Clinical pharmacology and therapeutic applications of the new oral angiotensin converting enzyme inhibitor, captopril

PROGRESS

IN CARDIOLOGY

Clinical pharmacology and therapeutic applications of the new oral angiotensin converting enzyme inhibitor, captopril Roger K. Ferguson,

M.D.,

and Peter H. Vlasses,

Pharm.D.,

The impending release this year of captopril, an orally active angiotensin converting enzyme inhibitor, makes available to the medical profession the first of a novel class of antihypertensive agents. Other drugs in this class are currently being developed and investigated. The mechanism of action and other characteristics of this drug represent a significant therapeutic advance for the treatment of several types of hypertension. In addition, the effects of this class of drugs will undoubtedly aid our understanding of the mechanisms responsible for high blood pressure in its several forms. Because of some of its adverse effects and the relatively brief experience with the drug, the FDA is granting approval for the marketing of captopril (Capoten) only for use in resistant hypertension. The purpose of this article is to provide indications and guidelines for its clinical use, including an evaluation of its benefits and risks. It should be recognized that some of these observations may change as more experience with the drug is accumulated. CLINICAL

PHARMACOLOGY

Captopril (Fig. 1) was developed as a specific inhibitor of the enzyme (peptidyldipeptide carboxyhydrolase) that converts angiotensin I and angiotensin II.’ In normal man, small dosesof captopril have been shown to inhibit the hypertensive effects of angiotensin I but not angiotensin 11 injections.’ Studies in hypertensive patients have also demonstrated significant reductions in blood pressure after single oral doses.3 The hypotensive effect can be prolonged by increments in the dose which is then consistent with a threshold concentration of drug to

From the Division Jefferson Medical Received

of Clinical Pharmacology and Department College of Thomas Jefferson University.

for publication

Jan.

12, 1981;

accepted

Feb.

of Medicine,

10, 1981.

Reprint requests: Roger K. Ferguson, M.D., Professor of Medicine Pharmacology, Director, Clinical Pharmacology, Jefferson Medical lege, Thomas Jefferson University Hospital, Philadelphia, ?A 19107.

650

and Col-

Philadelphia,

Pa.

maintain effectiveness. Captopril is effective after long-term treatment? with some patients having been treated for more than 3 years. Captopril is rapidly absorbed from the gastrointestinal tract and the onset of hypotensive effect occurs as early as 15 minutes after an oral dose, with the maximal action occurring at 60 to 90 minutes. Approximately 70% of a single dose of captopril is absorbed and subsequently eliminated in the urine as unchanged drug (58%) and various metabolites (42%), including the disulfide dimer.j Food may interfere with the absorption of captopril taken within 2 hours of a meal. Though none occurred in patients with uncomplicated essential hypertension6 accumulation of captopril and its metabolites has occurred in patients with chronic renal failure.’ The metabolic changes after acute and chronic captopril therapy are summarized in Table I. After the initial dose of captopril in hypertensive patients, the decrease in blood pressure is accompanied by concomitant changes in the renin-angiotensin system (Fig. 2). Plasma renin activity (PRA) increases abruptly due to removal of feedback inhibition by angiotensin IL3 Angiotensin II, plasma aldosterone, and serum converting enzyme activity decrease in parallel with the decline in blood pressure; urinary aldosterone excretion also decreases while sodium excretion increases in the first 48 to 72 hours.a. a Initially, plasma potassium rises slightly, but then returns to baseline. In spite of the rather abrupt fall in blood pressure, no appreciable change in either plasma catecholamine or cortisol concentrations occur.8, y Plasma bradykinin concentrations increase acutely, but do not remain elevated with chronic administration.iO, I1 The major metabolite of prostaglandin E, is elevated in the urine after captopril.‘? The significance, if any, of these latter two changes to the hypotensive response to captopril is unclear. Captopril does not reduce blood pressure acutely in anephric patientsI The response to captopril may 000%8703/81/050650

+ 07$00.70/001981

The C. V. Mosby Co.

Volume Number

101 5

Captopril

I. Metabolic and cardiovascular alterations assqciated with captopril therapy in hypertensive patients

Table

Metabolic Plasma Renin activity Angiotensin II Aldosterone Converting enzyme Potassium Catecholaminea Cortiaol Bradykinin Urine Na+ K+ Aldosterone

activity

Acute

Chronjc

4 4 + c

4 +

f + I 4 P

in hypertension

CH “3 HS-CH2- CH - CO-N q

651

cootj

Fjg. 1. Chemical structure of captopril (D-2-methyl-3mercaptopropanoyl-l-protine). The converting enzyme has an affinity zinc ion binds

for the terminal carboxylgroup the sulfur of the thiol group.

while

its

to

0

4

0 0 0

Cardiovascular

Blood pressure Heart rate-supine Heart rate-standing Total peripheral resistance Cardiac index Stroke index Plasma volume Renal blood flow Glomerular filtration rate Filtration fraction

therapy

+ 0 0, 4

0

be predictable from the pretreatment measurement of PRA or aldosterone.14 The changes in PRA, angiotensin II, and aldosterone persist with chronic administration,“. ISthough often not at the same amplitude, even in combination with a diuretic.“. I6 These later adjustments may account for some waning of the antihypertensive activity in the first few days of captopril therapy’?; hence the chronic effect on blood pressure of captopril may be less than the initial response.‘s The acute and chronic cardiovascular effects of captopril are likevirise summarized in Table I. The decrease in blood pressure following captopril is associated with a decrease in total peripheral resistance.lY. 20Heart rate and cardiac output are not changed acutely, but increase after chronic administration; pulmonary vascular resistance does not change.?’ Plasma volume increases slightly in those patients who maintained a blood pressure response to captopril.19 Renal plasmla flow increases, glomerular filtration rate does not change, and filtration fraction decreases after captopril.” Renal function may improve, however, ‘in patients with heart failure if the reduction in myocardial afterload results in an increase in cardiac output. Captopril alone or in combination with propranolol has no discernible effect on the cardiovascular response to static or

dynamic exercise.?” Tolerance to captopril’s antihypertensive effect in combination with a diuretic does not appear to develop.24Rebound hypertension does not occur on abrupt cessation after either short- or long-term administration of captopri18. 24 THERAPEUTIC

INDICATIONS

FDA-approved. Captopril has FDA approval for hypertension resistant to multiple conventional drugs or for patients in whom these agents produce intolerable side effects; this represents a minority of hypertensive patiepts.z5 In such patients, captopril in combination with a diuretic has proved to be a valuable therapeutic alternative’“, X. Z7; in some casesaddition of a third drug such as propranolol is necessary to achieve adequate control. The relative efficacy and risks of captopril versus minoxidil in drug-resistant hypertension requires further investigationZ8 Captopril has proved to be especially effective in those forms of hypertension associated with increased activity of the renin-angiotensin system (Fig. 3). In patients with renovascular hypertension, captopril alone or. in combination with a diuretic may produce normalization ofblood pressure.3.+.8:3y Other forms of hypertension associated with increased renin activity and in which captopril has been shown beneficial are the renal crisis of scleroderma,30 malignant hypertension uncontrolled by other drugs,3*hemodialysis-resistant hypertension:? and hypertension due to a renin-producing tumor.3” Captopril has proved effective in children without additional problems being noted; caution is advised in pregnant women. Unapproved uses. Captopril has been found to be effective in mild to moderate hypertension, especially in combination with a diuretic agent. The riskto-benefit ratio in comparison with other therapies requires further investigation (see Adverse effects). Even patients ,with low-renin essential hypertension will respond, although perhaps not to the same degree as normal- or high-renin patients.34. 35Captopril in uncontrolled studies has been effective in the

52

Ferguson and Vlasses

EFFECTS OF CAPTOPRIL N CONVERTING ENZYME

VaSOconstricton

10 inactive

)-

-

-

products

- - Captopril

Kinin

) --_--

i

stimulation inhibition

Fig. 2. Effects of captopril on the angiotensin-converting enzyme (peptidyl-dipeptide carboxyhydrolase), which is synonymous with kininase II. Inhibition decreases angiotensin II (AII) formation and thus reduces vasoconstriction, aldosterone secretion by the adrenal cortex and feedback inhibition of renin release. In addition, kinin degradation by kininase II is inhibited. Kinins are vasoactive and stimulate release of prostaglandins, but their accumulation is uncertain due to the presence of other kininases.

acute and chronic management of refractory congestive heart failure,““. ai but further trials are necessary to confirm its relative efficacy. In one report, captopril was beneficial in idiopathic edema.38 CLiNICAL

USE

The usual recommended starting dose of captopril is 25 mg three times a day; this should be continued for 1 to 2 weeks. If the reduction of blood pressure is inadequate, the dose may be increased; the manufacturer’s maximum recommended daily dose is 450 mg. After another 1 to 2 weeks, a diuretic agent should be added if the blood pressure is not controlled. Most patients who respond can be controlled by this combination, although in some cases a third drug will be needed. An indicator of the eventual response to captopril is whether an initial fall in blood pressure (8 to 30 mm Hg diastolic) occurs. lG.I7 The duration but not the magnitude of the decrease in blood pressure is dose-dependent; increases in the dose may prolong its duration of action for up to 12 hours.” Monitoring of blood pressure shortly after a dose of captopril is not necessarily indicative of blood pressure control throughout a dosing interval. When combined with a diuretic, a similar dose-response relationship exists, but at lower doses.‘6.39 There have been reports of marked hypotension on first administration of captopril in patients who have volume depletion due to diuretic treatment,

marked sodium restriction, or following hemodialysis.“. XJIn these cases, the etiology of the hypertension has often been renovascular, or the patients had received other drugs. For this reason, if other antihypertensive drugs and particularly diuretics were used previously, it seemssafer to stop them for a few days when possible, before introducing captopril. The presence of other drugs may increase the initial effects of captopril; however, withdrawal reactions from stopping other drugs (such as clonidine) may obscure it**l Once blockade on the renin-angiotensin system has been achieved, diuretics and other drugs, if indicated, can be added safely. Renal insufficiency may reduce the excretion of captopril and prolong but not enhance its antihypertensive effect; metabohte accumulation, moreover, may lead to increased toxicity. Therefore, once an effect is obtained dose reduction is recommended for varying degrees of renal impairment (Table II). In some patients, however, it may not always be possible to adhere strictly to these recommendations and still maintain an adequate antihypertensive effect. USE WITH OTHER

DRUGS

As mentioned, a diuretic agent will need to be added to captopril in most patients in order to achieve adequate control of blood pressure. Even though diuretics stimulate renin activity, the increase is effectively blocked by the inhibition of

Volume101 Number 5

Captopril

I”

therapy

in hypertension

RECURRENT PULMONARY EDEMA (*) IN RENOVASCULAR HYPERTENSIVE PATIENT CONTROLLED WITH CAPTQPRIL

Fig. 3. This 58-year-old diabetic male had severe renovascular hypertension resistant to conventional therapy and complicated by nine episodes of acute, life-threatening pulmonary edema (*) in the previous year. Renal arteriography had revealed severe stendeis (100% on right, 50% on left); piasma renin activity on drugs was 14 ng/ml/hr with a $1 (right/left) ratio of renal vein renin measurements. Medical therapy was indicated since the patient was a poor surgical candidate and percutaneous transluminal renal angioplasty had been unsuccessful. In 1978, captopril was substituted for his previous treatment and then a diuretk was subsequently added (see figure) because of erratic control. Until the patient’s death from unrelated causes 1 year later, he &as well corkrolled with no further episodes of pulmonary edema. enzyme. It appears that the antihypertensive effect of the combination is additive, not synergistic.‘l, 35A diuretic can be added to captopril or the two agents can be initiated simultaneously with few problems.lG, 4?With the exception of diuretics, the combination of captopril and other antihypertensive drugs has not been studied in a eystemtitic manner. In casesof resistant hypertension, it may be necessary to add a thirdl drug to adequately control the patient’s blood pressure. This has been done effectively with beta-blockers such as propran0101or metoprolol (Fig. 4), which is interesting’in that it supports a hypotensive mechanism~of these agents beyond the suppression of renin release.26.43 Agents such as hydralazine and prazosin have only been tried in reSistant cases with little additional benefit.. converting

ADVEl?SE

EFFECTS

Captopril produces a number of characteristic unwanted side effects. Among the most common is a maculopapular rash which in some patients may be accompanied by fever or angioedematous eruption. The c&se of the rash is unknown, but it has been

proposed that it is related to increases in plasma kinin activity. 44 It usually appears in the first 2 weeks after starting therapy or a dose increase, dnd often disappears within the dose or timporarily

7 to 10 days after

reducing

stopping the drug. Antihistamines will ameliorate the symptoms of pruritis

Table II. Suggested captopril for varying Creatinine clearanbe (mUmin)

15-30 5-15 <5

approximate dose adjustments degrees of renal insufficiency Captopril

of,

dose

Cm&

loo-150 50-100 25- 50

and have been used chronically in persistent cases when captopril is required for blood pressure control. Captopril-related pemphigus and aphthous ulcers have been reported.‘j, A6 A transient loss of taste (ageusia) has been reported.A7 Although some weight’loss may result, it too disappears or improves with reduced dose OF temporarily stopping captopril. Proteinuria and, less frequently, nephrotic syndrome have been reported. 48 In one study, 6 of 81 ‘patients on long-term captopril manifested these effects but they cleared or subsided despite continued treatment; in two patients renal biopsy showed mild membranous nephropathy.“g Reversible renal failure and hyperkalemia also have been reported.j”, j1 Agranulqcytosis has been reported, mainly in seriously ill patients who received captopril albng with multiple dyugs.j’ Though reversible with drug discontinuation,j3 the potential for resultant infection has raised concern for additional informa$i& on relative incidence. The

664

Ferguson

and V/asses

P

ADDfTlON RESISTANT

OF PROPRANOLOL TO CAPTOPRIL

IN A PATIENT AND DIURETIC

Fig. 4. A 56-year-old man with severe hypertension had been refractory to large doses of antihypertensive medications for several years. Because he was not well controlled on a trial of standard triple therapy, captopril and hydrochlorothiazide were substituted. When his blood pressure remained high, propranolol was reinstituted. Within 24 hours, the patient reported loss of taste which persisted until the propranolol was discontinued. The blood pressure again rose and propranolol was restarted; the ageusia did not recur, but the patient’s blood pressure again improved (not shown). He has remained reasonably well controlled on these three drugs for more than 2 years. The temporary ageusia was most probably related to captopril; the mechanism is unknown.

only drug interaction reported thus far has been a neurologic syndrome occurring in association with cimetidine.“’ In contrast to many antihypertensive drugs, captopril lacks effects on the central nervous system or

on sexual function. Sodium and water retention and hirsuttim, side effects of minoxidil, another agent used in the management of severe hypertension, do not occur after captopril administration. There also appears to be little or no effect on blood glucose, uric acid, plasma lipids, or hver enzymes.jj It should be emphasized that the risk of developing symptomatic hypotension in the majority of patients is small. If it should occur, the patient may only experience transient dizziness relieved by lying down; in cases of marked hypotension, the intravenous infusion of saline has proved effective. Standing tachycardia may be increased by the addition of a dmretic; in patients who are symptomatic or have coronary artery disease, low doses of a beta-blocking agent, if not contraindicated, may be added for control. MONlTORING

OF

CAPTCWRiL

T~~RA~~

A baseline urinalysis with quantitative protein determination is indicated before starting patients on long-term captopril therapy. Baseline and periodic white cell counts with differential should be

obtained (see manufacturer’s recommendations). Renin and aldosterone profiling, in general, are not necessary prior to starting captopril. In the absence of measurement of drug concentrations, the determination of serum angiotensin converting enzyme activity (CEA) may be useful in assessing compliance with captopril therapy. Although the antihypertensive effect may outlast the depression of CEA, especially after chronic therapy,j6 it would indicate the presence of the drug.5i CONCLUSIONS

Captopril represents an important advance in the chronic treatment of resistant hypertension. Whether its long-term administration proves useful in other forms of hypertension and conditions such as normotensive congestive heart failure requires further investigation. Post-marketing surveillance will assist in the evaluation of the risks and benefits of this new agent with a unique mechanism of action. REFERENCES I.

2.

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Captopril

2i.

therapy

in hypertension

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All manuscripts and all queries regarding publication should be addressed to the Editor, Dr. Dean T. Mason, 132 E Street, Suite 3E, Davis, California 95616. Telephone (916) 758-1670.

my 1981 Heart Journal