John D. Irvin

Effects of enalapril, a new converting enzyme inhibitor, in hypertension

The new angiotensin converting enzyme inhibitor enalapril maleate was given in single oral doses of 2.5, 5, and 10 mg to 11 hospitalized patients with uncomplicated essential hypertension who were on a 150‐mEq sodium diet. All doses of enalapril induced reduction of mean seated diastolic blood pressure (SDBP). The magnitude of the initial SDBP reduction was not dose related, but the duration of effect was longer (>12 hr) after the 5 and 10 mg. After dosing, mean plasma angiotensin converting enzyme activity (ACE) and aldosterone concentration (PAC) fell, while plasma renin activity (PRA) rose. Serum concentrations of the active diacid form of enalapril increased linearly with dosage; ACE was inhibited maximally at concentrations above 10 ng/ml. During repeated dosing in the outpatient trial there was attenuation of the antihypertensive effect (12 to 24 hr after dosing) in eight of 10 patients. Despite dose increases only two patients achieved SDBP control (≤90 mm Hg). In the five patients in whom 50 mg/day hydrochlorothiazide was added near the end of the trial mean SDBP was further reduced. Enalapril was well tolerated. Further studies of the drug, especially in combination with diuretic, are needed.

Safety profiles of the angiotensin converting enzyme inhibitors captopril and enalapril

The safety profiles of the angiotensin converting enzyme inhibitors, captopril and enalapril, are the focus of this review. Adverse effects are reviewed as those associated with sulfhydryl compounds and as those considered class-specific adverse effects of angiotensin converting enzyme inhibitors. Specifically discussed are the incidences of the adverse effects of rash, taste disturbance, neutropenia, and proteinuria, which are characteristic of compounds containing sulfhydryl moieties, such as captopril. It is concluded from the review of these safety data that enalapril is well tolerated, has few class-specific adverse effects, and may offer a potential advantage over captopril by having fewer sulfhydryl-related adverse effects.

Enalapril: A Review of Human Pharmacology

SummaryEnalapril, an orally-active, long-acting, nonsulphydryl angiotensin-converting enzyme (ACE) inhibitor, is extensively hydrolysed in vivo to enalaprilat, its bioactive form. Bioactivation probably occurs in the liver. Metabolism beyond activation to enalaprilat is not observed in man. Administration with food does not affect the bioavailability of enalapril; excretion of enalapril and enalaprilat is primarily renal. Peak serum enalaprilat concentrations are reached 4 hours post-dose, and the profile is polyphasic with a prolonged terminal half-life ( >30 hours) due to the binding of enalaprilat to ACE. Steady-state is achieved by the fourth daily dose, with no evidence of accumulation. The effective accumulation half-life following multiple dosing is 11 hours. Higher serum concentrations and delayed urinary excretion occur in patients with severe renal insufficiency.Enalapril reduces blood pressure in hypertensive patients by decreasing systemic vascular resistance. The blood pressure reduction is not accompanied by an increase in heart rate. Furthermore, cardiac output is slightly increased and cardiovascular reflexes are not impaired. Once- and twice-daily dosage regimens reduce blood pressure to a similar extent. Enalapril increases renal blood flow and decreases renal vascular resistance. Enalapril also augments the glomerular filtration rate in patients with a glomerular filtration rate less than 80 ml/min. Enalapril reduces left ventricular mass, and does not affect cardiac function or myocardial perfusion during exercise. There is no rebound hypertension after enalapril therapy is stopped.Enalapril does not produce hypokalaemia, hyperglycaemia, hyperuricaemia or hypercholesterolaemia. When combined with hydrochlorothiazide, enalapril attenuates the undesirable diuretic-induced metabolic changes. Therapeutic doses of enalapril do not affect serum prolactin and plasma cortisol in healthy volunteers or T3, rT3, T4 and TSH in hypertensive patients. Enalapril has natriuretic and uricosuric properties.The antihypertensive effect of enalapril is potentiated by hydrochlorothiazide, timolol and methyldopa, but unaffected by indomethacin and sulindac. No interactions occur between enalapril and frusemide, hydrochlorothiazide, digoxin and warfarin. The bioavailability of enalapril is slightly reduced when propranolol is coadministered, but this does not appear to be of any clinical significance.Enalapril increases cardiac output and stroke volume and decreases pulmonary capillary wedge pressure in patients with congestive heart failure refractory to conventional treatment with digitalis and diuretics. Exercise capacity improves during chronic treatment. Human experience to date (6000 patients/subjects) indicates that enalapril is safe and well tolerated.

Comparative Antihypertensive Effects of Enalapril Maleate and Hydrochlorothiazide, Alone and in Combination

Abstract: Enalapril maleate is an investigational oral prodrug whose hydrolyzed diacid metabolite is a potent angiotensin‐converting enzyme inhibitor. Fourteen patients with mild to moderate hypertension were evaluated after receiving placebo, and two weeks of treatment with each of the following: enalapril maleate (20 mg b.i.d.), hydrochlorothiazide (25 mg b.i.d.), and the two in combination. In comparison to placebo, the magnitudes of the blood pressure reduction after enalapril and hydrochlorothiazide alone were comparable. The reduction in blood pressure following enalapril was evident throughout the 12‐hour dosing interval. The combination of enalapril and hydrochlorothiazide resulted in a marked further reduction in blood pressure that was greater than that predicted from the responses to the individual drugs (P < 0.05). Biochemical parameters confirmed inhibition of angiotensin‐converting enzyme during enalapril treatment; serum angiotensin‐converting enzyme activity proved an excellent monitor of compliance. Enalapril was generally well tolerated. Adverse effects included symptomatic hypotension in three patients when enalapril was first added to hydrochlorothiazide and hyperesthesia of the oral mucosa without a loss of taste in one patient on enalapril. Enalapril maleate alone and especially in combination with hydrochlorothiazide appears to be an effective, well‐tolerated converting enzyme inhibitor with at least a 12‐hour duration of action.

Antihypertensive Effect of Enalapril in Essential Hypertension: Role of Prostacyclin

The effects of enalapril alone and in combination with the cyclooxygenase inhibitors sulindac and indomethacin on blood pressure (BP), plasma aldosterone, renin activity and converting enzyme activity were evaluated in 29 patients with mild to moderate essential hypertension, 26 of whom had low plasma renin activity. Patients were randomly assigned to one of three treatment groups. All patients underwent a 4-week placebo phase (phase I), then received enalapril (20 mg BID) for 4 weeks (phase II). In phase III, group I (n = 10) continued on enalapril alone; group II (n = 9) received sulindac 200 mg BID plus enalapril, and group III (n = 10) received indomethacin 50 mg BID plus enalapril, all for 4 weeks. Enalapril lowered BP significantly (mean supine BP 149/100 in phase I vs. 134/90 in phase II, p < 0.05) without inhibiting aldosterone production. The BP effect was not blunted by concomitant administration of sulindac or indomethacin. Enalapril lowered converting enzyme activity to 25% to 30% of baseline and tended to increase renin activity. In the 10 patients who received indomethacin (group III), the effects of enalapril alone and enalapril plus indomethacin on urinary excretion of 6-keto prostaglandin F1α (PGF1α, a stable metabolite of prostacyclin (PGI2), were examined. Enalapril increased urinary 6-keto PGF1α in group III from 118 ± 23 to 194 ± 38 ng/g creatinine (p < 0.05), while addition of indomethacin reduced 6-keto PGF1α to basal levels (138 ± 26 ng/g creatinine). There was no significant correlation between the fall in blood pressure and the increase in 6-keto PGF1α excretion in enalapril-treated patients. These data indicate that the antihypertensive effect of enalapril in essential hypertension occurs in the absence of an active renin-angiotension system and is associated with increased excretion of 6-keto PGF1α but is not blunted by cyclooxygenase inhibitors. These findings indicate (1) enalapril administration is associated with enhanced prostacyclin production in this patient group but (2) the antihypertensive action of enalapril is not critically dependent on prostacyclin, since blockade of prostacyclin production with a cyclooxygenase inhibitor does not blunt the antihypertensive effect of the drug.

Indacrinone: Natriuretic and Uricosuric Effects of Various Ratios of Its Enantiomers in Healthy Men

Indacrinone is an investigational loop‐acting diuretic. To evaluate the natriuretic and uricosuric effects of varying ratios of its enantiomers, 10 healthy men, on a controlled Na (100 mEq) and K (80 mEq) diet, participated in a double‐blind, randomized, balanced incomplete block, multiple‐dose (one week) study of a fixed daily dose (10 mg) of (–) enantiomer combined with increasing doses (40, 90 and 140 mg) of (+) enantiomer versus 50 mg hydrochlorothiazide and placebo. On day 1, mean 24‐h urinary Na increased (p < 0.01) comparably (–285 mEq) after each enantiomer combination and hydrochlorothiazide; however, the enantiomer combinations had marked uricosuric and hypouricemic effects that were enhanced with increased (+) enantiomer doses. By day 7, while enantiomer combinations and hydrochlorothiazide demonstrated comparable natriuretic activity, mean serum uric acid levels (mg/dl), in comparison to placebo, were increased (p < 0.05) with hydrochlorothiazide but progressively decreased with increases in (+) enantiomer. Thus varying the ratio [(+, uricosuric):(–, natriuretic)] of the enantiomers of indacrinone caused natriuresis similar to hydrochlorothiazide, but had an opposite effect on serum uric acid.