ANGIOTENSIN-CONVERrING ENZYME INHIBITORS: A COMPARATIVE REVIEW JohnJ. Raia, Jr., Joseph A. Barone, Wesley G. Byerly, and Clifton R. Lacy
ABSTRACf: The chemistry, pharm acology, pharmacokinetics, adverse effects, and dosages of the three currently available angiotensinconverting enzyme (ACE) inhibitors are reviewed. This class of agents effectively inhibits the conversion of angiotensin I to the active vasoconstrictor angiotensin II, a hormone that also promotes, via aldosterone stimulation, increased sodium and water retention . The ACE inhibitors, therefore , are capable of lowering blood pressure primarily by promoting vasodilitation and reducing intravascular fluid volume . Captopril , the first orally act ive. commercially available ACE inhibitor, is a sulfhydryl-co ntaining compound. Captopril was followed by the introduction of enalapril and lisinopril. two non-sulfhydryl ACE inhibitors . The phannacokinetic profiles of these three ACE inhibitors differ. Captopril has rapid onset with relatively shor t duration of action , whereas enalapril and lisinopril have slower onset and relatively long duration of action . Captopril is an act ive ACE inhibitor in its orally absorbable parent form . In contrast. enalapril must be deesterified in the liver to the metabolite enalaprilat in order to inhibit the converting enzyme; this accounts for its delayed onset of action. Lisinopril does not require metabolic activation to be effective; however, a slow and incomplete absorption pattern explains the delay in onset of act ivity. Captopril and its disulfide metabol ites are primarily excreted in the urine with minor elimination in the feces . Approximately two-thirds of an administered enalapril dose is excreted in the urine as both the parent drug and the metabolite enalaprilat; the remainder of these two substances are excreted in the feces . Lisinopril does not undergo measurable metabolism and approximately one-third is excreted unchanged in the urine with the remain ing parent drug being excreted in the feces. The ACE inhibitors lower systemic vascular resistance with a resultant decrease in blood pressure. Their efficacy is comparable to diuretics and beta-blockers in treating patients with mild, moderate, or severe essential and renovascular hypertension . In those patients with severe congestive heart failure (CHF) the ACE inhibitors produce a reduction in systemic vascular resistance, blood pressure, pulmonary capillary wedge pressure , and pulmonary artery pressure . These drugs may produce improvement in cardiac output and stroke volume and , with chronic administration. may promote regression of left ventricular hypertrophy. The antihypertensive effects of the ACE inhibitors are enhanced when these agents are combined with a diuretic. Captopril and enalapril have been shown to be of particular benefit as adjunctive therapy in patients with congestive heart failure, both in terms of subjective improvement of patient symptoms, and in improving overall hemodynamic status . Although only captopril and enalapril are currently approved by the Food and Drug Administration for the treatment of CHF. early datawith lisinopril JOHN J. RAIA, JR. , Phann .D .. is an Assistant Professor of Clinical Phannac y; JOSEPH A. BARONE, Phann.D. • is an Associate Professorof Clinical Pharmacy, and the Chairman, Department of Pharmacy Practice and Administration ; WESLEY G. BYERLY. Phann.D.• is an Assistant Professor of Clinical PharmacY. CoUegeof Pharmacy. Rutgers University.Piscataway. NJ. andRobert Wood Johnson UniversityHospital. New Brunswick. NJ; and CLIFTON R. LACY, M.D., is an AssistantProfessorof Medicine, Division of Cardiovascular Diseases and Hypertension, UMDNJ-Robert WoodJohnsonMedicalSchool andUniversityHospital, New Brunswick. NJ. Reprints: John J. Raia, Jr.• Phann.D.
This article is approved for continuing education credit.
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A. CAPTOPRIL (actMo drug)
B . ENALAPRIL (prodrug)
C . ENALAPRILAT (active drug )
D. L1SINOPRIL (act..... drug)
Figure I . The graphic formulas of captopril (A). enalapril (B), enalaprilat (C ). and lisinopril (D).
suggest beneficial effects comparable to those of captopril. Several unapproved, experimental uses for ACE inhibitors have recently been reported and include treatment of prote inuria, scleroderma renal crisis , idiopathic edema, Raynaud's syndrome , and hypertensive emergency. The ACE inhibitors as a group are generally effective and well tolerated in most patients, although the adverse effect profile may vary somewhat among individual agents.
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are the three orally active angiotensin-converting enzyme (ACE) inhibitors currently available in the U.S. Enalaprilat, the active metabolite of enalapril, is available as a parenteral preparation. This article reviews the chemistry, comparative pharmacology. pharmacokinetics, and toxicity of these ACE inhibitors and critically compares them as treatment modalities for hypertension and congestive heart failure. CAPTOPRIL, ENALAPRIL, AND LISINOPRIL
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Development and Chemistry ofthe ACE Inhibitors . The development of the ACE inhibitors began with the discovery of a "bradykinin potentiating factor" in the ve~om of the South American pit viper Bothrops jararaca,' This factor was determined to be a mixture of peptides that inhibit kininase II, an enzyme that catalyzes the breakdown of bradykinin. 2 Kininase II is the only known enzyme capable of converting angiotensin I to angiotensin II and is, therefore, also known as angiotensin-converting enzyme. 2 One component of the snake venom is teprotide which, although useful as an ACE inhibitor, has a short half-life and is effective only when administered parenterally. 3 Based ?n findings with teprotide, chemists synthesized captopnl, the first orally active ACE inhibitor," ACE inhibitors may be classified according to their structural element that interacts with the zinc ion in the converting enzyme. 5 Captopril is a dipeptide thiol (sulfurcontaining) compound known chemically as L-proline, ~-[(~~-3-mer~~pto-2-oxopropyl](Figure IA).6 Captopril 's inhibitory activity results primarily from the interaction of its sulfhydryl moiety with the zinc ion in the converting enzyme: The strength of this bond causes captopril to have an affinity for ACE that is many times greater than that of the naturally occurring substrate; angiotensin I. 7 Th~ sUI~ydryl component of captopril has been implicated in various adverse effects experienced with this drug including skin rash and loss of taste sense." Researchers attempted to formulate non-sulfur-containing ACE inhibitors an~, ~s a result, developed enalapril and lisinopril. Enalapnl IS a mono-ethyl ester of a substituted N-carboxymethyl dipeptide in which the two constituent amino acids forming the dipeptide are L-alanine and t.-proline." Enalapril is known chemically as L-proline I-[N-[l- (etoxycarbonyl)-3-phenylpropyl]-L-alanyl-,(S)-,(Z)-2- butenedioate (Figure IB). 6 Enalapril is an orally active prodrug that is hepatically metabolized via ester hydrolysis to the active inhibitory form, enalaprilat. Enalaprilat, which is much less effective when administered orally, is available as a ~arenteral preparation and is known chemically as t-proh.ne, 1- [N-I-carboxy-3-pheny Ipropyl)-L-alanyl]-, dihydrate.rS) (Figure IC).6 Lisinopril, the most recently introduced ACE inhibitor is a lysine analog of enalaprilat (Figure 10). It is know~ chemically as L-proline, Nl-(1-carboxy-3-phenylpropyl)L~lysyl)-~ihydrate, (S) (Figure 10).10 Unlike enalapril, lisInopnl.ls no.t a rrodrug, and therefore does not require metabolic activation to produce inhibition of ACE. U
Angiotensin-converting enzyme is a rather nonspecific metalloenzyme (containing zinc) that is widely distributed throughout the body, including the lungs, kidneys, brain, and blood vessels." Angiotensin I is converted via ACE t? angiotensin II, an octapeptide with potent vasoconstrictive properties. In addition, angiotensin II stimulates the adrenal cortex to synthesize and secrete aldosterone, a hormone that acts on the cortical collecting tubules of the kidney to promote reabsorption of sodium and water and i~crease e~cretion of potassium. The presence of angioten~m ~I: and Its degra?ation prod~ct angiotensin III, normally mhlbl~s furt.her rem~ release via a negative feedback loop, effectively mterruptmg the RAA cascade." Angiotensin II formation therefore results in vasoconstriction and expansion of blood volume, which usually produces an increase in systemic BP. . In addition.to the conversion of angiotensin I to angiotens~n II, AC~ IS ~apable.of degrading bradykinin (a vasodilator) to mactive peptides." ACE, which is identical to kininase II, therefore promotes both the formation of the ~asoconstrictor angiotensin II and enhances the degradation of the vasodilator bradykinin, although other endogenous enzymes are also capable of catalyzing bradykinin. 12 It has.bee~ found that bradykinin activates phospholipase, resultmg In the formation of vasodilatory prostaglandins. Further, bradykinin causes the release of another vasodilator, histamine." It is clear that inhibition of the ACE enzyme may have widespread effects on the vascular system d~e to the many actions of angiotensin II, kinins, and associated prostaglandins. 12 A diagrammatic summary of the RAA system and the important consequences of ACE inhibition appears in Figure 2.
A
Prostaglandins
t
Bradykinin
I
Renin
BP t
IACEIJ
Angiotensin I t
_
--------.-
vascccnsmcsen
The renin-angiotensin-aldosterone (RAA) system plays a major role. in the maintenance of blood volume, blood pressure, and electrolyte homeostasis. 12 Renin is an enzyme released from renal juxtaglomerular cells at the vascular pole ofthe kidney in response to: (1) a fall in systemic blood pressure from any cause (e.g., reduction in blood volume, drop in systemic resistance, decrease in cardiac output), (2) a reduction in sodium load to the kidneys, and (3) sympathetic nervous stimulation secondary to a fall in blood pressure (BP), painful stimuli, or stressful emotional states." Renin, in turn, catalyzes the conversion of angiotensinogen to angiotensin I, a relatively inactive decapeptide prohormone."
Inactive Kinins t Angiotensin II t
f ••
Na·t Volume
I
I
t ..- Aldosterone Release t Prostaglandins t
B
R~m~n~mm~~~rone~~m
J.
~
Angiotensinogen
nun.- +
J.
t
Bradykinin t
~
Angiotensinogen
t
BP,
+
IACEIJ Inactive Kinins J. Angiotensin I r --------.- Angiotensin II J.
tRenin -----.-
_
"""",,,,"-, • •
Na·J. Volume J. . . - Aldosterone Release
I I
J.
Figure 2. Diagrammatic summary of the major components oflhe renin-angiotensinaldosterone system and. below. the consequences of ACE inhibition.
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Comparative Clinical Pharmacology ofACE Inhibitors
The ability of angiotensin-converting enzyme to convert angiotensin I to angiotensin II is markedly reduced during therapy with captopril, enalapril, enalaprilat, and lisinopri\. The effects of ACE inhibitors on the RAA system generally depend on the state of activation of this system, and the overall pathophysiologic state of the patient. The complex clinical effects of ACE inhibition appear to be a result of inhibition of the RAA system as well as interference with a breakdown pathway of vasodilating kinins, both in the plasma and in tissues . Bradykinin is also degraded by enzymes other than ACE, which may affect the overall impact of ACE inhibition on the kinin system." After administration of captopril, enalapril, or Iisinopril, there is a marked reduction in plasma angiotensin II and aldosterone and an increase in angiotensin I and plasma renin activity. IS
STRUCTURE-ACTIVITY RELATIONSHIPS
An effective ACE inhibitor must be designed as a compatible molecule to occupy obligatory angiotensin I binding sites on ACE, with a high degree of specificity and enhanced affinity." As a result, angiotensin I is denied access to these binding sites on ACE and subsequent cleavage to the active angiotensin II molecule does not occur. The inhibitory molecule should also possess a relatively long therapeutic half-life, which is a desirable characteristic for optimal clinical utility. Captopril is hypothesized to interact with ACE via five chemical bonds including the sulfhydryl-zinc binding site." A conceptualized model of captopril binding to the obligatory sites of the ACE enzyme is shown in Figure 3A. Captopril is a stable inhibitor since it cannot be cleaved by ACE or by most other peptidases." Enalaprilat, the active metabolite of enalapril, is proposed to have seven binding sites to the ACE molecule (Figure 3B).17 The portion of enalaprilat that binds with the zinc atom of the ACE moledule is a carboxyl group, which is relatively weak when compared with the sulfur-zinc ligand of captopril." However, the addition of more binding sites (seven for enalaprilat vs. five for captopril) compensates for this deficiency and actually produces an ACE inhibitor that is even more potent than captopril. S Lisinopril, the lysine analog of enalaprilat, probably exhibits an analogous binding pattern with the ACE molecule as well (Figure 3C). The substitution of lysine on the enalaprilat molecule results in a converting-enzyme inhibitor that is orally absorbed in its active form and has a potency and affinity for the ACE molecule equal to that of enalapril."
Figure 3A. A conceptualized model of captopril, iIIuS1rllling 1he five proposed binding sites 10 a representation of the angiotensin-converting enzyme (ACE).
Figure 38 . A conceptualized model of enalaprilat, illustrating 1he seven proposed binding sites to a representation of the angiotensin-converting enzyme (ACE).
PHARMACOKINETICS
Captopril Absorption. Radiolabeled captopril has been shown to be rapidly absorbed from the gastrointestinal tract, following oral administration in healthy fasting individuals , with plasma concentrations being detected in as little as 15 minutes .P' Studies examining urinary excretion of radioactive captopril determined that approximately 60-70 percent of a 100-mg dose of captopril was absorbed orally.21.22 The bioavailability of captopril has been reported to be as high as 91 percent in normal fasting subjects after the administration of 100 mg of the drug. 23 508
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Figure 3C. A conceptualized model of lisinopril, illustrating the seven proposed binding sites to a representation of the angiotensin-converting enzyme (ACE).
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ACE Inhibitors Review
In one study, ten normal subjects were given captopril 100 mg po, with a resultant mean time to maximum concentration (lmax) in the blood of 0.93 ±0.08 hours and a range of 0.5 and 1.5 hours. Wide intersubject variation in maximum concentrations (C max ) of captopril was observed with a mean of 3681 ± 350 nmollL and range of 2347 - 6029 nmollL. 21 In another study, administration of radiolabeled captopril 10 mg po to normal subjects was shown to result in a mean tmax value of 0.70 ± 0.05 hours and a mean C max value of 318 ±38 nmol/L." Despite the variability of mean C max values reported in these studies, evidence of dose proportionality does exist in terms of observed serum concentrations of captopril. There is some debate concerning the effect of food on the bioavailability and/or clinical efficacy of captopril. Singhvi et al. administered 100 mg of radiolabeled captopril to normal volunteers using a two-way crossover design, in which subjects were either fasting or were given a standard meal just prior to dosing. Total urinary recovery of labeled captopril in subjects given food was found to be approximately 65 percent of that seen in volunteers in the fasting state, indicating that the bioavailability of captopril is decreased approximately 35-50 percent when administered with a meal. One would suspect, therefore, that food could alter the effect of captopril. On the other hand, a longer-term study of patients randomly given captopril with and without concomitant food intake showed peak plasma concentrations and area under the plasma concentration-time curve (AUC) to be only slightly reduced when captopril was administered with food.P' In addition, Salvetti et al. examined the acute and chronic effects of food on captopril's ability to lower blood pressure. In both the acute and chronic phases of the study, there was no significant difference in the extent or duration of mean BP decrease in patients who were given captopril either in the fasting state or immediately after a standard meal. 2S It is highly probable that the vasodilator effect of captopril (and all ACE inhibitors) is dependent on the inhibition of angiotensin II formation and not a direct action of the drug on vascular tone. It may therefore be reasonable to hypothesize that even if food were to reduce captopril bioavailability, sufficient drug is still available to bind to ACE and prevent angiotensin II formation. 26 For exam pie, the pressor response to angiotensin I in normal subjects given captopril 10 mg has been shown to be similar to patients given 20 mg of captopril. The observed duration of hypertensive effect was shorter, however, after the IO-mg dose compared with the 20-mg dose."
Enalapril Absorption. When normal volunteers were given enalaprillO mg, urinary recovery oftotal drug (enalapril plus enalaprilat) indicates an overall absorption of at least 61 percent. Peak serum concentrations were found to occur between 0.5 and 1.5 hours after administration." In another study, Irvin et al. compared the absorption of enalapril adminstered in doses of 5,10,20, and 40 mg po, with enalaprilat 5 mg in 10 healthy subjects. The percent absorbed (59-73 percent) was comparable for the different dose strengths, with the exception that it was greater for the lO-mg dose. Using the intravenous enalaprilat as a reference, the oral bioavailability of enalapril as enalaprilat was found to be 36-44 percent. 27 Following a lO-mg oral dose of enalapril, the mean C max for the parent drug was found to be 140 ± 52 nmollL and the
mean C max for enalaprilat was 116± 50 nmol/L." A delay in mean tmax of 4.0 ± 1.5 hours was observed in this study and is consistent with the finding that intact enalapril is detectable in the blood for four hours or less. An examination of enalaprilat serum concentrations versus time profiles following oral administration of enalapril 5, 10, 20, and 40 mg indicated that serum C max was proportional to dose." A high degree of correlation exists among plasma enalaprilat levels, degree of ACE inhibition, and decreases in BP after both acute and chronic enalapril administration in hypertensive patients. 28 The effect of food on enalapril bioavailability was investigated in 12 normal subjects following the oral administration of 40 mg, either in the fasting state or after a standard breakfast. The results indicated that, in terms of C max ,tmax, and AUC, there was no significant difference between enalapril taken in the fasting state, compared with administration following a standardized meal. 29 Therefore, food may not affect the absorption and bioavailability of enalapril as it apparently does with captopril. Lisinopril Absorption. The absorption and bioavailability profile of lisinopril was examined in 12normal male volunteers who were given 10 mg/d. The absorption of lisinopril was found to be slow and incomplete in these subjects. Ninety-seven percent of the dose administered was recovered as unchanged drug. A mean of 69 percent was found in the feces and a mean of 29 percent in the urine." Other studies, using doses ranging from 5 to 80 mg, have determined that the mean extent of absorption based on urinary recovery of drug is 25 percent, with a large interpatient variability (range 6-60 percent). 30 Mean 1max of 10 mg of lisinopril has been determined to be 6-8 hours with a C max value of 95 nmollL. 19 Mojaverian et al. studied the effect of food on the rate of lisinopril absorption in 18normal subjects. In this crossover study, volunteers received a single 20-mg oral dose of lisinopril either in the fasting state or immediately after a standardized breakfast. Timed blood and urine samples were collected after the administration of each dose. Mean C max was determined to be 195 ± 109 nmol/L for the fasting state and 156 ± 43 nmollL for those who received a standardized meal. Time to peak serum concentration was found to be 6.2 ± 1.1 hours and 6.8 ± 1.0 hours for the fasting and fed states, respectively. In addition, the mean urinary recovery of lisinopril was 27.2 ± 15.0 percent for the fasting state and 25.7 ± 10.0 percent after the standardized meal. It is concluded, therefore, that food does not affect the absorption or bioavailability of lisinopril. Captopril Distribution. In an animal model, radiolabeled captopril has been shown to distribute rapidly into most tissues, with the exception of the central nervous system. 2O It is not known if captopril crosses the placenta in humans; but studies of pregnant rats show that the drug will reach the placenta.P Captopril is apparently not readily secreted in the breast milk of humans, with detectable concentrations being less than one percent of peak blood con-
centrations." Captopril is approximately 30 percent protein-bound. 32 Studies of its disposition in animal models indicate that it exhibits the characteristics of a two-compartment open model, with drug being distributed through the central compartment (blood and highly vascularized organs) and to a peripheral tissue compartment." One study of cap-
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topril disposition in humans reported that the calculated volume of distribution (Vd) of the central compartment was 0.22 Llkg and the Vd during the elimination phase was 2.05 Llkg. The Vd at steady-state (V:) in this study was 0.7 Llkg.22 Migdalof et al. report the Vd of captopril as being 0.6 Llkg. 3s These data indicate that there is extensive partitioning of captopril into the tissues and that the drug's disposition may best be described by a three-compartment model consisting of two peripheral compartments in addition to the central compartment. 34
Enalapril Distribution. The precise nature of enalapril tissue distribution in humans has yet to be determined. 8Enalaprilat apparently does not penetrate into the central nervous system in the dog." It is not known if enalapril or enalaprilat transfers across the placenta or enters into breast milk." Enalaprilat has been reported to be less than 50 percent bound to human plasma protein." Davies et al. identified two binding sites for enalaprilat to plasma protein, one with low affinity and high capacity and another with high affinity and low capacity, with the latter conceivably representing enalaprilat binding to circulating ACE. 36 It is probable that the level of ACE inhibition in various tissues, rather than the binding to circulating ACE, is of more relevance to the antihypertensive effect of enalapril. 8 The V: of enalaprilat has been calculated in a group of healthy elderly volunteers (aged 65-76 years) and a group of healthy young volunteers (20-27 years) with both groups receiving 10 mg iv. The V: of enalaprilat for the elderly group of subjects was found to be lower (0.28 ± 0.08 Llkg) than that for the young subjects (0.38 ± 0.06 Llkg).37 It is possible that these differences are attributable to alterations in tissue-binding capacity encountered in the geriatric population. Lisinopril Distribution. Lisinopril apparently does not bind to plasma proteins other than ACE.38 The significance of this lack of binding to other proteins has not yet been ascertained. Ajayi et al. studied the pharmacokinetics of oral lisinopril with the use of a computer model that provided mean population parameter estimates using a one-compartment open model. The apparent Vd was calculated using the relative bioavailability (F). The derived mean Vd/F was determined to be 124 ± 16 L in the population studied. 39 Captopril Metabolism and Excretion. In the presence of plasma, captopril is partially oxidized at the sulfhydryl group to form several metabolites, including a disulfide dimer of captopril, a captopril-cysteine disulfide, and other mixed disulfides with endogenous thiol compounds. 20 Kripalani et al. administered radiolabeled captopril to normal subjects and found that at tmax, 52 percent of the total radioactivity in the blood was in the form of unchanged captopril, 10 percent as the unchanged dimer, and the remainder as polar metabolites." Captopril and its disulfide metabolites are primarily excreted in the urine with minor elimination in the feces. 20 Following oral administration of radiolabeled captopril to healthy volunteers, 67.5 percent of the total radioactivity recovered appeared in the urine and 18.3 percent was found in the feces." The fecal excretion of captopril observed in humans may represent unabsorbed drug because negligible biliary excretion was found in the dog and monkey following intravenous administration." In humans, the excretion of captopril and its metabolites is relatively rapid, with about 50 510
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percent of the dose recovered in the urine during the first four hours after administration. 22 Duchin et al. recovered 68 percent of an administered dose of captopril from the urine, with 24 percent being unchanged drug. 22 The body and renal clearances (C1r ) of captopril have been calculated to be 775 ± 23 and 388 ± 31 mLlkg/h, respectively. Tubular secretion is the primary means of renal excretion and accounts for 78 percent of radiolabeled captopril recovered in the urine.:" Studies have indicated that the coadministration of probenecid, an inhibitor of organic acid secretion, to subjects receiving captopril reduced the C1r of captopril. 40.41 Duchin et al. found that the elimination half-life (13tY2) of radiolabeled captopril in humans was 1.7 hours after oral dosing and 1.9 hours following intravenous administration. 22 The rate of urinary captopril excretion in patients with varying degrees of renal dysfunction (creatinine "clearance [Cl cr ] 0-56 mLlmin) was shown to decrease with decreasing renal function. The tY2 of captopril and its metabolites increased and was especially pronounced at a C1cr 300 mg) for 12 months and had a cumulative discontinuation rate of 8.5 percent due to adverse reactions. The dose of captopril was reduced in subsequent studies and was accompanied by a significant reduction in adverse reactions experienced and subjects discontinuing therapy.72 The multicenter Veterans Administration Cooperative Study Group examined the efficacy oflow-dose captopril in 495 men with uncomplicated hypertension (diastolic BP 92-109 mm Hg). Patients were randomized to one of five captopril treatment regimens at the following doses taken three times a day: 12.5,25,37.5, or 50 mg or placebo. Following seven weeks of therapy, BP reduction with each dose of captopril (mean decrease 10.2-14.2 mm Hg systolic/8.6-1O.5 mm Hg diastolic) was significantly greater (p>0.003) than in the placebo group (mean decrease 1.6 mm Hg systolic/3.2 mm Hg diastolic). In addition, there were no notable differences in the antihypertensive responses among the various doses of captopril at the end of the seven-week treatment period. 73 Patients who were in the placebo group during the first seven weeks were subsequently given hydrochlorothiazide 25 mg along with placebo for an additional seven weeks, and those subjects who received captopril during the first seven weeks received either a combination of captopril (originally assigned dose) and hydrochlorothiazide 25 mg, or captopril with placebo. The reduction in BP at the end of the second seven-week period averaged 12.0 mm Hg systolic and 8.7 mm Hg diastolic in those patients taking captopril alone. In contrast, the reduction in BP in those given the captopril/hydrochlorothiazide combination averaged about 25 mm Hg systolic and 16 mm Hg diastolic. The results of this study indicate that captopril given alone in doses as small as 37.5 mg/d is effective in reducing BP, and that the addition of hydrochlorothiazide greatly enhances the antihypertensive response. 73 A worldwide postmarketing surveillance study (6737 subjects) examined the efficacy of captopril given alone or in combination with a diuretic to patients who were previously uncontrolled by or who encountered unacceptable adverse effects with standard antihypertensive therapy. The
population studied consisted of individuals with all degrees of hypertension and included patients with impaired renal function. Prior to entry into the study, subjects were receiving an average of 2.3 medications with approximately 10 percent receiving no therapy. A majority (81.7 percent) of the subjects studied were white and 9.7 percent were black. The dose of captopril was to begin at 25 mg tid before increasing, if necessary, to 50 mg tid. A thiazide diuretic could be added if required and further titrations of captopril to a maximum of 450 mg/d were permitted to adequately control BP. BP was evaluated every three months for one year. The mean sitting entry BP despite medication was 183 mm Hg (systolic) and 111 mm Hg (diastolic), indicating that most patients had moderately severe to severe hypertension. The mean daily captopril dose was 152 mg at 3 months and 158 mg at 12 months. Captopril alone (21 percent of patients) or in combination with a diuretic (42 percent) were the only drugs administered to a majority (63 percent) of the population studied. Thirty-one percent required the addition of another antihypertensive agent (usually a beta-blocker) to their regimen of captopril and a diuretic. Depending on time of assessment, captopril given alone or in combination with other agents reduced mean sitting BP in all patients to 148-152 mm Hg systolic and 90-92 mm Hg diastolic. In addition, the results of this study indicate that total daily doses of captopril
ABSTRACf: The chemistry, pharm acology, pharmacokinetics, adverse effects, and dosages of the three currently available angiotensinconverting enzyme (ACE) inhibitors are reviewed. This class of agents effectively inhibits the conversion of angiotensin I to the active vasoconstrictor angiotensin II, a hormone that also promotes, via aldosterone stimulation, increased sodium and water retention . The ACE inhibitors, therefore , are capable of lowering blood pressure primarily by promoting vasodilitation and reducing intravascular fluid volume . Captopril , the first orally act ive. commercially available ACE inhibitor, is a sulfhydryl-co ntaining compound. Captopril was followed by the introduction of enalapril and lisinopril. two non-sulfhydryl ACE inhibitors . The phannacokinetic profiles of these three ACE inhibitors differ. Captopril has rapid onset with relatively shor t duration of action , whereas enalapril and lisinopril have slower onset and relatively long duration of action . Captopril is an act ive ACE inhibitor in its orally absorbable parent form . In contrast. enalapril must be deesterified in the liver to the metabolite enalaprilat in order to inhibit the converting enzyme; this accounts for its delayed onset of action. Lisinopril does not require metabolic activation to be effective; however, a slow and incomplete absorption pattern explains the delay in onset of act ivity. Captopril and its disulfide metabol ites are primarily excreted in the urine with minor elimination in the feces . Approximately two-thirds of an administered enalapril dose is excreted in the urine as both the parent drug and the metabolite enalaprilat; the remainder of these two substances are excreted in the feces . Lisinopril does not undergo measurable metabolism and approximately one-third is excreted unchanged in the urine with the remain ing parent drug being excreted in the feces. The ACE inhibitors lower systemic vascular resistance with a resultant decrease in blood pressure. Their efficacy is comparable to diuretics and beta-blockers in treating patients with mild, moderate, or severe essential and renovascular hypertension . In those patients with severe congestive heart failure (CHF) the ACE inhibitors produce a reduction in systemic vascular resistance, blood pressure, pulmonary capillary wedge pressure , and pulmonary artery pressure . These drugs may produce improvement in cardiac output and stroke volume and , with chronic administration. may promote regression of left ventricular hypertrophy. The antihypertensive effects of the ACE inhibitors are enhanced when these agents are combined with a diuretic. Captopril and enalapril have been shown to be of particular benefit as adjunctive therapy in patients with congestive heart failure, both in terms of subjective improvement of patient symptoms, and in improving overall hemodynamic status . Although only captopril and enalapril are currently approved by the Food and Drug Administration for the treatment of CHF. early datawith lisinopril JOHN J. RAIA, JR. , Phann .D .. is an Assistant Professor of Clinical Phannac y; JOSEPH A. BARONE, Phann.D. • is an Associate Professorof Clinical Pharmacy, and the Chairman, Department of Pharmacy Practice and Administration ; WESLEY G. BYERLY. Phann.D.• is an Assistant Professor of Clinical PharmacY. CoUegeof Pharmacy. Rutgers University.Piscataway. NJ. andRobert Wood Johnson UniversityHospital. New Brunswick. NJ; and CLIFTON R. LACY, M.D., is an AssistantProfessorof Medicine, Division of Cardiovascular Diseases and Hypertension, UMDNJ-Robert WoodJohnsonMedicalSchool andUniversityHospital, New Brunswick. NJ. Reprints: John J. Raia, Jr.• Phann.D.
This article is approved for continuing education credit.
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A. CAPTOPRIL (actMo drug)
B . ENALAPRIL (prodrug)
C . ENALAPRILAT (active drug )
D. L1SINOPRIL (act..... drug)
Figure I . The graphic formulas of captopril (A). enalapril (B), enalaprilat (C ). and lisinopril (D).
suggest beneficial effects comparable to those of captopril. Several unapproved, experimental uses for ACE inhibitors have recently been reported and include treatment of prote inuria, scleroderma renal crisis , idiopathic edema, Raynaud's syndrome , and hypertensive emergency. The ACE inhibitors as a group are generally effective and well tolerated in most patients, although the adverse effect profile may vary somewhat among individual agents.
D1CP Ann Pharmacother 1990;24:506-25.
are the three orally active angiotensin-converting enzyme (ACE) inhibitors currently available in the U.S. Enalaprilat, the active metabolite of enalapril, is available as a parenteral preparation. This article reviews the chemistry, comparative pharmacology. pharmacokinetics, and toxicity of these ACE inhibitors and critically compares them as treatment modalities for hypertension and congestive heart failure. CAPTOPRIL, ENALAPRIL, AND LISINOPRIL
1990 May. Volume 24
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Development and Chemistry ofthe ACE Inhibitors . The development of the ACE inhibitors began with the discovery of a "bradykinin potentiating factor" in the ve~om of the South American pit viper Bothrops jararaca,' This factor was determined to be a mixture of peptides that inhibit kininase II, an enzyme that catalyzes the breakdown of bradykinin. 2 Kininase II is the only known enzyme capable of converting angiotensin I to angiotensin II and is, therefore, also known as angiotensin-converting enzyme. 2 One component of the snake venom is teprotide which, although useful as an ACE inhibitor, has a short half-life and is effective only when administered parenterally. 3 Based ?n findings with teprotide, chemists synthesized captopnl, the first orally active ACE inhibitor," ACE inhibitors may be classified according to their structural element that interacts with the zinc ion in the converting enzyme. 5 Captopril is a dipeptide thiol (sulfurcontaining) compound known chemically as L-proline, ~-[(~~-3-mer~~pto-2-oxopropyl](Figure IA).6 Captopril 's inhibitory activity results primarily from the interaction of its sulfhydryl moiety with the zinc ion in the converting enzyme: The strength of this bond causes captopril to have an affinity for ACE that is many times greater than that of the naturally occurring substrate; angiotensin I. 7 Th~ sUI~ydryl component of captopril has been implicated in various adverse effects experienced with this drug including skin rash and loss of taste sense." Researchers attempted to formulate non-sulfur-containing ACE inhibitors an~, ~s a result, developed enalapril and lisinopril. Enalapnl IS a mono-ethyl ester of a substituted N-carboxymethyl dipeptide in which the two constituent amino acids forming the dipeptide are L-alanine and t.-proline." Enalapril is known chemically as L-proline I-[N-[l- (etoxycarbonyl)-3-phenylpropyl]-L-alanyl-,(S)-,(Z)-2- butenedioate (Figure IB). 6 Enalapril is an orally active prodrug that is hepatically metabolized via ester hydrolysis to the active inhibitory form, enalaprilat. Enalaprilat, which is much less effective when administered orally, is available as a ~arenteral preparation and is known chemically as t-proh.ne, 1- [N-I-carboxy-3-pheny Ipropyl)-L-alanyl]-, dihydrate.rS) (Figure IC).6 Lisinopril, the most recently introduced ACE inhibitor is a lysine analog of enalaprilat (Figure 10). It is know~ chemically as L-proline, Nl-(1-carboxy-3-phenylpropyl)L~lysyl)-~ihydrate, (S) (Figure 10).10 Unlike enalapril, lisInopnl.ls no.t a rrodrug, and therefore does not require metabolic activation to produce inhibition of ACE. U
Angiotensin-converting enzyme is a rather nonspecific metalloenzyme (containing zinc) that is widely distributed throughout the body, including the lungs, kidneys, brain, and blood vessels." Angiotensin I is converted via ACE t? angiotensin II, an octapeptide with potent vasoconstrictive properties. In addition, angiotensin II stimulates the adrenal cortex to synthesize and secrete aldosterone, a hormone that acts on the cortical collecting tubules of the kidney to promote reabsorption of sodium and water and i~crease e~cretion of potassium. The presence of angioten~m ~I: and Its degra?ation prod~ct angiotensin III, normally mhlbl~s furt.her rem~ release via a negative feedback loop, effectively mterruptmg the RAA cascade." Angiotensin II formation therefore results in vasoconstriction and expansion of blood volume, which usually produces an increase in systemic BP. . In addition.to the conversion of angiotensin I to angiotens~n II, AC~ IS ~apable.of degrading bradykinin (a vasodilator) to mactive peptides." ACE, which is identical to kininase II, therefore promotes both the formation of the ~asoconstrictor angiotensin II and enhances the degradation of the vasodilator bradykinin, although other endogenous enzymes are also capable of catalyzing bradykinin. 12 It has.bee~ found that bradykinin activates phospholipase, resultmg In the formation of vasodilatory prostaglandins. Further, bradykinin causes the release of another vasodilator, histamine." It is clear that inhibition of the ACE enzyme may have widespread effects on the vascular system d~e to the many actions of angiotensin II, kinins, and associated prostaglandins. 12 A diagrammatic summary of the RAA system and the important consequences of ACE inhibition appears in Figure 2.
A
Prostaglandins
t
Bradykinin
I
Renin
BP t
IACEIJ
Angiotensin I t
_
--------.-
vascccnsmcsen
The renin-angiotensin-aldosterone (RAA) system plays a major role. in the maintenance of blood volume, blood pressure, and electrolyte homeostasis. 12 Renin is an enzyme released from renal juxtaglomerular cells at the vascular pole ofthe kidney in response to: (1) a fall in systemic blood pressure from any cause (e.g., reduction in blood volume, drop in systemic resistance, decrease in cardiac output), (2) a reduction in sodium load to the kidneys, and (3) sympathetic nervous stimulation secondary to a fall in blood pressure (BP), painful stimuli, or stressful emotional states." Renin, in turn, catalyzes the conversion of angiotensinogen to angiotensin I, a relatively inactive decapeptide prohormone."
Inactive Kinins t Angiotensin II t
f ••
Na·t Volume
I
I
t ..- Aldosterone Release t Prostaglandins t
B
R~m~n~mm~~~rone~~m
J.
~
Angiotensinogen
nun.- +
J.
t
Bradykinin t
~
Angiotensinogen
t
BP,
+
IACEIJ Inactive Kinins J. Angiotensin I r --------.- Angiotensin II J.
tRenin -----.-
_
"""",,,,"-, • •
Na·J. Volume J. . . - Aldosterone Release
I I
J.
Figure 2. Diagrammatic summary of the major components oflhe renin-angiotensinaldosterone system and. below. the consequences of ACE inhibition.
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Comparative Clinical Pharmacology ofACE Inhibitors
The ability of angiotensin-converting enzyme to convert angiotensin I to angiotensin II is markedly reduced during therapy with captopril, enalapril, enalaprilat, and lisinopri\. The effects of ACE inhibitors on the RAA system generally depend on the state of activation of this system, and the overall pathophysiologic state of the patient. The complex clinical effects of ACE inhibition appear to be a result of inhibition of the RAA system as well as interference with a breakdown pathway of vasodilating kinins, both in the plasma and in tissues . Bradykinin is also degraded by enzymes other than ACE, which may affect the overall impact of ACE inhibition on the kinin system." After administration of captopril, enalapril, or Iisinopril, there is a marked reduction in plasma angiotensin II and aldosterone and an increase in angiotensin I and plasma renin activity. IS
STRUCTURE-ACTIVITY RELATIONSHIPS
An effective ACE inhibitor must be designed as a compatible molecule to occupy obligatory angiotensin I binding sites on ACE, with a high degree of specificity and enhanced affinity." As a result, angiotensin I is denied access to these binding sites on ACE and subsequent cleavage to the active angiotensin II molecule does not occur. The inhibitory molecule should also possess a relatively long therapeutic half-life, which is a desirable characteristic for optimal clinical utility. Captopril is hypothesized to interact with ACE via five chemical bonds including the sulfhydryl-zinc binding site." A conceptualized model of captopril binding to the obligatory sites of the ACE enzyme is shown in Figure 3A. Captopril is a stable inhibitor since it cannot be cleaved by ACE or by most other peptidases." Enalaprilat, the active metabolite of enalapril, is proposed to have seven binding sites to the ACE molecule (Figure 3B).17 The portion of enalaprilat that binds with the zinc atom of the ACE moledule is a carboxyl group, which is relatively weak when compared with the sulfur-zinc ligand of captopril." However, the addition of more binding sites (seven for enalaprilat vs. five for captopril) compensates for this deficiency and actually produces an ACE inhibitor that is even more potent than captopril. S Lisinopril, the lysine analog of enalaprilat, probably exhibits an analogous binding pattern with the ACE molecule as well (Figure 3C). The substitution of lysine on the enalaprilat molecule results in a converting-enzyme inhibitor that is orally absorbed in its active form and has a potency and affinity for the ACE molecule equal to that of enalapril."
Figure 3A. A conceptualized model of captopril, iIIuS1rllling 1he five proposed binding sites 10 a representation of the angiotensin-converting enzyme (ACE).
Figure 38 . A conceptualized model of enalaprilat, illustrating 1he seven proposed binding sites to a representation of the angiotensin-converting enzyme (ACE).
PHARMACOKINETICS
Captopril Absorption. Radiolabeled captopril has been shown to be rapidly absorbed from the gastrointestinal tract, following oral administration in healthy fasting individuals , with plasma concentrations being detected in as little as 15 minutes .P' Studies examining urinary excretion of radioactive captopril determined that approximately 60-70 percent of a 100-mg dose of captopril was absorbed orally.21.22 The bioavailability of captopril has been reported to be as high as 91 percent in normal fasting subjects after the administration of 100 mg of the drug. 23 508
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Figure 3C. A conceptualized model of lisinopril, illustrating the seven proposed binding sites to a representation of the angiotensin-converting enzyme (ACE).
1990 May, Volume 24
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ACE Inhibitors Review
In one study, ten normal subjects were given captopril 100 mg po, with a resultant mean time to maximum concentration (lmax) in the blood of 0.93 ±0.08 hours and a range of 0.5 and 1.5 hours. Wide intersubject variation in maximum concentrations (C max ) of captopril was observed with a mean of 3681 ± 350 nmollL and range of 2347 - 6029 nmollL. 21 In another study, administration of radiolabeled captopril 10 mg po to normal subjects was shown to result in a mean tmax value of 0.70 ± 0.05 hours and a mean C max value of 318 ±38 nmol/L." Despite the variability of mean C max values reported in these studies, evidence of dose proportionality does exist in terms of observed serum concentrations of captopril. There is some debate concerning the effect of food on the bioavailability and/or clinical efficacy of captopril. Singhvi et al. administered 100 mg of radiolabeled captopril to normal volunteers using a two-way crossover design, in which subjects were either fasting or were given a standard meal just prior to dosing. Total urinary recovery of labeled captopril in subjects given food was found to be approximately 65 percent of that seen in volunteers in the fasting state, indicating that the bioavailability of captopril is decreased approximately 35-50 percent when administered with a meal. One would suspect, therefore, that food could alter the effect of captopril. On the other hand, a longer-term study of patients randomly given captopril with and without concomitant food intake showed peak plasma concentrations and area under the plasma concentration-time curve (AUC) to be only slightly reduced when captopril was administered with food.P' In addition, Salvetti et al. examined the acute and chronic effects of food on captopril's ability to lower blood pressure. In both the acute and chronic phases of the study, there was no significant difference in the extent or duration of mean BP decrease in patients who were given captopril either in the fasting state or immediately after a standard meal. 2S It is highly probable that the vasodilator effect of captopril (and all ACE inhibitors) is dependent on the inhibition of angiotensin II formation and not a direct action of the drug on vascular tone. It may therefore be reasonable to hypothesize that even if food were to reduce captopril bioavailability, sufficient drug is still available to bind to ACE and prevent angiotensin II formation. 26 For exam pie, the pressor response to angiotensin I in normal subjects given captopril 10 mg has been shown to be similar to patients given 20 mg of captopril. The observed duration of hypertensive effect was shorter, however, after the IO-mg dose compared with the 20-mg dose."
Enalapril Absorption. When normal volunteers were given enalaprillO mg, urinary recovery oftotal drug (enalapril plus enalaprilat) indicates an overall absorption of at least 61 percent. Peak serum concentrations were found to occur between 0.5 and 1.5 hours after administration." In another study, Irvin et al. compared the absorption of enalapril adminstered in doses of 5,10,20, and 40 mg po, with enalaprilat 5 mg in 10 healthy subjects. The percent absorbed (59-73 percent) was comparable for the different dose strengths, with the exception that it was greater for the lO-mg dose. Using the intravenous enalaprilat as a reference, the oral bioavailability of enalapril as enalaprilat was found to be 36-44 percent. 27 Following a lO-mg oral dose of enalapril, the mean C max for the parent drug was found to be 140 ± 52 nmollL and the
mean C max for enalaprilat was 116± 50 nmol/L." A delay in mean tmax of 4.0 ± 1.5 hours was observed in this study and is consistent with the finding that intact enalapril is detectable in the blood for four hours or less. An examination of enalaprilat serum concentrations versus time profiles following oral administration of enalapril 5, 10, 20, and 40 mg indicated that serum C max was proportional to dose." A high degree of correlation exists among plasma enalaprilat levels, degree of ACE inhibition, and decreases in BP after both acute and chronic enalapril administration in hypertensive patients. 28 The effect of food on enalapril bioavailability was investigated in 12 normal subjects following the oral administration of 40 mg, either in the fasting state or after a standard breakfast. The results indicated that, in terms of C max ,tmax, and AUC, there was no significant difference between enalapril taken in the fasting state, compared with administration following a standardized meal. 29 Therefore, food may not affect the absorption and bioavailability of enalapril as it apparently does with captopril. Lisinopril Absorption. The absorption and bioavailability profile of lisinopril was examined in 12normal male volunteers who were given 10 mg/d. The absorption of lisinopril was found to be slow and incomplete in these subjects. Ninety-seven percent of the dose administered was recovered as unchanged drug. A mean of 69 percent was found in the feces and a mean of 29 percent in the urine." Other studies, using doses ranging from 5 to 80 mg, have determined that the mean extent of absorption based on urinary recovery of drug is 25 percent, with a large interpatient variability (range 6-60 percent). 30 Mean 1max of 10 mg of lisinopril has been determined to be 6-8 hours with a C max value of 95 nmollL. 19 Mojaverian et al. studied the effect of food on the rate of lisinopril absorption in 18normal subjects. In this crossover study, volunteers received a single 20-mg oral dose of lisinopril either in the fasting state or immediately after a standardized breakfast. Timed blood and urine samples were collected after the administration of each dose. Mean C max was determined to be 195 ± 109 nmol/L for the fasting state and 156 ± 43 nmollL for those who received a standardized meal. Time to peak serum concentration was found to be 6.2 ± 1.1 hours and 6.8 ± 1.0 hours for the fasting and fed states, respectively. In addition, the mean urinary recovery of lisinopril was 27.2 ± 15.0 percent for the fasting state and 25.7 ± 10.0 percent after the standardized meal. It is concluded, therefore, that food does not affect the absorption or bioavailability of lisinopril. Captopril Distribution. In an animal model, radiolabeled captopril has been shown to distribute rapidly into most tissues, with the exception of the central nervous system. 2O It is not known if captopril crosses the placenta in humans; but studies of pregnant rats show that the drug will reach the placenta.P Captopril is apparently not readily secreted in the breast milk of humans, with detectable concentrations being less than one percent of peak blood con-
centrations." Captopril is approximately 30 percent protein-bound. 32 Studies of its disposition in animal models indicate that it exhibits the characteristics of a two-compartment open model, with drug being distributed through the central compartment (blood and highly vascularized organs) and to a peripheral tissue compartment." One study of cap-
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topril disposition in humans reported that the calculated volume of distribution (Vd) of the central compartment was 0.22 Llkg and the Vd during the elimination phase was 2.05 Llkg. The Vd at steady-state (V:) in this study was 0.7 Llkg.22 Migdalof et al. report the Vd of captopril as being 0.6 Llkg. 3s These data indicate that there is extensive partitioning of captopril into the tissues and that the drug's disposition may best be described by a three-compartment model consisting of two peripheral compartments in addition to the central compartment. 34
Enalapril Distribution. The precise nature of enalapril tissue distribution in humans has yet to be determined. 8Enalaprilat apparently does not penetrate into the central nervous system in the dog." It is not known if enalapril or enalaprilat transfers across the placenta or enters into breast milk." Enalaprilat has been reported to be less than 50 percent bound to human plasma protein." Davies et al. identified two binding sites for enalaprilat to plasma protein, one with low affinity and high capacity and another with high affinity and low capacity, with the latter conceivably representing enalaprilat binding to circulating ACE. 36 It is probable that the level of ACE inhibition in various tissues, rather than the binding to circulating ACE, is of more relevance to the antihypertensive effect of enalapril. 8 The V: of enalaprilat has been calculated in a group of healthy elderly volunteers (aged 65-76 years) and a group of healthy young volunteers (20-27 years) with both groups receiving 10 mg iv. The V: of enalaprilat for the elderly group of subjects was found to be lower (0.28 ± 0.08 Llkg) than that for the young subjects (0.38 ± 0.06 Llkg).37 It is possible that these differences are attributable to alterations in tissue-binding capacity encountered in the geriatric population. Lisinopril Distribution. Lisinopril apparently does not bind to plasma proteins other than ACE.38 The significance of this lack of binding to other proteins has not yet been ascertained. Ajayi et al. studied the pharmacokinetics of oral lisinopril with the use of a computer model that provided mean population parameter estimates using a one-compartment open model. The apparent Vd was calculated using the relative bioavailability (F). The derived mean Vd/F was determined to be 124 ± 16 L in the population studied. 39 Captopril Metabolism and Excretion. In the presence of plasma, captopril is partially oxidized at the sulfhydryl group to form several metabolites, including a disulfide dimer of captopril, a captopril-cysteine disulfide, and other mixed disulfides with endogenous thiol compounds. 20 Kripalani et al. administered radiolabeled captopril to normal subjects and found that at tmax, 52 percent of the total radioactivity in the blood was in the form of unchanged captopril, 10 percent as the unchanged dimer, and the remainder as polar metabolites." Captopril and its disulfide metabolites are primarily excreted in the urine with minor elimination in the feces. 20 Following oral administration of radiolabeled captopril to healthy volunteers, 67.5 percent of the total radioactivity recovered appeared in the urine and 18.3 percent was found in the feces." The fecal excretion of captopril observed in humans may represent unabsorbed drug because negligible biliary excretion was found in the dog and monkey following intravenous administration." In humans, the excretion of captopril and its metabolites is relatively rapid, with about 50 510
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percent of the dose recovered in the urine during the first four hours after administration. 22 Duchin et al. recovered 68 percent of an administered dose of captopril from the urine, with 24 percent being unchanged drug. 22 The body and renal clearances (C1r ) of captopril have been calculated to be 775 ± 23 and 388 ± 31 mLlkg/h, respectively. Tubular secretion is the primary means of renal excretion and accounts for 78 percent of radiolabeled captopril recovered in the urine.:" Studies have indicated that the coadministration of probenecid, an inhibitor of organic acid secretion, to subjects receiving captopril reduced the C1r of captopril. 40.41 Duchin et al. found that the elimination half-life (13tY2) of radiolabeled captopril in humans was 1.7 hours after oral dosing and 1.9 hours following intravenous administration. 22 The rate of urinary captopril excretion in patients with varying degrees of renal dysfunction (creatinine "clearance [Cl cr ] 0-56 mLlmin) was shown to decrease with decreasing renal function. The tY2 of captopril and its metabolites increased and was especially pronounced at a C1cr 300 mg) for 12 months and had a cumulative discontinuation rate of 8.5 percent due to adverse reactions. The dose of captopril was reduced in subsequent studies and was accompanied by a significant reduction in adverse reactions experienced and subjects discontinuing therapy.72 The multicenter Veterans Administration Cooperative Study Group examined the efficacy oflow-dose captopril in 495 men with uncomplicated hypertension (diastolic BP 92-109 mm Hg). Patients were randomized to one of five captopril treatment regimens at the following doses taken three times a day: 12.5,25,37.5, or 50 mg or placebo. Following seven weeks of therapy, BP reduction with each dose of captopril (mean decrease 10.2-14.2 mm Hg systolic/8.6-1O.5 mm Hg diastolic) was significantly greater (p>0.003) than in the placebo group (mean decrease 1.6 mm Hg systolic/3.2 mm Hg diastolic). In addition, there were no notable differences in the antihypertensive responses among the various doses of captopril at the end of the seven-week treatment period. 73 Patients who were in the placebo group during the first seven weeks were subsequently given hydrochlorothiazide 25 mg along with placebo for an additional seven weeks, and those subjects who received captopril during the first seven weeks received either a combination of captopril (originally assigned dose) and hydrochlorothiazide 25 mg, or captopril with placebo. The reduction in BP at the end of the second seven-week period averaged 12.0 mm Hg systolic and 8.7 mm Hg diastolic in those patients taking captopril alone. In contrast, the reduction in BP in those given the captopril/hydrochlorothiazide combination averaged about 25 mm Hg systolic and 16 mm Hg diastolic. The results of this study indicate that captopril given alone in doses as small as 37.5 mg/d is effective in reducing BP, and that the addition of hydrochlorothiazide greatly enhances the antihypertensive response. 73 A worldwide postmarketing surveillance study (6737 subjects) examined the efficacy of captopril given alone or in combination with a diuretic to patients who were previously uncontrolled by or who encountered unacceptable adverse effects with standard antihypertensive therapy. The
population studied consisted of individuals with all degrees of hypertension and included patients with impaired renal function. Prior to entry into the study, subjects were receiving an average of 2.3 medications with approximately 10 percent receiving no therapy. A majority (81.7 percent) of the subjects studied were white and 9.7 percent were black. The dose of captopril was to begin at 25 mg tid before increasing, if necessary, to 50 mg tid. A thiazide diuretic could be added if required and further titrations of captopril to a maximum of 450 mg/d were permitted to adequately control BP. BP was evaluated every three months for one year. The mean sitting entry BP despite medication was 183 mm Hg (systolic) and 111 mm Hg (diastolic), indicating that most patients had moderately severe to severe hypertension. The mean daily captopril dose was 152 mg at 3 months and 158 mg at 12 months. Captopril alone (21 percent of patients) or in combination with a diuretic (42 percent) were the only drugs administered to a majority (63 percent) of the population studied. Thirty-one percent required the addition of another antihypertensive agent (usually a beta-blocker) to their regimen of captopril and a diuretic. Depending on time of assessment, captopril given alone or in combination with other agents reduced mean sitting BP in all patients to 148-152 mm Hg systolic and 90-92 mm Hg diastolic. In addition, the results of this study indicate that total daily doses of captopril
