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Chapter 28

Angiotensin-Converting Enzyme Inhibitors, Antagonists and Calcium Blockers

Marc Harrold

The Renin-Angiotensin Pathway

The ren in -angio tens in system is a complex, h ighly regula ted pa thway tha t is in tegra l in the regu la t ion of

b lood volume, e lect ro ly te ba lance, and a r ter ia l b lood p ressure . I t cons is ts o f two ma in enzymes , ren in and

angio tens in -conver t ing enzyme (ACE), the pr imary purpose o f wh ich is to re lease ang io tens in I I f rom i ts

endogenous p recursor , ang io tens inogen (Fig . 28 .1) . Ang iotens in I I is a potent vasoconst r ic tor tha t a f fects

per ipheral res is tance , rena l func t ion, and card iovascu lar s t ruc ture (1) .

History and Overview of Pathway

Histor ical ly , the ren in -angio tens in system da tes back to 1898, when T iegersted t and Bergman demonst ra ted

the ex is tence o f a p ressor substance in crude k idney ext racts . A l i t t le over 40 years late r , two independent

research groups d iscovered tha t th is pressor substance, which had prev ious ly been named ren in , ac tua l ly

was an enzyme and tha t the t rue pressor substance was a pep t ide formed by the ca ta ly t ic ac t ion o f renin .

Th is pep t ide p ressor substance in i t ia l l y was ass igned two di f feren t names, ang io tonin and hyper tens in;

however, these names eventual ly were combined to p roduce the curren t des ignat ion, ang io tens in . In the

1950s, i t was d iscovered tha t angio tens in ex is ts as bo th an inact ive decapept ide , ang io tens in I , and an

act ive oc tapept ide , angio tens in I I , and tha t the convers ion of ang io tens in I to ang io tens in I I i s ca ta lyzed by

an enzyme d is t inct f rom renin (3 ) .

Ang iotens inogen is an α2

-g lobu l in w i th a molecula r we igh t of 58,000 to 61 ,000 da l tons. I t con ta ins 452

amino ac ids, i s abundant in the p lasma, and is cont inua l ly synthes ized and sec reted by the l i ve r . A number

of hormones, inc lud ing g lucocor t ico ids, thyro id hormone, and ang iotens in I I , s t imulate i ts syn thes is . The

mos t impor tan t por t ion o f th is compound is the N-te rminus , spec i f ica l ly

the Leu10

-Val11

bond. This bond is c leaved by ren in and produces the decapept ide angio tens in I . The Phe8

-

His9 pept ide bond o f ang io tens in I i s then c leaved by ACE to produce the octapept ide angiotens in I I .

Aminopept idase can fur ther conver t ang iotens in I I to the act ive heptapept ide angio tens in I I I by remov ing

the N-te rminal arg in ine res idue . Fur ther ac t ions of carboxypept idases , aminopept idases, and

endopept idases resul t in the fo rmat ion o f inact ive pept ide f ragments. An addi t ional compound can be

fo rmed by the act ion o f a p ro ly l -endopept idase on angio tens in I . C leavage of the Pro7 -Phe8 bond of

angio tens in I p roduces a heptapept ide known as ang io tens in 1 -7. The act ions o f a l l o f these compounds a re

d iscussed be low.

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Fig. 28.1. Schematic representation of the renin-angiotensin pathway. The labile peptide bonds of angiotensinogen and angiotensin I are highlighted.

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Clinical Significance

The t rea tment o f hyper tens ion and congest ive hear t fa i lu re (CHF) has improved s ign i f ican t ly w i th the

in t roduct ion of ang iotens in -conver t ing enzyme (ACE) inh ib i to rs , angiotens in receptor b lockers , and

calc ium channe l b lockers. The SARs and s t ructu ra l mod if i ca t ions of these agents have produced ma jor

therapeut ic advances. These drugs have become cornerstones of therapy today. For example, more

than 25 years ago, cap topr i l was the f i rs t ACE inhib i to r to be deve loped. Subsequent mo lecular

mod i f i ca t ions led to the development of newer agents , such as l i s inopr i l . A l though l i s inopr i l exer ts

comparable ACE inhib i t ion , i t possesses a super io r pharmacokine t ic prof i le . Ins tead o f hav ing to

adminis te r captopr i l three t imes dai ly , l i s inopr i l can be adminis te red once dai ly .

Med icat ion compl iance is no to r ious ly poor in card iovascu la r pat ients . Admin is te r ing an ACE inh ib i tor

such as l is inopr i l once da i ly resu l ts in g rea t ly enhanced medica t ion compl iance. The therapeut ic

ou tcomes of pat ien ts w i th hyper tens ion and CHF have improved immense ly as a resu l t . S imi lar

molecula r enhancements have been made wi th ang iotens in receptor b lockers and ca lc ium channe l

b lockers.

The appl ica t ion o f bas ic sc ience in mod ify ing the chemica l s t ructu re of these agents has u l t imately

resul ted in pat ien ts l iv ing longer and suf fe r ing fewer cardiovascu la r events , such as myocardia l

in farc t ion o r worsening CHF. Importan t ly , thei r day - to -day qua l i ty o f l i fe is p reserved as we l l .

Thomas L. Rihn, Pharm.D.

Sen ior V ice Pres iden t and Ch ie f Cl in ica l Of f icer

Univers i ty Pharmacotherapy Associa tes

Associate Pro fessor of C l in ical Pharmacy

Duquesne Univers i ty

Schoo l o f Pharmacy

Actions and Properties of Renin-Angiotensin Pathway Components

Renin is an aspar ty l p ro tease tha t dete rmines the rate of ang iotens in I I product ion. I t is a much more

speci f ic enzyme than ACE. I ts pr imary funct ion is to c leave the leuc ine-val ine bond a t res idues 10 and 11 of

angio tens inogen. The s t imulat ion o f renin re lease is con t ro l led very c lose ly by hemodynamic , neurogen ic ,

View Figure

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and humoral s ignals (Fig . 28 .2 ) . Hemodynamic s ignals involve the rena l juxtag lomeru lar cel ls . These cel ls

are sens i t i ve to the hemodynamic s t retch o f the af fe rent g lomeru la r a r ter io le . An increase in the s t re tch

imp l ies a ra ised b lood p ressure and resul ts in a reduced re lease of ren in , whereas a decrease in the s t re tch

increases ren in secre t ion . Addi t ional ly , these cel ls a lso are sensi t i ve to NaCl f lux across the adjacent

macula densa. Increases in NaCl f lux across the macu la densa inh ib i t ren in re lease , bu t decreases in the

f lux s t imula te re lease . Fur ther , neurogenic enhancement o f renin re lease occurs v ia act iva t ion o f β1

recep tors . F inal ly , a var ie ty of hormona l s igna ls in f luence the re lease of ren in . Somatosta t in , at r ia l

na t r iu re t ic facto r , and ang io tens in I I inhib i t renin re lease , whereas vasoact ive intest ina l pept ide,

para thyroid hormone, and glucagon st imu la te ren in re lease (4 ) .

In cont ras t, ACE, a lso known as k in inase I I , is a z inc pro tease that i s under m in imal phys io log ica l con t ro l . I t

is no t a ra te - l im i t ing s tep in the genera t ion of angiotens in I I and is a re la t ive ly nonspec i f i c d ipep t idy l

carboxypept idase tha t requ i res on ly a t r ipep t ide sequence as a

subst ra te . The on ly s t ructura l fea ture requi red by ACE is that the penu l t imate amino ac id in the pep t ide

subst ra te cannot be p ro l ine. For th is reason, ang io tens in I I , which conta ins a pro l ine in the penul t imate

pos i t ion, i s not fu r ther metabo l ized by ACE. The lack o f spec i f ic i ty and con tro l exhib i ted by ACE resu l ts in

i ts involvement in the b radyk in in pa thway (Fig . 28 .3 ) . Bradyk in in is a nonapept ide tha t acts loca l ly to

produce pain, cause vasod i la t ion , increase vascular permeab i l i ty , s t imu la te p rostag land in syn thes is , and

cause bronchoconst r ic t ion . S imi la r to angiotens in I I , bradyk in in is p roduced by p ro teo ly t ic c leavage of a

precursor pep t ide . Cleavage o f k in inogens by the protease ka l l i k re in p roduces a decapept ide known as

e i ther ka l l id in o r l ysy l -bradyk in in . Subsequent c leavage o f the N-te rminal lys ine by aminopept idase

produces b radyk in in. The degradat ion o f b radyk in in to inact ive pep t ides occurs th rough the act ions o f ACE.

Thus, ACE no t only p roduces a po ten t vasoconst r ic to r bu t a lso inact ivates a po ten t vasodi la to r (1,4 ,5) .

Ang iotens in I I is the dominant pep t ide produced by the renin -angio tens in pathway (Fig . 28 .2 ) . I t i s a po ten t

vasoconst r ic to r tha t increases tota l per iphera l res is tance th rough a var ie ty of mechanisms: d i rec t

vasoconst r ic t ion , enhancement o f bo th ca techo lamine re lease and neurot ransmiss ion w ith in the per iphera l

nervous system, and increased sympathet ic d ischarge. The resul t of a l l these ac t ions is a rapid pressor

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View Figure

Fig. 28.2. Summary of the factors involved in renin release and the effects medicated by angiotensin II.

View Figure

Fig. 28.3. Schematic representation of the bradykinin pathway and its relationship to ACE and the renin-angiotensin pathway.

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response. Add i t iona l ly , ang io tens in I I causes a s low pressor response, resu l t ing in a long te rm stabi l iza t ion

of a r ter ia l b lood p ressure . This long- te rm e f fect is accompl ished by the regulat ion o f rena l func t ion.

Ang iotens in I I d i rect ly increases sod ium reabsorpt ion in the p rox imal tubu le . I t a lso a l ters rena l

hemodynamics and causes the re lease o f a ldoste rone f rom the adrena l cor tex. F ina l ly , angiotens in I I

causes the hyper trophy and remodel ing of bo th vascu lar and card iac cel ls th rough a var ie ty of

hemodynamic and nonhemodynamic ef fects (1) .

A l though secondary pept ides, ang iotens in I I I and angiotens in 1 -7, a lso a re thought to cont r ibute to the

overa l l e f fects o f the renin -angio tens in pathway, angiotens in I I I is equipo tent w i th ang io tens in I I in

s t imu lat ing a ldos terone secret ion ; however, i t is on ly 10 to 25% as po tent in inc reas ing b lood p ressure . In

con t rast , ang io tens in 1 -7 does not cause ei ther a ldosterone secret ion o r vasoconst r ic t ion , but i t does have

po ten t ef fects that a re d is t inc t f rom those o f ang io tens in I I . S imi la r to angio tens in I I , ang io tens in 1 -7

causes neurona l exc i ta t ion and vasopress in re lease . Addi t iona l ly , i t enhances the p roduct ion of

prostagland ins v ia a receptor -med iated p rocess that does not involve an increase in in t race l lu la r ca lc ium

leve ls . I t has been proposed to be important in the modula t ion o f ce l l - to -cel l in teract ions in cardiovascula r

and neura l t i ssues (6) .

Role of The Renin-Angiotensin Pathway in Cardiovascular Disorders

Because the renin -angio tens in pathway is cen t ra l to the main tenance of b lood vo lume, a r ter ia l b lood

pressure , and elec t ro ly te ba lance , abnormal i t ies in th is pathway (e.g . , excess ive re lease of ren in and

overproduct ion o f angiotens in I I ) can con t r ibu te to a var ie ty of card iovascular d isorders . Speci f ica l ly ,

overact iv i ty of th is pa thway can resu l t in hyper tens ion or hear t fa i lu re v ia the mechan isms prev ious ly

descr ibed . Abnormal ly h igh leve ls of ang iotens in I I can cont r ibute to hyper tens ion through both rapid and

s low pressor responses. Add i t iona l ly , h igh levels o f ang io tens in I I can cause ce l lu la r hyper t rophy and

increase both a f te r load and wa l l tens ion . A l l o f these events can cause or exacerbate hear t fa i lu re .

High b lood pressure is a re la t ive ly common d isorder , a ffect ing more than 50 m i l l ion Amer icans. I t is more

preva len t in ma les than in females and in b lacks than in Caucasians. Onset usual ly begins dur ing the th i rd,

four th, and f i f th decades of l i fe , and the inc idence o f the d isorder increases wi th age . Hyper tens ion is

c lass i f ied as e i ther p r imary or secondary . Pr imary hyper tens ion, a lso known as essent ia l hyper tens ion, i s

the mos t preva len t form o f the d isorder and is de f ined as h igh b lood p ressure o f an unknown e t io logy. Most

cases o f p r imary hyper tens ion a re thought to resu l t f rom a var ie ty o f under ly ing pa thophys io log ical

mechanisms and no t f rom a s ingle, spec i f i c cause . Add i t iona l ly , genet ic facto rs appear to be importan t in

the deve lopment o f p r imary hyper tens ion . Secondary hyper tens ion is assoc ia ted w ith a speci f ic d isorder

(e.g . , ch ron ic rena l d isease , pheochromocytoma, and Cush ing's syndrome), is present in approx imately 5%

of ind iv iduals wi th h igh b lood p ressure and, in some instances , i s poten t ia l l y curab le . Secondary

hyper tens ion is much more common in ch i ldren than in adul ts (7 ) .

Hear t fa i lu re (prev ious ly des ignated as congest ive hear t fa i lu re ) af fects approx imately 5 mi l l ion Amer icans

and is the most common hosp i ta l d ischarge diagnos is in pa t ien ts o lder than 65 years. The overa l l 5 -year

surv ival ra te is approx imate ly 50% fo r a l l pa t ien ts , wi th women hav ing an overa l l lower mor ta l i ty rate than

men. The d isease resul ts f rom cond i t ions in wh ich the hear t i s unable

to supp ly b lood a t a ra te su f f i c ien t to meet the demands o f the body . S im i lar to hyper tens ion , th is

pa thophys io log ical s ta te can occur v ia a var ie ty of mechanisms. Any pa thophys io log ica l even t tha t causes

e i ther systo l ic or d ias to l ic dys funct ion wi l l resu l t in hear t fa i lu re. Systo l ic dysfunc t ion, o r decreased

con t ract i l i ty , can be caused by d i la ted cardiomyopathies, vent r icu la r hyper t rophy, or a reduct ion in musc le

mass. Dias to l ic dysfunct ion , or res t r ic t ion in ven t r icu la r f i l l ing , can be caused by increased ven t r icu lar

s t i f fness, mi tra l or t r icusp id va lve s tenosis , or per icard ia l d isease. Both vent r icu la r hyper t rophy and

myocardia l i schemia can con t r ibu te to increased vent r icu lar s t i f fness. Angiotens in I I causes and/or

exacerbates hear t fa i lure by increas ing sys temic vascular res is tance , p romot ing sod ium retent ion ,

s t imu lat ing a ldos terone re lease , and s t imu lat ing ven tr icu lar hyper t rophy and remode l ing (8) .

Overview of Drug Therapy Affecting The Renin-Angiotensin Pathway

Because ang io tens in I I p roduces the ma jo r i ty o f the ef fects a t tr ibu ted to the ren in -angio tens in pathway,

compounds tha t can b lock e i ther the synthes is of ang iotens in I I o r the b ind ing of ang iotens in I I to i ts

receptor shou ld at tenuate the act ions o f th is pathway. Indeed, enzyme inhib i to rs o f bo th ren in and ACE, as

we l l as receptor an tagonis ts o f ang io tens in I I , have a l l been shown to p roduce benef ic ia l e f fects in

decreas ing the act ions o f ang io tens in I I . Inhib i to rs o f ACE were the

f i rs t c lass o f compounds to be marke ted . This occurred in 1981 w ith the approval by the U.S . Food and

Drug Admin is t rat ion o f cap topr i l . Four teen years la ter , losar tan was approved as the f i rs t ang iotens in I I

recep tor b locker (p rev ious refe rred to as an ang iotens in I I recep tor an tagonis t ) . The development ,

s t ructure–act iv i ty re la t ionsh ip (SAR), phys icochemica l p roper t ies, in te ract ions, and ind ica t ions o f these

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c lasses o f drugs a re d iscussed be low.

Development of Orally Active Renin Inhibitors

Renin is a very speci f ic enzyme. The octapeptide, His-Pro-Phe-His-Leu-Leu-Val-Tyr, is the

smal lest substrate recognized by the enzyme and is s imi lar to the e ight-amino-acid sequence,

His6-Pro

7-Phe

8-His

9-Leu

10-Val

11- I le

12-His

13, which is found in angiotensinogen. Using th is

octapeptide, Boger (9) replaced the labi le Leu-Leu bond wi th the stable dipeptide mimic stat ine

and replaced the two C-terminal residues (Val–Tyr) with s imi lar hydrophobic amino acids (Leu-

Phe).

The resul t ing compound, N-isovaleryl -His-Pro-Phe-His-Sta-Leu-Phe-NH2 (SCRIP), showed

effect ive, al though short - l ived, inhib it ion of renin when given intravenously ( IV). Infusion

experiments wi th SCRIP were the f i rst to demonstrate that a small molecule renin inhib itor could

maintain a lowered blood pressure for an extended per iod of t ime. Suscept ib i l i ty to proteolyt ic

cleavage, however, l imi ted the therapeutic ut i l i ty of SCRIP and other analogous pept ides.

Structure–activi ty studies wi th SCRIP revealed that the N-terminal His-Pro-Phe sequence could

be replaced with an acylated phenylalanine or tyrosine without any signif icant loss in inhib itor

act ivi ty. Addi t ional changes to SCRIP resul ted in the c l in ical drug candidate enalk i ren, a lso

known as A-64662 (Fig. 28.4). The h ist idine residue (His6), which is present in angiotensinogen

and al l previous inhib i tors, was thought to be essent ia l for enzyme recogni t ion and was left

unchanged. The acylated tyrosine protects the compound from aminopeptidase enzymes and

also contr ibutes to enzyme active-si te recogni t ion. The remainder of the molecule is a stable

dipeptide isostere. The cyclohexylmethylene and iso-butyl s ide chains are l ipophi l ic and

approximate the l ipophi l ic s ide chains present in Leu10 and Val11 of angiotensinogen.

Addi t ional ly, the use of a C-terminal alcohol instead of a C-terminal carboxylate protects

enalk i ren from carboxypeptidase enzymes (10,11).

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Enalki ren has been extensively studied in precl inical and cl inical tr ials and has been shown to

be eff icacious i f g iven IV. I t lacks signi f icant bioavai labi l i ty , however, mainly because of a lack

of l ipid solubi l i ty . A more l ipophil ic analogue, zankiren (A-72517) (Fig. 28.4), has demonstrated

increased oral bioavai labi l i ty and ef f icacy. Precl in ical and cl in ical tr ia ls wi th oral ly administered

zankiren showed good bioavailabil i ty and signi f icant reduction in b lood pressure (11,12).

Zankiren has since been wi thdrawn f rom cl inical tr ials for undisclosed reasons; however, the

FDA recently approved Aliskiren (Tektournan), the f i rst , non-peptidic ora l ly act ive renin inhib itor.

I t is approved for the treatment of hypertension and wil l be avai lable for use in 2007. See Drug

update: http:/ / thepoint. /www.com/foyebe.

Attempts to deve lop ora l ly act ive , b ioava i lable ren in inh ib i tors ac tua l ly p redate the development of ACE

inhib i to rs . Research in th is a rea con t inues today; however, one o f the ma in a t trac t ions o f renin inhib i to rs ,

spec i f ic i ty , has proven to be a s ign i f i cant hurdle to the c l in ica l development (9 ) of these agents .

Angiotensin-Converting Enzyme Inhibitors

Current ly , there a re 11 ACE inhib i to rs approved fo r therapeut ic use in the Un i ted Sta tes. These compounds

can be subclass i f ied in to th ree g roups based on thei r chemical composi t ion : su l fhydry l -con ta in ing inhib i to rs

(exempl i f ied by captopr i l ) , d icarboxy late -con ta in ing inhib i to rs (exempl i f ied by enalapr i l ) , and phosphonate-

con ta in ing inhib i to rs (exempl i f ied by fos inopr i l ) . Captopr i l and fos inopr i l are the lone representa t ives of thei r

respect ive chemica l subc lass i f i ca t ions , whereas the ma jo r i ty o f the inhib i to rs con tain the d icarboxy la te

funct ional i ty . A l l o f these compounds ef fect ive ly b lock the convers ion o f ang io tens in I to ang io tens in I I and

have s im i lar therapeut ic and phys io log ical ef fects . The compounds di f fer p r imar i ly in the ir po tency and

pharmacok inet ic p ro f i les (1 ) . Add i t iona l ly , the sul fhydry l g roup in cap topr i l i s responsib le fo r cer ta in e f fects

no t seen wi th the o ther agents . Deta i led desc r ipt ions o f the ra t iona le fo r the deve lopment o f cap topr i l ,

enalapr i l , and fos inopr i l are p rov ided be low.

Sulfhydryl-Containing Inhibitors: Development of Captopril

In 1965, Ferre i ra e t a l . (13 ) repor ted that the venom o f the South Amer ican p i t v iper (Bothrops ja ra raca )

con ta ined fac tors tha t po tent iated the act ion o f bradyk in in . These facto rs , o r ig ina l ly des ignated as

bradyk in in -po ten t ia t ing fac to rs (BPFs) , were iso lated and found to be a fami ly of pep t ides con ta in ing 5 to 13

amino ac id res idues. The i r ac t ions in po ten t iat ing b radyk in in were subsequent ly l inked to thei r abi l i ty to

inhib i t the enzymat ic degradat ion o f bradyk in in . Soon thereaf te r , Bakhle et a l . (14) repor ted that these same

pept ides a lso inhib i ted the enzymat ic convers ion o f angio tens in I to angio tens in I I . This lat te r enzyme, ACE,

is now known to be iden t ical wi th the fo rmer b radyk in inase enzyme (k in inase I I ) . Even a t the t ime o f these

in i t ia l d iscover ies, however, BPFs were seen as lead compounds fo r the development of new

an t ihyper tens ive agents , because they possessed dua l act iv i t ies—inhib i t ion of the degradat ion o f

bradyk in in , a potent vasod i lato r , and inh ib i t ion o f the b iosyn thes is o f angiotens in I I , a po ten t vasoconst r ic to r

(15) .

View Figure

Fig. 28.4. Structures of enalkiren and zankiren.

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A nonapept ide , SQ 20 ,881 ( tepro t ide) , iso la ted f rom the or ig ina l BPFs had the grea tes t in v ivo potency in

inhib i t ing ACE and was shown to consis ten t ly lower b lood p ressure in pa t ien ts wi th essent ia l hyper tens ion.

I t a lso exer ted benef ic ia l e f fects in pa t ien ts wi th hear t fa i lu re ; however, because o f i ts pept ide natu re and

lack o f ora l act iv i ty , tepro t ide had l im i ted act iv i ty in the therapeut ic t rea tment o f these diseases (15 ,16 ) .

Cushman, Ondet t i , and coworkers (17 ,18 ,19 ) used SQ 20 ,881 and other pept ide ana logues to prov ide an

enhanced understand ing of the enzymat ic p roper t ies of ACE. Using knowledge o f subst ra te -b ind ing

speci f ic i t ies and the fact that ACE has proper t ies s imi la r to those o f pancreat ic carboxypept idases , these

researchers deve loped a hypothe t ical mode l o f the enzyme act ive s i te. Carboxypept idase A, l i ke ACE, is a

z inc -con ta in ing exopept idase . The b ind ing of a subs trate to carboxypept idase A invo lves th ree major

in teract ions (Fig . 28 .5A).

F i rs t , the negat ively charged carboxy la te te rminus o f the am ino ac id subst ra te b inds to the pos i t ive ly

charged Arg-145 on the enzyme. Second, a hydrophobic pocket in the enzyme prov ides spec i f i c i ty for a C-

te rminal aromat ic or nonpo la r res idue . Th i rd, the z inc a tom is located c lose to the lab i le pep t ide bond and

serves to s tab i l ize the negat ively charged te t rahedral in te rmedia te, which resul ts when a mo lecu le o f water

at tacks the carbony l bond be tween the C- te rminal and penul t imate amino ac id res idues (20) . S im i lar ly , the

b ind ing of subst ra tes to ACE was proposed to invo lve th ree o r four majo r in te rac t ions (Fig . 28 .5B). Fi rs t ,

the negat ively charged carboxy la te te rminus o f ang io tens in I and o ther subst ra tes was assumed to occur v ia

an ion ic bond wi th a pos i t i ve ly charged am ine on ACE. Second, the ro le o f the z inc atom in the mechanism

of ACE hydrolys is was assumed to be s im i lar to tha t o f carboxypept idase A. Because ACE c leaves

d ipep t ides instead of s ingle amino ac ids, the pos i t ion o f the z inc a tom was assumed to be loca ted two

amino ac ids away f rom the cat ion ic cente r fo r i t to be ad jacent to the lab i le pep t ide bond. Thi rd , the s ide-

cha ins R1 and R2 cou ld con tr ibu te to the overa l l b ind ing a f f in i ty ; however, ACE, unl ike carboxypept idase A,

does no t show speci f i c i ty fo r C- te rminal hydrophob ic amino ac ids and was no t expected to have a

hydrophobic b ind ing pocke t . Final ly , the term inal pep t ide bond is non labi le and was assumed to p rov ide

hydrogen bonding between the subst ra te and ACE.

The deve lopment of cap topr i l and o ther o ra l ly act ive ACE inh ib i tors began wi th the observa t ion tha t D-2-

benzy lsucc in ic ac id was an ext remely po ten t inh ib i tor o f carboxypeptidase A (17 ,18 ,19 ) . The binding o f th is

compound to carboxypept idase A (Fig . 28 .6A) is very s imi la r to that seen fo r subs t rates w i th the except ion

View Figure

Fig. 28.5. A model of substrate binding to carboxypeptidase A (A) and ACE (B).

P.743

Página 7 de 51


tha t the z inc ion b inds to a carboxy la te g roup instead o f the labi le pep t ide bond. Byers and Wol fenden (21 )

proposed tha t th is compound is a by -product analogue that con ta ins s t ructu ra l fea tu res of both products o f

pept ide hydrolys is . Most o f the s t ructu ra l fea tu res of the compound are ident ica l to the term ina l amino ac id

of the subst ra te (Fig . 28 .5A), whereas the add i t iona l carboxy la te g roup is ab le to m imic the carboxy late

group that wou ld be p roduced dur ing pep t ide hydro lys is (21) . App ly ing th is concept to the hypothe t ical

mode l o f ACE descr ibed above resul ted in the synthes is and eva lua t ion of a ser ies o f succ in ic ac id

der ivat ives (Fig . 28 .6B). Because prol ine was p resent as the C-te rminal am ino ac id in SQ 20 ,881 as we l l as

in other po ten t , inh ib i to ry snake venom pept ides, i t was inc luded in the s t ruc tu re of newly des igned

inhib i to rs . The f i rs t inh ib i tor to be syn thes ized and tested was succ iny l -L-pro l ine (Fig . 28 .7) . Th is compound

proved to be somewhat d isappoin t ing. A l though i t prov ided reasonab le speci f i c i ty for ACE, i t was on ly

approx imately 1 /500 as po ten t as SQ 20 ,881.

Subst i tut ion o f other amino ac ids in p lace o f pro l ine p roduced compounds that were even less po ten t ;

hence, a l l subsequent SAR stud ies were conducted us ing ana logues o f L -pro l ine (Fig . 28 .7 ) . The add i t ion of

a methy l g roup to the 2 pos i t ion of succ iny l -L -pro l ine to mimic the am ino ac id s ide cha in , R2

, o f the

subst ra te enhanced act iv i ty bu t on ly margina l ly . D-2-Methy lsucc iny l -L -pro l ine had e f fects s im i lar to SQ

20 ,881 bu t was s t i l l on ly 1/300 as potent . The D- isomer, ra ther than the L - isomer normal ly seen for amino

ac ids, was necessary because o f the isos ter ic rep lacement o f an NH2 w i th a CH 2 p resent in succ iny l -L -

pro l ine. A compar ison o f the R2

g roup o f the subst rate (Fig . 28 .5B) wi th the methy l group o f D-2-

methy lsucc iny l -L -pro l ine, i l lus t ra tes tha t th is methy l g roup occup ies the same b ind ing s i te as the s ide cha in

of an L -amino g roup.

One of the most importan t a l tera t ions to succ iny l -L-pro l ine was the replacement of the succ iny l carboxy la te

wi th o ther g roups hav ing enhanced af f in i ty fo r the z inc atom bound to ACE. Replacement of th is carboxy la te

wi th a su l fhydry l group produced 3 -mercaptopropanoyl -L -pro l ine. Th is compound has an IC50 va lue o f 200

nM and is grea ter than 1000- fo ld more po tent than succ iny l-L-pro l ine (Fig . 28 .7 ) . Add i t iona l ly , i t is 10 - to

20- fo ld more po tent than SQ 20,881 in inh ib i t ing con t ract i le and vasopressor responses to angiotens in I .

Add i t ion o f a 2 -D-methy l group fu r ther enhanced act iv i ty . The resu l t ing compound, cap topr i l (Fig . 28 .7) , is a

View Figure

Fig. 28.6. Inhibitor binding models of (A) D-2-benzylsuccinic acid to carboxypeptidase A and (B) succinic acid derivatives to ACE.

View Figure

Fig. 28.7. Compounds prepared in the development of captopril.

Página 8 de 51


compet i t i ve inh ib i to r o f ACE wi th a K i va lue o f 1.7 nM and was the f i rs t ACE inhib i to r to be marke ted .

The sul fhydry l g roup o f cap topr i l proved to be responsib le no t on ly for the excel len t inh ib i to ry act iv i ty of the

compound bu t a lso for the two mos t common s ide e f fects , sk in rashes and taste d is tu rbances (e .g. , metal l ic

taste and loss o f tas te ) . These s ide e f fects usua l ly subs ided on dosage reduct ion or d iscont inua t ion of

cap topr i l . They were at t r ibuted to the p resence of the sul fhydry l g roup , because s imi lar e f fec ts had been

observed w ith pen ic i l lamine , a sul fhydry l con ta in ing agent used to t rea t Wi lson 's d isease and rheumato id

ar th r i t is (22 ,23 ) .

Dicarboxylate-Containing Inhibitors

Development of Enalapril

Researchers a t Merck (24) sought to deve lop compounds that lacked the su l fhydry l g roup of cap topr i l ye t

main ta ined some abi l i ty to chelate z inc . Compounds hav ing the genera l s t ruc ture shown be low were

des igned to meet th is object ive.

These compounds are t r ipep t ide subst ra te analogues in wh ich the C-te rminal (A) and penu l t imate (B ) am ino

ac ids are re ta ined but the th i rd amino ac id is i soste r ical ly replaced by a subst i tu ted N-carboxymethy l group

(C) . S imi lar to the resu l ts seen in the deve lopment o f cap topr i l , C - te rminal pro l ine ana logues prov ided

op t imum act iv i ty . The use o f a methy l g roup at R3 ( i .e . , B = A la ) and a phenyle thy l g roup a t R 4 resul ted in

enalapr i la t (Fig . 28 .8 ) . In compar ing the act iv i ty of cap topr i l and ena lapr i la t , i t was found tha t ena lapr i la t ,

wi th a Ki o f 0 .2 nM, was approx imate ly 10- fo ld more po tent than captopr i l . S tudies invest iga t ing the b ind ing

of ena lapr i la t revea led tha t i ts ab i l i ty to che la te the enzyme-bound z inc a tom was s ign i f ican t ly less than

tha t of captopr i l . The enhanced bind ing was p roposed to be caused by the ab i l i ty to m imic the t rans i t ion

s tate of ang iotens in I hydro lys is . As shown in Figure 28.8 , enalapr i la t possess a te t rahedral carbon in p lace

of the lab i le pep t ide bond. The secondary am ine, the carboxy l ic ac id , and phenylethy l groups a l l con t r ibu te

P.744

View Figure

Fig. 28.8. A comparison of enalaprilat and the transition state of angiotensin I hydrolysis by ACE.

Página 9 de 51


to the overal l b ind ing of the compound to ACE. The secondary amine is loca ted at the same posi t ion as the

labi le amide ni t rogen, the ionized carboxy l ic ac id can fo rm an ion ic bond w ith the z inc atom, and the

phenylethy l group m imics the hydrophobic s ide cha in of the Phe amino ac id , wh ich is present in ang io tens in

I .

Desp i te excel len t IV ac t iv i ty , ena lapr i la t has very poor o ra l b ioava i labi l i ty . Es te r i f icat ion o f enalapr i la t

produced ena lapr i l (Fig . 28 .9 ) , a compound w ith super ior ora l b ioava i labi l i ty . The combina t ion of s t ructu ra l

fea tures in enalapr i la t , especia l ly the two carboxy la te groups and the secondary amine , a re respons ib le for

i ts overa l l low l ipoph i l i c i ty and poor ora l b ioava i labi l i ty . Zw it te r ion format ion a lso has been suggested to

con t r ibu te to the low oral ac t iv i ty (25) , and a compar ison o f the pK a va lues fo r the secondary amine of

enalapr i la t and ena lapr i l suppor ts th is exp lanat ion . Ion iza t ion o f the ad jacent carboxy la te in enalapr i la t

grea t ly enhances the bas ic i ty of the secondary amine such tha t the pK a o f the amine in th is compound is

8.02, whereas in ena lapr i l , i t i s only 5 .49 . Thus, in the smal l in test ine , the amine in ena lapr i la t w i l l be

pr imar i ly ionized and fo rm a zwi t ter ion w i th the adjacent carboxy la te , bu t the amine in enalapr i l w i l l be

pr imar i ly un- ionized (26 ) .

In t ravenous adminis t ra t ion of e i ther ena lapr i l or enalapr i la t p roduced s imi lar e f fec ts on ang io tens in I I

product ion

desp i te the fac t tha t enalapr i l showed a 1 ,000- fo ld dec rease in in v i t ro ac t iv i ty . Subsequent s tudies showed

tha t enalapr i l undergoes b ioact ivat ion and , thus, i s a p ro -drug of ena lapr i la t . Because human p lasma was

repor ted to lack ena lapr i l este ro ly t ic act iv i ty , b ioact ivat ion by hepat ic esterases (Fig . 28 .9 ) has been

sugges ted as the mos t p robab le mechan ism for enalapr i la t fo rmat ion (27 ,28 ) .

P.745

View Figure

Fig. 28.9. Bioactivation of enalapril.

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Additional Dicarboxylate Inhibitors

Eigh t o ther d icarboxy la te inh ib i tors (Tab le 28 .1 ) have been approved fo r var ious therapeut ic ind ica t ions;

however, sp irapr i l has never been marketed. L is inopr i l is chemical ly un ique in two respects . F i rs t , i t

con ta ins the bas ic amino ac id lys ine (R1

= CH2

CH2

CH2

CH2

NH2

) ins tead of the s tandard nonpo lar a lan ine

(R = CH3 )

res idue . Second, i t does no t requi re b ioac t iva t ion , because nei ther o f the carboxy l ic ac id g roups a re

este r i f ied ( i .e . , R2 = H) . L is inopr i l was deve loped a t the same t ime as enalapr i l . Despi te the addi t ion of

another ion izab le group, the o ra l absorpt ion o f l i s inopr i l was found to be super io r to tha t o f ena lapr i la t bu t

less than tha t o f enalapr i l . In v i t ro s tud ies o f ena lapr i la t and l is inopr i l showed l i s inopr i l to be s l igh t ly more

po ten t than enalapr i la t (27 ,28) . L is inopr i l , a long wi th cap topr i l , curren t ly are the only two ACE inh ib i tors

tha t are not p ro -drugs.

The major s t ructu ra l d i f fe rence among the remain ing ACE inhib i to rs is in the r ing o f the C-te rminal am ino

ac id . L is inopr i l , l i ke enalapr i l and cap topr i l , con ta ins the pyrro l id ine r ing o f p ro l ine , whereas a l l the o ther

compounds conta in larger b icyc l ic o r sp i ro r ing systems. Studies of indo l ine ana logues o f captopr i l

indica ted tha t a hydrophobic pocket s imi lar to tha t seen in carboxypept idase A also was p resent in ACE.

Th is led to a mod i f ica t ion (Fig . 28 .10 ) of Ondet t i and Cushman 's or ig inal mode l and the deve lopment of

inhib i to rs that con ta ined la rger hydrophobic r ing systems (29 ) . A l though th is modi f ied mode l was p roposed

fo r cap topr i l ana logues, i t is read i ly adaptab le to inc lude ena lapr i la t ana logues. In genera l , the var ied r ing

View Table

Table 28.1. Additional Dicarboxylate-containing Angiotensin Converting Enzyme Inhibitors

P.746

View Figure

Fig. 28.10. A modified model of ACE inhibitor binding.

Página 11 de 51


systems seen in benazepr i l , moexip r i l , per indopr i l , qu inapr i l , ram ipr i l , sp i rapr i l , and t rando lapr i l p rov ide

enhanced b ind ing and potency. They a lso lead to d i f fe rences in absorpt ion, p lasma prote in b ind ing,

e l im inat ion, onse t o f act ion , dura t ion of act ion , and dos ing among the d rugs. These di f ferences are

d iscussed in more de ta i l in Pharmacokine t ic Proper t ies be low.

Phosphonate-containing Inhibitors: the Development of Fosinopril

The search fo r ACE inh ib i to rs tha t lacked the sul fhydry l g roup a lso lead to the invest igat ion of

phosphorous -con ta in ing compounds (30) . The phosph in ic ac id shown in Figure 28.11 is capab le o f b ind ing

to ACE in a manner s im i lar to ena lapr i l . The inte ract ion of the z inc a tom w ith the phosphin ic ac id is s imi la r

to that seen w ith su l fhydry l and carboxy late g roups. Addi t ional ly , th is compound is capab le of fo rming the

ionic , hydrogen, and hydrophob ic bonds s imi la r to those seen wi th enalapr i l and o ther d icarboxy late

analogues . A fea tu re un ique to th is compound is the ab i l i ty of the phosph in ic ac id to more t ru ly m imic the

ionized, te t rahedral in te rmedia te o f pept ide hydrolys is . Unl ike enalapr i l and o ther d icarboxy late ana logues,

however, the spacing of th is te t rahedral spec ies is shor te r , being only two a toms removed f rom the p rol ine

n i t rogen. Add i t iona l ly , the spacing be tween the p ro l ine n i t rogen and the hydrophob ic phenyl r ing is one

atom longer than tha t seen in the d icarboxy lates.

St ructura l modi f icat ion to inves t igate more hydrophobic , C- te rminal r ing sys tems, s im i lar to tha t desc r ibed

above fo r the d icarboxy late compounds, lead to a 4 -cyc lohexy lpro l ine ana logue of the o r ig ina l phosph in ic

ac id . Th is compound, fos inopr i la t (Fig . 28 .12) , was more po ten t than cap topr i l bu t less po ten t than

enalapr i la t . The above-ment ioned d i f fe rences in the spacing o f the phosph in ic ac id and phenyl g roups may

be responsib le fo r th is la t te r d i f fe rence in potency. S imi la r to the d icarboxy la tes , fos inopr i la t was too

hydroph i l i c and exhib i ted poor o ra l act iv i ty . The pro -drug fos inopr i l con ta ins an (acy loxy)a lky l g roup tha t

a l lows be t ter l ip id solubi l i ty and improved bioava i labi l i ty (30) . B ioact ivat ion v ia este rase act iv i ty in the

in tes t inal wa l l and l ive r p roduces fos inopr i l (Fig . 28 .12 ) .

Mechanism of Action

The ACE inh ib i to rs a t tenuate the ef fects o f the renin -angio tens in system by inhib i t ing the convers ion o f

angio tens in I to angio tens in I I (Fig . 28 .1) . They a lso inh ib i t the convers ion o f [des -Asp1 ]angio tens in I to

angio tens in I I I ; however, th is act ion has on ly a minor ro le in the overa l l ca rd iovascu la r e f fec ts of these

drugs. They a re select ive in that they do no t d irect ly in te r fere w i th any o ther components of the ren in -

angio tens in system; however, they do cause other ef fects that a re unre la ted to the decrease in angio tens in

I I concent ra t ion . Inh ib i tors of ACE inc rease bradyk in in leve ls tha t , in turn, s t imu la te p rostagland in

b iosynthes is (Fig . 28 .3 ) . Both o f these compounds have been proposed to cont r ibute to the overa l l act ion o f

ACE inhib i to rs . Add i t iona l ly , decreased angiotens in I I leve ls increase the re lease o f ren in and the

product ion o f ang io tens in I . Because ACE is inh ib i ted ,

angio tens in I i s shunted toward the produc t ion o f ang io tens in 1 -7 and other pep t ides . The cont r ibu t ion of

these pept ides to the overal l e f fec t of ACE inh ib i tors is unknown (1 ) .

View Figure

Fig. 28.11. The binding of phosphinate analogues to ACE.

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Fig. 28.12. Bioactivation of fosinopril.

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Structure–Activity Relationships

The st ructura l characte r is t ics fo r ACE inh ib i to ry act iv i ty are g iven in Tab le 28 .2 . Ang io tens in -conver t ing

enzyme is a s tereoselect ive d rug ta rget . Because curren t ly approved ACE inh ib i to rs act as e i ther d i - or

tr ipep t ide subs trate ana logues, they must con tain a s te reochemis t ry that i s cons is ten t w i th the L -amino

ac ids present in the na tu ral subs t ra tes. Th is was estab l ished very ear ly in the deve lopment o f ACE

inhib i to rs when compounds wi th carboxy l - te rminal D-amino ac ids were d iscovered to be very poor inh ib i to rs

(31) . La ter work by Patchet t e t a l . (24) re in forced th is idea . They repor ted a 100- to 1 ,000- fo ld loss in

inhib i to r ac t iv i ty whenever the con f igura t ion o f e i ther the carboxy late or the R1 subst i tuent (Tab le 28 .1 ) was

a l tered . The S,S,S -con f igura t ion seen in enalapr i l and o ther d icarboxy la te inh ib i tors meets the above -stated

cr i te r ia and prov ides fo r op t imum enzyme inh ib i t ion.

Physicochemical Properties

Captopr i l and fos inopr i l a re ac id ic d rugs, bu t a l l o ther ACE inhib i to rs a re amphoter ic . The carboxy l ic ac id

at tached to the N- r ing is a common s truc tu ra l fea ture in a l l ACE inh ib i tors . I t has a pKa in the range o f 2.5

to 3 .5 and wi l l be ionized p r imar i l y a t phys io logica l pH. As d iscussed above

wi th ena lapr i l , the pKa

and ion iza t ion o f the secondary am ine in the d icarboxy la te ser ies depends on

whether the ad jacent funct ional g roup is in the pro -drug or act ive fo rm. In the p ro -drug fo rm, the amine is

ad jacent to an ester , i s less bas ic , and is pr imar i ly un- ionized a t phys io log ica l pH. Fol low ing b ioact iva t ion,

the amine is adjacent to an ionized carboxy l ic ac id tha t enhances bo th the bas ic i ty and ioniza t ion o f the

amine. S imi la r ly , the bas ic n i t rogen enhances the ac id i ty o f the ad jacent carboxy l ic ac id such tha t i t usua l ly

has a lower pKa than the carboxy l ic ac id a t tached to the N-r ing . As an example , the pK a va lues o f ena lapr i l

are 3 .39 and 2 .30. These va lues correspond to the carboxy l ic ac id on the N-r ing and the carboxy l ic ac id

ad jacent to the amine , respect ively . The ana logous values fo r these funct iona l g roups in l is inopr i l are 3 .3

and 1 .7 (26) .

View Figure

P.748

View Table

Table 28.2. Structure activity relationship of ACE inhibitors.

Table 28.3. Pharmacokinetic Parameters of ACE Inhibitors

Página 13 de 51


DrugCalculated Log P

Oral Bioavailability (%)

Effect of Food on Absorption

Active Metabolite

Protein Binding (%)

Benazepril 5.504 37 Slows absorption

Benazeprilat >95

Captopril 0.272 60–75 Reduced NA 25–30

Enalapril 2.426 60 None Enalaprilat 50–60

Enalaprilat 1.545 NA NA NA —

Fosinopril 6.092 36 Slows absorption

Fosinoprilat 95

Lisinopril 1.188 25–30 None NA 25

Moexipril 4.055 13 Reduced Moexiprilat 50

Perindopril 3.363 65–95 Reduced Perindoprilat 60–80

Quinapril 4.318 60 Reduced Quinaprilat 97

Ramipril 3.409 50–60 Slows absorption

Ramiprilat 73

Spirapril 3.162 50 — Spiraprilat —

Página 14 de 51


The calcu lated log P va lues (26) a long wi th o ther pharmacokinet ic parameters for the ACE inhib i to rs a re

shown in Tab le 28 .3 . Wi th th ree notab le except ions, cap topr i l , ena lapr i la t , and l is inopr i l , a l l o f the

compounds possess good l ip id so lub i l i ty . Compounds that con ta in hydrophobic b icyc l ic r ing systems are

more l ip id so lub le than those tha t conta in pro l ine . A compar ison o f the log P va lues of benazepr i l ,

fos inopr i l , moex ip r i l , per indopr i l , quinapr i l , ramipr i l , sp i ropr i l , and trandolapr i l to those for cap topr i l and

enalapr i l i l lus t ra tes th is fact . As p rev ious ly d iscussed, enalapr i la t i s much more hydroph i l i c than i ts este r

pro -drug and is curren t ly the on ly ACE inhib i to r marked fo r IV admin is t ra t ion. In terms of so lub i l i ty , l i s inopr i l

probab ly is the mos t in terest ing compound in that i t is the mos t hydrophi l i c inh ib i tor , yet unl ike enalapr i la t ,

i t i s ora l ly act ive . One poss ib le explana t ion fo r th is phenomenon is that in the duodenum, l i s inopr i l w i l l ex is t

as a d i -zwi t ter ion in wh ich the ion ized g roups can in terna l ly b ind to one another . In th is manner , l i s inopr i l

may be ab le to pass th rough the l ip id b i layer w i th an overa l l net neut ra l charge.

Metabolism

Lis inopr i l and enalapr i la t a re exc re ted unchanged, whereas a l l o ther ACE inh ib i tors undergo some degree o f

metabol ic t ransfo rmat ion (1 ,32 ,33 ,34) . As p rev ious ly d iscussed and i l lus t ra ted (Figs. 28 .9 and 28 .12) , a l l

d icarboxy la te and phosphonate pro -drugs must undergo bioact iva t ion v ia hepat ic esterases. Add i t iona l ly ,

based on the ir s truc tu ra l fea tures, spec i f i c compounds can undergo metabo l ic inact ivat ion v ia var ious

pa thways (Fig . 28 .13) . Because of i ts su l fhydry l group , cap topr i l i s sub ject to ox idat ive d imer izat ion o r

con jugat ion. Approx imate ly 40 to 50% of a dose o f cap topr i l i s excreted unchanged, whereas the remainder

is excreted as e i ther a d isul f ide d imer or a cap topr i l -cyste ine d isu l f ide . G lucuronide con juga t ion has been

repor ted for benazepr i l , fos inopr i l , qu inapr i l , and ramipr i l . This conjuga t ion can occur e i ther wi th the paren t

pro -drug or w i th the act ivated d rug . Benazepr i l , w i th the N-subst i tuted g lyc ine , is especia l ly suscept ib le to

th is reac t ion because of a d i f fe rence in s te r ic h indrance . For a l l ACE inh ib i to rs , except

benazepr i l , the carbon atom d irect ly adjacent to the carboxy l ic ac id is par t of a r ing sys tem and prov ides

some ste r ic h indrance to con juga t ion . The unsubst i tu ted methy lene group ( i .e . , –CH2–) of benazepr i l

prov ides less s te r ic h indrance and, thus , fac i l i ta tes con jugat ion . Moex ip r i l , per indopr i l , and ramipr i l can

Trandolapril 3.973 70 Slows absorption

Trandolaprilat 80

NA, not applicable, —, data not available.

P.749

Página 15 de 51


undergo cyc l izat ion to p roduce d ike topiperaz ines. Th is cyc l izat ion can occur w i th e i ther the parent o r ac t ive

fo rms of the d rugs .

A compara t ive s tudy of the metabo l ism and b i l iary excre t ion of l is inopr i l , ena lapr i l , per indopr i l , and ramipr i l

revea led tha t whereas nei ther l is inopr i l nor ena lapr i l underwent any apprec iab le metabol ism beyond

bioact iva t ion o f ena lapr i l to enalapr i la t , bo th per indopr i l and ramipr i l were ex tens ive ly metabo l ized beyond

the in i t ia l b ioact ivat ion . I t was p roposed that these d i f fe rences in hepat ic metabol ism could be expla ined , in

par t , by the la rger , more hydrophob ic r ings present on per indopr i l and ram ipr i l (35) .

Pharmacokinetic Parameters

The pharmacok inet ic parameters and dos ing info rmat ion for ACE inhib i to rs a re summar ized in Tab les 28.3

and 28 .4 , respect ively (1 ,32 ,33 ,34 ) . The oral b ioava i labi l i ty o f th is c lass o f d rugs ranges f rom 13 to 95%.

Di f ferences in bo th l ip id solubi l i ty and f i r s t -pass metabo l ism are most l i ke ly responsib le fo r th is w ide

var ia t ion . Both parameters shou ld be considered when compar ing any two or more compounds. With the

except ions of enalapr i l and l is inopr i l , the concurrent admin is t ra t ion o f food adverse ly a f fects the o ra l

absorpt ion o f ACE inh ib i to rs . P roduct l i teratu re speci f ica l ly inst ructs tha t cap topr i l should be taken 1 hour

be fore mea ls and that moexip r i l shou ld be taken in the fast ing s tate . A l though no t spec i f i ca l ly s ta ted ,

s im i lar inst ruct ions a lso shou ld benef i t pat ien ts tak ing an ACE inh ib i tor whose absorp t ion is a f fected by

food.

The exten t o f p rote in b ind ing a lso exh ib i ts wide var iab i l i ty among the d i f feren t compounds. The data

sugges ts tha t th is var iat ion has some corre lat ion wi th the ca lcu lated log P values fo r the compounds (Tab le

28 .3 ) . Three of the more l ipophi l ic compounds—fosinopr i l , quinapr i l , and benazepr i l—exh ib i t prote in b inding

of g rea te r than 90%, whereas three of the least l ipoph i l i c compounds—lis inopr i l , ena lapr i l , and cap topr i l—

exh ib i t much lower prote in b inding. The lack o f a p rote in b ind ing value fo r sp irapr i l p revents a more

de f in i t i ve s ta tement on th is corre la t ion .

Rena l e l iminat ion is the p r imary rou te of e l imina t ion fo r most ACE inh ib i tors . With the except ions o f

fos inopr i l and sp irapr i l , a l te red renal funct ion s ign i f ican t ly d imin ishes the p lasma c learance of ACE

inhib i to rs , inc luding those that a re e l im inated p r imar i ly by the feces. There fore, the dosage o f most ACE

inhib i to rs should be reduced in pat ients w i th rena l impa irment (1 ) . Stud ies o f fos inopr i l in pa t ien ts wi th

hear t fa i lu re demons trated tha t i t is e l im inated by bo th renal and hepat ic pa thways and does not requi re a

dosage reduct ion in pat ien ts w i th rena l dysfunct ion (36 ) . Spi rapr i l a lso exhib i ts s imi lar p roper t ies ; however,

i t i s no t current ly ava i lab le fo r use. I t shou ld be no ted tha t the l i te ratu re da ta fo r rou tes o f e l imina t ion a re

no t a lways consis tent . The des igna t ion of renal e l imina t ion is qui te c lear , bu t i t i s d i f f i cu l t to cor re la te what

some sources ca l l rena l /hepat ic e l imina t ion w i th what others ca l l rena l / feca l e l iminat ion . Addi t ional ly , i t i s

uncer ta in whether the des igna t ion o f fecal e l imina t ion a lso inc ludes unabsorbed drug . As a resu l t , there is

some var iab i l i ty fo r majo r routes o f e l im inat ion l is ted in Tab le 28 .3 .

Wi th one except ion, a l l ACE inh ib i tors have a s imi lar onset o f ac t ion, durat ion o f act ion , and dos ing

in terval . Captopr i l has a more rapid onset o f ac t ion; however, i t a lso has a shor ter dura t ion and requi res a

more f requent dos ing in terval than any o f the other compounds. When ora l dos ing is inappropr ia te ,

enalapr i la t can be used IV. The normal dose adminis te red to hyper tens ive pat ien ts is 0.625 to 1.25 mg

View Figure

Fig. 28.13. Metabolic routes of ACE inhibitors.

P.750

Página 16 de 51


every 6 hours. The dose usual ly is adminis te red over 5 minutes and may be t i t rated up to 5 mg IV every 6

hours.

Chemical/Pharmacological Classes Used to Treat Hypertension

Diuret ics (see Chapter 27), ACE inhibi tors, angiotensin I I blockers, calc ium channel blockers

(see Chapter 28), central α2-agonists, per ipheral α

1-antagonists, β -blockers, gangl ionic

blockers, and vasodilators (see Chapter 29).

Therapeutic Applications

The ACE inh ib i to rs have been approved for the t rea tment o f hyper tens ion, hear t fa i lu re, le f t ven t r icu la r

dys funct ion (e i ther post–myocardia l in fa rc t ion [MI ] o r asymptomat ic) , improved surv ival post -MI , d iabe t ic

nephropathy, and reduct ion of the r isk o f MI , s t roke , and death f rom cardiovascu la r causes . A l though a l l

ACE inhib i to rs possess the same phys io log ica l act ions and, thus , should produce s imi la r therapeut ic

ef fects , the approved ind icat ions d i f fe r among the curren t ly ava i lable agents (Tab le 28 .4 ) .

Inh ib i to rs o f ACE have been des ignated as f i rs t - l ine agents fo r the t rea tment o f hyper tens ion (37) and a re

ef fect ive fo r a var ie ty of card iovascular d isorders . They can be used ei ther ind iv idual ly or w i th o ther

c lasses o f compounds. They a re especia l ly usefu l in t rea t ing pa t ien ts wi th hyper tens ion who also su ffe r

from hear t fa i lu re , le f t ven t r icu la r dysfunct ion, o r d iabe tes . Ar te r ia l and venous d i la t ion seen w i th ACE

inhib i to rs not only lowers b lood p ressure bu t a lso has favorab le e f fects on bo th p re load and a f te r load in

pa t ien ts wi th hear t fa i lu re. Add i t iona l ly , the abi l i ty o f ACE inh ib i to rs to cause regress ion of le f t ven t r icu la r

hyper t rophy has been demonst ra ted to reduce the inc idence o f fu r ther hear t d isease in pat ien ts w i th

hyper tens ion . The use o f ACE inh ib i tors in pa t ien ts wi th MI is s imi lar ly based on the abi l i ty o f ACE

inhib i to rs to decrease morta l i ty by p revent ing post infa rc t ion lef t ven tr icu lar hyper t rophy and hear t fa i lure .

Current recommendat ions to g ive ACE inhib i to rs to a l l pat ients w i th impa i red lef t ven tr icu lar

systo l ic impai rment regardless o f the presence o f observab le symptoms a lso a re based on the ab i l i ty of

these inhib i to rs to b lock the vascu lar and card iac hyper trophy and remodel ing caused by angio tens in I I .

Inh ib i to rs o f ACE a lso have been repor ted to s low the p rogress ion of d iabet ic nephropathy and , thus, a re

pre fe rred agents in the t reatment of hyper tens ion in a pa t ients w i th d iabetes. I t a lso has been suggested

tha t ACE inhib i to rs be used in pa t ien ts wi th d iabet ic nephropathy regardless o f the presence or absence or

hyper tens ion (1,7 ,8,33 ) .

P.751

P.752

Table 28.4. Dosing Information for Orally Available ACE Inhibitors

Generic NameTrade Name(s)

Approved Indications

Dosing Range (Treatment of Hypertension)

Maximum Daily Dose

Dose Reduction with Renal Dysfunction

Benazepril Lotensin Hypertension 10–40 mg q.d. or b.i.d.

80 mg

Yes

Captopril Capoten Hypertension, heart failure, left ventricular dysfunction (post-MI), diabetic nephropathy

25–150 mg b.i.d. or t.i.d.

450 mg

Yes

Enalapril Vasotec Hypertension, heart failure,

2.5–40 mg q.d. or

40 mg

Yes

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left ventricular dysfunction (asymptomatic)

b.i.d.

Fosinopril Monopril Hypertension, heart failure

10–40 mg q.d.

80 mg

No

Lisinopril Prinivil, Zestril

Hypertension, heart failure, Improve survival post-MI

10–40 mg q.d.

40 mg

Yes

Moexipril Univasc Hypertension 7.5–30 mg q.d. or b.i.d.

30 mg

Yes

Perindopril Aceon Hypertension 4–8 mg q.d. or b.i.d.

16 mg

Yes

Quinapril Accupril Hypertension, heart failure

10–80 mg q.d. or b.i.d.

80 mg

Yes

Ramipril Altace Hypertension, heart failure, reduce risk of MI, stroke, and death from cardiovascular causes

2.5–20 mg q.d. or b.i.d.

20 mg

Yes

Trandolapril Mavik Hypertension, heart failure, left ventricular dysfunction (post-MI)

1–4 mg q.d.

8 mg Yes

MI, myocardial infarction.

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Combination Products That Include an ACE Inhibitor

ACE Inhibi tor/Diuret ic: benazepri l /hydrochloroth iazide, captopr i l /hydrochlorothiazide,

enalapr i l /hydrochlorothiazide, fosinopri l /hydrochlorothiazide, l is inopr i l /hydrochlorothiazide,

moexipr i l /hydrochlorothiazide, and quinapri l /hydrochloroth iazide

ACE Inhibi tor/Calc ium Channel Blocker: benazepri l /amlodipine, enalapr i l / felodip ine,

trandolapr i l /verapamil

Unlabeled Uses

Hypertensive cr ises, renovascular hypertension, neonatal and chi ldhood hypertension, stroke

prevention, migraine prophylaxis, nondiabetic nephropathy, chronic k idney d isease, diagnosis of

scleroderma renal cr is is, and Bart ter 's syndrome (32,33)

Peptide Mimetics: Design of Agonists/Antagonists

Peptide mimetics have been defined as molecules that mimic the act ion of pept ides, have no

peptide bonds (i .e ., no amide bonds between amino acids), and a molecular weight of less than

700 Daltons. In comparison wi th peptide drugs, peptide mimetics have numerous pharmaceut ical

advantages. Foremost among these are increased bioavai labil i ty and increased durat ion of

act ion. The major i ty of known peptide mimetics have been discovered by random screening

techniques; however, this process is cost ly, labor intensive, and unpredictable.

A more logical and rat ional approach is de novo pept ide mimet ic design (40), and an example of

this approach is i l lustrated in Figure 28.14. In th is example, the overal l process is d ivided into

three steps (A–C). Ini t ial ly , the amino acids that comprise the pharmacophore of the pept ide

must be identi f ied. Thus, a knowledge of the SARs for the pept ide under considerat ion is

essent ia l. In Figure 28.14A, the side chains present on amino acid residues 1, 3, and 5 of a

hypothetica l heptapeptide are assumed to comprise the pharmacophore, and the remainder of

the peptide is assumed to provide the proper st ructura l support for these key groups. In the

second step of this de novo design process, the proper spatial arrangement of the

pharmacophoric groups must be elucidated. Nuclear magnet ic resonance spectroscopy, x -ray

di f fract ion studies, and molecular modeling programs that al low energy-minimization procedures

and molecular dynamics s imulat ion can be used to construct a model of the biologically act ive

conformation. Returning to the example, the side chains representing the pharmacophore are

assumed to be located on the inside of the pept ide, whereas the remaining residues are

assumed to be located on the outside of the pept ide (Fig. 28.14B). In the f inal step of the

process, the pharmacophoric groups must be mounted on a nonpeptide template in such a

manner that they reta in the proper spatial arrangement found in the or ig inal pept ide. This is

shown in Figure 28.14C, where s ide chains 1, 3, and 5 of the or iginal peptide are connected to a

rig id template (represented by the polygon). A var iety of aromatic r ing systems (e.g. , benzene,

biphenyl , phenanthrene, and benzodiazepine) can be used to provide the r igid template, and

appropr iately placed a lkyl groups can be used to enhance spacing and increase f lexib i l i ty .

Addi t ional ly, isosteres of the or iginal pharmacophoric groups may be used to c ircumvent specif ic

synthetic problems (41).

View Figure

Fig. 28.14. A general process for the rational design of peptide mimetics: (A) identification of crucial pharmacophoric groups, (B) determination of the spatial arrangement of these groups, and (C) use of a template to mount the key functional groups in their proper conformation. Groups highlighted with an asterisk comprise the pharmacophore of the heptapeptide. (From Harrold MW. Preparing students for future therapies: the

Página 19 de 51


Adverse Effects and Drug Interactions

The mos t preva len t or s igni f i can t s ide e ffects o f ACE inh ib i tors are l is ted be low wh i le d rug in teract ions fo r

ACE inhib i to rs a re l i s ted in Tab le 28 .5 (1,32 ,33 ) . Some adverse e f fec ts can be a t t r ibu ted to spec i f ic

funct ional groups wi th in indiv idua l agents , whereas o thers can be d irect ly re lated to the mechan ism of

act ion o f th is c lass of compounds . The higher inc idence of macu lopapu la r rashes and taste d is tu rbances

observed fo r captopr i l have been l inked to the p resence o f the sul fhydry l g roup in th is compound. A l l ACE

inhib i to rs can cause hypotens ion, hyperkalemia , and a d ry cough. Hypotens ion resul ts f rom an extens ion o f

the des i red phys io log ical e ffect , whereas hyperka lemia resu l ts f rom a dec rease in a ldosterone sec ret ion

secondary to a decrease in angio tens in I I p roduct ion . Cough is by fa r the most prevalen t and bo thersome

s ide ef fect seen wi th the use o f ACE inhib i to rs . I t is seen in 5 to 20% of pat ien ts , usual ly is no t dose

re la ted , and apparent ly resu l ts f rom the lack o f select iv i ty o f th is c lass o f drugs. As p rev ious ly d iscussed,

ACE inhib i to rs a lso p revent the b reakdown of b radyk in in (Fig . 28 .3 ) , and because bradyk in in s t imula tes

prostagland in synthes is , p rostagland in leve ls a lso increase. The increased leve ls of both bradyk in in and

prostagland in have been proposed to be responsib le for the cough (38) .

The use o f ACE inhib i to rs dur ing p regnancy is con t ra ind icated. Th is c lass o f compounds is not te ra togen ic

dur ing the f i r s t t r imes te r , but admin is t ra t ion dur ing the second and th ird t r imeste r is assoc ia ted wi th an

increased inc idence of fe ta l morbid i ty and morta l i ty . Inh ib i tors of ACE can be used in women of chi ldbear ing

age; however, they shou ld be d iscont inued as soon as p regnancy is con f i rmed.

Adverse Effects of ACE Inhibitors

Hypotension, hyperkalemia, cough, rash, taste d isturbances, headache, dizziness, fat igue,

nausea, vomit ing, diarrhea, acute renal fai lure, neutropenia, proteinur ia, and angioedema

development of novel agents to control the renin-angiotensin system. Am J Pharm Educ 1997;61:173–178; with permission. )

Table 28.5. Drug Interactions for ACE Inhibitors

DrugACE Inhibitor Result of Interaction

Allopurinol Captopril Increased risk of hypersensitivity

Antacids All Decreased bioavailability of ACE inhibitor (more likely with captopril and fosinopril)

Capsaicin All Exacerbation of cough

Digoxin All Either increased or decreased plasma digoxin levels

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Angiotensin II Receptor Blockers

From an his to r ical perspect ive, the angiotens in I I receptor was the in i t ia l targe t for developing compounds

tha t cou ld inh ib i t the renin -angio tens in pathway. E ffo r ts to deve lop ang io tens in I I recep tor antagon is ts

began in the ear ly 1970s and focused on pept ide-based ana logues o f the natu ra l agon is t . The pro totyp ica l

compound tha t resul ted f rom these s tudies was sara las in , an octapept ide in wh ich the Asp1

and Phe8

res idues o f ang io tens in I I were rep laced w ith Sar (sarcos ine, N-methy lg lyc ine) and I le , respect ively .

Saralas in as we l l as other pep t ide analogues demonst rated the ab i l i ty to reduce blood pressure; however,

these compounds lacked oral b ioava i lab i l i ty and expressed unwanted par t ia l agon is t ac t iv i ty . More recent

ef fo r ts have used pept ide mimet ics to c i rcumvent these inheren t p rob lems wi th pept ide-based antagon is ts .

The culmina t ion of these e f for ts was the 1995 approval of losar tan , a nonpept ide angio tens in I I receptor

Diuretics All Potential excessive reduction in blood pressure; the effects of loop diuretics may be reduced.

Iron Salts Captopril Reduction of captopril levels unless administration is separated by at least 2 hours

K+ preparations or

K+-sparing diuretics

All Elevated serum potassium levels

Lithium All Increased serum lithium levels

NSAIDs All Decreased hypotensive effects

Phenothiazides All Increased pharmacological effects of ACE inhibitor

Probenecid Captopril Decreased clearance and increased blood levels of captopril

Rifampin Enalapril Decreased pharmacological effects of enalapril

Tetracycline Quinapril Decreased absorption of tetracycline (may result from high magnesium content of quinapril tablets)

NSAIDs, nonsteroidal anti-inflammatory agents.

Página 21 de 51


blocker (ARB) (1 ,39 ) .

Development of Losartan

The deve lopment of losar tan can be t raced back to two 1982 paten t publ icat ions (42) , wh ich descr ibed the

an t ihyper tens ive e f fects o f a ser ies o f im idazole -5 -ace t ic ac id ana logues. These compounds a re exempl i f ied

by S -8308

(Fig . 28 .15 ) and were la ter found to b lock the angio tens in I I receptor spec i f i ca l ly . A l though these

compounds were re la t ive ly weak antagon is ts , they d id no t possess the unwanted agonis t act iv i ty prev ious ly

seen in pep t ide analogues. A computer ized mo lecu la r mode l ing over lap o f angiotens in I I wi th the s t ructure

of S -8308 revealed th ree common s t ruc tura l fea tures: The ionized carboxy late of S -8308 corre la ted w ith the

C-te rminal carboxy la te o f ang io tens in I I , the imidazo le r ing o f S -8308 corre la ted w ith the imidazole s ide

cha in o f the His6 res idue , and the n -bu ty l g roup o f S-8308 corre la ted w ith the hydrocarbon s ide cha in of the

I le5 res idue (Fig . 28 .15) . The benzy l group o f S -8308 was proposed to l ie in the d irect ion o f the N -te rminus

of ang io tens in I I ; however, i t was no t be l ieved to have any s igni f ican t receptor in terac t ions .

From S-8308, a number o f mo lecu la r modi f i cat ions were carr ied ou t in an a ttempt to improve receptor

b ind ing and l ip id solubi l i ty , w i th the la t ter be ing importan t to assure adequate o ra l absorp t ion . These

changes resu l ted in the preparat ion o f losar tan , a compound w i th h igh receptor af f in i ty ( IC50 , 0 .019 M) and

ora l act iv i ty (Fig . 28 .16) .

P.753

View Figure

Fig. 28.15. Structural comparison of S-8308, an imidazole-5-acetic acid analogue, with angiotensin II. (Adapted from Timmermans PB, Wong PC, Chiu AT, et al. Angiotensin II receptors and angiotensin II receptor antagonists. Pharmacol Rev 1993;45:205–213; with permission. )

View Figure

Fig. 28.16. The development of losartan from S-8308.

Fig. 28.17. Structures of losartan analogues. The highlighted portions of candesartan cilexitil and olmesartan

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Additional Angiotensin II Receptor Blockers

Valsar tan, i rbesar tan, te lm isar tan , candesar tan, and o lmesar tan a re b ipheny l ana logues o f losar tan (Fig .

28 .17) . These compounds possess s t ructu ra l fea tu res tha t are s imi la r to those seen in losar tan. Va lsar tan ,

named fo r the va l ine por t ion o f the compound, is the f i r s t non imidazo le -con ta in ing ARB and is s l igh t ly more

po ten t ( IC50 , 0 .0089 µM) than losar tan . The amide carbonyl o f va lsar tan is isoste r ic wi th the imidazo le

n i t rogen o f losar tan and can serve as a hydrogen bond acceptor s imi lar to the im idazole n i t rogen.

Irbesar tan is a spi ro -compound tha t lacks the pr imary a lcoho l o f losar tan but that has a 10- fo ld g reate r

b ind ing af f in i ty ( IC50 , 0 .0013 µM) for the ang io tens in I I receptor . Hydrogen bond ing, o r ion–dipo le b ind ing,

of the carbonyl group can mimic the in te rac t ion o f the p r imary a lcoho l o f losar tan, whereas the

spi rocyc lopentane can prov ide enhanced hydrophob ic b ind ing . Bo th candesar tan c i lex i t i l and te lmisar tan

con ta in benzim idazole r ings tha t prov ide some enhanced hydrophobic b ind ing, s imi la r to tha t seen wi th the

spi rocyc lopentane r ing o f i rbesar tan. Bo th candesar tan c i lex i t i l and o lmesar tan medoxomil are p ro -drugs

tha t are rapid ly and comple te ly hydro lyzed dur ing absorpt ion f rom the gast ro intest ina l t rac t to the i r ac t ive

carboxy l ic ac id metabol i tes, candesar tan and o lmesar tan, respec t ively . These carboxy l ic ac ids l ie in exact ly

the same locat ions as the hydroxy l group o f losar tan, the carboxy l ic ac id o f va lsar tan , and the ketone o f

i rbesar tan and can par t ic ipa te in bo th ionic and dipole in teract ions.

Eprosar tan was deve loped us ing a d i f fe rent hypothes is than that fo r losar tan (Fig . 28 .18 ) . S im i lar to the

rat iona le for losar tan , the carboxy l ic ac id o f S -8308 was thought to mim ic the Phe8

( i .e . , C - te rminal )

carboxy la te o f angio tens in I I . The benzy l group of S -8308 was proposed to be an impor tan t s t ructura l

fea ture that mimicked the a romat ic s ide cha in o f Ty r4 p resent in the agon is t . Thus, the ma jo r s t ructu ra l

change was not an extens ion of the N-benzy l g roup but , ra ther , an enhancement of the compound's ab i l i ty

to mimic the C-te rminal end of ang iotens in I I . Th is was accompl ished by subs t i tu t ing the 5 -ace t ic ac id group

wi th an α - th ieny lac ry l ic ac id . In add i t ion , a para-carboxy la te (a funct iona l g roup invest iga ted dur ing the

deve lopment of losar tan) a lso was added. The th ieny l r ing isoste r ical ly mimics the Phe8 phenyl r ing of

angio tens in I I and , a long wi th the para-carboxy la te , i s responsib le fo r the exce l lent potency ( IC50 = 0.0015

View Figure

medoxomil are hydrolyzed via esterases to produce their respective active, carboxylate metabolites.

P.754

View Figure

Fig. 28.18. The development of eprosartan from S-8308. The Phe8

residue of angiotensin II contains the C-terminal carboxylic acid.

Página 23 de 51


µM) of th is compound (39 ) .

Mechanism of Action The angio tens in I I receptor ex is ts in a t leas t two sub types , type 1 (AT1 ) and type 2 (AT 2 ) . The AT1

recep tors are located in bra in, neurona l , vascula r , rena l , hepat ic , adrena l , and myocard ia l t i ssues and

med iate the cardiovascu la r , rena l , and cen t ra l nervous system (CNS) ef fects o f angio tens in I I . A l l cu rren t ly

ava i lable ARBs are 10 ,000- fo ld more se lect ive fo r the AT1

recep tor sub type and act as compet i t i ve

an tagonis ts a t th is s i te. In terms of re lat ive af f in i ty fo r the AT 1 recep tor , candesar tan and o lmesar tan have

the grea test a f f in i ty ; i rbesar tan and eprosar tan have a somewhat lower af f in i ty ; and te lmisar tan , va lsar tan,

and losar tan have the lowes t a f f in i ty . A l l ARBs prevent and reverse a l l o f the known ef fects o f ang io tens in

I I , inc lud ing rap id and s low pressor responses , s t imu lato ry e f fects on the per iphera l sympathet ic nervous

system, CNS e f fec ts , re lease o f catecho lamines, secre t ion of a ldosterone, d irec t and ind i rect rena l e f fec ts ,

and a l l g rowth-promot ing e f fects . The funct ion o f the AT 2 recep tors is no t as we l l characte r ized; however ,

they have been proposed to media te a var ie ty o f growth, deve lopment , and d i f fe rent iat ion p rocesses . Some

concern has a r isen tha t unopposed st imu la t ion of the AT2

recep tor in con junct ion wi th AT1

recep tor

an tagonism may cause long- te rm adverse ef fects . As a resu l t , compounds tha t exh ib i t ba lanced antagon ism

at both receptor subtypes are curren t ly be ing sought (1,43 ) .

Structure–Activity Relationships

Al l commerc ia l ly avai lab le ARBs are ana logues of the fo l lowing general s t ructu re :

1. The “ac id ic g roup ” is thought to mim ic e i ther the Tyr4

pheno l o r the Asp1

carboxy late o f angio tens in

I I . Groups capable o f such a ro le inc lude the carboxy l ic ac id (A ) , a phenyl te t razo le (B) , o r a pheny l

carboxy la te (C) .

2. In the b iphenyl ser ies, the te t razole and carboxy late groups mus t be in the o r tho pos i t ion for op t ima l

act iv i ty ( the te t razole group is super ior in terms o f metabo l ic s tab i l i ty , l ipophi l ic i ty , and oral

b ioava i labi l i ty ) .

3. The n-bu ty l g roup o f the mode l compound prov ides hydrophob ic b inding and, most l i ke ly , m imics the

s ide cha in o f I le5 o f ang io tens in I I . As seen wi th candesar tan, te lm isar tan , and o lmesar tan, th is n -

bu ty l g roup can be replaced wi th e i ther an e thy l e ther o r an n -propy l g roup .

4. The imidazo le r ing o r an isoster ic equiva len t i s requi red to mimic the His6 s ide cha in o f angio tens in

I I .

5. Subst i tut ion can vary at the “R” pos i t ion. A var ie ty of R groups, inc lud ing a carboxy l ic ac id , a

hydroxymethy l group, a ke tone, o r a benz imidazole r ing, a re present in cur ren t ly avai lab le ARBs and

are thought to inte ract w i th the AT1

recep tor th rough ei ther ion ic , ion–dipo le, o r d ipole–dipo le

bonds.


Al l ARBs are ac id ic drugs. The tet razo le r ing found in losar tan , va lsar tan , i rbesar tan , candesar tan , and

Página 24 de 51


olmesar tan has a pK a o f approx imate ly 6 and w i l l be a t least 90% ionized a t phys io log ical pH. The

carboxy l ic ac ids found on valsar tan, candesar tan, o lmesar tan, te lm isar tan, and eprosar tan have pK a va lues

in the range 3–4 and also wi l l be p r imar i l y ion ized . Curren t ly , ava i lable agents have adequate , bu t no t

excel len t , l ip id solubi l i ty . As p rev ious ly ment ioned, the te t razo le group is more l ipophi l ic than a carboxy l ic .

Add i t iona l ly , the four n i t rogen atoms present in the te t razole r ing can crea te a grea ter charge d is t r ibu t ion

than that ava i lable fo r a carboxy l ic ac id . These proper t ies have been proposed to be responsib le for the

enhanced b ind ing and b ioavai lab i l i ty of the te t razo le -con ta in ing compounds (44) . S im i lar to ACE inh ib i tors ,

the s tereochemist ry of va lsar tan is cons is tent w i th the L -amino ac ids in the na tural agonis t .

Metabolism

Approx imate ly 14% of a dose of losar tan is ox id ized by the isozymes CYP2C9 and CYP3A4 to p roduce EXP-

3174, a noncompet i t i ve AT1 recep tor an tagonis t tha t is 10 - to 40- fo ld more po tent than losar tan (Fig .

28 .19) . The overa l l ca rd iovascu lar e f fects seen w ith losar tan resu l t f rom the combined act ions o f the parent

drug and the act ive metabol i te ; thus, losar tan shou ld no t be considered to be a p ro -drug (1) . As p rev ious ly

ment ioned, candesar tan c i lexe t i l and o lmesar tan medoxomi l a re rap id ly and comple te ly hydrolyzed to

candesar tan and o lmesar tan , respect ively , in the in test inal wa l l .

None o f the o ther compounds are conver ted to act ive metabol i tes. A l l o f these compounds a re pr imar i ly

(80%) excre ted unchanged. Approx imately 20% o f valsar tan is metabo l ized to inac t ive compounds v ia

mechanisms tha t do not appear to invo lve the CYP450 system. The pr imary c i rcula t ing metabo l i tes for

i rbesar tan , te lmisar tan and eprosar tan , are inact ive g lucuron ide con juga tes. A smal l amount o f i rbesar tan is

ox id ized by CYP2CP; however, i rbesar tan does no t subs tan t ia l l y induce or inh ib i t the CYP450 enzymes

normal ly involved in d rug metabo l ism (1 ,32 ,33 ,34 ) .


The pharmacok inet ic parameters and dos ing info rmat ion for angiotens in receptor antagon is ts are

summar ized in Tab les 28.6 and 28 .7 , respect ively (32 ,33 ,34 ) . Wi th the except ion of i rbesar tan (60–80%)

and, poss ib ly , te lmisar tan (42–58%) , a l l o f the compounds have low, bu t adequate, o ra l b ioavai lab i l i ty (15–

33%) . G iven the fact that most o f the compounds a re exc reted unchanged, the most probab le reasons fo r

the low b ioava i lab i l i ty a re poor l ip id solub i l i ty and incomple te absorpt ion . Ef fects o f food on the absorp t ion

of losar tan, eprosar tan , valsar tan, and eprosar tan is to reduce absorpt ion ; however, these e f fec ts have

been deemed to be c l in ical ly ins ign i f ican t ; thus, the compounds can be taken ei ther w i th o r wi thou t food. A l l

o f the compounds have s im i lar onse ts , are h igh ly p ro te in bound, have e l im inat ion hal f - l i ves tha t a l low once-

or tw ice-da i ly dos ing, and w ith the except ion o f o lmesar tan , are p r imar i l y e l imina ted v ia the feca l rou te.

Candesar tan and te lmisar tan appear to requ ire a s l ight ly longer t ime to reach peak p lasma concent ra t ions.

As w i th ACE inh ib i to rs , l i te ra ture des igna t ion of feca l e l imina t ion is unc lear regard ing whether i t inc ludes

unabsorbed drug .

Candesar tan c i lexe t i l , losar tan, and olmesar tan d i f fe r f rom the o ther compounds in severa l respects . They

are the only compounds w i th act ive metabo l i tes, and they have the h ighest renal e l imina t ion o f a l l o f the

agents . Produc t labe l ing indica tes tha t renal impa i rment does not requi re a dosage reduct ion for losar tan ,

bu t area under the curve values a re increased by 50% in pa t ien ts wi th

a crea t in ine c learance o f less than 30 mL/min and are doub led in hemodia lys is pa t ien ts . These increases

P.755

View Figure

Fig. 28.19. The metabolic conversion of losartan to EXP-3174 by cytochrome P450 isozymes.

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Página 25 de 51


are not seen fo r the other agents . Losar tan and te lmisar tan are the only two agents tha t requ i re in i t ia l dose

reduct ions in pat ien ts w i th hepat ic impa i rment . Because o f s ign i f i cant ly inc reased p lasma concent ra t ion ,

pa t ien ts wi th impai red hepat ic funct ion or b i l iary obst ruct ive d isorders shou ld avoid the use o f te lmisar tan .

Table 28.6. Pharmacokinetic Parameters of Angiotensin II Receptor Blockers

Drug


Active Metabolite

Protein Binding (%)

Time to Peak Plasma Concentration (hours)

Elimination Half(hours)

Candesartan Cilexetil

15 Candesartan 99 3–4 9

Eprosartan 15 None 98 1–2 5–

Irbesartan 60–80 None 90 1.5–2.0 11

Losartan 33 EXP-3174 98.7 (losartan) 99.8 (EXP-3174)

1 (losartan) 3–4 (EXP-3174)

1.5(losartan)6–(EXP3174)

Olmesartan Medoxomil

26 Olmesartan 99 1.5–3.0 10

Telmisartan 42–58 None 100 5 24

Valsartan 25 None 95 2–4 6

Página 26 de 51



Al l ARBs are current ly approved fo r the t reatment o f hyper tens ion and, a long w ith ACE inh ib i tors , d iuret ics ,

β -b lockers, and calc ium channe l b lockers, have been des ignated as f i rs t - l ine agents e i ther a lone o r in

Table 28.7. Dosing Information for Angiotensin II Receptor Blockers

Generic NameTrade Name(s)


Dosing Range (Treatment of Hypertension)

Maximum Daily Dose

Initial Dose Reduction with Hepatic Dysfunction

Candesartan Cilexetil

Atacand Hypertension, heart failure

8–32 mg q.d.

32 mg

No

Eprosartan Teveten Hypertension 400–800 mg q.d. or b.i.d.

900 mg

No

Irbesartan Avapro Hypertension, nephropathy in type II diabetics

150–300 mg q.d.

300 mg

No

Losartan Cozaar Hypertension, nephropathy in type II diabetics, hypertension with left ventricular hypertrophy

25–100 mg q.d. or b.i.d.

100 mg

Yes

Olmesartan Medoxomil

Benicar Hypertension 20–40 mg q.d.

40 mg

No

Telmisartan Micardis Hypertension 40–80 mg q.d.

80 mg

Yes (avoid)

Valsartan Diovan Hypertension heart failure

80–320 q.d.

320 mg

No

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combina t ion wi th o ther an t ihyper tens ive agents (37) . A l l ARBs are avai lab le as s ing le agents and as

combina t ion produc ts wi th hydroch lo r th iaz ide . Addi t ional ly , i rbesar tan and losar tan have been approved for

the t rea tment o f nephropathy in type I I d iabetes, losar tan fo r the t rea tment of hyper tens ion wi th le f t

ven t r icu la r hyper t rophy , and candesar tan and va lsar tan for the t rea tment o f hear t fa i lu re . Based on thei r

ab i l i ty to a t tenuate the ren in -angio tens in system, one should expect a g radua l inc rease in the number o f

uses and approved ind icat ions fo r th is c lass o f agents .

Adverse Effects

The mos t preva len t s ide ef fects o f ARBs are l is ted above and d iscussed be low. (1 ,32 ,33 ,34) . Overal l , th is

c lass o f agents is wel l to lerated, w i th CNS e f fec ts be ing the most commonly repor ted complain t . S im i lar to

ACE inhib i to rs , some of the adverse e f fects a re d i rec t ly re lated to a t tenuat ion of the ren in -angio tens in

pa thway. Notab ly absent a re the dry cough and angioedema seen w ith ACE inh ib i to rs . Because ARBs are

speci f ic in the ir act ions, th is c lass of d rugs does no t a f fect the leve ls of b radyk in in o r pros tag landins and,

thus, does no t cause these bothersome s ide ef fects . L ike ACE inh ib i tors , the use o f ARBs dur ing p regnancy

is con t ra indica ted , especia l ly dur ing the second and th i rd t r imes ters . The use o f ARBs shou ld be

d iscont inued as soon as p regnancy is con f i rmed un less the benef i ts outweigh the poten t ia l r isks.

Adverse Effects of Angiotensin I I Receptor Antagonists

Headache, dizziness, fat igue, hypotension, hyperkalemia, dyspepsia, diarrhea, abdominal pain,

upper respiratory tract in fect ion, myalgia, back pain, pharyngi t is , and rhini t is

Drug Interactions

Coadminis t ra t ion of ARBs wi th potass ium sa l ts , po tass ium-spar ing d iu re t ics , or d rosp irenone may cause

hyperka lemia. Nonste ro ida l ant i - in f lammatory drugs may a l te r the response to ARBs and other

an t ihyper tens ive agents ( inc lud ing ACE inhib i to rs and ca lc ium channel b lockers) because o f inhib i t ion of

vasod i la tory prostag land ins. S tud ies have shown tha t indomethac in , naproxen, and pi rox icam have a

grea ter p ropensi ty for caus ing th is in te ract ion . Telmisar tan has been repor ted to increase d igox in levels

and to s l ight ly dec rease warfa r in levels ; however , the reduced war fa r in leve ls were no t suf f i c ien t to a l te r

the in terna t ional norma l ized ra t io . R i fampin, because of i ts ab i l i ty to induce CYP3A4, can decrease the

p lasma levels o f losar tan and i ts act ive metabol i te, EXP-3174. The c l in ical s ign i f icance of d rug inte ract ions

be tween ARBs and compounds tha t can inh ib i t e i ther CYP3A4 or CYP2C9 has ye t to be establ ished.

Role of Calcium and Calcium Channels in Vascular Smooth Muscle Contraction

Calc ium is a key component o f the exc i tat ion-con t ract ion coup l ing p rocess that occurs w i th in the

cardiovascula r sys tem. I t acts as a cel lu lar messenger to l ink in te rna l or exte rnal exc i ta t ion wi th cel lu lar

response. Increased cytoso l ic concent ra t ions o f Ca2+ resul t in the b inding o f Ca2+ to a regu la tory prote in ,

e i ther t ropon in C in cardiac and ske le ta l muscle o r ca lmodu l in in vascu la r smooth muscle . Th is in i t ia l

b ind ing of Ca2+ uncovers myosin b ind ing s i tes on the act in molecule, and subsequent in te rac t ions be tween

act in and myos in resul t in muscle con t ract ion . A l l o f these events are reversed once the cytoso l ic

concentrat ion o f Ca2+ decreases . In th is s i tuat ion , Ca2+ b ind ing to t ropon in C or ca lmodu l in is d im in ished or

removed, myosin b inding s i tes are concealed , act in and myosin can no longer inte ract , and muscle

con t ract ion ceases (45 ,46) .

Mechanisms of Calcium Movement and Storage

The regu la t ion of cy toso l ic calc ium leve ls occurs v ia spec i f i c in f lux , e f f lux, and sequeste r ing mechanisms

(Fig . 28 .20 ) . The in f lux o f ca lc ium can occur th rough receptor -operated channe ls (s i te 1 ) , the Na+ /Ca2+

exchange process (s i te 2 ) , “ leak ” pa thways (s i te 3 ) , and potent ia l -dependent channe ls (s i te 4 ) . Inf lux v ia

e i ther receptor -operated o r vo l tage-dependent channe ls has been proposed to be the ma jor en t ry pathway

fo r Ca2+ . Receptor -operated channe ls have been def ined as those associa ted wi th cel lu lar membrane

receptors and act iva ted by spec i f i c agonis t–receptor in teract ions. In cont rast , potent ia l -dependent

channe ls , a lso known as vo l tage-dependent o r vo l tage-ga ted ca lc ium channels , have been de f ined as those

act iva ted by membrane depo la r iza t ion . The Na+ /Ca2+ exchange process can promote e i ther in f lux or e f f lux,

because the d irect ion o f Ca2+ movement depends on the re la t ive int race l lu la r and ex t racel lu lar rat ios of

Na+ and Ca2+ . The “ leak ” pa thways, wh ich inc lude unst imulated Ca2+ en t ry as we l l as ent ry dur ing the fas t

inward Na+ phase o f an ac t ion po ten t ia l , p lay on ly a minor ro le in ca lc ium in f lux.

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Eff lux can occur th rough ei ther an ATP-dr iven membrane pump (s i te 5) o r v ia the Na + /Ca2+ exchange

process p rev ious ly ment ioned (s i te 2) . In add i t ion to these in f lux and e ff lux mechan isms, the sarcop lasmic

ret icu lum (s i te 6) and the m itochondr ia (s i te 7 ) func t ion as inte rnal s to rage/ re lease s i tes . These s torage

s i tes work in concer t w i th the inf lux and e f f lux p rocesses to assure tha t cytoso l ic ca lc ium levels a re

appropr iate for cel lu lar needs. A l though inf lux and re lease processes a re essent ia l for exc i ta t ion–

cont ract ion coup l ing, e f f lux and sequester ing p rocesses a re equa l ly impor tan t fo r te rmina t ing the cont ract i le

process and fo r protect ing the ce l l f rom the de lete r ious e f fects of Ca2+ over load (47 ,48) .

Potential-Dependent Calcium Channels

The pharmacologica l c lass o f agents known as ca lc ium channe l b lockers p roduces the i r ef fects th rough

in teract ion w i th po tent ia l -dependent channe ls . To date , s ix funct ional subc lasses, o r types , o f potent ia l -

dependent Ca2+ channe ls have been iden t i f ied : T , L , N, P , Q, and R. These types d i f fe r in loca t ion and

funct ion and can be d iv ided in to two major groups: low-vol tage ac t iva ted (LVA) channe ls , and high -vol tage

act iva ted (HVA) channe ls . Of the s ix types, only the T ( t rans ien t, t iny ) channel can be rap id ly ac t iva ted and

inac t iva ted w ith smal l changes in the ce l l membrane po ten t ia l . I t i s thus des ignated as an LVA channe l . A l l

o f the o ther types of channels requi re a larger depo la r izat ion and are thus des igna ted as HVA channe ls .

The L ( long- last ing , la rge) channe l i s the s i te o f act ion fo r curren t ly ava i lable calc ium channe l b lockers and ,

there fo re , has been extens ively s tud ied. I t i s loca ted in skele ta l , cardiac , and smooth muscle and , thus, i s

h igh ly invo lved in o rgan and vessel cont ract ion w i th in the card iovascu lar system. The N channe l i s found in

neuronal t issue and exhib i ts k inet ics and inh ib i tory sens i t i v i ty d is t inc t f rom bo th L and T channe ls . The

funct ions, sens i t i v i t ies , and proper t ies of the o ther th ree types o f channe ls a re not as we l l known. The P

channe l has been named for i ts p resence in the Purk in je ce l ls , whereas the Q and R channels have been

characte r ized by the ir ab i l i t ies to b ind to cer ta in polypept ide tox ins (49 ,50 ,51) .

The L channe l i s a pentamer ic complex consis t ing o f α1

, α2

, β , γ , and δ po lypept ides (see Fig . I I .12) . The

α1 subuni t is a t ransmembrane-spanning p rote in that cons is ts o f four domains and that funct ions as the

pore- fo rming subun i t . The α1 subuni t a lso conta ins b ind ing s i tes for a l l the

cur ren t ly avai lab le ca lc ium channel b lockers. The o ther four subuni ts surround the α1 por t ion of the channe l

and con t r ibu te to the overal l hydrophobic i ty of the pen tamer. Th is hydrophob ic i ty is important in tha t i t

a l lows the channel to be embedded in the ce l l membrane. Addi t ional ly , the α2 , δ , and β subuni ts modu late

the α1 subuni t . Other types o f po tent ia l -dependent channe ls a re s imi la r to the L channel . They a l l have a

cen t ra l α1 subuni t ; however, mo lecu la r c loning s tud ies have revealed that there a re a t least s ix α1 genes:

α1S

, α1A

, α1B

, α1C

, α1D

, and α1E

. Three o f these genes, α1S

, α1C

, and α1D

, have been associa ted w ith L

channe ls . The L channe ls found in ske leta l musc le resul t f rom the α1S gene; those in the hear t , aor ta , lung,

and f ibrob last resu l t f rom the α1C gene; and those in endocr ine t i ssue resul t f rom the α1D gene. Bo th α1C

and α1D a re used for L channels in the b ra in. Thus, there a re some d i f fe rences among the L channels

loca ted in d i f fe ren t organs and t issues. Addi t ional ly , d i f ferences in α1

genes as we l l as d i f fe rences among

the other subuni ts a re respons ib le fo r the var ia t ions seen among the other f ive types of poten t ia l -dependent

channe ls . As an example , the N channe l lacks the γ subuni t and con ta ins an α1 subuni t der ived f rom the

α1B gene (49 ,51 ) .

Cardiovascular Disorders Associated With Potential-Dependent Calcium Channels

As desc r ibed above, the movement o f calc ium under l ies the bas ic exc i ta t ion–cont ract ion coup l ing p rocess.

Thus, vascu la r tone and cont ract ion p r imar i l y are dete rmined by the avai lab i l i ty o f ca lc ium f rom

View Figure

Fig. 28.20. Cellular mechanisms for the

influx, efflux, and sequestering of Ca2+.

ROC, receptor-operated Ca2+ channels;

PDC, potential-dependent Ca2+ channels; SR, sarcoplasmic reticulum; M, mitochondria.

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ext race l lu la r o r in t race l lu la r sources. Po ten t ia l -dependent Ca2+ channe ls are important in regula t ing the

in f lux o f Ca2+ ; therefo re , inhib i t ion o f Ca2+ f low th rough these channe ls resu l ts in both vasod i la t ion and

decreased ce l lu la r response to con t rac t i le s t imu l i . Ar te r ia l smooth musc le is more sensi t i ve to th is act ion

than venous smooth musc le . Addi t ional ly , coronary and cerebra l a r te r ia l vesse ls are more sensi t ive than

other a r te r ia l beds (48 ,51) . As a resul t of these act ions, ca lc ium channel b lockers a re usefu l in the

trea tment o f hyper tens ion and ischemic hear t d isease . A b r ie f overv iew o f hyper tens ion is p rov ided in the

ren in -angio tens in sect ion o f th is chapter .

The term “ ischemic hear t d isease, ” encompasses a var iety o f syndromes . These inc lude ang ina pecto r is ,

s i lent myocard ia l ischemia, acu te coronary insu f f ic iency , and MI. The overa l l inc idence of i schemic hear t

d isease is h igher in men than in women and increases wi th age. Myocard ia l in farc t ion is the pr imary in i t ia l

even t in men, whereas angina is the most common in i t ia l presentat ion in women. The average annual

inc idence ra te ( i .e . , number o f new cases /popu lat ion) o f angina pec tor is is 1 .5% and depends on the

pa t ien t 's age, gender, and r isk - facto r p rof i le . A 1998 es t imate f rom the Amer ican Heart Associa t ion p laces

the preva lence of ang ina at approx imately 6 .4 mi l l ion (52 ) .

Ang ina pecto r is is a c l in ica l man ifesta t ion that resu l ts f rom coronary a therosc lerot ic hear t d isease. I t i s

characte r ized by a severe cons tr ic t ing pain in the ches t tha t o f ten rad ia tes to the lef t shoulder , the lef t a rm,

or the back. C l in ica l ly , ang ina pecto r is can be c lass i f ied as e i ther exer t ional , var ian t, o r uns tab le .

Exer t ional ang ina , o therw ise known as s table angina o r exerc ise- induced angina , i s the most common fo rm

and resu l ts f rom an imba lance be tween myocard ia l oxygen supp ly and demand. Var iant ang ina , otherwise

known as Pr inzmetal 's ang ina , resu l ts f rom the vasospasm o f large , sur face coronary vessels o r branches .

Unstable angina is the most d i f f icu l t to t rea t and may occur as a resul t of advanced a therosc le ros is and

coronary vasospasm (53 ) .

Exc i tat ion–cont ract ion coup l ing in the hear t i s d i f fe rent f rom that in vascular smooth muscle in tha t a

por t ion of the inward cur ren t is car r ied by Na+ th rough the fas t channe l . In the s inoat r ia l and

at r ioven t r icu la r (AV) nodes , however, depola r izat ion depends p r imar i l y on the movement o f Ca2+ th rough

the s low channe l . A t tenuat ion of th is Ca2+ movement p roduces a negat ive inot rop ic ef fect and decreased

conduc t ion th rough the AV node. Th is la t ter e f fect is especia l ly use fu l in t rea t ing paroxysmal

supravent r icu lar tachycard ia (PSVT), an a rrhythmia p r imar i l y caused by AV noda l reent ry and AV reen t ry

(51) .

Calcium Channel Blockers

Historical Overview

Ident i f icat ion o f compounds tha t could b lock the inward movement o f Ca2+ th rough s low cardiac channe ls

occurred in the ear ly 1960s. Verapami l and o ther phenyla lky lam ines were shown to possess negat ive

inot rop ic and chronot rop ic e f fects tha t were d is t inct f rom other coronary vasodi la to rs . Fur ther invest iga t ions

revea led tha t these agents mimicked the cardiac ef fects o f Ca2+ w i thdrawa l: they reduced con t rac t i le fo rce

wi thout a f fec t ing the act ion potent ia l . The e f fects of these compounds cou ld be reversed by the addi t ion of

Ca2+ , thus sugges t ing tha t the negat ive inot rop ic e f fec t was l inked to an inh ib i t ion o f exc i ta t ion–cont ract ion

coup l ing . Subsequent ly , der ivat ives o f verapamil , as we l l as other chemica l c lasses o f compounds, were

shown to compet i t i ve ly b lock Ca 2+ movement th rough the s low channe l and, thus, a l ter the cardiac ac t ion

po ten t ia l . There fo re , ca lc ium channel b lockers a lso a re known as s low channel b lockers, ca lc ium ent ry

b lockers, and calc ium an tagonis ts (47 ,51 ) .

Chemical Classifications

Overview

Current ly , n ine calc ium channe l b lockers are ava i lab le fo r therapeut ic use . These compounds have d iverse

chemica l s t ructu res and can be g rouped in to one of four chemica l

c lass i f i cat ions (Fig . 28 .21 ) , each of which produces a d is t inct pharmaco logica l p ro f i le : 1 ,4 -d ihydropyr id ines

(1,4 -DHPs; e .g. , n i fedip ine) , phenyla lky lamines (e .g. , ve rapami l ) , benzoth iazep ines (e .g . , d i l t iazem), and

diam inopropanol e thers (e .g. , bepr id i l ) . The ma jor i ty of calc ium channe l b lockers are 1 ,4 -DHPs, and a

de ta i led descr ip t ion of the SAR fo r th is chemical c lass is prov ided be low. In con t ras t , verapamil , d i l t iazem,

and bepr id i l are the lone representa t ives of thei r respec t ive chemica l c lasses and, thus, a re d iscussed as

indiv idua l agents . Verapami l and di l t iazem are d iscussed a long w ith the 1 ,4 -DHPs. Bepr id i l i s a

nonselec t ive agent tha t i s no longer ava i lab le in the Un i ted Sta tes.

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1,4-Dihydropyridines

History and development

The chemist ry o f d ihydropyr id ines can be t raced back to an 1882 paper in which Hantzsch desc r ibed thei r

ut i l i ty as in termediates in the synthes is of subst i tu ted pyr id ines . F i f ty years la te r , in terest in th is chemica l

c lass o f compounds inc reased when i t was d iscovered tha t a 1 ,4 -DHP r ing was responsib le for the

“hydrogen- transfe r” proper t ies of the coenzyme NADH. Numerous b iochemical s tudies fo l lowed th is

d iscovery; however , i t was no t un t i l the ear ly 1970s tha t the pharmaco logica l p roper t ies of 1 ,4 -DHPs were

fu l ly invest iga ted . Loev and coworkers a t Smi th , K le in & French laborato r ies invest iga ted the ac t iv i t ies o f

“Hantzsch- type” compounds. As shown in Figure 28.22 , the Hantzsch react ion p roduced a symmetr ica l

compound in wh ich bo th the este rs ( i .e . , CO2

R2

) and the C2

and C6

subst i tuents ( i .e . , CH3

) are iden t ica l

wi th each o ther . St ructu ra l requi rements necessary fo r ac t iv i ty were iden t i f ied by sequent ia l ly mod ify ing the

C4 subst i tuent ( i .e . , the R1 g roup) , the C 3 - and C5 -este rs ( i .e . , the R2 g roups) , the C2 - and C 6 -a lky l groups ,

and the N1 -H subst i tuen t (54 ,55 ,56 ,57 ) .

Bepridi l is unique among al l the calc ium channel blockers in that i ts act ions are not based solely

on its abil i ty to block potent ia l -dependent L-type ( i.e., s low) Ca2+ channels (32,51). Unlike other

calc ium channel blockers, beprid i l also b locks fast Na+ channels as well as receptor -operated

calc ium channels. These addi t ional act ions are responsib le for bepridi l 's abi l i ty to inhibi t cardiac

conduction, to s low AV nodal conduction, to increase the ref ractory per iod, to s low the heart

rate, and to prolong the QT interval .

Bepridi l was indicated for the oral t reatment of chronic stable angina pector is; however, i ts

manufacturer voluntar i ly removed it from the U.S. market, pr imari ly because of i ts abil i ty to

cause torsades de pointes. I t a lso should be noted that beprid i l was never highly prescr ibed,

most l ikely because of the signif icant number of cardiovascular warnings and contraindicat ions

associated wi th i ts use.

View Figure

Fig. 28.21. Chemical classes of calcium channel blockers.

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Structure–activity relationships

The SARs for 1,4 -DHP der iva t ives (see General St ructu re in Tab le 28 .8 ) indica tes tha t the fo l low ing

s t ructura l fea tures a re important fo r ac t iv i ty :

1 . A subst i tu ted phenyl r ing a t the C 4 pos i t ion opt imizes ac t iv i ty (he teroaromat ic r ings, such as

pyr id ine , produce s imi la r therapeut ic ef fects but a re no t used because o f observed an imal tox ic i ty ) ,

and C4

subst i tut ion w i th a smal l nonp lanar a lky l or cyc loa lky l group decreases act iv i ty .

2. Phenyl r ing subst i tut ion (X) is impor tan t for s ize and pos i t ion rather than fo r e lect ron ic na ture .

Compounds w ith or tho or meta subs t i tu t ions possess op t ima l act iv i ty , whereas those tha t a re

unsubs t i tu ted or tha t con ta in a para-subst i tut ion show a s ign i f i cant dec rease in act iv i ty . Despi te the

fact that a l l commerc ia l ly avai lab le 1 ,4 -DHPs have e lect ron-wi thdrawing o r tho and/or meta

subst i tuen ts , th is is no t an abso lute requ irement . Compounds w ith e lect ron-donat ing groups at these

same pos i t ions a lso have demonst ra ted good act iv i ty . The importance o f the or tho and meta

subst i tuen ts is to p rov ide suf f i c ien t bu lk to “ lock ” the con fo rmat ion o f the 1 ,4-DHP such tha t the C4

aromat ic r ing is perpendicu la r to the 1,4 -DHP r ing (Fig . 28 .23 ) . Th is perpend icula r confo rmat ion has

been proposed to be essent ia l for the act iv i ty o f the 1 ,4 -DHPs.

3. The 1,4 -DHP r ing is essent ia l for act iv i ty . Subst i tu t ion a t the N1 pos i t ion o r the use of ox id ized

(p iper id ine) or reduced (pyr id ine) r ing systems great ly decreases o r abo l ishes act iv i ty .

4. Ester groups at the C3 and C 5 pos i t ions op t imize ac t iv i ty . Other e lect ron-wi thdrawing g roups show

decreased antagon is t act iv i ty and may even show agon is t ac t iv i ty . For example, the rep lacement o f

the C3

este r o f i s rad ip ine wi th a NO2

g roup produces a calc ium channe l act iva tor , o r agon is t (Fig .

28 .24) . Thus, the term “calc ium channe l modu la tors” is a more appropr iate c lass i f i ca t ion fo r the 1 ,4 -

DHPs.

View Figure

Fig. 28.22. Synthesis of 1,4-DHPs using the Hantzsch reaction.

View Table

Table 28.8. Structure of the

Dihydropyridine Ca2+ Channel Blockers

P.760

Página 32 de 51


5. When the este rs a t C3 and C5 a re non ident ica l , the C4 carbon becomes chi ra l , and s te reoselec t iv i ty

be tween the enant iomers is observed . Add i t iona l ly , ev idence suggests tha t the C3 and C5 pos i t ions

of the d ihydropy r id ine r ing are not equ iva lent pos i t ions. Crys ta l s t ructures o f n i fedip ine, a

symmetr ica l 1 ,4 -DHP, have shown tha t the C3

carbony l i s synp lanar to the C2

-C3

bond bu t tha t the

C5 carbony l i s ant iper ip lanar to the C5 -C6 bond (Fig . 28 .25) . Asymmetr ica l compounds have shown

enhanced se lect iv i ty for spec i f ic b lood vesse ls and are be ing pre fe ren t ia l ly deve loped. Ni fed ip ine ,

the f i rs t 1 ,4 -DHP to be marketed , i s the on ly symmetr ica l compound in th is chemica l c lass.

6. With the except ion of amlod ip ine , a l l 1 ,4 -DHPs have C 2 and C6 methy l groups . The enhanced

po tency o f am lod ip ine (vs. n i fedip ine) sugges ts tha t the 1 ,4 -DHP receptor can to le ra te la rger

subst i tuen ts at th is pos i t ion and that enhanced ac t iv i ty can be ob ta ined by a l ter ing these g roups.

Mechanism of Action

Desp ite the name, ca lc ium channel b lockers do not s imp ly “p lug the hole ” and phys ica l ly b lock the Ca2+

channe l . Instead , they exer t the ir ef fects by b inding to spec i f ic recep tor s i tes located w i th in the cen t ra l α1

subuni t of L - type , po tent ia l -dependent channe ls . Three

d is t inct , but a l loster ical ly in teract ing, receptors have been ident i f ied fo r verapami l , d i l t iazem, and the 1 ,4 -

DHPs. As shown in Tab le 28 .9 , the b ind ing of verapami l to i ts receptor inhib i ts the b ind ing of both d i l t iazem

and the 1 ,4 -DHPs to the ir respect ive receptors . L ikewise , the b inding o f e i ther d i l t iazem or the 1,4 -DHPs

inhib i ts the b ind ing of verapami l . In cont rast , d i l t iazem and the 1 ,4 -DHPs mutual ly enhance the b ind ing of

each other (54) .

Poten t ia l -dependent channe ls can ex is t in one o f three confo rmat ions: a rest ing s ta te , wh ich can be

s t imu lated by membrane depola r izat ion ; an open s tate , wh ich a l lows the Ca2+ to ente r ; and an inact ive

s tate , wh ich is re f ractory to fu r ther depo lar iza t ion . Ca lc ium channel b lockers have been shown to be more

P.761

View Figure

Fig. 28.23. Molecular models of nifedipine. The ortho-nitro group of nifedipine provides steric bulk and ensures that the required perpendicular nature of the phenyl and dihyropyridine rings is maintained.

View Figure

Fig. 28.24. Structures of isradipine and its analogous 3-nitro derivative.

Página 33 de 51


ef fect ive when membrane depo la r iza t ion is e i ther longer , more in tense , or more f requent . This use-

dependency suggests that these compounds p re feren t ia l ly in teract w i th the i r recep tors when the Ca2+

channe l i s in e i ther the open or inact ive s tate . This s ta te dependence is not ident ica l fo r a l l c lasses of Ca2+

b lockers and , in combinat ion w i th the d i f feren t b inding s i tes , a l loste r ic in terac t ions , ac id i ty , and so lub i l i ty ,

may be responsib le fo r the pharmaco log ical

d i f ferences among verapamil , d i l t iazem, and the 1 ,4 -DHPs. A summary of these d i f fe rences is l is ted in

Tab le 28 .10 . The 1 ,4 -DHPs, as exempl i f ied by n i fedip ine, a re pr imar i ly vasod i la tors , whereas verapami l and

di l t iazem have bo th vasod i lato r and card iodepressant act ions. The increased hear t rate seen wi th n i fed ip ine

resul ts f rom a ref lex mechan ism tha t tr ies to overcome the vasodi lat ion and subsequent d rop in b lood

pressure caused by the 1,4 -DHPs. In con t rast , the compensatory mechan ism does no t occur to the same

exten t w i th e i ther verapamil o r d i l t iazem. Th is is caused, in par t , by the ab i l i ty o f verapamil and d i l t iazem to

b lock AV noda l conductance and, in par t , by the inc reased ab i l i ty of 1 ,4 -DHPs to act iva te the baroreceptor

ref lex . Ul t imate ly , these pharmacolog ical d i f fe rences a re ref lected in the c l in ica l use of these agents

(48 ,53 ,54) .

Ziconotide: An N-Type Calcium Channel Blocker

Ziconotide is a synthetic analogue of a natural ly occurr ing conopept ide found in the p iscivorous

marine snail (Conus magus ). I t is structural ly, mechanist ical ly, and therapeut ically di f ferent f rom

the other calcium channel blockers discussed in this chapter. Structura lly, i t is a polybasic

peptide containing 25 amino acids and three disul f ide br idges.

I t se lect ive ly binds to N-type potential -dependent calc ium channels located on the pr imary

nocicept ive (A-d and C) afferent nerves in the superf ic ia l layers (Rexed laminae I and I I) of the

dorsal horn in the spinal cord. Analgesic ef fects resul t from a blockade of neurotransmitter

re lease and a disruption of normal nocicept ive s ignal transmission. Ziconotide is indicated for

the management of severe chronic pain in pat ients who are intolerant of or ref ractory to other

systemic analgesics, adjunct therapies, or intrathecal morphine. Because of i ts peptide

P.762

View Figure

Fig. 28.25. Conformation of the C3 and

C5 esters of nifedipine (Ar = 2-

nitrophenyl). The C3 carbonyl is

synplanar to the C2–C3 bond, and the C5

carbonyl antiperiplanar to the C5–C6

bond.

Página 34 de 51


structure, z iconotide is not effect ive ora lly. I t is administered by continuous intrathecal in fusion.

The in it ia l recommended dose is 2.4 µg/day (0.1 µg/hour) and can be t i trated up to a maximum

dai ly dose of 19.2 mg (0.8 µg/hour). Ziconotide has a hal f- l i fe of approximately 4.5 hours. I t is

metabol ized by endopeptidases and exopeptidases in numerous organs and t issues. Common

adverse ef fects of ziconotide include d izziness, nausea, confusion, headache, somnolence,

nystagmus, asthenia, and pain. The most ser ious adverse ef fects appear to be the development

of severe psychiatr ic symptoms and neurological impairment. As a result , z iconotide should not

be used in patients with a preexist ing history of psychosis. Frequent moni tor ing for evidence of

cognit ive impairment , hal lucinat ions, or changes in mood or consciousness is essential . These

effects are potentia l ly addi t ive with those of other CNS-depressant drugs (32,33,58).


A compar ison o f the ac id -base proper t ies of verapami l , d i l t iazem, and the 1 ,4 -DHPs reveals that whereas a l l

o f the compounds a re bas ic , the 1 ,4 -DHPs are considerab ly less bas ic than verapami l and d i l t iazem.

Verapamil and di l t iazem both con tain te r t iary am ines wi th pKa

va lues o f 8.9 and 7.7 , respect ive ly (26) . In

con t rast , the n i t rogen of the 1 ,4 -DHPs is par t o f a con jugated carbamate . I ts e lect rons are invo lved in

resonance delocal izat ion and are much less ava i lable fo r p ro tona t ion. Thus , a t phys io log ical pH, verapami l

and d i l t iazem are pr imar i ly ionized, whereas 1,4 -DHPs are pr imar i ly un - ionized. There a re two except ions to

th is . Amlod ip ine and nicard ip ine conta in bas ic amine groups as par t o f the s ide cha ins connected to the 1 ,4-

DHP r ing . A l though the 1,4 -DHP r ing of these compounds is un - ionized, the s ide-cha in amines w i l l be

pr imar i ly ionized a t phys io log ica l pH. Because ion ic a t t ract ion of ten is the in i t ia l in teract ion between a d rug

and i ts receptor , the d i f fe rences in bas ic i ty be tween the 1 ,4 -DHP r ing and the ter t ia ry amines o f verapamil

and d i l t iazem are consis tent w i th the p rev ious ly no ted fact tha t the b inding s i te fo r the 1 ,4 -DHPs is d is t inct

from those fo r verapami l and d i l t iazem.

The calcu lated log P va lues fo r the ca lc ium channel b lockers a re l i s ted in Tab le 28 .11 (26 ) . As ev idenced by

the da ta, a l l o f these compounds possess good l ip id so lub i l i ty and, hence, exce l len t o ra l absorp t ion (no t

shown in Tab le 28 .11) . Wi th in the 1,4–DHP c lass, enhanced l ip id so lub i l i ty occurs in compounds tha t

con ta in e i ther larger ester groups or d isubst i tuted phenyl r ings. A compar ison of the log P va lues o f

n i fed ip ine and niso ld ip ine i l lus t rates th is fact . I t shou ld be noted tha t the ca lcu lated log P values l is ted in

Tab le 28 .11 a re for the un - ionized compounds. These va lues s ign i f i cant ly decrease for the ionized fo rms of

amlodip ine, n icard ip ine , verapami l , and d i l t iazem such tha t the la t ter th ree agents possess su f f ic ient water

solubi l i ty to be used bo th ora l ly and paren teral ly .

Table 28.9. Actions of Calcium Channel Blockers and Interactions Among Their Receptor Sites

Calcium Channel Blocker

Effect on Ca2+ Channel

Allosteric Effect on the Binding of

Verapamil Diltiazem 1,4-DHPs

Verapamil Antagonist; blocks channel

NA Inhibits Inhibits

Diltiazem Antagonist; blocks channel

Inhibits NA Enhances


Antagonist/agonist; can either block or open channel

Inhibits Enhances MA

NA, not applicable.

Table 28.10. Comparison of the Cardiovascular Effects of Verapamil,

Página 35 de 51


Diltiazem, and Nifedipine

Cardiovascular Effect Verapamil DiltiazemNifedipine (a 1,4-DHP)

Peripheral vasodilation ○○ ○ ○○○

Blood pressure • • •

Heart rate Variable • ○○

Coronary vascular resistance

• • •

Coronary blood flow ○○ ○○ ○○○

Atrioventricular node conduction

•• • NE

Contractility • NE/• NE/○

The number of circles represents the magnitude of response: ○, = increase; •, decrease; NE = no effect. Adapted from Swamy VC, Triggle DJ. Calcium channel blockers. In: Craig CR, Stitzel RE, eds. Modern Pharmacology with Clinical Applications, 5th Ed. Boston: Little, Brown, 1997:229–234 and Triggle DJ. Drugs acting on ion channels and membranes. In: Hansch C, Sammes PG, Taylor JB, eds. Comprehensive Medicinal Chemistry, vol 3. Oxford, UK: Pergamon Press, 1990:1047–1099; with permission.

P.763

Table 28.11. Pharmacokinetic Parameters of Calcium Channel Blockers

DrugCalculated Log P


Effect of Food on Absorption

Active Metabolite

Protein Binding (%)


Amlodipine 2.76 64–90 None None 93

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Felodipine 4.69 10–20 Increase None >99

Isradipine 3.19 15–24 Reduced rate, same extent

None 95

Nicardipine 4.27 35 Reduced None >95

Nifedipine 2.40 45–70 None None 92–98

86% (SR)

Nimodipine 3.14 13 Reduced None >95

Nisoldipine 3.86 5 High-fat meal increases immediate release but lowers overall

Hydroxylated analogue

>99

Página 37 de 51


Al l ca lc ium channel b lockers, w i th the except ion o f n i fed ip ine , conta in a t leas t one ch i ra l cen te r ; however ,

they are a l l marke ted as the i r racemic m ixtu res. As p rev ious ly noted, 1 ,4 -DHPs w ith asymmetr ica l ly

subst i tuted este rs exh ib i t s tereose lect iv i ty be tween the enant iomers. Addi t ional ly , the S -(– )-enant iomers o f

verapamil and other phenyla lky lamines a re more potent than the R-(+) -enant iomers. Very few SAR studies

are avai lab le fo r d i l t iazem; however, the c is a r rangement o f the acety l ester and the subst i tuted phenyl r ing

is requi red fo r act iv i ty (54) .

Metabolism

Al l ca lc ium channel b lockers undergo extens ive f i r s t -pass metabo l ism in the l i ve r and are subst ra tes fo r the

CYP3A4 isozyme (32 ,34) . Add i t iona l ly , severa l o f these compounds can inh ib i t CYP3A4. A l l 1 ,4 -DHPs are

ox idat ive ly metabo l ized to a var ie ty o f inac t ive compounds. In many cases, the d ihydropyr id ine r ing is

in i t ia l l y ox id ized to an inac t ive pyr id ine ana logue (Fig . 28 .26) . These in i t ia l metabo l i tes are then fur ther

transfo rmed by hydrolys is , con jugat ion , and add i t ional ox ida t ion pa thways. Niso ld ip ine a lso is subject to

these p rocesses; however , hydroxy la t ion o f i ts i sobu ty l es ter p roduces a metabol i te that re ta ins 10% of the

act iv i ty of the parent compound. In addi t ion to the d rug–drug in teract ions l i s ted be low (see Tab le 28 .13) , an

in terest ing d rug–food inte ract ion occurs w i th the 1,4 -DHPs and grapef ru i t ju ice (59) . Coadminis t ra t ion of

1,4 -DHPs w ith grapefru i t ju ice p roduces an inc rease system ic concent ra t ion of the 1 ,4 -DHPs. The

mechanism o f th is in te ract ion appears to resu l t f rom inh ib i t ion o f in tes t inal CYP450 by f lavano ids and

fu ranocoumar ins speci f i ca l ly found in grapef ru i t ju ice (see Chapter 10 ) . I t has been proposed tha t l im i t ing

da i ly in take to e i ther an 8 -oz. g lass of g rape f ru i t ju ice or ha l f o f a f resh grapef ru i t would l i ke ly avo id

s ign i f i cant d rug inte ract ions wi th mos t CYP3A4-metabol ized drugs (60) .

Verapamil is pr imar i ly metabo l ized to the N-demethy la ted compound, norverapami l , wh ich re ta ins

amount

Phenalkylamines

Verapamil 3.53 20–35 (SR form only) Reduced

Norverapamil 90

Benzothiazepines

Diltiazem 3.55 40–60 None Deacetyl-diltiazem

70–80

Tmax time to maximum blood conentration; IR, immediate-release product; CR, controlled

sustained-release product; IV, intravenous administration.

Página 38 de 51


approx imately 20% o f the pharmacologica l act iv i ty of verapami l and can reach or exceed the s teady-state

p lasma levels o f verapamil . In te rest ing ly , the more act ive S - (–) - isomer undergoes more extens ive f i rs t -pass

hepat ic metabol ism than does the less act ive R - (+) - isomer. This is important to no te , because when g iven

IV , verapamil pro longs the PR in te rva l to a g reate r exten t than when i t is g iven o ral ly (61 ) . Th is is because

the pre fe ren t ia l metabol ism o f the more act ive enant iomer does not occur w i th parente ra l

adminis t ra t ion . D i l t iazem is p r imar i l y hydrolyzed to deacety ld i l t iazem. Th is metabol i te re ta ins 25 to 50% o f

the coronary vasodi lato ry e f fects of d i l t iazem and is present in the p lasma a t leve ls of 10 to 45% of the

parent compound.


The pharmacok inet ic parameters and oral dos ing info rmat ion for calc ium channe l b lockers are summar ized

in Tab les 28.11 and 28 .12 , respect ively (32 ,33 ,34 ) . Some doses (spec i f i ca l ly , those for d i l t iazem and

verapamil ) may vary fo r e i ther spec i f ic indica t ions ( i .e . , hyper tens ion versus ang ina) or d i f fe rent b rand

names, and the reader shou ld consu l t the produc t l i tera tu re fo r add i t iona l in format ion . The pr imary

d i f ferences among the compounds are onset o f ac t ion, hal f - l i fe , and o ral b ioavai lab i l i ty . A l l ca lc ium channel

b lockers have exce l len t o ra l absorp t ion ; however, because they a lso are sub ject to rap id f i rs t -pass

metabol ism in the l ive r , the actual ora l b ioava i lab i l i ty o f these compounds var ies considerab ly depending on

the exten t o f metabo l ism. A l l compounds a re h igh ly p lasma pro te in bound and pr imar i l y e l imina ted as

inac t ive metabo l i tes in the ur ine. Because o f extens ive hepat ic t ransfo rmat ion , ca lc ium channel b lockers

shou ld be used caut ious ly in pa t ients wi th hepat ic d isease . Recommendat ions for these pa t ients inc lude

dosage reduct ions,

carefu l t i t ra t ions , and c lose therapeut ic mon ito r ing . Di l t iazem and verapamil a lso requ ire dosage

ad justments in pa t ien ts w i th rena l dysfunct ion , because rena l impa irment can s igni f ican t ly increase the

concentrat ions o f the ac t ive metabo l i tes of these compounds. Dosage ad justments usua l ly a re no t requ ired

fo r the o ther seven compounds, because s ix o f them produce inact ive metabo l i tes and niso ld ip ine produces

act ive metabol i tes w i th s ign i f ican t ly lower ac t iv i ty .

P.764

View Figure

Fig. 28.26. Oxidation of the 1,4-dihydropyridine ring of nifedipine.

P.765

Table 28.12. Oral Dosing Information for Calcium Channel Blockers

Generic NameBrand Name(s)


Normal Dosing Range

Maximum Daily Dose

Precautions with Hepatic Dysfunction


Amlodipine Norvasc Angina (V, CS), 5–10 mg 10 mg Reduce

Página 39 de 51


hypertension q.d. dosage

Felodipine Plendil Hypertension 2.5–10.0 mg q.d.

10 mg Reduce dosage

Isradipine DynaCirc CR

Hypertension 5–20 mg q.d.

20 mg Titrate dosage

Nicardipine Cardene, Cardene IV

Angina (CS), hypertension

20–40 mg t.i.d. (SR: 30–60 mg b.i.d.) (IV: 5–15 mg/hour)

120 mg

Titrate dosage

Nifedipine Procardia, Adalat

Angina (V, CS), hypertension

10–20 mg t.i.d. (SR: 30–60 mg q.d.)

180 mg (SR: 90 mg)

Reduce dosage

Nimodipine Nimotop Subarachnoid hemorrhage

60 mg every 4 hours for 21 days

360 mg

Reduce dosage

Nisoldipine Sular Hypertension 20–40 mg q.d.

60 mg Closely monitor blood pressure

Phenylalkylamines

Verapamil Calan, Covera, Isoptin, Verelan

Angina (V, CS, U), hypertension, atrial fibrillation/flutter, PSVT

80–120 mg t.i.d. or q.i.d. (SR: 240–480 mg q.d. or b.i.d.)

480 mg (540 mg for Covera HS only)

Reduce dosage

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Unlabeled Uses

Migraine headache, Raynaud's syndrome, pulmonary hypertension, preterm labor, and

hypert rophic cardiomyopathy

Fe lod ip ine and niso ld ip ine a re on ly ava i lable as susta ined-re lease (o r extended -re lease) fo rmu la t ions.

Ni fed ip ine , is rad ip ine, n icard ip ine , verapami l , and di l t iazem are ava i lable as both immediate - re lease and

sus ta ined-re lease fo rmu la t ions. The la t ter three compounds a lso a re ava i lable as paren te ral preparat ions.

Un l ike regu la r table ts and capsu les, susta ined-re lease (o r extended- re lease) fo rmu la t ions cannot be

chewed or crushed, because th is may lead to an immedia te , rather than a susta ined , re lease o f the

compound. Th is e ffect not only w i l l decrease the durat ion o f the dose bu t a lso could produce an overdose

and subsequent tox ic i t ies in the pa t ien t . Paren te ral p reparat ions o f n icard ip ine and verapamil a re

incompat ib le w i th IV so lut ions con tain ing sod ium b icarbonate. In each case , sod ium b icarbonate increases

the pH of the solut ion, resu l t ing in the p rec ip i tat ion o f the calc ium channe l b locker . A l though th is in te rac t ion

is no t l i s ted for d i l t iazem, i t i s reasonab le to assume that a s im i la r in terac t ion may occur . Add i t iona l ly ,

n icardip ine is incompat ib le w i th lacta ted Ringer 's so lu t ion , and verapamil wi l l p rec ip i tate in so lu t ions hav ing

a pH greate r than or equa l to s ix (32 ,33) .


As i l lus t rated in Tab le 28 .12 , calc ium channe l b lockers have been approved fo r the t reatment of

hyper tens ion , ang ina pecto r is , subarachno id hemorrhage, and speci f ic types o f arrhy thmias (32 ,33) . A l l

ca lc ium channe l b lockers cause vasod i lat ion and decrease per ipheral res is tance . With the except ions o f

n imodip ine, a l l are approved to t reat hyper tens ion . Recent s tud ies have ind icated tha t immed ia te -re lease

fo rmu lat ions o f shor t -act ing ca lc ium channe l b lockers, espec ia l ly n i fed ip ine , can cause an abrupt

vasod i la t ion tha t can resu l t in MI . As a resu l t , only the susta ined-re lease fo rmu la t ions of n i fed ip ine and

di l t iazem shou ld be used in the t rea tment of essent ia l hyper tens ion (62) . Five o f the n ine agents a re

approved for the t rea tment o f angina pec tor is . Verapami l i s the most versat i le agent in tha t i t is indica ted

fo r a l l three types o f ang ina : vasospast ic , chron ic s table, and uns tab le . Amlodip ine, n i fedip ine, and

di l t iazem are ind icated fo r both vasospast ic and chron ic s table angina , whereas n icardip ine is ind icated

Benzothiazepines

Diltiazem Cardizem, Dilacor

Angina (V, CS), hypertension, atrial fibrillation/flutter, PSVT

30–120 mg t.i.d. or q.i.d. (SR: 120–480 mg q.d.)

540 mg

Reduce dosage

Types of angina: V, vasospastic; CS, chronic stable; U, unstable; CR, controlled release; SR, sustained release; IV, intravenous; PSVT, paroxysmal supraventricular tachycardia.

Página 41 de 51


on ly fo r chron ic s tab le ang ina . N imod ip ine is un ique in tha t i t has a g reate r ef fect on cerebral a r ter ies than

on other ar te r ies . As a resul t , n imodip ine is ind icated fo r the improvement of neuro log ical de f ic i ts because

of spasm fo l low ing subarachno id hemorrhage f rom ruptu red congeni ta l in t racran ia l aneurysms in pa t ients

otherwise in good neuro log ica l cond i t ion a f te r the ep isode. Verapami l and d i l t iazem are pharmacologica l ly

d i f feren t from the 1,4 -DHPs in that they b lock s inus and AV noda l conduc t ion. As a resu l t , IV fo rmu lat ions

of verapami l and d i l t iazem are indica ted for the t rea tment o f at r ia l f ibr i l la t ion , at r ia l f lu t te r , and PSVT.

Verapamil a lso can be used ora l ly , e i ther a lone ( fo r prophy lax is o f repe t i t i ve PSVT) o r in combina t ion w i th

d igox in ( for a t r ia l f lu t ter or a t r ia l f ib r i l la t ion) .

Adverse Effects of Calcium Channel Blockers

Edema, f lushing, hypotension, nasal congest ion, palp itat ions, chest pain, tachycardia,

headache, fat igue, d izziness, rash, nausea, abdominal pain, constipat ion, diarrhea, vomit ing,

shortness of breath, weakness, bradycardia, and AV block

Adverse Effects and Drug Interactions

The mos t preva len t or s igni f i can t s ide e ffects o f ca lc ium channel b lockers a re l i s ted below (32 ,33 ,48 ,51 ,53) .

Drug in teract ions fo r ca lc ium channel b lockers a re l i s ted in Tab le 28 .13 . In most instances , these s ide

ef fects do not cause long - te rm compl icat ions, and they o f ten reso lve w i th t ime or dosage adjus tments. Many

of these e ffects a re s imply extens ions of the pharmaco log ical ef fects o f th is c lass o f compounds. Excess ive

vasod i la t ion resu l ts in edema, f lush ing, hypotens ion , nasa l congest ion , headache, and d izz iness.

Add i t iona l ly , the pa lp i ta t ions, ches t pa in , and tachycard ia seen w ith 1,4 -DHPs are a resu l t o f sympathe t ic

responses to the vasodi lato ry e f fec ts of th is chemica l c lass. The use of a β -b locker in combinat ion w i th a

1,4 -DHP can m in im ize these compensatory ef fects and can be very usefu l in trea t ing hyper tens ion.

Verapamil and di l t iazem can cause bradycardia and AV block because of thei r abi l i ty to depress AV noda l

conduc t ion. Because o f r i sks assoc ia ted wi th addi t ive card iodepress ive ef fects , they shou ld no t be used in

combina t ion wi th β -b lockers.

Chemical/Pharmacological Classes Used to Treat Angina Pectoris

Organic n it rates, β -blockers (see Chapter 26), and calc ium channel blockers

P .766

Table 28.13. Drug Interactions for Calcium Channel Blockers

DrugCalcium Blocker(s) Result of Interaction

Alpha1-Blockers

(Prazosin, Terazosin)

Verapamil Increased prazosin and terazosin levels

Amiodarone Diltiazem, Verapamil

Increased bradycardia and cardiotoxicity; decreased cardiac output

Aspirin Verapamil Increased incidence of bruising

Azole Antifungals Felodipine, Isradipine, Nifedipine, Nisoldipine

Increased serum concentrations of the calcium channel blockers

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Barbiturates Felodipine, nifedipine, Verapamil

Decreased pharmacological effects of the calcium channel blockers

β-Blockers All Coadministration may cause additive or synergistic effects; increased cardiodepressant effects (more extensive with verapamil and diltiazem); inhibition of β-Blocker metabolism by diltiazem, isradipine, nicardipine, nifedipine, and verapamil

Buspirone Diltiazem, Verapamil

Increase buspirone levels

Carbamazepine, Felodipine, Diltiazem,

Carbamazepine and oxcarbazepine decrease felodipine levels; verapamil and diltiazem

Oxcarbazepine Verapamil increase carbamazepine levels

Cimetidine All Increased 1,4-DHP levels

Cyclosporine Felodipine Nicardipine, Nifedipine, Diltiazem, Verapamil

Increased cyclosporine levels when used with all of these except for nifedipine; cyclosporine increases felodipine and nifedipine levels

CYP3A4 Inhibitors All Potentially can increase the plasma levels of calcium channel blockers

Digoxin Nifedipine, Diltiazem, Verapamil

Increased digoxin levels

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Disopyramide, Flecainide

Verapamil Additive cardiodepressant effects

Dofetilide Verapamil Increased dofetilide levels

Doxorubicin Verapamil Increased doxorubicin levels

Erythromycin, Clarithromycin

All Increased 1,4-DHP levels and increased toxicity

Fentanyl All Severe hypotension and/or bradycardia

General Anesthetics

All Potentiation of the cardiac effects and vascular dilation associated with anesthetics

HMG CoA Reductase Inhibitors

Diltiazem, verapamil

Increase levels of HMG CoA reductase inhibitor

Imipramine Diltiazem, verapamil

Increased imipramine levels

Lithium Diltiazem, Verapamil

Decreased lithium levels with verapamil; neurotoxicity with diltiazem

Lovastatin Isradipine Decreased effects of lovastatin

Melatonin All Decreased therapeutic effects of calcium channel blockers

Methylprednisolone Diltiazem, Verapamil

Increased methylprednisolone levels

Midazolam, Diltiazem, Increased effects of these

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Triazolam Verapamil benzodiazepines

Moricizine Diltiazem Increased moricizine levels; decreased diltiazem levels

Phenobarbital All Decreased bioavailability of calcium channel blocker

Phenytoin All Decreased effectiveness of calcium channel blocker due to induction of metabolism

Quinidine Diltiazem, Nifedipine, Nisoldipine, Verapamil

Variable responses: Quinidine decreases AUC of nisoldipine, but increases actions of nifedipine; Diltiazem and verapamil increase the effects of quinidine; while nifedipine decreases quinidine levels and actions

Rifampin Diltiazem, Isradipine, Nicardipine, Nifedipine, Verapamil

Decreased levels of calcium channel blocker

Sirolimus, Tacrolimus

Diltiazem, Nifedipine, Verapamil

Increased sirolimus and tacrolimus levels

St. John's Wort Nifedipine Decreased nifedipine levels (St. John's wart most likely increases the metabolism of all calcium channel blockers)

Theophylline Diltiazem, Verapamil

Increased theophylline levels and toxicity

Página 45 de 51


Case Study

Victoria F. Roche

S. Will iam Zito

BB is a 58-year-old d ivorced woman who owns her own t ravel agency. She has a family h istory

of alcoholism, and that, coupled with the socia l nature and constant pressures of her job, led BB

to become an alcohol ic. Five years ago, BB was diagnosed wi th d iabetes, and since then, she

has jo ined Alcohol ics Anonymous and been successful in contro l l ing her drinking. Her d iabetes

is under control with g lybur ide (5 mg dai ly wi th breakfast) . Late ly, however, she has

experienced a loss of energy and di f f icul ty breathing on her dai ly walk uptown to her off ice. In

addit ion, BB often wakes dur ing the n ight fr ightened by a sense that she has stopped breathing

and f inds i t necessary to prop herself up wi th a couple of p i l lows to get a good night 's sleep. On

physical examinat ion, her physic ian not ices a tender abdomen with sl ight hepatomegaly and

pedal edema, and an echocardiogram reveals cardiomegaly. A diagnosis of mi ld congestive

heart fai lure was made, and BB was prescr ibed captopr i l (25 mg t. i .d. ) and advised to contro l

sa lt intake and to continue her normal exercise routine. On a fol low-up vis i t to her physic ian,

BB's symptoms have moderated, but she complains of an i rr i tat ing cough and rash, that her

medication makes everyth ing taste l ike rust , and that her l ips feel l ike they have si l icon

implants. BB's physic ian wants to change her medication, and you have the fol lowing choices

avai lable. What do you th ink?

1. Identi fy the therapeutic problem(s) in which the pharmacist 's intervention may benef it the

pat ient.

2. Identi fy and pr ior i t ize the patient-speci f ic factors that must be considered to achieve the

desired therapeut ic outcomes.

3. Conduct a thorough and mechanist ica l ly or iented structure–activi ty analysis of al l

therapeutic a lternatives provided in the case.

4. Evaluate the SAR f indings against the pat ient-speci f ic factors and desired therapeut ic

outcomes, and make a therapeut ic decis ion.

5. Counsel your patient.

Valproic acid Nimodipine Increased nimodipine levels

Vecuronium Verapamil Increased vecuronium levels

Vincristine Nifedipine Increased vincristine levels

P.767

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