Acebutolol
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alonso Alvarado, M.D. [2]
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Overview
Acebutolol is a Template:Beta-adrenergic blocker that is FDA approved for the {{{indicationType}}} of hypertension, ventricular arrhythmias. Common adverse reactions include dizziness, headache, fatigue.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
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Off-Label Use and Dosage (Adult)
Guideline-Supported Use
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Condition 2
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Non–Guideline-Supported Use
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Pediatric Indications and Dosage
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Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
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Condition 2
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Non–Guideline-Supported Use
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Contraindications
- Persistently severe bradycardia
- Second-degree AV heart block
- Third-degree AV heart block
- Overt cardiac failure
- Cardiogenic shock
Warnings
Cardiac Failure
Sympathetic stimulation may be essential for support of the circulation in individuals with diminished myocardial contractility, and its inhibition by beta-adrenergic receptor blockade may precipitate more severe failure. Although beta-blockers should be avoided in overt cardiac failure, acebutolol can be used with caution in patients with a history of heart failure who are controlled with digitalis and/or diuretics. Both digitalis and acebutolol impair AV conduction. If cardiac failure persists, therapy with acebutolol should be withdrawn.
In Patients Without a History of Cardiac Failure
In patients with aortic valve disease or mitral valve disease or compromised left ventricular function, continued depression of the myocardium with beta-blocking agents over a period of time may lead to cardiac failure. At the first signs of failure, patients should be digitalized and/or be given a diuretic and the response observed closely. If cardiac failure continues despite adequate digitalization and/or diuretic, acebutolol therapy should be withdrawn.
Exacerbation of Ischemic Heart Disease Following Abrupt Withdrawal
Following abrupt cessation of therapy with certain beta-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 2 weeks. (If therapy with an alternative beta-blocker is desired, the patient may be transferred directly to comparable doses of another agent without interruption of beta-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 beta-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 BETA-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 a theophylline or a β2-stimulant, should be made available in advance with instructions concerning its use.
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
Beta-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
Beta-adrenergic blockade may mask certain clinical signs (tachycardia) of hyperthyroidism. Abrupt withdrawal of beta-blockade may precipitate a thyroid storm; therefore, patients suspected of developing thyrotoxicosis from whom acebutolol therapy is to be withdrawn should be monitored closely.
Risk of Anaphylactic Reaction
While taking beta-blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reaction.
Adverse Reactions
Clinical Trials Experience
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Condition 2
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Clinical Laboratory Findings
Acebutolol, like other beta-blockers, has been associated with the development of antinuclear antibodies (ANA). In prospective clinical trials, patients receiving acebutolol had a dose-dependent increase in the development of positive ANA titers and the overall incidence was higher than that observed with propranolol. Symptoms (generally persistent arthralgias and myalgias) related to this laboratory abnormality were infrequent (less than 1% with both drugs). Symptoms and ANA titers were reversible upon discontinuation of treatment.
Postmarketing Experience
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Drug Interactions
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Use in Specific Populations
Pregnancy
Pregnancy Category (FDA):
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Labor and Delivery
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Nursing Mothers
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Pediatric Use
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Geriatic Use
Acebutolol has been used successfully and without problems in elderly patients in the U.S. clinical trials without specific adjustment of dosage. However, elderly patients may require lower maintenance doses because the bioavailability of both acebutolol and its metabolite are approximately doubled in this age group.
Gender
There is no FDA guidance on the use of Acebutolol with respect to specific gender populations.
Race
There is no FDA guidance on the use of Acebutolol with respect to specific racial populations.
Renal Impairment
Studies on the effect of acebutolol in patients with renal insufficiency have not been performed in the United States. Foreign published experience shows that acebutolol has been used successfully in chronic renal insufficiency. Acebutolol is excreted through the G.I. tract, but the active metabolite, diacetolol, is eliminated predominantly by the kidney. There is a linear relationship between renal clearance of diacetolol and creatinine clearance. Therefore, the daily dose of acebutolol should be reduced by 50% when the creatinine clearance is less than 50 mL/min and by 75% when it is less than 25 mL/min.
Hepatic Impairment
Acebutolol should be used cautiously in patients with impaired hepatic function.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Acebutolol in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Acebutolol in patients who are immunocompromised.
Administration and Monitoring
Administration
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Monitoring
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IV Compatibility
Solution
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Variable
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Y-Site
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Admixture
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Variable
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Syringe
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TPN/TNA
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Overdosage
Acute Overdose
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Management
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Chronic Overdose
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Pharmacology
Acebutolol
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Mechanism of Action
Acebutolol is a cardioselective, beta-adrenoreceptor blocking agent, which possesses mild intrinsic sympathomimetic activity (ISA) in its therapeutically effective dose range.
Structure
Acebutolol hydrochloride is a selective, hydrophilic beta-adrenoreceptor blocking agent with mild intrinsic sympathomimetic activity for use in treating patients with hypertension and ventricular arrhythmias. It is marketed in capsule form for oral administration. Acebutolol Hydrochloride Capsules, USP are available in two strengths which contain 200 mg or 400 mg of acebutolol as the hydrochloride salt. The inactive ingredients are povidone, pregelatinized starch and stearic acid. The empty gelatin capsules contain D&C Red No. 28, D&C Yellow No. 10, FD&C Blue No. 1, FD&C Red No. 40, gelatin, sodium lauryl sulfate and titanium dioxide. In addition, the imprinting ink contains black iron oxide, D&C Yellow No. 10 Aluminum Lake, FD&C Blue No. 1 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake, FD&C Red No. 40 Aluminum Lake, propylene glycol and shellac glaze.
Acebutolol hydrochloride, USP is a white or slightly off-white powder freely soluble in water, and less soluble in alcohol. Chemically it is defined as the hydrochloride salt of (±) N-[3-Acetyl-4-[2-hydroxy-3-[(1-methylethyl)amino]propoxy]phenyl] butanamide.
Pharmacodynamics
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:
Vascular Effects
Acebutolol has less antagonistic effects on peripheral vascular β2-receptors at rest and after epinephrine stimulation than nonselective beta-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 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 three 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/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
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 mg 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 2- to 3-fold increase in its half-life. For this reason, the drug should be administered with caution in patients with renal insufficiency. 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 2-fold, probably due to decreases in the first-pass metabolism and renal function in the elderly.
Nonclinical Toxicology
Chronic oral toxicity studies in rats and mice, employing dose levels as high as 300 mg/kg/day, which is equivalent to 15 times the maximum recommended (60 kg) human dose, did not indicate a carcinogenic potential for acebutolol. Diacetolol, the major metabolite of acebutolol in man, was without carcinogenic potential in rats when tested at doses as high as 1800 mg/kg/day. Acebutolol and diacetolol were also shown to be devoid of mutagenic potential in the Ames Test. Acebutolol, administered orally to two generations of male and female rats at doses of up to 240 mg/kg/day (equivalent to 12 times the maximum recommended therapeutic dose in a 60-kg human) and diacetolol, administered to two generations of male and female rats at doses of up to 1000 mg/kg/day, had no significant impact on reproductive performance or fertility.
Clinical Studies
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Storage
There is limited information regarding Acebutolol Storage in the drug label.
Images
Drug Images
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Package and Label Display Panel
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Patient Counseling Information
Patients, especially those with evidence of coronary artery disease, should be warned against interruption or discontinuation of acebutolol therapy without a physician's supervision. Although cardiac failure rarely occurs in properly selected patients, those being treated with beta-adrenergic blocking agents should be advised to consult a physician if they develop signs or symptoms suggestive of impending CHF, or unexplained respiratory symptoms.
Patients should also be warned of possible severe hypertensive reactions from concomitant use of alpha-adrenergic stimulants, such as the nasal decongestants commonly used in OTC cold preparations and nasal drops.
Precautions with Alcohol
Alcohol-Acebutolol interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
Brand Names
There is limited information regarding Acebutolol Brand Names in the drug label.
Look-Alike Drug Names
- (Paired Confused Name 1a) — (Paired Confused Name 1b)
- (Paired Confused Name 2a) — (Paired Confused Name 2b)
- (Paired Confused Name 3a) — (Paired Confused Name 3b)
Drug Shortage Status
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References
The contents of this FDA label are provided by the National Library of Medicine.