Penbutolol

Penbutolol is a β-1, β-2 (nonselective) adrenergic receptor antagonist. Experimental studies showed a dose-dependent increase in heart rate in reserpinized (norepinephrine-depleted) rats given penbutolol intravenously at doses of 0.25 to 1.0 mg/kg, suggesting that penbutolol has some intrinsic sympathomimetic activity. In human studies, however, heart rate decreases have been similar to those seen with propranolol.

Penbutolol antagonizes the heart rate effects of exercise and infused isoproterenol. The β-blocking potency of penbutolol is approximately 4 times that of propranolol. An oral dose of less than 10 mg will reduce exercise-induced tachycardia to one-half its usual level; maximum antagonism follows doses of 10 to 20 mg. The peak effect is between 1.5 and 3 hours after oral administration. The duration of effect exceeds 20 hours during a once-daily dosing regimen. During chronic administration of penbutolol, the duration of antihypertensive effects permits a once-daily dosage schedule.

Acute hemodynamic effects of penbutolol have been studied following single intravenous doses between 0.1 and 4 mg. The cardiovascular responses included significant reductions in heart rate, left ventricular maximum dP/dt, cardiac output, stroke volume index, stroke work, and stroke work index. Systolic pressure and mean arterial pressure were reduced, and total peripheral resistance was increased.

Chronic administration of penbutolol to hypertensive patients results in the hemodynamic pattern typical of β-adrenergic blocking drugs: a reduction in cardiac index, heart rate, systolic and diastolic blood pressures, and the product of heart rate and mean arterial pressure both at rest and with all levels of exercise, without significant change in total peripheral resistance. Penbutolol causes a reduction in left ventricular contractility. Penbutolol decreases glomerular filtration rate, but not significantly.

Penbutolol decreases plasma renin activity in normal subjects and in patients with essential and renovascular hypertension. The mechanisms of the antihypertensive actions of β-receptor antagonists have not been established. However, factors that may be involved are: (1) competitive antagonism of catecholamines at peripheral adrenergic receptor sites (especially cardiac) that leads to decreased cardiac output; (2) a central nervous system (CNS) action that results in a decrease in tonic sympathetic neural outflow to the periphery; and (3) a reduction of renin secretion through blockade of β-receptors involved in release of renin from the kidneys.

Penbutolol dose dependently increases the RR and QT intervals. There is no influence on the PR, QRS, or QTc (corrected) intervals.

Following oral administration, penbutolol is rapidly and completely absorbed. Peak plasma concentrations of penbutolol occur between 2 and 3 hours after oral administration and are proportional to single and multiple doses between 10 and 40 mg once a day. The average plasma elimination half-life of penbutolol is approximately 5 hours in normal subjects. There is no significant difference in the plasma half-life of penbutolol in healthy elderly persons or patients on renal dialysis. Twelve to 24 hours after oral administration of doses up to 120 mg, plasma concentrations of parent drug are 0% to 10% of the peak level. No accumulation of penbutolol is observed in hypertensive patients after 8 days of therapy at doses of 40 mg daily or 20 mg twice a day. Penbutolol is approximately 80% to 98% bound to plasma proteins.

The metabolism of penbutolol in humans involves conjugation and oxidation. The metabolites are excreted principally in the urine. When radiolabeled penbutolol was administered to humans, approximately 90% of the radioactivity was excreted in the urine. Approximately 1/6 of the dose of penbutolol was recovered as penbutolol conjugate while the remaining fraction was not identified. Conjugated penbutolol has a plasma elimination half-life of approximately 20 hours in healthy persons, 25 hours in healthy elderly persons, and 100 hours in patients on renal dialysis. Thus, accumulation of penbutolol conjugate may be expected upon multiple-dosing in renal insufficiency. An oxidative metabolite of penbutolol, 4-hydroxy penbutolol, has been identified in small quantities in plasma and urine. It is 1/8 to 1/15 times as active as the parent compound in blocking isoproterenol-induced β-adrenergic receptor responses in isolated guinea-pig trachea and is 1/8 to 1 times as potent in anesthetized dogs.

There was no evidence of carcinogenicity observed in a 21-month study in mice or a 2-year study in rats. Mice were given penbutolol in the diet for 18 months at doses up to 395 mg/kg/day (about 500 times the Maximum Recommended Human Dose (MRHD) of 40 mg in a 50 kg person). Rats were given 141 mg/kg/day for the same length of time. Mice were observed for 3 months and rats for 5.5 to 7 months after termination of treatment before necropsy was performed.

No evidence of mutagenic activity of penbutolol was seen in the Salmonella mutagenicity test (Ames test), the point mutation induction test (Saccharomyces), and the micronucleus test.

Penbutolol had no adverse effects on fertility or general reproductive performance in mice and rats at oral doses up to 172 mg/kg/day.