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 micrograms/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.

Three new long-acting converting-enzyme inhibitors: relationship between plasma converting-enzyme activity and response to angiotensin I.

Three new angiotensin converting-enzyme inhibitors were given orally to 20 men in single doses ranging from 1.25 to 40 mg. Two of them induced comparable marked inhibition of both the blood pressure response to exogenous angiotensin I and plasma converting-enzyme activity. Onset of action was relatively slow, but 21 to 24 hr after drug plasma converting-enzyme activity was still clearly reduced. The third was less active. There was a close correlation between blood pressure response on administration of angiotensin I and plasma converting-enzyme activity. There were no adverse effects. These new drugs are interesting because of their long duration of action. The measurement of plasma converting-enzyme activity seems useful for monitoring efficacy of converting-enzyme blockade and compliance to therapy.

Efficacy and safety of lisinopril in older patients with essential hypertension.

Angiotensin-converting enzyme inhibitor therapy has been thought to be more effective in hypertensive patients with normal or elevated levels of renin in the plasma. However, several studies have challenged this concept by demonstrating the efficacy of angiotensin-converting enzyme inhibitors (captopril and enalapril) in older patients, among whom a low level of renin activity in the plasma is common, and in other patients with low-renin essential hypertension. Lisinopril, a new long-acting angiotensin-converting enzyme inhibitor, also has been shown to be an effective antihypertensive agent in older patients. This report examines data from 97 older and 710 younger hypertensive patients enrolled in four multicenter trials of eight to 12 weeks' duration. In these trials, the dose of lisinopril was titrated until a diastolic pressure of less than 90 mm Hg was reached, or to a maximal dose of 80 mg per day. In general, the antihypertensive effect achieved in older patients with lisinopril was equal to or greater than that achieved in younger patients. The drug was generally well tolerated. Lisinopril can be expected to be used frequently in older patients.

Enalapril: a review of human pharmacology.

Enalapril, 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 (greater than 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.(ABSTRACT TRUNCATED AT 400 WORDS)

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.

Dose-response studies with benazepril in mild to moderate hypertension.

The dose-response curve for benazepril, a new angiotensin-converting enzyme inhibitor, has been established from a systematic series of controlled clinical studies in patients with mild to moderate essential hypertension. The studies included a dose-ranging study, four dose-response studies (placebo-controlled or crossover), and four titration trials. The dose-response studies involved 803 patients and evaluated doses from 2 to 80 mg. Analysis of the data revealed the existence of a dose-response relationship over the dosage range of 10 to 80 mg given once daily. Efficacy of once-daily administration was shown by the persistence of significant blood pressure reduction over the 24-h dosing interval. In addition, the net trough-to-peak ratio (an indicator of net antihypertensive effect at the end of the dosing interval) was generally greater than 50%. The dose-determination studies with benazepril were conducted according to a well-designed strategy in which parameters were carefully defined. Based on these trials, the initial dosage for benazepril appears to be 10 mg once daily. Additional response may be observed at dosages up to 80 mg once daily.

The use of benazepril in hypertensive patients age 55 and over.

Benazepril, a newer angiotensin-converting enzyme inhibitor, has been evaluated for the treatment of mild to moderate hypertension in patients 55 years of age and older. The results of the clinical trials conducted to date indicate that benazepril provides effective antihypertensive therapy in this population, with efficacy comparable to that demonstrated in younger patients. Benazepril does not produce precipitous decreases in diastolic blood pressure following the initial dose, and is well tolerated by the elderly. It has a safety profile similar to that of placebo and generally better than that of hydrochlorothiazide.

The clinical pharmacology of enalapril.

Enalapril, a long-acting, non-sulfhydryl, angiotensin converting enzyme (ACE) inhibitor, is well absorbed after oral administration, and hydrolised to its bioactive form, enalaprilic acid (EA). Administration with food does not affect its bioavailability; elimination is predominantly renal. Peak serum EA concentrations occur 4 h after an oral dose; its serum half-life is approximately 35 h, and steady state is achieved by the fourth day of treatment. Enalapril controls blood pressure in essential and renovascular hypertension without affecting heart rate or cardiovascular reflexes. It also decreases serum concentrations of ACE (for greater than 24 h), angiotensin II and aldosterone, and increases plasma renin activity. Once and twice-daily regimens are equally effective. In patients with congestive heart failure refractory to digitalis and diuretics, enalapril increases cardiac output and decreases pulmonary capillary wedge pressure. Long-term treatment produces improvement in NYHA functional classification, exercise capacity and ejection fraction. Human experience to date indicates that enalapril is safe and well tolerated.

Clinical pharmacology of enalapril.

Enalapril is administered as the ethyl ester of the potent angiotensin converting enzyme (ACE) inhibitor enalaprilat. As such, it is 60% absorbed and 40% bioavailable as the active species. Absorption is not affected by food. Serum concentrations are proportional to dose, less a small drug residue apparently bound to the enzyme. The half-life for accumulation is approximately 11 h. The drug is eliminated by the kidney without further metabolism. Maximum inhibition of plasma ACE occurs 2-4 h after administration and persists for more than 24 h with clinical doses. ACE inhibition is associated with increases in plasma renin and angiotensin I levels, decreases in angiotensin II and aldosterone concentrations and reduction in blood pressure. All of these events are closely correlated when analysed statistically. The clinical and haemodynamic effects of these actions are addressed in other papers.

Long-term clinical experience with enalapril in essential hypertension.

This study was undertaken to evaluate whether, after long-term enalapril administration tachyphylaxis to the blockade of angiotensin II (Ang II) generation occurs. After a mean follow-up of 24 months, six patients taking enalapril once daily with or without an associated diuretic were studied for 7 h in hospital. Blood pressure, heart rate, plasma converting enzyme activity, angiotension I (Ang I), Ang II and aldosterone were measured before and 2, 4 and 6 h after the morning dose of enalapril. While blood pressure remained unchanged after drug administration, Ang II and aldosterone levels fell following enalapril to very low levels, similar to those observed during the initial study, at the time of peak effect of enalapril. After enalapril administration, there was no correlation between plasma Ang I and Ang II suggesting that blockade of Ang II generation was complete, excluding the possibility of Ang I related interference with the Ang II measurements. These results indicate that virtually complete angiotension converting enzyme inhibition can still be achieved after prolonged use of enalapril.

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 (approximately 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 less than or equal to 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 reductions 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.

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 hypertrophy in enalapril-treated hypertensive patients. Enalapril 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.

Dopaminergic control of aldosterone secretion in hypertensive patients chronically treated with an angiotensin converting enzyme inhibitor.

To investigate whether dopamine plays a role in the regulation of aldosterone secretion during long-term blockade of the renin-angiotensin system, we studied the effect of metoclopramide, a competitive antagonist of dopamine, in 6 patients with essential hypertension chronically treated with the angiotensin converting enzyme inhibitor enalapril. All but one of these patients received a diuretic in addition to enalapril. Six hours after the daily morning dose of enalapril (10-40 mg p.o.) a 10 mg bolus dose of metoclopramide was injected intravenously. In one patient a hypotensive episode developed following metoclopramide administration. In the 5 other patients plasma aldosterone significantly rose within 30 min after metoclopramide from 51 +/- 8.7 to 128.2 +/- 29.2 pg/ml. This metoclopramide-induced release of aldosterone occurred in the absence of concomitant changes in circulating angiotensin 11, potassium and ACTH levels. Metoclopramide given during chronic blockade of the renin-angiotensin system caused anxiety and agitation in 2 patients. The increase in plasma aldosterone following competitive dopamine blockade in the face of chronic angiotensin converting enzyme inhibition, unchanged plasma potassium and ACTH levels strongly suggests that in hypertensive patients, dopamine exerts a direct inhibitory effect on aldosterone secretion.

The pharmacokinetics of lisinopril in hospitalized patients with congestive heart failure.

1. The pharmacokinetics of the angiotensin converting enzyme inhibitor, lisinopril, were studied in an open, randomized, balanced, two-period, crossover design in 12 in-patients with stable, chronic congestive heart failure (CHF). 2. To evaluate the pharmacokinetics of lisinopril in CHF, lisinopril was administered orally (10 mg) and intravenously (5 mg) in each patient. Each dose was followed by a 72 h period with frequent blood sampling and fractional urine collections for radioimmunoassay of lisinopril. 3. Mean urinary recovery of lisinopril was 15 and 88% following oral and intravenous administration, respectively; absorption/bioavailability of lisinopril based on urinary recovery ratios was 16%, less than that found in normal subjects. 4. Serum concentrations of lisinopril following intravenous administration were higher in this study than those previously observed in normal subjects. 5. The results of this study suggest a reduced absorption of lisinopril in CHF and altered disposition, possibly associated with age as well as the disease state.

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.(ABSTRACT TRUNCATED AT 250 WORDS)

An overview of the clinical pharmacology of enalapril.

Enalapril maleate is a prodrug which when administered orally is hydrolysed to release the active converting enzyme inhibitor enalaprilat. Enalapril maleate is 60% absorbed and 40% bioavailable as enalaprilat. Both compounds undergo renal excretion without further metabolism. The functional half-life for accumulation of enalaprilat is 11 h, and this is increased in the presence of a reduction in renal function. Inhibition of converting enzyme inhibition is associated with reductions in plasma angiotensin II and plasma aldosterone, and with increases in plasma renin activity and plasma angiotensin I. Acute and chronic effects have been reviewed. When given with hydrochlorothiazide, enalapril attenuates the secondary aldosteronism and ameliorates the hypokalaemia from diuretics. Both acutely and chronically in patients with essential hypertension, enalapril reduced blood pressure with a rather flat dose-response curve. No evidence of a triphasic response such as seen with captopril has been demonstrated with enalapril, and blood pressure returns smoothly to pretreatment levels when the drug is abruptly discontinued. Once- or twice-daily dosing gives similar results. The antihypertensive effects of enalapril are potentiated by hydrochlorothiazide. Haemodynamically, blood pressure reduction is associated with a reduced peripheral vascular resistance and an increase in cardiac output and stroke volume with little change in heart rate. Renal vascular resistance decreases, and renal blood flow may increase without an increase in glomerular filtration in patients with normal renal function. In patients with essential hypertension and glomerular filtration rates below 80 ml/min/m2, both renal blood flow and glomerular filtration rates may increase.

Haemodynamic effects of atrial peptide infusion in heart failure.

The effect of a synthetic analogue of atrial natriuretic peptide (Ileu-ANP) on haemodynamic, hormonal, and electrolyte excretion indices was studied in 7 patients with chronic congestive heart failure. Patients received in random order placebo or Ileu-ANP infusions (5 micrograms/min) for 4 h on 2 separate occasions, at least 1 week apart. Compared with placebo, Ileu-ANP caused significant reductions in mean systemic arterial pressure, mean pulmonary artery pressure, pulmonary diastolic pressure, and right atrial pressure. These changes were sustained for at least 2 h after infusion. Cardiac output increased from 6.2 to 7.4 l/min at 60 min, then returned to pre-infusion levels. Despite considerable falls in systemic pressure there was no significant increase in heart rate or plasma noradrenaline. With Ileu-ANP infusion, plasma renin activity, angiotensin, arginine vasopressin, aldosterone, and cortisol values were not significantly different from placebo values. Plasma cortisol and aldosterone increased after stopping Ileu-ANP. Neither urine volume nor sodium excretion rate was significantly increased by Ileu-ANP.

Pharmacokinetics of the pivaloyloxyethyl (POE) ester of methyldopa, a new prodrug of methyldopa.

A prodrug of methyldopa, the pivaloyloxyethyl (POE) ester, was administered orally to healthy human volunteers at doses equivalent to 500 and 1000 mg of methyldopa and was compared to oral and intravenous doses of methyldopa. The time courses of availability of methyldopa to the general circulation were compared and contrasted with the model-independent estimates of total systemic availability. The POE ester of methyldopa is completely hydrolyzed on the first pass; delivery of methyldopa to the general circulation was faster, more uniform, and more extensive compared to orally administered methyldopa. The systemic availability of methyldopa averaged 64% of the dose with a coefficient of variation (CV) of 15% for the prodrug treatments compared to 27% of the dose with a CV of 63% for methyldopa. First-pass metabolism of drug to the mono-O-sulfate conjugate of methyldopa was lower for the POE ester than for methyldopa.

Pharmacokinetics of lisinopril (IV/PO) in healthy volunteers.

When three intravenous doses of lisinopril were administered to healthy volunteers, area under the curve (to infinity) vs dose was linear with a positive intercept. Subtracting area under the extrapolated terminal phase of the serum profile from zero to infinity retained the linear relationship, but shifted the regression line to a zero intercept. It is postulated that the terminal phase reflects binding of drug to angiotensin-converting enzyme (ACE). The half-life for the terminal phase (approximately 40 h) was not predictive of steady-state parameters when ten daily doses (q24h) of lisinopril were administered orally to healthy volunteers. The mean effective half-life for accumulation was 12.6 h. The mean accumulation ratio was 1.38. Steady state was attained after the second daily dose. The observations in these studies with lisinopril are similar to those reported for enalaprilat, the active metabolite of the ACE inhibitor, enalapril maleate.