Antihypertensive – Antianginal Agent
Action And Clinical Pharmacology: Acebutolol is a beta-adrenergic receptor blocking agent. In vitro and in vivo animal studies have shown that it has a preferential effect on beta1-adrenoreceptors, chiefly located in cardiac muscle. This preferential effect is not absolute, however, and at higher doses acebutolol also inhibits beta2-adrenoreceptors, chiefly located in the bronchial and vascular musculature. It possesses some partial agonist activity (or intrinsic sympathomimetic activity – ISA). It is used in the treatment of hypertension and/or prophylaxis of angina pectoris.
The mechanism of the antihypertensive effect has not been established. Among the factors that may be involved are: competitive ability to antagonize catecholamine-induced tachycardia at the beta-receptor sites in the heart, thus decreasing cardiac output; inhibition of renin release by the kidneys; inhibition of the vasomotor centres.
Pharmacokinetics: The mechanism of the anti-anginal effects is also uncertain. An important factor may be the reduction of myocardial oxygen requirements by blocking catecholamine-induced increases in heart rate, systolic blood pressure, and the velocity and extent of myocardial contraction.
Acebutolol is well absorbed from the gastrointestinal tract. It undergoes 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; 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.
Indications And Clinical Uses: Hypertension: In patients with mild to moderate hypertension. It is usually used in combination with other drugs, particularly a thiazide diuretic. However, it may be tried alone as an initial agent in those patients in whom, in the judgment of the physician, treatment should be started with a beta-blocker rather than a diuretic.
In patients with severe hypertension a beta-adrenergic blocking agent may be used as part of a multiple drug regimen which would normally include a diuretic and a vasodilator.
The combination of acebutolol with a diuretic or peripheral vasodilator has been found to be compatible and generally more effective than acebutolol alone. Limited experience with other antihypertensive agents has not shown evidence of incompatibility.
Acebutolol is not indicated in the emergency treatment of hypertensive crises.
Angina Pectoris: In the long-term management of patients with angina pectoris due to ischemic heart disease.
Contra-Indications: Acebutolol should not be used in the presence of: sinus bradycardia, second- and third-degree AV block, right ventricular failure secondary to pulmonary hypertension, congestive heart failure, cardiogenic shock, anesthesia with agents that produce myocardial depression, e.g., ether.
Manufacturers’ Warnings In Clinical States: Increase in antinuclear antibody (ANA) titre was observed in approximately 12.5% of patients on chronic acebutolol therapy. Rare instances (
Cardiac Failure: Special caution should be exercised when administering acebutolol to patients with a history of heart failure. Sympathetic stimulation is a vital component supporting circulatory function in congestive heart failure, and inhibition with beta-blockade always carries the potential hazard of further depressing myocardial contractility and precipitating cardiac failure. Acebutolol acts selectively without abolishing the inotropic action of digitalis on the heart muscle. However, the positive inotropic action of digitalis may be reduced by the negative inotropic effect of acebutolol when the 2 drugs are used concomitantly.
The effects of beta-blockers and digitalis are additive in depressing AV conduction.
In patients without a history of cardiac failure, continued depression of myocardium over a period of time can, in some cases, lead to cardiac failure. Therefore, at the first sign or symptom of impending cardiac failure, patients should be fully digitalized and/or given a diuretic and the response observed closely. If cardiac failure continues despite adequate digitalization and diuretic therapy, acebutolol should be immediately withdrawn.
Abrupt Cessation of Therapy: Patients with angina should be warned against abrupt discontinuation of acebutolol. There have been reports of severe exacerbation of angina, and of myocardial infarction or ventricular arrhythmias occurring in patients with angina pectoris, following abrupt discontinuation of beta-blocker therapy. The last 2 complications may occur with or without preceding exacerbation of angina pectoris. Therefore, when discontinuation is planned in patients with angina pectoris, the dosage should be gradually reduced over a period of about 2 weeks and the patient should be carefully observed. The same frequency of administration should be maintained. In situations of greater urgency, acebutolol therapy should be discontinued stepwise and under conditions of closer observation. If angina markedly worsens or acute coronary insufficiency develops, it is recommended that treatment with acebutolol be reinstituted promptly, at least temporarily.
Various skin rashes and conjunctival xerosis have been reported with beta-blockers, including acebutolol. A severe syndrome (oculo-muco-cutaneous syndrome) whose signs include conjunctivitis sicca and psoriasiform rashes, otitis, and sclerosing serositis has occurred with the chronic use of one beta-adrenergic-blocking agent (practolol). This syndrome has not been observed with acebutolol or any other such agent. However, physicians should be alert to the possibility of such reactions and should discontinue treatment in the event that they occur.
Severe sinus bradycardia may occur with the use of acebutolol from unopposed vagal activity remaining after blockade of beta1-adrenergic receptors; in such cases, dosage should be reduced.
In patients with thyrotoxicosis, the possible deleterious effects from long-term use of acebutolol have not been adequately appraised. It may give a false impression of improvement by masking the clinical signs of continuing hyperthyroidism or its complications. Therefore, abrupt withdrawal of acebutolol may be followed by an exacerbation of the symptoms of hyperthyroidism, including thyroid storm.
Pregnancy: Reproduction studies have been performed with acebutolol in rats and rabbits at doses of up to 60 mg/kg/day by the oral route and 18 mg/kg/day by the i.v. route. In one rabbit study where acebutolol was administered by the i.v. route, the following malformations were observed: rib defects, gastroschisis, ventricular septal defect, dysplasia of urogenital system and umbilical hernia. These results could not be confirmed in a repeat i.v. study and were not seen in a study using the oral route.
Studies have also been performed with diacetolol (the major metabolite) at doses of up to 450 mg/kg/day orally in rabbits and 1 800 mg/kg/day orally in rats. There was a significant elevation of postimplantation loss in rabbit dams receiving 450 mg/kg/day, a level at which food consumption and body weight gain were reduced; a nonstatistically significant increase in incidence of bilateral cataracts was also noticed in rat fetuses from dams treated with 1 800 mg/kg/day.
There has been no experience with the use of acebutolol in pregnant women; however, studies have shown that both acebutolol and diacetolol cross the placenta. Acebutolol should not be given to pregnant patients. Its use in women with childbearing potential requires that the anticipated benefit be cautiously weighed against possible hazards.
Lactation: Acebutolol and diacetolol appear in breast milk with a milk:plasma ratio of 7.1 and 12.2 respectively. Use in nursing mothers is not recommended.
Precautions: Patients with bronchospastic disease should, in general, not receive a beta-blocker. Because of its relative beta1-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 beta1-selectivity is not absolute and is dose-dependent, a beta2-stimulating agent should be administered concomitantly and 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.
There may be increased difficulty in treating an allergic type reaction in patients on beta-blockers. In these patients, the reaction may be more severe due to pharmacological effects of beta-blockers and problems with fluid changes. Epinephrine should be administered with caution since it may not have its usual effects in the treatment of anaphylaxis. On the one hand, larger doses of epinephrine may be needed to overcome the bronchospasm, while on the other, these doses can be associated with excessive alpha-adrenergic stimulation with consequent hypertension, reflex bradycardia and heart-block and possible potentiation of bronchospasm. Alternatives to the use of large doses of epinephrine include vigorous supportive care such as fluids and the use of beta-agonists including parenteral salbutamol or isoproterenol to overcome bronchospasm, and norepinephrine to overcome hypotension.
Acebutolol should be administered with caution to patients subject to spontaneous hypoglycemia, or to diabetic patients (especially those with labile diabetes) who are receiving insulin or oral hypoglycemic agents. Beta-adrenergic blockers may mask the premonitory signs and symptoms of acute hypoglycemia.
Acebutolol should be administered with caution to patients with impaired renal function. Acebutolol is excreted through the gastrointestinal 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. The daily dose should be reduced in patients with a creatinine clearance less than 50 mL/min.
Geriatrics: Acebutolol has been used in the elderly without specific adjustment of dosage. However, this patient population may require lower maintenance doses because the bioavailability of both acebutolol and its metabolite are approximately doubled in this age group. This increased bioavailability is probably due to decreases in first-pass metabolism and renal function in the elderly.
Acebutolol dosage should be individually adjusted when used concomitantly with other antihypertensive agents (see Dosage).
Liver function tests should be performed at regular intervals during long-term treatment.
Elective or Emergency Surgery: The management of patients being treated with beta-blockers and undergoing elective or emergency surgery is controversial. Although beta-adrenergic-receptor blockade impairs the ability of the heart to respond to beta-adrenergically-mediated reflex stimuli, abrupt discontinuation of therapy with acebutolol may be followed by severe complications (see Warnings). Some patients receiving beta-adrenergic-blocking agents have been subject to protracted severe hypotension during anesthesia. Difficulty in restarting and maintaining the heartbeat has also been reported. For these reasons, in patients with angina undergoing elective surgery, acebutolol should be withdrawn gradually following the recommendation given under Abrupt Cessation of Therapy (see Warnings). According to available evidence, all clinical and physiological effects of beta-blockade are no longer present 72 hours after cessation of medication.
In emergency surgery, since acebutolol is a competitive inhibitor of beta-adrenergic-receptor agonists, its effects may be reversed, if necessary, by sufficient doses of such agonists as isoproterenol.
Children: There is no experience with acebutolol in the treatment of pediatric age groups and therefore use in children is not recommended.
Drug Interactions: Catecholamine-depleting drugs, such as reserpine, may have an additive effect when given with b-blocking agents. Patients treated with acebutolol plus catecholamine depletors should, therefore be observed closely for evidence of marked bradycardia or hypotension which may present as vertigo, syncope/presyncope, or orthostatic changes in blood pressure without compensatory tachycardia.
Exaggerated hypertensive responses have been reported from the combined use of b-adrenergic antagonists and a-adrenergic stimulants, including those contained in proprietary cold remedies and vasoconstrictive nasal drops. Patients receiving b-blockers should be warned of this potential hazard.
No significant interactions with digoxin, hydrochlorothiazide, hydralazine, sulfinpyrazone, oral contraceptives, tolbutamide or warfarin have been observed.
Should it be decided to discontinue therapy in patients receiving beta-blockers and clonidine concurrently, the beta-blocker should be discontinued several days before the gradual withdrawal of clonidine. It has been suggested that withdrawal of clonidine in the presence of beta-blockade may exaggerate the clonidine withdrawal syndrome (see also prescribing information for clonidine).
Adverse Reactions: The incidence of treatment-related side effects is derived from clinical trials in 3 090 patients with hypertension, angina pectoris or arrhythmia.
The most serious adverse reactions encountered with acebutolol are congestive heart failure, severe bradycardia and bronchospasm occurring in less than 1% of patients.
The most common adverse reactions reported are fatigue (4%), dyspnea (2.5%), nausea (2%), dizziness (2%), hypotension (1%) and rashes (1%).
Adverse reactions grouped by systems are as follows: Cardiovascular: congestive heart failure (see Warnings); secondary effects of decreased cardiac output which include: syncope, vertigo, lightheadedness and postural hypotension; severe bradycardia; lengthening of PR interval; second- and third-degree AV block; sinus arrest; palpitation; chest pain; cold extremities; Raynaud’s phenomenon; hot flushes; pain in legs; edema.
CNS: headache, dizziness, mental depression, tiredness, drowsiness or somnolence, lightheadedness, anxiety, tinnitus, weakness, confusion, vivid dreams, paresthesia, insomnia.
Gastrointestinal: nausea and vomiting, heartburn, indigestion, flatulence, abdominal pain, diarrhea, constipation.
Respiratory: dyspnea, cough, shortness of breath, wheezing, bronchospasm.
Allergic-Dermatological (see Warnings): urticaria; pruritus; sweating; exfoliative dermatitis; psoriasiform rash; lupus-like syndrome with arthralgia, myalgia, dyspnea and pleuritic pain, reversible upon cessation of the drug.
EENT: blurred vision and nonspecific visual disturbances, itching eyes, conjunctivitis.
Miscellaneous: weight gain, loss of appetite, decrease in libido, shivering, micturition (frequency), nocturia.
Laboratory Tests: Occasional reports of increased transaminase, alkaline phosphatase and lactic dehydrogenase values. Positive antinuclear antibodies (see Warnings).
Symptoms And Treatment Of Overdose: Symptoms: The most common signs to be expected with a beta-adrenergic blocking agent are bradycardia, congestive heart failure, hypotension, bronchospasm and hypoglycemia.
Treatment: If overdosage occurs, in all cases therapy with acebutolol should be discontinued and the patient observed closely. In addition, if required, the following therapeutic measures are suggested: 1. Bradycardia: atropine or another anticholinergic drug.
2. Heart block (second- or third-degree): isoproterenol or transvenous cardiac pacemaker.
3. Congestive heart failure: conventional therapy.
4. Hypotension (depending on associated factors): epinephrine rather than isoproterenol or norepinephrine may be useful in addition to atropine and digitalis (see Precaution concerning the use of epinephrine in b-blocked patients).
5. Bronchospasm: aminophylline or isoproterenol.
6. Hypoglycemia: i.v. glucose.
Acebutolol and its major metabolite are dialyzable.
It should be remembered that acebutolol is a competitive antagonist of isoproterenol and hence large doses of isoproterenol can be expected to reverse many of the effects of excessive doses of acebutolol. However, the complications of excess isoproterenol should not be overlooked.
Dosage And Administration: The dose of acebutolol must always be adjusted to the individual requirements of the patient in accordance with the following guidelines:
Hypertension: Acebutolol is usually used in conjunction with other antihypertensive agents, particularly thiazide diuretics but may be used alone (see Indications).
Treatment should be initiated with doses of 100 mg twice daily. If an adequate response is not seen after 1 week, the dosage should be increased to 200 mg twice daily. In some cases, the daily dosage may need further increments of 100 mg twice daily at intervals of not less than 2 weeks, up to the maximum of 400 mg twice daily.
The maintenance dose is within the range of 400 to 800 mg daily. Patients who show a satisfactory response at a daily dose of 400 mg or less may be given the total dose once daily in the morning. Daily doses above this should be divided into 2 equal doses.
Angina Pectoris: The initial dose is 200 mg twice daily. If after 2 weeks a satisfactory response has not been obtained, the dosage should be increased to a maximum of 300 mg twice daily.
The usual maintenance dose in angina pectoris is in the range of 200 to 600 mg daily administered in 2 divided doses.
In patients adequately controlled on 400 mg daily, a lower maintenance dose of 100 mg twice a day may be tried.
Geriatrics: Older patients have an approximately 2-fold increase in bioavailability and are likely to require lower maintenance doses.
Impaired Renal Function: The daily dose of acebutolol should be reduced by 50% when creatinine clearance is less than 50 mL/min and by 75% when it is less than 25 mL/min (see Precautions).
Availability And Storage: 100 mg: Each white, film-coated, scored, round, biconvex tablet, marked “100” on one side and “WYETH” on the other, contains: acebutolol HCl 100 mg. Nonmedicinal ingredients: cornstarch, hydroxypropyl methylcellulose, lactose hydrous, magnesium stearate, methylcellulose, polyethylene glycol, propylene glycol, talc and titanium dioxide. Energy: 0.41 kJ (0.10 kcal). Gluten- and tartrazine-free. Bottles of 100 and 500.
200 mg: Each white, film-coated, oval, biconvex tablet, scored and marked “200” on one side and “WYETH” on the other, contains: acebutolol HCl 200 mg. Nonmedicinal ingredients: cornstarch, hydroxypropyl methylcellulose, lactose hydrous, magnesium stearate, methylcellulose, polyethylene glycol, propylene glycol, talc and titanium dioxide. Energy: 0.82 kJ (0.20 kcal). Gluten- and tartrazine-free. Bottles of 100 and 500.
400 mg: Each white to off-white, film-coated, capsule-shaped, biconvex, scored tablet, marked “400” on one side and “MONITAN” on the other, contains: acebutolol HCl 400 mg. Nonmedicinal ingredients: cornstarch, hydroxypropyl methylcellulose, lactose hydrous, magnesium stearate, methylcellulose, polyethylene glycol, propylene glycol, talc and titanium dioxide. Energy: 1.63 kJ (0.39 kcal). Gluten- and tartrazine-free. Bottles of 100 and 500.
Store at 15 to 30°C. Protect from light. (Shown in Product Recognition Section)
MONITAN® Wyeth-Ayerst Acebutolol HCl Antihypertensive – Antianginal Agent