Acebutolol is a cardioselective, beta-adrenoreceptor blocking agent, which possesses mild intrinsic sympathomimetic activity (ISA) in its therapeutically effective dose range.
β1-cardioselectivity has been demonstrated in experimental animal studies. In anesthetized dogs and cats, acebutolol is more potent in antagonizing isoproterenol-induced tachycardia (β1) than in antagonizing isoproterenol-induced vasodilatation (β2). In guinea pigs and cats, it is more potent in antagonizing this tachycardia than in antagonizing isoproterenol-induced bronchodilatation (β2). ISA of acebutolol has been demonstrated in catecholamine-depleted rats by tachycardia induced by intravenous administration of this agent. A membrane-stabilizing effect has been detected in animals, but only with high concentrations of acebutolol.
Clinical studies have demonstrated β1-blocking activity at the recommended doses by: a) reduction in the resting heart rate and decrease in exercise-induced tachycardia; b) reduction in cardiac output at rest and after exercise; c) reduction of systolic and diastolic blood pressures at rest and postexercise; d) inhibition of isoproterenol-induced tachycardia.
The β1-selectivity of acebutolol has also been demonstrated on the basis of the following vascular and bronchial effects:
Acebutolol has less antagonistic effects on peripheral vascular β2-receptors at rest and after epinephrine stimulation than nonselective beta-antagonists.
In single-dose studies in asthmatics examining effects of various beta-blockers on pulmonary function, low doses of acebutolol produce less evidence of bronchoconstriction and less reduction of β2 agonist, bronchodilating effects, than nonselective agents like propranolol but more than atenolol.
ISA has been observed with acebutolol in man, as shown by a slightly smaller (about 3 beats per minute) decrease in resting heart rate when compared to equivalent beta-blocking doses of propranolol, metoprolol or atenolol. Chronic therapy with acebutolol induced no significant alteration in the blood lipid profile.
Acebutolol has been shown to delay AV conduction time and to increase the refractoriness of the AV node without significantly affecting sinus node recovery time, atrial refractory period, or the HV conduction time. The membrane-stabilizing effect of acebutolol is not manifest at the doses used clinically.
Significant reductions in resting and exercise heart rates and systolic blood pressures have been observed 1.5 hours after acebutolol administration with maximal effects occurring between 3 and 8 hours postdosing in normal volunteers. Acebutolol has demonstrated a significant effect on exercise-induced tachycardia 24 to 30 hours after drug administration.
There are significant correlations between plasma levels of acebutolol and both the reduction in resting heart rate and the percent of beta-blockade of exercise-induced tachycardia.
The antihypertensive effect of acebutolol has been shown in double-blind controlled studies to be superior to placebo and similar to propranolol and hydrochlorothiazide. In addition, patients responding to acebutolol administered twice daily had a similar response whether the dosage regimen was changed to once daily administration or continued on a b.i.d. regimen. Most patients responded to 400 to 800 mg per day in divided doses.
The antiarrhythmic effect of acebutolol was compared with placebo, propranolol, and quinidine. Compared with placebo, acebutolol significantly reduced mean total ventricular ectopic beats (VEB), paired VEB, multiform VEB, R-on-T beats, and ventricular tachycardia (VT). Both acebutolol and propranolol significantly reduced mean total and paired VEB and VT. Acebutolol and quinidine significantly reduced resting total and complex VEB; the antiarrhythmic efficacy of acebutolol was also observed during exercise.
Pharmacokinetics and Metabolism
Acebutolol is well absorbed from the GI tract. It is subject to extensive first-pass hepatic biotransformation, with an absolute bioavailability of approximately 40% for the parent compound. The major metabolite, an N-acetyl derivative (diacetolol), is pharmacologically active. This metabolite is equipotent to acebutolol and in cats is more cardioselective than acebutolol; therefore, this first-pass phenomenon does not attenuate the therapeutic effect of acebutolol. Food intake does not have a significant effect on the area under the plasma concentration-time curve (AUC) of acebutolol although the rate of absorption and peak concentration decreased slightly.
The plasma elimination half-life of acebutolol is approximately 3 to 4 hours, while that of its metabolite, diacetolol, is 8 to 13 hours. The time to reach peak concentration for acebutolol is 2.5 hours and for diacetolol, after oral administration of acebutolol hydrochloride, 3.5 hours.
Within the single oral dose range of 200 to 400 mg, the kinetics are dose proportional. However, this linearity is not seen at higher doses, probably due to saturation of hepatic biotransformation sites. In addition, after multiple dosing the lack of linearity is also seen by AUC increases of approximately 100% as compared to single oral dosing. Elimination via renal excretion is approximately 30% to 40% and by non-renal mechanisms 50% to 60%, which includes excretion into the bile and direct passage through the intestinal wall.
Acebutolol hydrochloride has a low binding affinity for plasma proteins (about 26%).
Acebutolol and its metabolite, diacetolol, are relatively hydrophilic and, therefore, only minimal quantities have been detected in the cerebrospinal fluid (CSF).
Drug interaction studies with tolbutamide and warfarin indicated no influence on the therapeutic effects of these compounds. Digoxin and hydrochlorothiazide plasma levels were not affected by concomitant acebutolol administration. The kinetics of acebutolol were not significantly altered by concomitant administration of hydrochlorothiazide, hydralazine, sulfinpyrazone, or oral contraceptives.
In patients with renal impairment, there is no effect on the elimination half-life of acebutolol, but there is decreased elimination of the metabolite, diacetolol, resulting in a two- to three-fold increase in its half-life. For this reason, the drug should be administered with caution in patients with renal insufficiency (see PRECAUTIONS). Acebutolol and its major metabolite are dialyzable.
Acebutolol crosses the placental barrier, and is secreted in breast milk.
In geriatric patients, the bioavailability of acebutolol and its metabolite is increased, approximately two-fold, probably due to decreases in the first-pass metabolism and renal function in the elderly.