Angiotensin-converting enzyme inhibitors were developed

Transcription

1 Cardiovascular Drugs Angiotensin-Converting Enzyme Inhibitors Nancy J. Brown, MD; Douglas E. Vaughan, MD Abstract ACE inhibitors have achieved widespread usage in the treatment of cardiovascular and renal disease. ACE inhibitors alter the balance between the vasoconstrictive, salt-retentive, and hypertrophic properties of angiotensin II (Ang II) and the vasodilatory and natriuretic properties of bradykinin and alter the metabolism of a number of other vasoactive substances. ACE inhibitors differ in the chemical structure of their active moieties, in potency, in bioavailability, in plasma half-life, in route of elimination, in their distribution and affinity for tissue-bound ACE, and in whether they are administered as prodrugs. Thus, the side effects of ACE inhibitors can be divided into those that are class specific and those that relate to specific agents. ACE inhibitors decrease systemic vascular resistance without increasing heart rate and promote natriuresis. They have proved effective in the treatment of hypertension, they decrease mortality in congestive heart failure and left ventricular dysfunction after myocardial infarction, and they delay the progression of diabetic nephropathy. Ongoing studies will elucidate the effect of ACE inhibitors on cardiovascular mortality in essential hypertension, the role of ACE inhibitors in patients without ventricular dysfunction after myocardial infarction, and the role of ACE inhibitors compared with newly available angiotensin AT 1 receptor antagonists. (Circulation. 1998;97: ) Key Words: angiotensin blood pressure bradykinin drugs renin Angiotensin-converting enzyme inhibitors were developed as therapeutic agents targeted for the treatment of hypertension. Since the initial application of these agents, several additional clinical indications have been identified and approved. This review summarizes the pharmacology of ACE inhibitors and their current clinical indications. Mechanism ACE, or kininase II, is a bivalent dipeptidyl carboxyl metallopeptidase present as a membrane-bound form in endothelial cells, in epithelial or neuroepithelial cells, and in the brain and as a soluble form in blood and numerous body fluids. 1 ACE, or kininase II, cleaves the C-terminal dipeptide from Ang I and bradykinin and a number of other small peptides that lack a penultimate proline residue. Thus, ACE is strategically poised to regulate the balance between the RAS and the kallikrein-kinin system. The RAS plays a pivotal role in blood pressure regulation (Fig 1). Reduced sodium delivery at the macula densa, decreased renal perfusion pressure, and sympathetic activation all stimulate secretion of renin by the juxtaglomerular cell, the classic source of renin in the circulating RAS. 2 Alternatively, renin may be produced locally in tissues. 3,4 Renin cleaves the inactive decapeptide Ang I from the prohormone angiotensinogen, a noninhibiting member of the serpin superfamily of serine protease inhibitors. 5 Ang II is then cleaved from Ang I by the action of ACE. 6 Ang II is a potent vasoconstrictor, acting directly on vascular smooth muscle cells. 7 In addition, Ang II interacts with the sympathetic nervous system both peripherally and centrally to increase vascular tone. 8 Ang II causes volume expansion through sodium retention (via aldosterone 9 and renal vasoconstriction) and fluid retention (via antidiuretic hormone). 10 At the cellular level, Ang II promotes migration, proliferation, and hypertrophy Most of these effects of Ang II appear to be mediated through the AT 1 receptor, although recent studies are defining roles for the AT 2 and AT 4 subtype receptors. 16 As mentioned earlier, in addition to catalyzing the formation of Ang II, ACE (or kininase II) catalyzes the degradation of bradykinin. 6 In specific tissues or organs, bradykinin causes smooth muscle contraction (eg, uterine and ileal), increased vascular permeability, stimulation of peripheral and C fibers, and augmentation of mucous secretion. 17 More importantly, however, bradykinin promotes vasodilation by stimulating the production of arachidonic acid metabolites, nitric oxide, and endothelium-derived hyperpolarizing factor in vascular endothelium. 18 In the kidney, bradykinin causes natriuresis through direct tubular effects. 19 Most of the physiological effects of bradykinin appear to be mediated through the B 2 receptor. 20 In summary, ACE regulates the balance between the vasodilatory and natriuretic properties of bradykinin and the vasoconstrictive and salt-retentive properties of Ang II. ACE inhibitors alter this balance by decreasing the formation of Ang II and the degradation of bradykinin (Fig 1). ACE Received August 11, 1997; revision received January 28, 1998; accepted January 29, From the Departments of Medicine and Pharmacology, Vanderbilt University Medical Center (N.J.B., D.E.V.), and the Veterans Administration Medical Center (D.E.V.), Nashville, Tenn. Correspondence to Nancy J. Brown, MD, 560 MRB-I, Vanderbilt University Medical Center, Nashville, TN nancy.brown@mcmail.vanderbilt.edu 1998 American Heart Association, Inc. 1411

2 1412 ACE Inhibitors Selected Abbreviations and Acronyms Ang angiotensin MI myocardial infarction PRA plasma renin activity RAS renin-angiotensin system inhibitors also alter the formation and degradation of several other vasoactive substances such as substance P, 21 but the contribution of these compounds to the therapeutic or adverse effects of ACE inhibitors is uncertain. Pharmacology ACE inhibitors differ in the chemical structure of their active moieties, in potency, in bioavailability, in plasma half-life, in route of elimination, in their distribution and affinity for tissue-bound ACE, and in whether they are administered as prodrugs. ACE inhibitors may be classified into three groups according to the chemical structure of their active moiety. Captopril is the prototype of the sulfhydryl-containing ACE inhibitors; others are fentiapril, pivalopril, zofenopril, and alacepril. In vitro studies suggest that the presence of the sulfhydryl group may confer properties other than ACE inhibition to these drugs, such as free-radical scavenging and effects on prostaglandins 22,23 ; however, the clinical relevance of these effects remains to be demonstrated. Fosinopril is the only FDA-approved ACE inhibitor that contains a phosphinyl group as its reactive moiety. The majority of the other ACE inhibitors contain a carboxyl moiety. The half-lives and routes of elimination for selected ACE inhibitors appear in Table 1. Captopril differs from other ACE inhibitors by its short half-life. With the exception of fosinopril, trandolapril, and spirapril, ACE inhibitors are cleared predominantly by the kidney. For this reason, dose reductions are required in the setting of impaired renal function. The majority of ACE inhibitors are administered as prodrugs that remain inactive until esterified in the liver. These prodrugs have enhanced oral bioavailability compared with their active drugs. ACE is present in plasma as well as in tissues, and there are differences in the relative tissue affinity of ACE inhibitors. For example, Fabris and coworkers 24 examined the binding of various ACE inhibitors to heart homogenates and found the order of potency to be quinaprilat benazaprilat perindoprilat lisinoprilat fosinoprilat. Several investigators have shown that the effects of ACE inhibitors on blood pressure correlate better with tissue ACE levels than with circulating Figure 1. Schematic of RAS and kallikrein-kinin system. ACE is strategically poised to regulate the balance between Ang II and bradykinin. ACE, 25,26 but the clinical significance of differences in tissue binding has not been established. Humoral Effects The effects of ACE inhibitors on the RAS in humans is well documented. ACE inhibitors block the pressor response to intravenous Ang I but not Ang II. 27 When ACE inhibitors are given short-term, endogenous levels of Ang II and aldosterone decrease, whereas PRA and Ang I increase, 28,29 at least in part because of loss of feedback inhibition. 30 The resulting increase in Ang I levels may result in degradation of Ang I to Ang 1 7, a vasodilator, 31 or in formation of Ang II via non ACE-mediated pathways, although the role of these alternative degradation products in humans is controversial. With chronic ACE inhibition, Ang II and aldosterone levels tend to return toward pretreatment levels The contribution of bradykinin to the hemodynamic effects of ACE inhibitors in humans is uncertain. ACE inhibitors potentiate the hypotensive effects of intravenous bradykinin in humans. 38,39 However, endogenous bradykinin is difficult to measure because of its short half-life, and investigators have reported that bradykinin levels are either increased 40,41 or unchanged during ACE inhibition. Similarly, prostaglandin levels have been reported to be increased or unchanged in patients treated with ACE inhibitors. 40,45 51 The recent availability of specific bradykinin (B 2 ) receptor antagonists 52,53 has begun to shed light on the contribution of bradykinin to the actions of ACE inhibitors. In animal models, coadministration of a bradykinin antagonist attenuates the antihypertensive effect of ACE inhibitors. 54,55 Recent data suggest that B 2 antagonism blunts the hypotensive effects 56 and reduces the endothelium-dependent vasodilator effects in humans as well. 57 Hemodynamic Effects ACE inhibitors decrease systemic vascular resistance but cause little change in heart rate In normotensive and hypertensive subjects with normal left ventricular function, ACE inhibitors have little effect on cardiac output or pulmonary capillary wedge pressure In the kidneys, ACE inhibitors cause increased renal plasma flow and promote salt excretion Glomerular filtration is usually unchanged; thus, filtration fraction is decreased. Clinical Indications Hypertension ACE inhibitors effectively lower the mean, systolic, and diastolic pressures in hypertensive patients as well as in salt-depleted normotensive subjects The acute change in blood pressure correlates with pretreatment PRA and angiotensin levels, such that the greatest reductions in blood pressure are seen in patients with the highest PRA However, with long-term therapy, a greater percentage of patients achieve a decrease in blood pressure, and the antihypertensive effect no longer correlates with pretreatment PRA The mechanism for this increased efficacy with chronic administration is not clear but may involve the kallikrein-kinin system or production of vasodilatory prostaglandins. 77

3 Brown and Vaughan April 14, TABLE 1. Pharmacology of ACE Inhibitors Approved in the United States Captopril Enalapril Lisinopril Benazepril Quinapril Ramipril Trandolapril Moexipril Fosinopril Zinc ligand Sulfhydryl Carboxyl Carboxyl Carboxyl Carboxyl Carboxyl Carboxyl Carboxyl Phosphinyl Prodrug No Yes No Yes Yes Yes Yes Yes Yes t max active drug, h t 1/2 active drug, h , 25 terminal Triphasic 4, 9 18, terminal Route of elimination Kidney Kidney Kidney Kidney Kidney Kidney Kidney, liver Kidney Liver, kidney Dosage range, mg F, %* *F indicates bioavailability. Although ACE inhibitors are generally effective in reducing blood pressure, they appear to be less potent in hypertensive blacks than whites. In a Veterans Administration Cooperative Study Group trial, captopril reduced blood pressure significantly more in white patients with mild to moderate hypertension than in black patients at 7 weeks. 78 Similarly, ACE inhibitors and -blockers were less effective than calcium channel blockers in young and elderly black men. 79 One possible explanation for these data is that hypertensive blacks tend to have low renin levels more often than do whites In support of this, coadministration of drugs that increase PRA, such as diuretics, abolishes the racial differences in response to ACE inhibitors. 78 Weir et al 83 suggested that the mechanism through which ACE inhibitors lower blood pressure differs in blacks and whites. This group observed a dissociation between the potency of ACE inhibitors for decreasing plasma ACE activity and their antihypertensive potency in blacks; however, in some dose groups, baseline ACE activity was higher in the blacks than in the whites studied. Nevertheless, this study underscores the need to use higher doses of ACE inhibitors for blacks. One of the hallmarks of ACE inhibitors is that they lower peripheral vascular resistance without causing a compensatory increase in heart rate The lack of heart rate response to ACE inhibitors contrasts with the effect of other vasodilators, such as calcium channel blockers and direct-acting vasodilators, on heart rate and may reflect an effect of ACE inhibitors on baroreceptor sensitivity as well as inhibition of the normal tonic influence of Ang II on the sympathetic nervous system During ACE inhibition, heart rate responses to postural changes and exercise are not impaired. 87 The goal of antihypertensive therapy is not only to lower blood pressure but, more importantly, to alter the risk of end-organ damage and mortality. To date, trials of ACE inhibitors in the treatment of essential hypertension have focused on the end point of blood pressure reduction. For this reason, the Joint National Committee for the Detection, Evaluation, and Treatment of High Blood Pressure VI has not recommended ACE inhibitors as first-line therapy for uncomplicated hypertension. ACE inhibitors are indicated for the treatment of hypertension with coexistent conditions such as congestive heart failure and diabetic nephropathy. 88 Clinical trials testing the effect of ACE inhibitors on cardiovascular mortality in patients with essential hypertension are under way. These include the Captopril Prevention Project 89 and the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). 90 It should be emphasized that existing data suggest that ACE inhibitors will have a favorable effect on cardiovascular mortality. ACE inhibitors lack adverse metabolic effects, 91 and they have been shown to cause regression of left ventricular hypertrophy. 60,92,93 Finally, they have already been shown to reduce mortality in patients with congestive heart failure and diabetic nephropathy. 99 Congestive Heart Failure and Left Ventricular Dysfunction ACE inhibitors favorably alter hemodynamics in patients with systolic dysfunction. ACE inhibitors reduce afterload, preload, and systolic wall stress such that cardiac output increases without an increase in heart rate. ACE inhibitors promote salt excretion by augmenting renal blood flow and by reducing the production of aldosterone and antidiuretic hormone. Since 1987, several large, prospective, randomized, placebo-controlled trials have demonstrated that treatment with ACE inhibitors results in a reduction in overall mortality in patients with congestive heart failure due to systolic dysfunction These trials are summarized in Table 2 and have had a major impact on the management of congestive heart failure. The reduction in mortality has been seen even in patients with asymptomatic left ventricular dysfunction. 110,111 This reduction in mortality results primarily from a reduction in progression of congestive heart failure, 94,96,97 although the incidence of sudden death 96 and MI 110 may also decrease. As mentioned earlier, it is not yet clear to what extent bradykinin contributes to the beneficial therapeutic effects or adverse effects of ACE inhibitors. Since the advent of specific AT 1 antagonists, a number of studies comparing ACE inhibitors with AT 1 antagonists are now under way. The first of these, the Evaluation of Losartan in the Elderly (ELITE) study, reported nearly equivalent effects of losartan and the short-acting ACE inhibitor captopril on the progression of congestive heart failure in elderly patients; however, there was an unexpected reduction in the incidence of sudden death in the losartan group. 112 There was no difference between captopril and losartan in the incidence of renal insufficiency. Whether large-scale trials comparing AT 1 receptor antagonists with longer-acting ACE inhibitors will confirm these data remains to be seen. Although ACE inhibitors improve outcome in patients with systolic dysfunction, many patients with hypertension expe-

4 1414 ACE Inhibitors TABLE 2. Clinical Trials of ACE Inhibitors in Congestive Heart Failure and LV Dysfunction Study Patient Population ACE Inhibitor Studies in LV dysfunction alone rience congestive heart failure due to diastolic dysfunction related to left ventricular hypertrophy. In animal models, ACE inhibitors have been shown to reverse ventricular remodeling by blocking the trophic effects of Ang II on cardiac myocytes. 113,114 ACE inhibitors have been shown to reverse left ventricular hypertrophy in patients with hypertension. 60,92,93 A meta-analysis of the effects of several antihypertensive agents suggested that ACE inhibitors were the most effective agent in reducing left ventricular hypertrophy. 115 Studies examining mortality in patients with congestive heart failure due to diastolic dysfunction are needed. Left Ventricular Dysfunction After MI On the basis of studies demonstrating that ACE inhibition could reduce progressive enlargement after MI in experimental animals 116 as well as in humans, 117 it was hypothesized that ACE inhibition might improve clinical outcome in patients after MI. Several large, prospective, randomized trials have now examined the effect of ACE inhibitors on mortality after MI (Table 2). 97, The vast majority of these trials have shown a decrease in cardiovascular mortality and a slowing of the progression to congestive heart failure in patients treated with ACE inhibitors. The optimal timing and dosage of ACE inhibitor after MI are not known. In CONSENSUS II, intravenous enalaprilat was administered within 24 hours of MI. 118 There was a significant increase in early hypotension in Time of Administration After MI Treatment Duration Outcome Reference CONSENSUS NYHA IV (n 253) Enalapril vs placebo 1 d 20 mo Decreased mortality; decreased CHF SOLVD-Treatment NYHA II and III (n 2569) Enalapril vs placebo mo Decreased mortality; decreased CHF V-HeFT II NYHA II and III (n 804) Enalapril vs hydralazine, isosorbide SOLVD-Prevention Asymptomatic LV dysfunction (n 4228) y Decreased mortality; decreased sudden death Enalapril vs placebo mo Decreased mortality; decreased CHF hospitalizations Studies in LV dysfunction after MI* SAVE MI, decreased LV function Captopril vs placebo 3 16 d mo Decreased mortality 110 (n 2231) CONSENSUS II MI (n 6090) Enalaprilat/enalapril vs placebo 24 h d No change in survival; hypotension with enalaprilat 118 AIRE MI and CHF (n 2006) Ramipril vs placebo 3 10 d Minimum of Decreased mortality 97 6 months ISIS-4 MI (n ) Captopril vs placebo 24 h 28 d Decreased mortality 119 GISSI-3 MI (n ) Lisinopril vs control 24 h 6 wk Decreased mortality 121 TRACE MI, decreased LV function Trandolapril vs placebo 3 7 d mo Decreased mortality 98 (n 1749) SMILE MI (n 1556) Zofenopril vs placebo 24 h 6 wk Decreased mortality 120 LV indicates left ventricular; CHF, congestive heart failure. *Study involved patients with MI. the enalaprilat-treated group and, in contrast to other studies with enalaprilat, there was no improvement in survival. On the other hand, zofenopril, captopril, and lisinopril started within 24 hours after MI in the SMILE, 120 ISIS-4, 119 and GISSI-3 trials, 121 respectively, did reduce mortality. In the majority of trials, ACE inhibitor was administered 3 to 16 days after MI. It is likely that patients are more sensitive to the hypotensive effects of ACE inhibitors in the immediate post-mi period. An extensive discussion of the issues surrounding the administration of ACE inhibitors after MI is beyond the scope of the present review, but these issues were recently reviewed by Pfeffer 122 and by Borghi and Ambrosioni. 123 Atherosclerotic Vascular Disease Studies in patients with left ventricular dysfunction have suggested the possibility that ACE inhibitors decrease the frequency of ischemic events. For example, in the SAVE and SOLVD trials, ACE inhibitors reduced the incidence of recurrent MI and angina in patients with left ventricular dysfunction or mild congestive heart failure by 20%. 110,111 Nevertheless, it is not known whether ACE inhibitors will prevent ischemic events in patients with normal ventricular function. However, there is experimental evidence that ACE inhibition can retard the development of atherosclerosis. In animal models of atherosclerosis, including apolipoprotein E

5 Brown and Vaughan April 14, knockout mice, 124 Watanabe rabbits, 125 and cholesterol-fed monkeys, 126 ACE inhibitors have been shown to reduce the extent of vascular lesions. Furthermore, ACE inhibition has been shown to reverse endothelial dysfunction in normotensive patients with CAD, in hypertensive patients, and in patients with non insulin-dependent diabetes mellitus. 127 ACE inhibition is thought to improve endothelial function by attenuating the vasoconstrictive and superoxide radical generating effects of Ang II while simultaneously enhancing the bradykinin-dependent induction of endothelial nitric oxide production. ACE inhibitors also promote ischemic preconditioning, probably through a bradykinin-mediated mechanism. 128 Studies in vitro and in humans suggest that ACE inhibitors favorably alter fibrinolytic balance, both by decreasing Ang II, a potent stimulus to plasminogen activator inhibitor synthesis, 129,130 and by increasing bradykinin, a potent stimulus to tissue plasminogen activator secretion. 131,132 Several ongoing clinical trials are designed to address the hypothesis that ACE inhibitors prevent ischemic events in high-risk patients without left ventricular dysfunction. 133,134 TABLE 3. Side Effects Class effects Hypotension Cough Hyperkalemia Renal failure Fetal anomalies Angioedema Dysgeusia Sulfhydryl-related effects Neutropenia Rash Nephrotic-range proteinuria Diabetic Nephropathy The RAS and increased glomerular capillary pressure have been implicated in the progression of renal dysfunction due to a number of renal diseases, including diabetic nephropathy. 135 ACE inhibitors decrease glomerular capillary pressure by decreasing arterial pressure and by selectively dilating efferent arterioles. 136 In addition, Ang II causes mesangial cell growth and matrix production. 137,138 Numerous animal studies and small clinical trials have suggested that ACE inhibitors significantly reduce the loss of kidney function in diabetic nephropathy. 139 ACE inhibitors prevent progression of microalbuminuria to overt proteinuria. 140 A large, prospective, placebo-controlled study has now shown that captopril slows the progression of nephropathy in patients with insulindependent diabetes mellitus, as measured by the rate of decline in creatinine clearance and the combined end points of dialysis, transplantation, and death. 99 A second large-scale, prospective, double-blind study extended these observations by showing a protective effect of ACE inhibitors in patients with a variety of renal diseases, including glomerulopathies, interstitial nephritis, nephrosclerosis, and diabetic nephropathy. 141 The exception was polycystic kidney disease. Importantly, the protective effect of ACE inhibition was independent of the severity of renal insufficiency. Ongoing studies will determine whether ACE inhibitors other than captopril are also effective in slowing progression of nephropathy and will also clarify the value of ACE inhibitors in slowing progression of renal disease in patients with non insulin-dependent diabetes mellitus. This is particularly relevant when one considers that, whereas 89% of the patients in the captopril trial were white, 99 non insulindependent diabetes mellitus is two times more prevalent among blacks than whites. 142 As mentioned above, blacks are resistant to the antihypertensive effects of ACE inhibitors; thus, it remains to be determined whether there are ethnic differences in the renal protective effects of ACE inhibitors. Other individual factors may determine the impact of ACE inhibitors on the progression of renal insufficiency. In particular, Rigat et al 143 described an insertion (I)/deletion (D) polymorphism in the ACE gene that correlates with ACE activity such that ACE levels are highest in patients who are homozygous for the ACE D allele, lowest in patients homozygous for the ACE I allele, and intermediate in those who are heterozygous. Yoshida et al 144 reported a greater decrease in proteinuria in response to ACE inhibition in patients with IgA nephropathy who were homozygous for the DD allele. In contrast, other investigators have reported a worse response to therapy in patients who carry the ACE D allele. 145 Obviously, large-scale studies are needed to define the impact of genetic factors on the renal protective effects of ACE inhibitors. Adverse Effects The adverse effects of ACE inhibitors (Table 3) can be divided into those that are specific to the entire class and those that are related to chemical structure (specifically, related to the presence of a sulfhydryl group). Like all antihypertensive agents, ACE inhibitors can cause hypotension. The frequency of hypotension is greater in renindependent states, such as during low sodium intake and diuretic use, 146 and it is recommended that lower starting doses be used under these conditions. ACE inhibitors can cause hyperkalemia because of a decrease in aldosterone. 147 This effect is usually not significant in patients with normal renal function. However, in patients with impaired kidney function or in patients who are taking potassium supplements (including salt substitutes) or potassium-sparing diuretics, hyperkalemia can occur. 148,149 ACE inhibitors can cause a reversible decline in renal function in the setting of decreased renal perfusion, whether this is due to bilateral renal artery stenosis, 150 severe congestive heart failure, 151 or volume depletion. 152 The mechanism is illustrated in Fig 2. When perfusion pressure or afferent arteriolar pressure is decreased in the glomerulus, glomerular filtration is maintained by efferent arteriolar vasoconstriction, an effect of Ang II. Blocking the formation of Ang II, 153 and perhaps increasing the formation of bradykinin, 154 causes selective efferent arteriolar vasodilation and results in a decrease in glomerular filtration in this setting.

6 1416 ACE Inhibitors Figure 2. Mechanism by which ACE inhibition can cause a decrease in glomerular filtration in setting of hypoperfusion. Decreased perfusion activates RAS. Whereas most vasoconstrictors predominantly modify afferent tone, Ang II causes efferent arteriolar and afferent vasoconstriction, increasing pressure across glomerulus. Glomerular filtration is maintained. Thus, during ACE inhibition, efferent arteriolar resistance decreases 153,154 and glomerular filtration declines. Cough is a frequent side effect of ACE inhibitors. The mechanism is not known but may involve increased levels of bradykinin or substance P and stimulation of vagal C fibers. 155 The frequency of cough varies among different patient populations; the rate appears to be 10% in white populations but may be as high as 44% in Asian populations. 156 Cough is more frequent among women than men. 157,158 The cough tends to be a dry, mildly annoying cough, but it often requires cessation of therapy. Angioedema is a rare but potentially life-threatening side effect of ACE inhibitors. It is characterized by localized swelling of the lips, tongue, mouth, throat, nose, or other parts of the face. 155 The mechanism appears to involve bradykinin or one of its metabolites. 155 The rate of angioedema has been reported to be 1 to 2 per 1000 in primarily white populations 159 but appears to be increased in blacks. 160 Although the rate of angioedema is highest within the first month of ACE inhibitor use, angioedema may occur years after the initiation of therapy. 160 Therefore, patients should be advised to recognize early warning signs of localized edema and to discontinue the drug should they occur. If administered in the second or third trimester of pregnancy, ACE inhibitors can cause a number of fetal anomalies, including oligohydramnios, fetal calvarial hypoplasia, fetal pulmonary hypoplasia, fetal growth retardation, fetal death, neonatal anuria, and neonatal death. 161,162 For this reason, ACE inhibitors should be used with caution in women of child-bearing potential and must be stopped immediately in any woman in whom pregnancy has been diagnosed. Adverse effects that appear to be related to the presence of a sulfhydryl group are neutropenia, nephrotic syndrome, and skin rash. 163 Neutropenia occurs in 0.05% of patients. 70 The incidence is higher in patients who have renal insufficiency or collagen vascular disease. 164,165 Skin rash occurs in 1% of patients 166 and usually consists of a pruritic maculopapular eruption; rarely, exfoliative dermatitis has been reported. 167 The rash appears to be dose-related. 77 Other ACE inhibitors may cause a rash with a much lower frequency than captopril, 98 and there does not appear to be cross-reactivity among ACE inhibitors. 168,169 Drug Interactions As mentioned above, concurrent administration of potassium supplements, potassium-sparing diuretics, or salt substitutes may precipitate hyperkalemia in ACE inhibitor treated patients in whom aldosterone is suppressed. Patients taking diuretics may be particularly sensitive to the hypotensive effects of ACE inhibitors. 146 Nonsteroidal anti-inflammatory drugs may attenuate the antihypertensive effects of ACE inhibitors. 47,50,170,171 This effect appears to be more prominent in patients with low renin levels. 172 Cost Captopril is the only ACE inhibitor currently available in a generic form. The average wholesale price per 100 U ranges from $3.41 for 12.5-mg tablets to $14.97 for 100-mg tablets. At present, contract pricing makes the relative cost of the other agents vary from institution to institution. In general, these agents are priced such that the average wholesale price per 100 U runs from $60 to $80. The limited selection of ACE inhibitors available on many formularies today often precipitates patients being changed from one ACE inhibitor to another. However, given the differing potencies, tissue affinities, and bioavailabilities among ACE inhibitors, it is not clear that all agents are equal. Rigorous studies comparing potencies among ACE inhibitors are needed. Future Directions This review focuses on the pharmacology of ACE inhibitors and on the broadening clinical applications of this class of compounds. Clearly, the beneficial cardiovascular and renal effects of ACE inhibitors go beyond the original, limited indication for the treatment of hypertension. Although current clinical efforts are directed at the emerging role of ACE inhibitors in preventing cardiovascular events in normotensive subjects, further work needs to be done to characterize molecular and cellular mechanisms responsible for the clinical effects of ACE inhibitors. In particular, the role of bradykinin remains enigmatic. Although ACE inhibition after MI appears to have an established role in clinical practice, the ongoing controversy over the selective versus nonselective use of ACE inhibitors after MI is unlikely to be resolved in the near future. Clinical studies will compare the efficacy of ACE inhibitors and specific AT 1 receptor antagonists in the treatment of cardiovascular and renal disease. Finally, studies will determine to what extent individual characteristics such as race and ACE genotype determine responses to ACE inhibitors. It is clear that ACE inhibitors represent one of the major advances in cardiovascular therapeutics over the past 20 years. It is highly doubtful that even the most enthusiastic advocate of these agents could have anticipated their broad clinical applications. Furthermore, ACE inhibitors, in very tangible terms, have catalyzed research into molecular and cellular mechanisms of vascular disease that is paying large dividends. Acknowledgments This work was supported by NIH grants R01-HL (Dr Vaughan) and R29-HL (Dr Brown) and by a Clinical Inves-

7 Brown and Vaughan April 14, tigator Award from the Veterans Affairs Research Administration (Dr Vaughan). References 1. Skidgel RA, Erdos E. Biochemistry of angiotensin I-converting enzyme. In: Robertson JIS, Nicholls MG, eds. The Renin-Angiotensin System. New York, NY: Raven Press Ltd; 1993: Sealey JE, Laragh JH. The renin-angiotensin-aldosterone system for normal regulation of blood pressure and sodium and potassium homeostasis. In: Laragh JH, Brenner BM, eds. Hypertension: Pathophysiology, Diagnosis, and Management. New York, NY: Raven Press Ltd; 1990: Danser AH, van Kats JP, Admiraal PJ, Derkx FH, Lamers JM, Verdouw PD, Saxena PR, Schalekamp MA. Cardiac renin and angiotensins: uptake from plasma versus in situ synthesis. Hypertension. 1994;24: Dzau VJ. Vascular renin-angiotensin system and vascular protection. J Cardiovasc Pharmacol. 1993;22(suppl):S1 S9. 5. Doolittle RF. Angiotensin is related to the antitrypsin-antithrombin ovalbumin family. Science. 1983;222: Erdos EG. The angiotensin I converting enzyme. Fed Proc. 1977;36: Folkow B, Johansson B, Mellander S. The comparative effects of angiotensin and noradrenaline on consecutive vascular sections. Acta Physiol Scand. 1961;53: Zimmerman BG, Sybertz EJ, Wong PC. Interaction between sympathetic and renin-angiotensin system. J Hypertens. 1984;2: Biron P, Koiw E, Nowaczynski W. The effects of intravenous infusions of valine-5 angiotensin II and other pressor agents on urinary electrolytes and corticoids including aldosterone. J Clin Invest. 1961;60: Padfield PL, Morton JJ. Effects of angiotensin II on argininevasopressin in physiological and pathological situations in man. J Clin Endocrinol. 1977;74: Bell L, Madri J. Influence of the angiotensin system on endothelial and smooth muscle cell migration. Am J Pathol. 1990;137: Daemen MJ, Lombardi DM, Bosman FT, Schwartz SM. Angiotensin II induces smooth muscle cell proliferation in the normal and injured rat arterial wall. Circ Res. 1991;68: Itoh H, Mukoyama M, Pratt RE, Gibbons GH, Dzau VJ. Multiple autocrine growth factors modulate vascular smooth muscle cell growth response to angiotensin II. J Clin Invest. 1993;91: Dostal DE, Booz GW, Baker KM. Angiotensin II signalling pathways in cardiac fibroblasts: conventional versus novel mechanisms in mediating cardiac growth and function. Mol Cell Biochem. 1996;157: Huckle WR, Earp HS. Regulation of cell proliferation and growth by angiotensin II. Prog Growth Factor Res. 1994;5: Timmermans PB, Wong PC, Chiu AT, Herblin WF, Benfield P, Carini DJ, Lee RJ, Wexler RR, Saye JA, Smith RD. Angiotensin II receptors and angiotensin II receptor antagonists. Pharm Rev. 1993;45: Proud D, Kaplan AP. Kinin formation: mechanisms and role in inflammatory disorders. Annu Rev Immunol. 1988;6: Vanhoutte PM. Endothelium and control of vascular function: state of the art lecture. Hypertension. 1989;13: Stein JH, Congbalay RC, Karsh DL, Osgood RW, Ferris TF. The effect of bradykinin on proximal tubular sodium reabsorption in the dog: evidence for functional nephron heterogeneity. J Clin Invest. 1972;51: Regoli D, Barabe J. Pharmacology of bradykinin and related kinins. Pharmacol Rev. 1980;32: Cascieri MA, Bull HG, Mumford RA, Patchett AA, Thornberry NA, Liang T. Carboxyl-terminal tripeptidyl hydrolysis of substance P by purified rabbit lung angiotensin-converting enzyme and the potentiation of substance P activity in vivo by captopril and MK-422. Mol Pharmacol. 1984;25: Zusman RM. Effects of converting-enzyme inhibitors on the reninangiotensin-aldosterone, bradykinin, and arachidonic acid-prostaglandin systems: correlation of chemical structure and biologic activity. Am J Kidney Dis. 1987;10: Mira ML, Silva MM, Manso CF. The scavenging of oxygen free radicals by angiotensin converting enzyme inhibitors: the importance of the sulfhydryl group in the chemical structure of the compounds. Ann N Y Acad Sci. 1994;723: Fabris B, Jackson B, Cubela R, Mendelsohn FAO, Johnston CI. Angiotensin converting enzyme in the rat heart: studies of its inhibition in vitro and ex vivo. Clin Exp Pharmacol Physiol. 1989;16: Cohen ML, Kurz KD. Angiotensin converting enzyme inhibition in tissues from spontaneously hypertensive rats after treatment with captopril or MK-421. J Pharmacol Exp Ther. 1982;220: Sakaguchi K, Chai SY, Jackson B, Johnston CI, Mendelsohn FAO. Inhibition of tissue angiotensin converting enzyme: quantitation by autoradiography. Hypertension. 1988;11: Biollaz J, Burnier M, Turini GA, Brunner DB, Porchet M, Gomez HJ, Jones KH, Ferber F, Abrams WB, Gavras H, Brunner HR. Three new long-acting converting enzyme inhibitors: relationship between plasma converting enzyme and response to angiotensin I. Clin Pharmacol Ther. 1981;29: Brunner HR, Gavras H, Waeber B, Kershaw GR, Turini GA, Vukovich RA, Mckinstry DN, Gavras I. Oral angiotensin-converting enzyme inhibitor in long-term treatment of hypertensive patients. Ann Intern Med. 1979;90: Gavras H, Brunner HR, Turini GA, Kershaw GR, Tifft CP, Cuttelod S, Gavras I, Vukovich RA, Mckinstry DN. Antihypertensive effect of the oral angiotensin converting enzyme inhibitor SQ in man. N Engl J Med. 1978;298: Vander AJ, Geelhoed GW. Inhibition of renin secretion by angiotensin II. Proc Soc Exp Biol Med. 1965;120: Ferrario CM, Brosnihan KB, Diz DI, Jaiswal N, Khosla MC, Milsted A, Tallant EA. Angiotensin-(1 7): a new hormone of the angiotensin system. Hypertension. 1991;18(suppl III):III-126 III Okunishi H, Miyazaki M, Toda N. Evidence for a putatively new angiotensin II-generating enzyme in the vascular wall. J Hypertens. 1984;2: Urata H, Healy B, Stewart RW, Bumpus FM, Husain A. Angiotensin II-forming pathways in normal and failing human hearts. Circ Res. 1990;66: Urata H, Kinoshita A, Misono KS, Bumpus FM, Husain A. Identification of a highly specific chymase as the major angiotensin II-forming enzyme in the human heart. J Biol Chem. 1990;265: Juillerat L, Nussberger J, Menard J, Mooser V, Christen Y, Waeber B, Graf P, Brunner HR. Determinants of angiotensin II generation during converting enzyme inhibition. Hypertension. 1990;16: Biollaz J, Brunner HR, Gavras I, Waeber B, Gavras H. Antihypertensive therapy with MK-421: angiotensin II - renin relationships to evaluate efficacy of converting enzyme blockade. J Cardiovasc Pharmacol. 1982;4: Lijnen P, Staessen J, Fagard R, Amery A. Increase in plasma aldosterone during prolonged captopril treatment. Am J Cardiol. 1982;49: Bonner G, Preis S, Schunk U, Toussaint C, Kaufmann W. Hemodynamic effects of bradykinin on systemic and pulmonary circulation in healthy and hypertensive humans. J Cardiovasc Pharmacol. 1990;15: S46 S Brown NJ, Ryder D, Gainer JV, Morrow JD, Nadeau J. Differential effects of ACE inhibitors on the vasodepressor and prostacyclin responses to bradykinin. J Pharmacol Exp Ther. 1996;279: Swartz S, Williams G, Hollenberg N, Levine L, Dluhy R, Moore T. Captopril-induced changes in prostaglandin production. J Clin Invest. 1980;65: Tanaka S, Shimamoto K, Ando T, Nakahashi Y, Ura N, Hosoda S, Ishida H, Yamaji I, Yokoyama T, Masuda A, Iimura O. Role of reninangiotensin and kallikrein-kinin systems on the mechanism of the hypotensive effects of converting enzyme inhibitor, alacepril. Clin Exp Hypertens. 1987;A9: Dzau VJ, Swartz SL. Dissociation of the prostaglandin and renin angiotensin systems during captopril therapy for chronic congestive heart failure secondary to coronary artery disease. Am J Cardiol. 1987;60: Johnston CI, Millar JA, McGrath BP, Matthews PG. Long-term effects of captopril (SQ-14225) on blood pressure and hormone levels in essential hypertension. Lancet. 1979;2: Shoback DM, Williams GH, Swartz SL, Davies RO, Hollenberg NK. Time course and effect of sodium intake on vascular and hormonal responses to enalapril (MK 421) in normal subjects. Cardiovasc Pharmacol. 1983;5: Stanek B, Silberbauer K. Acute and chronic effects of captopril on bicyclo-pgem, the stable bicyclic end product of prostaglandin E 2 in essential hypertension. Nephron. 1986;44:40 45.

8 1418 ACE Inhibitors 46. Vlasses PH, Ferguson RK, Smith JB, Rotmensch HH, Swanson BN. Urinary excretion of prostacyclin and thromboxane A 2 metabolites after angiotensin converting enzyme inhibition in hypertensive patients. Prostaglandins Leukot Med. 1983;11: Witzgall H, Scherer B, Weber PC. Involvement of prostaglandins in the actions of captopril. Clin Sci. 1982;63:265S 267S. 48. Gerber JG, Giuliano F, Byyny RL, LoVerde M, Nies AS. The hypotensive action of captopril and enalapril is not prostacyclin dependent. Clin Pharmacol Ther. 1993;54: Hornych A, Safar M, Simon A, Levenson J, Bariety J, Milliez P. Effects of captopril on prostaglandin and natriuresis in patients with essential hypertension. Am J Cardiol. 1982;49: Ogihara T, Maruyama A, Hata T, Mikami H, Nakamaru M, Naka T, Ohde H, Kumahara Y. Hormonal responses to long-term converting enzyme inhibition in hypertensive patients. Clin Pharmacol Ther. 1981; 36: Omata K, Abe K, Tsunoda K, Yasujima M, Chiba S, Sata M, Kudo K, Yoshinaga K. Role of endogenous angiotensin II and prostaglandins in the antihypertensive mechanism of angiotensin converting enzyme inhibitor in hypertension. Clin Exp Hypertens. 1987;A9: Hock FJ, Wirth K, Albus U, Linz W, Gerhards HJ, Wiemer G, Henke S, Breipohl G, König W, Knolle J, Schölkens BA. Hoe 140 a new potent and long acting bradykinin antagonist: in vitro studies. Br J Pharmacol. 1991;102: Wirth K, Hock FJ, Albus U, Linz W, Alpermann HG, Anagnostpoulos H, Henke S, Breipohl G, Konig W, Knolle J, Scholkens BA. Hoe 140 a new potent and long acting bradykinin antagonist: in vivo studies. Br J Pharmacol. 1991;102: Bouaziz H, Joulin Y, Safar M, Benetos A. Effects of bradykinin B 2 receptor antagonism on the hypotensive effects of ACE inhibition. Br J Pharmacol. 1994;113: Linz W, Scholkens BA. A specific B 2 -bradykinin receptor antagonist HOE 140 abolishes the antihypertrophic effect of ramipril. Br J Pharmacol. 1992;105: Gainer JV, Morrow JD, King DJ, Brown NJ. HOE 140 attenuates the hypotensive effect of captopril in humans. Hypertension. 1997;30:497. Abstract. 57. Hornig B, Kohler C, Drexler H. Role of bradykinin in mediating vascular effects of angiotensin-converting enzyme inhibitors in humans. Circulation. 1997;95: Lund-Johansen P, Omvik P. Long-term haemodynamic effects of enalapril (alone and in combination with hydrochlorothiazide) at rest and during exercise in essential hypertension. J Hypertens. 1984;2:S49 S Ibsen H, Egan B, Osterzeil K, Vander A, Julius S. Reflex-hemodynamic adjustments and baroreflex sensitivity during converting enzyme inhibition with MK-421 in normal humans. Hypertension. 1983;5(suppl I):I-184 I Dunn GF, Oigman W, Ventura HO, Messerli FH, Kobrin I, Frolich ED. Enalapril improves systemic and renal hemodynamics and allows regression of left ventricular mass in essential hypertension. Am J Cardiol. 1984;53: Simon AC, Levenson JA, Bouthier J, Maarek B, Safar ME. Effects of acute and chronic angiotensin enzyme inhibition on large arteries in human hypertension. J Cardiovasc Pharmacol. 1985;7:S45 S Cody RJ, Tarazi RC, Bravo EL, Fouad FM. Haemodynamics of orallyactive converting enzyme inhibitor (SQ 14225) in hypertensive patients. Clin Sci Mol Med. 1978;55: Fouad FM, Tarazi RC, Bravo EL. Cardiac and haemodynamic effects of enalapril. J Hypertens. 1983;1(suppl 1): Fagard R, Amery A, Reybrouck T, Lijnen P, Billiet L. Acute and chronic systemic and hemodynamic effects of angiotensin converting enzyme inhibition with captopril in hypertensive patients. Am J Cardiol. 1980; 46: Tarazi RC, Bravo EL, Fouad FM, Omvik P, Cody RJ. Hemodynamic and volume changes associated with captopril. Hypertension. 1980;2: Muiesan G, Alicandri CL, Agabiti-Rosei E, Fariello R, Beschi M, Boni E, Castellano M, Moniti E, Muiesan L, Romanelli G, Zanielli A. Angiotensin-converting enzyme inhibition, catecholamines and hemodynamics in essential hypertension. Am J Cardiol. 1982;49: Mimran A, Brunner HR, Turini GA, Waeber B, Brunner D. Effect of captopril on renal vascular tone in patients with essential hypertension. Clin Sci. 1979;57:421S 423S. 68. Hollenberg NK, Meggs LG, Williams GH, Katz J, Garnic JD, Harrington DP. Sodium intake and renal responses to captopril in normal man and in essential hypertension. Kidney Int. 1981;20: Atlas SA, Case DB, Sealey JE, Laragh JH, Mckinstry DN. Interruption of the renin-angiotensin system in hypertensive patients by captopril induces sustained reduction in aldosterone secretion, potassium retention and natriuresis. Hypertension. 1979;1: Vidt DG, Bravo EL, Fouad FM. Captopril. N Engl J Med. 1982;306: Todd PA, Heel RC. Enalapril: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in hypertension and congestive heart failure. Drugs. 1986;31: Pool JL, Gennari J, Goldstein R, Kochar MS, Lewin AJ, Maxwell MH, McChesney JA, Mehta J, Nash DT, Nelson EB, Rastogi S, Rofman B, Weinberger M. Controlled multicenter study of antihypertensive effects of lisinopril, hydrochlorothiazide, and lisinopril plus hydrochlorothiazide in the treatment of 394 patients with mild to moderate essential hypertension. J Cardiovasc Pharmacol. 1987;3:S36 S Case DB, Atlas SA, Laragh JH, Sullivan PA, Sealey JE. Use of first-dose response or plasma renin activity to predict the long-term effect of captopril: identification of triphasic pattern of blood pressure response. J Cardiovasc Pharmacol. 1980;2: Given BD, Taylor T, Hollenberg NK, Williams GH. Duration of action and short-term hormonal responses to enalapril (MK-421) in normal subjects. J Cardiovasc Pharmacol. 1984;6: Waeber B, Gavras I, Brunner HR, Cook CA, Charocopos F, Gavras HP. Prediction of sustained antihypertensive efficacy of chronic captopril therapy: relationships to immediate blood pressure response and control plasma renin activity. Am Heart J. 1982;103: Waeber B, Brunner HR, Brunner DB, Curtet AL, Turini CA, Gavras H. Discrepancy between antihypertensive effect and angiotensin converting enzyme inhibition by captopril. Hypertension. 1980;2: Ujhelyi MR, Ferguson RJ, Vlasses PH. Angiotensin-converting enzyme inhibitors: mechanistic controversies. Pharmacotherapy. 1989;9: Veterans Administration Co-operative Study Group of Antihypertensive Agents. Racial differences in response to low-dose captopril are abolished by the addition of hydrochlorothiazide. Br J Clin Pharmacol. 1982;14:97S 101S. 79. Materson BJ, Reda DJ, Cushman WC, Massie BM, Freis ED, Kochar MS, Hamburger RJ, Fye C, Lakshman R, Gottdiener J, Ramirez EA, Henderson WG. Single drug therapy for hypertension in men: a comparison of six antihypertensive agents with placebo. N Engl J Med. 1993;328: Freis ED, Materson BJ, Flamenbaum W. Comparison of propanolol or hydrochlorothiazide alone for treatment of hypertension, III: evaluation of the renin-angiotensin system. Am J Med. 1983;74: Creditor M, Loschky U. PRA in hypertension. Am J Med. 1967;43: Wisenbaugh PE, Garst JB, Hull C, Freedman RJ, Matthews DN, Haddy M. Renin, aldosterone, sodium and hypertension. Am J Med. 1972;52: Weir MR, Gray JM, Paster R, Saunders E. Differing mechanisms of action of angiotensin-converting enzyme inhibition in black and white hypertensive patients. Hypertension. 1995;26: Dusing R, Kayser G, Wagner S, Scherf H, Glanzer K, Predel HG, Kramer HJ. Baroreflex setting and sensitivity in normal subjects: effects of pharmacologic inhibition of the angiotensin I converting enzyme. Am J Cardiol. 1987;59:50D 54D. 85. Guidicelli JF, Berdeaux A, Edouard A, Richer C, Jacolot D. The effect of enalapril on baroreceptor mediated reflex function in normotensive subjects. Br J Clin Pharmacol. 1985;20: Ajayi AA, Campbell BC, Meredith PA, Kelman AW, Reid JL. The effect of captopril on the reflex control heart rate: possible mechanisms. Br J Clin Pharmacol. 1985;20: Giannattasio C, Grassi G, Seravalle G, Morganti A, Zanchetti A, Mancia G. Investigation of reflexes from volume and baroreceptors during converting-enzyme inhibition in humans. Am Heart J. 1989;117: Sixth report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI). Arch Intern Med. 1997;157: Hansson L. The Captopril Prevention Project (CAPPP): description and status. Am J Hypertens. 1994;7:82S 83S.