Hector J. Gomez

The Clinical Pharmacology of Lisinopril

Lisinopril is an orally active, nonsulfhydryl angiotensin-converting-enzyme (ACE) inhibitor that is not metabolized or bound to protein. Peak serum concentrations occur 6–8 h after oral dosing. Lisinopril bioavailability (∼25%) is not significantly affected by food, age, or coadministration of hydrochlorothiazide (HCTZ), propranolol, digoxin, and glibenclamide. Lisinopril is excreted unchanged in the urine. Steady state is achieved in 2–3 days with little accumulation. Significant accumulation occurs in patients with severe renal impairment (creatinine clearance ≤30 ml/min). Lisinopril inhibits ACE activity, thereby reducing plasma angiotensin II and aldosterone and increasing plasma renin activity. Lisinopril produces a smooth, gradual blood pressure (BP) reduction in hypertensive patients without affecting heart rate or cardiovascular reflexes. The antihypertensive effect begins within 2 h, peaks around 6 h, and lasts for at least 24 h. Lisinopril produces greater systolic and diastolic BP reductions than HCTZ. Lisinopril is similar to atenolol and metoprolol in reducing diastolic BP, but superior in systolic BP reduction. Lisinopril and nifedipine produce comparable reductions in systolic and diastolic BP. When lisinopril is given once daily as monotherapy, the range of BP reduction is 11–15% in systolic and 13–17% in diastolic. HCTZ addition enhances its antihypertensive effect. Lisinopril does not produce hypokalemia, hyperglycemia, hyperuricemia, or hypercholesterolemia. Lisinopril has natriuretic properties; renal blood flow remains stable or increases. Lisinopril increases cardiac output, and decreases pulmonary capillary wedge pressure and mean arterial pressure in patients with congestive heart failure refractory to conventional treatment with digitalis and diuretics. Human experience to date (2,800 patients/subjects) indicates that lisinopril is well tolerated and has a good safety profile.

Dose-dependent effect of atrial natriuretic peptide on blood pressure, heart rate, and skin blood flow of normal volunteers.

Synthetic atrial natriuretic peptide, containing 26 amino acids in the rat sequence, L-364, 343 (Ileu-ANP), was infused intravenously at increasing rates (1-40 micrograms/min) into four normal volunteers. Mean intraarterial blood pressure decreased and heart rate increased in cumulative-dose-dependent fashion. Skin blood flow as measured with a laser Doppler device rose already with a cumulative dose of 55 micrograms Ileu-ANP and further rises were directly related to dose. The only side effects observed were those accompanying symptomatic hypotension at higher doses. These findings provide strong evidence that Ileu-ANP acts as a vasodilator in normal volunteers.

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.

A comparison of hypotensive responses after oral and intravenous administration of enalapril and lisinopril in chronic heart failure

The acute hypotensive response to oral and parenteral enalapril (E) and lisinopril (LI) was assessed in 24 patients with chronic congestive heart failure in two open, randomized, balanced, crossover studies. In the E study, 12 patients received each of three treatments: a single oral dose of 10 mg E, a single intravenous bolus of 5 mg E, and a single intravenous bolus of 5 mg enalaprilat (ET). In the LI study, 12 patients received each of two treatments: a single oral dose of 10 mg LI and a single intravenous bolus of 5 mg LI. Intraarterial blood pressure was measured continuously. Significant decreases from baseline in mean arterial pressure (MAP) were observed in all cases, starting at 15 min. The maximal hypotensive effect (MAP; mean ± SD) was greatest and the nadir earliest for intravenous ET (– 30 ± 7 mm Hg at 75 min) compared with oral E (– 25 ± 10 mm Hg at 210 min) and intravenous E (– 19 ± 10 mm Hg at 195 min). Oral E and intravenous E had similar onsets of action. The maximal reduction following oral LI (– 19 ± 13 mm Hg at 210 min) was similar to oral E and intravenous E. The effect of intravenous LI ( −25 ± 9 mm Hg at 105 min) was similar to that of intravenous ET. Among the parenteral treatments, E produced the most gradual and least pronounced reduction in blood pressure, and may be best suited for use in the acute situation to minimize the risk of abrupt hypotension. All treatments were well tolerated, except for one patient who received an angiotensin II infusion because of symptomatic hypotension following parenteral ET.

Pharmacokinetics of synthetic atrial natriuretic peptides in normal men

The kinetics of atrial natriuretic peptides (ANP) and the kinetic profile of their effect on blood pressure and renal hemodynamic and electrolyte excretion were investigated in 20 salt‐loaded healthy volunteers during and after constant rate infusion. At steady state, mean plasma concentrations of ANP were measured at 210, 430, and 2990 pg/ml and mean systemic clearance was 2.6, 2.5, and 1.7 L/min for ANP infusion rates of 0.5, 1, and 5 μg/min, respectively, which corresponds to the clearance rate of other vasoactive peptide hormones. The apparent volume of distribution averaged 17 L and the mean half‐life was 4.5 minutes. ANP induced dose‐related effects on systemic and renal hemodynamic, as well as urinary electrolyte excretion, albeit with a time lag between onset and full effect.

Atrial natriuretic peptides: Reproducibility of renal effects and response of liver blood flow

SummaryTo assess the variability of the response to exogenous atrial natriuretic peptide (ANP), it was infused at the rate of 1 µg/min for 2 h in 6 salt-loaded normal volunteers under controlled conditions on 2 occasions at an interval of 1 week. The effect on solute excretion and the haemodynamic and endocrine actions were highly reproducible. The constant ANP infusion caused a delayed and prolonged excretion of sodium, chloride and calcium, no change in potassium or phosphate excretion or in glomerular filtration rate but a marked decrease in renal plasma flow. Blood pressure, heart rate and the plasma levels of angiotensin II, aldosterone, arginine vasopressin and plasma renin activity were unaltered. The effect of a 2-h infusion of ANP 0.5 µg/min or its vehicle on apparent hepatic blood flow (HBF) was also studied in 14 normal volunteers by measuring the indocyanine green clearance. A 21% decrease in HBF was observed in subjects who received the ANP infusion (p<0.01 vs vehicle). Thus, ANP infused at a dose that did not lower blood pressure decreased both renal and liver blood flow in normotensive volunteers. The renal and endocrine responses to ANP were reproducible over a 1-week interval.

Enalapril in congestive heart failure: acute and chronic invasive hemodynamic evaluation

Following hemodynamic evaluation using invasive and noninvasive methods, 73 patients were treated in an open, uncontrolled, multicenter study with single oral doses of enalapril maleate 1.25 to 40 mg until the optimal dose for each patient (based upon hemodynamic response) was achieved. Diuretics were withheld and reinstituted only if necessary. Hemodynamic measurements were made at 0 (predrug), 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours postdrug. Patients were discharged on their optimal dose, treated 1 to 4 months and then rehospitalized for repeat hemodynamic measurements. The optimal enalapril single dose was associated with the following mean peak responses: increased cardiac index 42% (SE = 6) and decreased pulmonary capillary wedge pressure 40% (SE = 3), systemic vascular resistance 39% (SE = 2), and mean arterial pressure 23% (SE = 1.5). These changes persisted during chronic therapy. Chronic treatment with enalapril also improved exercise capacity 40% (P less than 0.01), ejection fraction 18% (P less than 0.05) and clinical status (N.Y.H.A. functional class, P less than 0.01). Ten and 20 mg/day, taken as once- or twice-daily regimens, were the most commonly effective doses.

Enalapril: Benefit-to-risk Ratio in Hypertensive Patients

Enalapril is an effective agent in the treatment of mild to severe hypertension. It is equally effective in elderly and young adult patients but appears to be more effective in white than in black hypertensive patients. Following treatment with enalapril, an assessment of maximum exercise performance found a decrease in total peripheral resistance without significant changes in cardiac output, heart rate, or stroke volume compared with pretreatment values. In addition, there have been reports of reversal of left ventricular hyperophy in enalapril-treated hypertensive patients. En-alapril is also effective and well tolerated in hypertensive patients with renal impairment of varying etiology. The most common adverse experiences reported in controlled clinical trials were headache (5.2%), dizziness (4.3%), and fatigue (3.0%). In high-risk hypertensive patients, no enalapril-treated neutropenia, proteinuria, dysgeusia, or ageusia were reported. It may be concluded that the benefit-to-risk ratio of enalapril is among the best of the antihypertensive therapies currently available.