIC soIl·ems. Acid hydroly~is yields strep:ldll"lC: and streplOoiosamine. the compound Ihat is a combination of 1.Streptose and N-mclhy l-I.-gluCOl\amine. ~
RIIIg I is crucially Important forcharat1erislk broad-specrum IIllibactcrial actiVIty. and h , ~ the primary target for bltlrrial inlk:livaling enzymes. Amino functions 31 6' and particularly important as tanamycin B (6"3I11ioo, 2'· ....oJ IS rrlOfe acth'c than kanamYCin A (6'·amlllo. :Z'·hy"'hid! in tum is mort: acl i'~ than l3namycin C (6'II)tkulyl, 2'-aminol. Methy lation at either the 6'-carbon or .. 6' 'fl luioo po~ition s doe~ not lower appreciably anlibaclC·
tyoI - l - Htl'",OH
SIr8p!kione
""
r.wt .rl).
IIIIIICII\;t)' :md confers resistance 10 enzym~lic acetylation ~tbI: 6'·.nuoo group. Remo\-al of the )'-hydroxyl or the r.J\~dro~yl group or both in the I;anamycins (e,g .. 3'.4'. dideot) kanamyci n
I
1
•
R ()I" dibekacin ) does
n:Sitle+bind + IIJ wcs In bacterial n~~. n.. modJflCalton~ of nng II (liemystrep:amine) runc IiDlaI lrouPS are posSible ... ithout appreciabl~ loss of activity • IOOlIt of tile aminoglycosides. 1lic I-amino group of 1;811a· ~ A ean be acyl DIed (e.l .. umi l acin). however. with ...nil)' largely retwned. Netilnllcm ( I-N-c:lhylsisomicin) rc!be antibacterial potcncy of ~iJ;Omicin and is ~istant 'Htl'ml addi t;oual bacteria·inactlvating cnzyme~ . 2"- l-I y· m~slwnucin is claimcd to be re:~i~HUll to b!lcterial slrnin ~ . . acknylate !be 2"- hydroJl yl group of ring Ill . whereas ~tno!liwmkin t~htb1l~ good activity llIainst bacterial JI2IIIS that elaborate 3-occtylatlng en/ymes. Rlnl III functional groups appc:ar to be somewhat less ft!oIOI'C to structural changes than those of either ring I o r l1li11 Although the 2" -deo" ygentarnlCins are slgnificlUltly actJI·t than theIr 2" -h)' dro~yl countCfJXlrts. the 2" -amHlo *"1"3111'1:3 (se idomycill.) are highly acth·e. The J"-ammo pwpOfgenlanlicins may be primary or secondary with high •• _Imal potcncy Furthermore. the 4"-hydroxyl group ..,. ~ Q.fl/ll or 'c~idic l ink~ v. ere ass umed 11,1 be tl'. Hucllcnrnuch III later sUGgested. howcver. Ih:U both of the dihmmu sUI,::trs in nromycin C ha\'cthe Il·gluc~ cunfigu!'lItioo Qnd that the gl)..osidic link j . {j 111 !he one attached 10 D-nbose. The lana Siereochc:ollSlry has been confirmed by the tOlaI synthesll lll Qf ne~mycin
n
cn
e
Paromomycin Sl,Ilf~te, U5P. 1lle isolation Qf ~ m)'cin (li Ulllalln) was reported in 1956 froon a fennt:Dlatl(ll Wlttz ~ SIrt'pltJmYCtS sp. ( PO ().t998). a Stram s'[ud 11,1 resenmk S. mnosus very closely. l1le parent organism had been Dbtllin..'ti from soil sumplcs collected in Culombia. ParomortI)'· Cln, however, motl: closely resembles neumycin ItI1d stn'ptO11I)'cin ill anU biotic IICtiv ily than it dOCli uxyletrucyctlllt," un liblotic ubtained from S. rim05US.
nora
',",
_ c .,if. . "{'\ ~
Deoxystreptamine
_c
[).RlX It
--
'.
"';) t;'\.... NeosamiM 8 Of C
-~f.er~1..... ~
,
o-OIuce77~
Neomyci n as !he 5Ulfatc sail I~ 11 ... hite 11,1 shghtly yelluw. crySlalline powder mat is \cry 'IOluble in lValer. It is hygro§l:opic and photosensiu"e (but SUlbIe Q\'er B wide pH r.mge and to autoclaving). Noomycm su lfYle clants in aqueou~ 'IOlutions of the add ~ II" (Table 10-7). The paniculill' funcuOflnl l! l"OUp< responsibk for each of the themlOd) IIIl1nic pK. ,'alut, \Io ere determilled by Leeson et alYo as sho\lon in the dlllgmm belo\lo. The'C ~pmgli had been identified pre .. iou~ly by Slephens el al. I' a.~ the sIte;; for prot0nauOtl, bul their earher assignmem). \Ioh ich produced Ihc: ..alues re~pomi bk for PI1. '" 1kM, doxycycline and rninocyclinc: nre a~bed more COI\II*td! follo .... ing oml administnttion. exhibit higher rr.octlM!" r
Chap(~r
TABLE 10-8
',C
"•
, , -.
" ••
"- N
•d ,
"II 0
OH
"
-,
"
,--
-,,•
•
,
~
~,
~,
OH
""
1,( 'y N',
,~,
00
-I
0
0
b~
O ItVlb :11or> _1vh1)
...
n~
~
~,
h",,_
~
~"
~
,-,
~-
em""""'"
'.7) "" I
1~1iU6
~
,~~
'" · I(l~
~
'!-'101
_n
~n ~
1.10
~
Il0. J R• ..., ~ Iond. S, Adv ""'" , ' 01. ClIo ..... ",1 6 1. '\ _ _ ..... QoIu.... J 1...-.1 K- . ~ a.; I ___ s.: ~lII l lo1. 1W>9
"
II
1101...... of
!\ht, b.d Or ..I,
,~
~,
, I ....~
r
..
,. ,. ,. .... 5.'· "' , " ..... "... , '"'" 0" , , , '" ,. " " boo" ...... , '" " ",,01.10 " ." " " () .\........... r""" ~
,,...P'
-.. ,., --" ,., -"'"" " . " " " ... " • , ... ""• >. "" '" ,. " " " " . n" ,." " . " '" "
'. ~w.,..
Subotll-.b
, ......yd...
......... CH.
'"
I
"•
"•
345
PharmlKoklnetic Proptlrties· of Tetracyclines
"
•
HI • AnlllNlC'lrntli Anllbim,a
II
~"
IM · ~
,s-,~
1 ~71 ,
•
•,
, ,,• ,
• •
j
-, , •
,,
•
-, •
,
•
•• •
r
plow protem bmdmg. and II:wc higher ,'oIUme5 of di stribuIIlII and 10\\"('1" renal dC31110CC r'J I l'~ than lhe COITC~pondin!; "" ytttrao:yc liM's. Pobr subsll lucnts (i.e .. h)drox)'1 gll)(lil"i) 31 C -5 and C-6 c lipid versus .....ater solubility of the tctTllCycline!i. Tbt 6 positiOn is. hmI·e,·cr. cOllsiderably lOOn: sensit!>c titan LIIr ~ po>lti on to thi s effecl. Thus. dox)·t)'cline (6-dcQ"y-S.}1Ctrxycilllcj ha~ a much higher partition coeffidenl than tetrat"ydine or oxytell1lC)"clinc. Nonpolar SUbsliluems with posith'e IF \'alue\: see Chapter 2). for example. 1-4i1neth)l;unino. 7--chloro. and 6-melhyl. ha\e tbe OPPOSIIC dfca. Accordingl). the part ilion oocfficienl of chlor1ctTllCy. . is ~ubstllllli3i1y ,reater than Ihal of letrncyclmc and ply creal.:r than that of dcmecloc)·ellne. IntcR$tingly . .mocycline (S-demclhyl·6·deox y-7-dimelhylmninOtell1lCya. ) has tbe highc:sl parmion cocfrlCicnl of tbe commonly
1_
water-soluble COllI oxytclrllC)'clinc can be IIllributcd to In i their oompamtivc difficuhy in IIr k! membrancs. lhe tetracyclines JH1l'bat rI1Ctal ions in the gut acid--catalYlcd de'lrtlclioo in the stomach. With bdillf)' excretion of I 10 cause a higher incidence from rc~i~lanl microbial ~l l1Iln~ 111e rTlOI'e ,~,'. howe\er. are extretcd In higher ronccn In urine (e .g .. 60% for ICtnlCycline and 70% 1IrOJ:)IWllC)"Clinc) than the more lipid-soluble romroonds !q.. 3)% for doxycycline and only 11% for minocycline). fanl passi\'e renal tubular rcabso,puon coupled with '-fI1Ictlon~ of protein blndmg 00I11 nbute.~ to the lower ItlOR\
renal clearllllCC and longer dUTllli{)ru; of action of doxycycline lind minocycli ne compared ..... Jlh Il105e of the OtiK'r ICtracyclines. especially letl'1lC)"chroc and oxytctnlCytJine. MlllOCy cline al'. It differs from cliionetnlcychne on ly ;olhe Qbsence of the nleth)"1 group on C-6.
...
o ,r
"-
(hytelracydlne Hydroe/'lloride
O.. )\CIllICycii ne hydrochloride IS II IXlIc yellow. bluer. ~ltioe
rompound. The amphoteric ba.c , ~ool)' sli,hlly soluble in waleI' and ~ hghll y soluble in alcohol. It is odortc.~~ IIId stable in all' but dar~ en~ un exposure to ~I rong sunlight . ~ hydrochloride '>l'I 1I is:l. stabk: yellow powder lhal is !nore bIntr than 1M r~ b:be. h is much more soluble in ,,",uer.
II
dissol~Hlg
in 2 mL. and
n~
soluble
In
alcohol than
_ free buse. Boll! compouoo$ are inacli ,·ph.'d rapidl y by albli hydru~idcs lind by lICid M:lJmioos below pH 2. 8 01h ~ of oxylclfllCy, line are absorbed rnpidly and equally d from the d'gestl\c 1tOCt. 'iO the ()I1ly real oo\'anuge the ~ base offen over lhe hydrochlomk a ~trongl ye llowy10acidic dark .~~~;~d~cr, because the cstolW, 1Il0le eJ.tcn 'i~cly protcin bound thnn crythromycin it~lf MellSured fr.tCtions of plasma protc:in binding forl'l')~ c;n·2'·propionate and ef)thromycin base range fTOOl O,~" 0,98 for the fomler and from 0,73 to 0.90 fOl' the 101C1C1. indicanng a much higher levd of free erythromycin p\a.'ima. Bioavailablhty studlCJ; eompanng eqUi\'a\ttlt of thc t:'nteric-eootcd ha5C, tile Sicamlc ~~I1. toc t:'th)lsuconail' ester. and the 1!.~1I)1~le I!.~tcr in hunmn "oluntCt:'l'SllI1. showed dt'llyed but shgbtly higber bloon,ilablht) for free base than fOf the stearJtc, clhyl~ucclna'e, or estblt One study , oompanng lhe: clinical cffcctl\croe~ offttllll mended dosc~ of the ~lCaratc:. C'\!olatt'. cthyISUCCi~. free base: in the trealment of ",spir-J tory tfOCt In~ fa.iltd 10 tlcmol1!itnuc substanlial differences among thtm. Two other clinical st udies. rompanng the: effeet.i\'CIICSI
"'II.
111*
dle de,·clopment of atherosclcrosis lind is known to occur in diabelc.~,
Severe hyperlipidemia may lead to life-Ihremcning macks of ocute pancreatitis. II also seems Ihm Soevere hyper~pidemia cnusts xanthoma . Considering !.he effeclS of insu~n on lipid metabolism, as summarized above. one can rarionali7.e th~t in type II diabetes, in which the patient may lIttuaJly have an absolute e~cess of insulin, in spite of the ~,ide~ of glucose tolerance tCSts. the effcct of the e~CC'S51"e insu lin on lipogenesis in lhe Ii "er llIay suffice to increase ilK Ie,-ds of circulating triglyccrides and VLDL, In type I diabeles. with a deficiency of insulin. lhe c irculating Icvd rn lipid~ may rise because too much precursor is available. fIlth fatly acids and cnrbohydnues going to the livcr, The: relalionship \)ct,,'een the carbohydrate metabolic rnanifc5lations of diabetes and the devciopment of microand macrovascu lllf diseases /las been studied cluensivcly. se.. l>l lt is becoming increasinglyclcllf thm hyperglycemia plays I major role in the developmem of vascular complica tioflS Ii dJntes. including i11lcrcapi lIary glOJncrulosclerosis. prelIl3Jure atheroscleros is, relillOp.1lhy with its specific micll)lIJIeury~ms and retinitis prolifenms. leg ulcel'!!. and limh ganFtrlC', Fi~t , hyperglycemia caust~ an increase in the act ivity a( lysine hydroxylase and golactosyl trunsferasc. t""O importan! tnzynH's involved in glyroprotein syn lhesis. Increased !Iytop~ein syn thesi~ in the collagen of kidney oosement o:moome may lead to the developmem of diabetic glomcruklsclerosis. Second. increased upmke of gl ucose by non-insu.lin-sensitivc tissues (c.g .. nerve Schwann cc lls and ocular \ellS cells) OCCUr5 during hyperglycem ia. Intracellular gl uCI'lIt is conve ned enzymatically first to sorbitol and then to fruct~. ll1e bui ldup of the.'iC sugar.; inside Ihc cells intIl:llSeS lhe o:.mOlic pres~ure in ocular lens cells arid Schwann cells. r~ulting in increased walcr uptake and impamng cell functions. Some forms of diabetic Cal:lraC\s and diJbetic neuropathy are be lieved to be caused by this pathlI'l1y. Third, Ilyperglyccmia may precipilllle IlOI1cnzym"tic
TABLE 25-7
glyrosy illtion of a variety of protein~ in lhe body. including hemoglobin. serum albumin. lipoprotcin. fibrilHlgen, and basement membrane proIein , Gl ycosylalion i~ believed to alter the tertiary structures of proteins and possibly their rule of metabolism. The rate of glycosylation is a function of plasma glucose eoncen\mtion und lhe duration of hyperglycemia. Needless to say. lhi~ mechani~l1ll1light pl ay an important role in both macro- and microvascular lesion •. Finally. hyperglycemia increases the rute of aggregation and agglutinizution of circulating plalelets, Platelets play un imponam role in promoting atherogenesis. The increase in the rate of platelet aggregation and ag glutin i:rution leads to the development of mi CTQCmboli, which can cause tran sient cerebral ischemic allacks, strokes. and heart attacks.." Concepls of the therapeutics of diabetes mellitus havc been reviewed by Maurer.60 Thi s review cmphas.i7.es that insulin therupy docs rIOI always prevent ~rious complic ations. Even diabetic patient~ con~idcred under insulin Iherapeutic control experience wide fluctuations in blood glu~'OSC concenlration, arid i\ is hypothesil.ed Ihat these fluctuations eventually cause the seri ous complications of diabetes (e.g .. kidney damage. retina l degenerntion, premature atherosclcrosis. cataraclS. neurological dysfunction. and a predisposi tion to gangrene),
Insulin Prepararions, The various commercially avail_ able insulin preparations are listed in nhle 25-7, Amorphous insulin w...~ lhoe fi~t fonn made available forciinical U.' C, Further purification afforded crystalline insulin, which is now commonly called' 'I't'gular insulin." htsulin injection. Usp, is made from line insulin crystllis. For some time:, regular insulin so lutions have been prepared al II pH of 2.8 10 3.5; if the pll were increased above tile acidic rangc. panicles would be fomlcd, More highly purified insulin , bowc\'er. can be maintained in solution over a widc:r pH rnnge. even whcn unbuffered. Nelllral insu Ii n solutions have
Insulin Preparations "'rtide Sizc
~
(~m)
Action
....., ""'""
....,,1,. mJ'1 -36
Intenned, ...
Glooln' ' ZnCI, .. ,"""I'n
~4--).8
1~18
Loos,.,ung
1'\vWn,"'" + ....ulla + ZQ
1_1_7,4
Pror"",,""'7.nCt, in.",hn
1,1_7,4
''''
~fi"
'Oar .. oI_c ....
"
"'""'-
11,0-1--' ".t100 USf' ...... ofiooutin, _ .. ' , " (O.l-O.6 ..,.100 USP ..... , of,_I .. ~ . , .
I'
' "
.
+ LnCI,
Imermeti,"e
'OIobIo (.\1>-',0 ".tlOO USP ""'" 01 i........ oJ ",,,.«1 fn>m
S-,
1..... lin
""",,"IX and m t elucil.lmcd by Celtner,! 19 The structure consists of IWO sugol" and a 14ring designated an nle(lllflofidc . Orte of tnc 1'K'.'iCm In erythTOlll)'cin: the other sugan; arc IHlked gl)'cosidil-.. lly to lhe POSItionS. respectively . of oleanoolide ,
...•,DI,
""
H.c-......., /
01,
0-.,
lINCOMYClNS lllC l incom} cm~ art' sulfur-comainlng antIbIOtics isolau:d from Sfrt'IIWIIJ'CI'S lincQ/I1(,"l;$. Lincolnycin i~ tile must ac live ~nd medically useful of tile compotJnl.l' nblaitlCd frum fenncnlalion, Extemi\c cffons to nM.k lify the lincom)'dn SIJ'UI.'urt' to 11lI['II'O,e its antIbacterial an(] pharmacological propeni~ f1!,ultcd m the prcparutioo of the 7-cbI0f1l-7deeny derivuli\c elin(]atn)'cin Of lhe two ani ibiOlin, clinda· mycin appear.; 10 have tile gn:;:Ilcr antibaclerial f/Olcrw:y aoo beth:r ph;trln:K:o~ i ne:tic provcrties. L",coll1ycin~ re;;cmblc macrolidc~ In antiba for scven: outside !he central system. not be used to treat rutor)' 1l'lII:t i caused by bacteria sensllne 10 !NIfcr antibiotics or in prophylaxis. i I Clindamycin is absorbed rapidly from uact. e\'en in the pre,sence of food. It IS avai lable IS crystalline. watcr-soluble hydrochloride h)'dr.t1C: und the 2-palmittue ester hydrochloride salts in
.,,.,
forms and as the 2-phosph.ate e.-,ter in Details of the binding ..'en: eluci dated by the elegant NMR Sludics of Willillltl!lOll ct al.m TIle action of ~ancomycin leads to lysis of the bacte rial cell. The antibiotic docs not uhibit cross·resistance to .B-Ioctilms. bacitraein. or cycloserine. rrom whIch il differs in medunism. Resistance to Vancotn)'C1O among Grum·posilil·e cocci is rare. Hi gh-le~eI resistance in clinical isolates of enterococci has been reponed. however. This resistance is in resJIOO!ie to the inducible production of a pmtein. encoded by vatlCOm)'cin A. that IS an altered hgase enlymc thai cauS" the iocOlpOlation of a t>-alllnlne·o--loclll1e dePSIPCptide in · stead of the usuaI1l-3Ianine-D-alanlllC dipeptide in the peptidoglycan terminu s.UII The resu lt ing peptidoglycan can seUI undergo cross-li nking but no longer binds vancomycin.
"'0 ""·
0 0
MO,,,
I
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Vancomycin hydrochloride h alwny~ adm inblercd inll'll\en()\l~iy (ne"er imlllnluscuiarly), either by ~Iow inj«tiOfl or by l'()nllnuOilS infu510n. for the lre.llme m of syslemic infcctiom. In V,OfHerm therapy. the to~ic ~Ide reactions an: uwally ~ht:ht. but cOfltinued U.'ie may lead to Imp:ufl'd :mdi· tory acuity. renal d:unage. phleblus. and roshcs, Because il is not absort>t:d or signlfi('lllllly degl'3dcd In !he gaslrointestinal truel. \aOCOlTl)CIn may N administered orally for the In:alment of 5taphylococcal enterocolitIS alld for pseudomcmbraIlOOS colitis llW)Cialcd IHlh C\indam)cl1\ therapy. Soo-.e.COflversiOfltO aglucovancomycin likely {)Ccu"" III the low pH of lhe MOl1lao:h. The 13uer retain~ about thl'l.'C-foun hs of the octil'lly of l'ullCOl11ydn. Te/Cop/im/n. Teicoplanin (Telcholn)'cin A J • Targocid) is a mlllUre of five closely related glycopcp4ide antibiotics pruduted by the actmomycete ACfill()P/IU1~S f~icllO"IW:t'li· cus.1-., 1.011 The leicoplan in factors differ only In the acyl group m the IIOI'1hcmmost of 1\100 glOCOf,llnuJIeS glycmidically hnlcd to lhe cyclIC pcpIidc aglycone. AlIO(hcr sugar. Il-manrtOllC is common to all of the: tClcopi3nlns. The Slructu ~ of the: telooplanm factors ",ere determined independently by a combination of chcmkal dcgradationl-O I and Sp«tI'O'oCOPIC.u· l .tl methods In three differem groups in t~.
The: tcicorl 3nin complex IS ~i milllr 10 v311comycin stmc· lurolly 3n.d microbiologically bUI has umque physical propcrtie..~ lhal conlri bute some potentially usefu l D(h am:lgcs.J.U While retaining excclk:nt watl!r solubllily. tcicoplanin hru; Significantly greater li pid solubili ty thall vancQmyci li . Thus. teiwplan m is di'itribulcd rnpldly Into IlSSUl!S and pc:nctnuCIi ph.allocytc.~ ""ell. 11Ic. CQfI1plcx has D long elimination halflife. nnglng from 40 10 70 hou~ rt'SUltlng from a combin:lnoo of $low USliUC release: lind a high fmellOn of proIein binding in lhe plasma (approxmkltely tJ(')%). Unhlc vancom)·cln . tClCOplanln i~ not imlallng 10 tissue" and may be adnnmsterro by mtDmuscul1lf Of m,rn,'eoou~ inJCC, ion. Be· caust' of ils IoIlg half-life. Idcoplamn may be ad nll nistered
on a once·a-da), dos.ing t.ehc:dulc. Orally adnllnl",em! IncopJani n is not abwrbcd ~ignincanll y alld is n:t:Ol'Cred4(l" unchanged in lhe (-leu- l-Trp- o-Leu. c- Trp-
CO< I
",,_ 0
I l-Val-Gly-
0-""'" I..Trp-NHI
......... o-Leu- l -A!a·
I)-Val·l·V.~
'''\'* o-va/- l-Trp- C)-Leu- .-Phe- D-L..... . ·Trp· c-leu- l-T.p-NH
Vah -1I'1mk:idin
e
?"
(CH,),
I ........ !;>-l""- l -A/a· D-Vlll-l-VaJ- D-V8I- L·Trp- o-l _ .-Phe- p. ....... L-Trp- o-Lau- .-Trp-NH
II mixture of lyrocid1l-.es A. 8 , C. and D. ,,~ struclu~ hau: been dclcnnirtCd by Craig and l'O",ori;ns.:·~ m n.e 5), nlhe,;J of tyrocidme A WIIS reported by OIino el :II. lI'IO Tyrocidiroc:
L-Val
j.
-
L'Om -
I-
,.".
lIfiUiJdi ..... ,.. l\ioodllio'lfl B
_0
T)'I'OCIIine C;
.-Leu _
,-
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...,
Z
NO. 30. Douaf>cny. ., al. A...... ocM> A"",U Cheon. l.. J B:ocomollj'!Il.
s.""-.,,.
I....
"
,,..
Fosfomycin is a Drood-'IJCCtrum. bactericidal antibactcrial tIw InhIbits tbe growth of £.. co/i. S. nun-lIS. and Mrmllu. Klt'bm-liit. CitmOoclu. Entu/ICOCCUY, and l:."fllrro/xJc'tr spp. at a COllCClltr.lIion k:~~ th:!n 64 mgIL. Currenlly f(».fum)'!.'in is n:commcodcd tIS ~ tnilit-dol.c ther~py for ulK:Qmpli · catcd unnary tnct mfcctions. It possesses in \ itro efficacy stnuJar 10 thai of nori1o~lICm and trimcthopnm.sulramc!hcn . 31.01c. "oo;fomycin covale ntly inOClivatcs Ihe ti~1 ClIl.)rnc in the bacteriall'e11 ""all b.os)nthesis pathway. UDP-N-acctylgluco..:unme enolpyrul'}l Ir~nsfcra.~ (MurAl by ull}I:111on of the cysleine -! Ij re~;due. The inactivation ll'3Cuon ac ... u.... through llueloophillC opening of Inc !.'po~idc ring . Rc~islallcc 10 fO!'fomycin can occur IhfOllgh ... hrumo~omal mutations thaI ll'~u1t in rcdllC\"d u))tale or reduced MurA affinll y for tnc inhibitor. Plasnlid·rnediatcd resistance nlCChamsms in"olve conjugative bioinoctil'alion of tnc antibiotic ",ith ghnm hi01"1('. 1be freqlJ('OCY of rcsi~tant nllJlDntS in in vilro Sludie' hal; been low, and there arP'"ao; to be linle CrosS-I"CSlstance bet\\"('('n r~fomydn and other IlJUlh"lCtcriaJ~.
c~
n,
H. Du .... IC. JIbt.1 Al"nl> """ a..mothmop)'. ChioI. Rov 1993. aI.: BioI:hcm""}' 1J,,98. 1974.
n,ns.
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~
1976, 1981. 14 ], 1974
• P. G. (rtl.).
H_
Antimoorob. A...... Cherno CheMllllbor. I~ :~ 14. 1918, We,""ojll, hi J.. 01 01.' J. M.... Chen •. 6:463. 1%J. Cooper. D. J.• .. oJ.: J I.fed. Oi • . 119,)42. 1\16'). Cooper. D. i .....1" J. C1>em. Soc. C 1126,1971. Machi. II.. l1l-! 231 SkOm. D II .II.....,.~ ... I, K. S~ and S ..... n... "'. P Ii, An"u, lie" Ilia-
...,......Oonnoolber
""' m 01(0:723. 1m !.l2. McC.noucl. M
aI AnI:i~ An","", I'1SS_IIlSto. New yurt... M.... Ea:y1)011. I'l'IJ 2J9 Pomon. F .. ., 01 .' 1 A ... boot:. (foLyol 3 1.27/i. 1978. II .~
240. 1I.voI....., M II .. I'II~. M .. and C _ l1i. C .; I, Anflbiul. (I'''k)'\l) JU71l. 1918. l~ I Co.unclli. C .. ., II .. J An~bklI. (Tot~,,) 3762 I. In-t
2-12 IIun!. A II.. ~ 01. I Am. Chem s.oe 106.4891. 19lIooI, 2-13 8a/ll&. I C I .. .. al ,I Am. Chem. Sue. 106.• 891, 1\1801 W 8 .......... R. N~ andl'l:lm.. 0 H. ON, • • un. 1'l'U 2.3 1010-. 8 A~" aI. Sc •• u I02.J76, 19-1' N6. SIoIfel. W ~ ond C.... L C' I Am Cheal, Sue, 1],145. l\IIb) 247 R....... C.,owIKa>lclibr.O.V, I Am.Cbeoro,So. 101 ....... SIOU. Soc, Chem. Jpu. 19 17.\8. 19M 261.
262, M} ~
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266. 267 2b1!
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no.
211
271. 213 27. 275. 276
m.
278 IN
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A ...... AIMlmoft. 0 S I Meml>r 11001 $\lU1, 1"1 8o,hch. I .... al' Scio;ncc 106:417. 1'141. CootroUli .. I.• ot aI, : I, Am. Clc .... So.;, 7 1:2J6.3. 1114I. p. 119 SbaI, •• L and Marl .. 'I. I. 211;111. 19$4 KauIT...... R. E. • ., aI. I. ~_ 99%3. 1981 K•• W 0 ... aI. J, CWo, PbaomIocoJI. 24 .1 81. 1\1801 Shoml. C, 11. • ., aI. J Am. Ckm. So.: 78: 1170. 111:16 Ikcbrlna. 11.. .,.1, J Am. Chern. Sox, 782019. 19.1oto S,.,,,,e •. C II .... al • I Am . Chom Suc. 78265'. 19$6.. $p:..:n. C .. .. 01. I Am. Soc, 8&. 140. IIISS. Gellon.. 104 .... al ",""", Naol Sci II. S. A. 13 4·41•. I"" SU,I ..... A~ .. 01 .. I'rt>.. Nail ,,&ln. E. B.• and Md"-. O~ J Cbem. Soc'. Pnl •• T..... , I ~
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Antiviral Agents KltIN M BEAlE, JR. \1!U1It!i
,• ,
"
an: unique
organi~ms.
ThUnuunded by an uncompli proIem COOl. Some of the mooR: complu viruses hu,-c : IIIpd blllycr mcmbr.me sUll'OUooing the nucleic acid. 1 Vi· mu>1 replicate In Ii, Ing cells. whICh has Led many to II\.lI \ iru'iCS an:' IlOI c,'cn th'ing organisms but thai , MJIllL'how ui" III tht interface of Lhc IiYlng and the Hng.' n.e rfIO!,[ !»sic requirement is for the virus 10 clll\tr prufoolld or subtle changes In the host cell 50 liral geJ1('~ are replicated and viral proicins ure ex· ...~ _Thi, will rt'_~ull in the formation of new yiru.'ieS. Iy mall)' more than the number Ihu\ Infected tile cdl Ily_ Viru"-!" cond uct no metabolic Pfocc~scs on their : me)' depend mIldly on a host cell, which they invudc • piI"lSlllI.e to subvcn subcell ular machinery. They use l1li of the cdl'J cqulpmcm for . i of viral nuc leic IIId (',pression of , irul cel l' s protcin all cell's eneraY Store! that . llle VIruS tums I cell 10 ilJi Oll!noq ,,""
"~ N_
N_
N_
N_
An. "IN virus (d(""" ••""",
RI"',ir'in
a.. .w. hal''''''''''' hnat/hItn,. • 'N>
"",,">My. )'!lCJ1ioI .-iN!
lIo.piritory Ipf. HurLn ·. lymplofwna
0-.:"'........ (_101
,,-
1'Ip>oo.. , ,n!.<
"opo II"",~' """ 1'uI~"m."'"",
l'tdJ!IbyU..
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II_pod .., or,!>
t_",lIO(d ",bum, htty
11qIMi",B',n..
cll'«u,t)
v..,..,..... ("",po. lt"orr ...."',;,t)
"tn,,, """ II~ ...."'''''' HI9
Et)lhenoa. ""'->1)1'"
,.
induce an effeah'e amibody re.~poo>e. elen in very yoong pa. tic-nb: the nlCcill(" must 1101 cause the dl5Cae acUle' infections. 1be chronic casc~ are mtlCh more compllCmcd. It i~ difficult 10 ol·e!'l.'Of11C Ihe lendency of 'OIlIC viru are ,cry reliablc& and are in w,d\:."pread u-.c for the propagation of virus panicle,. bU I they an: ilion: dlf1iCUIt 10 pcrform than lheir bacterial counlcrparts. HeIICC. drug-..c!'Cening tcehniqllC§ ""nh VIfUSC'\ ha"e Inen longer to ~.:uch up with t~ In
b;loCteria. Another po~sib1e reason for the Jag in ami l i,w de, elopnlC"l1t lie' in lhe comp3rutive "'ochemlCal ~.1llJlh;:t of \ mIstS I';s-!.-I' is bacteria and their U.)C of the biodltw processe~ of a 00eases may ha'e contnbWd. a relali,e lock ufint..:"rest in ant!I irul chenlOtherapy. A'* feRlllre of mild I' irul inFl'Cllons. such a~ is thai clinical syrnpiulitS do 001 appear n ,\ .. ell eslabh,hcd and the immune processes of the ha' c begun !o moum a succes,ful challenge:_ Thu.\. fOf common I'irdl infections. dlCIIIOtherul'Y is Simply Il0l • • proprla!c choi~'t of trcatnICI1I. Chcmotherupcuti~ 3gt'nlS" nc:edcd. ho" e,er. 10 comlmt I'irosc.' Iha! cau!iC ~I~" chronIC infecllons. stICh a .. cncephaliti ~II p scnI r-uo:.n. ,n,'oh'cd ,n the n:phcailOn IM ..... esa. Tbe "raJ pro!nil\. modify the: hoM l-cll ,uxhUow the \1m gn>ome 10 rq.liclOl,
"" "",n~ bo),t and \lral C"qllJel;, l1Ic mcch,m "-!tadine and riinantadillt.' are appru"ed In ,he UlIlted forpre"elllion and treatmenl of innuenl~ltype A \ IruS ,Senonal prophyluis .... Itlt ellher dmg i~ about
70 to 'iCSSc:S a trinuommc:lh) I group in5lead of 3n lodillC alom al lhe 5 po!>itioo of the pyrimidine ring. The von uer Waals r.tdiu~ of the trinuofQmcthyl group is 2.44,.\. somewhal larger Ihan thlll of Ille iodine 1110m. Like idoxllndine. the antiviral mechanism or lrinuridinc innllvc:s inhibition of ~,raI DNA synthesis. Trinutidinc 1II0llOplw:lSphate is an imwcTlIible Inhibilor of thymidylalc synthetasc.llnd the biologically gcncflltcd triphosphate COlli· petitively inhibits Ihymidine: tri~phate incorpornlioo illlo DNA by DNA polpncra'ie. [n addition. trifluridinc in its triphosphale fonn is incorporuted inlO viral alld ~lJ ular DNA. creating f!"llgile. poorly fuoeMn;ng DNA.
o
",C>. I
1be antivirul
~ction
of vid arabinc i, complctcly 10 DNA ,·iruscs. Vidarobine inhibits vir-oil DNA )yntltell! En7ylllC!i wilhin the cd l phospho!') laiC vidaDbine: 10 tbt IIphosphale. ""hlch competes willi dc:o~}'adc:OOSIlle: IrlJiDpilate for virul DNA polymerase. Vkl~ntbine In~ also i/lCorporutCd into ce llu lar and ~ir-JI DNA. where ild as a chain tl'mlinator. The triphosphate form of ~id:lnltit! also inllibits II 'iel of en7ymc:s lhat aTe: inH)h ed 11\ mt:tItj.a. lion of undine 10 IlIym.dine: ribonl.lCko'"de redl.lCt~se. R.'i.~ polyadcnyl asc. and S-lII.lelKlSylhornocySI~ine hydrolase. Alone: tinIC in the United Statcs. introvellOUli \'id:ora/iI! .... as appnwed for usc: against HSV c:ncc:phall\l i. ~:: herpes. and herpes or varicella ~o:ste:r in immUlWX\lihj'" mised patienlS. Acyclovir has supplanled \'idarublnc dl1Jg of choi ce: in lhese ca>cs. In the Ircmment of \'Iral enI h) drol»' cellu: acts u., ITP). O-
of ,-,ra1 ,ro..... ing
fo$Qmet Sodium.
Trisoti1um pho\phoooformmc I' an Jlyrophosphate analot;.uc llul inlllblt' ",p1i~at iOIl .bld liCSliruse.~ (C M Y. HSY. and YSY)allll rctroviruses I ~IV),"" FOloCamet ( FOSC!lvir) is talen lip slowly by thc ~cl" aldoes IlOl. undcrgo 'ignifi~lIni lIunlCcllular rnct3boli'm. :lI'TIe1 i~ Q l'C'\cl"ibJc. OO!lCI1IJ"IClllilc i nhibit(lr al Ihc P)~te·bindlng .itc of 11M: I'iml DNA pol >l1lCra~ and "lfI"oC' lranscri(llll.~. "The ulll m.1te cll"i:~t I' inhibllion of t~ 'lit or pyrophosphate from deoll}I1OClcotide 101'110'>IIId a cessation of the IIICOI'1'O"IIIOIi of lIueleo,;i(\e ... f'I\.o.le., and piln. the hands and fed) and paocreatins (nausea. abdonu nal pllil. clcvated amylase ) are the major ~li lTli ting 10lCici\1('S of didanosine. Did:mosine is ghen or~JI} in the fann 0( buff· ered chew~ble tablel.'l or as II solution prepared from tht powder. 80th oral do>.age form_ are buffered to prelell acKl icdccom~uion of dd l to h)'poltanthinc: in tlv:: stl.WlUdt. Despite the buffering of tlv:: dosotge fom' ~. oral bio(l\':lIbb!~ ity is quile low and highly I'llliable. Le~s than 20% ofa ~ is excreted in the urine:. which suggc.sts elC tensl\'c mrtD lis m..56 Food interferes with ab.o;orption. so the oral drug mw be given at least I hour before or 2 hours after meals. II.p. dose therapy can cause hypcruncemia In some plltimtli brcause of the iocn::ascd pu rine Io.m.
o
o DidaI1JJI 'Ie
Zakitabine. USP. ZalCltabll1t". 2'.3'-dKko~ycytidtDt. ddCyd. is an anal0l:uc of cytosine thai demonStruu:s :leU'" against HI V- I and H IV ·2. inc ludmg stnlins resistant to AIr Tbe potency (in JlC'ri ~ral blood monon\lClcilfcclls)is ~ lar to that of AZf, bUI the drug is mo re aell vc in populD!I* of monocy tC!l and macrophagcs as .....ell liS in m./;ng (dh. Zak itabi ne cntcrs human cells by eatrier· facl htW:d di sion and undergoes initial phosphory lalioo by doo~yC)tidllc kinase. Tbe monophosphor)' lated compound IS funhcr tabolizal 10 the activc ntclaboille. dideOlt)'C)1idlll('S'* phosphate (ddCTP). by cellular kinases.11 ddCTP itlbiilo reverse tnlnseri plase by oompetilll e inhibition "Ith den' Mosl likel y. ddCTP causes termi nation of the vintl DNA chain. Zalcitabine inhibi ts ~t ~i ~~."'~~~.~~'N~~ "~~~~1 low concentrations. Th is cffect mal contnbu le 10 it tOlt ici ty.5t The 01"111 bioouil ability ZlIldlablnc: adul l5 and I e.rrco:t is thesias. Iowa do
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entl months o f therapy ., . A potcntlally pancreatit is is an{)l hcr tOXic effect of treatment .... ilb tU:. Tbe drug has betn approved for the treatment of III V·
lIdu lLS wIth IIdvanccd disease \O.ho an: irnokrnnt to AIr or ",110 have dlst'alIe progression .... hilt' rea-ivin8 AZT. d.iC is combulCd .... uh AZT for the tre:llment of advan,,_ed lilV infeclion. tioQ
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5gvudiM, SlanM/irIC, 2'3'-diJT. Zeri l). is an unsaluraled pyrimidillC nucleoside \hit h rdaled to thymidine. 1lw drug inhibits thoe replication of HIV by • nl«nanism similar to that of ilS close ~"OI1ger1('r. W '" SLavudillC is bi03C1iv:tte:d by c-c:lIular c:nzylIlCS 10 a ~.
The triphosphate oompcmh'dy inhibits the in · wj.b'atlOll of thymidine triphosphate (lTP) into retml'iral !)SA by reve:rse Irunscriptllst'.61 SlIIvudine al.'lO causes lermi· "M of viral DNA elongation through ils illOOipoialion
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II is interesting thai the untlalurnl stereoisomer (- }-{.\j. ddC exhibi lS grealer !lIl1i"lrW 3C1i\lly against IlIV than the natural enantiOl"ller( + KS}-ddC.~ Both tnanllOlI~ are bi· oactivoted by cell ul!lf kinascs 10 the c('lfTc:spolld ntg lriphu!.· ph3tcs.'" II00h SddCTf' 'sonler.. inhibit HIV n:verse tnrn· ~pca.se and are incurportUoo into vlrW DNA to caU$e cham te""ination. (+ ).S-ddCTP inhibIts cellular DNA polylfl('r· ases mIlCh nMlre strongly than (- }-SddCTP, upl:lIning lhoe greater lox icity aSSOCioted with (+ )·(S)·ddC. Initial meta· bolic comparison of SddCTP isomers has failed 10 explain the ~Ier poIency of the (-).bomer against HIV. There· fore, although the ;ntracellullll' >iCX\llllulatiQll o r (- )-S-d .... as twice that of (+ )-S-ddCTl'. the lauer .... as I ~ time~ more potem as an inhibitor of H1V reverse tl'lln scri ptasc. and the t .... o isomers were incorporated into vil'lll DNA !II ooll1parnble rotes. 1lle puUIc: .... lIS soh'cd wilh the disro,'c:ry of a celluhlt 3'S-eXQIloclc:ase. ""hlch was found to deave lenninal (+ )·S-ddCMP incorporated into virJI DNA 6timcs faster than (- )·S-dllCMP fll)ll1lhe viral DNA terminus. ResislllllCe to lami\'tldme de,'clops ropldly as a result of a mutation in oodon 184 of the gene thai encodes HIV· RT ",'hen the drug is used as monothcrap), for HIV infection ,'" When combined with AZT. hu.... e"er, lan\ivudine cau'\ed s.ubstanliaJ increases in C()4 ' cOlints, elevated COlintS 7 wet"c: sustained over the course of thenpy.1> 1lle codon mutation Ihat causes I"C$lstlllK'C 10 lannnldine suppresses AZT resislIllICe.&7 thus increasing the suscepcibility of the virus to the drug combination ,
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"" Suvudtne is available 11$ capsulCf for ocaI adminislIlUion. acid stable and .... ell absorbed (aboot 90%) fol· has a short hlllf·life e~cn:ted largely ulIChanged As .... ith ddC. the primary dosepc:npheral neuropathy. At the reoom· ":;:;~~~II; 151020% orpatie:nls ape)C I neuropathy. St3vudinc is m::)I' treaunent of adults with advlllICed HIV
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IIkKIeosId. Anti.".'eboltt.. Ri bavi rin, USP. Ribavirin is 1. ,8-t>-ribofurlU"lOSyl.l.2.4MIK.I~n •• II.
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side arutlOlue ",llh I moiety. The struclure of ribavirin
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activltv again.~1 ~tudied,t>J· 601 Pn:limi. siudies indicated Ihnt il exhibited good - - 80';1:) and a plasma half·life: of
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r Ribavinn mhibits the replicaTion of I very wKie Varlety of RNA and DNA viruses." includmg orth(lmYllO\';ruSCS. paramyxuviruses. arenaviNSC:S, bunyaviru~s.. herpes... ifUSCS. adc:novlruscs, po~virus. vaccinia. innuenza \';NS, parainnucfl7J1 vil\ls. and rtlinovirus. In spi lt of the brood sptCtrum of IICIIY;ly o(riblwirin. 11M: drug has been appro\'ed for only one lhenlptutic indiclllOll-lhc In:atment of seven: lower ~plrnlory mfeclions caused by RSV in carefully selected ho~pilaJi~ed infnnllo lind young chi ltlren. The mechanism of acllon of ribavirin i~ 001 known. The broad anTiviral spectrum of ribavirin. however, suggests multiple modes of ac1Wn."" The nuclco!litle is bioanh'ated by viral and hoIil cellular ~ina.'ieS 10 give the monophosphalC: (RMP) and Ihe triphosphaTe (RTI'). RMI' inhibiTS inosi ne rnonopho.\phatc (IMP) dehydrogenase. Thereby pre\'cnting the OOIWen:iOll of IMP 10 xanthine mooophosph:ue (XMP). XMP is required for llullllOSine lriphosphale (GTP) syntllesis. RTP inhibi TS viral RNA polymerase•. It nlso pn:: ~ents the end capping of ~iral mRNA by inhibi ti ng guanyl-N'methyltransfenlSC. Emergence of~iraJ resiStance to riba~irin has not been documented. Riba~irin IX!CUIl:l$I. white. crystallillC. polymorphic solid that is soluble in wmer and che mi cally stublc. 11 i~ supplied as Y powder to be recoostltutec.l in an IIqIlCOOS a/:":rosol CO[\taining 20 mglmL of stenle water. The lI(' osoj is administered with I. smull-panicle aerosol generator(SPAG). Dct.eriOf""Jtion in respirJtOf)' function. bacterial pneumonia. pncumotho"'J~, and apnCH hu~e been reponed in severe ly ill infnms and children with RSV in fection. 1"1le rule of rilxtvirin in these e,ems has not ~n determined. Anemia. headache. abdominal pain. and lethllf1!Y ha,'e been i\'ported in patients ~eivin g or,L1 rilxlvirin. Un labeled uses of ribavirin inelude 3c:rosol treatment of innucnu typeJ A and B lnd 0flI1 treatmetlt ofhcpatitis. genita! be'jKs-' and I asS/! fe'·er. Ribaviri n docs not proteCt cells ngnlnst tIM- cytoto~ ic effeas of the AIDS virus.
NEWER AGENTS FOR THE TREATMENT OF HIV INFECTION When HIV-I was chamctctilCd and Identified as the cnuSlltive agent of A [DS in 1983.1'CI. 11 scicnti~u from all ower the world joined in the search for a prevention or cure for the disease. Mapping tnc HIV- I genome and eluci dating the replication cycle of tnc virus hll\'e supplied key informauon,n Biocncnllcal targets. many o f ... hich arc protelllS invol,'cd in the replication cycle of the ~ il\ls. ha"e been clooed and sequenced. These have been used to devclop mpid. nlCChanism-bWiCd a.o;says for the virus to complement tissue cu Iture 5Cn"CnS for whole ~irus. St"eral of tnc biocncmic.al sleps thaI ha~'e been chnmctcrized have served 11$ targets for clinical candidates as well as for succcMfu lly hcensed drugs.7J. l' Despite the many ad~ances in tnc lutdc:rstanding of Inc HIV ~irus and ils tf"C8tmetlt. IhcTc is rKlI yet a cure for the Infection. Emergent resislIlnce1' 10 clinically pro,'c n drugs such a.~ tnc rc~crsc t.-.mscriptase inhibitors and the protease inhibitors hu complicated the picture of good thcmpcutic targets. Thot idea of us.ing I vattine as a tncrapeutlc tool has
been complicated by tnc fact trun the vattine apparently ClII modu late its antigenic structures In lIS chronic inf«1iOltl $Iate.7tI
V.cdnes.
Thot chronology of \'lICcine de\"dopment mj uo;e in the 20th century is nothing shon of. medial mli"ll(it. DIseases 5IJCh 11$ smal lpox and polio . ... hlCh once: tIIVlIgaI large populations. hal'c become distant memories. 1bc ted!niq ue of sensiti]ing a human immullC \ystem by e~posurt to an antigen so that an anaml1($tic response is gei"oClM on subsequent Clpoliurt seems quite sinlple on the surfatt Hence. it is natural that a ~~"Cinc approach to prnrotul! AIDS be tried. The SUCl-C:SSC~ IIChic~ed so far have invohtd liveJl1l1cnUlllcd or killed .. hole-l-c:1I vlICClncs and. in _ recenttimcs. lUombinant coat protems. Succes.~ with vaccines of the li,c/allcnualCd (10 ... ·1,.. lenee). killed ",hole I'irus or the recombmant coat prI)\nIl types havc primarily involved acute vlml disea. typic ~aria",s ortk IU V en~cJopc glycopmu:in @pl20~ tained by recombinant DNA tcchniqUt.'i . This t:ugct ...1Ilo~ n because of coocems .bout the ~fet)' of li'c/lltmuan ~acci l1($. The gpl20 glycoprotein i~ • coat protein. -'" grem ~are is take n. a ~irus· free vaccine is obminablc..\Imover. glycoprotein gp 120 i~ tilt primary target for III"\ItraIii. ing antibodies associated with tnc liN (anachmel'll)SlqI. HIV infeaion.n Early \"acciilC!l were SO incff«1i~·e!hl!. NaTional InSli lutc§ of Health §USjKnded plans for masw , cl inicaltrilll~ in high-ri~k individuals.?· Thcre are I numht of fCUOOS why the vaccine failcd.'19 There arc multiplf" types of the \liru~ throughout tIM- ...·orld; the virus can by means of both cell- free and cell-associated ft:lflm; • virus has demonstrated it~ own immunosupprt5SIIC. , _ nopathological. and infcction-enhancing pmjKnics of ~ of the envelope gl)'copt'Qle;n; and vacciocs rn.~·c IIOIIICaI able to stimulate and maintam high enough !e'"els of Unity to be cffectlve. T he failure of the first generation of AIDS vxcinn III to I rce~amin~tion of the .. hole A IDS \·accinecfTort." As guide for resc~h efforts. I. number of cntem for IlII . . . A IDS vaccine ha'"e been de,·clopcd. 1"1le "idcaJ" AIDS III: ci!1C shou ld (II) be safe. (b} dicit a protective imm"'lfsponse in a hi gh ph.It)()j'\ion of vaccimucd indiwidulh, stimulale both cellular and humoral branches of the ",.;.
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.-optiate $pon«e:. 1I to (l those: ofscrum. The drug is e~tel1sivcly tnltlsformcd by cytOchrome 1'-450 to inllCti\"e h)'dro~y latal metaOOlltc:.~: il mny undcrgo clllcrohcp;,tic recycling. The half-life dccll':ase~ fll)rn 45 to 23 hoon; o,·er a 2- to 4-",·eek period bctause of autoillduc.ion. Elimination occurs through the tldney . w,th less than 3% ofthc parentl"Ompound CJlcreu.'d in the urine .r.l [}osage forms arc supplied as a 50 mg/5 mL oral suspension anti II. 200-mg tabiet.
n.d HIV- I re~erse trullscrip use fltCilit3lC5 the ",tidy of • dTec1s of a 1lO\·cl compourKi on the '.anctics of the ~n ~ ftaodom screening of ehemical In'emories by the ~ullcal
irKiusU)' !las led to the di.scovC'ry of !>evcnl '"\Rlls of the enzymc. These Inhibitors represcnt seve:ral ftllnUy distinct clusscs. The NN RTh ~hnre 0 Ilumber of ~biochcmica.1 and phannOCtllogk:nl prope:nie~. u . ".11 tlllkc the nuc:Jcoside antimcmOOIiI~s. the NN RTls do nOl ~.rt blOOClivation by ~inusc, to yield ph&.;phMe estcrs. "!'ley I\"e 1101 Incorporated into thc gro .... ing DNA cha in. In~y bind to an allosleric site lhat i~ distinct from the (nuclOOloide triphosphate}- bindlllg site of reverse pease. The inhibitor ean oombillt with eitho!r free: • MhIu1IC·boulld enzyme. int~rfenng With the ac1ion of Suell blndlllg diSlom the enl.)" nlC .Ml Ihal II cannul die c:nzyme - Illbstr-'le eomplell yt liS normal ralc. ... o.ct formed • •he complo doI':s nul decompose a. the !lie 10 )·ie:kI products. Increasing the substrate .:mtM.J0II does not re'·crse these effects. Hence. \'iRTI~ nh.bit 1\ c lassical \1IJrl(."Qmpcti'i ..e ;nhibilfon pat_Ill! the cn·'yn\C. Ibt NNRTls arc c)ltrenlCly poIcnt in in vitro lOCI! cu lture Mi)' and Inhibit HrV~ , at nanornolur l"lll'CCl1lrutions. ..... RTlt mhibit re,'crse Irolnkripta~ ~Iec:ti Ycly: lhey do not ... tbt transcriptases of other re,ro\·lruSC$. inHIV ·2 and simian immunodefieiency virus (S IV). 1'."XRTIs hI,e high therapeUIIC indiccs (In COIlumt to III-.D:oodc:s) and do not inhibIt mammali:m DNA poly. The NRTI s aOO NNRTIs are e~pccted to e)lhlbil a effect on Ht V. SInce they inlCTaCt with diff~ll':n' on the eru:ynlC. The chief problem wnh the iI. the rapid emergence of resIStance amoog HI V ....: ... Resislance is due to poinl mutations in the gene
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OeliJlfiniine. Dclavl rdlllt (RcIICrip!or)ll must be used with :II least t .... o IIddmonal antill'tro,·iral ag~nUi to tl1':31 IIIV I infectioos. The oral absQrption of tk:la~irdillt is rapid, and pea~ plasma conantrouons develop ID I hour. Elltensi\e metabolism OCCutt III lhe li\"~r by eytochrome P-450 (CYP) isozynlC 3A (CYP JA)orpossiblyCYP 21>6. Blo&vailabl iny is 85"'-. Unlile nevirolpme... hich is 48% protem bOtllld, delavirdinc is more than 98'}, protein bourld. The half-life is 2111 II hours. alld elimination is 44 M.. ...:I I..,.. loy. P M. (Mol F_h ICI .1 V,"*">"...... 0... _ . R. S C.1191 721. 1997, 11 Don'...·.lI. K S .• [I ...",,,,,,. C. 11. .. Ikll. I~
U. Sid ..·.(L 11.. W. eI aI. Se..""" 117:ro:l. 1'l71 iii 1I.otM.... R. ': a-.. EnI- ~ J.... 27'21. 19k> 70. Colk>, II. C.. 0, .1 Scilic druJl~ :Ire highl), lO~ic to the patien! and must be Iidnllni5lercd .... lth e~treltle caution. Some of them rcquill': a cl mical ~tung "here ~upponl1e care i~ a, ailable. The: tOlliCiI) usually uw ohes r.lpldl)' rroli(~r"JIll1g M~ue.~. ~uch as bonc m~rrow and lhi: 1l11e,lmal epithelium, Individual drogs produce distincth'e IO~ic effech on the hem. lungs.. kid,IC)'!i. and other OIlan~. ho",.ler, ChcmoItlCmpy is seldom the 1II111al treatment u'iCd a£aln ... cancer. Ir the. cancer i, well defi~d and aece~~lble, "Irlery i, prcfem:d. Skin cancer; und cenain localil.cd tuillon; are trealed by rlKIlothempy. GcrICr~l1y. chemotherupy i~ ImporInnl ... hen the tumor is 1I1OfX'r.lble Of" has mela.\l .. \lled. ChcnJothcr.lpy i~ findlllll ,ncreasing uSt" a, an "adJu'~Jm " after ~urgery to en~ure thut re" eel" n.-main 10 I"Cl:lencnlle lhe pan:m tumor. 1llC er'll of chemolhcr'llpy of mahgnant dlscase ,,~ born III 194 I , '" hen lIuggllls dcnlOOstnued Utatthe lldnumstnlllon orestrogen~ produced regreuioJls ofrnetastalic pnJ!ilateeaneer.' In the follOWing year, Gilman and Otl\l:fs began clnn eal studies on the nllrogen mustards:uid dlscovcred that mcchlort:thammc ""as effecul'e ag;lIIm HoogLm's dl-.t'a~ and Iymphosarrotrul..~ 'J'be$e same two disca.-.es werc ~atcd with cOr1isone acetate III 1949. and dr~malle,lll1hough temporary. remissions resulted.'o The IlelIt decade ",as marKed b) the desi£ll and dlscolery of anlnl'lClabohte.\; nlCtOOtreute III
au
!'N\). 6-nlCrtaptopunrIC III 1952. and s- nuorouracil in 1957, Additional aIL)I.ttmg agenb ~ueh as I1lClphalan .nd qdo· pho effon had c,·olveU into a mrgclcd thr delc-Iopll\ent program. A massl.e SoCTttnmg sy~tcm 111.11 t\' tabli!ihed to dlsco'·er new Itad comJlOllnd). and I~ ur ..:unple~ huve been 'UbnI1I1L-d to il. The: current hlgbly autQmaleU NCltumor ccll cullurt loCl"Celll ng s~slc'n oclllC''nl oper.ttlUnal qalus m 1990. It cmphasi/.c~ rigorousc-nd p!lID6 .. uch lIS roel cc-Il I.,illing and tumor rtll~sion. r.ttht'r \hII earher gm"th-inhIDl\ory end point>. alliin u>o a wide I1n· cty of ~pce t fic Iype~ of C,UlCer, Including many solid tunu model~. III the i nllial stage of ~n.-cnmg. Ne,,' drull Candldael ITe being screened al a rate of about 20.000 per )ear._lIIt input dividal aboul ct]u~lIy bet .. een pure compound!." c~mlC"" or frolCliOOS frurn Ilatuml products. The proent it ~I'm o;crccning panel contain, 60 human tumor cell lirlr\. arr~nged in 5t:len subparoeb that rerre .... nt dil'en.c hisloiorie\: leu~cmia. melanoma. lung. colon, I. Pigllll' 11, ) ~hov.~ thall'o!on cancer cell lines art: mon: senSItII'f" a't:rJ.gc to s-nuoroufllCll (S·FU). "hereM cent",1 fIt~. ~ystem (CNS) canctr ce lillne~ arc mort re~iqant than J\U' age to il. 12
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-
Fig ure 12-3 • NallOl"lalll"lSll tules of Health teslll"lg result profI le fOf 5· fluOfouraol
A seoondary ~tage of prel iminary scrun;ng on selected compoonds IS perfOlTl1C'd In \'i,'O in xeooa;l'llft models b), using a ~ulY;ct of ceJllines found co be active in the primary In vitro scrun. Two xenogr.lft models in CUrrent use arc the se"ere CQIllbllloo immuooder..:ieocy (SC ID) mouse and the alh)'mic node I1lO1.lSC. 8 0th of chese mouse uJOdeI~ have defi cient Immune responses tMt pemlit tr.&llSplalltacionofhuman cumor cells \\ ithouC rejection. Consequencly. po(ernial ant itunlOrdrugs rna)' be \I'sted againM hu man IUmors in un in vivo model. llIese models pudlCt human cli nical tumor responses bener than the older allograft modcl~ that \\ere based on trdnsplaming mouse cunlO/"i such :tS 1'388 leukemia imo che same strain of mouse (s)'ngenelC tumon). TIle importam anhlUmor drug pachtuel was discovered b)' using a ",enogrnft model. An in ~ill'O s),stem lhat is II good pudictor of human clinical octivicy i~ che hu man-lUmor-colony-forming assay ( HTCFA). Thi~ system uses fresh human tuulOr tissue: from individual pallents. n It is valuable In selecung chcmothcnpeut ie agel1\~ for individual tumor types and o,,:ca~iOllall y ~ific patients. but II~ USC' in large·scale primary sc-rc:ening has IKlI been feasible. Compoolids with ~ignificanl amilumor IICdvity urc sub· j«ted 10 preclinical pharrnacology :tnd tO~Jcology evaluation in mice and dogs. Clinlc~1 trill l~ ma), be underwrinen b), the NCI. They involve thrcc discn:te phasc:s. Phao;e I is the clinical pharmacology stage. 'f'be ~ge iiChedu le is developed, and lo\i cit), paramcters an: e~labh~hc:d in it. Phase II invoh'cs the tktemlination of activit), against a "signal" tumor panel, wltich include:!. both solid and hematological type •. A broad·based mu Iliccmer study IS usullll)' undCrlnken in pha...e III. It features fllnOOmil.:ltion schemes designed to S13uSlically ~Dhdatc: tnc cfficacy of the new drug in CQIllparison to ullcrna lh'c modal ities of themp),. As might be antici · pated, the design of chnical trials for antil\CQPlastic agents is very CQIllpllCatOO, especially in the mailer of controls. Ethical con~idc:rations do nOl pemliL patient~ to be left untreated if an)' ll'a5OII:I;ble thenpy is possible. A number ofpharmaceuticaJ industry laboratories and foreign IIls11tutions hal'e made significW1t contributions to the del'dopmt'nt of anticancer drugs. OrganizutiOflll 5UCh as the: Uniled Kingdom's Cancer Rc.warch Campaign. the Eu~ pc:an OrganilJ1tion for Research on lhe Trc:ahfICm ofCanne hytlrochlunde and 90 mg or MJdlum chlori givcn to control malignam effusions. The n iridiniullI ioo formctl from mechlorethamine UI body Iluids iJ; hIghly react,,·e. It act) on \!ed by liler microMlmcs 10 become aclilt. Amonllthe mct"bolite~. phos· phorumide mUSlam has antitumor actil il). and acrokm is tOXIC 10 lhe unnary bbddcf. Tbe ocroleill toxicity ClIn be decreased by intral enous or I)ml ad,nill1,tratlt»1 of the ~o dlUm :l3.lt of 2-mercaptocthane ~ulronlC acid (n.:sna) .... tto6 It is • lo ...·melting \Oo·hne powder that changes to an Oily hquKl at 2rc. This change is considered a sign of decomposition. and Mlo;:h !i.:lmples should be db· carded. Cannu5t ilIC is most stable in petroleum ethcrorwater at pH 4. It is tWminlsteR:d intra,·enou5Iy because nl(:tabohsm i,~ ,ery rapid. Sonle of the dcgmdation prodlK."ts. however. ha,·c prolonged half·li'·e.ph3I c,.9. 111c~ "PCCK':S inhibIt Ihc' same enzymes tllal un: mhibilcd by 6-nlCrcapto,. 'Iluoguaninc is abo incorponatcd illlo RNA. und Its «my mc:ubolite is incorporuted into I)NA. The sigmfi o(~ "frnudulenl-- nucleic acids in IClhaillY 10 nco-
:;;;01'
;;;~ is ulll"nain.~j
!r.l-I uamples of mllonal drug design_'OI Slarting with the obscr"allIIn ,hat III cenalrt tumors urolCll wa, used more ,hart orotic acid. lire maJor p~ursor for nllClelC acid pyrimidine bio-;ynIhcsi< in normal ris.,uc. he c:helne 12-7). Ihu ~ diminishmg DNA biOS) mhoe~is. Fluorine ehostn ~ lhe substltuenl hccau-.e the increased octdny caused by ,''' IndUC' li,c cffect ... a~ e~pcclcd to eau-.e 11M: rnolc1:ulc 10 bInd ~trongly 10 ell /) lnc~. Thc.-.e ehoiee, ... tll' ... 'ell founded. a\ j.lluorouro\CiI soon bccanlC one: or .he nlOSl ... id.:ly u..ed anlincopla~tie I's.:nl~. II i, a main,'a) III Ihc IhcrJpy ade_ lIocarCllloma of Ihe eul"n lind ~tllm, Side effcc.~ are both dose and ...:hcdule dcpcrwlcm . 'They IIw:11.Idt: ut}'elosuppre .... ~ion on boIu, ad"nnisU"allon and mucO!oni~ on prolonged infusions. Chhc:r\\.I'oC. the drug;~ "'ClilOlcr-.aled. 5-Fluorour-.lC11 I~ OCt"31W by lInaboli\1I1 10 5-1100n:r-2 de'Olyurid)"he acid. Th,s COf1\eTSJOf, may pnxttd by 1...·0 roulcs, In one: roule. 5-l1uorouro\Crln:acl' .... ,'11 nboA. Ihat of tnnuoroth)'mldylic acid is eJl traordin:uil~ labile. Ii react ~ .... ,Ih glycine to gil e an anlide: UI neulrnl pi I . I 0 Kinc:t1C ~tudie' hal e sllo.... n lhat thl~ reaction 1Il\"oh'cs initial nucleophilIc all!lCk al position 6. followed by los~ of !IF 10 I!ilc the highly reactile din uororrlelh) Icoc group. III Glycirle then IIdds to this group and hydrolysi~ oftbe remnlning IV.O n oonroc atoms follo\lt~ (SchenlC 12-8). The in leBCtion of lri nUOl"l)jh~tnidylic acid wilh thynl1d~la l e s~mhclase apparenlly fo llows II si mil ar course. Th us. nfler prcinculxtlio n. it bccollle~ IlTCvcrsibly bound 10 ItIC Cn/~Il\e. aod the kinet ics are noncompetitl,e. IOI Cylosllle nroDlIloside was s) mhcsiled III 1959! I: alld 1~ler found lIS II fermc:nlalion prod\iCt. III Its ' truc .... re is notcwor· thy in thai the' IlrabHlo~ 1ll00c:ty is epimeric Illlhe 2' posillOO \It It II ribose. This mod,flClitlon. after :mabolism to the: tnphosphatC, ('lI.use~ II 10 inhibll the ron,'U predomHllUllly in lhe S pha.o;eorlhe CC'11 cycle. Tumorcc:1I resistance is ba.~ 011 low lel'cl, of dc:o~)c)'tidine kina!lC and the elabor,I\iOll of deaminases that COIl"cn cytosirll' arablllO~lde mlO uridlne LUlIbHlosKX. m Panially purified Cytidine deanimase is 111hlbl ted by letrahydrourid,rll'. 119
'llroI'J""
The IC1fl1hydrofuranyl dcrival l\c of !i-fluorouracil. ICgafur IAcnfur), \lias prepared in R us.~ill. 100 11 i~ active: in cli nical (attand less myelosuppte>;. ;ve than S- n uorourncll. II has p.trOlnlestinal and eNS toxici ty. however. T egarur is a..ly metabol ilcd 10 5·fluorouracil : Ihu§. II ma y be consill·
!!lid I prodl\lg.lible fC11l hl Y impai nncnt. lcr~tOllcnicily. hypocrbiltmblncnll;l. nnd hlll1dmouth syndrome. DruJ; imcr'.lCtiolls occur \\lIh anlacid, and
mw
l ....~ is indica led primaril y for irldocing the remlS-
Penmstalin. 2' -dcoX)'Coform)CHl. dCF. NSC·21832 1. (H.., 3-(2-deo~ y-.tNH"l)tllropctllofumnosyl}3.6.7.8-Ielr.lh)'droimidll/o14.5·d 11 1.3 }dIUl.cpin·8-o1. Tlti. compound is obtained fr'(lm extraciS of SIUplfH1ll,{,t'S UllI/bi· Q{icltil7~ :lnd formuloll:d 10 100mg vials a~ a lyopliili1.ed po.... dcr. Mllunno.] (50 mg) and sodiu m hydroxide (10 adju~1 pH) are incllldc:d. 1\ is admlm~lcred IIItmH:nouomc 7 - h)droxymclhotre~ate is f"und folio ... rng hiXh·do!oC tlltrapy. I>las.ma leI el decay r~ brpha,ic or tJOl'sibly triphaSic. MtlhotreAaIC binds tightly 10 dihydrofolate I'!'ductase. blocling the reduetion of dih)'drufolale to tClmh)drufolate. lhe ach'"e form of the ooenzyn1Co\cry Ihat mcthotrc~ate affo«lc:d a hrgh percentage of apparently pc:mlal1cd in the treatment of cytlc lind grunulocylk leu~cmi:l~.!\! TOlie bone mafro" dcpres'JOIl. '-tomalU ts. alopecia. artd Ic~l inal d"IUm;ttu."e s. Al htght'r dose~. eardiac ck\l.'lop. Sen'f"(' and progrcs~"e: ~-oogest "e may full,," imlial tachycardia a.nd anflythm.as. The usual dose of d.:lUnorublC in is 30 10 45 for 3 d3)'" II i, udmmi~lcrcd inlr~,cllou,t)'. ta~.nl jl'f"e,ent I.'Xtr~\·a'l;ltiOIi. Doxorubicin Hydrochloride_ USP. drochloridc. Adrium)ci n.,N"IS;·"C,~',,' ~23127. rnycm. is uOIamed from ..' I llJ Vat. filI'JUU. The orange-red 1I~"dles 1IIId ulcohols. l)olorubieln hydrochlondc is free/.c-dried 1JO",dc:r in IWO dilTerenl ~i7.cS: 10 rng of Lactose:. U5 P. and 50 250 USP. The'\C' I
bod;;u;ssucs. ,.. lI h about le lllS. II is u len~i\"ely rneuboli/cd ;ltId as gtucllT'(lmdc conJ"g"'e~ or the parenl hydroxyl redu"ion prodUCI.
ilibe 7-deQl y:q;J)'COIIt' aJ.o i~ formed. Dispo!IlIioo ;md eh",-
--.n C3I1 be
C'\plairw=d by
a two-compaf1ntc'lIt or II Ihll'C-
model. I1PQSOmt-cncapsu];!'lcd do:o.orubicm
formuhUlOOS forchnicll.l trials.
The model! of OOl(orubicin al\' sum lar 10 those hnbcd for daurlf effecti '-c IIlltltUmor agent~. kbI5 been usro succe\sfulJy !O produce "'gfl'ssiom in acute letl;tmms, Il odgkin's dier. the ex tent of ~tnbol ism during the 2-hour reten mitomycin and 10 mg of m3JInitol or 2Q rTql of milOmycm
and 40 mg of rtUIl1nilOl are supplied, The unrocoo~litutc:d prodllCl is suable at room tempcnl1ure for al least 2 years. The drug I ~ rocoo~litulllllle mitosl$ follOWing boef exposure 10 other Vitll;3 alla loid~ IIfler the,e cornpoullds are wilh · df"Jwn.l71 A plant prodoct of hi~h current inlel"Cl't in cancer chcJ1"lOtherapy is p;lClitaxel (Taxol). Thl~ compound was isolated from the bar .. of tnc PacifIC )CW IItt Ttulu brt'l'iji>lio by Wam CI al. III 1971.179 At that lime. II .... as found to h.a\C antitumor achvlly : ho"""el·U. thc're W-JS hllle cnthusiasm for its funner (lcwlOplllent until ~l1lly . ... hen Its potential for human clinical actll;!y wa.~ suggested by screening against human lun~ in immunodeficient miee. II is now lhe world' ~ Ica.:hng unl incopla.~ue ugen t in Icrn.s of bales. Pacli· laxel is active again~1 refractory ovariun cuncer. metastatic 1M\:as.t CllllCCf. mctastatic melanoma . nnd non -smallcciliung cancer. Pacliuuel mh.biL~ mitOSIS by ocllng lIS II. spmdle polson : however. ic acts by a unique mechant sm In prumofing tnc assembly ofnllcrotubules and Slabilll.lng chem &gam!;! ark of Ta.l"us br~,·ijo/;a. II. slow -gro ... ing u"!:e conlailling only a ~mall amounl of the drug. 11m procc~~ IS expcnsi\'c aud a threac to f()fl.$1 ('COlo&) . Con~ucntly. the manufacturer. BriSIOI· Mycl1i Squibb. tJo:o\cloped a tOOtc based on partial synthesis from 100dcacciylbaccl4tin III .... hich is obtailled from lhe needles of TU.lUS mlccll/a. a Europellll ye .... tree . Becau>c needles are ropidly regcnerated. Ihis I' a les~ desCf\lt:ti\ c !m-Ihod for obtaimng pachtQxel. Furthennore. 10deacctylhaccatin 1 1I!~:111 important intcnncdi~te for chc s) nthesis of analoglM:$. One such lIIlalogue. docclaxel (TBXotere). has been pR'pared aI RhOne-Poule!1I; Rorer. It I~ more '" ater soluble Ihllll paditaxel and reponed to be fIl()f"I: potent agairu;t solid tumon. bill it is n:llII.i\"ety more toxic lhan pach Ul.\d.Zl I DocelaXeI is approved for nICI.IISlallC breast cancer and for 1IOn-5mall «II lung c~ after patie nts havc failed prior cncmodH:rnpy.
,
- ." ~
H,OO
"
HO
f
~
H,OOC;;""",-OH
"
"
,
Cd clinically for this pull'O'\C. howevt'l". lts main use is in terminating IIC\Ite Illtacu of gOUI. Among colchicine derivuti\'es, demecolcine (Colccmid) is aclive against myelocytic lcukrmill. but only lit ncar-toxic Ooscs. Colchicincs have WI unusual tri cyel ic structure con· taining a trop:Ilone ring. Tllc:y inhibit mitosis It mrtllphne by diliOrieming the organi/.lltion of the spi odIe and listen.m
CH,O...,..,,- /--.., )- NHR
°
QCH, CoieI'oo .. R .. ccx::H 3 Ct*:etTild. R. CH 3
lrinoteean 1I11..~ been approved recently for fifliHine ther· apy, in combination with S-FU and leucovorin. for patients wnll metastatic colon or rectal carcioomas. It i~ a semisynThetic analogue of Clmptothecan.l l l Camptothecin was isolated from CamJllOlhtca Qcuminll/(I. WI ornamrntal tree found in China.u.o It is very insoluble in water. but its sodium !IlIlt. prl'pared by alkaline hydrolysis of the laclOOl: ring. ~'ed promising lIIltitumor activity. Cli nical tria ls ,,"'ere evenTually dlsconllnued because or unpredictable tOllic effeelS. lrinotCClin luis a basic tcniary amine group. which cUn be prolOllated to solubil i1.e the drug. Tllc: lactone rinll nemain.~ inlaC1 and in.crea.' bung factor producc:d by recombinant DNA technology). Hypcr.c:nsithny (J(:curs in -oIllC patients within 10 minute$. St:utm8 an infusion. II has been suggesletlthatthe allergen .s lhe Cremophor El dilucnl.- RC"m!iblc pcriphcnllllCUropalhy is common WIth pffllonged infusions. Bradycardia. gastrointestinal disturbances. nu·li~e ,ymptoms. bud tOlbl body alopecia aJ..., occur.
or
bgands ...... :mil ormaplalin. a 1'1. ( IV ) complex WllO'ie!oJl ligandli include four chloriOcs and I.Z-diaminocydoheunr Ommplatin must be reduced 10 thchloro-J.2-di amlllOCydo· heone PI (II) for acthation. 10"1
Docetaxel.
[)ocetaxel. TWlOlere. RP_56967 . NSC628503. i~ prepared from II. precursor obcairICd ffflm lleedles of the }ew plant.m It is supplied !IS a 2O-mg sample In 0.5 ml of poIY'>OfOOtC 80 or a) an 8O-mg su.lnple in 2 ml of polysorbate 80, both In single-dose vial~ with diluclIl ~uita ble for mjection. Samples ~hould be kcpt al 2 t(J SoC and be proICCled from light R('C(lmmcnded dos« are 60 to 100 m,) m~ IV O"cr I hour every 3 weeks for breast C:lJlCCl'" or 75 mglm] for non - small cell IUllg callCCf Docclallei is indicated for breast cancer after failure of prior chemochenlpy and for non- '\I11lI1i IUllg carcinoma after failure of platinum-based therapy. To~ic tffecL~ include neu tropeni:l. nuid retcn tion . mutagenesis. rash. and rlCuffllogical symploms,.m Pcripheral blood ooums ~hou ld be performed because of myelowppres~ion. Ph:umacokinetics indicatc a thRe_comp:lnmem model ""'Ih half·liH'! of 4 and 36 minules alld 11.1 houl'll. n.c drug i~ 1)4% protein hound.
MISCELLANEOUS COMPOUNDS In 196.5. Rosenberg Invcsligatcd lhe effects of electrical r.elds on OOctenll lind found tmu Escll,.nchia coli fom"ICd long liIaments Lllslead of d ividi ng. - ~le ,ubsequently d;~ coverro ,hal this effecl wa~ cnused not by the electrical cur",nl. 001 by a compla. [PI (CI).(Nlhhf fomle(l from the plat,nUIlI eleclfude in the presence of ammollium lind chloride IonS.)!IO This d,i,Covery wa$ followed by !eSTlllg I variely of pl atinum neulml comp le~c.~ against 1Uml'rs. with lhe reslill that ciHlichiorod lammincplatillum II (dspbtin) c\entually became el tablishcti as a dil1lclIl agent,.IOl Thi~ platinum L"{}Illplex i, II potcnt inhibitor of DNA poly· mcmse . li S aC"tivity and tOllid ,y rese mblc those of the al kylatinll agellis. Con~idcrablc evidence has been obtained fOf" DNA DII,,/jng by !he plalinuHl I;"QrrIple,O . 111 "hich lhe 1"0 chloride.-. Wl.' dj~plrxcd by lllirogen or 01ygcn IIlom. of purioos. "ln~ evidence inc illdc:.~ focilitutL'tl renatLLr.ltion. increa.'\I'd sedil1lC':ntation coeffiCient. hyperchmmidty of the DNA lI1tr~ ... iolet spectrum. and seicroro. l16 Tumor resi~l uocC i. basal on the development (If ISpInlglllc ,ynthctase hy the tumor ce ll s.'17 Pcsasp.ugali01TIt: remisslons in refl1lClory casc..~ breast cancer. maltgnam melanoma. and OCUle myelocyuc lcukcmHI. Leukopenia is the limiting toxicily .m m-AMSA (aJl)~ril1C) is an acridine rn,ri~atlve that is thought to bind to DNA through intercalation. It does not affect DNA synthesis. howe,·cr.·1) TImi compound was rationally desIgned as one member of a groupofacridmyluminomethane.~ulfonam ides.J2· Pn.::viOt"ly. a number of other acridirIC derivativcs hll/J shown anliwmor activity.
....} of liS octions arc relaled to the fUIK1ions of spermidi nc. ~Iidt IllCSemblcs in structure . Thus. n competes .... il h sper~.fOf the: Inmspon carner and inlr.lCeliular binding site. llko IMinns spenmdme biosynlhesis. lIS amiprolifernth e 5 on ccll~ can be jlfI:vellled by udrnini~lering spenni. . III M:my other bi,(guanylhydntJ.oncs) have Ix~n pre"ml. but nonc: has proved s uperior 10 the melhylglyo)(aJ
DCH,
The clinical importance of :1IIthnIC)'cJines SlImulated the synlhe.~is lind
screening of IlJIthraquinones wnh panlal anIhracyclme siructures. One of the be~t of these anulogucs i~ mitountrone ..... hich tms two hydro,;yl and 1\000 2-[ (2hydrollyethylamillO)eth)" lIamino wtKIi tucnts on the anthrnqui fIOI1C nuck'us. 2!l ule ooxOIUbocon, mito'(llntlUOC" Interca' ,nhibits DNA tOJ'lOlsomcrnsc [I '~: bowlates onto DNA and evcr. it i, not a sub~1r.l!e for reductases and does IlOt form o)(ygcn-free mdkal) in a redm cycli ng procc.~,. Consequclltl y. il is less cardiolOxic th.an do\orubicin. M itoxantrooe is apptmed forinducmg remissions in acute nonlymphocytic leukelma. usually in combi nation \Ooilh cytarabine. HO 0 NHCH,CH, NHCH ,CH ,OH
tnl'JtJll'.
NH
CH3
NH
II
I
II
NHCH,CH,NHCH ,CH,OH
H~NCNHN-C-CH=NNHCNH2 M,lQgl"rone (~ 8Is(~IIlO"oII )J
H,NCH2CH~CH2NHCH2CH2CH2CH2NH, Spe!rrodI oe
PUl)Xalllrone IS :111 anthrdpyr.uole Structur:al1y relall~d 10 milountrone in h:l\'mg two phenolIC hydrox)' ls and ;;ide cha ins ~'OOtaining I1l11ino g roups: Ilowevcr. its qu inone ring
is modified to form part of a pyrazole ring with a nitrogen atom on the next ring. J : 1 'The mode of action of piro~antrooe is intcrcalation lind interfercnc.: wi th DNA synthcs i~ by lem· plate inhibition. Cardiotoxicity is low ~ause il doe'i IIOt urKlc:rgo redox cycling, '11 Piru_anttU/lC' is pre..;ently in clini· cal lrials.
hne been de\'e loped in an cffon to limit side eff«ts. o.e of these se lecti\'e agenl~. beluU'otene, has bttn lIIlf"O."ai lor usc in patients with eut41lCOUs T-ce ll ~mphoma that If Il' fractO!')' in previous syMe rnic thcnapy . }II It is adtninbtl'fftl ornlly in gelatin capsu les,
o OH CH,
HICH,I,NH,
The 3ntipant~itic !.lrug suramin sodi um (Chaptcr 8) has long been used to treat trypanosomalllll!.l filari al infeetioos. II also inhibits re,'ersc tru"~ripWsc in RNA tumor vil\l5t's. Antitumor activi ty was demonstnued m hormornIlly refrnc· ti l'e prostate cllrlCt'r'lI> and a!.ll'anced 0\ IInan cnremoma. Sur· amin acts by a variety of biological rncc hun isrns. ind uding mhlhiuon of hyaluron idase. urease. hcxokinase. RNA polymena'ie. DNA topo1wmel'llSC II. and ly'iO!iOlTl:ll enlymcs. no II affects ATP ~ynthesis and degradation and inhibitS mitochond rial en/ynll'S, Signal transduction in cells is inhibited by SUnimin bin!.ling to tumor growth facton; and protein k,nases.)JI Summin may al'ioO mhihit anglDgCnesls and induce normal ce llulltt differentiation by increasing tissue glyeO'laminoglyeans. 1U Although :mlitumor acuvlty was found for ga ll iu m nit mle in phase II clinical trial s. m its approved use is for the treatn"K:nt ofcanccr·relale\.'e and oxygen to form spccic.~ thul allack DNA cleavage. This ~ is used for palliPlion completely obstruCted esophageal non -smllll cell lung cancer.JoOIl !
p--
Cisplatin. Cisplat in. Platioot NSC- II9875. COOP,;,;', prepared by treati ng potas.~il.lm ehloropl:llinite With. nia ..Kii It is u water·soluble while solid su pplied in ~ials coolllining 10 mg of eisplatin as a lyophil ized ....... ' . For reco(l§titution. 10 ml of sterile .... aleT is added ... . resulti ng solution is diluted in 2 l of 5'k delltro!ie ia 0.33 N saline contllinins 37.5 g of m~nnitol .j4l Cisplaun ha~ a triphasic disappcaruoce cur. e I... ith ... lives of 20 minutes. 4810 70 minutes. and 24 hours. ;Iriabty Ill}cosyhltcd in the y~~st. oierww prqmrouon. L.cukinc dlffen frum native 5l1rgrurnos.by rubstnuuon oflcuc1nealpo"lIIon 23 and byadlfferent ..tIoIl) •.Inlle maleup II h.as a 'pecilic OCUII;I)' of about 5 • lOT Vlmi of protein. l..cukine is available commercially al}ophllized povo'der in 25(). and SIX)."'I!: amoum~. It is ICroII>IltUIW luth 1.0 mL of SIt'flle Wale!" for In,e€:lIon. lSP, to yield II clear i~olOnic Mllullon m pH 7.4. Funhcr ~ions In Q,en- ~hul11 chlondc should mcludc O.I'if: \ I ofll\unan serum albumin to reduce :ldsorption to thl:: wrf;JCc. Vials should be di~arded wuhin (I hOUN of rrron.tilulion because there is "0 Ptllib;ictcria1 prc~""':lIhe. !1Ie also i~ $upplicd HI 250- :lIId 300-,ui l;al5 and is _"!luted lilt Leukmc. l.cuoom:u. is aVHllable for m\c~' -..iooal use fmm the Schering CorpomliOl1, M OSt ~~ of ",:"",;m are adnunblen:d by in fusion. although n IS ..1I.e by lhe subcut:meoo§ rouiC • Sargllln)()§.lIm IS u~'d Iu prorl1()le bone m~rrow !"COO"!!!), .prMI("l'> urKkrguing aUlOlogou~ bone marrow lransplanla"' II aJso redUttS lhe J;e1'Cnly and dural.1OI1 of neutrofollo",lnll ~ulld:1fl1 chemolherapy "Ith mydol-uyptophan ..MIl It is :";';';clas t/lt parnoate salt, ... hich pro ... ide) a depot form ...-ut duration ... ben gJ"C'n OI'1IlIy. Gorupionate, 2anw:thyldih~drowilosteror""
propiullatc. i.~ prepared from dih}'drolC5IOS1Crone ill D route inlul ~ing condcnSlluon .... ith ethyl forro.ale fol1o"'cd by hydro~nal ioo to gil'e the 2amethyl deri"3I1ve uOO then reacl ion with propionic ullhydridc:J'}° ThecompoUiod is supp lied in rubber-stoppered vials l'OOlainmg SOO mg dromoslanolone propionate In 10 mL of sesame oil. wilh O.5'ed. PotienlS develop a nu-like syndrolllr, eNS effects . and canJiovlISCu lar effectS. including hypotension. anhythmia, or tachycardia . In terferonAlfa -n3. Interferon II.lfa-n] is. glycoprotem produced from cultures of human Iwcocytes lreated with Sendat \·irus. It IS purified initially by chrommosroplly usm, a mouse monoclonal antibody that binds 10 multiple species of human inlerfcron. Sub5c:qUCJ1l purifICation involves incuhation at 40C and pH 2 to kill viruses and gel riltrution chromnt~rap/ty. It then has D specirIC aclivity of about 2 X 108 4 IU. ! The drug is supplied in l -mL vials containing I rnL of phosphate buffered saline sol ution, phenol as a preserva· tive, and I mg of humbn serum albumin liS a stabilizer. This solution shou ld be krpt at 2 10 !!"C. l1!cropeutic indications and side rffects or interferon alfa-nJ are similar 10 those Uescribed for interferons alra ·2a and alfa-2b.
Aldesleukin. 11..-2. aldesieukin, ProJeutin, Trcclcukin. interJeutin_2, 11..-2, T-cell growth faclor, in the human form is produced in mature T lymphocytes. Cleavage of the 21}amino acid signal sequence then results in an active protein
containing 133 anuno acids. It I~ glycosylmed and has 001: disulfide bond. .... hich is e$.~ntjal for acth·lty. Rooombinlim IL-2 i~ produced by £. that carri~ Insrrted. modified human IL-2 gcnes. Teceleukin I~ oonglycosylared but con· fonns to natural IL-2 in amino acid sequence. e~cept for an addiuonal N-terminal methLOnilM: . Proku!.:111 i$ not gl)'OO5"ylated ond differs fmm the nnlural protein In lacking the tenni. nal alanll'lc and having $Crine rather thaI! ey,tei ne for residue 12.5. 1L-2 acth'u) is SUllldutblCd 10 IU m an a.~y based 0 11 stimulat ion of T -cell growth in \·itro. ProIeu!.:m IS Iwall abk ill glaM vials COI1tain ing 1.2 mg of Iyophil;;':ed powder (22 million IU) plus o;()(hum decyl ~ulfate It is reconstituled with 1.2 mLo f wluuon supplied to gi~c 18 11lIl1lon IUlm L. Tl~leu!.:i ll i~ )upplied in vials containing 100 II1g of IL-2. 25 mg of human albumin. and.5 IlIII of mannitol per million IU. It I< reoon SUluted ..... Ilh Sodium Chlondc for Injection. US P All formu lations of [L-2 require 5tornge at 4 to 11"JIry bul care fully regukltcd COtnllOnem of normal polll!h arid \\OUllU healing. Uncontrolled IlngiogenC!iis i~ a dnolng factOf in wlid tumor gro.... th. TIle proc('~s of angio~I' I~ CQ11lplCl 311d requires the coordinated inlC1'lK:lion tllalhiplc cdl t)1lCS. Multiple sites for dNa Intervention ole (\pettea .... ' Endogenous angiogelM!!iis mhibltors .... ere • In umx:~ weh as carti lage ... hkh lack blood \'CS5Cls. ~an:h afforded a proIein named c:anilagt'-Ouil't'J /II, ."'l Lanllnm i~ a mapoolllponcm ofoo'iCmcnt memhit. f'epti(k."li balCd on il~ struc1ure, ~l.lCh ;.., CDP(;Y· XlSRNH:. mhlbn angIogenesis and ..ollt! I\JrnOf growlh.. 19M .w 11..... It, C J 8~ AI~)I."n. AfCM' 1..ondun. H"'...... ooIIl.
52. H 54. 55. .56. 57
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Alltn. I~ M . rt aI C....,... T",a, 6IH~I . 1'I7fI. I..~. P I . rt.1 1. 0, ... 0n00I ~ 5ll. 1'lSf>. Cm ..... I' 1_ rt II. C-"" T-. Rep . .'lII~55. 1976. 8ertcl. F. _ S40ck. J A. J Cho.. Sue laOII. 19S-' E...... T L . rI II. CIICeI" o..mochcr 1'hwmoaoI, I; V, ....... II .. .. II N MIl. J M7.290. 1\).15. M Ih."h,", .. G. 1I .• nd Elion, G . 8 , ..."'. a."m. II ... 2:202. I'M. 85. Elion. G, H.. rtll I Aon. CIoen,. ","", 74~11.19n. 86. Hru;:I.nwi. II W Ad~ Cani1 and Co.; Bel •. r,*", 671j37. 1967 ManlLJ J•• INlCchao.S S .. C ... , R.., 27:152A.1%1 BriM.. J J .. and O. A ~ c..cer R4. O"",tman. R W.. tI.oI.; C"""", Ita. 01&.1610. 19111), T_" W.-C .. till.' M.p.. ien, .. 20:202. 19M 122. 1Ianb. L J,,'I oJ,: AnlUnil.
148. ZIIlIIn. S.. 01 :01" 8ioohem I'IIann.ool )):0I. N.ow DruK' 2,359. ! 984. m. RelI .... Y. II.: N",,,", 218;19],19611. III Roo. K. V . CI al.: AnUM. a.."""I>er. 12: IS2, 1962. )1 . NIY'''''. 11 _. e\ al~ FEBS Len . .loO:U7. 1973. m GaIou, O. F.: OI,,,,,,,,~,,,. cI\ronlOOl),IIodll loon .. D. J. (cds.). Hard>ooI: of E>.pcnmomal 1'!wtttacoIogy. vol. 38. part 2. N... Yon.. SpringOf.Vt11.,. 1975. 1"1'. 670-694 275. Romctl . C. J .... II.: J. Mtd. Chern. 21 :88. 1m.
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216. Rons&. K. G •• and MII ... ic. N>ll. Mad ScI. U. S. A. 11. I~I. 19W. 281. Rum •. H.• .....1.: No .. onl"' ....... In l'in«k>. H. 101 (.:d.). CancerClcmem. SoI«/uooklar I) 2M. 1CflIy I~ hberated on the fonn of. ,..~ Eumple: '~Ra-'~R n
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CHARACTERISTICS OF DECAY
Radiation DetaclOo"S
Figure 1 ] - ] • Sc:hematic dlilgram of a Compult'llle\f .utailomography «(An system thaI producP5 thin cross-sec1.lOOaI,mages of the body. An _-faY lubf rotales around the pattent, and 1M Iransmllleoo of radiotrnCers. The. pUl"p05C of tile gamma camera is to record the location and Intcnsity of the radiatlQn ",jibin the imaging field. Rudiation in the form of gamma photons (occasionally,,;rays) imti:llly enters tlx: camera through IIx: collimator, which usually is a sheet onead with multiple sma ll . precisely made holes. II CO\'ers the detector crystal. 11x: purpose of the COllin13lor is to decR:ao;.e scanered rodiation and increase 11x: o\'crnl1 rcsolullon of the 5)'~em. Photons lhat are not blocLed by the col limator then entcr a large Mldiulil iodide (with a small amotlnt of thallium) crystal that absorbs .,.. l1Iys. The absorbed cuellO' III the cry~tal is emilled as a nash of light (called a scintillllliQII), which is proportional to the energy of the .,..ray. Coupled 10 the bad: of tile Na l('ll) cry~l an: photomultiplier ( PM) lUbes 111.11 CCNlVert the light nashcs to electrical pulses IHOj)()f"\lQnal to tile amount of light To 1000Jliu tlx: original source of the photon (and create an image). a computer assigns )l- Y spatial coordinates to the vanouJ .,..rays coming from the p.1tient and stores this information in a matri~. After collection. the digital image is COlwerted into an analogue \'ideo signal for display on a
. '"
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Figur' 13-4 • Schematic: diagram of sontl llatlQn UIfIlI1 (Angef) system WIth a mu/tlt1Ole lead colhmate. alla:htd eliminate ~allered ")"fays), wn.ch IS used 10 VisualIZe I!S$i.It!I anECf systems usc one to thn:c scintillation tOB that rotllle about the ti SPEer is wilen i sioDal . organ~. 13·1 llcpicts a perfusion .san
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Figure 13- 5 • DynamIC study of the Irvef ,md blllc1~cystJl!S, thl!-radlOtlacer would not hallt' eotefed the gallbladder. Tl'1e.mow in frame 16 shows the
normal locatlOO of IN! gallbladdef
,,- TV_ Computer
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-
Figure 13- 6 • Schematicdlagramof oil rotating tuple-detector sclntdl.:lbon CMOefa system for Single photon erT\ISSIOO computed IOmogIclPhy (SPECl) demomtratlng" "cold" spot IeSltIO If'I the bro1ll'l on me sagittal VIfW (opM MI'OW)
Figure 13- 7 • SPECT rTl)'OCtannous n uoride. or s!OnllOUS tartnlte). A ftcr prcparnof1hc radiOl'hammeeutical. wsts for radiochcmical pu. ;a, !Muld be eamed out to ensure thm the radiotmeer is in nght tllemical form. The anal),tical I\1Ct!lodS used i~lude ~antllhin_layer chromatography. column chrornatograI t e)l traction. Likel)' radiochemical impuritjes sodium pertechnetate (N a'>9", I cO.), some insoluble (i.e .. reduced hydrol)'1.ed technetium tTC021 or f colloid). and a complex different fmm lhe (i.e .. 'l'im-fc-monodcntme rJthcr than ~'c-
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bidentatc ligand). 11Ie ~tcrile serum vial~ comaini ng the StWlnous sal t anti the ligand are I)'oph ilized under a sterile incn gas atmosphere (i.e .• ni1rogen or argon). The ligand in the l"Caclion vial dctennincs the final chemical Structure of the \l9n'Tc-comple~ and the hiol ogical fate after illlrnvenous in· jection of the radiophammceutical.
Tec;hnetium Radiopharmaceutlcals Technetium (l"" Tc) Albumin Injection. ·~~"'T I c albu min for injection is a sierile. colorless 10 p.11e )'cllow solut ion containing human albumin (MW -60.000) rudiolabeled with Tc-99m JlCneehne1ale. 11M: reducing agent is ,tanl1OUS mnrnlc. which reduce) tile '>9n' l C04 - to an unknown oxid~ lion state and is " 'eatl)' chelated b)' the tarlrnte and posslbl), fomlS a CQmplex wilh su lfh)'dryl groups on the albumin b)' ligand exchange. The precise slructure of the stanoow. technelium - albumin complcx is currentl ), unknown . TIle p.1tient n:ceivc.~ an intravenous injecti on of 25 mCi (925 MBq ) of Tc-99m albumi n, Mulli ple images of the blood in the hean are tate" b)' electrocardiogram gating ( R·R interval). The rising portion of tile R wave "."oincidcs with end-diastole. These i mages are stored in u com pUler to reconstruct a 1II0Vle of lhe bealing hean. This procedu re i~ somelimes called II m"I';g/l/cd uc1I,,;siriulI ( MUGA) or a ratli''''''c/ide \·clllriculogm/ll. InformatiOlI obtui ned b)' this tec hnique irn;ludcs cardiac chamber wall III00ion and calcu lation of ejection fraction. Indications for ~he procedure inelude evaluation of e!TeetS of coronary ancr)' disease. foll ow·up of coronary anery b)'pliss Ilm£! pa tients. heart failure. Ilean lransplant evalumion (preoper.uive and postoperalive). eardiom)'opat hie~. and dl'ccts of eardi· OIoxic drug, (i .e .. doxorubidn).
Technetium (""' Tc) Albumin Aggregated.
""tII I c-al-
bumin aggregated is II steri le whilc su>pcnsion of human albumin aggregates formed b)' denaturing human albumin b)' healing at SO"C at pH 4.8 (isoclectric paim of albumin). The precise struclure of the stannous technetium-albumin ag.gregaled cOlllplex i. nntno,,",n at this time. 11M: particle sir-e nnd number can be e~timated with a hemoc)'tomeler grid. The panicle ~iJ.c of the suspension should be between 10 and 100 J.UTl. with no panicles greatcr than 150 foIm. This agem is used clinicall), to image the pulmonary microcircu lation for pulmonary embolus and 10 assess I"Cgional pulmonary func tion for surgery (i.e .. hmg trnnsplant~ or resection). The paucm receives an intravenous injection of 2 to 4 mCi (74 10 148 1\1Bq) of lhe Tc-99m- albumin aggregate,>. which lodge in '>Ome of the ,m"l1 pulmonary nnerio1e~ Hnd capillarics. and the distribution can be imased.11M: numbcrufaggregates recommended for good image qualit)' alld o;.afe~)' is 100.000 10 500.000 p.:1I1 icle~: thu~. onl), a small frJction of lhe 280 billion capillaries ~rc occluded. Multiple ima ges of Ihe lung are obtained 10 ass.ess lung perfusion. 'lbe distribulion of the p.'nic1e~ in the lung is a function of regional blood now: consequentl)'. in the nOfmnl lung. the panicles are di~!ribated umforml), througooullhe IUllg. When blood flow is occludL-d because of emboli. multiple UlIclion. lltc patient receh'es a bolos intraVCJlOO5 injection of JO mCI (370 MBq) of T c-99m mertilltide. aud dynamic images arl! obtained every 3 to 5 seconds to study blood flow to lhe kidneys. S«ju.cnlial slatic images arc then oblained for 20 10 30 minUles 10 evallJ.llle renal cortical upIJllc, ClIcrt'tioo. and tubu lar clearance. Delayed images may be required to e\'alullIe ]XItiems with obstruCtion or renal failure. Normally. IhcTe IS prompt sylT1l1'lWic bilateral perfusion. good con i,al accumulalion bilalerally with visual iution or the collecling systems by 3 to 5 minulCS poslinjecllOll, and rnpiducrellon imollle bladder. with oodelaylo iodielle partial or compkle OOsIrul stale " SI.1blr in aqueous solutioM.
Gallium f1Ga) Citra Ie.
TIle gaillum (III)-c llmc c:a.-
plex is formed by IId.:.hng the requi~ amount of·~" citratc (0. 15 M ) to gallium ( Ill) chloride and adJustl1ll pil io 4.5 to S.O wllh 50(lIum hydroxide. The ptoposc.l ~ IU~ of gallium ('7Ga) citr.lte i. shown below.· The patd rCCC"ivcs ~n imravenous injection of 5 to 10 mCi ( 185 11).1 MlJq) of gallium (b1Ga J citnne.llnd wholt-body ima,cslft Ihen obtained 24, 48.lIl1d 72 hOllrs after injection. Galli_ loca]i:f.es at sites of in fl ammat ion Qf inf~tion Ill> wcll varicty o{tumors. It is used in clinIcal prnttice in the and evaluation of rtturrcncc of lymphomas. Gallium il.t!l normally in thI: Ii\'er and spleen, bone. n~ lacnmaJ glands. and bn-ast tis.~uc.'. There is alw some ~ lion in lhe bowcl; conscqucmly. the patient may trquIItl luative wullor eoemas to e\'IICUJte this radioacti~ily pm 10 the 4S-hour inUlge, A~ more specific radiOlfll(."I'~ bee" t.lcveloped. Inc nouspeci fic I1OI1nallocali/.llllon 1ium radioactivity luis limne\l ils clmical use.
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IODINE RADIOCHEMISTRY
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GAlUUM RADIOCHEMISTRY The only rndioi'iOlope of gallium thaI is presently used is ga11i um·67. wh Ich i~ produced in a cyc lotron by r,roton bombardment of Uline lI1el3ltarge\ by H "'Zn(p.2n) 'Oa nuclear reaction . Oalliu\l1·67 (I, f.! - 78.2 hours) decays by electron
The useful radioisotopes of iodine iodine· I)I:and iodine-l23 because i i cal characteristics. lodll'lt- I) I is obtained rrom production 0{ tellurium- I) 1. tion m U(n.fiuion)nlTe or lurium- 131 (I'I"! - 25 minutes) sian to iodine- I) I. Iodine- I) I (1 ,12 by {j decay to stable xCllolI- I)I . wilh fi\'c ell1i~siou~ or 80 to 723 keV. The major (82%) provides good tis)ue pc:oetration .;..,~
Chapt .... U • Qr iodlne-131 are the high rudi:mon long half-lire. and the poor )"111)'~. lodmc- 123 {I~ Caplure to teUunum-123. cmt~ion of IS9 leV (83%). ",hich of iodine for organ tmaging reduced radia i is in 11 cyclotron .....a.n antimony meTal target with 0 partielc~ IICl~iSh (o:r.2n)IH reaction or an iodine target protons by lhe IW(p.5n)IH nuclear reama. The localwlllon of .he Ilxilum (Ill) chloride In bone nllllTOW i~ prob,lbly expl~ incd hy its nb lli1y to bchnvc.lnt:13bolically lil e 1I'0Il and yel not be incorporated inlO hemoglobm in the RBC~ In lhe hone marrow. "The localil(alion o( the radiolt'llecr in IUllX)f'S lind lIb$ccsses is probably due to increased blood now and capi llary pellll¢ability in the area of1issuc: damage. Tmn"(cmn rece ptor; h.:tI'C been iiuggestcd a~ II mcan. of loc~li]..at ion but not pro~'ed al thi . lime:. Indium r "l n) Capro~ b PendetHk. Indium capromub pcndClidc IS a new IlIdiotracer for $tagi ng paticnts with ne ... ly d iag~ proslalc cnncer and for those with sus· pected reQCCurrcnce btu a negalive loculizalion w;lh II stan· d~rd clal uation. Indium ( Hll n) Oncosclnt CRIOV (Sarumomabpendetide). 1l'l' ~lInpl lrted structure of indium (1II In) satumo.. mllbpcndctide is shown be low. Antibotlics are ~ hcterogc nc· OO~ group o f proIcill5 i!iOlmted from human and ani mal serum and are called immIlRus/o/",/hu, They are di vided into ciu.SC:II on lhe IxIsi~ of diffcrclX."ean. Al'IOd'ier IIrtbod of radiolabeli ng Icukoc)tc' that ha.\ become: popular Il'ott Tc-99m- HMP AO (he.'llamcthylpropylcnciln'llDC o.l in'le) . Fmally. IndH.m ("l ln HabcJed platelets are u!oed to detecl *umboc;cs. mcasure platelet li fc span. and monilOr the soc~ of lidllCy transplanl'.
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Indium ('''In) Pentetate (''' In-DrPA). T he IIldiurn WI-pcnlctatc complex is fo nned by ILdd mg the required _u of calc.um or sodium pcntelUlc (I)TPA) 10 the in(III) chlonde and adjus1 inj; lhe pll 10 7.0 10 8.0 wilh "::: h~Urox ide and/or hydrochloric acid. A ~d EJI It of indium (Ill ) pentc!atc is \hown below. "flxo paundergoes a lumhar punctLire under "mle coodl tions .-I ftCC'i\'cs an mtr:lthecal injCCtion of 0.5 10 1.0 mC I ( 18.5 J1.0 MRq) o( indium (II 'In) penlet:l.ll.'..... hlCh dl~trlbul'-'" Ihc cerehmsp'lIal fluid (CS I'). 1ml.al itnaJ:es an: ob_ " 10 en'>IJI'I: a good intr:llheeal IDJCCIlon lmage\ of the , ana] and CSF spaces of the bn!.!n IlI'C acquired at 0 71 boors 10 IISSC'S CSF flow or leak ugc from the nom la! {~'PJCe. TIle normal CS F flow p;!ncm ,ho""~ Ihu1 the ipllamlllCCu tical asce nds to the bu,i lar ciste rn ' in 2 10 4 flQw~ over the cercbru l ron\'exilic~ in 24 hOlIr;. 10 72 hour;. there sltould be II i:f'.ldual c leaf'JI\(.'C Ihc CSI' ~ ia lhe choroid pICJlu'. CiSlemogrophy I' helpIII tlot!u;Umg (or ~'Ommunleatlllg h ydl'QCC'phaJ II~ becauliC IS lIboormal CS F no .... InlO the laterul "enuielc:s o ( Inm 10 thl~ d isease. Then:: iJ 31-0 an MR1 method for ng thIS type of hydrocephalus. 1111 ~ dlCd in lung "cnlilalion stUdies mu>! lit chemically inert and. al lhe conccmrntlon~ used, be ph))io. lo~icDlIy irocrt. Xcnon-I)) i~ chemICally LIlcrt IIJ1d LIlsolubk in waler. v.hich make, II msoluble In body nuids. Unfo''OItIlle phy,icnl char!ICicriSlicsof xcnon- I)) includc poor i~ quali ly becnuo,c uf thl: low tissue pcnc:trntion of the 10.energy )'"ray. increased patienl docardial t,,~ue. Con'CT'Io!ly. in clil1ical imaging s1Utli&:.~. the an:a~ of ntyocardial infarction (not vlllhle '\Car) are ~i~un t il.ed as nonpcrfused C'rotd ") ureas. Although the Tc-99" t-oosed myocardial pcrfu~ion r.tdlotmc-c~ (seslumibi and tctroforfU)lon abnormality beC8U'\C areas of significant arterial narrow inK cannot !'e.'pood to the increased blood now demands of the 'ltn:."!l as well as the normal aneries can. Imagt':'i o f the hean arc: obIruned iml11C1.lIate1y after Stress. and the damagetl myocardium shows less 11-201 chlonde uplake than surrounding normal heart mU!'elc, Four hours aftcr S1Jl!.\S. the feS.ting pmicnl i~
,,
injeclL-..l with 1.0 mei ()7 M Bq) of '11-201 chloride to pr0vide informll1 ion under normal cond l' ion ~. An clDl1lplc ilo shown In Figure 1)-7.
Xenon Radlapharmac:eutlcals XlMon rJJXe' Gas. Radioactive xcnon g:L\ I~ 'iIIppIla:I at ~tandard pressure and room lempcrnturt' In • ~!lIII o;ealcd glass vial (2 mL) in ~,of 101020 mG (371h~ 740 MBq). The g lll.'~ \'ial can conl"in atmOlOpheric ainu mixlllre of 5% ~cnon and 95% c~rboo dioxide and I~ sulubk for Inhalation by the p.:&tient for dlDgl1O§tK: e"alu3nOll of p!IIimonary function and ilT\:tging. The general ~ure. volves mixing the ~cl1On-IJJ gas In airoro~y~n in ac~ circUIt ~pirometcr ~~~Icm thai del;'c,-.; the rodiooct;lC PI and KbK~ l hing t])e go_ tl1ixtu~. The inhalation Slully OODsi'l ~ of equilibrium and W:L,houl pha.o;es. v.ith the paid Sluing or supme . In the .... ashoul Mudy. the pahent elhlJfl, the \cnon-IJJ ga.~ inlO an actIvated charcoal ltap 10 poeOd e~JIO!'ure of Ille lechnologist. Im;lg" are obtained COIlt ... oumaIler. .... ell-dJreclt'd gradIen t field~ 10 selectively excite hydrogen nuclei (protons) in a selected small vol ume of the patient"s body. 1llc exci tat ion is done by use of radiofrequcllC'y fields. and once the exCitation fields are removed. the excited protons lose the energy they ga ined . 'fhey emit a weak. but detectable. rollJio wave. whose ~m!llgth and manner of decay CIUI be used 10 gcnemte diagnostic medical images. The tesla (T) has been adopted lIS the official ullit of magnetic field strength for the intematiorwl system of units . The conventional unit. the gauss (Gl. i\ 10.000 urnes smaller. MRI is normally performed at 0.5 to
L5 T. 1be images produced by MRI are $uperficially similar 10 the cross-sectiooaJ images of the body produced by CT. MR I. however. has the "'kkd advantage of not uSlllg IOIIt1:lII& radiation. such lIS ~ - rays or ,.rays. and easi ly prodU«j ex quisite soft tissue images of the body in any desj red plane (coronal. axial. sagi nal . oblique. etc.). With MRI. image 00II -
h vascular analomy of the patll'rlt'!. AVM 101M (aW', a dJ91lill !.Ublfacuon t«hooque was used m whICh dtg,t.)1 ,mages obtained pnoI to InjI/'CtiOn of thr contrast agent were wbtractt'd from the conl1asl agent Images by computer
~
!ltallng illfeclion or spillallllJury. and the uSlrojlltc~1 illallnlCI studie, arc u«tllO d iagllose pept ic acid die char.K:teri~lIc~ are UctcrtulJted by the panicle ~izc: of lire barium su'p!'llsiolJ. ib ~ isco,ily, and it~ pH. which in tum are dctermiJred by the addition of'm:11I amounts of flol'oring agents. suspending a~em'. and so funh. lbese additi,'es are lhe proprietar) secret of tIM: manufactun:r and do impn:!'·c tiM: diagnoslic pmpcni!'s oflhe barium colloidal ~uspcn slOll for GI r.tdiolOjliCIII StudlCS. Barium sulfate prcpMalioru. are u5C'd to study tiM: ewpIta. gus., stomach. and duodenum as pan of l1li ..SOf>IIagr:lm or UG I serie!! and are gl"en OI"'Jlly. M ost pilhent., find thoc laSte of these dense mi.\Hlres acc.:plable (Ihey arc: u,uidly li'en II stra .... berry or lemon na\or). but they d"lr~e tIM: hea\y texture or the barIUm. Barium sulfat!' ~u~pensions are alo;o gi\'en OflIlly to ~Iudy tire enlin: ,mall bol'>cJ (S8FT) or t'\.'\.'lall y to examine Ihe colon (IlE) ( !-ig. 13- I 8). Typical b.,rium ~uspensions range from 30 to more thun 120% weight/volume ( .... Iv). and bet'ause they are collOidal suspensions. they I;'IInJlOl be gi'·en imrJI'Ilsculatly: ti>c l"OlloidaI panktes would produce fatal pulmonary !'mbolrsllI 'The barium suspell$iom uo;ed forUG I or BE studies an: too dense 10 be used fOf gut op;lCificahOll dunng cr Mudle, of tiM: abdorn!'n, because they ~ unacccplllbic roldlOlr:ap/lie amf!lC1s. Instead. conmw.'reial barium prcP.lr:ltIOllS an: dl ' luted to I to 4'1> \l1v.
Diatriroate.
DiDlril.oate is classified as an Ionic tltonnmene contrnSI agent arid is a~ailable in the rncglulllure, oWdium. or eombinUIIOI] of mcgluminc ~nd sodium '1I1h of lhe fully sub~titulcd triiodubcnl.oic acid. II ha. a l1loli.'\.'ulor wcight of 614. and the organicully boutld iodine I;'ontenl is 62%. It s IilIlts ore used mainly for angiogrophy Dnd excretory urography, 'The diutriwatc. mcglununc (66~) and d latril.(JDlC sodium (10'1» combintlllOlI may be used orally or reaally to delineate the GL tracl . Thl' p"'jXlmtlOll I~ loolCaled \I hen !he use ofl)anum sulfate iSpo(enual1y wngeruu' (i.e .. .... hene\'er a suspecled perfomllon of tiM: Gltract exists). becau\e watc-r-50lu blc contras.t agents are Ijuid:ly absorbed throoj;h the peritoneal surfllCC . TIl.: high oo>moiaiity pre,ents "'Dtet absorption lind kllCls to r:lpid IrallSil Ihrough the G1 tllM."l..
"
," ~
"C
;j 1
-'" / oj
, orl ph) ()~t
Figure 11- 19 • lymphanglOgrarn of a I'\CJ(malleg after EthlOdoI iIdm!nlSlfatlOO. The r""glumine saIL dilute solution (1 8% w/v) is u'\ed for cystography after >l.cnie eathctcritation of the bladder.
Ethlodol, Ethiodol is a sterile preparation containing ethyl eSlefl; o f the iodina ted fally Ildd~ of poppy-seed oil and it is used for lymphangiography, It cont ains 35 10 39% of Ofganicall y bound iodine that has been added to the double bonds of the fatty acids. Because Ethiodol is an oi ly substance and IlOl miscible with plasma. it can not be adminrs.tert q.Mt m;r.\i&nal'oCW;. A typtcal norrn.al\ymphangiogrum of the lower leg is illustrated in Figure 13- 19.
lodjpamide Meg/umine. ludip:nnidc meglunllJle is. i-onic d imeric contra~t agent lind i~ giH'n a~ the me~_ ~l t . .... hich is highly w.ucr oefr.
Wll~",!..
1m.
Ko·... t.\~. R. 1,, 1lfIII I.."y. I R Rwlioph'''''lICCUhC"I,In N...,t... \Ioi d"" l'raI:I=. Nl,,.ul\. c t'. Al'I'lelon & l"""'lIo. 1987. Kun'lICI...,henliaot "'"""'P'< ,a lhe I""'P"rllk" of 1Cclo· "," urn ,odiphannKru"cah. In SMipOO C 8 ted 1. TC.lbooO, or T1iNf)o """ I'no;IICC_ 2nd cd. No... y",1... Gordoii A ll roach. 1990l " U)Cbluen..O K ......... )'loII20:R6~. 1995 j. Scti .. oc"",,. K , A".., ... C'tIem 1111 F.d. E:nJl lJ:2""'..38. 199-1 6. lun""",- S.. CI .... CheRI. IUv 93 I t17, 1993. 7. CO>Iollo_C. fl. ...... I. N""I Metl. 24.\53. L9IIJ 8. Ju,hWII. S .. CI al .. 1""'1· 0.."" 2!I.341. llIIl6. 9 L.."'-c. 102:2476. 1980 10 de L..ln~. C. l., C< -'.. N..,t. Med.. ""~. 17 161. 1990 II. t.koRni.. J L. C< 01. I.... J 1'1..,1 toted B..... I Ltlll. t980l 12. 0hQ. It _C< 0I~ CI,n. Nucl. Med. 10".j(Ml t""'
Pros"'''
"""":pI""IK)'
11 IIkw1cC"'i considered in of ncunlfla] lICtivity in thoi: cenlr~J ~oos ~~~Icm (eNS), Ihall~. Inc br.lln and spinal coni. In IIIOSI ca5/.'l the bruin is the inLt'ndcd larget. In a kw cases. "in \kclctal mu in OOnllTlQn and like .... i"c an o_cmll boulertpper sh~pt Ihat has been D~~I)("iated with neuronal 1'01t. tal MJdlUm channel block. leading to decreased neuII:IIlI elc1tution. Channel blocl of other inorganic cations. IIOUIbly Ca:' . may conlribule ,ignificantly to Ol"ernll Ktioo in sortie insIlIllCt!$. AnlipsycOOClcs lite crouped InIO ...~ and Dtyplcal categorie,. BOlh cUlegorics \hare a ~'om fe.lllure . • dopamine-lile structure. often h)drophoIy ~u~tituted, This fc;)ture can be relaled to the most Iy {'lied llClion of lhe se ageflls. COrtlPOClIIll"C umage>of dop.:unine ( DA):1I D1 and DJ recepton in the: limbIC .;..~. In recombinant D: re"~rtoo relatioosh,p,'1 thcoril.ed as long aso a~ Johnson and EYflng 6 to be ~i tcs of a bioao:tl\'c protein. might sigmrlCantly be ~IIO$tcric modula101')' ~;ICS of the protein of GABA,\ TCt"eptors, Chmcally. Ilcncnl ancsthc!;.n for SUTllC'1') uses mull'ple drug TCsilllen§. Somc drugs rnay be used to augment the gcneral anesthc:tic ugcnt (c.S., neurol~ptic~ and oploid analgesicj), Other drugs /I1lly add an actiOfl (q; .. the: s~elctal
rm-
48S
mllscle relualUS). Also. drogs such as anticholiocrgics mlIy be used to decre:a.'IC: adverse crfect~. Conslilt a cllrnnt rlledical le~tbook for the ways in ... hith these agent~ are IIscd together. Our ptJtpOSe is to COIlsider OIlly the: lCocral anothetlC agent. General anesthetic agents can be bro.'ldly clltegorized as tho&!: useful by the: lfIhalation route and those u''iIImc euent
Sevoflurane. Se'o numr~. FC(llh-O·CIt(CF1n. • an oillgas partition coeOicienl about one_half that of i~ line, and the blood/gas panilioo codficienl is aboul one.... thai or i~flurune. PhamracokinClkally. it reponedly~. ad\'anta~ orrapid uptakcrurd rapid elimi nation It 1 1·
." (b-uepa te Dipotassium. CIorv.c:patc dlpol::l'isiullI. l-d\1oro·2.J·dih) dro-2·(-,,0·5·~ny l · ll1- 1 .4-bcn1.OOial.e ,.·3-carboxyl ie acid dipolus~iu m sail mo nohydrate (Trun· Ide). c~n be considered a prodrug. Inactive itself. il underraptd loss of water alld then d< ,fier.
appear 10 exen J11()61 of their characteri stic CSS effects by binding [0 an allosteric ~ogni tion site on GABA ... n:C' may be N III infanc)l. but the di"Ca!iC does Il()I enlC'Tgc until III !he s«ond decade Of in lhe th ird decade of life. BasiQIy lbephn, sy>lc m has dilTlClIlty discnnllnating between .xl im:Ie\'81l1 stimuh . i'ert:t'pt'on IS illogical. Profll)lll this, thought and :IC1ion~ bc:coIne illogical. AI_ thIl' actual slllICtural ()( nrnllomical k~lons (all: not .... the basic defect appears to In"oll'e OVCrnctJ\lI)1 of IopBlnrrgic IICUrollS in the mcsolimblC J)I. lbc long \'-IIL~1 §ulY.ilimcm could help prorlIOIc m.:c:ptor lIf1ini!), and produce receplor amagt)l1i~1l1 activity andlor in~c:rsc ago,>Ill"
Some membc..... of thc: d:l.Sli nrc extrt:rne ly poIent antipsy dIou Iowcr affinity. appeal'> 10 \ ;"Idate the: Ihlorul.uIIlC ~nd apJICu ..... to alluw n~ !iC1«1ivlI)' I)~ Il.'I.'eptors. Lc~S(:ning blocks on. for elllmpk. l\.'Ccptor,. and possibly mcsoconical D: rec.:ptro eoo ld prolluee drug, Ihat ure much Ie' .. unplcawlI (lalienl. Addiliolloliy. a less Jntcnsc: D1 block ~0II1d the effc:c,-~ of other blocls to male up IOOR.' of the lota l OClion (e.g .• S· HT trul"JIUf\cr block). Sc-o"ffl!l;';
rprt!(ul 5 ,,"Ith hu~ re~ic~.
.b~ycholics
have nngs with ellh~lIced nuclcopllility. Of ."(1IIfSe. otllc _ effCCls can be lldequalcly controlled. use of lhe- 1m. iCily of IilhllJllt. Ihere i~ ~ub~tamia l 11\. ...;IDde DIIolw:Io. T c ... .. ..... Joo(td.) .." ..
Mtdic",,", WId ~ .... ppollOO. P \I J M«L, " ". .,e, )t
12. 3}, 34 13
:!OIII. Kort-. It .. .. 01 . I'Wc NOlL Acid. Sc>. lJ S. A 9U6~, Lc-.. ,.. D. A Pro-
38. 1(. . . . C_
-c:"'~';:;,"'!!:"';,._:';;;",,:~hobc ........]a Wolff.... pouI ltI. 4110 ed. No..
.ut_ .,
o.u,....."
I IMemIlIbtoxyJ or mct hylencdioxy ~1I~t i tution on the rq lend s to produce psychotomimetic agcllls, sUggestiRllnIpiStil for dop.ulllnergic (0 2 ) receptors, N-methylation Increa,Cular effects than .....lIro isomer. For most medkal uses. the dextrorotatory IIOIlltr is preferred. OUrroamphetamine Sulfate, USP, and o.KtroamphetIIIIiM Phosphate. Dex troomp/letamine. (+}-(S)W) IpIle11Cthylamine. fonns ~11tS with sulfuric acid (Dexe.me) and with phosphoric acids. The p/lo)pllate i~ the more Qer·soluble Sill! and is prefcrred if parentcral admi nistra_ tal i~ ~uired. The dc~trorotatory io;omer lIa~ the (S) con· ip"atiOhentemline h;I5 a qUllt('rnary carbon atom wi th une methyl oriented Iike lhe methyl of (S}-amphet:nnine and 0111' ,nethy l oriemed like lhe methyl of (H)-amphetaminc. and it ~poncdly has ph~nnacological propcnks of both lhe ( N) and (S) isomers of amphetamine. "The compound is used as an appetile ~uppre,sanl and is a Schedu le IV agent. indicating less abttse potential than deXtroamp/lctamine . BenzpMtamine Hydrochlori~. 8en/p/letanllne hydrochlonde. C+ )- N. benzyl-N.a-dimethylphenethylamine hydrochloride. ( + )-l.phcn)·1-2-{N-methy l-N-bew.yllmine)propane hydrochloride (Didrex). is N-beru:yl·wbsU1utOO mc:lhamp/let(lmine. The lar1!\' (benzyl) N-substiluenl decrea\0e5 eJlcitulory properties. in keeping IOoilh lhe gC/l('T'JI structure - activity relationship (SAR) for the group. Anore;o;iam propenie~ are retained. C laSSically. amphctamine-like drugs ... hh I(lrger thun N-mclhyl substi\Uenls ure ciled as W"IOf"l:xian t lhrough cemral p agonism . No claims f("K ~c1cc tivity anMlng ,B-receplor 'ubtypes ha"e been made in such citallons. The compound sha~s mechanism-of·action characteristiC$ with nlethylphenioote. Overall. it is said 10 reduce appetite wilh fewer eNS excitalory effeclS than de.\lllXImphetamine. D~rhylproplon Hydrochloride, USP. Becausc it has two l:l1ge (~Iath'e to II or methyl ) N·altyl WbsIl\I.l('OIS. di -
ethylpropion hydrochloride. l-phenyl-2-diethylnmmClprOpa n- I-f.II1C hydrochloride (Ttnuate. T epanill. has fewer sym. patlMlnti nlCtic. cardiovascular. and eNS-stimulatory effects than antp/letUl11 ioc. It is reponedly an aoorexiunl agent that can be uSC'd for lhe treat ment of obesity in patients with hypenen~ioo and eardiovascu lar disease. According 10 the generali1.llliOl1 loog used for this group of drugs. inc~asing N-al kyl ~il.e reduces centrul a, effects and increa.-;es {J efree\). e\en though lhe effects are ht~ly medialed principally by indirect NE release.
FenfluramlM Hydrochloride. Fennunulllne hydrochloride. ( ::!: )N-eth)I-a-lTICthyl-m-{trinuoromethyl)phene_ thy lamine hydrochloride (Pondimin). is unique in thi5 group or drugs. in that it lends to produce sedatiOl1 rather than
UCIUltion. Effects are pit! to be mediated principally by ccnt!'lll serotooinergJc, !'lither thlUl centrol nuradrenergic. mechanislTI5.. In large. doselI In expenmemaJ animals. the drug IS a serolonin neurotoxin.l~ It was Wlthdra""TI from human use anCT reportS of heart valle damage and pulmonary hypc.nen~Ion. From its SItuC1ure. more upolur or hydroIlilobi echarnc:terthan amphetamine. tropism for serotonincr· gic neurons wou ld be expected. U lewise. the structure ~ugge~ts an illdirect mechan ism. If un Indirect mechanism were opc."l1Itil·e. tnen all postsynuptic 5-HT receptors could be activated. Evidence frotn :.el'erul studies indicatcs thai the 5lrr l• and tne 5HT1(: receptors an:: most I"eSIXHLsible for the !l3licly effcct~ orS· UT. S·1fT may llsoinnuellCC the type of food selected (e.g .• Jov,'er faller food intake).' I 1lIe (+) isomer. dexfennummine ( Redux). has. greateT tropt$m for 5·1fT sy ... ems than the r....."Clmc l1uxture. II. too. was " ithdr~wn because of toxici ty_
PMndimetraziM Tartrate. USP. The opticall y pun:: compound phcndimctnll'.ioo tannllC. (2S.3S}-3.4-dimethyl2-phenylmorpholinc· ..· ( + Hllnrutc (l' lcgine). is ~"()f1sidcred an effective aoon:x iam thai j, Ics~ ~bu'iC pronc Ih~nllmphct amine. TIle stcreochemistry of ( +)phendimetrazillC is as shown. 110 H
HaC - N
I
H,C
o
keted compound and " about 400 limes 8.' potent t i tht: f!r)"thro ncemate_1l 1lIc absolute configul1ltion of earn ci the Ihftl.Jultin, In h igheT $ynaptic of NE and 5-HT. could account for lhe eNS cffccts. oompound was then reinlrodoccd inlo Ihn"npy as an .....~o;ant agent. It stimulattd WI intcnse mtere!.t In hyIlllIDeS and h)·dr"'l.ide~ :IS antidetlrt'SS3IlIS and i Mugurdt~d .I'kru\~ drug tnatment of depressio n.12 It contillued to be "'" in themp)' for sevcrd l yea'" bllt e,ent ll~lIy W3S wllhht,ft becuuse o f hcpatOloxici ty. The prtSCnl clinica ll y usefu l irrevenoibit inaclivllloni can .~rt'd nl« ha"i~nt·b;a>l..'d inh ihitors of MAO.v T hey .o."OII,·cncd by MAO to agcnls thaI inh Ibit the cll7yme. CMl form reaclants lhat bond co"alently with the en or tbcofXlor. A lXlflSCQUCI1Ce ofim:verstble inactiva• !hit the action o f lhe agents may continue for up to ...n\ dler admm islnllion i~ dio;conlmucd. Comcquem ly. *up IkgBded by M AO or drugs that ele\ale !e,'cls \tAO subslrulCS canIKM be adminiSiL-rcd dunng that timc. for ~ long till1C'. bca\use the agents thnt opened the field .. ta OOnunated il were im:versiblc ,nact.v~tor. MAO
1(.
!fecI 1011 ~u .re ..
.\
[[1:(:1. A
thm
QIlC
merea...:
lsI d ll'ected
typc and
dlustrnte~
PhefJelzirH! SUlfafft, USp, PheIlCI1., ne $11lf1l1e. 2..(phe· nylelhyl)hydnu.lne $ulf:ase (Nardil). IS an effecti\'e antide· pressant agent. A nNXhDl1ism-ba.~ itlaClivator, it .rre,'tnibly inactivates the e n:rylnc or its cofactor. presumably after oxid.lllon to the dialinc. wh ich ClII1 then break up inlO nLOlccu lar nitrogen, a hydrogen alom, and Q pbcncthyl free mdicaJ. TIle latter would be the octile species in irreversiblc in hibition. l.~
Tranylcyp romlrH! Sulfa fft, USP. Tranylcypromine ~ul fate, ( ± )-mms.2'phcnylcyclopropylamine s ulfate (I>-ol/"' nate). WIIS syntt.e.il.ed 10 be an amphetamine IUUllogue (v\SU . alil.e the a-nlCth).t of amp/lctaminc coodcn.scd 0010 the ~ c:ubon atorn).:" It docs ha"c -.orne ampllC'tanunc-hte ",opcrties, which may be why II has more immediate eNS Slimu· lant effects than agcnb that al1 by MAO inhiblt.on alone. For MAO ,nhibition . there may be two components 10 the
TABLE 15-4
Monoamine Oxidase Inhibitors
GeM.k Name f'r"tJpMtMY N. TM
.-
Structu..
A. t •••• , ...",
""", ,
ICtlon of this agen!. One is thouj!ht to Dri~ bccau'\C mmyky~ rromme hIlS strucwral fealUrc5 (the basic nitrogen and the qua~l-lI' ch.arxter of the 0- and .8-cyclopropilne carbon 1II0ms) that approximatc the tr.lnsitlOl'l stIIte in a rotlle of nle1l1bohsm of ,8-ary lllmlJ'It).J1- 21 As a- and ,8-hydrogen atom5 are temo\ed from the normal wb>.tI'lll.c of the enzyme. the quasi · 1Tcharaclcr dcveloplo o\'er the a ..8-carboo syMem. Duplication of the transition ~3te pennlts c\tremely Strong. but rc,·cntble. attachment tl) tIM: enzyme. Addittonally. tran· ylcypromine h I mcc hant'm·based inactlvRtor. 11 i~ metaooti/.cd by MAO. with one ciL"Ctrun or tile nitrogen pai r lost to Onvin. This. in tum. produ\:cs homo lytic Ihsion of a cnrbOIl - carbon bond of cyclopropane. with (lI\e etl"t,"Iron from the fission pairin~ with the remain ing lonc nitrog.:n electron to gcnerntc an imine (protonated ) and with the other residing 00 I methylene carbon. Thus. a free radical is ronncd thai re3iC:tS to form I covalent bond wtth the en/yntc 01" with redllCed nav;n to tnactivale the enlyme.;I'J
Monon .. Ine Reuptnke Inhibitors Origt!lnlly. the lllOll()/Imine reuptake inhibi tors" ere a group of clo:;dy related agents. the tricyclic antidepressants. but now they are quite dh'ct"'>C chemically. Almos t all of the agems block neurona l reuptake o f NE or 5· HT or both (i.c .. lire selccti""). Rcupta ke inhibition by thC"tein bourn! that dial y\i' i~ in.cffCC1i\'e.
PRODUCTS Im;prami~
Hydrochloride, USP.
ImtprarnJIlC' h chloride . 5·IJ.(dtmeth~lamit1())ptopyll · 1 0.1 l -di h) dm-\II dibe:nllbJlazepine mooohydrochioridc (Tofl'll.nil) . •~ tbt bf cornpourn! of the TeA s, It is also a dose. relati\ e elf. antt~yrhol1Oulnone Epinephrine and NE each pos!iC$S It thuS. each can exist as an enantiomeric e nanl iomcr ..... ilh lhe (H) configuratIOn I~ lhe body and posw:s.CngcN iflO!,ltol -1.4.5- tri · phosphatc I l n~I.4.5)P ,1 and 1.2-rliacylglyccrol (nAG). Ins( 1.4.5)PJ Mrmulatcs the relell."C of CII!' from the sarc0plasmic reticulum , .... hile: DAG 1lC1;",:IIe:S protein ~ina.e gcrl('r:l.1 structure ,:onS;!>IS of !>e\cn tr:l.n~mtmbrane a-hehcal J;egmcllls and '" ho 10 dru~ actillg at thC'.sc rccc:pt<
in'i('~ a guamdino molel), ICNHC( - NH)NH!I ... hich i~ attached 10 either an alicyclie or an aromalic hpophillC group. llltSe structural featum an: seen in gU:lJlCthidine (lsmelin) and gu:madrel (Hylofd), which ure uscO dmically in the treatment ofhypcrtension.llIt pn:SCIlU" of the vel)' ba~ic gUlll1idino group (p K. > 12) in the'>C dlllg< mean, Ihm III phySIological pH they IIrt es~ntt:llly tomplete ly pmton nletl. Thus • thes.c: agents do nUl gCI into the e NS .
NH
II
N ............... NHCNH:!
.. 111
/'~
e ,m
0
II
~
OC- ~
GuanettDle
"OCH,
on< lieaL
libl-
I, a
$ICP
'111 po14I:
R' •
OCH", ~.
0111 ;6'"• . R' • H. ~. - . j"-OCH,
"""
-
'oi-'ben n::serpirw: IS gil'l.':l1 orally. it ma~inlUm effcct is secn ... I couple of weeks. A sustuincd eff«t up 10 ~vtral '". I~ sec:n after the last dose has been 81'en. Reserpine ~"."". I'dy mtlabolil..ed through hydrolysis of the tStCf 111 ~IIIOIt 18. This yields nlClh)·J rescrpale and "-..\.tnntethoxybc:n1.Oic acid. As is tYPICal of many Indole ~.;... I't'>trpine i~ ~usceplible 10 tlc:cumPOSIUOII by hsht .. ~.bllon . 80th lhe pure alkalOId and the po..-dI=d
•
Although gUDnelhidllle and guanadrel have vlnu.lI), the !i1IJl1C mechanism of action on sympmhC'lic neuron~. thC'y differ in lhC'ir phannaookinetic plOpet1ie~. For example, "'hile guanethidIne 1\ aMorbtd incomplelel y afler oral admini-.rolion (3 to ,SOIl.1'luanadn:1 is well aMorbC'd. with a bioavailablhly of 8SIJ. J These IWO agents also differ in terms of half-life: Guancthldint: has a half-life of aMt S day5 .... hert'a) gu:madrel has a half·llfe of 12 houl1!. Both agenls are partially nlCtaboli 7.ed (-~) hy the lhcr. and both arc ust'd to treat modcrote,to-scvcre hyperte nSIon, ei lher alone or in combumllon wilh another am ihypcnr.nsl~e agent. Bretylium Tosy/afe. Ar'IOther AeuNnal hlocking ab~m is the aromallc quatern:l.l)' arnnlOlliurn compound bn:iyhum losy late (Brelylol ). Thl\ ~ent is used as an antiafThythmlC drug. [t$ antiarrit)thrllic IICliOlts are not belie~ed 10 be dl.le to its neurOf\llI blocllllS effect~, oo..'C'"er. This agenl is diScussed 11\ more detail in ChaplCl' 19.
CH,
B, Bretyli..rnTosy\a1e
SYMPATHOMIMETIC AGENTS SymplIlOOmmlotik agcnts pnxtuce effec1s re.o;embling lOOse produced by slimulatioo of Ilk: symp:uhctic nervou s system , They may be classified as agents thai pm duce effects by
:I
direct, indirect, Of milled llJo1Xhanism of action. Direct-acting agents elicit a symPllIhomirlJelic ~sponsc by interacting direttly with adrenergic rc:ccplOn. Indirec1-lcllns agents produo:c effeels prinwily by causing the Il'Ju.C'rgic TCceptor 3gonl\tS hOl'e been reviewed,u·15 The paJ'l:nl SU\ICfor many of the ~y mpmhomimetic dnlg~ is ,tJ.phenylethylamine. The manner in which ,tJ.phcnylethylll.mine is substi tuted 011 the ,"t'll and para positioo s of the aromatic nng and on the anuno. 4'. and 13 posItions of the ethylamioc side ehain innuences 001 only the mechanism of sympathomimetic action bot al",/",,, NHCH(CH al2
h
OH
OH
Resorcinal
He
Metaproterenot
HO
N-/6f1-Butylnorepineptvlne (Colterol)
Mrthyl or e1hy l substitu tion on the If-Carboll of the elllchain reduces d irect n..-ccplor
Imperium!),. i
agoni~1
howc~cr.
an
acliyn), /'t'nl~yl
of action ofthc Ilhenylcthylam -
. I by IIIU\;lIlg tile conlpoun(l re.~iSlam 10 metabolic Ii by MAO. Such rompoulld~ often exhibIt en0IlI1 cffecu \cne;s arid greater eNS VII)' than their ~s that do 001 contain an a-alk)' l llrotJP' a-Subsualso i affects ~cplOr ~lecli v lI)'. In the
a..,.
Albuterol
Mtxlifical10n of the catl'Chol ring Clill also bring aboul selectivity al a reccpto" as il appeao> that the calechol moiely i~ more imporlam fOf agonist IOCli vilY at a~ fC(;eptors Ihan al «, receptors. I'ot e~amplc. removal of the: II-hydroxyl gI"QUp from epinephrine givl!,~ phenylephrine:. "hid. in 1.'0/1trasl to ep;ncphrill advantage of the drug 's potent ~t imu latOf)' cffects 011 Q If· ceptors. The ability of epinephrillC' to stilllu l:otc Ih. ~r has led to II~ usc: by injecllon and by inhaLatIOn 10 bronchial ~lTlooth lllu~;cIc in a.~thm:t and III anaph) 11Cl1C~' tions. Sel-cr'dl oVCr-the-counter prcpanltlOllS (e.g .. fill. lIIatcne. Bron~ aid) used for treating broilChiaJ ~hll\a II'( epl nephnne. Epinephrine is uo,ed in the tll:al ment of open-angle Jl» coma. whe~ it app;.rcll,ly rl-uucC$ intraocu lpr Itrel\Sllrf '" incrca~illS 'hc nne of ou,l1o .... of aqueous humO!' from Ihr anterior chambcrof ,he c)'e. 1bc ini'ation often cxpc~ on in~tillation of epinephrine imo the eye has led 10 III! dc ,-eloprne m of OIher prcparutions of lhe drug llut pokao hally are not: as 'mlllllng. One such uample is d'l'I,cll1l
*
mn
PI.,
-
In doses slightly higher than th()';C reqUired 10 increase renal blood no ..... dopamine stimulates lhe P, I'CCl'ptOl'll of the heart to increase eard iac output. Some of 'he effects of dopamine un ,he heart are al..o due 10 NE relcasc. Infu~ioll at a MI'C sn:a1er than 10 #slkg per minute rc..u lts in Mimula· tion of '"'I I'CCcpl Of'l. lcading tu vasoconstriction und an in· crease in ancrial blood pressure.
Dipilfefrin. I)'p...cfnn (d,pi\'alyl cpinephnn~. ~ i~ a prodrug of epi nephrinc Uw is formed by the C)(mfg. tion of the ca/echol hydroxyl groups of epinep/lnne plvalie acid. Di pi,errin i~ much IfIO(e lipophilIC than. nephrinc. 3nd it a.chle>-~5 much bener pcnelr." ion ofthe~ when admi ni~tered topically !I$ 3n aqueous WlUliOll (Of trca ' me n! o r pnm:ory open.ang le glHIIComa, It IS con,-encd. epinephrinc by e~ter'.I~~ in the l'Ornca ami ~nLerior ch.lJrillJ Di phefrin offers the alIvamuge of being Ic~s irriWliJll_ the ~yc than epinephrine. IlIkI because of ilS more tfflCa trol'hpon into the e)'l'. Jl can be used on lower concerH .. _
*
than ~pml'phrille.
Nort!pinephrine (NE). NE (Levophcd) i~ u~ to ll1ainuun blood ~re III acute h)"potcnsh'e states fCSuil ,ng from $IIrgical or IlOIlSlIrgical trauma, central \'asomoIor depression. ~nd hcmorrlulge. Like theOlhercndogcnou~ catecholamines. it is a suhmatc for IxMh MAO and COMT and thus is not: cffective by the oml routc of admini\trnllon. It is gh en by intral'ellOOs injection. Epinephrine. Epinephrine (AdrenoHn) filld\ usc in 3 number situatiuns because of its pOIent illlulUlOf}' efrects on both (f- Hnd ,8- adrenergic l\.""cplo""'. Litc the other ca tc· cholam il1C.~. epinephrine is ligh t sensiti\c ami ea~ily ox idllcd on c~posure to airbccause of tile catechol nn!; sy\'cm. The development of a pink to brown color indicatcCu\"lty 1S taJ,.e~ 00 arc· eccptOl"l to reho: :tIC rc",,'
_g.. Pn· hma usc
gle glau· :ssurc by
eptq1hrinc and norcplllCphrinc (NE). It I' IICU\ C100 tlcn g,,'clec· Ilvity for I~ aradrencrgle rttcplOf, n.e 0'1:t,2 "'"0 1\ 3(X):I . Under certain condition", weh as inlravcnous infu5ioo. clonldinc c~n brieny e~hibit ,·.socQ'hcrieti,c ao:.1t\ity as II R'W II of stlmulatioo 0( penphcml n-a.Jrencrglc rcccp-
10I'"'l. Ho ..... ever. this hypenen ~ive effecl. if it (I(.'Curs. is fol lowed by a IIIuch.longer lasting hypotensi"e effcci lls a result of the ubiTi ly of clnnidin.e 10 Cl1ler il1to che CNS and ~'imu IlIcc ~ fCC\:plor.. 10c;,IOO in regions of the bram. ~uch as tile nudeu\ traclUS 'KlIilarius. Stimulation of these (II reccptOl' bring.~ aboot a decrease in ~ympatlletlC outflow from the: CNS. "'hich in tum leads 10 decrca'ICs in peripheral .-ascular resistance and blood presStlre..Il~ .. Bf1ldyeanlia i~ al'>O rroduccd by cionJdme as II J"C)IJ lt of a r:entr:lll) ind~cd facilita_ tion of tile vagus llCn'e and Slilnulatioo of cardiac prf:Junc· liOlUlI a :-oorenergic I\:CCplOfS. W TllCse phannocolOj;IClII ilCtion' have made domdmc qUlle u'ICful in the trealment or h.ypcnen~ion,
-
CI
H N
N=< J N H
half-life o f clooid inc r~n!;cs frt>m 20 to 25 hour) ... hile tItI; for guanfocinc i~ about 17 houl"!l. Guan abcnl has the 5hontII durntion of action of!hese t~e agerns. wi th a tulf·Jifr Ii about 6 hours. Clon odine .nd guanfacine :m: cxcn:tcd_ changed in the urine to the extent of 60 and 5()'i,. ~. t,,·ely. Very lillie of guall:lbenJ; I~ Cllcreted unch:lllgtd_. unne.
CloI'Ikine: R • H
CI
NH
.-Hydroxyclorlicline: A . OH
II
CH=NNHCNH2
ApfacIonIdine: R . NH2
1'he:ibl\\\y of claa.ru.ne ud ,'" an:t.1~ 10 u.m an 1U\l1hypcnensl\'l: effect depend~ on the ability of I ~ cornpounds 001 only 10 Internet .... nh rIM: III n.-ccpcor bUIIII'>O \0 gai n enlry jmo riM: eNS. I'or example. in the ca;;e or donidine. the b:L~iciIY of the guanidine group (Iypicall y pK. I3,6) is decll!',,-~d 10 8.0(rhc pK. ofclonidmeJ bccau'ie ofitsdll1,X1 allachme'1I10 the dlchlorophcn) I ring. ThU$, at ph)'\lologicaJ pH. dOI'll(ilne .... 11 exi'-lIO a 51gmlicanr Ulcnl In the nomooil.cd form requlI'ed for ~I!e Into the eNS. Surn.lilUI;OI1S 00 the aromal ic ring also affe(!\ Ihe ublli,y of cloni dlllc and ils analogue, 10 !luin cntry into Ihe eNS 10 produce un IUIti hypertensive ceTl'Ct. Altlloogh various halogl'lI and allyl '\lIbqi lulioos cun be placed al the two orll",
positions of the (phi:nylimioojumd37.()lidine nuclel,l\ \\w.n' tbltea (...-cur during laser surgcry on the eye. Brimonidine u fronl .pula! (I in tcmcuron s.oU.
~ _N
,
N
-
~
Br
iI
H N
N=iSOlllcr of amhylnoRpmcptmnc. IOhich po6SeSSC's!he (RJ configuraIII lhc cW'boo wnh the P.hydroxyl group and the (S) ~'Igunuion aL the c:1lrbon WIth the a-mcthyl ~lIbslilUcnl fil. 16..(j). 11 IS postuhued that o--mt'thylnorcpirn:phnne acts • OJ m:cplOf1 in the CNS in the lic ac· nons probably 'OIlIribule 10 'I~ va'iQtliiatory acti vity . Its hiS, tamine-It t.:e effects inc lude stimulation of 8a.~1ne in the pmphyiluas of migraine headaches and in the theropy follo".. inS myoearlilal infarctlOfl. Sotalo1 is used us an anuarrhythrnic in tn:aling ventricu lar arrtoythm iall and alnalfibnllallOfl be· CIlU'>e in additIon 10 its P.adrenerglC bloddng aCllv lly, this agent bloeh lhe in",'aru K • eum:ntlhal dela)~cardlac n:polam.:auon. Caneolo!. llmolol.lc:>obunolol. and IlICtIPflUlOIoi are used topi cally to treat open-angle glauL"Onul . TItese agents lower intraocular pl"CSSure ... ith vll1uaJly 110 cffect on pupil 'IJ.e or 31,.'cornmodation. 11Ky Ihus o ffer WI 3I(hanlllge over many of lhe OIher drug~ u.'mdolol pOS•.'iC'St'S modest rnembr:lIle-,whili /jn!; acU\ it y and signifK.'""oInl inmnsic ,8-agoni\llc acti vity . Prnblltolol and ca n c:olol al~ ha,'c panlal agon;,tic tlCt ivily but not 10 the: degree lhal pindoiol doe$. The P antagotll'ts .... nh partlnl 3gonistk activity cause ies> ~Io'" ing of thc fUIiOI hean nile than do agen ts wlthoul this capabi lity. 110e panial agOllistlc activit y may be beneficial in patIents ,,100 an: IIlel) 10 e;o; hlbit severe: bradycardia or ,,110 have lillie canlillC 1\'''-' ...... 1.' . Timolol. pllloolal. PI." nbuloloi. and I.'OInooloi ha'e h;olf-life vatuCll In the Sll lIIe mnge as proprouolol. 11Ic Iuolf-hfc of nadolol. howe \·cr. IS about 20 houl"$. mali:mg " one of the longesHK.'Iing {J bloekel"l>. Timolol undcrgoe~ fil"lot-pass metabolism but not to the ~me c~ lent that propranolul does. Tirnolol and penbutolol are metaboli1ed Cl. "ilh the: remaining 4O'J, being e.\cn:1oo in the unne unchanged. In oontrast. 11000101 undergoes ~ery linle hepatic nlol.'taboil srn. Most of this drug is e~creted unchanged in the urine.
/:I,-SElECTIVE BLOCKERS
;, Q
can ~ur·
latc'
,-
"".-
1bc dio;covery that,8-bloeli:lllg
O~NHCH(CH,)2
OH
Otfwr Nonselective P Blockers. Several other nonselCC!J\t {J blockef5 are used cl inieally . These include nadolol (~). plndolol (Visken). pc:nhulolol ( Le~'alol ). cal1eo-
agcnL~
u~ful
m the: treatmenl of canllOYoisculardl~lIse, sueh ~ h}perten ~ion . SlInllllau:d a .;careh fO( cardi(}!;Cleetive Pbtockcl"l>. Canliosekct l\'c P anlagonists are df\lIlS Ihal ha~'e a greatCl" affinny for the P, receptors of the hcarllhan for p: receptOf' In other ,,~ues Such eardioselc:etl\'c IlgCnt~ should provide t .... o ImpoMUm therapeutic :ld valll.:lges. The fir\! :M.h:uullJC ~hould be the lack of all antagonlSllc effe:!.' on the p: rc:ceplOfelecli-'t blodCB. LIke propranolol. mc'lopfolol has low bioo vai labllity because of significant first-pass metabolism. Although !he bioavaHabil. it)' o f bcla~oIoi is \'cry hIgh. It is metaboh;ted t'~ I(,llShc l)' by lhe Ii~cr. wilh very liule uochanged drug c~crclcd in [hoe UrillC. Atcoolol. li~c lladoloi. Ilas low lipid solubi lity and does not readily cross the blood- braul bamn-. h IS absorbed incomplete ly from the gastrOlnlCSllrlal UlI.::t , the ()fII] bioavailability being appro:tim31c1y~, Link of the absori:led po",oo o f the dose IS melllbohzcd; IT10iSI o f it IS r:tcreted UJlCh~lniled in the urine . In the cw;e of bisoprolol. about 50% of II dose undergoes I\c:patic metabolism, I' bile the remai ning 5O'if. is e:tcrc:ted in the unne unchanged, Ace butolol i_ , one of the very few /J blockers .... hose me· tabolite pLays II sigl1irlCant rok in its ph;!rrl\aCoIOJ;ICI] actions. This drug is IIbsorbc:d well fmm the gaslmlmestlnal tnoet. bUI il undergOl'Sexleusil'e firsl -p:lS5 metnbolic con"ersion todi3C't1oloi . Diac:erolol i~ formed by hydrolyllC convn-sioo of the amide group 10 the ami llC . followed by lICelylatioo of lhe IImirIC (Fig. 16- 11 ). After oral admim Stnllioo. plasma k,-cls of diacc:tolol are higher than tho!;(- of IICC'btJtolol. Dill' celolol i~ also II selective /JI-receptor pntagooist Wi lh partial
Labe!alol. Labctalol (Nonnodync) is ~ phcnykthalJol. anllroc derivan.e that i~ ~ compcti ti"e inhibitor It bolh fJr IUld ,8:-adrenergic receptors IUld al lhe ai -adrenergic 1«aool Thor 61:1, If'! 17. ILlr.S\iIoltI.J.M.,ond ll...t>lp. Thtt. 121480.
~.
".;I 81Id., 1 W MClS"J.ICft..... 1 S: I_BII.I961.
21 1 ," A. 101 _. .. 111-' 1'1...... 21091. 1%1 U AfclI. J RM N.. ~.109 Ill). 1984 ~. G" ....... A. 0 .: A~nu. R.~ 8;""1>. A. S•• and Ruffolo, R. It. Jr Su"", .... ''''''''It ", ... """",;", .... "" 5.......... por .....,.... and ~,"' .. In Ruffolo. II It . •• led). "'Ailn:noocI, Kqrt. 1991. P 75 J! HodIIIrd a-.. '8:3-1 I', 1m. 1I0I1n1:.1. D 8 , CAa«h. 10th .... , New Yorl. ~kGr-.. ,..·Jhll. 2001 . p. 115 ~bln. II 0, ' ,8-Admtlor SIIe:. A compari!iOfl of the cholinergiC octivuy of 3 ~ries of alJ.:yhriUlCth),lammoni um compounds IRN • (CI'h). R - CI -C~ I show. n-amyltrintelhy lammon_ iu m.JI which may be considcrcd to hal'e It si l.l' and ma ~, Similar to lholoe of ACh and to be one magnitude lO.·cakcr a~ II mu scarin ic agonist. Thc presencc of the acetyl group in ACh is not as critical as the si/..t: of the rnolc:culc. StudYing a sencs of n-alkyllrilTlClhylammooium J.llits re\"calcd1'l thaI fOl" maltimal muscarinic (ll:tivity. the quatcrnary ammonium group ~ Id be follo ..·cd by a chain of fh·e atoms: this has been rcfcnal to as the[il't'-I>tt)
,
2.!1 (Gu' .... 1"11
"" '''''
IZ (11."".0
"
S· 1M.
,
" '" ,n '" 01 """'
,
d - L47),
• "
.,
c.t Blood PRuu..
'"
J01Gu..... "'a) 2,~ ,\
"
.,"" , ,,.,
10.003"
" "
.
'"n,
0.. _ _ e I,... II II I ' I _ .. Clot I ;;. I I ... """ . .... . ]'iJocarp;ne '~;:;:: curs u_~ shining white erysti11 ~ 11131 arc not h) are ligtll !.Cnsilive. It is soluble in water {I : (I :75) but insoluble in chloroform and I'lher. lions lite slightly acid 10 litmu s and may be the autocla'·e. The allaloid is incompatible: ....·rlh iodide.~. si I"ef nitr~lc. and rc::tgenls Ihal
,
in lhe:
ond lhe:ir iUbs!nllC
,AILE 17- 5 Hydrolysis of Various 5ubsb'ates by AChE and BuChE
."" &1I1'IM
substr.t.
Sou.,.
1I. ",tl...
\.:rI)khol.".
lIu .... til """Inc ItRC
\.:rI\ k"""''''~lnc ~) 1·~·"1bl'lt Iortr)'lWochn)il'lt
Ii"""," MRC 800-,... MIK" 80>,.. MRC
~
,~
f-,I--
.....,1dooI, .. ~~ItoIIt)IIml< lI~pI .. m:.
........
,10>0"" pi......
,
,, "'""" Hwnanpboo_
ml
H",,_ pbI.ma I..."" pa.mo
,.."..,"'......
'"
Human IUK"
'I0000 pi ......
1'0." - ........ .......,....
.I4opooI ill,. ''''''' ' ) " Ool~ "'~ onoIIloIM.,
>, E·ACh
>,
'\
c
ale is ckaved by II gtocl1ll ":'~••~:::: generate the f~ cn/.ymc. h is indicated by kj .
Carbam:ucs Sitch as cru1xlc1lo1 SUbstnlCS f()l" I mcdi ate (E ). the nllc of acC'tylation. of the carbamyl -cn~yme
a~
also able
i is than th.:lt of ils acetyl countcrpart. 'The !'iue limits the o pli llUll runelionn! capadty IIlg carbamate subslralcs to be senllre,·cr..iblC'
AChE. In the mechani sm aOO,"c. depends not only on the
'- A
>, (
" ,0
k) b
E •
· ·
., ,
CX
,.",
,
"\
,
'-c - "_
,.
C
_ _ ex· c..twllylill>ng .....~
~
blu ultlys(>slIg mine. nlool; with Olhcr cholinomimetic dru gs acting In the CNS, has been ~llIdl~'d ror use In lhe In::umenlof Althei· m·e' s di~lISC.loO Cholinomimctics Ihal are CU lTcnll y us..>d or which have been reccntly evalualed in the treatment of Alz· heimer"' dlscllSC include donepelil. galantaminc. rnctriro-
', ••"lbI.lnhlbltors
lan stcp ;eNc ..,
ne inter· :..,·er rh:r.n tylmiool ~ slo ... er !droly~i~
~
alltl"'·
bI t""' of
e nne ! l
1'IIys00figmlne, USP. Physostigmine i. an alhloid ob-.d (TOtn the dried ripe seed of I'h)"sos/lgma '·f'/U'llosunr. l~ as a whitc, odorless, microcry~tamne powder that \/iihtly soluble in water and fr« ly lIOluble in alcohol, db";onn. and tIM: fixed oils. The alkaloid, as Inc fltt oo.yridostigmioe bromide: is about one·fifth a~ toxic as ncoStigmltle. It appe3R to function to a maimer sinu lar 10 thai of neostigmioe and is the nlO6t widely used anlicholineslerolSl: agent for treati ng myu~thenia gra\· i~. The li"er enzymc:~ and pla.Ql\3 cholillCSterase nlClabolizc the drug. 1lIc pnnclpal metabolite is 3- hydroxy-N-metllylpyridini um. Orally administered pyritloo»tigmioe has a half.Me of 90 minutes and a dunltion of action or between 3 and 6 hour;;.
Ambenon /um Chloride. Ambenonium chlondc:. IonIyl bis ( i m inoo:th yleoe ) I bis [ ( ,,-ell lorohen-,y I )d Iet hylaml1K\11 -
NllbeilOll'um ChloflOO
;'1111] dichloride (MytclllSC chloride). is a " hnc. odorlcs.s po,,·der. soluble in water and alCQhoI. slightly soluble on chlorofurm. and prucuc all y insoluble in etller and atct~. AI1Ibc'.oonium chloride b used for the trelltmem of myas· then la gr:a\is 111 patients ,,00 do not !"e'\flOOd SIItisfllCtorily 10 1M.'OStlgmllle or pyrido>.t igmin.c. This drug acts by ~u pprcs5ing the act ivily of ACI!E. It pclSsc"S5('lI a relalL"ely prolon~cd durdtion of oction and causes fe wer side C ffl~ts in the GI tnll;t than the other anli · cholilM!$u:rnsc agents. The dosage requirements ~ary con~id· erdbly. and the dosage must be ind" idual i1.ed according to the re.~pon~ and to!cronce of the lXuicm. Because of its qUhtcm ary am l1H)flium 51ruual cause of death. The organophosphatc in\CCtiddes of low toddty. such as III3laIhioo. gcroerdll y cause poiwmng only by inge!.tion of rtlati~cl y large doses. Pllrtlth ion or rTll!thylpar.lIhiun. hown·e\". COIU5C poi$Ol1ing by inh~lation or dermal abSOfption. '«-\lse these compounds are so long aclin g. cumu l:r.til·e and tmOI.IS lo.d e manifestation s may result after sc'erdl small
o H,C"
II
CH- O - P - F
H,C/
I
CH,
'1 4 ducts IJofluorphoJte. USP. lsontlOl"phate. diisopropylphQ ~W ~)nthclH;
unatogu"'>
S)"mhc:uc amlrKllllooholl'lle",
Amlllooknhot tl~n; Aminoaleohols Ammoom'Je. ~ hstfll:ule...
,,<
• P""", ~r:ta0U'-
The chemICal clnsMncalion o f anlicholincl'l1 'C5 actlllJ 01 parasympathetic pmtganglionie nerve ellding~ is compIl' cated somewhat because \QITlC agents. especially the quaII:I' nary ammonium deri~athes. act 00 the ga.ngha that ha.l." I mu~arin ic component 10 !heir ~timulaliOll pallcm anl_ hi gh dosc~. at the ncurolllu"...ular JUIICt ion ill skc lClallllUSCI!. There ore §c\'eral way~ in ",hich !he ~lruc\tJre-lCtiI~ relationship cOli ld be COO~ldered. but m thl' d l ~SSIOll_1 follow. m aener"JI. the oomideralions of Long I.'t al .... . . ba.
'W hed
.ons of
bllie HnpaHlTlrol of accommod:l1ion. takes place III aboul 30 mlnules, and lhe eye relurn~ 10 norm al in 2 10 3 hours. Gl ycopyrrolull'. 3·hydro~y- I .I · dimrth}tpyrroJidin ium bromide tf-CyelopcntylmalKklate IRobmul). OCCUr'S as a ... hl le. "'ryWlllme JlO" del' 111:11 iJ SQlubIc In ... ater or alcohol but pracl i",ally insoluble in ",h\on).. form or ether.
G/ycopyrro/ate, U5P.
Methantheline Bromide, U5P. MClhamh.clme bronude:. d icth), I( 2-h ~dro~ ~et h)' I)mc:th ~ Inmmoniu m brolll ilk xunthclloC-9-carboxyl:Lle (8anlhillC Bromide ). i~ a .... hlll'. ~ lightl ~ hygrtl!!O!:opic. crystalline: salt that is ..alu blc: In ...·lIter to producc: solulion.~ .... "h a pU of about 5. Aqueous solullOll:! 1m: not qabJe :md hydrolya in a fe ... days. 1bc: broInlde fonn is pn:femblc: to the "cry h}groscopic chloride:.
/
nc hy· :arooll'
"
~qMo r
" , lhan
I Glyl::q:lYl'fotal8
he neu· ,kettle
on. firsl ;IS asS()j for its
.. panoc.seful on fl.
c h)'dro~.2,6- tO:I ·
OS!oC:S.\CS
he early toe acld.c a bcn/J>• pro~id · :olubk Ifl tI ahuo"l
GlycopYfTOlate is a typicu l antic holi nergic and poso;es,."es are probabl ~ ablic:nl bccau!oC: of the teniary chanlCter of the molecule . This III:ti~ily is in COntrast .... Ith that of compounds that couple anlilnuscarinic (l(;IIOn wilh gangliOIllC blocking action . '1lI.! tel'1 i;lry ~hnrnctcr of the nitrogcn pronlO(es intestinal absorpuon of the molecule. Pemaps the lnoe;t signiflCanlllC' tll'ity of this COOlpound is its marl;ed ab>1il~ 10 reduce both the vol ume and lhe acid conlent ofthc ga\lric juic'es. a ~r able action in \ iew of the more recent hyJlOlhc"pasm. nnd functional bowel syndrome. II is t'Ol1truindicated. as nre OIher nn ticholinergics. in pnlients with proslntic hypertrophy and ,Jllucoma. Propanfh~ine
Bromide, US,.. PmpanwJine bromide. 2-hydroxy-ethyl)di i5OpfOpylmcthylammonium bromide ,anthene·9-cnrbo~)lhte (Pro-Banthinc). is prepared in a manner exactly analogous 10 Ihal used for met hamhocline bromide. It is 11 while. waler-soluble. crystalline substance. lIo-ith proptrtics quite similar 10 lOOse of methanlheline bromide. lis chicf difference. from melhanthelinc bromide is in lIS poIenty. ,,'hlCh has been esumaled variously 10 be 2 to , limes as gn:at.
I Benztropi~
Mesylafe, USP. Bcnzlropine rnesylak, 3""(di~n)'lmethoxy)-1 aU .Sall-tropane methanesulfon.1le (Cogenti n). has 8ll1icholinergic. antihi~aminic, and local ... esthetIC proptnies. Its IIIlticholinergic eff«t makes il appltcable as an antipatk insonian agent. It is about as potent_ anticholinergic as atropine and 5han:S 51:lIlIe of the sidt dfect' of this drug. such I1S mydriasis and dryness of mouth. JmponaotJy, however. it does not produce centllli stimulation but instead uerts lhe chaTllCleriSlic sedlIt i\e effect of the antihistamines.
o-c",
•
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,, 1
I
"" •
BonZlroplll$
Mos~te
The tremor and rigidity charnctensllc of partin:sonJYll m
The nmi noalcohol elhers thus far introduced have be~n used Ill- antiparki nsoni:m drugs ralher Ihan as CQnVentiOllal an ticholincrgies (i .e .. as ~pasmolytics or mydrialics). In IcneruJ. they may be considered closely relaled 10 the antihistaminics and. indeed. dQ ~SCS$ substlllltiallllltihist:uninic properties. In tum, the antihistamu-.es possess anltcholinergic activity and have been u.'ICd as ~miparkinsonian agents. Comparison of chlorp!lenoxaminc and OI'phenoorine willi lhe antihistn_ rninic di~nhydrJmine iI1uslrute.~ the el= similarity of SltuCture. The use of diphcnhydromine in parkinsonism has been Cited abo'·e. Iknztroplne may aJ.50 be oonddcred • structur.al relalh~ of diphenhydramine. though the .minoal· coho! portion b tropine and.llierdore. ~ dislamly related than chlorphenoxamine and orphcnadrinc. In lhe slructure of bem.tropine, u thn:e-carbon chai n in ter.'cncs betwee n the niltOgen and o~)'gen functions, wherca.~ the others e\·lnce a IWO-Carbon chain. However. the rigid ring slructure possibly oneo,," the nltrogcn and Ol!ygen functions inlo ~ nearl)'
,
,
".
Ami .... lc.hol Ed:.. , s
,
n:lie\ ed by benzlropine mesylate. and it is panicu l:u1y ,-mt ble for those patienlJ; who Catino( tolerute central ucilaUol (e.g .. aged patienlS). It may also have a useful effect in IIlIIim izing drooling. sialorrhea. ma.~ k -l ik e facie.,. oculogytK" crises. and muscular clllmps. The usual caution exercised wi th any anticholiqic_ glllllOO'lla and prostatic hype"rophy is ~rvcd ..... ith dis drug .
Orphenadrine Citrate. Orphenadrine citrute. N.N4met hy 1-2-( II-me th y I- a-phen)' IbenI.y lox y jet hYIII mine citrw ( I : I) (Norflex). introduced in 19S7. is cJoscI)' n:lated 10 "phenhydramine wucturo lly but has much Io..... er taminic activit), and much higher anticholinergic XIQ. Li kewise. it laclr:.'l the 5Cdat"·e effcclJ; characteristic u "" ~nhydraminc. Pharmacological tcsting indiclIlCS IIw it. not pri mari ly a peri pherully acting antichol inergic bti il has only w~ak effects on smooth muscle. on the c}'e." 00 secretory glands. It does reduce voluntlU')' muscle spi1& however. by a central inhibitory actioo on cerebral _ areas. a centrol effect simi lar to thaI of atropine.
an_
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1959. has a rdati"ely w..ak vie weal: anticholinergic efrecLS add 10 il5 uscfulness in Par~lnson 's ~} ndrome by nllmmi1.lIlg Side effech.
is apparIy of IhI" discrep--
Orphenadrlne Cltralo
ltsy lme . ulfooalc l)Cal anIt apphDlcm an Side c f. moulh. 1Ilmulatffect of
Thi s drug b u'il.-d for the symP1olll~ tl e 1rt':nmelll of Parkin 100" disea.'oC. II reltc,e~ rigidll) bencr Ihan II docs 10: 11101', and in ccn ai n cuses, II may OCL'CI1IU;,le the laller. TIle lIrug wmb31s Incntal slu", ~hnes). Ilkinesi;,. ad)IIUl1l1a. and lad: ri mobility, but this effect seems 10 lIlIlIini,h rulher r~pidly "1m prolonged use. It is best U>cd a~ an I«IJU 11loch a.... bcn/.ir0JlIIIC. pnlC)ehdlnc, crcrimlllc. and lrihu >·phcmd yl. in Ille trca l melll uf l'ymp.1lholyt;cs 1940s. Ie ",as \OOfl cstablishl"d, ho ....e'·cr.
tism arc , 'lI.lulI · cnalion n mimilogyric
~,N-di
cilmlc :110 dl ' jnhhi~
actiOl1, : o f di · IlIt it I( JeCausc ye. and spasm.
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lOOk piaComa,eith~ r known or~uspectccomeltlOniom
" N,cotlnie ChO\\ne,Qi POSTG.\NGUONIC NEURON
COPalll/n
bIod'e sitd is the absence in lhe ronner of a membrane barrier or sheath that en~elopcs the ganglia or constitules the blood - brain barrier. This is import.ant in the accessibility of the si~ of action to drugs. particularly Quaternory ammonium compounds. because they pass through living membranes w'th considerably greatcr difficulty and selectivity th:m do compounds tluit can niSI: in a nonioni~ species. The es.stntially bare nature (i.e .. lack of lipophilic barriers) of the myoneural junction "ennilS ready IICCCSS by qUDternary ammonium COmpotlnds. In addition. cumpounds with considr:rable moleculardimen sions are accessible to the IceeplOl'S in the myoneul1l1 jutIC· lion. As a ('('suI! of this property. vlltlations In the chr:mical ~truc\\Jre of qU3tcmariC$ hal'e linle innucnce on the potential ability of the molecule to reach the cholincrgic receptor in the neuromu§cu11I/' jUllCllon. Thus. the following types of neuromuscular junction blockeT$ have been noted.
Nondepol.rtzlng Blockl... Ag."ts
reduction "')' msuffiI Cf'rcbrnl 13\1:
S89
CH.
Tr.tdi tionally. nondepoluri:ing blocking agrlllS is a term applied to calegorize dnolll that compete with ACh for the recognition site on the niCOl' nic ra:eplor by pre"cnling depolarization of the end plate by the neurottansmiller. ThUs, by decr'r;lIliing the effective ACh- receptoroombirumons. the end plate potenlial becomes too small to initiate the propaioted aetion poIent'a!. T his rc.~u lts in paralysi s of neuromu~ eu ill/' tl1Ul:Smi.'lSion. 'The action of thc:sc drugs is quite analogous 10 that of atropine 81 the muscarinic reccplOl' sittS of ACh. M:m)' experiments suggest that the agonist (ACh) and
the :mtagonist compete on a Of\C-to-one basl~ for the end plate receptOl'll. OnJgs in this class are tubocurarine. dimethyltubocumri n.e . pallCuronium. ~nd gallami ne.
D.po........,.., Blocking Agents l)'Illgs in Ihe category of dcpolari/ing blocking agent s dcpolari7.e the membrnnc of the mU5Cle end plate This ckpolarilat;on I~ qUite similar to Ihat produmi nal opmnions) was obilltnable only wl lh "de~p" aneMhe!;ia "'Ith the: oruinary general an('sthelicw. Tubocul"1lline pt'nnitJi I liper plane of anesthesia, .... ilh no 5:OCnfice in thc: musck relal.lt.on so important 10 lhe: surgC(ln . A redOCM dost o f tubocurarine is admini~ered ",ilh eth('r btcausc elher ;lse lf l1li curve-like action.
Curat"t. unul relalh·ely I"tCCnllimcs. remall10ed lbe only ~. ful cUl1ln lmg agent: and it. too. ~uffercd from a lad of SUt.ndardi/.lltion. 1lle original pronour".'cmcnt in 19)5 of the structure of (+ I-tubocurarine chloride. unchullenged for )5 years. led Olher workers to hope for octi> lIy III ~yntheti~ suhstanec.~ of le~s eompl('1\ily. TIn: (jllatemul)' Iltllftlonium chal1lCtcr of lhe curare alkaloids coupled Wi th the known activity of the I'llfious si mple onium cOlnpOIJlld~ h.ardly scemed 10 be coincidental. and il was naillral for rc'(' fol lo .. ed. A trlJcurium Sesy/a te. Alrncurium bcs)'late. 2-(2-carbox y~lhyl }-l ,2.3.4-lctrahydro-6. 7-diflletho~y-2.mcthyl-l ve IllII)' Jisoq u inolm iu m beou.enesu If onatc pc ntamclhy letIC ~ (Tracrium). is II nOlldcpolari:ting neuromu'\(.'ulor block· ing agcnt Ihat is approximately 2.5 li mes more potent than rf·hlbocumrine. Its duml io n of oclion (h~ l f- l ife. 0.33 hours) is much shoner Ihun thaI of d-Iubocuranne. 1"hc druG is 1111:laboi ized IlIpidl y and noncn1.ymatical ly 10 yie ld laudallO!iltIC and a ~ majler ljua\(131)' rompou nd (Fig. 17-20). which do not have neuromuscular blocking x,ivily. [n "11m e~peri· mcms show thaI alfilCunum bcsy[ale breaks down al p1/7.4 and 37"C by. Hoffman elimination ~ac1iOll." Atrncunum bes)I~le undergoes cn1.)'nl.lllic decomPOSlllon of lIS ester funcuon 10 yie ld an tnac1 ivc qualemary alcohol and Ijuaternal)' acid. AChE inhibilOl"5 such as IlCOIiligminc. edrophonium. and pyridostlgmltIC anlagonize par:o.JYMS by atmcurium besylale.
IffefOCurine Iodide, USP. Metocun ne iodide. (+} Q.O'·dmM."thylchondmcurnn ne duodlde (Metubll!e iodidl'). iipn:pared from natural crudecurttR: by extlllCling In.;, ~u~ "Ith methanolic potaSsium hydroxide . When lhe: ('."(trnct i. trela/cd with an ellces~ of methyl iodide. Ihe (+ HubocuraIIIlC I~ convened 10 the diljua lemm)' di Illelhyl ether and cl)'slalll1.es out as the iodide (S1.. e\.J.; MIll 1'batmKoI. Todeol )0:129. 1979 II ; ............ V p~ Tmoob 1"IIr"r' l Sci. 1.312. 1986. :9 N 'e. T .. 8IId Grob, D~ J Ncwo a",,", Am ..:i:2J1lJ. 19j1. lfL T",mpp-Kalh",,~"'. S.... II.: J Med. Oorm. J5:J44l\. 1'H2. 17 T""k. D. J.. .. II~ J Mcd. Chern. -".ll6:1. 1'»1 11 ....-. E. J.. ..! S"......;· A.. M 1ft ~ H. 1«1.). QIwIU\al"~ " " _ 1ft 1'IIIrmIooIoo. A.......-dIm. 1,1"' ..... 1969 1'1 InJ. II II Sden", 1(»:26-4. 1'1019 1Q. I~~ 1>1 .. .. II 80- J. I'IIaImacoI 110: 14 13. 1991. II • tr 1m A.. ood 8m'" ...1Iot. R. W" ...... Drul R.. 2.141.
""PI"'.
"M.
! acllOI1 drug i~
lurntiOl1 iUludole ' !Illable.
nero
III
omptly. tions n.~
or 10111' sc\crnl
Il Ita!. L. N.. Nobnc. T .. . "" Chlbo. S , J C.llhov. "" . PIurmofLOl, 22: ~1 . 1991 Il.w.:n-. K. L..! V~ . P M. 8, J 1'twmaroI, 106~n. 1992. " .,....... M A .. and II""""","",,·H _ . E. I.: J. I'\wm, Sci. 6.)716. 19'1••
595
'" WIlliamooII. Berlin. Sp"'jO refem:d 10 as the rum di!ilOltubulr). comW!Cling moole (also re ferred 10 as the Imt fli!iIOIII'huI~). and lhe cofh eal and medullary coilectillJ tubules. Each of these nephron 'iegmenlS COlL~ists ofuliTtilNCtumlly and fUlIClionally u.uquc cell types. 1l1e ph~ioln&K"1J role of lhe glomerulus and each nephron sc:gnw:nt i, di .. cussed below Il.~ n rd:ncs 10 tnc handlingof lIuponmusoltnn lind waler in nonnlllly hydr~tetl (nornlO,olem,e) and !Ic~). dr-ned (hypovolemic) persons and in pallenl~ ut"flicled w,th various edematous disorders (e.g .. rongesti>e hean fll1urt.. C1lmosis of the Ih·er "" th ascite~. and the I\t'phmtic 1)11dromel.
fUNCTION F.nctlon of the Nephron When the ph'S. Voillme Is NOill al (Nal iIIovoiemla or Euvolemla' As blood is deli'erect 10 each glouw:",lu.~. many (bul 001.01 of its componen ts are filtered into 80", man· ... ~p;Ke tMIuP the "pores" In lhe glome rular Capillary Ioopl.. !;c"enl cochemk1l1 properties of each blood L"OlLlponen\ dictale tlIr extent to ",hio::h it IS renlO"c:d from the blood b) glolllcnU filtrnuon. These mc1ude the ooruponenl's rel.nil·e n,..,k....br ma" (M,). o"el'1l l1 charge (applie~ primarily 10 large mokeu1es). and degree and nalure of bindmg to pla~ma pi . .1Ii. For example. plasma proIelllll ,,"h an M, in e\~of~fYJl D~ and red blood Ct'1I ~ are 1101 read,ly filtered .... heITOIS "",. M .. IIOII - prolein.bound cmnponents (e.~ .• Na', Ie, 0. IlCO.) -, ,10c0se. and ami no acids) an: readily IiItelTd.' 111e mit' of filtrauon of pl ..... ma componenlS that ~ un M, of less thun 50.000 l)a alld arc 1101 bound 10 pb!./III
""'\I-
protein~
• IXpends d,ltt1!y 011 Uw: h)drauhc (II)Uro:iratic l pit \"11' the ren!! ,·a.culalUn: (Crealed b) rhe pumpon, htanl." 1cnth 10 drive "".'er and o.oIUI~ ()U' of tile glomeoular ~ IeII into 8000.man·, split .. • Keillri m"c~ly 10 the pb._1na .... "IlI..: ~... re ( the~" ""'''lure crealed by the pla,nu proI~,n ...... h," tho , .... lure) ...... hieh tends I.orptioo of
• l:$$Cnt rall~ 100'l0 of the fi Irered load. of glue"""" .",rno xid~. and Iow_M, pr'OIel", IO
_ _ Oensa ~ Cells
0""'"
SITE 1
UI"I''''
Etterent Anarlola
phlsma
of ... al~'
ics (Fig. 18-1). Each minute only I mL of urine is formed from the 125 mL of glomcnLlIIf fiJtr~te .s Thus, appro~i malely 99% of the glomerular filtrate is nonnally reabsartx·d. The IWSflJWr qUl/ntiry of each filtrable pla,ma componenl that rraches Bo,"'man'\ "{I3CC-lhe jillt'rrlllO/ul of a substance- depends directly on the GFR 3nd the concentr,ll.ron in plasma of lhe porIion of lhe filtrable substance thaI is not bound to plll!ilTla proIems. ThoIt is. the filtered load of. SU~lance equals the GFR (in millilucl'1I per minute)lil11('li the ooncentllltion of unbound, filtrable sub'\lIJJIU\'C luminal e'l'"ironn)('nl dmes I"l1Oft' callom ,K' , Cll~' , Mr ' ) from the lumen Into the mlen;tiperlICClIularly (i.e .. between the thick asceodrng limb dtl.1O, II The combined activities o fthi' No . IK '-ATPasc-
"the
or
dNa' .'" !lIthe reabsorptionofup 1020 lo3O'l>O(the fillered load of Cal ' ,'0 the rnairlCcnancc of the high osmolality o f the medullary imCf'Slilium (which is absolutely critical for the norm~1 (un.ctioning of the human roephmn).' l and the ability of lhi ( nephron SCgl1leOl [0 reabsorb more Na' ~nd Qlher solu les than usu31 when proximallUbu le Na ' transpon has been inhibited.&. " Th is latter CQIllpC'IISD10l')' phenomenoOn ClI.pluins .... hy diuretic, that IICt primarily al s ue 1 are 001 particularly efficacious. The descending limb of Henle's loop is responsible for the conccntf1!ltion of lu minal fluid (i.e .. Il!mova] of .. ater and addition o f Na'), whi le the thick ascendmg hmb is Il!sponslble for the di lution of lUminal fluid (i.e .. rt'moval 0( solute from the luminal fluid without eoncomitant removal o(wDter). lie~. colleclivl'ly, thrse two nephron segments produce a mas~ive o\'craU reduction of luminal fluid \'olunIC and solute contcnt. Inten:stingl y. IhI' osmolal ity of the lun.i nal fl uid in tile tenninal portion of tile thk k ascending limb of l-knle'~ loop i~ tlOI much different from that of the fluid that I'mI'" the dc)oCending portion of the loop (though drastic changcs take place in between). As the luminal fluid leaves the thick asceo(lI na 11mb of Henle's loop, it come~ into contact ..-ith the m(lcu/(I dt'IIS// ttl/s, II speciahled group of tubu le cells that communicate wllh the gnlnulor cell~ of the affertnl arteriole be10nlling to the same nephron" (fiB. 18-2). The macula densa cells are like the thick ascendmg hmb cells. in that they house b(! K ' '" ,.
tl\'ely pumps it into !he intel'1Otitium .... ilh subsequenl passage into lhe ~urrounding vasco l:llure: IfItr.occ:llulpr C I- enters the intcf1illtium through channels in the antiluminal membrane, Appro~ i m.atcly ,5 to 8% of thc filtered load of Na ' is reab~ at si te: 3,.. tl I
'ri!t! fUc!
SITE 4 The connecting tubule: (i,e,. laie: distAl tubule) and the: conical rollc:ctmg tubule: house the foonh and final major si te: for the reabsorption of Na t from !he luminal flui(!l' (Fig, 186), 11us portion of the: nephron is composed of twO distinct ~'(:II type$: the principal ulls and the inlumlllft'd ulls, The: priocipal ",lis nrc: important for Nu - reabsorption and K ~ !;CCretion, whereas the imercalate:d cdls (subtype A) are im· portant for the: generation and §ccretion of H ~ , The intercalated cells possc:.~s only small quantities of the: Na '/K ~ ATPuo;c on their ami luminal membrnne:s. bUlthey conlain abundant qllllnii ties of imraccllular CA, which C:IIal1'/,l:5 the formation of carbon ic IICld from COl and .... ater, Thc: carbOlllc acid ioni1.c:S, yielding H ~ lind HCO)-, The H ' is thc:n pumped IlCth'ely imo the luminal fluid by the luntinal membrunc: - boond H ~ -A TP:isc:, The driving fon:c: for the: reabsorption of Na · in the principal ee:lls is once: again the: deficil ofimral,'el!ular Na ' crea ted by the Nil '/K" , AT~o;c on the lllltiluminal mcmbranc:, ",hlCh coumc:nr.mspotls 3 Na ' uphill from the principal cells mlO the IIItCflilitium and 2 K " uphill from the interstitium into the principal cells, In =ponsc to the deficit of Na ' in the principal ccIL~, the Na" in the luminal nU ld mo\'e$ downhill inlo the principal cc:.Jls through Nu ' channels in the lum(nal mcmbr~nc: and i~ sub§C(jucn tly pumped Bai"cly into the i olersti ti urn by the unl iluminal nll:mbranc:- bound Na '/K " , ATPa.lllomcrulat f«dback)' . 1j ~
j T~1"C
.. ..... rfOlWTli~
( RmeK)
C),n~ of mctolawne and indapamidc, ' 2 This is p.1nicularly importantt!) indivi duals with pree~ iSli ng impairc:d renal funclion woo rc:quire diuretic Iher~py. Thiazide ~nd thiozide-like drugs are frequenlly ineffecti ve in indi vidu3 1 ~ \\i00 have a GFR below 15 to 25 mUminute, Mctola7.one· l , ." 016, 53.'" urn! indapamide'2 may be useful in such cireumstances, ThillZide and thiazide-li ke diuretics can be invoh.~' COI1lbi natioo diuretic lher.lpy (i.c.. a thiazide or thl37 ldc-h l e diuretic plus II K +~p;lnng dmretic) may p!'CVCnt K ' loss under tl'w=se drt:ume of va sodilator)' prost;lglandins. Fift", they induce a redistriootion of intrarenal blood flow that i~ tbought to par1lcipille In a positi"c way towan! the magnitude of the dlure$is,n All diuretics that act at sitc 2 are equally cfflcacious alld faT Il'M)I'e cfficacious than diuretics that act II sites I, J, or 4, As mentioned abovc, becau'\C of thcir sitc of action alld dru;lI(:y. these agclll~ IU'C clHnmonly refcrred to as 111011 and h.[(h·teiling diuretics." Iligh-cc iling diuretics secondarily cnhancc the urinary loss of K ~ and U ~. Fil'lit. by inhibillng the INa " I K 'naCl'lWUlsport ~'QIllpl('.'( at site 2. they preven t the gencrution of a lumen·positive lrun;.epithclial voltagc and. tilerc:fore. the panrccllular reabsorption of K' and other callons. Second. inhibition of Na' reabsol'ption at sitt 2 ultimately (\elivcl"!i n~ of the filtcred load of No ' . al a faster ratc. to liite 4. Th IS leads to an cnhanced CAch:mge of the Nu' in the lumi· nal fluid for !he K" in thc principal cdls and the H ' in the inteocalutcd ~Ils (Fig. 18·6). When the loop diuretkll are used in "slIbmuimal" doses for the treatmenl of hypcTlen~ion , lhcy nre uHcndcd 10 create a diUI'l'Sis similar in InagnitOOc 10 that produced by the Ihiatide alld thilll.idc-li kc diuretics, Undcf' these ci~umstances, loop diu~lics usunlly !If\! associate" with a lower frt:queocy of hypokokmia than the lhilll.idc and thiazide· likc dmretics becaus.c their dUlll.tion of action is sllOncr, and the kidneys havc more limc to n::adjus!. 'IU. ~1 When the loop diuretic~ IU'C lIsed to treat acUtC edema. howe,'cr. higher dosages lITe freqUC'ntly used. and !he Na" and K " 106$C~ exceed tho!;e accompanying thia/Jdc therapy,JIC When the loop dIuretICS inhIbit the I Na '/I K" ncl- cotransport system ill the luminal me:mbrnneofthlck ascending limb cells. they in turn decrease the IUlnen·posill'e trun>epl' thelial voltage that promoIeS the p.-traCC'l1ular mo,'cme:nt of luminal fluid cation s such as Ca:' inlO the interstitium (Fig, 18-4), Hence. loop diuretics may illducc the renal CAcretion of up to 20 to JO% of the filtcred load of Cal ... provided the pla~m~ \olumc is OOt allOwed to decrease.'o I( plasma volume: decreases 115 I result of the dmresis. there iJ an ac· companying compensatory Incre351: in !he prm.imal tubulc reabsorption of fluid and solutes. About 60% of the filtered load of Ca" IS reabsorbed in the proximal lUbuk during normovolcmia. and the percentngc ofpro~imaUy reabsortled Ca z , wiH increase in n statc of pla.~m3 volunle reduction. n.crefore. during diuretic·induced hyp:wolcrnia. less Ca" is dellvcred \0 the thIck ascending limb for the loop diuretics to inhibi t. which will blunt the loop diurctic '5 calciureuc effect.
AOVERSE EFFECTS Four highly predictablc advcrse effects are a5!iOCi2led. fUTUsemilk lind oometanide: I. lIypoblnnic albkwil; ~IIS from ~ cnhancro c~~ lamlnal flu'" N.' for ,ntracellular K' or II ' lOllS" SlIt' CaUl"", IJoould be ucrci.ed when ronc"mlll Ihrnrpy .,111 drun:IJCS IIId CardlX gI~ " InstJlulCd ~ ~."; 2,
k ll'" inlcn~l rlQ the lOX ICIlY of lhe cardiac ,Iy~rcb.·' IlIlhe ~ ICI1!I. and Cleclrutylc tOllSoCll may DOl be ~ panied by chanJU in the GFR beausc of ~ nfCCl!:l'" IIcnts Oft the tubuloglornenll.. r«dboct 1'11«11:1111'Cussed classes (If dillretic~ in current uo;e i> Ih~ttllcy increa.'ie tile renal excre.ion rate of K ' and thus can tnduce hypokalemia. OVCl'" the yean.. thl'« c~mically distinct diurellC) ha~'e emerged thm IPc~a~ Na and CI excretion without a cQl1COmiU1fl1 inl'rea-c in the un nary c>;crelion r.ue of K ~, 1bes.e agcnL~ are Imown as poIlll~';um"'IHmng diurt'lics or tJllI,koUurelic ilgents. Although lhe K ' -sparillg dturetil."s are derived from completely different chemicul root~. they act aI si te 4 (though not all by the same mc:chani'IIlJ. ha"e ~i milar efficacies and electrolyte eJtcmion pallcmS. and shan: cmain ad"erse e ffects. The K ' -"Pa nn g diurelic~ indude spironolactone (a spirolaclone).• rianllcrenc: (a 2.4.7 -tri:lPlHl(r 6-arylpteridine), and am.loIidc (a pyrvinoylguamdine). A m:ent ly appro,'ed 'pirolaclone. eplerel1Olle. i, diSCUSsed latcr in thi ~ chapler.
H
0
0
7 0'-(acclyhhio}- 17P.h)dro~y-J,o.lop~gn-4~nc-21- carboxylic acid .,..lactonc: (Aldactonc). is shown in Figu~ 18-14. STRUCTURE- ACTIVITY RELATIONSHIPS
In the mtd -195O:1n-mely mild di10 n-mol'e edema fluid in Individuals ..... lth CQrlgestive (allun-. cirrhosis of the liver with a.scnes. or lhe nc;.;;~ t')'ndrome or In an amihypenens"'e agent . lIS pri_ 1151:. however. has b«n in CQIllbinalion wnh diutttlc$ :C' - II si~ 2 or 3 in an iIllempi to reduce the urinary K ' ~Ialed ..... Ith the!ie latter group" of diuretics. ~ •• '
·T'&.ml_-6-arylpterldlnes
Slructure of lriunllerene. 2.4.7:::::~';;'~~£~;d;ThdIWbide
STRUCTURE - ACTIVITY RELATIONSHIPS
An utensil'c screeni ng procedure that C'XlI.mi ned O\'er 25.000 agents was undertaken in an attempt to disco\'ct an anlikaliuretlC agcnt that did AClt !la\'C o\crlapping hormonal activity likc that of sPlroooJac1Olle. 101 Promi sing OCtlvlty '" as OOItd with appropriately subsututed pyraziooylguanidmes. Optimal diuretic llCtivity in this series is ob... ,mcs
-
_IK - l.mp'llrcardillC pafommnce anddarnage hcan. brain. lid bdlll:y '·~lS. 'OI Second. dIU~Iic."-Ir>duccd reductions • plasma volume lIlilllcr increased §Yl1lpalhchC 10Ile ~nd iI:rtascd renal §ttrcUon of renin and. ulurrwcly. incn:ased plasma levels of angiotensin II. In addition 10 bemg a poeent 'l\OConstnCIOI". angiotensin II slimulatcs al~lC:ronc. secrclion. Allhough the mechanism of aldos,crone'~ octions at
"'-
IIIC 4 in lhe nephron have been ~llOwn for " 1008 !illM:. its lIb'ilrenalllCtioos have largely been ignored. Recently. ;1 has
,
~
"" I'"tUfbmces. ifill If this finding is confillTlCd in addi: chrueal studies. epltrenone or an/o~rhlnide,
USP (Me' ahydrin, Naqua, GMefic) Ora!: 2., 4.mg ta ble ts Xif»mide (Aquaphor, Dluff!"anJ Not available in the United States
Loop or High·Ceil ing DiuretiC'l BllmeUln/de, USP (Bume", Generic)
Ora l; 0, 5·, 1_, 2·rng tab let'i Parente rlll: 0.25 mglrnl for IV or 1M use EthiIoynlc Add. USP (EdecrlnJ Or" l: 25-. 5O-mg tablet. Pa re n te ral, SO-mg (billie) for IV use furosemide, USP (U s/", GMefic)
Or,,'; 20-. 40-. 8O-mg tablets: 8·, 10· mglmL oral solution P a renl ~ral : ' 0 mgfmL lor IV or 1M use Torsemi~ (Derna~")
Orll; 5·, 10'. 20-, , (1O. mg I"blen Parente,al: ' 0 mglmL lor IV use
It · - S~ ri ng Oiu retiC'l Amiloride Hydrochloride. USI' (Mldamot', Generic) 0.-11 : S·mg tablets EpIe~ (Insp'a) Ora l: 25·. 50-. loo·mg tablets Spirono/;K'one, USP (AidmOlle, Generi(J Or~ l; 25·, 50-, l00-mg tablets Trillrnfel'el>e (Oyrenium) 0,,1; SO " loo·mg t~blets; SO'. l00-mg Cilp\ules Diuretic Combination. Atnlloridfo/Hydrochlorot hlulde, USP (Modure ric:. Generic) Orlll: 5 mg amllorlde hydroch loride/50 mg hydrochlorothiazide Spirono"'ctonelHydroch/orathin~, USI' (AldM'azHh) Oral: 25 mg splronolactonel25 mg h yd. ochlorothiazlde 50 mg spi.onolKtonelSO mg hyd.o. anatomy. and ~. In V......... A. J (~d,). lte ....1 I'hylliol ..... h, 4O!i:34. 1981. 2J 51 ..",.. M R_ and ScuU",,,,.. h. II Bull. Juhno Hopltm....,. 41 . 1938, 24 . M..,n. T.,:utd Koihn. It., N~tu ... 14(,'1(,.1. 1!I--l(l. l!I. Ilocl."",n. W W.. ...1., I. Ch" In't>-i. 1~:63'. I~ 26. Mil.... W . ... 1k>........ M.• lnd Rublin. R.O 1 .....,0- . 72:4893. 1950 17 ROO"n. It. O. and Clapp. J W J Am Cbc:m. Soc, lH8"ll 28. S ......,.... J \! In Gould. R F (.,,1.1, M,,,,",,ul. Design. Adv~ 'nChomi 'lJ) ~ ~5, Wa""",«a DC.n Chemic. 1 Soci"y. t\l64, PII. 87· WI, 29 M... n. Til' I'hy,,I. Rev, H3~S, 1967. 30 Allon. It C,' In C.-.go< . •~ I . t.,d,), DtuJetk,_ChomtWy, ~~; '-'BY and M«I"',.... New York. J...... W,ley" Son .. lila.!. PI' 31. Be),ilY. 2nd 0. 1980.pp. 145 -161. 34, Wt..IIOn. "- : Arn. J. Cltdiol. S7:2A. 198(>. 3' &ik. A "='on. G. and WnrhL F S.: AcI:l1'll) ....... x-II 1982. », Wiko • • C. S.,o.U"'hC'. fn 1.1"""...... 1.1 .\f (... ,'.II......... "' ..." The KIdnodilutors ulldergo metabolic tr~llSformation in
, ......'
eo"
---------::::::; 9--------Ca'do.m eNoMtI
~ ~-------
c;a2.
AIC8\l1Of
Flgur.
19- 2 . RegUlatlOl1
smooth muscle ContriICtIOII (CJIIl1acltOn IS trtggered
by an
II'I~
Ca 1 • . The lflCrease ofiree Cr'
eM
af
bindll'l9 10 CdImoduhn (e M) Ca10 -CM complex btnds to hg hl -tNln kIflaSt' (Ml O O and Its actrva\JOO (Ml(K') MtCK'IiO-
Wi i """'"
MlCK' .,-
j
-'--
-
_,
pI1or',{ates
- - MlCI( - - M)'08irH.C-PO.
.
MLCK- iPO.h
- -+.
Myoain-lC
j
"'" smooth mU4'ia. II is prepared by ~an:rlll1y addmg glyccnn to a mixture of nitric and fuming su lfuric acids. This rcllCtion is Cllothennic. alld lhe re:.c1ion mi~lurc mU'it be cook'il tQ bct we~n 10 and 2ifC. 1'he: eSl.cr is II ooIorlcss oi l. with a sweet. burning laste. It is only slightly solublc In "'akr. but It is soluble III orgllflic solvents.
.lI!oOdilating IICt ion and. because it is absorbed tllrough tht skill . is prone to Io'8 U!o/: headaches llmong ... orl.cl'S i.SSCXWN With II ~ manufuclurc. Thi~ trans.dcmulI pcnctrJliOiI is IIIIIy mtroslyecrin IS uscful in a pa,~h formula'ion. In medltine. II has the: action t)"pi~al o f nitrite~. but liS action denlopl more ~lo""ty and is of lon];CT dUl1luOli. Of all the ~I coronary vlI,·,OOillllory df\Jg~. nilrogly~erin is the onlyonr capable of SI inllliating the production Qf l'Of'OlUlry collatml circu lation and lhe only one ablc 11,1 pre'cm C"pcriilkh~ myocanlial infarction by coronary occlusion. Previoosly. Ilk- nitrates were thought tQ be hydrolrlC'd IIId reduced in the body to nitrite~ .... hich then lo ...·cred Lhc bIool pressure. This i~ not lrue:. ho ... cvcr The mechanism di 11111011 of nitroglyccrlll through ils formation of NO IS described al)()\·c. Nitroglycerin tablet illSiabi lity WII$ reponed in moIdod sublingual tablets.' The tablcts. although uniform ... Il!'o _ ufllCtured. lost pou~l\Cy boIh because of ,·ulaliliwtIOll ci II1roSI)·ccrin into the ~umJolII\ding nmlcrials in lhe con..unaand inteTUblet migrallQn of the octile ingredie nt. Niuql)" enn may be htab,lu:cd \1\ molded tablcts by lI\1;orpcniIIIIl "fi~lIIg·· agcnl ~uch as pol)'cthylcnc glycol 400 or poI}'" ylcllC glycol4000.~ Ln additIOn 10 sublingual tablets. the: thr has becn rormuLated intu an equally efTccli\'c hngual ~. .' for patlcnts woo h:ne problems ",ilh dissolution of gual preparJtions becau~ ofdry mucoos IIlf'mOOIlCS. T dermal nitroglycerin preparalions appe ar to be less clfmtll Ihall other long·lleling nilr~'e.~. :t5 absorp:ion from the: i§ "Ilritible.
of,_
Diluted Erythr;tyl Tetranltrate, USP. Erythntol_ nitrate. 1.2.3.4-butallClCtroi. tCll1lnllratc (N- • ~HCanii i~ the tetraniln:tlc cslcr of crythritol and nitric acid, II II,.,. pan.'il III a manner analogous 10 that used for nilroal) The result is a solid. crysrallil'll: matcrial. This .:>ter II Ycry uplos"·c and is diluted with lactose or inen dllUC1lts to PpolalllatlOll and repoiaruallOfl Notf that p/'Ia5ti 0 alld ] of !hi! membr.me acbOn potential correspond III lime to the ,nscnptton of the QRS and T waves. respectIVely. of the local electrogram. hean is mcdimed by two inwardly du"t'C:ted iomc c um:nts. Wilen the cordioc cell poIentiaJ rcacllCll its threshold , ion channels in the ITlCmbrane art. opened, 000 No' enten the cell lhrough ion channels. lbese channel s give nse to the fast sodium current that is responsib le for the rapidly rising pha.o;e, pha.matIC repr~t.lbOll of ao IOfl chanoel an equilibnum 01 rt'StlO9 (II'), operi (0), ilnd 1n«1l-
629
m~ t hnuc,
anliunginaJ. and antihypertensl,t acth lly. 1lIc:) lkprcs~ tile cardi ac neurul 1lC1\\-ort, and so ~ Iow \inus node aU10maticity, prolong atrioventrieular (A V) ood.:iJ cond uctance. and dcpR:ss myocardial oontr.lC1i1ity. as \\·cll as reduct' peripheral VlIscular resI.mntc to PfC"ent a roronary vuscu lar spasm. Nifedipine and OIher 1.4-dihydrop),ndlllC'l are more cffecti vc at causing ,·asodllation than affecllng ~mal.et" and tension ["C!;po!Iscs III the hean. This is opeciall y trllportanl hccause ..clcclivity occurs a~ 11 conscq\ll,'ncc of di sc asc Sli'Iles. Uypencnsm:: 'mlOIlth muscle is more sensl tllc to Cal ' channel blockcrs than IS llOI'Tl1OIen'ille tiss ue . to This makcs vernpami l and dillilll.C:m more u~eful in l'iChemic conditions. as they havc a more profound effcct Oft CardlOC muscle calcium channels.l~ The inhibition of Ca l · Influx 11110 Cardia!.· lIS~ue by Cu~' alllugonbt> is also the basis fOf" the usc of these drugs as arttiarm}thmic age-nts" The Ca~' channr l blocL~ dampen Cal . -dependent automaticity in the regu lar pao:cmake-r ce lls in the sinootrial (SA) node und depress the origination of tttoplC roci. Culcium unl.llgonists can block reentry p.:Ith ways in myocardial ti,~ uc. an intcgrnl component or arrhythmias. Nume rous side efrcct ~ III llie hcan. sl.K:h as bradycardia. dt:creased cardiac l.'Ontruculi ty. and reduced AV conductancc. an: tr.ICW to Cal ' channel - blockmg activity.
PRODurn
Ve-rapamJl, 5-1 J.4-d imetlx)1 ),phC"llCth )'1)I1l('tnylumilM) 1-2-( 3.4-dirnetoox yphen yl}-2- i~yl vlllcro nitrile (Cli lan , lo;opcin), was introduced 111 1962 as It Ver;,,,.. mil.
l."OfUI1ary vasodilutor and is the proIOf)pe of the Cal. antagoni'll! usn! in cardiovascular discases. [t is used in the- t11'31me m of angi na pectoriS. arrhythmias from ;el"lc mie myocardial ~yndrorllC$. and "'p.....e-mricular :uril) thmia.~. Vt'I1l.pamirs major effecl is on the slow Cal. channel. The n:.o,ult is a slowing of AV conduction and the si nu ~ ..~te. Thi ~ inhi bition of the action potential inhibi1s one limb of the reentry circuit belie,'w to undc:l'"lic most paroxysmal supr.Iventricular tachycardias that uC\sing slighl ~truc lU rnl similarity to papal·crilletivd y. !>oreti tide has high specifICity for the tklu) ..-d rcctiflCr poIass.um c"rrents.~\
Doferilide.
o
" II II o
"-S-O!,
lbutmde. IOOtilide. N· 14· 14..(elllylheplyhunioor I-hy· droll.ybutyllphenyllmethanesulfonanudc (Conm). a class III amiwm)thmic belonging 10 the. rncth:meliulfOllanilidc class of agents. is indkated for rapid eorm:'rsion of auial fibnllauon or alnal nunc,'r 10 nonnal smus rfl),thm. Unlike tIofetilidC'. il is IK)( highly specific for the dchl)ed n:clirlCT potauiulI! rorrenlS (luI and (jl ~ within ccnain lI'sues 10 produce a ";ooch-.. lory effecl (Fig. 19-15). BradyklOin i~ conl'ened 10 li'I3ctJIt prodUCl!i by ACE and other earbo~ypcptjdalb. A ACE causes acti vatlOO of aJ1giotcns.in and lnactllatP III brndykinln. actions tMt appellr to be oppo!ille. lhe ba' I of lhe ~y~tcll1 seems to ravor vu:;ocollstriction. ACE is a mcmbmnc·boulld enzyme anchored "a.... mcmbrnnc through a ~ll1gle Iransmc:mlJomc, donwn '" IIC;If the carboxy-temuna l cXlrenllly. The enzyme IS. contulntllg glycoprotcm with II MW aboul 130.000.lt is nonspecific peptidyldlpeptide hydrolase. widely diwituel In mammalian tio;sI/CS, tMI Clclll"CS dlpeptides from IIIeCl' boxy terminUS or I number or endogcnotls pepudeJ. Til minimum S\ruclur::ll requIrement for binding and MI. of a sub\trllle by ACE i~ thai it be a tripeptide ... ,tIl I carboxylute group. A gel1Cl1Il ('J(ception is lhat lhl~ docs not clca,-e peptlduet,
Vuoc"H •
Figur. 19- 15 • B,adyk.mn formatlOfl iIIld «t1CJI
Chaptn III • Curow''UJr ,,/m' "'~"fj
645
I
I I I I I I I 1""(...· I
'---------,~ ,----------' ------'
I
""
(~ ,
:> the ('ell
-" figu ... " - '6 • Model ~ng d l'oJv9 of the histidine-phenylalanine res!u of angIOtensin I by ACE to form tne ll\apt'Il1Jde Mtj()lemin 11 and thfo dipeptde I!5Idut of tu5ttdine Clod leucine
I
I
Zn-
()H
/
Ii
'.
•• •• 0
H. H.
\
NH
~
C~
C",
/~
NH ,
1-\ NV
~.
,C=o
"JYU"-Suc gll1ndllls 1a. (~1
10-11
11.0
", " 1:1-17
647
Mode of bo.tlon
....,- ,
,'''''''''''' ........ RmW'I..,. 1
pyrrohdlllt: of coaJapnJ hall ~n replaced ..... uh an oclllr! dromoole systcm. Much likc cnalaprilate. IJ'lIndobpril_ be hydroly/.cd 10 tninOlaprilate . .... hich IS the blO:lai.'e 'lit"
ties.
Ram/prj/. Ramipril. (lS. 3&S. 6aS}- 1-(fSj-N' I{S}-I-cMboxy - 3 -phcnylpropyl] alanyl] octahydrocydopenlll ] b 1 pyrroIe-2~;uOO~ylie acKl l-ethyl cster (Allin). is hydrolyt.cd to rlmupnlal. its acti ve diacid form. foster u..an enalapri l is hydrol)'1.cd 10 ilS acl ..·c diacid fonn. J>l:aL ~l\Jrn concc:ntTlltlOlt~ from a singlc oml dltm. ... hich mOSI lilely plays II 1IIII0000n.~m
11 rttc:p:or similarly
role in bmdmg
lhe acidte pun~,n II. AllIO. lhe: Imid:uole 5y)I('1I1 has tlllI I bC'nllmldazok possessing an eIkr nlUSl be hydrolyud 10 lhe: free (l)lwer;ion wl..C'S i~ ltl!
·1
,
",
the
10
Ih,)
, I
~'Qt\\'ersion to the free
til much
10
-2-c;arbo.ylic acid I"hcmhs). does !lOt appar 10 ~ar any blrul:lura] relationship 10 this class. but there is actually a greal deal of 01 crlap 111 the chemical architecture '*llh OIller agt'nts. The first, and 1110Iimulant to uterine contractions. for insomn ia. and panicularly for tile In';atment of in~a n ity. Jill uSC' in hy~nension was rc:corded in the Indian literllture in 19] II. but not unti I 1949 did hypolensive properties of Rarl'K'oIjio spp. appear in the Wesle rn l i terlilUre.~l Rllu"'oIji(J preparations were introdueed in psychiatry for the tremmc:rll of schiJ.ophrenia in the early 1950s. following confirntllli on of the folk remedy repons on their use in mc:n· tally tkranged palients. By the end of the 1%Os. however. the drug had bc:cn replaced by more: efficacious neurouupic agents. Reserpu\e and its preparations remain useful in the control of mild essential hypertcn5ion. The effects of reserpine do not corre late well with tissue levels of lhe dr\lg. The pharmacological effects of re.o;erpinc ....-ere still rnsc:m in anilNIs .... hen il could 00 longu be detc:cted in the bnr.in. jJ Resc rpioc: depletl:$ catc:cholaminc:s and scroto,."n from ce ntral and periphend neurons by interferi ng "'ith the uplake of these amilleS from the cytosol into the vesicles and grunules."'·" As a consequence. norepi· nephrine cannot be stored intr.mc:uronall y in adrenc:rgic neurons. and much orthe I1OI"Cpmcphrinc in the cytosol IS metabolized by mOllomninc ollidase (Fig. 19- 19). Thc bindin g of reserpine to the stOl1lgc vesic lc membrane is finn. ~nd as a !tSUJI. the storage grallUIf: is destroyed. reducing the ability of the net\e 10 COOCt'ntnlte and store norepinephnne. Since reserpine: actS on both centrul and peripher:al OOrencrgic neu· roll~. its antihype rteru;i\'c effC:Cls ma y result rrom l\Curotransmitter depltlion from both of thelic ~itcs. QM:mlCal m" csligalions of the acth'c components of R. se/'ptnlm(J roots ha" e yielded sever-.Il allaloids (e.i.. ajmahne. ajmalicinc. ajmal ininc. serpentinc. and scrpentininc).
.,..
SCd m the treatment of mIld or modo • hypenension or in combrnm ion with OIher hypolmsM agents in '\even: hypertc nslon.
Reserpine, USP. Reserpine (Serpasi!' Rcscrpoid. fYI. Sal. Santiril) is a while 10 light yellow, crystalline ..ti Mid practically ",soluble in water. obtamcd frum "arious \pm!!> of Raulwljill. In eornrllQn with otlier eompounds "' Ith. indole nucleus. il is suscl.'JItiblc 10 dccompositioo by tip and oxidation. especially ....·Ilen in solution. In the dry discolonll ion occurs rapid ly when rc.'II:rpinc is u~. li ght. bul Ihc loss in jXltcncy is usually ~malJ. In sohrOOl reserpine: may break down with 110 apprc:ciablc colordlqt" ....hen Cllposcd to li ght. e~pecially in clear glass COIII'fI'",," thus. color change cannot be used ali an rndell of lhe of lkcomposit1on. Reserpine ISeffecti vc omlly and pan:nteMlll y for the uumenl or hy])Crtension. After a smslc intra\"C.fIOU5 iJoo,oe. lIr onsct of antlhypertensi\'c action u'iUally begins In ~ hour. After InlTllmu!ICular injcctlon. the: lTWimum effMDI: curs within approx imately 4 hours and last.-. about 10 Whcn it i~ gillcn or.illy. tile mu imulII effect occur, ... about 2 .... ec:b and may persiSI up to 4 wecks ~fter tIx 00sc. When used in conjunction "rlh other hy.,wdrugs in the treatmc:nt of sevcre hypertension. the \bil) varies from 100 to 250 ~g .
Guanethidine and Related Compounds.
fIgure 19- 19 • ActIOfl of reserpH"le al ildrenef9IC nerve ending
dine has bc:cn classified traditionally lIS an ~nergio; IDi ing agenl bccuu"l: it con prevent thc release of 1l(Ht""'~ rine fTUfll postganglionic IlCUronS In response: 10 stimulation. GuanethIdIne and OIller compound!; di in thi5!1CC1ion ha\e OIher actions on eatccholammc Ii~m arid can couse significant depIction of these antiDCl I IIdn'nergic rlCurons. llIey do nOl illlenCre with rele. " epinephrine from the adrenal medulla.
-
kul.. ,'-
~ than ~ yu· '~P
.,
/
!J
'\,
,
~
.o;)!,·cva. 1I1IIC' some sc:dati\C' ~ that afC' undc:sll'llble; it al\O may cause conSl1paiIII1l~d drync:ss uf the l1Iouth, Oonidme hydrochloride is distribu ted throughout the kd)o. ""ith the highest concentnllions found in the organs .dimmatlon: kidney, gUl, and li\'er. Bram t'Ol1Cl:nll'lllion< • low but higher than plnsmll c(llll:cntl'lltions. 100 high IIIILtliUlllK)II in the gut is due: to an c:ntcrohc:palic ('y(' Jc in .... donidinc: hydrochlonde is secreted into the bilC' in . . . hIgh concentrati ons, The half·llfe in humans is aboul II hours. Clonidll1C' hydrochloride: is metabolized by the Iiod) 10 fann two major metabohtes. p-h)'drox)cJon,dinc: alll$ glucuronide:. p· H ydro~yclonidine doe1I not cms.~ the Iiood -brai n barricr and h.as no hypotensivc cffect in hu-
.....11. II
kit hllnll'
0
"
C>=:· "" """"'"..
~
II
0
"..,.
Guanabenl acetlltc. [(2,6-dichloro.yllllene)aminolguanidinc monoacelalc (Wytcnsin ). is ayadt'tnergic qonist thaI red~ the release of
norepinephrine from the neuron when sllmulat~-d . The cffect of the drug resu lt.ed for severe hypencnsion tllllt is d,fficult to cOlltrOl ... ,,11 other anllhypencn'''·e agents.. 'The drug ~s 'iOniC of lhe CharllClcriSlic side cffecUi of dirc:ct \ a.~ilalor) drugs. It cau ...... ~ium and ..·aler rc:tenlion and may reqUIre: coadmlnislratlon of a dlurt'uc. Mlno~id,1 also cau't'S ~nc~ tDChyurdia. "'h,,,,h can be controlled by usc of. P.1KIrencrgic blocking agent. MillOxidil topica l )(llution is used 10 treat alopecia n,idrogenilica (male pUllcrn bal dncs'). Allhough tbe mcchani~m is nOl clearl y undcriwod. lopieal miooxidll i~ believed I() ;nC1\'a~ CUl af)('Q(lS blood now. v.-hicb may ~tilllu1ale hair growth. The '" 1II0I:llioo of hair growth IS allnbuled 10 VD-'iUdilation in the ~ idnity or applicallon of lhe drug . re:~u hinll in beller nouri~hmcnl of the lornl hair follide\.
fQ/lt dl('mical decQmposilJon aflcr MOr.I.ge al room ure for 2 y..ars. \Vll('n the: solution is C.\posed 10 II darl.cn.~ .
.
~~
01 urml
rag di l -
fU"
rn
j'"i'\'Jc
"'r,""',"'"
o
......
of the
j"el\
or
~t)< ...- )
Ii ~er.
b, "'" ~u[fC1
Minoxidil. 2.4-dlamlno.. 6-pipendlllOI[)('oJ-OXide (Loniten). wa.~ de\·c lopcd a.~ a rt'sult of ~Iaccmcnt of a uiamlnOlri:wne mo,ely by triamiTImldlne. The triaminotnuine< were inillally observed Ie polen! \·liSOdiiators in eat~ and dog,~ following their of N"oxlI.lc~ in lhe:se animals. The tnu,nes ......... :tMin humans because ofthc:ir inability to foon N-oxide ll:llllnllte~: this led to the diOlides pot;sess WI unsutur.lled butyrulllCtolll: ring. ..... hile the buflld ienolidcs ha,'e an n-pyrooc ring. Phamlocologirnlly. boIh have ~imilar proprn ies and are found In many oflhe ume natuml SOtm:cs. Including pllUlt and lOad species. By far. the mOSI Imponam source.~ include 1>i,illJlis purpuuu arid D. hilUm•• In 1785. William Withering published .• An Account of 11M: Fo~glo"e and ItS Moolcal USC's: With Prnctical Rl'mar\~ on Dropsy and Other Disea5e!i.·' in which he describes the bencficial use of fO~lllove in dropsy (edI!'ma). which oOcn clIists in C HF. Even with n:cem advances in synthetic orgnme chcmimy coupled with the usc of rombinntorial chemistry. no new therapeutics have di~pl!K:ed the cardiac glycoside's. Funhcr1TIOfe, the perennial U~ of these agents o"er mlUlY centuries is c,'en more remarluablt' " 'hen one WIIsiders the useful life of a ""block buster"" drug In tOOaY's markctplllCl'. This remarkable fact I~ ba.o;cd. qui te simply. on the unique: ability of nature to produce elltraortli narily b,oactive substances. which chatllCteristically possess boIh a lipophi lic ponion;n too steroidal ring nnd a hydrophilic moiety in the glycO$idic ri ngs. Thc thempeutic u~ of these agents depends largely on a balance between the different solubility chanlCtcristicl. o f !he ~teroid AfUClure. and the type and number of sugar unilSattached to II. Although the fundamental pharmacological proflt'noe$ reside with the Ac:roidai nucle.a. the sugars play 11 crillcal role In !he bioloeical dfe-2-metllyl·6-0"ol.HlIpyridine-5..:arbonilnle (Pnmaoor). I~ :tnoIher dipyri6ne f'hmphodieslerase F-lII inhibitor Ihm possessc~ phar..cologiclIl prope"ie~ similar 10 Ihll'\t: of amrinone. The IlbiblllO!'l of the dcgrudation of eA M I' resu lts in un iocll';ase • !lie cardiac muscle' s ()(Ce of conlraction.
o
657
underlying disease involving the li ~er. kidney. jXlllCll';:I.S. or IhYll)id. or il may IlOI be anributllble to any recosmzable dio;easc:. In recent year.!. lipids ha,e been imphcat«lln the de\'eloprnen\ of atherosclerosil 111 hullUlRS. At~fOI(;lt'tmis may be defined as degcllCra\ ....e change. in lhe II1tima of uM:dlum and large pneries. This degeneration Inelulle, the accumulation of lipids. complu carbohydrates. blond. and blood prodllCts and is accompanied by lhe formation of fibrous tissue and calc ium deposItion on lhe inl1m11 of the blood vessels. 11!ese deposits Of"/lllIqUt'S db; I ease the lumen of the artery. reduce its elasticity. lind may I:ll';ale foci for Ih romb; and subsequent occlusion of the blood vessel. 1111
Lip'pr"Oteln Clasns LiP('f'rrlftiru ate mllCll)molecule~ consisting of IiII'd subst3m:es (I:holcstcrol. lriglyceridc~) IIOncovalcntly bound " 'jlh protein IIIld carbohydrate. These combinations solubi· h/.t the lipids and prevent lhem from forming insoluble aggreglltes in the plasma. They h:lve II, 'pherical ~pe and con~I,~1 of a 00111'01 .... core sUll'UUndcd by a monolayer of phosphohpids whose polar groups IU'e oriented toward the lipid phase of Ihe plu'ma. Included in the phospholipid rl1OllOlayer lire a small number of ch.ole.~terol molecules and proteins tenned "(1QllpoprOl",i1lS. The apolipoproceinsappear to be: IIble 10 solubilize lipid~ for InIn'\pOf1 111 an aqueous ~ulTOllnding such as plumll (Fig . 19-23). The VllriOUS hpoprotei ns foond in plasma can be: separated by ultracemrifugal tethllique~ inlo chy lonlicrons. vcry-lowlIen);ly lipoprotein (V LOL). intcrmcdiate-dcnsity lipoprolein (IOL). Iow·den.~ity lipoprotell1 (LOL). and hlgh-dc:nsity lipoprotein (HOL). The.se correlale with the clcclrophomic seplll"diions of the lipoproteins as follows: ehylonllcrons. Pll';,8-lip0pr04c in (V1.DL). broad ,8-lIpuprotein (l OL). ,8-lipoprotein (LOL). and a-lipoprotcin ( IlJ)L). Chylomicrons contain 9()% triglyccrides hy lI>el&ht and on,inate from u:ogel1Ol.ls fat from lIIe diet. They are the least dense of tile lipoprotems and mlgr.uc!he lea.\! underlhe
"'ilmona (Primecorl
AHTIHYPERLIPIDEMIC AGENTS
.. \IJ> (X'f' iunl lc~-
CIIUSC of death in the Western workl loday is dlsc:llle. of which the most pn:\1Iknl form is mhen>...ID"_oo.hean disc:llle. Although many clIuS3th'e fllClOl"5 of . diltase 11ft: rerognl led (e.g .• smoking. s\rcss. diet). alhdiscllsc CUll be treliled through medicalion or
H~~~,~:~·~:,~,~":,,;most jl(e\'aknt lndicalor for 5U~ep
:
hean diSC"''''; il is a tC!l1ll used to ::~:',~IcVlled plasma le\'el$ of lipIds Ihat all'; usually in lipoproteins. l-typerl ipidcmill may be Cllused by •
Figure 19- 23 • HypothetICal mode-I col lipoprotein partICle.
Innuence of IIJ1 eleclric currem, Ch), lo,nicron) ~re normally abolenl in pla..~'TUI ancr 12 10 24 hourcd frortt plasma, I.e> els of LDL reccplOl'S >'ary dependmg on thr of c~tr.thepa'ic ti,sl.K':S to b,nd LDL to II~ ~'holeslerol, nr extrahepatic lI~ue sutr...'tcrs formcd b) the en/,),OIe lecithin-cholcsterol fcra;;.c (LCAT), llIesc C'.teN l\R: lJ"~nsfcrred from HIl. VLOL or LOL m plasma 10 completc the c}ck. lbr: .... ays for plasma lipoprolctn OICiabohsm by Ihc.~"'~ and endogenou .. «Iutcs are Sho .... n in Figure 19-24
fltt:;:
tfypet'llpoprotelnl:::oI_
are,::;:~:~j~:!;~~;~ hypcrlipoprotciocmias ha\c been I' 0li~mb7 thm CR.-ale Lipid d,SOf'dcN
":::: (~
ellCh of .... hich i~ trealc:d differently (fable 19-6), The abnormal lipoprotern "",Item characteristic is call5Cd decrea~ in the acu~ilY of I in
the pla,ma . Bccause the Iriglyceridcs found
conlt pr1n1.ui ly from c\ogenous 'iOU"~~·~~~.:~:i poprott'inemia may be tn'aled by , dlctary fal . There are 110 drugs al pn'~n' 10 counteract type I hyperlipidcnua Type II hypt'rlipoprotcincmia has IJe(:n lIa and JI b, T ype Ila i~ chal'aCterilcd by dC"IIIa! LOL (P.lipoprotcrll$) and normal lC\cls of This subtype dIsorder is ,'ery common and hy disturbed catabolism of LOL. Type I lI a. in thai this hyperl ipiOcmlu has elevated additioo to LDL le .. el ~. Type II II oftcn clearly familial and frequcnl1y nul domilWlt IIbnornulity '" IIh complete upres.\ ion in IOfancy , PallCnts h,·c been dictary I'CStriCllonS on cholc\terol and o;:J!urola! type of hypcrl ipopmccinernin re.\ponds 10 SOllIe
....
TABLE 19-6
...,
Characterization of Hyperl ipoprotel nemia Types Abnr.o .... ,ity
-
ItJp.rllpoprot.I ...... I.
•
.''"" ,"
1
EllKboph_I,
of
P'"sm.-
M..... -e fb~I""""""",,mla
Clear. ' ....111) I., ... of
~upopnllo'1ItId
l. """a,d
DnlIId 1\-11,......"'..;n """"
VIJ)UU)l. "" ."'M>nI"Iai
..... -r.·h,.'.(1jeln' ek> ~
VLOI. inrft'......t
""' ,..., ,...,
1'fe.1I-l'P"I."'" dc, Md. my k"""', 01"'''''.
\lUlL, ... , , .J. C . Oofibrute also regu lates cholc,terui ~ynlhesis '11 tit.t li lcr by Inhlb,tlng microsomal n:tlUClion of 3-hydroxy·3· metbylgIUlaryl-CoA (II MG ·CoAl. cutalyzl"il by HMG-CoA n:tlUCt~. C lofibrulc may lower plasma lipids by n1l.'ans otttCr than impainnl'n1 of choleSlcmI bIosynthesis. \ uch as iocreaslng uCre1iOll through the !>tliary tract. Clofibrute i.\ tOler-lied \\'ell by most pallents: the ntoSl COU1tll0n ) idc effects ore nau-.ea und. to a smaller extent. other gaSlrorntl'stillal dbu"C)s. The UQ ....se of ant icoagu lant•. if usctl in conjulICt iOfl \\ollh this drug. shou ld be reducctl by one: th,rd 10 ottc half. depending 00 the iodi\iduIII responsoe. 50 lhal the prothrombIn ti lllC may be "cpt willlin the desired I1nllts.
•
CH~
0
I
U
-r-0-C-C-O-~
I
OH,
Clofibrate (Atromid)
Gemfibrozil.
Gemfibrw:il. 5-(2.5-d imeth)lpheooxy)2.2-dintcth) lpentanOlc acid (Lopid ). ;! a congener of e1ofibr~tc lhat wa.. nsed fiN In the tremment of hypcrhpoprotciocmia in Ibc mid -1970s. Its mechanism ofacuon DOO use an: siulIlnr to those of dofibrale. Gcmfibro1il reduces plll~ma le" d s of VLDL In glycerides and \lImulales clearance of VLDL from pla~l1la. 1ltc drug has lillie effe\., 00 cholesterol pla.ma ieI'd. but docoi cuuse un incn:ase of II DL Gcmfibro/.il i\ uosorhed quidly fmm lhe gilt alld excfI';led
ullChanged in the urine. The drug hag • plasma lull(· life of 1.5 hoor'S. btH reductioo of plasma VLDL conccntmtioo takeli between 2 and S days 10 become evident. TIle peak effect of ilS hypolipidemic OClion may lake up to" weeks to beconle manifeM.
,
"'-
J----O'-
r
}--,CH,-Cl-l-CXXlM
,
U!ie of thyroxillC in the treatment of
hyperlipi{\('mi~ ~
not ...·"hout ~d\'el'l>e eff~l~.
FenofibriJttll. FenofibrJte.2-[4-{4-chI0l00c:nzoyl)phenoxy!-2-mcth)lpropanoic acid 1'I1lC'\hyleth)1 ester (Tricor), has structural featurn Itpi'"Cs.ented In cloIibfate. The primary difference Involves the second aromaue ring. This imparts a greater lipophilic charncter lhan exiSts In clofibrate. resulting in a much 1lI0re potent hypocholtsterulcmic und triglyc· eride-Iowering ugent . Also. this structurnl modification resullS in D lower dose requirement than with clofibrute or geml1brolil. " I " 0I / '"' O- C -C-o-CH
I
Feno/ibratl
""
,
""
(TrIcor)
Dtilxtrothyro)(irHt Sodium, USP. DextfOlhyrol ine sadium. 0.( 4-hydroxy-3.5-di iodophcnyl}3.S-dii!JOO.[)-Iy~ sine mooosodium sail hydl1lle. phil", ,k",",iln. pillclCf (1)/_ I. aN,hattopholic fattot A ~ (1'fCl. CIoro_ lCfw'ac"". II .................1>0" II .
y,
'Vl1l "
.,...,.. ......."1.,,,,'11_ ' ' lOr......
x
" '"
11"80""'" [,,;00'
VI ' • Thao,'C( I 1"1
II'
__I
IW'
Iv Co"" ~
,.
" ........,....,. -
nbrin ...... hri ... r....". fibnR4iC ",hen thrombin and factor Xa. forlll~"e,,,,een :ulcium .&
~[epi'
n vivo.
lu\allon J1lnn~ I C
up Ie romprotein ~,,'d~
1y - Arj! IlIIHlUS. ~nu:.
;win gel
:.en
the
,..glu-
IIlte 1~
the
con-
ge.,ted thut vitllm in K dril·c., the carbo!l.yla.se rt'actlon by ab'ilntcung a pmton (rom lhe l'CIah lely unreacll I"C melhyknc: carbon (If the Illu lamyl residue. fOffili ng :1 2.3-cpo1 ide. Oral anllcoagulants intcrfcre with thc: }'-C;lIbo~ ylation of g lu lamk acid 1"\'._ldllC'\ by pll',c:nhng the Il'ducnOil of Illamin K to liS h)
"..
1: 1""
ro.
0,
o o
"vv~"
o
Figure 19- 27 • MNhafirsm 01 olCtlOl1 of V1tamon K and $lIes of ilctN)n of wilrlar,n
are likened to the SlOI1Igc grunulcs II.~SOCialed wllh adJ\"llcr!!ic !leurons. IncJ\"ascd levels of cAMP inhibit platelet aggregation. cAM P acth-all:s ~pecific dl:'pendenl kiRII.'ieS. which form proIem- pnosph:uc oompleJIcs thai che la.e C1llcium ions. The rWUC«Ile\'el~ of calcium inhibit aggregation (Fig. 19-28), lnhibitOl'!; of platelet aggregation can increll5C cAM P levels by I.'lIher 51imuhuing adenyl;uc cyclase or inhi biti ng phosphodicSIt'rase.n SubSlllnCC:ll such as glocagoo. adenosine, and isoproterenol increa!ie cAMP level s and inhibit platelet ~gregalion . Drugs such as IheophyiliBe. aminophylline. dip)'ramidole. papa\"crine, and adeOO5HlC inhibit ~ies lerose aoo aggregation of plalcicls. Epinephri!le. collagen. and serolonin inhibillldenyiale cyc lase and ~,i mulme platelet aggregalion.n The role of plmelel5 in arterial thrombosis is
ATP
"-'
5' AMP
3',5' Cyclic AMP
....... j
ProIeon ... F"hospt\ate _
0.&.101' 01 Cs'cun Fftle C*ium ( C a " ) - 8culd Cab"rn neaH"')' lor ••1ibQ iiiOItll!iJM"'ll ~ 1iGO'''Y-or;
Figure 19- 28 • Role of adenosme 3'.s'-cy. fatty acids arc prescm in the phospholipids of ~l! . . bninc:~ofDJI mammalian ti~s.ucs. Th.e main ~ursorull"' taglandms is ar..chidonic add. AllIChidonic Kid IS Idr from membrane phospllOliptds by the clU,yn:w:: pho! A~. Once re leased , arachidonic acid is mcwboil1.ai ~ cydooxy&cnase ~yntheta.'iC to room .ms tablecydic oxides, PGG1 and I'C HI' which subsequently art funned into PG ll and Ihrumboxane A l (TXA 1). The~. 5ion to TXA! is aided by the enzyme: thrombou« synthel.l5e. 1llc: formation of PCI! can oc:cur _~ cally. Blood pluteleTS cOllven arachidonic :reid 10 ~ whereas PG ll is formed mainl y by the vascular emlodldltoll
Cluaptt r 19 • C..niim'tIJC..lar At.rmJ
Ik.tI PGII and TXA: are unsmblc :\I physiologk-oll pH and IClfljJti ..IUI'«. Their half-lin'S aK 2 10 3 minutes. PGll inhibiu; platelc:l agglt'gatioo by stimul:uing adenylMe cyc-Iasc to inm'ase cAMP Ic,-cls in the platelets. PGll is also • VIIs(xlilalor and, as II Te$ult. ~~ pote:n! hypolensivc fIfOPCrtles when given intr.l\"er'lOll~ly or by intni-ancriDJ lid· IlimSlMltion. TXA 1 induces platelet asgregmion . Togclhcr with PG I:. TXA1 plays II role in lhe muintcnnncc of vuscular IIomeo!!lasi~. In uddil ion 10 being a platelet agg.rcgator,
TXAl is II polen! vasoconstriCtor. Retllroalion of clolling is impor1llnl in blood tranSfusions. III ."oid thrombosis after surgery or from ocher causes. 10 pm'cn' rtttJlll'nllhrombosis in phlebili~ and pulmonary em· IioIlsm. hnd 10 lessen the propagation of clocs in thecoronary tItme$. nus relarti:llion may be acoompli..ncd by .gents Nt mac1iv,le thrombin (heparin) or 5ub:i;Ulnces thaI pre~1 fir formation of proIhrombin in the li,'cr (the coumarin deIJ\loU,'e! and .he phen)'lindanedionc dem'ati\'cs). Although heparin ,s a u~ful lllllicoogulanl. 11 h:ls limited applications. MlUly of the anticoagulllllts in us.e today were 1It"eloped followin, the discovery or dicumurol. an antico"ulan! present in spoiled sweet clover, The,
-
}---o -pC agenl~ lend III ha\'t I rapid 0!lSC1 and a !ilion dUI1IIiOll 0( action, Muctl lkI: the MJlronylun::~. these indl.JCC insulin release: from lill('honlng p:lI1crc:Ilic p cells. 1bc: mechanism of action for
lilt metag.inides. however. differs from lIulI o(the sulfonyl_ llle mochanism of action is through bmdmg 10 spc_ aIk tcx:cplors in the p..ccll n~mbr.lI1e.Ie:lding to the closure
o
o
I
-
(PrandirI)
Nateglinirk.
Although natcglinide. N-(4-ililOprOpyl_ cyclohexanecarbonyl}-I).phenylilianine (S tanix ). belongs to the mctaillinides. il is a phen),lalanine den"al;ve and reP'll!itnts a oo"cl drug in the management of type 2 diabetes.
o
II ATP-dt:pendc:nl K ~ channels. l1Ie K ' channel blockade: oiepoIari~u the ,8-cc1l mcmbrnne, which in 10m I~ads to (a!' innu~. im:rcasc:d inltll~"i:llllJDr Cal ~. and Stimulation rI Hlsuli n secretion. OceauS!: of this different mechanism of I:\JOIl from the ~ulfol1yJun::lI~. there an: two major differ. between these seemingly similar clas>Cs of agents. The liM i~ thai the metaglinilk~ cause much faslcr insulin ,.xJuc1ion than the wlfonylureas. A~ a I\'..,uh.the metaglin_ lib lobould be taken during meals. lIS the p;mcn'as .. ill prokt lD54Jhn In I much shonerperiod. The.'i«Ond dlffereoce • IIIIlthe effecl'l of the mct;tglinid6 do IlOl las! as long as Ibt: effects 0( the sul fonylureas. The effe-cl~ of Ihis class IppCIC 10 laSlIess Ihan I hour . ... hile sulfonylurcas continue IhllnlUlate insulin production for seveml hours. One itdvan... of a short dUmlion of actiort i~ thai thel't! is less risk of
o
-
~lyccmJa.
101-
ylic ~lInide. Repaglinidc. (+ }-2-Cltlo~y-4-IN_[ 3_ .tllyl·1 (SH 2·( I- piperidinyl ) phenyl [butyl Ic~rbamoyl W)llben1oic acid (Prandin). n'prtSCnts II new cJllSS of _ Ifonylurea or.JJ IInXlglycemic agents. Witll. fast onset . . . iJIon dunnion of action. thc medication AAotilu be .... lth meals. II ;soxidized byCYP )A4. and thecarbox!Itt It1d may be COIljugaled 10 inxllve ConlpoundS. Less . . 0.2'1: is excreted unchanged by the ~Iuncy. which may Ire an acJl'lIntage (Of ekkrly patients "'00 ~ renally imjIIIn'd. The mOSI common side cff",'Ct involves hypoglyce-
T1IbtzoUndlones The thiu.oIindiones n'prt'lICnl a 00\,,1 nonsulfon),lurea c lass o(hypoglycemic agcnts for the treatment of NIDDM. MIlCh like the sulfonylun'as, the use of these agents requirtll a functioning pantn'as that can successfull y .'leCn'lc inWlin from P cells. Although in~ulin may be relea.~ in normal levels from lhe: cells. pt'ripheraJ sen.,ilivity to thili hormone may be r(.'duced ()( IlICking. The thiamJ idillC'd lollC.'Ii are highly selecti ve agOlli sls fOl' lhe pero~isome prolifcrntor-J1!.1h'stcd l'C(.'I,'ptor-l'(PPAR which is responsible fOl' impm~ing gly_ cemic control. primanly through the implt)\'cmc:nt orinsulin sensiti \'ily 111 muscles and adiJXllit tissue. In addillon. they inhibit hepatic gluconeogenesis. These agents nomuJlI.e ,IuCOSt metabohsm and reduce the amount of insul;n nc:cdcd 10 achievc gly~'CmlC cOlltrol. 1bey are only eff~he 111 the pn:seoce of II1suhn .
n.
Rosiglita.zone.
Rosightazone. (:t: )-5-[ [4-[2-(melhyl-2_ pyridinylamino)etho~y Iphenyllrnethyl}-2,4-thiazolidinedione
o
(Avuoolu). i~ a .... hitc 10 off·whi le solid "'ilh pK.. values of 6,S and 6. 1. Ros:igllla7.o!1C is readily ",Iuble In ethanol and • buffeml aqlleOU~ 'iOIution wilh pH of 2. 3; 'iOIublhty decreases "'llh increasing pH in the phy~iological rungc . The molel:ulc h.as a ~ingle chinll center and IS pre..~nt ~ a r.JCemIItl'. E,'cn !iO. tile l'nanliomcl1> are funo:.11Qnaily indistin-
gUishable because o r rapid ;nlcrcOll\CI'lOIOfI.
-
.
o ",
...-\I"' -
PiogJilazone. I'ioglnazonc. ( :!: )-~_ 1I4_[ 2-(5.ethy l-2pyndmyl)c'lho.\'J [phenylimethyIJ-2.4-lhlllOOhdlllccry similar 10 a sugar. wi,h lhoe hetc:roc)'chc ntlr'llp serving as an i50Sleric I'qllacClTII'nt Oof the sugar O~ ~gc:n. n. feature allows reU. 1983 U Yaol. A . J . Mol. I'IoannamI. ~-iul 8:ll.! I'" 48. r . . f _ ....a 11.1...... 0 A J up Mod 11 :19. 1dir. P I' B. J PIwoaOOC\Jl . fJ.P. Thtr 118 IW. 19St1 }I. ItiMner.N J 8001 Cbent.2372111. 1961. \l .... f.a .... U S .. -.I LiihaJl.O. I' .. I... , J N",,~. 2;127. 19bJ J6. MuI"'" J M.• Sch~n"'. Eo. Ind 8nn. II J . fu. ... 19S1. fl. U'Pnctwd. D.. fI oJ . f...... J ~. ~87. 1978. • ! 5''''. 5 z.. orr.! c. ..erv, I. Hy~ D11. 1980. " sun.., K~ 8IId MOIMCI. II; l'1ou""","",\3c\lkIo' 12:1013, I~7.l. 10. .~. K I) Dora-l·Kl,.. VWIC today . In the ne:XI 30 or so lCafS :lftcr the synthesis of procJ-I}kIdol9
the 3CClanilide :lrmloguCli he had synthe$IlL-d :'IS poIcntli antipyretic agenL~ also c)lhibiled IOCIII W"IC~thetic aclil il). l~ 1931. his synthetic ",-00. lcd to lhe produclion of cloclKntnr (Nupercaine:). a Iong-ocllng local anesthetic th:lt ..... as ~ larly useful in spi nal anesthesia.
At aoo..n the 1W1T\C tinle that ~'iocllllCainc was develop«!. an invcslig.ation of the chemic:ll siruciure of the at~.10.:1 gramme al Siockholm Unh'ersily resulted in ErdIITWl ~ thesi:dng its i large fibers. However. this order is not stnetly followtd III practice. Some mydinaltd librrs are blocktd wilh lower concentrations of local anesthetics than some nonmyelinaltd fibers .... hile Inrge fibers are often blocked before smaller fibers. FunhemlOl"C. in experimenlal work, the outer libe rs in llle nerve are affecltd lirsl. regard· less of their nature. fupcrimcntal won: by "runt. and Pc~ In 1974 suppontd by the work of Chill and Ritchiel.l in 19&4 suggem INII the diffcre:ntial blocking of roc,",'C fibers depends on the lengtb of non Ihat has 10 be e~poscd 10 lhe local anesthetic 10 bring about ane..~tlM:sia. Shotter nerve fibers have ~hotter internodal dislances and in the early stages of llIlt~thesia are fully e~posc:d 10 thl: local 3ncSlhetic. with the i'tSultthat they are moce readily blocktd than longer fibers. In mosl patients. the iCnsaaion of pain is the first 10 be lost. followtd by tern· perature and touch. pH of tIM btracell.1ar and Intr• •llular
Flu.... L...ocal 3llCSll'Ietics are normally weal bases (pK. - 8.5). which are only sligh!!y soluble in waler. Consequ.::ntly, they are usually marketed as aqucou~ soIution$ o f their more "DIu· ble salts. TIlese solutions are often quite acidic. which makes them less prooe to bacterial and fungal CO
Eleclron ..... "'IlIOf1 decrMH poIanutitwl of C!utlOi'1l group
van :: WaaII' fIr.HMn..... ·11 "lie ..:IQoIe allnocloon
Figure
the btndlng 01 an ester-type local oJr"It'SthetlC otge'I1l to a
receptor Slte
die ~1'11 membrane, Lipid solubilit y plays an important pan 'litho! action of local ancsthttic,.\. since: ,he,. action depends Illlllleir ability to penetrate: the cell membrane of the lUOO. The hydroplllilc center provides the local 3nesllieuc agent "lib some of ils ..... ater solubility. This iJ an rsscmial factor Ulll1lnsponing the drug \0 the membrane a!ld. once in~ide !he cell. 10 the recc:plOr. 1be hydrophili c center also allows !he drug to pcnclr'.lle 11M: pol~r OUler face of the cell membnI.IIe, cnabl ing the drug 10 n:ach the lipid hean of the mem!nne. II also allows !he drug to pa.'iS through the inroer polar flee of the mcmMnc IntO the cdl. The hydrophilic eemer iJ also believed \0 be jnval-'ed in the binding of the: drug 10
-
lilt ttCepior. The beSllocal anesoc"'' ''''. GuHlc 10 MNiara Md Dnop. Qodal........ U K.. C _ Librw)' l1000. J 9112.
}. Albcru. BM""'1. D.• u-w... J~ d aI. MoIoao.. 80010&1 .): Ref"" ... lI«>IIY Ikfj, • • SpnoftI' V~I9tU
I~
" 'lk. 8 · ..".,.,..,..ip. vol. Ill. Nt... Von. "'ad III"' - . 1912. P.
UJ
SelECTED READING Nul. M J MedICal I'll""""""",, • • Cw.:.. . .mI ed. OL.;l ",ell SIry. An Inl .. >d ..... iIe Acetic Add Riboside
figure 21-4 • Metabohsm ollllslilmlnf ALD-DH, alclehyde dehydrogenase, PRT I~""
T_inatl_ of His" hlne Action 1m principal ways cxiS! 10 t('nnillOle the physiological dferu ()( hisllImUIt): • Cd/III", 1Ip'"tr ArumaJ studies 1\.1.·c dox\IlUI'/l1al the uplal.c Jt~J;'i:PI;"" of alII. Some II, ~-co... ~ininli !lSSIlC' uhibll ~ hon"-'lcnro\I.' Ion of sen"II.,ty 10 (he actions of Ioo>wmoc. pc:rI\ap!< as I mull b also block histamillC relea'iC. 1bc COllCentrations requlIN. howe'·cr. are coosidernbly higher than tnose required tOj» duce sign lflCllnt hist.:llnmc receptor blockade. The H,IIIIU!t onists do 1101 block antibody production or an tigen-antlbodj interactions. 1M
Structu... -Actlvfty Aebltion5hlps 'Jb.: H1 antagooists are now conunon ly subdivided mto 111"0 broad groups-tile first. gener~tion. or , Iassical. anlihlSl»mines and the second-gcllCrntioo. or . ·non~'11 ing.·· antihhtlmines-ba.wd prim:uily on their general phannaoolop;!ll profilc.;.'' 19 The differences betwccn lhe~ t... o series 1ft discussed in more detail III the scction$ that follow. lltr most dclllilcd publ ibhcd SA lt analyws for H, antagoailb. OOwever. focus on the Siructural requin:nlCm~ for the lint· gCIICr:ltion agents. I•. I~ From these studies. the basic 5tIW. tural requ irell1cnl~ for H ,-rect'plor antagonism ha,'e 11M identified as thme shown III Figure 21·5. In this SIfU(1tue.N is aryl (incillding phenyl. SIIbstilllltd phenyl. and hetno.)l groups such liS 2-pyridyl): AI is a second aryl or aryl~ group; X is a I:onnecting :110111 of O. C. or N: (CH1i, rtj1t5Cnts a carbon chain. usuall)' dhyl: ww.I NHR' rc:ptUCIll'iI basic. tCTTl1inal amillC function. The nature mtlle ~ atom. as well as the diaryl substitution pattern and _ moiety. has been ue"eral oflhe phel10lhiazines ha ve limited use in Parkinson· lile syndroull'!i lIS II. result of their ability to bloc!; central muscarinic receptors.tl. 19 And . a number of alllihistamiocs. iociliding pronletha1.i1lC. pyrilamine. tri · pelennamine and diphenhydram ine. display local anesthetic activity that may be tnerapcuricaHy useful. Zoi As the gencr.l pharmocological profiles ubo,'c suggest. most ,mtihbtamines cuu intcnlCt with a variety of neutotrallSmiller receptors and other biomacromolcculat ta.rgets. This is most evident among the first -generation arenlS. many of which fUI"ICtion as antagonists al muscarinic receptOl'S and. 10 a lesser extent. adn:nergic. serotooergic. and dopamine receptors.l~ II. 19 Although some of these non-Iarg~ -m:cp tor interactions may h:1\"e !iOIIIC therapeutic value (as dt .... cussed abo,·c). more frequ~ntly they am manifested as ad· verse reaction~ that limit drug use . This iii particularly true or the peripherM anticholinergic cffects produced by Ihc.r,c dro&S and of intemctions with a number of neurolransmiller system s in the CNS Ihat resul t in sedation. fatiguc. and diu.iness.'''' II. I~ TIM: primary objecuvc of antihistamine research over the past 10 to 15 ycars has centered on de"eloping new drugs with higher selectiVIty fOf HI receplOl'5and tacting undesira· ble CNS action§. TIle: pronounced sedalive effects of some of the first-generation agents wcre attributed 10 the abIlity of these drop to penetrnt~ tlx: blood- brain barrier (BBH ) because of lheir lipophilic nature and then block ~,tbial H I m:cpl~ and pot;sibly other receprors.'" Thus research cfforts wcre initiuled to design 1lO"cI antihistamines wilh reduced ability 10 penetrnte the eNS and decreased affinity for central histamine m:cptors.1lte.r,c cfforts led 10 the inll"OdUClioo of the sccond·gcnerntion antihistam ines. ",hich are nonsedating and have lillie antagonist activity at olher llCurotTllnsmillcr m:~ ptors at therapeutic cOilCcnlrDlions. The ph.armacological prupenics of these agen ts are discussed in ntOre detail below. Surprisingly little information is available concerning the phaonarotinr:tlC and biodisposition profiles of the first -generation antihistamines..lJ Generally. the compounds ate orally active and well absorbed. but oral bio:... ailability may be limited by first -pass metabolism. TIw: metabolilCli formed depend on drog stltlClu\"t' to ~ large t)l t( nl but commonly involve the teniary amino moiety. Thi s functionality may be
subjeCt to ~uccess.i\·l' O.UdatlVl' N-dcalkylalJon. dcamination. and amino acid conjugation of the resuhant lICid. 1lte amme group may 1110;0 undergo N-oxidation. which mlly be reversibil'. or direct glucuronide conjugation. FiISl -lIel1o!nllion agents with unsubstituted and activated aromatlC nngs (phenothtal.mtS) may undergo aromatIC hydroxylanon 10 yield phcllOl s. which may be di'l1in~lcd as conjugule..~.lJ More deta,1ed ph:tnT\lOCOl.;incl ic data are available for the seco.1Cl-l!cnern tlon IIlents and are il'lCtuded in the l1'lOI1C)graphs thai follow. The H I :mtugoni~IS display II variety nf s'gnilicant dru g Imeractiom ... hen eoaodmmislered with OIher thcr.!pCutic agents. For ('JI.umplt. MAO inhibit~ prolong and intl'nsify tnc nntichohnergic action ~ of the I1l1t ihiSlamil1(':~. '''' I" I•• lJ Also. the set\;lli vc effect_~ of these IIgents may potcntiute the depn::s..o;:am 8Cm lIy of barbllunllcs. akohol, narcocic analge· 5ic~, and ochct- depressums. Rccemly. il was discoverW that )Cvtntl of the propylimlnl!S_
MecJiz/ne Hydrochloride. USP. Meclilinc h)'drochloride. l.(p('rolonin llCIi~ Ily. In c:arly rc.rrnt:. lIl..iltudll1C exhlblled nrorc than 311nle' lhe poIeocy of c hlOfphc:ninllnillC III rhe i..olalL-u gUloca pi, i ICUlilloCTt:en and more Ihan 7 times the oral poteJlCy of chlorphcnirnOll11C in protC'CUOll of guinea pigs against II double lethal do!ie of mtm,enou~ly udmimstc~ histamine. ') The
R
Figure 21 - 11 • Gemorill $\ructure of the dibenzocydohep-
teoes and dlbenzocydOOepta!leS.
00_"
llsual dosage is I to 2 nlg twice daily. A7.aladi!1t' is available in I-mg tablets. U,,,,,I &dull I)a;.:,j~
oo.e: Oral,
1-2 mg h.i.d .
fOl1115 Tabkts
\
/
---,
CHCOOH
• II
CHCOOH
,
~Ko 'emJdine Hydrochloride. Fcxofenadine ~ chloride. ( .:t H -I l-hydroJ{y-4-I4-(hydroJ{yd iphcnylmtlh)t~
ICH,
I-piperinyl fb\Jtyl-IJ.o--dimclhylhen7.cncact"tic kid ( gra), OCl:urs as II while to off-wllile crystalline po.,,,irr II1II is flttly soluble in mc:tllanol and ethanol. sl ightly toIubk I chl0r0fonn and water. and insoluble in ileUM. llu! pourld is mar1\eted lIS a f1ICCmate and exists &.'l • ~""Ium. in aqueous media at physiological pH. Fe~orenadine is Dprimary o~idal i ~e melaboille Of~rff"
Secand·Cen...atlon ..... Ant·.onlst D.a.
°asses The second-generation anlihislamillC1l are more si milar pharmacologkally than structurally. As dil'oCussed above in this chapter, Ihcse compounds ..... err Oevtloped as sckclivc HI-
~
rttCplor antagooi~s with rdatiH:I), high pou:ncy. MOIl 4 these ~'()mpounds also produce prolonged antihistrumnlCcf. feelS as a result of slow dissociation from Ii , ra:cpIOn-' lhe formation of aclive ITIelaboiiles ",uh similar Ita,*, binding profilC5. I~ 1be second-generation agcnt~ hnV( I,a affimty for muscarinie. lIdrencrg;c., or stl'OlonelJlC nn(U1 and. therefore, di~play II tower incidence of side effect!, aQO.. i,led With anlagoni~m al these ~or.;;. T1v::ir afflDibel; for these receptors vary §OI11Cwhat. as indicated in the me.> graphs below. Pemaj1li fflOSl imponam ly. all of these rof. pounds lock seliat;ns effects al tlltrapeutic cono:;eMl_ bccaLISC of poor eNS penetration and, J>OI'sibly, lo .... errc!l{· finities for central histaminic.''' c holillef1!lC, and whu",p: reccptors. The first mcrnber~ of ,hiS anli histamlne subcJ-. introduced in tilt United States induded tmcnadilll: lSI'dane) and astemizole ( H i~manal) (Fig. 21-12). AltIIo!IP these o:;ompoonds offered scI'era] IIdvllllluges over thc:d. .· cal uo lihiSlUmines. widespn:1Id usc n:~aled ~ therapeulic limi'ut ion~. I1lO'>t notably the ability to pnxb::r life-'h~lening arrhythmias "'hen used concUtm\lJ) ... drugs thot inhibit their rnctaboli sm. Thi s drug imC11ldIOl! lilt been I1lO'>t evident wi th the imi12 hours) HI amugoois( with linle affinil,. for ~nic. 6efU(OrIergic, or ~nergk reccptoo;. 1be hista-
_
~~ Iyl}-
\11c-
,"",
kin m
w
,-
."
~ptor
affinity of this
COITIpOIInd
Unlike its parem drug. (01)' 5'1> of the lOIal dose of fexofenlldine is metabolir.ed. TlIc. remainder is excreted in II!(' bile 1100 urine; the mean elimination half-life is llbout 14 houl5.lf>. 17
is belie"ed to be
rtI*tI primarily 10 the pic&CllCe of the dip/lcnylmethy lpiperlime moiety. The prolonged action TCsulls from very slow ~ialion from these receptors. II Tht: lack ofanticholincrp:. .nncrgie. or krolOl1ergic IIClioru; appears to be Holed 10 !be ~llCe of the N-phcnylootanol substituent. This IIIbsullltnl also limits distribution of terfenadine 10 the CNS,'" JJ Terfenpdine undergQe!l ~ignifiellnl firsT-pass me.. lIboIisrn, with the predominant nw:o.llIbohte being fuofcna· • . In active metabolite miu ll ing from nltlll)'t group oxi....... When druss that inhibit this tnlI1§fomlluion. such as • lnuduole anlifungals and rIllICrolides. Il/'e used COlI(!urmuly. terfcnadine levels may rise to toxic level s. resulting • potentially fDtal heart rhythm problems. TlIc. observation . . fuofenadine dlspla)'$ antihistalllinic activity companl~ with that of tcrfenadine but is less cardiOlo,lic led to its i!r.e!npmcnt as an alternative to terfenadlne for the relief 0{ ~ symptoms of SCll'iOfIal allergies. J6 Fu()/'C'1Iadine i5 • selective peripheral H I- receptor blocker _like terfenadlne. produces noclinically 5ignificam ami· I.tohnergic effects or ai -adrenergic =pIor blockade al tlmpeutic dolies. No sedative or other e NS effects have )em repol1ed for this dru g. and animal studies indkale that klofenadine does not cross the 888 . In "jtro ~udies also ....-Sllhal unlike terfenadine. fexofenadine does not block jum channels in cafdioc)'te5. Funl!('lltl()I'e. in drug inII'IIClion studies no prolongation of the QTc interval or reIIIIlI bean rftythm abnonnalities .... en: detected when (u okaiine was administcm;l concurrently with erythromycin • i.ttot'ona7.ole. If>. )1 Ihofenadinc: is nlpidly lIbsorbed after oral adminislnl. . peak serum concentr.ll.ions in about 2.5 , ~.~producing • Ftxofenadine is W to 70'1> plasma prot:ein bound.
U.u..al adult doM;e: Oral. 60
Dosage form: Clpsutes
rn, b.l.d.
LontMii M . USP. LoratlKIine. 4-(8< hloro-5,6-(!ihydro] I H-belUO/ 5.6J. " Loruuldine is rapidly absortJed aflcr oral lidm inislrnrion. producing pc-ak plasma levcls in aboul 1.5 hours. Thl\ drug is eXlcnsil'cly IlIClaboliu,d. pnmruily 10 the: descarboclhuxy nlCtaoolite. which retains SOUle Mlihistaminic activity . Both parent drug and melllbohlC have climmation half-lI\'c\ ranging from 8 to 15 hourll. The IlIClaooHle is excreted re:nall y a.~ 11 COl1jugate. U.u~1
oouil dow: 0.-...1. to- 4O niB da,ly
Cetirizine. US,.. Ccliril.ine. 12-14-1(4~hlorophcnyll phenyhncthyIJ-I-pipcrozinyl \ClOOXY\lICClic acid (Zynec). i~ a racemic compound available a, a whitc eryslalline powder that is waleI' sol ublc. CCliri zine is lhe primary acid metabolite of hydroxYline. resulung from compklC oxKlariOfi of lhe primary alcohol lnoicty. Th is compound is 't.WlllcriOIllC and relali l'cly polar and thus does not pcnetnlle the IJOB readi ly. Before its inttoducuon in !he: United Slale.~. ct:lirizinc was 0fJC of the most widely prc'C drugs inhibn lhe rdca.'>C of IculcoItIa (C4. D4. &II and ~lIglandins. In ~Ilro !lhmalle cffCCb' of ncdocronlll OllIy al'\O in.1IIY!: inhibition of uon rdlellcs. Axon refle'l'lI may be prodIm! by brady"m," m the pre located on the basoiatml mc:mbr.lIle, inc:luding hi ~tamine 8goni~m of HI n::ttptrn (cellular), gaslrin activit), al G rettplOt'!i (blood). and 1Ca)'~ choline (ACh) at M l mU!ICannic rc:cepiOB (neuronal ) (fit: 2 1.1 3).
injection....."'taches. and rhinitis. This drug product is for CX'ular admimstration only and DOl for injection or on! use. Keloofen 5OIution should be used with caution during pregnaney or while nursing. since its safety has 001 been stud ied under these circumstaoces,""
HISTAMINE H2 ANTAGONISTS Drugs ....·hose pharmacological action primari ly invoh'c$ antagonism of the action of hi'ilaJlline al ilS H2 ~plors find therapt"ulic applicntion in the U"ealment of acid· peptic disorders rang;n&: from hcal'lbum to pept ic ulcer disease. Zol linger-Ellison syndrome. gllStroeSOphagcaJ reflu disease (GER D). acute stJ'e§S Llkers, and erosions.:IO. 51
P.ptlc Uk ... DI.....D Peptide ulcer disease ( PUD) is a gruup of uptXl' GI In;! disordc:n thai result fmlll 1m.: erosive aclion of acid and pepsin . Duodenal ulccr(DU) and gastric u1cer (GU) pre the nul common fonns.. although PUD may occur in lhe e w . or small inlestine. FactOl"ll involved III lhe pathogenc:si~_
Peptk Add s.cretlon A chamclerislK; fcall.m:: of the IlUImmalian stomach j~ its ability 10 !lCe.cle acid as pan of ils i n~'oI"cmcm in digesting food for absorpIion loter in lhe intestine. The ~ of
"" G lEUio,
~ ~
"
t ,"'.,
" " '. •
'.
~~-----~
co
--.t (Ca:~----------_ '
---
EB
.• • •
--
,-
--------.. ,., /
-- '-- '-"''oN I ~p I---~--" "- / '"
W IK',
. ~
Ell .
·5
GulrIo
,. G
Ell
• --
'\
"""
...
eo,
.....
"'ad oIdonIc
." Ellao,,'. 0tI Fig ure 21 - 13 • Ilo.. nona]
~~1lOn
of clCod secretIOn by Pilnetal cells.
00,0.
1tCUm:nceuf PUD include h)'pel>eCretion of IIdd and pepsin MId 01 mfectlon by Ht'lirobarlt'r pylori. a Gram-negati\'e 5plf31 bacterium. H. pylori h:ls been found in "inuaJly all paticnl5 with DU and appro;dmau~ly 75% of patients with GU. Some mk flC'looo as ....... iated with t'eCUm!1'ICe or PUD Include cigarelle sn)(ll;i ng. chronic use of ulcerogenic drugs le.lI .. nonsteroidal Imi-infl.ls are prodrugs Ihal are rapidly coo"cncd 10 ~ ~ulfcnalnidc '"termedi· ate in the hlahly acKiic envII'Oflrnent of gastnc pariffill tdl!;.. The .....eally basic bcnllmidamle PPls accumulate," !be.< 3(:llIic oompanmcms on the luminal Side of lhe tubu, C5101'noll canalicu lar Structures of the paflctal cells. The bellllmj. dai.ole PPls are chemically ooo"ened by acid to a sulfag. mide intennediatllthat inhibt15 lhe proton pump via CO\alent interaction .... ith rystelllt residues (813 or 822) of thr ptIIqI H • f K • -ATI>a.~ (Fia. 2 I -15 ).~ The IICKi IlIIlLlity of the beaz· lIuidll?ole PJ>ls dictates tltutthcse drugs mu,1 be fonnulaud as delayed-release. tmeOc-coated g.ranular dosIIge forms. The PPIs an: nLOfe crfecll"e in lhe short leon than \be' Hrblockers in healing duodenal ulcers and eros,,·c e.~.a and can heal esophagitis n:mtant to treatment with the H:blockers. H In addition. the benztnndal,oIe PPI ~ h3\"C amiacrobilll oct,vlty against H. II"/ori and thus possess dfKa"} in treating gm.lrie ulcers or wi lh one or moOre antimlcrobioil~ In eradicating infection by Ih i~ org.mism. Four bcnltmMlt101~ PPI~ are cUrTently appro\ ed for m;tr\:etlng III thr: Umkll States (Table 21-3). Ad"ersc effecl profiles of the \:tn(lII PPI , are difficult to compare becaure Il.'(tensi,·e use III pallents. The PPls are elnllmoted olmosl coti l'd y by rapid n~ 11'>ffi to inactive or less active metabolltcs (Fig. 21.161" Vinuall)' 00 unchanged drug ,s ucretcd In the unlit ... feI ~ contai n a chiml sul fur . . that forms un cnantiomeric pai r Ihat is stable and insolulJlr under standard conditiom. The S isomer of QOl('prnok III slightly greater PPI acti vity. and il5 imnnsic clemntt. appro_imate]y 3 IH~ lower than that of R 0II1qIrlIl0IeU' versus 43 ,",Um in). 1be loweT deamnce or ~ is rel oted to slower metabolic c leam ncc by the cyp 2C1~ isozyme. Although R·oIDCpr1I7.ole is primarily tnmsf«a!l to the 5·hydro_y meillbolitc. the S isomer is metaboIlltd" O-demelhylation and w lro:u dation. .... hich conuibu~ to intrinsic clcarano:e. Usual lIduh do/;e: Eros,~e
Omeprnzole j, approved for the treatment and redUCI;Ofl of nsk ofrecum:nccof duodenal uker. GERD. gD5ttie uker, and pathological hyper (T ..... ), A~l ute bloovailabili ty for • 2().1IC orol tablet of mbcprnzolc (vel"'us IV admUli~lrJlion ) 15" pro~ imalcly 52~. The plasma ha lf-life ofrnbeprawk r1n&t' from I 102 hours. l1Ic effects of food on the absorptlOllll rnbepBZOlc Iia\'e not !:Ieen C\QluaIM . Rabeprarolc is 96..J'f bound to humall plasma protci llS. Rabcpr.u.ole IS e~lC1lSivd}' mclaboli;£ed ill the liver. The thll)etiler alld sulfooe are pri mary metabolites mea.~ured in human pl".~ma resultilll from CY P 3A OXidaTion. Additionally. desmethyl Tabq:rawk is formed via the actlOli of CYP 2C 19. Appnuillllldy 90% of tbe drug is eliminated In the urine. primarily .. tbtoether carboxylic acid and ns glucuronide and 11le1'tlIj)IIn acid metabolites. The remai nder of The dose I~ reco"cmj ill the feces. Total rorovery of radioactil'ity w,,' 99.SIi. M unctlanged rnbepralole WIIS ~\'e«:d in tbe unne or r('('Q.
w
Ui-IW "ult 00..:, Oral. 20 "'I once dad) (duodenal aim 1or4 ..."ttlu;~ CMI"e or Ukel1llh'c GERO for4- 8 "'ccll); ~ hYI"'r.;c-
"~~
""
I [""CHI». lHA I~ ,I ""I
!1• • 81010..-.l Y 2210 31)
OR
The producllabcling Slale~ Ih:1I Inc simull:meous IIdrnini ~ nllon of sUoCralftlle rna)' mluce the bioa~Dilal>ili' y of cCrlain .nlS (t.g,. letr:loC)cill1e. pkn)'toin. dlj!oJlin. or clI1lCudinc). 11 funhef- n:commcrKls reslOl'"Jlion of bioavwlabi lily by !it'paIJUn& adnHnj~U1l1iOll of these agems from lh:1I of sucralfalc by 2 hours. Presulllllbly. sUC'l1Ilfule blllds these agents in the G! lr:t\-1 . The I00I\1 frequently ft'portl'd adverse I'l'at'lioo 10 ~ucr.al hie I~ conSllpauon (2.2'1). Antacids may be pn'.'\Cribcd as -.led bul shoold 1M)! be la~cn "" dun one-balf hoor before
OIlfitr wcnMale. I).ual oouh 00...,: Orut. I I II "d. on an empty mlln:..:h IA, ... form ,_, ~lIC11I l r.(C ubkb
PROSTAGlANDINS
n.: pmoilDglandms an: endogenous 2(k,aroon
un-aluralcd filly lI(:ids bios)'nllw:ucatly dc:ri~ct! from arachidonic lICit!. TW!.e booactJ\c su~llIl~ and their synthetic dcn~an\l~~ 111\( been of ronsidc:fl1ble ~~an;h and de~eJopment inlc:re>t • potential therapeutic agents bc:~ause ..f their wide_prcoo ~~ical and plwmaoologlCal actions on the cardiovas· • ~}.tem, G l smooth muscle, the ~protIucti\'e sy~lem. • I\tl'VOUS ~}stcm. platckts. kidney, the c)e, elc.ft! I'rosID' (llD:hns of the E. F. and I sene~ are round in Slgnifieanl roIICI:ntrauons throughout the Gl tmel . 11le GI :Ietions of _ prostaglandins include inlllbiuon of b;asal and '\Iullulaled JNfIC acid and pt"p!oin ...... ,etion In addJlH)f1 to pol!lention d.ukcrogen or ImlanHnducctl gro'~ l!lucO\UI ie.ions uf Ihe --..:h and in,\:Stllle (temll.'d n·UJllrolf"(y•• 01, 1&12. Nn. VorL. ~.y.n.c. 1978. p. I" I~ . ..... " ••• D T · Itnliallt, p'" In lIu..... A led.l, ,,~.RII Che"""'y. 11\1 cd. N .... Yms. Dnli II .. W:3'. 1....,12 1 !).nat. G J. o-I~". C II~ '" M I'· J Med Oitm 18 1 91~
p.....,.,,,
,n
I C..,. A f · Tk S"'"" 1'-. McdlII. 1954
11le heterocycle componcnl of Ih ,\ grl1C'ral stroclllre is ~ CQf1llllonly D 4-nlOllO>lIbstilulrd irnid:llole or bI01SOSI· me eq uiva lcnt , Chai ns A and 11 can be of va rious SI/UC\tJ res .... lengths. and there j, also wide 1:1111001: in !he $truc11l1'1l1 .renll'tlls ror lhe polar );l'OlIp. II nlogen:ued phenyl. C)"doalkyl. and hclCfQal)"1 ~lruCIUrcs ate IIsually found for till: lipophilic iI'IOiNy (Fig. 2 1- 19). Thioper,unidc wa.~ lhe pot!'n( II , amagon,,' (0 be ~hed. This agen! enhlloccs arousal and/or ~ igl lnm pat. ICIlISIn ado!.c-dependent fllShlon in amma]~. suggesting posIi>k IISC o r CNS·lW:ti ng Ii) 3ntllgoni)ls 1n u'Cllling ~Iccp dis· onlc:rs Ch3l1lCICrizcd by cxcc~~jvc tloYlimc ~IL-cp, sud1 as un:otepliy. Other II ,·anl:lgooi q struclU res are silo\\. n be lo ...... .lltluding lhe: n:lIl1r.d product verong3nll nc, isolaled fron, a Ita sponge.
9OS--9Oi.
.,.1Il>,
l!I. """"Y." k W .. -.F C.....,., . J. A 0 , J It"", I'IIY'i! 'H~I. 1956:lh Sclla)",. k W 8""'ne". of h..u:.""" In ROC ... " S.h ... M Icd.). 1l_lhoUI. 01 ""pon-.I ~J. rot 11112. New Yorl. Spnafcr.V...... 1971. p. 109 21. \\. mUi>U .. Rccep....., 1II. I IH.Jl bJl,lll'T.!. "', T..... M I"".. Todoy 21_211-1 1. 1'192. oIl. ~kT",,"". D. _ M Orup .lIIn.~800. L9f19 "9. Man.n. U~ aad lloo-. Il Itn.........'ocIf"""""".21:71O 111. 1m. I"kln,;on. M .. ...... Bun .... ME.: N. 1'....., J Mtd. )D 1612- 1680.
S YotIc. plO ........ 197). S;PI'Y. H W J.\MA 2»2l92. 19IJ ~. J H ~ ..... diO01flC dueed. All havc the common morphine
nloe
morphine. "hldl al..o ~ born obtained surv;"ed as II good analgesiC and cough dcpress.:lnl.
Cba plf r 22 •
""" , ,'"
TABLE 22- 1
Synthetic Oa rlv . llves of Morphine
N.I"..
R
R'
.' ,.,. I
H
s.om. ..........
MM;...,.." 10".". ,
c,.tt.
1-1
" •• 11*'.
0ilI1PII .... .......,
-US)
,,"" ,.
...
~p
~"'
~"y.
11,\. a
.. cllij!Ul , }old.
DI
........ ....".'
-~ "'dlpu-
--"
.... I0" ~
--
"...... 000 ..1
00) •••••
01.
00
'by Il!t,o),," .....
'''' 10m.
~
but
• lia-
pre· text,
01,"'"' .........
s.m. .. 01 •
..
._--
..,...o
2C_
"
cuLe.
""' ""p,
2C
pdId
ilaot
""'"
..,. .;
C/Io:r'Opl_
1-1
....... In
--. ".,. ...n. ......
"I"C
"'"
~.
,=
.",""0' ., ~
",'"
~hcr
o~ycOodlJnc,.
M ORPHINE M OD IFICATIONS INITIATED BY TH E RESEARCH O f SM A LL A ND EDDY
01,
"
it ob,iously is closely related 10
,c
"';.alg'", \POI obI.od on
SIble. il might be: pos.~ible to find other synl hetic rnoh"cules ~hhout ctli~ unde~ir~ble propeny. Pr0ceeding on these aSsumptions. these wortcrs first exnm .. Jed lhe morphine: molecule exhaustively. A~ a staning poim , morplunc: offered lhe advantages of ready availabiht)', pro~'en po!cncy, and ease of alter:uioo. In addition to its addlClIve lendency, they hoped Ihal other lIabllilies (e.g .. resptllltOl')' depression. emcllc propcnlcs. and glL'itromtc\ti nlll llllct .tInd circu lalOf)' di5t urbance~) cou ld be minimil.ed or abolished as well. Because: early modificlitiolls of morphmc (e.g .. acetylation or alky lauon of hydro;o;yts ~nd qu:ucnlll1llion of the: nitrogen ) caused vanations In the addICtive p0tency, they felt that the physiological errects of morphine could be relaled, at leas! In pan, 10 lhe peripheral groops. It ..... as nOl known if the acllonsofmorplllllC "'ere primarily H fuoclion of the peripheral groups or of the slnictural skele too . Thi~ did not mailer. however. because nHldificatioo of the: group" ..... ould alter activity III either case. ~ gt'OUp!o and lhe dT«lS on acU\ Ily by modifyin, !hem an: IiSlcd In T able 22-2.. 'The results of these and earher studies· ha\'C not always shown the: df«lS of simple modifications IHl the analgesiC action of morphme quantitatively, but they do indicate the direction in which the activity i~ l i ~ely 10 go. The slUdic.~ are far ll101'e comprehensive thall Table 22-2 indicates. and \he conclusions usually depend on more than Ollt p.11r of compounds. Unfonunatc:ly . lhese: sIudICS on mor· piu ne did not eliminate the addictIOn potential from lhese compounds, In fact, the studies suggested that any moolfiQl uon thai iocreascd thoc analgesic activit y caused II concomi tanl increase: ill addictioll liubility. The second pltase: of the: st udics' dealt with 11M: attempted syntIM:sis of substances ..... ith central ~oti C and. especially. analgesic action. The mOfplunc molecule rorual1\s certam wel1-dur,,' Re l"tionships in th4' Morphine MoletOo1! 1000jffOpI_) -CH =-=CH - - - CH,Ct-t.-!dnyooomolplvw)
-CH=CH---Oi,Cl-i.-{codl .. 10 ~oc:O(a "leJ
, ,./CH, /N-CH. /N, ()CH,
01»0. og 01 nIIrogeti tong (morphmev..l
"" "'" ". """
600 (o.n.,do .. ' .............. c:totI)'d'o no,..._ o.
390 CDoI¥:troc'X'E
let..,. dtryIlt,> ,."..,.,..
looo iDf¥Ioornoophooevs.
OoIIro,d ·?'l J (at jlOUlOI1 611 ~OIUjA" ",)
Mar1o.ed dllctea)ll
S30"
1'1 ~
2SO (Clto)(o,,'Uj)5"W"oOtle "" (IIIyOlupi ... ",1
'"
(DII'I)O( ..
',.O.....
~0d0'lit)
33 [1:lIt!yQ .. ,opi •• ""
5-~olopi.",)
.90 {(lh,.oo.; k'\il ity. In addi"OI'I. these compounds coun teracted the efftd~ morphillC und oIher morphine- like analgesics and an: d. kno.... n as nm'{'(/fic amll.~on;,U. The I'CI'C"1'Sa1 of IIrthil) if ~ase~ from elh)'l. to propyl. to allyl ..... uh the e)'cloprOjijI mClhyl usually being ma~ i l11111. Thi ~ propen) was tlUe" on ly for motphlllC buL also for {)(her .nalgcsic~. N-AII)'lrIornlOl'ptnne (nalOfptnne:) ... a~ the first of the~ bur bel: of side etTl'Cts wa., t:r.~en off the R1:r.rk el. Le ~aIlOf]lh:ul. tk CQlTCSpondllll! allyl analogue or 1c,·orphanol. ruLiooOlie I\allylnoroxymorpbonel. :r.nd nallrexone: (N-cyckJj'up)1 oxymorphonc) nrc too lhn:e narcot ic antagonbts 1\0\1 on tilmarket. Naloxone and nal lrcxOOC' appear 10 be purt"~ nr"'~ with no morphllle- or nakKphllle- lr~e effects. Tk)' block rhe effccts or otoor antagonists. These drug~ an: to pl'Clent, dlillmbh. or abo!r\1! many o f the IICtlOlb side effcas encountered .... lIh the LI:u'OOlIC analgesics. of thc!ic ~rc respirnlory and eLrculmory dcpres"OfI. at " ' . nausea. drow~illCss. anaJge,\ia. and hyperg lycemoa. The). !houghl ro act by cOOlpetlng With the analge>.re ~~ for attachmcnt at liS. or a closely related. receptor s.rl~ TIt OOscrnlion thai SOIne: nareotlC ant.agorllSlS thai lad IIIrX lion liabil ity :11\. also ~trong IInalgesK-~ spuiTC..:! ~~
(J.
,
,mae."l In them. » lhc N-cyclopropylmelhyJ compounds mentioned are.he nl(K1 pmen! aJ1lagoni51~ btH appear 10 pr0duce psychotomimetIC effecls lind may IIOl be useful as anal~ One of these, bu~lKJIllhll1c. has shown In InterestInll ~tudy profile. howe'cr, and tm.~ been inlrod~ in Europe and in the U",I~ Slates as II potent anall!:~."" II IS being InirudOttd as a U'ealmcnl for Ml'C(J(ic addicts '" • IO\ICI tn:auncnt program. Omce Based Opioid Treatment \080'1). provided by private physicians rather than formal In'.lIncnl chnics.1>l 0Iher efforts have been under ""lI)' 10 develop narrol K: OWIugonhts Ihal call be used to trcal narcotic addiction."" The cootinuQ\ls admiolstMion of an antagonist will block
• • •
•
,•
,
been qucstioned.7'1 Additional ~t udi C5 ind ll'at e that deall.:)'l· ation does OC(:ur in the br.lin. although il.'i ellOCt role is rKlI clear.'" It is clea... from the N-aralkyl ckl'iVIUVes di~ssN above. that a small group is IIQI neCu\sion ~ho"'s thaI several exceplions 10 rencrallJAlliolls e~ l"c in the SlnJCIUres of compounds !ul'e been sy ntht$il,ed in the past 5CI'eral yeal'1l. Eddy» d~'iCUS5Cd the IIll>1'l: ,ignificant exceptions. Relative co It fll'Sl feature mentioned. e~tensile studies of the action .... " ... I"';lIIe have sho..... n thaI it ~~ analgesic acti vtIuI approllimates that of morphine. In humans. it is about founh a~ !!Ctive as morphine ",hen tldministert.'d intray. but il .... as shghtly ItlpeOor to morphine ",hen III i~ lDtl'llCiSlt'mall{.- On the has's of the IaSI-mencffect, Beckeu ct al. ' poslulated th~t N-deall.:ylation I51CJl in the ~hanis.m of ItIIalgesic action. This has
-:::,brl
O,N
Diampromide: (III) and 'IS related anili~ ha"e potencies thai ~ comparable ",ith those of morphllle;" they hal'e sho"n addiction liabilit y. however. and ha ve no! aPPC;lfl!d on the marleet. The closely relatcd cyclIC dmvati~e fentanyl (Table 22-3, A- I7) is used in wrgery. The bc:nzimidalo!es. such as etonita7.e1lC (IV). are very potent analge~icl< 001 show the highest addIction liabilities yel enoountered.lll, IJ Po&ibly an uception 10 fealure 3. and tbe only oroe that has been enooumered. may be tbe cydohc~yl analogue of A-6 (Table 22-3). which has significanl activity. &Idy" mentions IWO possible uceptions 10 femure " in ;I(lJ1l1Oll to fentanyl . The many sludies on moleculcs of varying type, that possess analgesic octivity revcaled thm octi,ily was a.~wciatcd not only ",ith cenain struclUral realWl'~ but liso ",ith the siu and the shapeofthe molecule. The hypothesi~ of Beckett and Cnsy"" has dominated thinking fo, K: cenlcr. allow -
i"- .-an lief Waals bondmllO. n;O surface on 1[1(' IC:CCptol' " Ie to ",Inforce
J . A sIluai>ty •
tne _'" bond
f'OSn~
Ihrcc.-Ui""'n~ional
the f1a1 aroman!:
pis. Fundamental 10 the,r proposal WlI,~ thai slICh a n.'cep'or was eSsenti1.lIy inl1 ex ible LInd that 1. loc k-and- keytype situatioo existed. S ubsequcml y, the unnaturnl ( + ). I00I'ptune ...'as symhc!iizai and shown to be inactive.'? Although the f~going lIy~is appeared to fil the facts qUIte well and was a useful hypothesis for 5e\"(.'rnl years. it IIOW appears thut certain anoma lies ex ist that canrlOt be accom modated by it. For C1;a mple. tile more IlCti ve enami orner of tr-metlllldol is rIOt relined oonfigur~tionall y to (R}alamne. in COIllnSt with the methadone and Ihiambutenc !;C'rleJ;. This i~ alS() lrue for the earbelhox y analoguc of methadone (V) and for d,ampromide (III) and its nnalogucs. AnOIher factor that was implicIt in COfI~idering a proper receptor fi l for the motpItlnc molecule and lIS congeners WIIS Ihal the phen)'1 rinS allhc 4 position oflhe piperid ine moiety shoold be III the ax ial orientation for muimum acli,·uy. llIe fael that suucture VI hal; only an equalorial phen)'1 group. ),et possesses acu vity equal to tlllli of morphinc ..... oold seem to ca.'1 doubt on tllc necessity for nllial oricntation n.~ 11 receptorfit requirement .
Q Forx:.
'
2Hs
C
0
H
H
OH (-
Pkw~"h.~.
Figure 22 - 1 • Dlagrdm of the surface of the analQi'5IC rKfIIo tor !ilte WIth !he COilesponci'ng Iowef !>UrfdCe of the drug rule The Ulri!'NI,rTll'flSIOIlal fe.aturf'S of !he molecule /lie VIOWl by the bonds. - . - - -. and - -. wtnch represent III front rI, berllnd, and III the plane 01 the paper. r~trvely (from Go,r. ley. 0 R. H Prog Drug Res 736. 1964 ]
the hypothesiS cnn be applied to the IllCthaOOl iUlOIll.Ily I illustr:ucd in Figure 22-2. After considering acti,ity changes in .ariOllS stru!ubihty in water. compared wllh the ~ul. fate. thi ~ saIl 1\ u,Cularly. 01' inlravcnow;ly at 3- to 6·hour i~ wi th a ma.~imal dally dose of 160 mg.
to.
Oxycodone Hydrochloride. Oxycodonc hY ••~';.: ride. d;hydrohydro~ycOOeinooe h)·drochloride. i~ pr by the elllltlYlic redue.ion of hydroxycodcmone pt't'p.1Il'd hydroscn peroxide: (in acetic acid) oxidation of tloc! ThIs derivative of morphine OC'CUTll u a ... lUte powder (hat is soluble in .... ater ( I : 10) or alcohol solutions nlay be s lcrili7.l'~y'
\ poIeu!
e \0 no >ic than IagOfli~1
~ nalo~·
u..... as
II
III "'Pier
)dobu1cavage :Juration iabllity. !ne, TIle ;of1\rol~.
1'Illon or onunua· al ~ij!n~,
k 10 th~1 It higher ulld bu lion. lind , caut loll ",.
....,
;hlJlCry.
120 mp I1COOsly. ntervlll~.
droch loJll'l!parcd
pored by thebaine. l'sUlllill(' Aqueou~
this drug II i, "!)Id products
Nom!tHphil'H!!. Normorphlllc may be prepared by N-deIIleIhylalion or IllOrphirlC. ,2 I n h.uman~. by nonllal routes of adnllPI'\tr;lhon. it is about one fourth liS :lethe liS morphine in producing IInalge.~ia btH hIlS II much lower physical !lepenikll(e capacity. Its lmulgesic e/Teets are nearly equal by the lIIlr1I>'('nlricu lllr 11)1.11Or_ phine and codeine. but it sho .... s lillIe tendency toward hyp_i$. II h indie-ated fOf" the ...,Iief of pain in 1nO:!;' p:.uent~ for .. nom morphine and OIhcr alkalotds of ClpLum genemlly are used. btu u IS especially ,·aluable ... hen lhc pain is due to sJXlStic conditions of inld;line. uterus, bladder. bronchi. und loO (011. It~ mosl important U''e 10 .. far the lrCalmenl of myocardial inr:on:tioo or other caninK ~ krm. Other ad~·erse effects include a high ,nc.dence ofoela· tion and, le:ss frequently. nausea.. headacbc, vc.-n,co. and W:. l,ines$.'·1 It 15 available as ~ parentc.-raJ for intramuscular and II\U"aI'rnous adminiS\fIlliOn in II dose of I or 2 mg e>el) 3 til 4 hours. with II nlll.\imal single dose: of 4 mg. It is al-.o DvailJblt as a na5ll1 sprny (Stadol NS ).
""pi".
8uprenorphine Hydrot,nllu.ocinc: in a p;an'l1u.'ml do'-C of 30 mg or an or,,1 do:se of SO mg is about as effective us 10 mg of morphine in most pa! ienL~. There is some e~idcncc Ihal th-c :lI1nlgesic IIClioo tl'\ides princip;aU} in th-c (-) i'o()tllI.'r. and a dose of 25 m~ IS ilpprOx unalcly equi,·nlem 10 10 mg o r morphinc: sulf~tc. Orcasionnlty. doo;etof 40 to 60 mg may be rm1nred PentalI)Qne'~ plasnl:l half-life IS about 3.5 hours.. tO Allhe 10000·CI'" dosage levels, it appem; to be .....elltolerated. although JOmC tabllon occu~ In about one third of pel"!KJrl~ re«i~mg it_ The incidence of other IllOI"phlllc-lilc side effects is as high a with morphine lind OIher narcotic Wlalge by Ii II-anunobcnwie ac id is ustd. The derivati,'cs of salicylic acid are of two types II :lnll II (a and b) I:
, "'-
In wlulion. IXlrticularly 111 thoc prclicllCe of sodiu m bitar· bonulC. Ihe salt will dnrkcn on standing (Ioee sa licylic acid). Thi~ d ..u1..emng may be Icssetw:d by the lI4klilion of sodi um sulfite or '\Odium blsulfile. Also. use of recently boiled dis· lilIed "'altl' and dif,pC'flSing m amm-CQ1orcd bOllks Ies~ color change. Sodium &alicylale forms ~ eutectic mixture "'lib unllpyrine and produces a " iokl color.t tion with iron or lIS ..alcs. Solulion~ of the compound mu'" be neut ....11 or ~ Ii ghtly basic 10 prellcnt pl"l.>.::Ills. erefernbly . df) dosage forms (i.e .. tablets. capsuIc!.. po.nlers) should be used. ~inc\' asplnn " some .. hat '".''': in aquC()U~ medill. In tablet prepanl1ions. the use a(':» washed Ulk impm\'CS the ~tabi lity ofaspinn.n" AI~ .... has been found 10 break do .... n in the pre"C.'OC\' ofphrn)'~ rine hydrochloride:. llIU A.pirin in IIqlleou~ medl3 .. ill .,
, ,•
!
almo1ng spondylrllS in a ISO- to ~ dose. twice datly. "7. r'M II i< avaIlable as tablcts (ISO . . 200 Illg).
Tolmetin Sodium, USP. ToImctin sodium. I -~~ S-(p-toluoyl)pyrrole-2-acetale dlh) dralt sodium. McN·B9I (Toleclin). is an arylacetic acid derivative wnh a pynolt .. the: aryl group. This drug is absorbed rapidly ..... ith Ilfllth'ely 'han plasma halr-Irfe ( I hour). I, i~ rt'CQmlllC'ndtd ' " u>e in the: managemc:nt of IICUtc: ano.I chromc RA. It Wm similar. bulles$ frequent. ad'erse effects .... rlh a~pinn. 1tdDI:J oot potentrole coomarin·1 il.:e drug~ nor altcr tile blood !em. of su ](on ylureas or insulin. Like OIller drugS in thi~ it inhibits prtJl:ilaglandin synthetase and Jowen J'GE levels.
c_
OR,
"
>-~4CH'COO "'. 1
CH, TotmcI.. fur ....·.:
R, -Cl-t 3 R._H R, - a R. - CI-t.
Available as tahlelS (200 and 600 mg l and a capsulel mg). a drn.c: of 400 mg 3 limes daily . with a mallmUlllrl 2.000 mg. is recommended. Cl inical trial s indicate I daily dose or 1.200 mg IS COIn(XIr:lble 10 relref 10 19 I' aspinn and ISO Illg or indomethacin per day.I'"
Ibuprofen, USP. lbuprorcn. 2-{4-isobul) lphenyl~ onic add (MOIrin. Ad"i!. N oprin ). '" a.< introdu.:ed rnrodili-
• cal pncllce follow Ill! Ulen~I'C clinical lnilis. IIllppears to be rompaf"~blc 10 a.~pirin In the treatment of RA ..... llh 11 10....·a" llIo.:M.lcncc: of ~1(Jc: effCCb. lIll It has abo been appro"ed f(M" uoc in PD.
~, ./CHCH, CH,
-0-
R 1 CHCO~ H
lbJpIoIen R. CH 3
In Ihi~ serkll uf l'UTllpoonds. poIeocy wa~ cnhaocoo by irnrodUCIion of the a-methyl group on the aceuc acid moicty. 1k pn'('UJ":\OI" lbufcnac (R = II ). wluch WIlS abandoned (1'/11"1 to hepatOlo~lcity. WIlS less potent. Mo«o,er, the 111;DI'II) ~Idc!; In the.> (SH +) isomer. IlOl on ly In ibuprofen Iu throughoollhe lU)1occtie acid series.. Funhermor\", lhese IWlIllCl . an' lhe more potenl inhibll00i of IJ'I"Of'laglandin syn1Iicwc. IOI The recommended dos.age i~ 400 mi. Ibuprofen II aOO '"'ailable o.er-ll!eo(.'OOnter IlS 2(X).mg IIlblels. Napro~en.
(+ ~mel hoxy-a-mcthyl acid (Anaprox. Naprosyn). oceol"" as ,,1Iill:" 10 off-lI·hi lc cry~l al' lhal an: ~paringl)' sol ubl e in acidic ). A ~Iead)'-"-Dlc blood k-el is usua ll) IIChle,ed afler fOOT 10 fil'e dose~. Nilproxen 110 ,~ hl",ly !'fOIcm bound lUld d isplaces most !'fOIdnbotIrIddrul-t. ~ oflhese mUSI be adjusted lICConlingly.
~ CH,OA./ ",r
CH,
COO
0-0,
lbufenac R _ H
~)Cell. U5P. ~'JI3rhlh~lcncacelic
gastrointestinal bleeding. ulce". dyspcp;.ia. naU'i('a, ,lceplness. and dil.lioe~s reponed hI a lowcr incidence than wilh aspirin. II inhIbits ~Iagland," ~)·nll!elase. =
CH, COOH
~arroxen
is n.~ommcndcd for U.'iC in rhcunlUloi d and Ulyanhrili,. II ~how~ good analgesic oclivi l)'-400 I1 lg romp;!mbk 10 7~ 10 150 mg of 01"".1] mependinc and ~upe· 10 65 mg of propoxyphene and 32S IlIg of aspirin plus III; of codelnc. A 220- 10 3JO..mg dose I~ CQfIlp;ullblt 10 mg of aspirin alone. II reportedly product'~ di7.1joc~s. "ness. and nause:!. ..... ilh infrequent mennon ofgaslroil1UlIC1 Imllllioll. lil.:e aspi ri n. il inhlbil' pro:slllgiandin -.e and prolongs blood-clotting time. II i~ IlOl n:.:omfor pregnalll ()I" ]octalmg wOll~n or children under 1>1 It IS .1'10 a\lulablc O"er-Ihc-coumer as 200-mg lablCl. ,lJtle ).
Fcnoprofcn calci um . q. 'all.n d 5·pyrnl.Olune. Some cun be relaled 10 J.5· pynuolidinal~
( ) C'N-H ( 'N-H I I I H H H pY"'~
' M o W
Pyrazon
I2N-H
I
H
Pyr"""."'..v. o
~-H OAN~ N I H
Ludwig Knorr. a pupil of Emi l Fi~her .... htk scam....: for antipyrellcs of the quinolllle type, in 188·40 dLIro', Ui4 the '·pym7.olorte now koo .... n as mrlipyrint!. Tht S di!;(Olel)' initiated the beginnings of the great German drug ulllulll)' ttuu domi nated the field for about 40 yC3J!i. KIlOIT. all al firsl mistakenly bclie~ing Ihat he lIad a quioohllNyp' OOflrpound. soon recOgnl1.ed IIt< crT\)!". and the coo,.. I .... as mlctpreted correctly as a pyra1.olone. Witlun 2 len t/1o(' arntlg~ic propc'nlcs of thiS compound became: when fnl'OnIble rcpor1s began 10 appe3T in the hlet", particularly wi th refcrence: 10 liS use til headaches and n.:rnIgi:as. Since then. it lias rt:tuined some o f ils populartt~ II_ an alge~ic, nhtlougll it~ uw as UII antipyretic lias dccliid steadi ly. Sioct! its introduction inlo mcdicine. lhere In been more tllan 1.000 compollnds made in an efTon 10" others .... ilh more potent atlalge~ic action combined to.'(ici t)'. Many modificallons of the: basic COOIpOIInd been made. The few denl'lttt,-es :and modificallQllil marlet:art: listed in Tables 22·8 and 22·9. !'hen)1 alr hougll aMlgesic ibC"lf, wll.~ origmallydc:'·clopc:du . ... bilizC1' for IBe insoluble am illQpyonc. II is now belli( for tBe relief of many form~ of llrlhrili s. in .. hich;'d it 111 0;0 relIuces s.... elling and ~pa!i11l by an anti·tnnam~ IICtion .
"',m
01"
1:201.
'AILE 22--8
Derivatives of 5·P')',.azol.
,,!Uco~
~~
00')'-
iphcr;elani "Cfore, l'l'Cog-
,,"''i " " ."'. R E>C ••• I...... 2002 . 7, A.........,." Phar~;':"1 Auoc;,n...: Achie"n, ()pI."....1 11",. II"'''' I", OuIComeo. ".m NonpR->llCOOl>On IIowd.O'.....
...
..... 01 COOI_,"",'''. 1 04~ ~ koct.C C,andCloe~, K. K . f'N. ""'" S20I. lIMo ~ 1 5«a. C. C~ _ 0 - . 110 110 J Pi Up. Thor 17J>3. 1.l. V • lAMA 188'1 12. 1%4 62 Fra.... It F. and ROlWnbe", D. E..: I. I'harrnxol up. Thor. 1.3 DtKomf~1d.
T , I . II1II 1\:..... I W 1. _ _
&p . ....... 1.... 11. 19boI f>.I IkMIo. R W 8 •. I. 0 ... "'""""""'- 7:297. 1m. U Ham .. O. 5 .. ft 01. l>noJ Ak:ohoIOfpmd. 6 1 1lS. :!IXXI. M.n;~ .
W R. Ph>nnorol
R~ .
19463. 1967. 61. lulou>,D.. """ R.... "I'. I', lbp< ... L: .....-.1. pg, .. $c .... 122. 1914 81"'''''''1. It ...... Do),,,,,. It II In K"""";" ... II .. V,llJrKaJ. J ,,_ I""'). """"" IIJIII.1oo1 '*"""'- od*lt L 0 ~""""''''' .... Allied.,.,.,. T _ U""m.~y "" T.,..,." """'" 19';1. II .. IIIIdA'!oil. I> M ""luu'""_A&nt"-'oI. 1 ·'C Soct.17
1'00........,.
'n
s........
1",.m;olicln;aJ F.JIC)"droxyprogcsterooe can be produced directly from progoteronc. although this is not a majorpalhv;ay in humans. Sequential action or2l-hydro~ · ) lone (Cyp21 J and I I ,8-hydro~ )'Iase (Cyp [ [ 8 [ I provide hydroo:.:onisone .. the key glucoooniooid in humans. If PfOiIeSlcrooe is directly acted on by 2 1 - h)dro~)lase (Cyp21) .. ll-deo.xyron icostcronc: IS produced. a precursor to lhe mincTlllocortiroid aldosterone. In tiSSUe!> v; here aldosTerolle is ,)·mhesized. the mullifunctional enz)'nlC aldosterone \ynthaloC (Cypl 182) nlCdiHlc~ (he hydroxylation at Cil as well ~ the two-stcp o~ idation ofC I8to an aldehyde. prol id· mg aldo!;Terone. v;hich exi~T ~ prcdonnnantly in the c)'clk hcml~lal form.
CHEMICAL AND PHYSICAL PROPERTIES OF STEROIDS With fev; exceptions. the S1eroilb lire white crystalline solids. 1"hey may be in the fonn of needles .. leaflets .. pl3ldeTs .. or amorphous panicles .. dependini o n the paniculllI compound. the so lvent u-cd In crysllllli1J1tion, and the skill and luck of the C'hc m i~l . As the steroids hale 17 or morecurbon lIcoms. it is not \urpri ~i ng th31 lhocy lend to be waler inso luble. Addition of h)'drox)'l or OIher pollir groups (or decreasing C'lU'bons) lIIereases wllter solubility slightly. lIS expected. Salts are the most watcr soluble. Ex amplCli ~re soov;n in T ab le 23- 1.
CHANGES TO MODIFY PHARMACOKINETIC PROPERTIES OF STEROIDS As v; Ith many OIher compounds tkscribed In PR'vious chapters. the STeroids can be made more lipid I1'().
oaII
It)'dtu.;.;JrJ._
lI)olroo;~1 In the nl"tar..,,:~ IlonIM"1C =qliu, ~omrlc ~c- ""I'I ,,-, dm"""; 1hr dlll.."t lUll' "II"", a"·.,, to bnllI IIdlf ,Ue,. 1l\t, nUdC'·ray ery~tal ,ttoctun:) of the 'teroid honnorlC!; them·
'*'
,
~1I:roids
The prog,,-,tCI'QI)e rec:epto,· can 01..0 be found III t .... o fIer. one regu b le lhe hypolhalnmu~ ant.llhc: amerior jlIlUItar}'" a rC('dback inhibillOO proce" thai decreases GnR II. Ul._ FS. I pnxiuchon. The resuh 1\ 1M, funher OVUlal1(lf1 is ~ Ilcll. As described below in 1111' ehnpter. ,his is the pn~ n1CCh:uti~m by IIhleh sterood birth conn'Ol prodUCtS InI'ubot
,0
They arc clilled gonadOll1l1';1IS because of their acti()ll~ on the gonads. As ~hown in Figure~ 23·9 through 23·" . lhey con trol ovulation. ~pcrrnatogcnesis. and lIc,clopmcnl of ~~ organs. and Iht:y nlaimain ("Il"egnancy. An addnional pcpll&::. gonadotropin·releasing homlOllC (GnRH). rt'gulales release of 1iH; gOlladoLropin~. Includcll in Ihi, group ;lre the fol· lowing: • ~ln·relca..lnl! honnone (Gn RH) • LUleinl,.ing ho,nll>OO (LIt) • FoIlidc·"lmul~ltnl hormone (FS H) • CbonOOIf; ~ropin rCG; hCC .5 hunWl ~rortn). 3 III)topcpude produced by lhe p:oanla. ll~ pharm:ocologlf;al """,ions an: c.s,;cnlially lhe 0Iart1e ~ lhose of Li t
o,·olalion. If renilll.~lion OOcs nOl occur by aboUI lIay 25. lhe CQ1M lu,cum begins 10 degencrnte, ~k111 inl! (k,wn its producl1orl ct
C.... N The hypothalamu s n:lcase~ Gn RH. a pcplillc 111111 stimulule..~ the anlerior pilllllat)' 10 SC'CR:lc LH and FSH In males and females. TIus pcphde control" and regul:ttC!i boI:h male and rCllmle reproduction (Figs. 23·9 and 23- 10). GnR H b a rllod·
,,'I•,, ,,, ,,, , ,
"-"'"""
,
I
""""
'"
I ......,
Ntleo ...
•
A.• '. ' .... , ____ _LH
=
•
SH
E1I.0(I00I
~
,,,,/
"---.
----- ••••. -
,,
CT'jM
"---. U<
/
TMlO$Ierone
,
~~~I I
OwaclOl.ltCS Figure 23 - 10 • Regul.ltJoo of 5pe(malogeoeSlS. $e)c
1
1 1 4 11
""
21
Figure 23 - 11 • Hofmooe changes In thfo normal
"'"
~. .
·Trp-So!rte at the ~ peptide: .. thm are
ruions between octi"e and In.:ICU'e metabolites.
BIOSYNTHESIS The estrogens arc synthesil.ed by IIle acuon of the enl)'tne atOOlatuse on undlU!>lencdione or testosterone (Fig. 23-,5). T1Iey are normally produced In relall\ely large quan1Hld In the o\'lIries und plucenla. in lower amouOlS in tile . 11:11 glands. and in trace quanlLlics In the: testes. In postmenopau. sal womcn. I1100St estrogens are synlhesi/.cd In ad ipose tissue WId other LlOIlOvarian site~ . About SO to 3.50 ,uglday of CSlnI' diol are prodllCed by the ovanes (t'Spccililly the OOfllUS lu· teum) during tile menMrua l C)'ele. Du ri ng the lirs! months o f pregnancy. tn.e corptJ) luteum produces larger :unoullIs of t'Stradiol and other estrogen~: the ploccOla produces IOOlot of the circulating hormone in laiC pregnancy. During preg . nancy. IIle estrogen blood lenls an: up to 1.000 hl1lC~ higher thlln dunng the mcn~lnml c~cle.
METABOlISM OF ESTROGENS
Thc metabolism of ILlLtural e!\lr08ens has been R:'"icwed
In
17
dct:li l. 1bc Ihree pnm:ll) c.,tmgens In women are 17,8e,lradio !. CSU"OI1C. lind est riol ( 16a.17,8-e!iuiol). Although 17,8-estradiol IS prodoccd III !he greatest Ilmounb. II is quickly o~idi t.cd (~ Fi g. 23-12) \0 estrone. the eslrogen fou nd in highest conccnlnlion III the plasma. &trone. In tum. IS con\,erted 10 estnol, IIle major estrogen found III human urine, by hydro~~I:lIIoo at C I6 (to pro\'ide the 16!lhydmxy1) and rcduclLon of tile CI7 I..etonc (l7.8-h~dro~)'I). E.~t!lldiol can Dbo be direct ly convened to estri ol. In lhe human placenta, the nlOSt abundant estrogen synthesi/.ed is estriol. In both pregnant ond nonprt'gn:lIlt \lomen , howel'ct. lhe thn:c: primary estrogens are al so mctllboli1.ed to ~rnall amounts of other deri\'atin~;s (e.g .. 2· h.)droxycstronc , 2· met ho):~eStrollC. 4-h}droxye~t(onc, and 16P.h)drl))(y- 17,8e5Iradlol). Onl ~ ILbout .50% of thera~ulLcally administered eslrogens (and their variOO5 mct.1boltte~) an: excreled III IIle un ne during tile fi r.>t 24 hours. Thc remainder are excreted into the: bile and reabsorbed: cons.cquently. r;e"('IlI1 days are required for complete ncrct,on of II gl,en dm.e . Conjugation appean; to be ,'cry important in estrogen ttllJlspor! and mctaboll~m. Although the estrogens an: uncon· jug.1lcd in the ovarie~. significant UlllOllnts of conjugated e~trogcns may pn:dominate in the plasma and other 1t!>Sue!-. Most oflhe~)
-0
I
~
oe
A
0 Coume,1rQI
Daldzeln
Genliloin
Figure 2]- 13 • Coo","""
active because the OH-w-OH uj,mllt'.:: j, rnumllli lleu. [n the /hrtQ isomer, OOwc\'cr. there is ~tcrk repul,iorl of the IWO ethyl groups. 11M: 1"0 phenol groups fOlate to relic:,'c the repulsion. !he Q U-Io-OH distance i$ changed. and conse quently. the 11r"" iSOfllCr i ~ inach\'C (Fig. 2)· 1.5). Phytoestrogefls. s.:,'crnl nalu .... 1 plam ,ubslunces Ihal have gl:fleruJ slNClUrul fcalum. SImilar 10 those of DES and eslnldiol also ha,'c estrogenic effectS and h.me b«n lenned phJf~S'1'(,gttU.J'I 'These il'ltludc: genistein, from so}btans
and a spcciC'S of clover; daiul.cm. from soybeans; and coumemol. foum] in cenain
legullle~.
Geni stein and daidtein are
c~amplell
of isonll,ollts. These and OIhcr~ have amifrrum,. acli~il)' In amrnols ..oo Many cl aim s ha\ e been made aOOulllli: bcndici:d c:ffoo~ of coo~umin8 product) ~-OOIIlJnInl! __ _ ph)1oeSlrogelIS. mcluding prI:\enling and lr'C'ahng c;mlio,oI cular di"'Ogen~ is for Inhlbitioo "'()\1Jl~tion.
in combin,ltiOlI " ilh progeslin,. Steroidal bir1h IIItroI agenb CQIIlaining estTOl!cns are d'!lell sscd In the~on dlemical L-ontrna:pllOO laler In Ihl~ chapter.
OH
OH
Treatment of Advanced. Inoperable Breast Cancer In M@n and PostfJl@nopalisal Women and of Advanced, E!.lrogens are Inoperable Prostate Canc@r in Men. uscd to tre"t inopemble !)rea_! callcer in mc n and III postmcnopausal women. but estrogen thempy can ac1Ually 5timulale ellisting breast cancC:1li III prc:mcoopaus.ol wOlllt'n . The tradiol but lOOfe act ive than its metabolite. estriol. As the sa lt of its 3·sulfute ester. estrolle is the primary ingredient in conjugated estrogens, USI'. and e&Ierilied eslrogens, US!'. AhOOugh originallyobtailled from the: urine: of pregnant mares (about 10 mgIL). estrone is now prepared synthetically. P1 P'1!IU'W;o; t£lR()'O ~ SUU'Ant (J-SUI.I ox, ·1:!IT1U_1.J,5i 10)u lIl:",- 17-o"'II I'II't:IlAZINII SA I.Tj, USP. All the estrone 3-sulfale sahs have the obvious pharmacrutical advantage of in . creased water solubiHly and better oml absorption. Acids OOIWffl the salts to the f~ )-sulfale esters and cause some lIydrolysis of the es ter. This does ROt seem to affect aholorplion adversely. but precipitation of the free SUlfate esters in acidic phannoceutical prepamtion~ shou ld be a,·oided. The dibasie piperazine: molecule actS as a buffer. giving it $Olllewhat greater stability. CO!'IJl'GAn:O EnltOtir~..,., US". 1loc term C'lHIju811t~d ~Slro g~ns refers to the mill of sulfate conjugalcs of estrogenic components isolated from prtgnantllWre urine (Prtmarin). These compounds ore also referred to as CEE (conjugated equine estrogens). Conjugated estroge ns contain 50 to 65~ sodium ewone sulf,te und 20 to )5% sodium equ il in sulfate (oosed on the total estrogen cootent ofthc: product). Premarin also conlllins the: sulfate csten o f J7ft'-eStrudiol. J7o-dihydrocqui lin. and l7.8-dih)·droequilin, in addition to other minor componc:nl$. Although most cOl1lmooly ustd in BRT to treDI postmenopausal symptoms. The conjugated estrogens are used for the e ntire range of indk,tions described abo,·c. except binh control. Sv", IInle CONJL"(]ATW f....."T1t()GI;/'is, A. Celll'!itin is a millture of nine estrogenic substances (Fig. 23· 13): sodi um estrone sulfale, sodium equilin sulfate, .sodium equilenin \ ulfate. s0dium 17a-esu adjol ",Ifate. sodium 17,B-csuadiol sulfate. §0dium J7o-dihydroequilin ",Ifate, sodium J7.8-di hydroequi lin sulfate. sodium J7a-dihydroequilenin sulfate, and sodium 17P-dillydroequilenin sulfatc. These estrogenic substanceS lin: synthesized from soy sterols. The term ,yntMlic has been added before conjugated estrogens to indicaTe that
this product is distiBCI from (not equivulent to) the conjllgated estrogcn~ dcri-cd from mare urine:. The "A" fol~· ing the narne indicatell that this is tile finot approved mi~l\IR of ~ynthetic coojugatcd c:.lrogens. Subsequent S)'ntheuc ~ JUllllled esuugc:n prod ucl$ will be named in ordf,r. witlllbe final descript~ " 8 . C, 0 :' elc. Cenc:su n is upproo.ed for the tn'alrnent of moderate-to-SC:"a1: ,asonlOlor symptOllfl lmd vu lv1U' and vagmal acroph y associated with rm'~ t::.,.....uum;u t':~·IMOGl~~S. USI'. Esterified estrogens (Esuaub. Mme5I ) contain some of the same iu lfme conJugates of~· trogcns prescm in conjugated estrogens. but tlx' ralios III these components and the composi tion of millOf oon~nn o f the products differ. 'These products contain 75 10 83 .sodium estrone sulfatc and 6 to l 5'l> .sodium equilin sulfllt, in such proport ion that the total of the.'iC 2 componcnu IS 90% of the total esu:ri fied estrogens ~'()Iltem. The eskrifltd estrogens find tile same u>es as the conjugat ed est~, Estriol, USP. E.~triol. eSTra· I,3,5(IOj-tri ene-3,16n. J7,. triol. is available for compoundmg into a nUlllberof dllfm. formu lations for U'iC in liRT. IT can be u:oed alone or ill combinatioos with e.'tnidlol ( Bi-E\l:) or Ilrant (Fig. 2]-16). T"o
tagonl,t effects of Ihco;c tyJICS of compounds on Ihe ER. dependini on the 5p:cifk tissue. u new tenll wa.~ coillCli; stll"l"/.I·t' t!!/rtJfltll rl'l'tIJlIJr modullllors (SERM~). A SERM i~ a drug that has IIssuC·,pecirlC estrogcnic ocll lil),. AI . though mllny compouOOs exhibit SERM act;'il)'. a few agems are antagoniSl.~ m all "'MIe\. 'T'helic
I
Tamoxi/(in (NoYaIde.,
Zuc:IomIp/lene [CIomtpheoe (CiOOlodJ • • rnilttu .. 04 ............. lUdomtphene and ijldOIllIf)I....J
I~
b~ ~iol
o
l.......N-CH~
h) 1~~tC-
1\0.,.
,b
CH,
HO
o
o d
T()(eI'!lIlena (Fa!IISIOO)
~nt~ : to
,,,.
abuly,
....
HO
~.
~I'
ate.
t.uoIo>;iIene (CP-336 t56 )
wptOf modulators (SERMs) and anllt'Strogens_
TUIlIO"fen ha., ~n c~lcnsi~c usc In trealing pnmary bn:asl callCrr!l thai are ER depcrwknl.:It cancer only in ,",omen al hll!h n~l.:. Women Without
a fumily
hl~tory
of breast cancer or ocher ri5h should nl)!
usc larnoxifen in thi S m:mner. Ralolti fcnc is nllOlher SER/I·1. but us profile of lIt'llv;l), differ; from Ihal of mmoxi fcn. Ra loxifcnc is an ER muagoniSl In both breast and endometrial lIS.'Iue. bul has agonist action 00 bone alld aclS as an e~lTOgen agooist in lowering tOlal ehole~terol WKI low-dcnsily lipoprotein (LOL.), 'The wbtle )trucl\Jr:t1 diffel'!'nces betVl'ttn tnc twO drugs undc:rlie tnc di,tinct aclivity proliles.~) 1lIc agonist llCtion on bone ti !>S~ i, the basis for the usc of thiS drug for Irl'ating osteopo\"Ol;1'.
A ley questlOO is why do COll1pound.~ like tamOllifen and rJloxlfene c~hlbi l amngoolst OCIiOO in somc u~ucs. but ago. ni~1 action In other ti_sues? Major dc"dopments in the pasl ',wl'cars arc beginning 10 pro~idc w an~\\er to thi~ question. 1. .l6. 27. '"' Tamo~ifm,~ raloxlfent. and eSlradlol(1 all billd to the ER at the ~anle 'itc. but their binding Il"lOtlel; arc dlffcl'!'nt. In IIddmoo. cxh Induces a dll cancer ticnt~ receiving adjuvanllumoxifcn Ihcr.. py. It i~ alsodfcclIve in the t. \I ~hou"'J be protected from t. . The major IllC'tilbo!nc of tamoxlfcn I~ N-dc5mc:thYII';';~ fen. VI hieh ll'achCl> k\eb hIgher Ihan tamO.IUIJI ilSelf. Ii IS belie\cd significantly 10 Ihc overall II . tabolitc. 4-hydroxytaloo\lfcn. IS II more than tamo.\ifen . but bccau ...... 11 IS only a IlIn)Oxifen. It probably does not contribute
In,.
"
"";"-, ""
-",~;, ,.
in pharmacologICal Studies of the'iC reccptOl).. concentmllons llfC reduced if coadnllni\t~ WIth a cytochrome P-450 inducer.
Toremifene Cltrat~, USP. ehlorn- 1,2· diphenyl·
I: b.",
... a~ lhe repound;. thal "ifene elln 4-lIydro~y-
"Irogen :te)rOSleopo-
\uccc" rlli as an O'U' aw GIIRU pr'e\IlIn,produced :arK!l'lI ui1\ an' low llRH ll1e 100 ofUI (i.ulat ion ). Suppon d b) '('\1\ 'a~ 110 e r1\
d b pallc nl, 1I"e
ne ... -
'l of the out 14, thl' C 19 t'arllon " oJ( ld:ltj.ely elea\ro ttl f'1IT11I1le. " h)dndc rea,1 C:lflcer, Iniually. arom~'3SC inhibitor. ... ere U)('tlll~ ~ond·hnc: lhempy ill jl'O'olll1enopau,al WOftlCn who failed 011 talllO, ife n lherapy. RCC'ocy of the hypothalamic pu lse generator and I ncre~ the ampliwde of LH pulse$ rdease0
. ..
II. A. .. ole
~I< '
"
I "it ur..:..
fiI Ooe
I I 1100
81rth Control. A significam U~ of the progl."Shn •• as of !he c lrogcns, I~ Inhlbitio" of u\'ul31 ion. SlcroidaJ bln h COII!fOIlI,gents are dbcu~scd In ,he following houkll1Ol bc u«ed In place' of ~urgcry, I".tdlotion, or chemotherapy, Progestins fo, Premenstrua' Syndrome (PMS), There have bun claims that progt~ttl'Ol'lC may reducc the tffeets of PMS, Conl1nucd anoly~, of V:lriou, studies indi .:aIC, ho",elf lacl.:~ proge..',ullional :Jetlvity. 1lIc caproate ester is gIVen only Inirnmuscullirly. The ester greatly illCfl'ases oil
MedroxyprogestefOlle Acetilte. U5P. Mtdrol) progesterone acetale. 1 7-accl)'Io\)'OO-fTII:thyr~ 3.2O-dionc (Proler.. ). add~ a 6cr-lnclh~ 1 group 10 the 17n-hydroxYPfogcMerone ~truc1Urc to greatly decn'w ttr rule of reductJon of the 4-cnc-3-onc ~ySlem. ~ 17(}-~~. group also decno:lSeS reducuon of the 20-0ne. similar 10 l7cr-caproate. MedroxyprOj!C!>terone ) is ta'J' IICllve orully (o;ce Table 23-2) and has such a I of action intramuscularly thaI II cnnlIOI be inlramuscularly for InolllUlg many lIlC'nslrual inlramuscul ar formul:mon I~ useful in lhe paillru,,~ ~ menl of advanl,:ed endonl('trial. brea!>l. wid nonal c=i,~. . MPA also ha~ an Imponam role in SCleral bn1h control UCIS (Depo-Prol'cra. Lu nclle). Megestrol Act't~te. U5P. MCgolrol llC\'1:ue. 17~ dmxy-6-melh)'lprcgnn-4.6-diene- ~.2O-dione ace). IS a progestin used pnmanly for the mem of l"CCurrelll. illopernblc. or i for appetite enhllOCl'mcnl 111 AIDS paueTll.s. oosis for Ihi _ use of nll,
+.- ((
I "'I
Ed.)'oodi! "'-'~. I fill "~.O,.~IIIJ
~ln5
Jj
Onh,,·Nm'lJll1
IIJ~
M~~
"«-'OIl O~l'
O.Yl~
"I'lIWolI.
Ni:r' 1(17 ~forc. OUEA or can l'Ia"e androgenIC acIlOll\. btH (111)' aner I]VO cOI1'ero;ion to tc.\IO"ICrone and DIIT. OHF..A and ~:encthone lItr. howe'er. also pn:eul'liOf' 10 the nltocstfOl'!cnic IIClions may also occur.
Testosterone i$ rapidly ron"ened TO 5a- OHT 10 many I1!'i'lueepcodmg on the tissue. Ihl~ is eilm 10 acti vate te-~
7tl IllI
" " ,ro ""
"'" ,~
'"
.. ~
"'"'
1:!()·1~ ,~
"'" "" "
"
-
17o-Me!hyfItiIoIlerone CT-.trwd)
TUIOSItIi .....
(1iIololeSbnj
, 7f!-EII_ Commerotlly AYIIH.1JI,f 110< 1M 1njecIIDn): Also teslO81erone propic)f\(Ue (10< COf'I'IP(IUr'Id)
o
VO~
-
T'nll'....... ~1(1
"'" 0xyTr... ,......
Melhandroat...alone (o..l\MlOI)
(~l
r--".-c.-v.-.../ " "
-
Narodo ........ slll·EIII,... COmrnefdaIy A... ~atJla Nencholoo" ~I'
FiGur. 23- 24 •
T~tO'l«,r()(\('
and
-
¥1,ht\w:: anabolIC androgenIC ste-
'"
at d,rrerent
""
"'" AAS have been sym hc~ilCd :md studied. The pi or many ~ynthetic progr.ull$ wa~ 10 make Mcompound ... po( coronary d,!,.,a... >lrul~. U .... .uuclCd bk>Ud w"...:I, locn:ased ~oo and antl«lC1a1 1Lch;!.\lor I~" _ "~lCro,d
"'SC''''
Li .'~r !Un,.,..... pelOOC.'1l1 nl 3 milch hlgl!er steadysImI! coo.:emr.llion Ihnll i~ fl ulanude. cmllribUlc.~ a ~ignin· cant amount mille anualllirogcn action o flh" drug. A limitmg foctor III lhe use of flU!:lInJdc IS hepalOto\icily In from I 10 5% of patlcnls. AlIhoul!:h toc hepalo(Oxicity \15\1:111)' i< fC\'crsiblc following cc,~mion of m:atrnclll. rnre C3"':S of death a"c in blood volume: Slimulate$ kidneys to . in that it lad.s thc lL~ual 170:.11_diol systcm of the other> (Fig. 23-31). Currently. it is used only for treatment Df innammation of the eyes. Methylprednisolone, USP. Mcthylprednimo1. SInIIlSoi 1111· 1!1. EI 47. r."",·t:m·iJif. L. II ...h. F_ E.. 1100'·.... 1t.·••. , ...1 8r J c~ U.llO-JH.2OO1 4!L. Sd:n"dcr. J .• Gn:cnbIiII:. O. J .. """ MoIil.c. 1_ 1.. eI al .• J a 'ft. "I>::.nlXOl.J719J-:!OO.1\297 49. M"~_ioL. S 8 . UruJou 58108 Ill. 2001 jO. C - . F J au: n..,. 2-11§00pp4 CtCl-2.5. :!OU! jl Corl_. R. W. RmIIC.......... It... Tr..... 7~S""'" 1) 52l-J!. :!ou2. d,,,, ... __ S)I ~~. 52. M,,,,, O ,on.lWhi:cho;o.l,M.Cun Op;n OtNeI. G)1Im>I U>J·68.
''''
,." ,,,.
57. Owdor, It U.. """ Ih ilbo&)l. G" J
a. •. ()n(oI
16cM
-I~,I,
SS, W...n.y. A M 1111. I a," 1',.,:1 ~ ~-.lCW. :!OOl oW. GoIdll. ~_ II. CI) ..... C. Rubin. G . .. aI. Ann. WILI 1)Qoo>d~ M Hb 1>0'1""- 2.5;,ws - fJO!.
,."
9J
99
B Gmor. Tit .. 510:... J I'. Ill) lilt. H U... 221 .. Proc Sal AcId Sci U 5 It ~141~· 14110. 1\291, Sol S/LMa. Y.• """ Bh1\2I11. M SC~ •• "".~ M24M-!~.1OOl. ~. Slu.oo. A K.. IIat>IOd. D . loo.i&. P M . eI 01. C~1I9S"'!7-937. 1'198 ~. Kom'n. 1l S.. and l.)1t i l.JIdo..LOl M M..d. 19126·1-10. \\ ". r. c.: Cll ... Chtm. 4J; 1289 · 1192. 19'J7 FDA Ilni. Bull 1127.19117. Hic h. J D.. I)id'"""'. IlI·.. fdl .... A.. rnooo-..ki. W P I R...,..oo. M«' '!10M 7• • III'J(l-.d",. . . 74_ Wnlructurully ~aried hydropOObic materials. panicularty cu-
bo~ylic
aeids and phcoolic anlloudallIs. Imphes !heir AI .. cepublhl)' 10 Influence b)' a "31icly CJlogellOlJ~ly adnums. tered agellis. Ba:aulol;: 11'1OlIt arQInatlC drug IlIOlecuics ulllkflu t>ep;lIic hydroxylation, phenolic Ikri ... al i, e~ of a,hmni~trTd drugs become readily available III vivo. Even mon: direcd). aromatIC ITI()lceulc:s on ;n vi lro ulCubatH:m with mICrosomal PGH synthase will ""-"(M11(' h)dro~yl3ted dutt'lly ~ arnchldonlC !lCid metaooh~m. m Q procco;" labeled c...... ~· ,IfHI." ThL~ coo~idml\'e prtx:es~ Pf'C_umably ()CCUI'S dunlll lhe p!;'ro~ida.-e mnler;l()n of 1'GG: to PCH!. "hich effc\;. lively mal;es a"ailable a lIOn"fICCifiC oxidlllnil .:qUI'''' llIe COO~ldaUon process has been unplic3ted in the a< He
,
,
f
Chwpltr 24 • 1'",slOg//II"/"u. '~~>frlt~s. and OIMf Eict>ulnoNls
82S
TABLE 24-2-ConrlOUt'd
••
•
Tf'~ue,*"
,-''''I=If'\/"'. COOH
"
-""
1lI'· ,"",POur IIR1ZIIc1
lOP,
'"'...... "-
Bu,""""" fm''''fI''JIIOlJ
tilm"/impb".:m",,
No!
Te."
NoI.,..,l>I>Ic
t~AMPIG.
lQo.u,-,",
G""rocI..,,,...,..,ory G."",*,',Oj"O'OIt "'ounVI.-oIl"" L"~"""""""'_
U_ _
T,..",""""
81",",,,p"'"
"
,p(jl,
1·"iI·.......·iIJt'PI_
,,"--w_
e.."....
UItG~I"'Q
""",. TXA, Sol-U
Kidnoy"'/kmM _"""'" (TlItlul Ms been modified tu pre>·cnl metabolic o~ idat,on IS-poslllon alcohol fUIICI1011.
nus denvali,c
is adrn inbtc ....:d
,II
I I po!>tpanU11l hemolThage.
a dose: ()f 2.'iO J.lg by to mncl io-
Prostaglandin E•• USP. PGE,. alpro:.tooll (ProsJ.on VR Pedialnc). is a naturally OC'("urring pro;taglandin that lias found partlculur usc on ma,nrainmg If patent (opened) dll("lus ancrioOI'l of the IrimcthylammOlllum sail of
PGF.... (S.O mglmL).
EI(QSANOIDS IN CUNICAL DEVELOPMENT f OR HUMAN TREATMENT \umtrotJ, pm~laglandin analog\leS are under invCSllllmtOn btlle treatmenl of human discasc~ (sec Table 24· 2). Effons nbl:mg foclI~ QI'Ilhe an:asof gaSlroproll."diQl'l for anhu lm tb::flIP)'. fertlhly c:ootrol. lhe u.c,nlQpment of Ihromoo~11CS fc.g .. JIfO!itxychll or Ihromooxanc synlhellbe mhlbl1m) 10 treal cerebrovascular 01' (:(It"{)IUU")' ancry diseases. and
tie deH:lopmenl of allliasthmallCJ Ihrough lnodulatloo of lilt hpo~)"I~cn:hC palhway. FUlure applicallOO of cicmal\Old~ 10 !he treatment of cancer. hYlX"nension. 01' Immune ~)')lem
JtionIers cannot be ruled OIl!. holt,·e\"cr. Thus. although progre!>~ hll.~ btC of eicos:\noiru. or rK'QSlIooid onalogues U lhernpcutic age!)ls in the fulure i~
alnJOclIlakJII. 1'1... CRC rm... 19It9. 1"1'. .1$-16 ~ 1'InoblIn, M 1.. l)oy. R. O .. -..d V., """ II .... W I:l : AJ(''''' """",, 'I ,CI45 ("1'9. 1994 1 T.... A.-I_. -.I Kol""",... R. I . """,-,,1.00.'" o."", I.lpo.! Mtd,.,,,,,
&l:Ht·2S-1 . 2O.XI I Smoth. W I " """ 0.""1. I) L: Adv In.. """",, 102:1&7 215. 1\1%, •. YaM. J R.. 1:l.~~Ie. Y. S .. .....t Botunl. II. M Anno. R.~ l'IIamuo..'UI Tu,iroI \II Y7 - I:!II. 19'Jlt I . " W l' M """",, !MIdi ... tzut.,. F.."'.... I'-IY lie"" 11.1 IU · 126. 2000 I ~-.ya. S. Y.. ..... WIItLIIbi. f PIIj'W lie' "N: 11~1 · 1126. 1999 11 K...... \I .... >t,'C""'t .... J. A ., " al N",",c 138, 129. IY72.
J(l
SElEaED READ ING R..Ic-y. J M 1 rIIuy _" . bn. ""'" Mni. Chmo. 2'l1 -f)~. l'Hl R. I( (od); II.."" Hforu .)' lIe.w .~. Ad. u.p, M«I lIi1l!19.1-421 . 19lI9 t\dq.'i .... 1.. 10.. and l(indahl. 1I ( Von. Abo 11 I~ .... 1919 S,""Jt""',Iol.. .... P • K,f... R It . MMl 101 ....... 11 t:. HeaIdo BJ.n. 011'1;)1,.... _ _ Fony ~ ... 5eal"Od .. Ncv. V.. k. A, - I Inltructurt' and inletaclions.' The chams ( R !:fOIJPI") 0( various amioo acids ha,'C It)lttx:W'bon moieties that an: h) drophoblC. and they h:l\'c to as~illle ","h .. atCT mol('(:uJrt ~",~ are qn:N1gly IS50Cinted through hy· 1lrogen "hydropllobic R groups tend 10 get ~ Io.J 000 aOOlhcr, with exclu~ioo of watcr mol('(:ule.~. 10 form "bolld ~" between different 'lei:Jnents of the chain or
:
".de
" Figure 25- 1 • DiagrammatIc representat10A of a fulty ex' tended polypeptide chain With the bond lengths and the bood angles denved from crys\.ill SlllKtures and othef expet.menliil e.oodeno::e. (From COfey. R B.. aoo PauI!r\g. L . Proc R Soc Lond 5ef. 814110. 1953)
between differellt chains. 11Iese arc often lermed hyJror'ho· bic bottd.f. hw/m,HII'bir !orcts, or hl'/lropJwbic i"'UI'CIIOIts. The stu dy o r protein structure hll~ rcquin.-d .ev.:rnl phy,i· cochemical methods of analysi~.4 Ul tlllviolct ~pcctropho.J... IOOlelry has been applied 10 the assessmcnt of cooforrna· tional changes thai proteins Ui'\(ierIlO. Cooformahonal changes COIn be in"CSligated by the direct plotling of the dtfference iO absoi'plioo or the prOIem under "moos .sets of cotidiIlOO~. X·rdY an31.\'~ls has been ITlO\t u!idul in lhe elucidation or lhe structures of seve",l proteins (e.g .. myo-II lobulin and lyS(1)'mc). Absolute Y:sy:, anAlO1 ylic propcrbeS, ha ... ~n isolated from the European fire·bellied frog. Although out a complete list of the peptidc ... Isolated from frogs. tocse provide an insight into the: ancient dcfem.:: meehmisnts these repi iles po!;SCss and Ihe po_sibi lit y of c~pIOlla· 1100 for ~uch U>CS us analgctics. a "ti!11icroblld~ (e'p,:eiall y apinst resismnt organisms). ~nd cllrdio"'a'ICu br agents.
rroc
Nu(/eopro tei n$. The nucleoproteins menlloned abole lte found in tile: nuclei and cYloplasm of all et'lls, They cnn br dt'protelllu,ed by selel1lJ melhods. The compounds lhal om.u- in yeaS! are usually treated by gnn(ilng .... ,th a IeI)' dilute MJlution of potassiulli h) droxide. IKkImg plC'rie a.cid in nces~, and ~Ipnaung lhe: nucleiC adds .... nh h)drochlorie K'id, Ie;l\ing the profein in solution. The nucle ic acids an: purirlCd by dis.'IOI",mg in dilute pocaS$;UI11 h~droJ;lde, fiiterml- addifylllS ",ilh a!.'Clic acid. ~nd finally prttlpimhng wuh ,luge excc,s of ethanol. The nuclCQprotclIls ft)und in Ihe nueleu~ of eukaryOlic «lis include a variety of en~ymc~. such h~ DNA and RNA polYllleTU.'IC:" (in ... olved III nudeie acid 5ynthe~is). nudeases lil1l'olvOO 111 the hydrolytic cleavage of nuclcOllde bonds). 1SOI11Crusc.~,:utd OlllCrs. The nu relICtIon 10voh'es the loss of thts pos;II\'e charge Sl lUullallCOUSly .,.Ith the auack ofthc nucleophilic reagent (abbreviated Nu, H ). Roberts~ used nlllVgcn- 15 (" N) NMR to ~t l.>l.ly tnc I1k'Chanis!1l of protcase catalySIS. A scnClI)atiin(ogcnj. and ilhlliin.
C~) I
• °H
A- C- N- R'
A
'. •
K_ , C:~) I
°
.RCOD
Dill synthesized on the ribosomes . They pass a4:r1)SS the mem~ bnme of the endoplasmic n:ticu lum into the cisternae and directly into a smooth vesicular structure. which dfect!; further transportation. They are finally stored in highly concen· InIted funn within membrane-bound granules called ~'''IQ g~" grt",uin The ex portable protein conlcnt of zymogen granules may reach a value of 40% of the t01al protcin of the gland cell. In the enzyme sequenccs abo,·e. the new ly synl hcsiJ.ed exponable protein (enz)'me) is not free in the cell sap. The stored exportable digestive enzymes are released into 11M: exulICellul;lr milieu and the homlOt1es inlo adjacent capillaries. Release of these proteins is initialed by specific inducers. For e.t ample . cholinergic agents (but not epi nephrine) and Ca~ · effect a discharge of amylase. lipa.-;c. orothers into the rm:dium. increased glucose levels sti mulate the secretion of insul in. and SO on. This release o f the reserve enzymes und homlones is complctely indepcndent of the synthetic process. as long as the stores in lhe granules are not depicted. Energy oxidative phosphorylation does not play an important rolc in these releases. Electron microscope studics indicate a fusion of the 1.ymogen gn1l1ule membranc with the cell membrunc so that the gTanule opens directly in to the extracellular lumcn of the gland.
Bes ides the en zy mes mentioned. it contai ns some b')JlSlllllgen ..... hich tun be activated by intestinal enterokillaS(: cb)· motrypsinogen. which is convcned by trypsin to chymooyp' sin; lind carboxypepti dase. Pancreatin is used 11Irgely for predigestion or food and Ii:r the preparution of hydrotysUlc~. The ,·nluc of it!; ClIl)lIIr::I orally must be very sm all because: they are digested by J'ICt ~in lind acid in the stomach. although some of them !lIlY escape into the intestines without change. Even if the) In: protected by entcric coatings. it is doubtful they could be It gTCat assistance in digestion .
Classification
Pancrelipase, U5P. Pancrelipase (Cot .. ~ym) lias I greater lipolytic iIC1ion than other p.:mcremic en1.yme iJItPi' rJtiOIlS. Helice. it is used 10 help control steatOl'Tbe,IIId. other condit ions in which pancreatic in>ufficiency UlIpIiI the digcstion of fats in the diet.
11lere are various systems for the classi ficution of en;r.yme.\. The Internutional Union of Biochemistry system includes some of the tenninology used in the literature of medicinal chemistry. I1I1d in milny insHmces tile tenn~ lire sci f·explana· tory . For example. transferases cataly£c transfer of a group (e.g .. methyltransfernse); hydrolases catalyze hydrolysis reat1ions (e.g .• eliterases and amidases); and Iyases Clll3 ly.tC non hydrolytic removill of groups. leaving dooble bonds. There are also oxidoreductascs. isomerJscs. and ligases. Olher systems are sometimes used to cl assify and characterizc cnzyrm:s. und the following terms are frequently CJlCountcred: /iptlSt'. ~,,,idllse. fUV/eIlJt'. phosplilltaIt'. kj,wse. $),"Ih~/(lSe, d..hydrog~IIlJSe. oxidast'. and rt!f/UCllISt'.
Proch...:ts Phannaceuticlllly imponant enzyme products are listed in Table 25-3. Pancreatin, U5P. Pancreatin (Panteric) is a substancc obtained from the fresh pancreas of the hog or the OK and contains a mixture of en7ymcs. principally paJlCreatic amyla.;e (amylopsin). protease. and pancreatic lipase (steapsin). It e011vens not less than ~ times its weight of US P Potil\O Starch Reference Standard into soluble carbohydrates nnd not less than 25 times its weight of casein inlo protroscs. P:tncre~tin of hi gher digestive power may be brought to this Sll1l1danl by admixture wi th lactose:. sucrose: comaining not more than 3.25% o f S1~h. or pancrentin of lower digestive power. Pancreuti n is a cream-colored amorphous powder with a fainl. characteristic. but not offensive. odor. It dissolves slowly bUI incompletely in water and is in;;oluble in alcohol. It aCIS best in ncutml or faintly alkaline media. and excessh·c acid or alkali renders it inen. Puncreatin can be prepared by extracting lhe fresh gland with 25% alcohol or with water lind subsequently precipitating with alcohol.
Trypsin Crys tallized, USP. Trypsin crystallized ~, proteolyti c enzyme crySlal lil~d from an e,'ltroct of the rcn::1S gland of the ox. Bas Imm ..~. It occurs as a while ID yellowish white. odorless. crystalline or amOlphous po!I.kr. and 500.000 US P trypsin units are soluble in 10 mLof .. :ur or saline 1'S. Trypsin has been used for sever,1I conditions In wfMch its proteo[ ytic acti\itil!.~ relic\'e cc nain inflammatory SI*I. liquefy tenacious sputum. and so forth. I\ lany side: 1l'attDr, are cncountered. how·ever. particularly when it is usN JlIRI" terally. which mitigate against its use.
Chymotrypsin, USP. Chymotrypsin (ChyrtWJ IS n· trueted from mammalian pancreas and is used in C3WIr.'1 surgery. A dilute solution is u-cd to inigJ te the pilIItfia chamber of tile eye to dissoh'c the linc filan10enlS tlw hold the len,. Dornase Alpha, U5P. Doma.ith Imt:l.llts 1oIIdI .. turpentine and CTOlon oil (granu loma pouch tlXhniqut) ....... anase is available in .5O.000·Un;1 lablet~ for 0tU1 USC'. Dlasr~se.
Dilll>la!le (Taka-DlaslU IIloaI in doses of 0,3 to ].0 g In the ~arne ~ondilion ~ as mAt iiistaSt'S ;;,'~:;~;,
addition 10 Stimulaung the lhe release of proloclin_ It
Chaptrr 25 • 1}~1lI dT«ts tl1:lt h;o;I'C been elaluated for antKlcjn.'\S:Int
drImlpeulIC pxenual. but the results of clinical lOt yet COII\idered rooclusile.
S4udi~
arc:
Gonadohbenn, as tile name: imrhes. IS tile padolropm. .cltas.ng ho rmooe (Gn- RHJ. also J.:nown llli lutemizlng horlIIOIIt- releaslng hon1'l()l1l: (LH-RH). Th i ~ hYpol:h.ahmllc de• • pude stimulates the l\"lease Oof lutein ili ng hunnone (LH ) and follicle-~tln1Ul~hng hormone (l'SII) by the pituitary. LH . RH is ron~id. .. ,Ih 24-hou, U"IM: oollcrllQn eacll day
... !. 1l1C solulOOIl lIa~ a pH runge of 3.0 to 7.0 and is usc(] for ilN adrcnoconicolropic :>(.1;\'hy. Repository Corticotropin InjKtion. USP. rilied (ACTII,80. cortiCQ(roplll gel. purified
ACTH po~,"or1 i!,!otroplll )
is con icotl'Oplll in II solultoo of parually hydrolyad gt~ to be u..etl imr:lI11uscularly for a more unironn and rnaimcnan~ of ~clivily .
Sterile Corticotropin Zinc HydroKlrk SIISpf'IWIWlO US!'. SI'J.
I
G', I
Asp
AJa
I
I
GlnlO- Ser
Cotlicoltopon
(osyntropin,
CO!>yntropin (Comusyn) i ~ n s ymhetic ptptide containing the fi rst 24 am ino acids of natural corticotropin, Cusyntropin is used as a diagll()!;tic agent to test fOT mnal conical deficiency. Plasma hydrocortiSOlli: conce nl!3Iion is determined before and 30 minutes after the admini>lrJtion of 250 ~I! of cO!>yntropin. Mosl nonnal respon ses ItSUtc in an appro~imale doubling of the basal hydrocorti , ~. COflCenlr.uion in 30 10 60 minmes. If the responsc is !Ill! nonnal , adrenal insufficiency is indi cated. Such udrcnal iIrs~fficiency could be due to " ither adrenal or pituitary malfUllC1ion. and furthcr lest in g is required to dist in guish be !uoen the two. Cosyntropin (250 ~g infused within" to 8 ; . (80 to 120 Ulday for 3 to " days) is • i t with functional adrenal ti ssue shou ld i dosage. Paliems who respond accordingly of hypopituitarism.' the I 'n be by other tests for il Ii ; n who or no response.
CorticOTelin. Corticorelin (Acthrel) is a synthetic peptide thm may be used as un injectable in the dctenninalion I i responsiveness. It possesses tho: omino acid scin corti cotropi n-releasing hormone that is re'f'OIlsible rOf" ~timulating lhe releasc of ACfH. t.4HANOTROPINS (MELANOCYTE -STIMULATING OORMONE)
Melanocyte-stimulating honnone ( MS H) is elaborated by ;ntennedinte lobe of the pituitary gland and regulates of s~ i n in Ii,h. al11ph ib;an~. and. to a lesser t. humans. Altered sccn:tion of MS H has been impl; cau sing chJnges in s~in pig.menllltion during the I I . The Iwo major types of melaredcri\"ed from ACfH and ·n. a- MSH con lai ns IIw: same amino , 13 amino acids of ACfH: ,8-MSH 18 amilM) acid residues. A Ihird melanOlropi n. l"me laoo-
tropin, is derived from a larger peptide precursor. proopiomcianocortin ( POMC). Some im portant endocrinological correlations include inhibi tory IICtions of hydrocorti5011e on the r.ecretion of MSH and the inhibitory effects of epinephrine and IJOfcpinephrine on MS H acti on. LlPOTROPINS (ENKEPHALINS AND ENDORPHINS)
Opiates. such as opium and morphine. ha\"e been known for cenluries as substances thaI relieve pain and suffering. NeuropharmocologistS ha ve theori1.ed that opiateS internet with rrceptors in the brain that are affected by endogenous substances that function as regulatOl1! of pain perception. The important breakthrough came in 1975. with the iso lalion of twO peptidcs with opiate-li~e activ ily20 from pil!: braios. Thesc n:laled penlapcplides. ca lled methionine-enkephalin (metenkephalin) and Icucine-enkcphalin (leuenkcphalin). are abundant in ccrtllin IlCrve tenninals and have been foond in the pituitary gland.
' T~
' T~
oJ,
I
G, G,I
G, I
eI.I
eI.I
5Met
IMe!IEnkephalin
'T~
I
G,
I
As n20 -AJa
I Ly. I
G,
Phe
I
I L"" I Tl" I Val 'S I L" I
Phe
I I Tl" I Se, I
5 Me!
G,
'L""
l LeujEMep"IaIf1
P'o
I I L,.. Tl" I I
lOSer-Gin
I
II.
I
'I"
L,.. I I
"'"" Ala
I H" I L,.. I Ly. I
G, ~
I
Glo /I ·EI'.:bp/"oiol (_spl
An examination of the structures of enkephalins revealed lhal !hi:: amino acid sequence of metenkephalin was identical wim the sequence of residues 61 to 65 of ,8-lipotropin (,8LPH). a larger peptide found in !he pilOitary gland. Thi s discowry suggcsted that ,8-LPH might be a pn:cursor for OTher larger peptides containing the melenkephalin sequence. Soon afler the structural relationship between fJLPH and melcnkcphalin was established. longer pept;dcs. called t!JIdorph;'u. were isol aled from lhe inlenne"" .......... "'I ... ~
-,.,
-..,
tM 01 SC.1j...10 U u.d orq j ......
tM crSC,l~HlllUL ... q.iI a
M."""o......, ,"'......1. Z-4lLf/d1y....
\I~f·'~leri{)f pttuilury Unil$: expimtion date. 3 )caJ"S.
V.sopn!uln
Tiln~t..
Vasopn:~sin
tannate (Pitl"CS.'illl Tannate) is a "" ater-ill!>Olubie tannale of vas.opn:ssin adrnm1\oICffiJ IIltramuJioCularty ( 1.5 10 5 pre$.Opl"essot Ihan i~ 1)'slne: \'asopre~in and is reoom· surgel) to minlmiu blood flow. cspecially in 01 '1 and g)'TIL'C()logy.
Inc
-:::':.1,;'"
~'~" i~ s)'nlheuc S-I.·I)',,1ll' ~asopres ~ul1Jlar
10 ADH. The lys lIle analogue: is a. It was isolated originally in IWO different foons. In one of the forms. the tyrosine residue in pot;ition 12 is sulfuted. Both (Ofm s are biologICally &Ctiv... Otolmergic response 10 tlw:: pre.'\ence of food in the ga~trointesTinal tract provides the stimulus for gaslrin llioma on chalyw _ noI "" dill,.. ........ , 'In ktoo»'or. •..... ttl "· W..:wd . - ,.. {o.c ........ 19'101; Ii'" ... 0( _mi' """'"'" '" d"'lioCld>t,opy ''1*10'lI0 .. ,,*,
T~~lmtnI
Ell UUy" Clndi.ilap"h .. IN)
"""''''''' •
."""'. i.ONA "",,1'1) .... Inp:I;'"
_lin
H.IOI... ,.....Io .. (rOSA
01'1".,
lull')' .,.11 "'ul. 001" the de""", sene from lhe: ICoomk libnry ( ICIk'S Dr m'CrobiJI « lis lhat are blnwn 10 1Ia\'e rapKll1lle!l of all dI Yi~lon. TI) IICPOiwl 'rOfIA
,,*,~I
P''' "..,
....w as '-t~ _
ytt>I "",U5. \fammaloan «lit.. Ad!. ChH1l'!Oe iiamsla' 0' ary edl", IIf"C useoJ ",hen gl)'CO'yl;oOOll .,... rDNA. lkm·cd proIcon i, ~senual for blDlOiical kll"I.Y (c.J. C1')11>""", .."'n). NO/1/TIammali211 celli cannot I:1)C/lIylllc ...... cc1~
_~IOI
,
b'O'Oll of rDNA-dm,ed protein From ... ~1 miJ.mn: conulin.ng b.:ICnal proteins. «11 ~ che micals U>ed in pn:pnringl he media. el~. iwlali nllnd punf}. in, 'hc de!iirW hu"""" prutc'ln IS a Ib.unlln, IN indeed. TM wit m:ju,~ ~oplm.tkatwlwl~uOll .echn"lues. such. C'-I I I j fillnollOlls. 1'R"'1p!lalions. and HPLC. ~ pnmary pi.,.. .... punficlllion pmc:_ IS II) ensull' lIIal IIIi:: proce," 1$OI:tICd d 1l'111II" IIIIi: btologiclll aclivilY o f lhe " allye proIein in the bod:o. n.: r" NA-dm,·w proIcon is then fi;ll'Tlllllalcd imo. p/Iaol..... · icII producI lhat il Kable dunn, Imlo,portltion. 51.,..." admoni~l"mon 10 a pMocnl,
""'"l'
des,,,,,,
(o ~ )
-1.If"•
eM
&.1 ... _
p,rofy po I
I
Fig u re :Z 5-7 • Summary 0 1 olmolymc). is a mucolytic cru:yme idcmical wnh the nmural hUrrnln DNAo;e and b u0I an..! Gil...... •• .,.". l'barmro:'*'Iic .. 0"';. "' ......... ptIIIlC. 10lI0 rd N. 11>.:19'J, 1\181 21 Bn.oc",,_..K •. II .... 1'rplotdma. I 0 . ond I, I oJ. L I~ ( .....1. GoodInoto oa.l Gi ...... · • .,.". /'IIa" ........ """ S-Ql/ ........ poul .... 10th «l New Yori.. M_Ibn. 2001, PI' 1332-lill 87. USI' 1)1 Drul Inf'mIII"'" r.. lhe Iblth Cite I~""'_ " i' ul ..... L 22nd N . Rod"ill0........ Mell" .... 9dr td. I.. W··..... Eli Ully .I: C,,_ 1918. (".011_ A.. P . 1'"""""- 0( "'_'" 1/000).......".. 1ft llrodetfloff.. II .• ...J Jeuen. II. 0 (tdU. UpoI)"" ""Iy...... N.,.. Y",,", ""-...., Preu. 197'.I'P.lJ l -~41,
HarIImIwr.) 0 • .,,01 I.. m!);rd. L I' (td,.). CloJman """ O,in..,,", The ~ II~. 0(Thc10p0"ic>. 10111 cd. N... Y..t. MlCmll·
....
,."
II,..... • ""')". R. II . arod do 1,-,,,,,. E' Cltruoo
~ o( ..... ymot-.
_ . ~ 8...,"".. 4U79. 1914 Itnob) . V I. do ChI, ... C. 0 ...... M ~iJe and roU)' 000 I>nt.IID;.oo,ct)', vol 4, IiIII td. Ne.. y.,n;. John WIley It: Son •. 21))1
K.'·.......
ItaU, W r . Cauly'" In Chembllyarod Eru:ymlosY. N... YOft. M«lnI... •
Hill 1%9
..... ,""" In"""'m. I•. 1..: An I"trod"",."" 10 S"",io:-mlc.1 Ro",,,,, .. Mo1 • .I/In$ .... M I ~. arod M.nafI> _~to...
C'd,h..
~"'"
""' " "'"",,".. 2S_-...o ,'-'"
..
.'"
A2 (all-trans) 3.4- Dehydroretmol or Oehydrore tirlol V~!lmm
Dietary rennyl estcrs are hydrol)'l.cd in the intc\t uml lumen by vmOlls hy.:lrol3se:s. The n:tinol is .bsori:Jcd Intu the emeroc}lC:S by facilit.:Ued diffusion in normal concentl'1ltKln~. At ph3l'1l1llCOlogkai ~. ho ...·e~'er. rennul can be absorbed by passi~'e diffu~ion.17 Within the> c:nterocytCl>. the: reti nol is 1.'~leriried by IWO enzyme~. acylcoenlYmc A (CoA): relinol acy ltransfcrd.\C (A RAT) and ledthin:rctinal acyltransferoiSC (LR AT ). LRAT eSleri fies ret inol bound 10 an tntll\(:ellu lnr protein. cellular retinol-binding protein Iype 11 (CRBP 111 1). while ARAT can esterify unbound relinol. II lias been ~ thaI LRAT estenfiCl> refinol at normal doses. "hlle ARA T est",rifics exccss retinol. II TIle n:tinyL estCT!i an: iltCOipClIaled inlo ehylomif:ror1~. ... hlch In tum enler the I}mph. Once in lhe generoll circuln111,11'1. chylomicrons are con"ened into chylumicron n:111nami, ... hich an: cleared primarily by Ihe liver. As lhe C\tcrs cn t",r Ih", hcpalocyles, they un: h}droIYl~'d. III It"" elidaplllSmic n:ticulum. lhe n:tinol i~ bound 10 retinol-bim!tng proIein (RBP). Th is com ple.\ i,~ released into lhe bLood or tnmsfelT'Cd to liver stellate ec:11.~ for storng"" Wimm the ~Icl lale eells. tlK' retinol is bound to C RBP(I ) and esterified for WJrlIgC b) ARAT :rnd LRAT, Slellatc cells contain up 10 95%ofthe li,'er vitamin A bton:S, TIle RBP- n:nnol conlplu J't'leased into !he gcnel'lll circululion from hcpalOC}le~ or slel late cells, In tum. is bound to trolnsthyn:tin (TI'R). which pro4ect~ reli nol from nlt U~ contain CRB I,( I) and CR BI,{ Il ). These: intlllCCllular pro4eins function in the tl1ln~por1 und melabolism of n:tl nol and ret inok acid by wlubili£illg tl""lII in aqUl'OU' medlu ~nd presenting the m to the appropriate enzymes while prot«ting them from catabolizing eIl1_YI1Ie~.lU The.; Mlbseqoc:nt c:stcnficaIlOO,:1 Reunol is su>ccpuble 10 glucuronide ConjUgatlOll, folIo...·cd by cllteroix-palic recycling. [I may be. oxidil.ed tu reu noie lII;:i d by two en1.yrnes. rchnol dchydrogen~ und retmal dehydrogenase, wim the fonller being rate-li mit ing .l ) U n li ~e retinol. retinoic acid has no specific carrie r in the blood. Retinoic lICK! undergoes decarboAyl~lion. fol lowed by glururonidc conj ugation, Normally, no unchanged n:uooll'Ji u creted. Reunal. rc:1inok lICid, and Oihcr metabolites are. 110... e"er. found in the UrillC and f«es. Although fish liver oils are used for their vJlamm A CQIltent. purified orroncemrated foom of vitamin A are of gn:at COf1lnlCrcl al signifl(: ance. These are prepared in three ways: fa) supon ificmion of the oil aod concen tration of ttle vitami n A in the nonsaponiliable mnller by soh'ent e:'ulIm;n A lower than .he
Imalc reqUired (or .hor!-tenn tmieny but ~uJl above thal requirrd by the body can lead 10 1000g·term efftcts. II'Icluding the lil: m. liver. cemrul nervous s)"tcm. and bone. Although the amount reqUired .arid. doses 3.lIiow lIS 15.000 IV/d.,)' hal'C Jed 10 some IKlve~ effCl:\s. although higher doses.. generally above" 100,000 IU/day. an: required 10 S« alllhc reponed adverse effects. In palien.s .... ith low body "'!'lghl, malnutnlion, or hler or mllIJ dlscase . the do!;c$ ",. quired for long·ternl adverse effects may be lo ...·er Mill. Dermatological ad. CI'C effcclS Include !If} Ing of the ,kin effect~ 00
and murosa. dermautis. prunlu~. swelling and fi ~surilli of the lips. and homeln1lCS) loss of body IIlllr. I tepUlle effects include hypel1rophy and hyperplasia of IhI= 110 ecll~ (whkh SlIlrC malmn AI. hcpalomegaly. fibrosis. and cirrllosis.
.... hkh can lead 10 portal hypcneru;ion. ~ile5. and jaundice. Spknomc:galy i~ ~Iso secn. Centml nervous sysu:m effects mcludc: HlCre:a.'\c:d intracranial pressure: (pseudotumor ec:n:bti) lealime as normal Individuals. Oi'lCQntinuancc of lhe drug resultll in II relWll of hyper;cn si t"·ity. P.Carolcne doe!; 001 function as II sunscreen in normal pallent. Ind ~[d I1QI be used as .weh. The dot;agc:. mnge is 30 to 300 mglday m a smgle or dl,·oded doric, usually adminis tered with food beeauct calcium abSOl"plion i~ seen within 2 hours or administtnlKln . h~ half-life is J 10 8 hours. and II> dUr1llion of action is I to 2 days. Cakitfiol is the most acli'e form of Vitam in OJ. It IS Indt· cared in patients woo an: receiving long-ttrm renal dial)si5 or who cannot properly meluboli1.c erglX."slciferol. Cakipotriene. Caicipolrienc. (laJ,B.5Z 7£ .22£.2& 24-cyciopropyJ·9. JO-sccochola·!J, 7, I 0( 19).22· tctrnenc· rJ, 24-triol , calcipolriol (Dovoll('~), is a synthetic vitamin 0, analogue iudicaled ror topical application 11\ the ~ of moderate plaque psoria~is. It has the 5Drne affinity fortbt villlmin D n.-.::eptor as calellnol . but ils e(f«1 on c:Uc1W1l metabuli sm is 100 to 200 t ime~ I.::ss. CalclpotriellC inhLbtb epidennaJ cell proliferation and enhances cell diffcrenu.
I
I Dihydrotachysterol
""" •
I
25-HydrOllydihydrOlaehysterol
Cha pler 2Ci • tlOO. lt rcducc.s ccll numbers and total DNA contcnt."'" Anti · proIifffilU\c cffects are caused by a reduction in !he mRNA lel'els of a cellular QflCogcllC associated with prolifcrallon, c·m\'(". The IfKIClw1i~m resulting in diffcrtnlialion changes I~ notC(lmplelciy known but InI'OI\'CS lhe secondary messen· ~rs inosilol lriphOsp/late (IP)} and diacylglycerol ( DAG ).7'O
I _ "'" ..,..
()H
Cak;lpolrlenl
Doxerc.lciferol. DoxercalciferoJ, ( I a.J,B,5Z 1£,22£)·9. I().SC'OOl"rgosta·5.7 .10( 19).22·tetrxne- [.3-phate produce hemolytic symptoons (reticu locyll~i~. i11Cre;J.~ in Heinl. bodies) in lK: .... bom. premature infants when given in t"ceo;si\c doses (1Il()fe t!u.n 5 to 10 mglli). In severe case-.. o.en Ix-:moI)'tic IlrICnll3 .... lIh hemoglobinuria may occur. The increased red ceJllx'cakdown may lead to hyperbilil"\Jbintlllla IUld kemiClt.'1"\IlI. lkse compounds may also mterfere "'Ith bile pogment secretion. Ne .... bom~ ..... iLh a congeturn). In 1934- 1935. nicotinamide was obtained f..the hydrolysis of a COCn7.ynlC ilOlatcd from hone red bIootf cells. This coenzyme .... as I;ncr named CQtm,""'C III11ld il oow more common ly called niCOIilNlmiuc udcninc d;nurlfo. ,idc phosphmc (NADI'J.
OH
"""""" Generous
"",,0
of lhis vi tamin Include pork. Iamb. aid bee f livers: hog kidneys : yeaslll: pork: beef long~ ; hean!. lean me31ll: wheal &enn : pe:tnut meal: and grccn pta~. Nicoti nic acid can be synthemed by almosl all plant!J and l1lirnals. T I)'Jltophan can be metllboliled 10 • nicoume I0Il nuckolide in animals. bul the C'fficlel1CY of lhis mulllSlql pI'OCClIS Yarlcs from species to species. Plams and many l1licroorganiSllls symllcs.izc this viwmin Ihrough al!ctn.1lilo'C routes by use of aspan ic add. In the human. nicot inic acid n:acts ""Ih S-phosphorioo.)" I-pyrophosphate 10 roml nlcOlinic acid moootlllCltoto:k. .... hich!hen reacts with AT!' 10 produce: dc:wrtioo.NADitllc inlc mlCd iate dinoc leotide .... im !he nicotinic acid lIlOItIy~ Finally. the loltcr intcmlCdimc is coove rted to NAD (on", nal ly called coen:.)·/Ilt I) by LflInsfomulIion of lhe carbox)l orthe nicolinic acid moiety to the amide by glulamlilt n. final step is cataJylCd by NAD syntbetase: NADP IS . . . doced from NAD by An> under kinase catalysis.' 'IQIII'CCS
Calcium Pan to thenate. USP. Calcium pantothcnlltc. calcium o-panIOlhen:llc. is a "lightly hygroscopic. while. odorless. bincr powder that i~ stable in air. It is insoluble in IlkohoI and IOhlble 1:3 In "'Dler. aqutOUS IOlulions have a pH of aboul 9 and j er]o _ +25 to +27.5". AUloelaving ~alcium p:lnHlthenate al 12O"C for 20 minutcs mill' cau aqueous solutiOll has a pH of 6. Nicotinic acid has a pI(. of 4 .g~. Nicotinic ncid is stable under normal stornge cooditions. It sublimes wilhout decompositiOll. Serious derlCiency of niacin or tryptophan may lead to pellagra (from the Imlian, ~II" Ilaro. for "rough skin "). The major systems affected are Ihe gastrointestinal tract (diarrhc'a. enteritis. SlIMmltitis). the skin (dermatitis). and the central 1'ICTV000S system (hradochr. dizziness. depression). Se\ere ca.'ie.'l may result in delusions. hallucinations. and (kon1('nlia. In the United Stales. pclla1!r.I hIlS become rare because flour is wpplemcnted ","11 nicollnlc acid. Chronic aJcohoti~m is the chicf cause of pellagm and is associated ..... ith multiple vitamin deficicllCy. The symptoms of pcllagru an: completciy revcrsed by niacin: thcref~ . it is indicated for the treatment and prt\'emion of the defICiency. Adverse effect~ of ni!lein are most COlllmonly ~n when thi s vitamin is u'\td at phan1UlCological doses abovc I gfday in the (realment of dyshpidemiL Notable adverse effecl'! ndude noshmg due 10 vasodilatation: dermatological cf· fects iucluding dry skin prurilllS nnd hyperterntosi~: gastrointestinal effects includin& peptic ulcer. stomach pain. nau· sea. and dlarrilc:tt; ckvations in serum uric acid and glucose; and hoeP.1l0l0licity. m . llol Niacin (but not niacinamide) is ulso indicated in hyperl ipidemia to Iov.'cr triglyccndes and cholesterol. Triglycerides. VLDu, and LOLs are mjuced; HDLs are Increased. 1lIe eloct ml"Chani~m is not known. Because niacin al high doses ha~ a direct va!lOdiiatory effect bel ieved to be mediated throogh the prostaglandins, the dose required (I to J g 3 times dally) oftcn limits thoe usefulness. Niacin is absorbed readily from the gastrointesti nal t11lCl and distributed widely. At physiological doses, lillie niacin is excreted unchanged. Most is excreted 115 N·methylniacin or The glycine COfljugatc (nicoununc acid). After admi ni ~tra· tion of large tlo!Ics. ni!lein can be found in the urine un· ch.lnged. Niaclfl~ mick.
USP. Nluciuamide. nicotina mide, nicotinic acid amide. is prt'pIlrtd by the amidatlon of esters of nicOIinic acid or by passing ammonia Sas imo nicounic acid at J2O"C. NicOlinamide Is a while crystalline po .... der that is odorless. or nearly so. and biller. Olle gram is soluble in about I mL of .... ater. I .S mL of alcohol. and about 10 mL 0( glycenn. Aqueous lIQlutions arc neutrnl to litmus. For occum:nce. 1IC1i0Il, and uses. sec nlOOf;n ic ueid. Niuei n:unide has pI(. villues of 0.5 and 3.3S.
EII¥
Nicotlll31e
-
Niootlnamde
Like nikin. niacinamide is Indicated m the tn:aln1Cnt IDd pre\'ention of ddicicncy 5tatcs. Unlike niacin . niacinarm-k has no vasodilatory effect, whiCh may be of thel'llpcutic imponancc for compliance reasons. Niacinamide: has nodfta on triglycerides and lipoproteins. This product is formulatal with potassium iodide and used as an iodine 5upplemcllL Niacinamide hydrochloride is alSQ available. It i s _ stable in solution and more compatible ""ilh thiamine cI\Ioo ride in wlution .
Alboflavln (Vitamin B 3 J Although crystalline ribollav;n was IKlI isolated until ;., interest in this compound as a pigment dates back 1(1 .'.: in connection with the color in the whey of milk. In
ribona~in was i"Olated as It from yeast by WarbtJrg and ydlo... (),fidarion !ermenl.
~'~:::'~~":;~:':.~ ~I i
~~C ~ ••
..
"""" '" Ribolla\'ln is synthesized bb:,;~01:~',:~:''':':;::,:::!!~; bacteria and fungi. .... Ithough y' t !.Iairy products. legu mes. 1 meats an: the major SOlutes the diet. The preeursor is a guanosine phosphalC "'::':':";: oot the e.o;act synthetic stepS leading to the vitamin understood completely. In higher mammal s. ribonavin I~ absorbed n:adi ly till: intestines and distributed to all tissues. ';;:~~: In the bll)Synthcsis Qfthe cocn1.ymes navin n (FMN) and navin 3dcnine dinocleotidc (FAD). The bulic functions oithis vitami n invol"e ~~~~:~o,:~: which par1icipate in numerous "ital ( processcs. FMN (ribon3vin S'·pho:sphatc) is producal The vitamin and ATP by lla\'okinase cllt aJysi~. Thl ~ be inhibited by phenothia7jncs and 1M tricyclic s.mlS. FAD origmates from an FMN and An> involvt:.'!\ reversible dinucleotide fonnatiOll I vin nucleotide pyrophosphorylase. These c:ocnxymes lion in combination With sevcrnl en7ymes ro,~",".-'" lyrne complexes. o ften cha11lCleril.ed a.~j1a1·oprotti/U.
as
Ftavin Mononucteotlde
Chwptu 26 • VilOmiJIs WId
Rtllll~
CDm{JOfUIIh
89 1
lumichrome
OH
~
fiavoproteins function in aerobic or anaerobic cood,tionli as o~idases and dchydrogcnasc..~. 8:.amplcs include r;lucose o"idasc, xanthine o"ldase. cytochrome reductase. and acy l·CoA dehydrogena.-c , The riboflavin moiety of the complex is coo~idcred a hydrogcn' lrnnspon ing agcnt (carrier) functioning as a hydrogen acceptor: the hydrogen d0nors may be NA I)H , NA[)I'H, or some suitable su bSlr~te. The isoallon;tine rings accept twO hydridcutcpwi!;C to fonn the di hydroribo fiavin deri vat i~e ,
y O
"
1llc vitamin is commercially .vailable 15 nboO.vm. riboflavin .'i-phosphate. and riboflavin 5·phl)5phate sodIUm. "The phosp/late esters a~ usaj comn.... dally on ly in multivitamin preparations. and they ~ hydrolyltd before aMorpI:ton occurs.. Absorption (,IIIXUQ through an active transport S)'$tem in \\'hich riboflavin i5 phosphorylated by the intestinal mu · cosa during absol'ptton. Fuod and bile enhallCC absorpt.on. Riboflavin is distributed widely in the body, with limited Sl0rt'5 in the Ih ·er. spleen. hean. and kidneys. Con\ersion to FA D occurs primari ly in the liver. FMN . nd FAD circulate primarily protein bou nd. Only small amooms ( -lJ'l,) ~ excreted in the urine uncllanged. Larger alJl(Mlms can be found after adm inistr3tion of large doses, Severe riboflavin defidency is known as uriboj1(JI'inosis. Its major S)'mplOms include cheilosis. IiCborrhcic dcooatiti s. and vasculariUltion of lhe cornea. Ariboflavinosis occurs in chronic alcoholism in combi nation with other vi lBmin defi · cie ncies. It has also resulted from phenothill1.ine, lricyclic IlfItidcpn::s~anl, and probenecid thcrupy. Riboflavin hM no pharmacological action and is relatively nonto~ic. 1be on ly approved indicalion is in the 1tealmc nt and preventioo of aribofla vinosis.
QII··"1d Speclll
P"ldoxl_ [n 1935. the term I'i/(lmin 8 6 was applied 10 lhe principle
PRODUCTS Ribof la",;n, US" . Rlboflav,", loctofla\i n, vi lamin B~. Vlwmn G. is a yellow to orange-ydlow, crylitlllline pov.'dcr '''1m. slight odor. It is soluble in WAter 1:3.000 10 1:20.000 mL '11m the ~ariall()l1 in ~Iubili ly bemg due to diffelcnc::es ID internal cryStalline ~lIUCl u~. but il is IT1(l('e !IOluble in an OOtonic so!utton of ~lium chloride. A salUrutcd aqueous solution has a pH 0(6. R lbofla~m ha$ a pI{" of 10.5, It is less soluble in Ilkoholand insoluble in et~r 01' chloruform, Benzyl alcohol (3% ), gennsic acid (3%). urea in varying IIIlOUnIS, and niacmamlde a~ used to solubil i1-t riboflavin ... hen relacively high concentrations orit a~ needed for par· rntcr.lI solutions. Gentisic cmlU'lOl amide and sodium 3·hy· dro~y·2 ·nnphthoate alC is fourK! in many cell types. ahhouglt other enlYIllCli Invuh'ed in the irneI"Colwersions are oot elF pres.'itd in all cells. ' l j Aithouglliarge amounts orlhe \ltaJrul are fourK! in the liver. the mU t)nl 3in ~ glycoside of pyridoxol. which is inc luded in "i,amln cootcnt determinations. Although this conjugate is ubsofbo:d. it IS IlOI used wdl. ~ Thi~ may explain the klwer Irioavailability of the vitumin frum planl sources than (rom 3nimlll wurcc:s. OH OH OH
5-~~IYCOaPYfanosyl) Pyrldoxol Vitamin B~ is obsomoo via passive diffusion. chieO y in the jt'junum, :II1d transported to lhe liver. The: liver is a majocorgan of Storage (1610 27 mS). ntetabolism. and interronveTsion betwet':n the three forms. Excess B~ is oxidized to 4· p)'ridoxic acid. This acid is lhe primary form found in the urine. accounting for up 10 60% of ingesled ~ilU lllln B~. In the Ih·eT. all tiutt fOlmS are COO\'erled to p)'ridoxal 5phosphute. which circulates in the blood bound 10 albumin .
SilI_
Befon: entry into cells. the phosphate must be cIc:~. lated.lnside the t"etls. pyridoxpl kinase ~phosphorylalestht vitamin. Thi s kil\llSe is found in many cell types. uhhoup other enzymes involved III the interconver$ioru aI"e not n· p~.ssW in all cells. 'u Although large amounts of the vitarni~ are found in the Ih·er. the muscle, conlam higher arnIlUIII.I in lhe fonn of glycogen phosphol"ylusc.':ZII> This vitamIn 80 is nQI ~adily avullable. ho .. ner. dunngdeficiency sules. 1TI Pyridoxal 5·phosphate is a coen/ynle I~. '19 that perfOlllli many vilal functions in human metabolism. II fUOCliOlll ~ the trnnsammations and decarboxylmions thaI amlllo aclCh gencnal1y ulldergo. For eumple, il funclioos lIS a OOIfl\1\samJ' nase In the lI'11l1saminauOIl of alanine to fonn pyf\l\lc ICId and u a eudecarbox yla~ in the Oi:cllfbox)'lD.lion of dopa ICI form dopamine. 0Iher biological trlnsfonn:IIlOlls :" 11:1 ci ' amino acids in wh Ich pyridoxal can function are nlCelTilntion. Chmmalion of the a-hydrogcn together with a ,B-sumut· uent (i.e .. 0 11 or SH) or a ,..wb$tnu~nI. and probably th: !'C\·t'TSible elea\'lI8c of ,B-hydroxyarnioo Kids 10 Glycine . . carbon),1 compounds. An eleclromeric displacemem of electron~ from 1:IoIxb a. b. or c (see diagnam below) wou ld ~II in !he ~leasc cil c:II;on (H. R'. or COOH) and. sub.equently. lead 10 II\( van· ely of ~actlons obsCl ,'Cd with pyridoxal. The: CJ.lent IQ.,.iIIdt one of these di~placemcnts pmrominatcs over othel'! titpend~ 00 !he structu~oflhe amino acid and the en\'iron_ (pH. ~ol~cnl. calaly~ts. en/) 1nC5. and sueh). When thI SItIC'dIanism applies in vh·o. the p),ridoxal component is hnlt(! III the en/)'mt through tile: phosphate or tile: h)droxymrtlt)l group. Metals such lIS iron and aluminum. which markedly c:uIy/_e nonen/,ymatic ttalls:aminmions in vitm. probably do 10 by protllOling fonn:llion of !he SchilT base and m:ullWllilJ planari ty of the conjugulcd system Ihrough clle:lalc nng ((I'. m:llion. which rtquill's the prt'SI:t1Ce of the pht:noIic poop This chelaled metal ion also provides an addniooai ebb..
------------------------------------------.....
b
heterocyclic nUl'Ogen alom (or nuro group), \hercl>y increasmg the clecuoo displacemcnts from the a"C already obtained vi tamin B ,~, The only dtclary plan! pr(MI.
'''$lou.
4-Desoxypyrldo.,! Because of ioadequate diets, Kimel in fants suffer from scvere vitamin 8 6 deficiencie$ that can Icad 10 cpi lepsy-li t t t"oovulsive M'izu!\'.'i, and the convul~ions can be COfllrol1ed by trealmeot "'ith pyrido~me. I The l"UllVulsions arc bel ieved to be dill: to belo",·normalavallllbihty of the centrlll IICn."OUS
R.
-CHa
R,. -OH
Hydtoxycobalamin M&thyleobatamlll Adenosylcobalamill (Vitamin BI2 coenzyme)
IICtS
COIlIDIDlng the v;r.mm are legumes. because of wlr
qmblo.o>Is with mk"roorganjsnl~. Ikcausc dietary vitamlJl Su is protei n bound, the lirst lIep in absorption is il~ I'I:lc~ISC in the ~Iomach. I(clcpsc is enhanced by gaslnc pH and plmcrcalK: protcases. llIe freed vitamin i5 bound immediately to a glycopmtein. the inlrlmic /«,1"', SCCR:u:d by pancml ccll~ of the gastric nulCosa. The ' iwnin a u-intri nsic factor complex is ~ed 10 the InlaUIIC:S, II-here it bulds With rteepl~ in !be ileum. Absorpuon Ii m;unly by an :len,'c PO IXCI\J... tlleh can be salUtlUed by 1.5 10 3 ~g of, iUt/mll BIl _fuccss amountS may be absorocd pas.~I \·cly.
'n the intesti nal cetl~. the comple)!. iq broken 1100 "hamin H'l is abSOl'bc:d into the blood. wllere it bi nds 10 tnlnscooolamin II , 11 ,8-globu lin, for distribution. In the liver. the vi la min is ronlerted 10 the :.clive form (IrId Slon:d lIS such. Up .. ~ of rhe vitamin (j 10 I J Illg) iJ 51on:d in rhe Im:l". Vltamm 8 ,~ i~ ncrcted through the bile and undergoes ex!mS11"C reabsorption . In the bio in carrotS. Folic acid occurs in ,he Iliet as pteroylpolyglutllmates thaI mUSI be hydroly1.cd to the monoglutamates before absorption. The hydrolysis is cal ul ylCll by pteroyl·y-g lutumy l carboxy-peptidase. fouoo in the membrane of the intestinal mu cosa. The monoglutrunate5 an: absorbed lICIively io the jejuoum lind upper duodenum . This absorptioo is pll seMitive and is facilitated by the slightly acidic coodi,iom fouod in these regiOO5. 1lIC vitamin is transported as mooogluta· males bound to album.n.
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n • I • Pteroylglutamic acid o • 6. Pteroylpolyglutamic acid Although the mucosa in these regions pO..'SM dlhydrofolate reductue. moS! rrouclioo aod methylatioll occur In the liver. TI-IF A .s diSlributaJ 10 aJl lissues. where it is siored as polyglutamatl':5. The N'.mcthyl derivati,'e is the roam transpor1 asid storage fonn in the body. 1lIC body 51~S 5 to 10 mg. approxinmtcly 5O'l> in the liver. 1lIC major elimination pathway for the vilamin is bil iary c~cl'Clioo :t5 the N'-methyl derivlltive. Elltensive reabsorptioo occu~. Only lrac:e amounts ure found in the urine. Large doses thut exceed the lUbular reabSOrpiion limil . however, resul! in subs1Dntial arnOllnls io the urine. As with vilamin 8 1:. folic acid defICiencies m.ainly result from malabsol'ptioo or alooholism. No neurological abnormalit>es are aSJocialed with folic acid defICiency. llII': resulling mcgalob'lLStic anemia is indistinguishable from that uused by vit3min Hu because both vitamins are in\'olved in the c rilical biochemical step. Folic acid can CUllect the anemia caused by vitamin 8 11 deficiency. but it has- no effecl 00 the neurological damage. Thus, oo ly small amounts Ire foond in over-the-counler preparatioos. Folic acid !MIministcred to healthy !MIu Its in a daily do!;e of IS mg for I month rt'Sul1ed in gastrointeslinal disturbances (inc luding anOl"ell ia, nausea and pain) aod ccntr:ll nervou s syste m effe for III the war bet"tE01 Sweden .md RIJSW (most h~eIy lhe march of Charles X1t mlO !he Ukraone in the ........ ler of t 708- 1709) alrOO'!iI ,H 0/ the sokf:.s of !he S·"etlosh army ~ ncapKltilted by ~ But further plogress of the ~ was slOWitilol. meso-inosi tol (lPI)'()o ioositol. ITIQIlse antiaJopccia factor). is prepared from nalUral sourttS such as com steep hqUOl"li IUld is available in limited commercial qUlllltities. It is a ",hite crystalline po"'lder thai t.S soluble In water 1:6 and in dilute akohol. It is slightly soluble 111 llioohol. the usual organic solvenlS. and fixed oi ls. It I~ stable under normal storage conditions.
InO'I,ol ha, bo.'Cn found in mosl pl:un aud IIrllmaJ h'loUh. II h:t.~ been i.;oll,tOO from ce~al g ..~ins. other planl part!. cgg~. blood. nllll;. li'·cr. bmin. lldllCY. hean mu to be fully undeNood. Cyclic pipsphoinositol deri .. ati, t"S appear al 67. AHPS """ In(.. .VlOO:!OOO BttIIQda. MD, """" • • Srx'oft! ~ IkakIt-Syoaeoa Pboqoy:, ..... 2(l(/. p. 1!7j bit Mdbuoh) . E.: I .. ,t 1.107. 1919 til lIukl>o..hl!\ll.). K..: Dbcb. Mtd. ....... l>trIo·_. J Vin,m. I","". (1.r&I •. "'ft! . .lOU1· 8-11,1,",,-, l!l 1Idr= K • • ~.t N F...,t . J ....od. ]).11.l6') 1173. l~ J6 ..... aId, O· /'IM_ 21'1"800. 1\161. .17. Mo--. R. A 11_ SnIs. PIty""'- 711'111.)). 1972 3S. \(JilC'".O S, and Men,... F_ L: Ace. Chern. Ite. 8.MI. 1975. 19 11uIlbc-1. W L. Aa:. 0.. .... II.... 1975, -10. ltoml, B•• Cl.l, A,, /)tl( ft!. New Yorl. McGn ... -lhll. 1971. lIP 1173-1171 4S Bmy. II. J. C........ " J • ..J RMo.h. II II I 8d 0..•. 164 92.11. 1'I8\l 46. s-i. J. C. ad 8,,,,, 'I- 1..: BoopIr) .. Aal711>.l66. 1982.
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101 'hhN!;k. 8 , - ' SInIlo. J I'n>:, !'1M:!. An." $ci, U. S A.. 71 1312-U I6. 1981 102. So"lk'. J . W FASE8 J , ... '....cI2. 199) IOJ. 5 'ow ..... J A~ ft Ii., SW ..1Ift . . , I ,"" 0( _ . _ 01 ....... lI: 'Of I • • ' In f\oIler, L . aood Ilinh. J (e*-.I. Oral .... ,~ 101.
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drug5 has been nearly IlOOI:lliSlent f(M" years. Henct', hc:rbIl users are left In their n,,'Tl dc"ires regarding dlOlCI:. _tty, and qualily of the herb chosen. Until 1882.s a numbcr nr drug~ were IIlOnOJrIPhed IDlI describtd in The United SWl~S PhtJrmlK~i(J. Gin>eag. f(M" example. was clearly etlarllcl~rized as a dru! and In 1916. the Nanonal Formulary of the Unued SlaIC!i ltSlal the root5 of both Ii.. tJIrgumfolltJ and E. (Nrl/llia as otr... iaI. and the diqincllon belween the two begall to be forb'Ollell. In about 1950, E, l'urpurM was introduced a" the pl1ltllf) medicinal plant In Europe, Of the tiutt ~ICS. £. pall" is the most "iddy culli\'atcd.. the !allesl. and h:b the ~ flowers. Thr~ i~ considered the official prcraraJion In IIIr Uni ted States. 1-;' pur/lJlfta root preparalloos are SOiTlC1ltm lIuulternted "'Ith u ~I mtlar-luo~i!lg plam called PIJrthlfllU/II illll'wifolium. HPl.C lmaly"s ,'an em;ll), octect the adullm1100. 21 TIle alll,we show~ how dlffi.;ul! it is to ~tlnr:lard!lr echmacca rrcparatiollS. Addmonaliy. oplmOll~ dIffer about Yo hich plant OOl11po01l('nt ,~ the: be:;t anal) tIcal loI:1nd3nll1l_ tion of the drug, l~hinace~l conl,lin~ a series of phenyl]l1'O]!lnoid glyeosiun. t'Chm~ioc. ~erbascosl(\c. 3nd 6-0el)' wcll possess IICtivity. One notable: effect is Lhc !illti-inflammatol)' cffcct of II high-molccular-wciahtlllllbinogaJactan thot is about as po-
Feverfew. TfI"OCft/UIfI {J(Jrfhf!,,;Utn (L. ) Schull]. Sip.l . is an herb Ihal was u...cd in ant iqui ty to reduce fever and pain. TIM: litcrawl"e is replete with anecdotal cvidencc of the usefulness of the: herb. and ~nt clinical studies !Ia"e added more: suppon. Fe,'crfcw is a membCl" of the :lStcrfdaisy family. llIc plant tissues havc a pungcnt smell and very biucr taste. 'The Ill('dieinal principle of feverfew is (:oncelilratcd in hall)' tri.:.:homcs on the: chI)'5aIlthe:mum·l i1o:e lea\cs.J1 TIlC plant displ~ys clusters of daisy-likc flowcrs with ycllow ttntcrs and radiating "hllc fl()l1:ts. Rc:cent USC$ of fc>'crfcw arc: for migrJinc and anhrilis. although the indica lloo for anhritis is disputable . 1bc anecdotal evidcocc thai an herb oould sua:c:ssfully ~at acondil;oo soch as migraine headache nalul3lly begged for sorl1e ~ic:ntific proof. Two prospective el inkaJ sludic:s IIs;ng dried whole fever· few leaf have been pcrformedl.l· "", to assess the value of the herb in migraine. T1ic: IWO tear studies OIl migraine prov;Ocd good supponh'c evidence for lICtiVl ty or the herb agaillSt m;~inc. Both studies ,,·ere double blinded. pl:nbo con trol led. gnd standardized on 0.54 m@ panhe:lIOlillc per capsule. In both §ludics. the fevcrfew group demonstrated si@nificant dec~ in frequency. scven ly of attacks. and
nausea and vomiung. No OO\'erse effecu ...-crt: obscnied of the oonstcroHlal anti-inflamnuuOly drug fNSA IO) type.
MECHANISM OF ACTION Fevcrfew Inhibils prostaglandin synthc~I~. but not through 3n effect on COX.'" The he:rb alS() inhibIts lhe synthesis of thl'QmbQ~:me . ~ain by a COX.illdepclldenl mechanism. Addiuomdly. fC"crfew inhibits the syn thc~is of pho!;pholipaile Al in platelets..II>. ·n preventi ng the liher--IlioJl of ar--IChidonie acid from mcmbrnoe pllospiloJipids for sub!;cqucm convcr;ion to prostaglandins and Ihrombonoe. Fcvcrfew also inhibil ~ the ADP-. collagen-. and thrombin-ind~d~ grt:gation of platelcts. Mlggc>ting th:1I the hcrb ha~ a greater thrombotic effect. In another. similar siudy. dried leaves of fC"erfcw inhibited prostaglandin and thrt)mbQ~!U~ sy nthesis In platclcl:s and inhibitoo plotclc! ~gatlOll mlti:II~'d by AnI' and collagen.'" Surprisingly. this stud) st.o-..ed that fcverfew inhibited the p!:lIelcl·rdeasc rcacuon by "'hich Inlrucc:llular StOl1lgc granules are rt:lcascd. 19 ~ stor...gc gnll1ules contain serotonm, a positj,'c cffector In migrdine headoche. Some of tile more surpri~j nl findings for fcvcrfcw arc that il appear.; to be a selectivc inhibitor of iruluciblc COX_2.oo and it has clear effects on voscular tone in unim:,1 models. The phlLnnacologically active eon~t ltucnl in feverfew luis typically been eQIIsitlered to be purthenolide,"' an amphiphi lie sc:squiterpcoe lactone that i~ blosymhc:siud from the germocl'llnolidc eauon. Panhenolide I~ ~nt In much greater quanmies than any of the OIhereon~titucnts. and illl ~nce docs 5«m toco.. datc with IIctL~ity. alleast In dried lea\·es,. Panheoolide is an a-mcthylcoe lactone,": an O'.,8-uns:uuruted nMi1ecu1e that can.serve a.~ an OC«plOf III the: Michael reac1lOn. In the Michael rcac\K)l1, a dorIOr nutlcophile such u a thiQl can allack" the acceptOf 10 fonn a covalent adduct. If .,..rthenolide functions thi s way, a biological nutleophile such as II thiol on an enqmc eoo lll be bound. inactivating that enzyme, The likelihood of Ih,s mcch:lIlislII has been sllo..... n by successfully forming adduct ~ with parthenolide ;\SClf in vivo ....... 11le other eOlllpooen\li-canin, (lJleca-
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3-1\. Hyd'OXVJl'LI U.,.101k1e nino !.ecOllLllIIlXlrlheno hde. and 3-,8-hydroxyparthenolide-arc pre'iC'J\! in lower concentrnlions."' 1nci. cff«tS rl1:ly be Important to the activity of fe\'crfew, Out !.IllS I> impossible to judgc at prestnt. One Mudy that used aneAInC\ of the leaf wilh known par1henolidc content failed to sIlOII' acll~ ily. so qLJeiuoru; still rcma,".
Saint John's Wort Saint John 's won (Hy~riC'um ~rf(),/jfum) IS II mcdlCio.al herb that has been used since tile tillle of PlIracdsus ( 149J- IS4I ) to treat II variety of psychiatric dl~ Today, lho! herb rt:mains one of the: IJlO§t imponunt psy.hotropic drugs in Germany and Western Europe for the tfnl' t1~nt of dcpfC.~sion . anxiety. and ner\·oosness.* The: has recently beCQITIC popul;lr among cOIlSu mc!'5 in the Uruted States. The demand for the drug in the United StaltS ~ been fueled by Gennan ~tuditS that reported that St John'l won ..... 3.'1 equierrecti~e with nuo~etine In the trcatmenl of deprt'SSion. Some Imeruting cm:umstances give the herb tlllllall\"The plant t~ I low-growing shrub that gruv.·s '" lid In Europtand Western Asia \\'llh yellow n'lWel'S that bloom .rt.lWIII June 24, the trad1lJ'lnai b,rthdate of St. John. If the nO'Wl"Cn IITl: rubbed. a rt.'d pigment is rt:leascd. Thl~ red subsiMlft has tntditionally bec'n associaled with the: blood of St. JdJI rcle~d at his beheading. The medicinal components of SI. Johll '~ won arc den_til frolll the nowerillg toP). A 200 1 study in JAMA, howc,·tt. negate.~ uOOut 30 previoosly publ i~hcd trial~ and showed \h.JI SI. John '~ woo failed to improve major depressi"e dl!oOldcr in the fircntS up to 1.5% of thoe plant. Two majOf compone nts in the oleoresin (among sever,d) ure capsaicin and 6.7- oi l. consisung of
Anticancer drugs derilled from biological 'lQUn:es ~ faIrly common arid ore among the n1O!it important in the therapeutIC armamcntanum. Drugs like doxorublCLII. mitOl11ycin C, mithramycin. and bleomycin ha ..e been around for a 1008 time arid have shed much light 00 the tl't'atme m of cancer. Thl't'e pl ant-derived drugs thai ha lle found lheir way through clinical tnals dc:scTlle menuon IIcre. T \\.·o of the m~t famou~ arc .. incri,tine arid vinblastine. "llK'..e arc compounr.!s i~., In ....... ,.",. I.. D~ ..... 0-.. II (edl.). PIor-",,,- 01 ~, ~ - ' O~"' . . al AcU"zy. A......cIIII Chet.oeaI Sox"'y S)D.- I".. Se· rie!.. New V",l. o.r.... Un .. n~ny"""" 11l9ll. pp. I jj- I ~
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402.M_9Il. 1997 ~. F.• -t 'ldnu. C. "")"",,"'nuwy 2U$4J - 2!I49. I9I!. K~pI, )94"-165. 1917, 1I. ""n",II. S.• A........ D. V C .. D• .....".. B. A ... II.. J l'harm. i'IIan'RaroI • .u:.l9I - J')'. 1992. ()cl".'~ f! ~...... ~ 1999 It""..... II O~ Ck,, ' ,T ..... hioIocr 01 1St. JduI'. Won). h. L.o,,'_. L 0 .. IZJ'd Bauer. It. Ir,. I.. II~ '" lIubl .. n. I Il. " , , tc ... _ ). IJIilI ..... 1'11,)"1"1",, Fcboluy l1lt: by computational chemists. In reality. drug discovery is so ulldcniably ~'Omplicated that no one si ngle method geller-oIUy can be crediTed for the complete dc5ign of a drug. An arsenal of methods frOlO di\'crse scientific areII-' is brought 10 bear on drug diSCQvery problems. TIM: scientists involved ha\'c 10 interpret the dum. Although molecular modeling methods are just Mother tool 10 help scicn· tisl.~ make infonncd decisions on what lead compound~ to pursue alld whaT stnlctural featureS should be rnodified to
91.
enhance btoioglCliI activity. there is an Inherenl lIppcal IIS5Odated ..... ith \,isuali/,utiOfl and predictions. In the final analysi~. scientists.. not computcrs. "dcsign" drugs. CA DD has IWO fundamental roles to play in drug research: lefUl disl'Ol'ery and InuJ dt'l~lopmerll. OuOIl8 the late 20th ~nlury. there were many case hiSlOo nes of accurale predictions of in vitro biologIcal activity ba.'itd on so-called rllliOltlli urug design aJlllfOKhe~. In the 197Ol;, Corwin Hanseh demon~t.rated tnat simpk- rt'gression swi~ics cou ld be used to COfttlate bioloJlical activity indiIUdy 10 molecular structure through physkal propen io ~uch as hydrophobici ty (log I'). electron ic (u). and slcnc (ET) effects (Chap!eT 2). 'The seminal COIltnbotions of Han-'iCh dcmooSlrnled the povoer of QSA R and he lped 10 usher in the era o f com pule r-based model ing for molecular design. Beginning in the 1980s. there .....ere many reporu or com· puler· bilset:\ predtChOOS of tn vi tro biolo&ical activi ty. TIlls IS 110( unreasonable. ~ince then: are fe .....er pharmacodynamic and phanll3Cokinetic variables 10 be considered with in vilro testing than wi lh in vivo tc-~Ii ng. 'The use of slructure-ba..'itd design has gro ....·n in imponance since the carly 1980s. Today. there are many ex.amples of drug.' on the market or in cliniul tria ls for which COIllputcr-b,lsed melhods. particularly ~truct ure·based drug design. have played cenu"dl wle... in thei r developn'lelM. No si ngle chapter can provide all the dellli ied infOffl1lltion necessary to master this specia lty. which ra nges from quan. tum phy~ics t03D iliuabac;c searching. Many of the subtopks discussed hase h3d entire boots or 5('rie' of bool5 Ue\·oted to them. and a complete discus..~;on of each topic i~ simply bocyond the scopeofthiHhaptcr and the purpose of thc book. Instelld. the gool of this chapt er is to provide a brief and accurote ovel'\liew of a select Sl'I of compullitiOllOlI chemistry and CADD methods. highlighted wi th examples when ap_ propriate. In SQme cases. the COllCCptS arc simplified or gt:net'1lli/.cd 10 ma ke sense of them in a few pages. but this is done wi thoul SlI(:rifidng accuracy SO thai the interested reader can continue future studies with a solid foundation in the fundamcnlals. Finally. compu ter-based methods do not Il,'plllCe C)(penml'n tal me thods. In rllCL the purpose of CA DI) i~ to aid pharmaceut ical scientists in the discovery proce~s ..... hether thtoogh simple \ 'isualiuuion or the com· piC)( formulation o f a pharmacophore model and SllItislical modI'ling.
COMPUTER GRAPHICS AND MOLECULAR VISUALIZATION Ever since chemist~ have la.vgni1.cd Ihal molecu lcs are made up of atonts, there have bee n cFfons 10 represent 11100 ... lecular structures accuflltely. One of the. first allemp's to de\'elop molecular models can be traced 10 the earty ISOOl> \\-Ilcn John Dalton used \\-'oodcn spheres dri lled wilh holes to accept meta l rod lin kers as representations of at()m s and chemICal bond.o;;. respectivcly. 'The origi nal mechanical mode ls are on display at the London MUSel.lm ofScicnce. l . l Prior to compu ter graphics. the fundamen tal pri nci ples now associated with CA DD (or nlO lecular modeli ng) wen: used for some landmark diSCO\'mes in structural biology. Unqucslionably. one of the most widely n:oognlud scien-
tirlC achie\'ementli WIIS the conSirueUOl1 of a DNA model proposetl by Walson and Crick in 1953.l 1lle structure 1m wi thstood the te~t of time. lelldmg to II shared Nobel I'n..if for Wlltson and Cnck and seu ing the stage for the age of biotechnology. Imllally. crude moOel~ ..... ere crafted from cardboard. Once a beller un.Jc,...tandm, of !he structural 11:. quircments of the nucletc acid~ was de\doped. liMn ami· rate physiealmodc ls \\-en: prcpull,'d from IllCtal. OngHl dooe years ago wlIh h:mdhdd modd~, it i~ relat ivel), easy to query II compuler-genemted molecular di imposslbk- IO answer by experimcnl\ alQIIC . Just whUI kind of predictions can be made ? Energy-oosed calcul0l;on5 have been used 10 predict and to understand molecu lar geonrctry. chemica l condition,. chemical reaction pathways, and transi tion Sillies. as we ll as phySical. AD M!!. and biological propertit~. Usually. computer ~imuiatioos arc k:ss CJlpen~lve and rcquire les.s time than carrying oot phy \ ical eJiperiments. In gel1l'r:tl, rotrf/lrlllll;OIIol Chtmrslry n:fers to enl''l)'based methods. CADO IS a moR: all-cncomp.us'"g term. ineluding not only energy-b.tscd calculations but also QSA R. database !!Carching. and phaml3Cophore perception methods. Computational chemistry approachcli can be di· vided IntO two brood categories: quantum mechan ics-based and classkal n1C1;hanics-based. The former co~el'!l the areas of semiempirical. ab initio. and density flll\ChOn~1 theory. Till- luner re fers to force field (molecular mechlll1ic~) calculatiom arKI n10lcculllt dynamic~ si rnu lmions. Each nlCthod h.as its Mrengt h~ and wcai;:l)Csse,IlIT L.J n, .. "," LJI' Tobie 28-1 _IM,)IIS tile three pos~iblc axial and Cilualorial confomlalions. SUb§lilulion in Equat ion 28·27 gcnt:r.lIc~ tile calculated rulio of each confomxr. Because MMf'l'94 was parameterized 10 reproduce Ihe quantum mechanical calculations. il Ii IIlustrntl\t 10 loot al the ,,11;0 calculated wilh MMFF9.$. The BoIl7.m:mn-a>erogcd dids down the road. OOt w;th a ~ probabili ty 0{ lirld ing all tbe pothol es. S~stemat ic sea!'l:hing gcnernlly ca n001 handle: soh·em ... and the method IS oo ly amenable to ~arc hing fcwcr Ihan 10 dihedral ang lc,~, becau geocrated rise!! exponentially wllh the: number of I:Jonch rolilted, Torsion anGlc driving ;s GS ..... hile the reS! uf lilt stt'\lClure ( .... ith the C~CCplJ()I1 of the 101'51011 bemj; ~y\lemau ca lly rotat ed) i ~ ellCrgy nunnniled. Many pmgnuTlS have tI1is fealure, arid accurate conformallooal enr:rgino arc obtained with lhe minimi/,lllhm. NoosyslCmalJc ClIssion for the: drug- protein binding). TIrere ute 110'0 t}lpes of mOllon (hannonK: and stochustlCl thm may be siodied by MD simullltiQn~. Ifllnllom r: siml/II/' liolls refer to o!ICiJl:11 ions ncnr equi librium (i.e .. near the min· IlIIum of a pll(cnl inl energy II ell). SIQt:hllSlic refet!i t(, SI11IUia · lioo~ Ihal Ic:ad from 011( local minimum 10 another loenl nnnnnum. From a harmonic OI'Cillmor.lhe frcqUO!:ocle\ may be caJculatrd occording 10 Equa!ion 28-42 ..... here k is lhe: stretching comllln! and m is the 1n35\. Exlending lhe: conccpt from II ~lDglc 11Iass held to a surface by n spring 10 N pnl1icles r.:quires un eXlension of lhe Taylor series expan)iOfl (Eq. 28·13) \0 II m~lri~ fonnululioll of partin] ..cco11d deril' ~li I'es. f:.ach rnode has as.socialed il5 own fun.-e constant. f rt'qucncy. lU1d 3N ll']auI'e dlspl:icenloC11IS , TIre norm:1I mode~ are asSigned 10 the: experimental 1M or Raman spectrum.
• MD simulalions hal'e Ilcen npplicd 11.1 gcncrute new CQnfonllmiOI1~.l'. 88 TIle oo\ic ide:1 is to itdd ClIO\lllb IJrermJ] entrgy (through high tempc:rutures) and calTY out the ~i lllu latiQns looli: ellO\lgh ror rhe molcculur systems to OIerrome conformational barric,," After the: simulalions are com pleled. the: lrujeclory Clln be rel·leVled. 100 lemptnllure of rile syqe m caro be eook'd OOVl'n to sample poIential new conformations. MO ~Irnulations are ) uit:rble for larger molecules. and soh'cm may be irocJuOed. No sUill., ticnl or gt'Ometrical means Ilrt' u-.ed to deterrn; nc their ~'OI11pleteOC!os. In 1.'C'lCrul, M0 NinrulHliQn~ are 1104 us cfIkicnt as stochaSlic or dbumce gc:omcll)' methods.
QUANTUM MECHANICS Ooe of the grent Ih~'Of'Ctical accomplishments of the 20th ccntury .... a\ the development of qU1lnlum mechaniI:S." The phi lo!>Ophi~al illlcrprelaliollS of quantum nll.-chani~~ lI1ay he comidered weird from the ~talldpoillt of our practical everyday eApc:ricnee, in lhe macroscopic Vlurld. Nelcrthek,s. the applications of quantum mechanics 10 I:he:mical bonding hale changed the: VI ay l:he:misl' Ihml. about molCC1.llar st1\lC· ture~ and hall: made: chemi,tr)' u \tJbdi\Ciphne of phys ics. MlIIIy uneAplamed che:nucal effech may be undcrMood in lhe conlext of molecular orbilal (MO) calculallon~. For ('J.ample . the nnomcric effect Seh of GT functions (e.g .. 6-31IG ). I}oO An a(kh!looul SCt ofvcry dIffuse: funclion" cun be added 10 the model to help calculate roep· li,-ciy charged species or hydrogen bolllJing. denoted by Ihe plu s ~ign in the e"amplcs 6·3 1 + G(d.p) and (). 311 +G(d .PI.m I"., An ilCrtlti.e iOOlutiOfl of the Hartree· Fock· Rootllaan I:qUJ· !lOll! is requiR:d for semK'mpiricaJ and all iniuo quanrum cbemleal calculatlon~. I)7. I "" lbc: approach i~ abo callft! tb: ,,,,If-C'Ollsistent field (SCf) IIpproach. In SCF calculatlOR\, each sillgle electron' , positiun in space IS optlmlled in tb: cloonc field of all the other electrons. Thl~ ptOttdurt tl I'!'pealed unlll all lhe electroo posilion ~ M' e beocn npllIm/td. and there IS no further significant drop III enerar IhrouP lhe adJuSllncl1l of the electron positions. lhrtree·Fock (H~l calC'ulntion~ gi\c good resulL~. lbe bcw:r the b~IS 'itt. tb: luwcr the CI1I:'1l1Y according to the variational theorem, Thrn contes a point of dimini~hillg returns. huwc\·er. in thai lhe: crlergy appruoches a limit known as the Hunree-Fod hlllll, No further ooJllstment in the basis !OCt breaks thi S barril:l'. lbc: H w1ree· Foc~ limil ocrUI'l' because the el«tron mota is comlated. aoo this is not accoullted for in a ~inGIc: SI~\eI dctermmanl. Thai ' So the adjustmc:nt of one electron aITo:cb the pos.UOfl of the other electrons. and thi s is not fully talCII onto accounl by the SCF approach. Tu circum'cllt not Wlna: electron com:latlOll into account, post·SCF calculJtlOlll mu't be used in the fonn of coofigur:ltion IIltCDCIIOl1 Of ~rturblllioo rncthods.
Ctuop. ~r
211 • Compwmru",,,/ Clwmi. J, The often-dted design of the fir1lt angiotensinoCnts one of the first successful Siruclllre·ooscd drug de,~ign approacllcs . 'There is 3 growing body of successful eKomples using S/ructure·ba~
drug design approaches. Today, many of these Ita,-", re.whed in approved drugs. 'These methods are applied widely when IllipiopriaJe experimental dala are available. Struclure-Nscd drug design is now consKkn:d a standard approach 10 drug design. ai>d the question posed early can be answered wilh specific cumples. In the 191ID>. the target cnlymc for Inhibitor design was DHFR. as di'\eu,sed above. In the 1990s, the larget cn~yme
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'''' Figu re 28- 25 • WIth the atd of xray data and molecular mo(le-Im!!_ SCe'1l!Sts designed tnmethopnm (TMP). 13. ana~ues that had up to SS-fold h.gher enzyrTM! afllnity thaf1 the parenl InhIbitor
In the IDle 1990s. seyer.1 H IV-I proIease inhIbitors "'"CfC introduced inlO the: market that ....at designed u:sing 1111(lure-based methods (Fig. 28_27).'.H.. 139 llolTmann _La Rodlt scienliSIS used modeling methods to desig n S:lquina,'u 'flO (Fonovast, hwira.o;e ) 15. which was the fil'$! protease in/ubilor 10 be appro,·ed. The drug was \1lade a vailable In JUIII: 1995 through a cOfnpassionlUe treatment program. ID\'1I_ was giycn Food and Drug Administflliion (FDA) appro,A. Ottember 1995. and FonOVIiSC .... as appro'·w in NOlcmbrr 1997. hld inavir • (Cnxi~an). 16. W1IS dc"e1opa.i by MtTtt ' ' scientists and gi~en qu~1t approval in only 42 days in M.m::It 1996. In March 1996. Abbotl re(;elvcd approval for Rnonayir'fef1t of Cosopt. was the f!f';\ dUlg desf9n«I WIth structure-based (ADD methock to become oommel'oaIty available "11(-927, 21, IS a clost structural 'r'Iere .s a linuled SCI of conformations that all acli,'c compoond (Wi th approprialt functional groups) ma)' adopt. BIOLogIcal inocu\"lIy I~ assumed. as a tirst apprOllunalioo. 10 re,u lt fTOfI! Ihe competition between .mall moIccu les and rhe rccePlor foroccup;ltion of the same phySical iluct_ 10 /)"7"""" M«hIz>. i. U
figure 28- 30 • PfedictrveADME IS becom'ng more ,mportAnt 11 t/1f .inly stag !s of drug ckos>gn, Orug-drug and food-drug nteac:bOOS have lesulted If) two fOA·appro.ed dlugs. m,bf. fr~l (PosIcor), 23, and terlenadi~ (Seldelne), 24, being IefIlO.ed from tM market IfI reeenl years_
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Wilson and Gisvold's Textbook of
ORGANIC MEDICINAL AND PHARMACEUTICAL CHEMISTRY E L
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Edited by
John H. Block, Ph.D., R.Ph. Professor of Mt.:dicinul Chemistry
Department of Pharmaceutical Sciences College of Phanl1acy Oregon State Uni versity Corvallis. Oregon
John M. Beale, Jr., Ph.D. Associate Profcs!iOr of Medicinal Chenl istry al1d Director of Pham13ceul ical Sciences 51. Loui ~ College of PhamlllCY 51. Louis. Mi!osouri
A
•
lipPINCOTT WILLIAMS & WILKINS " WoI!rn Klu ..·.,. Companv
Phil.ldelphia • 1l~lt"no..., • New York • london Bu".,os ",,~ . Hong Kong • Sydn.~y • Toky.:>
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All rip'" ",,,,, .... od. '"111, booIt .. ~ ..,. ""P)'riaht. No put of lI1i, boil)' ofTe~'Js. Dr. DcISado tru~ele(] extcnsively in Mexico and South Ameri ca to prc.'!elll IectU/"e,'lOIi pharm!II,:eulical education. Jarme Delgado's first conlributions to the T,wbook lyOrg(Uli(- "'1"/'cil1l,1 (.1/1/1 Phllmlfl«u/icll/ C~m. iJfry ... ere made as II chapter author in lho: ~\'enlh and ..i,hlh edilklnS. Much oflhe malerial he pf\:StnlC'd cam.. from his Iec,ure notes. Although he was proud of the.o;c OOOlribulions.... hich ....en: upandcd III the nrnl h and tenth edilions. he ooosidf:orod hiJ role as coedilor in lhe Iauer edilions one of the highlr ghls of hIS diSlinguished career. Jaime wa.~ II lrue gentlell1an 1100 a pleasure 10 ha\'e as II collaborulOl'. He will be greatly mi",-';cd by the edilon;. 3I11hor~. and prorc.~sional staff for the TI'.nbook,
P
Wi/bllm A. Rt'mt'f$
Charles O . WilSfio
1'11 _2002
A
s the ,hapler,,: for the elel'ellth edition
,,'e~ being sent to the publisher. I was llO(iflC(lthat my
oollea¥\IC and fritnd. Charles Wil~. had died '\honly aftcr Chrisnnas. He was a product of the I'ocific Northwest hal ing received all of his degrees from the Unil·~ny of WashinglOO. HIS first tcaching job was 1Il the now diSl:ontinuro ph~y school at George Wa'\hingtoo Unil'ersity and then he 11101·cd to tile Unlve,..;ity of Minnesota. Charles. alooS with (Miler medicinal chemistry faculty at the Unil·ersity of Minnesota. saw the need for tex tbooks thai prellCnted modem medicinal chemi stry. In 1949. he and Professor Ole Glsvold ediled Organic Chl'misll',), in Ph(lI'"m(IC\·. "hiCh became the first edition of the Tl'XIIHKn: of M edici,wl mill PIJUrmllUfu;cill Chtm;.flry. Conli nu 109 in this tradition. Charles and Profeso.or Taito Soinc a.~!iumtd the: aulhoJship of Hogl"·J InorganiC' Phl/muluu/kill Chl'mi!/,)". which included eight edition~ before its di.oominuanct:. Finally. Charles and l"rof!!S5Of Tony Jones staned the AnrtriC'Qn Drug /ooa series. Charles continued his publishing lK.1ivities after moving 10 the University of Texas llnd then assumed the position of Dean of On:lon St:IIC Uni\'~uy'5 School of l'hamUiCY. where he overSllw a major cx pansion of ils faculty and physical plant. Ahhoul!:h a medicinal chemist. Charles devoted considerable time to his chosen plwmacy profession. Siudents. and communily. ChIlf1e.~ " ·as an activc member of the Amelic.1ll Pharm:l\;eullcal ASSOCiation lIS well as lhc phall11:lC")l associations in exh stale ....·here he lil·ed. In addition. he was a registcrW pharmacist in eacll stale where he taugllt: Wasllington. MinllC5Ota. Te.):as. On:gon, and the Oi~trict of Columbia. Charles chllired nauonal commiuces and .seclions of !he American Pharmaceulical Association and lhe A merican Association of College5 of I"II:lrmacy. Rt'laled to these, hiS IOYllity 10 $tudcms il"lCluded organi1.ing 5tudcnl bral"lChocs o(the American j'lIannaceutical Associauon 31 Georgc Washington University. the Umvcrsity of MinllCSOlll. and the Univcn;l1y ofTuas. He "'"ali IIClilely involved in the local AmcriclU1 Red Cross blood progrum and tOOk the lead in del·eloping the lIugely success(ul .student cenlcn:d blood dtil·es at ~goo Stale Unh·~ity . In 1960. Charles llnd his ,,"Ifc. Vaughn. helped launch the AFS (American Field Service) in Corvallis. an inlemational high-!iChooi uchangc program. lIe voluIl\cen:d for Mcal ~ on Wheels (or 0~C1" 30 yCarl aftcr his rctircrnent. We cl:" lIIn ly ml~s thiS fine gentleman and leaderof phDrmacy C"dllCatlOll and the p/larm:lcy profes5ion.
John II. Bkd
PREFACE
For almost six UccHdcs. Wilsoll all/I Gijl'Old's T~Albook of Organic Medicil'ml lII.d PI)(1rmOCtiuliC(Ji Chemim)' hru; been a S1and~rd in the litcnl1un:: of med icinal c/lcmistry. Generations of sl udenlS and focully have depended on this textbook 11Q\ onl)' for undergr.lduDlc courses in medicinal chemistry but also as a supplement for graduate studies. Moreover. sUldem. in other hcalt ll scicnrofessor Emeritus PhannJtCOlogy and ToJdeology Universily or ArizOIla Tucson, ArilOna
/.
If
ContribulO'S
THOMAS N. RILEY, I'H.D.
GARETH TI:IOMAS, I'H.I).
School or PhalltUlt"y Auburn Unherslly Auburn. Alabama
Associate Senior L«1urer TlJc School of Pharmacy and Biomedical Scicnces UnivcrsilY of PonslTlOUlh Portsmouth. England
.' ORR ..:sr T . SMITH. )' H.D.
T . KENT WALSH, 0 .0 .
Associale Professor {)cpattmtnt of Pharmacal Scicoce!i School of Pharmacy Auburn Univcrslty Auburn. Alabama
Direclor Nuclear Medicine Program Southern Ari:rona V.A. Health CIl«: System Tucwn. Arizona
Pmfc!uor of Medicinal Chrmistry {)cpattmcnt of l'hann Drug...... MclIKuIes Supports iWId Unk.er.; SokJIIOn-Ph.Jsf Combooatooal Ch.rm~lry I'ooIIng Sl!ateglfS Dtt«IIOrt, F'uflfocatoon•• nd An.lIysrs EntOdirrg CombroatonclillbrMIeS Hrgh-Throughput SCret'!'lmg {HTS) VlI'\lJaI (an S,1Ico) 5cret'!'l,ng ClWrliCal DNersrty and library DesIgn I\cfIM Card OIl Combroatooal Chemrstry: Has II Worted ?,
" .•..
Rtsor.-te. for Combroatonal Chemistry ConOnalooal Chemtstry Termonology .
...." 49 50
"" 53 54 55
58 60 60
KAPTl R.
MtlObolic Changts of DrIlgs and R t latt d Orgullic Compol/llds ................. . SIc, t "J C.rl.r Wtd Jolm If BJ"d Gfnefcll Pathways of Orug Metabolrsm '>rl~ of Drug BIOtransformatIOn
(hemal Deitvery Systems
"
66
144
.
1S2
IS'
CHAPTER6
Wotecl",Q!ogy alld DrIlg Discol.try
• • • • • •
160
Jolm M /k,d•. Jr
BlOte1 and Our-mon of Anesthesia 5«~ Pharmac.oIogIColI Ac.tlOll
StructurE Amon HAPTER
.......
67' 67' 68S 687 687 688
68'
'90
21
lIistamine alld AlltihisUlmilll'c Agel/ts l7Ir_
NR,",. tutd Jr>rl:
SterOId NomeodaturE. Stefecxhernrslty. and Nu mber'ng SterOId BIOSynthesis _ Chemical and Physocal Propertll!S of 5teroods Changes to Mod,fy Pharmacol(ll'-.etlC PropertIeS of Steroods SterOId Hormone RKeptors GnRH and GonacIotrOplllS Sex Hor/TlOfleS . Chermcal ConltaceptlYe Agents Androgens Adlenal Cortex Hom"IorIe$
767 768 770 770 770 773 775 789 797 803
CHA PTER24
und Gwr1l' If. C""'JU' J
20
!,1"IIp J. Prol~""
622
ArltIanqIrIolI Agents.;md V.nodilators
HA~TER
Steroids and Therapeutically Related Compounds ... . ..... ................ 767
696
INRw"~r
Htsumme ufe C.,.cIe HtsU!l"llt\l! H, Antagonl5ts (Antlhlstam,nlC Agents)
'96 '" 700
Prostaglandil/s, Leukolriettes, alld Ollrer Eicosalloi(I!.' .... ..................... 8 r8
n...-.u J. 1/01_1. Jr HIStory of D&OYefY ElCosarlOfd Biosynthesis Drug ActiOn Medlated by Eorosanoods COX·2 .,hobotors DesIgn of Eorosanood Orugs DewlOf)rTlenl of Prostacyd,n..()e(lved Products ElCosanood RKeptors EICOSCInoods Approwed for HutI'Ioln CIIflICaI U!.e Prostaglandl~ for Oph\halmtC lise Vetellnary Uses 01 Pl"ostanoicls . EKosanotds In ClinICal Development for Human Treatment
818 81B 822 822 823 823 825 827 828 828 829
(HA~TEA2S
Proteill$, EII1,J'mes, alld Peptide HormOl.es ........................... 830 Sir/Wit J.
C.'II~r
/gut/o
lipid-SOluble Vitamln~ Wilter-Soluble Vitamins MIscellaneous ComIdl>I'illlOilS
86' 885
900
(HAPTER21
All II/trodflctioll to the Medici" al Chem istry of Herbs .................. . 904
J I'MI/lp HI,....." Computer GraphICS iII1d Molecular VlSUide of traditional pilarlll~y disuibo.nion chanoel$. It is imponant rOl" the pharmaciSt and the public te undel1iland the rigor thai 15 mjuired for plt:M:ription-only and rnA -approved oonPfUCripuon productS to be approved rdat;\c 10 the nomrlldilionul prodUCts. II also is imponom for all pcuple in the health can: ricld alld the public 10 realize thai .... helhcr these nontraditional prodllClS are effective as clain1l:d or nOl. many of the altcm:llc medicillCS contain plwmacological1y aclin' ageRIS that eM potentiple or interfere with ph)'~ician -pre;.cribed lliempy. Hundrals of Ihousands of new organic chemicals an: prepared annually throughoullhc world, and many of them are entered inlo pharmacological scret'ns \0 delennine wbether they ha~ useful bimogicaJ ICti vLty. n"s 1)I"'es.~ of rundom screening has been considered inefficient. but it has m;ulted in the idcntincalion of new lead compounds who!ie structures have been optimiud 10 produce cllnlcalllgenlS . Sometintrs. a lead de\'elops by careful obseT\'alLon of the pharmacological behavior of an existing drug. "The discovcry thm am:ILLladine pnxt:CtS and IreatS early innuenza A came from a generol ~n fill" antiviral agents. The usc: of amamadmc in long·tenn can: faciliti es showed that it aJ'iO cou ld be used to treat partillSQllian di§Ofders. More recently. automated high-throughpul.\Creening systcm~ utiliJ.ing cdl culture syslem~ wi!h linked enzyme asALys and receptor molecules derived from gene cloning have greatl y iLlcreased the dficicocy of random screening. It i, now practical to!iC1ttn e~ libnuies of peptide!; and nocicic acids obtained from combinatorial chemistry procedureol. Rational design. the ~lIe approach to high· volu me screening. is also nourishing. Significant :.dvaoces in ",-ray crysallogrl.phy and noclear IIUIgnetic Te.'iOOlI11Ce have made it possible to obtain detailed representations of enl.YIlll:5 and o!hcr drug recepton.. Thc techniques of molecular gruphics and compullltional chemlSlry have provided nowl chemical su'uctures that llave led to new drugs with poklll medn:mal activities. Development of H IV prote~ inhib'l ors and all· giotcnsin-coovening enzyme (ACE) inhibllOl"$ came from an understanding of the geomelry and chemLcal character of the I'l:spective enl,Yllle's aclive site. Even if lhe recepuJI" MtuCture is not koo.... n in detail. mILonnl approaches based on the physiClXhrmical propcnic.~ of lead compounds can provide new drugs. For example. the development of cimcli · dine as an antinuclear drug involved II careful s1udy of the ch:u1ges in antagonism of Hr histaminc n:ceptOl' induced by varying the physlclll propcnics of Mrocture5 based on I
histamine. Statistical methods Ixoscd on tIM: Com:lallOlI of physicocIM:mic~1 properties with biologicpl potency arc used to CJlpl~in and opumize biological act;\';ty. As you proceed through tnc chapters. thm" or ... hat pr0blem the medicinal chcmiq i~ trying to solve, Why ...en: CC1"tain .'II.ruClUrcS selected? What l1Iodifiealion~ were mnde to
produce more focused activny or reduce a(h~ or prodUl'e better ph~nllaceutical pmpc:nics? Was t typical molecule dhcovered rrom nlJ1dom ~,. medicinal chemist !Ia\'e a structural concept or an u~andlll8 oflhediscase process tnat mUSlIll" i ruptoo "
(
H
A
p
T
E
R
2
Physicochemical Properties in Relation to Biological Action ~H.
BLOCK
\!oJdtm drug design. romp.m:d with the pOllh-lel'J mau a change 011 (In e.flSllng
clas~lCal ap('Qm(N/IHld QI'
Siruct.. ", und ue "'hal JUlI'pt'IU-COIlI;n~we.oh·c rnpidly as an approoch to soh.. inS a drug design probknl. '"The comblllution of increasing po","cr and decn:a§1111 ro.l of dc!;ktop compuTing has had a major impact on JOlI~mll drug t1c~ign problem s. Whil e drug design incrcaslolly I' ba'lCd 011 modem computMio nal chcmical technlG~\.. II 1.1-0 U'C$ sophisticated knowlcdge of disease IIIt(l\aImms ~nd n'("Cpcor properties . A good understanding If !low the drug is tr.tnsported inlo tt..: body. di~t ributed Ihroughoutthe bod) companmcnt~.melaholicl.lly ahered by tIr Ihtr lind other organs. and Cllcn:led from ~ patlenl ~ ~u~ ~g ","ilh the struclural r;-h:lt1lCleriSlles of the 1«'pI« Acid- base chemistry i~ u~ to Iud In formul:allon IIILI btodlSirioolion. Structural allribulCllilnd substill,K'nl palIL'fll.'; ~~iblc for optimum pll:ulnarologic:al activity can IIIll'll be prtdictcd by statisticallechniqucs soch as n:gn:~slon ~I)"s", Compulcn/..cd conform:1tion:ll nnalysi~ pcmUls ~ medicinal chem"l to predici the drull'~ Ihn:c-dimcn~ional ~ ilia! i~ 1UII by the receptor. With the isol:uion lind W1IC!urtl determination of sp::c ific n"l:cpcors and the IIvailabilll)" ('()InpuTer $Oftwnre thai can estimatc the three-diraemionItl wpc of the rra-pcor. il is possiblc to dc.~ign moleC\j~!IuI will MIow an optimum fit to the n"e (free anullc) is the SpeclCS most readily cffl\~i ng tile noopolnr """mbnmes (Fig, 2-4). Ct)n~ider tile dmnging pH environ ment eJpeneoced by tl'lc drug molecule orally admin iical chemicml I.",oen), equals l~l To understand lhe COIlCCl'onuOf)' fUllIM:1 model and ... hm lIClUil UYOCCllr.J in the body iJ Ihal ,he panihoning in the fUlinei will reach an c:qui librium at which the rule of chemkallca~ing the aqucous phase and rnlenng the organ ic phase will eq ual the rale ofthechemical moving from the organic phase 10 the aquwu.~ ph.1SC.'. This ., I'lOl the physiological SI\U:il,on. Refer 10 Figure 2-1 and noo: thaI dynamic changes an: occurring 10 !hi: d rug. such as II being metllbolilcd. bound 10 SC,'nun albtJrnm, e;J.erclcd from the body. and bound to m:cplOf'lO, The CTlY IIl:m mcnt for the drug is not Sialic. Upoo a(!numstr.lllon. lhe drug will be palhtd Ihmugh the mcmbnanc:s because of lhe high concenIflIItion of drog in the extrace1!ular flU id s relali"e 10 lhe conCCTllmlioo In the inlrocellu lar compan me nlli. In an lInem pi 10 maintain «juilibrium r.uios. lhe 110w of lhe drog will be from fy~tI: l1lk circulation through the "lClnbnme~ ooto the I'f«p101'l1, As the drog is mctaboli zed and c~cr~l ed fmm the body. II will be pufl~(J back across the membral\e.~. hnd the C(JOCen\rallQll of d rug at the I'«eplo~ will decn:a"e. Because much of lhe lime the drug's !1lo,enw.-"t across membranes b a panitionin8 process. the paI1l1lOn coefficient has become tnc most COlJlmon phySioochcnllCliI propcny. The que'IICIIl lhal now must be asked is "'hal IImniSol;ibk: l'IOIIpOIar w ln'llI systcm best mimics the "'"aterllip,d memboOliok b.:uners found in the OOdy'! II i~ no . . . realil.cd Ihal the II-octaool/walcr sy~em i~ an e~cc lk: nt eitimatOl" of drug rmnluoning in biologICal syqcm~. Indeed . on.e could argue tIw II "'as fortuitous thall1-octanol WI" available In n:a~na ble purity for the early partition codfic icm dctcm .inati o ns. Tuappn:dute why Ihi , is so. one mU~1 undel"Stund ItlC che minl nalure of the lipi d membrane •. 1lIc'IC membranes are nOi cxclu~h'c l y anhydrOll~ fany or oily structure~. As II !irst appro~imJtIOIl. they can be coo,ido:rtd bilD)"\'T!; composed of lipid, oon~l,tl ng of II polar cap and large h)'drophobic !!Iii. ~f'hol:IYl-eridcs ~ major components of lipid bilayer'S. OIhcr grOlJJ') of bifunctional bpids indude the sphingQln)ehnOpropoxy at R,; mett\()\y. propoxy. and bulO~y III R1: IlIl three mtrophcnoxy substltucnt" lit R,; and thio III ~ signifiC3l1tly Influence tile biolog~al rl:Sponsc:. lbc predicted )og IffiR fIJI' lhe: COItlpound. \\here RI .. meth)'1. Rl .. propo~)'. Rl _ 4-nitrophe noxy. olld R.. ". thio. would be calcu lmed from &iuation 2-29:
TABLE 2-9 coefficienb fOl" Subsmuenb In a set of Acetylcholinesterase InhibitOR"
It\aJ1I1ll1/.e
,.
~.
R, ~ O k C,II" QCH,. OC,!! •. OC,H,. OC,CI1.11 R, _ OCI!.. OC,II" OC,II ,OClC'H,.,. OC.II.
R, _ ----eno.,,;}
"""
. IHoi
0.0
O~!
".,
t .67)
0.61 1
··0.164 0.786
TIor_off_IO _ _ IIIII .............. _ · I: . . . . . . . . '"
II - . I ....
!r«..............
Ii . . . . . . - - . .• ., of ....
•
.,
,
N
0
' I
"C -IOC-1lC fIC·'JC- IOC·IIC·1 X"
tIC· 7C-8C-'lIC-1OC·1IC 6C.1(" · ' X·IIC· tOC 7C·IIC-9C · toe ·IIC- LlC 7(". 1]("· I IC'·tOC-ull i~ thai for e\U a moderate-si/..!': molecu le tYPIcal of InOI>t drugs. Ihnc can be 50 10 100 \'lInablc.~. TIle lecrunquc i5 to devdop a Luge SCI of ~heflljca" well eh:nC1emed in terms of the biological llell ... it)' that IS going 10 be' pmllCled. nils IS kllOwn as lhe lromillj/ u r. Ideally. n Ce from the utcriDec'i(mgcn rc.emse hy org anic pho!;pha'e\.
CI
Efh.~,ynlc
sufficient for a "able rombmation. COOS«jlOC'nlly. drop atl· Ing by \ 'inuc of tocir SIRIClural specirlC!!)' will bind 10 the rfi'CplOI' sile by hydrogen bonds. ionic bollds, IOIH.llpo1e and dipole-dipole 1I1 1Cl1llClion~. and ,an der Waal s' and 11),drophobk forces . Com ldcnng !he wide variel)' of funclionaJ groups found on a drug molecule and rttephX, !here will be h "ariel)' of secondary bomJing forces. 10ni7.:lI;on at physiologic:ll pH
Ac i d
eli,
H
\ .fi' .....OipECH
o-~~CHJ S"'Qllinf
Keep in mioo lhat i1 is ~i rablc 10 ha'l: most drug effects re'"co;iblc:. For lhi~ 10 occur. relal llely .... cak fOll-'es must be ill \'olved in the drug - rcccplOr complex yel be Strong enough 1hm (>\her bmding sites will 001 cOIllp:titi\'ely depl ete the .ile of action. Com pound ~ wil h hl!!h stfuctuml specificity lila)' orient $C,"eml weakly bindillg gnltlp$ so Ihatlhe summation of their imer.ll.1ions wilh 'pcriricpJly oricmc:U comple· memary groups on the receptor pru\'ide~ a l{)Ial bood strength
would nOflllully occur wilh lhe carboxyl. su lfonarnido. and alrprnn ic ammo j;TOUPS. as ""e ll as lhe qumemary ammOl1lum group al uny I'll. These !i()Urces of poIenlial ionIC hoods are frequently found in lICll ve drugs. Diffen:l1oI."eS in eleClTOnegaIInty berwce.n carbon aod OIho!r alom!l. such lIS oxygen and nnrogen.lead 10 In asymrnelric dlStributioo of eLectron s (dipoles) th;u arc also capable of fOrTInng weak bood~ .... lIh reglOrl~ of high 01' low elee.ron density. ~lICh as 100) or 0I1ler dipoles. CartxHl)'I. ester. amide:. ether. nitrile, and related glOOps lhat corl1a;n ~lICh dipolar furoction~ :ill: frequently found in cqu lvulel1l loca lions in muctur~lly specirlC drugs, The re lal lve impo:lI1ance of lhe hFfrogrll boml in lhe for· malioll (Jf 11 drug - receptor com plex is di fficult 10 U!IO.q,'SS, M uny drugN POS~Sb groups ~uc h as cu rbonyl. hydroxyl. ammo. and imillo, wilh the structural capabilities of :!Cling us lICCC plOI'!i or donors in the formation of hydrogen bond.., Howe.er. such groups ",ed to validate a hyd rophobic- bonding "lOde!. Then: an: tl'lO problcm.~ with thi~ ro~'('pt, Firl't. the term hl"droplwbic- Implies repul~ion. The ternt for Utt racllon is hydro{Jltllidll'. Secund . rind pa_ h~p~ mun: impon~l1I. there i. no truly ..... mer-frec region 1m Ihe n:ceptor. Thi, i. true even m the area. populuted by the oonpohlt ammu acid side l·haJn$. An aheroote approach is to coo'1dc:r only the C(IflCept o f tlydrophlhclty and lipopllll1clly. 1lIc ~inallng WaIC\'cnl h po,,"cr of thedistance:. Although inuividually \\euk. the ~ummut ion of their forres proVIde. a $lgmfic3m bolldmg factor In hlj;her.,Jccular· ..·elghll"Qmpound~. For example, II is not Jl'O'sible 10 di~lIJ1 /lOITIlal allane$ ""th more Ihan 80 carbon ~lontS. heeau.... the: energy of -80 "cal/mol required to sep;ullle the: mlecull'S is a pprm.,malc1y equal to the encrg) o,:qu ircd to bi'tak a c:ubon-carbon ro\ale:n1 bonLI. flat Slruo:Wr'($. suc h baromatlc nng~. pennI! do ..... npproach of Ulllrn~. W ilh VUIl tier Waals' forces of -0.5 to 1.1l " c:a llmo l for ew.:h mom. Iboot six carbons (a benlCne ri ng) would be IlCCe.·,ary to ilWch lbe Sln::nglh of :a h)drogen OOtid. 1lIc urom :ltle ring
Regan.!I.:...." of' the ultimale IlJeCh.II1"1I1 by ... hich the drug alldl/le receptor Interact. the urug mlhtllpproach the n:cep4Uf alld fit OmeN is often hrgh cnough for their illdepcndelll CArSICIlCC and tl:OCl lOO. Dlfferencrs in rt::lC1i ... uy offullC\lollal groups or intel1lCtion "'rm bIologICal n:'I:eptOf"'l may be due to differences in sterM: requrn:mcnls of lhe ~rpt()f1. In certlun semirigid nnll ~ystcm,. conf{lrl1lationallo;on~rs silo .... significant diffcrcoces in biological activilics. MClhods for caku· Iatin8 the.'iC cne'l'Y barriers IIfC discussed in ChapoCT 28. ~n chaln~ of (IIOnl!!. ",hrcb form an Important p:1rt of m.any drug nlolecules. are IlOl equally free 10 assumr all possiblc oonformallons; some are SlCrtelLll y preferred. En· ergy barriers to frec rt)Iation of lhe cha tll~ an: present. be· cause of interactions o( ItOltbont.led IItom~ . For cxample. the atoms tend 10 position them5('l\es in spacc so IMtlhey (If. tupy staggered positloos. "'tlh rtO 1.... 0 atom.~ d'~lly facmg each Oilier (eclipsed). Noobondcd imrroctlOrls III poI~.ncthy · lenc chains ICnU 10 favor the must exleltded anti conforma· tion~. althougn SOtllC of the partially e.>;lcndcd grmcht tonfonnalioo ~ also CJ( iSI. Intramolecular bondmg bcl ... een
E-Clomlphene
Z ·CIomIphene
'"
.
Z ·OOXep!n: R,' CH,C"'~It. ~ • H E·Ooxepin: R,' It ~. CH.,cti,N(CH,1t
Figure 2- 14 •
Z-Cefprwll:
R"H;Rt·~
E-CefprozH: R, • CH,: EKampiesofEandl~
~.
H
• ",• k
•• •,,, "• ~
y
I' analo,>golls IU tile fragment approach for C'"Jlcul~tinll oct.anol/ll-mer ranillOn coclTicicnu;. lltc 'altlCs f{ll" lhe frugmenb and the IK'compan)lI1g oonn;lion faelor; an: delermined b)' cumpnring \."alcuIH\L'Il panllion coefficicnls with a large popul~lion or c.~pcrllllcnlall)" determIned panltion l'Oemcicnl'.
Three-DlnMlnslonal Quantlt.tl"e Stnldure-Activlty Relationships WIth molccul3l' modehng bcm belllg isolalcd and cloned. TIus means that it IS po!osiblc to tktennine their ",rues 1IRl> Ma;! an: protcin" ..... hlCh means detcmuning their JIlllOO acid scqucrx:c. This can be tlone clther by dcgr.iding lbt protein or by obtaining the nucleotide cveral diffcrent chemical das~s and Sub>l.HUC.'1l1 JXluerns an: represented, (Sec dl!CUSSIOli of isostcrbm in the ne)( t st(1.ioo.) TIle first Step is to colllert the trudlhonal 01" histoocal t .... o-dnTlCnstOnal molecule. inlo three-dImensional structum;; whose inlramolecular tliSlarx:c~ an: known. Keeping in mind the prott.k'nL~ of finding the "co.. ",,," oonflll'TfUlhon fOl" nC'lblc molecule, f'!.Iso:: hit. and misses might n:o;ult from the scarch. Nc~t, the dimen~!(IIl" of the active ,ite nl\l~1 be !.ktennincd. lde:llly, the receptor has been CrySI3I1l/.Ctl, and from the coor· dinille", tile intrumolecular di'larx:es bet ......:en .... hat an: 1lSsUITlCd to be ley localiOllS III\: obtaincd.lf!he recep:orcannot be cry'ilallizcd, then: an: methods rOl" csti mating the: three· dllllen)ional ~hoIpc: oosed 011 ~arching cry~tul1ogrJphic data ooscs 800 matching arnino acid sequence, .of proteins .... hose: tcrti11l)' SlruCture hn.o; been delcm.incd. Fortunately. the cry~al structures .of IItcrolly tho\lsands of prutems hale been detemuncd, and their SlIlICtures havc been MOred in the Brookhn,cll PrOlein Databank. It ,. 110..... known that proteins .... ith .imilar fuoctions have similar ammo acid 5CqUCIlCCS in vwioos n:glOn~ of the pn)lein TIlese s.equcnccs tcoo to 51MI.... the ~Ille shapes III terms of u he lix. parallel and 8ntip;lmllel ~-plclltcd forms, lurns in lhe chain. etc. U\ing thi, informauon plus molecular mcchallics JXlrmTlCtc~, lhe Wpe of the protein and the dimcn~ions .of !he acti\e site can be estimated, Fil1un: 2-18 contalllS the , igmficPnt componelllS of a hypotheucal acll"C Sile. Notice that touramioo acltl residues at posilMlliS 25, 73.102, alld 147 ha"c been identified us importalll ejtl~r for binding the lig.1nd to the sile or for the reccplOr' s intnnsic aclh'ity, Keep in nllnd that Figun: 2-18 is a t.... o-dimensioo.al n:~ntatlOll of a three-dIlTlCllsional image:. ~f~. the diSUUlCC' between amino acid rc.,iduc.~ lnuSltalc into accoum the fact that each rc.'sitluc: is ahovc Of belo .... tile planes of the other thn:c residues. For an ilnlflClal ligund to "dock:' or fit into IIw:: ~i te. six t11"'lUlCC!i must be considen:d: A., LY$- G lu: 8 . Glu - Phe: C, PIle - Set; J), Ser- Lys; E, GIII- Phe: and F. Ly~ - Phe. In reality, not all SIX distaocc~ may be important. In selCC1illg potential ligunds, c.1ndidate>l might include D Pll'il ti"cly charged residue (protooated anune). aromatic ring . hydmgell bond donor or acceptor (hydroxy. phenol, amine. ni tro). and hydrogen oond acceptor 01" a negath'ely charged residue (carb())lylate) that ..... ill inter.lCt with IIw:: partate. phcn)' lalanine, pan of a di fferenl funcllonal group. 11wl. nilro,~n i~ pan of II plaU:Ir slru~'lure in the nitro group bill furrtllo lbc IIfIl'" of. p)'f1Im.(!a1Siruciure m amrnortia alld
""'If...
' OS'CRt
"'IIl1
OIlIWIC!..
Grou~
of alom~ Ih~t impan ,imilar physical
or chemical
pruptrtic'\ tu I
molecule btxauloC uf sindlarilic, m si1.1'. dce· Il'IIIIC'ptil'lly. or Slcreochemlsuy are (lOw fM:l.jllcntly n:ferrcd (() b) tile gcr.eraJ lenl! of j£w.tt'rC'. The early n:cognit iOTl Ihal tornI9t and Ihioph('uc "'C'Il.' alike in many of lheir propcnlC':'i IN III !/Ie term ""K ~quilYll~"'£ for the 'Io)'lcne group (- -CH",CII - ) alld divalent sulfur (- S-). Thi~ conccpt b.. Ictllll ~nl of thl' sulfur YIOm in thC' phC'nothi...1fIt rin~ ,yo;tem of 1f:lI1quil lliog agen" wilh the \'i nyleoc poop !II produce the dl bcnzodlW.I'pll1C cla~" of amidc:pre' , drup 1-« O1.aptcr 14). 1l1c vinylcnc group III an aro.wac: nng ')"\Icm may be I"C'placed by other alom~ i_len c \oj 1IIlrur. loch as o~yg~'n (fu ran) Of NH (pynule): ho\\cI'cr. iII_h C,"l-.K aromalic cllarncter is 'lg.nilieam ly decreased. E.umpIr-.Fn:I.dcll~ lAG E.hlml h(lpJ/Www ... .o.»>t • .cduIenllln«nn&khc~hnnlmonle.hlmt
-COSI!
hnpJ/www.clunel.eduIBiol)C:.·I .. m.nliI~lk:ry.hlm
-i-Pr
. Cornpound~ nmy be altered by II..- S,milanty [n [>noa Oo;;,n Nf... yon.. Chap...... " H~II . 1m n.,.,I1."" J .... lIabboon. AT .• (N).1: Topol"lIocaI 11In'","" 199(> Leo. ..... I~h. C.. and IIotLrnan. O. E>.rfun ... OS",R ...... 1. Itydroplloboo. EIf,c"""ic. ond St.eric" C............ w........... lX'. ............ 0..",1...[ s...:1C1y. 1995. M&'IiIl, Y C. ~ ............ de!.ip. In GAl.......... G (N.~ Modic_ R....d •• ...,. B. /Ikw Yl. y,ho leIIy\ in 96·y,ell mitrnIliCT platt'S and even using laboratory robotic::. for pi. perunl and anaJ)·sis. 1lte bottleneck had heI.."OfllC lite "ynt!te~ of lite compounds to le,l. Chemists reahl.ed thaI symhe-.es could abo be condUCted by u,inj; n parJ Ile! npprooch. The: tmn rontbinil/(lrilll cht'mi./n y,os coined to n:fer to the paralkl,UI... wion of all po!>~lblc combinmimu of substilucnLS orrompotlCnlS in a S)nthelK: expcrimcm. Whereas !he yield from.!Ielia1synthe;is is a Si ngle compound. lhe yield from 3 combnt3torial synthesis i~ II chemica! IilJmry. Figure 3-1 Ibows 11'."0 common types of ~ltcrnical libraries-a st'orrie Wnry. based 011 • Jingle pat""l'nt or IoC •
• ChapCn" j •
poipncr. In wch c:t...:s. If the molccule~ :are 100 lightly packed 011 lhoe pol)n1cr. the cnl.yrne nlokculc~ canlKll gain ~! 10 the: 'ubtOII ,hrorrul"V"p/l).
• T.... ur(;..:1 ~II!I. PoIy.I)"'''''' III ,,10..-11 )00lIe of the phenyl trouP!! poly~htlcroc II)L'1>I (I'EG) IIroo~ ~uoche1m. ptJ"II,OIl . The free 011 groups ur !he I'EG allow the .... achlllenl 0( l":M"ptJUlKb: 10 be ,yn'''''' il.c:(i. • I'oIYK1'llJomkl., r"ITI~. U" "super .11.IIe:' Ihc. .. reSIn, " . dl beucr ,n pullU .... ' ·(nl) W>C solulion-pha.c combllla· lonal elK:llli~lry III s~n1hc~ile. fOf eU IllJlIe. N-aryl-\ulfllnamide structures. llti:: resu lt mg mh lure of PEG-bound w ifooamides can be separ~ted by use llf ehromatogmphy. Another type of SQlublc SlI]lp()11 i~ dcndrinlCl"lI. The~ are large. highly branched molecules wllh termirl.1l ammo groups Ihat can be used h~e the 011 groups of PEG for the allachmcnl of products. Finally •• cillSS o f molecules lllO\hon Str~nds of oomplt'lll(':nlJry DNA Of RNA 10 lbe SlruCtures 10 "1.lp" the Structures togelher and promote reaclion. The DNA i, then rerl1QI·e!l. yielding product Ihnt would nOl OIhcrwi~c be synthes.i,~'d. Using thl ~ mcillod makes it possible to pn:~ent reaclion o( cenuin P.~I~ of 51ruCiures 11.. well.
I,
Al
COOH
o
~
R2-NH"
... R3-{
•
H
o
'"
H
,,)l~Jy~D "
R'
-
0
/
RO
Q-NC-
-
o
N-'"
R
\
R'
N-{
,
0
H
3-1~~.~~~~1~~§~[
,. A tomb,nalOf\i1I mO(· and each can be furt~
the I f'tqure reilCted to 9'V1! a lUll" 01
redrawn from descriptIOn
hom Keating. T
'!OC)Idfl,de If! the
component coodensahoo
be ..,n",l) In lhe Ih,nt """p. Sm"c II " ,n Ihc I",n! aroup. "'t In..... I C ,n posouon 3 is IIttdffi fur 11 AAC +
POOLING STRATEGIES Although $OIne solid-pha.o;e romblnatonal chernis.,y is ('011dUCIed by use of the ooc-bt:ad onc-compoond ~Ir,uegy. chenllotie!. and IU'om;ouon. tIoc pmbIerru \/o'ere redoced, and 10(13),. probably
,,,'en
mo the ~nolCl!J firsf dc«cn ..... 20 ~lIN ago whcn comt>on:r.torul chcn".uy ,,·u MOIIled. Ike,"'''''''' Fi,llre J-3 aNi ''''''g''''' M~'''i '" .he botlom u( tIoc: fillure ....h three UOOI'" "r bead;. E.:h ~p I\;ls bc:ads tM.:u-
in,. vanc1y of compuunds. but . ,....... , .nonure 1)111)' "I'JII':tr'S in 0IIl' ,,( Ihe ,roups. SlippoliC the 1IC1",'C io/l'IIClure is ARC (w" prele.od hen: Ihcrc i. ""I)' "",,_in reihl)' lhe,.., proh;,bly
,,',11
LI9' four-
sec
HAC + CAe. ARC + BOC + CBe. mild ACC + + COC, .... e do ."" by ~l,pp'''i 1M Ialil oc. "r poohn, mo.n ,n Figure 1•.1. Nil'" .. hen we SC""'n ' he", m",uf'C$, "'C find IICHvn)' ,n 1M m,dlll" ,roup of bead5. Th~ 'ell~ u, that • 8 i~ po6""'" 2 " I'CqlnrC\l rIlf'IICH,·i l),. Tho final >lep I> '0 syn.he"", Aile. IIBe. und CDC, ~~p\n G "",on ",p.:or.ue.1Ond ...:rco:n (,..10,
•
10 find Aile :oJ the UCII\e .ioIl\lClun:. S"h' noc' h'~ d l!('o",·ulu'iun. Thi, " ",milar 1" ilC:r~th c tX\:oo.
.oluII"" bul Us/.·, rcg~1 "'j) 1J;,e. n~I1Ic1)'. ka. e 001 a (UllCllom) ,mup. and ,f ;ol ,mportant fU""KlnalllffiUl". A redUl-'W 1ibr~ry '''''''a,nml! only,""'" (unc,i,,,,,,t lI,R1uf"I i~ lhen ~pared, md the miN lICU,'c compuund" arc ido:ntirted by c"hct ,)nlhe"s Ilf' 'teno". ~ dccoo ... olulion. • IIOI:'b~OIt, ddK.iun, Th'$ bcg 'n~ ""II g~""l1Ilml aIII;I """",ninillhe e"Urc hhnlry as I single ""'lUre. If act"' ,ly i, OCIt.'lUlIOII I.'Unl4lni" , I~ rompouoili. lu IN: analYI.n1 i~ pa'M-"Il",,'er Ihruugh "" dcclrinliy c~ capiLlary. The droplc:ls 11\:01 ""~rp: frum I~ capillary bear ioIronl "k\:tric cl\:lrges !hen.....,I",,~. and Ihty hl"",lIy ··",I'INlc·' ;,,1-Ol"-n;~h l (1'01/\ LI) I. TOF). Otoue a moolhful. il .imply mo:un . Ir,c, s:"lIpl" .s embcddc:d ill ~ $Ohd m.lIri~ (c .• .• 2.~-d.h)·ilro1lbc:llI.- ~) IIIIId tbc:n rombm\bl ... ,th I I.a_. Sample mokt:ulo are , ..po.ved and ionwxl In • ··(!Cllllc·· f ...,h",,, Ih~1 ali""" '" huIc: · rooIc of the 100al). Enzymes make up the nell largcst group (28%). fol lowed by horrnoot's ( 11 'llo). unknown.~ (7%). ion channels (S~). ftl.K'lear TeCCplOA (2%). and finally DNA (2%).zs II is apcclcd lh:u the anOOllltion of the human genome ....iII add adt\iliooal UUicts. although the rote of this addition is IK)t koo"o"O, New targets must be: part of _ regulatot)' pathwa), in the: ce ll and should be: sc:nsilh'e 10 some disease: State, IK)t be: e~prc:sscd allihe time: and everywhere in the cell, llIe: nc:~t concern in HTS is the: library 10 be: screened, Throughout our discuSliion, we ha,'e perhaps offered the impression thai a gh'en library for a par1iculur project was the o nly ilCl of ~'Qf1Ipounds thai ""en: ever screened for acli vil),. In facl. much !iTS invol,·c:.~ screen ing compomlds that are part of Ihe corporate blorehouse of ~'Qmpounds S)·llIhe· si7..ed in the: past. or the)' may be: a librdry purchased from a vendor. Such libraries usuall), coosist of microtncr plates containing fmun or dried $3lllples of compound - perhaps onl)' miCl'OlllllllUi per welL The: size of such hbntnes mOl)' range from I few thousand compound> 10 rocarl)' 11 million. 111e cost of completel)' §cTCemng such a library &galnst JUSt 11 single L'\Sa)' rna)' amount to o,'cr $300.()(x). so such lutgc:sclle JCfc:ens are conducted flUhn infrequentl)'. compared with routine dII)" lo-day screens, It I1as been esum atoo that one: must screen at lea't 120.()(x) • 'quality" compounds (I.e .. di"erse dlllg·like: structu res) to disco... er a $ingle- Iead series for a therapeuticoll), sound mrgel.:-e. As disc ussed above in the S«1ion o n pooling Mralegics. one can redu~"e the SCIl.'t'ning cffon by pooling groups of structures and running asS. This also cooservd reagenlS and biological material . has smaller storage n:quireme:nlS. and requirc:s fewer jK·rsonnc:J. TlIcre an. potentiol problems ",ith poolmg. A number of fact0f5limit the number of different compounds we can te..'1 in a given ""ell. including ionization. react;'ity. alld w1ubil ity. Compounds can !'!ltc-r a screening program in a nonrandom ~. such that D Gi~en assay platc may ha,'e compoullds thaI are highly similar structurdlly . This may gh'e rise 10 folse-positive hits. False·negative hits an. less likely to orise from pooling. Another concern is thoc usc of !'CpUc atc:s--compoulld~ from the ~ame series - in a given a~say. If only one representative of a gi\"en series is pre.ent. the chance of mi~ing that stries a.~ a possible lead series is greater than if multiple members 31l.' pn:stnt. Therefore. it is common 10 inc lude: st"crnl me:mbe:f1i of each senes In a given assay when pos\ible. To be: efftrth·e. a gh'c-n compound muSt dJo;.soh·e complete ly in the assay medium. It is common 10 add a small amount ( I'll» of dimethyl su1fo~idc: (0:'C pans of the sUbsttUle nooting In the sol ution will be tOO far from the beads 10 cause any nuorcsccncc. The presence of f1lKlf"CSC1:fICC implies that the lesl compound inhibi ted the enl.}nlC. The ad .. nntage of SPA O\'er filtration is lhat no fillering of the solution is needed, so bcads can be: lidded din::ctly 10 the assay IlI.IXlure in "ells 01" lest tubes. Also. speciul Sl.." inlillalJon nuid i~ not needed. The bead!; for SPA call be: engineered 10 altllCh a varlety of Substr81e types. Oilter HTS a5!111y ad.-ances include lhe use of rrucmorga· ni sms 5UCh as bacteria and yeast. the cloning and expression of mammalian receptors in microorganisms. probing pro. tein-protein intCfllCtions. and I'ery imponanlly, DNA and proIein armys. l1tesc arc: tOO 1II,'olled to discuss here, bul excellent reviews uist.~- ~7 "The incrtasing use of HTS to 'iCTttn for . nlOi«ule·. absorpt ion. distribution. rr'lCtabolism. excn::tlon, and tOXICity (Am.lET) propel1lCS has been cov· en::d ru; well.~'
VIRTUAL (IN SILlCD) SCREENING Virtual. or in silioo. ~nmg refen 10 lhe u:soe of computers 10 predict whcth~r D compound Will !;how dc:Slred properties or ocri .. ity on the basis of its two-dimensional (20) or Ihree· dimensional (30) chemical ~ruclUn:: or 115 phySICOChemical propertie~. The lIIori vnt ion for USIIIII vi rtual screeninl arises from the nuod of ncw struclUreli coming from CQlIlbmalorial d'ICmISlry. the expense and time reqUired 10 run COfI\"Cntronal lITS. the ethical c()n(."crn~ about u~;ng amlllaltls~ue Instead of prediClil'e modd ~. and IlJt increasing failuJl: role for struc· tul'Oi cormng out of CQmbll\3lorial progllllns. In gencnl. a vinual screening proglllm attcmpts to answer ooe or both of lhe.-.c queslions:
.Ie, •
SOOsIrale(')
)-- CO S'.....-, FilTER
•
<
EN)'IIIe
co
SubIIrIIe(')
511...1.... ,
t
$ N\'IIIe(') ~
t lnI'IIbIIoI
CO S'''''lfIIla,''' s..t>wale( ' )
CG-sut..lla", - SubsI.. I&! ')
b Figure 3- 1) • Compatlson of filtrallOll and sClntlllatlOll proXImity auays • . In f,ltrallOll assay. the emyme, substrate. and mhibllor all' n'IIJIed. the un,nh,b,ted enzyme splits the radro.KlM! portIOn (. ) off the !oUhstratl'. and filtenng lhe rrulC!ule. fojlowed by measunng the radroacllv.ty of the fllle!", teHs much InhlbrllOrt has OCCUlTed b.1n SPA, the same mlXtlJre IS tr~ted with resin beads contaIning a ~ntlll3nl lhat lluoresces only In dose proJUm,ry to the radooactM! source Any ladlOaCtrlrty that won splrl off by the enzyme does not need to be ftltl'led In SPA.
now
Chllplfr J • Co...bUtmorUll C~ ...ls"Y
"" \nd, ~I'
e
i~
live
r"
: of
"'d(';lel"1iotl, J.: Uni\local ..c:lechOl1 proccdtlre-s ,hal. if fol ......·w. ",II m:llc "mon: h~cly lbul POllua"u,...,) IhaI. " 'c pocl......., and......., di..- JUbstt;; 1l1c!Cad of A. T. G. Ind C. the ba>c:
deSllrnlUOfI is JUst t or 0). Wc II.at1 by se'''''',nl random IInnlls of Is and Os 10 reprc-.cm .he seoomc Each slrina is mea~urctl for .Ile d"'c~;ty lhe mu~tul'\'.' In the Mnnl rcprc-.cnt. Th,s is ~alled lhe fillltu uf .... wing. Tht-n. "'c a;>ply .he Kenct lC per-llionI,Hn()l.Ir ""'Je ....,·'MOdin. : 1:.nood,"I techn.que or ~ library hI ....J on (he
I"tw:ax ...
"
•
of 11&1 00 • belld.
Thu~,
the >aJucoce 011001 ...... 1C'l! doe coltlponcn l ~ lo~. "'och
""".\If\'
~ I e~ ~
I.
•
-
, • ,
,,
but !)t,e" ...
chlIrJ. Iut In !Ie'~ pool$ impliel Ihal a lIven member is Il'Spott!wt !lm,lar b,oloa;..:;!) OC"'·,ly ,
l'roIr the elec.ronic !le\'ices ,hal emil radiofrcljUerK:> \'£ll'l1> upon .... mul!uioll with an eI«""OI'UI~""'k '>mctime,. "'s"'~ an: simply ">Cd 10 >ln be:Kb ~ u~d to ~pam1~ compouJllb by >lI.c Of hy the: charge on a molecule, lI"lnlbc:sis: J>reparotlon of ,ndindual "",mile", III" ~uboic" of a romblllau:",.l library. 10 follow up 00 SOnl" Pr'Ujlelly of
I""
,
,_.
,,,
,
, , ,
, ,
,
, •
An cnzy"", th~l can R" 'crse lrdn,;cribe RNA inlC "~';.iIUl'IIt. Si'a'tngfr m in : A rc.sin inlroduo:cd mlO I combina lOll.1 eXJleri IIkM 10 rcacl ""h uTKlc:os,ruble mall:nals (,,"cess ",agcnt III" wdc: prodllC1S) and remove 1hem from the eXllen"",.I1. 1t~,·1'Il>1' lnlU~r1pIMst':
J • C"",b;tlllI(m'o/ Cht"ds.ry
63
St'kdh-Ity: Measure IIf a oompound' ~ tendency to bind only to • cenain largeL =11101, Onlg molecules ,hould ha,'e high sc:i«li\',ty lIS " 'ell ~s potency. Solid s upport : Insoluble. fUJlCtionalizeli by u>e of L'Omputahorull mood. AIM) called '" ~",m U'.... M/"I/.
""""'Oft'!
REFERENCES M.mr.. k/. II II Solid pha", PCPlldo: ,)"'I1o.,,,. ! The » 'n,,,,,,,, of I to ,,," Pelt,n", """. Dnoa DeI,v. II... nJ-2!l. 1991, )4 Opa. T I. Vithool ......'" ,. "'-d d"...,,~ry: • , ..... I""nt. Mo»
dna.
"" .... ,;!1 I-62,lOO2 ()pn:1. T. I.. and (lo"rnloc 01"• .1.. . 1M..... Modrl . GrapII. 11:2f>1 -214. 1 W9.,~ . _ l&. 7...... I.. .. II "falol ..... "", " ,ce",,,, filter r"" ..,....,_. NXI 3... 4 ioohibolIm ,...I_y 1_.All""";", onaIyIoI. C\In. MftI. ~ 1:98S- 99I. 1001 )K S".lIme)'CI. D. C ... no! GmoI .......... P I) I IIccmt .... ,'c lopo .... " io """«01.. dln'"'t~ ' "",,,,,,,~00BlJ 1_ r"" .....
k10.11. M.. S ~ LInd """ Dno, Oi_.... ry Today ' ; 143_ U6. :/000.
dj""".,..,
• •
,,
•
•( d
"
n"
•"
"
~
(
H
p
A
T
E
R
...
4
Metabolic Changes of Drugs and Related Organic Compounds SITPHEN 1 CUTLER AND JOHN H. BLOCK \kuboIt'-"1 pla)'~
C~Tllral role: in the c:hnunJlion of df\Jg~ C{)fI1pound~ (.ft..,Qbit/l;N) from the body.
a
IIId OIho:r fOR'lgn A ~id underslandmg of llJ and ph/uf' II (cunjugmiOfl) rc:acIi0llS. 1. 1 Phase I. 01' fuocuooalizahon rc:actlOns. include oxi dallve. reducl i~·e. and hydrolytic bioU"lIllSformulloos (Table 4.1)! The I)U.-pose of Ihese rcaction~ IS 10 introduce a functional polar group(s) (e.g .. OH. COOH. N U ~. 511) into the xenobiotic molecule 10 produce 0 iliOn: WAter soluble COlllpoUnd. ThIs can be :.c!uC\cd by dlr..'' odoh,·~
ruc:toom.
1If'd.... ln 1I....do"~ 1INIIo:!_ f oldrb)ola """ l~1 1I~1on rtf iii ......... ..., """'P"-
_II'"
\t..'1:1~ IUI.WlO It) d....) ... M.......... lI)oln~)'li, f NOn.oo omole' U)dnlllOO Qf -
'" '" ~
,
:ld
~mo h"otOpOr!lhv,!n 110 pon ..... ... It~ " Activat.cl O'VIIII'''
HOOC
4-2 • ~mphf~ depICtIOn of the "cp»ed « tNate' deactivated aromatic rings (c .g .. tho\.c containing clcctron· withdrawi"g gTOO11S e l. ·N' R.. eOO H. S02NUR ) life gC!lenl.lly slow ()I" resiscall1 to hydrmy lation. The ~lI l'l1tin! groups (a. -N ' H =e) prescnt in tM Intihypcncnsivcclonldine (Catapt"Cs) m~y uplain why thj~ drug undergoes linle aromatic hydroJ.ylaliOfl III hurrums.)I,.)OO 1llc ufJCosuric agent probenecid (Bt:'ncmid). ",lIh its clcctron-wi thdrJ"'ing car·
XCnobIOlic~ .
7
7 "'0
lvae
Ai ... 0I0dD
-
7
"
'l
T
OH
""'"
f~igl1 CUll1potJnd_~ comainmg aromati c IllQieli~ nrc ~usttpuble to arom:l.lic oxidation. In hu mans. amm:llk h) -
1\1""1
b<
droxylauon is 3 major TOOtC of nlCtnbohsm for many drug.\ COfuai ning phenyl ,roups. Impol1untlhempoeul ie a~nts such II) proprunolol..... ~ phenobarbital ..... phenytoin ..... "ohc nyl· bullll.OOC'.SI Crious ~"('l1ular damage.'_ '" Thi ... in pan. helps nplain why benzcoe can be so tO~ IC 10 mammalian )ystcnl '.
0'Y'Y0y"(-"0
coo OH
,uoo-
e ge nvali ng cloni : little !lient
C~O~CI I'oIpCl"lbOllll1lC
H
B4lI.'I'I "' ........
~ 3 7 &-T..'id .... ·> ...
V'IH'J
a
a-
H N
"-=( H N
a
COOH
J
H
Rtcenl tnvironmental pollutant .•. such a_, polychlorin:ttci.l ~a) Is (PCB~) :uK! 2.3.7 .8-leII"llCbIQl"(xlltlCnlo-p-dioxin (TOXlJ. ha.·c .lIrnCtc:d conside ..."hle public ~m over Ibtif lO~kil)" aoo health hazanls. lhcsc: compoulKb appc;ar ~ be reslstmt to aromatic o.'idatioo because of the nunlCrOl.l~ riectroorrati"e chlorine: atoms in their aromatic rings. l1Ic ItICIabobc Mabtlity coupled to the lipophllicit y of these env ifllI'lIletUIll contaminants protmbly ~~x~ai ns their long peTSi,... w.:t III the bOOy once absorbc:d.
'-!(XS'f"l
N~a I
CH 2CH aCH 1N{CH 3)2
-
CI
Quan titatively. the most impunant detoxilicalion reaction for arcnc ollide~ is the spoIllancous n:arraogcment to Uri le_porltling arellOl ~. Often. this n:arrungcllIent is accompanied by a lIO\·cl intl1lmolecu lar hydride fdcuteride) migrat ion called the ··N IH sh ift . "~7 [t was named aft('1' the Natiooal [m:tilUtes of Health ( NIH) llIbor~tory in 8ethe~. Maryland. lI'hen: Ihis process was dio;coverOO. 11M: genenll feOlull'$ of the NIl I shift an: ilIustrnted with the miled-function aft)o matlC oxidmion of 4-deult'noanisole to ) ·i.leulcri0-4-lIyi.lroxyanisole in Figure 4-6 ..-! Aftcr il\ metabolic fommtlOn. the Hrcrle o.~ ide rillg opens in the i.lil'\:etion Ihal gcncl1lll:S the n~ n:son.:mcC-SUlbihl.Co carbocation (positive charge on C-3 carbon" resonance smbililed by the OCH J group). The f.winerionic !>pec~ (posi ti.c charge on the C -3 carbon atom and negative charge 00 tile oxygen alom ) then undel"J!Ot:s a 1.2-di:uteride 'hifl (N il I shift) 10 form the dieoonc . FinaltraosromJalIOil of the dieIIOne 10 3·deu len0--4-hydro.,yani'lOle occurs .... nh lhe preferential loss of ~ "",,on because of lhe ....ealer boni.I energy of the C- II bond (compared with the C · D bood). Thus. the deuterium b (('Iained in the molecuie by UndergOIll!! this intl'llmolccular NIH shi ft. The experi mc:ntal observatioo of an NI H Miifi for arom:uic hydroxylation of adrug or xcnobiOIk i~ taken as indirect ev;(ie nee for Ihe io,·oll ement of lin 3l"\'IIC oxide. In addition to .he N IH shift. the zwiucrionic species may undergo direct 10l>S of D' to gcoer.tle: 4· hydroxyani'\()lc:. in IIhich there is 00 rctenuon of deutcrium (Fig. 4-6).11lc ultern~t;Ve pillhway (direct loss of D ' ) may be more fa'·OT'~ble than the N IH shift III some arommk ox idation re:lC1ion s. Tht:rcforc. depetJding on the sub~titl.lent group 00 the ~ne. ~1lC IUOlltatk hyi.lro~ylaliOil reaclion~ do IlOl dl ~play .ny NIH shift. T wo cxtremely imponant cllqlOatic re~ions lllso IUd III neull1ll il ing the reactivity of urclle o};id.::s. 1bc firlil of tile.'ll: involves the hydrntioo (i.e., nucleophilic allX~ of watcr on lhe epo~ ide) of arc:1lC o~ide~ 10 yid d inactive: mlll.N l ihydrodiol n ll.'t.abolit~ ( Fi!!. 4-05). n ils reaction is cmaly-LCd by
-
R
R
Reanaol()l!tT*ll
o"
J' H
OH
H
R R OH
,
H R
•
I
,I
OH
•
R M...................... 1IICIducI CO'JiI~
boo.nd TO
M .. DNA. RNA
Of proIfti'I
M
o
Fi9ur. 4- 5 • ~ble rNdJol'l palhways tOf ar_ ~. (D tOO. because fO"II:lIioo of d.h)drodiols i~ blocked. For cumpk:, the nJUtage""f} of bcn/.olalp)'n:nc-4.5-()~Ide. ns meas ured by the: : StJlmiJlu>l/lI Il"phimurium lest sy~tcm, is potemiated : tycloht~cne oxide isaddcd. lI Dihydrodiol mctabolltes bctn ICpOIlOO In the mct~boIi sm of sc\"C:rul aromatic ~dnxillbon. (e.g., naphthalene. benw{ll]pyrene, und ocher polycyclic arorHa1,C hydrocarbons),· l A few drugs 1t.J-, p/IelI)toin,n phcnobarbital.7J glutethimide u ) also ..rlI dihydrodiol productS as minor 1rK'labolites ;n humans. Otb)drodioI products Wll susI.:epllble 10 conjugation wilh ic acid. as v.eU lIS cl17ym:uic dchydrogenanoo to o.mespoodms catechollllctabolite. iI) exemplified by the IIIttlbolism of phenytoin.71
.,;.»:
.k?,H a e- T 3
H
o
!. \ j·lndDopropMll
,'-»
A SC(;ond cnl.)'matic rea(.,ion involvcs nudeoph illc ring openi ng of the urcne: o~ide by the sulillydryl group ~""'nt m cs" 10 yield the corresponding frruu-1.2-dihydro-l·S. glul.athiooyl·2·hydro~y adduct. or GS H adduct (Fig. 4-5) ..... The reaction i~ catalYl.ed by varioos GS ~I S.tr:m,fcl'1lSU. 7J Becau'
-;~" ()ooo,
!
I
..
OH H~C.
HN-VV
DAN ....
.H
HN
OH
O""'N .... H
CN......:o MoIM)OIoe
~ed. glIcu~)
TSG ""
"".-
--
"",oQ '
jHCOCH 3
_ ... S
OH
..... ci:i;'cOOH
DIr~z1'"
was confimlCd by UlIC of rndiolabckd brnmobcnl'.clIC. "..., sewnl)' of n«rosi~ com:lated well ", lIh lhe lLmoum of covalent bindinlltO hepati c ti s~ue . Use of dicthy l maleate or large doses of bromobenzcllC in rolts ~howcd lhallhe dcpletioo of hr'palic GS U led 10 lnocc 5C'a"C liver necrosis.
'"
'"
'"
SG PoIycyclK: IImmanc hydrocarbons are ubiqullous en,iroomenial contllminants thai are fQl'Tlle(! fmlll aUlD emission. refuse bumHlg, ,ndusmaJ polX(Sses. cigarette ~mole. and
OIMr combustion pl'lJoCC:!;scs. Benlol a Jpyrene. a JIOIent carcinogenk agent. i~ perhaps the most exu:nsh-ely studied of lhe po lycycl ic arOlllulic hydrocarbons.'N Inspection of it~ structure revel,l s thai lItOn1alic hydro.l yln!ion of be n:m[ u lpyrenccan occur at II. numbct-ofpositions. Tllc ido!mificat ion of sc:ver~J dihydrodiol mctllbolites is viewed a~ indirect evidence for (he form:m oo pod inmh'enl('nt of :lrel1C oxides in the metabolism of benzot ajpyrenc. Although l'Crlain arenc ollide$ of beTv.oI ajpYr'I'ne (e.g .. 4.5-ollllk. 7.8-oxide. 9.10o~ide) 8pp:'3I' to d lspl .. y some mUUlgt'ni c aod tumorigenic activily. it doe.~ 1101 appcar that they represent tile: ul ti mate reacti ve spec ies responsible for ben!.o[ a[pyre ne' s carc inogenicity. In rece nt ycal'll. Cllilensi VI! s\tllli e., havc lell 10 tile: charactCriZlllion o f a .. pccific seq uencc of rtlctllbol ic ",octions (Fig. 4-7 ) IIw gcncnnc I highly reactivc i,IIcrmL'diate that CQ\'alcntly bind$to DNA. Mcmbohc activallon ofbenzo{alpyrellC to !he uillmatc c~inogenic speciC$ invol\'e~ an initial cpo.' lIdatioo ",action to form the 7,8-oxtde. \00 hlCh ;s then
CQI1vcrlcd by cpoxitk hydrn...e 10 (-).7{ H).8( H}-dihyUro~y, 7.II-d lhytlrobc nzola )pyrenc. 1IO Tlie two-SlCP enzymatic form~lion of thi s mm,,-u ihydrodiol is ~tcreospeei fic. Subsequcnt cpoxidatioo lit the 9.IO-dooble bond of the laller IIlCtlioolite gener.llcs predominam ly (+ }-7(H).8(S)-dihy lim, y-9( H).! 0( H}-ox)' -7 .8.9 .1 O-Ie truhydrobcn-,-01 trI p)'renc or (+)7.lkIioJ-9. IO-cpoxidc. II IS thi5 kcy elcctrophilic d.oI epoxidc IfIttabolite that realily reactS wl\h DN A to form m.my covalcntl y bound adduc\$.M' 1..1 Carefu l dcgntdatlon stud ies han' shown that the principal adduct in~olves DIIOCl of the C-2 amino group of droxygu1l/lOSinc al C-I O of lhe Iliol cpox idc. Clearly. t hc~ f'Cactions are responsible for gcnc(ic code al1crnlion ~ that .dlimmdy leoo to tnc m~ l ign.~nt tron.!! _ s,bly in humans. WI
\ I
'H Sl1'
"""""',,¥!
H2.$-01I It1C1U1J' • -2,.,M"ICIP!OC*'III (I:lOM)
j
7 \' ~'·TetrllhyO-~
77
DebflilOQ!W1
3·I.!elh'¥UlOltI1ttv_
Figure 4- a • Examples of drugs and I«!flObooIICS undergoing benzylic hydroll)'lauon Arrow Il"OdlCil les of hydrol()'latlOl'l
~te
a
a,~
OCH,
2.H)t¥lro-2·(N'~
l-trtdIOlJaIIaIuxi' 8,
H
H
I
CI
C "
~ --"
H
".,H'.,,,.
OH
Ha,Aov c 011';4= '·
: hoi
",,"
H
C
CF3CH~O/ ""CH 2
""""" CH,
-AbJd Mac"'"
e
~ S02NHCNHC.H
T
c.-,..Me. AllcmlItively. the alcohol metabolites may undergo glucuronide conjugation. Aliphatic w and "" - I l'Iyliroxylations oommooly lake place: in dlUg moI«ules with straight or branched al~yl chains. ThUs, the amitpilcptic agent vaJproic acid (1Xpa • kene) undcrgoes lxMh wand w - I oxidation to the .5.h)'droxy and 4-hydroxy metabolites. n:speclively. 101. "l Further OJ.idation of the 5-l'Iydroxy metabolite yields 2-I1-propylglularic ocid . Numerous barbituruteli and oml hypoglyt-emic sulronyl un:as also havc aliphatic side chains th aI arc susceptible 10 oxidation . Note Il'Ial the scdlltive l'IypnOlic amobarb1tlll (Amyull ) undergocs extensive w - I oxidation to the com:· sponding 3'-h)'droxylaled metabolite. ' 6j Other [)arbituroJcs. such as pentobarbil1lJ. 1' 5 ,." Il'I iamy lal. In and sccob;ubllal."l reportedly are mctabolil.cd by way of wand w - I oxidauon . TIw: l1-popyi side chain attactled 10 the oral hypoalyccmlC agcnt chklt'propamide (OiabillC!iC) undergoes e~lensivc 1» I hydmx),latlon 10 yie ld the KCOnd:uy alcohol2'-hydroxy. chlO primary aromile ImIIlC drug~ or metabolites. N--oxldation con stItutes 1liiy . minor pathway In comparison Wilh other biOlrdnsfoc· IIIlion palh ...·a~~, such as N·acetylatiOfl and aromalic hy· ",,-)·l;,tlOll. in humans. Some N--olygcrl31ed metabolites iIIIe i)r(on n:por1l-d. howevcr. For c~ample, the nnlileproiic dapwnc and its N·acetylatl-d melnbolitC' lin: mc:tabo:.II \l1I"flCalltly 10 lhelr corresponding N·bydro.ylanHIIC *"laUI e5.2z& The' N· hydroxy metabolites are further l"Onju· pIfd III Ilh glucuronic acid. ~lt!hemoglobmemia to~idly i ~ caused by :Ivl¥ 0 ..... Ide 0. .......
~
..!::J Coula
~
BordoliQ ('91« I e
IUOf'GI
, w.o '
........ XR
p..QlucutOllldB (JI .r.IQogB at C-,)
HO
,
-UDP
U"dne~'~' ~ ACid (l..IOI"Go\)
("~,,C-'I
Figure 4- 11 • Forma\lOll of UOPGA and ,8-gIucuromde (onj!.lga t~
T.cnIorOWl1 ....
.t.c.Ioi •• """'''"'
--
CH,
I
CH
.,-
'CCOH
,~.
n drua
:ohohc
a.n.o.:. toO. 1'1 _ H
/" . , lriazr*!.. !H ... ]phll , " _
coo+<
o
,.,:tul. _, CH CNHNH II l
2+
N«irW1On
j
6 --
Cytod1o orne p ..fOO
As EW.. •
Medialed
,'.UW
.• -
u.. ""'- .-- :C~ .~~.~1II Bn.:Iii "III
E
'"r
""
&'''1'1.
Mclh)1auon ~actions play an im ponanl role in the bios)'nb rI many endogcllOUS compounds (e.g.• epinephrine -.I mdIIOnin) and in !he inacti v'lion of numerous physioq.aJly IC'!iI'Cbiogenic amines (~ .. IlOrCpinephrinc, dopa. _ , semtoIIin, and histamine), Methylation. oowt'-cr. \* '11J11e1 onJy. minor p3lhway for conjugating drogs and 1CIIObIoI1CS. Methylation ~llC'rnll y does no! lead '0 poll1T or ""·~ub!c ~Ilbol jtes. CACCpl when it cltale$ II qUllter..,. JIIUIQIjum deriYlllivt. Moo methylated products uend 10 be p/IarTrIIroIosicall y ill3Clivt. althoogh there are II few
"''''' ~""'''OH 1481 • • R_H
No ' hiltarlilPlW" . R _ OH
nr romzyme in\'olved in mclhyl:uion rnclions is S-ad· ~htthtonillC' (SAM). TIM: Ir.lIIsfer of the activated MII)'I JI'OUP from Ihis coen~yme to the acceptor Subslnlle C.!;·~ '!Y;;""~by various C)'t~lasmic and micro6omal methyl. :'" (fiCA. I7)..... MClhy llrllnsr~ ofpanicu· IwIll!pOlW1CC in the meloiloli sm of foreign oompounds indrIck ClkXhoI-O-flll:tby hransfel"1lSC (COMn. phenol -O-
methyhnlllsfl!'flISC'. and non~pocific N-methyltnlllsrerJ..Op)'",m\tlo:
"""'"""" ""'"'""'" "'jIOWIIi""
"'....,..
~.,,!I.
Etbi"yl~
1':lIIw>" .... dc: l'q'l
'
,
",Ind,,,,,,,,
,,"nllllyl
' ,,",,_10
Ind,tlllvit
'""",""" ""'..-
"",I
"-K',,,,_
,
$cnr:tll""
,
,~-
1..-11t1"w.
....
CYP 1M
Trl l, . - • Alf." .... '!
Primuolt
,~loo.tI
,.,.,...
"nIillridll"n~
l'hon~lOin
lIil"llJlml'''"
'~yl
........ ,-
..-..
' -. """ t:f...tftlI
C..... ~
F..thooo.,,.,....
o.id.oob)'NI
" -"' OOt •• >tdlnc
Mdaronot
Nr,.'rlf'I'"
""~~
o...tz X,'"
.-
1'!otno1bttbiW ",""ylOOn
"""""
Ct)"lII'QIII)'OII n",,~ed ..
""",0.
n............".
1I,1'abIII", 1\1(...."..
ttdi ..., ...
Rlfr.pcnlltlt St. Jnha ·~.....,
-"',
...
t ~ ..... ,~
"'*-'"'"
..,.....
"'.""" .... ·roIe
M..;oo.'OI< Noilitllly"
N.r.dlpo.. No:.11ounn
Q,,,'"
R'ION ....
.. b ,,,,",O may cnhance the IItIabohsm of endogenous compounds. such liS ~teroidal lroo"kHld and bilirubi n. For inqance. phenobarbital clln inata1> Allhough DUmerotlS OIher examplC'i of substnne SlereQ!iC':lectivity or en:lnlioseleclivity in drug metabolism exist, the e~amples ]IIT senk"d sholli d suffice to emphasize the poinl.lIIl. H I
F
OIlier fac1~ I1lso may illOucllC.'C drug mtlabolism. Diewy facl~. such 11$ the protein-to-1 Thus. bioreduction of ketone xenobiOlies. as a gcl1t'rol rule. produces predominantly ont stereoisomeric .Icohol (on-
i)(-)"",,In-xol
1
-
C
V"'-JOH
HN
CAN'A, H
Rl + HH.·Hy(Ir~·
-~
f 34
Wi...."'" ulllj (Jil ,'Old',
T~.rl"'''1Ic
"f O,gllt/ie M~,lirilll" iIIul
/'Iu,,·mt,u~rK:al
Chl'mix/n'
-
CH, N/
CH 2
fA,
-
I
C
....... Co?' ....... CH OH
I
• ~ •
'
H
+
CHl
Q
a a a
HO
HO
Q
~
~
0 -1I)(lh)'lmion 0Ci:1I1'! ... ~dus ivcly with the phenolic hydro~)' group al C_3.~74
~
... ~
Ph.... uologlc.lly Active Meu.boIlte. The traditional nOlion thai drug mctobolites are illacli ve mid insiglliflCan! in drug themp), has changed dr.lmatically in rel:"t"Ill )·eaoo. Increasi nj,; cvidence indicales Ihal m:lII)' drugs nrc blOll"lln~fOOTltd to phatm:loCOlogicaJly act,,'e metaboli tes lhm COOtnbu le 10 lhe thern.pcutic 3.~ .... ell as 10.\1C effecls of lhe pa~nt compourld. MC1abolucs ~hown 10 rul\'e )ig mficam lhempeutic al:tiYII)' in humalls are li'l~d in Tanl e 4-4 .1. H'I 'The (XIrcn! drug from ""hich the metaboli te is dcrio'ed and lhe blOlr.lllsfonnll uon rrocess Involved al50 are gi~en. How SIgnificantly an actioe metaboille COOtribul~ to !he therapeullc or tO~IC effects :l.'oCribcd to the parellt drug deperld.~ 011 ils relali ..e acl;"Il)' and (IUamitali>'c unponanc.: (e.g .. piasilla oorn:cn t Illt ion). In adl.lilion. II helher the mcwbolile !lCCul1ll,,]ate\ after "'pealed adrnin ;\tralion (e.g .. desrneIhykilll1.cpam in genalnc patients) or in pat ienlS .... ilh rellal failure is dclcmllnant. From a clinical standpoinl. lII,'1ive melaboliles are e~pe dall)' important ill patients with decreased renal fUllClion . If renal C:Jlcn: tion is the major (XIl hway for climin:uion of the lICtive metllbolile. lhen lICCulllulallOli is liJ.c1y 10 occur in (XIlienb "" Ith rcnal fallure. Espccially wilh drugs soch as proc:unamidc. clofibr~te, and dJgIII)~ln. ~ution ,lIOU ld be exercio;ed in treating palienls wilh renal failure .l. 411 Many of the tQ~ir effecis St.~n for Ihee drugs hn~e bt.~n anributcrJ [() hij;.h plasma Ie~els Qf their :acth'e metabolites. Por exumpie. the combinalion of severe muscle ..... CIlJ.ncss and tenderIIl'!i-'I ( m)opalh ) ) l)'1lc Idd Oeslpr,m lne Phef'IObartldolrme
Mesorldnlne
N-Demethylilion N-Oemethytat ion IIef1zy1ic hydrl*)'l.tlon O-Deethylltlon ...... omatic h'fdroxylllion Ketone reduction HydrolC)'latlon wid ooodiotion to ketone N·Acetyl.tlon Aromatk hydro>l)'1l1lon Allylic hydro..y1.1Ion Sulfoxicle reduction S-wldilIIOf"I
Wlrt"'n akohok
Ket_ recluction
~~
.,...,.Uin
I'ItdNsone "'"' ib...
o-H)'dfl*)'methylmetoprolol Acetaminophen OlC)'boJtazone
Predn,soIone Pherlobarbltal N-Acety!prOUllnllmide . ·ttydrolC)'propr anolo!
IIId )·h)droxylau:d mcmbolile of dia1.epum (Vulium). and -..ialtlll: (Serenli l) is the: sul foxide meboolite of the -.pI)~ilotic agent Ihioriduinc (Mtllaril ). AlIlIllnm tIt.lllR used in lreating herpes sim plex virus. 1~1I~·WMer virus. and/or human cytomegalovirus must be lNoiIctivllro.,JI Thc:sc: include acyclovir, v:.locyclovir. )!CICII:lo>lr. famc:iclovir, and gllllCiclovir. which must be . ., !bltd on the pt't1tose-like side chai n to the triphos~ dniuta·c to Ix: cffective in inhibiting the cm;yme Dl\A poIymense. The anliviml ci dovi. is dispensed as II .K~tt and only n«ds to Ix: diphosphylated for ..... eI\IOII!O the: .... i\"e tripho .......... , .... C_epU. ..... _ ........ DC• .....,."..,.. c.'1cmocal SoccIy. Im.p I .l6. T"..,.... W f. In T...u. B (cdo..~ C_ 80ca II ....... Ft.. CIIC ........ 1996. U GucntJCri. J M . et 0'" Pouc. NOlI, lIy. II C .• et aI.'!'roc, N>jl ""'" S.
Dni,
13:132. 19711
an.. o. P
R~ et 01 . An:h. 8"",lu •. lI""",p. 197:ll~ 1919. 111. Ortiz .... M"nICJI.... ~ P R.... I i 8~_m'lIry 2 i Il! I. 1911:2, 114 8ccl.. ,. A. II . _ 1IO'O'iand. M J P!wm 1'I>arm:oool. 17;628. 111M
I ll.
IIS. IJnftc.LG~ etal
8"","""'. J.116,~ll.I970.
I II>. Mc.\l ...... It E. In 8nJd>e. 8 8 .• _GOIIm1 0 ..... 1'Nnna;QI. ThCf 17""". 197', 120. Sen_r.O D . etal_ Dno. Melob, (')0."," 1:28!.197$. 111 Ton. Sholl M.. M~' 0 .... II I .............. Eop."'" 293i2,
1
L."''''
c..
~B. 200).
122. 123. 11-1 Ill, 1lf> 121 Ill.
1:IorJ:. K. 0 .. "'01 . Ac'. Ph>m........ T, J.... 01. (1>.). 8M:>1o,INl ltt"'t... I ~Wts. New y..n.. Plenum~. 1977. p. I~ 1'1 \10 """"'" P G ... >I. CMcer It... 36: 1686. 1916, 1)6. GonitJ,", S ... >I.: In Usd,n. I!.. 1'om:>I. r (td .. ). P,,)'t~lIerape"l", DnitJ. PM 2. Nc:'Wo M~I OcUet, 1m. p. 1039. III Gm:obIaII. D J.... .d.: Oin . l'h>rmacol. The, 17: 1. 1975. ItS. Y.... Y. ft oJ.: X~a S:24S. I CI .,""" J l _ 0IId SooI~ II .: Psycbo\>lW11"""""1i1 ~:461. I%(). I~' 'hIlo, A .. oDd _..,.,. R.' An:h. 1'IIarm. (Wc:inhclml 2\l(I:1 45.
\Ie"'*"
''''
1611 0.-. L F.... II.: P
In I~
11'
I" III Ie
1",1 1Il0l
liS I'" III I~ ~
1'iO
PIwmaI>. 0.'1"'>- 3:337. 1973 Wrigll' . J." I I. 7;257. 1977 118 Gal. I .. daL Itt •. Coon"",n. Cll M Bi«l>n, J.- Ir no... III
I97S
5SS. 1972.
266 7.ehndn. K.. .. al 8,...-. 1"harma..'01 II"~. 1962 lfol "'''' .... S. 1.. DI... Nnv. Syll. .\tJ;4801. 19n 268. T~Ior. D. C ... aI. Dnoi Mtry. 1975. p. "2. 21" S Oup"", 1,322. I97J Pi. 5 _ _ • Sf.. .. aL 0..., ~Ietob . DI\pIIO. 3:1110, t'J75, 276, Mdley. to: 11 ... al.; Dnil MeIoob 6: I)l. 1971. DIodIey. K II .. .. 01. Mctoh Oi.,..,.. 2103. 197~ II p~. M, L MMl III""",,", P S Dni. ~ .... iU:y 172&.1.
o..m.
... w_.
,
Droo,
0...,.,..
'lS7 to:.....,11I.U 1I~ ""Loe.V 11 L:Ad,I'In:noc, W.II•• T .. .. '" Fed. F"n:>.: . lS.I>M. 191b. 367 ...... IIe. T .... al.: Din. 1'IwtnIcot. no... 26;167. 1m .l6Il II..,,, _ S.. .. 01 J Alii. 0...... Soc. 76'IMO. 1934 369 So"".!!. J. I. alII. 1'haormocoI. 1'316. 1973. 310. lie ........ A.. tI "'~ J Pharm. Sci. 61739, 1972. 371 R.. ",.. A..... aI.; J 1'1.",-' up. Tbcr I 149. 1971. 312. 81id", •• 1 W.. " -'. B""htrn. ' I i8,~7. 1970 37) GiIKooo. T.. ..... .. Br J Cb • . "*""-'I. 2:2)3. 1973 l74 T$U"",,1'" T . ..... I.e,,),. G J. PIwm Sci 61Il00. 1971. 375 1'Ilr1et. Co C~ .. 01 DNa Mttoob. l Ii9. 191$, l76 a.-toun.N K.... aI., Ilnoc MaaIo. Do"{U. IJ72. 19711. lTI S,w. I), S..."" ",..... h.ll. I) P J Phltmoocol. f... p. Thtt.. 1114 m.
0..,..,..
""
In. l.oiiliiuI.c. 1:572. 1971 - - .... H _..... Vcn""wt. A" Acta l'hysiol Sand ~8 ,8a, 1960. I!.. CI ".: 8iochem. ' 65 41 7. 1~7,
«I' ..,.... C aor. A. B : Bioc:I>J 1Iani.. II I!IIhoJ i"""'. Ne1O' Yorl. PIonum Pre ... 19n. p. 2«7. (')_, j. L F In Ari ... I. M . and Ja1oby. W R ,"",.) Glutolho· _ Mcyo. J D, (...b ) Glulllthionc S· T-'cmIet. .-I CIrf'i' DI .. IOUn. 1970 4M. A.......·Sqo>I .. O . l>ru., 121>9. 197b. 466. 1I~1Ob'. P.>r1 2. 11nt,... Spri"p' V.na,. 1971. r
""
469 MI7dd. S. I( In rlOhmlll. W II (td.). MeuboIiI: C"""o........ M"lboIiI: U)'droIyoi .. 001. ) New Y '" M.. Londun. T.)"" & nW":;j. 19'111. 1I.""ie. B B. """Gil"" ... I Il (ech ). C""""P" ,. a..... ha' ....""'!'born: ,4· "1)' . ..... 1. &do.. Spn V' V~ ""1 Caklw". W D. , ..... ): BooIuf:""'l fkw~iflc"h... 1'1 ..... Yon:. Andoml< ~. 191B C"akl-'dL J~ ..... 1'aItI_. G 0 (td< I' Foml~ C" •• """"", M.lliboti .... t...Id
".,,,..r
' - ''''
o.M.".... F . 0IId Locl. p~ A 1011" r 501«"1" ") ..., M,*"",,t. M _ R....... at Toili.}, London. Manni" .... 1'I!l7. 011'1'10. A , Mkholjdll. C J •• ond Yo ~'IiIIwJn. E K "1rtabuI'WII at oht,_ ...... ,.. ,"" Pfw. 01. n..r ~7 26!1. Ifl' I . I) E., . U ""i.~ _bolo,., at dono .. WId .): The ''''''''''''''' 0( nn., M...boh.m Sruu,; .... S'crted by al.O reductase enZyJnes in the
age and generulion of UllIirlOSlllicyl ie acid prior 10 ubsorplioo
gUllO sulfani lamide. the aclive species (Scheme S_ IS).
prevents lht systemic absorption of tnc agenl and helps con· centrate the active agcll! al the si le of action.
H'
QlibaRyi C.lltp •• "ds
H(
Allhough pronlosil is 00 looger u~ a_~ lin anli~tC'rial. this Iype of lin~age appears in sulfasala1.ine, which is used in the treatment of ulccr.uive 00lili5. The 111.0 linkage is broI.en in Inc &UI by the action of am r..-doctases produced by microtlon.. Thi~ relc~ the ac1ivc agent. aminosalicylic acid..... hich lias an anti-inflammatory effect on lhe rolon. and sulfllPyoomc (Scheme 5-16). The advantage of this prodrug approoch is Ihal the combination of clcavageofthe u.o link-
CH.
A number of different funt"(ionalities have been enluated as prodrug dl:rivatives of carbonyls (e.g .• akkh)dcs and l eo lones). although this approach h:H no! roond wilk clinal use. 11lese nave cenerally invol\'ed derivati ves in .... hich !he
N (C H l~
OH
,
OH ....0
OH
CONH:I
0
•
OH
•
I
H.O OH
0
f'... " aldehyde
•
HNC] P)".......
Sp l
hyt
dil.ed c nitroge !ionali!
exampl
(P""ug) 0
CJ
CO NH - CH:I
Rca lThKrch
• C H,
,:,(CH:I~
CH., OH
(Sellen unne, '
o
H,N -
0
o
0
>-. =. -
0
11
>-S- NH ,
g
'H, Prork,
11
>-S- NH , II
o
&Matt': t " (Ac:IiYe Drug)
•
•
r
• H,
'H, Ses, pho!;phoryla· lion introduces a lea,jng group. "'hkh can be di splaced by an incomin, nucleopl1de . This is secn. for curnplc. in the synthesis of DNA and RNA , in which nucleutidcs are added 10 the J' end of D growing chain of DNA or RNA (Scheme 5·21). PhosphoI)lhlion IS t"Oln)nonly required for the b,oacllva· tion of antiviml agent'!. These: agents an: commonly nucleosides, which must be convened to the nucleutides to h:we
0
I 0
0
I
ce" " "'
-"
I
(XN 'N I A
0 ,
~
I
I
'
0 T1" p.lluml,..
f'\ 0,'
,
,.... NH, OH
0,
I C( ~ " " ..., ,
. OH
ONA eo.. ~Sb ..-.d
Scheme 5- 20 • ReduttIve ClCtJ'iil-
Brut ,
bOn of Inap.lZMnIn!'
activity. Most oflen . :lJlli ~ir.. 1 ag,mls di~TUpt the synthesis or fUrlCiion of DNA or RNA. ",hlch is gl!rICrully accomplislled by oonversion 10 the lri phosphate. Since oo/'l11al cells are al-o invohcxl in Ihl." synlhe'i~ or DNA and RNA. ~>()mpollnds have bcl'n sought Ihal would be converted 10 Ihe \riphosphnlcs. the act;.c fonn , in greater an'KH.mI ~ in infecled cells
than In normal celLs. 'lllcrrfon:. nuckmilk$ lhll have higher affinil)' for the viral kinase en.,.)'nlC~ than the mammalian kUlll.'iC'S art' dt'1;ir.lble and hal e grt'aler sclooh'c lo.llt-it)'. This can be seen in the prodrug idoxlIndilll'. whICh was lhe fillil agenl \0 show clinical cffectl\CIlCSS against viruSoe$ (Scheme 5_22) ..10 11Ie nucl ~ide tnlers IllC't:XpOr.ltion Into DNA. II hlch mul1J in 1IIC00lCCt base .,.unng that dis.rupl'l the ability of DNA 10 funcllo n as a templot e foc DNA and RNA syntheSIS. In addlhOil to the SC ler of dlllg.~ to tile eNS. 'The approoch Ila-~ ~n described as a chenllcaJ dclh', cry ~)"MClll. riOt j U,1 a prodrug designed 10 pcn.ctrah: the
blood- brnin barrier. II> Th IS process i~ a 111l111iSlqJ procedure i Ilvoh inl: dd t H~ry of the drug-dihydrop)'ndH~ derivathc 10 the brain via fllCile diffusiOl1 across Ihe blood- bmin hamer. follO\\'ed by o.U(iatK)Ioida. U. M .• Sa",. N .. d aI' I. l. C_ ... \4 121~.
.or
""
lot O""y. W It Eur J M.... CIotm. 'I6oSn. ~I " ~I". V. J J M... CIotm 23 117S. 1'180. 36. 1WdW
or
a tremendous increllllt In tnc number bIOleChnoJogy-re. lated phal'TTl3iCCUlical products in tk"elopmem. and. number of important new drugs progressed Ihrough trials and mlO tile el lllie. A good n: neclion of the irnpilCl o r bioltchoology is Ihe GcnBank tialaba,. or species. AOOIhc:r I"'pew' tant distinclion IS tlklt the fragn"ICnt of DNA from cukaf)'OI11: chr0m0s0mc:5 will cootllin uom ( prolcin coding 'iCgrnt'nlJ] and introns (noocoding segments bct .. ccn nons). """reM in cDNA th.e ;nlrons are sphced out .
Res1:rktlon Endonudeases..· • 1 The restriction endonuclcase (or rcstricl ion enzymc:) is probably besl dcscnbcd as a o;('t of "m()lc:culor o;ciSSln" in tIalure. RC5triclion I'ndonuclC'aJiCS are bactcriaJ e'n:tymC$ tha. lIS the name impl ies, cica"e intemal phosphOOieSlcr bond! of a DNA moleculc . ll1C cicavage ~lIe on a segment ofOI'A lies within a specific: nllCleotode 'iCq1lC1lCC of about j;1~ to eight base pau~ . More than .50) n:strittion endonuck~'ib have becn d isco\cred. aoo thc'IC rc;lc l wnh man: than 100 d iffen:nl clcavage silCll. The chcmlC"lll ~action of the rest"" lion endoollCk:asc releases the 3' cnd of One.' base as an aJco. hoi and lhe 5' elid as a ~phale . 'The general react~ is shown in Figure 6-6. TIle n:cogniliOIl ., ites ror restriction endonuclease, !lit specific palin(/ro,nic scquctlce.~ of DNA 8J II()( more .han 8 bp long . A number ()f lhese palindro",c~ arc: lisled in Table 6-2. A palindrome is II Sl..oqucncc of lellcrs Iltal reads tM s,1 me .... ay forward and bad.""ard. for mst~: "A man.1 plan, a canal: Pananu!:' " DNA · land," " Did Hannah «< bee~1 Hannah did." Kc.ICd 10 gc nerutc .,tW~, to the heterologous domams and for other bio~uWts. SometulIcs. fusiQll prote ins are made to ... ~ Ila'OOIbllunt protein that un be {'asily identified. AI (UII!PC of tillS I!. • tectmique called tpjl(J~ t(lICSi"S, in wt.ct. ,,(II~lenlcd anlibody TttOgnilion ~i tes IlIl: kIal .. nh recombinant protcins. Thc res uHing recombinant
""1Ik'
inln
hormone reccp-
One of the QUtCOlllC$ of the progre.~s lhat has boxn made In the id(ntiflCotion and cloning of genes is that mauy proteins cncodeeS. thoc genes themselves may repreSCnt the ultimate tBrget for the treatment of a tep. t'ipttiaUy if "t".filtralion is "sed. "1ft",1 "..ri/iro/w... TIle iml,~J purir~_ of the ml:>.t""'. somc:tll1leS attOIllphMled by prl'C'pttalion of lhe proIClIII. \lsm& a ~tow. stepwise ",crease of lhe tOI1ic w'n~lh of IhI: solution (iiallmg ()III). Ammon,um sulf.te i. alyplCal_" C;lII be u~ In coklaqUfOlJ< '-OluUo..... W"" .m1Sl;ibkOlJMl' ';01"'''1' iuch Il.< tochloro:>cellc :>c,d ~nd potyclhylo:fII' II)tOI chan,c lhe dicl«trK- coostl nl 01' the IOlutlon and also dr~ pra:ipit3Uon 0( prole, ..... Inlrnn~Ii"'r "..rl/iorli"". In this -"a~. the proteins 1liiy lit (l1ll1yzcd aiMIMI ",aIel 10 I'CrrIO\'C sah~ Ihal wen: u«:tl in Ill! prn:ipttltllOO filep. 100 uc""'"te chroonMop:iphy II weollD .. rrIXI m some", h:1I crude oqw'aIlOII of the proIeln) based 01 lheir behavior in ~ pU or Slilt &rndicm on the: ,~,n. AnoJIhcr filep thlot may be taken is 5il.e 1!l\( lusion (Jot; • ~1'I1Cti,," chrom~tDiI"'.phy. and -lilt excluMoo clJro. m.ltognphy_llM: protein frael"""':u-e simply collecled "'bert they dute from the Cl')Iumn .nd ...., roncmtnlil!d and for QoCtiv i,y . Sr",ili""/",, mod J.",.... /ati(lft . This Mep I:lln be lIIXOmpli;bal by uhtafiltllllion 10 n:fOO''C PYrogcns or by he""1IJ if the ~ teln Qn ... ilhstand Ihli. ForrnubllOO milhl involve Itt. :t II lion inlO !>table 5OIuuons for adm,n islr:l1ion or delcrmminl Ill! opumum oonditiool for !>tab,t" y '-'hen summlti", for cllm
as.
•
Inal,.
Complicating facton mciude (a) proteins unfolding illlO an inactive conformation during po ocusing (il may 00l be possible to refold the protein correctly) and (h) proteasc:s tNt are commonly produced by bacterial. yeasl. and mammahM cells. which may partially degrade ,lit protein.
Chupll'r (; • RIf)In:h""logy WN1 OrMII OI.Icu,·u,.
ftlARMACWncs OF RECOMBINANT DNA _I-PRODUCED AGENTS Di~
,,.,
illCrbtJlb h.t>e fac1lilllled the production of "ery pure, ill)' u'o('ful proIeins, 10e physicochemical and ~11I.'tl J!IOPCnie8 of l!lese agen!' are [hose of pro..... h.:h mean.> that rhJ'mac:i~l~ must undeOitllnd the . . . ~ IMIl lilt chm1iS1ty of inSUlbility) of proteins 10 . ., 'pll(. dio;pense. reoonslilule. and admml~tet' thcq ,.... (i:ru~. In~labllllies amollg proIci ns may be physical • . ;aI. In lhe fonner case. lhe proIein might stick 10 __ \~I\ or Oocculllie. altering lhe dose lhat lhe patienl ~>t In the lalla casc. dICmICal reaction~ taking ,we 00 IhI: protrtn may alII." the type or slerco(:hcU)i\lf)' "1IIt;mu1lO lCid~. dmnge the position of diwlfide bollds, Ib.o I~PUJe ch.:IJl15 themsc:h~s, and "Iter the charge ofli1c proICm. Any oflhese can cause unfolding lion) of the proI~in and In,s of activity. rendering ., molecule usc-ic-)s as a drug. Chcmieal instability call be I dunnl the puriraclllion staid of a proIe;n .... hen D>b:ult mlctn be subp:led to acids or ba.~. bul in~lJI ) ~kI oceUI al the point of admini,tmtion when. for
*
.
ro:;'~ ~~'" ,,~"'
.
1l1c pharn\;!· I fl OOIICepiS of the chemical and rmulKhtyof proIcms to predici and il:mUlc potential
"
• H ...... H) ... "h mi~tul'e'I of L· and D ,11:001 confi,unllOIl> The n:tlC'loon hould he ClpeocIro. the Mab,li:y of lhe carb:on...1lIIIruI. the "lie of tho: "'''''lion. Asp, which unde'llClCS ~~.¥KIII 'III • cydoc rml(ir:: mtel IIIuco-.'try
s.:.nautrn, the first recombin:lnl prepar.uion, imroductd 1985. rontIJlIS the natural 191 -aminQ add primary.'iCpI~1 one ~_~~~oo~ yl midlK' on the N-tenninal tnd. all cootain tbe 19 t ·amil1() add :Ie' wlIh tI'Ie hGH produced by the pilu;-
••10
~~"'~'i_~;~~im~.~nSlOnal with mostcrystal of its structure nOllpolnr show, amino
~
toward the interior of the mole-
I identical wilh IIlItunl]
";,.;l,yophi. tee Typi· :.~~,~poWdercd i good. If Slorcd at 2 10 sl cell harbonng the virus (Fil . 6-13). IntcTferoru then induce a state of I',ral resIstance in cells in the immediate I·ieinity. preventing s~ad of the virus. AdoJitiooally. interferoos induce a CllScade of antivlrnl proteins from the target cell. C. 1M. onr",_
""1"""1<
R· I,if
,'lIion 17, :1$ docs the nam-e molecule, Naturaj IFN ,,B and interferon beta- I a are glyc()II~'\U:d th:u the vials be ,hnwc:d In a rdTlgCr1llOf at ~ WIf(' for Ie" than 24 !loot('ntion of sc'ere:
1upcnia. It reduces the IltCd for platclet transfu&I\rr m)do'Ml~'''e chemotherupy in patlenlS wilh ... ekIId malignancies" ho are al high risl; for severe:
...
thromboc)topema. EflicllCY h.;\l, been den)()l1Stmled m persons "hu ha"e e\pcnenccd 'it"ere thromboc)topenla (01. Io","g a pt"e\'lOU( chemotherapy cycle. Opn:h'elm cau~ many ad,'el"!il" re:llCIIClnS. Among these IU"e edema. neutropenic fe\er. headache. n:lusca and/or ,omiting. dY'PIlea. and tach) cardia. PallentS must be momlorcd clotiely. Oprcr. ekin i~ ,uppl ied 1'~ a Iyophi li/.c:d pu\\'der for reconstitution . E~eipients Include glycine hnd pho~phnlc buffer componenl'. TIle puwdc:r has a shelf life of 24 month s. It should be stotCd al 2 10 8"C. If it is frolen. thaw it before /l'CQfhtllulion.
Tumor Necrosis FKtor (RecombinanQ.'J.J· lJs
11le TNF\ (Elancrcepl. Enbrel) lire: member> of a family of cylolines that 1U"t produced pnmarily in the innal~ Immune ~y§ tem by acti,·ated mononuclear phagocytcs. Along wi th ILl. TNF is typICall y the first cytol.inc 10 be: prodocetl upon infection. and liS rcact;OOIi can be both positive :l.IId negali~e. On the one hand. TNF can cau~ cytOloxiCl ty and ;nnanU1l3 lion. nnd on lhe other h:md. II servcs as a ~ignallo the lIdapl i\'e irn rnuII~ rc~punse. The TNI'~ are ull endol:lenou~ pyro~cl1s. and Ihc) cnllSt chill s. fe,er. and nu-like ~ympt oms. There arc IWO fonn, ofTNF: TNF-a(coc/ic(;lIn) and TNFp (1ymphotol ;n ). 80th bind to the same rc:cc:plOr and cau~ (Imilar tffec1.~. Elalll.-rcept is a d,meric fllSlon proIe'n COIlS"Ung of the Cllr..ccllular ligand-b1llding portion of the hunlan 75-kOa (p75) TNF fe'('('ptor (TNFRJ hnled 10 the Fc portion of human 'SO/ ypc IgG " 11le Fc component of tlilnercept contains theCH: dom:un. the CIl, domain. and lhe htnge region. btu 001 the C H I dom.ain of IgG I. lbesc re:a;'on~ 11K rcspunst· ble for the biological effccts o( immunoglobulins. Etancrccpt is produ(:ed In rec:umbmanl C HO cullul\'~. II OO/I""ts of II peplidc cham of 934 31111110 acids and has a nlO]eO that tIM: rrucc" of regeneration can bf:,gin. Normally Ihl s process is highly localil.cd 10 the damaged reg'on. so thai
the: hc:mO/llullc rc.:e doe~ nul cauloC Ihrombi to migrate to dl~tl1lll 5l te~ or pen.I'e al:IS dil'tttly ",. catalY-li ng the cleavage of plasminogen and i niliating Ih l'Qlllbolysis.. It halo high thrombolytic pot~ncy. A compamon at nltepla!i(' and releplase IS gin'n in T able 6-9. Tenecteplas~. 'J7
Tcnect~plu.'ie
is a IPA produced b) recombinant C HO ~.... II,. The molecule is a 527-amino a.ctd glyoopl"Olci n t1cvelopcd hy inlrooocing lilt fol lowi ng modifi· cations 10 the: c DN A eonSlllK.': Thrl1>l 10 Asp. ASPIIl IO GIn, boI:h w.lhin lhe kringle-l domain. and a tctraalarulll: su~i lar ion 31 I mino ocids 296 10 299 In the: protease d0main. llx: drug is a Sterile. Iyoptuhud po ....dc:r ICCOiUmended for si ngle intmn'notIs bolas !ItIml nislralion ann ~ conSlilu rion wilh ' Ierilc water. TCrlCCtepla'iC shou ld bt administered immedl alely after n:cooMilUrion .
Factor VIII.'''
Anlihemophi lic fKlor VIII (n::cornI!Inant ). ROCOftlbinaiC. Kogen:ttc. Blot ille. Helixale... I plasma protei n Ih~1 functions in the normal b.Jood-c1oru1ll eascade by increasing the V mo, for lhe actl, arion of dotlJI'f factor X by factor IXa In lilt presence of calcium ion!,mJ negatively ch~rged phospholipids. FaclOr VIII IS used 111 tb: In:alml'm of hcmophlha A. Hcmophilia A is a COI1gt'1IIIIl disorder characteriled by bleed;n!!:. 11M: mtroduction off~· lor VIII as I drug has Improved the qualn y of life and tb: life ClIpect.ancy of Individuals .... illl thl ' disorder. Unfor1llnately. ir has been ncccssary 10 re ly 00 an unsure SOUfa (human plasma) for rhe fill-"lor. Exposure of palien", 10 alloant igens and vi ru ses hps b..'C n a conccrn. F:lCtOf VIII dcnllll from a recombl nam SOUrtt .... ill poIcnti~lIy eliminate of these problems and proVide an c:ssc:nrially unlinllled Mpply o f the: drug. F3Clor VII1 is biosynrhesiLL'd as a ~ingle-chail1 polYPI? lide of2.332 am ino acids. The protein i~ very he~\'ily ,1)\'1). s)' lalcd. Short ly ofler biosy1llhc:sis. peptide cleav age I)CC\I\ ol"ld pl asma fal:tor VIII cil\"ulatcs a~ an SO·lOa light chM associated .... irh a series of heavy chai"~ of appro~imatd? 210 kDa 111 a mellli Ion-stabih led COOlplU . FacIO!" VIII put'iCW'S 2.5 potenlial N-Itnked gl)'CQ'iy lalion suc;s and 22 c,. re~idllCS. TIll: 21().k Da ht-avy chain is further clea\ed II! protease, 10 yie ld a kinetlc ' . rll mete r
t:n..ct'IIiOc~, The molccu l:lr mass of the mole· cule i~ about 29 kDa. D~Ase I i~ an cnOOnucleao;c lhal clca,·('1; double·\lrnnded DNA (and to '>(llnC Ulcnt t!. . All opposilc SIrdlcgy ntlghL be ronsiden:!d for the lreatment Qf c.aoccr. llhereby tr~nsplumed cells ~-ould be used 10 target cancer cells. Inrn:asing loclIl cell·mediated Immune reo;porucs. 1lie trun~fer of gcnes from Ol1C organbm 10 IUlOIhcr i~ termed tnulJgrmcs•• nd an anImal lnal has r"CCe1\'ed such a IflInsgcne is referred to as a trtllugrnic flrtinllli. If the transgenc IS Incorpor-.otcd IntO the grrm cells (eggs and sprrm). il II ill be inhtriled and JXI~ on to socceMive gencrdt ioos. If the Imnsgcnc i~ Il14--orporated into other cells of lhe body (somatiC crlls}. It ....·i ll be expressed only as long as the IlCwly ~'rcatcd Ir:Uls~nic ~-.: lI s are alive. Hence. if a tcm,inally dlff~'TCnnated. poo;utulotic cell recehcs a tfllnsgenc it will 11001 undergo furthl.'r cell diVIsion. wlK-rell~ If a trnnsgellC i~ crellted III an undllTcn"ntlated ~tem cell. the prodUCI .... ,11 continuoosly be upresse;i in new cells.
,roc:
AFTERWORD C ltarly. biot~hnology has becoI'Iwe lUI inlcgr.iI part of pilar. lllaCcutical care. l>tlarm:tCisl~ need to become comfurtablt with biotechnology and II!. languOIge to delher thi ~ kind rJ care 10 lheir patient!;. 1'1tis ~haplcr has tried to preM'nt II! OH'r\I;eW Qf the major biOle..:hoologlcal arenas present i. the lear 2003. 11lc: field i~ a!hllncing rnpidly. lind elety phJn naci~1 must . ta y current with the litC'T'll1ure on biolecfo. nology.
Acknowledgments PontOns of thiS Chapter lIlcludeli matenal from lhe kntb edit iOil chap4tr by John W. Regan. The author b grnlcflll for the U'iC of Ihis conlent.
REFEREN CES I NCIIL. NUl. NlII. lI.d......... MD 20894 C·II\II,'
"'ruG'.........
ft,h ......
2. ikn...... O 3_ Gen8anl..
'OI'.lIimt ~
~
RcoaIdo ..aM... ~f.......... A ~_oation_ ,""",. MtdJ.
"'...... ,n BIOIe·~'R. Ii C T",,""'~. lle:.lth cw. ~ 1I1~ 133. t99l\ 10. SIC ..." . C F. and ~lcnu .... R A: Am I I .....r I'IIarm 46( II s."I 21:5-' -SIl. 1'189 21 Tonti. J.• O/IIJ Ih""•. R I' t~,..,."P} 16(4):527- '36. I n . Kooll_ J I/oop PIIlInn.
~ 1(8)
t7Y1--t7M. 1990.
7.ano .. S. A. CIIIT CChtjliO ' ...... I'IIalJ. w.o lIId Wallcd... p .nAlu ~.S Am Ph:wm.NSI'o(II)'_9.1'19S j.I, (jI"L, B It.. MIl I'tio1 MoIf I, B,o"ham\llCetuiQI Dru, 0.:..", ... T _ .. NI. lIu"""", PrnOI. 1999. pp 39-Ml lit> I'~U •• P L.. ~_ iii Mok....l ... 1I>01of)' Bo!.IooI. WCB M~On" Ihll . 191\11. I'P In_n~ n. RUJon.,l ul. Y.. l)oUa. S.- In w"~Pt"'I. S. 1I1)j......... ul. Y I""s.!. U"'JIhiwnUlCtul",.1 Ono, D ..... II R I..... ) 11 ,,,,«,,,,,,,,'1,) ..... I'hIm>ac) "' .... YOIt.. 1991. PI'- l2~ ·In I',""", IOId C'>mf'IU1""'" 51 1.00... MO ...."', ..... CI"..,...., ........ 2000. pp. 287,290 "'''''''''IID " "'p',.1 ")"nulary SC .... iWk ,n Moj..,,,(ao Ihol"" '>n ... I"",,,,,,,,,,,,,, ON". SI. Lou ... MO. I'''''tr. and C.lftlpan ...... 2flO2. 1'1' ~11 and ''''~ 11Ic~,n VoIioli.. O.. dal. :AnnOnrol IH' ):9~- loo.2000. IJnbr:ruIC'ft. I O. (Omc: \0 form /JluJgmyso·
ErythrOqttH .nd P~"'''
New St.m Celli
7' 1 1
"""".
A4ymmetric /
I
My.101d Br.nch
Ptur!pot. nt "" Stem C.1Is
"-
I """.h...
:--
G,.nulocylO
L _"
/
•
/
L,.....""kI
.'.Mh
"-
•\IIropnl ~
TL~H
?
?
N.tur.1 Klier Cd
Scheme 7- 1 • LIfl&lgeS of blood cell~, AJI blood cells denYe from a piur lpoleol stem cell. A vallet)' of cytok,nes direct the cells ,nto the'r specific popula\lons
S()flU's.
'The antimicrobial rompourld~ in lhe phagosome~ and
1)'!IOS()me!; kill lhe rngutred palhogen and coL)'maucally clea\'(: its ",m::nll!l into !>ITIalier pieces,
EosI_phlisS Eosinopllll~ 3'" ~yte,. but much
gr.mulocY Ie!; Ihal can function II:> pha!Oless effieientl), than IICutrophiis un. They arc: pn:scnt as 2 10 4% of blood lell~ocyle~ , Their name deri yc,s from the in tense Slaining I'l:OCll00 uf lhclr Inlmcellu· lar gnmult~ with the dyt eo,in, ~i nuphil gr.mulc) con tain IIlnRmmatoty med,atOrll such a~ hi,t~ lninc ~nd lcu ~OIricrleS. SO 11 makes sense that !hee. Clues to the funcuon\ of OCISinophilsCQIfIC from thei r behavior in certain di!>('a;.e ~t ate'. Eos inophil counts a", clevated aoo\'c IlUflIlaI In me ussuc~ In many dlffe",nt di'leases. but they are rels. Eosinopllils can physically ~urroond a large paras lie. fonmng a cell ~()Ut around the invlkler. E~inophil grllnole~ rclen., e o\idal ;"... ,ub Ibr ma,t «-II tu ". Ikcause of IlIlIbilizmg units. 1be general ~tlUClure of tlte Ig looks ';';"nllt~e a Y..... nh lite antlgen-bm(itng regions :;Itlhe Wlllnltd tOO. In Ihis area arc peptKle sequences that ore "~blc" by (he immune ~ystem to allow lhe Ig II) IIlX1pue Dlarge number of anligc n~. TJt~ment .... ith either of IWO cn/ymes. papain Of pe~in.
\ ....."""/'.
J
I~
b'_ "·"·
;I •
I
J
Fig ure 1- 4 • ClassICal (ompllmoe-rlI
palhw~
AnIigeo' B do", RegIoo. (Fab)
Fe Regioo'
V.-IabIe R""",os
Figure 1- 5 • Structure of ,mmuoogJobullll G OgGl. showong an!lgen-blnd,"'9 regoons ¥III ttey of the rnoleculr
Tlt'atmcnt of the same Ab with pepsin yicld~ the two Fab units JoillCd hy the disulfide bond. plus t\\oo of the diStal peptide chains. Thesc distal units havc been crystaJl il.ed ~nd. hence. are temll"d the R: fragmcnt (fOl" '"cryMallllable'"). The disulfide bond. thelt'fore, provides a demarcation between the two molecular rcgiOlls. The oomellClature of an Ab includes a hlgh-molccular-\\o·eight. 01" heavy. chai n on the inside and II low-molecular-weight. 01" Ioght. chain on the OtJI.Mdc.
elemen~
incorporJl.e them IntO their cytoplasm ... here the anllgens_ fragmented. The fl""JgllocnlS an: then combillCd with MHC· 11. di~played on the cell membrane of the macrophage. aDd presented 10 the immunc sy5lcm. The presented anlip interact with B cells. causing differentiation to plllsma alb and Ab 5eC1\'t1on. T-helpcr celLs also interact with the 1ft"" sented antigen and arc stimulated to cause the B cells ko proliferate and mature. Plasma cells an: monoclonal (genttocally identical) lind produce monoclonal Ab. The pn:I«N.
tMPOfITANT FEATURES Of ANTIBODY MOLECULAR STRUCTURE·' , As 'lUted above. the tip end of the Fab region bind~ ant igen. Then: an: tWO of I~ regiom. tful. puttm!! labora· tory technici:ms at n~k: and (d) the pallent may upcnellC' abnonnal and h:lnnfu l ll.'''ponsts. such ill> fe. cr. oon.-ulslOns. and death. These \"X"C"lnes t)pocaJ ly arr \'iewed Wi ··dln)·· vaccines. and .;orne. hl.e the pcnu.'i..~is \liCCine. h:l~e bc:c:n associalcd " .th probkms ~rious enough 10 ..·ltrJm their tcmpor.lty rem()\:!1 from the mart et.
Uve/Attenuated Pathogens. The word /II"mrmrd fur oo r purpose$ .~ill1ply nocun§ ·· Iow vlrulcnce:' The true palhogen i~ a he~d phcllOlypicaUy so that it cannot ill"adc the hUlllDn ho~t ulO cunliOl gel ahead of Ihe ho~"s illll1l1111C system. 1.(lw·pathogen icity 'it,..ins such as these were ongi· nally obtained by passage uf the IIIkrul:lt'~ thrvugh mallY geoer:uions of hosl anilnals. The jdc,a ...." th:lt lhe animal and the pathogen. if both "ere to su .... ive, needed to adap! 10 Iovc With cach OIher Without either panner bcmll t Illed. Poliovirus IS attenualed in this f3Shion in monkey tidney lissue. In a !i"e!aucllllmed vaccine. allhgcllIcllY is sI11I ",. qu ill.'d. as i~ i llfecti~i ty (polIO vaccine )'idds all InfeclKH1), but Inc: ho!.l·' 1I'lmllllC sy~tcm must be able IU sUly ahead of the mfeclloo. The I.ey problems are: fa) t/w:: '·ac~UIC c.nnOl be u'\ed if the paliclll is Immunocompronll~d, ha, rClCr or m~1 ign nney. or IS taking IInmuoosupprts>ive drugs: (b) IheM! vacci lll:S ~hou ld not be used duri ng preg.nancy: and ft"J the nucn uutcd o rganh m commonly ",'en s to the virulent ~t,..in. which wu~ the: reasoll for the foi lure of .;ome cll(ly polio vaccines. T oday. blologkal quality cootrol i~ 'cry slrlllgelll. and th.c.;c probl.ms ll:I"e been eliminaled. Live/Attenuated Relitled Strain. Il.'latcd ~t ralll is anugenlcally related so that" cnn provide Cf"OS5·,mmllnily to the pathogen. r-orcumple, OO>\poJx viru~ can be u~ In place o f smallpox ' irus. The '\1r~lIlS are !Illt,· gcmcally ~Imllar cnough..o thai the host's munllllC system reacts to the Il.'lalcd SlrDJn to pro,ide proIcctioo agalll,t the 00"",11 pathogen. The maill advant age is thul a true pathogen is not being u'\C:d X ' 1 ~hOI.
~ ~lOCCi""
Paeteml PIMmkI DNA
2. In a "",llIple..Jrui"g oeglfncn. se"cnJ
ReAlction EnOo"""II,.
o
3.
n
"".,.......... aurlace prole ...
- .. ~
InMIt pIatmod .., E ooIi
-:
,
Grow in batch aAllft
of oil
1 .he In,":o1 mult,pIe lirs! pIIl"'"t agc5. ..~ A .... 1... i. immunily. Also. boo!;ters ure usa! if a pallenl i, lion schrdulc
// 0 L/
Prep.JfolltlOfl
h""_
Types of Dosing.
o
V"'ONA
,th
3. .~" A pQJ>~"lJI~", VIICC" ", i, prcpartd from two or """'" tlla! Catl!oC d,ffen:m di ......••. PoIYI'I.Jem ~1'CdOlCi ore conl-en~. rrilnUlly Ml tlt3t a eMd can 1M: , .."eft nllher than ,",veral. n.. n"ll)l"'-!t!um~ - ",belia (MMItI eu>c: is 0( tIM: poIP"IIlent I) 1'1'.
Vhlt Surfaoo Protein
VlIlIIONA
,.nJ
~
. . ;• •
••
•
I!f\9lneered Ab
i~_
Of
pcaed 10) 1LI,'e mn up'en: infcct, on. Thi s phenomenon is known as pmtpolio muscle atrophy (PPM A). PPMA i~ oot a rein fection or reactivation of the virus but I~ prob;lbl y a fonn of rapid agi ng m polio su ..... hors. There are t ... o types of polio v1lC"Cmes. Inactivated Polio Vacci". (IPV). Thcreare severnl 5ynOII}'ms for the IPV "accine: IPV , e- IPV. e p-IPV. and the Sal ~ vaccine (l9~4 [I POL. Alcnus- Pastellr l). e- l rV is an enhanced potency poliov irus. ITIOf"e potent and immuoogenic than any of the previous IPV formulations. e·I PV is ,ecommended for all four infant doses because of lhe incidence of rare CIIS('S of orul pol io vlICeine (Or V)-as...ociated paralytic POhOnl)'ditis. e·l r V i~ also preferred for adults for the '>ame rea!iO!l. IPV is a tri valent (,troins I. 2. 3) voecine gro...·n in monkey kidney cu ltu re and subjected to elaborate preCllutiom; to en'illre inactivation (typicall y, f0ll11aldeil yde is used). llll' anllgen fonn is .... hoIe virus. 111e anugen type is protci n. The v1lC"CUlC is IllJCCted to CIlUse Induction of IICti ve systemic immllnity from pIio 001 does not Stop polio cafriers. "'00 shed lhe virus from lhe om! and nasal cavitie!>.
Trivalent Oral Polio Vaccine (TOPV). rol'V (Sabin I·accine. 19(0) ,s a Ih'c altcnnated whole virus vaccine (lntigen type. proIein) eoolilining polio straios I. 2. and J. The virus culture is grown o n monkey kidney t i~sue witll lise of an elabor.lle allenllatioo proIocol. Oml adminisu1I.tioo of the "acclne yields I local G I infectIOn. and the initial Immune response is via lilA (mueosal. local to the GI tract). llIe Ig A- ant igen complex undergoes tmnSCytosi~ IICrob the mllmsaJ memoone. and sy~temie immun ity is induced as IgM and IgG form . A nlajor caution with TOPV is tllat it is a li ve val."(;inc und mu st never be injcct~'d . Ind icatioll~ an: o Mas. >7IfXmauon eampail'lS to control OUtbn:w of pual}11C polio. o Cn"lICI;"inalW chi~n ... hoc) will tra~cI in k)~ th;In 4 ...·IIC~' 10 arelIII ... ""re polio ... enderruc. o Ch,ldrm of ~nts "'00 00 not aooepI tM rn:om!llC"Oded IlIImbc:r of vattmc: injecuon!. 11lesc children may ."o",·e OPV only for lhe Ihull or fourth do!io: or both. In ~uch ca§C$. the b:'ahll ~ pnwillo" .w-.ould .mun'Sier OPV only after IitSCIIS~ nll !he ri.\k of OPV_ IL'l.WJC,atl,d p;lnIl)·tlC poIiomydlll' ... ,th paretlt~ or curellJvcrs. • t- IPV it m;(Nnnoen such as ...·eltbn and loc alized oulbreaks. Ou tbreuks are vcry eom mon I! neighborhoods lind schools. One of 10 ehildR.'n contractl~ measles will de\'elop an ~ar infection Of pneumonia. Measb mlly infcct the bnun (eoccphali tis) and lead to cunvu ls.ton$. hearing I~. and Illental di5.abil ity. In the United Statb-l of every SOO to 10.000 chi ldren controcting mea.~les dies
J .,
,,'"
.x.-m: ~Klneu
and death are more COIllI1l(M1 in ".0IIId .lullli tb.:m in elellX'nlllJ}' schoolc hild ren or lten~ Maos~ bas been Jinkt'dlo multiple sc leros is. In 1917. ICme epilkmlC occurrW in tnc: United Stales. and 50,000 "0\' rtpJrIw. Only 60% of tile popu laliun was Yace;· II.
vaoxinc is romposcd or live!:luenlWW meask~ . . I) grown on chick embryo culture with an auenun·
Ino:llcatiQns are •
~,,1IIdU:'bOn of lIC't,ve munum.), IIj!lllnlll. mc~1n ~'"'~.
. 1~ ...I... MMR '~I~
i,tllt I'rdel1l'd immuomng form for _ d1aldron and o,:my aduhi. • AI_ .U chiOJllCn ~nd many !ldulls ~ui~ moll: than one M..t \LI,JR. • f'rg 10 lOItiioatMJol;lllrl~l. prnons ,u'lCel'l.lblo: 10 _n y 0( the ,. .. ,..., Poiold ~Ive tM l ingle-anl'gen ,'XC'IIC OI'.he ~ . . ."XCI..... ~.
_+
Ita,-"
• \Ii>II paM*> bam bd.n 1956 arc Iolel) 10 ~o:d ..-.II)' lind an: IlOl ronsldemi JU~p"ble • fb . . to:n afIer 19:16 0I'th!Ke ,,110 tack ~ua!e donImcn,j 1u"o,1ud the dl'C'ase 5hou ld Ix: Va0 ron: uposoJ to ~hlC ~ enpCl to """eh ·e vlricCU.·I.."lcr immune ,Iobulln (VZIG). • In eklcrly ~rson~. vlII"icell~ vactlllC: can boc:JM Immllnny to varicella·ro>ter '·I!'US and ..... y pre,·tnt or attcnuate herpes lOS""'" (~,ngb) IIIlXh.
HEPATInS VACO NES-
Hepatitis i.~ a comple:< of diseases that causes fe' cr. naw;ca, abdomillal pain. jau ndlcc. liver faillln:. and tk'ath. lben: an: fi vc clinically 1Cl;0gnized lype' (A, 8 . C, O. and E) .
of
Hepa t itis A Va«iflf!. Hepatnis A virus (HAV; IO feetious hcpaUtl~) cauSoQ an acute d, sea. _
~_o( ' '''
.. ,.'c ...' ..... 1"'....,,"";.. 00.,.. _
\,,,,,,,, ... '" be Ji ... if IW'"iowIy ' ... R«oo ... , ''II io . . , _ ....... _ _
00-
_o_ po1 /0110111'11. VI.4t No. ... 12,0eIMg 10 boost the ability lhe 10 TCSiSl the infection. In adults. dm:c doses should be .~'II O. I. and 6 months. In c llildo: n. the vacl.'iroe h give n MIt. I mlollth. and 9 lIIonths. AdPl1in istr~tiOC"nUJisls ' ·a.ccine has been hillhly l"Olltro'er.;ial in ",,"'Cnt ),eOll"S. The original ,';Jj,,,cinc con~i\tetl of killed pertussis bacil h (B. pertussis) and wa.~ ConSidered somewhal ··dirty." S ide effects such lIS fever and C()fIvuL~iOf1.'li .....e re common, and IK-alth au thorities In Lhc United 5t;lte5. Japan, and the United Kingdom decided Ihat the no;],; of the vaccine out weighed the ri sk of CQIltr.IClinll the di ~ase. In all thrtt of Ihe'\C countries. pertussis VOC"CUIC was removed from the routine imrnuni1.lition schedu les. AlnlQl.t immediatel y. penussis, which had been he ld in ehed, begun 10 occur in epidemics. In 1992. a new vaccine WIIS de"eloped thaI consists of baclerilll fraclions. combi ned wllh teUlnus and diphtheria t010ids. Thi s vaccine. ca lled Acell · lmmuoc. Of DTaP. i~ SlIfe and highly effective and hWi bc:cn added to the routillC inullumzauOll schedule. The VacclllC is adsorbed and is used fOf routine immuniwio n ... the poIY"alent preparation dlphtheria- tctanus-penussi( (DTP) (at 2. 4. 6. and I S months and It 4 to 6 yean). Pcnussis ~lICCinaliOn is recommended for nlO!il children . There i~ abo a dlphthcria-Iet:mus-pcrtu ~sis whole-cell pertussis vllcdne (DT.... P ) 00 the martel. but il Is considered to be higher in si(k effects Ihan DTaP. Lastl y. a DTapnlib vaccine prepar.ulon IS on the mw1.;et and is recollllllCnded fOf U!oC only Ib the fourth dol. E. e.. 0fId "II .... M I Setnln. Virol 4213_1~3. 19'H 38. Hl 1es1 cu ltures of Swplrylococ..us /IUIl'II$) incrcase •iIt molecular w('ighl until the 8 !I:niary. Ot-spi(e thi ~ filet, 2-prol).]rlo l (i~o I~!"'~)I alcohol) is used commercially in~lcad of lI -prop),1 7': ,b«ausc It is less e.l:pensi~c. lloOpIUpyl alcohol is y ~ acth'e (han cthyl alcohol against vegetati~'e _'Will £l'OYo lh, but both alcohols are large ly ineffective spoies. The: acti"i!), of alcohols againsl microorga· I) due to the abili!)' of alcohol, (0. denature important and carbohydrates.
IkoItoI.
Ethanol (eth) 1 1l1roho1. wine spiri t) is a • roIoticss, volatile liq uid wilh a burn ing ta~te and a
USP.
characlCrislic pka~nt odor. It is flammable, miscible lIo'Uh water in all proport ionS. and sol uble in fflO5t OI'Xalllc $01vents, CommercIal ethanol coolUins -9SSf> ethallOl by \'01· ume. Thi s concenlr,lI ion fonns an a1.C01rope w,lh I'o ;Ucr th:u wSliIls al 1S.re. Alcohol has been known for centuries as a product of fcml('ntation from gr.!in and man)' OIller carboh)drates. E!h:mo l ~ Dn also be prepared s),nthetica ll y by the sulfuric add -cDlIllYlCd hydrntion of clhylelle The commcrce in. lind uo;c of. alrollol in the Unitcd StDtes is strictly cont rolled by thc Treasury Dcp;lrtmc m, y.hlch ha.~ provided lhe folloy. Ing definit ion for "alcohol": "The Icnn a/co.hol mcans tnal substance known as ethy l alcohol. hy· drated oxide of elh) I. or spint of wine. from ,,'hatel'cr source or wl!:u e\'cr proces.~ produced.. havlIIg a proof of 160 or mon: and not inc ludmg the substances commonly t oown as whiskey, brandy, rum. or gin ," ~,,(lfur~d alcohol IS cthanolthat has been renderro unfit for usc In IIIto.Xicah ng be\'crngcs by tM add ition of othc:r subsianccs. Co",p/~/"')' '/f'nlllu rro o/",hv/ COl'lIalll~ added wood alcohol (methanol) and benune and I~ ul\$ullablc for either internal or extcrnal use. S~f'iall\' ilcllllIr"f'd alt;tJho/ i ~ cthanol trealed with one or more Sub~lanCe' !IO th~1 its usc may be perrnitled for a speda lb:ed purpose. Ex amples are iodin.c in alco.hol for lincture of iodine. I1IClhanol, unu OIlier substances in mouthwashes and aftt'r..lmve 101iuns. and nICthanol in akohol for preparing plant utracts. The: pn mary medi Cinal usc o.f alcohol is utcrnal, as an anliseptlc. prt-'iCn'a!i"e. mild coullicrirri!ant. or sol"em. Rubbing alcohol is u'lCd as an astring('nl, robefacicm , and • mild local II.fICSlhelic, lllc anesthetic effect is due 10 the eVap0r3ti"e refrig('runt aclion of alcohol "hen appl i('d 10 tIM: skin, Ethanol ha~ c\'en been mjec!ed ncar flC'nc\ and &angha 10. allev iate pain, Ii has a low narc()lic pOIency and has been used inlemall y in diluted form a.~ II mild sedallve. a ",('ak "asodil ator. and a elll1n;nut;\·e. Alcohol i~ nICluOOli7.Cd in lhe human body by a "-
toxicit) in mfants bathed ill hexachlorophene and in bum pouents deansed wnh the agenl prompled the FDA to ban its us(: in over-the-counter (OTC) anu>eptic and cosmetic prepanuions. IO HexlIChloropnene is still avai lablc by preSoCnpl ion.
Cresol. NF. !llenc
•'Crrsor' IS IICluall) a mhwre of l!tree iso-
methylplll;'llol~:
Eugenol, USP,
4-Allyl-2-llIclho~yphcnol
is obtained pnmarily from clo,'c o il. It ill a pule )'ellow liquid .... lIh I 'ItOng atOnia of cloves and II pungem taste. Eugenol I~ onI) ~hghlly '\Oluble in .... ater but i~ miscible .... ilh alcohol IlnII othet" organic !I01I·enls. Eugenol possesses both local IDC>Ihetic and antio;cptic attivity and can he directly apphed a. I piece of COitOO 10 I'l'Jieve tOO4h:1chc~. Eugenol is also uSC\l in mouth .... ashes because of i.." anusepck propcny and ~ ant tast~. 1llc phcool coeffieicnt of eugenol i~ 14-",.
OH OH
I
EogeooI
H,
The nll~ t urc OCCUr! as II yello .... to bm",msh-ydlow hquid thai has II charoctcri ~lk: OlIor of cn:Q~ote. Crc~ol i~ obIailled from cool tar or petrolnun by allaline extraction into aque0I1~ medium. lICidllicalion. and fr-.telional dlsullmion. The mixture is Dn ine\pcn~ive anliseplic and disi nfectanl . It pas~se~ a phellol cucfficiem ofZ.5. C~ IS sparingly soluble III wmer. ahboough ukohoh and OIhcr org.ln1C ~I~enl~ will soluhili/.c ii , The drn .... back to it~ U'\e as an anti septic IS its unpleasant odor.
Chlonxresol, NF.
4-Chloro-3-mclhylphenol occur! as coIorldi> cry.~IIII~, Cblorot~ i~ only IIM to gcner~'e o.\ygcn and oxygen rodicals. Other oxl~ asents.. -~
'hit: 'Ulcr
cad'~Hs
CH)(CH;,)n-
I.
N
t
Q'
C2HS
H5
AI the right roncentrntion (the critical
tion). tke molecules concentrnte Dttlle: Interface bctwttl! u.. miSCible solvents. such as water and li pid. and water-in .... or oil-in-watcr emu lsions may be formed with the ammo· mum head group in the wDter layer and the nonpolar hy~ earbon chain assoc iated wi th the oil phase. The ~)"nllnl and IU1timiuobial actions of the member.. of this clau af compouoos were first reported In 1908, but it .... as the pioneering work of Gerhard Domagl; in 1935" lhatlllte.· tion "~.IS directed to thei r u.sefulness as anuscplic~ dislnltc tanlS. and preserv:llh·cs. The cationic surfOCtDnts ucrt a bactericidal action agaillll a broad spectrum ofGrom-positl,·e and Gram-lle,atil"C t.:teria. They are also actm:~ agDin~t scveral pathogenic spme! of fungi and proi07.0II. All ~I)(m:s resist the.se agents. 'Ill! mechanism of octioo probably in\"oh·es dissolution of tIIr surfllClant in co the microbial cell membrnnc. deslabJIi7""" and subsequcnt lysis. The surfacumts may alw interferc1rG enzymes associolCd with the ce ll membralle. The cD llonic surfactants pos!leS!i .severnl OIher IMope'''''' In addition to the ir broad-spectru m antimicrobial actll"'!
not'"
ChlOroazodin Oxychlorosene Sodium. O~ych lorosenc (C lorpactin) is a complex of !he SQ(Iiul1l salt of dodecylbcnzencsul fooic acid and hypochlorous acid. The complex slowly relcases hypochlol'QUs ocill in solution. O~ychloroseneoccun; as an amorphous "t organic solvents. k" used as a preo;avativc. primarily to man! ye:ut grov.·lh. I'rqI) lparnbcn sodium i, a WaICT-M)lublc o;odium sal t of the 4·phcllOl ifOOp. ~ pI I of solutiuns of propylJXI ...Jbcn sodiam IS basic (pll - 10)_
:r· ;r-
o
I3cnl)'1 ~lcOOol (phcnylcarbmol. phcn)lmelhanol ) occurs nalumlly as lhe uneSierified form in oi l of jasmine and in esters of acetic. cinnamic. and henlOic acids in Gum bcnloin, .. tor.!.' ~~in. Peru balsmll. tolu balsam. and some volatile oi ls_ II i ~ w lubk in W'Jler and alcohol and is a cleat' liquid ... i!h an nTOIllatic odor. Scn;tyl lLlcohol is commonl y u...cd us II Pf... ~rvulhe in vial~ of injectable druGS in eonccnl ....!tlOn~ of I to 4'l> in ....ater or saltllC solution_Rcnlyl alcohol h aal admin11 is unstable wbcn heated In aqueou~ solution,
Sod/urn Benzoate, NF.
Sod ium ben100 IC is 0 while cryMallinc MJlid Illal is soluble in water and alcohol. It is u..cd as a preservati \e in acidic l iqUid prt'p.'ltatIOllS in which hcnloic acid IS released,
Sodium Propionate, USP. SodIULn propionate OC'Curs as tmo sp;t~nl colorless crysm ls that ute IIOluble in waler alJd alcohol_ II is an effectiYe allllfungal . n l thai is used as a preservalwe. Sodium propionate is mOoM effa.1h·e at low pH .
Sorbk Acid, NF. 2.4-He"adienoic acid is an effective antifungal preservative. It is sparingly soluble in water and has a pK. of 4.8. Sorbic acid is used 10 prescrve syrups. elixirs. ointments. and Il)(ioll$ con taining n". in pallents on Immunosuppressive ~ and In pm.on~ with AIDS . Oppor1unisl~ can grow in al} e.'(f)' circu m., umce in which a p:1Iienl'5 immune 5Y5' ... is romprorniSt organic solvents. 1lIe greater acidity of salicylic acid and its lower solubil ity in water compare! with p-hydroxybenl.oic liCid an-. the conseqtl('OCe of intramolecu]ar hydrogen bonding.
o ,:Y ~
"".. ••
I
.. ""..
.•
from light b«ause the CQtnpound is photoseru;iun. II ~ progin i~ a,·ailable as a solution and a cn:am. both in a 1'1 COIJC('ntnuion. Iialoprogm is probably 001 the first topICal agent that should be m:OlnllK'nded. While the eore rotcs fOf topical funglll infections are relatively high, they come as a hi gh price. TllC 1c,ion typically Wor5ClI!l bcfOfe it impr aVllilable.
•~ d
a
PHENOLS AND THEIR DERIVATiVeS
Severnl phcools and their dcrivative~ possc,s lOllieal ant ifon· 81,11 propc:rties. Some of tliese, 5"'1'11 U!l hcxyln.'SQrciool s and parncllioromctuxyleool (below) have been ... .;ed for the treat· ment of tinea infections. T wo pheool ic CQmpounds, cl ioqui· 001 and haJoprogin. ~ still official In the US P. A third agent, ciclopirox olamine . is 001 a phenol btu ha..~ propcnies like tllosc or phenols.. All of these: agell ts IIptlCaJ" to interfere WIth cell membrane integrit y and f ... octlon in s... Sttpliblc fungi .
H
Cidopirox OIClmln., USp.1S 6-Cydohcxyl. !·h)!WlIOyl ...... rnethyl.2(IIl).pyridioonc: ethanolamine salt (Lorro"o' is a broad· spectrum anlifungal agenl intended only for .... caluSt'. It is active Aiamsi derm:lIopnytcs as .... ell as petIt.Igenie yeast.'i (c. albic-mrs) thai :Ill: c;l.Usali\e allents for wpn. rlCial fongal infections.
,OH
H. loprogin, USP.
J.. lodo-2.propynyl.2.4,S.trichlorophm)l ether (Halotex) crystallizes as .... hite to pale yellow foo lib that are sparingly soluble 111 WAter and very .'IOlobl(' in ethanol. It IS lUI ethereal defh·ati,·c of a phenol. Haloprogin is o~ as A I'it; cream for the treatment of ~upt:rfK:ialtinea infections. Formulations of haloprogin shou ld be protected
Cidopirox i ~ coo)idercd all agent or ehoice tn tht lINment of eotaneous candidiasis. linea corpori s. unca ~ tinea pedis. and tinea versicolor. It is a !>eCOnd·1ine lIP lhe trenlme nt or onychomycosis (.;ng.....ol"ll1 of the Loproll is rorm\lllllcd as a cream and II 100ion. ellCh
"H
III 1'10 of the WlIIer-wluhle cthanolamille ~Jt_ Ciclopirox I btlJe,ed 10 act on cell membranes of wscepuble fungI at .... ronccntr.III011S 10 block the Ir.UlSpon o f ammo acids 11110
lie ccll~. At higher 1.:onccmtrluions.
lIIembr~1lC'
.nlegrity is
and cellular cooSiduems leal 011\.
llludeos ift Antthlngals Flucytotlne, USP.x S-Fluorucytositle. 5-FC, 4·um;noHuoro- 2( III )·pyri milli none, 2- hydrox y-4 -urn i n{)- S-n uorop)nmidinc (An.:obon). 5- F1uorocyu>sine IS an UrdU )' active
.. rungal agent with a w:ry narrow ~1)C(:trum of act;v;ty. [t II illlllcaltd only for the treatment of serious systemic infcc_;~~;u~d by sUinc t1a.~ been -::~ 10 dew] and is prescnLed ill Figure g·3. n.c dru g ~ !he fungpJ cell by acth'e IIlUlSpon 00 ATPases thai II)' lr.ln'fJOf1 pynmldines. Once inSlik the cdl. 5-l1uork)1OU1lC I~ dl:aminated in 11 reaction caullp.oo by t")105ilM.' .1Ib" to yield j·nuorooracil (j·AJ). j·Auorouracil is tit 1CI1,"e metabohte of lhe drug. 5-"'uorourucil eml.'rs inlO 11}\ of boch ribonucloolide and dcollynbonuc1eotide ~~ 1"hr; nLK)f'llli bonucleoude triphosphale5 an. incorinlO RNA. causi ng fnu lly RNA synthe~I~. This pmh· (1~~ ce ll death. In the dcollynbonucleotide !ierie.~. 5· ~yuridine monophosphate (f.·d UMP) blllds to S,1(l.mclli}lcllclctl1lhydrofol ic aci d. intemlpting tile one· cabon pool su bstrnlc thai feeds thymi dylutc sy nthesis. ht. DNA synthesi s is blockoo. Ilni\lance 10 5· r-C is \'1.'1)' COIllIIlQll. attd il occurs ~ t a
The
mecl1an i~ m
POLYENE5
A numbc!r of structurally compleJI. anlifungalltnllbiOlics ha,'e been i""laled from soli bai;:tCrla of Iht.- genus Srrtpmm)"ces. The compounds an. ~lmi1ar, in thai tlley corlliun a system of conjugated double bonds In mllCTUCydil: lactone rings. They differ from the erythromycin-Iype structures (rnacrohde\: see Ch.'\plcr 10). in thai they an: largeT and conlain the conJu· ga ted ~11t' ~yste Jll of double boods. Hencc. they nil! callet1 the /1OI)"t'II(' ulilibimiC"S. The c linica ll y useful polyellC's fnll into tWO groupings on tile basis of the si1.c of the macrolidtl ring. The 26- rnclllbcrcd ·rin g polyenes. ~uc h a! IlI1lalllycin (pima ricin). fonn one gl'Ollp .... hil e the 38·membcred macrocycle~. such lIS amphotericin B and nysto!ill. fom! the other group. Al'iO common to the polycoe.~ are (u ) a stiles
OFU", -
SFC~
-J.+.
_.
5FUDP -
5-fUTP
.
5·FdUOP ___ 5-FdUTP
\ SFC. - -- "
"'U
I 5FdUMP -
Inhibitory
CoIlfllex dUMP
OTMP
• treat-
cruri\. cnt f~'If n:1II\).
;mla; n-
5,lo-Melhytene-THF
7,B-DHF
136
Wil.oon aM Gm'Old'J Twbook
of O"6Mk MttlkirtllllPld PllamJUCtu,;rol
of hydroxyl groups 00 the acid-dcri ved portion of t/we rin~ and (b) a glycosidicaJly linked deo~yaminohe~O$C called ml'COS{lIl11nt. The: number of double boods in the macrocydk: ring dlffer1 also. Nautmyci n. lhe snuUlesl mllL'roCyck. is • pcmaene: nystatin is II. hexlIC'ne: and amphoferici n B is a hep!3C:ne. The poIyenes ha,'e no lClivity agaill5t bacteria. rict eHs ia. or viruses. oot they are highly potent. !)road-spectrum antirunga l lI.h~nUl. Thocy 00 have activity a~ainSI cenam pratowa. such as Ltishmllniu ~pp. They are effective against patbogenk yeasts. molds. and derm:uophytes. Low COfKCTl' Iflllion5 of the polyenes in Vi trO will inhibit Candida spp.. Coccidioidu immiliJ. CryP'OC/ICC" J ntojomums. Hump/llJmt' r upsufalum, Bl/J.JlomyctS dtnruJlilidis. Mucor mllCtdo, ;'spt'gi/l..s jwniglJllU, CtpMloJporium spp., and FllSorium spp.
The use of the polyeoes (or the Ul'atmetlt o ( systemic infections tS limited by the toxicities of the dru gs. their low water solubilities, and their poor chemlcaJ stabilnia;. Amphotencin B. the only polyene usefu l for the treatment of serious systemic tnfectioos.. must be: solubi lized wi th a deter· gent, The IXher polyeoes are irldi cat~'d only a.~ topical agents for superficial fungal in fections . The mechamsm of aC1ion of the polyenes has been studied in some detail. Because of their three-dimensional shape. a barrel·hte oonpolar struclLlre capped by a polar group (the sugar). they penetrate the fungal cell membr.mc. acti ng 8!l "false membnne components." and bind close ly with cr· gmterol. causing membr.11IC disruption. cessatIon of membronc enzyme actI vity. and /Q$s of cel lu larconsti tu.ents. especially potllS$iurn ions. In fact. the first observable in vi tro n:aclion upon Irl:alin¥ a fungal cu lwre with amphofericin B i~ the loss of potassiu m ions. The drug is fungi SIalic at low roncc:nrnltions and fungicidal at hi gh CQIlCentralions. This suggests that at low concenlr.uions the polycncs birld 10 a membnlne· bourld enzyme component. such 8!l an An>ase,
Amphotrridn S, U5P. 11lc isolation of IlfIlphoteridn B (Fungi;wne ) wns reponed III 1956 by Gold el al.2\I The compound WlIS purified from the ferment.,ion beer of a soil culture o f the aclinomycele S'f'+(Ii myristoyl phosphatidy l~ (3 pans) to create a suspen~ion of ri bbon-I ike Sheels; _1ipo5omaI amphotericin B (AmBi'lOlne). II small laminar ~tion consisti ng of an appro!\imately 1: 10 IliIIO 0( amphoIericin B and lipid (hydrogenated 80)' Idyl choline. cholesterol. and diSiearQ)' lphosphati~ldIoIlnc In II 10:5:4 ratio) for an aqueous suspenskll1. ~ rationale behi nd these lipid prcpanlliollS is simple: .mcln B should have II greater avidity for the lipid >dI.ckdlan for cholesterol in ce ll membrane..\. Hence. toxic· " Ihould be reduced. LiPld·associated .mphotcricin B be 1,\n....11 i!lto the mlculoeudothe lilll system. concenIn the Iymphalic ussocs. spleen. liver. and lungs. IIIIM mft:Ctiou, fungi tend \0 locate. Li pase.~ elaborated by .Id~ ~ the host ~hou ld re lease the: drug from the li pid cam. making il aVailable 10 bind crgOlilerol in fU/lBal cell ":,m~ tonr:n its fungiSialic and fungicidal Kt;"ilies. I..... lISe' of each of the: approved lipid pltl'lIT"dlions • 'IolIlIltduced renal tOAicily. UposomaJ amphotericin • brm *I'P0.-edspecirlCally for the tre8nnenl of pulmo-II) ~Ik$s ~ause of its demonSlr:lled superiority to tr ~.Lum lIco~ychol ule -sIDhi li1.cd suspension. AIIIpIIotnK:1R B IS also used topically \0 treal cutaneous -' ..:o:ut;wws m)'COSC!i caused by C. al/m:unI. 1"'h/, .., ~ wppIJed In II ,-ariety of topical forms. including a a-. I 3'1 Jouon. ~ J% omunenl. and a 1000mglmL III The {)nil suspen~ion is imended for the: treat.oforallnd ptwyn~'f'al candidiasis. The patiem should
"....,.ber
sw i ~h the su'pension In hl~ or her mouth and swallow II. The ,u_pc:n~jon has a v~ry bad tasle. anulurlQ viginal cream and tablets of 100 mg II"C Ivai lable for Yulvovagi nal candidiasi s. Ii eumnely Stable. wi th a shelf life of mon:
,
"
"...
' 0
dOlnmal.0te i§ effective against a variety of well absorbed OI1I.ll y. it i I disturba/ICcs. It is al50 ellle n, Mll("e, is noI considered optimall y CIotnmuole IS noI considered suilab-le for the oi S)"Sl~ nllc Infections.
" EcOOlUOk: is used
1% cream for the topical treatment of Joeal tinea infections and cutaneous candidiasiS,
in wal"f and nlOSt organic SQlvenl5.
a~ It
8utoconazole Nirrate, USP. 1-(4-(4-Chloropheny l)-2((2.6-]Willgly sol uble in wa ler but o;olubie in cl hanoL The !;:lit is U'ioCd in a solut ion and II cn:am in I % concentration for the trenlmcnt n f local linea ;UfCCliol1S. ~lIch as jock ilCh. Plhlele's f(Jot. and ringll. orm .
Mkonilzole N;t~te. USP. 1 -1 2-(2.4- I:>!ch lorophenyl~ 2·[2.4-dlchloroplM:-ny l IIIlI'IOOx y )clhyl I-I II-nmdmlle nlOllOnilrute (Monl!>l3t. t.h cali n) is a we3];: base '" Ilh :a pK. of 6.65 The nitric ucid '\all occu.... as while cryslals thaI an:: ~paflni~ solub lc in Wlilcr lind most organic solvents. TIle fn..oe ba.e I~ :Ivililable in an injct;l ~ble form . w lubi loud witb polyc lh y1cnc glyoo l and castor oi l. and inlcrKled fCJ: the trelltment of .'lCrious ~ySlc mic fungal i nfecl ion ~. SUCh 11\ candidiasis. coccidiOldomycnsi~. cryptI)'
_I:lI1OS1erol 14a-demclhylasc is illhibitell in mammal s as 'til as in fungi . Iligh doses hav e ulso bee n reponed to lower
oJ
1e$IOS1emne arK! conicoslerone levels. re neet;ng 111u s dcmlatophytic infections nOI re!p!Iive to topicalthl':rnpy or oral grio;eofulvin . The antifunof kclocolUllOle and Ihe polyene antibiotic ~In B are reported 10 alllagonize each mher. ~a/.oIe is also used topically in II 2% conccmntt io n •• trtam aod in a Miampoo for tlte m;1nagCl1lent of cu ta_nndidiasis and til1l:;1 infec tion s.
".mons
am-
~~") I " N==
.J
'"
#
Itra conazole.
U5P.
4-14-[ 4-14-112-(2.4- Dichloropheny l)-2-1 H- I.2.4-triazol - l-y lrncthy l)- I.J-diOllolan-4-yl )nICth-
o~ytplic n y l !- I -piper.uinyllphcny l l·2.4-dihydro-2·( ]-n"ICth
ytprupyl)·3H- I. 2.4-lriul.Ol· 3·one (Spur.mox) is II. unique membc:rofthe azo le class that contains twO triazolc moietics in its stroclUn::. a we3kly basic 1.2.4-tri:u.ole and a nonoosic 1.2.4-lriuzo1-3-one. ltraconawle is an orally active . broad-spectrum am ifunllal agent that has become an impor1;l/\t IIlternmil'e to ketoconaznk. An acidic environnICnl is required for optimum solubi lization ~nd oral !lbsorption of itracona'l.Ole. Drugs such as H 2-histamine antagonists und antacids. whi ch reduce ~tom ach acidity. n::duce its gaSlroint ..stina] absorption . Food
f)
()--{ ) H
) 1. "
I "" #
c.
greatly enhances the ab.o;orption of Itraconazole. nearly doubling its ontl bioayailability. 1llc drug is av idly bound to plaslll3 pmlCnl!i (nearly 99'10 at clinically effecth'e concentrauons) and extensively melabolil.ed in the liver. Only one of the numerous metllbolile!l. namely l-hydmxyitraron:QOle, has ~lgnifiC'ant 3.fItifungai acilyity. Virtually I1OOt' of the unchanged drug is excreted in lhe uriJIC. Thus. the dosage need not be adjusted in patientJ; wilh renal impairrnenL The tenni nal eliminadon half.life of ltrllComt"lole mnges from 24 to 40 hour!.. The primary indICations fOl" itraronv.ole are for the treatment of systemic fungal infections including blastomy,osis, hIstoplasmosis (i ndud ing patients infected with human immuoodefK: lency virus lHIVI). oonmeningeal coccidioidomycosis. par".tC(lCICidioidomyCO!iis. and sporotrichosis. It may also be effective in the lJ"Catmcnt of pergellosis. disseminated and deep organ ,andidiasis. coccidioidal meningili ~. and CryptOOOCCOSIS.
In general, lInK:onll7,olc is more effective and beneT tolerated!han is ketOCOfUl7.o1e. Unli ke ketoconarole, it is not hC'patOlo.\k and docs not cause adrenal or Ie!lticular suppression in recommended therapeutic doses. I" Nonetheless. ill1ll:ol1a:wlec:an inhibit cylochrome P-4SQ oJli-dases involved in drug lind JlenOOiOilc metabolism and is known to inc~ase phlSIIl3 level!> of the antihislaminic drugs terfenadine and lISlemizoie.
00 hepatic melllbolism and i$ txcrcted substantially un· changed in the urine. A small amount of unchanged n~ zoic (- 10'10) is txcretcd III the fcca. S ide effect!; of fl~ azole lITe largely coofincd to mlllOf gastmintc:stiR.1l symptoms. Inhibi tion of C'ytochrome P-450 oxidase! by flu· COIlaloie C'an giye nse to clinically significant IIltcnctlOM inyolying increased plasma Icvels of cyclosporine. pllen)· loin, and the oroll hypoglyct'.mic drugs (tolbulllmide, ghpi. ride, and glyburidc). Auoonawle does IlOl appear to InIn· (ere wilh cotliCO!ileroid or andillgen biosynthc.~is in dosagc$ used to treat systemic fungal in(octions. AU~'Of1D:wle is recommended for the lreatmcnt and prophyluis of disseminaled and deep organ candidiasis. It II also used 10 conlrol cwphageal and oropharyngc:al ,andidUsis. Because of its efficient penetration into CSF. nucooa:tOlt is an agent of dV>tCe fOl"lhe treatment 0{ Cl)'ptococcal mall. gilis and for ptophyla.tb against cryplococcosis in AIDS patients. Although fillC(llUlZ.Ole is generally less eff(dj\f than either ketoronawle or ill1lCona.wle against 00Il1fltllltgeal coccidioidomyc(Kis, il is preferred therapy for coccKj. oida! mcnlllgitiJ. Auronl1,oIe lends itself to one-dose Ihmpies for vaginal condidiasis. NEWER ANTIFUNGAL STRATEGIES
A new v.ole. vorironv.ole," is presently in cl inical \ri.Ib
Fluconazole, U5P. a-(2.4-Dlfluoropheny l)-a-( 1"-1.2. 4-tria:wI-I-ylmethyl)-1 H _I ,2,4-tn:u:oIe- I -ethanol or 2,4difluoro-a,a-bls( I H·I. 2,4-trialol· l -ylmethyl}bcnzyl alcohol {Diflucanj is II walet"-'\(jlublc: bis- triazole wi th broadspectrum antifungal propcnies Wt is sU IUlble for both oral and intr~yenous admin istration a.~ the free ba~ . Intt:lvenous solutions o f nucoov.ole conlain 2 mg of lhe free base in I mL of isotonic sodium chloride or 5~ deJltrose vehicle.
in the United Statcs.
,
OH
(" ,_I ,
-,
1 '"
g..
'=_====_ H!~
"
l eN,
N
/
"0"
0"
HO' Figure 8- 6 • iofl,zatlon equilibria ,n the qUlnoione ,mbbaocteflal drugs.
"
"f'i.
" '0I
I N
~I-J . A 2:1
chelate of a Mg1'
I0I'l
by c!p-
L
P"
">..
,
"~"" 1
It is recommended for the treatlMnt of unnary tracI inf((;tions t aused by strai ns of Gram -negative bacteria s.uscepdble to these .~ts. Early tlinic.aJ 5ludies indicate that the drug pos~esV$ pharmacokmetic )H opt:rues supenor to tho5e of either of its p~deces.soB. Thus. followi ng 01111 administlll don. htJher urinarycontenlrations of ciooxacin than of nali dixic acid or oxolinic acid are ochie,ed. Cinoucin appears to be more completel y absorbed and less protein bound than nalidulC acKl I-Ethyl-6-fluoro- l ,4-dihydr0-4-0xI)-7-( 1piper~l.in~ I)- 3-quinolinecarboxylic add (Noroxin) is a pale ye llow crystalline powder that is sparingly sol uble in water. Thi5 quinoline has broad-spectrum activity against Gramnegative and GrdITl-positive aerobic bacteria. The nuorine atom pruvides increased potency against Gram -posi ti ve organisms, ",hc,rellS the pipenl1jne moiety improves antipseudomonal activ it y. NoriloltllCin is indicated for the trea tment of urinary tr.ICI inf((;tions caused by E. coli. K. pneumonia,. EnruOOaclu dQiIC(le, Proll'us m;mbilis, indole-posid ve Prolelu spp. including P. I'ulgaris. Prol'ilfencill rel/geri, Morgonelfa """sami, P. MrugmO$O, S. auulU, and S. epidermidis, and group D ~treplOCOCci , It is gel1l.'r~l1y not eff((;tive against obligate anaerobIC bacteria. Noriloxacin in a single 800-ml!; Or.tl dose hil.~ also been approved forthe treatment of uncomplicated gonorrhea. The om l absorption of norfIoxacin 15 about 4O'lo. The drug IS Ij'll> protein bound and is metabolized in the liver. The 1" hi~r ... the parenlrntl dose for a given irwlicalion. PlObcnedd wgluflCantly ~lICC'S the renal dearnnce of cipronQucin. pn'SIIITI3bly by Inhibi ting its acu~e wbuillf secretion. CiproOo~acln IS widely distributed 10 vu'tually all pam; of the bCldy. Including the CSF. and is gClICrally C()Ilsldercd \0 pro"ide the beSt distribution of the current ly marketed ,!uino~. This propeny. together with the poh!OC)' and broad IIIllbactc:nal 5p«lrum of ciprofloxaci n. accoun l~ for the numerous therapeutic indica tions for the drug. Ciprol1oxacin 1110 exhibits hig.tw:r poIeoc)' agai n~1 most Grnm -negative blncri31 spedc!!. including I'. /lc rug;nI)5U, than other quino-
.....
CipronOll;ICin is an agent of choice for Ihc lre;mncn l of bIctcnaI gastmcntains caused by Gmm-negatlve bacilli ... as cnlcropal~nic E. coli. 53lmonella (inclLKImg S. nplltt SIt"t/llI spp .. Vibrio spp.. and Mromt.mlIs hvdrol'hi.. II is widely used for the treatment of respiratory tmet 1If«tions and is panicu illfly effecli ve fOf controlling brondIIus .nd pneumonia caused by Grnm·ncg':llive bacteria. C i,oRoucin IS also used for combating infectioM of the sk in. idtllrnlCS. bones, andjoinlS. BoIh UllOOlliplicated and compInled urinal)' tract infections c:wo;ed by Gram·negati ve t.;t~ria cun be m~ated e rfecri~cly with ciprofloxucin. It is ptUCularly ustful for the control of chronic infec tions char1CItri1.ro by renal tissLM! invot-·emcnt. The drug also has ~t applications in controlling vcnereal diseases. A roriltll3lion of ciprofloxacin with the cephalosponn IUltibi• cd"triUone is recommended as the treatn"ICOi of ehoice b dlS$m1.m:ned gononi"Jea. while a singlc-dose lTtatmc:nt mciproflo)adn plus doxycyc line. a tetrdCycline antlblO(ic 10). can usually tflIdicalC gonoooc o f an oral dose i ~ excreted In the unne wilhin 24 hours in the form of numerous met:ibolites as .....ell as the unchanged drug. Allhough the metabolt~m of i-.onialid is ~cry complex, the principal path of inactivation JIl. volvu IlCet)laliOll of the plimary hydra711lC mtrogcn. In additlOll to lICC1ylisoniaztd. the IwmCQfin)1 hydr.l1.ones of pyruvic and &-ketoghllaric acids, t.onkounic lICid. and isonicotinuric lICi d Iulvc been isolated a.~ me t aboli te.~ in hllmans.lJ 1lte capacity 10 lnactl\ale iSQniuid by ocetyLatlOll is an inhented characteri~tie III humans. Approll imatcly Iullf of pel"'>OIIS in the population are fa~t acet ylntOl"ll (plasma hhlftife, 45 to 80 minutes). and the remainder ~low acctylllll)l"!l (plasma half-lift, 140 to 200 mmules).
Ethionamide, USP.
2-Ethyhhioisonicotinamide (Tree· ator SC) Ot'(:Ut'S as. ~11ow cryqaltinc materia! that i, sparmily soluble in ..... atn-. This nieOllnamidl-ltas ..·cllk bac:1trK>sth tic activity in vilro but. becuuse o f it ~ !tpid :I(llubllity, is em~ctiye in vivo, In COfltnl~t III the isonilll.id 5C ric~. 2· .subule form , S)'mptoms of gastTUlnt~ nul irritation arc common wilh both lhe ocid and the iIOdlla sal t A "ariety of enlcrk.cOOled fonllS have bm used in an . 0thcI'
,
i
I
. . . Im an anion
aluminum i is 1lIc oral absorption of and it is widely d i~t ributed into ti,sues, with the e~ceptiou of the III i 1c:\·cI~. significantly lower. It is excreted primari ly in the unne_ both unchanged drug and metnbohtet. 11Ic N·~)I tl\'e is the principal metabolite.. ..... nh siglllfK:llnl Tnc glycine oonjug~te also being fOl",ed. When ..... ith isonilll.ld (which also unt.lcrgoe~ increases the level of free isoniazid. 1lIc of PAS is about :2 Iloors. The mcch:mi~m of antibactcriltl lII:'lion to tNt of the s.ulfonamidcs. Thus. n 15 the incOlpOl"~tion of p-aminobcnzOIc acid ( PABA) dihydrofolic acid molecule catalp.ed by the drofolatc: $ynthcmSl:. Structure- activity i that the amino and carboxyl group!> must other and free: thus. c:.~ten; ond umiOO mUST hydrolysis in Vi\'O to be effecti"e, The: be onlm or IMrtlto the carbollyl Is seen in the former. For mMy yeIIf'I., PAS W35 thecbcmothel1lpy of tuberculosIs and was in combination regimens with isoniazid I-Iowc:"c:r. the introduction of the more ally better tolernte. Extensi yC first· pass metabolism and signifICant bllia!) excmion of the droll occur. with about 30 and 53% of tbr ontIly administcred dose exereted.largcly as meta~itcJ. 1I the feces ~ urine:, respecti vely . The 25·0-des'lC"I) I _ 31.hydro_y metabolitcs of rifabutin have been idcntir1Cd. The pan'nl dru, i~ 85 % hound to plasma proteins in a co. cenlr.tl.ion.independem mnnnc:r. Despile its greater poIt~ against M . lu~rculo.i;s in vitro. rifabutin is considered 10ft· rio.- to rifampin for the short·term lllerapy of tubert:ulOSll becau!Oe of its significant ly lo ..... er plasma cooccntnllions. A !though rifnbu tin is believed 10 cau~ less Jw:patOioxicit) and induction of cytochromc P-4SO enzyn>es than ri fampm. thc!Oe properlics should be home in mind wilen the dlllill used prophyloctically. Rifubuti n and its metabolitC5 Iff highly colored compounds that can discolor ~k in. un~ tear'S. feces. ctc.
eH,
eH,
,
./If/j/ is IIll obligate imracellular protozoan Ihat is beSt kflOwn for cau"ng blindness in l1I.·()Ilales. To~o plasmosis. the disseminated fOl'TTl of the dl"C'ar.e in IO.ohich the Iympltatic syst('m. ~keletal muscles. heart. bn"'n. eye. and placenta may be affected. has becOlTlC illC'fCasingly P'l'\alent in a.....wciation .... lth UlV mfection. A combmallon ofche ami· folate pynJ11("\hamine (Ch3p1cI'9) and the sulfa drug wlfadiaZ111C OOflStllUlts the most eff",.."'I;\(' thempy for toxoplasmos is. Varioos fonns of Lrypallosomiasis. chronic Iropical dis· eascs caused by p.:Itho~enic mctnbtTS oflhe family Trypanosomidac:. oct"Ur both in human5 and in livestock. The pO ncip.al dise:u;.c III human~. 5k:c:-ping sickness. can be broadly clllSliifled into t.... o mam geQgl1lphlc and ellolOGIeal &'lJUp!i: Afncan sleeping siclllCs-, caut been sYllthesi 7.cd in various labllnltuncs throughoul til: world. Mctronidazole was firsc nlarketed for the topical tll:'JI' ment of TriclllHlWlIll$ ,'ugm(J/is vagimlls. 11 has since bta mown to be e.ffectin·, orally Ipmst both lhe lICute and C1ll'm stales ofchediscasc:. 1l1e drug also pos5CSS('s useful amebalIal actJvny and is. III facl. effCClI\e agalllSt boIh lIlteSlll1ll and hepatIC IInICbiaJ;is. 11 has alo;o been found of usc lIIl11r creaCllloClI1 of MlCh OIN-r proIo:wa1 disca5C:I as giardiasi, ani Metronidazole,
balanl1dl asl~.
Mort recently. melronida~oIe Ilas been foond to po$_ efficacy again'\! obligate anaerobic bacceria. but il is incff(\"· tive against facultmive anaerobes or obligate acrobo. It a paniculurly active against Gram-negnt,,'e anaerobes. SId as 80cftnmlfs and Flisr/lJocfC'nlllll spp. II is also effeai>li a.gIlJllSl Gram-poslli\'e al1iltrOblc bacilli (e.g .• CloJfridiJa spp.) and coet:i (e.g .. Pt'P//JCOCCus and Ptlllidos/rtploromtJ spp.). B«ause or ilS b:oclC'ricitbl action. metmnil.lll.ok_ become an important agent forthe lreacmcnt ofscrious 1111« tions (c.g .. SCplleemia. pneumoma. penlon;l1s. pelvic !nfC!; tions. abscc~sc~. ,nc.nin gitis) caused by mnacrobic battma. 1l1e C01111110n charoclenqic of IIHcroorgllnisms (b3CIenl and prOl07.()ll) sells;ti ve 10 nIClroniduole i~ that Che:y on: .. aerobic. It h:ls been speculDtl'tl thaL I reactivc intemlCdia formed in lhe microbial reduChon of the 5-nitro grwp II metronidazole oovalt:m ly bl11ds to the DNA of the microu gamsm. II1ggenng the lethal effect .... POIenllal reacti"e __
,
, , , ,• •
••
1IIld131e~
IlIClude the nitroxidc. nit«Jt;O. hydroxylamine, and __ The abtln)' of mctrollIdalole to act as a rlKhosensilll,Igc:I1l IS abo relau:tI !O II ~ reduction potential. I>ktronidal ol e is it pale yellow cryM:tllir.e substance that 'lpan n&ly soluble In .... ater II is stable In air but is light ll'II\ili.c. Despite its low .... aler solubility . IllCtronidazole is ;absorbed followmg oral admlmSlJllllon. It has it large:
well known. Aqueous !IOludOfl~ of ....-id saIlS of oxioe. partw;;ularly the sulfale (Olloosol , Qumosol). In COllCemr.lllons of 1:3.000 10 1: 1.000. luive bc:cn used as topicalllfltiseptics. 11Ie Cd ruullllcly for trnlcler' s di~a.
",;:':"':;~'''::. of metronidazole: base are slable for ~. . BOIh solutions should be protecll.-d from Furnmidc. or tulamidc , i~ the 2-furoI il II , I various 01.("1:lell'-I ty in vitro. are also :lCuve. and
I,. I
,
of th-e
are more potent than polar OfICS . i ';;;;;;;;;~ -,;;;; in the treatment of a-symptomalic carhi.u"/yllro . Its tlTecthtoe~s against OCUle inlts·
,
Emetin. and Dehydroem. tine. 111C alkaloid_ enlCtine. and dc-hydruelnetine lire obtained by scp;arJtion from exuacls of ipecac. "They occur as le:VOf"OIaHlI"y , hghl ·sen''',,'c white po .... l.krs Ihat IU'I: inwluble in water. The alkalo ids readily form ..... atCT-,-olubJe sall~. Solution s o fthc h)druehloride salts inlendcd for inlrnlllu.",·ulpr injectlOll should be adJUSted 10 pll 3.5 WId stored in lighl-roi \ Ulnl container;.
H1C"""-O
9"""'Y/"
jsa
N
orally only as 500-mg tablel~ and lIIay in the United States from the COC In Allanta,
H"
E"",""
••
...
...
,
V
.....CH1
H"
""
qumophcnol. or O.l'.yqulfrom \\- hich the Ilflllprotozool . The antibacterial and antl and its denvalhe~, which are be· abil ity to chelate nlCtal ions. an: O ;U IlC.
and dehydrocmc llI"Ie ex en a direct amtbl cldnl action OIl various rml11s o f E. hiJlQI) l icu. They an: protopl:llirnlC poisons that ,"h'btt proIc in s)" nthesis ,n protol.ool and mal11malian cell~ by prevcnting protein elongauon. Because th-ei r crfect in Intestinal amcbia-sis is solely s)mptomEnlClIlIC
alic IU1d lhe cure nile is only 10 10 IS.... lhey should be used only III oombir\3lion wi lh other Iscnls. 'TlIe high conccmrauons of the allalonls IIChievrd in the h"cr and OIher lissues .flcr mlramUSC'lllar injcctioo provide the basis for their high cff«uvene.~ against hepalic alxccsSClIlIlld other cllOtraintcstinnl forms of the disease:. Toxic cffects limit the usefulness of cmc1illC. It caulilt. II may [\I
I or orolly. Approd· excrcted in 11M! urinc. is facili laled by in-
,
, , ,
,
"'"
llgmflCllnl and potentially usefu l aoti·
c.-mlually led 10 disco.'cry of partK'Ular
~.;,~,. activity.
Melarsoprol.
2-p . (4.6 -Oi anll00-I - triuin- 2·)' I'IIm; no)
phenyl-4-hydm:tymc:lhyl - I.J.2-dllhia~l llle
(Mel B. ANOball is pn:pan:d by l'C'doclion of a com:sponding pentavalent arsani13te to the trivalent ~noxide followed by ",:JC1;on of the biter ..... ith 2.J-dil1'lcrcaplu.l-prop'lrIol (Bnlish anti-Le ..... islle. BAL). It hilS become the drug of choice for the treat ment of the Imer stages of both forms of African trypanosomia.~is. Mclarwprol ha.' the advantage (If exedlent pene trntion into the CNS and, therefore. is effective against meningoencephalitic fonn, of T. !:{/mbi..nstl mid T. rbWtsinu ... Trivalent IIniCnical~ tC11d to be more toxic to the host (as we ll as the par:J$i tes) than the Com:spondil18 pentavalcm compounds. TIle: boo(ilng of arsenic .... ith sulfur atoms tends to l'C'ducc host toxicity. incn:asc chemical stabllIt)' (to o~idatioo), and improl'e di stribuuoo ofthr compound to the ar5CnoXide. Mclllt1IOfII'Ol shares the toxic properties of other arsenicals. howelcr. 'iO illl usc muS! be monitored for ~igns of ar.;.enic toxic;'), .
OH
'" ,b
compounds
IS
mrunimox beT. end. the
American trypanosomiasis. In only clinically pro"cn romt~ of the di:sea..o;e.
. .~. is Idminjsl~ omll}'_ Oral biouvuilubilil y is OOIblderuble firo;,-pass metabolism occurs. The
•~:~r:'::;:':~:d';~"~ :4~;hoo;~~"~,,~The drug is poorly i
vomiting. abdom~ ~.IIIOII:J.il reponed. S),mptoms of cenlml lind nermus 5~Sl~m toxicit), also fretJu~ntl)' occur
..
I
Sodium Stibogfuconare. Sodium al1timony gluconale (P!:ntostam) is a pc:ntu\'ulent untmlOlli31 compound intendl.-d prim.:lri l)' for the treatmc:nt of various foons ofk:ishrnatlia~iJ. It IS aVllilubk: from the COC as the dl.Slxhum salt. "hlCh I~ chemicall)' slIIblc and free ly .IOluble in water. The 10% aqueOII.!I solution uscd for ellht-r intr,lInuscu lar or intra\'enoo s injeclioo has a pH of - :U:. Li~e all 311timonial drugs. thiS drug has a low therapeutic ind!:~. and patients undcrgoil1g thon) and the tn\'asl\'c phase: of lnchinOSI" , In addition 10 its usc in human JIlI:dicine. thiubendazole is widely used in \'eu:nnary practkc 10 control mtestinal helmtnths in livestock,
M*lHmd.Jzole. USP. M ('th~ 1 5· bcnloyl·2· bcllltnnduolC('arbarnale (Vernl()~) i~ II broad·.~pc'::l rum anthelmintic that is effl'l:tJ\'~ agam\1 a ~1Ine'ly of JlCnt;uodc: infestations, including ... hlp"ool1. pin\\-OITn. roundworm. and hookworn!, Mcbcndazole ilTC\'cJ~ibly brock_~ glucOloC uplake in suscepti ble helminths. thereby deplcung gl)'cogcn 51on.:d in
the parasile. lt apparmlly docs no! affect glucose metabolism III the hosL It also in/liDiu ~II divIsion in ncmalodcs. '1
"
from relell5e of I,,'c ova from worm segments danlaltd II! lhe drug.
a
0\-/",
}-~
•,,
P
I
/' -""'J'--'N
•"
• Mebcndv.ole is poorly abSOf'btd by the ond route. Adverse: reactions are UlI(ommon and usually l"OOSISI of abdommal dlscomfon. It is ler:lIogenic lD laboralory animals alld therefore. shoukl not be given during pregl1:lIlcy.
Alftrtdil:tok, USP.
MelhyIS-{propyhhio}-2.ben1JmidaJ;okcaromn.ato! (Eskuole, URIc!) is a brood-spectrum ant-
helmmtlc thaI is not currently marketed in North America. 11 is Iwailable from the manufacturer on " compassionate use treaunclll for a.l\Cari!l~is. New and Old WorlU hookworm infectioru. and trichuriasis. M uh iplc-dose therapy with aJbenda7.o1c C'.lI1 eradicw lc pinwolTlI. threadlO.orm. capli lanasis. clooon:hiasis.. and hydatid disease. The Cffec1I\'cncss of albendazok against \lIp!:wonns (ceslodes) is gellrnllily more Vllriablc and less imprt'Ssl~e.
"
"
8ithiOftoi.
2.2'·Thiobi.s(4.6-dicMorophc:nol). or bI$Il, hydroxy-],5-dichlorophcnyl)~u tfjde (Lorothidol . Bithinl,l chlorinated blsphcnol. was formerly used in :;oaps and COlmelic~ fOf its antimicrobial properties but was retOOled the market for topical use beo:ause of repofts of conflICt pm. toocmlmi;is. Bi thionol has u'>C fu l :mlhclminlic (lft!pe/1it! "nd has been uglyec:mie drug tolbutamide:. the diuretic furmcmidc:. and the diuretic chlorthalidollC. In phaml3Ccuticul chemi stry. p~ vuluc~ are 1101 used to compare compounds that 1111;: uwis ~. I ~ead. if a pK.. of an amine is given. " ref~ to its ~ah octing as the eooJugate acid. For example. aniline with a pK. of 4.6 Iders tu
fABLE 11-7 Ther.py With Sulfonamide Antlbact.rlals Dlse.HllnfKtion
Svlfon.mldes Commonl, Ihed
Tro.,IIICI1' ",ill pI'IIp/Iyl.o,i. f I'>tt..-,Jri• .... rin" P'''''''''''''" f. rn orr ..... JI""IPI)Ia".ofa:,eboal I'iM IIIIK~ ,,( IIf''''''' he! .ft~ fiwoo tIImopy' """''''K''",," 1n:1Imt... 1!bocltrial ,nl«_, ~
P)'nT" ... mi ........ lfodwJ ...
Tn"'"'hopnm· .... '~ Sil.u ..,lr:Pod,,,,i.... nd "",f~"HIc
Sod,um MllfKmtzIzoIo Combo".;o..~ WE'" quEn,OIC. odwl
C"'1.I"""'''''' IIId .. I...,.) ..."",r,."al ocular ",fn:liI>no Cl\kImqw ......... ZIl
Tri~m·."lf"".. d..........
malanal~9)
Sulf"..... ~
r.o.:.v;..... Sn=
Tn ...... hoprim'e; e, ptn",q,ft O. amP'C,111A. !If ('itivc and Gnno-negative hacleria. OIX"lInha. Clllam)"diu trflChotrttl/iS. and some proIo/.llL Some cmenc bacteria. slICh as E. col; and Klebl lt'l/lI. Sillmonfl/lu. Shillt'illI. and EnltmHxlclt'r spp. aro onhibited. Sulfon-
o
o
o
NH
O-~II--q
N~
.\
HQ"'-
dUUP
.....,..
Other 6)!arT1)lea of folata-requlrtng ona-carbon pool reaction. :
c_ _ N'" ·F~·FAl-\, N'Jr-MIIIhyIeM-FN\
N'-Formyt-FAH.
MeI ·IANA
"',O"i.
•
Fu....,.. M.. _!RNA
"
Ptllfldjne Diphospl!l:Ie
,• •, • ,••• ,•• • ,•••
SulIon.rnide. Sulforlu
:
_Add , •
~'' - a7J""
'0
,.
TABLE 1-1 pK. Values fCH" Cli n ically Useful Sulfornomldes
Sutn1lO.U>'Ole
,S..lr-"'>\Ql....
,.• "
,I pi
..
'"
." o
erysulluri.a and tIM pIC.. fko,pne the tremendous abil ity of sul fanila illide 10 l' ffcct CUrl'S of jXl thogenic bacteria. its benefits .... ere often offsct by the propen~ity of the drug 10 ca use C to a ~ution of \IIIfisoxawle 10 bnn& lnc p~II O aboul 7_5. It is used lIS I sail to mll~e the rJru g morc soluble in,nc physiolo~ieal pH nJ.n&C: of 6.0 to 7.5 and il used in solution for ~ystc lll ic admini5ll'l· lion of Inc drug by SlOw inmwenous. intramuscular. or wbculllneil}' '" PreI.>. 1970. 25. lliod1. lt "",,"ino. F.ndl. }1 ·1J09. 1'81. 26. I'OOIk . A.. _ s.:1IoI. Mn!. 1z.t,91t. 19116. 12. lon~",pl. R.. ~ at.: Cill. ~1IeI. 23:279. 1992. n , liven. 11. L . - ' Ikuinl. R I'n)c. P.. p. B..... MeoI. 76:'1J. I"t 34 . P.n1. ... J II ''''''.): "'.... ,i l'" I'roIozo&. 2nd cd &In ","",. A on human hi~tory is fascinating bul. fortunately, ;1 nlOid) h.storical . 1be laller three dJse~s do reappear. but the CIII:I are isolated. Plague i~ treated effcctively ... uh anuoon and there are vaeeioes for yellow fevCT and polio, The publ ic i~ aware of oclluircd ImmunodcflCieocy s,.. drome (A IDS) bccaullC:. il is a disca .... Ihal "U1I~eI5" b! human carriers IU1d has mfccled and killed pronllncnt ~ ...110 are citi1.cns in ccOllOmieally developed countritl. Nc\"enhekss, compare the 200 1 ligure~ for AIDS lIId_ laria, After appro ... im~tely 20 yeao" 40 million pcopIt l1l'i been infccted with the human immunodi:flt;errcy ,inI (UI V). of ... hom 5 million ....ere illfCC1W and J m,llIo• • in 2001 , For North America, 940,000 haye])e(."OITl( Inr~ III the past 20 years. or .... hom 45.000 ....ere ,"f«ltd" 20.000 died in 2001 . In eomr.lst. nppro ... imately l '
"J-OH 0 ,J-o-L"" L l~xykhe ~
_....... ------
(OOXP)
J H,C-""
, 1,_
H,C--o~
HO-~" I
0
II
~CH1-o-$P-OH
L
Figure 9- 13 • No!lmt\lak!nilte
" ...."
TAllE 9- ' -Co"tI,,~
... .. •
D'lIqIOOnl' ond l DO ..... profu ..... 1 PnlJuJ,i~ tulXn 6l.~
at< """""" IOId
,......",
"'I
:u "'I
,.• •14.. .. 'k"n 1-2"'Y' prior 10 *1*'''"' ond «"II.,...... rat 7 cb)''lfIcr n:t\IOlI
.. -•
.-
Oi
C
'""
1··)~IIIbIm ..
• -"'II< douJy olow 1M.......
,~betuI
.or,"
AJ./u: I
-.to
""*' ",Iy
r . - TIIl.. . . . "nlkoboo
ror ~ _ _ "'oIa)"
auld"", 1-1 pNi"''''' IINtu II • lind< Jajly ....... b.allild 0.
... dlh,
"""iiI<
Adult>: rI ",bk1i ... dally olow for ) _>«:\Ill", do)"
""""'1W... .,101bI I' PIt"'1""""''''';M INMII'II Ichklruqll,.-.I .... If_line--..,.nmnIIaniJoo
6 ...1.... IIl I«tJgn,;
Plop/,,.....;,. Oily t:o.v-III
1-2 doY' btf.... 1n...1 ..... (or
4.....eU.,la,,,,, .. .a. ............ -....111 .... ." ...".,...4".......
0-101 .... 2 . . P''''''Y up 10 IOO-cAloy ,....."" l00 . . ~ob'11
TtnI ...... ' of P. /ak.".,rw.
1' .....
,..."" $00
"'I CY!X'rio.. N... VIlfl. FOlT¥. SInO!i .t GO ....... 2002. 3 ~oi. f..: SOrne of the older Wltibiotics allest to the spectacular suo;cess of thi \ approach as It has bcapt'd PotU; 1"- can"'" ~ It ,~nor yer dear "'ho!rller Inhlblloon of PBI' J 'S [;:rhal to 1M
I pure compound and ex.hlbltcd varying ocli\ lIy among gm. pie!;. it was IlCCC!iSllr)' 10 evalLIIUe 1\ b)' 1I11croblQlogicai as!>lIy. 1lre IlIo.:cdure for ..~y ...as dco'eloped al Ox.ron!. England.. ~nd tllC voluc became known ali the O.iford ,mil: t Oxford L1nit is defined lIS the smallest amount of penicill in that ""1M
TABLE 10-2 Structur. of Pen icillins
o
....L.H Chemlu l Nam.
R Group
""==
• PBI'!. 4 Ihrough 6 Ire: cubo~)'lX'plr" I""",dll,n HO crcl¥rm.
1-"..... lIOfyoollltlib.
...c_)' t.en, ~ I·
r .....'..I'"
...c..m..)·l-ltUortIll,
-,~llhn
Chtop'rr 10 • Anllbucll,nal AIlI/biUlin TABLE 1~2--ernlly prescnt (ic .. 2.2.dimcthyl ~nd 3-carboxyl). A thi rd {onll. followed in this chapter. uses tril ial nomenclature to nartlC' the entire 6-carbon_ ) laminopL'lIIcd lanii: acid ponlon of the molecu lc jIl'niClllrn and thell di~lIngui.he~ compou,xh on the basl~ of the R group of lhe acyl portion of the molecule, Thu ... po:niclili n Gis IIllI1lN benlylpo:nicillin. penicillin V i, p/lo."ll()t)mcth • ylpcnicilli n. methicill in is 2.6-dimcthoxyphen)Jpcnlcl lim. and so 00. For the """t pan. tlx- laner two ')~tem .• ~I'\c "iell for nllmmg and comparing close ly similar po:n;clllin StruclUn:S. but they are 100 n:strictive to be applied to Com. pounds with unusual \lIb .... ituents ono ring- modified deriva_ tives .
SterelKhemlstry
lllllibll. In ~illu. the growth of I SUlIi" of SU!phdorot:cuJ in '4 rnl. of cullUr~ medium under specified rondiuons. Now .. pure crystalline penicillin is available. the UOl/ell Staff'S ~w (US P) defines unil a.o. the arllibiOIlC lICIivily 0I0lt 111 of US P penicillin G sodium n:fen:ncc sl!Uldani.
H.
H.
CH.
TlIr'll'clghl - uni, n:lationship o f lhe penicillins varies with ... flf')1 sub!.Ii1tlem and with the ~It fonned of the rite acid: I III of peniclllirl G sodium i~ equ ivalent 10 t .667 units. I \ll'penicillin G procaim: i~ equ iva len t 10 1,009 units. mid 1l1li of penicil lin G poca~iurn is cquivalenll o 1.530 units. The l'OI1HncrciaJ production of peuiciUi n hilS iJlCll':t.'>Cd roly ,incc ils imrodUC1ion. As production irKTea'!ed, IIrr l'05I drtl(lJled COI l espondingly. When penicillin was first bilk. 100.000 units sold fOl' $20. Currently. the same ~'P:COSI~ less IlIan I penny. F1lJ('lualions in the producrJ penicillins through the years have ~ nccted manges _lilt: m..Ule populmty of broad-spectrum ant ibiotICS and • n!llM. the development of penicill in· resiWUlt strains of ,om! pathogcns. lhe more t\"Ccnt introduclion of 5emisyn_ " . penICI llinS. the use of po:nidlhns in animal f~ocds and 1I1dmnary purposes. and the inc~a..c lht"C'(': a:nters. TItc clubon atom bcannll tlx- lICylamino group (C-6) has the .. ronfigUr.tIlOfl .... hen:as the c:.. rbon 10 ... hich the carbo~yl group is IIl1:1oChcd ha.~ the 0 confil!ur:ltion. Thus. the lIC} lamino and carbo~yl groups au frtllU to cach other .... ith the former in the a (Illd lhe lallcr In the fJ onclllahon relative to the pen:un rin!: syslem. The UlOO1S comp!)',!ng lhe: 6-am inopenicill un ic acid portIon of the SlnJCIUt'll arc denvcd biosynthcl1cally from t .... o lun itlO bcitis, I ·cysld ne (S_I. C . S. C-6. C-7. lind 6-mmno) and I.-valine (2,2-dimcthy1. C-2. Col. N4. and l-ciltboxyl). The absolute slc,,:uchc miqry of the penicillin' i, deslgnal..-d lS:S R:6R. as ~ho .... n belt.... .
,
.
~
Ct., ': ,, _ _
'"
-,.
,,-..( H
OJ
1
~
-
~
304
-
•
Wilson and Gisvold's Textbook of Organic Medicinal alld Pharmaceutical Chemistry
Synthesis
natural penicillins are strongly dextrorotatory. The solubilit) and other physicochemical properties of the penicillins are affected by the nature of the acyl side chain and by the cations used to make salts of the acid. Most penicillins are acids with pK. values in the range of 2.5 to 3.0, but some are amphoteric. The free acids are not suitable for oral or parenteral administration. The sodium and potassium salb of most penicillins, however, are soluble in water and readily absorbed orally or parenterally. Salts of penicillins with or· ganic bases, such as benzathine, procaine, and hydrabamine, have limited water solubility and are, therefore, useful as depot forms to provide effective blood levels over a 10n1 period in the treatment of chronic infections. Some of the crystalline salts of the penicillins are hygroscopic and mu~ be stored in sealed containers. The main cause of deterioration of penicillin is the reactiv· ity of the strained lactam ring, particularly to hydrolysis. The course of the hydrolysis and the nature of the degradatioo products are influenced by the pH of the solution. IS. 19 Thul. the ,B-lactam carbonyl group of penicillin readily undergoes nucleophilic attack by water or (especially) hydroxide ion to form the inactive penicilloic acid, which is reasonably stable in neutral to alkaline solutions but readily undergoes decarboxylation and further hydrolytic reactions in acidic solutions. Other nucleophiles, such as hydroxylamines, aI· kylamines, and alcohols, open the ,B-lactam ring to form the corresponding hydroxamic acids, amides, and esters. It has been speculated 20 that one of the causes of penicillin aller!) may be the fomlation of antigenic penicilloyl proteins iJ vivo by the reaction of nucleophilic groups (e.g., E-aminol on specific body proteins with the ,B-lactam carbonyl group. In strongly acidic solutions (pH < 3), penicillin undergoo a complex series of reactions leading to a variety of inactile degradation products (Fig. 10-3).19 The first step appeaJliO involve rearrangement to the penicillanic acid. This process is initiated by protonation of the ,B-Iactam nitrogen, followell by nucleophilic attack of the acyl oxygen atom on the ~ lactam carbonyl carbon. The subsequent opening of the ~ lactam ring destabilizes the thiazoline ring, which then aI~ suffers acid-catalyzed ring opening to fOJ III the penicillan( acid. The latter is very unstable and experiences two maj~ degradation pathways. The most easily understood path in· volves hydrolysis of the oxazolone ring to form the unstab~ penamaldic acid. Because it is an enamine, penamaldic aria easily hydrolyzes to penicillamine (a major degradaiioo
Examination of the structure of the penicillin molecule shows that it contains a fused ring system of unusual design, the ,B-lactam thiazolidine structure. The nature of the ,B-lactam ring delayed elucidation of the structure of penicillin, but its determination resulted from a collaborative research program involving groups in Great Britain and the United States during the years 1943 to 1945 14 Attempts to synthesize these compounds resulted, at best, in only trace amounts until Sheehan and Henery-Logan 15 adapted techniques developed in peptide synthesis to the synthesis of penicillin V. This procedure is not likely to replace the established fermentation processes because the last step in the reaction series develops only 10 to 12% penicillin. It is of advantage in research because it provides a means of obtaining many new amide chains hitherto not possible to achieve by biosynthetic procedures. Two other developments have provided additional means for making new penicillins. A group of British scientists, Batchelor et al.,16 reported the isolation of 6-aminopenicillanic acid from a culture of P. chrysogenum. This compound can be converted to penicillins by acylation of the 6-amino group. Sheehan and Ferris 17 provided another route to synthetic penicillins by converting a natural penicillin, such as penicillin G potassium, to an intermediate (Fig. 10-1), from which the acyl side chain has been cleaved and which then can be treated to f01l1l biologically active penicillins with a variety of new side chains. By these procedures, new penicillins, superior in activity and stability to those fOllllerly in wide use, were found, and no doubt others will be produced. The first commercial products of these research activities were phenoxyethylpenicillin (phenethicillin) (Fig. 10-2) and dimethox yphenylpenici IIi n (methicill in).
Chemical Degradation The early commercial penicillin was a yellow to brown amorphous powder that was so unstable that refrigeration was required to maintain a reasonable level of activity for a short time. Improved purification procedures provided the white crystalline material in use today. Crystalline penicillin must be protected from moisture, but when kept dry, the salts will remain stable for years without refrigeration. Many penicillins have an unpleasant taste, which must be overcome in the fOllllation of pediatric dosage forms . All of the
c (
t
f
n n r
d n
f( IT
o
•
s
•
tI,
I-I!-I-OI+I-a-r" ......2
I
1-11
W
I
cc
~
B ar •
111
th if he R
•
R
\(f
va
,u , Figure 10-1 • Conversion of natural pellic .
to synthetic penicillin.
tht tio
Cha pter III • AIIII/1a hyacidic fonn a liCe-
l'cmcilioic
:acid!-substituled penicillins, exempl ified by llI.1ociliin. 11lt:1Jocillin. arKI piperncill in. exh ibit great('1'" !lCllv"y against cenain Grom·nc:gati,·e bacilli thaJt carbenici llin. Although the aeylurcidc>penicillins are aeylated derlvatl\'elj of ampicillin. the anllbactenal ~Itum of activity or the ,roup is more like thaI of carbenicillin. 1l1e acylu",idopenictl lllls 1If!.". however. ~upcrior to carbenicillin against K/t'bsit'lla spp .. I;."IIIerobaclt'r spp .. and P. tJrru.s,·· "OM. Thi~ enhanced activity is apparently not due to ,Blar:tam:I.'-C rt:S1st:mce. in !hat both inducible and plasmidmediated ,B- Iactama.C\UI!' from I variety of sl;in arKI mucous membrdne rashes 10.., fe>'er and anaphyla~ls, COllslltote the major probkm ti-«lated ",ith the usc of this class of anublOl,icl. £'>I1II1:Itl:5 pbr the preYalence of hypcrsen~itivity to penic illin G throoglXW the world between I and 1(Xf of the poputallon. In the L'. State> pnd other indostriali"tcd COOlllne5. It is ~am ~ higher fisure. rankins peniCillin IIII!' Ol(ht commOll CIiI!t. drug·induced allergy. The penkillin' most fn:quently" Uled in allergic reactmnS are penicillin G and amp.-iF Vinua ll y 1111 commc:reially available I il . ho-.ol"a. have bcc:n reponed to cause: such en. sens it ivity among m()),t chcmkal classes ici ll anic add derivative, has been The c hemical mechanislllS by I lions becoIne antigenic dcnee !Wggcst!i that peniclllllU or their ~arron¥eH1tI' odS formed in vivo (e.g .. penic,lIcnic acilb)"'1 n:act. lysine t-amino groups of protein. 10 fonn penlC;]~! ~ lei ns, which are major untigcnic: determinnnb. u , E-'! clinical observations wi th the biosynthelic pcnicllhns (j. V ilKhcatcd a higher incidence of al~ic rcactlOllS. onpurified, amorphous prcparuliOOS than with highly fted. crystalline forms. suggesting Ih3t small 3""- ' high ly antigenIC penlcilloyl proteins present In ~mple~ were a eause. l'olymeric impurilie' in
Ctuo plfr 10 •
~
~
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...,,g-
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he
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1 pt'nicillina- ..... aminob are also not inacli\'llioo by dan I InhibitOl'li.
~ ~x
chai .~
"",
Produtb C/avu/anate Potan;um, USP.
C!a>'ul:mic acid i~ Dn!llltlbiotic isolau:d from Srr''I,mm\"Cr'J dlll"uligfri.r. Structur· all y. it i~ II I -()~opennm lacking lhe 6-llCylnmiliO side chllin of penicillins but posscs.~ing D 2-h ydro.l.ycthytide~ moiety al C-2. Cilindanic aci d e~hibilS >'cry weak antibacterial activity. t"OfllI);lr:lbk: willi tlutt of 6-A PA IllMl. lherdon:. is not UK.fula~ !Ill anlibiOlic. II i~. ho,,·ever. P pOIenl inhibitlll" of S. (IIIft'U.r ,8- lactamase and plllSlllid-met.hall'd ,8-lanamases elabonued by Gnlm-negati>'e biocilh.
,"
"~,
Th< C-2.
Fill.oo-dosc cOlllbi n:lt;ons of ampici ll in sodium aIlll ... bactam sodium. markeled under the trode name: Unas)'lIa 5teri~ powders for injection, have bet:n approved for II$t iI the Unt ted Stales. TIlC..o;e I:ombinations are recommended for the lrelilment of skin. tissue. intra-abtlornlllaJ. and I)'neel' logical infect,olu caused by P.lacl.llmase-pnxIucmg 5InIII of S. IllImlJ, £. coIj, KIr'bsir'lkl spp .. P. m;rabilis. 8. fro. and i::nlt'robuc,,., and ACtnetiJbaC"ltr spp. Tazobactam. USP. Tu.obactam is a pcnicill:lIl1( a:tI sulfone thlll IS "inlliar in struclure 10 sulbacl.am. It is._ potent P.lacIHI1I~SC: IIIhibilOT lhan sul bactal1l H and No I slightly broader spe('lrurn of activity than c1avulanic has very weak ~nt ibacterial ac. i~i.y, T a7.0bactam i~ 1l'·:IlI.tblt: in fi~td·dosc. injecl~b1c combinJtions with pi\X'l1ICl lhn.1 broa(hpcc:tru'll peni('illin consisting of an lI: I nl1 io of p!ptI. acillin sodium 10 t~.tobal.'tam sodium by wei,ht an.J .. ki.'Ied under the trude nlIHle 'losyn. lbe pharmaoo~incllO" lhe 1"0 drug~ are \'el)' Similar. BOIh halC shon half·~~ (I. - I hour). a", mimmally protein bound. ClIpcncnct" ~ lillIe metaboh~m. and excreled in acth'e fom\! urioc In high conc:c:nlr.lllons.
aod..
" Cumbinmions of
amo~ ici llin
nnd Ille potu~slum sail of elavulanic acid are available (AuXIl"ICntin) in a variety of fixoo·dose oral dosage forms intended for the I",annenl of Skill, re."PlllIt(ll")'. ellr. and urinary lract mfeelions caused by ,8-1actama.;e-producing bacterial ~t r.aln~. 1lle'lC" I:ombinalionS a", dfecU\'e agaill5t ,8-htclamilSt'-produci ng "'r:lIllS of S. uurl"u.r. £. rtlli. K. f'm!u'lUHliul". i::11Il"robtlOler, 11. injlur'n;tlr'. Moru.rr'//ll CUf/lrrllllli.r. and II. duerr',·i• .. hich lilt ttSislanl to alTlOticilhn alone. The oml bioa\'llilllbility of anlO~i dllm lind pot:lSl'iu'll clavulan~le .. ~"lIIlar, Clavutanic ~id is acid·st ab~ , It cannOl undergo pcnidllanic ocid formation beeause il locks an ~rnide side chain. 1'001I!.s ium d a\'ulanatc ~nd the e~lendoo-)pcctrurn penici llin 1karci Ilin havc been COlnb; nl-d in II fi.l.ed-dose . injectable form for the t'ootrol of seriOlIS i'lft'Clions I:llu..ed by,8- lactamase-producing bacterial s!r:lins. This rou lb; nation has been recommended fill" scptiCo.'mia, lo .. cr rcspirnt(ll")' trocl info::· !Ions. and unnary tract infeclion~ cau~d by ,8- lactamaseproducing Klr'bs;r'//a lipp.. E.. cmj, P. Ul'rox;nQSlI and other PSr'IIi1lJ11lOnm spp.. CitrobtlC"ll!f ~pp., C",uOOocurspp .. Su'mill nIllrcr'sC't'ns. and SlIlph"'(i'C(XXllf IIUrt'II.~. It ;tISQ is used III 00ne and joint infections eaused by lhe..;e organi~ms. 11le combmallon rolllams 3 g ofticlIfd lhn disodium and 100 mg of potas~i um cJa>'ulanalc in I ~'erile: powder fill" injection (Timenun). Sulbactam, USP. Sul baclam is penicil1anic acid su lfonc Ill" I, I-dioxopc:nicillanic acid. This ~yrnho:lic penicillin deri>· ali\(: ;s II potent inhibitor of S. UIITf:U.f ,8- lacuulI~sc as " 'ell a.~ many ,8-lactamases clabonllcd by Cr:lrn-neg~ti,e bal:iIli. SullxlClllm ha~ " 'C8 intrinsic ~ntibactcrial :IoC\l1 ity but potenuate~ the acli .."y of ampid1lin and curbc:nicillin agaillst ,8lactl1ll\ase·producing S. aurt'11f and mcmbcl"$ of the Emerobactcoxc;\C fam;ly. II Iloe-i nOI. howe>·n. syroergi.te with cilhet" carbenicillin or licarcilJin against P. IluuRinosli stnlillS I'!'$ismnt 10 lhese agents. Failu", of sulb.K1l1m 10 pcnctnllc the cell cnl'c!opc is a posSible explanation fill" the lack of S~llC rgy ,
are
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, n baCl(
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.-
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b "", Ihien: "~ A.
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moo IlIItibi s),ste. III its
Approved i combination lum cndomctriti ~.
for lhe
"«d,,, !lvati( of lhe ~I~
by caused by ;njlu",,::pe.
CAR BAPENEMS Thienamycln. Thicnamycin is a novel ,8-1ac:larn'" OIic fi"" isolHled nnd Ident ified from femlenlne;o'l of It of Struclure WId absolute spcclroscupic~JJy und by t fealu",~ of thicnamycin a", (('phalosponn~: II fUM'd lacuun and lin other respects. panu", from the elie system con"i~'s urbapcocm containin; • bond between C-2 lind C-3 (i.e .• il is • 2-cartare-." .J1-carba\X'llCl1l. system). The double bond in lhe
drolyt
ChaIMer 10 . A",ibnc,malA""InOlin
I
.!IUo.'1urc: creates COf1sider:lblc ring strain and increa.t extensive ('linical evaluauon.f>6 lt has reOffie
SemJsynthetk Deriv.tlves To date, the more uo;efu! scmi'ymhctie modifications of the basiC 7-ACA nucleus have rt'Sulted from :toCylations of the 7 -a mino ifOUl) with diffcrcllt acids Of" nuckopbilic sub~tilu tion or redlM.!lion of the acctO~) I group. Slructure-ac"~lty relation~hips (SARs) among the ccphalosporins appear to paralkllOOsc amoogthe penidllins insofar as the acyl group is concerned. The presence of an IIl1ylie accto;\yl function in the 3 position. howe\C:J". prm'itks II react"·c ~ Ile at which various 7 ·ucyhlminoccphal~nic acid structure( can easily be varied by nucleophilic displacement reactions. ReductiOll of the 3-acrtOXYlllethylto a 3-~thyl substituent 10 pre. potrc 7-amil1Odesao:.:etylccphal~pomnic OCIU (7·AIX:A) derivativC:5 can be accomplished by catalytic hydrogenation. but the proce.ss curremly used for Ihc ~"()i1lillercial synlhesis of 7-AOCA derivati\'cs invoh'es the rcalTllllgl'l11('1l1 of the corresponding penicillin su lfOlridc.l~ Perhaps the nlOSl note\Io"Ol1hy deveJopmcnt thus far ,~ the disco\'e!")' thaI 7-phcnylglycyl derivatives of 7·ACA and especially 7-AOCA lite active orally. In tho:: prepotrntiOll of semisynthetic ccphalosponn~. the following improvements are sough!: (a) increased lICid sta· bility. (b) improved phannacokincuc properties. particularly better oral a~ ion, (c} broadened IIm,rn lcrobial 'peclrum. /d) increa...:cd aclivity against resi~tam microorllan,sm~ (a~ a result of resistance 10 enqmatic dcstruction. impro\'ed pene. tration. increased receptor affinity. etc.). ( t'} t.leed allergemci1y. and (j) Increased tolernnce ufte r JXlrellicrnl adminisIr.Ition. Structures of cephaJO/oporins cum:ntly nturiell'd ill thoc United Stales are 5hown III Table 10-4.
chemk_' Oegrada-tlon C ... phalosporins experience a \'ariety or hydrolytIC degrada lion rehctrons whose speci fic nmure depends 011 the intli~id.
TABLE 10-4 Structure of C.phalosporlns ORAL CEPHALOSPOR INS
"
" -0',
...
....."'" CefU",. in-.. .. till
00
-s-
00
5
s-
00
...
00-
Cd,...,nl
"
- 00
--CO"
c,.....
,
-ctfopo nns IS bc:lie\td to gi\'c inilially ceph:dosporoic acids (in "hlch the R' group is stable. e.g., R' - H or S helerocycle) or P'X>lbly anhyrlrodc:.'illCelylct:phalosporoic acids (for the 7'lICylamlllocephaJosporJnic acids). It has 001 been llOS,ible to i~nle either of these milial hydrolysis producl ~ in aque. OtIS sySlems. Apparenlly. both types of c.:phalo,pornnic ocid undergo fmgnloCntmion reactions that h3\'e 1101 ~n ch:II1~ teriud fully . Studie~ of the in vivo nloCtaboli~mlO of ornlly admlnlstcred cephalosporins, however, have dcmonSlrnted IIr) I:lCCtylgJ~cines und arylacemmidoethanols ... hich are be· liC\ed co be formt'd from the corresporl(hng aryl:.:etylumi · rlOOC\'laklchydcs by ml!tabolic 0~id3uon arKI reducllOn. rcqICClI\·cly. The aJdeh)dcs. oodoulM. ari)C from noocnl.ymatic hydruly5i~ of~ COITeSJlOfIdlllg cephalosporoic acitb. No cvidence for lhe intnllnolC'(.."u lar opemng of lhe P.lacUlm nng by ~ 1 'lICylamioo o~ygen 10 form ouzolooes of lhe pcmcillamc acid t)·PC: has been found in the ceph3losporins. At neutral 10 alkaline pH. howe\cr. ii1tr~lllOleculllf
aminolysis of tne P.llICtam ring by the a-amioo group in Ik 1·ADCA derivall"es cephaloglydn. cephroldme. and cdldro~il OCCUI"$. fanning dilctopipenu.ine deri\'ati\'es?~ 1Ol'bed orally, presumably beeause or ... yolysis ofthe 3-aceto~~1 group in the low pH of the SlOI1lIII1 'TOO l'l'Sulting 3·h)·dro~ yl porins are signi lkantl) le~ NeIlS;U I ethan all butthc ,B-Iactamase-re~istant penicillins to hydroly~is by the enqmc:s frolll S. tJljrtUS and Bacillus sIIb/ilis. 1lIe "pcnicillinase" resi~Ulw:e of cephalosponns appcan to be. propeny of the blcyc lic ccpllem ring ~yMem rother than of the 8C) I group. \)csplte nalUral resistance to staphylococcal p. lacuma.se. the different ccphalosporins n~hlblt considemblc variation in rates of hydrolysis by tl1c enzyme?' ThU). of several cephalo~porin, tested in vitro. cephu lOlhi n and ccroxitin life the most resistant. and ~phalondine and ccflUo lin life the least resistant . 1llc same lleyl functionaliti~ that impan ,B-luctanlBsc resistance in the pen icitlin~ un fortunately render ~'CphalO!>pori ns vinWllly inactive against S. IIUrtUS IU1d other Gram-positive bact,",ria. ,B-Lactamases elaborated by Gram·negatl\·e bacteria present an exceedi ngly complex picture. Well over 100 different enzymes from various spcci,",s ofGram-neglltive bacilli rowe been identified and charactenled,~~ differing wido:ly in s~· ificilY for vurious ,B-llICtam amibiOlics. M()rnl features confer broadly based resi~anctll .8- l llCtaflla.se~ among the ~phalosporins: (a) an alkoximHID function III the anll ll()llC)'1group and (hI a methoxy l ~bst ... ent 8t the 1 j)O"Joit'oo of the cephem nucleu~ h.a~lIIg a stmoclle mistry. The "tfllClun:s of sevcm l ,B-IlICHimase-n:sI>/at cephalosporins, including ccfuroximc:. cefotaximc. cefli./m· ime, and certriaxonc. feawn: a methoox illlino aC)"1 group. p. L.octama indicated thaI OIher factOfli. such !IS perrneabi~ lIy and intrinsic IICli ~ily. are frequently mort important. TIle L-mandeJoy l isomer is Significantly less ICII'e than !bE D isomer. Cefamandole lIafate i~ very unslable in solution and h)· drolyteS rupidly 10 release cefam:mdole and formate. Then: is no loss of potency. ho....e>cr....·heu ~UC:h soIuliom IIr stored for 24 hours at room lempIet.l a.odlWII ~.
r.lcWrin Sodium, Sterile, USP.
Ccfoxitin (Mefoxm) I Knu,)nthetic derivllt;\'e obtained by modification of ."~YClll C. n 7(\'-nletho.y -subst ilUted cephalO!'e desacelyl mtTabolile. ApproximaTely 20% of the metnbolile and 2S r:l of Inc parcnl drug are excreted in the urine. The patt"nt druB reaches the cerebrospinal n uid In suffICient concenlration 10 be effecl ive in !he Ireatment of nWo!ningilis. Solutioo.~ of ~"C:fOOlxime sodium should be ue Pro/t UJ spp .. and S. marcesctnJ. CeftilO~ifOC' is claimed 10 be mo re &clive than eefoxitin againSI D. /roSiUs. II is also ,'cry acti\"e aguinst Gram· posili>e bacteria. its octivJly agalnS! P. fltrvSUWMI is sonIC"hal variable and lower than that of either cefOiax imt or cefOfXra,~ -
""
6 '-
1-
k
~
4' o
'0
", "
"""""'. USP
Tbt ct)I)lparllthely 1000g half-life of cefixime (I. is J
.
10 4
) .lIows ilto be administered on a tWlce·a·dlIy schedn:absorption and a relatively hIgh fl'llCtlon binding (about 6S % )contnbute to the 1000g two o"IlI dosage forms: 2()()" Of 4()(). for the pn:par.uio n of an aqueous
Sodium, Sterile, USP. the fim thIrd-generation
I., It 's
(Cla-
wbe
;;;I;;:~
&ch'e moxalactum againM organisms. Many ,8- loctllmasc-producing straill5 are S('nsi tin: to cefoc.a.\lmt. including ~pp .. H . inj/'WIIWt, S, flUrtlU, no! all. PstudomoooJ SlnUns an: Enlei .......... d and U s/tna mQfioc"fORtllt~' are re~i5IfIOI'e
Ceftizoxime i ~ not melabolized in vivo. It i ~ excreTed largely unch:tJ\ged in the urine. AdeqUaTe le>'cls of The drug 1lIe ochie>'w in the cerebro&pinal nu.d for the IreUTnWo!nl of GrJIll -llCgalive or Grdm-positi>"C: bacterial meningitis. It mUSI be iIodminiSlered on a thnce4aily dosing schedule because of it s relatively s tlorT hal f-life. Ceftizoxime 50dium is >'ery stable In the dry state. SoIutiOO!l mainTain potmcy for up \0 24 hOllI"$ al room lempenllure and 10 days when refrigermed.
Ceftriiuone Disod;um, Sterile, USP.
Ceflriaxone (Roa:phin) if a ,8-1lll!l.ilmaSC-rc:$i51anl cephalosporin ..... ilh an t)ttrenWo!ly long serum half. Ii{¢. Once·daily OOsing suffices for most indlC'lltions. Two factors contribute to the prolonged
duration of :lCtlOll of ceftna:lIOne: high protein bmdlng in the pillsma and slow unnUly e)(~rerion. Ceftriaxone is eKI.:«:tcd in both the bile and the urine . Its urinary excretion is not afftaed by piobenc:cid. Despite lIS romparati\'dy low volume of disrrilmtion, it reach~s the cerebrospinal fluid in conCC"IItr1II.lORS that are effecti\e in n~ningltjs. Noo linelll" pharmacol;.metiC!l are obseo·ed. ~.
('
wres: (oj a 2-mcthylproptOflloouo\lnooeyl group !hat c0nfers ,8- lactama.o;e rt's islance and. possibly. 11lCrt'lISed pcrTMability through the porin channelS or the cell envelope. and (b;a pyndinium group at the )' pi)S.lioowa1 C()(Ifers l:WI~ ionic propenies 00 the molecule. Cefta7.idimc is administered parenterally 2 or 3 timn daily_ dependin!! 011 the Rlmt)' of the infectlOll. lUi serum hair-life is about l .tI hours. It has been used effta"'ely for the treatment of meningitis caused by H. irif1lum~ and N
or ,r ~
"
m~njngilidis.
••
".
NEWER CEPHAlOSPORIN5
CeIInuone DIE 'llun
Ceftrillone CQIltains a highly acidi c ocu:rocyclic sy~tem 01\ the 3_thiOlllethyl group. Thi ~ unu~ual dioxouiazine rinll system is bel ieved It! confer lilt! unique phannocokinclic I'lOperties of th" lI,I;ent. Ceflriaxone hII~ been associated with sonographical1y detected "sludge:' or pscudohthiasis. In the gullbladderand COn1l1l00 bile duct .9J Symptoms of chole· cystitis may occur in suIlPs, in particular ,he POP 23 (or PBP2') of MRSA.l ' The o/):,en'mioo Ih.:it cenain catechol·substi tu ted cephalosporins uhlbil marked broad-spectrum arlllbacicnai act. ~i l )' led 10 the dl" c{wcry thlll ~uch l'Ompound~ and OIher ana· lotlucs capable of chl: lating irt)fl CQI,Ild mimic MiUra! ~idero phom; (imn-chchll ing peplides) and thus be actiyely Imnsponed iruo bactcnal cdls yia lhe /onB-dependc:nl irt)fllf1lnspon syslem.97. 9f; Thi~ provides a nl('uns of auacking bacl~riaJ Strains thai ~i'l ccllular penetntlion of ccphalosporin~ .
./ AJlepin) ;\ a p.vcn1hm I ~ chenucall), II alstitliled 1.3-diumlnocycloheunt cenhi ~: in kan:Ullycin. neomycin. gent:unicin. and tobra"Jtift. It IS (\eol(ystreptam.lll'. and in streptomycin. tt is *tpIIdme. 'The aminoglycos.des are mus strongly basic llCfiOUnd$ mal exist as polyutiOlls al physiological pH. ~ lDorzalllc acid salts are vel)' soluble in Wlter. All are nlabk as sulfates. SoluliQllli of the aminoglycoside ~IIS 1ft Sllblc to outoclavlng. The high walcr solubility of the >&I)'t'Nldes no doubt conlTibulC5 to their pharmarokipo¥r1ICS. TIley distribute well Into roost body nuids .. not into the ccntral nCrl/OIlS system. bone. or folly or • • live 1l$WeS. They tend to concentrate in the kKlneys are e.lcreted by glomerular filtrauon. Ammoglycoside!; _lI'PjlOlllinked tmllSfer of the aminoglyco«odc: through the ccll_ brane then oceUI");. Divalent ca lions ~ucb as Cal. and anlagoni:t.e the I mnspc:l(l of .mi llogl)Cosode.~ mlo '*'tnI cc li s by inlerferi ng wi tllt l'letr bin!.! ing to ce ll melllbra~ pbo!p/IOl ipid). The Il'SISIance of unael obic bacteria 10 t~ Ic*I action of the aminog lyCOSldcs IS apparently due to SCI1l,."e or the. ~pirntion-drh'e" actl\'e-lransport prom.! t r:ln~ I)OI"\lng lhe an tibiotICS.
OOse""'oo
Mr
tht"
Structure-Activity Re lationships Despite the coo. plexity inherent in various am,nogl)~. 5IructUTtS . ..onle conclusioru; o n S ARs in Ih is antibl(l(ic
ANT... •
\ IiO
/
m
'"
ANT·2". APH·2"
11
NH,--AAC~
Figure 10- 7 • Ir\actIValJOn of kilflMn)'Con B by I~ l.aj enzymes.
Chaptn 10 • An"~I~"'" N"'bltlIO('s
lllve been made. Ll' StICh cOIlC!uslon~ ha"1: been fonnulaled _the bMis of comp.1n50nS of nmuraliy occurring ~minogly cwde $IfUCtIII"eS. the ll.'IIullS of selective: semisynthetic modibIoos. and the elucidation of SlIe:!> of inlll,:'lll':llloo by bac· ImII enzyrtlCS. It I~ con ~enicnt 10 di!iCUs..~ sequentially .rnnoglyCQSidc SARs in IcmlS o f SllbslilUCnlS in ringl I. 11.
_m.
331
toward light and air. It is freely soluble in .. mer. fomllng solutions that ate slightly acidic or nearly neulral. It is vC'1)' slightly soluble m alcohol and I~ insoluble III IIlOSI ochtf organIC soIl·ems. Acid hydroly~is yields strep:ldll"lC: and streplOoiosamine. the compound Ihat is a combination of 1.Streptose and N-mclhy l-I.-gluCOl\amine. ~
RIIIg I is crucially Important forcharat1erislk broad-specrum IIllibactcrial actiVIty. and h , ~ the primary target for bltlrrial inlk:livaling enzymes. Amino functions 31 6' and particularly important as tanamycin B (6"3I11ioo, 2'· ....oJ IS rrlOfe acth'c than kanamYCin A (6'·amlllo. :Z'·hy"'hid! in tum is mort: acl i'~ than l3namycin C (6'II)tkulyl, 2'-aminol. Methy lation at either the 6'-carbon or .. 6' 'fl luioo po~ition s doe~ not lower appreciably anlibaclC·
tyoI - l - Htl'",OH
SIr8p!kione
""
r.wt .rl).
IIIIIICII\;t)' :md confers resistance 10 enzym~lic acetylation ~tbI: 6'·.nuoo group. Remo\-al of the )'-hydroxyl or the r.J\~dro~yl group or both in the I;anamycins (e,g .. 3'.4'. dideot) kanamyci n
I
1
•
R ()I" dibekacin ) does
n:Sitle+bind + IIJ wcs In bacterial n~~. n.. modJflCalton~ of nng II (liemystrep:amine) runc IiDlaI lrouPS are posSible ... ithout appreciabl~ loss of activity • IOOlIt of tile aminoglycosides. 1lic I-amino group of 1;811a· ~ A ean be acyl DIed (e.l .. umi l acin). however. with ...nil)' largely retwned. Netilnllcm ( I-N-c:lhylsisomicin) rc!be antibacterial potcncy of ~iJ;Omicin and is ~istant 'Htl'ml addi t;oual bacteria·inactlvating cnzyme~ . 2"- l-I y· m~slwnucin is claimcd to be re:~i~HUll to b!lcterial slrnin ~ . . acknylate !be 2"- hydroJl yl group of ring Ill . whereas ~tno!liwmkin t~htb1l~ good activity llIainst bacterial JI2IIIS that elaborate 3-occtylatlng en/ymes. Rlnl III functional groups appc:ar to be somewhat less ft!oIOI'C to structural changes than those of either ring I o r l1li11 Although the 2" -deo" ygentarnlCins are slgnificlUltly actJI·t than theIr 2" -h)' dro~yl countCfJXlrts. the 2" -amHlo *"1"3111'1:3 (se idomycill.) are highly acth·e. The J"-ammo pwpOfgenlanlicins may be primary or secondary with high •• _Imal potcncy Furthermore. the 4"-hydroxyl group ..,. ~ Q.fl/ll or 'c~idic l ink~ v. ere ass umed 11,1 be tl'. Hucllcnrnuch III later sUGgested. howcver. Ih:U both of the dihmmu sUI,::trs in nromycin C ha\'cthe Il·gluc~ cunfigu!'lItioo Qnd that the gl)..osidic link j . {j 111 !he one attached 10 D-nbose. The lana Siereochc:ollSlry has been confirmed by the tOlaI synthesll lll Qf ne~mycin
n
cn
e
Paromomycin Sl,Ilf~te, U5P. 1lle isolation Qf ~ m)'cin (li Ulllalln) was reported in 1956 froon a fennt:Dlatl(ll Wlttz ~ SIrt'pltJmYCtS sp. ( PO ().t998). a Stram s'[ud 11,1 resenmk S. mnosus very closely. l1le parent organism had been Dbtllin..'ti from soil sumplcs collected in Culombia. ParomortI)'· Cln, however, motl: closely resembles neumycin ItI1d stn'ptO11I)'cin ill anU biotic IICtiv ily than it dOCli uxyletrucyctlllt," un liblotic ubtained from S. rim05US.
nora
',",
_ c .,if. . "{'\ ~
Deoxystreptamine
_c
[).RlX It
--
'.
"';) t;'\.... NeosamiM 8 Of C
-~f.er~1..... ~
,
o-OIuce77~
Neomyci n as !he 5Ulfatc sail I~ 11 ... hite 11,1 shghtly yelluw. crySlalline powder mat is \cry 'IOluble in lValer. It is hygro§l:opic and photosensiu"e (but SUlbIe Q\'er B wide pH r.mge and to autoclaving). Noomycm su lfYle clants in aqueou~ 'IOlutions of the add ~ II" (Table 10-7). The paniculill' funcuOflnl l! l"OUp< responsibk for each of the themlOd) IIIl1nic pK. ,'alut, \Io ere determilled by Leeson et alYo as sho\lon in the dlllgmm belo\lo. The'C ~pmgli had been identified pre .. iou~ly by Slephens el al. I' a.~ the sIte;; for prot0nauOtl, bul their earher assignmem). \Ioh ich produced Ihc: ..alues re~pomi bk for PI1. '" 1kM, doxycycline and rninocyclinc: nre a~bed more COI\II*td! follo .... ing oml administnttion. exhibit higher rr.octlM!" r
Chap(~r
TABLE 10-8
',C
"•
, , -.
" ••
"- N
•d ,
"II 0
OH
"
-,
"
,--
-,,•
•
,
~
~,
~,
OH
""
1,( 'y N',
,~,
00
-I
0
0
b~
O ItVlb :11or> _1vh1)
...
n~
~
~,
h",,_
~
~"
~
,-,
~-
em""""'"
'.7) "" I
1~1iU6
~
,~~
'" · I(l~
~
'!-'101
_n
~n ~
1.10
~
Il0. J R• ..., ~ Iond. S, Adv ""'" , ' 01. ClIo ..... ",1 6 1. '\ _ _ ..... QoIu.... J 1...-.1 K- . ~ a.; I ___ s.: ~lII l lo1. 1W>9
"
II
1101...... of
!\ht, b.d Or ..I,
,~
~,
, I ....~
r
..
,. ,. ,. .... 5.'· "' , " ..... "... , '"'" 0" , , , '" ,. " " boo" ...... , '" " ",,01.10 " ." " " () .\........... r""" ~
,,...P'
-.. ,., --" ,., -"'"" " . " " " ... " • , ... ""• >. "" '" ,. " " " " . n" ,." " . " '" "
'. ~w.,..
Subotll-.b
, ......yd...
......... CH.
'"
I
"•
"•
345
PharmlKoklnetic Proptlrties· of Tetracyclines
"
•
HI • AnlllNlC'lrntli Anllbim,a
II
~"
IM · ~
,s-,~
1 ~71 ,
•
•,
, ,,• ,
• •
j
-, , •
,,
•
-, •
,
•
•• •
r
plow protem bmdmg. and II:wc higher ,'oIUme5 of di stribuIIlII and 10\\"('1" renal dC31110CC r'J I l'~ than lhe COITC~pondin!; "" ytttrao:yc liM's. Pobr subsll lucnts (i.e .. h)drox)'1 gll)(lil"i) 31 C -5 and C-6 c lipid versus .....ater solubility of the tctTllCycline!i. Tbt 6 positiOn is. hmI·e,·cr. cOllsiderably lOOn: sensit!>c titan LIIr ~ po>lti on to thi s effecl. Thus. dox)·t)'cline (6-dcQ"y-S.}1Ctrxycilllcj ha~ a much higher partition coeffidenl than tetrat"ydine or oxytell1lC)"clinc. Nonpolar SUbsliluems with posith'e IF \'alue\: see Chapter 2). for example. 1-4i1neth)l;unino. 7--chloro. and 6-melhyl. ha\e tbe OPPOSIIC dfca. Accordingl). the part ilion oocfficienl of chlor1ctTllCy. . is ~ubstllllli3i1y ,reater than Ihal of letrncyclmc and ply creal.:r than that of dcmecloc)·ellne. IntcR$tingly . .mocycline (S-demclhyl·6·deox y-7-dimelhylmninOtell1lCya. ) has tbe highc:sl parmion cocfrlCicnl of tbe commonly
1_
water-soluble COllI oxytclrllC)'clinc can be IIllributcd to In i their oompamtivc difficuhy in IIr k! membrancs. lhe tetracyclines JH1l'bat rI1Ctal ions in the gut acid--catalYlcd de'lrtlclioo in the stomach. With bdillf)' excretion of I 10 cause a higher incidence from rc~i~lanl microbial ~l l1Iln~ 111e rTlOI'e ,~,'. howe\er. are extretcd In higher ronccn In urine (e .g .. 60% for ICtnlCycline and 70% 1IrOJ:)IWllC)"Clinc) than the more lipid-soluble romroonds !q.. 3)% for doxycycline and only 11% for minocycline). fanl passi\'e renal tubular rcabso,puon coupled with '-fI1Ictlon~ of protein blndmg 00I11 nbute.~ to the lower ItlOR\
renal clearllllCC and longer dUTllli{)ru; of action of doxycycline lind minocycli ne compared ..... Jlh Il105e of the OtiK'r ICtracyclines. especially letl'1lC)"chroc and oxytctnlCytJine. MlllOCy cline al'. It differs from cliionetnlcychne on ly ;olhe Qbsence of the nleth)"1 group on C-6.
...
o ,r
"-
(hytelracydlne Hydroe/'lloride
O.. )\CIllICycii ne hydrochloride IS II IXlIc yellow. bluer. ~ltioe
rompound. The amphoteric ba.c , ~ool)' sli,hlly soluble in waleI' and ~ hghll y soluble in alcohol. It is odortc.~~ IIId stable in all' but dar~ en~ un exposure to ~I rong sunlight . ~ hydrochloride '>l'I 1I is:l. stabk: yellow powder lhal is !nore bIntr than 1M r~ b:be. h is much more soluble in ,,",uer.
II
dissol~Hlg
in 2 mL. and
n~
soluble
In
alcohol than
_ free buse. Boll! compouoo$ are inacli ,·ph.'d rapidl y by albli hydru~idcs lind by lICid M:lJmioos below pH 2. 8 01h ~ of oxylclfllCy, line are absorbed rnpidly and equally d from the d'gestl\c 1tOCt. 'iO the ()I1ly real oo\'anuge the ~ base offen over lhe hydrochlomk a ~trongl ye llowy10acidic dark .~~~;~d~cr, because the cstolW, 1Il0le eJ.tcn 'i~cly protcin bound thnn crythromycin it~lf MellSured fr.tCtions of plasma protc:in binding forl'l')~ c;n·2'·propionate and ef)thromycin base range fTOOl O,~" 0,98 for the fomler and from 0,73 to 0.90 fOl' the 101C1C1. indicanng a much higher levd of free erythromycin p\a.'ima. Bioavailablhty studlCJ; eompanng eqUi\'a\ttlt of thc t:'nteric-eootcd ha5C, tile Sicamlc ~~I1. toc t:'th)lsuconail' ester. and the 1!.~1I)1~le I!.~tcr in hunmn "oluntCt:'l'SllI1. showed dt'llyed but shgbtly higber bloon,ilablht) for free base than fOf the stearJtc, clhyl~ucclna'e, or estblt One study , oompanng lhe: clinical cffcctl\croe~ offttllll mended dosc~ of the ~lCaratc:. C'\!olatt'. cthyISUCCi~. free base: in the trealment of ",spir-J tory tfOCt In~ fa.iltd 10 tlcmol1!itnuc substanlial differences among thtm. Two other clinical st udies. rompanng the: effeet.i\'CIICSI
"'II.
111*
dle de,·clopment of atherosclcrosis lind is known to occur in diabelc.~,
Severe hyperlipidemia may lead to life-Ihremcning macks of ocute pancreatitis. II also seems Ihm Soevere hyper~pidemia cnusts xanthoma . Considering !.he effeclS of insu~n on lipid metabolism, as summarized above. one can rarionali7.e th~t in type II diabetes, in which the patient may lIttuaJly have an absolute e~cess of insulin, in spite of the ~,ide~ of glucose tolerance tCSts. the effcct of the e~CC'S51"e insu lin on lipogenesis in lhe Ii "er llIay suffice to increase ilK Ie,-ds of circulating triglyccrides and VLDL, In type I diabeles. with a deficiency of insulin. lhe c irculating Icvd rn lipid~ may rise because too much precursor is available. fIlth fatly acids and cnrbohydnues going to the livcr, The: relalionship \)ct,,'een the carbohydrate metabolic rnanifc5lations of diabetes and the devciopment of microand macrovascu lllf diseases /las been studied cluensivcly. se.. l>l lt is becoming increasinglyclcllf thm hyperglycemia plays I major role in the developmem of vascular complica tioflS Ii dJntes. including i11lcrcapi lIary glOJncrulosclerosis. prelIl3Jure atheroscleros is, relillOp.1lhy with its specific micll)lIJIeury~ms and retinitis prolifenms. leg ulcel'!!. and limh ganFtrlC', Fi~t , hyperglycemia caust~ an increase in the act ivity a( lysine hydroxylase and golactosyl trunsferasc. t""O importan! tnzynH's involved in glyroprotein syn lhesis. Increased !Iytop~ein syn thesi~ in the collagen of kidney oosement o:moome may lead to the developmem of diabetic glomcruklsclerosis. Second. increased upmke of gl ucose by non-insu.lin-sensitivc tissues (c.g .. nerve Schwann cc lls and ocular \ellS cells) OCCUr5 during hyperglycem ia. Intracellular gl uCI'lIt is conve ned enzymatically first to sorbitol and then to fruct~. ll1e bui ldup of the.'iC sugar.; inside Ihc cells intIl:llSeS lhe o:.mOlic pres~ure in ocular lens cells arid Schwann cells. r~ulting in increased walcr uptake and impamng cell functions. Some forms of diabetic Cal:lraC\s and diJbetic neuropathy are be lieved to be caused by this pathlI'l1y. Third, Ilyperglyccmia may precipilllle IlOI1cnzym"tic
TABLE 25-7
glyrosy illtion of a variety of protein~ in lhe body. including hemoglobin. serum albumin. lipoprotcin. fibrilHlgen, and basement membrane proIein , Gl ycosylalion i~ believed to alter the tertiary structures of proteins and possibly their rule of metabolism. The rate of glycosylation is a function of plasma glucose eoncen\mtion und lhe duration of hyperglycemia. Needless to say. lhi~ mechani~l1ll1light pl ay an important role in both macro- and microvascular lesion •. Finally. hyperglycemia increases the rute of aggregation and agglutinizution of circulating plalelets, Platelets play un imponam role in promoting atherogenesis. The increase in the rate of platelet aggregation and ag glutin i:rution leads to the development of mi CTQCmboli, which can cause tran sient cerebral ischemic allacks, strokes. and heart attacks.." Concepls of the therapeutics of diabetes mellitus havc been reviewed by Maurer.60 Thi s review cmphas.i7.es that insulin therupy docs rIOI always prevent ~rious complic ations. Even diabetic patient~ con~idcred under insulin Iherapeutic control experience wide fluctuations in blood glu~'OSC concenlration, arid i\ is hypothesil.ed Ihat these fluctuations eventually cause the seri ous complications of diabetes (e.g .. kidney damage. retina l degenerntion, premature atherosclcrosis. cataraclS. neurological dysfunction. and a predisposi tion to gangrene),
Insulin Prepararions, The various commercially avail_ able insulin preparations are listed in nhle 25-7, Amorphous insulin w...~ lhoe fi~t fonn made available forciinical U.' C, Further purification afforded crystalline insulin, which is now commonly called' 'I't'gular insulin." htsulin injection. Usp, is made from line insulin crystllis. For some time:, regular insulin so lutions have been prepared al II pH of 2.8 10 3.5; if the pll were increased above tile acidic rangc. panicles would be fomlcd, More highly purified insulin , bowc\'er. can be maintained in solution over a widc:r pH rnnge. even whcn unbuffered. Nelllral insu Ii n solutions have
Insulin Preparations "'rtide Sizc
~
(~m)
Action
....., ""'""
....,,1,. mJ'1 -36
Intenned, ...
Glooln' ' ZnCI, .. ,"""I'n
~4--).8
1~18
Loos,.,ung
1'\vWn,"'" + ....ulla + ZQ
1_1_7,4
Pror"",,""'7.nCt, in.",hn
1,1_7,4
''''
~fi"
'Oar .. oI_c ....
"
"'""'-
11,0-1--' ".t100 USf' ...... ofiooutin, _ .. ' , " (O.l-O.6 ..,.100 USP ..... , of,_I .. ~ . , .
I'
' "
.
+ LnCI,
Imermeti,"e
'OIobIo (.\1>-',0 ".tlOO USP ""'" 01 i........ oJ ",,,.«1 fn>m
S-,
1..... lin
""",,"IX and m t elucil.lmcd by Celtner,! 19 The structure consists of IWO sugol" and a 14ring designated an nle(lllflofidc . Orte of tnc 1'K'.'iCm In erythTOlll)'cin: the other sugan; arc IHlked gl)'cosidil-.. lly to lhe POSItionS. respectively . of oleanoolide ,
...•,DI,
""
H.c-......., /
01,
0-.,
lINCOMYClNS lllC l incom} cm~ art' sulfur-comainlng antIbIOtics isolau:d from Sfrt'IIWIIJ'CI'S lincQ/I1(,"l;$. Lincolnycin i~ tile must ac live ~nd medically useful of tile compotJnl.l' nblaitlCd frum fenncnlalion, Extemi\c cffons to nM.k lify the lincom)'dn SIJ'UI.'urt' to 11lI['II'O,e its antIbacterial an(] pharmacological propeni~ f1!,ultcd m the prcparutioo of the 7-cbI0f1l-7deeny derivuli\c elin(]atn)'cin Of lhe two ani ibiOlin, clinda· mycin appear.; 10 have tile gn:;:Ilcr antibaclerial f/Olcrw:y aoo beth:r ph;trln:K:o~ i ne:tic provcrties. L",coll1ycin~ re;;cmblc macrolidc~ In antiba for scven: outside !he central system. not be used to treat rutor)' 1l'lII:t i caused by bacteria sensllne 10 !NIfcr antibiotics or in prophylaxis. i I Clindamycin is absorbed rapidly from uact. e\'en in the pre,sence of food. It IS avai lable IS crystalline. watcr-soluble hydrochloride h)'dr.t1C: und the 2-palmittue ester hydrochloride salts in
.,,.,
forms and as the 2-phosph.ate e.-,ter in Details of the binding ..'en: eluci dated by the elegant NMR Sludics of Willillltl!lOll ct al.m TIle action of ~ancomycin leads to lysis of the bacte rial cell. The antibiotic docs not uhibit cross·resistance to .B-Ioctilms. bacitraein. or cycloserine. rrom whIch il differs in medunism. Resistance to Vancotn)'C1O among Grum·posilil·e cocci is rare. Hi gh-le~eI resistance in clinical isolates of enterococci has been reponed. however. This resistance is in resJIOO!ie to the inducible production of a pmtein. encoded by vatlCOm)'cin A. that IS an altered hgase enlymc thai cauS" the iocOlpOlation of a t>-alllnlne·o--loclll1e dePSIPCptide in · stead of the usuaI1l-3Ianine-D-alanlllC dipeptide in the peptidoglycan terminu s.UII The resu lt ing peptidoglycan can seUI undergo cross-li nking but no longer binds vancomycin.
"'0 ""·
0 0
MO,,,
I
"')"
0
•"
• "
'"
""
'"
I
'" '" ,
0
'"
0
"
",NIl, .
""
'"-'"
~
Vancomycin hydrochloride h alwny~ adm inblercd inll'll\en()\l~iy (ne"er imlllnluscuiarly), either by ~Iow inj«tiOfl or by l'()nllnuOilS infu510n. for the lre.llme m of syslemic infcctiom. In V,OfHerm therapy. the to~ic ~Ide reactions an: uwally ~ht:ht. but cOfltinued U.'ie may lead to Imp:ufl'd :mdi· tory acuity. renal d:unage. phleblus. and roshcs, Because il is not absort>t:d or signlfi('lllllly degl'3dcd In !he gaslrointestinal truel. \aOCOlTl)CIn may N administered orally for the In:alment of 5taphylococcal enterocolitIS alld for pseudomcmbraIlOOS colitis llW)Cialcd IHlh C\indam)cl1\ therapy. Soo-.e.COflversiOfltO aglucovancomycin likely {)Ccu"" III the low pH of lhe MOl1lao:h. The 13uer retain~ about thl'l.'C-foun hs of the octil'lly of l'ullCOl11ydn. Te/Cop/im/n. Teicoplanin (Telcholn)'cin A J • Targocid) is a mlllUre of five closely related glycopcp4ide antibiotics pruduted by the actmomycete ACfill()P/IU1~S f~icllO"IW:t'li· cus.1-., 1.011 The leicoplan in factors differ only In the acyl group m the IIOI'1hcmmost of 1\100 glOCOf,llnuJIeS glycmidically hnlcd to lhe cyclIC pcpIidc aglycone. AlIO(hcr sugar. Il-manrtOllC is common to all of the: tClcopi3nlns. The Slructu ~ of the: telooplanm factors ",ere determined independently by a combination of chcmkal dcgradationl-O I and Sp«tI'O'oCOPIC.u· l .tl methods In three differem groups in t~.
The: tcicorl 3nin complex IS ~i milllr 10 v311comycin stmc· lurolly 3n.d microbiologically bUI has umque physical propcrtie..~ lhal conlri bute some potentially usefu l D(h am:lgcs.J.U While retaining excclk:nt watl!r solubllily. tcicoplanin hru; Significantly greater li pid solubili ty thall vancQmyci li . Thus. teiwplan m is di'itribulcd rnpldly Into IlSSUl!S and pc:nctnuCIi ph.allocytc.~ ""ell. 11Ic. CQfI1plcx has D long elimination halflife. nnglng from 40 10 70 hou~ rt'SUltlng from a combin:lnoo of $low USliUC release: lind a high fmellOn of proIein binding in lhe plasma (approxmkltely tJ(')%). Unhlc vancom)·cln . tClCOplanln i~ not imlallng 10 tissue" and may be adnnmsterro by mtDmuscul1lf Of m,rn,'eoou~ inJCC, ion. Be· caust' of ils IoIlg half-life. Idcoplamn may be ad nll nistered
on a once·a-da), dos.ing t.ehc:dulc. Orally adnllnl",em! IncopJani n is not abwrbcd ~ignincanll y alld is n:t:Ol'Cred4(l" unchanged in lhe (-leu- l-Trp- o-Leu. c- Trp-
CO< I
",,_ 0
I l-Val-Gly-
0-""'" I..Trp-NHI
......... o-Leu- l -A!a·
I)-Val·l·V.~
'''\'* o-va/- l-Trp- C)-Leu- .-Phe- D-L..... . ·Trp· c-leu- l-T.p-NH
Vah -1I'1mk:idin
e
?"
(CH,),
I ........ !;>-l""- l -A/a· D-Vlll-l-VaJ- D-V8I- L·Trp- o-l _ .-Phe- p. ....... L-Trp- o-Lau- .-Trp-NH
II mixture of lyrocid1l-.es A. 8 , C. and D. ,,~ struclu~ hau: been dclcnnirtCd by Craig and l'O",ori;ns.:·~ m n.e 5), nlhe,;J of tyrocidme A WIIS reported by OIino el :II. lI'IO Tyrocidiroc:
L-Val
j.
-
L'Om -
I-
,.".
lIfiUiJdi ..... ,.. l\ioodllio'lfl B
_0
T)'I'OCIIine C;
.-Leu _
,-
"'"I - ,.""I - -
...,
Z
NO. 30. Douaf>cny. ., al. A...... ocM> A"",U Cheon. l.. J B:ocomollj'!Il.
s.""-.,,.
I....
"
,,..
Fosfomycin is a Drood-'IJCCtrum. bactericidal antibactcrial tIw InhIbits tbe growth of £.. co/i. S. nun-lIS. and Mrmllu. Klt'bm-liit. CitmOoclu. Entu/ICOCCUY, and l:."fllrro/xJc'tr spp. at a COllCClltr.lIion k:~~ th:!n 64 mgIL. Currenlly f(».fum)'!.'in is n:commcodcd tIS ~ tnilit-dol.c ther~py for ulK:Qmpli · catcd unnary tnct mfcctions. It possesses in \ itro efficacy stnuJar 10 thai of nori1o~lICm and trimcthopnm.sulramc!hcn . 31.01c. "oo;fomycin covale ntly inOClivatcs Ihe ti~1 ClIl.)rnc in the bacteriall'e11 ""all b.os)nthesis pathway. UDP-N-acctylgluco..:unme enolpyrul'}l Ir~nsfcra.~ (MurAl by ull}I:111on of the cysleine -! Ij re~;due. The inactivation ll'3Cuon ac ... u.... through llueloophillC opening of Inc !.'po~idc ring . Rc~islallcc 10 fO!'fomycin can occur IhfOllgh ... hrumo~omal mutations thaI ll'~u1t in rcdllC\"d u))tale or reduced MurA affinll y for tnc inhibitor. Plasnlid·rnediatcd resistance nlCChamsms in"olve conjugative bioinoctil'alion of tnc antibiotic ",ith ghnm hi01"1('. 1be freqlJ('OCY of rcsi~tant nllJlDntS in in vilro Sludie' hal; been low, and there arP'"ao; to be linle CrosS-I"CSlstance bet\\"('('n r~fomydn and other IlJUlh"lCtcriaJ~.
c~
n,
H. Du .... IC. JIbt.1 Al"nl> """ a..mothmop)'. ChioI. Rov 1993. aI.: BioI:hcm""}' 1J,,98. 1974.
n,ns.
~~~t~~~"":~"""~~'~"~5:
~
1976, 1981. 14 ], 1974
• P. G. (rtl.).
H_
Antimoorob. A...... Cherno CheMllllbor. I~ :~ 14. 1918, We,""ojll, hi J.. 01 01.' J. M.... Chen •. 6:463. 1%J. Cooper. D. J.• .. oJ.: J I.fed. Oi • . 119,)42. 1\16'). Cooper. D. i .....1" J. C1>em. Soc. C 1126,1971. Machi. II.. l1l-! 231 SkOm. D II .II.....,.~ ... I, K. S~ and S ..... n... "'. P Ii, An"u, lie" Ilia-
...,......Oonnoolber
""' m 01(0:723. 1m !.l2. McC.noucl. M
aI AnI:i~ An","", I'1SS_IIlSto. New yurt... M.... Ea:y1)011. I'l'IJ 2J9 Pomon. F .. ., 01 .' 1 A ... boot:. (foLyol 3 1.27/i. 1978. II .~
240. 1I.voI....., M II .. I'II~. M .. and C _ l1i. C .; I, Anflbiul. (I'''k)'\l) JU71l. 1918. l~ I Co.unclli. C .. ., II .. J An~bklI. (Tot~,,) 3762 I. In-t
2-12 IIun!. A II.. ~ 01. I Am. Chem s.oe 106.4891. 19lIooI, 2-13 8a/ll&. I C I .. .. al ,I Am. Chem. Sue. 106.• 891, 1\1801 W 8 .......... R. N~ andl'l:lm.. 0 H. ON, • • un. 1'l'U 2.3 1010-. 8 A~" aI. Sc •• u I02.J76, 19-1' N6. SIoIfel. W ~ ond C.... L C' I Am Cheal, Sue, 1],145. l\IIb) 247 R....... C.,owIKa>lclibr.O.V, I Am.Cbeoro,So. 101 ....... SIOU. Soc, Chem. Jpu. 19 17.\8. 19M 261.
262, M} ~
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no.
211
271. 213 27. 275. 276
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278 IN
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A ...... AIMlmoft. 0 S I Meml>r 11001 $\lU1, 1"1 8o,hch. I .... al' Scio;ncc 106:417. 1'141. CootroUli .. I.• ot aI, : I, Am. Clc .... So.;, 7 1:2J6.3. 1114I. p. 119 SbaI, •• L and Marl .. 'I. I. 211;111. 19$4 KauIT...... R. E. • ., aI. I. ~_ 99%3. 1981 K•• W 0 ... aI. J, CWo, PbaomIocoJI. 24 .1 81. 1\1801 Shoml. C, 11. • ., aI. J Am. Ckm. So.: 78: 1170. 111:16 Ikcbrlna. 11.. .,.1, J Am. Chern. Sox, 782019. 19.1oto S,.,,,,e •. C II .... al • I Am . Chom Suc. 78265'. 19$6.. $p:..:n. C .. .. 01. I Am. Soc, 8&. 140. IIISS. Gellon.. 104 .... al ",""", Naol Sci II. S. A. 13 4·41•. I"" SU,I ..... A~ .. 01 .. I'rt>.. Nail ,,&ln. E. B.• and Md"-. O~ J Cbem. Soc'. Pnl •• T..... , I ~
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2i3. Golt.t. J .• I'cny. II10tbef )7,)2. 19\13. 214
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SELECTED READING
00Id0nan. R. C. ' .....,..,.
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Antiviral Agents KltIN M BEAlE, JR. \1!U1It!i
,• ,
"
an: unique
organi~ms.
ThUnuunded by an uncompli proIem COOl. Some of the mooR: complu viruses hu,-c : IIIpd blllycr mcmbr.me sUll'OUooing the nucleic acid. 1 Vi· mu>1 replicate In Ii, Ing cells. whICh has Led many to II\.lI \ iru'iCS an:' IlOI c,'cn th'ing organisms but thai , MJIllL'how ui" III tht interface of Lhc IiYlng and the Hng.' n.e rfIO!,[ !»sic requirement is for the virus 10 clll\tr prufoolld or subtle changes In the host cell 50 liral geJ1('~ are replicated and viral proicins ure ex· ...~ _Thi, will rt'_~ull in the formation of new yiru.'ieS. Iy mall)' more than the number Ihu\ Infected tile cdl Ily_ Viru"-!" cond uct no metabolic Pfocc~scs on their : me)' depend mIldly on a host cell, which they invudc • piI"lSlllI.e to subvcn subcell ular machinery. They use l1li of the cdl'J cqulpmcm for . i of viral nuc leic IIId (',pression of , irul cel l' s protcin all cell's eneraY Store! that . llle VIruS tums I cell 10 ilJi Oll!noq ,,""
"~ N_
N_
N_
N_
An. "IN virus (d(""" ••""",
RI"',ir'in
a.. .w. hal''''''''''' hnat/hItn,. • 'N>
"",,">My. )'!lCJ1ioI .-iN!
lIo.piritory Ipf. HurLn ·. lymplofwna
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1'Ip>oo.. , ,n!.<
"opo II"",~' """ 1'uI~"m."'"",
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II_pod .., or,!>
t_",lIO(d ",bum, htty
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v..,..,..... ("",po. lt"orr ...."',;,t)
"tn,,, """ II~ ...."'''''' HI9
Et)lhenoa. ""'->1)1'"
,.
induce an effeah'e amibody re.~poo>e. elen in very yoong pa. tic-nb: the nlCcill(" must 1101 cause the dl5Cae acUle' infections. 1be chronic casc~ are mtlCh more compllCmcd. It i~ difficult 10 ol·e!'l.'Of11C Ihe lendency of 'OIlIC viru are ,cry reliablc& and are in w,d\:."pread u-.c for the propagation of virus panicle,. bU I they an: ilion: dlf1iCUIt 10 pcrform than lheir bacterial counlcrparts. HeIICC. drug-..c!'Cening tcehniqllC§ ""nh VIfUSC'\ ha"e Inen longer to ~.:uch up with t~ In
b;loCteria. Another po~sib1e reason for the Jag in ami l i,w de, elopnlC"l1t lie' in lhe comp3rutive "'ochemlCal ~.1llJlh;:t of \ mIstS I';s-!.-I' is bacteria and their U.)C of the biodltw processe~ of a 00eases may ha'e contnbWd. a relali,e lock ufint..:"rest in ant!I irul chenlOtherapy. A'* feRlllre of mild I' irul inFl'Cllons. such a~ is thai clinical syrnpiulitS do 001 appear n ,\ .. ell eslabh,hcd and the immune processes of the ha' c begun !o moum a succes,ful challenge:_ Thu.\. fOf common I'irdl infections. dlCIIIOtherul'Y is Simply Il0l • • proprla!c choi~'t of trcatnICI1I. Chcmotherupcuti~ 3gt'nlS" nc:edcd. ho" e,er. 10 comlmt I'irosc.' Iha! cau!iC ~I~" chronIC infecllons. stICh a .. cncephaliti ~II p scnI r-uo:.n. ,n,'oh'cd ,n the n:phcailOn IM ..... esa. Tbe "raJ pro!nil\. modify the: hoM l-cll ,uxhUow the \1m gn>ome 10 rq.liclOl,
"" "",n~ bo),t and \lral C"qllJel;, l1Ic mcch,m "-!tadine and riinantadillt.' are appru"ed In ,he UlIlted forpre"elllion and treatmenl of innuenl~ltype A \ IruS ,Senonal prophyluis .... Itlt ellher dmg i~ about
70 to 'iCSSc:S a trinuommc:lh) I group in5lead of 3n lodillC alom al lhe 5 po!>itioo of the pyrimidine ring. The von uer Waals r.tdiu~ of the trinuofQmcthyl group is 2.44,.\. somewhal larger Ihan thlll of Ille iodine 1110m. Like idoxllndine. the antiviral mechanism or lrinuridinc innllvc:s inhibition of ~,raI DNA synthesis. Trinutidinc 1II0llOplw:lSphate is an imwcTlIible Inhibilor of thymidylalc synthetasc.llnd the biologically gcncflltcd triphosphate COlli· petitively inhibits Ihymidine: tri~phate incorpornlioo illlo DNA by DNA polpncra'ie. [n addition. trifluridinc in its triphosphale fonn is incorporuted inlO viral alld ~lJ ular DNA. creating f!"llgile. poorly fuoeMn;ng DNA.
o
",C>. I
1be antivirul
~ction
of vid arabinc i, complctcly 10 DNA ,·iruscs. Vidarobine inhibits vir-oil DNA )yntltell! En7ylllC!i wilhin the cd l phospho!') laiC vidaDbine: 10 tbt IIphosphale. ""hlch competes willi dc:o~}'adc:OOSIlle: IrlJiDpilate for virul DNA polymerase. Vkl~ntbine In~ also i/lCorporutCd into ce llu lar and ~ir-JI DNA. where ild as a chain tl'mlinator. The triphosphate form of ~id:lnltit! also inllibits II 'iel of en7ymc:s lhat aTe: inH)h ed 11\ mt:tItj.a. lion of undine 10 IlIym.dine: ribonl.lCko'"de redl.lCt~se. R.'i.~ polyadcnyl asc. and S-lII.lelKlSylhornocySI~ine hydrolase. Alone: tinIC in the United Statcs. introvellOUli \'id:ora/iI! .... as appnwed for usc: against HSV c:ncc:phall\l i. ~:: herpes. and herpes or varicella ~o:ste:r in immUlWX\lihj'" mised patienlS. Acyclovir has supplanled \'idarublnc dl1Jg of choi ce: in lhese ca>cs. In the Ircmment of \'Iral enI h) drol»' cellu: acts u., ITP). O-
of ,-,ra1 ,ro..... ing
fo$Qmet Sodium.
Trisoti1um pho\phoooformmc I' an Jlyrophosphate analot;.uc llul inlllblt' ",p1i~at iOIl .bld liCSliruse.~ (C M Y. HSY. and YSY)allll rctroviruses I ~IV),"" FOloCamet ( FOSC!lvir) is talen lip slowly by thc ~cl" aldoes IlOl. undcrgo 'ignifi~lIni lIunlCcllular rnct3boli'm. :lI'TIe1 i~ Q l'C'\cl"ibJc. OO!lCI1IJ"IClllilc i nhibit(lr al Ihc P)~te·bindlng .itc of 11M: I'iml DNA pol >l1lCra~ and "lfI"oC' lranscri(llll.~. "The ulll m.1te cll"i:~t I' inhibllion of t~ 'lit or pyrophosphate from deoll}I1OClcotide 101'110'>IIId a cessation of the IIICOI'1'O"IIIOIi of lIueleo,;i(\e ... f'I\.o.le., and piln. the hands and fed) and paocreatins (nausea. abdonu nal pllil. clcvated amylase ) are the major ~li lTli ting 10lCici\1('S of didanosine. Did:mosine is ghen or~JI} in the fann 0( buff· ered chew~ble tablel.'l or as II solution prepared from tht powder. 80th oral do>.age form_ are buffered to prelell acKl icdccom~uion of dd l to h)'poltanthinc: in tlv:: stl.WlUdt. Despite the buffering of tlv:: dosotge fom' ~. oral bio(l\':lIbb!~ ity is quile low and highly I'llliable. Le~s than 20% ofa ~ is excreted in the urine:. which suggc.sts elC tensl\'c mrtD lis m..56 Food interferes with ab.o;orption. so the oral drug mw be given at least I hour before or 2 hours after meals. II.p. dose therapy can cause hypcruncemia In some plltimtli brcause of the iocn::ascd pu rine Io.m.
o
o DidaI1JJI 'Ie
Zakitabine. USP. ZalCltabll1t". 2'.3'-dKko~ycytidtDt. ddCyd. is an anal0l:uc of cytosine thai demonStruu:s :leU'" against HI V- I and H IV ·2. inc ludmg stnlins resistant to AIr Tbe potency (in JlC'ri ~ral blood monon\lClcilfcclls)is ~ lar to that of AZf, bUI the drug is mo re aell vc in populD!I* of monocy tC!l and macrophagcs as .....ell liS in m./;ng (dh. Zak itabi ne cntcrs human cells by eatrier· facl htW:d di sion and undergoes initial phosphory lalioo by doo~yC)tidllc kinase. Tbe monophosphor)' lated compound IS funhcr tabolizal 10 the activc ntclaboille. dideOlt)'C)1idlll('S'* phosphate (ddCTP). by cellular kinases.11 ddCTP itlbiilo reverse tnlnseri plase by oompetilll e inhibition "Ith den' Mosl likel y. ddCTP causes termi nation of the vintl DNA chain. Zalcitabine inhibi ts ~t ~i ~~."'~~~.~~'N~~ "~~~~1 low concentrations. Th is cffect mal contnbu le 10 it tOlt ici ty.5t The 01"111 bioouil ability ZlIldlablnc: adul l5 and I e.rrco:t is thesias. Iowa do
,~,;.,;, .'" ~
entl months o f therapy ., . A potcntlally pancreatit is is an{)l hcr tOXic effect of treatment .... ilb tU:. Tbe drug has betn approved for the treatment of III V·
lIdu lLS wIth IIdvanccd disease \O.ho an: irnokrnnt to AIr or ",110 have dlst'alIe progression .... hilt' rea-ivin8 AZT. d.iC is combulCd .... uh AZT for the tre:llment of advan,,_ed lilV infeclion. tioQ
In
5gvudiM, SlanM/irIC, 2'3'-diJT. Zeri l). is an unsaluraled pyrimidillC nucleoside \hit h rdaled to thymidine. 1lw drug inhibits thoe replication of HIV by • nl«nanism similar to that of ilS close ~"OI1ger1('r. W '" SLavudillC is bi03C1iv:tte:d by c-c:lIular c:nzylIlCS 10 a ~.
The triphosphate oompcmh'dy inhibits the in · wj.b'atlOll of thymidine triphosphate (lTP) into retml'iral !)SA by reve:rse Irunscriptllst'.61 SlIIvudine al.'lO causes lermi· "M of viral DNA elongation through ils illOOipoialion
DNA,
o
II is interesting thai the untlalurnl stereoisomer (- }-{.\j. ddC exhibi lS grealer !lIl1i"lrW 3C1i\lly against IlIV than the natural enantiOl"ller( + KS}-ddC.~ Both tnanllOlI~ are bi· oactivoted by cell ul!lf kinascs 10 the c('lfTc:spolld ntg lriphu!.· ph3tcs.'" II00h SddCTf' 'sonler.. inhibit HIV n:verse tnrn· ~pca.se and are incurportUoo into vlrW DNA to caU$e cham te""ination. (+ ).S-ddCTP inhibIts cellular DNA polylfl('r· ases mIlCh nMlre strongly than (- }-SddCTP, upl:lIning lhoe greater lox icity aSSOCioted with (+ )·(S)·ddC. Initial meta· bolic comparison of SddCTP isomers has failed 10 explain the ~Ier poIency of the (-).bomer against HIV. There· fore, although the ;ntracellullll' >iCX\llllulatiQll o r (- )-S-d .... as twice that of (+ )-S-ddCTl'. the lauer .... as I ~ time~ more potem as an inhibitor of H1V reverse tl'lln scri ptasc. and the t .... o isomers were incorporated into vil'lll DNA !II ooll1parnble rotes. 1lle puUIc: .... lIS soh'cd wilh the disro,'c:ry of a celluhlt 3'S-eXQIloclc:ase. ""hlch was found to deave lenninal (+ )·S-ddCMP incorporated into virJI DNA 6timcs faster than (- )·S-dllCMP fll)ll1lhe viral DNA terminus. ResislllllCe to lami\'tldme de,'clops ropldly as a result of a mutation in oodon 184 of the gene thai encodes HIV· RT ",'hen the drug is used as monothcrap), for HIV infection ,'" When combined with AZT. hu.... e"er, lan\ivudine cau'\ed s.ubstanliaJ increases in C()4 ' cOlints, elevated COlintS 7 wet"c: sustained over the course of thenpy.1> 1lle codon mutation Ihat causes I"C$lstlllK'C 10 lannnldine suppresses AZT resislIllICe.&7 thus increasing the suscepcibility of the virus to the drug combination ,
n.e
"",
~yO
"" Suvudtne is available 11$ capsulCf for ocaI adminislIlUion. acid stable and .... ell absorbed (aboot 90%) fol· has a short hlllf·life e~cn:ted largely ulIChanged As .... ith ddC. the primary dosepc:npheral neuropathy. At the reoom· ":;:;~~~II; 151020% orpatie:nls ape)C I neuropathy. St3vudinc is m::)I' treaunent of adults with advlllICed HIV
,m,:';
,~~':~~,~:1.~~~:, appro~ed
_rule
~r n:ec:i~ing
thernpics or I or mlllllll)ological deterioralhoese tlK.-rapie.\,
OH
IIkKIeosId. Anti.".'eboltt.. Ri bavi rin, USP. Ribavirin is 1. ,8-t>-ribofurlU"lOSyl.l.2.4MIK.I~n •• II.
thiu.ole-J..camo~amide ,
The: compound is a purine nucleomodirled base and I o-nbosc 5uglll'"
side arutlOlue ",llh I moiety. The struclure of ribavirin
.3' -dideo~y·3' -thia· I 3TC. or
activltv again.~1 ~tudied,t>J· 601 Pn:limi. siudies indicated Ihnt il exhibited good - - 80';1:) and a plasma half·life: of
Lamtwdine
",, /",-(,0
i~ ~hown
below,
r Ribavinn mhibits the replicaTion of I very wKie Varlety of RNA and DNA viruses." includmg orth(lmYllO\';ruSCS. paramyxuviruses. arenaviNSC:S, bunyaviru~s.. herpes... ifUSCS. adc:novlruscs, po~virus. vaccinia. innuenza \';NS, parainnucfl7J1 vil\ls. and rtlinovirus. In spi lt of the brood sptCtrum of IICIIY;ly o(riblwirin. 11M: drug has been appro\'ed for only one lhenlptutic indiclllOll-lhc In:atment of seven: lower ~plrnlory mfeclions caused by RSV in carefully selected ho~pilaJi~ed infnnllo lind young chi ltlren. The mechanism of acllon of ribavirin i~ 001 known. The broad anTiviral spectrum of ribavirin. however, suggests multiple modes of ac1Wn."" The nuclco!litle is bioanh'ated by viral and hoIil cellular ~ina.'ieS 10 give the monophosphalC: (RMP) and Ihe triphosphaTe (RTI'). RMI' inhibiTS inosi ne rnonopho.\phatc (IMP) dehydrogenase. Thereby pre\'cnting the OOIWen:iOll of IMP 10 xanthine mooophosph:ue (XMP). XMP is required for llullllOSine lriphosphale (GTP) syntllesis. RTP inhibi TS viral RNA polymerase•. It nlso pn:: ~ents the end capping of ~iral mRNA by inhibi ti ng guanyl-N'methyltransfenlSC. Emergence of~iraJ resiStance to riba~irin has not been documented. Riba~irin IX!CUIl:l$I. white. crystallillC. polymorphic solid that is soluble in wmer and che mi cally stublc. 11 i~ supplied as Y powder to be recoostltutec.l in an IIqIlCOOS a/:":rosol CO[\taining 20 mglmL of stenle water. The lI(' osoj is administered with I. smull-panicle aerosol generator(SPAG). Dct.eriOf""Jtion in respirJtOf)' function. bacterial pneumonia. pncumotho"'J~, and apnCH hu~e been reponed in severe ly ill infnms and children with RSV in fection. 1"1le rule of rilxtvirin in these e,ems has not ~n determined. Anemia. headache. abdominal pain. and lethllf1!Y ha,'e been i\'ported in patients ~eivin g or,L1 rilxlvirin. Un labeled uses of ribavirin inelude 3c:rosol treatment of innucnu typeJ A and B lnd 0flI1 treatmetlt ofhcpatitis. genita! be'jKs-' and I asS/! fe'·er. Ribaviri n docs not proteCt cells ngnlnst tIM- cytoto~ ic effeas of the AIDS virus.
NEWER AGENTS FOR THE TREATMENT OF HIV INFECTION When HIV-I was chamctctilCd and Identified as the cnuSlltive agent of A [DS in 1983.1'CI. 11 scicnti~u from all ower the world joined in the search for a prevention or cure for the disease. Mapping tnc HIV- I genome and eluci dating the replication cycle of tnc virus hll\'e supplied key informauon,n Biocncnllcal targets. many o f ... hich arc protelllS invol,'cd in the replication cycle of the ~ il\ls. ha"e been clooed and sequenced. These have been used to devclop mpid. nlCChanism-bWiCd a.o;says for the virus to complement tissue cu Iture 5Cn"CnS for whole ~irus. St"eral of tnc biocncmic.al sleps thaI ha~'e been chnmctcrized have served 11$ targets for clinical candidates as well as for succcMfu lly hcensed drugs.7J. l' Despite the many ad~ances in tnc lutdc:rstanding of Inc HIV ~irus and ils tf"C8tmetlt. IhcTc is rKlI yet a cure for the Infection. Emergent resislIlnce1' 10 clinically pro,'c n drugs such a.~ tnc rc~crsc t.-.mscriptase inhibitors and the protease inhibitors hu complicated the picture of good thcmpcutic targets. Thot idea of us.ing I vattine as a tncrapeutlc tool has
been complicated by tnc fact trun the vattine apparently ClII modu late its antigenic structures In lIS chronic inf«1iOltl $Iate.7tI
V.cdnes.
Thot chronology of \'lICcine de\"dopment mj uo;e in the 20th century is nothing shon of. medial mli"ll(it. DIseases 5IJCh 11$ smal lpox and polio . ... hlCh once: tIIVlIgaI large populations. hal'c become distant memories. 1bc ted!niq ue of sensiti]ing a human immullC \ystem by e~posurt to an antigen so that an anaml1($tic response is gei"oClM on subsequent Clpoliurt seems quite sinlple on the surfatt Hence. it is natural that a ~~"Cinc approach to prnrotul! AIDS be tried. The SUCl-C:SSC~ IIChic~ed so far have invohtd liveJl1l1cnUlllcd or killed .. hole-l-c:1I vlICClncs and. in _ recenttimcs. lUombinant coat protems. Succes.~ with vaccines of the li,c/allcnualCd (10 ... ·1,.. lenee). killed ",hole I'irus or the recombmant coat prI)\nIl types havc primarily involved acute vlml disea. typic ~aria",s ortk IU V en~cJopc glycopmu:in @pl20~ tained by recombinant DNA tcchniqUt.'i . This t:ugct ...1Ilo~ n because of coocems .bout the ~fet)' of li'c/lltmuan ~acci l1($. The gpl20 glycoprotein i~ • coat protein. -'" grem ~are is take n. a ~irus· free vaccine is obminablc..\Imover. glycoprotein gp 120 i~ tilt primary target for III"\ItraIii. ing antibodies associated with tnc liN (anachmel'll)SlqI. HIV infeaion.n Early \"acciilC!l were SO incff«1i~·e!hl!. NaTional InSli lutc§ of Health §USjKnded plans for masw , cl inicaltrilll~ in high-ri~k individuals.?· Thcre are I numht of fCUOOS why the vaccine failcd.'19 There arc multiplf" types of the \liru~ throughout tIM- ...·orld; the virus can by means of both cell- free and cell-associated ft:lflm; • virus has demonstrated it~ own immunosupprt5SIIC. , _ nopathological. and infcction-enhancing pmjKnics of ~ of the envelope gl)'copt'Qle;n; and vacciocs rn.~·c IIOIIICaI able to stimulate and maintam high enough !e'"els of Unity to be cffectlve. T he failure of the first generation of AIDS vxcinn III to I rce~amin~tion of the .. hole A IDS \·accinecfTort." As guide for resc~h efforts. I. number of cntem for IlII . . . A IDS vaccine ha'"e been de,·clopcd. 1"1le "idcaJ" AIDS III: ci!1C shou ld (II) be safe. (b} dicit a protective imm"'lfsponse in a hi gh ph.It)()j'\ion of vaccimucd indiwidulh, stimulale both cellular and humoral branches of the ",.;.
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.-optiate $pon«e:. 1I to (l those: ofscrum. The drug is e~tel1sivcly tnltlsformcd by cytOchrome 1'-450 to inllCti\"e h)'dro~y latal metaOOlltc:.~: il mny undcrgo clllcrohcp;,tic recycling. The half-life dccll':ase~ fll)rn 45 to 23 hoon; o,·er a 2- to 4-",·eek period bctause of autoillduc.ion. Elimination occurs through the tldney . w,th less than 3% ofthc parentl"Ompound CJlcreu.'d in the urine .r.l [}osage forms arc supplied as a 50 mg/5 mL oral suspension anti II. 200-mg tabiet.
n.d HIV- I re~erse trullscrip use fltCilit3lC5 the ",tidy of • dTec1s of a 1lO\·cl compourKi on the '.anctics of the ~n ~ ftaodom screening of ehemical In'emories by the ~ullcal
irKiusU)' !las led to the di.scovC'ry of !>evcnl '"\Rlls of the enzymc. These Inhibitors represcnt seve:ral ftllnUy distinct clusscs. The NN RTh ~hnre 0 Ilumber of ~biochcmica.1 and phannOCtllogk:nl prope:nie~. u . ".11 tlllkc the nuc:Jcoside antimcmOOIiI~s. the NN RTls do nOl ~.rt blOOClivation by ~inusc, to yield ph&.;phMe estcrs. "!'ley I\"e 1101 Incorporated into thc gro .... ing DNA cha in. In~y bind to an allosleric site lhat i~ distinct from the (nuclOOloide triphosphate}- bindlllg site of reverse pease. The inhibitor ean oombillt with eitho!r free: • MhIu1IC·boulld enzyme. int~rfenng With the ac1ion of Suell blndlllg diSlom the enl.)" nlC .Ml Ihal II cannul die c:nzyme - Illbstr-'le eomplell yt liS normal ralc. ... o.ct formed • •he complo doI':s nul decompose a. the !lie 10 )·ie:kI products. Increasing the substrate .:mtM.J0II does not re'·crse these effects. Hence. \'iRTI~ nh.bit 1\ c lassical \1IJrl(."Qmpcti'i ..e ;nhibilfon pat_Ill! the cn·'yn\C. Ibt NNRTls arc c)ltrenlCly poIcnt in in vitro lOCI! cu lture Mi)' and Inhibit HrV~ , at nanornolur l"lll'CCl1lrutions. ..... RTlt mhibit re,'crse Irolnkripta~ ~Iec:ti Ycly: lhey do not ... tbt transcriptases of other re,ro\·lruSC$. inHIV ·2 and simian immunodefieiency virus (S IV). 1'."XRTIs hI,e high therapeUIIC indiccs (In COIlumt to III-.D:oodc:s) and do not inhibIt mammali:m DNA poly. The NRTI s aOO NNRTIs are e~pccted to e)lhlbil a effect on Ht V. SInce they inlCTaCt with diff~ll':n' on the eru:ynlC. The chief problem wnh the iI. the rapid emergence of resIStance amoog HI V ....: ... Resislance is due to poinl mutations in the gene
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OeliJlfiniine. Dclavl rdlllt (RcIICrip!or)ll must be used with :II least t .... o IIddmonal antill'tro,·iral ag~nUi to tl1':31 IIIV I infectioos. The oral absQrption of tk:la~irdillt is rapid, and pea~ plasma conantrouons develop ID I hour. Elltensi\e metabolism OCCutt III lhe li\"~r by eytochrome P-450 (CYP) isozynlC 3A (CYP JA)orpossiblyCYP 21>6. Blo&vailabl iny is 85"'-. Unlile nevirolpme... hich is 48% protem bOtllld, delavirdinc is more than 98'}, protein bourld. The half-life is 2111 II hours. alld elimination is 44 M.. ...:I I..,.. loy. P M. (Mol F_h ICI .1 V,"*">"...... 0... _ . R. S C.1191 721. 1997, 11 Don'...·.lI. K S .• [I ...",,,,,,. C. 11. .. Ikll. I~
U. Sid ..·.(L 11.. W. eI aI. Se..""" 117:ro:l. 1'l71 iii 1I.otM.... R. ': a-.. EnI- ~ J.... 27'21. 19k> 70. Colk>, II. C.. 0, .1 Scilic druJl~ :Ire highl), lO~ic to the patien! and must be Iidnllni5lercd .... lth e~treltle caution. Some of them rcquill': a cl mical ~tung "here ~upponl1e care i~ a, ailable. The: tOlliCiI) usually uw ohes r.lpldl)' rroli(~r"JIll1g M~ue.~. ~uch as bonc m~rrow and lhi: 1l11e,lmal epithelium, Individual drogs produce distincth'e IO~ic effech on the hem. lungs.. kid,IC)'!i. and other OIlan~. ho",.ler, ChcmoItlCmpy is seldom the 1II111al treatment u'iCd a£aln ... cancer. Ir the. cancer i, well defi~d and aece~~lble, "Irlery i, prcfem:d. Skin cancer; und cenain localil.cd tuillon; are trealed by rlKIlothempy. GcrICr~l1y. chemotherupy i~ ImporInnl ... hen the tumor is 1I1OfX'r.lble Of" has mela.\l .. \lled. ChcnJothcr.lpy i~ findlllll ,ncreasing uSt" a, an "adJu'~Jm " after ~urgery to en~ure thut re" eel" n.-main 10 I"Cl:lencnlle lhe pan:m tumor. 1llC er'll of chemolhcr'llpy of mahgnant dlscase ,,~ born III 194 I , '" hen lIuggllls dcnlOOstnued Utatthe lldnumstnlllon orestrogen~ produced regreuioJls ofrnetastalic pnJ!ilateeaneer.' In the follOWing year, Gilman and Otl\l:fs began clnn eal studies on the nllrogen mustards:uid dlscovcred that mcchlort:thammc ""as effecul'e ag;lIIm HoogLm's dl-.t'a~ and Iymphosarrotrul..~ 'J'be$e same two disca.-.es werc ~atcd with cOr1isone acetate III 1949. and dr~malle,lll1hough temporary. remissions resulted.'o The IlelIt decade ",as marKed b) the desi£ll and dlscolery of anlnl'lClabohte.\; nlCtOOtreute III
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!'N\). 6-nlCrtaptopunrIC III 1952. and s- nuorouracil in 1957, Additional aIL)I.ttmg agenb ~ueh as I1lClphalan .nd qdo· pho effon had c,·olveU into a mrgclcd thr delc-Iopll\ent program. A massl.e SoCTttnmg sy~tcm 111.11 t\' tabli!ihed to dlsco'·er new Itad comJlOllnd). and I~ ur ..:unple~ huve been 'UbnI1I1L-d to il. The: current hlgbly autQmaleU NCltumor ccll cullurt loCl"Celll ng s~slc'n oclllC''nl oper.ttlUnal qalus m 1990. It cmphasi/.c~ rigorousc-nd p!lID6 .. uch lIS roel cc-Il I.,illing and tumor rtll~sion. r.ttht'r \hII earher gm"th-inhIDl\ory end point>. alliin u>o a wide I1n· cty of ~pce t fic Iype~ of C,UlCer, Including many solid tunu model~. III the i nllial stage of ~n.-cnmg. Ne,,' drull Candldael ITe being screened al a rate of about 20.000 per )ear._lIIt input dividal aboul ct]u~lIy bet .. een pure compound!." c~mlC"" or frolCliOOS frurn Ilatuml products. The proent it ~I'm o;crccning panel contain, 60 human tumor cell lirlr\. arr~nged in 5t:len subparoeb that rerre .... nt dil'en.c hisloiorie\: leu~cmia. melanoma. lung. colon, I. Pigllll' 11, ) ~hov.~ thall'o!on cancer cell lines art: mon: senSItII'f" a't:rJ.gc to s-nuoroufllCll (S·FU). "hereM cent",1 fIt~. ~ystem (CNS) canctr ce lillne~ arc mort re~iqant than J\U' age to il. 12
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Fig ure 12-3 • NallOl"lalll"lSll tules of Health teslll"lg result profI le fOf 5· fluOfouraol
A seoondary ~tage of prel iminary scrun;ng on selected compoonds IS perfOlTl1C'd In \'i,'O in xeooa;l'llft models b), using a ~ulY;ct of ceJllines found co be active in the primary In vitro scrun. Two xenogr.lft models in CUrrent use arc the se"ere CQIllbllloo immuooder..:ieocy (SC ID) mouse and the alh)'mic node I1lO1.lSC. 8 0th of chese mouse uJOdeI~ have defi cient Immune responses tMt pemlit tr.&llSplalltacionofhuman cumor cells \\ ithouC rejection. Consequencly. po(ernial ant itunlOrdrugs rna)' be \I'sted againM hu man IUmors in un in vivo model. llIese models pudlCt human cli nical tumor responses bener than the older allograft modcl~ that \\ere based on trdnsplaming mouse cunlO/"i such :tS 1'388 leukemia imo che same strain of mouse (s)'ngenelC tumon). TIle importam anhlUmor drug pachtuel was discovered b)' using a ",enogrnft model. An in ~ill'O s),stem lhat is II good pudictor of human clinical octivicy i~ che hu man-lUmor-colony-forming assay ( HTCFA). Thi~ system uses fresh human tuulOr tissue: from individual pallents. n It is valuable In selecung chcmothcnpeut ie agel1\~ for individual tumor types and o,,:ca~iOllall y ~ific patients. but II~ USC' in large·scale primary sc-rc:ening has IKlI been feasible. Compoolids with ~ignificanl amilumor IICdvity urc sub· j«ted 10 preclinical pharrnacology :tnd tO~Jcology evaluation in mice and dogs. Clinlc~1 trill l~ ma), be underwrinen b), the NCI. They involve thrcc discn:te phasc:s. Phao;e I is the clinical pharmacology stage. 'f'be ~ge iiChedu le is developed, and lo\i cit), paramcters an: e~labh~hc:d in it. Phase II invoh'cs the tktemlination of activit), against a "signal" tumor panel, wltich include:!. both solid and hematological type •. A broad·based mu Iliccmer study IS usullll)' undCrlnken in pha...e III. It features fllnOOmil.:ltion schemes designed to S13uSlically ~Dhdatc: tnc cfficacy of the new drug in CQIllparison to ullcrna lh'c modal ities of themp),. As might be antici · pated, the design of chnical trials for antil\CQPlastic agents is very CQIllpllCatOO, especially in the mailer of controls. Ethical con~idc:rations do nOl pemliL patient~ to be left untreated if an)' ll'a5OII:I;ble thenpy is possible. A number ofpharmaceuticaJ industry laboratories and foreign IIls11tutions hal'e made significW1t contributions to the del'dopmt'nt of anticancer drugs. OrganizutiOflll 5UCh as the: Uniled Kingdom's Cancer Rc.warch Campaign. the Eu~ pc:an OrganilJ1tion for Research on lhe Trc:ahfICm ofCanne hytlrochlunde and 90 mg or MJdlum chlori givcn to control malignam effusions. The n iridiniullI ioo formctl from mechlorethamine UI body Iluids iJ; hIghly react,,·e. It act) on \!ed by liler microMlmcs 10 become aclilt. Amonllthe mct"bolite~. phos· phorumide mUSlam has antitumor actil il). and acrokm is tOXIC 10 lhe unnary bbddcf. Tbe ocroleill toxicity ClIn be decreased by intral enous or I)ml ad,nill1,tratlt»1 of the ~o dlUm :l3.lt of 2-mercaptocthane ~ulronlC acid (n.:sna) .... tto6 It is • lo ...·melting \Oo·hne powder that changes to an Oily hquKl at 2rc. This change is considered a sign of decomposition. and Mlo;:h !i.:lmples should be db· carded. Cannu5t ilIC is most stable in petroleum ethcrorwater at pH 4. It is tWminlsteR:d intra,·enou5Iy because nl(:tabohsm i,~ ,ery rapid. Sonle of the dcgmdation prodlK."ts. however. ha,·c prolonged half·li'·e.ph3I c,.9. 111c~ "PCCK':S inhibIt Ihc' same enzymes tllal un: mhibilcd by 6-nlCrcapto,. 'Iluoguaninc is abo incorponatcd illlo RNA. und Its «my mc:ubolite is incorporuted into I)NA. The sigmfi o(~ "frnudulenl-- nucleic acids in IClhaillY 10 nco-
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!r.l-I uamples of mllonal drug design_'OI Slarting with the obscr"allIIn ,hat III cenalrt tumors urolCll wa, used more ,hart orotic acid. lire maJor p~ursor for nllClelC acid pyrimidine bio-;ynIhcsi< in normal ris.,uc. he c:helne 12-7). Ihu ~ diminishmg DNA biOS) mhoe~is. Fluorine ehostn ~ lhe substltuenl hccau-.e the increased octdny caused by ,''' IndUC' li,c cffect ... a~ e~pcclcd to eau-.e 11M: rnolc1:ulc 10 bInd ~trongly 10 ell /) lnc~. Thc.-.e ehoiee, ... tll' ... 'ell founded. a\ j.lluorouro\CiI soon bccanlC one: or .he nlOSl ... id.:ly u..ed anlincopla~tie I's.:nl~. II i, a main,'a) III Ihc IhcrJpy ade_ lIocarCllloma of Ihe eul"n lind ~tllm, Side effcc.~ are both dose and ...:hcdule dcpcrwlcm . 'They IIw:11.Idt: ut}'elosuppre .... ~ion on boIu, ad"nnisU"allon and mucO!oni~ on prolonged infusions. Chhc:r\\.I'oC. the drug;~ "'ClilOlcr-.aled. 5-Fluorour-.lC11 I~ OCt"31W by lInaboli\1I1 10 5-1100n:r-2 de'Olyurid)"he acid. Th,s COf1\eTSJOf, may pnxttd by 1...·0 roulcs, In one: roule. 5-l1uorouro\Crln:acl' .... ,'11 nboA. Ihat of tnnuoroth)'mldylic acid is eJl traordin:uil~ labile. Ii react ~ .... ,Ih glycine to gil e an anlide: UI neulrnl pi I . I 0 Kinc:t1C ~tudie' hal e sllo.... n lhat thl~ reaction 1Il\"oh'cs initial nucleophilIc all!lCk al position 6. followed by los~ of !IF 10 I!ilc the highly reactile din uororrlelh) Icoc group. III Glycirle then IIdds to this group and hydrolysi~ oftbe remnlning IV.O n oonroc atoms follo\lt~ (SchenlC 12-8). The in leBCtion of lri nUOl"l)jh~tnidylic acid wilh thynl1d~la l e s~mhclase apparenlly fo llows II si mil ar course. Th us. nfler prcinculxtlio n. it bccollle~ IlTCvcrsibly bound 10 ItIC Cn/~Il\e. aod the kinet ics are noncompetitl,e. IOI Cylosllle nroDlIloside was s) mhcsiled III 1959! I: alld 1~ler found lIS II fermc:nlalion prod\iCt. III Its ' truc .... re is notcwor· thy in thai the' IlrabHlo~ 1ll00c:ty is epimeric Illlhe 2' posillOO \It It II ribose. This mod,flClitlon. after :mabolism to the: tnphosphatC, ('lI.use~ II 10 inhibll the ron,'U predomHllUllly in lhe S pha.o;eorlhe CC'11 cycle. Tumorcc:1I resistance is ba.~ 011 low lel'cl, of dc:o~)c)'tidine kina!lC and the elabor,I\iOll of deaminases that COIl"cn cytosirll' arablllO~lde mlO uridlne LUlIbHlosKX. m Panially purified Cytidine deanimase is 111hlbl ted by letrahydrourid,rll'. 119
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The IC1fl1hydrofuranyl dcrival l\c of !i-fluorouracil. ICgafur IAcnfur), \lias prepared in R us.~ill. 100 11 i~ active: in cli nical (attand less myelosuppte>;. ;ve than S- n uorourncll. II has p.trOlnlestinal and eNS toxici ty. however. T egarur is a..ly metabol ilcd 10 5·fluorouracil : Ihu§. II ma y be consill·
!!lid I prodl\lg.lible fC11l hl Y impai nncnt. lcr~tOllcnicily. hypocrbiltmblncnll;l. nnd hlll1dmouth syndrome. DruJ; imcr'.lCtiolls occur \\lIh anlacid, and
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Penmstalin. 2' -dcoX)'Coform)CHl. dCF. NSC·21832 1. (H.., 3-(2-deo~ y-.tNH"l)tllropctllofumnosyl}3.6.7.8-Ielr.lh)'droimidll/o14.5·d 11 1.3 }dIUl.cpin·8-o1. Tlti. compound is obtained fr'(lm extraciS of SIUplfH1ll,{,t'S UllI/bi· Q{icltil7~ :lnd formuloll:d 10 100mg vials a~ a lyopliili1.ed po.... dcr. Mllunno.] (50 mg) and sodiu m hydroxide (10 adju~1 pH) are incllldc:d. 1\ is admlm~lcred IIItmH:nouomc 7 - h)droxymclhotre~ate is f"und folio ... rng hiXh·do!oC tlltrapy. I>las.ma leI el decay r~ brpha,ic or tJOl'sibly triphaSic. MtlhotreAaIC binds tightly 10 dihydrofolate I'!'ductase. blocling the reduetion of dih)'drufolale to tClmh)drufolate. lhe ach'"e form of the ooenzyn1Co\cry Ihat mcthotrc~ate affo«lc:d a hrgh percentage of apparently pc:mlal1cd in the treatment of cytlc lind grunulocylk leu~cmi:l~.!\! TOlie bone mafro" dcpres'JOIl. '-tomalU ts. alopecia. artd Ic~l inal d"IUm;ttu."e s. Al htght'r dose~. eardiac ck\l.'lop. Sen'f"(' and progrcs~"e: ~-oogest "e may full,," imlial tachycardia a.nd anflythm.as. The usual dose of d.:lUnorublC in is 30 10 45 for 3 d3)'" II i, udmmi~lcrcd inlr~,cllou,t)'. ta~.nl jl'f"e,ent I.'Xtr~\·a'l;ltiOIi. Doxorubicin Hydrochloride_ USP. drochloridc. Adrium)ci n.,N"IS;·"C,~',,' ~23127. rnycm. is uOIamed from ..' I llJ Vat. filI'JUU. The orange-red 1I~"dles 1IIId ulcohols. l)olorubieln hydrochlondc is free/.c-dried 1JO",dc:r in IWO dilTerenl ~i7.cS: 10 rng of Lactose:. U5 P. and 50 250 USP. The'\C' I
bod;;u;ssucs. ,.. lI h about le lllS. II is u len~i\"ely rneuboli/cd ;ltId as gtucllT'(lmdc conJ"g"'e~ or the parenl hydroxyl redu"ion prodUCI.
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formuhUlOOS forchnicll.l trials.
The model! of OOl(orubicin al\' sum lar 10 those hnbcd for daurlf effecti '-c IIlltltUmor agent~. kbI5 been usro succe\sfulJy !O produce "'gfl'ssiom in acute letl;tmms, Il odgkin's dier. the ex tent of ~tnbol ism during the 2-hour reten mitomycin and 10 mg of m3JInitol or 2Q rTql of milOmycm
and 40 mg of rtUIl1nilOl are supplied, The unrocoo~litutc:d prodllCl is suable at room tempcnl1ure for al least 2 years. The drug I ~ rocoo~litulllllle mitosl$ follOWing boef exposure 10 other Vitll;3 alla loid~ IIfler the,e cornpoullds are wilh · df"Jwn.l71 A plant prodoct of hi~h current inlel"Cl't in cancer chcJ1"lOtherapy is p;lClitaxel (Taxol). Thl~ compound was isolated from the bar .. of tnc PacifIC )CW IItt Ttulu brt'l'iji>lio by Wam CI al. III 1971.179 At that lime. II .... as found to h.a\C antitumor achvlly : ho"""el·U. thc're W-JS hllle cnthusiasm for its funner (lcwlOplllent until ~l1lly . ... hen Its potential for human clinical actll;!y wa.~ suggested by screening against human lun~ in immunodeficient miee. II is now lhe world' ~ Ica.:hng unl incopla.~ue ugen t in Icrn.s of bales. Pacli· laxel is active again~1 refractory ovariun cuncer. metastatic 1M\:as.t CllllCCf. mctastatic melanoma . nnd non -smallcciliung cancer. Pacliuuel mh.biL~ mitOSIS by ocllng lIS II. spmdle polson : however. ic acts by a unique mechant sm In prumofing tnc assembly ofnllcrotubules and Slabilll.lng chem &gam!;! ark of Ta.l"us br~,·ijo/;a. II. slow -gro ... ing u"!:e conlailling only a ~mall amounl of the drug. 11m procc~~ IS expcnsi\'c aud a threac to f()fl.$1 ('COlo&) . Con~ucntly. the manufacturer. BriSIOI· Mycl1i Squibb. tJo:o\cloped a tOOtc based on partial synthesis from 100dcacciylbaccl4tin III .... hich is obtailled from lhe needles of TU.lUS mlccll/a. a Europellll ye .... tree . Becau>c needles are ropidly regcnerated. Ihis I' a les~ desCf\lt:ti\ c !m-Ihod for obtaimng pachtQxel. Furthennore. 10deacctylhaccatin 1 1I!~:111 important intcnncdi~te for chc s) nthesis of analoglM:$. One such lIIlalogue. docclaxel (TBXotere). has been pR'pared aI RhOne-Poule!1I; Rorer. It I~ more '" ater soluble Ihllll paditaxel and reponed to be fIl()f"I: potent agairu;t solid tumon. bill it is n:llII.i\"ety more toxic lhan pach Ul.\d.Zl I DocelaXeI is approved for nICI.IISlallC breast cancer and for 1IOn-5mall «II lung c~ after patie nts havc failed prior cncmodH:rnpy.
,
- ." ~
H,OO
"
HO
f
~
H,OOC;;""",-OH
"
"
,
Cd clinically for this pull'O'\C. howevt'l". lts main use is in terminating IIC\Ite Illtacu of gOUI. Among colchicine derivuti\'es, demecolcine (Colccmid) is aclive against myelocytic lcukrmill. but only lit ncar-toxic Ooscs. Colchicincs have WI unusual tri cyel ic structure con· taining a trop:Ilone ring. Tllc:y inhibit mitosis It mrtllphne by diliOrieming the organi/.lltion of the spi odIe and listen.m
CH,O...,..,,- /--.., )- NHR
°
QCH, CoieI'oo .. R .. ccx::H 3 Ct*:etTild. R. CH 3
lrinoteean 1I11..~ been approved recently for fifliHine ther· apy, in combination with S-FU and leucovorin. for patients wnll metastatic colon or rectal carcioomas. It i~ a semisynThetic analogue of Clmptothecan.l l l Camptothecin was isolated from CamJllOlhtca Qcuminll/(I. WI ornamrntal tree found in China.u.o It is very insoluble in water. but its sodium !IlIlt. prl'pared by alkaline hydrolysis of the laclOOl: ring. ~'ed promising lIIltitumor activity. Cli nical tria ls ,,"'ere evenTually dlsconllnued because or unpredictable tOllic effeelS. lrinotCClin luis a basic tcniary amine group. which cUn be prolOllated to solubil i1.e the drug. Tllc: lactone rinll nemain.~ inlaC1 and in.crea.' bung factor producc:d by recombinant DNA technology). Hypcr.c:nsithny (J(:curs in -oIllC patients within 10 minute$. St:utm8 an infusion. II has been suggesletlthatthe allergen .s lhe Cremophor El dilucnl.- RC"m!iblc pcriphcnllllCUropalhy is common WIth pffllonged infusions. Bradycardia. gastrointestinal disturbances. nu·li~e ,ymptoms. bud tOlbl body alopecia aJ..., occur.
or
bgands ...... :mil ormaplalin. a 1'1. ( IV ) complex WllO'ie!oJl ligandli include four chloriOcs and I.Z-diaminocydoheunr Ommplatin must be reduced 10 thchloro-J.2-di amlllOCydo· heone PI (II) for acthation. 10"1
Docetaxel.
[)ocetaxel. TWlOlere. RP_56967 . NSC628503. i~ prepared from II. precursor obcairICd ffflm lleedles of the }ew plant.m It is supplied !IS a 2O-mg sample In 0.5 ml of poIY'>OfOOtC 80 or a) an 8O-mg su.lnple in 2 ml of polysorbate 80, both In single-dose vial~ with diluclIl ~uita ble for mjection. Samples ~hould be kcpt al 2 t(J SoC and be proICCled from light R('C(lmmcnded dos« are 60 to 100 m,) m~ IV O"cr I hour every 3 weeks for breast C:lJlCCl'" or 75 mglm] for non - small cell IUllg callCCf Docclallei is indicated for breast cancer after failure of prior chemochenlpy and for non- '\I11lI1i IUllg carcinoma after failure of platinum-based therapy. To~ic tffecL~ include neu tropeni:l. nuid retcn tion . mutagenesis. rash. and rlCuffllogical symploms,.m Pcripheral blood ooums ~hou ld be performed because of myelowppres~ion. Ph:umacokinetics indicatc a thRe_comp:lnmem model ""'Ih half·liH'! of 4 and 36 minules alld 11.1 houl'll. n.c drug i~ 1)4% protein hound.
MISCELLANEOUS COMPOUNDS In 196.5. Rosenberg Invcsligatcd lhe effects of electrical r.elds on OOctenll lind found tmu Escll,.nchia coli fom"ICd long liIaments Lllslead of d ividi ng. - ~le ,ubsequently d;~ coverro ,hal this effecl wa~ cnused not by the electrical cur",nl. 001 by a compla. [PI (CI).(Nlhhf fomle(l from the plat,nUIlI eleclfude in the presence of ammollium lind chloride IonS.)!IO This d,i,Covery wa$ followed by !eSTlllg I variely of pl atinum neulml comp le~c.~ against 1Uml'rs. with lhe reslill that ciHlichiorod lammincplatillum II (dspbtin) c\entually became el tablishcti as a dil1lclIl agent,.IOl Thi~ platinum L"{}Illplex i, II potcnt inhibitor of DNA poly· mcmse . li S aC"tivity and tOllid ,y rese mblc those of the al kylatinll agellis. Con~idcrablc evidence has been obtained fOf" DNA DII,,/jng by !he plalinuHl I;"QrrIple,O . 111 "hich lhe 1"0 chloride.-. Wl.' dj~plrxcd by lllirogen or 01ygcn IIlom. of purioos. "ln~ evidence inc illdc:.~ focilitutL'tl renatLLr.ltion. increa.'\I'd sedil1lC':ntation coeffiCient. hyperchmmidty of the DNA lI1tr~ ... iolet spectrum. and seicroro. l16 Tumor resi~l uocC i. basal on the development (If ISpInlglllc ,ynthctase hy the tumor ce ll s.'17 Pcsasp.ugali01TIt: remisslons in refl1lClory casc..~ breast cancer. maltgnam melanoma. and OCUle myelocyuc lcukcmHI. Leukopenia is the limiting toxicily .m m-AMSA (aJl)~ril1C) is an acridine rn,ri~atlve that is thought to bind to DNA through intercalation. It does not affect DNA synthesis. howe,·cr.·1) TImi compound was rationally desIgned as one member of a groupofacridmyluminomethane.~ulfonam ides.J2· Pn.::viOt"ly. a number of other acridirIC derivativcs hll/J shown anliwmor activity.
....} of liS octions arc relaled to the fUIK1ions of spermidi nc. ~Iidt IllCSemblcs in structure . Thus. n competes .... il h sper~.fOf the: Inmspon carner and inlr.lCeliular binding site. llko IMinns spenmdme biosynlhesis. lIS amiprolifernth e 5 on ccll~ can be jlfI:vellled by udrnini~lering spenni. . III M:my other bi,(guanylhydntJ.oncs) have Ix~n pre"ml. but nonc: has proved s uperior 10 the melhylglyo)(aJ
DCH,
The clinical importance of :1IIthnIC)'cJines SlImulated the synlhe.~is lind
screening of IlJIthraquinones wnh panlal anIhracyclme siructures. One of the be~t of these anulogucs i~ mitountrone ..... hich tms two hydro,;yl and 1\000 2-[ (2hydrollyethylamillO)eth)" lIamino wtKIi tucnts on the anthrnqui fIOI1C nuck'us. 2!l ule ooxOIUbocon, mito'(llntlUOC" Interca' ,nhibits DNA tOJ'lOlsomcrnsc [I '~: bowlates onto DNA and evcr. it i, not a sub~1r.l!e for reductases and does IlOt form o)(ygcn-free mdkal) in a redm cycli ng procc.~,. Consequclltl y. il is less cardiolOxic th.an do\orubicin. M itoxantrooe is apptmed forinducmg remissions in acute nonlymphocytic leukelma. usually in combi nation \Ooilh cytarabine. HO 0 NHCH,CH, NHCH ,CH ,OH
tnl'JtJll'.
NH
CH3
NH
II
I
II
NHCH,CH,NHCH ,CH,OH
H~NCNHN-C-CH=NNHCNH2 M,lQgl"rone (~ 8Is(~IIlO"oII )J
H,NCH2CH~CH2NHCH2CH2CH2CH2NH, Spe!rrodI oe
PUl)Xalllrone IS :111 anthrdpyr.uole Structur:al1y relall~d 10 milountrone in h:l\'mg two phenolIC hydrox)' ls and ;;ide cha ins ~'OOtaining I1l11ino g roups: Ilowevcr. its qu inone ring
is modified to form part of a pyrazole ring with a nitrogen atom on the next ring. J : 1 'The mode of action of piro~antrooe is intcrcalation lind interfercnc.: wi th DNA synthcs i~ by lem· plate inhibition. Cardiotoxicity is low ~ause il doe'i IIOt urKlc:rgo redox cycling, '11 Piru_anttU/lC' is pre..;ently in clini· cal lrials.
hne been de\'e loped in an cffon to limit side eff«ts. o.e of these se lecti\'e agenl~. beluU'otene, has bttn lIIlf"O."ai lor usc in patients with eut41lCOUs T-ce ll ~mphoma that If Il' fractO!')' in previous syMe rnic thcnapy . }II It is adtninbtl'fftl ornlly in gelatin capsu les,
o OH CH,
HICH,I,NH,
The 3ntipant~itic !.lrug suramin sodi um (Chaptcr 8) has long been used to treat trypanosomalllll!.l filari al infeetioos. II also inhibits re,'ersc tru"~ripWsc in RNA tumor vil\l5t's. Antitumor activi ty was demonstnued m hormornIlly refrnc· ti l'e prostate cllrlCt'r'lI> and a!.ll'anced 0\ IInan cnremoma. Sur· amin acts by a variety of biological rncc hun isrns. ind uding mhlhiuon of hyaluron idase. urease. hcxokinase. RNA polymena'ie. DNA topo1wmel'llSC II. and ly'iO!iOlTl:ll enlymcs. no II affects ATP ~ynthesis and degradation and inhibitS mitochond rial en/ynll'S, Signal transduction in cells is inhibited by SUnimin bin!.ling to tumor growth facton; and protein k,nases.)JI Summin may al'ioO mhihit anglDgCnesls and induce normal ce llulltt differentiation by increasing tissue glyeO'laminoglyeans. 1U Although :mlitumor acuvlty was found for ga ll iu m nit mle in phase II clinical trial s. m its approved use is for the treatn"K:nt ofcanccr·relale\.'e and oxygen to form spccic.~ thul allack DNA cleavage. This ~ is used for palliPlion completely obstruCted esophageal non -smllll cell lung cancer.JoOIl !
p--
Cisplatin. Cisplat in. Platioot NSC- II9875. COOP,;,;', prepared by treati ng potas.~il.lm ehloropl:llinite With. nia ..Kii It is u water·soluble while solid su pplied in ~ials coolllining 10 mg of eisplatin as a lyophil ized ....... ' . For reco(l§titution. 10 ml of sterile .... aleT is added ... . resulti ng solution is diluted in 2 l of 5'k delltro!ie ia 0.33 N saline contllinins 37.5 g of m~nnitol .j4l Cisplaun ha~ a triphasic disappcaruoce cur. e I... ith ... lives of 20 minutes. 4810 70 minutes. and 24 hours. ;Iriabty Ill}cosyhltcd in the y~~st. oierww prqmrouon. L.cukinc dlffen frum native 5l1rgrurnos.by rubstnuuon oflcuc1nealpo"lIIon 23 and byadlfferent ..tIoIl) •.Inlle maleup II h.as a 'pecilic OCUII;I)' of about 5 • lOT Vlmi of protein. l..cukine is available commercially al}ophllized povo'der in 25(). and SIX)."'I!: amoum~. It is ICroII>IltUIW luth 1.0 mL of SIt'flle Wale!" for In,e€:lIon. lSP, to yield II clear i~olOnic Mllullon m pH 7.4. Funhcr ~ions In Q,en- ~hul11 chlondc should mcludc O.I'if: \ I ofll\unan serum albumin to reduce :ldsorption to thl:: wrf;JCc. Vials should be di~arded wuhin (I hOUN of rrron.tilulion because there is "0 Ptllib;ictcria1 prc~""':lIhe. !1Ie also i~ $upplicd HI 250- :lIId 300-,ui l;al5 and is _"!luted lilt Leukmc. l.cuoom:u. is aVHllable for m\c~' -..iooal use fmm the Schering CorpomliOl1, M OSt ~~ of ",:"",;m are adnunblen:d by in fusion. although n IS ..1I.e by lhe subcut:meoo§ rouiC • Sargllln)()§.lIm IS u~'d Iu prorl1()le bone m~rrow !"COO"!!!), .prMI("l'> urKkrguing aUlOlogou~ bone marrow lransplanla"' II aJso redUttS lhe J;e1'Cnly and dural.1OI1 of neutrofollo",lnll ~ulld:1fl1 chemolherapy "Ith mydol-uyptophan ..MIl It is :";';';clas t/lt parnoate salt, ... hich pro ... ide) a depot form ...-ut duration ... ben gJ"C'n OI'1IlIy. Gorupionate, 2anw:thyldih~drowilosteror""
propiullatc. i.~ prepared from dih}'drolC5IOS1Crone ill D route inlul ~ing condcnSlluon .... ith ethyl forro.ale fol1o"'cd by hydro~nal ioo to gil'e the 2amethyl deri"3I1ve uOO then reacl ion with propionic ullhydridc:J'}° ThecompoUiod is supp lied in rubber-stoppered vials l'OOlainmg SOO mg dromoslanolone propionate In 10 mL of sesame oil. wilh O.5'ed. PotienlS develop a nu-like syndrolllr, eNS effects . and canJiovlISCu lar effectS. including hypotension. anhythmia, or tachycardia . In terferonAlfa -n3. Interferon II.lfa-n] is. glycoprotem produced from cultures of human Iwcocytes lreated with Sendat \·irus. It IS purified initially by chrommosroplly usm, a mouse monoclonal antibody that binds 10 multiple species of human inlerfcron. Sub5c:qUCJ1l purifICation involves incuhation at 40C and pH 2 to kill viruses and gel riltrution chromnt~rap/ty. It then has D specirIC aclivity of about 2 X 108 4 IU. ! The drug is supplied in l -mL vials containing I rnL of phosphate buffered saline sol ution, phenol as a preserva· tive, and I mg of humbn serum albumin liS a stabilizer. This solution shou ld be krpt at 2 10 !!"C. l1!cropeutic indications and side rffects or interferon alfa-nJ are similar 10 those Uescribed for interferons alra ·2a and alfa-2b.
Aldesleukin. 11..-2. aldesieukin, ProJeutin, Trcclcukin. interJeutin_2, 11..-2, T-cell growth faclor, in the human form is produced in mature T lymphocytes. Cleavage of the 21}amino acid signal sequence then results in an active protein
containing 133 anuno acids. It I~ glycosylmed and has 001: disulfide bond. .... hich is e$.~ntjal for acth·lty. Rooombinlim IL-2 i~ produced by £. that carri~ Insrrted. modified human IL-2 gcnes. Teceleukin I~ oonglycosylared but con· fonns to natural IL-2 in amino acid sequence. e~cept for an addiuonal N-terminal methLOnilM: . Proku!.:111 i$ not gl)'OO5"ylated ond differs fmm the nnlural protein In lacking the tenni. nal alanll'lc and having $Crine rather thaI! ey,tei ne for residue 12.5. 1L-2 acth'u) is SUllldutblCd 10 IU m an a.~y based 0 11 stimulat ion of T -cell growth in \·itro. ProIeu!.:m IS Iwall abk ill glaM vials COI1tain ing 1.2 mg of Iyophil;;':ed powder (22 million IU) plus o;()(hum decyl ~ulfate It is reconstituled with 1.2 mLo f wluuon supplied to gi~c 18 11lIl1lon IUlm L. Tl~leu!.:i ll i~ )upplied in vials containing 100 II1g of IL-2. 25 mg of human albumin. and.5 IlIII of mannitol per million IU. It I< reoon SUluted ..... Ilh Sodium Chlondc for Injection. US P All formu lations of [L-2 require 5tornge at 4 to 11"JIry bul care fully regukltcd COtnllOnem of normal polll!h arid \\OUllU healing. Uncontrolled IlngiogenC!iis i~ a dnolng factOf in wlid tumor gro.... th. TIle proc('~s of angio~I' I~ CQ11lplCl 311d requires the coordinated inlC1'lK:lion tllalhiplc cdl t)1lCS. Multiple sites for dNa Intervention ole (\pettea .... ' Endogenous angiogelM!!iis mhibltors .... ere • In umx:~ weh as carti lage ... hkh lack blood \'CS5Cls. ~an:h afforded a proIein named c:anilagt'-Ouil't'J /II, ."'l Lanllnm i~ a mapoolllponcm ofoo'iCmcnt memhit. f'epti(k."li balCd on il~ struc1ure, ~l.lCh ;.., CDP(;Y· XlSRNH:. mhlbn angIogenesis and ..ollt! I\JrnOf growlh.. 19M .w 11..... It, C J 8~ AI~)I."n. AfCM' 1..ondun. H"'...... ooIIl.
52. H 54. 55. .56. 57
It""
Alltn. I~ M . rt aI C....,... T",a, 6IH~I . 1'I7fI. I..~. P I . rt.1 1. 0, ... 0n00I ~ 5ll. 1'lSf>. Cm ..... I' 1_ rt II. C-"" T-. Rep . .'lII~55. 1976. 8ertcl. F. _ S40ck. J A. J Cho.. Sue laOII. 19S-' E...... T L . rI II. CIICeI" o..mochcr 1'hwmoaoI, I; V, ....... II .. .. II N MIl. J M7.290. 1\).15. M Ih."h,", .. G. 1I .• nd Elion, G . 8 , ..."'. a."m. II ... 2:202. I'M. 85. Elion. G, H.. rtll I Aon. CIoen,. ","", 74~11.19n. 86. Hru;:I.nwi. II W Ad~ Cani1 and Co.; Bel •. r,*", 671j37. 1967 ManlLJ J•• INlCchao.S S .. C ... , R.., 27:152A.1%1 BriM.. J J .. and O. A ~ c..cer R4. O"",tman. R W.. tI.oI.; C"""", Ita. 01&.1610. 19111), T_" W.-C .. till.' M.p.. ien, .. 20:202. 19M 122. 1Ianb. L J,,'I oJ,: AnlUnil.
148. ZIIlIIn. S.. 01 :01" 8ioohem I'IIann.ool )):0I. N.ow DruK' 2,359. ! 984. m. RelI .... Y. II.: N",,,", 218;19],19611. III Roo. K. V . CI al.: AnUM. a.."""I>er. 12: IS2, 1962. )1 . NIY'''''. 11 _. e\ al~ FEBS Len . .loO:U7. 1973. m GaIou, O. F.: OI,,,,,,,,~,,,. cI\ronlOOl),IIodll loon .. D. J. (cds.). Hard>ooI: of E>.pcnmomal 1'!wtttacoIogy. vol. 38. part 2. N... Yon.. SpringOf.Vt11.,. 1975. 1"1'. 670-694 275. Romctl . C. J .... II.: J. Mtd. Chern. 21 :88. 1m.
V 4.
C~a ..y.
216. Rons&. K. G •• and MII ... ic. N>ll. Mad ScI. U. S. A. 11. I~I. 19W. 281. Rum •. H.• .....1.: No .. onl"' ....... In l'in«k>. H. 101 (.:d.). CancerClcmem. SoI«/uooklar I) 2M. 1CflIy I~ hberated on the fonn of. ,..~ Eumple: '~Ra-'~R n
+
~lIc
+
l'"r'lIy
CHARACTERISTICS OF DECAY
Radiation DetaclOo"S
Figure 1 ] - ] • Sc:hematic dlilgram of a Compult'llle\f .utailomography «(An system thaI producP5 thin cross-sec1.lOOaI,mages of the body. An _-faY lubf rotales around the pattent, and 1M Iransmllleoo of radiotrnCers. The. pUl"p05C of tile gamma camera is to record the location and Intcnsity of the radiatlQn ",jibin the imaging field. Rudiation in the form of gamma photons (occasionally,,;rays) imti:llly enters tlx: camera through IIx: collimator, which usually is a sheet onead with multiple sma ll . precisely made holes. II CO\'ers the detector crystal. 11x: purpose of the COllin13lor is to decR:ao;.e scanered rodiation and increase 11x: o\'crnl1 rcsolullon of the 5)'~em. Photons lhat are not blocLed by the col limator then entcr a large Mldiulil iodide (with a small amotlnt of thallium) crystal that absorbs .,.. l1Iys. The absorbed cuellO' III the cry~tal is emilled as a nash of light (called a scintillllliQII), which is proportional to the energy of the .,..ray. Coupled 10 the bad: of tile Na l('ll) cry~l an: photomultiplier ( PM) lUbes 111.11 CCNlVert the light nashcs to electrical pulses IHOj)()f"\lQnal to tile amount of light To 1000Jliu tlx: original source of the photon (and create an image). a computer assigns )l- Y spatial coordinates to the vanouJ .,..rays coming from the p.1tient and stores this information in a matri~. After collection. the digital image is COlwerted into an analogue \'ideo signal for display on a
. '"
,_ ' . A
, •
PMT.....
Figur' 13-4 • Schematic: diagram of sontl llatlQn UIfIlI1 (Angef) system WIth a mu/tlt1Ole lead colhmate. alla:htd eliminate ~allered ")"fays), wn.ch IS used 10 VisualIZe I!S$i.It!I anECf systems usc one to thn:c scintillation tOB that rotllle about the ti SPEer is wilen i sioDal . organ~. 13·1 llcpicts a perfusion .san
,
"'~. A
~w,,_H'
uses ~~m;".
t
I
Figure 13- 5 • DynamIC study of the Irvef ,md blllc1~cystJl!S, thl!-radlOtlacer would not hallt' eotefed the gallbladder. Tl'1e.mow in frame 16 shows the
normal locatlOO of IN! gallbladdef
,,- TV_ Computer
,""
-
Figure 13- 6 • Schematicdlagramof oil rotating tuple-detector sclntdl.:lbon CMOefa system for Single photon erT\ISSIOO computed IOmogIclPhy (SPECl) demomtratlng" "cold" spot IeSltIO If'I the bro1ll'l on me sagittal VIfW (opM MI'OW)
Figure 13- 7 • SPECT rTl)'OCtannous n uoride. or s!OnllOUS tartnlte). A ftcr prcparnof1hc radiOl'hammeeutical. wsts for radiochcmical pu. ;a, !Muld be eamed out to ensure thm the radiotmeer is in nght tllemical form. The anal),tical I\1Ct!lodS used i~lude ~antllhin_layer chromatography. column chrornatograI t e)l traction. Likel)' radiochemical impuritjes sodium pertechnetate (N a'>9", I cO.), some insoluble (i.e .. reduced hydrol)'1.ed technetium tTC021 or f colloid). and a complex different fmm lhe (i.e .. 'l'im-fc-monodcntme rJthcr than ~'c-
.w-donor
.aoov.ll *'
,all ,~
,ra',~
'h'
~
bidentatc ligand). 11Ie ~tcrile serum vial~ comaini ng the StWlnous sal t anti the ligand are I)'oph ilized under a sterile incn gas atmosphere (i.e .• ni1rogen or argon). The ligand in the l"Caclion vial dctennincs the final chemical Structure of the \l9n'Tc-comple~ and the hiol ogical fate after illlrnvenous in· jection of the radiophammceutical.
Tec;hnetium Radiopharmaceutlcals Technetium (l"" Tc) Albumin Injection. ·~~"'T I c albu min for injection is a sierile. colorless 10 p.11e )'cllow solut ion containing human albumin (MW -60.000) rudiolabeled with Tc-99m JlCneehne1ale. 11M: reducing agent is ,tanl1OUS mnrnlc. which reduce) tile '>9n' l C04 - to an unknown oxid~ lion state and is " 'eatl)' chelated b)' the tarlrnte and posslbl), fomlS a CQmplex wilh su lfh)'dryl groups on the albumin b)' ligand exchange. The precise slructure of the stanoow. technelium - albumin complcx is currentl ), unknown . TIle p.1tient n:ceivc.~ an intravenous injecti on of 25 mCi (925 MBq ) of Tc-99m albumi n, Mulli ple images of the blood in the hean are tate" b)' electrocardiogram gating ( R·R interval). The rising portion of tile R wave "."oincidcs with end-diastole. These i mages are stored in u com pUler to reconstruct a 1II0Vle of lhe bealing hean. This procedu re i~ somelimes called II m"I';g/l/cd uc1I,,;siriulI ( MUGA) or a ratli''''''c/ide \·clllriculogm/ll. InformatiOlI obtui ned b)' this tec hnique irn;ludcs cardiac chamber wall III00ion and calcu lation of ejection fraction. Indications for ~he procedure inelude evaluation of e!TeetS of coronary ancr)' disease. foll ow·up of coronary anery b)'pliss Ilm£! pa tients. heart failure. Ilean lransplant evalumion (preoper.uive and postoperalive). eardiom)'opat hie~. and dl'ccts of eardi· OIoxic drug, (i .e .. doxorubidn).
Technetium (""' Tc) Albumin Aggregated.
""tII I c-al-
bumin aggregated is II steri le whilc su>pcnsion of human albumin aggregates formed b)' denaturing human albumin b)' healing at SO"C at pH 4.8 (isoclectric paim of albumin). The precise struclure of the stannous technetium-albumin ag.gregaled cOlllplex i. nntno,,",n at this time. 11M: particle sir-e nnd number can be e~timated with a hemoc)'tomeler grid. The panicle ~iJ.c of the suspension should be between 10 and 100 J.UTl. with no panicles greatcr than 150 foIm. This agem is used clinicall), to image the pulmonary microcircu lation for pulmonary embolus and 10 assess I"Cgional pulmonary func tion for surgery (i.e .. hmg trnnsplant~ or resection). The paucm receives an intravenous injection of 2 to 4 mCi (74 10 148 1\1Bq) of lhe Tc-99m- albumin aggregate,>. which lodge in '>Ome of the ,m"l1 pulmonary nnerio1e~ Hnd capillarics. and the distribution can be imased.11M: numbcrufaggregates recommended for good image qualit)' alld o;.afe~)' is 100.000 10 500.000 p.:1I1 icle~: thu~. onl), a small frJction of lhe 280 billion capillaries ~rc occluded. Multiple ima ges of Ihe lung are obtained 10 ass.ess lung perfusion. 'lbe distribulion of the p.'nic1e~ in the lung is a function of regional blood now: consequentl)'. in the nOfmnl lung. the panicles are di~!ribated umforml), througooullhe IUllg. When blood flow is occludL-d because of emboli. multiple UlIclion. lltc patient receh'es a bolos intraVCJlOO5 injection of JO mCI (370 MBq) of T c-99m mertilltide. aud dynamic images arl! obtained every 3 to 5 seconds to study blood flow to lhe kidneys. S«ju.cnlial slatic images arc then oblained for 20 10 30 minUles 10 evallJ.llle renal cortical upIJllc, ClIcrt'tioo. and tubu lar clearance. Delayed images may be required to e\'alullIe ]XItiems with obstruCtion or renal failure. Normally. IhcTe IS prompt sylT1l1'lWic bilateral perfusion. good con i,al accumulalion bilalerally with visual iution or the collecling systems by 3 to 5 minulCS poslinjecllOll, and rnpiducrellon imollle bladder. with oodelaylo iodielle partial or compkle OOsIrul stale " SI.1blr in aqueous solutioM.
Gallium f1Ga) Citra Ie.
TIle gaillum (III)-c llmc c:a.-
plex is formed by IId.:.hng the requi~ amount of·~" citratc (0. 15 M ) to gallium ( Ill) chloride and adJustl1ll pil io 4.5 to S.O wllh 50(lIum hydroxide. The ptoposc.l ~ IU~ of gallium ('7Ga) citr.lte i. shown below.· The patd rCCC"ivcs ~n imravenous injection of 5 to 10 mCi ( 185 11).1 MlJq) of gallium (b1Ga J citnne.llnd wholt-body ima,cslft Ihen obtained 24, 48.lIl1d 72 hOllrs after injection. Galli_ loca]i:f.es at sites of in fl ammat ion Qf inf~tion Ill> wcll varicty o{tumors. It is used in clinIcal prnttice in the and evaluation of rtturrcncc of lymphomas. Gallium il.t!l normally in thI: Ii\'er and spleen, bone. n~ lacnmaJ glands. and bn-ast tis.~uc.'. There is alw some ~ lion in lhe bowcl; conscqucmly. the patient may trquIItl luative wullor eoemas to e\'IICUJte this radioacti~ily pm 10 the 4S-hour inUlge, A~ more specific radiOlfll(."I'~ bee" t.lcveloped. Inc nouspeci fic I1OI1nallocali/.llllon 1ium radioactivity luis limne\l ils clmical use.
.1
of,.
o
HO HO
Ho l.~-N, 18 F
\
IODINE RADIOCHEMISTRY
OH
GAlUUM RADIOCHEMISTRY The only rndioi'iOlope of gallium thaI is presently used is ga11i um·67. wh Ich i~ produced in a cyc lotron by r,roton bombardment of Uline lI1el3ltarge\ by H "'Zn(p.2n) 'Oa nuclear reaction . Oalliu\l1·67 (I, f.! - 78.2 hours) decays by electron
The useful radioisotopes of iodine iodine· I)I:and iodine-l23 because i i cal characteristics. lodll'lt- I) I is obtained rrom production 0{ tellurium- I) 1. tion m U(n.fiuion)nlTe or lurium- 131 (I'I"! - 25 minutes) sian to iodine- I) I. Iodine- I) I (1 ,12 by {j decay to stable xCllolI- I)I . wilh fi\'c ell1i~siou~ or 80 to 723 keV. The major (82%) provides good tis)ue pc:oetration .;..,~
Chapt .... U • Qr iodlne-131 are the high rudi:mon long half-lire. and the poor )"111)'~. lodmc- 123 {I~ Caplure to teUunum-123. cmt~ion of IS9 leV (83%). ",hich of iodine for organ tmaging reduced radia i is in 11 cyclotron .....a.n antimony meTal target with 0 partielc~ IICl~iSh (o:r.2n)IH reaction or an iodine target protons by lhe IW(p.5n)IH nuclear reama. The localwlllon of .he Ilxilum (Ill) chloride In bone nllllTOW i~ prob,lbly expl~ incd hy its nb lli1y to bchnvc.lnt:13bolically lil e 1I'0Il and yel not be incorporated inlO hemoglobm in the RBC~ In lhe hone marrow. "The localil(alion o( the radiolt'llecr in IUllX)f'S lind lIb$ccsses is probably due to increased blood now and capi llary pellll¢ability in the area of1issuc: damage. Tmn"(cmn rece ptor; h.:tI'C been iiuggestcd a~ II mcan. of loc~li]..at ion but not pro~'ed al thi . lime:. Indium r "l n) Capro~ b PendetHk. Indium capromub pcndClidc IS a new IlIdiotracer for $tagi ng paticnts with ne ... ly d iag~ proslalc cnncer and for those with sus· pected reQCCurrcnce btu a negalive loculizalion w;lh II stan· d~rd clal uation. Indium ( Hll n) Oncosclnt CRIOV (Sarumomabpendetide). 1l'l' ~lInpl lrted structure of indium (1II In) satumo.. mllbpcndctide is shown be low. Antibotlics are ~ hcterogc nc· OO~ group o f proIcill5 i!iOlmted from human and ani mal serum and are called immIlRus/o/",/hu, They are di vided into ciu.SC:II on lhe IxIsi~ of diffcrclX."ean. Al'IOd'ier IIrtbod of radiolabeli ng Icukoc)tc' that ha.\ become: popular Il'ott Tc-99m- HMP AO (he.'llamcthylpropylcnciln'llDC o.l in'le) . Fmally. IndH.m ("l ln HabcJed platelets are u!oed to detecl *umboc;cs. mcasure platelet li fc span. and monilOr the soc~ of lidllCy transplanl'.
-
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o
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.Ileth-
fann rohy,ecuie
bod,. '"~ f 000-
,- -
= "' d north Tc-
Indium ('''In) Pentetate (''' In-DrPA). T he IIldiurn WI-pcnlctatc complex is fo nned by ILdd mg the required _u of calc.um or sodium pcntelUlc (I)TPA) 10 the in(III) chlonde and adjus1 inj; lhe pll 10 7.0 10 8.0 wilh "::: h~Urox ide and/or hydrochloric acid. A ~d EJI It of indium (Ill ) pentc!atc is \hown below. "flxo paundergoes a lumhar punctLire under "mle coodl tions .-I ftCC'i\'cs an mtr:lthecal injCCtion of 0.5 10 1.0 mC I ( 18.5 J1.0 MRq) o( indium (II 'In) penlet:l.ll.'..... hlCh dl~trlbul'-'" Ihc cerehmsp'lIal fluid (CS I'). 1ml.al itnaJ:es an: ob_ " 10 en'>IJI'I: a good intr:llheeal IDJCCIlon lmage\ of the , ana] and CSF spaces of the bn!.!n IlI'C acquired at 0 71 boors 10 IISSC'S CSF flow or leak ugc from the nom la! {~'PJCe. TIle normal CS F flow p;!ncm ,ho""~ Ihu1 the ipllamlllCCu tical asce nds to the bu,i lar ciste rn ' in 2 10 4 flQw~ over the cercbru l ron\'exilic~ in 24 hOlIr;. 10 72 hour;. there sltould be II i:f'.ldual c leaf'JI\(.'C Ihc CSI' ~ ia lhe choroid pICJlu'. CiSlemogrophy I' helpIII tlot!u;Umg (or ~'Ommunleatlllg h ydl'QCC'phaJ II~ becauliC IS lIboormal CS F no .... InlO the laterul "enuielc:s o ( Inm 10 thl~ d isease. Then:: iJ 31-0 an MR1 method for ng thIS type of hydrocephalus. 1111 ~ dlCd in lung "cnlilalion stUdies mu>! lit chemically inert and. al lhe conccmrntlon~ used, be ph))io. lo~icDlIy irocrt. Xcnon-I)) i~ chemICally LIlcrt IIJ1d LIlsolubk in waler. v.hich make, II msoluble In body nuids. Unfo''OItIlle phy,icnl char!ICicriSlicsof xcnon- I)) includc poor i~ quali ly becnuo,c uf thl: low tissue pcnc:trntion of the 10.energy )'"ray. increased patienl docardial t,,~ue. Con'CT'Io!ly. in clil1ical imaging s1Utli&:.~. the an:a~ of ntyocardial infarction (not vlllhle '\Car) are ~i~un t il.ed as nonpcrfused C'rotd ") ureas. Although the Tc-99" t-oosed myocardial pcrfu~ion r.tdlotmc-c~ (seslumibi and tctroforfU)lon abnormality beC8U'\C areas of significant arterial narrow inK cannot !'e.'pood to the increased blood now demands of the 'ltn:."!l as well as the normal aneries can. Imagt':'i o f the hean arc: obIruned iml11C1.lIate1y after Stress. and the damagetl myocardium shows less 11-201 chlonde uplake than surrounding normal heart mU!'elc, Four hours aftcr S1Jl!.\S. the feS.ting pmicnl i~
,,
injeclL-..l with 1.0 mei ()7 M Bq) of '11-201 chloride to pr0vide informll1 ion under normal cond l' ion ~. An clDl1lplc ilo shown In Figure 1)-7.
Xenon Radlapharmac:eutlcals XlMon rJJXe' Gas. Radioactive xcnon g:L\ I~ 'iIIppIla:I at ~tandard pressure and room lempcrnturt' In • ~!lIII o;ealcd glass vial (2 mL) in ~,of 101020 mG (371h~ 740 MBq). The g lll.'~ \'ial can conl"in atmOlOpheric ainu mixlllre of 5% ~cnon and 95% c~rboo dioxide and I~ sulubk for Inhalation by the p.:&tient for dlDgl1O§tK: e"alu3nOll of p!IIimonary function and ilT\:tging. The general ~ure. volves mixing the ~cl1On-IJJ gas In airoro~y~n in ac~ circUIt ~pirometcr ~~~Icm thai del;'c,-.; the rodiooct;lC PI and KbK~ l hing t])e go_ tl1ixtu~. The inhalation Slully OODsi'l ~ of equilibrium and W:L,houl pha.o;es. v.ith the paid Sluing or supme . In the .... ashoul Mudy. the pahent elhlJfl, the \cnon-IJJ ga.~ inlO an actIvated charcoal ltap 10 poeOd e~JIO!'ure of Ille lechnologist. Im;lg" are obtained COIlt ... oumaIler. .... ell-dJreclt'd gradIen t field~ 10 selectively excite hydrogen nuclei (protons) in a selected small vol ume of the patient"s body. 1llc exci tat ion is done by use of radiofrequcllC'y fields. and once the exCitation fields are removed. the excited protons lose the energy they ga ined . 'fhey emit a weak. but detectable. rollJio wave. whose ~m!llgth and manner of decay CIUI be used 10 gcnemte diagnostic medical images. The tesla (T) has been adopted lIS the official ullit of magnetic field strength for the intematiorwl system of units . The conventional unit. the gauss (Gl. i\ 10.000 urnes smaller. MRI is normally performed at 0.5 to
L5 T. 1be images produced by MRI are $uperficially similar 10 the cross-sectiooaJ images of the body produced by CT. MR I. however. has the "'kkd advantage of not uSlllg IOIIt1:lII& radiation. such lIS ~ - rays or ,.rays. and easi ly prodU«j ex quisite soft tissue images of the body in any desj red plane (coronal. axial. sagi nal . oblique. etc.). With MRI. image 00II -
h vascular analomy of the patll'rlt'!. AVM 101M (aW', a dJ91lill !.Ublfacuon t«hooque was used m whICh dtg,t.)1 ,mages obtained pnoI to InjI/'CtiOn of thr contrast agent were wbtractt'd from the conl1asl agent Images by computer
~
!ltallng illfeclion or spillallllJury. and the uSlrojlltc~1 illallnlCI studie, arc u«tllO d iagllose pept ic acid die char.K:teri~lIc~ are UctcrtulJted by the panicle ~izc: of lire barium su'p!'llsiolJ. ib ~ isco,ily, and it~ pH. which in tum are dctermiJred by the addition of'm:11I amounts of flol'oring agents. suspending a~em'. and so funh. lbese additi,'es are lhe proprietar) secret of tIM: manufactun:r and do impn:!'·c tiM: diagnoslic pmpcni!'s oflhe barium colloidal ~uspcn slOll for GI r.tdiolOjliCIII StudlCS. Barium sulfate prcpMalioru. are u5C'd to study tiM: ewpIta. gus., stomach. and duodenum as pan of l1li ..SOf>IIagr:lm or UG I serie!! and are gl"en OI"'Jlly. M ost pilhent., find thoc laSte of these dense mi.\Hlres acc.:plable (Ihey arc: u,uidly li'en II stra .... berry or lemon na\or). but they d"lr~e tIM: hea\y texture or the barIUm. Barium sulfat!' ~u~pensions are alo;o gi\'en OflIlly to ~Iudy tire enlin: ,mall bol'>cJ (S8FT) or t'\.'\.'lall y to examine Ihe colon (IlE) ( !-ig. 13- I 8). Typical b.,rium ~uspensions range from 30 to more thun 120% weight/volume ( .... Iv). and bet'ause they are collOidal suspensions. they I;'IInJlOl be gi'·en imrJI'Ilsculatly: ti>c l"OlloidaI panktes would produce fatal pulmonary !'mbolrsllI 'The barium suspell$iom uo;ed forUG I or BE studies an: too dense 10 be used fOf gut op;lCificahOll dunng cr Mudle, of tiM: abdorn!'n, because they ~ unacccplllbic roldlOlr:ap/lie amf!lC1s. Instead. conmw.'reial barium prcP.lr:ltIOllS an: dl ' luted to I to 4'1> \l1v.
Diatriroate.
DiDlril.oate is classified as an Ionic tltonnmene contrnSI agent arid is a~ailable in the rncglulllure, oWdium. or eombinUIIOI] of mcgluminc ~nd sodium '1I1h of lhe fully sub~titulcd triiodubcnl.oic acid. II ha. a l1loli.'\.'ulor wcight of 614. and the organicully boutld iodine I;'ontenl is 62%. It s IilIlts ore used mainly for angiogrophy Dnd excretory urography, 'The diutriwatc. mcglununc (66~) and d latril.(JDlC sodium (10'1» combintlllOlI may be used orally or reaally to delineate the GL tracl . Thl' p"'jXlmtlOll I~ loolCaled \I hen !he use ofl)anum sulfate iSpo(enual1y wngeruu' (i.e .. .... hene\'er a suspecled perfomllon of tiM: Gltract exists). becau\e watc-r-50lu blc contras.t agents are Ijuid:ly absorbed throoj;h the peritoneal surfllCC . TIl.: high oo>moiaiity pre,ents "'Dtet absorption lind kllCls to r:lpid IrallSil Ihrough the G1 tllM."l..
"
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Figure 11- 19 • lymphanglOgrarn of a I'\CJ(malleg after EthlOdoI iIdm!nlSlfatlOO. The r""glumine saIL dilute solution (1 8% w/v) is u'\ed for cystography after >l.cnie eathctcritation of the bladder.
Ethlodol, Ethiodol is a sterile preparation containing ethyl eSlefl; o f the iodina ted fally Ildd~ of poppy-seed oil and it is used for lymphangiography, It cont ains 35 10 39% of Ofganicall y bound iodine that has been added to the double bonds of the fatty acids. Because Ethiodol is an oi ly substance and IlOl miscible with plasma. it can not be adminrs.tert q.Mt m;r.\i&nal'oCW;. A typtcal norrn.al\ymphangiogrum of the lower leg is illustrated in Figure 13- 19.
lodjpamide Meg/umine. ludip:nnidc meglunllJle is. i-onic d imeric contra~t agent lind i~ giH'n a~ the me~_ ~l t . .... hich is highly w.ucr oefr.
Wll~",!..
1m.
Ko·... t.\~. R. 1,, 1lfIII I.."y. I R Rwlioph'''''lICCUhC"I,In N...,t... \Ioi d"" l'raI:I=. Nl,,.ul\. c t'. Al'I'lelon & l"""'lIo. 1987. Kun'lICI...,henliaot "'"""'P'< ,a lhe I""'P"rllk" of 1Cclo· "," urn ,odiphannKru"cah. In SMipOO C 8 ted 1. TC.lbooO, or T1iNf)o """ I'no;IICC_ 2nd cd. No... y",1... Gordoii A ll roach. 1990l " U)Cbluen..O K ......... )'loII20:R6~. 1995 j. Scti .. oc"",,. K , A".., ... C'tIem 1111 F.d. E:nJl lJ:2""'..38. 199-1 6. lun""",- S.. CI .... CheRI. IUv 93 I t17, 1993. 7. CO>Iollo_C. fl. ...... I. N""I Metl. 24.\53. L9IIJ 8. Ju,hWII. S .. CI al .. 1""'1· 0.."" 2!I.341. llIIl6. 9 L.."'-c. 102:2476. 1980 10 de L..ln~. C. l., C< -'.. N..,t. Med.. ""~. 17 161. 1990 II. t.koRni.. J L. C< 01. I.... J 1'1..,1 toted B..... I Ltlll. t980l 12. 0hQ. It _C< 0I~ CI,n. Nucl. Med. 10".j(Ml t""'
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11 IIkw1cC"'i considered in of ncunlfla] lICtivity in thoi: cenlr~J ~oos ~~~Icm (eNS), Ihall~. Inc br.lln and spinal coni. In IIIOSI ca5/.'l the bruin is the inLt'ndcd larget. In a kw cases. "in \kclctal mu in OOnllTlQn and like .... i"c an o_cmll boulertpper sh~pt Ihat has been D~~I)("iated with neuronal 1'01t. tal MJdlUm channel block. leading to decreased neuII:IIlI elc1tution. Channel blocl of other inorganic cations. IIOUIbly Ca:' . may conlribule ,ignificantly to Ol"ernll Ktioo in sortie insIlIllCt!$. AnlipsycOOClcs lite crouped InIO ...~ and Dtyplcal categorie,. BOlh cUlegorics \hare a ~'om fe.lllure . • dopamine-lile structure. often h)drophoIy ~u~tituted, This fc;)ture can be relaled to the most Iy {'lied llClion of lhe se ageflls. COrtlPOClIIll"C umage>of dop.:unine ( DA):1I D1 and DJ recepton in the: limbIC .;..~. In recombinant D: re"~rtoo relatioosh,p,'1 thcoril.ed as long aso a~ Johnson and EYflng 6 to be ~i tcs of a bioao:tl\'c protein. might sigmrlCantly be ~IIO$tcric modula101')' ~;ICS of the protein of GABA,\ TCt"eptors, Chmcally. Ilcncnl ancsthc!;.n for SUTllC'1') uses mull'ple drug TCsilllen§. Somc drugs rnay be used to augment the gcneral anesthc:tic ugcnt (c.S., neurol~ptic~ and oploid analgesicj), Other drugs /I1lly add an actiOfl (q; .. the: s~elctal
rm-
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mllscle relualUS). Also. drogs such as anticholiocrgics mlIy be used to decre:a.'IC: adverse crfect~. Conslilt a cllrnnt rlledical le~tbook for the ways in ... hith these agent~ are IIscd together. Our ptJtpOSe is to COIlsider OIlly the: lCocral anothetlC agent. General anesthetic agents can be bro.'ldly clltegorized as tho&!: useful by the: lfIhalation route and those u''iIImc euent
Sevoflurane. Se'o numr~. FC(llh-O·CIt(CF1n. • an oillgas partition coeOicienl about one_half that of i~ line, and the blood/gas panilioo codficienl is aboul one.... thai or i~flurune. PhamracokinClkally. it reponedly~. ad\'anta~ orrapid uptakcrurd rapid elimi nation It 1 1·
." (b-uepa te Dipotassium. CIorv.c:patc dlpol::l'isiullI. l-d\1oro·2.J·dih) dro-2·(-,,0·5·~ny l · ll1- 1 .4-bcn1.OOial.e ,.·3-carboxyl ie acid dipolus~iu m sail mo nohydrate (Trun· Ide). c~n be considered a prodrug. Inactive itself. il underraptd loss of water alld then d< ,fier.
appear 10 exen J11()61 of their characteri stic CSS effects by binding [0 an allosteric ~ogni tion site on GABA ... n:C' may be N III infanc)l. but the di"Ca!iC does Il()I enlC'Tgc until III !he s«ond decade Of in lhe th ird decade of life. BasiQIy lbephn, sy>lc m has dilTlClIlty discnnllnating between .xl im:Ie\'81l1 stimuh . i'ert:t'pt'on IS illogical. Profll)lll this, thought and :IC1ion~ bc:coIne illogical. AI_ thIl' actual slllICtural ()( nrnllomical k~lons (all: not .... the basic defect appears to In"oll'e OVCrnctJ\lI)1 of IopBlnrrgic IICUrollS in the mcsolimblC J)I. lbc long \'-IIL~1 §ulY.ilimcm could help prorlIOIc m.:c:ptor lIf1ini!), and produce receplor amagt)l1i~1l1 activity andlor in~c:rsc ago,>Ill"
Some membc..... of thc: d:l.Sli nrc extrt:rne ly poIent antipsy dIou Iowcr affinity. appeal'> 10 \ ;"Idate the: Ihlorul.uIIlC ~nd apJICu ..... to alluw n~ !iC1«1ivlI)' I)~ Il.'I.'eptors. Lc~S(:ning blocks on. for elllmpk. l\.'Ccptor,. and possibly mcsoconical D: rec.:ptro eoo ld prolluee drug, Ihat ure much Ie' .. unplcawlI (lalienl. Addiliolloliy. a less Jntcnsc: D1 block ~0II1d the effc:c,-~ of other blocls to male up IOOR.' of the lota l OClion (e.g .• S· HT trul"JIUf\cr block). Sc-o"ffl!l;';
rprt!(ul 5 ,,"Ith hu~ re~ic~.
.b~ycholics
have nngs with ellh~lIced nuclcopllility. Of ."(1IIfSe. otllc _ effCCls can be lldequalcly controlled. use of lhe- 1m. iCily of IilhllJllt. Ihere i~ ~ub~tamia l 11\. ...;IDde DIIolw:Io. T c ... .. ..... Joo(td.) .." ..
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.ut_ .,
o.u,....."
I IMemIlIbtoxyJ or mct hylencdioxy ~1I~t i tution on the rq lend s to produce psychotomimetic agcllls, sUggestiRllnIpiStil for dop.ulllnergic (0 2 ) receptors, N-methylation Increa,Cular effects than .....lIro isomer. For most medkal uses. the dextrorotatory IIOIlltr is preferred. OUrroamphetamine Sulfate, USP, and o.KtroamphetIIIIiM Phosphate. Dex troomp/letamine. (+}-(S)W) IpIle11Cthylamine. fonns ~11tS with sulfuric acid (Dexe.me) and with phosphoric acids. The p/lo)pllate i~ the more Qer·soluble Sill! and is prefcrred if parentcral admi nistra_ tal i~ ~uired. The dc~trorotatory io;omer lIa~ the (S) con· ip"atiOhentemline h;I5 a qUllt('rnary carbon atom wi th une methyl oriented Iike lhe methyl of (S}-amphet:nnine and 0111' ,nethy l oriemed like lhe methyl of (H)-amphetaminc. and it ~poncdly has ph~nnacological propcnks of both lhe ( N) and (S) isomers of amphetamine. "The compound is used as an appetile ~uppre,sanl and is a Schedu le IV agent. indicating less abttse potential than deXtroamp/lctamine . BenzpMtamine Hydrochlori~. 8en/p/letanllne hydrochlonde. C+ )- N. benzyl-N.a-dimethylphenethylamine hydrochloride. ( + )-l.phcn)·1-2-{N-methy l-N-bew.yllmine)propane hydrochloride (Didrex). is N-beru:yl·wbsU1utOO mc:lhamp/let(lmine. The lar1!\' (benzyl) N-substiluenl decrea\0e5 eJlcitulory properties. in keeping IOoilh lhe gC/l('T'JI structure - activity relationship (SAR) for the group. Anore;o;iam propenie~ are retained. C laSSically. amphctamine-like drugs ... hh I(lrger thun N-mclhyl substi\Uenls ure ciled as W"IOf"l:xian t lhrough cemral p agonism . No claims f("K ~c1cc tivity anMlng ,B-receplor 'ubtypes ha"e been made in such citallons. The compound sha~s mechanism-of·action characteristiC$ with nlethylphenioote. Overall. it is said 10 reduce appetite wilh fewer eNS excitalory effeclS than de.\lllXImphetamine. D~rhylproplon Hydrochloride, USP. Becausc it has two l:l1ge (~Iath'e to II or methyl ) N·altyl WbsIl\I.l('OIS. di -
ethylpropion hydrochloride. l-phenyl-2-diethylnmmClprOpa n- I-f.II1C hydrochloride (Ttnuate. T epanill. has fewer sym. patlMlnti nlCtic. cardiovascular. and eNS-stimulatory effects than antp/letUl11 ioc. It is reponedly an aoorexiunl agent that can be uSC'd for lhe treat ment of obesity in patients with hypenen~ioo and eardiovascu lar disease. According 10 the generali1.llliOl1 loog used for this group of drugs. inc~asing N-al kyl ~il.e reduces centrul a, effects and increa.-;es {J efree\). e\en though lhe effects are ht~ly medialed principally by indirect NE release.
FenfluramlM Hydrochloride. Fennunulllne hydrochloride. ( ::!: )N-eth)I-a-lTICthyl-m-{trinuoromethyl)phene_ thy lamine hydrochloride (Pondimin). is unique in thi5 group or drugs. in that it lends to produce sedatiOl1 rather than
UCIUltion. Effects are pit! to be mediated principally by ccnt!'lll serotooinergJc, !'lither thlUl centrol nuradrenergic. mechanislTI5.. In large. doselI In expenmemaJ animals. the drug IS a serolonin neurotoxin.l~ It was Wlthdra""TI from human use anCT reportS of heart valle damage and pulmonary hypc.nen~Ion. From its SItuC1ure. more upolur or hydroIlilobi echarnc:terthan amphetamine. tropism for serotonincr· gic neurons wou ld be expected. U lewise. the structure ~ugge~ts an illdirect mechan ism. If un Indirect mechanism were opc."l1Itil·e. tnen all postsynuptic 5-HT receptors could be activated. Evidence frotn :.el'erul studies indicatcs thai the 5lrr l• and tne 5HT1(: receptors an:: most I"eSIXHLsible for the !l3licly effcct~ orS· UT. S·1fT may llsoinnuellCC the type of food selected (e.g .• Jov,'er faller food intake).' I 1lIe (+) isomer. dexfennummine ( Redux). has. greateT tropt$m for 5·1fT sy ... ems than the r....."Clmc l1uxture. II. too. was " ithdr~wn because of toxici ty_
PMndimetraziM Tartrate. USP. The opticall y pun:: compound phcndimctnll'.ioo tannllC. (2S.3S}-3.4-dimethyl2-phenylmorpholinc· ..· ( + Hllnrutc (l' lcgine). is ~"()f1sidcred an effective aoon:x iam thai j, Ics~ ~bu'iC pronc Ih~nllmphct amine. TIle stcreochemistry of ( +)phendimetrazillC is as shown. 110 H
HaC - N
I
H,C
o
keted compound and " about 400 limes 8.' potent t i tht: f!r)"thro ncemate_1l 1lIc absolute configul1ltion of earn ci the Ihftl.Jultin, In h igheT $ynaptic of NE and 5-HT. could account for lhe eNS cffccts. oompound was then reinlrodoccd inlo Ihn"npy as an .....~o;ant agent. It stimulattd WI intcnse mtere!.t In hyIlllIDeS and h)·dr"'l.ide~ :IS antidetlrt'SS3IlIS and i Mugurdt~d .I'kru\~ drug tnatment of depressio n.12 It contillued to be "'" in themp)' for sevcrd l yea'" bllt e,ent ll~lIy W3S wllhht,ft becuuse o f hcpatOloxici ty. The prtSCnl clinica ll y usefu l irrevenoibit inaclivllloni can .~rt'd nl« ha"i~nt·b;a>l..'d inh ihitors of MAO.v T hey .o."OII,·cncd by MAO to agcnls thaI inh Ibit the cll7yme. CMl form reaclants lhat bond co"alently with the en or tbcofXlor. A lXlflSCQUCI1Ce ofim:verstble inactiva• !hit the action o f lhe agents may continue for up to ...n\ dler admm islnllion i~ dio;conlmucd. Comcquem ly. *up IkgBded by M AO or drugs that ele\ale !e,'cls \tAO subslrulCS canIKM be adminiSiL-rcd dunng that timc. for ~ long till1C'. bca\use the agents thnt opened the field .. ta OOnunated il were im:versiblc ,nact.v~tor. MAO
1(.
!fecI 1011 ~u .re ..
.\
[[1:(:1. A
thm
QIlC
merea...:
lsI d ll'ected
typc and
dlustrnte~
PhefJelzirH! SUlfafft, USp, PheIlCI1., ne $11lf1l1e. 2..(phe· nylelhyl)hydnu.lne $ulf:ase (Nardil). IS an effecti\'e antide· pressant agent. A nNXhDl1ism-ba.~ itlaClivator, it .rre,'tnibly inactivates the e n:rylnc or its cofactor. presumably after oxid.lllon to the dialinc. wh ich ClII1 then break up inlO nLOlccu lar nitrogen, a hydrogen alom, and Q pbcncthyl free mdicaJ. TIle latter would be the octile species in irreversiblc in hibition. l.~
Tranylcyp romlrH! Sulfa fft, USP. Tranylcypromine ~ul fate, ( ± )-mms.2'phcnylcyclopropylamine s ulfate (I>-ol/"' nate). WIIS syntt.e.il.ed 10 be an amphetamine IUUllogue (v\SU . alil.e the a-nlCth).t of amp/lctaminc coodcn.scd 0010 the ~ c:ubon atorn).:" It docs ha"c -.orne ampllC'tanunc-hte ",opcrties, which may be why II has more immediate eNS Slimu· lant effects than agcnb that al1 by MAO inhiblt.on alone. For MAO ,nhibition . there may be two components 10 the
TABLE 15-4
Monoamine Oxidase Inhibitors
GeM.k Name f'r"tJpMtMY N. TM
.-
Structu..
A. t •••• , ...",
""", ,
ICtlon of this agen!. One is thouj!ht to Dri~ bccau'\C mmyky~ rromme hIlS strucwral fealUrc5 (the basic nitrogen and the qua~l-lI' ch.arxter of the 0- and .8-cyclopropilne carbon 1II0ms) that approximatc the tr.lnsitlOl'l stIIte in a rotlle of nle1l1bohsm of ,8-ary lllmlJ'It).J1- 21 As a- and ,8-hydrogen atom5 are temo\ed from the normal wb>.tI'lll.c of the enzyme. the quasi · 1Tcharaclcr dcveloplo o\'er the a ..8-carboo syMem. Duplication of the transition ~3te pennlts c\tremely Strong. but rc,·cntble. attachment tl) tIM: enzyme. Addittonally. tran· ylcypromine h I mcc hant'm·based inactlvRtor. 11 i~ metaooti/.cd by MAO. with one ciL"Ctrun or tile nitrogen pai r lost to Onvin. This. in tum. produ\:cs homo lytic Ihsion of a cnrbOIl - carbon bond of cyclopropane. with (lI\e etl"t,"Iron from the fission pairin~ with the remain ing lonc nitrog.:n electron to gcnerntc an imine (protonated ) and with the other residing 00 I methylene carbon. Thus. a free radical is ronncd thai re3iC:tS to form I covalent bond wtth the en/yntc 01" with redllCed nav;n to tnactivale the enlyme.;I'J
Monon .. Ine Reuptnke Inhibitors Origt!lnlly. the lllOll()/Imine reuptake inhibi tors" ere a group of clo:;dy related agents. the tricyclic antidepressants. but now they are quite dh'ct"'>C chemically. Almos t all of the agems block neurona l reuptake o f NE or 5· HT or both (i.c .. lire selccti""). Rcupta ke inhibition by thC"tein bourn! that dial y\i' i~ in.cffCC1i\'e.
PRODUCTS Im;prami~
Hydrochloride, USP.
ImtprarnJIlC' h chloride . 5·IJ.(dtmeth~lamit1())ptopyll · 1 0.1 l -di h) dm-\II dibe:nllbJlazepine mooohydrochioridc (Tofl'll.nil) . •~ tbt bf cornpourn! of the TeA s, It is also a dose. relati\ e elf. antt~yrhol1Oulnone Epinephrine and NE each pos!iC$S It thuS. each can exist as an enantiomeric e nanl iomcr ..... ilh lhe (H) configuratIOn I~ lhe body and posw:s.CngcN iflO!,ltol -1.4.5- tri · phosphatc I l n~I.4.5)P ,1 and 1.2-rliacylglyccrol (nAG). Ins( 1.4.5)PJ Mrmulatcs the relell."C of CII!' from the sarc0plasmic reticulum , .... hile: DAG 1lC1;",:IIe:S protein ~ina.e gcrl('r:l.1 structure ,:onS;!>IS of !>e\cn tr:l.n~mtmbrane a-hehcal J;egmcllls and '" ho 10 dru~ actillg at thC'.sc rccc:pt<
in'i('~ a guamdino molel), ICNHC( - NH)NH!I ... hich i~ attached 10 either an alicyclie or an aromalic hpophillC group. llltSe structural featum an: seen in gU:lJlCthidine (lsmelin) and gu:madrel (Hylofd), which ure uscO dmically in the treatment ofhypcrtension.llIt pn:SCIlU" of the vel)' ba~ic gUlll1idino group (p K. > 12) in the'>C dlllg< mean, Ihm III phySIological pH they IIrt es~ntt:llly tomplete ly pmton nletl. Thus • thes.c: agents do nUl gCI into the e NS .
NH
II
N ............... NHCNH:!
.. 111
/'~
e ,m
0
II
~
OC- ~
GuanettDle
"OCH,
on< lieaL
libl-
I, a
$ICP
'111 po14I:
R' •
OCH", ~.
0111 ;6'"• . R' • H. ~. - . j"-OCH,
"""
-
'oi-'ben n::serpirw: IS gil'l.':l1 orally. it ma~inlUm effcct is secn ... I couple of weeks. A sustuincd eff«t up 10 ~vtral '". I~ sec:n after the last dose has been 81'en. Reserpine ~"."". I'dy mtlabolil..ed through hydrolysis of the tStCf 111 ~IIIOIt 18. This yields nlClh)·J rescrpale and "-..\.tnntethoxybc:n1.Oic acid. As is tYPICal of many Indole ~.;... I't'>trpine i~ ~usceplible 10 tlc:cumPOSIUOII by hsht .. ~.bllon . 80th lhe pure alkalOId and the po..-dI=d
•
Although gUDnelhidllle and guanadrel have vlnu.lI), the !i1IJl1C mechanism of action on sympmhC'lic neuron~. thC'y differ in lhC'ir phannaookinetic plOpet1ie~. For example, "'hile guanethidIne 1\ aMorbtd incomplelel y afler oral admini-.rolion (3 to ,SOIl.1'luanadn:1 is well aMorbC'd. with a bioavailablhly of 8SIJ. J These IWO agents also differ in terms of half-life: Guancthldint: has a half-life of aMt S day5 .... hert'a) gu:madrel has a half·llfe of 12 houl1!. Both agenls are partially nlCtaboli 7.ed (-~) hy the lhcr. and both arc ust'd to treat modcrote,to-scvcre hyperte nSIon, ei lher alone or in combumllon wilh another am ihypcnr.nsl~e agent. Bretylium Tosy/afe. Ar'IOther AeuNnal hlocking ab~m is the aromallc quatern:l.l)' arnnlOlliurn compound bn:iyhum losy late (Brelylol ). Thl\ ~ent is used as an antiafThythmlC drug. [t$ antiarrit)thrllic IICliOlts are not belie~ed 10 be dl.le to its neurOf\llI blocllllS effect~, oo..'C'"er. This agenl is diScussed 11\ more detail in ChaplCl' 19.
CH,
B, Bretyli..rnTosy\a1e
SYMPATHOMIMETIC AGENTS SymplIlOOmmlotik agcnts pnxtuce effec1s re.o;embling lOOse produced by slimulatioo of Ilk: symp:uhctic nervou s system , They may be classified as agents thai pm duce effects by
:I
direct, indirect, Of milled llJo1Xhanism of action. Direct-acting agents elicit a symPllIhomirlJelic ~sponsc by interacting direttly with adrenergic rc:ccplOn. Indirec1-lcllns agents produo:c effeels prinwily by causing the Il'Ju.C'rgic TCceptor 3gonl\tS hOl'e been reviewed,u·15 The paJ'l:nl SU\ICfor many of the ~y mpmhomimetic dnlg~ is ,tJ.phenylethylamine. The manner in which ,tJ.phcnylethylll.mine is substi tuted 011 the ,"t'll and para positioo s of the aromatic nng and on the anuno. 4'. and 13 posItions of the ethylamioc side ehain innuences 001 only the mechanism of sympathomimetic action bot al",/",,, NHCH(CH al2
h
OH
OH
Resorcinal
He
Metaproterenot
HO
N-/6f1-Butylnorepineptvlne (Colterol)
Mrthyl or e1hy l substitu tion on the If-Carboll of the elllchain reduces d irect n..-ccplor
Imperium!),. i
agoni~1
howc~cr.
an
acliyn), /'t'nl~yl
of action ofthc Ilhenylcthylam -
. I by IIIU\;lIlg tile conlpoun(l re.~iSlam 10 metabolic Ii by MAO. Such rompoulld~ often exhibIt en0IlI1 cffecu \cne;s arid greater eNS VII)' than their ~s that do 001 contain an a-alk)' l llrotJP' a-Subsualso i affects ~cplOr ~lecli v lI)'. In the
a..,.
Albuterol
Mtxlifical10n of the catl'Chol ring Clill also bring aboul selectivity al a reccpto" as il appeao> that the calechol moiely i~ more imporlam fOf agonist IOCli vilY at a~ fC(;eptors Ihan al «, receptors. I'ot e~amplc. removal of the: II-hydroxyl gI"QUp from epinephrine givl!,~ phenylephrine:. "hid. in 1.'0/1trasl to ep;ncphrill advantage of the drug 's potent ~t imu latOf)' cffects 011 Q If· ceptors. The ability of epinephrillC' to stilllu l:otc Ih. ~r has led to II~ usc: by injecllon and by inhaLatIOn 10 bronchial ~lTlooth lllu~;cIc in a.~thm:t and III anaph) 11Cl1C~' tions. Sel-cr'dl oVCr-the-counter prcpanltlOllS (e.g .. fill. lIIatcne. Bron~ aid) used for treating broilChiaJ ~hll\a II'( epl nephnne. Epinephrine is uo,ed in the tll:al ment of open-angle Jl» coma. whe~ it app;.rcll,ly rl-uucC$ intraocu lpr Itrel\Sllrf '" incrca~illS 'hc nne of ou,l1o .... of aqueous humO!' from Ihr anterior chambcrof ,he c)'e. 1bc ini'ation often cxpc~ on in~tillation of epinephrine imo the eye has led 10 III! dc ,-eloprne m of OIher prcparutions of lhe drug llut pokao hally are not: as 'mlllllng. One such uample is d'l'I,cll1l
*
mn
PI.,
-
In doses slightly higher than th()';C reqUired 10 increase renal blood no ..... dopamine stimulates lhe P, I'CCl'ptOl'll of the heart to increase eard iac output. Some of 'he effects of dopamine un ,he heart are al..o due 10 NE relcasc. Infu~ioll at a MI'C sn:a1er than 10 #slkg per minute rc..u lts in Mimula· tion of '"'I I'CCcpl Of'l. lcading tu vasoconstriction und an in· crease in ancrial blood pressure.
Dipilfefrin. I)'p...cfnn (d,pi\'alyl cpinephnn~. ~ i~ a prodrug of epi nephrinc Uw is formed by the C)(mfg. tion of the ca/echol hydroxyl groups of epinep/lnne plvalie acid. Di pi,errin i~ much IfIO(e lipophilIC than. nephrinc. 3nd it a.chle>-~5 much bener pcnelr." ion ofthe~ when admi ni~tered topically !I$ 3n aqueous WlUliOll (Of trca ' me n! o r pnm:ory open.ang le glHIIComa, It IS con,-encd. epinephrinc by e~ter'.I~~ in the l'Ornca ami ~nLerior ch.lJrillJ Di phefrin offers the alIvamuge of being Ic~s irriWliJll_ the ~yc than epinephrine. IlIkI because of ilS more tfflCa trol'hpon into the e)'l'. Jl can be used on lower concerH .. _
*
than ~pml'phrille.
Nort!pinephrine (NE). NE (Levophcd) i~ u~ to ll1ainuun blood ~re III acute h)"potcnsh'e states fCSuil ,ng from $IIrgical or IlOIlSlIrgical trauma, central \'asomoIor depression. ~nd hcmorrlulge. Like theOlhercndogcnou~ catecholamines. it is a suhmatc for IxMh MAO and COMT and thus is not: cffective by the oml routc of admini\trnllon. It is gh en by intral'ellOOs injection. Epinephrine. Epinephrine (AdrenoHn) filld\ usc in 3 number situatiuns because of its pOIent illlulUlOf}' efrects on both (f- Hnd ,8- adrenergic l\.""cplo""'. Litc the other ca tc· cholam il1C.~. epinephrine is ligh t sensiti\c ami ea~ily ox idllcd on c~posure to airbccause of tile catechol nn!; sy\'cm. The development of a pink to brown color indicatcCu\"lty 1S taJ,.e~ 00 arc· eccptOl"l to reho: :tIC rc",,'
_g.. Pn· hma usc
gle glau· :ssurc by
eptq1hrinc and norcplllCphrinc (NE). It I' IICU\ C100 tlcn g,,'clec· Ilvity for I~ aradrencrgle rttcplOf, n.e 0'1:t,2 "'"0 1\ 3(X):I . Under certain condition", weh as inlravcnous infu5ioo. clonldinc c~n brieny e~hibit ,·.socQ'hcrieti,c ao:.1t\ity as II R'W II of stlmulatioo 0( penphcml n-a.Jrencrglc rcccp-
10I'"'l. Ho ..... ever. this hypenen ~ive effecl. if it (I(.'Curs. is fol lowed by a IIIuch.longer lasting hypotensi"e effcci lls a result of the ubiTi ly of clnnidin.e 10 Cl1ler il1to che CNS and ~'imu IlIcc ~ fCC\:plor.. 10c;,IOO in regions of the bram. ~uch as tile nudeu\ traclUS 'KlIilarius. Stimulation of these (II reccptOl' bring.~ aboot a decrease in ~ympatlletlC outflow from the: CNS. "'hich in tum leads 10 decrca'ICs in peripheral .-ascular resistance and blood presStlre..Il~ .. Bf1ldyeanlia i~ al'>O rroduccd by cionJdme as II J"C)IJ lt of a r:entr:lll) ind~cd facilita_ tion of tile vagus llCn'e and Slilnulatioo of cardiac prf:Junc· liOlUlI a :-oorenergic I\:CCplOfS. W TllCse phannocolOj;IClII ilCtion' have made domdmc qUlle u'ICful in the trealment or h.ypcnen~ion,
-
CI
H N
N=< J N H
half-life o f clooid inc r~n!;cs frt>m 20 to 25 hour) ... hile tItI; for guanfocinc i~ about 17 houl"!l. Guan abcnl has the 5hontII durntion of action of!hese t~e agerns. wi th a tulf·Jifr Ii about 6 hours. Clon odine .nd guanfacine :m: cxcn:tcd_ changed in the urine to the extent of 60 and 5()'i,. ~. t,,·ely. Very lillie of guall:lbenJ; I~ Cllcreted unch:lllgtd_. unne.
CloI'Ikine: R • H
CI
NH
.-Hydroxyclorlicline: A . OH
II
CH=NNHCNH2
ApfacIonIdine: R . NH2
1'he:ibl\\\y of claa.ru.ne ud ,'" an:t.1~ 10 u.m an 1U\l1hypcnensl\'l: effect depend~ on the ability of I ~ cornpounds 001 only 10 Internet .... nh rIM: III n.-ccpcor bUIIII'>O \0 gai n enlry jmo riM: eNS. I'or example. in the ca;;e or donidine. the b:L~iciIY of the guanidine group (Iypicall y pK. I3,6) is decll!',,-~d 10 8.0(rhc pK. ofclonidmeJ bccau'ie ofitsdll1,X1 allachme'1I10 the dlchlorophcn) I ring. ThU$, at ph)'\lologicaJ pH. dOI'll(ilne .... 11 exi'-lIO a 51gmlicanr Ulcnl In the nomooil.cd form requlI'ed for ~I!e Into the eNS. Surn.lilUI;OI1S 00 the aromal ic ring also affe(!\ Ihe ublli,y of cloni dlllc and ils analogue, 10 !luin cntry into Ihe eNS 10 produce un IUIti hypertensive ceTl'Ct. Altlloogh various halogl'lI and allyl '\lIbqi lulioos cun be placed al the two orll",
positions of the (phi:nylimioojumd37.()lidine nuclel,l\ \\w.n' tbltea (...-cur during laser surgcry on the eye. Brimonidine u fronl .pula! (I in tcmcuron s.oU.
~ _N
,
N
-
~
Br
iI
H N
N=iSOlllcr of amhylnoRpmcptmnc. IOhich po6SeSSC's!he (RJ configuraIII lhc cW'boo wnh the P.hydroxyl group and the (S) ~'Igunuion aL the c:1lrbon WIth the a-mcthyl ~lIbslilUcnl fil. 16..(j). 11 IS postuhued that o--mt'thylnorcpirn:phnne acts • OJ m:cplOf1 in the CNS in the lic ac· nons probably 'OIlIribule 10 'I~ va'iQtliiatory acti vity . Its hiS, tamine-It t.:e effects inc lude stimulation of 8a.~1ne in the pmphyiluas of migraine headaches and in the theropy follo".. inS myoearlilal infarctlOfl. Sotalo1 is used us an anuarrhythrnic in tn:aling ventricu lar arrtoythm iall and alnalfibnllallOfl be· CIlU'>e in additIon 10 its P.adrenerglC bloddng aCllv lly, this agent bloeh lhe in",'aru K • eum:ntlhal dela)~cardlac n:polam.:auon. Caneolo!. llmolol.lc:>obunolol. and IlICtIPflUlOIoi are used topi cally to treat open-angle glauL"Onul . TItese agents lower intraocular pl"CSSure ... ith vll1uaJly 110 cffect on pupil 'IJ.e or 31,.'cornmodation. 11Ky Ihus o ffer WI 3I(hanlllge over many of lhe OIher drug~ u.'mdolol pOS•.'iC'St'S modest rnembr:lIle-,whili /jn!; acU\ it y and signifK.'""oInl inmnsic ,8-agoni\llc acti vity . Prnblltolol and ca n c:olol al~ ha,'c panlal agon;,tic tlCt ivily but not 10 the: degree lhal pindoiol doe$. The P antagotll'ts .... nh partlnl 3gonistk activity cause ies> ~Io'" ing of thc fUIiOI hean nile than do agen ts wlthoul this capabi lity. 110e panial agOllistlc activit y may be beneficial in patIents ,,100 an: IIlel) 10 e;o; hlbit severe: bradycardia or ,,110 have lillie canlillC 1\'''-' ...... 1.' . Timolol. pllloolal. PI." nbuloloi. and I.'OInooloi ha'e h;olf-life vatuCll In the Sll lIIe mnge as proprouolol. 11Ic Iuolf-hfc of nadolol. howe \·cr. IS about 20 houl"$. mali:mg " one of the longesHK.'Iing {J bloekel"l>. Timolol undcrgoe~ fil"lot-pass metabolism but not to the ~me c~ lent that propranolul does. Tirnolol and penbutolol are metaboli1ed Cl. "ilh the: remaining 4O'J, being e.\cn:1oo in the unne unchanged. In oontrast. 11000101 undergoes ~ery linle hepatic nlol.'taboil srn. Most of this drug is e~creted unchanged in the urine.
/:I,-SElECTIVE BLOCKERS
;, Q
can ~ur·
latc'
,-
"".-
1bc dio;covery that,8-bloeli:lllg
O~NHCH(CH,)2
OH
Otfwr Nonselective P Blockers. Several other nonselCC!J\t {J blockef5 are used cl inieally . These include nadolol (~). plndolol (Visken). pc:nhulolol ( Le~'alol ). cal1eo-
agcnL~
u~ful
m the: treatmenl of canllOYoisculardl~lIse, sueh ~ h}perten ~ion . SlInllllau:d a .;careh fO( cardi(}!;Cleetive Pbtockcl"l>. Canliosekct l\'c P anlagonists are df\lIlS Ihal ha~'e a greatCl" affinny for the P, receptors of the hcarllhan for p: receptOf' In other ,,~ues Such eardioselc:etl\'c IlgCnt~ should provide t .... o ImpoMUm therapeutic :ld valll.:lges. The fir\! :M.h:uullJC ~hould be the lack of all antagonlSllc effe:!.' on the p: rc:ceplOfelecli-'t blodCB. LIke propranolol. mc'lopfolol has low bioo vai labllity because of significant first-pass metabolism. Although !he bioavaHabil. it)' o f bcla~oIoi is \'cry hIgh. It is metaboh;ted t'~ I(,llShc l)' by lhe Ii~cr. wilh very liule uochanged drug c~crclcd in [hoe UrillC. Atcoolol. li~c lladoloi. Ilas low lipid solubi lity and does not readily cross the blood- braul bamn-. h IS absorbed incomplete ly from the gastrOlnlCSllrlal UlI.::t , the ()fII] bioavailability being appro:tim31c1y~, Link of the absori:led po",oo o f the dose IS melllbohzcd; IT10iSI o f it IS r:tcreted UJlCh~lniled in the urine . In the cw;e of bisoprolol. about 50% of II dose undergoes I\c:patic metabolism, I' bile the remai ning 5O'if. is e:tcrc:ted in the unne unchanged, Ace butolol i_ , one of the very few /J blockers .... hose me· tabolite pLays II sigl1irlCant rok in its ph;!rrl\aCoIOJ;ICI] actions. This drug is IIbsorbc:d well fmm the gaslmlmestlnal tnoet. bUI il undergOl'Sexleusil'e firsl -p:lS5 metnbolic con"ersion todi3C't1oloi . Diac:erolol i~ formed by hydrolyllC convn-sioo of the amide group 10 the ami llC . followed by lICelylatioo of lhe IImirIC (Fig. 16- 11 ). After oral admim Stnllioo. plasma k,-cls of diacc:tolol are higher than tho!;(- of IICC'btJtolol. Dill' celolol i~ also II selective /JI-receptor pntagooist Wi lh partial
Labe!alol. Labctalol (Nonnodync) is ~ phcnykthalJol. anllroc derivan.e that i~ ~ compcti ti"e inhibitor It bolh fJr IUld ,8:-adrenergic receptors IUld al lhe ai -adrenergic 1«aool Thor 61:1, If'! 17. ILlr.S\iIoltI.J.M.,ond ll...t>lp. Thtt. 121480.
~.
".;I 81Id., 1 W MClS"J.ICft..... 1 S: I_BII.I961.
21 1 ," A. 101 _. .. 111-' 1'1...... 21091. 1%1 U AfclI. J RM N.. ~.109 Ill). 1984 ~. G" ....... A. 0 .: A~nu. R.~ 8;""1>. A. S•• and Ruffolo, R. It. Jr Su"", .... ''''''''It ", ... """",;", .... "" 5.......... por .....,.... and ~,"' .. In Ruffolo. II It . •• led). "'Ailn:noocI, Kqrt. 1991. P 75 J! HodIIIrd a-.. '8:3-1 I', 1m. 1I0I1n1:.1. D 8 , CAa«h. 10th .... , New Yorl. ~kGr-.. ,..·Jhll. 2001 . p. 115 ~bln. II 0, ' ,8-Admtlor SIIe:. A compari!iOfl of the cholinergiC octivuy of 3 ~ries of alJ.:yhriUlCth),lammoni um compounds IRN • (CI'h). R - CI -C~ I show. n-amyltrintelhy lammon_ iu m.JI which may be considcrcd to hal'e It si l.l' and ma ~, Similar to lholoe of ACh and to be one magnitude lO.·cakcr a~ II mu scarin ic agonist. Thc presencc of the acetyl group in ACh is not as critical as the si/..t: of the rnolc:culc. StudYing a sencs of n-alkyllrilTlClhylammooium J.llits re\"calcd1'l thaI fOl" maltimal muscarinic (ll:tivity. the quatcrnary ammonium group ~ Id be follo ..·cd by a chain of fh·e atoms: this has been rcfcnal to as the[il't'-I>tt)
,
2.!1 (Gu' .... 1"11
"" '''''
IZ (11."".0
"
S· 1M.
,
" '" ,n '" 01 """'
,
d - L47),
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.,
c.t Blood PRuu..
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10.003"
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.
'"n,
0.. _ _ e I,... II II I ' I _ .. Clot I ;;. I I ... """ . .... . ]'iJocarp;ne '~;:;:: curs u_~ shining white erysti11 ~ 11131 arc not h) are ligtll !.Cnsilive. It is soluble in water {I : (I :75) but insoluble in chloroform and I'lher. lions lite slightly acid 10 litmu s and may be the autocla'·e. The allaloid is incompatible: ....·rlh iodide.~. si I"ef nitr~lc. and rc::tgenls Ihal
,
in lhe:
ond lhe:ir iUbs!nllC
,AILE 17- 5 Hydrolysis of Various 5ubsb'ates by AChE and BuChE
."" &1I1'IM
substr.t.
Sou.,.
1I. ",tl...
\.:rI)khol.".
lIu .... til """Inc ItRC
\.:rI\ k"""''''~lnc ~) 1·~·"1bl'lt Iortr)'lWochn)il'lt
Ii"""," MRC 800-,... MIK" 80>,.. MRC
~
,~
f-,I--
.....,1dooI, .. ~~ItoIIt)IIml< lI~pI .. m:.
........
,10>0"" pi......
,
,, "'""" Hwnanpboo_
ml
H",,_ pbI.ma I..."" pa.mo
,.."..,"'......
'"
Human IUK"
'I0000 pi ......
1'0." - ........ .......,....
.I4opooI ill,. ''''''' ' ) " Ool~ "'~ onoIIloIM.,
>, E·ACh
>,
'\
c
ale is ckaved by II gtocl1ll ":'~••~:::: generate the f~ cn/.ymc. h is indicated by kj .
Carbam:ucs Sitch as cru1xlc1lo1 SUbstnlCS f()l" I mcdi ate (E ). the nllc of acC'tylation. of the carbamyl -cn~yme
a~
also able
i is than th.:lt of ils acetyl countcrpart. 'The !'iue limits the o pli llUll runelionn! capadty IIlg carbamate subslralcs to be senllre,·cr..iblC'
AChE. In the mechani sm aOO,"c. depends not only on the
'- A
>, (
" ,0
k) b
E •
· ·
., ,
CX
,.",
,
"\
,
'-c - "_
,.
C
_ _ ex· c..twllylill>ng .....~
~
blu ultlys(>slIg mine. nlool; with Olhcr cholinomimetic dru gs acting In the CNS, has been ~llIdl~'d ror use In lhe In::umenlof Althei· m·e' s di~lISC.loO Cholinomimctics Ihal are CU lTcnll y us..>d or which have been reccntly evalualed in the treatment of Alz· heimer"' dlscllSC include donepelil. galantaminc. rnctriro-
', ••"lbI.lnhlbltors
lan stcp ;eNc ..,
ne inter· :..,·er rh:r.n tylmiool ~ slo ... er !droly~i~
~
alltl"'·
bI t""' of
e nne ! l
1'IIys00figmlne, USP. Physostigmine i. an alhloid ob-.d (TOtn the dried ripe seed of I'h)"sos/lgma '·f'/U'llosunr. l~ as a whitc, odorless, microcry~tamne powder that \/iihtly soluble in water and fr« ly lIOluble in alcohol, db";onn. and tIM: fixed oils. The alkaloid, as Inc fltt oo.yridostigmioe bromide: is about one·fifth a~ toxic as ncoStigmltle. It appe3R to function to a maimer sinu lar 10 thai of neostigmioe and is the nlO6t widely used anlicholineslerolSl: agent for treati ng myu~thenia gra\· i~. The li"er enzymc:~ and pla.Ql\3 cholillCSterase nlClabolizc the drug. 1lIc pnnclpal metabolite is 3- hydroxy-N-metllylpyridini um. Orally administered pyritloo»tigmioe has a half.Me of 90 minutes and a dunltion of action or between 3 and 6 hour;;.
Ambenon /um Chloride. Ambenonium chlondc:. IonIyl bis ( i m inoo:th yleoe ) I bis [ ( ,,-ell lorohen-,y I )d Iet hylaml1K\11 -
NllbeilOll'um ChloflOO
;'1111] dichloride (MytclllSC chloride). is a " hnc. odorlcs.s po,,·der. soluble in water and alCQhoI. slightly soluble on chlorofurm. and prucuc all y insoluble in etller and atct~. AI1Ibc'.oonium chloride b used for the trelltmem of myas· then la gr:a\is 111 patients ,,00 do not !"e'\flOOd SIItisfllCtorily 10 1M.'OStlgmllle or pyrido>.t igmin.c. This drug acts by ~u pprcs5ing the act ivily of ACI!E. It pclSsc"S5('lI a relalL"ely prolon~cd durdtion of oction and causes fe wer side C ffl~ts in the GI tnll;t than the other anli · cholilM!$u:rnsc agents. The dosage requirements ~ary con~id· erdbly. and the dosage must be ind" idual i1.ed according to the re.~pon~ and to!cronce of the lXuicm. Because of its qUhtcm ary am l1H)flium 51ruual cause of death. The organophosphatc in\CCtiddes of low toddty. such as III3laIhioo. gcroerdll y cause poiwmng only by inge!.tion of rtlati~cl y large doses. Pllrtlth ion or rTll!thylpar.lIhiun. hown·e\". COIU5C poi$Ol1ing by inh~lation or dermal abSOfption. '«-\lse these compounds are so long aclin g. cumu l:r.til·e and tmOI.IS lo.d e manifestation s may result after sc'erdl small
o H,C"
II
CH- O - P - F
H,C/
I
CH,
'1 4 ducts IJofluorphoJte. USP. lsontlOl"phate. diisopropylphQ ~W ~)nthclH;
unatogu"'>
S)"mhc:uc amlrKllllooholl'lle",
Amlllooknhot tl~n; Aminoaleohols Ammoom'Je. ~ hstfll:ule...
,,<
• P""", ~r:ta0U'-
The chemICal clnsMncalion o f anlicholincl'l1 'C5 actlllJ 01 parasympathetic pmtganglionie nerve ellding~ is compIl' cated somewhat because \QITlC agents. especially the quaII:I' nary ammonium deri~athes. act 00 the ga.ngha that ha.l." I mu~arin ic component 10 !heir ~timulaliOll pallcm anl_ hi gh dosc~. at the ncurolllu"...ular JUIICt ion ill skc lClallllUSCI!. There ore §c\'eral way~ in ",hich !he ~lruc\tJre-lCtiI~ relationship cOli ld be COO~ldered. but m thl' d l ~SSIOll_1 follow. m aener"JI. the oomideralions of Long I.'t al .... . . ba.
'W hed
.ons of
bllie HnpaHlTlrol of accommod:l1ion. takes place III aboul 30 mlnules, and lhe eye relurn~ 10 norm al in 2 10 3 hours. Gl ycopyrrolull'. 3·hydro~y- I .I · dimrth}tpyrroJidin ium bromide tf-CyelopcntylmalKklate IRobmul). OCCUr'S as a ... hl le. "'ryWlllme JlO" del' 111:11 iJ SQlubIc In ... ater or alcohol but pracl i",ally insoluble in ",h\on).. form or ether.
G/ycopyrro/ate, U5P.
Methantheline Bromide, U5P. MClhamh.clme bronude:. d icth), I( 2-h ~dro~ ~et h)' I)mc:th ~ Inmmoniu m brolll ilk xunthclloC-9-carboxyl:Lle (8anlhillC Bromide ). i~ a .... hlll'. ~ lightl ~ hygrtl!!O!:opic. crystalline: salt that is ..alu blc: In ...·lIter to producc: solulion.~ .... "h a pU of about 5. Aqueous solullOll:! 1m: not qabJe :md hydrolya in a fe ... days. 1bc: broInlde fonn is pn:femblc: to the "cry h}groscopic chloride:.
/
nc hy· :arooll'
"
~qMo r
" , lhan
I Glyl::q:lYl'fotal8
he neu· ,kettle
on. firsl ;IS asS()j for its
.. panoc.seful on fl.
c h)'dro~.2,6- tO:I ·
OS!oC:S.\CS
he early toe acld.c a bcn/J>• pro~id · :olubk Ifl tI ahuo"l
GlycopYfTOlate is a typicu l antic holi nergic and poso;es,."es are probabl ~ ablic:nl bccau!oC: of the teniary chanlCter of the molecule . This III:ti~ily is in COntrast .... Ith that of compounds that couple anlilnuscarinic (l(;IIOn wilh gangliOIllC blocking action . '1lI.! tel'1 i;lry ~hnrnctcr of the nitrogcn pronlO(es intestinal absorpuon of the molecule. Pemaps the lnoe;t signiflCanlllC' tll'ity of this COOlpound is its marl;ed ab>1il~ 10 reduce both the vol ume and lhe acid conlent ofthc ga\lric juic'es. a ~r able action in \ iew of the more recent hyJlOlhc"pasm. nnd functional bowel syndrome. II is t'Ol1truindicated. as nre OIher nn ticholinergics. in pnlients with proslntic hypertrophy and ,Jllucoma. Propanfh~ine
Bromide, US,.. PmpanwJine bromide. 2-hydroxy-ethyl)di i5OpfOpylmcthylammonium bromide ,anthene·9-cnrbo~)lhte (Pro-Banthinc). is prepared in a manner exactly analogous 10 Ihal used for met hamhocline bromide. It is 11 while. waler-soluble. crystalline substance. lIo-ith proptrtics quite similar 10 lOOse of methanlheline bromide. lis chicf difference. from melhanthelinc bromide is in lIS poIenty. ,,'hlCh has been esumaled variously 10 be 2 to , limes as gn:at.
I Benztropi~
Mesylafe, USP. Bcnzlropine rnesylak, 3""(di~n)'lmethoxy)-1 aU .Sall-tropane methanesulfon.1le (Cogenti n). has 8ll1icholinergic. antihi~aminic, and local ... esthetIC proptnies. Its IIIlticholinergic eff«t makes il appltcable as an antipatk insonian agent. It is about as potent_ anticholinergic as atropine and 5han:S 51:lIlIe of the sidt dfect' of this drug. such I1S mydriasis and dryness of mouth. JmponaotJy, however. it does not produce centllli stimulation but instead uerts lhe chaTllCleriSlic sedlIt i\e effect of the antihistamines.
o-c",
•
, , , , ,
,, 1
I
"" •
BonZlroplll$
Mos~te
The tremor and rigidity charnctensllc of partin:sonJYll m
The nmi noalcohol elhers thus far introduced have be~n used Ill- antiparki nsoni:m drugs ralher Ihan as CQnVentiOllal an ticholincrgies (i .e .. as ~pasmolytics or mydrialics). In IcneruJ. they may be considered closely relaled 10 the antihistaminics and. indeed. dQ ~SCS$ substlllltiallllltihist:uninic properties. In tum, the antihistamu-.es possess anltcholinergic activity and have been u.'ICd as ~miparkinsonian agents. Comparison of chlorp!lenoxaminc and OI'phenoorine willi lhe antihistn_ rninic di~nhydrJmine iI1uslrute.~ the el= similarity of SltuCture. The use of diphcnhydromine in parkinsonism has been Cited abo'·e. Iknztroplne may aJ.50 be oonddcred • structur.al relalh~ of diphenhydramine. though the .minoal· coho! portion b tropine and.llierdore. ~ dislamly related than chlorphenoxamine and orphcnadrinc. In lhe slructure of bem.tropine, u thn:e-carbon chai n in ter.'cncs betwee n the niltOgen and o~)'gen functions, wherca.~ the others e\·lnce a IWO-Carbon chain. However. the rigid ring slructure possibly oneo,," the nltrogcn and Ol!ygen functions inlo ~ nearl)'
,
,
".
Ami .... lc.hol Ed:.. , s
,
n:lie\ ed by benzlropine mesylate. and it is panicu l:u1y ,-mt ble for those patienlJ; who Catino( tolerute central ucilaUol (e.g .. aged patienlS). It may also have a useful effect in IIlIIim izing drooling. sialorrhea. ma.~ k -l ik e facie.,. oculogytK" crises. and muscular clllmps. The usual caution exercised wi th any anticholiqic_ glllllOO'lla and prostatic hype"rophy is ~rvcd ..... ith dis drug .
Orphenadrine Citrate. Orphenadrine citrute. N.N4met hy 1-2-( II-me th y I- a-phen)' IbenI.y lox y jet hYIII mine citrw ( I : I) (Norflex). introduced in 19S7. is cJoscI)' n:lated 10 "phenhydramine wucturo lly but has much Io..... er taminic activit), and much higher anticholinergic XIQ. Li kewise. it laclr:.'l the 5Cdat"·e effcclJ; characteristic u "" ~nhydraminc. Pharmacological tcsting indiclIlCS IIw it. not pri mari ly a peri pherully acting antichol inergic bti il has only w~ak effects on smooth muscle. on the c}'e." 00 secretory glands. It does reduce voluntlU')' muscle spi1& however. by a central inhibitory actioo on cerebral _ areas. a centrol effect simi lar to thaI of atropine.
an_
.•
,. ~
~
"-'"
,.
J" g'
,.'. '"'
'"D. q"
"" ho
'"
""
1959. has a rdati"ely w..ak vie weal: anticholinergic efrecLS add 10 il5 uscfulness in Par~lnson 's ~} ndrome by nllmmi1.lIlg Side effech.
is apparIy of IhI" discrep--
Orphenadrlne Cltralo
ltsy lme . ulfooalc l)Cal anIt apphDlcm an Side c f. moulh. 1Ilmulatffect of
Thi s drug b u'il.-d for the symP1olll~ tl e 1rt':nmelll of Parkin 100" disea.'oC. II reltc,e~ rigidll) bencr Ihan II docs 10: 11101', and in ccn ai n cuses, II may OCL'CI1IU;,le the laller. TIle lIrug wmb31s Incntal slu", ~hnes). Ilkinesi;,. ad)IIUl1l1a. and lad: ri mobility, but this effect seems 10 lIlIlIini,h rulher r~pidly "1m prolonged use. It is best U>cd a~ an I«IJU 11loch a.... bcn/.ir0JlIIIC. pnlC)ehdlnc, crcrimlllc. and lrihu >·phcmd yl. in Ille trca l melll uf l'ymp.1lholyt;cs 1940s. Ie ",as \OOfl cstablishl"d, ho ....e'·cr.
tism arc , 'lI.lulI · cnalion n mimilogyric
~,N-di
cilmlc :110 dl ' jnhhi~
actiOl1, : o f di · IlIt it I( JeCausc ye. and spasm.
"""~
lOOk piaComa,eith~ r known or~uspectccomeltlOniom
" N,cotlnie ChO\\ne,Qi POSTG.\NGUONIC NEURON
COPalll/n
bIod'e sitd is the absence in lhe ronner of a membrane barrier or sheath that en~elopcs the ganglia or constitules the blood - brain barrier. This is import.ant in the accessibility of the si~ of action to drugs. particularly Quaternory ammonium compounds. because they pass through living membranes w'th considerably greatcr difficulty and selectivity th:m do compounds tluit can niSI: in a nonioni~ species. The es.stntially bare nature (i.e .. lack of lipophilic barriers) of the myoneural junction "ennilS ready IICCCSS by qUDternary ammonium COmpotlnds. In addition. cumpounds with considr:rable moleculardimen sions are accessible to the IceeplOl'S in the myoneul1l1 jutIC· lion. As a ('('suI! of this property. vlltlations In the chr:mical ~truc\\Jre of qU3tcmariC$ hal'e linle innucnce on the potential ability of the molecule to reach the cholincrgic receptor in the neuromu§cu11I/' jUllCllon. Thus. the following types of neuromuscular junction blockeT$ have been noted.
Nondepol.rtzlng Blockl... Ag."ts
reduction "')' msuffiI Cf'rcbrnl 13\1:
S89
CH.
Tr.tdi tionally. nondepoluri:ing blocking agrlllS is a term applied to calegorize dnolll that compete with ACh for the recognition site on the niCOl' nic ra:eplor by pre"cnling depolarization of the end plate by the neurottansmiller. ThUs, by decr'r;lIliing the effective ACh- receptoroombirumons. the end plate potenlial becomes too small to initiate the propaioted aetion poIent'a!. T his rc.~u lts in paralysi s of neuromu~ eu ill/' tl1Ul:Smi.'lSion. 'The action of thc:sc drugs is quite analogous 10 that of atropine 81 the muscarinic reccplOl' sittS of ACh. M:m)' experiments suggest that the agonist (ACh) and
the :mtagonist compete on a Of\C-to-one basl~ for the end plate receptOl'll. OnJgs in this class are tubocurarine. dimethyltubocumri n.e . pallCuronium. ~nd gallami ne.
D.po........,.., Blocking Agents l)'Illgs in Ihe category of dcpolari/ing blocking agent s dcpolari7.e the membrnnc of the mU5Cle end plate This ckpolarilat;on I~ qUite similar to Ihat produmi nal opmnions) was obilltnable only wl lh "de~p" aneMhe!;ia "'Ith the: oruinary general an('sthelicw. Tubocul"1lline pt'nnitJi I liper plane of anesthesia, .... ilh no 5:OCnfice in thc: musck relal.lt.on so important 10 lhe: surgC(ln . A redOCM dost o f tubocurarine is admini~ered ",ilh eth('r btcausc elher ;lse lf l1li curve-like action.
Curat"t. unul relalh·ely I"tCCnllimcs. remall10ed lbe only ~. ful cUl1ln lmg agent: and it. too. ~uffercd from a lad of SUt.ndardi/.lltion. 1lle original pronour".'cmcnt in 19)5 of the structure of (+ I-tubocurarine chloride. unchullenged for )5 years. led Olher workers to hope for octi> lIy III ~yntheti~ suhstanec.~ of le~s eompl('1\ily. TIn: (jllatemul)' Iltllftlonium chal1lCtcr of lhe curare alkaloids coupled Wi th the known activity of the I'llfious si mple onium cOlnpOIJlld~ h.ardly scemed 10 be coincidental. and il was naillral for rc'(' fol lo .. ed. A trlJcurium Sesy/a te. Alrncurium bcs)'late. 2-(2-carbox y~lhyl }-l ,2.3.4-lctrahydro-6. 7-diflletho~y-2.mcthyl-l ve IllII)' Jisoq u inolm iu m beou.enesu If onatc pc ntamclhy letIC ~ (Tracrium). is II nOlldcpolari:ting neuromu'\(.'ulor block· ing agcnt Ihat is approximately 2.5 li mes more potent than rf·hlbocumrine. Its duml io n of oclion (h~ l f- l ife. 0.33 hours) is much shoner Ihun thaI of d-Iubocuranne. 1"hc druG is 1111:laboi ized IlIpidl y and noncn1.ymatical ly 10 yie ld laudallO!iltIC and a ~ majler ljua\(131)' rompou nd (Fig. 17-20). which do not have neuromuscular blocking x,ivily. [n "11m e~peri· mcms show thaI alfilCunum bcsy[ale breaks down al p1/7.4 and 37"C by. Hoffman elimination ~ac1iOll." Atrncunum bes)I~le undergoes cn1.)'nl.lllic decomPOSlllon of lIS ester funcuon 10 yie ld an tnac1 ivc qualemary alcohol and Ijuaternal)' acid. AChE inhibilOl"5 such as IlCOIiligminc. edrophonium. and pyridostlgmltIC anlagonize par:o.JYMS by atmcurium besylale.
IffefOCurine Iodide, USP. Metocun ne iodide. (+} Q.O'·dmM."thylchondmcurnn ne duodlde (Metubll!e iodidl'). iipn:pared from natural crudecurttR: by extlllCling In.;, ~u~ "Ith methanolic potaSsium hydroxide . When lhe: ('."(trnct i. trela/cd with an ellces~ of methyl iodide. Ihe (+ HubocuraIIIlC I~ convened 10 the diljua lemm)' di Illelhyl ether and cl)'slalll1.es out as the iodide (S1.. e\.J.; MIll 1'batmKoI. Todeol )0:129. 1979 II ; ............ V p~ Tmoob 1"IIr"r' l Sci. 1.312. 1986. :9 N 'e. T .. 8IId Grob, D~ J Ncwo a",,", Am ..:i:2J1lJ. 19j1. lfL T",mpp-Kalh",,~"'. S.... II.: J Med. Oorm. J5:J44l\. 1'H2. 17 T""k. D. J.. .. II~ J Mcd. Chern. -".ll6:1. 1'»1 11 ....-. E. J.. ..! S"......;· A.. M 1ft ~ H. 1«1.). QIwIU\al"~ " " _ 1ft 1'IIIrmIooIoo. A.......-dIm. 1,1"' ..... 1969 1'1 InJ. II II Sden", 1(»:26-4. 1'1019 1Q. I~~ 1>1 .. .. II 80- J. I'IIaImacoI 110: 14 13. 1991. II • tr 1m A.. ood 8m'" ...1Iot. R. W" ...... Drul R.. 2.141.
""PI"'.
"M.
! acllOI1 drug i~
lurntiOl1 iUludole ' !Illable.
nero
III
omptly. tions n.~
or 10111' sc\crnl
Il Ita!. L. N.. Nobnc. T .. . "" Chlbo. S , J C.llhov. "" . PIurmofLOl, 22: ~1 . 1991 Il.w.:n-. K. L..! V~ . P M. 8, J 1'twmaroI, 106~n. 1992. " .,....... M A .. and II""""","",,·H _ . E. I.: J. I'\wm, Sci. 6.)716. 19'1••
595
'" WIlliamooII. Berlin. Sp"'jO refem:d 10 as the rum di!ilOltubulr). comW!Cling moole (also re ferred 10 as the Imt fli!iIOIII'huI~). and lhe cofh eal and medullary coilectillJ tubules. Each of these nephron 'iegmenlS COlL~ists ofuliTtilNCtumlly and fUlIClionally u.uquc cell types. 1l1e ph~ioln&K"1J role of lhe glomerulus and each nephron sc:gnw:nt i, di .. cussed below Il.~ n rd:ncs 10 tnc handlingof lIuponmusoltnn lind waler in nonnlllly hydr~tetl (nornlO,olem,e) and !Ic~). dr-ned (hypovolemic) persons and in pallenl~ ut"flicled w,th various edematous disorders (e.g .. rongesti>e hean fll1urt.. C1lmosis of the Ih·er "" th ascite~. and the I\t'phmtic 1)11dromel.
fUNCTION F.nctlon of the Nephron When the ph'S. Voillme Is NOill al (Nal iIIovoiemla or Euvolemla' As blood is deli'erect 10 each glouw:",lu.~. many (bul 001.01 of its componen ts are filtered into 80", man· ... ~p;Ke tMIuP the "pores" In lhe glome rular Capillary Ioopl.. !;c"enl cochemk1l1 properties of each blood L"OlLlponen\ dictale tlIr extent to ",hio::h it IS renlO"c:d from the blood b) glolllcnU filtrnuon. These mc1ude the ooruponenl's rel.nil·e n,..,k....br ma" (M,). o"el'1l l1 charge (applie~ primarily 10 large mokeu1es). and degree and nalure of bindmg to pla~ma pi . .1Ii. For example. plasma proIelllll ,,"h an M, in e\~of~fYJl D~ and red blood Ct'1I ~ are 1101 read,ly filtered .... heITOIS "",. M .. IIOII - prolein.bound cmnponents (e.~ .• Na', Ie, 0. IlCO.) -, ,10c0se. and ami no acids) an: readily IiItelTd.' 111e mit' of filtrauon of pl ..... ma componenlS that ~ un M, of less thun 50.000 l)a alld arc 1101 bound 10 pb!./III
""'\I-
protein~
• IXpends d,ltt1!y 011 Uw: h)drauhc (II)Uro:iratic l pit \"11' the ren!! ,·a.culalUn: (Crealed b) rhe pumpon, htanl." 1cnth 10 drive "".'er and o.oIUI~ ()U' of tile glomeoular ~ IeII into 8000.man·, split .. • Keillri m"c~ly 10 the pb._1na .... "IlI..: ~... re ( the~" ""'''lure crealed by the pla,nu proI~,n ...... h," tho , .... lure) ...... hieh tends I.orptioo of
• l:$$Cnt rall~ 100'l0 of the fi Irered load. of glue"""" .",rno xid~. and Iow_M, pr'OIel", IO
_ _ Oensa ~ Cells
0""'"
SITE 1
UI"I''''
Etterent Anarlola
phlsma
of ... al~'
ics (Fig. 18-1). Each minute only I mL of urine is formed from the 125 mL of glomcnLlIIf fiJtr~te .s Thus, appro~i malely 99% of the glomerular filtrate is nonnally reabsartx·d. The IWSflJWr qUl/ntiry of each filtrable pla,ma componenl that rraches Bo,"'man'\ "{I3CC-lhe jillt'rrlllO/ul of a substance- depends directly on the GFR 3nd the concentr,ll.ron in plasma of lhe porIion of lhe filtrable substance thaI is not bound to plll!ilTla proIems. ThoIt is. the filtered load of. SU~lance equals the GFR (in millilucl'1I per minute)lil11('li the ooncentllltion of unbound, filtrable sub'\lIJJIU\'C luminal e'l'"ironn)('nl dmes I"l1Oft' callom ,K' , Cll~' , Mr ' ) from the lumen Into the mlen;tiperlICClIularly (i.e .. between the thick asceodrng limb dtl.1O, II The combined activities o fthi' No . IK '-ATPasc-
"the
or
dNa' .'" !lIthe reabsorptionofup 1020 lo3O'l>O(the fillered load of Cal ' ,'0 the rnairlCcnancc of the high osmolality o f the medullary imCf'Slilium (which is absolutely critical for the norm~1 (un.ctioning of the human roephmn).' l and the ability of lhi ( nephron SCgl1leOl [0 reabsorb more Na' ~nd Qlher solu les than usu31 when proximallUbu le Na ' transpon has been inhibited.&. " Th is latter CQIllpC'IISD10l')' phenomenoOn ClI.pluins .... hy diuretic, that IICt primarily al s ue 1 are 001 particularly efficacious. The descending limb of Henle's loop is responsible for the conccntf1!ltion of lu minal fluid (i.e .. Il!mova] of .. ater and addition o f Na'), whi le the thick ascendmg hmb is Il!sponslble for the di lution of lUminal fluid (i.e .. rt'moval 0( solute from the luminal fluid without eoncomitant removal o(wDter). lie~. colleclivl'ly, thrse two nephron segments produce a mas~ive o\'craU reduction of luminal fluid \'olunIC and solute contcnt. Inten:stingl y. IhI' osmolal ity of the lun.i nal fl uid in tile tenninal portion of tile thk k ascending limb of l-knle'~ loop i~ tlOI much different from that of the fluid that I'mI'" the dc)oCending portion of the loop (though drastic changcs take place in between). As the luminal fluid leaves the thick asceo(lI na 11mb of Henle's loop, it come~ into contact ..-ith the m(lcu/(I dt'IIS// ttl/s, II speciahled group of tubu le cells that communicate wllh the gnlnulor cell~ of the affertnl arteriole be10nlling to the same nephron" (fiB. 18-2). The macula densa cells are like the thick ascendmg hmb cells. in that they house b(! K ' '" ,.
tl\'ely pumps it into !he intel'1Otitium .... ilh subsequenl passage into lhe ~urrounding vasco l:llure: IfItr.occ:llulpr C I- enters the intcf1illtium through channels in the antiluminal membrane, Appro~ i m.atcly ,5 to 8% of thc filtered load of Na ' is reab~ at si te: 3,.. tl I
'ri!t! fUc!
SITE 4 The connecting tubule: (i,e,. laie: distAl tubule) and the: conical rollc:ctmg tubule: house the foonh and final major si te: for the reabsorption of Na t from !he luminal flui(!l' (Fig, 186), 11us portion of the: nephron is composed of twO distinct ~'(:II type$: the principal ulls and the inlumlllft'd ulls, The: priocipal ",lis nrc: important for Nu - reabsorption and K ~ !;CCretion, whereas the imercalate:d cdls (subtype A) are im· portant for the: generation and §ccretion of H ~ , The intercalated cells possc:.~s only small quantities of the: Na '/K ~ ATPuo;c on their ami luminal membrnne:s. bUlthey conlain abundant qllllnii ties of imraccllular CA, which C:IIal1'/,l:5 the formation of carbon ic IICld from COl and .... ater, Thc: carbOlllc acid ioni1.c:S, yielding H ~ lind HCO)-, The H ' is thc:n pumped IlCth'ely imo the luminal fluid by the luntinal membrunc: - boond H ~ -A TP:isc:, The driving fon:c: for the: reabsorption of Na · in the principal ee:lls is once: again the: deficil ofimral,'el!ular Na ' crea ted by the Nil '/K" , AT~o;c on the lllltiluminal mcmbranc:, ",hlCh coumc:nr.mspotls 3 Na ' uphill from the principal cells mlO the IIItCflilitium and 2 K " uphill from the interstitium into the principal cells, In =ponsc to the deficit of Na ' in the principal ccIL~, the Na" in the luminal nU ld mo\'e$ downhill inlo the principal cc:.Jls through Nu ' channels in the lum(nal mcmbr~nc: and i~ sub§C(jucn tly pumped Bai"cly into the i olersti ti urn by the unl iluminal nll:mbranc:- bound Na '/K " , ATPa.lllomcrulat f«dback)' . 1j ~
j T~1"C
.. ..... rfOlWTli~
( RmeK)
C),n~ of mctolawne and indapamidc, ' 2 This is p.1nicularly importantt!) indivi duals with pree~ iSli ng impairc:d renal funclion woo rc:quire diuretic Iher~py. Thiazide ~nd thiozide-like drugs are frequenlly ineffecti ve in indi vidu3 1 ~ \\i00 have a GFR below 15 to 25 mUminute, Mctola7.one· l , ." 016, 53.'" urn! indapamide'2 may be useful in such cireumstances, ThillZide and thiazide-li ke diuretics can be invoh.~' COI1lbi natioo diuretic lher.lpy (i.c.. a thiazide or thl37 ldc-h l e diuretic plus II K +~p;lnng dmretic) may p!'CVCnt K ' loss under tl'w=se drt:ume of va sodilator)' prost;lglandins. Fift", they induce a redistriootion of intrarenal blood flow that i~ tbought to par1lcipille In a positi"c way towan! the magnitude of the dlure$is,n All diuretics that act at sitc 2 are equally cfflcacious alld faT Il'M)I'e cfficacious than diuretics that act II sites I, J, or 4, As mentioned abovc, becau'\C of thcir sitc of action alld dru;lI(:y. these agclll~ IU'C clHnmonly refcrred to as 111011 and h.[(h·teiling diuretics." Iligh-cc iling diuretics secondarily cnhancc the urinary loss of K ~ and U ~. Fil'lit. by inhibillng the INa " I K 'naCl'lWUlsport ~'QIllpl('.'( at site 2. they preven t the gencrution of a lumen·positive lrun;.epithclial voltagc and. tilerc:fore. the panrccllular reabsorption of K' and other callons. Second. inhibition of Na' reabsol'ption at sitt 2 ultimately (\elivcl"!i n~ of the filtcred load of No ' . al a faster ratc. to liite 4. Th IS leads to an cnhanced CAch:mge of the Nu' in the lumi· nal fluid for !he K" in thc principal cdls and the H ' in the inteocalutcd ~Ils (Fig. 18·6). When the loop diuretkll are used in "slIbmuimal" doses for the treatmenl of hypcTlen~ion , lhcy nre uHcndcd 10 create a diUI'l'Sis similar in InagnitOOc 10 that produced by the Ihiatide alld thilll.idc-li kc diuretics, Undcf' these ci~umstances, loop diu~lics usunlly !If\! associate" with a lower frt:queocy of hypokokmia than the lhilll.idc and thiazide· likc dmretics becaus.c their dUlll.tion of action is sllOncr, and the kidneys havc more limc to n::adjus!. 'IU. ~1 When the loop diuretic~ IU'C lIsed to treat acUtC edema. howe,'cr. higher dosages lITe freqUC'ntly used. and !he Na" and K " 106$C~ exceed tho!;e accompanying thia/Jdc therapy,JIC When the loop dIuretICS inhIbit the I Na '/I K" ncl- cotransport system ill the luminal me:mbrnneofthlck ascending limb cells. they in turn decrease the IUlnen·posill'e trun>epl' thelial voltage that promoIeS the p.-traCC'l1ular mo,'cme:nt of luminal fluid cation s such as Ca:' inlO the interstitium (Fig, 18-4), Hence. loop diuretics may illducc the renal CAcretion of up to 20 to JO% of the filtcred load of Cal ... provided the pla~m~ \olumc is OOt allOwed to decrease.'o I( plasma volume: decreases 115 I result of the dmresis. there iJ an ac· companying compensatory Incre351: in !he prm.imal tubulc reabsorption of fluid and solutes. About 60% of the filtered load of Ca" IS reabsorbed in the proximal lUbuk during normovolcmia. and the percentngc ofpro~imaUy reabsortled Ca z , wiH increase in n statc of pla.~m3 volunle reduction. n.crefore. during diuretic·induced hyp:wolcrnia. less Ca" is dellvcred \0 the thIck ascending limb for the loop diuretics to inhibi t. which will blunt the loop diurctic '5 calciureuc effect.
AOVERSE EFFECTS Four highly predictablc advcrse effects are a5!iOCi2led. fUTUsemilk lind oometanide: I. lIypoblnnic albkwil; ~IIS from ~ cnhancro c~~ lamlnal flu'" N.' for ,ntracellular K' or II ' lOllS" SlIt' CaUl"", IJoould be ucrci.ed when ronc"mlll Ihrnrpy .,111 drun:IJCS IIId CardlX gI~ " InstJlulCd ~ ~."; 2,
k ll'" inlcn~l rlQ the lOX ICIlY of lhe cardiac ,Iy~rcb.·' IlIlhe ~ ICI1!I. and Cleclrutylc tOllSoCll may DOl be ~ panied by chanJU in the GFR beausc of ~ nfCCl!:l'" IIcnts Oft the tubuloglornenll.. r«dboct 1'11«11:1111'Cussed classes (If dillretic~ in current uo;e i> Ih~ttllcy increa.'ie tile renal excre.ion rate of K ' and thus can tnduce hypokalemia. OVCl'" the yean.. thl'« c~mically distinct diurellC) ha~'e emerged thm IPc~a~ Na and CI excretion without a cQl1COmiU1fl1 inl'rea-c in the un nary c>;crelion r.ue of K ~, 1bes.e agcnL~ are Imown as poIlll~';um"'IHmng diurt'lics or tJllI,koUurelic ilgents. Although lhe K ' -sparillg dturetil."s are derived from completely different chemicul root~. they act aI si te 4 (though not all by the same mc:chani'IIlJ. ha"e ~i milar efficacies and electrolyte eJtcmion pallcmS. and shan: cmain ad"erse e ffects. The K ' -"Pa nn g diurelic~ indude spironolactone (a spirolaclone).• rianllcrenc: (a 2.4.7 -tri:lPlHl(r 6-arylpteridine), and am.loIidc (a pyrvinoylguamdine). A m:ent ly appro,'ed 'pirolaclone. eplerel1Olle. i, diSCUSsed latcr in thi ~ chapler.
H
0
0
7 0'-(acclyhhio}- 17P.h)dro~y-J,o.lop~gn-4~nc-21- carboxylic acid .,..lactonc: (Aldactonc). is shown in Figu~ 18-14. STRUCTURE- ACTIVITY RELATIONSHIPS
In the mtd -195O:1n-mely mild di10 n-mol'e edema fluid in Individuals ..... lth CQrlgestive (allun-. cirrhosis of the liver with a.scnes. or lhe nc;.;;~ t')'ndrome or In an amihypenens"'e agent . lIS pri_ 1151:. however. has b«n in CQIllbinalion wnh diutttlc$ :C' - II si~ 2 or 3 in an iIllempi to reduce the urinary K ' ~Ialed ..... Ith the!ie latter group" of diuretics. ~ •• '
·T'&.ml_-6-arylpterldlnes
Slructure of lriunllerene. 2.4.7:::::~';;'~~£~;d;ThdIWbide
STRUCTURE - ACTIVITY RELATIONSHIPS
An utensil'c screeni ng procedure that C'XlI.mi ned O\'er 25.000 agents was undertaken in an attempt to disco\'ct an anlikaliuretlC agcnt that did AClt !la\'C o\crlapping hormonal activity likc that of sPlroooJac1Olle. 101 Promi sing OCtlvlty '" as OOItd with appropriately subsututed pyraziooylguanidmes. Optimal diuretic llCtivity in this series is ob... ,mcs
-
_IK - l.mp'llrcardillC pafommnce anddarnage hcan. brain. lid bdlll:y '·~lS. 'OI Second. dIU~Iic."-Ir>duccd reductions • plasma volume lIlilllcr increased §Yl1lpalhchC 10Ile ~nd iI:rtascd renal §ttrcUon of renin and. ulurrwcly. incn:ased plasma levels of angiotensin II. In addition 10 bemg a poeent 'l\OConstnCIOI". angiotensin II slimulatcs al~lC:ronc. secrclion. Allhough the mechanism of aldos,crone'~ octions at
"'-
IIIC 4 in lhe nephron have been ~llOwn for " 1008 !illM:. its lIb'ilrenalllCtioos have largely been ignored. Recently. ;1 has
,
~
"" I'"tUfbmces. ifill If this finding is confillTlCd in addi: chrueal studies. epltrenone or an/o~rhlnide,
USP (Me' ahydrin, Naqua, GMefic) Ora!: 2., 4.mg ta ble ts Xif»mide (Aquaphor, Dluff!"anJ Not available in the United States
Loop or High·Ceil ing DiuretiC'l BllmeUln/de, USP (Bume", Generic)
Ora l; 0, 5·, 1_, 2·rng tab let'i Parente rlll: 0.25 mglrnl for IV or 1M use EthiIoynlc Add. USP (EdecrlnJ Or" l: 25-. 5O-mg tablet. Pa re n te ral, SO-mg (billie) for IV use furosemide, USP (U s/", GMefic)
Or,,'; 20-. 40-. 8O-mg tablets: 8·, 10· mglmL oral solution P a renl ~ral : ' 0 mgfmL lor IV or 1M use Torsemi~ (Derna~")
Orll; 5·, 10'. 20-, , (1O. mg I"blen Parente,al: ' 0 mglmL lor IV use
It · - S~ ri ng Oiu retiC'l Amiloride Hydrochloride. USI' (Mldamot', Generic) 0.-11 : S·mg tablets EpIe~ (Insp'a) Ora l: 25·. 50-. loo·mg tablets Spirono/;K'one, USP (AidmOlle, Generi(J Or~ l; 25·, 50-, l00-mg tablets Trillrnfel'el>e (Oyrenium) 0,,1; SO " loo·mg t~blets; SO'. l00-mg Cilp\ules Diuretic Combination. Atnlloridfo/Hydrochlorot hlulde, USP (Modure ric:. Generic) Orlll: 5 mg amllorlde hydroch loride/50 mg hydrochlorothiazide Spirono"'ctonelHydroch/orathin~, USI' (AldM'azHh) Oral: 25 mg splronolactonel25 mg h yd. ochlorothiazlde 50 mg spi.onolKtonelSO mg hyd.o. anatomy. and ~. In V......... A. J (~d,). lte ....1 I'hylliol ..... h, 4O!i:34. 1981. 2J 51 ..",.. M R_ and ScuU",,,,.. h. II Bull. Juhno Hopltm....,. 41 . 1938, 24 . M..,n. T.,:utd Koihn. It., N~tu ... 14(,'1(,.1. 1!I--l(l. l!I. Ilocl."",n. W W.. ...1., I. Ch" In't>-i. 1~:63'. I~ 26. Mil.... W . ... 1k>........ M.• lnd Rublin. R.O 1 .....,0- . 72:4893. 1950 17 ROO"n. It. O. and Clapp. J W J Am Cbc:m. Soc, lH8"ll 28. S ......,.... J \! In Gould. R F (.,,1.1, M,,,,",,ul. Design. Adv~ 'nChomi 'lJ) ~ ~5, Wa""",«a DC.n Chemic. 1 Soci"y. t\l64, PII. 87· WI, 29 M... n. Til' I'hy,,I. Rev, H3~S, 1967. 30 Allon. It C,' In C.-.go< . •~ I . t.,d,), DtuJetk,_ChomtWy, ~~; '-'BY and M«I"',.... New York. J...... W,ley" Son .. lila.!. PI' 31. Be),ilY. 2nd 0. 1980.pp. 145 -161. 34, Wt..IIOn. "- : Arn. J. Cltdiol. S7:2A. 198(>. 3' &ik. A "='on. G. and WnrhL F S.: AcI:l1'll) ....... x-II 1982. », Wiko • • C. S.,o.U"'hC'. fn 1.1"""...... 1.1 .\f (... ,'.II......... "' ..." The KIdnodilutors ulldergo metabolic tr~llSformation in
, ......'
eo"
---------::::::; 9--------Ca'do.m eNoMtI
~ ~-------
c;a2.
AIC8\l1Of
Flgur.
19- 2 . RegUlatlOl1
smooth muscle ContriICtIOII (CJIIl1acltOn IS trtggered
by an
II'I~
Ca 1 • . The lflCrease ofiree Cr'
eM
af
bindll'l9 10 CdImoduhn (e M) Ca10 -CM complex btnds to hg hl -tNln kIflaSt' (Ml O O and Its actrva\JOO (Ml(K') MtCK'IiO-
Wi i """'"
MlCK' .,-
j
-'--
-
_,
pI1or',{ates
- - MlCI( - - M)'08irH.C-PO.
.
MLCK- iPO.h
- -+.
Myoain-lC
j
"'" smooth mU4'ia. II is prepared by ~an:rlll1y addmg glyccnn to a mixture of nitric and fuming su lfuric acids. This rcllCtion is Cllothennic. alld lhe re:.c1ion mi~lurc mU'it be cook'il tQ bct we~n 10 and 2ifC. 1'he: eSl.cr is II ooIorlcss oi l. with a sweet. burning laste. It is only slightly solublc In "'akr. but It is soluble III orgllflic solvents.
.lI!oOdilating IICt ion and. because it is absorbed tllrough tht skill . is prone to Io'8 U!o/: headaches llmong ... orl.cl'S i.SSCXWN With II ~ manufuclurc. Thi~ trans.dcmulI pcnctrJliOiI is IIIIIy mtroslyecrin IS uscful in a pa,~h formula'ion. In medltine. II has the: action t)"pi~al o f nitrite~. but liS action denlopl more ~lo""ty and is of lon];CT dUl1luOli. Of all the ~I coronary vlI,·,OOillllory df\Jg~. nilrogly~erin is the onlyonr capable of SI inllliating the production Qf l'Of'OlUlry collatml circu lation and lhe only one ablc 11,1 pre'cm C"pcriilkh~ myocanlial infarction by coronary occlusion. Previoosly. Ilk- nitrates were thought tQ be hydrolrlC'd IIId reduced in the body to nitrite~ .... hich then lo ...·cred Lhc bIool pressure. This i~ not lrue:. ho ... cvcr The mechanism di 11111011 of nitroglyccrlll through ils formation of NO IS described al)()\·c. Nitroglycerin tablet illSiabi lity WII$ reponed in moIdod sublingual tablets.' The tablcts. although uniform ... Il!'o _ ufllCtured. lost pou~l\Cy boIh because of ,·ulaliliwtIOll ci II1roSI)·ccrin into the ~umJolII\ding nmlcrials in lhe con..unaand inteTUblet migrallQn of the octile ingredie nt. Niuql)" enn may be htab,lu:cd \1\ molded tablcts by lI\1;orpcniIIIIl "fi~lIIg·· agcnl ~uch as pol)'cthylcnc glycol 400 or poI}'" ylcllC glycol4000.~ Ln additIOn 10 sublingual tablets. the: thr has becn rormuLated intu an equally efTccli\'c hngual ~. .' for patlcnts woo h:ne problems ",ilh dissolution of gual preparJtions becau~ ofdry mucoos IIlf'mOOIlCS. T dermal nitroglycerin preparalions appe ar to be less clfmtll Ihall other long·lleling nilr~'e.~. :t5 absorp:ion from the: i§ "Ilritible.
of,_
Diluted Erythr;tyl Tetranltrate, USP. Erythntol_ nitrate. 1.2.3.4-butallClCtroi. tCll1lnllratc (N- • ~HCanii i~ the tetraniln:tlc cslcr of crythritol and nitric acid, II II,.,. pan.'il III a manner analogous 10 that used for nilroal) The result is a solid. crysrallil'll: matcrial. This .:>ter II Ycry uplos"·c and is diluted with lactose or inen dllUC1lts to PpolalllatlOll and repoiaruallOfl Notf that p/'Ia5ti 0 alld ] of !hi! membr.me acbOn potential correspond III lime to the ,nscnptton of the QRS and T waves. respectIVely. of the local electrogram. hean is mcdimed by two inwardly du"t'C:ted iomc c um:nts. Wilen the cordioc cell poIentiaJ rcacllCll its threshold , ion channels in the ITlCmbrane art. opened, 000 No' enten the cell lhrough ion channels. lbese channel s give nse to the fast sodium current that is responsib le for the rapidly rising pha.o;e, pha.matIC repr~t.lbOll of ao IOfl chanoel an equilibnum 01 rt'StlO9 (II'), operi (0), ilnd 1n«1l-
629
m~ t hnuc,
anliunginaJ. and antihypertensl,t acth lly. 1lIc:) lkprcs~ tile cardi ac neurul 1lC1\\-ort, and so ~ Iow \inus node aU10maticity, prolong atrioventrieular (A V) ood.:iJ cond uctance. and dcpR:ss myocardial oontr.lC1i1ity. as \\·cll as reduct' peripheral VlIscular resI.mntc to PfC"ent a roronary vuscu lar spasm. Nifedipine and OIher 1.4-dihydrop),ndlllC'l are more cffecti vc at causing ,·asodllation than affecllng ~mal.et" and tension ["C!;po!Iscs III the hean. This is opeciall y trllportanl hccause ..clcclivity occurs a~ 11 conscq\ll,'ncc of di sc asc Sli'Iles. Uypencnsm:: 'mlOIlth muscle is more sensl tllc to Cal ' channel blockcrs than IS llOI'Tl1OIen'ille tiss ue . to This makcs vernpami l and dillilll.C:m more u~eful in l'iChemic conditions. as they havc a more profound effcct Oft CardlOC muscle calcium channels.l~ The inhibition of Ca l · Influx 11110 Cardia!.· lIS~ue by Cu~' alllugonbt> is also the basis fOf" the usc of these drugs as arttiarm}thmic age-nts" The Ca~' channr l blocL~ dampen Cal . -dependent automaticity in the regu lar pao:cmake-r ce lls in the sinootrial (SA) node und depress the origination of tttoplC roci. Culcium unl.llgonists can block reentry p.:Ith ways in myocardial ti,~ uc. an intcgrnl component or arrhythmias. Nume rous side efrcct ~ III llie hcan. sl.K:h as bradycardia. dt:creased cardiac l.'Ontruculi ty. and reduced AV conductancc. an: tr.ICW to Cal ' channel - blockmg activity.
PRODurn
Ve-rapamJl, 5-1 J.4-d imetlx)1 ),phC"llCth )'1)I1l('tnylumilM) 1-2-( 3.4-dirnetoox yphen yl}-2- i~yl vlllcro nitrile (Cli lan , lo;opcin), was introduced 111 1962 as It Ver;,,,.. mil.
l."OfUI1ary vasodilutor and is the proIOf)pe of the Cal. antagoni'll! usn! in cardiovascular discases. [t is used in the- t11'31me m of angi na pectoriS. arrhythmias from ;el"lc mie myocardial ~yndrorllC$. and "'p.....e-mricular :uril) thmia.~. Vt'I1l.pamirs major effecl is on the slow Cal. channel. The n:.o,ult is a slowing of AV conduction and the si nu ~ ..~te. Thi ~ inhi bition of the action potential inhibi1s one limb of the reentry circuit belie,'w to undc:l'"lic most paroxysmal supr.Iventricular tachycardias that uC\sing slighl ~truc lU rnl similarity to papal·crilletivd y. !>oreti tide has high specifICity for the tklu) ..-d rcctiflCr poIass.um c"rrents.~\
Doferilide.
o
" II II o
"-S-O!,
lbutmde. IOOtilide. N· 14· 14..(elllylheplyhunioor I-hy· droll.ybutyllphenyllmethanesulfonanudc (Conm). a class III amiwm)thmic belonging 10 the. rncth:meliulfOllanilidc class of agents. is indkated for rapid eorm:'rsion of auial fibnllauon or alnal nunc,'r 10 nonnal smus rfl),thm. Unlike tIofetilidC'. il is IK)( highly specific for the dchl)ed n:clirlCT potauiulI! rorrenlS (luI and (jl ~ within ccnain lI'sues 10 produce a ";ooch-.. lory effecl (Fig. 19-15). BradyklOin i~ conl'ened 10 li'I3ctJIt prodUCl!i by ACE and other earbo~ypcptjdalb. A ACE causes acti vatlOO of aJ1giotcns.in and lnactllatP III brndykinln. actions tMt appellr to be oppo!ille. lhe ba' I of lhe ~y~tcll1 seems to ravor vu:;ocollstriction. ACE is a mcmbmnc·boulld enzyme anchored "a.... mcmbrnnc through a ~ll1gle Iransmc:mlJomc, donwn '" IIC;If the carboxy-temuna l cXlrenllly. The enzyme IS. contulntllg glycoprotcm with II MW aboul 130.000.lt is nonspecific peptidyldlpeptide hydrolase. widely diwituel In mammalian tio;sI/CS, tMI Clclll"CS dlpeptides from IIIeCl' boxy terminUS or I number or endogcnotls pepudeJ. Til minimum S\ruclur::ll requIrement for binding and MI. of a sub\trllle by ACE i~ thai it be a tripeptide ... ,tIl I carboxylute group. A gel1Cl1Il ('J(ception is lhat lhl~ docs not clca,-e peptlduet,
Vuoc"H •
Figur. 19- 15 • B,adyk.mn formatlOfl iIIld «t1CJI
Chaptn III • Curow''UJr ,,/m' "'~"fj
645
I
I I I I I I I 1""(...· I
'---------,~ ,----------' ------'
I
""
(~ ,
:> the ('ell
-" figu ... " - '6 • Model ~ng d l'oJv9 of the histidine-phenylalanine res!u of angIOtensin I by ACE to form tne ll\apt'Il1Jde Mtj()lemin 11 and thfo dipeptde I!5Idut of tu5ttdine Clod leucine
I
I
Zn-
()H
/
Ii
'.
•• •• 0
H. H.
\
NH
~
C~
C",
/~
NH ,
1-\ NV
~.
,C=o
"JYU"-Suc gll1ndllls 1a. (~1
10-11
11.0
", " 1:1-17
647
Mode of bo.tlon
....,- ,
,'''''''''''' ........ RmW'I..,. 1
pyrrohdlllt: of coaJapnJ hall ~n replaced ..... uh an oclllr! dromoole systcm. Much likc cnalaprilate. IJ'lIndobpril_ be hydroly/.cd 10 tninOlaprilate . .... hich IS the blO:lai.'e 'lit"
ties.
Ram/prj/. Ramipril. (lS. 3&S. 6aS}- 1-(fSj-N' I{S}-I-cMboxy - 3 -phcnylpropyl] alanyl] octahydrocydopenlll ] b 1 pyrroIe-2~;uOO~ylie acKl l-ethyl cster (Allin). is hydrolyt.cd to rlmupnlal. its acti ve diacid form. foster u..an enalapri l is hydrol)'1.cd 10 ilS acl ..·c diacid fonn. J>l:aL ~l\Jrn concc:ntTlltlOlt~ from a singlc oml dltm. ... hich mOSI lilely plays II 1IIII0000n.~m
11 rttc:p:or similarly
role in bmdmg
lhe acidte pun~,n II. AllIO. lhe: Imid:uole 5y)I('1I1 has tlllI I bC'nllmldazok possessing an eIkr nlUSl be hydrolyud 10 lhe: free (l)lwer;ion wl..C'S i~ ltl!
·1
,
",
the
10
Ih,)
, I
~'Qt\\'ersion to the free
til much
10
-2-c;arbo.ylic acid I"hcmhs). does !lOt appar 10 ~ar any blrul:lura] relationship 10 this class. but there is actually a greal deal of 01 crlap 111 the chemical architecture '*llh OIller agt'nts. The first, and 1110Iimulant to uterine contractions. for insomn ia. and panicularly for tile In';atment of in~a n ity. Jill uSC' in hy~nension was rc:corded in the Indian literllture in 19] II. but not unti I 1949 did hypolensive properties of Rarl'K'oIjio spp. appear in the Wesle rn l i terlilUre.~l Rllu"'oIji(J preparations were introdueed in psychiatry for the tremmc:rll of schiJ.ophrenia in the early 1950s. following confirntllli on of the folk remedy repons on their use in mc:n· tally tkranged palients. By the end of the 1%Os. however. the drug had bc:cn replaced by more: efficacious neurouupic agents. Reserpu\e and its preparations remain useful in the control of mild essential hypertcn5ion. The effects of reserpine do not corre late well with tissue levels of lhe dr\lg. The pharmacological effects of re.o;erpinc ....-ere still rnsc:m in anilNIs .... hen il could 00 longu be detc:cted in the bnr.in. jJ Resc rpioc: depletl:$ catc:cholaminc:s and scroto,."n from ce ntral and periphend neurons by interferi ng "'ith the uplake of these amilleS from the cytosol into the vesicles and grunules."'·" As a consequence. norepi· nephrine cannot be stored intr.mc:uronall y in adrenc:rgic neurons. and much orthe I1OI"Cpmcphrinc in the cytosol IS metabolized by mOllomninc ollidase (Fig. 19- 19). Thc bindin g of reserpine to the stOl1lgc vesic lc membrane is finn. ~nd as a !tSUJI. the storage grallUIf: is destroyed. reducing the ability of the net\e 10 COOCt'ntnlte and store norepinephnne. Since reserpine: actS on both centrul and peripher:al OOrencrgic neu· roll~. its antihype rteru;i\'c effC:Cls ma y result rrom l\Curotransmitter depltlion from both of thelic ~itcs. QM:mlCal m" csligalions of the acth'c components of R. se/'ptnlm(J roots ha" e yielded sever-.Il allaloids (e.i.. ajmahne. ajmalicinc. ajmal ininc. serpentinc. and scrpentininc).
.,..
SCd m the treatment of mIld or modo • hypenension or in combrnm ion with OIher hypolmsM agents in '\even: hypertc nslon.
Reserpine, USP. Reserpine (Serpasi!' Rcscrpoid. fYI. Sal. Santiril) is a while 10 light yellow, crystalline ..ti Mid practically ",soluble in water. obtamcd frum "arious \pm!!> of Raulwljill. In eornrllQn with otlier eompounds "' Ith. indole nucleus. il is suscl.'JItiblc 10 dccompositioo by tip and oxidation. especially ....·Ilen in solution. In the dry discolonll ion occurs rapid ly when rc.'II:rpinc is u~. li ght. bul Ihc loss in jXltcncy is usually ~malJ. In sohrOOl reserpine: may break down with 110 apprc:ciablc colordlqt" ....hen Cllposcd to li ght. e~pecially in clear glass COIII'fI'",," thus. color change cannot be used ali an rndell of lhe of lkcomposit1on. Reserpine ISeffecti vc omlly and pan:nteMlll y for the uumenl or hy])Crtension. After a smslc intra\"C.fIOU5 iJoo,oe. lIr onsct of antlhypertensi\'c action u'iUally begins In ~ hour. After InlTllmu!ICular injcctlon. the: lTWimum effMDI: curs within approx imately 4 hours and last.-. about 10 Whcn it i~ gillcn or.illy. tile mu imulII effect occur, ... about 2 .... ec:b and may persiSI up to 4 wecks ~fter tIx 00sc. When used in conjunction "rlh other hy.,wdrugs in the treatmc:nt of sevcre hypertension. the \bil) varies from 100 to 250 ~g .
Guanethidine and Related Compounds.
fIgure 19- 19 • ActIOfl of reserpH"le al ildrenef9IC nerve ending
dine has bc:cn classified traditionally lIS an ~nergio; IDi ing agenl bccuu"l: it con prevent thc release of 1l(Ht""'~ rine fTUfll postganglionic IlCUronS In response: 10 stimulation. GuanethIdIne and OIller compound!; di in thi5!1CC1ion ha\e OIher actions on eatccholammc Ii~m arid can couse significant depIction of these antiDCl I IIdn'nergic rlCurons. llIey do nOl illlenCre with rele. " epinephrine from the adrenal medulla.
-
kul.. ,'-
~ than ~ yu· '~P
.,
/
!J
'\,
,
~
.o;)!,·cva. 1I1IIC' some sc:dati\C' ~ that afC' undc:sll'llble; it al\O may cause conSl1paiIII1l~d drync:ss uf the l1Iouth, Oonidme hydrochloride is distribu ted throughout the kd)o. ""ith the highest concentnllions found in the organs .dimmatlon: kidney, gUl, and li\'er. Bram t'Ol1Cl:nll'lllion< • low but higher than plnsmll c(llll:cntl'lltions. 100 high IIIILtliUlllK)II in the gut is due: to an c:ntcrohc:palic ('y(' Jc in .... donidinc: hydrochlonde is secreted into the bilC' in . . . hIgh concentrati ons, The half·llfe in humans is aboul II hours. Clonidll1C' hydrochloride: is metabolized by the Iiod) 10 fann two major metabohtes. p-h)'drox)cJon,dinc: alll$ glucuronide:. p· H ydro~yclonidine doe1I not cms.~ the Iiood -brai n barricr and h.as no hypotensivc cffect in hu-
.....11. II
kit hllnll'
0
"
C>=:· "" """"'"..
~
II
0
"..,.
Guanabenl acetlltc. [(2,6-dichloro.yllllene)aminolguanidinc monoacelalc (Wytcnsin ). is ayadt'tnergic qonist thaI red~ the release of
norepinephrine from the neuron when sllmulat~-d . The cffect of the drug resu lt.ed for severe hypencnsion tllllt is d,fficult to cOlltrOl ... ,,11 other anllhypencn'''·e agents.. 'The drug ~s 'iOniC of lhe CharllClcriSlic side cffecUi of dirc:ct \ a.~ilalor) drugs. It cau ...... ~ium and ..·aler rc:tenlion and may reqUIre: coadmlnislratlon of a dlurt'uc. Mlno~id,1 also cau't'S ~nc~ tDChyurdia. "'h,,,,h can be controlled by usc of. P.1KIrencrgic blocking agent. MillOxidil topica l )(llution is used 10 treat alopecia n,idrogenilica (male pUllcrn bal dncs'). Allhough tbe mcchani~m is nOl clearl y undcriwod. lopieal miooxidll i~ believed I() ;nC1\'a~ CUl af)('Q(lS blood now. v.-hicb may ~tilllu1ale hair growth. The '" 1II0I:llioo of hair growth IS allnbuled 10 VD-'iUdilation in the ~ idnity or applicallon of lhe drug . re:~u hinll in beller nouri~hmcnl of the lornl hair follide\.
fQ/lt dl('mical decQmposilJon aflcr MOr.I.ge al room ure for 2 y..ars. \Vll('n the: solution is C.\posed 10 II darl.cn.~ .
.
~~
01 urml
rag di l -
fU"
rn
j'"i'\'Jc
"'r,""',"'"
o
......
of the
j"el\
or
~t)< ...- )
Ii ~er.
b, "'" ~u[fC1
Minoxidil. 2.4-dlamlno.. 6-pipendlllOI[)('oJ-OXide (Loniten). wa.~ de\·c lopcd a.~ a rt'sult of ~Iaccmcnt of a uiamlnOlri:wne mo,ely by triamiTImldlne. The triaminotnuine< were inillally observed Ie polen! \·liSOdiiators in eat~ and dog,~ following their of N"oxlI.lc~ in lhe:se animals. The tnu,nes ......... :tMin humans because ofthc:ir inability to foon N-oxide ll:llllnllte~: this led to the diOlides pot;sess WI unsutur.lled butyrulllCtolll: ring. ..... hile the buflld ienolidcs ha,'e an n-pyrooc ring. Phamlocologirnlly. boIh have ~imilar proprn ies and are found In many oflhe ume natuml SOtm:cs. Including pllUlt and lOad species. By far. the mOSI Imponam source.~ include 1>i,illJlis purpuuu arid D. hilUm•• In 1785. William Withering published .• An Account of 11M: Fo~glo"e and ItS Moolcal USC's: With Prnctical Rl'mar\~ on Dropsy and Other Disea5e!i.·' in which he describes the bencficial use of fO~lllove in dropsy (edI!'ma). which oOcn clIists in C HF. Even with n:cem advances in synthetic orgnme chcmimy coupled with the usc of rombinntorial chemistry. no new therapeutics have di~pl!K:ed the cardiac glycoside's. Funhcr1TIOfe, the perennial U~ of these agents o"er mlUlY centuries is c,'en more remarluablt' " 'hen one WIIsiders the useful life of a ""block buster"" drug In tOOaY's markctplllCl'. This remarkable fact I~ ba.o;cd. qui te simply. on the unique: ability of nature to produce elltraortli narily b,oactive substances. which chatllCteristically possess boIh a lipophi lic ponion;n too steroidal ring nnd a hydrophilic moiety in the glycO$idic ri ngs. Thc thempeutic u~ of these agents depends largely on a balance between the different solubility chanlCtcristicl. o f !he ~teroid AfUClure. and the type and number of sugar unilSattached to II. Although the fundamental pharmacological proflt'noe$ reside with the Ac:roidai nucle.a. the sugars play 11 crillcal role In !he bioloeical dfe-2-metllyl·6-0"ol.HlIpyridine-5..:arbonilnle (Pnmaoor). I~ :tnoIher dipyri6ne f'hmphodieslerase F-lII inhibitor Ihm possessc~ phar..cologiclIl prope"ie~ similar 10 Ihll'\t: of amrinone. The IlbiblllO!'l of the dcgrudation of eA M I' resu lts in un iocll';ase • !lie cardiac muscle' s ()(Ce of conlraction.
o
657
underlying disease involving the li ~er. kidney. jXlllCll';:I.S. or IhYll)id. or il may IlOI be anributllble to any recosmzable dio;easc:. In recent year.!. lipids ha,e been imphcat«lln the de\'eloprnen\ of atherosclerosil 111 hullUlRS. At~fOI(;lt'tmis may be defined as degcllCra\ ....e change. in lhe II1tima of uM:dlum and large pneries. This degeneration Inelulle, the accumulation of lipids. complu carbohydrates. blond. and blood prodllCts and is accompanied by lhe formation of fibrous tissue and calc ium deposItion on lhe inl1m11 of the blood vessels. 11!ese deposits Of"/lllIqUt'S db; I ease the lumen of the artery. reduce its elasticity. lind may I:ll';ale foci for Ih romb; and subsequent occlusion of the blood vessel. 1111
Lip'pr"Oteln Clasns LiP('f'rrlftiru ate mllCll)molecule~ consisting of IiII'd subst3m:es (I:holcstcrol. lriglyceridc~) IIOncovalcntly bound " 'jlh protein IIIld carbohydrate. These combinations solubi· h/.t the lipids and prevent lhem from forming insoluble aggreglltes in the plasma. They h:lve II, 'pherical ~pe and con~I,~1 of a 00111'01 .... core sUll'UUndcd by a monolayer of phosphohpids whose polar groups IU'e oriented toward the lipid phase of Ihe plu'ma. Included in the phospholipid rl1OllOlayer lire a small number of ch.ole.~terol molecules and proteins tenned "(1QllpoprOl",i1lS. The apolipoproceinsappear to be: IIble 10 solubilize lipid~ for InIn'\pOf1 111 an aqueous ~ulTOllnding such as plumll (Fig . 19-23). The VllriOUS hpoprotei ns foond in plasma can be: separated by ultracemrifugal tethllique~ inlo chy lonlicrons. vcry-lowlIen);ly lipoprotein (V LOL). intcrmcdiate-dcnsity lipoprolein (IOL). Iow·den.~ity lipoprotell1 (LOL). and hlgh-dc:nsity lipoprotein (HOL). The.se correlale with the clcclrophomic seplll"diions of the lipoproteins as follows: ehylonllcrons. Pll';,8-lip0pr04c in (V1.DL). broad ,8-lIpuprotein (l OL). ,8-lipoprotein (LOL). and a-lipoprotcin ( IlJ)L). Chylomicrons contain 9()% triglyccrides hy lI>el&ht and on,inate from u:ogel1Ol.ls fat from lIIe diet. They are the least dense of tile lipoprotems and mlgr.uc!he lea.\! underlhe
"'ilmona (Primecorl
AHTIHYPERLIPIDEMIC AGENTS
.. \IJ> (X'f' iunl lc~-
CIIUSC of death in the Western workl loday is dlsc:llle. of which the most pn:\1Iknl form is mhen>...ID"_oo.hean disc:llle. Although many clIuS3th'e fllClOl"5 of . diltase 11ft: rerognl led (e.g .• smoking. s\rcss. diet). alhdiscllsc CUll be treliled through medicalion or
H~~~,~:~·~:,~,~":,,;most jl(e\'aknt lndicalor for 5U~ep
:
hean diSC"''''; il is a tC!l1ll used to ::~:',~IcVlled plasma le\'el$ of lipIds Ihat all'; usually in lipoproteins. l-typerl ipidcmill may be Cllused by •
Figure 19- 23 • HypothetICal mode-I col lipoprotein partICle.
Innuence of IIJ1 eleclric currem, Ch), lo,nicron) ~re normally abolenl in pla..~'TUI ancr 12 10 24 hourcd frortt plasma, I.e> els of LDL reccplOl'S >'ary dependmg on thr of c~tr.thepa'ic ti,sl.K':S to b,nd LDL to II~ ~'holeslerol, nr extrahepatic lI~ue sutr...'tcrs formcd b) the en/,),OIe lecithin-cholcsterol fcra;;.c (LCAT), llIesc C'.teN l\R: lJ"~nsfcrred from HIl. VLOL or LOL m plasma 10 completc the c}ck. lbr: .... ays for plasma lipoprolctn OICiabohsm by Ihc.~"'~ and endogenou .. «Iutcs are Sho .... n in Figure 19-24
fltt:;:
tfypet'llpoprotelnl:::oI_
are,::;:~:~j~:!;~~;~ hypcrlipoprotciocmias ha\c been I' 0li~mb7 thm CR.-ale Lipid d,SOf'dcN
":::: (~
ellCh of .... hich i~ trealc:d differently (fable 19-6), The abnormal lipoprotern "",Item characteristic is call5Cd decrea~ in the acu~ilY of I in
the pla,ma . Bccause the Iriglyceridcs found
conlt pr1n1.ui ly from c\ogenous 'iOU"~~·~~~.:~:i poprott'inemia may be tn'aled by , dlctary fal . There are 110 drugs al pn'~n' 10 counteract type I hyperlipidcnua Type II hypt'rlipoprotcincmia has IJe(:n lIa and JI b, T ype Ila i~ chal'aCterilcd by dC"IIIa! LOL (P.lipoprotcrll$) and normal lC\cls of This subtype dIsorder is ,'ery common and hy disturbed catabolism of LOL. Type I lI a. in thai this hyperl ipiOcmlu has elevated additioo to LDL le .. el ~. Type II II oftcn clearly familial and frequcnl1y nul domilWlt IIbnornulity '" IIh complete upres.\ ion in IOfancy , PallCnts h,·c been dictary I'CStriCllonS on cholc\terol and o;:J!urola! type of hypcrl ipopmccinernin re.\ponds 10 SOllIe
....
TABLE 19-6
...,
Characterization of Hyperl ipoprotel nemia Types Abnr.o .... ,ity
-
ItJp.rllpoprot.I ...... I.
•
.''"" ,"
1
EllKboph_I,
of
P'"sm.-
M..... -e fb~I""""""",,mla
Clear. ' ....111) I., ... of
~upopnllo'1ItId
l. """a,d
DnlIId 1\-11,......"'..;n """"
VIJ)UU)l. "" ."'M>nI"Iai
..... -r.·h,.'.(1jeln' ek> ~
VLOI. inrft'......t
""' ,..., ,...,
1'fe.1I-l'P"I."'" dc, Md. my k"""', 01"'''''.
\lUlL, ... , , .J. C . Oofibrute also regu lates cholc,terui ~ynlhesis '11 tit.t li lcr by Inhlb,tlng microsomal n:tlUClion of 3-hydroxy·3· metbylgIUlaryl-CoA (II MG ·CoAl. cutalyzl"il by HMG-CoA n:tlUCt~. C lofibrulc may lower plasma lipids by n1l.'ans otttCr than impainnl'n1 of choleSlcmI bIosynthesis. \ uch as iocreaslng uCre1iOll through the !>tliary tract. Clofibrute i.\ tOler-lied \\'ell by most pallents: the ntoSl COU1tll0n ) idc effects ore nau-.ea und. to a smaller extent. other gaSlrorntl'stillal dbu"C)s. The UQ ....se of ant icoagu lant•. if usctl in conjulICt iOfl \\ollh this drug. shou ld be reducctl by one: th,rd 10 ottc half. depending 00 the iodi\iduIII responsoe. 50 lhal the prothrombIn ti lllC may be "cpt willlin the desired I1nllts.
•
CH~
0
I
U
-r-0-C-C-O-~
I
OH,
Clofibrate (Atromid)
Gemfibrozil.
Gemfibrw:il. 5-(2.5-d imeth)lpheooxy)2.2-dintcth) lpentanOlc acid (Lopid ). ;! a congener of e1ofibr~tc lhat wa.. nsed fiN In the tremment of hypcrhpoprotciocmia in Ibc mid -1970s. Its mechanism ofacuon DOO use an: siulIlnr to those of dofibrale. Gcmfibro1il reduces plll~ma le" d s of VLDL In glycerides and \lImulales clearance of VLDL from pla~l1la. 1ltc drug has lillie effe\., 00 cholesterol pla.ma ieI'd. but docoi cuuse un incn:ase of II DL Gcmfibro/.il i\ uosorhed quidly fmm lhe gilt alld excfI';led
ullChanged in the urine. The drug hag • plasma lull(· life of 1.5 hoor'S. btH reductioo of plasma VLDL conccntmtioo takeli between 2 and S days 10 become evident. TIle peak effect of ilS hypolipidemic OClion may lake up to" weeks to beconle manifeM.
,
"'-
J----O'-
r
}--,CH,-Cl-l-CXXlM
,
U!ie of thyroxillC in the treatment of
hyperlipi{\('mi~ ~
not ...·"hout ~d\'el'l>e eff~l~.
FenofibriJttll. FenofibrJte.2-[4-{4-chI0l00c:nzoyl)phenoxy!-2-mcth)lpropanoic acid 1'I1lC'\hyleth)1 ester (Tricor), has structural featurn Itpi'"Cs.ented In cloIibfate. The primary difference Involves the second aromaue ring. This imparts a greater lipophilic charncter lhan exiSts In clofibrate. resulting in a much 1lI0re potent hypocholtsterulcmic und triglyc· eride-Iowering ugent . Also. this structurnl modification resullS in D lower dose requirement than with clofibrute or geml1brolil. " I " 0I / '"' O- C -C-o-CH
I
Feno/ibratl
""
,
""
(TrIcor)
Dtilxtrothyro)(irHt Sodium, USP. DextfOlhyrol ine sadium. 0.( 4-hydroxy-3.5-di iodophcnyl}3.S-dii!JOO.[)-Iy~ sine mooosodium sail hydl1lle. phil", ,k",",iln. pillclCf (1)/_ I. aN,hattopholic fattot A ~ (1'fCl. CIoro_ lCfw'ac"". II .................1>0" II .
y,
'Vl1l "
.,...,.. ......."1.,,,,'11_ ' ' lOr......
x
" '"
11"80""'" [,,;00'
VI ' • Thao,'C( I 1"1
II'
__I
IW'
Iv Co"" ~
,.
" ........,....,. -
nbrin ...... hri ... r....". fibnR4iC ",hen thrombin and factor Xa. forlll~"e,,,,een :ulcium .&
~[epi'
n vivo.
lu\allon J1lnn~ I C
up Ie romprotein ~,,'d~
1y - Arj! IlIIHlUS. ~nu:.
;win gel
:.en
the
,..glu-
IIlte 1~
the
con-
ge.,ted thut vitllm in K dril·c., the carbo!l.yla.se rt'actlon by ab'ilntcung a pmton (rom lhe l'CIah lely unreacll I"C melhyknc: carbon (If the Illu lamyl residue. fOffili ng :1 2.3-cpo1 ide. Oral anllcoagulants intcrfcre with thc: }'-C;lIbo~ ylation of g lu lamk acid 1"\'._ldllC'\ by pll',c:nhng the Il'ducnOil of Illamin K to liS h)
"..
1: 1""
ro.
0,
o o
"vv~"
o
Figure 19- 27 • MNhafirsm 01 olCtlOl1 of V1tamon K and $lIes of ilctN)n of wilrlar,n
are likened to the SlOI1Igc grunulcs II.~SOCialed wllh adJ\"llcr!!ic !leurons. IncJ\"ascd levels of cAMP inhibit platelet aggregation. cAM P acth-all:s ~pecific dl:'pendenl kiRII.'ieS. which form proIem- pnosph:uc oompleJIcs thai che la.e C1llcium ions. The rWUC«Ile\'el~ of calcium inhibit aggregation (Fig. 19-28), lnhibitOl'!; of platelet aggregation can increll5C cAM P levels by I.'lIher 51imuhuing adenyl;uc cyclase or inhi biti ng phosphodicSIt'rase.n SubSlllnCC:ll such as glocagoo. adenosine, and isoproterenol increa!ie cAMP level s and inhibit platelet ~gregalion . Drugs such as IheophyiliBe. aminophylline. dip)'ramidole. papa\"crine, and adeOO5HlC inhibit ~ies lerose aoo aggregation of plalcicls. Epinephri!le. collagen. and serolonin inhibillldenyiale cyc lase and ~,i mulme platelet aggregalion.n The role of plmelel5 in arterial thrombosis is
ATP
"-'
5' AMP
3',5' Cyclic AMP
....... j
ProIeon ... F"hospt\ate _
0.&.101' 01 Cs'cun Fftle C*ium ( C a " ) - 8culd Cab"rn neaH"')' lor ••1ibQ iiiOItll!iJM"'ll ~ 1iGO'''Y-or;
Figure 19- 28 • Role of adenosme 3'.s'-cy. fatty acids arc prescm in the phospholipids of ~l! . . bninc:~ofDJI mammalian ti~s.ucs. Th.e main ~ursorull"' taglandms is ar..chidonic add. AllIChidonic Kid IS Idr from membrane phospllOliptds by the clU,yn:w:: pho! A~. Once re leased , arachidonic acid is mcwboil1.ai ~ cydooxy&cnase ~yntheta.'iC to room .ms tablecydic oxides, PGG1 and I'C HI' which subsequently art funned into PG ll and Ihrumboxane A l (TXA 1). The~. 5ion to TXA! is aided by the enzyme: thrombou« synthel.l5e. 1llc: formation of PCI! can oc:cur _~ cally. Blood pluteleTS cOllven arachidonic :reid 10 ~ whereas PG ll is formed mainl y by the vascular emlodldltoll
Cluaptt r 19 • C..niim'tIJC..lar At.rmJ
Ik.tI PGII and TXA: are unsmblc :\I physiologk-oll pH and IClfljJti ..IUI'«. Their half-lin'S aK 2 10 3 minutes. PGll inhibiu; platelc:l agglt'gatioo by stimul:uing adenylMe cyc-Iasc to inm'ase cAMP Ic,-cls in the platelets. PGll is also • VIIs(xlilalor and, as II Te$ult. ~~ pote:n! hypolensivc fIfOPCrtles when given intr.l\"er'lOll~ly or by intni-ancriDJ lid· IlimSlMltion. TXA 1 induces platelet asgregmion . Togclhcr with PG I:. TXA1 plays II role in lhe muintcnnncc of vuscular IIomeo!!lasi~. In uddil ion 10 being a platelet agg.rcgator,
TXAl is II polen! vasoconstriCtor. Retllroalion of clolling is impor1llnl in blood tranSfusions. III ."oid thrombosis after surgery or from ocher causes. 10 pm'cn' rtttJlll'nllhrombosis in phlebili~ and pulmonary em· IioIlsm. hnd 10 lessen the propagation of clocs in thecoronary tItme$. nus relarti:llion may be acoompli..ncd by .gents Nt mac1iv,le thrombin (heparin) or 5ub:i;Ulnces thaI pre~1 fir formation of proIhrombin in the li,'cr (the coumarin deIJ\loU,'e! and .he phen)'lindanedionc dem'ati\'cs). Although heparin ,s a u~ful lllllicoogulanl. 11 h:ls limited applications. MlUly of the anticoagulllllts in us.e today were 1It"eloped followin, the discovery or dicumurol. an antico"ulan! present in spoiled sweet clover, The,
-
}---o -pC agenl~ lend III ha\'t I rapid 0!lSC1 and a !ilion dUI1IIiOll 0( action, Muctl lkI: the MJlronylun::~. these indl.JCC insulin release: from lill('honlng p:lI1crc:Ilic p cells. 1bc: mechanism of action for
lilt metag.inides. however. differs from lIulI o(the sulfonyl_ llle mochanism of action is through bmdmg 10 spc_ aIk tcx:cplors in the p..ccll n~mbr.lI1e.Ie:lding to the closure
o
o
I
-
(PrandirI)
Nateglinirk.
Although natcglinide. N-(4-ililOprOpyl_ cyclohexanecarbonyl}-I).phenylilianine (S tanix ). belongs to the mctaillinides. il is a phen),lalanine den"al;ve and reP'll!itnts a oo"cl drug in the management of type 2 diabetes.
o
II ATP-dt:pendc:nl K ~ channels. l1Ie K ' channel blockade: oiepoIari~u the ,8-cc1l mcmbrnne, which in 10m I~ads to (a!' innu~. im:rcasc:d inltll~"i:llllJDr Cal ~. and Stimulation rI Hlsuli n secretion. OceauS!: of this different mechanism of I:\JOIl from the ~ulfol1yJun::lI~. there an: two major differ. between these seemingly similar clas>Cs of agents. The liM i~ thai the metaglinilk~ cause much faslcr insulin ,.xJuc1ion than the wlfonylureas. A~ a I\'..,uh.the metaglin_ lib lobould be taken during meals. lIS the p;mcn'as .. ill prokt lD54Jhn In I much shonerperiod. The.'i«Ond dlffereoce • IIIIlthe effecl'l of the mct;tglinid6 do IlOl las! as long as Ibt: effects 0( the sul fonylureas. The effe-cl~ of Ihis class IppCIC 10 laSlIess Ihan I hour . ... hile sulfonylurcas continue IhllnlUlate insulin production for seveml hours. One itdvan... of a short dUmlion of actiort i~ thai thel't! is less risk of
o
-
~lyccmJa.
101-
ylic ~lInide. Repaglinidc. (+ }-2-Cltlo~y-4-IN_[ 3_ .tllyl·1 (SH 2·( I- piperidinyl ) phenyl [butyl Ic~rbamoyl W)llben1oic acid (Prandin). n'prtSCnts II new cJllSS of _ Ifonylurea or.JJ IInXlglycemic agents. Witll. fast onset . . . iJIon dunnion of action. thc medication AAotilu be .... lth meals. II ;soxidized byCYP )A4. and thecarbox!Itt It1d may be COIljugaled 10 inxllve ConlpoundS. Less . . 0.2'1: is excreted unchanged by the ~Iuncy. which may Ire an acJl'lIntage (Of ekkrly patients "'00 ~ renally imjIIIn'd. The mOSI common side cff",'Ct involves hypoglyce-
T1IbtzoUndlones The thiu.oIindiones n'prt'lICnl a 00\,,1 nonsulfon),lurea c lass o(hypoglycemic agcnts for the treatment of NIDDM. MIlCh like the sulfonylun'as, the use of these agents requirtll a functioning pantn'as that can successfull y .'leCn'lc inWlin from P cells. Although in~ulin may be relea.~ in normal levels from lhe: cells. pt'ripheraJ sen.,ilivity to thili hormone may be r(.'duced ()( IlICking. The thiamJ idillC'd lollC.'Ii are highly selecti ve agOlli sls fOl' lhe pero~isome prolifcrntor-J1!.1h'stcd l'C(.'I,'ptor-l'(PPAR which is responsible fOl' impm~ing gly_ cemic control. primanly through the implt)\'cmc:nt orinsulin sensiti \'ily 111 muscles and adiJXllit tissue. In addillon. they inhibit hepatic gluconeogenesis. These agents nomuJlI.e ,IuCOSt metabohsm and reduce the amount of insul;n nc:cdcd 10 achievc gly~'CmlC cOlltrol. 1bey are only eff~he 111 the pn:seoce of II1suhn .
n.
Rosiglita.zone.
Rosightazone. (:t: )-5-[ [4-[2-(melhyl-2_ pyridinylamino)etho~y Iphenyllrnethyl}-2,4-thiazolidinedione
o
(Avuoolu). i~ a .... hitc 10 off·whi le solid "'ilh pK.. values of 6,S and 6. 1. Ros:igllla7.o!1C is readily ",Iuble In ethanol and • buffeml aqlleOU~ 'iOIution wilh pH of 2. 3; 'iOIublhty decreases "'llh increasing pH in the phy~iological rungc . The molel:ulc h.as a ~ingle chinll center and IS pre..~nt ~ a r.JCemIItl'. E,'cn !iO. tile l'nanliomcl1> are funo:.11Qnaily indistin-
gUishable because o r rapid ;nlcrcOll\CI'lOIOfI.
-
.
o ",
...-\I"' -
PiogJilazone. I'ioglnazonc. ( :!: )-~_ 1I4_[ 2-(5.ethy l-2pyndmyl)c'lho.\'J [phenylimethyIJ-2.4-lhlllOOhdlllccry similar 10 a sugar. wi,h lhoe hetc:roc)'chc ntlr'llp serving as an i50Sleric I'qllacClTII'nt Oof the sugar O~ ~gc:n. n. feature allows reU. 1983 U Yaol. A . J . Mol. I'IoannamI. ~-iul 8:ll.! I'" 48. r . . f _ ....a 11.1...... 0 A J up Mod 11 :19. 1dir. P I' B. J PIwoaOOC\Jl . fJ.P. Thtr 118 IW. 19St1 }I. ItiMner.N J 8001 Cbent.2372111. 1961. \l .... f.a .... U S .. -.I LiihaJl.O. I' .. I... , J N",,~. 2;127. 19bJ J6. MuI"'" J M.• Sch~n"'. Eo. Ind 8nn. II J . fu. ... 19S1. fl. U'Pnctwd. D.. fI oJ . f...... J ~. ~87. 1978. • ! 5''''. 5 z.. orr.! c. ..erv, I. Hy~ D11. 1980. " sun.., K~ 8IId MOIMCI. II; l'1ou""","",\3c\lkIo' 12:1013, I~7.l. 10. .~. K I) Dora-l·Kl,.. VWIC today . In the ne:XI 30 or so lCafS :lftcr the synthesis of procJ-I}kIdol9
the 3CClanilide :lrmloguCli he had synthe$IlL-d :'IS poIcntli antipyretic agenL~ also c)lhibiled IOCIII W"IC~thetic aclil il). l~ 1931. his synthetic ",-00. lcd to lhe produclion of cloclKntnr (Nupercaine:). a Iong-ocllng local anesthetic th:lt ..... as ~ larly useful in spi nal anesthesia.
At aoo..n the 1W1T\C tinle that ~'iocllllCainc was develop«!. an invcslig.ation of the chemic:ll siruciure of the at~.10.:1 gramme al Siockholm Unh'ersily resulted in ErdIITWl ~ thesi:dng its i large fibers. However. this order is not stnetly followtd III practice. Some mydinaltd librrs are blocktd wilh lower concentrations of local anesthetics than some nonmyelinaltd fibers .... hile Inrge fibers are often blocked before smaller fibers. FunhemlOl"C. in experimenlal work, the outer libe rs in llle nerve are affecltd lirsl. regard· less of their nature. fupcrimcntal won: by "runt. and Pc~ In 1974 suppontd by the work of Chill and Ritchiel.l in 19&4 suggem INII the diffcre:ntial blocking of roc,",'C fibers depends on the lengtb of non Ihat has 10 be e~poscd 10 lhe local anesthetic 10 bring about ane..~tlM:sia. Shotter nerve fibers have ~hotter internodal dislances and in the early stages of llIlt~thesia are fully e~posc:d 10 thl: local 3ncSlhetic. with the i'tSultthat they are moce readily blocktd than longer fibers. In mosl patients. the iCnsaaion of pain is the first 10 be lost. followtd by tern· perature and touch. pH of tIM btracell.1ar and Intr• •llular
Flu.... L...ocal 3llCSll'Ietics are normally weal bases (pK. - 8.5). which are only sligh!!y soluble in waler. Consequ.::ntly, they are usually marketed as aqucou~ soIution$ o f their more "DIu· ble salts. TIlese solutions are often quite acidic. which makes them less prooe to bacterial and fungal CO
Eleclron ..... "'IlIOf1 decrMH poIanutitwl of C!utlOi'1l group
van :: WaaII' fIr.HMn..... ·11 "lie ..:IQoIe allnocloon
Figure
the btndlng 01 an ester-type local oJr"It'SthetlC otge'I1l to a
receptor Slte
die ~1'11 membrane, Lipid solubilit y plays an important pan 'litho! action of local ancsthttic,.\. since: ,he,. action depends Illlllleir ability to penetrate: the cell membrane of the lUOO. The hydroplllilc center provides the local 3nesllieuc agent "lib some of ils ..... ater solubility. This iJ an rsscmial factor Ulll1lnsponing the drug \0 the membrane a!ld. once in~ide !he cell. 10 the recc:plOr. 1be hydrophili c center also allows !he drug to pcnclr'.lle 11M: pol~r OUler face of the cell membnI.IIe, cnabl ing the drug 10 n:ach the lipid hean of the mem!nne. II also allows !he drug to pa.'iS through the inroer polar flee of the mcmMnc IntO the cdl. The hydrophilic eemer iJ also believed \0 be jnval-'ed in the binding of the: drug 10
-
lilt ttCepior. The beSllocal anesoc"'' ''''. GuHlc 10 MNiara Md Dnop. Qodal........ U K.. C _ Librw)' l1000. J 9112.
}. Albcru. BM""'1. D.• u-w... J~ d aI. MoIoao.. 80010&1 .): Ref"" ... lI«>IIY Ikfj, • • SpnoftI' V~I9tU
I~
" 'lk. 8 · ..".,.,..,..ip. vol. Ill. Nt... Von. "'ad III"' - . 1912. P.
UJ
SelECTED READING Nul. M J MedICal I'll""""""",, • • Cw.:.. . .mI ed. OL.;l ",ell SIry. An Inl .. >d ..... iIe Acetic Add Riboside
figure 21-4 • Metabohsm ollllslilmlnf ALD-DH, alclehyde dehydrogenase, PRT I~""
T_inatl_ of His" hlne Action 1m principal ways cxiS! 10 t('nnillOle the physiological dferu ()( hisllImUIt): • Cd/III", 1Ip'"tr ArumaJ studies 1\.1.·c dox\IlUI'/l1al the uplal.c Jt~J;'i:PI;"" of alII. Some II, ~-co... ~ininli !lSSIlC' uhibll ~ hon"-'lcnro\I.' Ion of sen"II.,ty 10 (he actions of Ioo>wmoc. pc:rI\ap!< as I mull b also block histamillC relea'iC. 1bc COllCentrations requlIN. howe'·cr. are coosidernbly higher than tnose required tOj» duce sign lflCllnt hist.:llnmc receptor blockade. The H,IIIIU!t onists do 1101 block antibody production or an tigen-antlbodj interactions. 1M
Structu... -Actlvfty Aebltion5hlps 'Jb.: H1 antagooists are now conunon ly subdivided mto 111"0 broad groups-tile first. gener~tion. or , Iassical. anlihlSl»mines and the second-gcllCrntioo. or . ·non~'11 ing.·· antihhtlmines-ba.wd prim:uily on their general phannaoolop;!ll profilc.;.'' 19 The differences betwccn lhe~ t... o series 1ft discussed in more detail III the scction$ that follow. lltr most dclllilcd publ ibhcd SA lt analyws for H, antagoailb. OOwever. focus on the Siructural requin:nlCm~ for the lint· gCIICr:ltion agents. I•. I~ From these studies. the basic 5tIW. tural requ irell1cnl~ for H ,-rect'plor antagonism ha,'e 11M identified as thme shown III Figure 21·5. In this SIfU(1tue.N is aryl (incillding phenyl. SIIbstilllltd phenyl. and hetno.)l groups such liS 2-pyridyl): AI is a second aryl or aryl~ group; X is a I:onnecting :110111 of O. C. or N: (CH1i, rtj1t5Cnts a carbon chain. usuall)' dhyl: ww.I NHR' rc:ptUCIll'iI basic. tCTTl1inal amillC function. The nature mtlle ~ atom. as well as the diaryl substitution pattern and _ moiety. has been ue"eral oflhe phel10lhiazines ha ve limited use in Parkinson· lile syndroull'!i lIS II. result of their ability to bloc!; central muscarinic receptors.tl. 19 And . a number of alllihistamiocs. iociliding pronletha1.i1lC. pyrilamine. tri · pelennamine and diphenhydram ine. display local anesthetic activity that may be tnerapcuricaHy useful. Zoi As the gencr.l pharmocological profiles ubo,'c suggest. most ,mtihbtamines cuu intcnlCt with a variety of neutotrallSmiller receptors and other biomacromolcculat ta.rgets. This is most evident among the first -generation arenlS. many of which fUI"ICtion as antagonists al muscarinic receptOl'S and. 10 a lesser extent. adn:nergic. serotooergic. and dopamine receptors.l~ II. 19 Although some of these non-Iarg~ -m:cp tor interactions may h:1\"e !iOIIIC therapeutic value (as dt .... cussed abo,·c). more frequ~ntly they am manifested as ad· verse reaction~ that limit drug use . This iii particularly true or the peripherM anticholinergic cffects produced by Ihc.r,c dro&S and of intemctions with a number of neurolransmiller system s in the CNS Ihat resul t in sedation. fatiguc. and diu.iness.'''' II. I~ TIM: primary objecuvc of antihistamine research over the past 10 to 15 ycars has centered on de"eloping new drugs with higher selectiVIty fOf HI receplOl'5and tacting undesira· ble CNS action§. TIle: pronounced sedalive effects of some of the first-generation agents wcre attributed 10 the abIlity of these drop to penetrnt~ tlx: blood- brain barrier (BBH ) because of lheir lipophilic nature and then block ~,tbial H I m:cpl~ and pot;sibly other receprors.'" Thus research cfforts wcre initiuled to design 1lO"cI antihistamines wilh reduced ability 10 penetrnte the eNS and decreased affinity for central histamine m:cptors.1lte.r,c cfforts led 10 the inll"OdUClioo of the sccond·gcnerntion antihistam ines. ",hich are nonsedating and have lillie antagonist activity at olher llCurotTllnsmillcr m:~ ptors at therapeutic cOilCcnlrDlions. The ph.armacological prupenics of these agen ts are discussed in ntOre detail below. Surprisingly little information is available concerning the phaonarotinr:tlC and biodisposition profiles of the first -generation antihistamines..lJ Generally. the compounds ate orally active and well absorbed. but oral bio:... ailability may be limited by first -pass metabolism. TIw: metabolilCli formed depend on drog stltlClu\"t' to ~ large t)l t( nl but commonly involve the teniary amino moiety. Thi s functionality may be
subjeCt to ~uccess.i\·l' O.UdatlVl' N-dcalkylalJon. dcamination. and amino acid conjugation of the resuhant lICid. 1lte amme group may 1110;0 undergo N-oxidation. which mlly be reversibil'. or direct glucuronide conjugation. FiISl -lIel1o!nllion agents with unsubstituted and activated aromatlC nngs (phenothtal.mtS) may undergo aromatIC hydroxylanon 10 yield phcllOl s. which may be di'l1in~lcd as conjugule..~.lJ More deta,1ed ph:tnT\lOCOl.;incl ic data are available for the seco.1Cl-l!cnern tlon IIlents and are il'lCtuded in the l1'lOI1C)graphs thai follow. The H I :mtugoni~IS display II variety nf s'gnilicant dru g Imeractiom ... hen eoaodmmislered with OIher thcr.!pCutic agents. For ('JI.umplt. MAO inhibit~ prolong and intl'nsify tnc nntichohnergic action ~ of the I1l1t ihiSlamil1(':~. '''' I" I•• lJ Also. the set\;lli vc effect_~ of these IIgents may potcntiute the depn::s..o;:am 8Cm lIy of barbllunllcs. akohol, narcocic analge· 5ic~, and ochct- depressums. Rccemly. il was discoverW that )Cvtntl of the propylimlnl!S_
MecJiz/ne Hydrochloride. USP. Meclilinc h)'drochloride. l.(p('rolonin llCIi~ Ily. In c:arly rc.rrnt:. lIl..iltudll1C exhlblled nrorc than 311nle' lhe poIeocy of c hlOfphc:ninllnillC III rhe i..olalL-u gUloca pi, i ICUlilloCTt:en and more Ihan 7 times the oral poteJlCy of chlorphcnirnOll11C in protC'CUOll of guinea pigs against II double lethal do!ie of mtm,enou~ly udmimstc~ histamine. ') The
R
Figure 21 - 11 • Gemorill $\ructure of the dibenzocydohep-
teoes and dlbenzocydOOepta!leS.
00_"
llsual dosage is I to 2 nlg twice daily. A7.aladi!1t' is available in I-mg tablets. U,,,,,I &dull I)a;.:,j~
oo.e: Oral,
1-2 mg h.i.d .
fOl1115 Tabkts
\
/
---,
CHCOOH
• II
CHCOOH
,
~Ko 'emJdine Hydrochloride. Fcxofenadine ~ chloride. ( .:t H -I l-hydroJ{y-4-I4-(hydroJ{yd iphcnylmtlh)t~
ICH,
I-piperinyl fb\Jtyl-IJ.o--dimclhylhen7.cncact"tic kid ( gra), OCl:urs as II while to off-wllile crystalline po.,,,irr II1II is flttly soluble in mc:tllanol and ethanol. sl ightly toIubk I chl0r0fonn and water. and insoluble in ileUM. llu! pourld is mar1\eted lIS a f1ICCmate and exists &.'l • ~""Ium. in aqueous media at physiological pH. Fe~orenadine is Dprimary o~idal i ~e melaboille Of~rff"
Secand·Cen...atlon ..... Ant·.onlst D.a.
°asses The second-generation anlihislamillC1l are more si milar pharmacologkally than structurally. As dil'oCussed above in this chapter, Ihcse compounds ..... err Oevtloped as sckclivc HI-
~
rttCplor antagooi~s with rdatiH:I), high pou:ncy. MOIl 4 these ~'()mpounds also produce prolonged antihistrumnlCcf. feelS as a result of slow dissociation from Ii , ra:cpIOn-' lhe formation of aclive ITIelaboiiles ",uh similar Ita,*, binding profilC5. I~ 1be second-generation agcnt~ hnV( I,a affimty for muscarinie. lIdrencrg;c., or stl'OlonelJlC nn(U1 and. therefore, di~play II tower incidence of side effect!, aQO.. i,led With anlagoni~m al these ~or.;;. T1v::ir afflDibel; for these receptors vary §OI11Cwhat. as indicated in the me.> graphs below. Pemaj1li fflOSl imponam ly. all of these rof. pounds lock seliat;ns effects al tlltrapeutic cono:;eMl_ bccaLISC of poor eNS penetration and, J>OI'sibly, lo .... errc!l{· finities for central histaminic.''' c holillef1!lC, and whu",p: reccptors. The first mcrnber~ of ,hiS anli histamlne subcJ-. introduced in tilt United States induded tmcnadilll: lSI'dane) and astemizole ( H i~manal) (Fig. 21-12). AltIIo!IP these o:;ompoonds offered scI'era] IIdvllllluges over thc:d. .· cal uo lihiSlUmines. widespn:1Id usc n:~aled ~ therapeulic limi'ut ion~. I1lO'>t notably the ability to pnxb::r life-'h~lening arrhythmias "'hen used concUtm\lJ) ... drugs thot inhibit their rnctaboli sm. Thi s drug imC11ldIOl! lilt been I1lO'>t evident wi th the imi12 hours) HI amugoois( with linle affinil,. for ~nic. 6efU(OrIergic, or ~nergk reccptoo;. 1be hista-
_
~~ Iyl}-
\11c-
,"",
kin m
w
,-
."
~ptor
affinity of this
COITIpOIInd
Unlike its parem drug. (01)' 5'1> of the lOIal dose of fexofenlldine is metabolir.ed. TlIc. remainder is excreted in II!(' bile 1100 urine; the mean elimination half-life is llbout 14 houl5.lf>. 17
is belie"ed to be
rtI*tI primarily 10 the pic&CllCe of the dip/lcnylmethy lpiperlime moiety. The prolonged action TCsulls from very slow ~ialion from these receptors. II Tht: lack ofanticholincrp:. .nncrgie. or krolOl1ergic IIClioru; appears to be Holed 10 !be ~llCe of the N-phcnylootanol substituent. This IIIbsullltnl also limits distribution of terfenadine 10 the CNS,'" JJ Terfenpdine undergQe!l ~ignifiellnl firsT-pass me.. lIboIisrn, with the predominant nw:o.llIbohte being fuofcna· • . In active metabolite miu ll ing from nltlll)'t group oxi....... When druss that inhibit this tnlI1§fomlluion. such as • lnuduole anlifungals and rIllICrolides. Il/'e used COlI(!urmuly. terfcnadine levels may rise to toxic level s. resulting • potentially fDtal heart rhythm problems. TlIc. observation . . fuofenadine dlspla)'$ antihistalllinic activity companl~ with that of tcrfenadine but is less cardiOlo,lic led to its i!r.e!npmcnt as an alternative to terfenadlne for the relief 0{ ~ symptoms of SCll'iOfIal allergies. J6 Fu()/'C'1Iadine i5 • selective peripheral H I- receptor blocker _like terfenadlne. produces noclinically 5ignificam ami· I.tohnergic effects or ai -adrenergic =pIor blockade al tlmpeutic dolies. No sedative or other e NS effects have )em repol1ed for this dru g. and animal studies indkale that klofenadine does not cross the 888 . In "jtro ~udies also ....-Sllhal unlike terfenadine. fexofenadine does not block jum channels in cafdioc)'te5. Funl!('lltl()I'e. in drug inII'IIClion studies no prolongation of the QTc interval or reIIIIlI bean rftythm abnonnalities .... en: detected when (u okaiine was administcm;l concurrently with erythromycin • i.ttot'ona7.ole. If>. )1 Ihofenadinc: is nlpidly lIbsorbed after oral adminislnl. . peak serum concentr.ll.ions in about 2.5 , ~.~producing • Ftxofenadine is W to 70'1> plasma prot:ein bound.
U.u..al adult doM;e: Oral. 60
Dosage form: Clpsutes
rn, b.l.d.
LontMii M . USP. LoratlKIine. 4-(8< hloro-5,6-(!ihydro] I H-belUO/ 5.6J. " Loruuldine is rapidly absortJed aflcr oral lidm inislrnrion. producing pc-ak plasma levcls in aboul 1.5 hours. Thl\ drug is eXlcnsil'cly IlIClaboliu,d. pnmruily 10 the: descarboclhuxy nlCtaoolite. which retains SOUle Mlihistaminic activity . Both parent drug and melllbohlC have climmation half-lI\'c\ ranging from 8 to 15 hourll. The IlIClaooHle is excreted re:nall y a.~ 11 COl1jugate. U.u~1
oouil dow: 0.-...1. to- 4O niB da,ly
Cetirizine. US,.. Ccliril.ine. 12-14-1(4~hlorophcnyll phenyhncthyIJ-I-pipcrozinyl \ClOOXY\lICClic acid (Zynec). i~ a racemic compound available a, a whitc eryslalline powder that is waleI' sol ublc. CCliri zine is lhe primary acid metabolite of hydroxYline. resulung from compklC oxKlariOfi of lhe primary alcohol lnoicty. Th is compound is 't.WlllcriOIllC and relali l'cly polar and thus does not pcnetnlle the IJOB readi ly. Before its inttoducuon in !he: United Slale.~. ct:lirizinc was 0fJC of the most widely prc'C drugs inhibn lhe rdca.'>C of IculcoItIa (C4. D4. &II and ~lIglandins. In ~Ilro !lhmalle cffCCb' of ncdocronlll OllIy al'\O in.1IIY!: inhibition of uon rdlellcs. Axon refle'l'lI may be prodIm! by brady"m," m the pre located on the basoiatml mc:mbr.lIle, inc:luding hi ~tamine 8goni~m of HI n::ttptrn (cellular), gaslrin activit), al G rettplOt'!i (blood). and 1Ca)'~ choline (ACh) at M l mU!ICannic rc:cepiOB (neuronal ) (fit: 2 1.1 3).
injection....."'taches. and rhinitis. This drug product is for CX'ular admimstration only and DOl for injection or on! use. Keloofen 5OIution should be used with caution during pregnaney or while nursing. since its safety has 001 been stud ied under these circumstaoces,""
HISTAMINE H2 ANTAGONISTS Drugs ....·hose pharmacological action primari ly invoh'c$ antagonism of the action of hi'ilaJlline al ilS H2 ~plors find therapt"ulic applicntion in the U"ealment of acid· peptic disorders rang;n&: from hcal'lbum to pept ic ulcer disease. Zol linger-Ellison syndrome. gllStroeSOphagcaJ reflu disease (GER D). acute stJ'e§S Llkers, and erosions.:IO. 51
P.ptlc Uk ... DI.....D Peptide ulcer disease ( PUD) is a gruup of uptXl' GI In;! disordc:n thai result fmlll 1m.: erosive aclion of acid and pepsin . Duodenal ulccr(DU) and gastric u1cer (GU) pre the nul common fonns.. although PUD may occur in lhe e w . or small inlestine. FactOl"ll involved III lhe pathogenc:si~_
Peptk Add s.cretlon A chamclerislK; fcall.m:: of the IlUImmalian stomach j~ its ability 10 !lCe.cle acid as pan of ils i n~'oI"cmcm in digesting food for absorpIion loter in lhe intestine. The ~ of
"" G lEUio,
~ ~
"
t ,"'.,
" " '. •
'.
~~-----~
co
--.t (Ca:~----------_ '
---
EB
.• • •
--
,-
--------.. ,., /
-- '-- '-"''oN I ~p I---~--" "- / '"
W IK',
. ~
Ell .
·5
GulrIo
,. G
Ell
• --
'\
"""
...
eo,
.....
"'ad oIdonIc
." Ellao,,'. 0tI Fig ure 21 - 13 • Ilo.. nona]
~~1lOn
of clCod secretIOn by Pilnetal cells.
00,0.
1tCUm:nceuf PUD include h)'pel>eCretion of IIdd and pepsin MId 01 mfectlon by Ht'lirobarlt'r pylori. a Gram-negati\'e 5plf31 bacterium. H. pylori h:ls been found in "inuaJly all paticnl5 with DU and appro;dmau~ly 75% of patients with GU. Some mk flC'looo as ....... iated with t'eCUm!1'ICe or PUD Include cigarelle sn)(ll;i ng. chronic use of ulcerogenic drugs le.lI .. nonsteroidal Imi-infl.ls are prodrugs Ihal are rapidly coo"cncd 10 ~ ~ulfcnalnidc '"termedi· ate in the hlahly acKiic envII'Oflrnent of gastnc pariffill tdl!;.. The .....eally basic bcnllmidamle PPls accumulate," !be.< 3(:llIic oompanmcms on the luminal Side of lhe tubu, C5101'noll canalicu lar Structures of the paflctal cells. The bellllmj. dai.ole PPls are chemically ooo"ened by acid to a sulfag. mide intennediatllthat inhibt15 lhe proton pump via CO\alent interaction .... ith rystelllt residues (813 or 822) of thr ptIIqI H • f K • -ATI>a.~ (Fia. 2 I -15 ).~ The IICKi IlIIlLlity of the beaz· lIuidll?ole PJ>ls dictates tltutthcse drugs mu,1 be fonnulaud as delayed-release. tmeOc-coated g.ranular dosIIge forms. The PPIs an: nLOfe crfecll"e in lhe short leon than \be' Hrblockers in healing duodenal ulcers and eros,,·c e.~.a and can heal esophagitis n:mtant to treatment with the H:blockers. H In addition. the benztnndal,oIe PPI ~ h3\"C amiacrobilll oct,vlty against H. II"/ori and thus possess dfKa"} in treating gm.lrie ulcers or wi lh one or moOre antimlcrobioil~ In eradicating infection by Ih i~ org.mism. Four bcnltmMlt101~ PPI~ are cUrTently appro\ ed for m;tr\:etlng III thr: Umkll States (Table 21-3). Ad"ersc effecl profiles of the \:tn(lII PPI , are difficult to compare becaure Il.'(tensi,·e use III pallents. The PPls are elnllmoted olmosl coti l'd y by rapid n~ 11'>ffi to inactive or less active metabolltcs (Fig. 21.161" Vinuall)' 00 unchanged drug ,s ucretcd In the unlit ... feI ~ contai n a chiml sul fur . . that forms un cnantiomeric pai r Ihat is stable and insolulJlr under standard conditiom. The S isomer of QOl('prnok III slightly greater PPI acti vity. and il5 imnnsic clemntt. appro_imate]y 3 IH~ lower than that of R 0II1qIrlIl0IeU' versus 43 ,",Um in). 1be loweT deamnce or ~ is rel oted to slower metabolic c leam ncc by the cyp 2C1~ isozyme. Although R·oIDCpr1I7.ole is primarily tnmsf«a!l to the 5·hydro_y meillbolitc. the S isomer is metaboIlltd" O-demelhylation and w lro:u dation. .... hich conuibu~ to intrinsic clcarano:e. Usual lIduh do/;e: Eros,~e
Omeprnzole j, approved for the treatment and redUCI;Ofl of nsk ofrecum:nccof duodenal uker. GERD. gD5ttie uker, and pathological hyper (T ..... ), A~l ute bloovailabili ty for • 2().1IC orol tablet of mbcprnzolc (vel"'us IV admUli~lrJlion ) 15" pro~ imalcly 52~. The plasma ha lf-life ofrnbeprawk r1n&t' from I 102 hours. l1Ic effects of food on the absorptlOllll rnbepBZOlc Iia\'e not !:Ieen C\QluaIM . Rabeprarolc is 96..J'f bound to humall plasma protci llS. Rabcpr.u.ole IS e~lC1lSivd}' mclaboli;£ed ill the liver. The thll)etiler alld sulfooe are pri mary metabolites mea.~ured in human pl".~ma resultilll from CY P 3A OXidaTion. Additionally. desmethyl Tabq:rawk is formed via the actlOli of CYP 2C 19. Appnuillllldy 90% of tbe drug is eliminated In the urine. primarily .. tbtoether carboxylic acid and ns glucuronide and 11le1'tlIj)IIn acid metabolites. The remai nder of The dose I~ reco"cmj ill the feces. Total rorovery of radioactil'ity w,,' 99.SIi. M unctlanged rnbepralole WIIS ~\'e«:d in tbe unne or r('('Q.
w
Ui-IW "ult 00..:, Oral. 20 "'I once dad) (duodenal aim 1or4 ..."ttlu;~ CMI"e or Ukel1llh'c GERO for4- 8 "'ccll); ~ hYI"'r.;c-
"~~
""
I [""CHI». lHA I~ ,I ""I
!1• • 81010..-.l Y 2210 31)
OR
The producllabcling Slale~ Ih:1I Inc simull:meous IIdrnini ~ nllon of sUoCralftlle rna)' mluce the bioa~Dilal>ili' y of cCrlain .nlS (t.g,. letr:loC)cill1e. pkn)'toin. dlj!oJlin. or clI1lCudinc). 11 funhef- n:commcrKls reslOl'"Jlion of bioavwlabi lily by !it'paIJUn& adnHnj~U1l1iOll of these agems from lh:1I of sucralfalc by 2 hours. Presulllllbly. sUC'l1Ilfule blllds these agents in the G! lr:t\-1 . The I00I\1 frequently ft'portl'd adverse I'l'at'lioo 10 ~ucr.al hie I~ conSllpauon (2.2'1). Antacids may be pn'.'\Cribcd as -.led bul shoold 1M)! be la~cn "" dun one-balf hoor before
OIlfitr wcnMale. I).ual oouh 00...,: Orut. I I II "d. on an empty mlln:..:h IA, ... form ,_, ~lIC11I l r.(C ubkb
PROSTAGlANDINS
n.: pmoilDglandms an: endogenous 2(k,aroon
un-aluralcd filly lI(:ids bios)'nllw:ucatly dc:ri~ct! from arachidonic lICit!. TW!.e booactJ\c su~llIl~ and their synthetic dcn~an\l~~ 111\( been of ronsidc:fl1ble ~~an;h and de~eJopment inlc:re>t • potential therapeutic agents bc:~ause ..f their wide_prcoo ~~ical and plwmaoologlCal actions on the cardiovas· • ~}.tem, G l smooth muscle, the ~protIucti\'e sy~lem. • I\tl'VOUS ~}stcm. platckts. kidney, the c)e, elc.ft! I'rosID' (llD:hns of the E. F. and I sene~ are round in Slgnifieanl roIICI:ntrauons throughout the Gl tmel . 11le GI :Ietions of _ prostaglandins include inlllbiuon of b;asal and '\Iullulaled JNfIC acid and pt"p!oin ...... ,etion In addJlH)f1 to pol!lention d.ukcrogen or ImlanHnducctl gro'~ l!lucO\UI ie.ions uf Ihe --..:h and in,\:Stllle (temll.'d n·UJllrolf"(y•• 01, 1&12. Nn. VorL. ~.y.n.c. 1978. p. I" I~ . ..... " ••• D T · Itnliallt, p'" In lIu..... A led.l, ,,~.RII Che"""'y. 11\1 cd. N .... Yms. Dnli II .. W:3'. 1....,12 1 !).nat. G J. o-I~". C II~ '" M I'· J Med Oitm 18 1 91~
p.....,.,,,
,n
I C..,. A f · Tk S"'"" 1'-. McdlII. 1954
11le heterocycle componcnl of Ih ,\ grl1C'ral stroclllre is ~ CQf1llllonly D 4-nlOllO>lIbstilulrd irnid:llole or bI01SOSI· me eq uiva lcnt , Chai ns A and 11 can be of va rious SI/UC\tJ res .... lengths. and there j, also wide 1:1111001: in !he $truc11l1'1l1 .renll'tlls ror lhe polar );l'OlIp. II nlogen:ued phenyl. C)"doalkyl. and hclCfQal)"1 ~lruCIUrcs ate IIsually found for till: lipophilic iI'IOiNy (Fig. 2 1- 19). Thioper,unidc wa.~ lhe pot!'n( II , amagon,,' (0 be ~hed. This agen! enhlloccs arousal and/or ~ igl lnm pat. ICIlISIn ado!.c-dependent fllShlon in amma]~. suggesting posIi>k IISC o r CNS·lW:ti ng Ii) 3ntllgoni)ls 1n u'Cllling ~Iccp dis· onlc:rs Ch3l1lCICrizcd by cxcc~~jvc tloYlimc ~IL-cp, sud1 as un:otepliy. Other II ,·anl:lgooi q struclU res are silo\\. n be lo ...... .lltluding lhe: n:lIl1r.d product verong3nll nc, isolaled fron, a Ita sponge.
9OS--9Oi.
.,.1Il>,
l!I. """"Y." k W .. -.F C.....,., . J. A 0 , J It"", I'IIY'i! 'H~I. 1956:lh Sclla)",. k W 8""'ne". of h..u:.""" In ROC ... " S.h ... M Icd.). 1l_lhoUI. 01 ""pon-.I ~J. rot 11112. New Yorl. Spnafcr.V...... 1971. p. 109 21. \\. mUi>U .. Rccep....., 1II. I IH.Jl bJl,lll'T.!. "', T..... M I"".. Todoy 21_211-1 1. 1'192. oIl. ~kT",,"". D. _ M Orup .lIIn.~800. L9f19 "9. Man.n. U~ aad lloo-. Il Itn.........'ocIf"""""".21:71O 111. 1m. I"kln,;on. M .. ...... Bun .... ME.: N. 1'....., J Mtd. )D 1612- 1680.
S YotIc. plO ........ 197). S;PI'Y. H W J.\MA 2»2l92. 19IJ ~. J H ~ ..... diO01flC dueed. All havc the common morphine
nloe
morphine. "hldl al..o ~ born obtained surv;"ed as II good analgesiC and cough dcpress.:lnl.
Cba plf r 22 •
""" , ,'"
TABLE 22- 1
Synthetic Oa rlv . llves of Morphine
N.I"..
R
R'
.' ,.,. I
H
s.om. ..........
MM;...,.." 10".". ,
c,.tt.
1-1
" •• 11*'.
0ilI1PII .... .......,
-US)
,,"" ,.
...
~p
~"'
~"y.
11,\. a
.. cllij!Ul , }old.
DI
........ ....".'
-~ "'dlpu-
--"
.... I0" ~
--
"...... 000 ..1
00) •••••
01.
00
'by Il!t,o),," .....
'''' 10m.
~
but
• lia-
pre· text,
01,"'"' .........
s.m. .. 01 •
..
._--
..,...o
2C_
"
cuLe.
""' ""p,
2C
pdId
ilaot
""'"
..,. .;
C/Io:r'Opl_
1-1
....... In
--. ".,. ...n. ......
"I"C
"'"
~.
,=
.",""0' ., ~
",'"
~hcr
o~ycOodlJnc,.
M ORPHINE M OD IFICATIONS INITIATED BY TH E RESEARCH O f SM A LL A ND EDDY
01,
"
it ob,iously is closely related 10
,c
"';.alg'", \POI obI.od on
SIble. il might be: pos.~ible to find other synl hetic rnoh"cules ~hhout ctli~ unde~ir~ble propeny. Pr0ceeding on these aSsumptions. these wortcrs first exnm .. Jed lhe morphine: molecule exhaustively. A~ a staning poim , morplunc: offered lhe advantages of ready availabiht)', pro~'en po!cncy, and ease of alter:uioo. In addition to its addlClIve lendency, they hoped Ihal other lIabllilies (e.g .. resptllltOl')' depression. emcllc propcnlcs. and glL'itromtc\ti nlll llllct .tInd circu lalOf)' di5t urbance~) cou ld be minimil.ed or abolished as well. Because: early modificlitiolls of morphmc (e.g .. acetylation or alky lauon of hydro;o;yts ~nd qu:ucnlll1llion of the: nitrogen ) caused vanations In the addICtive p0tency, they felt that the physiological errects of morphine could be relaled, at leas! In pan, 10 lhe peripheral groops. It ..... as nOl known if the acllonsofmorplllllC "'ere primarily H fuoclion of the peripheral groups or of the slnictural skele too . Thi~ did not mailer. however. because nHldificatioo of the: group" ..... ould alter activity III either case. ~ gt'OUp!o and lhe dT«lS on acU\ Ily by modifyin, !hem an: IiSlcd In T able 22-2.. 'The results of these and earher studies· ha\'C not always shown the: df«lS of simple modifications IHl the analgesiC action of morphme quantitatively, but they do indicate the direction in which the activity i~ l i ~ely 10 go. The slUdic.~ are far ll101'e comprehensive thall Table 22-2 indicates. and \he conclusions usually depend on more than Ollt p.11r of compounds. Unfonunatc:ly . lhese: sIudICS on mor· piu ne did not eliminate the addictIOn potential from lhese compounds, In fact, the studies suggested that any moolfiQl uon thai iocreascd thoc analgesic activit y caused II concomi tanl increase: ill addictioll liubility. The second pltase: of the: st udics' dealt with 11M: attempted syntIM:sis of substances ..... ith central ~oti C and. especially. analgesic action. The mOfplunc molecule rorual1\s certam wel1-dur,,' Re l"tionships in th4' Morphine MoletOo1! 1000jffOpI_) -CH =-=CH - - - CH,Ct-t.-!dnyooomolplvw)
-CH=CH---Oi,Cl-i.-{codl .. 10 ~oc:O(a "leJ
, ,./CH, /N-CH. /N, ()CH,
01»0. og 01 nIIrogeti tong (morphmev..l
"" "'" ". """
600 (o.n.,do .. ' .............. c:totI)'d'o no,..._ o.
390 CDoI¥:troc'X'E
let..,. dtryIlt,> ,."..,.,..
looo iDf¥Ioornoophooevs.
OoIIro,d ·?'l J (at jlOUlOI1 611 ~OIUjA" ",)
Mar1o.ed dllctea)ll
S30"
1'1 ~
2SO (Clto)(o,,'Uj)5"W"oOtle "" (IIIyOlupi ... ",1
'"
(DII'I)O( ..
',.O.....
~0d0'lit)
33 [1:lIt!yQ .. ,opi •• ""
5-~olopi.",)
.90 {(lh,.oo.; k'\il ity. In addi"OI'I. these compounds coun teracted the efftd~ morphillC und oIher morphine- like analgesics and an: d. kno.... n as nm'{'(/fic amll.~on;,U. The I'CI'C"1'Sa1 of IIrthil) if ~ase~ from elh)'l. to propyl. to allyl ..... uh the e)'cloprOjijI mClhyl usually being ma~ i l11111. Thi ~ propen) was tlUe" on ly for motphlllC buL also for {)(her .nalgcsic~. N-AII)'lrIornlOl'ptnne (nalOfptnne:) ... a~ the first of the~ bur bel: of side etTl'Cts wa., t:r.~en off the R1:r.rk el. Le ~aIlOf]lh:ul. tk CQlTCSpondllll! allyl analogue or 1c,·orphanol. ruLiooOlie I\allylnoroxymorpbonel. :r.nd nallrexone: (N-cyckJj'up)1 oxymorphonc) nrc too lhn:e narcot ic antagonbts 1\0\1 on tilmarket. Naloxone and nal lrcxOOC' appear 10 be purt"~ nr"'~ with no morphllle- or nakKphllle- lr~e effects. Tk)' block rhe effccts or otoor antagonists. These drug~ an: to pl'Clent, dlillmbh. or abo!r\1! many o f the IICtlOlb side effcas encountered .... lIh the LI:u'OOlIC analgesics. of thc!ic ~rc respirnlory and eLrculmory dcpres"OfI. at " ' . nausea. drow~illCss. anaJge,\ia. and hyperg lycemoa. The). !houghl ro act by cOOlpetlng With the analge>.re ~~ for attachmcnt at liS. or a closely related. receptor s.rl~ TIt OOscrnlion thai SOIne: nareotlC ant.agorllSlS thai lad IIIrX lion liabil ity :11\. also ~trong IInalgesK-~ spuiTC..:! ~~
(J.
,
,mae."l In them. » lhc N-cyclopropylmelhyJ compounds mentioned are.he nl(K1 pmen! aJ1lagoni51~ btH appear 10 pr0duce psychotomimetIC effecls lind may IIOl be useful as anal~ One of these, bu~lKJIllhll1c. has shown In InterestInll ~tudy profile. howe'cr, and tm.~ been inlrod~ in Europe and in the U",I~ Slates as II potent anall!:~."" II IS being InirudOttd as a U'ealmcnl for Ml'C(J(ic addicts '" • IO\ICI tn:auncnt program. Omce Based Opioid Treatment \080'1). provided by private physicians rather than formal In'.lIncnl chnics.1>l 0Iher efforts have been under ""lI)' 10 develop narrol K: OWIugonhts Ihal call be used to trcal narcotic addiction."" The cootinuQ\ls admiolstMion of an antagonist will block
• • •
•
,•
,
been qucstioned.7'1 Additional ~t udi C5 ind ll'at e that deall.:)'l· ation does OC(:ur in the br.lin. although il.'i ellOCt role is rKlI clear.'" It is clea... from the N-aralkyl ckl'iVIUVes di~ssN above. that a small group is IIQI neCu\sion ~ho"'s thaI several exceplions 10 rencrallJAlliolls e~ l"c in the SlnJCIUres of compounds !ul'e been sy ntht$il,ed in the past 5CI'eral yeal'1l. Eddy» d~'iCUS5Cd the IIll>1'l: ,ignificant exceptions. Relative co It fll'Sl feature mentioned. e~tensile studies of the action .... " ... I"';lIIe have sho..... n thaI it ~~ analgesic acti vtIuI approllimates that of morphine. In humans. it is about founh a~ !!Ctive as morphine ",hen tldministert.'d intray. but il .... as shghtly ItlpeOor to morphine ",hen III i~ lDtl'llCiSlt'mall{.- On the has's of the IaSI-mencffect, Beckeu ct al. ' poslulated th~t N-deall.:ylation I51CJl in the ~hanis.m of ItIIalgesic action. This has
-:::,brl
O,N
Diampromide: (III) and 'IS related anili~ ha"e potencies thai ~ comparable ",ith those of morphllle;" they hal'e sho"n addiction liabilit y. however. and ha ve no! aPPC;lfl!d on the marleet. The closely relatcd cyclIC dmvati~e fentanyl (Table 22-3, A- I7) is used in wrgery. The bc:nzimidalo!es. such as etonita7.e1lC (IV). are very potent analge~icl< 001 show the highest addIction liabilities yel enoountered.lll, IJ Po&ibly an uception 10 fealure 3. and tbe only oroe that has been enooumered. may be tbe cydohc~yl analogue of A-6 (Table 22-3). which has significanl activity. &Idy" mentions IWO possible uceptions 10 femure " in ;I(lJ1l1Oll to fentanyl . The many sludies on moleculcs of varying type, that possess analgesic octivity revcaled thm octi,ily was a.~wciatcd not only ",ith cenain struclUral realWl'~ but liso ",ith the siu and the shapeofthe molecule. The hypothesi~ of Beckett and Cnsy"" has dominated thinking fo, K: cenlcr. allow -
i"- .-an lief Waals bondmllO. n;O surface on 1[1(' IC:CCptol' " Ie to ",Inforce
J . A sIluai>ty •
tne _'" bond
f'OSn~
Ihrcc.-Ui""'n~ional
the f1a1 aroman!:
pis. Fundamental 10 the,r proposal WlI,~ thai slICh a n.'cep'or was eSsenti1.lIy inl1 ex ible LInd that 1. loc k-and- keytype situatioo existed. S ubsequcml y, the unnaturnl ( + ). I00I'ptune ...'as symhc!iizai and shown to be inactive.'? Although the f~going lIy~is appeared to fil the facts qUIte well and was a useful hypothesis for 5e\"(.'rnl years. it IIOW appears thut certain anoma lies ex ist that canrlOt be accom modated by it. For C1;a mple. tile more IlCti ve enami orner of tr-metlllldol is rIOt relined oonfigur~tionall y to (R}alamne. in COIllnSt with the methadone and Ihiambutenc !;C'rleJ;. This i~ alS() lrue for the earbelhox y analoguc of methadone (V) and for d,ampromide (III) and its nnalogucs. AnOIher factor that was implicIt in COfI~idering a proper receptor fi l for the motpItlnc molecule and lIS congeners WIIS Ihal the phen)'1 rinS allhc 4 position oflhe piperid ine moiety shoold be III the ax ial orientation for muimum acli,·uy. llIe fael that suucture VI hal; only an equalorial phen)'1 group. ),et possesses acu vity equal to tlllli of morphinc ..... oold seem to ca.'1 doubt on tllc necessity for nllial oricntation n.~ 11 receptorfit requirement .
Q Forx:.
'
2Hs
C
0
H
H
OH (-
Pkw~"h.~.
Figure 22 - 1 • Dlagrdm of the surface of the analQi'5IC rKfIIo tor !ilte WIth !he COilesponci'ng Iowef !>UrfdCe of the drug rule The Ulri!'NI,rTll'flSIOIlal fe.aturf'S of !he molecule /lie VIOWl by the bonds. - . - - -. and - -. wtnch represent III front rI, berllnd, and III the plane 01 the paper. r~trvely (from Go,r. ley. 0 R. H Prog Drug Res 736. 1964 ]
the hypothesiS cnn be applied to the IllCthaOOl iUlOIll.Ily I illustr:ucd in Figure 22-2. After considering acti,ity changes in .ariOllS stru!ubihty in water. compared wllh the ~ul. fate. thi ~ saIl 1\ u,Cularly. 01' inlravcnow;ly at 3- to 6·hour i~ wi th a ma.~imal dally dose of 160 mg.
to.
Oxycodone Hydrochloride. Oxycodonc hY ••~';.: ride. d;hydrohydro~ycOOeinooe h)·drochloride. i~ pr by the elllltlYlic redue.ion of hydroxycodcmone pt't'p.1Il'd hydroscn peroxide: (in acetic acid) oxidation of tloc! ThIs derivative of morphine OC'CUTll u a ... lUte powder (hat is soluble in .... ater ( I : 10) or alcohol solutions nlay be s lcrili7.l'~y'
\ poIeu!
e \0 no >ic than IagOfli~1
~ nalo~·
u..... as
II
III "'Pier
)dobu1cavage :Juration iabllity. !ne, TIle ;of1\rol~.
1'Illon or onunua· al ~ij!n~,
k 10 th~1 It higher ulld bu lion. lind , caut loll ",.
....,
;hlJlCry.
120 mp I1COOsly. ntervlll~.
droch loJll'l!parcd
pored by thebaine. l'sUlllill(' Aqueou~
this drug II i, "!)Id products
Nom!tHphil'H!!. Normorphlllc may be prepared by N-deIIleIhylalion or IllOrphirlC. ,2 I n h.uman~. by nonllal routes of adnllPI'\tr;lhon. it is about one fourth liS :lethe liS morphine in producing IInalge.~ia btH hIlS II much lower physical !lepenikll(e capacity. Its lmulgesic e/Teets are nearly equal by the lIIlr1I>'('nlricu lllr 11)1.11Or_ phine and codeine. but it sho .... s lillIe tendency toward hyp_i$. II h indie-ated fOf" the ...,Iief of pain in 1nO:!;' p:.uent~ for .. nom morphine and OIhcr alkalotds of ClpLum genemlly are used. btu u IS especially ,·aluable ... hen lhc pain is due to sJXlStic conditions of inld;line. uterus, bladder. bronchi. und loO (011. It~ mosl important U''e 10 .. far the lrCalmenl of myocardial inr:on:tioo or other caninK ~ krm. Other ad~·erse effects include a high ,nc.dence ofoela· tion and, le:ss frequently. nausea.. headacbc, vc.-n,co. and W:. l,ines$.'·1 It 15 available as ~ parentc.-raJ for intramuscular and II\U"aI'rnous adminiS\fIlliOn in II dose of I or 2 mg e>el) 3 til 4 hours. with II nlll.\imal single dose: of 4 mg. It is al-.o DvailJblt as a na5ll1 sprny (Stadol NS ).
""pi".
8uprenorphine Hydrot,nllu.ocinc: in a p;an'l1u.'ml do'-C of 30 mg or an or,,1 do:se of SO mg is about as effective us 10 mg of morphine in most pa! ienL~. There is some e~idcncc Ihal th-c :lI1nlgesic IIClioo tl'\ides princip;aU} in th-c (-) i'o()tllI.'r. and a dose of 25 m~ IS ilpprOx unalcly equi,·nlem 10 10 mg o r morphinc: sulf~tc. Orcasionnlty. doo;etof 40 to 60 mg may be rm1nred PentalI)Qne'~ plasnl:l half-life IS about 3.5 hours.. tO Allhe 10000·CI'" dosage levels, it appem; to be .....elltolerated. although JOmC tabllon occu~ In about one third of pel"!KJrl~ re«i~mg it_ The incidence of other IllOI"phlllc-lilc side effects is as high a with morphine lind OIher narcotic Wlalge by Ii II-anunobcnwie ac id is ustd. The derivati,'cs of salicylic acid are of two types II :lnll II (a and b) I:
, "'-
In wlulion. IXlrticularly 111 thoc prclicllCe of sodiu m bitar· bonulC. Ihe salt will dnrkcn on standing (Ioee sa licylic acid). Thi~ d ..u1..emng may be Icssetw:d by the lI4klilion of sodi um sulfite or '\Odium blsulfile. Also. use of recently boiled dis· lilIed "'altl' and dif,pC'flSing m amm-CQ1orcd bOllks Ies~ color change. Sodium &alicylale forms ~ eutectic mixture "'lib unllpyrine and produces a " iokl color.t tion with iron or lIS ..alcs. Solulion~ of the compound mu'" be neut ....11 or ~ Ii ghtly basic 10 prellcnt pl"l.>.::Ills. erefernbly . df) dosage forms (i.e .. tablets. capsuIc!.. po.nlers) should be used. ~inc\' asplnn " some .. hat '".''': in aquC()U~ medill. In tablet prepanl1ions. the use a(':» washed Ulk impm\'CS the ~tabi lity ofaspinn.n" AI~ .... has been found 10 break do .... n in the pre"C.'OC\' ofphrn)'~ rine hydrochloride:. llIU A.pirin in IIqlleou~ medl3 .. ill .,
, ,•
!
almo1ng spondylrllS in a ISO- to ~ dose. twice datly. "7. r'M II i< avaIlable as tablcts (ISO . . 200 Illg).
Tolmetin Sodium, USP. ToImctin sodium. I -~~ S-(p-toluoyl)pyrrole-2-acetale dlh) dralt sodium. McN·B9I (Toleclin). is an arylacetic acid derivative wnh a pynolt .. the: aryl group. This drug is absorbed rapidly ..... ith Ilfllth'ely 'han plasma halr-Irfe ( I hour). I, i~ rt'CQmlllC'ndtd ' " u>e in the: managemc:nt of IICUtc: ano.I chromc RA. It Wm similar. bulles$ frequent. ad'erse effects .... rlh a~pinn. 1tdDI:J oot potentrole coomarin·1 il.:e drug~ nor altcr tile blood !em. of su ](on ylureas or insulin. Like OIller drugS in thi~ it inhibits prtJl:ilaglandin synthetase and Jowen J'GE levels.
c_
OR,
"
>-~4CH'COO "'. 1
CH, TotmcI.. fur ....·.:
R, -Cl-t 3 R._H R, - a R. - CI-t.
Available as tahlelS (200 and 600 mg l and a capsulel mg). a drn.c: of 400 mg 3 limes daily . with a mallmUlllrl 2.000 mg. is recommended. Cl inical trial s indicate I daily dose or 1.200 mg IS COIn(XIr:lble 10 relref 10 19 I' aspinn and ISO Illg or indomethacin per day.I'"
Ibuprofen, USP. lbuprorcn. 2-{4-isobul) lphenyl~ onic add (MOIrin. Ad"i!. N oprin ). '" a.< introdu.:ed rnrodili-
• cal pncllce follow Ill! Ulen~I'C clinical lnilis. IIllppears to be rompaf"~blc 10 a.~pirin In the treatment of RA ..... llh 11 10....·a" llIo.:M.lcncc: of ~1(Jc: effCCb. lIll It has abo been appro"ed f(M" uoc in PD.
~, ./CHCH, CH,
-0-
R 1 CHCO~ H
lbJpIoIen R. CH 3
In Ihi~ serkll uf l'UTllpoonds. poIeocy wa~ cnhaocoo by irnrodUCIion of the a-methyl group on the aceuc acid moicty. 1k pn'('UJ":\OI" lbufcnac (R = II ). wluch WIlS abandoned (1'/11"1 to hepatOlo~lcity. WIlS less potent. Mo«o,er, the 111;DI'II) ~Idc!; In the.> (SH +) isomer. IlOl on ly In ibuprofen Iu throughoollhe lU)1occtie acid series.. Funhermor\", lhese IWlIllCl . an' lhe more potenl inhibll00i of IJ'I"Of'laglandin syn1Iicwc. IOI The recommended dos.age i~ 400 mi. Ibuprofen II aOO '"'ailable o.er-ll!eo(.'OOnter IlS 2(X).mg IIlblels. Napro~en.
(+ ~mel hoxy-a-mcthyl acid (Anaprox. Naprosyn). oceol"" as ,,1Iill:" 10 off-lI·hi lc cry~l al' lhal an: ~paringl)' sol ubl e in acidic ). A ~Iead)'-"-Dlc blood k-el is usua ll) IIChle,ed afler fOOT 10 fil'e dose~. Nilproxen 110 ,~ hl",ly !'fOIcm bound lUld d isplaces most !'fOIdnbotIrIddrul-t. ~ oflhese mUSI be adjusted lICConlingly.
~ CH,OA./ ",r
CH,
COO
0-0,
lbufenac R _ H
~)Cell. U5P. ~'JI3rhlh~lcncacelic
gastrointestinal bleeding. ulce". dyspcp;.ia. naU'i('a, ,lceplness. and dil.lioe~s reponed hI a lowcr incidence than wilh aspirin. II inhIbits ~Iagland," ~)·nll!elase. =
CH, COOH
~arroxen
is n.~ommcndcd for U.'iC in rhcunlUloi d and Ulyanhrili,. II ~how~ good analgesic oclivi l)'-400 I1 lg romp;!mbk 10 7~ 10 150 mg of 01"".1] mependinc and ~upe· 10 65 mg of propoxyphene and 32S IlIg of aspirin plus III; of codelnc. A 220- 10 3JO..mg dose I~ CQfIlp;ullblt 10 mg of aspirin alone. II reportedly product'~ di7.1joc~s. "ness. and nause:!. ..... ilh infrequent mennon ofgaslroil1UlIC1 Imllllioll. lil.:e aspi ri n. il inhlbil' pro:slllgiandin -.e and prolongs blood-clotting time. II i~ IlOl n:.:omfor pregnalll ()I" ]octalmg wOll~n or children under 1>1 It IS .1'10 a\lulablc O"er-Ihc-coumer as 200-mg lablCl. ,lJtle ).
Fcnoprofcn calci um . q. 'all.n d 5·pyrnl.Olune. Some cun be relaled 10 J.5· pynuolidinal~
( ) C'N-H ( 'N-H I I I H H H pY"'~
' M o W
Pyrazon
I2N-H
I
H
Pyr"""."'..v. o
~-H OAN~ N I H
Ludwig Knorr. a pupil of Emi l Fi~her .... htk scam....: for antipyrellcs of the quinolllle type, in 188·40 dLIro', Ui4 the '·pym7.olorte now koo .... n as mrlipyrint!. Tht S di!;(Olel)' initiated the beginnings of the great German drug ulllulll)' ttuu domi nated the field for about 40 yC3J!i. KIlOIT. all al firsl mistakenly bclie~ing Ihat he lIad a quioohllNyp' OOflrpound. soon recOgnl1.ed IIt< crT\)!". and the coo,.. I .... as mlctpreted correctly as a pyra1.olone. Witlun 2 len t/1o(' arntlg~ic propc'nlcs of thiS compound became: when fnl'OnIble rcpor1s began 10 appe3T in the hlet", particularly wi th refcrence: 10 liS use til headaches and n.:rnIgi:as. Since then. it lias rt:tuined some o f ils populartt~ II_ an alge~ic, nhtlougll it~ uw as UII antipyretic lias dccliid steadi ly. Sioct! its introduction inlo mcdicine. lhere In been more tllan 1.000 compollnds made in an efTon 10" others .... ilh more potent atlalge~ic action combined to.'(ici t)'. Many modificallons of the: basic COOIpOIInd been made. The few denl'lttt,-es :and modificallQllil marlet:art: listed in Tables 22·8 and 22·9. !'hen)1 alr hougll aMlgesic ibC"lf, wll.~ origmallydc:'·clopc:du . ... bilizC1' for IBe insoluble am illQpyonc. II is now belli( for tBe relief of many form~ of llrlhrili s. in .. hich;'d it 111 0;0 relIuces s.... elling and ~pa!i11l by an anti·tnnam~ IICtion .
"',m
01"
1:201.
'AILE 22--8
Derivatives of 5·P')',.azol.
,,!Uco~
~~
00')'-
iphcr;elani "Cfore, l'l'Cog-
,,"''i " " ."'. R E>C ••• I...... 2002 . 7, A.........,." Phar~;':"1 Auoc;,n...: Achie"n, ()pI."....1 11",. II"'''' I", OuIComeo. ".m NonpR->llCOOl>On IIowd.O'.....
...
..... 01 COOI_,"",'''. 1 04~ ~ koct.C C,andCloe~, K. K . f'N. ""'" S20I. lIMo ~ 1 5«a. C. C~ _ 0 - . 110 110 J Pi Up. Thor 17J>3. 1.l. V • lAMA 188'1 12. 1%4 62 Fra.... It F. and ROlWnbe", D. E..: I. I'harrnxol up. Thor. 1.3 DtKomf~1d.
T , I . II1II 1\:..... I W 1. _ _
&p . ....... 1.... 11. 19boI f>.I IkMIo. R W 8 •. I. 0 ... "'""""""'- 7:297. 1m. U Ham .. O. 5 .. ft 01. l>noJ Ak:ohoIOfpmd. 6 1 1lS. :!IXXI. M.n;~ .
W R. Ph>nnorol
R~ .
19463. 1967. 61. lulou>,D.. """ R.... "I'. I', lbp< ... L: .....-.1. pg, .. $c .... 122. 1914 81"'''''''1. It ...... Do),,,,,. It II In K"""";" ... II .. V,llJrKaJ. J ,,_ I""'). """"" IIJIII.1oo1 '*"""'- od*lt L 0 ~""""''''' .... Allied.,.,.,. T _ U""m.~y "" T.,..,." """'" 19';1. II .. IIIIdA'!oil. I> M ""luu'""_A&nt"-'oI. 1 ·'C Soct.17
1'00........,.
'n
s........
1",.m;olicln;aJ F.JIC)"droxyprogcsterooe can be produced directly from progoteronc. although this is not a majorpalhv;ay in humans. Sequential action or2l-hydro~ · ) lone (Cyp21 J and I I ,8-hydro~ )'Iase (Cyp [ [ 8 [ I provide hydroo:.:onisone .. the key glucoooniooid in humans. If PfOiIeSlcrooe is directly acted on by 2 1 - h)dro~)lase (Cyp21) .. ll-deo.xyron icostcronc: IS produced. a precursor to lhe mincTlllocortiroid aldosterone. In tiSSUe!> v; here aldosTerolle is ,)·mhesized. the mullifunctional enz)'nlC aldosterone \ynthaloC (Cypl 182) nlCdiHlc~ (he hydroxylation at Cil as well ~ the two-stcp o~ idation ofC I8to an aldehyde. prol id· mg aldo!;Terone. v;hich exi~T ~ prcdonnnantly in the c)'clk hcml~lal form.
CHEMICAL AND PHYSICAL PROPERTIES OF STEROIDS With fev; exceptions. the S1eroilb lire white crystalline solids. 1"hey may be in the fonn of needles .. leaflets .. pl3ldeTs .. or amorphous panicles .. dependini o n the paniculllI compound. the so lvent u-cd In crysllllli1J1tion, and the skill and luck of the C'hc m i~l . As the steroids hale 17 or morecurbon lIcoms. it is not \urpri ~i ng th31 lhocy lend to be waler inso luble. Addition of h)'drox)'l or OIher pollir groups (or decreasing C'lU'bons) lIIereases wllter solubility slightly. lIS expected. Salts are the most watcr soluble. Ex amplCli ~re soov;n in T ab le 23- 1.
CHANGES TO MODIFY PHARMACOKINETIC PROPERTIES OF STEROIDS As v; Ith many OIher compounds tkscribed In PR'vious chapters. the STeroids can be made more lipid I1'().
oaII
It)'dtu.;.;JrJ._
lI)olroo;~1 In the nl"tar..,,:~ IlonIM"1C =qliu, ~omrlc ~c- ""I'I ,,-, dm"""; 1hr dlll.."t lUll' "II"", a"·.,, to bnllI IIdlf ,Ue,. 1l\t, nUdC'·ray ery~tal ,ttoctun:) of the 'teroid honnorlC!; them·
'*'
,
~1I:roids
The prog,,-,tCI'QI)e rec:epto,· can 01..0 be found III t .... o fIer. one regu b le lhe hypolhalnmu~ ant.llhc: amerior jlIlUItar}'" a rC('dback inhibillOO proce" thai decreases GnR II. Ul._ FS. I pnxiuchon. The resuh 1\ 1M, funher OVUlal1(lf1 is ~ Ilcll. As described below in 1111' ehnpter. ,his is the pn~ n1CCh:uti~m by IIhleh sterood birth conn'Ol prodUCtS InI'ubot
,0
They arc clilled gonadOll1l1';1IS because of their acti()ll~ on the gonads. As ~hown in Figure~ 23·9 through 23·" . lhey con trol ovulation. ~pcrrnatogcnesis. and lIc,clopmcnl of ~~ organs. and Iht:y nlaimain ("Il"egnancy. An addnional pcpll&::. gonadotropin·releasing homlOllC (GnRH). rt'gulales release of 1iH; gOlladoLropin~. Includcll in Ihi, group ;lre the fol· lowing: • ~ln·relca..lnl! honnone (Gn RH) • LUleinl,.ing ho,nll>OO (LIt) • FoIlidc·"lmul~ltnl hormone (FS H) • CbonOOIf; ~ropin rCG; hCC .5 hunWl ~rortn). 3 III)topcpude produced by lhe p:oanla. ll~ pharm:ocologlf;al """,ions an: c.s,;cnlially lhe 0Iart1e ~ lhose of Li t
o,·olalion. If renilll.~lion OOcs nOl occur by aboUI lIay 25. lhe CQ1M lu,cum begins 10 degencrnte, ~k111 inl! (k,wn its producl1orl ct
C.... N The hypothalamu s n:lcase~ Gn RH. a pcplillc 111111 stimulule..~ the anlerior pilllllat)' 10 SC'CR:lc LH and FSH In males and females. TIus pcphde control" and regul:ttC!i boI:h male and rCllmle reproduction (Figs. 23·9 and 23- 10). GnR H b a rllod·
,,'I•,, ,,, ,,, , ,
"-"'"""
,
I
""""
'"
I ......,
Ntleo ...
•
A.• '. ' .... , ____ _LH
=
•
SH
E1I.0(I00I
~
,,,,/
"---.
----- ••••. -
,,
CT'jM
"---. U<
/
TMlO$Ierone
,
~~~I I
OwaclOl.ltCS Figure 23 - 10 • Regul.ltJoo of 5pe(malogeoeSlS. $e)c
1
1 1 4 11
""
21
Figure 23 - 11 • Hofmooe changes In thfo normal
"'"
~. .
·Trp-So!rte at the ~ peptide: .. thm are
ruions between octi"e and In.:ICU'e metabolites.
BIOSYNTHESIS The estrogens arc synthesil.ed by IIle acuon of the enl)'tne atOOlatuse on undlU!>lencdione or testosterone (Fig. 23-,5). T1Iey are normally produced In relall\ely large quan1Hld In the o\'lIries und plucenla. in lower amouOlS in tile . 11:11 glands. and in trace quanlLlics In the: testes. In postmenopau. sal womcn. I1100St estrogens are synlhesi/.cd In ad ipose tissue WId other LlOIlOvarian site~ . About SO to 3.50 ,uglday of CSlnI' diol are prodllCed by the ovanes (t'Spccililly the OOfllUS lu· teum) during tile menMrua l C)'ele. Du ri ng the lirs! months o f pregnancy. tn.e corptJ) luteum produces larger :unoullIs of t'Stradiol and other estrogen~: the ploccOla produces IOOlot of the circulating hormone in laiC pregnancy. During preg . nancy. IIle estrogen blood lenls an: up to 1.000 hl1lC~ higher thlln dunng the mcn~lnml c~cle.
METABOlISM OF ESTROGENS
Thc metabolism of ILlLtural e!\lr08ens has been R:'"icwed
In
17
dct:li l. 1bc Ihree pnm:ll) c.,tmgens In women are 17,8e,lradio !. CSU"OI1C. lind est riol ( 16a.17,8-e!iuiol). Although 17,8-estradiol IS prodoccd III !he greatest Ilmounb. II is quickly o~idi t.cd (~ Fi g. 23-12) \0 estrone. the eslrogen fou nd in highest conccnlnlion III the plasma. &trone. In tum. IS con\,erted 10 estnol, IIle major estrogen found III human urine, by hydro~~I:lIIoo at C I6 (to pro\'ide the 16!lhydmxy1) and rcduclLon of tile CI7 I..etonc (l7.8-h~dro~)'I). E.~t!lldiol can Dbo be direct ly convened to estri ol. In lhe human placenta, the nlOSt abundant estrogen synthesi/.ed is estriol. In both pregnant ond nonprt'gn:lIlt \lomen , howel'ct. lhe thn:c: primary estrogens are al so mctllboli1.ed to ~rnall amounts of other deri\'atin~;s (e.g .. 2· h.)droxycstronc , 2· met ho):~eStrollC. 4-h}droxye~t(onc, and 16P.h)drl))(y- 17,8e5Iradlol). Onl ~ ILbout .50% of thera~ulLcally administered eslrogens (and their variOO5 mct.1boltte~) an: excreled III IIle un ne during tile fi r.>t 24 hours. Thc remainder are excreted into the: bile and reabsorbed: cons.cquently. r;e"('IlI1 days are required for complete ncrct,on of II gl,en dm.e . Conjugation appean; to be ,'cry important in estrogen ttllJlspor! and mctaboll~m. Although the estrogens an: uncon· jug.1lcd in the ovarie~. significant UlllOllnts of conjugated e~trogcns may pn:dominate in the plasma and other 1t!>Sue!-. Most oflhe~)
-0
I
~
oe
A
0 Coume,1rQI
Daldzeln
Genliloin
Figure 2]- 13 • Coo","""
active because the OH-w-OH uj,mllt'.:: j, rnumllli lleu. [n the /hrtQ isomer, OOwc\'cr. there is ~tcrk repul,iorl of the IWO ethyl groups. 11M: 1"0 phenol groups fOlate to relic:,'c the repulsion. !he Q U-Io-OH distance i$ changed. and conse quently. the 11r"" iSOfllCr i ~ inach\'C (Fig. 2)· 1.5). Phytoestrogefls. s.:,'crnl nalu .... 1 plam ,ubslunces Ihal have gl:fleruJ slNClUrul fcalum. SImilar 10 those of DES and eslnldiol also ha,'c estrogenic effectS and h.me b«n lenned phJf~S'1'(,gttU.J'I 'These il'ltludc: genistein, from so}btans
and a spcciC'S of clover; daiul.cm. from soybeans; and coumemol. foum] in cenain
legullle~.
Geni stein and daidtein are
c~amplell
of isonll,ollts. These and OIhcr~ have amifrrum,. acli~il)' In amrnols ..oo Many cl aim s ha\ e been made aOOulllli: bcndici:d c:ffoo~ of coo~umin8 product) ~-OOIIlJnInl! __ _ ph)1oeSlrogelIS. mcluding prI:\enling and lr'C'ahng c;mlio,oI cular di"'Ogen~ is for Inhlbitioo "'()\1Jl~tion.
in combin,ltiOlI " ilh progeslin,. Steroidal bir1h IIItroI agenb CQIIlaining estTOl!cns are d'!lell sscd In the~on dlemical L-ontrna:pllOO laler In Ihl~ chapter.
OH
OH
Treatment of Advanced. Inoperable Breast Cancer In M@n and PostfJl@nopalisal Women and of Advanced, E!.lrogens are Inoperable Prostate Canc@r in Men. uscd to tre"t inopemble !)rea_! callcer in mc n and III postmcnopausal women. but estrogen thempy can ac1Ually 5timulale ellisting breast cancC:1li III prc:mcoopaus.ol wOlllt'n . The tradiol but lOOfe act ive than its metabolite. estriol. As the sa lt of its 3·sulfute ester. estrolle is the primary ingredient in conjugated estrogens, USI'. and e&Ierilied eslrogens, US!'. AhOOugh originallyobtailled from the: urine: of pregnant mares (about 10 mgIL). estrone is now prepared synthetically. P1 P'1!IU'W;o; t£lR()'O ~ SUU'Ant (J-SUI.I ox, ·1:!IT1U_1.J,5i 10)u lIl:",- 17-o"'II I'II't:IlAZINII SA I.Tj, USP. All the estrone 3-sulfale sahs have the obvious pharmacrutical advantage of in . creased water solubiHly and better oml absorption. Acids OOIWffl the salts to the f~ )-sulfale esters and cause some lIydrolysis of the es ter. This does ROt seem to affect aholorplion adversely. but precipitation of the free SUlfate esters in acidic phannoceutical prepamtion~ shou ld be a,·oided. The dibasie piperazine: molecule actS as a buffer. giving it $Olllewhat greater stability. CO!'IJl'GAn:O EnltOtir~..,., US". 1loc term C'lHIju811t~d ~Slro g~ns refers to the mill of sulfate conjugalcs of estrogenic components isolated from prtgnantllWre urine (Prtmarin). These compounds ore also referred to as CEE (conjugated equine estrogens). Conjugated estroge ns contain 50 to 65~ sodium ewone sulf,te und 20 to )5% sodium equ il in sulfate (oosed on the total estrogen cootent ofthc: product). Premarin also conlllins the: sulfate csten o f J7ft'-eStrudiol. J7o-dihydrocqui lin. and l7.8-dih)·droequilin, in addition to other minor componc:nl$. Although most cOl1lmooly ustd in BRT to treDI postmenopausal symptoms. The conjugated estrogens are used for the e ntire range of indk,tions described abo,·c. except binh control. Sv", IInle CONJL"(]ATW f....."T1t()GI;/'is, A. Celll'!itin is a millture of nine estrogenic substances (Fig. 23· 13): sodi um estrone sulfale, sodium equilin sulfate, .sodium equilenin \ ulfate. s0dium 17a-esu adjol ",Ifate. sodium 17,B-csuadiol sulfate. §0dium J7o-dihydroequilin ",Ifate, sodium J7.8-di hydroequi lin sulfate. sodium J7a-dihydroequilenin sulfate, and sodium 17P-dillydroequilenin sulfatc. These estrogenic substanceS lin: synthesized from soy sterols. The term ,yntMlic has been added before conjugated estrogens to indicaTe that
this product is distiBCI from (not equivulent to) the conjllgated estrogcn~ dcri-cd from mare urine:. The "A" fol~· ing the narne indicatell that this is tile finot approved mi~l\IR of ~ynthetic coojugatcd c:.lrogens. Subsequent S)'ntheuc ~ JUllllled esuugc:n prod ucl$ will be named in ordf,r. witlllbe final descript~ " 8 . C, 0 :' elc. Cenc:su n is upproo.ed for the tn'alrnent of moderate-to-SC:"a1: ,asonlOlor symptOllfl lmd vu lv1U' and vagmal acroph y associated with rm'~ t::.,.....uum;u t':~·IMOGl~~S. USI'. Esterified estrogens (Esuaub. Mme5I ) contain some of the same iu lfme conJugates of~· trogcns prescm in conjugated estrogens. but tlx' ralios III these components and the composi tion of millOf oon~nn o f the products differ. 'These products contain 75 10 83 .sodium estrone sulfatc and 6 to l 5'l> .sodium equilin sulfllt, in such proport ion that the total of the.'iC 2 componcnu IS 90% of the total esu:ri fied estrogens ~'()Iltem. The eskrifltd estrogens find tile same u>es as the conjugat ed est~, Estriol, USP. E.~triol. eSTra· I,3,5(IOj-tri ene-3,16n. J7,. triol. is available for compoundmg into a nUlllberof dllfm. formu lations for U'iC in liRT. IT can be u:oed alone or ill combinatioos with e.'tnidlol ( Bi-E\l:) or Ilrant (Fig. 2]-16). T"o
tagonl,t effects of Ihco;c tyJICS of compounds on Ihe ER. dependini on the 5p:cifk tissue. u new tenll wa.~ coillCli; stll"l"/.I·t' t!!/rtJfltll rl'l'tIJlIJr modullllors (SERM~). A SERM i~ a drug that has IIssuC·,pecirlC estrogcnic ocll lil),. AI . though mllny compouOOs exhibit SERM act;'il)'. a few agems are antagoniSl.~ m all "'MIe\. 'T'helic
I
Tamoxi/(in (NoYaIde.,
Zuc:IomIp/lene [CIomtpheoe (CiOOlodJ • • rnilttu .. 04 ............. lUdomtphene and ijldOIllIf)I....J
I~
b~ ~iol
o
l.......N-CH~
h) 1~~tC-
1\0.,.
,b
CH,
HO
o
o d
T()(eI'!lIlena (Fa!IISIOO)
~nt~ : to
,,,.
abuly,
....
HO
~.
~I'
ate.
t.uoIo>;iIene (CP-336 t56 )
wptOf modulators (SERMs) and anllt'Strogens_
TUIlIO"fen ha., ~n c~lcnsi~c usc In trealing pnmary bn:asl callCrr!l thai are ER depcrwknl.:It cancer only in ,",omen al hll!h n~l.:. Women Without
a fumily
hl~tory
of breast cancer or ocher ri5h should nl)!
usc larnoxifen in thi S m:mner. Ralolti fcnc is nllOlher SER/I·1. but us profile of lIt'llv;l), differ; from Ihal of mmoxi fcn. Ra loxifcnc is an ER muagoniSl In both breast and endometrial lIS.'Iue. bul has agonist action 00 bone alld aclS as an e~lTOgen agooist in lowering tOlal ehole~terol WKI low-dcnsily lipoprotein (LOL.), 'The wbtle )trucl\Jr:t1 diffel'!'nces betVl'ttn tnc twO drugs undc:rlie tnc di,tinct aclivity proliles.~) 1lIc agonist llCtion on bone ti !>S~ i, the basis for the usc of thiS drug for Irl'ating osteopo\"Ol;1'.
A ley questlOO is why do COll1pound.~ like tamOllifen and rJloxlfene c~hlbi l amngoolst OCIiOO in somc u~ucs. but ago. ni~1 action In other ti_sues? Major dc"dopments in the pasl ',wl'cars arc beginning 10 pro~idc w an~\\er to thi~ question. 1. .l6. 27. '"' Tamo~ifm,~ raloxlfent. and eSlradlol(1 all billd to the ER at the ~anle 'itc. but their binding Il"lOtlel; arc dlffcl'!'nt. In IIddmoo. cxh Induces a dll cancer ticnt~ receiving adjuvanllumoxifcn Ihcr.. py. It i~ alsodfcclIve in the t. \I ~hou"'J be protected from t. . The major IllC'tilbo!nc of tamoxlfcn I~ N-dc5mc:thYII';';~ fen. VI hieh ll'achCl> k\eb hIgher Ihan tamO.IUIJI ilSelf. Ii IS belie\cd significantly 10 Ihc overall II . tabolitc. 4-hydroxytaloo\lfcn. IS II more than tamo.\ifen . but bccau ...... 11 IS only a IlIn)Oxifen. It probably does not contribute
In,.
"
"";"-, ""
-",~;, ,.
in pharmacologICal Studies of the'iC reccptOl).. concentmllons llfC reduced if coadnllni\t~ WIth a cytochrome P-450 inducer.
Toremifene Cltrat~, USP. ehlorn- 1,2· diphenyl·
I: b.",
... a~ lhe repound;. thal "ifene elln 4-lIydro~y-
"Irogen :te)rOSleopo-
\uccc" rlli as an O'U' aw GIIRU pr'e\IlIn,produced :arK!l'lI ui1\ an' low llRH ll1e 100 ofUI (i.ulat ion ). Suppon d b) '('\1\ 'a~ 110 e r1\
d b pallc nl, 1I"e
ne ... -
'l of the out 14, thl' C 19 t'arllon " oJ( ld:ltj.ely elea\ro ttl f'1IT11I1le. " h)dndc rea,1 C:lflcer, Iniually. arom~'3SC inhibitor. ... ere U)('tlll~ ~ond·hnc: lhempy ill jl'O'olll1enopau,al WOftlCn who failed 011 talllO, ife n lherapy. RCC'ocy of the hypothalamic pu lse generator and I ncre~ the ampliwde of LH pulse$ rdease0
. ..
II. A. .. ole
~I< '
"
I "it ur..:..
fiI Ooe
I I 1100
81rth Control. A significam U~ of the progl."Shn •• as of !he c lrogcns, I~ Inhlbitio" of u\'ul31 ion. SlcroidaJ bln h COII!fOIlI,gents are dbcu~scd In ,he following houkll1Ol bc u«ed In place' of ~urgcry, I".tdlotion, or chemotherapy, Progestins fo, Premenstrua' Syndrome (PMS), There have bun claims that progt~ttl'Ol'lC may reducc the tffeets of PMS, Conl1nucd anoly~, of V:lriou, studies indi .:aIC, ho",elf lacl.:~ proge..',ullional :Jetlvity. 1lIc caproate ester is gIVen only Inirnmuscullirly. The ester greatly illCfl'ases oil
MedroxyprogestefOlle Acetilte. U5P. Mtdrol) progesterone acetale. 1 7-accl)'Io\)'OO-fTII:thyr~ 3.2O-dionc (Proler.. ). add~ a 6cr-lnclh~ 1 group 10 the 17n-hydroxYPfogcMerone ~truc1Urc to greatly decn'w ttr rule of reductJon of the 4-cnc-3-onc ~ySlem. ~ 17(}-~~. group also decno:lSeS reducuon of the 20-0ne. similar 10 l7cr-caproate. MedroxyprOj!C!>terone ) is ta'J' IICllve orully (o;ce Table 23-2) and has such a I of action intramuscularly thaI II cnnlIOI be inlramuscularly for InolllUlg many lIlC'nslrual inlramuscul ar formul:mon I~ useful in lhe paillru,,~ ~ menl of advanl,:ed endonl('trial. brea!>l. wid nonal c=i,~. . MPA also ha~ an Imponam role in SCleral bn1h control UCIS (Depo-Prol'cra. Lu nclle). Megestrol Act't~te. U5P. MCgolrol llC\'1:ue. 17~ dmxy-6-melh)'lprcgnn-4.6-diene- ~.2O-dione ace). IS a progestin used pnmanly for the mem of l"CCurrelll. illopernblc. or i for appetite enhllOCl'mcnl 111 AIDS paueTll.s. oosis for Ihi _ use of nll,
+.- ((
I "'I
Ed.)'oodi! "'-'~. I fill "~.O,.~IIIJ
~ln5
Jj
Onh,,·Nm'lJll1
IIJ~
M~~
"«-'OIl O~l'
O.Yl~
"I'lIWolI.
Ni:r' 1(17 ~forc. OUEA or can l'Ia"e androgenIC acIlOll\. btH (111)' aner I]VO cOI1'ero;ion to tc.\IO"ICrone and DIIT. OHF..A and ~:encthone lItr. howe'er. also pn:eul'liOf' 10 the nltocstfOl'!cnic IIClions may also occur.
Testosterone i$ rapidly ron"ened TO 5a- OHT 10 many I1!'i'lueepcodmg on the tissue. Ihl~ is eilm 10 acti vate te-~
7tl IllI
" " ,ro ""
"'" ,~
'"
.. ~
"'"'
1:!()·1~ ,~
"'" "" "
"
-
17o-Me!hyfItiIoIlerone CT-.trwd)
TUIOSItIi .....
(1iIololeSbnj
, 7f!-EII_ Commerotlly AYIIH.1JI,f 110< 1M 1njecIIDn): Also teslO81erone propic)f\(Ue (10< COf'I'IP(IUr'Id)
o
VO~
-
T'nll'....... ~1(1
"'" 0xyTr... ,......
Melhandroat...alone (o..l\MlOI)
(~l
r--".-c.-v.-.../ " "
-
Narodo ........ slll·EIII,... COmrnefdaIy A... ~atJla Nencholoo" ~I'
FiGur. 23- 24 •
T~tO'l«,r()(\('
and
-
¥1,ht\w:: anabolIC androgenIC ste-
'"
at d,rrerent
""
"'" AAS have been sym hc~ilCd :md studied. The pi or many ~ynthetic progr.ull$ wa~ 10 make Mcompound ... po( coronary d,!,.,a... >lrul~. U .... .uuclCd bk>Ud w"...:I, locn:ased ~oo and antl«lC1a1 1Lch;!.\lor I~" _ "~lCro,d
"'SC''''
Li .'~r !Un,.,..... pelOOC.'1l1 nl 3 milch hlgl!er steadysImI! coo.:emr.llion Ihnll i~ fl ulanude. cmllribUlc.~ a ~ignin· cant amount mille anualllirogcn action o flh" drug. A limitmg foctor III lhe use of flU!:lInJdc IS hepalOto\icily In from I 10 5% of patlcnls. AlIhoul!:h toc hepalo(Oxicity \15\1:111)' i< fC\'crsiblc following cc,~mion of m:atrnclll. rnre C3"':S of death a"c in blood volume: Slimulate$ kidneys to . in that it lad.s thc lL~ual 170:.11_diol systcm of the other> (Fig. 23-31). Currently. it is used only for treatment Df innammation of the eyes. Methylprednisolone, USP. Mcthylprednimo1. SInIIlSoi 1111· 1!1. EI 47. r."",·t:m·iJif. L. II ...h. F_ E.. 1100'·.... 1t.·••. , ...1 8r J c~ U.llO-JH.2OO1 4!L. Sd:n"dcr. J .• Gn:cnbIiII:. O. J .. """ MoIil.c. 1_ 1.. eI al .• J a 'ft. "I>::.nlXOl.J719J-:!OO.1\297 49. M"~_ioL. S 8 . UruJou 58108 Ill. 2001 jO. C - . F J au: n..,. 2-11§00pp4 CtCl-2.5. :!OU! jl Corl_. R. W. RmIIC.......... It... Tr..... 7~S""'" 1) 52l-J!. :!ou2. d,,,, ... __ S)I ~~. 52. M,,,,, O ,on.lWhi:cho;o.l,M.Cun Op;n OtNeI. G)1Im>I U>J·68.
''''
,." ,,,.
57. Owdor, It U.. """ Ih ilbo&)l. G" J
a. •. ()n(oI
16cM
-I~,I,
SS, W...n.y. A M 1111. I a," 1',.,:1 ~ ~-.lCW. :!OOl oW. GoIdll. ~_ II. CI) ..... C. Rubin. G . .. aI. Ann. WILI 1)Qoo>d~ M Hb 1>0'1""- 2.5;,ws - fJO!.
,."
9J
99
B Gmor. Tit .. 510:... J I'. Ill) lilt. H U... 221 .. Proc Sal AcId Sci U 5 It ~141~· 14110. 1\291, Sol S/LMa. Y.• """ Bh1\2I11. M SC~ •• "".~ M24M-!~.1OOl. ~. Slu.oo. A K.. IIat>IOd. D . loo.i&. P M . eI 01. C~1I9S"'!7-937. 1'198 ~. Kom'n. 1l S.. and l.)1t i l.JIdo..LOl M M..d. 19126·1-10. \\ ". r. c.: Cll ... Chtm. 4J; 1289 · 1192. 19'J7 FDA Ilni. Bull 1127.19117. Hic h. J D.. I)id'"""'. IlI·.. fdl .... A.. rnooo-..ki. W P I R...,..oo. M«' '!10M 7• • III'J(l-.d",. . . 74_ Wnlructurully ~aried hydropOObic materials. panicularty cu-
bo~ylic
aeids and phcoolic anlloudallIs. Imphes !heir AI .. cepublhl)' 10 Influence b)' a "31icly CJlogellOlJ~ly adnums. tered agellis. Ba:aulol;: 11'1OlIt arQInatlC drug IlIOlecuics ulllkflu t>ep;lIic hydroxylation, phenolic Ikri ... al i, e~ of a,hmni~trTd drugs become readily available III vivo. Even mon: direcd). aromatIC ITI()lceulc:s on ;n vi lro ulCubatH:m with mICrosomal PGH synthase will ""-"(M11(' h)dro~yl3ted dutt'lly ~ arnchldonlC !lCid metaooh~m. m Q procco;" labeled c...... ~· ,IfHI." ThL~ coo~idml\'e prtx:es~ Pf'C_umably ()CCUI'S dunlll lhe p!;'ro~ida.-e mnler;l()n of 1'GG: to PCH!. "hich effc\;. lively mal;es a"ailable a lIOn"fICCifiC oxidlllnil .:qUI'''' llIe COO~ldaUon process has been unplic3ted in the a< He
,
,
f
Chwpltr 24 • 1'",slOg//II"/"u. '~~>frlt~s. and OIMf Eict>ulnoNls
82S
TABLE 24-2-ConrlOUt'd
••
•
Tf'~ue,*"
,-''''I=If'\/"'. COOH
"
-""
1lI'· ,"",POur IIR1ZIIc1
lOP,
'"'...... "-
Bu,""""" fm''''fI''JIIOlJ
tilm"/impb".:m",,
No!
Te."
NoI.,..,l>I>Ic
t~AMPIG.
lQo.u,-,",
G""rocI..,,,...,..,ory G."",*,',Oj"O'OIt "'ounVI.-oIl"" L"~"""""""'_
U_ _
T,..",""""
81",",,,p"'"
"
,p(jl,
1·"iI·.......·iIJt'PI_
,,"--w_
e.."....
UItG~I"'Q
""",. TXA, Sol-U
Kidnoy"'/kmM _"""'" (TlItlul Ms been modified tu pre>·cnl metabolic o~ idat,on IS-poslllon alcohol fUIICI1011.
nus denvali,c
is adrn inbtc ....:d
,II
I I po!>tpanU11l hemolThage.
a dose: ()f 2.'iO J.lg by to mncl io-
Prostaglandin E•• USP. PGE,. alpro:.tooll (ProsJ.on VR Pedialnc). is a naturally OC'("urring pro;taglandin that lias found partlculur usc on ma,nrainmg If patent (opened) dll("lus ancrioOI'l of the IrimcthylammOlllum sail of
PGF.... (S.O mglmL).
EI(QSANOIDS IN CUNICAL DEVELOPMENT f OR HUMAN TREATMENT \umtrotJ, pm~laglandin analog\leS are under invCSllllmtOn btlle treatmenl of human discasc~ (sec Table 24· 2). Effons nbl:mg foclI~ QI'Ilhe an:asof gaSlroproll."diQl'l for anhu lm tb::flIP)'. fertlhly c:ootrol. lhe u.c,nlQpment of Ihromoo~11CS fc.g .. JIfO!itxychll or Ihromooxanc synlhellbe mhlbl1m) 10 treal cerebrovascular 01' (:(It"{)IUU")' ancry diseases. and
tie deH:lopmenl of allliasthmallCJ Ihrough lnodulatloo of lilt hpo~)"I~cn:hC palhway. FUlure applicallOO of cicmal\Old~ 10 !he treatment of cancer. hYlX"nension. 01' Immune ~)')lem
JtionIers cannot be ruled OIl!. holt,·e\"cr. Thus. although progre!>~ hll.~ btC of eicos:\noiru. or rK'QSlIooid onalogues U lhernpcutic age!)ls in the fulure i~
alnJOclIlakJII. 1'1... CRC rm... 19It9. 1"1'. .1$-16 ~ 1'InoblIn, M 1.. l)oy. R. O .. -..d V., """ II .... W I:l : AJ(''''' """",, 'I ,CI45 ("1'9. 1994 1 T.... A.-I_. -.I Kol""",... R. I . """,-,,1.00.'" o."", I.lpo.! Mtd,.,,,,,
&l:Ht·2S-1 . 2O.XI I Smoth. W I " """ 0.""1. I) L: Adv In.. """",, 102:1&7 215. 1\1%, •. YaM. J R.. 1:l.~~Ie. Y. S .. .....t Botunl. II. M Anno. R.~ l'IIamuo..'UI Tu,iroI \II Y7 - I:!II. 19'Jlt I . " W l' M """",, !MIdi ... tzut.,. F.."'.... I'-IY lie"" 11.1 IU · 126. 2000 I ~-.ya. S. Y.. ..... WIItLIIbi. f PIIj'W lie' "N: 11~1 · 1126. 1999 11 K...... \I .... >t,'C""'t .... J. A ., " al N",",c 138, 129. IY72.
J(l
SElEaED READ ING R..Ic-y. J M 1 rIIuy _" . bn. ""'" Mni. Chmo. 2'l1 -f)~. l'Hl R. I( (od); II.."" Hforu .)' lIe.w .~. Ad. u.p, M«I lIi1l!19.1-421 . 19lI9 t\dq.'i .... 1.. 10.. and l(indahl. 1I ( Von. Abo 11 I~ .... 1919 S,""Jt""',Iol.. .... P • K,f... R It . MMl 101 ....... 11 t:. HeaIdo BJ.n. 011'1;)1,.... _ _ Fony ~ ... 5eal"Od .. Ncv. V.. k. A, - I Inltructurt' and inletaclions.' The chams ( R !:fOIJPI") 0( various amioo acids ha,'C It)lttx:W'bon moieties that an: h) drophoblC. and they h:l\'c to as~illle ","h .. atCT mol('(:uJrt ~",~ are qn:N1gly IS50Cinted through hy· 1lrogen "hydropllobic R groups tend 10 get ~ Io.J 000 aOOlhcr, with exclu~ioo of watcr mol('(:ule.~. 10 form "bolld ~" between different 'lei:Jnents of the chain or
:
".de
" Figure 25- 1 • DiagrammatIc representat10A of a fulty ex' tended polypeptide chain With the bond lengths and the bood angles denved from crys\.ill SlllKtures and othef expet.menliil e.oodeno::e. (From COfey. R B.. aoo PauI!r\g. L . Proc R Soc Lond 5ef. 814110. 1953)
between differellt chains. 11Iese arc often lermed hyJror'ho· bic bottd.f. hw/m,HII'bir !orcts, or hl'/lropJwbic i"'UI'CIIOIts. The stu dy o r protein structure hll~ rcquin.-d .ev.:rnl phy,i· cochemical methods of analysi~.4 Ul tlllviolct ~pcctropho.J... IOOlelry has been applied 10 the assessmcnt of cooforrna· tional changes thai proteins Ui'\(ierIlO. Cooformahonal changes COIn be in"CSligated by the direct plotling of the dtfference iO absoi'plioo or the prOIem under "moos .sets of cotidiIlOO~. X·rdY an31.\'~ls has been ITlO\t u!idul in lhe elucidation or lhe structures of seve",l proteins (e.g .. myo-II lobulin and lyS(1)'mc). Absolute Y:sy:, anAlO1 ylic propcrbeS, ha ... ~n isolated from the European fire·bellied frog. Although out a complete list of the peptidc ... Isolated from frogs. tocse provide an insight into the: ancient dcfem.:: meehmisnts these repi iles po!;SCss and Ihe po_sibi lit y of c~pIOlla· 1100 for ~uch U>CS us analgctics. a "ti!11icroblld~ (e'p,:eiall y apinst resismnt organisms). ~nd cllrdio"'a'ICu br agents.
rroc
Nu(/eopro tei n$. The nucleoproteins menlloned abole lte found in tile: nuclei and cYloplasm of all et'lls, They cnn br dt'protelllu,ed by selel1lJ melhods. The compounds lhal om.u- in yeaS! are usually treated by gnn(ilng .... ,th a IeI)' dilute MJlution of potassiulli h) droxide. IKkImg plC'rie a.cid in nces~, and ~Ipnaung lhe: nucleiC adds .... nh h)drochlorie K'id, Ie;l\ing the profein in solution. The nucle ic acids an: purirlCd by dis.'IOI",mg in dilute pocaS$;UI11 h~droJ;lde, fiiterml- addifylllS ",ilh a!.'Clic acid. ~nd finally prttlpimhng wuh ,luge excc,s of ethanol. The nuclCQprotclIls ft)und in Ihe nueleu~ of eukaryOlic «lis include a variety of en~ymc~. such h~ DNA and RNA polYllleTU.'IC:" (in ... olved III nudeie acid 5ynthe~is). nudeases lil1l'olvOO 111 the hydrolytic cleavage of nuclcOllde bonds). 1SOI11Crusc.~,:utd OlllCrs. The nu relICtIon 10voh'es the loss of thts pos;II\'e charge Sl lUullallCOUSly .,.Ith the auack ofthc nucleophilic reagent (abbreviated Nu, H ). Roberts~ used nlllVgcn- 15 (" N) NMR to ~t l.>l.ly tnc I1k'Chanis!1l of protcase catalySIS. A scnClI)atiin(ogcnj. and ilhlliin.
C~) I
• °H
A- C- N- R'
A
'. •
K_ , C:~) I
°
.RCOD
Dill synthesized on the ribosomes . They pass a4:r1)SS the mem~ bnme of the endoplasmic n:ticu lum into the cisternae and directly into a smooth vesicular structure. which dfect!; further transportation. They are finally stored in highly concen· InIted funn within membrane-bound granules called ~'''IQ g~" grt",uin The ex portable protein conlcnt of zymogen granules may reach a value of 40% of the t01al protcin of the gland cell. In the enzyme sequenccs abo,·e. the new ly synl hcsiJ.ed exponable protein (enz)'me) is not free in the cell sap. The stored exportable digestive enzymes are released into 11M: exulICellul;lr milieu and the homlOt1es inlo adjacent capillaries. Release of these proteins is initialed by specific inducers. For e.t ample . cholinergic agents (but not epi nephrine) and Ca~ · effect a discharge of amylase. lipa.-;c. orothers into the rm:dium. increased glucose levels sti mulate the secretion of insul in. and SO on. This release o f the reserve enzymes und homlones is complctely indepcndent of the synthetic process. as long as the stores in lhe granules are not depicted. Energy oxidative phosphorylation does not play an important rolc in these releases. Electron microscope studics indicate a fusion of the 1.ymogen gn1l1ule membranc with the cell membrunc so that the gTanule opens directly in to the extracellular lumcn of the gland.
Bes ides the en zy mes mentioned. it contai ns some b')JlSlllllgen ..... hich tun be activated by intestinal enterokillaS(: cb)· motrypsinogen. which is convcned by trypsin to chymooyp' sin; lind carboxypepti dase. Pancreatin is used 11Irgely for predigestion or food and Ii:r the preparution of hydrotysUlc~. The ,·nluc of it!; ClIl)lIIr::I orally must be very sm all because: they are digested by J'ICt ~in lind acid in the stomach. although some of them !lIlY escape into the intestines without change. Even if the) In: protected by entcric coatings. it is doubtful they could be It gTCat assistance in digestion .
Classification
Pancrelipase, U5P. Pancrelipase (Cot .. ~ym) lias I greater lipolytic iIC1ion than other p.:mcremic en1.yme iJItPi' rJtiOIlS. Helice. it is used 10 help control steatOl'Tbe,IIId. other condit ions in which pancreatic in>ufficiency UlIpIiI the digcstion of fats in the diet.
11lere are various systems for the classi ficution of en;r.yme.\. The Internutional Union of Biochemistry system includes some of the tenninology used in the literature of medicinal chemistry. I1I1d in milny insHmces tile tenn~ lire sci f·explana· tory . For example. transferases cataly£c transfer of a group (e.g .. methyltransfernse); hydrolases catalyze hydrolysis reat1ions (e.g .• eliterases and amidases); and Iyases Clll3 ly.tC non hydrolytic removill of groups. leaving dooble bonds. There are also oxidoreductascs. isomerJscs. and ligases. Olher systems are sometimes used to cl assify and characterizc cnzyrm:s. und the following terms are frequently CJlCountcred: /iptlSt'. ~,,,idllse. fUV/eIlJt'. phosplilltaIt'. kj,wse. $),"Ih~/(lSe, d..hydrog~IIlJSe. oxidast'. and rt!f/UCllISt'.
Proch...:ts Phannaceuticlllly imponant enzyme products are listed in Table 25-3. Pancreatin, U5P. Pancreatin (Panteric) is a substancc obtained from the fresh pancreas of the hog or the OK and contains a mixture of en7ymcs. principally paJlCreatic amyla.;e (amylopsin). protease. and pancreatic lipase (steapsin). It e011vens not less than ~ times its weight of US P Potil\O Starch Reference Standard into soluble carbohydrates nnd not less than 25 times its weight of casein inlo protroscs. P:tncre~tin of hi gher digestive power may be brought to this Sll1l1danl by admixture wi th lactose:. sucrose: comaining not more than 3.25% o f S1~h. or pancrentin of lower digestive power. Pancreuti n is a cream-colored amorphous powder with a fainl. characteristic. but not offensive. odor. It dissolves slowly bUI incompletely in water and is in;;oluble in alcohol. It aCIS best in ncutml or faintly alkaline media. and excessh·c acid or alkali renders it inen. Puncreatin can be prepared by extracting lhe fresh gland with 25% alcohol or with water lind subsequently precipitating with alcohol.
Trypsin Crys tallized, USP. Trypsin crystallized ~, proteolyti c enzyme crySlal lil~d from an e,'ltroct of the rcn::1S gland of the ox. Bas Imm ..~. It occurs as a while ID yellowish white. odorless. crystalline or amOlphous po!I.kr. and 500.000 US P trypsin units are soluble in 10 mLof .. :ur or saline 1'S. Trypsin has been used for sever,1I conditions In wfMch its proteo[ ytic acti\itil!.~ relic\'e cc nain inflammatory SI*I. liquefy tenacious sputum. and so forth. I\ lany side: 1l'attDr, are cncountered. how·ever. particularly when it is usN JlIRI" terally. which mitigate against its use.
Chymotrypsin, USP. Chymotrypsin (ChyrtWJ IS n· trueted from mammalian pancreas and is used in C3WIr.'1 surgery. A dilute solution is u-cd to inigJ te the pilIItfia chamber of tile eye to dissoh'c the linc filan10enlS tlw hold the len,. Dornase Alpha, U5P. Doma.ith Imt:l.llts 1oIIdI .. turpentine and CTOlon oil (granu loma pouch tlXhniqut) ....... anase is available in .5O.000·Un;1 lablet~ for 0tU1 USC'. Dlasr~se.
Dilll>la!le (Taka-DlaslU IIloaI in doses of 0,3 to ].0 g In the ~arne ~ondilion ~ as mAt iiistaSt'S ;;,'~:;~;,
addition 10 Stimulaung the lhe release of proloclin_ It
Chaptrr 25 • 1}~1lI dT«ts tl1:lt h;o;I'C been elaluated for antKlcjn.'\S:Int
drImlpeulIC pxenual. but the results of clinical lOt yet COII\idered rooclusile.
S4udi~
arc:
Gonadohbenn, as tile name: imrhes. IS tile padolropm. .cltas.ng ho rmooe (Gn- RHJ. also J.:nown llli lutemizlng horlIIOIIt- releaslng hon1'l()l1l: (LH-RH). Th i ~ hYpol:h.ahmllc de• • pude stimulates the l\"lease Oof lutein ili ng hunnone (LH ) and follicle-~tln1Ul~hng hormone (l'SII) by the pituitary. LH . RH is ron~id. .. ,Ih 24-hou, U"IM: oollcrllQn eacll day
... !. 1l1C solulOOIl lIa~ a pH runge of 3.0 to 7.0 and is usc(] for ilN adrcnoconicolropic :>(.1;\'hy. Repository Corticotropin InjKtion. USP. rilied (ACTII,80. cortiCQ(roplll gel. purified
ACTH po~,"or1 i!,!otroplll )
is con icotl'Oplll in II solultoo of parually hydrolyad gt~ to be u..etl imr:lI11uscularly for a more unironn and rnaimcnan~ of ~clivily .
Sterile Corticotropin Zinc HydroKlrk SIISpf'IWIWlO US!'. SI'J.
I
G', I
Asp
AJa
I
I
GlnlO- Ser
Cotlicoltopon
(osyntropin,
CO!>yntropin (Comusyn) i ~ n s ymhetic ptptide containing the fi rst 24 am ino acids of natural corticotropin, Cusyntropin is used as a diagll()!;tic agent to test fOT mnal conical deficiency. Plasma hydrocortiSOlli: conce nl!3Iion is determined before and 30 minutes after the admini>lrJtion of 250 ~I! of cO!>yntropin. Mosl nonnal respon ses ItSUtc in an appro~imale doubling of the basal hydrocorti , ~. COflCenlr.uion in 30 10 60 minmes. If the responsc is !Ill! nonnal , adrenal insufficiency is indi cated. Such udrcnal iIrs~fficiency could be due to " ither adrenal or pituitary malfUllC1ion. and furthcr lest in g is required to dist in guish be !uoen the two. Cosyntropin (250 ~g infused within" to 8 ; . (80 to 120 Ulday for 3 to " days) is • i t with functional adrenal ti ssue shou ld i dosage. Paliems who respond accordingly of hypopituitarism.' the I 'n be by other tests for il Ii ; n who or no response.
CorticOTelin. Corticorelin (Acthrel) is a synthetic peptide thm may be used as un injectable in the dctenninalion I i responsiveness. It possesses tho: omino acid scin corti cotropi n-releasing hormone that is re'f'OIlsible rOf" ~timulating lhe releasc of ACfH. t.4HANOTROPINS (MELANOCYTE -STIMULATING OORMONE)
Melanocyte-stimulating honnone ( MS H) is elaborated by ;ntennedinte lobe of the pituitary gland and regulates of s~ i n in Ii,h. al11ph ib;an~. and. to a lesser t. humans. Altered sccn:tion of MS H has been impl; cau sing chJnges in s~in pig.menllltion during the I I . The Iwo major types of melaredcri\"ed from ACfH and ·n. a- MSH con lai ns IIw: same amino , 13 amino acids of ACfH: ,8-MSH 18 amilM) acid residues. A Ihird melanOlropi n. l"me laoo-
tropin, is derived from a larger peptide precursor. proopiomcianocortin ( POMC). Some im portant endocrinological correlations include inhibi tory IICtions of hydrocorti5011e on the r.ecretion of MSH and the inhibitory effects of epinephrine and IJOfcpinephrine on MS H acti on. LlPOTROPINS (ENKEPHALINS AND ENDORPHINS)
Opiates. such as opium and morphine. ha\"e been known for cenluries as substances thaI relieve pain and suffering. NeuropharmocologistS ha ve theori1.ed that opiateS internet with rrceptors in the brain that are affected by endogenous substances that function as regulatOl1! of pain perception. The important breakthrough came in 1975. with the iso lalion of twO peptidcs with opiate-li~e activ ily20 from pil!: braios. Thesc n:laled penlapcplides. ca lled methionine-enkephalin (metenkephalin) and Icucine-enkcphalin (leuenkcphalin). are abundant in ccrtllin IlCrve tenninals and have been foond in the pituitary gland.
' T~
' T~
oJ,
I
G, G,I
G, I
eI.I
eI.I
5Met
IMe!IEnkephalin
'T~
I
G,
I
As n20 -AJa
I Ly. I
G,
Phe
I
I L"" I Tl" I Val 'S I L" I
Phe
I I Tl" I Se, I
5 Me!
G,
'L""
l LeujEMep"IaIf1
P'o
I I L,.. Tl" I I
lOSer-Gin
I
II.
I
'I"
L,.. I I
"'"" Ala
I H" I L,.. I Ly. I
G, ~
I
Glo /I ·EI'.:bp/"oiol (_spl
An examination of the structures of enkephalins revealed lhal !hi:: amino acid sequence of metenkephalin was identical wim the sequence of residues 61 to 65 of ,8-lipotropin (,8LPH). a larger peptide found in !he pilOitary gland. Thi s discowry suggcsted that ,8-LPH might be a pn:cursor for OTher larger peptides containing the melenkephalin sequence. Soon afler the structural relationship between fJLPH and melcnkcphalin was established. longer pept;dcs. called t!JIdorph;'u. were isol aled from lhe inlenne"" .......... "'I ... ~
-,.,
-..,
tM 01 SC.1j...10 U u.d orq j ......
tM crSC,l~HlllUL ... q.iI a
M."""o......, ,"'......1. Z-4lLf/d1y....
\I~f·'~leri{)f pttuilury Unil$: expimtion date. 3 )caJ"S.
V.sopn!uln
Tiln~t..
Vasopn:~sin
tannate (Pitl"CS.'illl Tannate) is a "" ater-ill!>Olubie tannale of vas.opn:ssin adrnm1\oICffiJ IIltramuJioCularty ( 1.5 10 5 pre$.Opl"essot Ihan i~ 1)'slne: \'asopre~in and is reoom· surgel) to minlmiu blood flow. cspecially in 01 '1 and g)'TIL'C()logy.
Inc
-:::':.1,;'"
~'~" i~ s)'nlheuc S-I.·I)',,1ll' ~asopres ~ul1Jlar
10 ADH. The lys lIle analogue: is a. It was isolated originally in IWO different foons. In one of the forms. the tyrosine residue in pot;ition 12 is sulfuted. Both (Ofm s are biologICally &Ctiv... Otolmergic response 10 tlw:: pre.'\ence of food in the ga~trointesTinal tract provides the stimulus for gaslrin llioma on chalyw _ noI "" dill,.. ........ , 'In ktoo»'or. •..... ttl "· W..:wd . - ,.. {o.c ........ 19'101; Ii'" ... 0( _mi' """'"'" '" d"'lioCld>t,opy ''1*10'lI0 .. ,,*,
T~~lmtnI
Ell UUy" Clndi.ilap"h .. IN)
"""''''''' •
."""'. i.ONA "",,1'1) .... Inp:I;'"
_lin
H.IOI... ,.....Io .. (rOSA
01'1".,
lull')' .,.11 "'ul. 001" the de""", sene from lhe: ICoomk libnry ( ICIk'S Dr m'CrobiJI « lis lhat are blnwn 10 1Ia\'e rapKll1lle!l of all dI Yi~lon. TI) IICPOiwl 'rOfIA
,,*,~I
P''' "..,
....w as '-t~ _
ytt>I "",U5. \fammaloan «lit.. Ad!. ChH1l'!Oe iiamsla' 0' ary edl", IIf"C useoJ ",hen gl)'CO'yl;oOOll .,... rDNA. lkm·cd proIcon i, ~senual for blDlOiical kll"I.Y (c.J. C1')11>""", .."'n). NO/1/TIammali211 celli cannot I:1)C/lIylllc ...... cc1~
_~IOI
,
b'O'Oll of rDNA-dm,ed protein From ... ~1 miJ.mn: conulin.ng b.:ICnal proteins. «11 ~ che micals U>ed in pn:pnringl he media. el~. iwlali nllnd punf}. in, 'hc de!iirW hu"""" prutc'ln IS a Ib.unlln, IN indeed. TM wit m:ju,~ ~oplm.tkatwlwl~uOll .echn"lues. such. C'-I I I j fillnollOlls. 1'R"'1p!lalions. and HPLC. ~ pnmary pi.,.. .... punficlllion pmc:_ IS II) ensull' lIIal IIIi:: proce," 1$OI:tICd d 1l'111II" IIIIi: btologiclll aclivilY o f lhe " allye proIein in the bod:o. n.: r" NA-dm,·w proIcon is then fi;ll'Tlllllalcd imo. p/Iaol..... · icII producI lhat il Kable dunn, Imlo,portltion. 51.,..." admoni~l"mon 10 a pMocnl,
""'"l'
des,,,,,,
(o ~ )
-1.If"•
eM
&.1 ... _
p,rofy po I
I
Fig u re :Z 5-7 • Summary 0 1 olmolymc). is a mucolytic cru:yme idcmical wnh the nmural hUrrnln DNAo;e and b u0I an..! Gil...... •• .,.". l'barmro:'*'Iic .. 0"';. "' ......... ptIIIlC. 10lI0 rd N. 11>.:19'J, 1\181 21 Bn.oc",,_..K •. II .... 1'rplotdma. I 0 . ond I, I oJ. L I~ ( .....1. GoodInoto oa.l Gi ...... · • .,.". /'IIa" ........ """ S-Ql/ ........ poul .... 10th «l New Yori.. M_Ibn. 2001, PI' 1332-lill 87. USI' 1)1 Drul Inf'mIII"'" r.. lhe Iblth Cite I~""'_ " i' ul ..... L 22nd N . Rod"ill0........ Mell" .... 9dr td. I.. W··..... Eli Ully .I: C,,_ 1918. (".011_ A.. P . 1'"""""- 0( "'_'" 1/000).......".. 1ft llrodetfloff.. II .• ...J Jeuen. II. 0 (tdU. UpoI)"" ""Iy...... N.,.. Y",,", ""-...., Preu. 197'.I'P.lJ l -~41,
HarIImIwr.) 0 • .,,01 I.. m!);rd. L I' (td,.). CloJman """ O,in..,,", The ~ II~. 0(Thc10p0"ic>. 10111 cd. N... Y..t. MlCmll·
....
,."
II,..... • ""')". R. II . arod do 1,-,,,,,. E' Cltruoo
~ o( ..... ymot-.
_ . ~ 8...,"".. 4U79. 1914 Itnob) . V I. do ChI, ... C. 0 ...... M ~iJe and roU)' 000 I>nt.IID;.oo,ct)', vol 4, IiIII td. Ne.. y.,n;. John WIley It: Son •. 21))1
K.'·.......
ItaU, W r . Cauly'" In Chembllyarod Eru:ymlosY. N... YOft. M«lnI... •
Hill 1%9
..... ,""" In"""'m. I•. 1..: An I"trod"",."" 10 S"",io:-mlc.1 Ro",,,,, .. Mo1 • .I/In$ .... M I ~. arod M.nafI> _~to...
C'd,h..
~"'"
""' " "'"",,".. 2S_-...o ,'-'"
..
.'"
A2 (all-trans) 3.4- Dehydroretmol or Oehydrore tirlol V~!lmm
Dietary rennyl estcrs are hydrol)'l.cd in the intc\t uml lumen by vmOlls hy.:lrol3se:s. The n:tinol is .bsori:Jcd Intu the emeroc}lC:S by facilit.:Ued diffusion in normal concentl'1ltKln~. At ph3l'1l1llCOlogkai ~. ho ...·e~'er. rennul can be absorbed by passi~'e diffu~ion.17 Within the> c:nterocytCl>. the: reti nol is 1.'~leriried by IWO enzyme~. acylcoenlYmc A (CoA): relinol acy ltransfcrd.\C (A RAT) and ledthin:rctinal acyltransferoiSC (LR AT ). LRAT eSleri fies ret inol bound 10 an tntll\(:ellu lnr protein. cellular retinol-binding protein Iype 11 (CRBP 111 1). while ARAT can esterify unbound relinol. II lias been ~ thaI LRAT estenfiCl> refinol at normal doses. "hlle ARA T est",rifics exccss retinol. II TIle n:tinyL estCT!i an: iltCOipClIaled inlo ehylomif:ror1~. ... hlch In tum enler the I}mph. Once in lhe generoll circuln111,11'1. chylomicrons are con"ened into chylumicron n:111nami, ... hich an: cleared primarily by Ihe liver. As lhe C\tcrs cn t",r Ih", hcpalocyles, they un: h}droIYl~'d. III It"" elidaplllSmic n:ticulum. lhe n:tinol i~ bound 10 retinol-bim!tng proIein (RBP). Th is com ple.\ i,~ released into lhe bLood or tnmsfelT'Cd to liver stellate ec:11.~ for storng"" Wimm the ~Icl lale eells. tlK' retinol is bound to C RBP(I ) and esterified for WJrlIgC b) ARAT :rnd LRAT, Slellatc cells contain up 10 95%ofthe li,'er vitamin A bton:S, TIle RBP- n:nnol conlplu J't'leased into !he gcnel'lll circululion from hcpalOC}le~ or slel late cells, In tum. is bound to trolnsthyn:tin (TI'R). which pro4ect~ reli nol from nlt U~ contain CRB I,( I) and CR BI,{ Il ). These: intlllCCllular pro4eins function in the tl1ln~por1 und melabolism of n:tl nol and ret inok acid by wlubili£illg tl""lII in aqUl'OU' medlu ~nd presenting the m to the appropriate enzymes while prot«ting them from catabolizing eIl1_YI1Ie~.lU The.; Mlbseqoc:nt c:stcnficaIlOO,:1 Reunol is su>ccpuble 10 glucuronide ConjUgatlOll, folIo...·cd by cllteroix-palic recycling. [I may be. oxidil.ed tu reu noie lII;:i d by two en1.yrnes. rchnol dchydrogen~ und retmal dehydrogenase, wim the fonller being rate-li mit ing .l ) U n li ~e retinol. retinoic acid has no specific carrie r in the blood. Retinoic lICK! undergoes decarboAyl~lion. fol lowed by glururonidc conj ugation, Normally, no unchanged n:uooll'Ji u creted. Reunal. rc:1inok lICid, and Oihcr metabolites are. 110... e"er. found in the UrillC and f«es. Although fish liver oils are used for their vJlamm A CQIltent. purified orroncemrated foom of vitamin A are of gn:at COf1lnlCrcl al signifl(: ance. These are prepared in three ways: fa) supon ificmion of the oil aod concen tration of ttle vitami n A in the nonsaponiliable mnller by soh'ent e:'ulIm;n A lower than .he
Imalc reqUired (or .hor!-tenn tmieny but ~uJl above thal requirrd by the body can lead 10 1000g·term efftcts. II'Icluding the lil: m. liver. cemrul nervous s)"tcm. and bone. Although the amount reqUired .arid. doses 3.lIiow lIS 15.000 IV/d.,)' hal'C Jed 10 some IKlve~ effCl:\s. although higher doses.. generally above" 100,000 IU/day. an: required 10 S« alllhc reponed adverse effects. In palien.s .... ith low body "'!'lghl, malnutnlion, or hler or mllIJ dlscase . the do!;c$ ",. quired for long·ternl adverse effects may be lo ...·er Mill. Dermatological ad. CI'C effcclS Include !If} Ing of the ,kin effect~ 00
and murosa. dermautis. prunlu~. swelling and fi ~surilli of the lips. and homeln1lCS) loss of body IIlllr. I tepUlle effects include hypel1rophy and hyperplasia of IhI= 110 ecll~ (whkh SlIlrC malmn AI. hcpalomegaly. fibrosis. and cirrllosis.
.... hkh can lead 10 portal hypcneru;ion. ~ile5. and jaundice. Spknomc:galy i~ ~Iso secn. Centml nervous sysu:m effects mcludc: HlCre:a.'\c:d intracranial pressure: (pseudotumor ec:n:bti) lealime as normal Individuals. Oi'lCQntinuancc of lhe drug resultll in II relWll of hyper;cn si t"·ity. P.Carolcne doe!; 001 function as II sunscreen in normal pallent. Ind ~[d I1QI be used as .weh. The dot;agc:. mnge is 30 to 300 mglday m a smgle or dl,·oded doric, usually adminis tered with food beeauct calcium abSOl"plion i~ seen within 2 hours or administtnlKln . h~ half-life is J 10 8 hours. and II> dUr1llion of action is I to 2 days. Cakitfiol is the most acli'e form of Vitam in OJ. It IS Indt· cared in patients woo an: receiving long-ttrm renal dial)si5 or who cannot properly meluboli1.c erglX."slciferol. Cakipotriene. Caicipolrienc. (laJ,B.5Z 7£ .22£.2& 24-cyciopropyJ·9. JO-sccochola·!J, 7, I 0( 19).22· tctrnenc· rJ, 24-triol , calcipolriol (Dovoll('~), is a synthetic vitamin 0, analogue iudicaled ror topical application 11\ the ~ of moderate plaque psoria~is. It has the 5Drne affinity fortbt villlmin D n.-.::eptor as calellnol . but ils e(f«1 on c:Uc1W1l metabuli sm is 100 to 200 t ime~ I.::ss. CalclpotriellC inhLbtb epidennaJ cell proliferation and enhances cell diffcrenu.
I
I Dihydrotachysterol
""" •
I
25-HydrOllydihydrOlaehysterol
Cha pler 2Ci • tlOO. lt rcducc.s ccll numbers and total DNA contcnt."'" Anti · proIifffilU\c cffects are caused by a reduction in !he mRNA lel'els of a cellular QflCogcllC associated with prolifcrallon, c·m\'(". The IfKIClw1i~m resulting in diffcrtnlialion changes I~ notC(lmplelciy known but InI'OI\'CS lhe secondary messen· ~rs inosilol lriphOsp/late (IP)} and diacylglycerol ( DAG ).7'O
I _ "'" ..,..
()H
Cak;lpolrlenl
Doxerc.lciferol. DoxercalciferoJ, ( I a.J,B,5Z 1£,22£)·9. I().SC'OOl"rgosta·5.7 .10( 19).22·tetrxne- [.3-phate produce hemolytic symptoons (reticu locyll~i~. i11Cre;J.~ in Heinl. bodies) in lK: .... bom. premature infants when given in t"ceo;si\c doses (1Il()fe t!u.n 5 to 10 mglli). In severe case-.. o.en Ix-:moI)'tic IlrICnll3 .... lIh hemoglobinuria may occur. The increased red ceJllx'cakdown may lead to hyperbilil"\Jbintlllla IUld kemiClt.'1"\IlI. lkse compounds may also mterfere "'Ith bile pogment secretion. Ne .... bom~ ..... iLh a congeturn). In 1934- 1935. nicotinamide was obtained f..the hydrolysis of a COCn7.ynlC ilOlatcd from hone red bIootf cells. This coenzyme .... as I;ncr named CQtm,""'C III11ld il oow more common ly called niCOIilNlmiuc udcninc d;nurlfo. ,idc phosphmc (NADI'J.
OH
"""""" Generous
"",,0
of lhis vi tamin Include pork. Iamb. aid bee f livers: hog kidneys : yeaslll: pork: beef long~ ; hean!. lean me31ll: wheal &enn : pe:tnut meal: and grccn pta~. Nicoti nic acid can be synthemed by almosl all plant!J and l1lirnals. T I)'Jltophan can be metllboliled 10 • nicoume I0Il nuckolide in animals. bul the C'fficlel1CY of lhis mulllSlql pI'OCClIS Yarlcs from species to species. Plams and many l1licroorganiSllls symllcs.izc this viwmin Ihrough al!ctn.1lilo'C routes by use of aspan ic add. In the human. nicot inic acid n:acts ""Ih S-phosphorioo.)" I-pyrophosphate 10 roml nlcOlinic acid moootlllCltoto:k. .... hich!hen reacts with AT!' 10 produce: dc:wrtioo.NADitllc inlc mlCd iate dinoc leotide .... im !he nicotinic acid lIlOItIy~ Finally. the loltcr intcmlCdimc is coove rted to NAD (on", nal ly called coen:.)·/Ilt I) by LflInsfomulIion of lhe carbox)l orthe nicolinic acid moiety to the amide by glulamlilt n. final step is cataJylCd by NAD syntbetase: NADP IS . . . doced from NAD by An> under kinase catalysis.' 'IQIII'CCS
Calcium Pan to thenate. USP. Calcium pantothcnlltc. calcium o-panIOlhen:llc. is a "lightly hygroscopic. while. odorless. bincr powder that i~ stable in air. It is insoluble in IlkohoI and IOhlble 1:3 In "'Dler. aqutOUS IOlulions have a pH of aboul 9 and j er]o _ +25 to +27.5". AUloelaving ~alcium p:lnHlthenate al 12O"C for 20 minutcs mill' cau aqueous solutiOll has a pH of 6. Nicotinic acid has a pI(. of 4 .g~. Nicotinic ncid is stable under normal stornge cooditions. It sublimes wilhout decompositiOll. Serious derlCiency of niacin or tryptophan may lead to pellagra (from the Imlian, ~II" Ilaro. for "rough skin "). The major systems affected are Ihe gastrointestinal tract (diarrhc'a. enteritis. SlIMmltitis). the skin (dermatitis). and the central 1'ICTV000S system (hradochr. dizziness. depression). Se\ere ca.'ie.'l may result in delusions. hallucinations. and (kon1('nlia. In the United Stales. pclla1!r.I hIlS become rare because flour is wpplemcnted ","11 nicollnlc acid. Chronic aJcohoti~m is the chicf cause of pellagm and is associated ..... ith multiple vitamin deficicllCy. The symptoms of pcllagru an: completciy revcrsed by niacin: thcref~ . it is indicated for the treatment and prt\'emion of the defICiency. Adverse effect~ of ni!lein are most COlllmonly ~n when thi s vitamin is u'\td at phan1UlCological doses abovc I gfday in the (realment of dyshpidemiL Notable adverse effecl'! ndude noshmg due 10 vasodilatation: dermatological cf· fects iucluding dry skin prurilllS nnd hyperterntosi~: gastrointestinal effects includin& peptic ulcer. stomach pain. nau· sea. and dlarrilc:tt; ckvations in serum uric acid and glucose; and hoeP.1l0l0licity. m . llol Niacin (but not niacinamide) is ulso indicated in hyperl ipidemia to Iov.'cr triglyccndes and cholesterol. Triglycerides. VLDu, and LOLs are mjuced; HDLs are Increased. 1lIe eloct ml"Chani~m is not known. Because niacin al high doses ha~ a direct va!lOdiiatory effect bel ieved to be mediated throogh the prostaglandins, the dose required (I to J g 3 times dally) oftcn limits thoe usefulness. Niacin is absorbed readily from the gastrointesti nal t11lCl and distributed widely. At physiological doses, lillie niacin is excreted unchanged. Most is excreted 115 N·methylniacin or The glycine COfljugatc (nicoununc acid). After admi ni ~tra· tion of large tlo!Ics. ni!lein can be found in the urine un· ch.lnged. Niaclfl~ mick.
USP. Nluciuamide. nicotina mide, nicotinic acid amide. is prt'pIlrtd by the amidatlon of esters of nicOIinic acid or by passing ammonia Sas imo nicounic acid at J2O"C. NicOlinamide Is a while crystalline po .... der that is odorless. or nearly so. and biller. Olle gram is soluble in about I mL of .... ater. I .S mL of alcohol. and about 10 mL 0( glycenn. Aqueous lIQlutions arc neutrnl to litmus. For occum:nce. 1IC1i0Il, and uses. sec nlOOf;n ic ueid. Niuei n:unide has pI(. villues of 0.5 and 3.3S.
EII¥
Nicotlll31e
-
Niootlnamde
Like nikin. niacinamide is Indicated m the tn:aln1Cnt IDd pre\'ention of ddicicncy 5tatcs. Unlike niacin . niacinarm-k has no vasodilatory effect, whiCh may be of thel'llpcutic imponancc for compliance reasons. Niacinamide: has nodfta on triglycerides and lipoproteins. This product is formulatal with potassium iodide and used as an iodine 5upplemcllL Niacinamide hydrochloride is alSQ available. It i s _ stable in solution and more compatible ""ilh thiamine cI\Ioo ride in wlution .
Alboflavln (Vitamin B 3 J Although crystalline ribollav;n was IKlI isolated until ;., interest in this compound as a pigment dates back 1(1 .'.: in connection with the color in the whey of milk. In
ribona~in was i"Olated as It from yeast by WarbtJrg and ydlo... (),fidarion !ermenl.
~'~:::'~~":;~:':.~ ~I i
~~C ~ ••
..
"""" '" Ribolla\'ln is synthesized bb:,;~01:~',:~:''':':;::,:::!!~; bacteria and fungi. .... Ithough y' t !.Iairy products. legu mes. 1 meats an: the major SOlutes the diet. The preeursor is a guanosine phosphalC "'::':':";: oot the e.o;act synthetic stepS leading to the vitamin understood completely. In higher mammal s. ribonavin I~ absorbed n:adi ly till: intestines and distributed to all tissues. ';;:~~: In the bll)Synthcsis Qfthe cocn1.ymes navin n (FMN) and navin 3dcnine dinocleotidc (FAD). The bulic functions oithis vitami n invol"e ~~~~:~o,:~: which par1icipate in numerous "ital ( processcs. FMN (ribon3vin S'·pho:sphatc) is producal The vitamin and ATP by lla\'okinase cllt aJysi~. Thl ~ be inhibited by phenothia7jncs and 1M tricyclic s.mlS. FAD origmates from an FMN and An> involvt:.'!\ reversible dinucleotide fonnatiOll I vin nucleotide pyrophosphorylase. These c:ocnxymes lion in combination With sevcrnl en7ymes ro,~",".-'" lyrne complexes. o ften cha11lCleril.ed a.~j1a1·oprotti/U.
as
Ftavin Mononucteotlde
Chwptu 26 • VilOmiJIs WId
Rtllll~
CDm{JOfUIIh
89 1
lumichrome
OH
~
fiavoproteins function in aerobic or anaerobic cood,tionli as o~idases and dchydrogcnasc..~. 8:.amplcs include r;lucose o"idasc, xanthine o"ldase. cytochrome reductase. and acy l·CoA dehydrogena.-c , The riboflavin moiety of the complex is coo~idcred a hydrogcn' lrnnspon ing agcnt (carrier) functioning as a hydrogen acceptor: the hydrogen d0nors may be NA I)H , NA[)I'H, or some suitable su bSlr~te. The isoallon;tine rings accept twO hydridcutcpwi!;C to fonn the di hydroribo fiavin deri vat i~e ,
y O
"
1llc vitamin is commercially .vailable 15 nboO.vm. riboflavin .'i-phosphate. and riboflavin 5·phl)5phate sodIUm. "The phosp/late esters a~ usaj comn.... dally on ly in multivitamin preparations. and they ~ hydrolyltd before aMorpI:ton occurs.. Absorption (,IIIXUQ through an active transport S)'$tem in \\'hich riboflavin i5 phosphorylated by the intestinal mu · cosa during absol'ptton. Fuod and bile enhallCC absorpt.on. Riboflavin is distributed widely in the body, with limited Sl0rt'5 in the Ih ·er. spleen. hean. and kidneys. Con\ersion to FA D occurs primari ly in the liver. FMN . nd FAD circulate primarily protein bou nd. Only small amooms ( -lJ'l,) ~ excreted in the urine uncllanged. Larger alJl(Mlms can be found after adm inistr3tion of large doses, Severe riboflavin defidency is known as uriboj1(JI'inosis. Its major S)'mplOms include cheilosis. IiCborrhcic dcooatiti s. and vasculariUltion of lhe cornea. Ariboflavinosis occurs in chronic alcoholism in combi nation with other vi lBmin defi · cie ncies. It has also resulted from phenothill1.ine, lricyclic IlfItidcpn::s~anl, and probenecid thcrupy. Riboflavin hM no pharmacological action and is relatively nonto~ic. 1be on ly approved indicalion is in the 1tealmc nt and preventioo of aribofla vinosis.
QII··"1d Speclll
P"ldoxl_ [n 1935. the term I'i/(lmin 8 6 was applied 10 lhe principle
PRODUCTS Ribof la",;n, US" . Rlboflav,", loctofla\i n, vi lamin B~. Vlwmn G. is a yellow to orange-ydlow, crylitlllline pov.'dcr '''1m. slight odor. It is soluble in WAter 1:3.000 10 1:20.000 mL '11m the ~ariall()l1 in ~Iubili ly bemg due to diffelcnc::es ID internal cryStalline ~lIUCl u~. but il is IT1(l('e !IOluble in an OOtonic so!utton of ~lium chloride. A salUrutcd aqueous solution has a pH 0(6. R lbofla~m ha$ a pI{" of 10.5, It is less soluble in Ilkoholand insoluble in et~r 01' chloruform, Benzyl alcohol (3% ), gennsic acid (3%). urea in varying IIIlOUnIS, and niacmamlde a~ used to solubil i1-t riboflavin ... hen relacively high concentrations orit a~ needed for par· rntcr.lI solutions. Gentisic cmlU'lOl amide and sodium 3·hy· dro~y·2 ·nnphthoate alC is fourK! in many cell types. ahhouglt other enlYIllCli Invuh'ed in the irneI"Colwersions are oot elF pres.'itd in all cells. ' l j Aithouglliarge amounts orlhe \ltaJrul are fourK! in the liver. the mU t)nl 3in ~ glycoside of pyridoxol. which is inc luded in "i,amln cootcnt determinations. Although this conjugate is ubsofbo:d. it IS IlOI used wdl. ~ Thi~ may explain the klwer Irioavailability of the vitumin frum planl sources than (rom 3nimlll wurcc:s. OH OH OH
5-~~IYCOaPYfanosyl) Pyrldoxol Vitamin B~ is obsomoo via passive diffusion. chieO y in the jt'junum, :II1d transported to lhe liver. The: liver is a majocorgan of Storage (1610 27 mS). ntetabolism. and interronveTsion betwet':n the three forms. Excess B~ is oxidized to 4· p)'ridoxic acid. This acid is lhe primary form found in the urine. accounting for up 10 60% of ingesled ~ilU lllln B~. In the Ih·eT. all tiutt fOlmS are COO\'erled to p)'ridoxal 5phosphute. which circulates in the blood bound 10 albumin .
SilI_
Befon: entry into cells. the phosphate must be cIc:~. lated.lnside the t"etls. pyridoxpl kinase ~phosphorylalestht vitamin. Thi s kil\llSe is found in many cell types. uhhoup other enzymes involved III the interconver$ioru aI"e not n· p~.ssW in all cells. 'u Although large amounts of the vitarni~ are found in the Ih·er. the muscle, conlam higher arnIlUIII.I in lhe fonn of glycogen phosphol"ylusc.':ZII> This vitamIn 80 is nQI ~adily avullable. ho .. ner. dunngdeficiency sules. 1TI Pyridoxal 5·phosphate is a coen/ynle I~. '19 that perfOlllli many vilal functions in human metabolism. II fUOCliOlll ~ the trnnsammations and decarboxylmions thaI amlllo aclCh gencnal1y ulldergo. For eumple, il funclioos lIS a OOIfl\1\samJ' nase In the lI'11l1saminauOIl of alanine to fonn pyf\l\lc ICId and u a eudecarbox yla~ in the Oi:cllfbox)'lD.lion of dopa ICI form dopamine. 0Iher biological trlnsfonn:IIlOlls :" 11:1 ci ' amino acids in wh Ich pyridoxal can function are nlCelTilntion. Chmmalion of the a-hydrogcn together with a ,B-sumut· uent (i.e .. 0 11 or SH) or a ,..wb$tnu~nI. and probably th: !'C\·t'TSible elea\'lI8c of ,B-hydroxyarnioo Kids 10 Glycine . . carbon),1 compounds. An eleclromeric displacemem of electron~ from 1:IoIxb a. b. or c (see diagnam below) wou ld ~II in !he ~leasc cil c:II;on (H. R'. or COOH) and. sub.equently. lead 10 II\( van· ely of ~actlons obsCl ,'Cd with pyridoxal. The: CJ.lent IQ.,.iIIdt one of these di~placemcnts pmrominatcs over othel'! titpend~ 00 !he structu~oflhe amino acid and the en\'iron_ (pH. ~ol~cnl. calaly~ts. en/) 1nC5. and sueh). When thI SItIC'dIanism applies in vh·o. the p),ridoxal component is hnlt(! III the en/)'mt through tile: phosphate or tile: h)droxymrtlt)l group. Metals such lIS iron and aluminum. which markedly c:uIy/_e nonen/,ymatic ttalls:aminmions in vitm. probably do 10 by protllOling fonn:llion of !he SchilT base and m:ullWllilJ planari ty of the conjugulcd system Ihrough clle:lalc nng ((I'. m:llion. which rtquill's the prt'SI:t1Ce of the pht:noIic poop This chelaled metal ion also provides an addniooai ebb..
------------------------------------------.....
b
heterocyclic nUl'Ogen alom (or nuro group), \hercl>y increasmg the clecuoo displacemcnts from the a"C already obtained vi tamin B ,~, The only dtclary plan! pr(MI.
'''$lou.
4-Desoxypyrldo.,! Because of ioadequate diets, Kimel in fants suffer from scvere vitamin 8 6 deficiencie$ that can Icad 10 cpi lepsy-li t t t"oovulsive M'izu!\'.'i, and the convul~ions can be COfllrol1ed by trealmeot "'ith pyrido~me. I The l"UllVulsions arc bel ieved to be dill: to belo",·normalavallllbihty of the centrlll IICn."OUS
R.
-CHa
R,. -OH
Hydtoxycobalamin M&thyleobatamlll Adenosylcobalamill (Vitamin BI2 coenzyme)
IICtS
COIlIDIDlng the v;r.mm are legumes. because of wlr
qmblo.o>Is with mk"roorganjsnl~. Ikcausc dietary vitamlJl Su is protei n bound, the lirst lIep in absorption is il~ I'I:lc~ISC in the ~Iomach. I(clcpsc is enhanced by gaslnc pH and plmcrcalK: protcases. llIe freed vitamin i5 bound immediately to a glycopmtein. the inlrlmic /«,1"', SCCR:u:d by pancml ccll~ of the gastric nulCosa. The ' iwnin a u-intri nsic factor complex is ~ed 10 the InlaUIIC:S, II-here it bulds With rteepl~ in !be ileum. Absorpuon Ii m;unly by an :len,'c PO IXCI\J... tlleh can be salUtlUed by 1.5 10 3 ~g of, iUt/mll BIl _fuccss amountS may be absorocd pas.~I \·cly.
'n the intesti nal cetl~. the comple)!. iq broken 1100 "hamin H'l is abSOl'bc:d into the blood. wllere it bi nds 10 tnlnscooolamin II , 11 ,8-globu lin, for distribution. In the liver. the vi la min is ronlerted 10 the :.clive form (IrId Slon:d lIS such. Up .. ~ of rhe vitamin (j 10 I J Illg) iJ 51on:d in rhe Im:l". Vltamm 8 ,~ i~ ncrcted through the bile and undergoes ex!mS11"C reabsorption . In the bio in carrotS. Folic acid occurs in ,he Iliet as pteroylpolyglutllmates thaI mUSI be hydroly1.cd to the monoglutamates before absorption. The hydrolysis is cal ul ylCll by pteroyl·y-g lutumy l carboxy-peptidase. fouoo in the membrane of the intestinal mu cosa. The monoglutrunate5 an: absorbed lICIively io the jejuoum lind upper duodenum . This absorptioo is pll seMitive and is facilitated by the slightly acidic coodi,iom fouod in these regiOO5. 1lIC vitamin is transported as mooogluta· males bound to album.n.
""'Y'l" - ""~H"'y,N
I
,
n • I • Pteroylglutamic acid o • 6. Pteroylpolyglutamic acid Although the mucosa in these regions pO..'SM dlhydrofolate reductue. moS! rrouclioo aod methylatioll occur In the liver. TI-IF A .s diSlributaJ 10 aJl lissues. where it is siored as polyglutamatl':5. The N'.mcthyl derivati,'e is the roam transpor1 asid storage fonn in the body. 1lIC body 51~S 5 to 10 mg. approxinmtcly 5O'l> in the liver. 1lIC major elimination pathway for the vilamin is bil iary c~cl'Clioo :t5 the N'-methyl derivlltive. Elltensive reabsorptioo occu~. Only lrac:e amounts ure found in the urine. Large doses thut exceed the lUbular reabSOrpiion limil . however, resul! in subs1Dntial arnOllnls io the urine. As with vilamin 8 1:. folic acid defICiencies m.ainly result from malabsol'ptioo or alooholism. No neurological abnormalit>es are aSJocialed with folic acid defICiency. llII': resulling mcgalob'lLStic anemia is indistinguishable from that uused by vit3min Hu because both vitamins are in\'olved in the c rilical biochemical step. Folic acid can CUllect the anemia caused by vitamin 8 11 deficiency. but it has- no effecl 00 the neurological damage. Thus, oo ly small amounts Ire foond in over-the-counler preparatioos. Folic acid !MIministcred to healthy !MIu Its in a daily do!;e of IS mg for I month rt'Sul1ed in gastrointeslinal disturbances (inc luding anOl"ell ia, nausea and pain) aod ccntr:ll nervou s syste m effe for III the war bet"tE01 Sweden .md RIJSW (most h~eIy lhe march of Charles X1t mlO !he Ukraone in the ........ ler of t 708- 1709) alrOO'!iI ,H 0/ the sokf:.s of !he S·"etlosh army ~ ncapKltilted by ~ But further plogress of the ~ was slOWitilol. meso-inosi tol (lPI)'()o ioositol. ITIQIlse antiaJopccia factor). is prepared from nalUral sourttS such as com steep hqUOl"li IUld is available in limited commercial qUlllltities. It is a ",hite crystalline po"'lder thai t.S soluble In water 1:6 and in dilute akohol. It is slightly soluble 111 llioohol. the usual organic solvenlS. and fixed oi ls. It I~ stable under normal storage conditions.
InO'I,ol ha, bo.'Cn found in mosl pl:un aud IIrllmaJ h'loUh. II h:t.~ been i.;oll,tOO from ce~al g ..~ins. other planl part!. cgg~. blood. nllll;. li'·cr. bmin. lldllCY. hean mu to be fully undeNood. Cyclic pipsphoinositol deri .. ati, t"S appear al 67. AHPS """ In(.. .VlOO:!OOO BttIIQda. MD, """" • • Srx'oft! ~ IkakIt-Syoaeoa Pboqoy:, ..... 2(l(/. p. 1!7j bit Mdbuoh) . E.: I .. ,t 1.107. 1919 til lIukl>o..hl!\ll.). K..: Dbcb. Mtd. ....... l>trIo·_. J Vin,m. I","". (1.r&I •. "'ft! . .lOU1· 8-11,1,",,-, l!l 1Idr= K • • ~.t N F...,t . J ....od. ]).11.l6') 1173. l~ J6 ..... aId, O· /'IM_ 21'1"800. 1\161. .17. Mo--. R. A 11_ SnIs. PIty""'- 711'111.)). 1972 3S. \(JilC'".O S, and Men,... F_ L: Ace. Chern. Ite. 8.MI. 1975. 19 11uIlbc-1. W L. Aa:. 0.. .... II.... 1975, -10. ltoml, B•• Cl.l, A,, /)tl( ft!. New Yorl. McGn ... -lhll. 1971. lIP 1173-1171 4S Bmy. II. J. C........ " J • ..J RMo.h. II II I 8d 0..•. 164 92.11. 1'I8\l 46. s-i. J. C. ad 8,,,,, 'I- 1..: BoopIr) .. Aal711>.l66. 1982.
47. Wolf. (;. J 101,," Ihoc,,"m. U8-I-m, 19'10 48. I>. ' L . De, tl
IOS.IW7
M .".t~
•
Am. J K....,. DoL. J A."'" Srouie. J W . J. 8oe1
a.... 2-.
~7""-47u.. 1975 97 S ....Ik>.J.• ~.'- Pmc . NMI Acad.SIlerJI1. V W M . ~ .I UIot>J M 444--4S1. 1'lIlS
101 'hhN!;k. 8 , - ' SInIlo. J I'n>:, !'1M:!. An." $ci, U. S A.. 71 1312-U I6. 1981 102. So"lk'. J . W FASE8 J , ... '....cI2. 199) IOJ. 5 'ow ..... J A~ ft Ii., SW ..1Ift . . , I ,"" 0( _ . _ 01 ....... lI: 'Of I • • ' In f\oIler, L . aood Ilinh. J (e*-.I. Oral .... ,~ 101.
lOS. 106.
107.
. .,-", ~. AmoId. 199601 ..... It B.. .... Suruo, J W.: Vilanl.. IIomL :U.59_ IOI. 19n. Dowd, P., e of herbal
drug5 has been nearly IlOOI:lliSlent f(M" years. Henct', hc:rbIl users are left In their n,,'Tl dc"ires regarding dlOlCI:. _tty, and qualily of the herb chosen. Until 1882.s a numbcr nr drug~ were IIlOnOJrIPhed IDlI describtd in The United SWl~S PhtJrmlK~i(J. Gin>eag. f(M" example. was clearly etlarllcl~rized as a dru! and In 1916. the Nanonal Formulary of the Unued SlaIC!i ltSlal the root5 of both Ii.. tJIrgumfolltJ and E. (Nrl/llia as otr... iaI. and the diqincllon belween the two begall to be forb'Ollell. In about 1950, E, l'urpurM was introduced a" the pl1ltllf) medicinal plant In Europe, Of the tiutt ~ICS. £. pall" is the most "iddy culli\'atcd.. the !allesl. and h:b the ~ flowers. Thr~ i~ considered the official prcraraJion In IIIr Uni ted States. 1-;' pur/lJlfta root preparalloos are SOiTlC1ltm lIuulternted "'Ith u ~I mtlar-luo~i!lg plam called PIJrthlfllU/II illll'wifolium. HPl.C lmaly"s ,'an em;ll), octect the adullm1100. 21 TIle alll,we show~ how dlffi.;ul! it is to ~tlnr:lard!lr echmacca rrcparatiollS. Addmonaliy. oplmOll~ dIffer about Yo hich plant OOl11po01l('nt ,~ the: be:;t anal) tIcal loI:1nd3nll1l_ tion of the drug, l~hinace~l conl,lin~ a series of phenyl]l1'O]!lnoid glyeosiun. t'Chm~ioc. ~erbascosl(\c. 3nd 6-0el)' wcll possess IICtivity. One notable: effect is Lhc !illti-inflammatol)' cffcct of II high-molccular-wciahtlllllbinogaJactan thot is about as po-
Feverfew. TfI"OCft/UIfI {J(Jrfhf!,,;Utn (L. ) Schull]. Sip.l . is an herb Ihal was u...cd in ant iqui ty to reduce fever and pain. TIM: litcrawl"e is replete with anecdotal cvidencc of the usefulness of the: herb. and ~nt clinical studies !Ia"e added more: suppon. Fe,'crfcw is a membCl" of the :lStcrfdaisy family. llIc plant tissues havc a pungcnt smell and very biucr taste. 'The Ill('dieinal principle of feverfew is (:oncelilratcd in hall)' tri.:.:homcs on the: chI)'5aIlthe:mum·l i1o:e lea\cs.J1 TIlC plant displ~ys clusters of daisy-likc flowcrs with ycllow ttntcrs and radiating "hllc fl()l1:ts. Rc:cent USC$ of fc>'crfcw arc: for migrJinc and anhrilis. although the indica lloo for anhritis is disputable . 1bc anecdotal evidcocc thai an herb oould sua:c:ssfully ~at acondil;oo soch as migraine headache nalul3lly begged for sorl1e ~ic:ntific proof. Two prospective el inkaJ sludic:s IIs;ng dried whole fever· few leaf have been pcrformedl.l· "", to assess the value of the herb in migraine. T1ic: IWO tear studies OIl migraine prov;Ocd good supponh'c evidence for lICtiVl ty or the herb agaillSt m;~inc. Both studies ,,·ere double blinded. pl:nbo con trol led. gnd standardized on 0.54 m@ panhe:lIOlillc per capsule. In both §ludics. the fevcrfew group demonstrated si@nificant dec~ in frequency. scven ly of attacks. and
nausea and vomiung. No OO\'erse effecu ...-crt: obscnied of the oonstcroHlal anti-inflamnuuOly drug fNSA IO) type.
MECHANISM OF ACTION Fevcrfew Inhibils prostaglandin synthc~I~. but not through 3n effect on COX.'" The he:rb alS() inhibIts lhe synthesis of thl'QmbQ~:me . ~ain by a COX.illdepclldenl mechanism. Addiuomdly. fC"crfew inhibits the syn thc~is of pho!;pholipaile Al in platelets..II>. ·n preventi ng the liher--IlioJl of ar--IChidonie acid from mcmbrnoe pllospiloJipids for sub!;cqucm convcr;ion to prostaglandins and Ihrombonoe. Fcvcrfew also inhibil ~ the ADP-. collagen-. and thrombin-ind~d~ grt:gation of platelcts. Mlggc>ting th:1I the hcrb ha~ a greater thrombotic effect. In another. similar siudy. dried leaves of fC"erfcw inhibited prostaglandin and thrt)mbQ~!U~ sy nthesis In platclcl:s and inhibitoo plotclc! ~gatlOll mlti:II~'d by AnI' and collagen.'" Surprisingly. this stud) st.o-..ed that fcverfew inhibited the p!:lIelcl·rdeasc rcacuon by "'hich Inlrucc:llular StOl1lgc granules are rt:lcascd. 19 ~ stor...gc gnll1ules contain serotonm, a positj,'c cffector In migrdine headoche. Some of tile more surpri~j nl findings for fcvcrfcw arc that il appear.; to be a selectivc inhibitor of iruluciblc COX_2.oo and it has clear effects on voscular tone in unim:,1 models. The phlLnnacologically active eon~t ltucnl in feverfew luis typically been eQIIsitlered to be purthenolide,"' an amphiphi lie sc:squiterpcoe lactone that i~ blosymhc:siud from the germocl'llnolidc eauon. Panhenolide I~ ~nt In much greater quanmies than any of the OIhereon~titucnts. and illl ~nce docs 5«m toco.. datc with IIctL~ity. alleast In dried lea\·es,. Panheoolide is an a-mcthylcoe lactone,": an O'.,8-uns:uuruted nMi1ecu1e that can.serve a.~ an OC«plOf III the: Michael reac1lOn. In the Michael rcac\K)l1, a dorIOr nutlcophile such u a thiQl can allack" the acceptOf 10 fonn a covalent adduct. If .,..rthenolide functions thi s way, a biological nutleophile such as II thiol on an enqmc eoo lll be bound. inactivating that enzyme, The likelihood of Ih,s mcch:lIlislII has been sllo..... n by successfully forming adduct ~ with parthenolide ;\SClf in vivo ....... 11le other eOlllpooen\li-canin, (lJleca-
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Saint John's Wort Saint John 's won (Hy~riC'um ~rf(),/jfum) IS II mcdlCio.al herb that has been used since tile tillle of PlIracdsus ( 149J- IS4I ) to treat II variety of psychiatric dl~ Today, lho! herb rt:mains one of the: IJlO§t imponunt psy.hotropic drugs in Germany and Western Europe for the tfnl' t1~nt of dcpfC.~sion . anxiety. and ner\·oosness.* The: has recently beCQITIC popul;lr among cOIlSu mc!'5 in the Uruted States. The demand for the drug in the United StaltS ~ been fueled by Gennan ~tuditS that reported that St John'l won ..... 3.'1 equierrecti~e with nuo~etine In the trcatmenl of deprt'SSion. Some Imeruting cm:umstances give the herb tlllllall\"The plant t~ I low-growing shrub that gruv.·s '" lid In Europtand Western Asia \\'llh yellow n'lWel'S that bloom .rt.lWIII June 24, the trad1lJ'lnai b,rthdate of St. John. If the nO'Wl"Cn IITl: rubbed. a rt.'d pigment is rt:leascd. Thl~ red subsiMlft has tntditionally bec'n associaled with the: blood of St. JdJI rcle~d at his beheading. The medicinal components of SI. Johll '~ won arc den_til frolll the nowerillg toP). A 200 1 study in JAMA, howc,·tt. negate.~ uOOut 30 previoosly publ i~hcd trial~ and showed \h.JI SI. John '~ woo failed to improve major depressi"e dl!oOldcr in the fircntS up to 1.5% of thoe plant. Two majOf compone nts in the oleoresin (among sever,d) ure capsaicin and 6.7- oi l. consisung of
Anticancer drugs derilled from biological 'lQUn:es ~ faIrly common arid ore among the n1O!it important in the therapeutIC armamcntanum. Drugs like doxorublCLII. mitOl11ycin C, mithramycin. and bleomycin ha ..e been around for a 1008 time arid have shed much light 00 the tl't'atme m of cancer. Thl't'e pl ant-derived drugs thai ha lle found lheir way through clinical tnals dc:scTlle menuon IIcre. T \\.·o of the m~t famou~ arc .. incri,tine arid vinblastine. "llK'..e arc compounr.!s i~., In ....... ,.",. I.. D~ ..... 0-.. II (edl.). PIor-",,,- 01 ~, ~ - ' O~"' . . al AcU"zy. A......cIIII Chet.oeaI Sox"'y S)D.- I".. Se· rie!.. New V",l. o.r.... Un .. n~ny"""" 11l9ll. pp. I jj- I ~
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402.M_9Il. 1997 ~. F.• -t 'ldnu. C. "")"",,"'nuwy 2U$4J - 2!I49. I9I!. K~pI, )94"-165. 1917, 1I. ""n",II. S.• A........ D. V C .. D• .....".. B. A ... II.. J l'harm. i'IIan'RaroI • .u:.l9I - J')'. 1992. ()cl".'~ f! ~...... ~ 1999 It""..... II O~ Ck,, ' ,T ..... hioIocr 01 1St. JduI'. Won). h. L.o,,'_. L 0 .. IZJ'd Bauer. It. Ir,. I.. II~ '" lIubl .. n. I Il. " , , tc ... _ ). IJIilI ..... 1'11,)"1"1",, Fcboluy l1lt: by computational chemists. In reality. drug discovery is so ulldcniably ~'Omplicated that no one si ngle method geller-oIUy can be crediTed for the complete dc5ign of a drug. An arsenal of methods frOlO di\'crse scientific areII-' is brought 10 bear on drug diSCQvery problems. TIM: scientists involved ha\'c 10 interpret the dum. Although molecular modeling methods are just Mother tool 10 help scicn· tisl.~ make infonncd decisions on what lead compound~ to pursue alld whaT stnlctural featureS should be rnodified to
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enhance btoioglCliI activity. there is an Inherenl lIppcal IIS5Odated ..... ith \,isuali/,utiOfl and predictions. In the final analysi~. scientists.. not computcrs. "dcsign" drugs. CA DD has IWO fundamental roles to play in drug research: lefUl disl'Ol'ery and InuJ dt'l~lopmerll. OuOIl8 the late 20th ~nlury. there were many case hiSlOo nes of accurale predictions of in vitro biologIcal activity ba.'itd on so-called rllliOltlli urug design aJlllfOKhe~. In the 197Ol;, Corwin Hanseh demon~t.rated tnat simpk- rt'gression swi~ics cou ld be used to COfttlate bioloJlical activity indiIUdy 10 molecular structure through physkal propen io ~uch as hydrophobici ty (log I'). electron ic (u). and slcnc (ET) effects (Chap!eT 2). 'The seminal COIltnbotions of Han-'iCh dcmooSlrnled the povoer of QSA R and he lped 10 usher in the era o f com pule r-based model ing for molecular design. Beginning in the 1980s. there .....ere many reporu or com· puler· bilset:\ predtChOOS of tn vi tro biolo&ical activi ty. TIlls IS 110( unreasonable. ~ince then: are fe .....er pharmacodynamic and phanll3Cokinetic variables 10 be considered with in vilro testing than wi lh in vivo tc-~Ii ng. 'The use of slructure-ba..'itd design has gro ....·n in imponance since the carly 1980s. Today. there are many ex.amples of drug.' on the market or in cliniul tria ls for which COIllputcr-b,lsed melhods. particularly ~truct ure·based drug design. have played cenu"dl wle... in thei r developn'lelM. No si ngle chapter can provide all the dellli ied infOffl1lltion necessary to master this specia lty. which ra nges from quan. tum phy~ics t03D iliuabac;c searching. Many of the subtopks discussed hase h3d entire boots or 5('rie' of bool5 Ue\·oted to them. and a complete discus..~;on of each topic i~ simply bocyond the scopeofthiHhaptcr and the purpose of thc book. Instelld. the gool of this chapt er is to provide a brief and accurote ovel'\liew of a select Sl'I of compullitiOllOlI chemistry and CADD methods. highlighted wi th examples when ap_ propriate. In SQme cases. the COllCCptS arc simplified or gt:net'1lli/.cd 10 ma ke sense of them in a few pages. but this is done wi thoul SlI(:rifidng accuracy SO thai the interested reader can continue future studies with a solid foundation in the fundamcnlals. Finally. compu ter-based methods do not Il,'plllCe C)(penml'n tal me thods. In rllCL the purpose of CA DI) i~ to aid pharmaceut ical scientists in the discovery proce~s ..... hether thtoogh simple \ 'isualiuuion or the com· piC)( formulation o f a pharmacophore model and SllItislical modI'ling.
COMPUTER GRAPHICS AND MOLECULAR VISUALIZATION Ever since chemist~ have la.vgni1.cd Ihal molecu lcs are made up of atonts, there have bee n cFfons 10 represent 11100 ... lecular structures accuflltely. One of the. first allemp's to de\'elop molecular models can be traced 10 the earty ISOOl> \\-Ilcn John Dalton used \\-'oodcn spheres dri lled wilh holes to accept meta l rod lin kers as representations of at()m s and chemICal bond.o;;. respectivcly. 'The origi nal mechanical mode ls are on display at the London MUSel.lm ofScicnce. l . l Prior to compu ter graphics. the fundamen tal pri nci ples now associated with CA DD (or nlO lecular modeli ng) wen: used for some landmark diSCO\'mes in structural biology. Unqucslionably. one of the most widely n:oognlud scien-
tirlC achie\'ementli WIIS the conSirueUOl1 of a DNA model proposetl by Walson and Crick in 1953.l 1lle structure 1m wi thstood the te~t of time. lelldmg to II shared Nobel I'n..if for Wlltson and Cnck and seu ing the stage for the age of biotechnology. Imllally. crude moOel~ ..... ere crafted from cardboard. Once a beller un.Jc,...tandm, of !he structural 11:. quircments of the nucletc acid~ was de\doped. liMn ami· rate physiealmodc ls \\-en: prcpull,'d from IllCtal. OngHl dooe years ago wlIh h:mdhdd modd~, it i~ relat ivel), easy to query II compuler-genemted molecular di imposslbk- IO answer by experimcnl\ alQIIC . Just whUI kind of predictions can be made ? Energy-oosed calcul0l;on5 have been used 10 predict and to understand molecu lar geonrctry. chemica l condition,. chemical reaction pathways, and transi tion Sillies. as we ll as phySical. AD M!!. and biological propertit~. Usually. computer ~imuiatioos arc k:ss CJlpen~lve and rcquire les.s time than carrying oot phy \ ical eJiperiments. In gel1l'r:tl, rotrf/lrlllll;OIIol Chtmrslry n:fers to enl''l)'based methods. CADO IS a moR: all-cncomp.us'"g term. ineluding not only energy-b.tscd calculations but also QSA R. database !!Carching. and phaml3Cophore perception methods. Computational chemistry approachcli can be di· vided IntO two brood categories: quantum mechan ics-based and classkal n1C1;hanics-based. The former co~el'!l the areas of semiempirical. ab initio. and density flll\ChOn~1 theory. Till- luner re fers to force field (molecular mechlll1ic~) calculatiom arKI n10lcculllt dynamic~ si rnu lmions. Each nlCthod h.as its Mrengt h~ and wcai;:l)Csse,IlIT L.J n, .. "," LJI' Tobie 28-1 _IM,)IIS tile three pos~iblc axial and Cilualorial confomlalions. SUb§lilulion in Equat ion 28·27 gcnt:r.lIc~ tile calculated rulio of each confomxr. Because MMf'l'94 was parameterized 10 reproduce Ihe quantum mechanical calculations. il Ii IIlustrntl\t 10 loot al the ,,11;0 calculated wilh MMFF9.$. The BoIl7.m:mn-a>erogcd dids down the road. OOt w;th a ~ probabili ty 0{ lirld ing all tbe pothol es. S~stemat ic sea!'l:hing gcnernlly ca n001 handle: soh·em ... and the method IS oo ly amenable to ~arc hing fcwcr Ihan 10 dihedral ang lc,~, becau geocrated rise!! exponentially wllh the: number of I:Jonch rolilted, Torsion anGlc driving ;s GS ..... hile the reS! uf lilt stt'\lClure ( .... ith the C~CCplJ()I1 of the 101'51011 bemj; ~y\lemau ca lly rotat ed) i ~ ellCrgy nunnniled. Many pmgnuTlS have tI1is fealure, arid accurate conformallooal enr:rgino arc obtained with lhe minimi/,lllhm. NoosyslCmalJc ClIssion for the: drug- protein binding). TIrere ute 110'0 t}lpes of mOllon (hannonK: and stochustlCl thm may be siodied by MD simullltiQn~. Ifllnllom r: siml/II/' liolls refer to o!ICiJl:11 ions ncnr equi librium (i.e .. near the min· IlIIum of a pll(cnl inl energy II ell). SIQt:hllSlic refet!i t(, SI11IUia · lioo~ Ihal Ic:ad from 011( local minimum 10 another loenl nnnnnum. From a harmonic OI'Cillmor.lhe frcqUO!:ocle\ may be caJculatrd occording 10 Equa!ion 28-42 ..... here k is lhe: stretching comllln! and m is the 1n35\. Exlending lhe: conccpt from II ~lDglc 11Iass held to a surface by n spring 10 N pnl1icles r.:quires un eXlension of lhe Taylor series expan)iOfl (Eq. 28·13) \0 II m~lri~ fonnululioll of partin] ..cco11d deril' ~li I'es. f:.ach rnode has as.socialed il5 own fun.-e constant. f rt'qucncy. lU1d 3N ll']auI'e dlspl:icenloC11IS , TIre norm:1I mode~ are asSigned 10 the: experimental 1M or Raman spectrum.
• MD simulalions hal'e Ilcen npplicd 11.1 gcncrute new CQnfonllmiOI1~.l'. 88 TIle oo\ic ide:1 is to itdd ClIO\lllb IJrermJ] entrgy (through high tempc:rutures) and calTY out the ~i lllu latiQns looli: ellO\lgh ror rhe molcculur systems to OIerrome conformational barric,," After the: simulalions are com pleled. the: lrujeclory Clln be rel·leVled. 100 lemptnllure of rile syqe m caro be eook'd OOVl'n to sample poIential new conformations. MO ~Irnulations are ) uit:rble for larger molecules. and soh'cm may be irocJuOed. No sUill., ticnl or gt'Ometrical means Ilrt' u-.ed to deterrn; nc their ~'OI11pleteOC!os. In 1.'C'lCrul, M0 NinrulHliQn~ are 1104 us cfIkicnt as stochaSlic or dbumce gc:omcll)' methods.
QUANTUM MECHANICS Ooe of the grent Ih~'Of'Ctical accomplishments of the 20th ccntury .... a\ the development of qU1lnlum mechaniI:S." The phi lo!>Ophi~al illlcrprelaliollS of quantum nll.-chani~~ lI1ay he comidered weird from the ~talldpoillt of our practical everyday eApc:ricnee, in lhe macroscopic Vlurld. Nelcrthek,s. the applications of quantum mechanics 10 I:he:mical bonding hale changed the: VI ay l:he:misl' Ihml. about molCC1.llar st1\lC· ture~ and hall: made: chemi,tr)' u \tJbdi\Ciphne of phys ics. MlIIIy uneAplamed che:nucal effech may be undcrMood in lhe conlext of molecular orbilal (MO) calculallon~. For ('J.ample . the nnomcric effect Seh of GT functions (e.g .. 6-31IG ). I}oO An a(kh!looul SCt ofvcry dIffuse: funclion" cun be added 10 the model to help calculate roep· li,-ciy charged species or hydrogen bolllJing. denoted by Ihe plu s ~ign in the e"amplcs 6·3 1 + G(d.p) and (). 311 +G(d .PI.m I"., An ilCrtlti.e iOOlutiOfl of the Hartree· Fock· Rootllaan I:qUJ· !lOll! is requiR:d for semK'mpiricaJ and all iniuo quanrum cbemleal calculatlon~. I)7. I "" lbc: approach i~ abo callft! tb: ,,,,If-C'Ollsistent field (SCf) IIpproach. In SCF calculatlOR\, each sillgle electron' , positiun in space IS optlmlled in tb: cloonc field of all the other electrons. Thl~ ptOttdurt tl I'!'pealed unlll all lhe electroo posilion ~ M' e beocn npllIm/td. and there IS no further significant drop III enerar IhrouP lhe adJuSllncl1l of the electron positions. lhrtree·Fock (H~l calC'ulntion~ gi\c good resulL~. lbe bcw:r the b~IS 'itt. tb: luwcr the CI1I:'1l1Y according to the variational theorem, Thrn contes a point of dimini~hillg returns. huwc\·er. in thai lhe: crlergy appruoches a limit known as the Hunree-Fod hlllll, No further ooJllstment in the basis !OCt breaks thi S barril:l'. lbc: H w1ree· Foc~ limil ocrUI'l' because the el«tron mota is comlated. aoo this is not accoullted for in a ~inGIc: SI~\eI dctermmanl. Thai ' So the adjustmc:nt of one electron aITo:cb the pos.UOfl of the other electrons. and thi s is not fully talCII onto accounl by the SCF approach. Tu circum'cllt not Wlna: electron com:latlOll into account, post·SCF calculJtlOlll mu't be used in the fonn of coofigur:ltion IIltCDCIIOl1 Of ~rturblllioo rncthods.
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211 • Compwmru",,,/ Clwmi. J, The often-dted design of the fir1lt angiotensinoCnts one of the first successful Siruclllre·ooscd drug de,~ign approacllcs . 'There is 3 growing body of successful eKomples using S/ructure·ba~
drug design approaches. Today, many of these Ita,-", re.whed in approved drugs. 'These methods are applied widely when IllipiopriaJe experimental dala are available. Struclure-Nscd drug design is now consKkn:d a standard approach 10 drug design. ai>d the question posed early can be answered wilh specific cumples. In the 191ID>. the target cnlymc for Inhibitor design was DHFR. as di'\eu,sed above. In the 1990s, the larget cn~yme
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'''' Figu re 28- 25 • WIth the atd of xray data and molecular mo(le-Im!!_ SCe'1l!Sts designed tnmethopnm (TMP). 13. ana~ues that had up to SS-fold h.gher enzyrTM! afllnity thaf1 the parenl InhIbitor
In the IDle 1990s. seyer.1 H IV-I proIease inhIbitors "'"CfC introduced inlO the: market that ....at designed u:sing 1111(lure-based methods (Fig. 28_27).'.H.. 139 llolTmann _La Rodlt scienliSIS used modeling methods to desig n S:lquina,'u 'flO (Fonovast, hwira.o;e ) 15. which was the fil'$! protease in/ubilor 10 be appro,·ed. The drug was \1lade a vailable In JUIII: 1995 through a cOfnpassionlUe treatment program. ID\'1I_ was giycn Food and Drug Administflliion (FDA) appro,A. Ottember 1995. and FonOVIiSC .... as appro'·w in NOlcmbrr 1997. hld inavir • (Cnxi~an). 16. W1IS dc"e1opa.i by MtTtt ' ' scientists and gi~en qu~1t approval in only 42 days in M.m::It 1996. In March 1996. Abbotl re(;elvcd approval for Rnonayir'fef1t of Cosopt. was the f!f';\ dUlg desf9n«I WIth structure-based (ADD methock to become oommel'oaIty available "11(-927, 21, IS a clost structural 'r'Iere .s a linuled SCI of conformations that all acli,'c compoond (Wi th approprialt functional groups) ma)' adopt. BIOLogIcal inocu\"lIy I~ assumed. as a tirst apprOllunalioo. 10 re,u lt fTOfI! Ihe competition between .mall moIccu les and rhe rccePlor foroccup;ltion of the same phySical iluct_ 10 /)"7"""" M«hIz>. i. U
figure 28- 30 • PfedictrveADME IS becom'ng more ,mportAnt 11 t/1f .inly stag !s of drug ckos>gn, Orug-drug and food-drug nteac:bOOS have lesulted If) two fOA·appro.ed dlugs. m,bf. fr~l (PosIcor), 23, and terlenadi~ (Seldelne), 24, being IefIlO.ed from tM market IfI reeenl years_
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