Pharmacology of 4‐hydroxypropranolol, a metabolite of propranolol

Abstract

Summary1. 4-Hydroxypropranolol, a metabolite produced after oral administration of propranolol, has been shown to be a /3-adrenoceptor blocking drug. It is of similar potency to propranolol in antagonizing the effects of isoprenaline on heart rate and blood pressure in cats and against isoprenaline protection of guinea-pigs from bronchospasm. It is not cardioselective. 2. In rats depleted of catecholamine 4-hydroxypropranolol produced an increase in heart rate, suggesting that it has intrinsic sympathomimetic activity. 3. In anaesthetized dogs 4-hydroxypropranolol produced a decrease in heart rate and dP/dt and an increase in A-V conduction time at doses within the range 0 09-1 25 mg/kg. These effects are a result of /3-adrenoceptor blockade. In dogs depleted of catecholamines these same doses produced an increase in heart rate and dP/dt and a decrease in A-V conduction time. These responses were antagonized by propranolol, and were due to the intrinsic sympathomimetic activity of the compound. At higher doses (5-25 and 13'25 mg/kg) a further dose dependent decrease in heart rate and dP/dt and an increase in A-V conduction time occurred. This trend was also seen in animals depleted of catecholamines. These changes represent membrane stabilizing activity of 4-hydroxypropranolol.4. 4-Hydroxypropranolol is a potent /8-adrenoceptor blocking drug with both intrinsic sympathomimetic activity and membrane stabilizing activity.

The relationship between debrisoquine oxidation phenotype and the pharmacokinetics and pharmacodynamics of propranolol.

“…This assumes, however, that only unchanged drug contributes to the pharmacological effect. It has been shown in dogs that 4'-hydroxypropranolol and propranolol are equipotent in their /3-adrenoceptor blocking properties (Fitzgerald & O'Donnell, 1971). 4'-Hydroxypropranolol is formed in significant amounts only after oral dosing in man (Paterson et al, 1970) and indirect evidence based on a disparity between the extent of f3-adrenoceptor blockade achieved after oral and intravenous propranolol suggested that 4'-hydroxypropranolol contributes significantly to /3-adrenoceptor blockade after a single oral dose of drug (Cleavland & Shand, 1972;Coltart & Shand, 1970).…”

The assessment of beta‐adrenoceptor blocking drugs in man.

“…They showed that an active metabolite of propranolol, 4-hydroxy propranolol, can be detected in the plasma only after oral administration. This metabolite is not measured by the standard propranolol assay, but since it is equipotent to propranolol (Fitzgerald & O'Donnell, 1971) and achieves approximately the same circulating concentrations as the parent drug shortly after an oral dose (Paterson et al, 1970), the effects of the metabolite will add to those of propranolol. The presence of this metabolite after oral but not intravenous propranolol would appear to account for the twofold difference in the effective propranolol concentration by the two routes of administration.…”

Contrasts between pindolol and propranolol concentration‐response relationships.

“…Concentration-response curves of propranolol were parallel but the oral concentration-response curve was shifted to the left of the i.v. curve, indicative of probable pharmacodynamic interference by a metabolite, an observation first made by Coltart & Shand (1970) and thought to reflect the presence of 4-hydroxypropranolol, a metabolite which appears to exert similar 0-adrenoceptor blocking activity to that of propranolol (Fitzgerald & O'Donnell, 1971). The lack of any such shift in pindolol concentration-response curves, even in those individuals with the lowest systemic bioavailability, indicates that its metabolites do not appear to exert any effects on ,-adrenoceptors.…”