italization and/or diuretic, acebutolol therapy should be withdrawn. exacerbation of ischemic heart disease following abrupt withdrawal following abrupt cessation of therapy with certain β-blocking agents in patients with coronary artery disease, exacerbation of angina pectoris and, in some cases, myocardial infarction and death have been reported. therefore, such patients should be cautioned against interruption of therapy without a physician’s advice. even in the absence of overt ischemic heart disease, when discontinuation of acebutolol is planned, the patient should be carefully observed, and should be advised to limit physical activity to a minimum while acebutolol is gradually withdrawn over a period of about two weeks. (if therapy with an alternative β-blocker is desired, the patient may be transferred directly to comparable doses of another agent without interruption of β-blocking therapy.) if an exacerbation of angina pectoris occurs, antianginal therapy should be restarted immediately in full doses and the patient hospitalized until his condition stabilizes. peripheral vascular disease treatment with β-antagonists reduces cardiac output and can precipitate or aggravate the symptoms of arterial insufficiency in patients with peripheral or mesenteric vascular disease. caution should be exercised with such patients, and they should be observed closely for evidence of progression of arterial obstruction. bronchospastic disease patients with bronchospastic disease should, in general, not receive a β-blocker. because of its relative β1-selectivity, however, low doses of acebutolol may be used with caution in patients with bronchospastic disease who do not respond to, or who cannot tolerate, alternative treatment. since β1-selectivity is not absolute and is dose-dependent, the lowest possible dose of acebutolol should be used initially, preferably in divided doses to avoid the higher plasma levels associated with the longer dose-interval. a bronchodilator, such as theophylline or a β2-stimulant, should be made available in advance with instructions concerning its use. warnings, major surgery chronically administered beta-blocking therapy should not be routinely withdrawn prior to major surgery; however, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures. diabetes and hypoglycemia β-blockers may potentiate insulin-induced hypoglycemia and mask some of its manifestations such as tachycardia; however, dizziness and sweating are usually not significantly affected. diabetic patients should be warned of the possibility of masked hypoglycemia. thyrotoxicosis β-adrenergic blockade may mask certain clinical signs (tachycardia) of hyperthyroidism. abrupt withdrawal of β-blockade may precipitate a thyroid storm; therefore, patients suspected of developing thyrotoxicosis from whom acebutolol therapy is to be withdrawn should be monitored closely.

f about two weeks. use in older patients older patients have an approximately 2-fold increase in bioavailability and may require lower maintenance doses. doses above 800 mg/day should be avoided in the elderly.

increased bilirubin or alkaline phosphatase, fever, malaise, dark urine, anorexia, nausea, headache, and/or other symptoms have been reported. in some of the reported cases, the symptoms and signs were confirmed by rechallenge with acebutolol. the abnormalities were reversible upon cessation of acebutolol therapy. musculoskeletal: back pain, joint pain. respiratory: pharyngitis, wheezing. special senses: conjunctivitis, dry eye, eye pain. autoimmune: in extremely rare instances, systemic lupus erythematosus has been reported. the incidence of drug-related adverse effects (volunteered and solicited) according to acebutolol dose is shown below. (data from 266 hypertensive patients treated for 3 months on a constant dose.) potential adverse events in addition, certain adverse effects not listed above have been reported with other β-blocking agents and should also be considered as potential adverse effects of acebutolol. central nervous system: reversible mental depression progressing to catatonia (an acute syndrome characterized by disorientation for time and place), short-term memory loss, emotional lability, slightly clouded sensorium, and decreased performance (neuropsychometrics). cardiovascular: intensification of av block (see contraindications ). allergic: erythematous rash, fever combined with aching and sore throat, laryngospasm, and respiratory distress. hematologic: agranulocytosis, nonthrombocytopenic, and thrombocytopenic purpura. gastrointestinal: mesenteric arterial thrombosis and ischemic colitis. miscellaneous: reversible alopecia and peyronie’s disease. the oculomucocutaneous syndrome associated with the β-blocker practolol has not been reported with acebutolol during investigational use and extensive foreign clinical experience. f1931f84-figure-02 f1931f84-figure-03

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 post exercise; 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: vascular effects: acebutolol has less antagonistic effects on peripheral vascular β2receptors at rest and after epinephrine stimulation than nonselective β-antagonists. bronchial effects: 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 beta2 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 β-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 post-dosing 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 β-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, 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 nonrenal mechanisms 50% to 60%, which includes excretion into the bile and direct passage through the intestinal wall. acebutolol 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.

e 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 nonrenal mechanisms 50% to 60%, which includes excretion into the bile and direct passage through the intestinal wall. acebutolol 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.