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| __NOTOC__
| | #REDIRECT [[Penbutolol#Pharmacology]] |
| {{Penbutolol}}
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| {{CMG}}; {{AE}} {{SS}}
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| ==Clinical Pharmacology==
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| Penbutolol is a ß-1, ß-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.
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| Penbutolol antagonizes the heart rate effects of exercise and infused [[isoproterenol]]. The ß-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 anti[[hypertensive]] effects permits a once-daily dosage schedule.
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| 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.
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| Chronic administration of penbutolol to [[hypertensive]] patients results in the hemodynamic pattern typical of ß-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.
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| Clinical trial doses of 10 to 80 mg per day in single daily doses have reduced supine and standing systolic and diastolic blood pressures. In most studies, effects were small, generally a change in blood pressure 5 to 8/3 to 5 mm Hg greater than seen with a placebo measured 24 hours after dosing. It is not clear whether this relatively small effect reflects a characteristic of penbutolol or the particular population studied (the population had relatively mild hypertension but did not appear unusual in other respects). In a direct comparison of penbutolol with adequate doses of twice daily propranolol, no difference in blood pressure effect was seen. In a comparison of placebo and 10-, 20-, and 40-mg single daily doses of penbutolol, no significant dose-related difference was seen in response to active drug at 6 weeks, but, compared to the 10-mg dose, the two larger doses showed greater effects at 2 and 4 weeks and reached their maximum effect at 2 weeks. In several studies, dose increases from 40 to 80 mg were without additional effect on blood pressure. Response rates to penbutolol are unaffected by sex or age but are greater in caucasians than blacks.
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| Penbutolol decreases plasma renin activity in normal subjects and in patients with essential and renovascular hypertension. The mechanisms of the anti[[hypertensive]] actions of ß-receptor antagonists have not been established. However, factors that may be involved are: (1) competitive antagonism of [[catecholamine]]s 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 ß-receptors involved in release of renin from the kidneys.
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| Penbutolol dose dependently increases the RR and QT intervals. There is no influence on the PR, QRS, or QT c (corrected) intervals.
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| ===Pharmacokinetics===
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| 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.
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| 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 ß-adrenergic receptor responses in isolated guinea-pig trachea and is 1/8 to 1 times as potent in anesthetized dogs.
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| <ref name="dailymed.nlm.nih.gov">{{Cite web | last = | first = | title = LEVATOL (PENBUTOLOL SULFATE) TABLET [ACTIENT PHARMACEUTICALS, LLC] | url = http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=d241fc80-2c55-4dbb-bdb2-44f731afa137 | publisher = | date = | accessdate = 4 February 2014 }}</ref>
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| ==References==
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| {{Reflist|2}}
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| [[Category:Beta blockers]]
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| [[Category:Cardiovascular Drugs]]
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| [[Category:Drugs]]
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