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Chapter 28
Angiotensin-Converting Enzyme Inhibitors, Antagonists and
Calcium Blockers
Marc Harrold
The Renin-Angiotensin Pathway

T h e r e n i n - a n g i o t e n s i n s y s t e m i s a c o m p l e x , h i g h l y r e g u l a te d p a t h w a y t h a t i s i n t e g r a l i n t h e r e g u l a t i o n o f
blood volume, electrolyte balance, and arterial blood pressure. It consists of two main enzymes, renin and
a n g i o t e n s i n - c o n v e r t i n g e n z y m e ( A C E ) , t h e p r i m a r y p u r p o s e o f w h i c h i s t o r e l e a s e a n g i o t e n s i n II f r o m i t s
endogenous precursor, angiotensinogen (Fig. 28.1). Angiotensin II is a potent vasoconstrictor that affects
peripheral resistance, renal function, and cardiovascular structure (1).
History and Overview of Pathway

Historically, the renin-angiotensin system dates back to 1898, when Tiegerstedt and Bergman demonstrated
th e e x i s t e n c e o f a p r e s s o r s u b s t a n c e i n c r u d e k i d n e y e x t r a c t s . A l i t t l e o v e r 4 0 y e a r s l a t e r , t w o i n d e p e n d e n t
research groups discovered that this pressor substance, which had previously been named renin, actually
was an enzyme and that the true pressor substance was a peptide formed by the catalytic action of renin.
T h i s p e p t i d e p r e s s o r s u b s t a n c e i n i t i a l l y w a s a s s i g n e d t w o d i f f e r e n t n a m e s , a n g i o t o n i n a n d h y p e r te n s i n ;
h o w e v e r , t h e s e n a m e s e v e n t u a l l y w e r e c o m b i n e d t o p r o d u c e t h e c u r r e n t d e s i g n a t i o n , a n g i o t e n s i n . In t h e
1 9 5 0 s , i t w a s d i s c o v e r e d th a t a n g i o t e n s i n e x i s t s a s b o t h a n i n a c t i v e d e c a p e p t i d e , a n g i o t e n s i n I , a n d a n
active octapeptide, angiotensin II, and that the conversion of angiotensin I to angiotensin II is catalyzed by
an enzym e distinct from renin (3).
Angiotensinogen is an 2-globulin with a molecular weight of 58,000 to 61,000 daltons. It contains 452
amino acids, is abundant in the plasma, and is continually synthesized and secreted by the liver. A number
o f h o r m o n e s , i n c l u d i n g g l u c o c o r ti c o i d s , t h y r o i d h o r m o n e , a n d a n g i o t e n s i n I I , s t i m u l a t e i t s s y n t h e s i s . T h e
m o s t i m p o r t a n t p o r t i o n o f t h i s c o m p o u n d i s t h e N - te r m i n u s , s p e c i f i c a l l y
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th e L e u 1 0 - V a l 1 1 b o n d . T h i s b o n d i s c l e a v e d b y r e n i n a n d p r o d u c e s t h e d e c a p e p t i d e a n g i o t e n s i n I . T h e P h e 8 His9 peptide bond of angiotensin I is then cleaved by ACE to produce the octapeptide angiotensin II.
A m i n o p e p t i d a s e c a n f u r t h e r c o n v e r t a n g i o t e n s i n I I t o t h e a c t i v e h e p t a p e p t i d e a n g i o te n s i n I I I b y r e m o v i n g
th e N - te r m i n a l a r g i n i n e r e s i d u e . F u r t h e r a c t i o n s o f c a r b o x y p e p t i d a s e s , a m i n o p e p t i d a s e s , a n d
endopeptidases result in the formation of inactive peptide fragments. An additional compound can be
fo r m e d b y t h e a c t i o n o f a p r o l y l - e n d o p e p t i d a s e o n a n g i o t e n s i n I . C l e a v a g e o f t h e P r o 7 - P h e 8 b o n d o f
a n g i o t e n s i n I p r o d u c e s a h e p t a p e p t i d e k n o w n a s a n g i o t e n s i n 1 - 7 . T h e a c t i o n s o f a l l o f th e s e c o m p o u n d s a r e
discussed below.
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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View Figure
Clini cal S ignific anc e

The treatment of hypertension and congestive heart failure (CHF) has improved significantly with the
introduction of angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers, and
c a l c i u m c h a n n e l b l o c k e r s . T h e S A R s a n d s t r u c t u r a l m o d i f i c a t i o n s o f t h e s e a g e n ts h a v e p r o d u c e d m a j o r
th e r a p e u t i c a d v a n c e s . T h e s e d r u g s h a v e b e c o m e c o r n e r s t o n e s o f t h e r a p y t o d a y . F o r e x a m p l e , m o r e
th a n 2 5 y e a r s a g o , c a p to p r i l w a s t h e fi r s t A C E i n h i b i t o r t o b e d e v e l o p e d . S u b s e q u e n t m o l e c u l a r
m o d i fi c a t i o n s l e d t o t h e d e v e l o p m e n t o f n e w e r a g e n t s , s u c h a s l i s i n o p r i l . A l t h o u g h l i s i n o p r i l e x e r ts
com parable ACE inhibition, it possesses a superior pharm acokinetic profile. Instead of having to
administer captopril three times daily, lisinopril can be administered once daily.
Medication compliance is notoriously poor in cardiovascular patients. Administering an ACE inhibitor
s u c h a s l i s i n o p r i l o n c e d a i l y r e s u l t s i n g r e a tl y e n h a n c e d m e d i c a t i o n c o m p l i a n c e . T h e t h e r a p e u t i c
o u t c o m e s o f p a t i e n t s w i t h h y p e r t e n s i o n a n d C H F h a v e i m p r o v e d i m m e n s e l y a s a r e s u l t. S i m i l a r
molecular enhancem ents have been made with angiotensin receptor blockers and calcium channel
blockers.
T h e a p p l i c a ti o n o f b a s i c s c i e n c e i n m o d i f y i n g t h e c h e m i c a l s t r u c t u r e o f t h e s e a g e n t s h a s u l t i m a t e l y
resulted in patients living longer and suffering fewer cardiovascular events, such as myocardial
i n f a r c t i o n o r w o r s e n i n g C H F . I m p o r t a n t l y , t h e i r d a y - to - d a y q u a l i t y o f l i f e i s p r e s e r v e d a s w e l l .
Thomas L. Rihn, Pharm.D.
Senior Vice President and Chief Clinical Officer
U n i v e r s i t y P h a r m a c o t h e r a p y A s s o c i a te s
Associate Professor of Clinical Pharm acy
Duquesne University
School of Pharmacy
Actions and Properties of Renin-Angiotensin Pathway Components

Renin is an aspartyl protease that determines the rate of angiotensin II production. It is a much more
s p e c i f i c e n z y m e t h a n A C E . I t s p r i m a r y fu n c t i o n i s t o c l e a v e t h e l e u c i n e - v a l i n e b o n d a t r e s i d u e s 1 0 a n d 1 1 o f
angiotensinogen. The stim ulation of renin release is controlled very closely by hemodynamic, neurogenic,
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and humoral signals (Fig. 28.2). Hemodynamic signals involve the renal juxtaglomerular cells. These cells
a r e s e n s i t i v e to t h e h e m o d y n a m i c s t r e t c h o f th e a f f e r e n t g l o m e r u l a r a r t e r i o l e . A n i n c r e a s e i n t h e s t r e t c h
implies a raised blood pressure and results in a reduced release of renin, whereas a decrease in the stretch
i n c r e a s e s r e n i n s e c r e t i o n . A d d i t i o n a l l y , th e s e c e l l s a l s o a r e s e n s i t i v e t o N a C l f l u x a c r o s s t h e a d j a c e n t
macula densa. Increases in NaCl flux across the m acula densa inhibit renin release, but decreases in the
fl u x s t i m u l a t e r e l e a s e . F u r t h e r , n e u r o g e n i c e n h a n c e m e n t o f r e n i n r e l e a s e o c c u r s v i a a c t i v a t i o n o f 1
r e c e p t o r s . F i n a l l y , a v a r i e t y o f h o r m o n a l s i g n a l s i n f l u e n c e t h e r e l e a s e o f r e n i n . S o m a to s t a t i n , a t r i a l
n a t r i u r e t i c f a c t o r , a n d a n g i o t e n s i n II i n h i b i t r e n i n r e l e a s e , w h e r e a s v a s o a c t i v e i n t e s t i n a l p e p t i d e ,
parathyroid hormone, and glucagon stimulate renin release (4).
In c o n t r a s t, A C E , a l s o k n o w n a s k i n i n a s e I I , i s a z i n c p r o t e a s e t h a t i s u n d e r m i n i m a l p h y s i o l o g i c a l c o n t r o l . I t
is not a rate-limiting step in the generation of angiotensin II and is a relatively nonspecific dipeptidyl
carboxypeptidase that requires only a tripeptide sequence as a
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s u b s t r a t e . T h e o n l y s t r u c t u r a l f e a t u r e r e q u i r e d b y A C E i s t h a t t h e p e n u l t i m a te a m i n o a c i d i n t h e p e p t i d e
s u b s t r a t e c a n n o t b e p r o l i n e . F o r t h i s r e a s o n , a n g i o t e n s i n II , w h i c h c o n t a i n s a p r o l i n e i n t h e p e n u l t i m a t e
p o s i t i o n , i s n o t f u r t h e r m e t a b o l i z e d b y A C E . T h e l a c k o f s p e c i f i c i t y a n d c o n tr o l e x h i b i t e d b y A C E r e s u l t s i n
i t s i n v o l v e m e n t i n t h e b r a d y k i n i n p a th w a y ( F i g . 2 8 . 3 ) . B r a d y k i n i n i s a n o n a p e p t i d e th a t a c t s l o c a l l y t o
produce pain, cause vasodilation, increase vascular permeability, stimulate prostaglandin synthesis, and
cause bronchoconstriction. Similar to angiotensin II, bradykinin is produced by proteolytic cleavage of a
precursor peptide. Cleavage of kininogens by the protease kallikrein produces a decapeptide known as
e i t h e r k a l l i d i n o r l y s y l - b r a d y k i n i n . S u b s e q u e n t c l e a v a g e o f t h e N - te r m i n a l l y s i n e b y a m i n o p e p t i d a s e
produces bradykinin. The degradation of bradykinin to inactive peptides occurs through the actions of ACE.
T h u s , A C E n o t o n l y p r o d u c e s a p o te n t v a s o c o n s t r i c t o r b u t a l s o i n a c t i v a t e s a p o t e n t v a s o d i l a t o r ( 1 , 4 , 5 ) .
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 reninangiotensin pathway.
View Figure
A n g i o t e n s i n I I i s t h e d o m i n a n t p e p t i d e p r o d u c e d b y t h e r e n i n - a n g i o t e n s i n p a t h w a y ( F i g . 2 8 . 2 ) . It i s a p o t e n t
v a s o c o n s t r i c t o r t h a t i n c r e a s e s t o t a l p e r i p h e r a l r e s i s t a n c e th r o u g h a v a r i e t y o f m e c h a n i s m s : d i r e c t
vasoconstriction, enhancement of both catecholamine release and neurotransmission within the peripheral
nervous system, and increased sympathetic discharge. The result of all these actions is a rapid pressor
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response. Additionally, angiotensin II causes a slow pressor response, resulting in a long term stabilization
o f a r t e r i a l b l o o d p r e s s u r e . T h i s l o n g - te r m e f f e c t i s a c c o m p l i s h e d b y t h e r e g u l a t i o n o f r e n a l f u n c t i o n .
Angiotensin II directly increases sodium reabsorption in the proximal tubule. It also alters renal
h e m o d y n a m i c s a n d c a u s e s t h e r e l e a s e o f a l d o s t e r o n e f r o m th e a d r e n a l c o r t e x . F i n a l l y , a n g i o t e n s i n I I
c a u s e s t h e h y p e r tr o p h y a n d r e m o d e l i n g o f b o th v a s c u l a r a n d c a r d i a c c e l l s th r o u g h a v a r i e ty o f
hemodynamic and nonhemodynamic effects (1).
Although secondary peptides, angiotensin III and angiotensin 1-7, also are thought to contribute to the
o v e r a l l e f fe c t s o f t h e r e n i n - a n g i o t e n s i n p a t h w a y , a n g i o t e n s i n I I I i s e q u i p o t e n t w i t h a n g i o t e n s i n I I i n
stimulating aldosterone secretion; however, it is only 10 to 25% as potent in increasing blood pressure. In
contrast, angiotensin 1 -7 does not cause either aldosterone secretion or vasoconstriction, but it does have
potent effects that are distinct from those of angiotensin II. Similar to angiotensin II, angiotensin 1-7
causes neuronal excitation and vasopressin release. Additionally, it enhances the production of
p r o s t a g l a n d i n s v i a a r e c e p to r - m e d i a t e d p r o c e s s t h a t d o e s n o t i n v o l v e a n i n c r e a s e i n i n t r a c e l l u l a r c a l c i u m
l e v e l s . I t h a s b e e n p r o p o s e d t o b e i m p o r t a n t i n t h e m o d u l a ti o n o f c e l l - to - c e l l i n t e r a c t i o n s i n c a r d i o v a s c u l a r
a n d n e u r a l ti s s u e s ( 6 ) .
Role of The Renin-Angiotensin Pathway in Cardiovascular Disorders

B e c a u s e t h e r e n i n - a n g i o t e n s i n p a t h w a y i s c e n t r a l t o t h e m a i n te n a n c e o f b l o o d v o l u m e , a r t e r i a l b l o o d
pressure, and electrolyte balance, abnorm alities in this pathway (e.g., excessive release of renin and
overproduction of angiotensin II) can contribute to a variety of cardiovascular disorders. Specifically,
o v e r a c t i v i t y o f t h i s p a t h w a y c a n r e s u l t i n h y p e r t e n s i o n o r h e a r t fa i l u r e v i a t h e m e c h a n i s m s p r e v i o u s l y
described. Abnormally high levels of angiotensin II can contribute to hypertension through both rapid and
slow pressor responses. Additionally, high levels of angiotensin II can cause cellular hypertrophy and
i n c r e a s e b o t h a f te r l o a d a n d w a l l t e n s i o n . A l l o f t h e s e e v e n t s c a n c a u s e o r e x a c e r b a t e h e a r t f a i l u r e .
H i g h b l o o d p r e s s u r e i s a r e l a t i v e l y c o m m o n d i s o r d e r , a ff e c t i n g m o r e th a n 5 0 m i l l i o n A m e r i c a n s . I t i s m o r e
prevalent in males than in fem ales and in blacks than in Caucasians. Onset usually begins during the third,
fo u r t h , a n d f i f th d e c a d e s o f l i f e , a n d t h e i n c i d e n c e o f t h e d i s o r d e r i n c r e a s e s w i t h a g e . H y p e r t e n s i o n i s
classified as either primary or secondary. Primary hypertension, also known as essential hypertension, is
th e m o s t p r e v a l e n t f o r m o f t h e d i s o r d e r a n d i s d e f i n e d a s h i g h b l o o d p r e s s u r e o f a n u n k n o w n e t i o l o g y . M o s t
c a s e s o f p r i m a r y h y p e r t e n s i o n a r e th o u g h t t o r e s u l t f r o m a v a r i e t y o f u n d e r l y i n g p a t h o p h y s i o l o g i c a l
m e c h a n i s m s a n d n o t f r o m a s i n g l e , s p e c i fi c c a u s e . A d d i t i o n a l l y , g e n e t i c f a c t o r s a p p e a r to b e i m p o r t a n t i n
th e d e v e l o p m e n t o f p r i m a r y h y p e r t e n s i o n . S e c o n d a r y h y p e r t e n s i o n i s a s s o c i a t e d w i t h a s p e c i f i c d i s o r d e r
(e.g., chronic renal disease, pheochromocytoma, and Cushing's syndrome), is present in approximately 5%
of individuals with high blood pressure and, in some instances, is potentially curable. Secondary
hypertension is much m ore common in children than in adults (7).
Heart failure (previously designated as congestive heart failure) affects approximately 5 million Americans
and is the most common hospital discharge diagnosis in patients older than 65 years. The overall 5-year
survival rate is approxim ately 50% for all patients, with women having an overall lower mortality rate than
men. The disease results from conditions in which the heart is unable
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to s u p p l y b l o o d a t a r a t e s u f f i c i e n t t o m e e t t h e d e m a n d s o f t h e b o d y . S i m i l a r t o h y p e r t e n s i o n , t h i s
p a t h o p h y s i o l o g i c a l s t a te c a n o c c u r v i a a v a r i e t y o f m e c h a n i s m s . A n y p a t h o p h y s i o l o g i c a l e v e n t t h a t c a u s e s
either systolic or diastolic dysfunction will result in heart failure. Systolic dysfunction, or decreased
c o n t r a c t i l i t y , c a n b e c a u s e d b y d i l a te d c a r d i o m y o p a t h i e s , v e n t r i c u l a r h y p e r t r o p h y , o r a r e d u c t i o n i n m u s c l e
mass. Diastolic dysfunction, or restriction in ventricular filling, can be caused by increased ventricular
s t i f f n e s s , m i tr a l o r t r i c u s p i d v a l v e s t e n o s i s , o r p e r i c a r d i a l d i s e a s e . B o t h v e n t r i c u l a r h y p e r t r o p h y a n d
myocardial ischem ia can contribute to increased ventricular stiffness. Angiotensin II causes and/or
e x a c e r b a t e s h e a r t f a i l u r e b y i n c r e a s i n g s y s t e m i c v a s c u l a r r e s i s ta n c e , p r o m o t i n g s o d i u m r e t e n t i o n ,
s t i m u l a t i n g a l d o s t e r o n e r e l e a s e , a n d s t i m u l a t i n g v e n tr i c u l a r h y p e r t r o p h y a n d r e m o d e l i n g ( 8 ) .
Overview of Drug Therapy Affecting The Renin-Angiotensin Pathway

B e c a u s e a n g i o t e n s i n I I p r o d u c e s t h e m a j o r i t y o f t h e e f f e c t s a t tr i b u te d t o t h e r e n i n - a n g i o t e n s i n p a t h w a y ,
c o m p o u n d s t h a t c a n b l o c k e i t h e r t h e s y n t h e s i s o f a n g i o t e n s i n I I o r t h e b i n d i n g o f a n g i o t e n s i n I I t o i ts
receptor should attenuate the actions of this pathway. Indeed, enzyme inhibitors of both renin and ACE, as
w e l l a s r e c e p t o r a n t a g o n i s t s o f a n g i o t e n s i n I I , h a v e a l l b e e n s h o w n t o p r o d u c e b e n e f i c i a l e f fe c t s i n
d e c r e a s i n g t h e a c t i o n s o f a n g i o t e n s i n II . I n h i b i t o r s o f A C E w e r e t h e
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fi r s t c l a s s o f c o m p o u n d s t o b e m a r k e t e d . T h i s o c c u r r e d i n 1 9 8 1 w i t h t h e a p p r o v a l b y t h e U . S . F o o d a n d
Drug Adm inistration of captopril. Fourteen years later, losartan was approved as the first angiotensin II
receptor blocker (previous referred to as an angiotensin II receptor antagonist). The development,
s t r u c t u r e a c t i v i t y r e l a t i o n s h i p ( S A R ) , p h y s i c o c h e m i c a l p r o p e r t i e s , i n t e r a c t i o n s , a n d i n d i c a t i o n s o f th e s e
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classes of drugs are discussed below.
Dev elopment of Or ally A ct ive R enin Inhibit ors

Ren in i s a v e ry sp ec i fi c en zy m e. The octa pep ti de , H is -Pro -Ph e-His -Leu -Leu -Va l-Tyr, is the
sm al le s t s u bs trat e re co gn iz e d b y th e e nzyme an d i s si mi la r to th e e i ght -ami no -acid seq ue nce,
His 6 -Pro 7 -Ph e 8 -His 9 -Leu 1 0 -Va l 1 1 -Il e 1 2 -His 1 3 , wh ich i s fou nd i n a ng io ten sin og en. Usi ng th is
oc tap ep ti de, B og er ( 9) repl a ce d t he l abi l e Leu -Leu bo nd wi th th e sta bl e di pe pti de m im ic st ati ne
and rep la c ed the t wo C -term in al res i du es (V al Tyr) w it h si mi l ar h yd rop hob ic ami no a ci ds (L eu Ph e).
Th e re sul ti ng c om pou nd , N -is ov a le ryl -His-Pro -Ph e-His -Sta -Leu -Ph e -NH 2 (SC RIP ), sho wed
eff ec ti v e, al tho ug h s h ort -li v ed, i nh ib it io n of re ni n whe n g i ve n i n traven ou sl y (IV ). Inf usio n
ex pe ri m ent s wi th SC RIP we re t he fi rst to de mo nstra te tha t a sma ll m ol ecul e ren in i nh ib it or cou l d
mai nt ai n a l ow ered bl o od press ure fo r an ext end ed pe rio d o f ti me. S uscept ib il i ty t o p rote ol yti c
cl ea v age , h owe v er, li mi te d the th erap eu ti c uti l i ty of S CRIP a nd ot her ana l ogo us p ept id es.
Stru c ture ac ti vi ty st udi e s wi th SCR IP revea l ed tha t t he N-term in al Hi s-Pro -Ph e seq ue nce co ul d
be repl ac e d w it h a n a c yl a ted ph en yl al a ni ne or t yro sin e w it hou t any si gn if ica nt lo ss in i nh ib it or
ac ti vi ty . A ddi ti on al c ha ng es to S CRI P re sul ted i n the cli n ical d rug can di dat e e na lki ren , a lso
kn own as A -646 62 (Fi g . 2 8.4 ). The h is ti di n e re si du e (H is 6 ), wh ich i s prese nt in an gi ot ensi no ge n
and al l p re v io us i nh ib i tors , was t hou gh t t o b e e sse nt ia l for enzyme reco gni ti o n a nd was le ft
unch ang ed . Th e a cy l at ed ty ros i ne pro tects t he comp ou nd from a mi no pep ti da se e nzym es a nd
al so c on tri but es t o e nz y me acti v e -si te reco gni ti on . Th e re ma in de r of th e m ol ecul e i s a sta bl e
di pep ti de i so s tere . Th e c y c lo he xy l me thyl en e a nd i so -but yl si de cha in s are l ip oph i li c an d
app rox i mat e t he l ip oph i li c s id e ch ai ns p resen t i n Le u 1 0 an d V al 1 1 of an gi ote nsi no gen .
Ad di ti ona l ly , the u se of a C -term in al al coh ol i nste ad of a C-term in al carb oxyla te prot ects
ena lk i ren fro m c arb ox y pe pti da s e e nz y me s (10 ,11 ).
Pgina 6 de 51
Fig. 28.4. Structures of enalkiren and

zankiren.
View Figure
En al ki ren h as be en ex te ns i v el y s tud ie d i n pre cl i ni cal an d cl i ni cal tri al s a nd ha s bee n sh own to

be eff ic a ci ou s i f g iv e n I V. It la c ks si gn i fi ca nt bi oa va i la bi li ty, ho wever, ma i nl y be ca use of a l a ck
of li pi d s ol ubi l i ty . A m ore li po ph il i c an al og ue, zan ki ren (A -725 17 ) (Fi g . 2 8.4 ), ha s de mo nstrat ed
in cre as ed ora l bi oa va i la bi li ty and ef fi c acy. P recl in ica l and cl in ica l tria l s wi th oral l y ad mi ni stere d
za nk i re n sh owe d goo d b i oav a il ab il i ty a nd sig ni fi cant red ucti on i n b l ood p re ssu re ( 11 ,12 ).
Za nk i ren ha s si n ce be en wi th draw n f rom cl i ni cal tri al s f or u ndi sclo sed reaso ns; h owe ver, the
FD A rec en tl y app rov ed A li s k ire n (Te kt ou rn an ), t he fi rst , n on -pep ti di c ora ll y a ct ive ren in i nhi b it or.
It i s a ppro v ed for the tre atm en t o f h y pert ensi on an d wil l b e a va i la bl e f or u se i n 20 07. S ee Drug
upd ate : h tt p:/ /th epo i nt. /www .com/ foy e be.
A t t e m p t s t o d e v e l o p o r a l l y a c t i v e , b i o a v a i l a b l e r e n i n i n h i b i t o r s a c tu a l l y p r e d a t e t h e d e v e l o p m e n t o f A C E
i n h i b i t o r s . R e s e a r c h i n t h i s a r e a c o n t i n u e s t o d a y ; h o w e v e r , o n e o f t h e m a i n a t tr a c ti o n s o f r e n i n i n h i b i t o r s ,
s p e c i f i c i t y , h a s p r o v e n to b e a s i g n i f i c a n t h u r d l e to t h e c l i n i c a l d e v e l o p m e n t ( 9 ) o f t h e s e a g e n t s .
Angiotensin-Converting Enzyme Inhibitors

Currently, there are 11 ACE inhibitors approved for therapeutic use in the United States. These compounds
c a n b e s u b c l a s s i f i e d i n t o th r e e g r o u p s b a s e d o n t h e i r c h e m i c a l c o m p o s i t i o n : s u l f h y d r y l - c o n t a i n i n g i n h i b i t o r s
(exemplified by captopril), dicarboxylate-containing inhibitors (exemplified by enalapril), and phosphonatec o n t a i n i n g i n h i b i t o r s ( e x e m p l i f i e d b y f o s i n o p r i l ) . C a p t o p r i l a n d f o s i n o p r i l a r e t h e l o n e r e p r e s e n ta t i v e s o f t h e i r
respective chemical subclassifications, whereas the majority of the inhibitors contain the dicarboxylate
fu n c t i o n a l i ty . A l l o f t h e s e c o m p o u n d s e f f e c t i v e l y b l o c k th e c o n v e r s i o n o f a n g i o t e n s i n I t o a n g i o t e n s i n I I a n d
h a v e s i m i l a r th e r a p e u t i c a n d p h y s i o l o g i c a l e f f e c t s . T h e c o m p o u n d s d i f f e r p r i m a r i l y i n t h e i r p o t e n c y a n d
p h a r m a c o k i n e t i c p r o fi l e s ( 1 ) . A d d i t i o n a l l y , t h e s u l f h y d r y l g r o u p i n c a p t o p r i l i s r e s p o n s i b l e fo r c e r t a i n e f fe c t s
n o t s e e n w i t h t h e o t h e r a g e n t s . D e t a i l e d d e s c r i p t i o n s o f t h e r a ti o n a l e f o r t h e d e v e l o p m e n t o f c a p t o p r i l ,
enalapril, and fosinopril are provided below.
Sulfhydryl-Containing Inhibitors: Development of Captopril

In 1 9 6 5 , F e r r e i r a e t a l . ( 1 3 ) r e p o r t e d t h a t t h e v e n o m o f t h e S o u th A m e r i c a n p i t v i p e r ( B o t h r o p s j a r a r a c a )
contained factors that potentiated the action of bradykinin. These factors, originally designated as
b r a d y k i n i n - p o t e n t i a t i n g f a c to r s ( B P F s ) , w e r e i s o l a t e d a n d f o u n d t o b e a f a m i l y o f p e p t i d e s c o n ta i n i n g 5 t o 1 3
amino acid residues. Their actions in potentiating bradykinin were subsequently linked to their ability to
inhibit the enzymatic degradation of bradykinin. Soon thereafter, Bakhle et al. (14) reported that these same
peptides also inhibited the enzymatic conversion of angiotensin I to angiotensin II. This latter enzyme, ACE,
i s n o w k n o w n t o b e i d e n t i c a l w i t h t h e f o r m e r b r a d y k i n i n a s e e n z y m e ( k i n i n a s e II ) . E v e n a t t h e t i m e o f t h e s e
initial discoveries, however, BPFs were seen as lead compounds for the development of new
a n t i h y p e r t e n s i v e a g e n t s , b e c a u s e th e y p o s s e s s e d d u a l a c t i v i ti e s i n h i b i t i o n o f t h e d e g r a d a t i o n o f
b r a d y k i n i n , a p o t e n t v a s o d i l a t o r , a n d i n h i b i t i o n o f t h e b i o s y n t h e s i s o f a n g i o t e n s i n I I , a p o te n t v a s o c o n s t r i c t o r
(15).
Pgina 7 de 51
Fig. 28.5. A model of substrate binding to

carboxypeptidase A (A) and ACE (B).
View Figure
A n o n a p e p t i d e , S Q 2 0 , 8 8 1 ( t e p r o t i d e ) , i s o l a te d f r o m th e o r i g i n a l B P F s h a d th e g r e a t e s t i n v i v o p o t e n c y i n
inhibiting ACE and was shown to consistently lower blood pressure in patients with essential hypertension.
It a l s o e x e r t e d b e n e f i c i a l e f f e c t s i n p a t i e n t s w i t h h e a r t f a i l u r e ; h o w e v e r , b e c a u s e o f i ts p e p t i d e n a t u r e a n d
lack of oral activity, teprotide had limited activity in the therapeutic treatment of these diseases (15,16 ).
C u s h m a n , O n d e t t i , a n d c o w o r k e r s ( 1 7 , 1 8 ,1 9 ) u s e d S Q 2 0 , 8 8 1 a n d o t h e r p e p t i d e a n a l o g u e s t o p r o v i d e a n
enhanced understanding of the enzymatic properties of ACE. Using knowledge of substrate-binding
s p e c i f i c i t i e s a n d t h e f a c t t h a t A C E h a s p r o p e r ti e s s i m i l a r t o t h o s e o f p a n c r e a t i c c a r b o x y p e p t i d a s e s , t h e s e
researchers developed a hypothetical model of the enzyme active site. Carboxypeptidase A, like ACE, is a
z i n c - c o n t a i n i n g e x o p e p t i d a s e . T h e b i n d i n g o f a s u b s tr a t e t o c a r b o x y p e p t i d a s e A i n v o l v e s t h r e e m a j o r
interactions (Fig. 28.5A).
P.743
F i r s t , t h e n e g a t i v e l y c h a r g e d c a r b o x y l a t e t e r m i n u s o f th e a m i n o a c i d s u b s t r a t e b i n d s t o t h e p o s i t i v e l y
c h a r g e d A r g - 1 4 5 o n t h e e n z y m e . S e c o n d , a h y d r o p h o b i c p o c k e t i n t h e e n z y m e p r o v i d e s s p e c i f i c i ty f o r a C te r m i n a l a r o m a t i c o r n o n p o l a r r e s i d u e . T h i r d , t h e z i n c a t o m i s l o c a t e d c l o s e t o t h e l a b i l e p e p t i d e b o n d a n d
serves to stabilize the negatively charged tetrahedral intermediate, which results when a molecule of water
a t t a c k s t h e c a r b o n y l b o n d b e t w e e n t h e C - te r m i n a l a n d p e n u l t i m a t e a m i n o a c i d r e s i d u e s ( 2 0 ) . S i m i l a r l y , t h e
b i n d i n g o f s u b s t r a t e s t o A C E w a s p r o p o s e d to i n v o l v e th r e e o r f o u r m a j o r i n t e r a c t i o n s ( F i g . 2 8 . 5 B ) . F i r s t,
th e n e g a t i v e l y c h a r g e d c a r b o x y l a t e t e r m i n u s o f a n g i o t e n s i n I a n d o t h e r s u b s t r a t e s w a s a s s u m e d t o o c c u r v i a
an ionic bond with a positively charged am ine on ACE. Second, the role of the zinc atom in the mechanism
of ACE hydrolysis was assum ed to be sim ilar to that of carboxypeptidase A. Because ACE cleaves
dipeptides instead of single amino acids, the position of the zinc atom was assumed to be located two
amino acids away from the cationic center for it to be adjacent to the labile peptide bond. Third, the sidec h a i n s R 1 a n d R 2 c o u l d c o n tr i b u te t o th e o v e r a l l b i n d i n g a f f i n i ty ; h o w e v e r , A C E , u n l i k e c a r b o x y p e p t i d a s e A ,
d o e s n o t s h o w s p e c i f i c i t y f o r C - te r m i n a l h y d r o p h o b i c a m i n o a c i d s a n d w a s n o t e x p e c t e d t o h a v e a
h y d r o p h o b i c b i n d i n g p o c k e t . F i n a l l y , th e t e r m i n a l p e p t i d e b o n d i s n o n l a b i l e a n d w a s a s s u m e d to p r o v i d e
hydrogen bonding between the substrate and ACE.
T h e d e v e l o p m e n t o f c a p t o p r i l a n d o t h e r o r a l l y a c t i v e A C E i n h i b i t o r s b e g a n w i t h th e o b s e r v a t i o n th a t D - 2 b e n z y l s u c c i n i c a c i d w a s a n e x t r e m e l y p o t e n t i n h i b i t o r o f c a r b o x y p e p ti d a s e A ( 1 7 , 1 8 , 1 9 ) . T h e b i n d i n g o f t h i s
com pound to carboxypeptidase A (Fig. 28.6A) is very similar to that seen for substrates with the exception
Pgina 8 de 51
th a t th e z i n c i o n b i n d s t o a c a r b o x y l a t e g r o u p i n s t e a d o f th e l a b i l e p e p t i d e b o n d . B y e r s a n d W o l f e n d e n ( 2 1 )
proposed that this compound is a by-product analogue that contains structural features of both products of
peptide hydrolysis. Most of the structural features of the compound are identical to the term inal amino acid
of the substrate (Fig. 28.5A), whereas the additional carboxylate group is able to m imic the carboxylate
g r o u p t h a t w o u l d b e p r o d u c e d d u r i n g p e p ti d e h y d r o l y s i s ( 2 1 ) . A p p l y i n g t h i s c o n c e p t t o t h e h y p o t h e t i c a l
model of ACE described above resulted in the synthesis and evaluation of a series of succinic acid
d e r i v a t i v e s ( F i g . 2 8 . 6 B ) . B e c a u s e p r o l i n e w a s p r e s e n t a s t h e C - te r m i n a l a m i n o a c i d i n S Q 2 0 , 8 8 1 a s w e l l a s
i n o t h e r p o t e n t , i n h i b i t o r y s n a k e v e n o m p e p t i d e s , i t w a s i n c l u d e d i n t h e s t r u c tu r e o f n e w l y d e s i g n e d
inhibitors. The first inhibitor to be synthesized and tested was succinyl -L-proline (Fig. 28.7). This compound
proved to be somewhat disappointing. Although it provided reasonable specificity for ACE, it was only
approximately 1/500 as potent as SQ 20,881.
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.
View Figure
Substitution of other amino acids in place of proline produced com pounds that were even less potent;
hence, all subsequent SAR studies were conducted using analogues of L-proline (Fig. 28.7). The addition of
a methyl group to the 2 position of succinyl-L-proline to mimic the am ino acid side chain, R2, of the
substrate enhanced activity but only marginally. D-2-Methylsuccinyl-L-proline had effects sim ilar to SQ
20,881 but was still only 1/300 as potent. The D-isomer, rather than the L-isomer norm ally seen for amino
acids, was necessary because of the isosteric replacement of an NH2 with a CH 2 present in succinyl-Lp r o l i n e . A c o m p a r i s o n o f th e R 2 g r o u p o f th e s u b s t r a t e ( F i g . 2 8 . 5 B ) w i t h t h e m e t h y l g r o u p o f D - 2 methylsuccinyl-L-proline, illustrates that this methyl group occupies the sam e binding site as the side chain
of an L-amino group.
One of the most important alterations to succinyl-L-proline was the replacem ent of the succinyl carboxylate
with other groups having enhanced affinity for the zinc atom bound to ACE. Replacem ent of this carboxylate
with a sulfhydryl group produced 3 -mercaptopropanoyl-L-proline. This com pound has an IC50 value of 200
n M a n d i s g r e a t e r t h a n 1 0 0 0 - fo l d m o r e p o t e n t t h a n s u c c i n y l - L - p r o l i n e ( F i g . 2 8 . 7 ) . A d d i t i o n a l l y , i t i s 1 0 - t o
2 0 - fo l d m o r e p o t e n t t h a n S Q 2 0 , 8 8 1 i n i n h i b i t i n g c o n t r a c t i l e a n d v a s o p r e s s o r r e s p o n s e s t o a n g i o t e n s i n I .
Addition of a 2-D-methyl group further enhanced activity. The resulting compound, captopril (Fig. 28.7), is a
Pgina 9 de 51
c o m p e t i t i v e i n h i b i t o r o f A C E w i t h a K i v a l u e o f 1 . 7 n M a n d w a s t h e f i r s t A C E i n h i b i t o r t o b e m a r k e te d .
P.744
Fig. 28.8. A comparison of enalaprilat

and the transition state of angiotensin I
hydrolysis by ACE.
View Figure
T h e s u l f h y d r y l g r o u p o f c a p t o p r i l p r o v e d to b e r e s p o n s i b l e n o t o n l y f o r th e e x c e l l e n t i n h i b i t o r y a c t i v i ty o f t h e
c o m p o u n d b u t a l s o f o r t h e tw o m o s t c o m m o n s i d e e f f e c t s , s k i n r a s h e s a n d t a s t e d i s t u r b a n c e s ( e . g . , m e t a l l i c
ta s t e a n d l o s s o f t a s te ) . T h e s e s i d e e f f e c t s u s u a l l y s u b s i d e d o n d o s a g e r e d u c t i o n o r d i s c o n t i n u a t i o n o f
captopril. They were attributed to the presence of the sulfhydryl group, because similar effects had been
observed with penicillamine, a sulfhydryl containing agent used to treat Wilson's disease and rheum atoid
arthritis (22,23 ).
Dicarboxylate-Containing Inhibitors
Development of Enalapril
R e s e a r c h e r s a t M e r c k ( 2 4 ) s o u g h t t o d e v e l o p c o m p o u n d s t h a t l a c k e d t h e s u l f h y d r y l g r o u p o f c a p to p r i l y e t
m a i n ta i n e d s o m e a b i l i t y t o c h e l a t e z i n c . C o m p o u n d s h a v i n g t h e g e n e r a l s t r u c t u r e s h o w n b e l o w w e r e
designed to m eet this objective.
T h e s e c o m p o u n d s a r e t r i p e p t i d e s u b s t r a t e a n a l o g u e s i n w h i c h t h e C - te r m i n a l ( A ) a n d p e n u l t i m a t e ( B ) a m i n o
a c i d s a r e r e t a i n e d b u t t h e t h i r d a m i n o a c i d i s i s o s t e r i c a l l y r e p l a c e d b y a s u b s t i tu t e d N - c a r b o x y m e t h y l g r o u p
( C ) . S i m i l a r t o t h e r e s u l t s s e e n i n t h e d e v e l o p m e n t o f c a p t o p r i l , C - te r m i n a l p r o l i n e a n a l o g u e s p r o v i d e d
optimum activity. The use of a methyl group at R3 (i.e., B = Ala) and a phenylethyl group at R 4 resulted in
e n a l a p r i l a t ( F i g . 2 8 . 8 ) . In c o m p a r i n g t h e a c t i v i t y o f c a p t o p r i l a n d e n a l a p r i l a t , i t w a s f o u n d t h a t e n a l a p r i l a t,
w i t h a K i o f 0 .2 n M , w a s a p p r o x i m a t e l y 1 0 - fo l d m o r e p o t e n t t h a n c a p t o p r i l . S t u d i e s i n v e s t i g a t i n g t h e b i n d i n g
o f e n a l a p r i l a t r e v e a l e d t h a t i t s a b i l i t y to c h e l a t e t h e e n z y m e - b o u n d z i n c a t o m w a s s i g n i f i c a n t l y l e s s t h a n
th a t o f c a p t o p r i l . T h e e n h a n c e d b i n d i n g w a s p r o p o s e d t o b e c a u s e d b y t h e a b i l i t y t o m i m i c t h e t r a n s i ti o n
state of angiotensin I hydrolysis. As shown in Figure 28.8, enalaprilat possess a tetrahedral carbon in place
o f t h e l a b i l e p e p ti d e b o n d . T h e s e c o n d a r y a m i n e , t h e c a r b o x y l i c a c i d , a n d p h e n y l e t h y l g r o u p s a l l c o n t r i b u t e
Pgina 10 de 51
to t h e o v e r a l l b i n d i n g o f t h e c o m p o u n d t o A C E . T h e s e c o n d a r y a m i n e i s l o c a te d a t t h e s a m e p o s i t i o n a s t h e
l a b i l e a m i d e n i t r o g e n , t h e i o n i z e d c a r b o x y l i c a c i d c a n f o r m a n i o n i c b o n d w i t h t h e z i n c a t o m , a n d th e
phenylethyl group m imics the hydrophobic side chain of the Phe amino acid, which is present in angiotensin
I.
D e s p i t e e x c e l l e n t I V a c t i v i t y , e n a l a p r i l a t h a s v e r y p o o r o r a l b i o a v a i l a b i l i t y . E s te r i f i c a t i o n o f e n a l a p r i l a t
produced enalapril (Fig. 28.9), a compound with superior oral bioavailability. The combination of structural
fe a t u r e s i n e n a l a p r i l a t , e s p e c i a l l y t h e t w o c a r b o x y l a t e g r o u p s a n d t h e s e c o n d a r y a m i n e , a r e r e s p o n s i b l e f o r
its overall low lipophilicity and poor oral bioavailability. Zwitterion form ation also has been suggested to
contribute to the low oral activity (25), and a comparison of the pKa values for the secondary amine of
e n a l a p r i l a t a n d e n a l a p r i l s u p p o r t s t h i s e x p l a n a t i o n . I o n i z a ti o n o f t h e a d j a c e n t c a r b o x y l a t e i n e n a l a p r i l a t
g r e a t l y e n h a n c e s t h e b a s i c i ty o f t h e s e c o n d a r y a m i n e s u c h t h a t th e p K a o f t h e a m i n e i n t h i s c o m p o u n d i s
8 . 0 2 , w h e r e a s i n e n a l a p r i l , i t i s o n l y 5 . 4 9 . T h u s , i n t h e s m a l l i n te s t i n e , t h e a m i n e i n e n a l a p r i l a t w i l l b e
p r i m a r i l y i o n i z e d a n d f o r m a z w i t t e r i o n w i th t h e a d j a c e n t c a r b o x y l a t e , b u t th e a m i n e i n e n a l a p r i l w i l l b e
primarily un-ionized (26 ).
In t r a v e n o u s a d m i n i s t r a t i o n o f e i t h e r e n a l a p r i l o r e n a l a p r i l a t p r o d u c e d s i m i l a r e f f e c t s o n a n g i o t e n s i n I I
production
P.745
d e s p i t e t h e f a c t t h a t e n a l a p r i l s h o w e d a 1 , 0 0 0 - fo l d d e c r e a s e i n i n v i t r o a c t i v i t y . S u b s e q u e n t s t u d i e s s h o w e d
th a t e n a l a p r i l u n d e r g o e s b i o a c t i v a t i o n a n d , t h u s , i s a p r o - d r u g o f e n a l a p r i l a t . B e c a u s e h u m a n p l a s m a w a s
reported to lack enalapril esterolytic activity, bioactivation by hepatic esterases (Fig. 28.9) has been
s u g g e s te d a s t h e m o s t p r o b a b l e m e c h a n i s m f o r e n a l a p r i l a t f o r m a t i o n ( 2 7 , 2 8 ) .
Fig. 28.9. Bioactivation of enalapril.

View Figure
Pgina 11 de 51
Table 28.1. Additional Dicarboxylatecontaining Angiotensin Converting

Enzyme Inhibitors
View Table
Additional Dicarboxylate Inhibitors

Eight other dicarboxylate inhibitors (Table 28.1) have been approved for various therapeutic indications;
however, spirapril has never been m arketed. Lisinopril is chemically unique in two respects. First, it
contains the basic amino acid lysine (R1 = CH 2CH2CH2CH2NH2) instead of the standard nonpolar alanine
(R = CH3)
P.746
r e s i d u e . S e c o n d , i t d o e s n o t r e q u i r e b i o a c ti v a t i o n , b e c a u s e n e i t h e r o f t h e c a r b o x y l i c a c i d g r o u p s a r e
e s t e r i f i e d ( i . e . , R 2 = H ) . L i s i n o p r i l w a s d e v e l o p e d a t t h e s a m e t i m e a s e n a l a p r i l . D e s p i t e th e a d d i t i o n o f
a n o t h e r i o n i z a b l e g r o u p , t h e o r a l a b s o r p t i o n o f l i s i n o p r i l w a s f o u n d to b e s u p e r i o r t o t h a t o f e n a l a p r i l a t b u t
less than that of enalapril. In vitro studies of enalaprilat and lisinopril showed lisinopril to be slightly more
potent than enalaprilat (27,28). Lisinopril, along with captopril, currently are the only two ACE inhibitors
th a t a r e n o t p r o - d r u g s .
Fig. 28.10. A modified model of ACE

inhibitor binding.
View Figure
T h e m a j o r s t r u c t u r a l d i f f e r e n c e a m o n g t h e r e m a i n i n g A C E i n h i b i t o r s i s i n t h e r i n g o f t h e C - te r m i n a l a m i n o
acid. Lisinopril, like enalapril and captopril, contains the pyrrolidine ring of proline, whereas all the other
com pounds contain larger bicyclic or spiro ring systems. Studies of indoline analogues of captopril
indicated that a hydrophobic pocket similar to that seen in carboxypeptidase A also was present in ACE.
T h i s l e d t o a m o d i f i c a t i o n ( F i g . 2 8 . 1 0 ) o f O n d e t t i a n d C u s h m a n 's o r i g i n a l m o d e l a n d t h e d e v e l o p m e n t o f
inhibitors that contained larger hydrophobic ring system s (29 ). Although this modified m odel was proposed
fo r c a p t o p r i l a n a l o g u e s , i t i s r e a d i l y a d a p t a b l e t o i n c l u d e e n a l a p r i l a t a n a l o g u e s . I n g e n e r a l , t h e v a r i e d r i n g
Pgina 12 de 51
systems seen in benazepril, moexipril, perindopril, quinapril, ram ipril, spirapril, and trandolapril provide
enhanced binding and potency. They also lead to differences in absorption, plasma protein binding,
elim ination, onset of action, duration of action, and dosing am ong the drugs. These differences are
d i s c u s s e d i n m o r e d e ta i l i n P h a r m a c o k i n e t i c P r o p e r t i e s b e l o w .
Phosphonate-containing Inhibitors: the Development of Fosinopril

T h e s e a r c h f o r A C E i n h i b i to r s th a t l a c k e d t h e s u l f h y d r y l g r o u p a l s o l e a d t o t h e i n v e s t i g a t i o n o f
phosphorous-containing com pounds (30). The phosphinic acid shown in Figure 28.11 is capable of binding
to A C E i n a m a n n e r s i m i l a r t o e n a l a p r i l . T h e i n t e r a c t i o n o f t h e z i n c a to m w i t h t h e p h o s p h i n i c a c i d i s s i m i l a r
to t h a t s e e n w i t h s u l f h y d r y l a n d c a r b o x y l a t e g r o u p s . A d d i t i o n a l l y , th i s c o m p o u n d i s c a p a b l e o f f o r m i n g t h e
ionic, hydrogen, and hydrophobic bonds similar to those seen with enalapril and other dicarboxylate
analogues. A feature unique to this compound is the ability of the phosphinic acid to more truly m imic the
i o n i z e d , t e t r a h e d r a l i n t e r m e d i a te o f p e p t i d e h y d r o l y s i s . U n l i k e e n a l a p r i l a n d o t h e r d i c a r b o x y l a t e a n a l o g u e s ,
h o w e v e r , t h e s p a c i n g o f t h i s t e t r a h e d r a l s p e c i e s i s s h o r te r , b e i n g o n l y t w o a t o m s r e m o v e d f r o m t h e p r o l i n e
nitrogen. Additionally, the spacing between the proline nitrogen and the hydrophobic phenyl ring is one
atom longer than that seen in the dicarboxylates.
Fig. 28.11. The binding of phosphinate

analogues to ACE.
View Figure
S t r u c t u r a l m o d i f i c a t i o n t o i n v e s t i g a t e m o r e h y d r o p h o b i c , C - te r m i n a l r i n g s y s t e m s , s i m i l a r t o t h a t d e s c r i b e d
above for the dicarboxylate compounds, lead to a 4 -cyclohexylproline analogue of the original phosphinic
a c i d . T h i s c o m p o u n d , f o s i n o p r i l a t ( F i g . 2 8 . 1 2 ) , w a s m o r e p o t e n t t h a n c a p t o p r i l b u t l e s s p o te n t t h a n
enalaprilat. The above-mentioned differences in the spacing of the phosphinic acid and phenyl groups may
b e r e s p o n s i b l e f o r t h i s l a t t e r d i f f e r e n c e i n p o t e n c y . S i m i l a r t o th e d i c a r b o x y l a t e s , fo s i n o p r i l a t w a s t o o
h y d r o p h i l i c a n d e x h i b i t e d p o o r o r a l a c t i v i ty . T h e p r o - d r u g fo s i n o p r i l c o n t a i n s a n ( a c y l o x y ) a l k y l g r o u p t h a t
allows better lipid solubility and improved bioavailability (30). Bioactivation via esterase activity in the
i n t e s ti n a l w a l l a n d l i v e r p r o d u c e s f o s i n o p r i l ( F i g . 2 8 . 1 2 ) .
Mechanism of Action
The ACE inhibitors attenuate the effects of the renin-angiotensin system by inhibiting the conversion of
a n g i o t e n s i n I t o a n g i o te n s i n I I ( F i g . 2 8 . 1 ) . T h e y a l s o i n h i b i t t h e c o n v e r s i o n o f [ d e s - A s p 1 ]a n g i o te n s i n I t o
angiotensin III; however, this action has only a minor role in the overall cardiovascular effects of these
drugs. They are selective in that they do not directly interfere with any other components of the renina n g i o t e n s i n s y s t e m ; h o w e v e r , t h e y d o c a u s e o t h e r e f f e c t s t h a t a r e u n r e l a t e d t o t h e d e c r e a s e i n a n g i o te n s i n
II c o n c e n t r a t i o n . I n h i b i t o r s o f A C E i n c r e a s e b r a d y k i n i n l e v e l s t h a t , i n t u r n , s t i m u l a t e p r o s t a g l a n d i n
biosynthesis (Fig. 28.3). Both of these compounds have been proposed to contribute to the overall action of
ACE inhibitors. Additionally, decreased angiotensin II levels increase the release of renin and the
production of angiotensin I. Because ACE is inhibited,
P.747
a n g i o t e n s i n I i s s h u n t e d t o w a r d th e p r o d u c t i o n o f a n g i o t e n s i n 1 - 7 a n d o t h e r p e p t i d e s . T h e c o n t r i b u t i o n o f
th e s e p e p t i d e s t o t h e o v e r a l l e f f e c t o f A C E i n h i b i t o r s i s u n k n o w n ( 1 ) .
Fig. 28.12. Bioactivation of fosinopril.
Pgina 13 de 51
View Figure
StructureActivity Relationships
The structural characteristics for ACE inhibitory activity are given in Table 28.2. Angiotensin -converting
enzyme is a stereoselective drug target. Because currently approved ACE inhibitors act as either di- or
tr i p e p t i d e s u b s tr a t e a n a l o g u e s , t h e y m u s t c o n t a i n a s t e r e o c h e m i s t r y t h a t i s c o n s i s t e n t w i t h t h e L - a m i n o
a c i d s p r e s e n t i n t h e n a t u r a l s u b s t r a te s . T h i s w a s e s t a b l i s h e d v e r y e a r l y i n t h e d e v e l o p m e n t o f A C E
i n h i b i t o r s w h e n c o m p o u n d s w i t h c a r b o x y l - te r m i n a l D - a m i n o a c i d s w e r e d i s c o v e r e d t o b e v e r y p o o r i n h i b i to r s
( 3 1 ) . L a t e r w o r k b y P a t c h e t t e t a l . ( 2 4 ) r e i n f o r c e d t h i s i d e a . T h e y r e p o r t e d a 1 0 0 - to 1 , 0 0 0 - fo l d l o s s i n
i n h i b i t o r a c t i v i t y w h e n e v e r t h e c o n f i g u r a ti o n o f e i t h e r t h e c a r b o x y l a t e o r t h e R 1 s u b s t i t u e n t ( T a b l e 2 8 . 1 ) w a s
a l t e r e d . T h e S , S , S - c o n f i g u r a t i o n s e e n i n e n a l a p r i l a n d o t h e r d i c a r b o x y l a te i n h i b i t o r s m e e t s t h e a b o v e - s t a t e d
c r i te r i a a n d p r o v i d e s f o r o p t i m u m e n z y m e i n h i b i t i o n .
Physicochemical Properties
Captopril and fosinopril are acidic drugs, but all other ACE inhibitors are amphoteric. The carboxylic acid
a t t a c h e d t o t h e N - r i n g i s a c o m m o n s tr u c tu r a l f e a t u r e i n a l l A C E i n h i b i t o r s . I t h a s a p K a i n th e r a n g e o f 2 . 5
to 3 . 5 a n d w i l l b e i o n i z e d p r i m a r i l y a t p h y s i o l o g i c a l p H . A s d i s c u s s e d a b o v e
P.748
w i t h e n a l a p r i l , t h e p K a a n d i o n i z a ti o n o f t h e s e c o n d a r y a m i n e i n th e d i c a r b o x y l a t e s e r i e s d e p e n d s o n
w h e t h e r t h e a d j a c e n t fu n c t i o n a l g r o u p i s i n t h e p r o - d r u g o r a c t i v e f o r m . I n t h e p r o - d r u g fo r m , t h e a m i n e i s
a d j a c e n t t o a n e s t e r , i s l e s s b a s i c , a n d i s p r i m a r i l y u n - i o n i z e d a t p h y s i o l o g i c a l p H . F o l l o w i n g b i o a c t i v a ti o n ,
th e a m i n e i s a d j a c e n t t o a n i o n i z e d c a r b o x y l i c a c i d th a t e n h a n c e s b o t h t h e b a s i c i ty a n d i o n i z a t i o n o f t h e
a m i n e . S i m i l a r l y , t h e b a s i c n i t r o g e n e n h a n c e s t h e a c i d i t y o f th e a d j a c e n t c a r b o x y l i c a c i d s u c h t h a t i t u s u a l l y
has a lower pKa than the carboxylic acid attached to the N-ring. As an example, the pKa values of enalapril
a r e 3 .3 9 a n d 2 . 3 0 . T h e s e v a l u e s c o r r e s p o n d to t h e c a r b o x y l i c a c i d o n th e N - r i n g a n d t h e c a r b o x y l i c a c i d
a d j a c e n t t o t h e a m i n e , r e s p e c t i v e l y . T h e a n a l o g o u s v a l u e s f o r t h e s e f u n c t i o n a l g r o u p s i n l i s i n o p r i l a r e 3 .3
and 1.7 (26).
Table 28.2. Structure activity

relationship of ACE inhibitors.
View Table
Table 28.3. Pharmacokinetic Parameters of ACE Inhibitors
Pgina 14 de 51
Drug
Oral
Effect of
CalculatedBioavailabilityFood on
Log P
(%)
Absorption
Active
Metabolite
Protein
Binding
(%)
Benazepril
5.504
37
Slows
absorption
Benazeprilat
>95
Captopril
0.272
6075
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
2530
None
NA
25
Moexipril
4.055
13
Reduced
Moexiprilat
50
Perindopril
3.363
6595
Reduced
Perindoprilat
60
80
Quinapril
4.318
60
Reduced
Quinaprilat
97
Ramipril
3.409
5060
Slows
absorption
Ramiprilat
73
Spirapril
3.162
50
Spiraprilat
Pgina 15 de 51
Trandolapril
3.973
70
Slows
absorption
Trandolaprilat
80
NA, not applicable, , data not available.
The calculated log P values (26) along with other pharm acokinetic parameters for the ACE inhibitors are
s h o w n i n T a b l e 2 8 . 3 . W i t h t h r e e n o t a b l e e x c e p t i o n s , c a p to p r i l , e n a l a p r i l a t , a n d l i s i n o p r i l , a l l o f t h e
com pounds possess good lipid solubility. Compounds that contain hydrophobic bicyclic ring systems are
more lipid soluble than those that contain proline. A comparison of the log P values of benazepril,
fo s i n o p r i l , m o e x i p r i l , p e r i n d o p r i l , q u i n a p r i l , r a m i p r i l , s p i r o p r i l , a n d tr a n d o l a p r i l t o t h o s e f o r c a p t o p r i l a n d
enalapril illustrates this fact. As previously discussed, enalaprilat is much more hydrophilic than its ester
p r o - d r u g a n d i s c u r r e n t l y t h e o n l y A C E i n h i b i t o r m a r k e d f o r I V a d m i n i s t r a ti o n . I n t e r m s o f s o l u b i l i t y , l i s i n o p r i l
probably is the m ost interesting compound in that it is the most hydrophilic inhibitor, yet unlike enalaprilat,
i t i s o r a l l y a c t i v e . O n e p o s s i b l e e x p l a n a t i o n fo r t h i s p h e n o m e n o n i s t h a t i n t h e d u o d e n u m , l i s i n o p r i l w i l l e x i s t
a s a d i - z w i t t e r i o n i n w h i c h t h e i o n i z e d g r o u p s c a n i n t e r n a l l y b i n d t o o n e a n o th e r . I n t h i s m a n n e r , l i s i n o p r i l
may be able to pass through the lipid bilayer with an overall net neutral charge.
Metabolism
L i s i n o p r i l a n d e n a l a p r i l a t a r e e x c r e te d u n c h a n g e d , w h e r e a s a l l o th e r A C E i n h i b i t o r s u n d e r g o s o m e d e g r e e o f
metabolic transformation (1,32,33,34). As previously discussed and illustrated (Figs. 28.9 and 28.12), all
dicarboxylate and phosphonate pro-drugs must undergo bioactivation via hepatic esterases. Additionally,
b a s e d o n t h e i r s tr u c tu r a l f e a t u r e s , s p e c i f i c c o m p o u n d s c a n u n d e r g o m e t a b o l i c i n a c t i v a t i o n v i a v a r i o u s
pathways (Fig. 28.13). Because of its sulfhydryl group, captopril is subject to oxidative dimerization or
conjugation. Approxim ately 40 to 50% of a dose of captopril is excreted unchanged, whereas the remainder
is excreted as either a disulfide dimer or a captopril-cysteine disulfide. Glucuronide conjugation has been
reported for benazepril, fosinopril, quinapril, and ramipril. This conjugation can occur either with the parent
pro-drug or with the activated drug. Benazepril, with the N-substituted glycine, is especially susceptible to
th i s r e a c ti o n b e c a u s e o f a d i f f e r e n c e i n s t e r i c h i n d r a n c e . F o r a l l A C E i n h i b i to r s , e x c e p t
P.749
b e n a z e p r i l , t h e c a r b o n a t o m d i r e c t l y a d j a c e n t t o t h e c a r b o x y l i c a c i d i s p a r t o f a r i n g s y s te m a n d p r o v i d e s
som e steric hindrance to conjugation. The unsubstituted methylene group (i.e., CH2) of benazepril
p r o v i d e s l e s s s t e r i c h i n d r a n c e a n d , t h u s , f a c i l i t a te s c o n j u g a t i o n . M o e x i p r i l , p e r i n d o p r i l , a n d r a m i p r i l c a n
Pgina 16 de 51
undergo cyclization to produce diketopiperazines. This cyclization can occur with either the parent or active
fo r m s o f t h e d r u g s .
Fig. 28.13. Metabolic routes of ACE

inhibitors.
View Figure
A comparative study of the m etabolism and biliary excretion of lisinopril, enalapril, perindopril, and ramipril
r e v e a l e d t h a t w h e r e a s n e i t h e r l i s i n o p r i l n o r e n a l a p r i l u n d e r w e n t a n y a p p r e c i a b l e m e ta b o l i s m b e y o n d
bioactivation of enalapril to enalaprilat, both perindopril and ramipril were extensively m etabolized beyond
th e i n i t i a l b i o a c t i v a t i o n . I t w a s p r o p o s e d t h a t t h e s e d i f f e r e n c e s i n h e p a t i c m e t a b o l i s m c o u l d b e e x p l a i n e d , i n
p a r t , b y th e l a r g e r , m o r e h y d r o p h o b i c r i n g s p r e s e n t o n p e r i n d o p r i l a n d r a m i p r i l ( 3 5 ) .
Pharmacokinetic Parameters
The pharmacokinetic param eters and dosing information for ACE inhibitors are sum marized in Tables 28.3
and 28.4, respectively (1,32,33,34 ). The oral bioavailability of this class of drugs ranges from 13 to 95%.
Differences in both lipid solubility and first-pass metabolism are most likely responsible for this wide
variation. Both parameters should be considered when com paring any two or more compounds. With the
exceptions of enalapril and lisinopril, the concurrent administration of food adversely affects the oral
absorption of ACE inhibitors. Product literature specifically instructs that captopril should be taken 1 hour
before meals and that moexipril should be taken in the fasting state. Although not specifically stated,
sim ilar instructions also should benefit patients taking an ACE inhibitor whose absorption is affected by
fo o d .
The extent of protein binding also exhibits wide variability among the different compounds. The data
s u g g e s ts t h a t t h i s v a r i a t i o n h a s s o m e c o r r e l a t i o n w i t h th e c a l c u l a t e d l o g P v a l u e s f o r t h e c o m p o u n d s ( T a b l e
2 8 . 3 ) . T h r e e o f t h e m o r e l i p o p h i l i c c o m p o u n d s fo s i n o p r i l , q u i n a p r i l , a n d b e n a z e p r i l e x h i b i t p r o t e i n b i n d i n g
of greater than 90%, whereas three of the least lipophilic compoundslisinopril, enalapril, and captopril
P.750
exhibit much lower protein binding. The lack of a protein binding value for spirapril prevents a more
definitive statement on this correlation.
R e n a l e l i m i n a t i o n i s t h e p r i m a r y r o u t e o f e l i m i n a t i o n fo r m o s t A C E i n h i b i t o r s . W i t h t h e e x c e p t i o n s o f
fo s i n o p r i l a n d s p i r a p r i l , a l t e r e d r e n a l f u n c t i o n s i g n i f i c a n t l y d i m i n i s h e s t h e p l a s m a c l e a r a n c e o f A C E
inhibitors, including those that are elim inated primarily by the feces. Therefore, the dosage of most ACE
inhibitors should be reduced in patients with renal impairm ent (1). Studies of fosinopril in patients with
h e a r t f a i l u r e d e m o n s tr a t e d t h a t i t i s e l i m i n a t e d b y b o t h r e n a l a n d h e p a t i c p a t h w a y s a n d d o e s n o t r e q u i r e a
dosage reduction in patients with renal dysfunction (36 ). Spirapril also exhibits similar properties; however,
it is not currently available for use. It should be noted that the literature data for routes of elimination are
n o t a l w a y s c o n s i s t e n t . T h e d e s i g n a t i o n o f r e n a l e l i m i n a t i o n i s q u i t e c l e a r , b u t i t i s d i f f i c u l t t o c o r r e l a te w h a t
som e sources call renal/hepatic elimination with what others call renal/fecal elimination. Additionally, it is
uncertain whether the designation of fecal elimination also includes unabsorbed drug. As a result, there is
s o m e v a r i a b i l i t y f o r m a j o r r o u t e s o f e l i m i n a t i o n l i s te d i n T a b l e 2 8 . 3 .
With one exception, all ACE inhibitors have a similar onset of action, duration of action, and dosing
interval. Captopril has a more rapid onset of action; however, it also has a shorter duration and requires a
m o r e f r e q u e n t d o s i n g i n t e r v a l t h a n a n y o f t h e o t h e r c o m p o u n d s . W h e n o r a l d o s i n g i s i n a p p r o p r i a te ,
enalaprilat can be used IV. The normal dose administered to hypertensive patients is 0.625 to 1.25 mg
Pgina 17 de 51
e v e r y 6 h o u r s . T h e d o s e u s u a l l y i s a d m i n i s t e r e d o v e r 5 m i n u t e s a n d m a y b e t i tr a t e d u p to 5 m g I V e v e r y 6
hours.
Chem ical/P ha rm acologic al C lasses U se d t o Treat Hy pert ension

Diu reti c s (s ee Cha pte r 27 ), A CE in hi bi to rs, a ngi ot en si n II bl ockers, ca lci um cha nne l bl ockers
(s e e Cha pte r 28 ), c en tral 2 -ago ni s ts , p eri ph eral 1 -ant ago ni sts, -bl ockers, g an gl io ni c
bl ock ers, a nd v as od il at ors (s ee Cha pte r 29 ).
Therapeutic Applications
The ACE inhibitors have been approved for the treatment of hypertension, heart failure, left ventricular
dysfunction (either postmyocardial infarction [MI] or asymptomatic), im proved survival post-MI, diabetic
nephropathy, and reduction of the risk of MI, stroke, and death from cardiovascular causes. Although all
ACE inhibitors possess the same physiological actions and, thus, should produce similar therapeutic
e f f e c t s , t h e a p p r o v e d i n d i c a t i o n s d i f fe r a m o n g t h e c u r r e n tl y a v a i l a b l e a g e n t s ( T a b l e 2 8 . 4 ) .
P.751
In h i b i t o r s o f A C E h a v e b e e n d e s i g n a t e d a s f i r s t - l i n e a g e n t s f o r t h e t r e a t m e n t o f h y p e r t e n s i o n ( 3 7 ) a n d a r e
e f f e c t i v e f o r a v a r i e t y o f c a r d i o v a s c u l a r d i s o r d e r s . T h e y c a n b e u s e d e i t h e r i n d i v i d u a l l y o r w i th o t h e r
c l a s s e s o f c o m p o u n d s . T h e y a r e e s p e c i a l l y u s e f u l i n t r e a t i n g p a t i e n t s w i t h h y p e r t e n s i o n w h o a l s o s u ff e r
fr o m h e a r t f a i l u r e , l e f t v e n t r i c u l a r d y s f u n c t i o n , o r d i a b e t e s . A r t e r i a l a n d v e n o u s d i l a t i o n s e e n w i t h A C E
i n h i b i t o r s n o t o n l y l o w e r s b l o o d p r e s s u r e b u t a l s o h a s f a v o r a b l e e f fe c t s o n b o t h p r e l o a d a n d a f te r l o a d i n
p a t i e n ts w i t h h e a r t f a i l u r e . A d d i t i o n a l l y , t h e a b i l i t y o f A C E i n h i b i to r s t o c a u s e r e g r e s s i o n o f l e ft v e n t r i c u l a r
hypertrophy has been demonstrated to reduce the incidence of further heart disease in patients with
hypertension. The use of ACE inhibitors in patients with MI is similarly based on the ability of ACE
i n h i b i t o r s t o d e c r e a s e m o r t a l i t y b y p r e v e n t i n g p o s t i n f a r c t i o n l e f t v e n tr i c u l a r h y p e r t r o p h y a n d h e a r t f a i l u r e .
C u r r e n t r e c o m m e n d a t i o n s t o g i v e A C E i n h i b i t o r s t o a l l p a t i e n t s w i th i m p a i r e d l e f t v e n tr i c u l a r
P.752
systolic impairment regardless of the presence of observable symptoms also are based on the ability of
th e s e i n h i b i t o r s t o b l o c k t h e v a s c u l a r a n d c a r d i a c h y p e r tr o p h y a n d r e m o d e l i n g c a u s e d b y a n g i o t e n s i n I I .
In h i b i t o r s o f A C E a l s o h a v e b e e n r e p o r t e d t o s l o w t h e p r o g r e s s i o n o f d i a b e t i c n e p h r o p a th y a n d , t h u s , a r e
p r e f e r r e d a g e n t s i n t h e t r e a t m e n t o f h y p e r t e n s i o n i n a p a ti e n t s w i t h d i a b e t e s . I t a l s o h a s b e e n s u g g e s t e d
th a t A C E i n h i b i t o r s b e u s e d i n p a t i e n t s w i t h d i a b e t i c n e p h r o p a t h y r e g a r d l e s s o f th e p r e s e n c e o r a b s e n c e o r
hypertension (1,7,8,33 ).
Table 28.4. Dosing Information for Orally Available ACE Inhibitors
Trade Name Approved

Generic Name (s)
Indications
Dose
Dosing RangeMaximumReduction
(Treatment of Daily
with Renal
Hypertension)Dose
Dysfunction
Benazepril
Lotensin
Hypertension
1040 mg
q.d. or
b.i.d.
80
mg
Yes
Captopril
Capoten
Hypertension,
heart failure,
left ventricular
dysfunction
(post-MI),
diabetic
nephropathy
25150
mg b.i.d.
or t.i.d.
450
mg
Yes
Enalapril
Vasotec
Hypertension,
heart failure,
2.540
mg q.d. or
40
mg
Yes
Pgina 18 de 51
left ventricular
dysfunction
(asymptomatic)
b.i.d.
Fosinopril
Monopril
Hypertension,
heart failure
1040 mg
q.d.
80
mg
No
Lisinopril
Prinivil,
Zestril
Hypertension,
heart failure,
Improve
survival postMI
1040 mg
q.d.
40
mg
Yes
Moexipril
Univasc
Hypertension
7.530
mg q.d. or
b.i.d.
30
mg
Yes
Perindopril
Aceon
Hypertension
48 mg
q.d. or
b.i.d.
16
mg
Yes
Quinapril
Accupril
Hypertension,
heart failure
1080 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
2.520
mg q.d. or
b.i.d.
20
mg
Yes
Trandolapril
Mavik
Hypertension,
heart failure,
left ventricular
dysfunction
(post-MI)
14 mg
q.d.
8 mg
Yes
MI, myocardial infarction.
Pgina 19 de 51
Com bina tion P roduct s That Include an AC E Inhibit or

ACE I nhi bi t or/Di ure ti c : be naz e pri l/ hy dro ch lo roth i azid e, capt op ril /h yd rochl oro thi a zi de ,
ena la pri l /hy dro c hl orot hi az i de, fo s in opri l /h yd rochl oro thi azi de , l i sin opri l /hyd rochl oro thi azi de ,
moe x ip ril /h yd roc hl oro thi a zi de , a nd qu i nap ril /h ydrochl o ro th ia zi d e
ACE I nhi bi t or/Ca lc i um Ch ann el B l oc k er: be naze pri l/ aml o di pi ne , e nal a pri l/ fel od ip i ne,
tran dol ap ril /v e rapa mi l
Unlabeled U ses
Hyp ert ens i v e c ri se s , re nov a scu la r hy p erte nsio n, ne ona ta l and chi l dh ood h yp erte nsi on, stroke
prev en ti on , m ig rai ne pro phy l ax i s , n ond i abe ti c ne ph ro pa thy, chron ic ki dn ey d ise ase, di ag no si s of
sc l erod erm a re nal c ri s is , an d B art ter' s syn dro me (32 ,33 )
Pe ptide Mim etics: De sign of Agonist s/Ant agonist s

Pe pti de mi m eti c s ha v e b een d efi ne d as mo l ecul es t hat m im ic t he acti on o f p ept id es, ha ve no
pep ti de bo nds (i .e ., no am i de bon ds b etw ee n a mi no aci ds), and a mo le cu l ar we i ght of l ess th an
700 Da lt ons . In c om pari s on wi th pe pti de d ru gs, pe pti de mi m eti cs ha ve n ume rou s ph arma ce ut ical
adv a nta ges . Fore mos t am ong th es e are i ncrease d b io avai l ab il i ty a nd in cre ased d urat io n o f
ac ti on . Th e m aj ori ty o f k no wn pe pti de m im eti cs ha ve b een d iscovere d b y ran do m scree ni ng
tec hn i que s ; h owe ve r, t hi s pro ce s s is c o st ly, la bo r i nte nsi ve , a nd un pre di ct ab le .
A m ore l ogi c al a nd rati o nal a pp roac h i s de no vo pe pt id e m i met ic d esi gn (40 ), an d an exam pl e of
thi s ap pro ac h i s i l lu s trate d in Fi g ure 28. 14 . In th i s exam pl e, th e o ve ral l pro ce ss is d i vi de d in to
thre e s te ps (A C). I ni ti al ly , th e a mi no aci ds t hat com pri se t he ph arma co ph ore of the p ept id e
mus t be i den ti fi ed . Th us , a k no wl edg e of the S AR s for the pe pt id e u nd er con sid erat io n is
es se nt ia l. In Fi g ure 28. 14 A, th e si de c ha in s pre se nt on am i no aci d re si d ues 1 , 3 , a nd 5 of a
hy po the ti ca l he pta pe pti de a re a ss u med to com pri se t he ph arma co ph ore, an d the rem ai nd er o f
the pe pti d e i s a ss um ed to pro v id e t he pro per st ructu ra l supp ort fo r the se ke y grou ps. In the
se co nd s te p o f t hi s de no v o d es i gn proce ss, the p rope r spa ti al arra nge me nt of the
pha rmac o pho ric grou ps m us t b e el uc i dat ed. Nu cle ar m agn et ic re sona nce sp ectro sco py, x -ra y
di ffra ct io n s t udi es , an d m ol ecu la r mo de li ng pro gram s th at al l ow e ne rgy -mi ni mi zati on p ro cedu res
and mo l ec ul ar d y nam i cs s i mu la ti on c an be use d t o co nstruct a mod el o f t he bi ol og ica ll y act ive
co nfo rma ti on. Re turn in g t o the ex a mpl e , th e si de cha in s rep resen ti ng the p harm acop ho re a re
as su me d t o b e lo ca te d o n t he i ns id e of the p ept id e, whe rea s the rem ai ni ng resi du es a re
as su me d t o b e lo ca te d o n t he ou ts i de of the p ept id e ( Fi g . 2 8.1 4B ). In th e fi nal ste p of the
proc es s , the ph arm ac op hori c g ro up s mu st be m oun ted o n a no np ep ti de tem pl at e i n such a
man ne r tha t the y reta in t he prop er s p ati al a rrang em en t fo un d i n th e o rig in al p ept id e. Thi s i s
sh own i n Fi g ure 28. 14 C, wh ere s id e c h ai ns 1 , 3 , a nd 5 of the ori gi n al pe pti d e a re co nne cted to a
ri g id te mpl a te (re pre se nte d by th e pol y go n). A va rie ty o f a ro ma ti c rin g syste ms (e. g. , b enze ne,
bi phe ny l , p he nan thre ne , a nd be nz od ia ze pi ne ) can be use d t o p rovi de the ri gi d tem pl at e, and
app ropri at el y pl ac e d a lk y l gro up s ca n be used to en ha nce sp aci ng an d i ncre ase f le xib il i ty.
Ad di ti ona l ly , is o st eres o f t he ori gi na l ph arma coph ori c gro ups may b e used to circu mven t spe cif ic
synt he ti c prob l ems ( 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
Pgina 20 de 51
development of novel agents to

control the renin-angiotensin system.
Am J Pharm Educ 1997;61:173178;
with permission. )
Adverse Effects and Drug Interactions

T h e m o s t p r e v a l e n t o r s i g n i f i c a n t s i d e e ff e c t s o f A C E i n h i b i t o r s a r e l i s t e d b e l o w w h i l e d r u g i n t e r a c t i o n s f o r
A C E i n h i b i t o r s a r e l i s t e d i n T a b l e 2 8 . 5 ( 1 , 3 2 ,3 3 ) . S o m e a d v e r s e e f f e c t s c a n b e a t t r i b u t e d t o s p e c i f i c
fu n c t i o n a l g r o u p s w i t h i n i n d i v i d u a l a g e n t s , w h e r e a s o t h e r s c a n b e d i r e c t l y r e l a t e d t o t h e m e c h a n i s m o f
a c t i o n o f th i s c l a s s o f c o m p o u n d s . T h e h i g h e r i n c i d e n c e o f m a c u l o p a p u l a r r a s h e s a n d t a s t e d i s t u r b a n c e s
o b s e r v e d f o r c a p t o p r i l h a v e b e e n l i n k e d t o t h e p r e s e n c e o f th e s u l f h y d r y l g r o u p i n t h i s c o m p o u n d . A l l A C E
inhibitors can cause hypotension, hyperkalemia, and a dry cough. Hypotension results from an extension of
th e d e s i r e d p h y s i o l o g i c a l e ff e c t , w h e r e a s h y p e r k a l e m i a r e s u l t s f r o m a d e c r e a s e i n a l d o s t e r o n e s e c r e t i o n
s e c o n d a r y to a d e c r e a s e i n a n g i o te n s i n I I p r o d u c t i o n . C o u g h i s b y f a r t h e m o s t p r e v a l e n t a n d b o t h e r s o m e
side effect seen with the use of ACE inhibitors. It is seen in 5 to 20% of patients, usually is not dose
r e l a te d , a n d a p p a r e n t l y r e s u l t s f r o m t h e l a c k o f s e l e c t i v i t y o f t h i s c l a s s o f d r u g s . A s p r e v i o u s l y d i s c u s s e d ,
ACE inhibitors also prevent the breakdown of bradykinin (Fig. 28.3), and because bradykinin stimulates
prostaglandin synthesis, prostaglandin levels also increase. The increased levels of both bradykinin and
p r o s t a g l a n d i n h a v e b e e n p r o p o s e d t o b e r e s p o n s i b l e f o r th e c o u g h ( 3 8 ) .
T h e u s e o f A C E i n h i b i t o r s d u r i n g p r e g n a n c y i s c o n t r a i n d i c a t e d . T h i s c l a s s o f c o m p o u n d s i s n o t t e r a to g e n i c
d u r i n g t h e f i r s t t r i m e s te r , b u t a d m i n i s t r a ti o n d u r i n g t h e s e c o n d a n d t h i r d t r i m e s t e r i s a s s o c i a t e d w i t h a n
increased incidence of fetal morbidity and mortality. Inhibitors of ACE can be used in wom en of childbearing
age; however, they should be discontinued as soon as pregnancy is confirm ed.
Adve rse E f fe cts of A C E Inhibitor s

Hyp ot ens i on , h y perk al e mi a, co ug h, ras h, ta st e d i st urba nces, he ada che, di zzin ess, f ati g ue,
nau s ea, v om it in g, di arrhe a, acut e re na l fai l ure, n eut rope ni a, pro tei nu ria , a nd an gi oe de ma
Table 28.5. Drug Interactions for ACE Inhibitors

Drug
ACE
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
Pgina 21 de 51
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.
Angiotensin II Receptor Blockers

From an historical perspective, the angiotensin II receptor was the initial target for developing compounds
th a t c o u l d i n h i b i t t h e r e n i n - a n g i o t e n s i n p a t h w a y . E ff o r t s t o d e v e l o p a n g i o t e n s i n I I r e c e p to r a n t a g o n i s t s
began in the early 1970s and focused on peptide-based analogues of the natural agonist. The prototypical
com pound that resulted from these studies was saralasin, an octapeptide in which the Asp1 and Phe8
residues of angiotensin II were replaced with Sar (sarcosine, N-methylglycine) and Ile, respectively.
Saralasin as well as other peptide analogues demonstrated the ability to reduce blood pressure; however,
th e s e c o m p o u n d s l a c k e d o r a l b i o a v a i l a b i l i t y a n d e x p r e s s e d u n w a n t e d p a r t i a l a g o n i s t a c t i v i t y . M o r e r e c e n t
efforts have used peptide mim etics to circumvent these inherent problems with peptide-based antagonists.
The culmination of these efforts was the 1995 approval of losartan, a nonpeptide angiotensin II receptor
Pgina 22 de 51
b l o c k e r ( A R B ) ( 1 ,3 9 ) .
Development of Losartan
T h e d e v e l o p m e n t o f l o s a r t a n c a n b e t r a c e d b a c k t o t w o 1 9 8 2 p a t e n t p u b l i c a t i o n s ( 4 2 ) , w h i c h d e s c r i b e d th e
antihypertensive effects of a series of im idazole-5-acetic acid analogues. These compounds are exemplified
by S-8308
P.753
(Fig. 28.15 ) and were later found to block the angiotensin II receptor specifically. Although these
com pounds were relatively weak antagonists, they did not possess the unwanted agonist activity previously
s e e n i n p e p ti d e a n a l o g u e s . A c o m p u t e r i z e d m o l e c u l a r m o d e l i n g o v e r l a p o f a n g i o t e n s i n I I w i t h t h e s t r u c t u r e
of S-8308 revealed three common structural features: The ionized carboxylate of S-8308 correlated with the
C - te r m i n a l c a r b o x y l a t e o f a n g i o t e n s i n II , t h e i m i d a z o l e r i n g o f S - 8 3 0 8 c o r r e l a t e d w i t h t h e i m i d a z o l e s i d e
chain of the His6 residue, and the n-butyl group of S-8308 correlated with the hydrocarbon side chain of the
Il e 5 r e s i d u e ( F i g . 2 8 . 1 5 ) . T h e b e n z y l g r o u p o f S - 8 3 0 8 w a s p r o p o s e d t o l i e i n t h e d i r e c t i o n o f t h e N - te r m i n u s
o f a n g i o t e n s i n I I; h o w e v e r , i t w a s n o t b e l i e v e d t o h a v e a n y s i g n i f i c a n t r e c e p t o r i n t e r a c ti o n s .
View Figure
Fig. 28.15. Structural comparison of S8308, 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;45:205213; with
permission. )
F r o m S - 8 3 0 8 , a n u m b e r o f m o l e c u l a r m o d i f i c a t i o n s w e r e c a r r i e d o u t i n a n a tt e m p t t o i m p r o v e r e c e p to r
binding and lipid solubility, with the latter being important to assure adequate oral absorption. These
changes resulted in the preparation of losartan, a compound with high receptor affinity (IC50, 0.019 M) and
oral activity (Fig. 28.16).
Fig. 28.16. The development of losartan

from S-8308.
View Figure
Fig. 28.17. Structures of losartan

analogues. The highlighted portions of
candesartan cilexitil and olmesartan
Pgina 23 de 51
medoxomil are hydrolyzed via esterases

to produce their respective active,
carboxylate metabolites.
View Figure
Additional Angiotensin II Receptor Blockers

Valsartan, irbesartan, telm isartan, candesartan, and olmesartan are biphenyl analogues of losartan (Fig.
28.17). These com pounds possess structural features that are similar to those seen in losartan. Valsartan,
named for the valine portion of the compound, is the first nonimidazole-containing ARB and is slightly more
potent (IC50, 0.0089 M) than losartan. The amide carbonyl of valsartan is isosteric with the imidazole
nitrogen of losartan and can serve as a hydrogen bond acceptor similar to the im idazole nitrogen.
Ir b e s a r t a n i s a s p i r o - c o m p o u n d t h a t l a c k s th e p r i m a r y a l c o h o l o f l o s a r t a n b u t t h a t h a s a 1 0 - fo l d g r e a t e r
b i n d i n g a f f i n i t y ( I C 5 0 , 0 . 0 0 1 3 M ) f o r th e a n g i o t e n s i n I I r e c e p t o r . H y d r o g e n b o n d i n g , o r i o n d i p o l e b i n d i n g ,
of the carbonyl group can mimic the interaction of the prim ary alcohol of losartan, whereas the
s p i r o c y c l o p e n t a n e c a n p r o v i d e e n h a n c e d h y d r o p h o b i c b i n d i n g . B o th c a n d e s a r t a n c i l e x i t i l a n d t e l m i s a r t a n
contain benzim idazole rings that provide some enhanced hydrophobic binding, similar to that seen with the
spirocyclopentane ring of irbesartan. Both candesartan cilexitil and olm esartan m edoxom il are pro-drugs
th a t a r e r a p i d l y a n d c o m p l e t e l y h y d r o l y z e d d u r i n g a b s o r p t i o n f r o m t h e g a s t r o i n t e s t i n a l tr a c t t o t h e i r a c t i v e
c a r b o x y l i c a c i d m e t a b o l i te s , c a n d e s a r t a n a n d o l m e s a r t a n , r e s p e c t i v e l y . T h e s e c a r b o x y l i c a c i d s l i e i n e x a c t l y
th e s a m e l o c a t i o n s a s t h e h y d r o x y l g r o u p o f l o s a r t a n , t h e c a r b o x y l i c a c i d o f v a l s a r t a n , a n d t h e k e t o n e o f
irbesartan and can participate in both ionic and dipole interactions.
P.754
Fig. 28.18. The development of

eprosartan from S-8308. The Phe8
residue of angiotensin II contains the Cterminal carboxylic acid.
View Figure
E p r o s a r t a n w a s d e v e l o p e d u s i n g a d i f f e r e n t h y p o t h e s i s th a n t h a t f o r l o s a r t a n ( F i g . 2 8 . 1 8 ) . S i m i l a r t o t h e
r a t i o n a l e f o r l o s a r t a n , t h e c a r b o x y l i c a c i d o f S - 8 3 0 8 w a s t h o u g h t t o m i m i c t h e P h e 8 ( i . e . , C - te r m i n a l )
c a r b o x y l a te o f a n g i o t e n s i n I I . T h e b e n z y l g r o u p o f S - 8 3 0 8 w a s p r o p o s e d t o b e a n i m p o r ta n t s t r u c t u r a l
fe a t u r e t h a t m i m i c k e d t h e a r o m a t i c s i d e c h a i n o f T y r 4 p r e s e n t i n t h e a g o n i s t . T h u s , t h e m a j o r s t r u c t u r a l
change was not an extension of the N-benzyl group but, rather, an enhancem ent of the compound's ability
to m i m i c t h e C - te r m i n a l e n d o f a n g i o t e n s i n I I . T h i s w a s a c c o m p l i s h e d b y s u b s ti t u t i n g t h e 5 - a c e t i c a c i d g r o u p
w i t h a n - th i e n y l a c r y l i c a c i d . I n a d d i t i o n , a p a r a - c a r b o x y l a te ( a f u n c t i o n a l g r o u p i n v e s t i g a t e d d u r i n g t h e
d e v e l o p m e n t o f l o s a r ta n ) a l s o w a s a d d e d . T h e t h i e n y l r i n g i s o s t e r i c a l l y m i m i c s t h e P h e 8 p h e n y l r i n g o f
a n g i o t e n s i n I I a n d , a l o n g w i t h t h e p a r a - c a r b o x y l a te , i s r e s p o n s i b l e f o r t h e e x c e l l e n t p o t e n c y ( I C 5 0 = 0 . 0 0 1 5
Pgina 24 de 51
M) of this compound (39 ).
Mechanism of Action
T h e a n g i o t e n s i n I I r e c e p t o r e x i s t s i n a t l e a s t t w o s u b t y p e s , ty p e 1 ( A T 1 ) a n d t y p e 2 ( A T 2 ) . T h e A T 1
r e c e p t o r s a r e l o c a t e d i n b r a i n , n e u r o n a l , v a s c u l a r , r e n a l , h e p a t i c , a d r e n a l , a n d m y o c a r d i a l ti s s u e s a n d
m e d i a t e t h e c a r d i o v a s c u l a r , r e n a l , a n d c e n t r a l n e r v o u s s y s t e m ( C N S ) e f f e c t s o f a n g i o te n s i n I I . A l l c u r r e n t l y
a v a i l a b l e A R B s a r e 1 0 ,0 0 0 - fo l d m o r e s e l e c t i v e f o r t h e A T 1 r e c e p t o r s u b t y p e a n d a c t a s c o m p e t i ti v e
antagonists at this site. In term s of relative affinity for the AT 1 receptor, candesartan and olm esartan have
th e g r e a t e s t a f f i n i t y ; i r b e s a r t a n a n d e p r o s a r t a n h a v e a s o m e w h a t l o w e r a f f i n i t y ; a n d t e l m i s a r t a n , v a l s a r t a n ,
and losartan have the lowest affinity. All ARBs prevent and reverse all of the known effects of angiotensin
II , i n c l u d i n g r a p i d a n d s l o w p r e s s o r r e s p o n s e s , s t i m u l a t o r y e f f e c t s o n t h e p e r i p h e r a l s y m p a t h e t i c n e r v o u s
s y s t e m , C N S e f f e c t s , r e l e a s e o f c a t e c h o l a m i n e s , s e c r e t i o n o f a l d o s t e r o n e , d i r e c t a n d i n d i r e c t r e n a l e f f e c ts ,
a n d a l l g r o w t h - p r o m o t i n g e f f e c t s . T h e f u n c t i o n o f th e A T 2 r e c e p t o r s i s n o t a s w e l l c h a r a c t e r i z e d ; h o w e v e r ,
th e y h a v e b e e n p r o p o s e d t o m e d i a t e a v a r i e t y o f g r o w t h , d e v e l o p m e n t , a n d d i f f e r e n t i a t i o n p r o c e s s e s . S o m e
concern has arisen that unopposed stimulation of the AT2 receptor in conjunction with AT1 receptor
a n t a g o n i s m m a y c a u s e l o n g - te r m a d v e r s e e f f e c t s . A s a r e s u l t , c o m p o u n d s t h a t e x h i b i t b a l a n c e d a n t a g o n i s m
at both receptor subtypes are currently being sought (1,43 ).
StructureActivity Relationships
All commercially available ARBs are analogues of the following general structure:
1.
T h e a c i d i c g r o u p i s t h o u g h t t o m i m i c e i t h e r t h e T y r 4 p h e n o l o r t h e A s p 1 c a r b o x y l a t e o f a n g i o te n s i n
II . G r o u p s c a p a b l e o f s u c h a r o l e i n c l u d e t h e c a r b o x y l i c a c i d ( A ) , a p h e n y l te t r a z o l e ( B ) , o r a p h e n y l
c a r b o x y l a te ( C ) .
2.
In t h e b i p h e n y l s e r i e s , t h e t e t r a z o l e a n d c a r b o x y l a t e g r o u p s m u s t b e i n t h e o r t h o p o s i t i o n f o r o p t i m a l
activity (the tetrazole group is superior in terms of m etabolic stability, lipophilicity, and oral
bioavailability).
3.
T h e n - b u t y l g r o u p o f th e m o d e l c o m p o u n d p r o v i d e s h y d r o p h o b i c b i n d i n g a n d , m o s t l i k e l y , m i m i c s t h e
s i d e c h a i n o f I l e 5 o f a n g i o t e n s i n II . A s s e e n w i t h c a n d e s a r t a n , t e l m i s a r t a n , a n d o l m e s a r t a n , t h i s n butyl group can be replaced with either an ethyl ether or an n-propyl group.
4.
The imidazole ring or an isosteric equivalent is required to mimic the His6 side chain of angiotensin
II .
5.
Substitution can vary at the R position. A variety of R groups, including a carboxylic acid, a
h y d r o x y m e t h y l g r o u p , a k e to n e , o r a b e n z i m i d a z o l e r i n g , a r e p r e s e n t i n c u r r e n t l y a v a i l a b l e A R B s a n d
are thought to interact with the AT1 receptor through either ionic, iondipole, or dipoledipole
bonds.
A l l A R B s a r e a c i d i c d r u g s . T h e t e t r a z o l e r i n g f o u n d i n l o s a r t a n , v a l s a r ta n , i r b e s a r t a n , c a n d e s a r ta n , a n d
Pgina 25 de 51
olmesartan has a pKa of approxim ately 6 and will be at least 90% ionized at physiological pH. The
carboxylic acids found on valsartan, candesartan, olmesartan, telm isartan, and eprosartan have pKa values
in the range 3 4 and also will be primarily ionized. Currently, available agents have adequate, but not
excellent, lipid solubility. As previously mentioned, the tetrazole group is more lipophilic than a carboxylic.
Additionally, the four nitrogen atoms present in the tetrazole ring can create a greater charge distribution
th a n t h a t a v a i l a b l e f o r a c a r b o x y l i c a c i d . T h e s e p r o p e r t i e s h a v e b e e n p r o p o s e d t o b e r e s p o n s i b l e f o r th e
enhanced binding and bioavailability of the tetrazole-containing com pounds (44). Sim ilar to ACE inhibitors,
P.755
th e s t e r e o c h e m i s t r y o f v a l s a r t a n i s c o n s i s t e n t w i t h t h e L - a m i n o a c i d s i n th e n a t u r a l a g o n i s t .
Fig. 28.19. The metabolic conversion of

losartan to EXP-3174 by cytochrome
P450 isozymes.
View Figure
Metabolism
A p p r o x i m a te l y 1 4 % o f a d o s e o f l o s a r ta n i s o x i d i z e d b y t h e i s o z y m e s C Y P 2 C 9 a n d C Y P 3 A 4 t o p r o d u c e E X P 3 1 7 4 , a n o n c o m p e t i t i v e A T 1 r e c e p t o r a n t a g o n i s t t h a t i s 1 0 - to 4 0 - fo l d m o r e p o t e n t t h a n l o s a r t a n ( F i g .
28.19). The overall cardiovascular effects seen with losartan result from the combined actions of the parent
drug and the active metabolite; thus, losartan should not be considered to be a pro-drug (1). As previously
mentioned, candesartan cilexetil and olmesartan medoxomil are rapidly and completely hydrolyzed to
c a n d e s a r t a n a n d o l m e s a r t a n , r e s p e c t i v e l y , i n t h e i n te s t i n a l w a l l .
None of the other compounds are converted to active metabolites. All of these compounds are primarily
(80%) excreted unchanged. Approximately 20% of valsartan is metabolized to inactive compounds via
mechanism s that do not appear to involve the CYP450 system. The primary circulating metabolites for
i r b e s a r t a n , t e l m i s a r t a n a n d e p r o s a r t a n , a r e i n a c t i v e g l u c u r o n i d e c o n j u g a te s . A s m a l l a m o u n t o f i r b e s a r t a n i s
o x i d i z e d b y C Y P 2 C P ; h o w e v e r , i r b e s a r t a n d o e s n o t s u b s ta n t i a l l y i n d u c e o r i n h i b i t t h e C Y P 4 5 0 e n z y m e s
normally involved in drug m etabolism (1,32,33,34 ).
T h e p h a r m a c o k i n e t i c p a r a m e t e r s a n d d o s i n g i n f o r m a t i o n f o r a n g i o t e n s i n r e c e p t o r a n t a g o n i s ts a r e
s u m m a r i z e d i n T a b l e s 2 8 . 6 a n d 2 8 . 7 , r e s p e c t i v e l y ( 3 2 , 3 3 , 3 4 ) . W i t h th e e x c e p t i o n o f i r b e s a r t a n ( 6 0 8 0 % )
and, possibly, telmisartan (4258%), all of the compounds have low, but adequate, oral bioavailability (15
3 3 % ) . G i v e n t h e f a c t t h a t m o s t o f th e c o m p o u n d s a r e e x c r e t e d u n c h a n g e d , t h e m o s t p r o b a b l e r e a s o n s f o r
th e l o w b i o a v a i l a b i l i t y a r e p o o r l i p i d s o l u b i l i t y a n d i n c o m p l e t e a b s o r p t i o n . E f f e c t s o f fo o d o n t h e a b s o r p ti o n
o f l o s a r t a n , e p r o s a r ta n , v a l s a r t a n , a n d e p r o s a r t a n i s t o r e d u c e a b s o r p t i o n ; h o w e v e r , t h e s e e f f e c t s h a v e
b e e n d e e m e d t o b e c l i n i c a l l y i n s i g n i f i c a n t ; t h u s , t h e c o m p o u n d s c a n b e t a k e n e i t h e r w i t h o r w i t h o u t fo o d . A l l
of the compounds have sim ilar onsets, are highly protein bound, have elim ination half-lives that allow onceo r t w i c e - d a i l y d o s i n g , a n d w i t h t h e e x c e p t i o n o f o l m e s a r ta n , a r e p r i m a r i l y e l i m i n a t e d v i a t h e f e c a l r o u t e .
Candesartan and telmisartan appear to require a slightly longer time to reach peak plasma concentrations.
A s w i t h A C E i n h i b i t o r s , l i t e r a t u r e d e s i g n a t i o n o f f e c a l e l i m i n a t i o n i s u n c l e a r r e g a r d i n g w h e th e r i t i n c l u d e s
unabsorbed drug.
C a n d e s a r t a n c i l e x e t i l , l o s a r t a n , a n d o l m e s a r t a n d i f f e r f r o m t h e o th e r c o m p o u n d s i n s e v e r a l r e s p e c t s . T h e y
a r e t h e o n l y c o m p o u n d s w i t h a c t i v e m e t a b o l i t e s , a n d th e y h a v e t h e h i g h e s t r e n a l e l i m i n a t i o n o f a l l o f t h e
agents. Product labeling indicates that renal impairment does not require a dosage reduction for losartan,
but area under the curve values are increased by 50% in patients with
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a creatinine clearance of less than 30 mL/min and are doubled in hemodialysis patients. These increases
Pgina 26 de 51
a r e n o t s e e n f o r t h e o t h e r a g e n t s . L o s a r t a n a n d te l m i s a r t a n a r e t h e o n l y t w o a g e n t s t h a t r e q u i r e i n i t i a l d o s e
reductions in patients with hepatic im pairment. Because of significantly increased plasma concentration,
p a t i e n ts w i t h i m p a i r e d h e p a t i c fu n c t i o n o r b i l i a r y o b s t r u c t i v e d i s o r d e r s s h o u l d a v o i d th e u s e o f te l m i s a r t a n .
Table 28.6. Pharmacokinetic Parameters of Angiotensin II Receptor Blockers
Drug
Oral
BioavailabilityActive
(%)
Metabolite
Time to Peak
Plasma
Elimination
Protein
ConcentrationHalf
Binding (%) (hours)
(hours)
Candesartan
Cilexetil
15
Candesartan
99
34
Eprosartan
15
None
98
12
Irbesartan
6080
None
90
1.52.0
11
Losartan
33
EXP-3174
98.7
(losartan)
99.8
(EXP3174)
1
(losartan)
34 (EXP3174)
1.5
(losartan)
6
(EXP
3174)
Olmesartan
Medoxomil
26
Olmesartan
99
1.53.0
10
Telmisartan
4258
None
100
24
Valsartan
25
None
95
24
Pgina 27 de 51
Table 28.7. Dosing Information for Angiotensin II Receptor Blockers
Trade
Generic Name Name(s)
Approved
Indications
Initial Dose
Reduction
Dosing RangeMaximumwith
(Treatment of Daily
Hepatic
Hypertension)Dose
Dysfunction
Candesartan
Cilexetil
Atacand
Hypertension,
heart failure
832 mg
q.d.
32
mg
No
Eprosartan
Teveten
Hypertension
400800
mg q.d. or
b.i.d.
900
mg
No
Irbesartan
Avapro
Hypertension,
nephropathy
in type II
diabetics
150300
mg q.d.
300
mg
No
Losartan
Cozaar
Hypertension,
nephropathy
in type II
diabetics,
hypertension
with left
ventricular
hypertrophy
25100
mg q.d. or
b.i.d.
100
mg
Yes
Olmesartan
Medoxomil
Benicar
Hypertension
2040 mg
q.d.
40
mg
No
Telmisartan
Micardis
Hypertension
4080 mg
q.d.
80
mg
Yes
(avoid)
Valsartan
Diovan
Hypertension
heart failure
80320
q.d.
320
mg
No
All ARBs are currently approved for the treatment of hypertension and, along with ACE inhibitors, diuretics,
-blockers, and calcium channel blockers, have been designated as first-line agents either alone or in
Pgina 28 de 51
com bination with other antihypertensive agents (37). All ARBs are available as single agents and as
com bination products with hydrochlorthiazide. Additionally, irbesartan and losartan have been approved for
th e t r e a t m e n t o f n e p h r o p a t h y i n t y p e II d i a b e t e s , l o s a r t a n f o r t h e t r e a t m e n t o f h y p e r t e n s i o n w i t h l e f t
v e n t r i c u l a r h y p e r t r o p h y , a n d c a n d e s a r t a n a n d v a l s a r ta n f o r t h e t r e a t m e n t o f h e a r t f a i l u r e . B a s e d o n t h e i r
a b i l i ty t o a t t e n u a t e th e r e n i n - a n g i o t e n s i n s y s t e m , o n e s h o u l d e x p e c t a g r a d u a l i n c r e a s e i n t h e n u m b e r o f
uses and approved indications for this class of agents.
Adverse Effects
T h e m o s t p r e v a l e n t s i d e e f f e c t s o f A R B s a r e l i s t e d a b o v e a n d d i s c u s s e d b e l o w . ( 1 ,3 2 , 3 3 , 3 4 ) . O v e r a l l , t h i s
c l a s s o f a g e n t s i s w e l l to l e r a t e d , w i t h C N S e f f e c t s b e i n g t h e m o s t c o m m o n l y r e p o r t e d c o m p l a i n t . S i m i l a r t o
A C E i n h i b i t o r s , s o m e o f t h e a d v e r s e e f f e c t s a r e d i r e c t l y r e l a t e d t o a t te n u a t i o n o f t h e r e n i n - a n g i o t e n s i n
p a t h w a y . N o t a b l y a b s e n t a r e t h e d r y c o u g h a n d a n g i o e d e m a s e e n w i t h A C E i n h i b i to r s . B e c a u s e A R B s a r e
s p e c i f i c i n t h e i r a c t i o n s , t h i s c l a s s o f d r u g s d o e s n o t a f f e c t t h e l e v e l s o f b r a d y k i n i n o r p r o s ta g l a n d i n s a n d ,
th u s , d o e s n o t c a u s e t h e s e b o t h e r s o m e s i d e e f f e c t s . L i k e A C E i n h i b i t o r s , th e u s e o f A R B s d u r i n g p r e g n a n c y
is contraindicated, especially during the second and third trimesters. The use of ARBs should be
discontinued as soon as pregnancy is confirm ed unless the benefits outweigh the potential risks.
Adve rse E f fe cts of A ngiote nsin II R ec eptor Ant agonist s

Hea dac h e, di zz i ne s s, fa ti gue , hy po ten si o n, hype rka le mi a, dyspe psi a, di arrhe a, ab dom i nal p ai n,
upp er re sp i ra to ry trac t in fec t io n, my al gi a, b ack pa in , p ha ryn gi ti s, a nd rhi ni ti s
Drug Interactions
C o a d m i n i s t r a t i o n o f A R B s w i t h p o t a s s i u m s a l t s , p o ta s s i u m - s p a r i n g d i u r e t i c s , o r d r o s p i r e n o n e m a y c a u s e
hyperkalemia. Nonsteroidal anti-inflammatory drugs may alter the response to ARBs and other
antihypertensive agents (including ACE inhibitors and calcium channel blockers) because of inhibition of
vasodilatory prostaglandins. Studies have shown that indom ethacin, naproxen, and piroxicam have a
greater propensity for causing this interaction. Telmisartan has been reported to increase digoxin levels
a n d t o s l i g h t l y d e c r e a s e w a r f a r i n l e v e l s ; h o w e v e r , t h e r e d u c e d w a r fa r i n l e v e l s w e r e n o t s u f f i c i e n t t o a l t e r
th e i n t e r n a t i o n a l n o r m a l i z e d r a ti o . R i f a m p i n , b e c a u s e o f i t s a b i l i t y t o i n d u c e C Y P 3 A 4 , c a n d e c r e a s e t h e
p l a s m a l e v e l s o f l o s a r t a n a n d i ts a c t i v e m e t a b o l i t e , E X P - 3 1 7 4 . T h e c l i n i c a l s i g n i f i c a n c e o f d r u g i n t e r a c t i o n s
P.757
b e t w e e n A R B s a n d c o m p o u n d s t h a t c a n i n h i b i t e i t h e r C Y P 3 A 4 o r C Y P 2 C 9 h a s y e t to b e e s t a b l i s h e d .
Role of Calcium and Calcium Channels in Vascular Smooth Muscle

Contraction
Calcium is a key component of the excitation-contraction coupling process that occurs within the
cardiovascular system. It acts as a cellular m essenger to link internal or external excitation with cellular
response. Increased cytosolic concentrations of Ca2+ result in the binding of Ca2+ to a regulatory protein,
either troponin C in cardiac and skeletal muscle or calmodulin in vascular smooth muscle. This initial
binding of Ca2+ uncovers myosin binding sites on the actin m olecule, and subsequent interactions between
a c t i n a n d m y o s i n r e s u l t i n m u s c l e c o n t r a c t i o n . A l l o f th e s e e v e n t s a r e r e v e r s e d o n c e th e c y t o s o l i c
c o n c e n tr a t i o n o f C a 2 + d e c r e a s e s . I n t h i s s i t u a t i o n , C a 2 + b i n d i n g t o t r o p o n i n C o r c a l m o d u l i n i s d i m i n i s h e d o r
rem oved, myosin binding sites are concealed, actin and myosin can no longer interact, and m uscle
contraction ceases (45,46).
Mechanisms of Calcium Movement and Storage

The regulation of cytosolic calcium levels occurs via specific influx, efflux, and sequestering mechanism s
( F i g . 2 8 . 2 0 ) . T h e i n f l u x o f c a l c i u m c a n o c c u r t h r o u g h r e c e p t o r - o p e r a t e d c h a n n e l s ( s i te 1 ) , t h e N a + /C a 2 +
e x c h a n g e p r o c e s s ( s i te 2 ) , l e a k p a t h w a y s ( s i t e 3 ) , a n d p o t e n t i a l - d e p e n d e n t c h a n n e l s ( s i te 4 ) . I n f l u x v i a
e i t h e r r e c e p t o r - o p e r a t e d o r v o l ta g e - d e p e n d e n t c h a n n e l s h a s b e e n p r o p o s e d t o b e t h e m a j o r e n t r y p a t h w a y
fo r C a 2 + . R e c e p t o r - o p e r a t e d c h a n n e l s h a v e b e e n d e f i n e d a s t h o s e a s s o c i a te d w i t h c e l l u l a r m e m b r a n e
receptors and activated by specific agonistreceptor interactions. In contrast, potential-dependent
c h a n n e l s , a l s o k n o w n a s v o l ta g e - d e p e n d e n t o r v o l t a g e - g a t e d c a l c i u m c h a n n e l s , h a v e b e e n d e f i n e d a s t h o s e
a c t i v a t e d b y m e m b r a n e d e p o l a r i z a t i o n . T h e N a + /C a 2 + e x c h a n g e p r o c e s s c a n p r o m o t e e i t h e r i n f l u x o r e f f l u x ,
b e c a u s e t h e d i r e c t i o n o f C a 2 + m o v e m e n t d e p e n d s o n th e r e l a t i v e i n t r a c e l l u l a r a n d e x t r a c e l l u l a r r a t i o s o f
Na+ and Ca2+. The leak pathways, which include unstim ulated Ca2+ entry as well as entry during the fast
i n w a r d N a + p h a s e o f a n a c t i o n p o te n t i a l , p l a y o n l y a m i n o r r o l e i n c a l c i u m i n fl u x .
Pgina 29 de 51
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.
View Figure
E f f l u x c a n o c c u r t h r o u g h e i t h e r a n A T P - d r i v e n m e m b r a n e p u m p ( s i t e 5 ) o r v i a th e N a + /C a 2 + e x c h a n g e
p r o c e s s p r e v i o u s l y m e n t i o n e d ( s i t e 2 ) . In a d d i t i o n t o t h e s e i n f l u x a n d e ff l u x m e c h a n i s m s , t h e s a r c o p l a s m i c
r e t i c u l u m ( s i t e 6 ) a n d t h e m i t o c h o n d r i a ( s i t e 7 ) f u n c ti o n a s i n t e r n a l s t o r a g e / r e l e a s e s i t e s . T h e s e s t o r a g e
sites work in concert with the influx and efflux processes to assure that cytosolic calcium levels are
appropriate for cellular needs. Although influx and release processes are essential for excitation
c o n t r a c t i o n c o u p l i n g , e f f l u x a n d s e q u e s t e r i n g p r o c e s s e s a r e e q u a l l y i m p o r ta n t fo r t e r m i n a t i n g t h e c o n t r a c t i l e
process and for protecting the cell from the deleterious effects of Ca2+ overload (47 ,48).
Potential-Dependent Calcium Channels

The pharmacological class of agents known as calcium channel blockers produces their effects through
i n t e r a c t i o n w i t h p o t e n t i a l - d e p e n d e n t c h a n n e l s . T o d a t e , s i x fu n c t i o n a l s u b c l a s s e s , o r t y p e s , o f p o t e n t i a l d e p e n d e n t C a 2 + c h a n n e l s h a v e b e e n i d e n ti f i e d : T , L , N , P , Q , a n d R . T h e s e t y p e s d i f f e r i n l o c a t i o n a n d
fu n c t i o n a n d c a n b e d i v i d e d i n t o tw o m a j o r g r o u p s : l o w - v o l t a g e a c ti v a t e d ( L V A ) c h a n n e l s , a n d h i g h - v o l t a g e
a c t i v a t e d ( H V A ) c h a n n e l s . O f t h e s i x t y p e s , o n l y t h e T ( t r a n s i e n t, t i n y ) c h a n n e l c a n b e r a p i d l y a c t i v a t e d a n d
inactivated with small changes in the cell membrane potential. It is thus designated as an LVA channel. All
of the other types of channels require a larger depolarization and are thus designated as HVA channels.
T h e L ( l o n g - l a s t i n g , l a r g e ) c h a n n e l i s t h e s i t e o f a c t i o n fo r c u r r e n t l y a v a i l a b l e c a l c i u m c h a n n e l b l o c k e r s a n d ,
th e r e fo r e , h a s b e e n e x t e n s i v e l y s t u d i e d . I t i s l o c a t e d i n s k e l e ta l , c a r d i a c , a n d s m o o t h m u s c l e a n d , t h u s , i s
highly involved in organ and vessel contraction within the cardiovascular system. The N channel is found in
n e u r o n a l t i s s u e a n d e x h i b i t s k i n e t i c s a n d i n h i b i t o r y s e n s i t i v i ty d i s t i n c t f r o m b o th L a n d T c h a n n e l s . T h e
fu n c t i o n s , s e n s i t i v i ti e s , a n d p r o p e r t i e s o f t h e o t h e r t h r e e t y p e s o f c h a n n e l s a r e n o t a s w e l l k n o w n . T h e P
channel has been nam ed for its presence in the Purkinje cells, whereas the Q and R channels have been
characterized by their abilities to bind to certain polypeptide toxins (49,50,51).
The L channel is a pentameric com plex consisting of 1, 2, , , and polypeptides (see Fig. II.12). The
1 subunit is a transmem brane-spanning protein that consists of four domains and that functions as the
p o r e - fo r m i n g s u b u n i t . T h e 1 s u b u n i t a l s o c o n t a i n s b i n d i n g s i t e s f o r a l l t h e
P.758
currently available calcium channel blockers. The other four subunits surround the 1 portion of the channel
a n d c o n t r i b u t e t o t h e o v e r a l l h y d r o p h o b i c i ty o f t h e p e n t a m e r . T h i s h y d r o p h o b i c i t y i s i m p o r t a n t i n t h a t i t
allows the channel to be embedded in the cell membrane. Additionally, the 2, , and subunits modulate
th e 1 s u b u n i t . O t h e r t y p e s o f p o t e n t i a l - d e p e n d e n t c h a n n e l s a r e s i m i l a r t o t h e L c h a n n e l . T h e y a l l h a v e a
central 1 subunit; however, molecular cloning studies have revealed that there are at least six 1 genes:
1S, 1A, 1B, 1C, 1D, and 1E. Three of these genes, 1S, 1C, and 1D, have been associated with L
channels. The L channels found in skeletal muscle result from the 1S gene; those in the heart, aorta, lung,
a n d f i b r o b l a s t r e s u l t f r o m t h e 1 C g e n e ; a n d th o s e i n e n d o c r i n e t i s s u e r e s u l t f r o m t h e 1 D g e n e . B o t h 1 C
and 1D are used for L channels in the brain. Thus, there are some differences among the L channels
l o c a t e d i n d i f f e r e n t o r g a n s a n d ti s s u e s . A d d i t i o n a l l y , d i f f e r e n c e s i n 1 g e n e s a s w e l l a s d i f f e r e n c e s a m o n g
th e o t h e r s u b u n i t s a r e r e s p o n s i b l e f o r t h e v a r i a t i o n s s e e n a m o n g t h e o t h e r f i v e t y p e s o f p o t e n ti a l - d e p e n d e n t
channels. As an example, the N channel lacks the subunit and contains an 1 subunit derived from the
1B gene (49,51 ).
Cardiovascular Disorders Associated With Potential-Dependent Calcium

Channels
As described above, the movement of calcium underlies the basic excitationcontraction coupling process.
T h u s , v a s c u l a r t o n e a n d c o n t r a c t i o n p r i m a r i l y a r e d e t e r m i n e d b y th e a v a i l a b i l i t y o f c a l c i u m f r o m
Pgina 30 de 51
extracellular or intracellular sources. Potential-dependent Ca2+ channels are important in regulating the
influx of Ca2+; therefore, inhibition of Ca2+ flow through these channels results in both vasodilation and
d e c r e a s e d c e l l u l a r r e s p o n s e t o c o n t r a c t i l e s t i m u l i . A r te r i a l s m o o t h m u s c l e i s m o r e s e n s i t i v e t o t h i s a c t i o n
th a n v e n o u s s m o o t h m u s c l e . A d d i t i o n a l l y , c o r o n a r y a n d c e r e b r a l a r t e r i a l v e s s e l s a r e m o r e s e n s i t i v e t h a n
other arterial beds (48,51). As a result of these actions, calcium channel blockers are useful in the
tr e a t m e n t o f h y p e r t e n s i o n a n d i s c h e m i c h e a r t d i s e a s e . A b r i e f o v e r v i e w o f h y p e r t e n s i o n i s p r o v i d e d i n th e
renin-angiotensin section of this chapter.
The term ischemic heart disease, encompasses a variety of syndrom es. These include angina pectoris,
s i l e n t m y o c a r d i a l i s c h e m i a , a c u t e c o r o n a r y i n s u f f i c i e n c y , a n d M I. T h e o v e r a l l i n c i d e n c e o f i s c h e m i c h e a r t
d i s e a s e i s h i g h e r i n m e n th a n i n w o m e n a n d i n c r e a s e s w i t h a g e . M y o c a r d i a l i n f a r c t i o n i s t h e p r i m a r y i n i t i a l
event in men, whereas angina is the most common initial presentation in wom en. The average annual
i n c i d e n c e r a t e ( i . e . , n u m b e r o f n e w c a s e s /p o p u l a t i o n ) o f a n g i n a p e c t o r i s i s 1 . 5 % a n d d e p e n d s o n th e
p a t i e n t' s a g e , g e n d e r , a n d r i s k - fa c t o r p r o f i l e . A 1 9 9 8 e s ti m a t e f r o m t h e A m e r i c a n H e a r t A s s o c i a ti o n p l a c e s
th e p r e v a l e n c e o f a n g i n a a t a p p r o x i m a t e l y 6 .4 m i l l i o n ( 5 2 ) .
Angina pectoris is a clinical manifestation that results from coronary atherosclerotic heart disease. It is
c h a r a c t e r i z e d b y a s e v e r e c o n s tr i c ti n g p a i n i n t h e c h e s t t h a t o f t e n r a d i a t e s to t h e l e f t s h o u l d e r , t h e l e f t a r m ,
o r t h e b a c k . C l i n i c a l l y , a n g i n a p e c t o r i s c a n b e c l a s s i f i e d a s e i t h e r e x e r t i o n a l , v a r i a n t, o r u n s ta b l e .
Exertional angina, otherwise known as stable angina or exercise-induced angina, is the most common form
and results from an im balance between myocardial oxygen supply and dem and. Variant angina, otherwise
k n o w n a s P r i n z m e t a l ' s a n g i n a , r e s u l t s f r o m t h e v a s o s p a s m o f l a r g e , s u r fa c e c o r o n a r y v e s s e l s o r b r a n c h e s .
Unstable angina is the most difficult to treat and may occur as a result of advanced atherosclerosis and
coronary vasospasm (53 ).
Excitationcontraction coupling in the heart is different from that in vascular smooth muscle in that a
portion of the inward current is carried by Na+ through the fast channel. In the sinoatrial and
atrioventricular (AV) nodes, however, depolarization depends prim arily on the movement of Ca2+ through
th e s l o w c h a n n e l . A t t e n u a t i o n o f t h i s C a 2 + m o v e m e n t p r o d u c e s a n e g a t i v e i n o t r o p i c e f f e c t a n d d e c r e a s e d
c o n d u c ti o n t h r o u g h t h e A V n o d e . T h i s l a t t e r e f f e c t i s e s p e c i a l l y u s e f u l i n t r e a ti n g p a r o x y s m a l
supraventricular tachycardia (PSVT), an arrhythmia prim arily caused by AV nodal reentry and AV reentry
(51).
Calcium Channel Blockers

Historical Overview
Id e n t i f i c a t i o n o f c o m p o u n d s t h a t c o u l d b l o c k t h e i n w a r d m o v e m e n t o f C a 2 + t h r o u g h s l o w c a r d i a c c h a n n e l s
occurred in the early 1960s. Verapamil and other phenylalkylam ines were shown to possess negative
inotropic and chronotropic effects that were distinct from other coronary vasodilators. Further investigations
r e v e a l e d t h a t t h e s e a g e n t s m i m i c k e d th e c a r d i a c e f f e c t s o f C a 2 + w i t h d r a w a l : t h e y r e d u c e d c o n t r a c t i l e f o r c e
without affecting the action potential. The effects of these compounds could be reversed by the addition of
Ca2+, thus suggesting that the negative inotropic effect was linked to an inhibition of excitationcontraction
coupling. Subsequently, derivatives of verapam il, as well as other chemical classes of com pounds, were
s h o w n t o c o m p e t i t i v e l y b l o c k C a 2 + m o v e m e n t t h r o u g h t h e s l o w c h a n n e l a n d , t h u s , a l t e r th e c a r d i a c a c t i o n
p o t e n t i a l . T h e r e fo r e , c a l c i u m c h a n n e l b l o c k e r s a l s o a r e k n o w n a s s l o w c h a n n e l b l o c k e r s , c a l c i u m e n t r y
blockers, and calcium antagonists (47,51).
Chemical Classifications
Overview
Currently, nine calcium channel blockers are available for therapeutic use. These compounds have diverse
c h e m i c a l s t r u c t u r e s a n d c a n b e g r o u p e d i n to o n e o f f o u r c h e m i c a l
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classifications (Fig. 28.21 ), each of which produces a distinct pharmacological profile: 1,4-dihydropyridines
( 1 , 4 - D H P s ; e . g . , n i f e d i p i n e ) , p h e n y l a l k y l a m i n e s ( e . g . , v e r a p a m i l ) , b e n z o t h i a z e p i n e s ( e .g . , d i l t i a z e m ) , a n d
d i a m i n o p r o p a n o l e th e r s ( e . g . , b e p r i d i l ) . T h e m a j o r i t y o f c a l c i u m c h a n n e l b l o c k e r s a r e 1 , 4 - D H P s , a n d a
detailed description of the SAR for this chemical class is provided below. In contrast, verapam il, diltiazem ,
a n d b e p r i d i l a r e t h e l o n e r e p r e s e n t a t i v e s o f t h e i r r e s p e c ti v e c h e m i c a l c l a s s e s a n d , t h u s , a r e d i s c u s s e d a s
individual agents. Verapamil and diltiazem are discussed along with the 1,4-DHPs. Bepridil is a
nonselective agent that is no longer available in the United States.
Pgina 31 de 51
Fig. 28.21. Chemical classes of calcium

channel blockers.
View Figure
1,4-Dihydropyridines
History and development
The chemistry of dihydropyridines can be traced back to an 1882 paper in which Hantzsch described their
utility as intermediates in the synthesis of substituted pyridines. Fifty years later, interest in this chem ical
c l a s s o f c o m p o u n d s i n c r e a s e d w h e n i t w a s d i s c o v e r e d t h a t a 1 , 4 - D H P r i n g w a s r e s p o n s i b l e f o r th e
h y d r o g e n - tr a n s f e r p r o p e r t i e s o f t h e c o e n z y m e N A D H . N u m e r o u s b i o c h e m i c a l s t u d i e s f o l l o w e d t h i s
discovery; however, it was not until the early 1970s that the pharmacological properties of 1,4-DHPs were
fu l l y i n v e s t i g a te d . L o e v a n d c o w o r k e r s a t S m i th , K l e i n & F r e n c h l a b o r a t o r i e s i n v e s t i g a t e d t h e a c t i v i t i e s o f
H a n t z s c h - ty p e c o m p o u n d s . A s s h o w n i n F i g u r e 2 8 . 2 2 , t h e H a n t z s c h r e a c t i o n p r o d u c e d a s y m m e t r i c a l
c o m p o u n d i n w h i c h b o t h t h e e s t e r s ( i . e . , C O 2 R 2 ) a n d t h e C 2 a n d C 6 s u b s t i t u e n t s ( i . e . , C H 3 ) a r e i d e n ti c a l
w i t h e a c h o t h e r . S t r u c t u r a l r e q u i r e m e n t s n e c e s s a r y f o r a c t i v i t y w e r e i d e n ti f i e d b y s e q u e n t i a l l y m o d i f y i n g t h e
C4 substituent (i.e., the R1 group), the C 3- and C5-esters (i.e., the R2 groups), the C2- and C 6-alkyl groups,
and the N1 -H substituent (54 ,55,56,57).
Be pri di l is u ni qu e a mo ng al l th e c a lc i um chan ne l bl ockers i n tha t i ts a cti ons are not ba sed sol el y
on it s ab il i ty to bl o ck p ot ent ia l -dep en den t L -type (i. e., slo w) C a 2 + chan ne ls ( 32 ,51 ). Un li ke oth er
ca lc i um c ha nne l bl oc k ers , bep rid i l al so b lo cks f ast N a + chan ne ls a s we ll a s recep tor -ope rate d
ca lc i um c ha nne l s. The se a ddi ti o nal a c ti ons a re re spon sib le fo r be pri di l 's a bi l it y to in hi bi t ca rdi ac
co nd uc ti on , to s l ow AV n oda l c ond uc ti on , t o i n cre ase the ref ractory p eri od , t o sl ow th e h eart
ra te , a nd to prol o ng the QT i nt erv al .
Be pri di l was i nd i ca ted f or th e oral t reat men t of ch roni c sta bl e ang i na pect ori s; ho weve r, i ts
man ufa c ture r v ol un tari l y remo v ed it fro m t he U.S . ma rke t, pri mari l y be ca use of it s ab il i ty to
ca us e tors ad es d e p oi nt es . It a l so s ho ul d b e not ed th at bep rid i l was n ever hi ghl y p rescri be d,
mos t li k el y b ec au se of th e si gn if ic a nt nu mbe r of card io va scu la r wa rni ng s and con trai n di ca ti on s
as so c ia ted wi th i ts u se .
Pgina 32 de 51
Fig. 28.22. Synthesis of 1,4-DHPs using

the Hantzsch reaction.
View Figure
Structureactivity relationships
The SARs for 1,4-DHP derivatives (see General Structure in Table 28.8) indicates that the following
structural features are im portant for activity:
Table 28.8. Structure of the

Dihydropyridine Ca2+ Channel
Blockers
View Table
P.760
1.
A s u b s t i t u te d p h e n y l r i n g a t t h e C 4 p o s i ti o n o p t i m i z e s a c t i v i t y ( h e t e r o a r o m a t i c r i n g s , s u c h a s
pyridine, produce similar therapeutic effects but are not used because of observed anim al toxicity),
and C4 substitution with a sm all nonplanar alkyl or cycloalkyl group decreases activity.
2.
Phenyl ring substitution (X) is important for size and position rather than for electronic nature.
Compounds with ortho or meta substitutions possess optimal activity, whereas those that are
u n s u b s ti t u te d o r t h a t c o n t a i n a p a r a - s u b s t i t u t i o n s h o w a s i g n i f i c a n t d e c r e a s e i n a c t i v i t y . D e s p i t e t h e
fa c t t h a t a l l c o m m e r c i a l l y a v a i l a b l e 1 , 4 - D H P s h a v e e l e c t r o n - w i t h d r a w i n g o r t h o a n d / o r m e t a
s u b s t i t u e n ts , t h i s i s n o t a n a b s o l u t e r e q u i r e m e n t . C o m p o u n d s w i t h e l e c t r o n - d o n a t i n g g r o u p s a t t h e s e
s a m e p o s i t i o n s a l s o h a v e d e m o n s t r a t e d g o o d a c t i v i t y . T h e i m p o r t a n c e o f t h e o r th o a n d m e t a
s u b s t i t u e n ts i s t o p r o v i d e s u f f i c i e n t b u l k t o l o c k th e c o n f o r m a t i o n o f t h e 1 , 4 - D H P s u c h th a t t h e C 4
a r o m a t i c r i n g i s p e r p e n d i c u l a r t o th e 1 , 4 - D H P r i n g ( F i g . 2 8 . 2 3 ) . T h i s p e r p e n d i c u l a r c o n f o r m a t i o n h a s
been proposed to be essential for the activity of the 1,4-DHPs.
3.
T h e 1 , 4 - D H P r i n g i s e s s e n t i a l f o r a c t i v i t y . S u b s t i t u ti o n a t t h e N 1 p o s i ti o n o r t h e u s e o f o x i d i z e d
(piperidine) or reduced (pyridine) ring systems greatly decreases or abolishes activity.
4.
E s t e r g r o u p s a t t h e C 3 a n d C 5 p o s i ti o n s o p t i m i z e a c t i v i t y . O t h e r e l e c t r o n - w i t h d r a w i n g g r o u p s s h o w
d e c r e a s e d a n t a g o n i s t a c t i v i ty a n d m a y e v e n s h o w a g o n i s t a c ti v i t y . F o r e x a m p l e , t h e r e p l a c e m e n t o f
th e C 3 e s t e r o f i s r a d i p i n e w i t h a N O 2 g r o u p p r o d u c e s a c a l c i u m c h a n n e l a c t i v a t o r , o r a g o n i s t ( F i g .
28.24). Thus, the term calcium channel m odulators is a more appropriate classification for the 1,4DHPs.
Pgina 33 de 51
5.
When the esters at C3 and C5 are nonidentical, the C4 carbon becom es chiral, and stereoselectivity
b e t w e e n t h e e n a n t i o m e r s i s o b s e r v e d . A d d i t i o n a l l y , e v i d e n c e s u g g e s t s th a t t h e C 3 a n d C 5 p o s i ti o n s
o f t h e d i h y d r o p y r i d i n e r i n g a r e n o t e q u i v a l e n t p o s i t i o n s . C r y s ta l s t r u c t u r e s o f n i f e d i p i n e , a
s y m m e t r i c a l 1 , 4 - D H P , h a v e s h o w n t h a t th e C 3 c a r b o n y l i s s y n p l a n a r t o t h e C 2 - C 3 b o n d b u t t h a t t h e
C5 carbonyl is antiperiplanar to the C5-C6 bond (Fig. 28.25). Asym metrical com pounds have shown
enhanced selectivity for specific blood vessels and are being preferentially developed. Nifedipine,
th e f i r s t 1 , 4 - D H P t o b e m a r k e t e d , i s t h e o n l y s y m m e t r i c a l c o m p o u n d i n t h i s c h e m i c a l c l a s s .
6.
With the exception of amlodipine, all 1,4-DHPs have C 2 and C6 m ethyl groups. The enhanced
p o t e n c y o f a m l o d i p i n e ( v s . n i f e d i p i n e ) s u g g e s t s t h a t t h e 1 ,4 - D H P r e c e p t o r c a n t o l e r a t e l a r g e r
s u b s t i t u e n ts a t t h i s p o s i ti o n a n d t h a t e n h a n c e d a c ti v i t y c a n b e o b t a i n e d b y a l t e r i n g t h e s e g r o u p s .
Mechanism of Action
Despite the name, calcium channel blockers do not simply plug the hole and physically block the Ca2+
c h a n n e l . I n s t e a d , t h e y e x e r t t h e i r e f f e c t s b y b i n d i n g t o s p e c i f i c r e c e p t o r s i te s l o c a t e d w i t h i n t h e c e n t r a l 1
s u b u n i t o f L - ty p e , p o t e n t i a l - d e p e n d e n t c h a n n e l s . T h r e e
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distinct, but allosterically interacting, receptors have been identified for verapamil, diltiazem, and the 1,4D H P s . A s s h o w n i n T a b l e 2 8 . 9 , t h e b i n d i n g o f v e r a p a m i l t o i ts r e c e p t o r i n h i b i t s t h e b i n d i n g o f b o t h d i l t i a z e m
and the 1,4-DHPs to their respective receptors. Likewise, the binding of either diltiazem or the 1,4 -DHPs
i n h i b i t s t h e b i n d i n g o f v e r a p a m i l . I n c o n t r a s t , d i l t i a z e m a n d t h e 1 ,4 - D H P s m u t u a l l y e n h a n c e t h e b i n d i n g o f
each other (54).
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.
View Figure
Potential-dependent channels can exist in one of three conformations: a resting state, which can be
s t i m u l a t e d b y m e m b r a n e d e p o l a r i z a t i o n ; a n o p e n s t a t e , w h i c h a l l o w s th e C a 2 + t o e n t e r ; a n d a n i n a c t i v e
state, which is refractory to further depolarization. Calcium channel blockers have been shown to be more
Pgina 34 de 51
effective when mem brane depolarization is either longer, more intense, or m ore frequent. This usedependency suggests that these compounds preferentially interact with their receptors when the Ca2+
c h a n n e l i s i n e i th e r t h e o p e n o r i n a c t i v e s t a t e . T h i s s t a t e d e p e n d e n c e i s n o t i d e n t i c a l f o r a l l c l a s s e s o f C a 2 +
b l o c k e r s a n d , i n c o m b i n a t i o n w i t h t h e d i f f e r e n t b i n d i n g s i t e s , a l l o s t e r i c i n t e r a c ti o n s , a c i d i t y , a n d s o l u b i l i t y ,
may be responsible for the pharmacological
P.762
differences am ong verapam il, diltiazem , and the 1,4-DHPs. A summ ary of these differences is listed in
Table 28.10. The 1,4-DHPs, as exem plified by nifedipine, are primarily vasodilators, whereas verapamil and
d i l t i a z e m h a v e b o t h v a s o d i l a t o r a n d c a r d i o d e p r e s s a n t a c t i o n s . T h e i n c r e a s e d h e a r t r a t e s e e n w i t h n i fe d i p i n e
r e s u l t s f r o m a r e f l e x m e c h a n i s m t h a t tr i e s t o o v e r c o m e t h e v a s o d i l a t i o n a n d s u b s e q u e n t d r o p i n b l o o d
pressure caused by the 1,4-DHPs. In contrast, the compensatory mechanism does not occur to the same
extent with either verapamil or diltiazem . This is caused, in part, by the ability of verapam il and diltiazem to
block AV nodal conductance and, in part, by the increased ability of 1,4-DHPs to activate the baroreceptor
reflex. Ultimately, these pharm acological differences are reflected in the clinical use of these agents
(48,53 ,54).
View Figure
Fig. 28.25. Conformation of the C3 and

C5 esters of nifedipine (Ar = 2nitrophenyl). The C3 carbonyl is
synplanar to the C2C3 bond, and the C5
carbonyl antiperiplanar to the C5C6
bond.
Ziconot ide: A n N - Ty pe Ca lcium C hanne l B loc ker

Zi c on oti d e i s a s yn the ti c an al og ue of a nat ural l y occurri ng con ope pt id e f oun d in th e p i sci vorou s
mari ne s na il ( Con us ma gu s ). It i s s truc tu ral ly, me ch an isti cal l y, a nd the rape ut ica ll y di ff eren t f rom
the ot her ca l ci um c ha nn el bl o ck e rs di scu sse d i n thi s cha pt er. S tru ctura ll y, i t is a p ol yb asi c
pep ti de c ont ai ni ng 2 5 a mi no ac i ds a nd th re e di su l fi de bri dg es.
It s e le c ti ve ly bi nds to N -ty pe po ten ti al -dep en den t ca lci um chan ne ls l o ca te d o n t he pri ma ry

noc i c ept iv e (A -d a nd C) a ffe rent ne rve s i n t he supe rfi cia l la yers (Rexe d l am i nae I an d I I) o f t he
dors al h orn i n t he s pi nal c o rd. An al ges i c ef fe ct s resul t from a bl ockad e o f n eu ro tran smi tte r
re l eas e an d a di s rup ti on of no rmal n oc i ce pt ive sig na l tran sm issi on . Zi cono ti de i s in di cate d for
the ma na gem en t o f s e ve re c h ro ni c pa i n i n pat ie nt s who are i nt ol eran t o f o r ref ractory t o oth er
sy s te mi c an al ge si c s , a dj unc t th erap ie s , o r i ntra the cal mo rph in e. Be ca use of i ts pe pti d e
Pgina 35 de 51
st ruc ture , z i c ono ti de i s no t e ffe ct iv e ora ll y. I t i s a dmi n iste red by con ti nu ou s in trat heca l in fusi on .
Th e in it ia l rec om me nde d dos e i s 2.4 g/d ay (0. 1 g/h our) and can be ti tra te d u p t o a m axim um
dai l y do se o f 1 9.2 mg (0. 8 g/h our). Zi co no ti de has a h al f-li fe of ap proxi ma te ly 4 .5 ho urs. I t i s
met abo l iz ed b y end op ep ti das e s and e xo pe pti da ses i n num erou s org an s and ti ssue s. Co mmo n
adv e rs e ef fec ts of zi c on oti de i nc l ud e d izzi ness, nau sea , con fusi on , h ea dach e, so mn ol en ce ,
ny st ag mus , as th en ia , a nd pa in . Th e m ost seri ous a dverse ef fects a pp ea r to be th e d evel op me nt
of se v ere ps y ch ia tri c s ym pt oms a nd ne uro lo gi cal i mpa i rm en t. As a resu lt , zi co no ti de shou l d n ot
be us ed i n p ati e nts w it h a pre ex i st in g hi st ory o f p sycho sis. Frequ en t m oni to rin g for evid en ce o f
co gn it iv e im pa irm ent , h al l uc in at io ns , or cha ng es i n moo d o r con sci ou sness i s essen ti al . These
eff ec ts a re p ote nti a ll y ad di ti v e w it h t ho se of ot he r CNS -dep ressant dru gs ( 32 ,33 ,58 ).
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
1,4Dihydropyridines
Antagonist/agonist;
can either block or
open channel
Inhibits
Enhances
MA
NA, not applicable.
A comparison of the acid-base properties of verapamil, diltiazem , and the 1,4-DHPs reveals that whereas all
of the compounds are basic, the 1,4-DHPs are considerably less basic than verapamil and diltiazem.
V e r a p a m i l a n d d i l t i a z e m b o t h c o n t a i n te r t i a r y a m i n e s w i t h p K a v a l u e s o f 8 . 9 a n d 7 . 7 , r e s p e c t i v e l y ( 2 6 ) . In
c o n t r a s t , t h e n i t r o g e n o f t h e 1 , 4 - D H P s i s p a r t o f a c o n j u g a t e d c a r b a m a te . I t s e l e c t r o n s a r e i n v o l v e d i n
r e s o n a n c e d e l o c a l i z a t i o n a n d a r e m u c h l e s s a v a i l a b l e fo r p r o t o n a ti o n . T h u s , a t p h y s i o l o g i c a l p H , v e r a p a m i l
and diltiazem are primarily ionized, whereas 1,4-DHPs are primarily un -ionized. There are two exceptions to
th i s . A m l o d i p i n e a n d n i c a r d i p i n e c o n t a i n b a s i c a m i n e g r o u p s a s p a r t o f t h e s i d e c h a i n s c o n n e c t e d t o t h e 1 , 4 DHP ring. Although the 1,4-DHP ring of these compounds is un -ionized, the side-chain amines will be
primarily ionized at physiological pH. Because ionic attraction often is the initial interaction between a drug
a n d i t s r e c e p t o r , t h e d i f f e r e n c e s i n b a s i c i t y b e t w e e n t h e 1 , 4 - D H P r i n g a n d t h e t e r ti a r y a m i n e s o f v e r a p a m i l
and diltiazem are consistent with the previously noted fact that the binding site for the 1,4-DHPs is distinct
fr o m t h o s e f o r v e r a p a m i l a n d d i l t i a z e m .
The calculated log P values for the calcium channel blockers are listed in Table 28.11 (26 ). As evidenced by
th e d a t a , a l l o f t h e s e c o m p o u n d s p o s s e s s g o o d l i p i d s o l u b i l i ty a n d , h e n c e , e x c e l l e n t o r a l a b s o r p t i o n ( n o t
s h o w n i n T a b l e 2 8 . 1 1 ) . W i t h i n t h e 1 , 4 D H P c l a s s , e n h a n c e d l i p i d s o l u b i l i t y o c c u r s i n c o m p o u n d s th a t
contain either larger ester groups or disubstituted phenyl rings. A comparison of the log P values of
n i f e d i p i n e a n d n i s o l d i p i n e i l l u s t r a t e s t h i s f a c t . I t s h o u l d b e n o t e d th a t t h e c a l c u l a t e d l o g P v a l u e s l i s t e d i n
T a b l e 2 8 . 1 1 a r e f o r th e u n - i o n i z e d c o m p o u n d s . T h e s e v a l u e s s i g n i f i c a n t l y d e c r e a s e f o r t h e i o n i z e d f o r m s o f
a m l o d i p i n e , n i c a r d i p i n e , v e r a p a m i l , a n d d i l t i a z e m s u c h t h a t t h e l a t t e r th r e e a g e n t s p o s s e s s s u f f i c i e n t w a t e r
solubility to be used both orally and parenterally.
Table 28.10. Comparison of the Cardiovascular Effects of Verapamil,
Pgina 36 de 51
Diltiazem, and Nifedipine

Cardiovascular Effect
Verapamil
Diltiazem
Nifedipine (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, 1997:229234 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, 1990:10471099; with
permission.
P.763
Table 28.11. Pharmacokinetic Parameters of Calcium Channel Bloc
Drug
Oral
Effect of
CalculatedBioavailabilityFood on
Log P
(%)
Absorption
Active
Metabolite
Protein
Binding
(%)
Amlodipine
2.76
6490
None
None
93
Pgina 37 de 51
Felodipine
4.69
1020
Increase
None
>99
Isradipine
3.19
1524
Reduced
rate,
same
extent
None
95
Nicardipine
4.27
35
Reduced
None
>95
Nifedipine
2.40
4570
None
None
92
98
86% (SR)
Nimodipine
3.14
13
Reduced
None
>95
Nisoldipine
3.86
High-fat
meal
increases
immediate
release
but lowers
overall
Hydroxylated
analogue
>99
Pgina 38 de 51
amount
Phenalkylamines
Verapamil
3.53
2035
(SR form
only)
Reduced
Norverapamil
90
4060
None
Deacetyldiltiazem
70
80
Benzothiazepines
Diltiazem
3.55
Tmax time to maximum blood conentration; IR, immediate-release product; CR, controlled
sustained-release product; IV, intravenous administration.
A l l c a l c i u m c h a n n e l b l o c k e r s , w i t h t h e e x c e p t i o n o f n i f e d i p i n e , c o n t a i n a t l e a s t o n e c h i r a l c e n te r ; h o w e v e r ,
th e y a r e a l l m a r k e t e d a s t h e i r r a c e m i c m i x t u r e s . A s p r e v i o u s l y n o t e d , 1 , 4 - D H P s w i t h a s y m m e t r i c a l l y
substituted esters exhibit stereoselectivity between the enantiomers. Additionally, the S-()-enantiomers of
verapam il and other phenylalkylamines are m ore potent than the R-(+)-enantiomers. Very few SAR studies
are available for diltiazem ; however, the cis arrangement of the acetyl ester and the substituted phenyl ring
is required for activity (54).
Metabolism
A l l c a l c i u m c h a n n e l b l o c k e r s u n d e r g o e x t e n s i v e f i r s t - p a s s m e t a b o l i s m i n th e l i v e r a n d a r e s u b s t r a te s f o r t h e
CYP3A4 isozyme (32,34). Additionally, several of these compounds can inhibit CYP3A4. All 1,4-DHPs are
oxidatively m etabolized to a variety of inactive compounds. In many cases, the dihydropyridine ring is
initially oxidized to an inactive pyridine analogue (Fig. 28.26). These initial metabolites are then further
tr a n s f o r m e d b y h y d r o l y s i s , c o n j u g a t i o n , a n d a d d i t i o n a l o x i d a t i o n p a t h w a y s . N i s o l d i p i n e a l s o i s s u b j e c t t o
th e s e p r o c e s s e s ; h o w e v e r , h y d r o x y l a ti o n o f i t s i s o b u t y l e s t e r p r o d u c e s a m e ta b o l i te t h a t r e t a i n s 1 0 % o f t h e
activity of the parent compound. In addition to the drugdrug interactions listed below (see Table 28.13), an
i n t e r e s t i n g d r u g fo o d i n t e r a c t i o n o c c u r s w i t h t h e 1 , 4 - D H P s a n d g r a p e f r u i t j u i c e ( 5 9 ) . C o a d m i n i s t r a t i o n o f
1 , 4 - D H P s w i t h g r a p e fr u i t j u i c e p r o d u c e s a n i n c r e a s e s y s t e m i c c o n c e n t r a t i o n o f t h e 1 , 4 - D H P s . T h e
m e c h a n i s m o f t h i s i n t e r a c t i o n a p p e a r s t o r e s u l t f r o m i n h i b i ti o n o f i n t e s t i n a l C Y P 4 5 0 b y f l a v a n o i d s a n d
fu r a n o c o u m a r i n s s p e c i f i c a l l y f o u n d i n g r a p e f r u i t j u i c e ( s e e C h a p t e r 1 0 ) . It h a s b e e n p r o p o s e d t h a t l i m i t i n g
daily intake to either an 8-oz. glass of grapefruit juice or half of a fresh grapefruit would likely avoid
significant drug interactions with most CYP3A4-metabolized drugs (60).
Verapamil is primarily m etabolized to the N-demethylated compound, norverapamil, which retains
Pgina 39 de 51
approximately 20% of the pharmacological activity of verapamil and can reach or exceed the steady-state
plasma levels of verapamil. Interestingly, the more active S-()-isomer undergoes more extensive first-pass
h e p a t i c m e ta b o l i s m t h a n d o e s t h e l e s s a c t i v e R - ( + ) - i s o m e r . T h i s i s i m p o r t a n t t o n o t e , b e c a u s e w h e n g i v e n
IV , v e r a p a m i l p r o l o n g s t h e P R i n t e r v a l t o a g r e a t e r e x t e n t t h a n w h e n i t i s g i v e n o r a l l y ( 6 1 ) . T h i s i s b e c a u s e
th e p r e f e r e n t i a l m e t a b o l i s m o f t h e m o r e a c t i v e e n a n t i o m e r d o e s n o t o c c u r w i t h p a r e n t e r a l
P.764
administration. Diltiazem is primarily hydrolyzed to deacetyldiltiazem . This metabolite retains 25 to 50% of
th e c o r o n a r y v a s o d i l a t o r y e f f e c t s o f d i l t i a z e m a n d i s p r e s e n t i n th e p l a s m a a t l e v e l s o f 1 0 t o 4 5 % o f t h e
parent compound.
Fig. 28.26. Oxidation of the 1,4dihydropyridine ring of nifedipine.

View Figure
The pharmacokinetic param eters and oral dosing information for calcium channel blockers are summarized
i n T a b l e s 2 8 . 1 1 a n d 2 8 . 1 2 , r e s p e c t i v e l y ( 3 2 , 3 3 ,3 4 ) . S o m e d o s e s ( s p e c i f i c a l l y , t h o s e f o r d i l t i a z e m a n d
v e r a p a m i l ) m a y v a r y f o r e i t h e r s p e c i f i c i n d i c a t i o n s ( i . e . , h y p e r t e n s i o n v e r s u s a n g i n a ) o r d i ff e r e n t b r a n d
n a m e s , a n d t h e r e a d e r s h o u l d c o n s u l t th e p r o d u c t l i t e r a t u r e f o r a d d i ti o n a l i n f o r m a t i o n . T h e p r i m a r y
d i f f e r e n c e s a m o n g t h e c o m p o u n d s a r e o n s e t o f a c ti o n , h a l f - l i f e , a n d o r a l b i o a v a i l a b i l i t y . A l l c a l c i u m c h a n n e l
blockers have excellent oral absorption; however, because they also are subject to rapid first-pass
metabolism in the liver, the actual oral bioavailability of these compounds varies considerably depending on
th e e x t e n t o f m e t a b o l i s m . A l l c o m p o u n d s a r e h i g h l y p l a s m a p r o t e i n b o u n d a n d p r i m a r i l y e l i m i n a t e d a s
inactive metabolites in the urine. Because of extensive hepatic transformation, calcium channel blockers
should be used cautiously in patients with hepatic disease. Recommendations for these patients include
dosage reductions,
P.765
c a r e f u l t i t r a t i o n s , a n d c l o s e th e r a p e u t i c m o n i t o r i n g . D i l t i a z e m a n d v e r a p a m i l a l s o r e q u i r e d o s a g e
adjustments in patients with renal dysfunction, because renal impairm ent can significantly increase the
c o n c e n tr a t i o n s o f t h e a c t i v e m e t a b o l i t e s o f t h e s e c o m p o u n d s . D o s a g e a d j u s t m e n t s u s u a l l y a r e n o t r e q u i r e d
fo r t h e o t h e r s e v e n c o m p o u n d s , b e c a u s e s i x o f t h e m p r o d u c e i n a c t i v e m e t a b o l i t e s a n d n i s o l d i p i n e p r o d u c e s
a c t i v e m e ta b o l i te s w i t h s i g n i f i c a n t l y l o w e r a c t i v i t y .
Table 28.12. Oral Dosing Information for Calcium Channel Blockers
Generic Name
Brand Name Approved

(s)
Indications
Normal
Dosing
Range
Precautions
Maximum with Hepatic
Daily Dose Dysfunction
Amlodipine
Norvasc
Angina (V, CS),
510 mg
10 mg
Reduce
Pgina 40 de 51
hypertension
q.d.
dosage
Felodipine
Plendil
Hypertension
2.510.0
mg q.d.
10 mg
Reduce
dosage
Isradipine
DynaCirc
CR
Hypertension
520 mg
q.d.
20 mg
Titrate
dosage
Nicardipine
Cardene,
Cardene
IV
Angina (CS),
hypertension
2040
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
1020
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
2040
mg q.d.
60 mg
Closely
monitor
blood
pressure
Angina (V, CS,

U),
hypertension,
atrial
fibrillation/flutter,
PSVT
80120
mg t.i.d.
or q.i.d.
(SR:
240480
mg q.d.
or b.i.d.)
480
mg
(540
mg for
Covera
HS
only)
Reduce
dosage
Phenylalkylamines
Verapamil
Calan,
Covera,
Isoptin,
Verelan
Pgina 41 de 51
Benzothiazepines
Diltiazem
Cardizem,
Dilacor
Angina (V, CS),

hypertension,
atrial
fibrillation/flutter,
PSVT
30120
mg t.i.d.
or q.i.d.
(SR:
120480
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.
Unlabeled U ses
Mi grai ne h ead ac he , R ay na ud' s s y nd rome , p ul mo na ry hype rt en si on , p ret erm la bor, an d
hy pe rt roph i c ca rdi om yo pa thy
Felodipine and nisoldipine are only available as sustained-release (or extended -release) formulations.
Nifedipine, isradipine, nicardipine, verapamil, and diltiazem are available as both im mediate-release and
sustained-release formulations. The latter three com pounds also are available as parenteral preparations.
U n l i k e r e g u l a r t a b l e ts a n d c a p s u l e s , s u s t a i n e d - r e l e a s e ( o r e x t e n d e d - r e l e a s e ) f o r m u l a t i o n s c a n n o t b e
chewed or crushed, because this m ay lead to an imm ediate, rather than a sustained, release of the
c o m p o u n d . T h i s e ff e c t n o t o n l y w i l l d e c r e a s e t h e d u r a t i o n o f t h e d o s e b u t a l s o c o u l d p r o d u c e a n o v e r d o s e
and subsequent toxicities in the patient. Parenteral preparations of nicardipine and verapamil are
i n c o m p a t i b l e w i th I V s o l u t i o n s c o n t a i n i n g s o d i u m b i c a r b o n a t e . I n e a c h c a s e , s o d i u m b i c a r b o n a t e i n c r e a s e s
th e p H o f t h e s o l u t i o n , r e s u l t i n g i n t h e p r e c i p i t a t i o n o f th e c a l c i u m c h a n n e l b l o c k e r . A l t h o u g h t h i s i n t e r a c t i o n
i s n o t l i s t e d f o r d i l t i a z e m , i t i s r e a s o n a b l e t o a s s u m e t h a t a s i m i l a r i n t e r a c ti o n m a y o c c u r . A d d i t i o n a l l y ,
nicardipine is incom patible with lactated Ringer's solution, and verapam il will precipitate in solutions having
a pH greater than or equal to six (32,33).
As illustrated in Table 28.12, calcium channel blockers have been approved for the treatm ent of
h y p e r t e n s i o n , a n g i n a p e c t o r i s , s u b a r a c h n o i d h e m o r r h a g e , a n d s p e c i f i c ty p e s o f a r r h y th m i a s ( 3 2 , 3 3 ) . A l l
calcium channel blockers cause vasodilation and decrease peripheral resistance. With the exceptions of
nimodipine, all are approved to treat hypertension. Recent studies have indicated that immediate-release
fo r m u l a t i o n s o f s h o r t - a c t i n g c a l c i u m c h a n n e l b l o c k e r s , e s p e c i a l l y n i fe d i p i n e , c a n c a u s e a n a b r u p t
vasodilation that can result in MI. As a result, only the sustained-release formulations of nifedipine and
diltiazem should be used in the treatment of essential hypertension (62). Five of the nine agents are
approved for the treatment of angina pectoris. Verapamil is the m ost versatile agent in that it is indicated
fo r a l l t h r e e t y p e s o f a n g i n a : v a s o s p a s t i c , c h r o n i c s t a b l e , a n d u n s ta b l e . A m l o d i p i n e , n i f e d i p i n e , a n d
diltiazem are indicated for both vasospastic and chronic stable angina, whereas nicardipine is indicated
Pgina 42 de 51
o n l y fo r c h r o n i c s t a b l e a n g i n a . N i m o d i p i n e i s u n i q u e i n t h a t i t h a s a g r e a t e r e f f e c t o n c e r e b r a l a r t e r i e s t h a n
on other arteries. As a result, nimodipine is indicated for the improvem ent of neurological deficits because
o f s p a s m f o l l o w i n g s u b a r a c h n o i d h e m o r r h a g e f r o m r u p t u r e d c o n g e n i t a l i n t r a c r a n i a l a n e u r y s m s i n p a ti e n t s
o t h e r w i s e i n g o o d n e u r o l o g i c a l c o n d i t i o n a f te r t h e e p i s o d e . V e r a p a m i l a n d d i l t i a z e m a r e p h a r m a c o l o g i c a l l y
d i f f e r e n t fr o m t h e 1 , 4 - D H P s i n t h a t t h e y b l o c k s i n u s a n d A V n o d a l c o n d u c ti o n . A s a r e s u l t , I V f o r m u l a t i o n s
o f v e r a p a m i l a n d d i l t i a z e m a r e i n d i c a t e d f o r th e t r e a t m e n t o f a t r i a l f i b r i l l a t i o n , a t r i a l f l u t t e r , a n d P S V T .
V e r a p a m i l a l s o c a n b e u s e d o r a l l y , e i t h e r a l o n e ( f o r p r o p h y l a x i s o f r e p e ti t i v e P S V T ) o r i n c o m b i n a t i o n w i t h
d i g o x i n ( f o r a t r i a l f l u t t e r o r a t r i a l f i b r i l l a ti o n ) .
Adve rse E f fe cts of C alcium C hannel B loc kers

Ed ema , f lu s hi ng , h yp ote ns i on , n as al c on ge st io n, pa lp it ati o ns, ch est p ai n, ta ch yca rdi a,
hea da ch e, fat ig ue , d iz z i ne ss , ras h, na usea , a bd omi na l pa in , co nsti pa ti on, di a rrh ea , vom i ti ng,
sh ortn es s of bre ath , wea kn es s, b rady c ard ia , a nd A V bl ock
Adverse Effects and Drug Interactions

T h e m o s t p r e v a l e n t o r s i g n i f i c a n t s i d e e ff e c t s o f c a l c i u m c h a n n e l b l o c k e r s a r e l i s t e d b e l o w ( 3 2 , 3 3 , 4 8 , 5 1 , 5 3 ) .
Drug interactions for calcium channel blockers are listed in Table 28.13. In most instances, these side
e f f e c t s d o n o t c a u s e l o n g - te r m c o m p l i c a t i o n s , a n d t h e y o f t e n r e s o l v e w i t h t i m e o r d o s a g e a d j u s t m e n t s . M a n y
o f t h e s e e ff e c t s a r e s i m p l y e x t e n s i o n s o f t h e p h a r m a c o l o g i c a l e f f e c t s o f t h i s c l a s s o f c o m p o u n d s . E x c e s s i v e
v a s o d i l a t i o n r e s u l t s i n e d e m a , fl u s h i n g , h y p o t e n s i o n , n a s a l c o n g e s t i o n , h e a d a c h e , a n d d i z z i n e s s .
Additionally, the palpitations, chest pain, and tachycardia seen with 1,4 -DHPs are a result of sympathetic
r e s p o n s e s to t h e v a s o d i l a t o r y e f f e c t s o f t h i s c h e m i c a l c l a s s . T h e u s e o f a - b l o c k e r i n c o m b i n a t i o n w i t h a
1 , 4 - D H P c a n m i n i m i z e t h e s e c o m p e n s a t o r y e f f e c t s a n d c a n b e v e r y u s e f u l i n tr e a t i n g h y p e r t e n s i o n .
Verapamil and diltiazem can cause bradycardia and AV block because of their ability to depress AV nodal
c o n d u c ti o n . B e c a u s e o f r i s k s a s s o c i a te d w i t h a d d i t i v e c a r d i o d e p r e s s i v e e f f e c t s , t h e y s h o u l d n o t b e u s e d i n
combination with -blockers.
Chem ical/P ha rm acologic al C lasses U se d t o Treat Angina P ect oris

Org ani c n it rate s, -bl oc k ers (s ee Cha pte r 26 ), an d ca lci um cha nne l bl ockers
P.766
Table 28.13. Drug Interactions for Calcium Channel Blockers

Drug
Calcium 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
Pgina 43 de 51
Barbiturates
Felodipine,
nifedipine,
Verapamil
Decreased
pharmacological effects of
the calcium channel
blockers
-Blockers
All
Coadministration may
cause additive or
synergistic effects;
increased
cardiodepressant effects
(more extensive with
verapamil and diltiazem);
inhibition of -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
Pgina 44 de 51
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
Pgina 45 de 51
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
Pgina 46 de 51
Valproic acid
Nimodipine
Increased nimodipine
levels
Vecuronium
Verapamil
Increased vecuronium
levels
Vincristine
Nifedipine
Increased vincristine levels
P.767
Cas e S tudy
Vic tori a F. Roche
S. Wi lli am Zi to
BB i s a 58 -ye ar -ol d d iv o rce d w oma n who ow ns he r o wn t ravel a gen cy. S he ha s a f am il y h isto ry
of al co ho li s m, an d t ha t, c o upl e d w it h t he so cia l na ture an d co nsta nt pressure s of he r jo b, l ed BB
to bec o me an al c oh ol ic . Fiv e years a go , B B wa s di ag nose d wi th d ia be tes, and si nce the n, she
has j o in ed Al c oh ol ic s A no ny mo us a nd be en successf ul i n co nt ro l li ng he r d ri n ki ng . H er d ia be tes
is u nd er c on trol w it h g ly b uri de (5 m g dai l y wi th brea kfast). La te ly, how ever, she ha s
ex pe ri e nc ed a lo ss of ene rgy a nd di ffi c ul ty b rea thi ng o n h er d ai ly wal k up to wn t o her off ice. In
add it io n, BB o fte n wak es duri ng th e n i ght fri gh ten ed by a sen se t hat she ha s stop pe d b rea thi ng
and fi nd s i t n ec es s ary t o p rop he rs e lf up wi th a coup le o f p il l ows t o g et a goo d ni ght 's sl ee p. On
phy s i ca l ex am in at io n, he r ph ys i c ia n n ot ices a t end er a bd om en wi th sl i gh t h epa to meg al y an d
ped al e dem a, an d a n e c hoc a rdi og ra m re veal s card io me gal y. A di agn osi s of mi l d co nge sti ve
hea rt f ai lu re w as m ade , a nd B B w as p rescri be d ca pt opri l (25 mg t. i. d. ) an d a dvi se d t o co ntro l
sa lt i nta k e a nd to c on ti nue he r n orma l exerci se rou ti ne . On a fol l ow -up vi si t t o h er p hysici an ,
BB 's sym pto ms h av e m od erat ed , b ut sh e co mp la in s of an i rrit ati ng cou gh an d ra sh , tha t h er
med ic a ti on ma ke s ev ery th i ng tas t e l i ke rust , a nd tha t h er li ps f ee l li ke t he y have sil i con
im pl an ts. B B 's p hy s ic i an wa nts t o c h ang e her med i ca ti on , a nd yo u have th e f ol lo wi ng cho ices
av ai la bl e. W hat do y ou th i nk ?
1.
Ide nti fy t he th erap eu ti c prob le m(s) i n whi ch t he ph arma cist' s i nt erven ti on ma y ben ef it th e
pat ie nt.
2.
Ide nti fy a nd pri ori ti z e the pa ti en t -sp eci fi c facto rs th at mu st be con si d ered to ach ie ve t he
des i red th erap eut ic out c ome s .
3.
Con duc t a t ho roug h a nd me c han i st ica ll y ori en te d stru ct ure acti vi ty ana lysi s of al l
the rape uti c a lt erna ti v es p ro v id ed i n t he ca se.
4.
Ev al ua te th e S A R fi nd i ngs a ga in st t he pat i ent -sp eci fi c facto rs an d d esi red the rap eut ic
out co me s, an d mak e a the rap eut ic d eci sio n.
5.
Cou ns el y ou r pa ti en t.
Pgina 47 de 51
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P h a r m a c o l o g y w i t h C l i n i c a l A p p l i c a t i o n s , 5 t h E d . B o s to n : L i t t l e , B r o w n , 1 9 9 7 : 2 2 9 2 3 4 .
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The Renin-Angiotensin Pathway

History and Overview of Pathway

Fig. 28.1. Schematic representation of

Clini cal S ignific anc e

Actions and Properties of Renin-Angiotensin Pathway Components

Fig. 28.2. Summary of the factors

Fig. 28.3. Schematic representation of

Role of The Renin-Angiotensin Pathway in Cardiovascular Disorders

Overview of Drug Therapy Affecting The Renin-Angiotensin Pathway

classes of drugs are discussed below.

Dev elopment of Or ally A ct ive R enin Inhibit ors

Fig. 28.4. Structures of enalkiren and

En al ki ren h as be en ex te ns i v el y s tud ie d i n pre cl i ni cal an d cl i ni cal tri al s a nd ha s bee n sh own to

Angiotensin-Converting Enzyme Inhibitors

Sulfhydryl-Containing Inhibitors: Development of Captopril

Fig. 28.5. A model of substrate binding to

Fig. 28.6. Inhibitor binding models of (A)

Fig. 28.7. Compounds prepared in the

Fig. 28.8. A comparison of enalaprilat

Fig. 28.9. Bioactivation of enalapril.

Table 28.1. Additional Dicarboxylatecontaining Angiotensin Converting

Additional Dicarboxylate Inhibitors

Fig. 28.10. A modified model of ACE

Phosphonate-containing Inhibitors: the Development of Fosinopril

Fig. 28.11. The binding of phosphinate

Fig. 28.12. Bioactivation of fosinopril.

Table 28.2. Structure activity

Table 28.3. Pharmacokinetic Parameters of ACE Inhibitors

NA, not applicable, , data not available.

Fig. 28.13. Metabolic routes of ACE

Chem ical/P ha rm acologic al C lasses U se d t o Treat Hy pert ension

Table 28.4. Dosing Information for Orally Available ACE Inhibitors

Trade Name Approved

MI, myocardial infarction.

Com bina tion P roduct s That Include an AC E Inhibit or

Pe ptide Mim etics: De sign of Agonist s/Ant agonist s

Fig. 28.14. A general process for the

development of novel agents to

Adverse Effects and Drug Interactions

Adve rse E f fe cts of A C E Inhibitor s

Table 28.5. Drug Interactions for ACE Inhibitors

Either increased or decreased

Potential excessive reduction in

Reduction of captopril levels

Elevated serum potassium

Increased serum lithium levels

Decreased hypotensive effects

Decreased clearance and

NSAIDs, nonsteroidal anti-inflammatory agents.

Angiotensin II Receptor Blockers

Fig. 28.15. Structural comparison of S8308, an imidazole-5-acetic acid

Fig. 28.16. The development of losartan

Fig. 28.17. Structures of losartan

medoxomil are hydrolyzed via esterases

Additional Angiotensin II Receptor Blockers

Fig. 28.18. The development of

M) of this compound (39 ).

Fig. 28.19. The metabolic conversion of

Table 28.6. Pharmacokinetic Parameters of Angiotensin II Receptor Blockers

Table 28.7. Dosing Information for Angiotensin II Receptor Blockers

Adve rse E f fe cts of A ngiote nsin II R ec eptor Ant agonist s

Role of Calcium and Calcium Channels in Vascular Smooth Muscle

Mechanisms of Calcium Movement and Storage