VA Class:CV100
Acebutolol hydrochloride is a short-acting β1-selective adrenergic blocking agent (β-blocker).1, 2, 17, 18, 113
Acebutolol is used for the management of hypertension1, 280, 1200 and ventricular arrhythmias (to suppress and prevent the recurrence of frequent ventricular premature complexes [VPCs], including uniform and multiform VPCs and/or coupled VPCs, and R-on-T complexes1, 2, 137, 185, 186, 187, 188, 189, 190, 193, 194, 195, 196, 197, 198, 199, 201, 204 in patients with primary arrhythmias or arrhythmias secondary to various cardiac disorders [e.g., coronary artery disease,137, 185, 186, 187, 188, 189, 194 myocardial infarction (MI),137, 186, 187, 193, 194, 195, 196 valvular disease]).185, 186, 187, 189, 190 The drug also has been used for the management of angina†, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 220, 221, 222, 223, 224, 225 myocardial infarction†, 289, 290, 293 and various supraventricular arrhythmias†.191, 192, 196, 200, 202, 203, 256, 266
The choice of a β-adrenergic blocking agent (β-blocker) depends on numerous factors, including pharmacologic properties (e.g., relative β-selectivity, intrinsic sympathomimetic activity, membrane-stabilizing activity, lipophilicity), pharmacokinetics, intended use, and adverse effect profile, as well as the patient's coexisting disease states or conditions, response, and tolerance.35, 36, 37, 38, 269, 270, 271, 272, 273, 274, 275, 278, 355 While specific pharmacologic properties and other factors may appropriately influence the choice of a β-blocker in individual patients,1235 evidence of clinically important differences among the agents in terms of overall efficacy and/or safety is limited.35, 37, 38, 269, 270, 271, 272, 273, 274, 275, 278 Patients who do not respond to or cannot tolerate one β-blocker may be successfully treated with a different agent.37, 38, 269, 270, 273, 275, 278 Because of its relative β1-selectivity and mild intrinsic sympathomimetic activity, acebutolol hydrochloride may be particularly useful in patients in whom these properties may be of potential value (e.g., patients with bronchospastic disease, diabetes mellitus, or peripheral vascular disease, or those who experience excessive bradycardia with another β-blocker).6, 7, 35, 37, 38, 269, 270, 272
Acebutolol is used alone or in combination with other classes of antihypertensive agents in the management of hypertension.1, 280, 1200
Current evidence-based practice guidelines for the management of hypertension in adults generally recommend the use of drugs from 4 classes of antihypertensive agents (angiotensin-converting enzyme [ACE] inhibitors, angiotensin II receptor antagonists, calcium-channel blockers, and thiazide diuretics).501, 502, 503, 504, 1200 Most guidelines no longer recommend β-blockers as first-line therapy for hypertension because of the lack of established superiority over other recommended drug classes and evidence from at least one study demonstrating that β-blockers may be less effective than angiotensin II receptor antagonists in preventing cardiovascular death, MI, or stroke.361, 501, 503, 504, 515, 1200 However, therapy with a β-blocker may still be considered in hypertensive patients who have a compelling indication (e.g., prior MI, ischemic heart disease, heart failure) for their use or as add-on therapy in those who do not respond adequately to the preferred drug classes.501, 502, 503, 504, 523, 524, 527, 800, 1200 (See Considerations for Drug Therapy in Patients with Underlying Cardiovascular and Other Risk Factors under Uses: Hypertension, in Atenolol 24:24 and in Metoprolol 24:24.) Ultimately, choice of antihypertensive therapy should be individualized, considering the clinical characteristics of the patient (e.g., age, ethnicity/race, comorbid conditions, cardiovascular risk factors) as well as drug-related factors (e.g., ease of administration, availability, adverse effects, costs).501, 502, 503, 504, 515, 1200, 1201
A 2017 multidisciplinary hypertension guideline of the American College of Cardiology (ACC), American Heart Association (AHA), and a number of other professional organizations generally recommends a target blood pressure goal (i.e., blood pressure to achieve with drug therapy and/or nonpharmacologic intervention) of less than 130/80 mm Hg in all adults regardless of comorbidities or level of atherosclerotic cardiovascular disease (ASCVD) risk.1200 In addition, a systolic blood pressure goal of less than 130 mm Hg generally is recommended for noninstitutionalized ambulatory patients 65 years of age or older with an average systolic blood pressure of at least 130 mm Hg.1200 These blood pressure goals are based upon clinical studies demonstrating continuing reduction of cardiovascular risk at progressively lower levels of systolic blood pressure.1200, 1202, 1210 Previous hypertension guidelines, such as those from an expert panel of the Eighth Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 8), generally have recommended initiation of antihypertensive treatment in patients with a systolic blood pressure of at least 140 mm Hg or diastolic blood pressure of at least 90 mm Hg, targeted a blood pressure goal of less than 140/90 mm Hg regardless of cardiovascular risk, and used higher systolic blood pressure thresholds and targets in geriatric patients501, 504, 536 compared with those recommended by the 2017 ACC/AHA hypertension guideline.1200 The blood pressure thresholds used to define hypertension, the optimum blood pressure threshold at which to initiate antihypertensive drug therapy, and the ideal target blood pressure values remain controversial.501, 503, 504, 505, 506, 507, 508, 515, 523, 526, 530, 1200, 1201, 1207, 1209, 1222, 1223, 1229
Acebutolol appears to be safe and effective in the management of hypertension in patients with chronic renal impairment.2, 146, 149, 157 Although acebutolol appears to be more effective in reducing blood pressure in patients with normal or elevated plasma renin concentrations,141, 143 the drug also lowers blood pressure in patients with low renin hypertension.139
Most patients with hypertension, especially black patients, will require at least 2 antihypertensive drugs to achieve adequate blood pressure control.1200 In general, black hypertensive patients tend to respond better to monotherapy with thiazide diuretics or calcium-channel blocking agents than to monotherapy with β-blockers.355, 359, 360, 501, 504, 1200 Although β-blockers have lowered blood pressure in all races studied, monotherapy with these agents has produced a smaller reduction in blood pressure in black hypertensive patients; however, this population difference in response does not appear to occur during combined therapy with a β-blocker and a thiazide diuretic.500 (See Race under Hypertension: Other Special Considerations for Antihypertensive Drug Therapy, in Uses in Atenolol 24:24 and Metoprolol 24:24.)
Tolerance to the antihypertensive effect of acebutolol apparently does not occur during long-term administration.2, 4
For additional information on the role of β-blockers in the management of hypertension, see Uses: Hypertension, in Atenolol 24:24 and in Metoprolol 24:24. For information on overall principles and expert recommendations for treatment of hypertension, see Uses: Hypertension in Adults and also see Uses: Hypertension in Pediatric Patients, in the Thiazides General Statement 40:28.20.
Acebutolol hydrochloride is used to suppress and prevent the recurrence of frequent ventricular premature complexes (VPCs), including uniform and multiform VPCs and/or coupled VPCs, and R-on-T complexes1, 2, 137, 185, 186, 187, 188, 189, 190, 193, 194, 195, 196, 197, 198, 199, 201, 204 in patients with primary arrhythmias or arrhythmias secondary to various cardiac disorders (e.g., coronary artery disease,137, 185, 186, 187, 188, 189, 194 MI,137, 186, 187, 193, 194, 195, 196 valvular disease).185, 186, 187, 189, 190 In short-term clinical studies, acebutolol therapy produced at least 60-90% suppression of VPCs in about 40-90% of patients;137, 185, 186, 187, 188, 189, 190, 193, 194, 195, 199, 204 in many patients, essentially complete suppression of uniform and multiform VPCs1, 2, 137, 185, 186, 187, 188, 189, 190, 193, 194, 195, 196, 199, 204 and/or asymptomatic, nonsustained ventricular tachycardia may occur.2, 185, 186 Acebutolol is effective in suppressing VPCs during exercise, as well as at rest or during ambulation.1, 2, 187, 189, 190 The efficacy of acebutolol appears to be largely sustained in a majority of patients during long-term therapy;2, 194, 195 however, as with other antiarrhythmic agents, the degree of suppression of ventricular arrhythmias and/or proportion of patients with an adequate therapeutic response may diminish with prolonged acebutolol therapy, and additional evaluation of long-term efficacy is needed.2, 194, 195 IV† acebutolol has also been effective in acutely suppressing VPCs in a limited number of patients.191, 197
There have been relatively few studies directly comparing acebutolol and other antiarrhythmic agents in the management of recurrent stable ventricular arrhythmias, but results to date suggest that the efficacy of acebutolol is similar to that of propranolol189, 198, 199, 201, 204 or quinidine190, 198 in suppressing and preventing frequent VPCs and/or asymptomatic, nonsustained ventricular tachycardia.189, 190, 198, 199, 201, 204 It remains to be determined whether antiarrhythmic agents, including acebutolol, have a beneficial effect on mortality or sudden death.137, 187, 198
Acebutolol hydrochloride may prove to be useful for the management of various supraventricular tachyarrhythmias†, but the effects of the drug have not been evaluated adequately to date.191, 192, 196, 200, 202, 203, 256, 266
Acebutolol has been used in the management of chronic stable angina pectoris†.205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 220, 221, 222, 223, 224, 225 Like other β-blockers, use of acebutolol in chronic stable angina pectoris may reduce the frequency of angina attacks,205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 222, 224 allow a reduction in nitroglycerin dosage,205, 206, 207, 209, 210, 211, 212, 213 and increase the patient's exercise tolerance.205, 208, 209, 210, 211, 212, 213, 220, 221, 222, 224, 225 The efficacy of acebutolol in the management of chronic stable angina appears to be similar to that of other β-blockers.210, 211, 212 Some authorities state that β-blockers are the anti-ischemic drugs of choice in geriatric patients with stable angina.348
In patients who do not respond to maximal dosages of a β-blocker or nitroglycerin alone, concurrent use of the 2 drugs may be beneficial.215, 216 Combination therapy with a β-blocker and a nitrate appears to be more effective than either drug alone because β-blockers attenuate the increased sympathetic tone and reflex tachycardia associated with nitrate therapy while nitrate therapy (e.g., nitroglycerin) counteracts the potential increase in left-ventricular volume and end-diastolic pressure and wall tension associated with a decrease in heart rate.348 Combined therapy with a β-blocker and a slow-release or long-acting dihydropyridine-derivative calcium-channel blocker also may be useful because the tendency to develop tachycardia with the calcium-channel blocker is counteracted by the β-blocker.348 However, caution should be exercised in the concomitant use of β-blockers and the nondihydropyridine calcium-channel blockers verapamil or diltiazem because of the potential for marked fatigue (with high-dose verapamil or diltiazem), extreme bradycardia, or atrioventricular (AV) block.348 (See Drug Interactions: Drugs Affecting Cardiac Conduction.)
Unstable Angina and Non-ST-Segment Elevation Myocardial Infarction
While a β-blocker is recommended as part of the standard therapeutic measures for managing unstable angina† or non-ST-segment elevation MI† (e.g., with aspirin and/or clopidogrel, low-molecular weight or unfractionated heparin, and nitrates),347 the American College of Cardiology (ACC) and American Heart Association (AHA) state that β-adrenergic blockers without intrinsic sympathomimetic activity are preferable in such patients.350 (See Uses: Non-ST-Segment-Elevation Acute Coronary Syndromes, in Metoprolol 24:24.)
Acebutolol has been used to reduce cardiovascular mortality in patients who have survived the acute phase of a MI†.289, 290 Evidence from a large, controlled, multicenter study (APSI Trial) indicates that chronic oral therapy with acebutolol initiated within 11 days after an acute MI can reduce long-term (at 45.4 weeks) mortality, at least in moderate- to high-risk patients.289, 290, 293 Efficacy in low-risk patients was not determined.289, 290, 293 In this study, the mortality rate was substantially reduced in those receiving acebutolol compared with placebo.289, 290 While evidence prior to the APSI Trial generally indicated that β-blockers like acebutolol, which possess appreciable intrinsic sympathomimetic activity, may be less effective in reducing long-term mortality after an acute MI than those that do not,294, 295, 296, 297, 298, 299, 300, 301, 302, 303 and many clinicians recommend that agents possessing such activity generally be avoided for secondary prevention in this condition,293, 294 the mortality reduction observed in the APSI Trial seems to compare favorably with reductions for patients receiving other β-blockers.289, 290 Additional study is needed to further elucidate the role of agents with intrinsic sympathomimetic activity in the post-MI period.293
Acebutolol hydrochloride is administered orally.1, 2 Acebutolol hydrochloride has also been administered IV†, 25, 27, 28, 29, 41, 191, 192, 196, 200, 202, 203, 266 but a parenteral dosage form of the drug is currently not commercially available in the US.
Dosage of acebutolol hydrochloride is expressed in terms of acebutolol.1
Dosage of acebutolol must be individualized and adjusted according to the patient's response and tolerance.1, 2, 4 If long-term acebutolol therapy is to be discontinued, dosage of the drug should be reduced gradually over a period of about 2 weeks.1, 2 (See Cautions: Precautions and Contraindications.) When another β-adrenergic blocking agent (β-blocker) is to be substituted for acebutolol, the new drug should be initiated at a comparable dosage without interruption of β-blocker therapy.1, 2
The fact that the β-adrenergic blocking selectivity of acebutolol hydrochloride diminishes as dosage is increased should be considered.1
For the management of mild to moderate hypertension, the initial adult dosage of acebutolol is 200-400 mg daily, usually given as a single daily dose;1, 245, 321 however, for 24-hour blood pressure control, some patients may require administration of the daily dose in 2 divided doses.1, 142, 143, 144, 145, 149, 155 Optimum response usually occurs at dosages of 400-800 mg daily,1, 140, 142, 143, 144, 145, 149, 150, 151, 152, 153, 154, 245, 246, 247 but some patients may achieve adequate blood pressure control with a maintenance dosage as low as 200 mg daily.1, 4 In patients with more severe hypertension or those in whom adequate reduction of blood pressure does not occur, dosage of acebutolol may be increased up to a maximum of 1.2 g daily given in 2 divided doses1, 2, 4, 140, 142, 143, 144, 145, 149, 150, 151, 152, 154, 155 or another hypotensive agent (e.g., a thiazide diuretic) may be added.1, 2, 4, 142, 144, 157, 158, 160, 161, 165, 166, 168 Some experts state the usual dosage range is 200-800 mg daily, administered in 2 divided doses.1200
Blood Pressure Monitoring and Treatment Goals
Blood pressure should be monitored regularly (i.e., monthly) during therapy and dosage of the antihypertensive drug adjusted until blood pressure is controlled.1200 If an adequate blood pressure response is not achieved, the dosage may be increased or another antihypertensive agent with demonstrated benefit and preferably with a complementary mechanism of action (e.g., angiotensin-converting enzyme [ACE] inhibitor, angiotensin II receptor antagonist, calcium-channel blocker, thiazide diuretic) may be added; if target blood pressure is still not achieved with the use of 2 antihypertensive agents, a third drug may be added.1200, 1216 (See Uses: Hypertension.) In patients who develop unacceptable adverse effects with acebutolol, the drug should be discontinued and another antihypertensive agent from a different pharmacologic class should be initiated.1200, 1216
The goal of hypertension management and prevention is to achieve and maintain optimal control of blood pressure.1200 However, the optimum blood pressure threshold for initiating antihypertensive drug therapy and specific treatment goals remain controversial.505, 506, 507, 508, 515, 523, 530, 1201, 1207, 1209, 1222 While previous hypertension guidelines have based target blood pressure goals on age and comorbidities,501, 504, 536 the 2017 American College of Cardiology/American Heart Association (ACC/AHA) hypertension guideline incorporates underlying cardiovascular risk into decision making regarding treatment and generally recommends the same target blood pressure (i.e., less than 130/80 mm Hg) for all adults.1200 Many patients will require at least 2 drugs from different pharmacologic classes to achieve this blood pressure goal; the potential benefits of hypertension management and drug cost, adverse effects, and risks associated with the use of multiple antihypertensive drugs also should be considered when deciding a patient's blood pressure treatment goal.1200, 1220
For additional information on target levels of blood pressure and on monitoring therapy in the management of hypertension, see Blood Pressure Monitoring and Treatment Goals under Dosage: Hypertension, in Dosage and Administration in the Thiazides General Statement 40:28.20.
For the suppression and prevention of frequent ventricular premature complexes (VPCs), the usual initial adult dosage of acebutolol is 200 mg twice daily.1, 187, 196 Dosage is increased gradually until an optimum response is attained.1, 185, 186, 195, 198, 204 Optimum response generally occurs at a dosage of 600-1200 mg daily.1, 2, 4, 185, 186, 189, 190, 195, 199, 204 For the suppression and prevention of frequent VPCs, twice-daily dosing of the drug appears to be more effective than once-daily dosing.4, 185, 186, 188, 189, 195, 198, 199, 203, 204, 248
For the management of angina pectoris†, the usual initial adult dosage of acebutolol is 200 mg twice daily.4, 205, 208 Dosage is increased gradually until optimum control of angina is attained.4, 205 Optimum response usually occurs at a dosage of 800 mg or less daily,4, 206, 207, 208, 209, 210, 211, 212, 213, 214 but patients with severe angina may require higher dosages.4, 205, 209, 211 Dosage of β-blockers in angina pectoris usually is adjusted to clinical response4, 205 and to maintain a resting heart rate of 55-60 beats/minute.211, 216 For the management of angina pectoris, there is some evidence that once-daily administration of acebutolol may be as effective as administration in divided doses.4, 208, 249
Dosage in Renal and Hepatic Impairment
Because the active metabolite of acebutolol is eliminated principally by the kidneys,123, 125 doses and/or frequency of administration of acebutolol must be modified in response to the degree of renal impairment in patients with impaired renal function.1, 2, 86, 123, 124, 125, 126, 127 The usual daily dose of the drug should be reduced by 50% in patients with creatinine clearances of 25-49 mL/minute and by 75% in patients with creatinine clearances of less than 25 mL/minute.1, 2, 124 Since acebutolol and diacetolol are removed by hemodialysis,1, 125, 127 dosage of acebutolol must be individualized carefully in patients with severe renal impairment who undergo chronic intermittent hemodialysis.124, 125
Acebutolol should be used with caution in patients with impaired hepatic function.1, 2 Limited data suggest that the presence of cirrhosis does not substantially affect the pharmacokinetics of acebutolol or diacetolol, but the effects of hepatic impairment on the elimination of the drug have not been fully evaluated.128
When acebutolol is used in geriatric patients, reduction of maintenance dosage may be necessary,1, 2 since peak plasma concentrations and areas under the concentration-time curves (AUCs) of acebutolol and diacetolol in these patients may be approximately twofold those observed in younger patients.1, 2, 122 Dosages greater than 800 mg daily should be avoided in geriatric patients.1, 2
Acebutolol hydrochloride shares the toxic potentials of β-adrenergic blocking agents (β-blockers).1, 2, 4, 7, 34, 35, 36 In therapeutic dosage, acebutolol usually is well tolerated and has a low incidence of adverse effects.1, 2, 4, 6, 142, 150, 151, 152, 153, 154, 155, 156, 157, 158, 162, 163 Most adverse effects of acebutolol are mild,1, 2, 158 do not require discontinuance of the drug,1, 2, 158 and tend to decrease with time.1, 2 In geriatric patients, the frequency of acebutolol-induced adverse effects appears to be higher in females.2 The most common adverse effects of acebutolol are nervous system and GI effects,1, 2, 4 and the most common adverse reactions requiring discontinuance of the drug are nervous system, GI, and cardiovascular effects.2 Adverse effects requiring discontinuance of acebutolol therapy occur in about 5-6% of patients.2, 6 Abrupt withdrawal of the drug should be avoided, especially in patients with coronary artery disease, since it may exacerbate angina or precipitate myocardial infarction.1
Potentially serious adverse cardiovascular effects of acebutolol may occur in up to 2-5% of patients1, 2 and include bradycardia,1, 158, 195 hypotension,1, 145, 158, 162, 192 chest pain,1, 2, 159, 199 edema,1, 150, 152, 158, 205 and heart failure.1, 34, 150, 152, 158, 185 Adverse cardiovascular effects requiring discontinuance of the drug occur in about 1.4% of patients.2
At the first sign or symptom of impending cardiac failure during acebutolol therapy, patients should receive adequate treatment (e.g., cardiac glycoside, diuretic) and should be observed closely; if cardiac failure continues, acebutolol should be discontinued, gradually if possible.1 (See Cautions: Precautions and Contraindications.)
Other adverse cardiovascular effects of acebutolol include intensification of AV block;1, 193 peripheral ischemia;150, 152 coronary ischemia;158 palpitation;157, 159, 190 peripheral vasodilation;157, 158 and signs of worsening arterial insufficiency, including claudication,158, 207 Raynaud's phenomenon,145 and coldness or pain in the hands and feet.6, 144, 145, 157, 158, 171
Despite relatively minimal distribution of acebutolol and diacetolol into the CNS,8, 104 adverse nervous system effects are the most common adverse reactions of acebutolol.1, 2, 4, 6 The frequency of adverse nervous system effects tends to increase with dosage, occurring in about 9, 13, and 17% of patients receiving 400, 800, and 1200 mg daily, respectively.1, 2 Adverse nervous system effects requiring discontinuance of acebutolol therapy occur in about 1.9% of patients.2
The most common adverse nervous system effect of acebutolol is fatigue,1, 2, 6, 150, 151, 152, 154, 170, 185, 198 which occurs in about 5-11% of patients.1, 2, 6 Dizziness1, 2, 157, 158, 159, 170, 198 occurs in about 4.5-6% of patients,1, 2, 6 headache1, 2, 157, 158, 159, 198 in about 2.6-6%,1, 2, 6 insomnia1, 2, 155, 157, 158, 159 in about 3%,1, 2 and mental depression1, 2, 157, 158 and unusual dreams1, 2, 157, 158, 162, 171 in about 2%.1, 2 Anxiety1, 2 and hyperesthesia or hypoesthesia1, 2 occur in up to 2% of patients.1 Drowsiness,145, 153, 171, 189 confusion,158 lethargy,199 hemiparesis,158 paresthesia,158, 171 and decreased libido171 also have occurred.
Adverse CNS effects seen with other β-blockers that may occur with acebutolol include reversible mental depression progressing to catatonia, short-term memory loss, emotional lability, slightly clouded sensorium, and decreased performance on neuropsychometric tests.1
Adverse GI effects of acebutolol occurring in about 3-4% of patients1, 2 include constipation,1, 2, 6, 145, 157, 158, 159, 171 diarrhea,1, 2, 6, 158, 163, 171, 190 dyspepsia,1, 2, 6, 155, 158, 162 flatulence,1, 2, 150, 158 and nausea.1, 2, 6, 152, 154, 157, 158, 159, 190, 198, 200 Vomiting1, 2, 6, 157, 158, 159, 198 and abdominal pain1, 2 may occur in up to 2% of patients.1, 2, 6 Dry mouth,158, 207 anorexia,158, 159 epigastric distress,170, 207 and thirst157, 159 also have occurred. Adverse GI effects requiring discontinuance of acebutolol therapy occur in about 1.4% of patients.2
Mesenteric arterial thrombosis and ischemic colitis have been reported in patients receiving other β-blockers.1
Despite the relative β1-selective blocking activity of acebutolol, β2-adrenergic blockade leading to bronchoconstriction and wheezing may occur with the drug.1, 68, 150, 152, 170 Dyspnea1, 2, 150, 152, 154, 158, 162, 192, 196, 198 occurs in about 4% of patients,1, 2 rhinitis1, 20 in about 2%, pharyngitis in up to 2%,1, 2 and cough in about 1%.1, 2 Asthma,155 shortness of breath,145, 158, 159, 198, 207 and bronchospasm60, 155, 158, 162 also have occurred. Adverse respiratory effects requiring discontinuance of acebutolol therapy occur in about 0.5-0.9% of patients.2, 158
Genitourinary and Renal Effects
Urinary frequency1, 2, 150, 158, 159, 214 has occurred in about 3% of patients receiving acebutolol,1, 2 and dysuria,1, 2 nocturia,1, 2, 150 and impotence1, 2, 144, 150, 152, 214 have occurred in up to 2% of patients.1, 2 Elevations of BUN and serum creatinine concentration have been reported rarely.152
Peyronie's disease has occurred with other β-blockers.1
Pruritus1, 2 or rash1, 2, 150, 154, 158, 170, 185, 198, 199 has occurred in up to 2% of patients receiving acebutolol.1, 2, 150, 154, 158 Sweating145, 151, 155, 158 and reversible alopecia1, 194 also have occurred. Adverse dermatologic effects requiring discontinuance of the drug occur in about 0.5% of patients.2
Abnormal vision,1, 2, 150, 152, 158 conjunctivitis,1, 2, 158 dry eye,1, 2, 150, 152 and eye pain1, 2 have occurred in up to 2% of patients receiving acebutolol.1, 2 Sore or gritty eyes158, 136 and tinnitus159 also have occurred. Adverse ocular effects requiring discontinuance of acebutolol therapy occur in about 0.5% of patients.2
The oculomucocutaneous syndrome associated with another similar β-blocker, practolol (not commercially available in the US), has not been reported to date in patients receiving acebutolol.1
Antinuclear antibodies (ANA),1, 144, 152, 154, 156, 185, 227, 230, 232, 233 sometimes associated with generally persistent arthralgias1, 154 and myalgias1, 154 (in less than 1% of patients),1, 4 may develop in up to about 10-30% of patients receiving acebutolol.4, 227 Prospective studies indicate that the frequency of acebutolol-induced positive ANA titers is dose dependent and greater than that occurring with propranolol.1 The frequency of acebutolol-induced positive ANA titers may be higher in females and may increase with age.267 ANA titers and accompanying symptoms have been reversible following discontinuance of the drug.1, 4 A lupus erythematosus-like illness, characterized by polyarthralgia, fever, myalgia, pericarditis, pleurisy, arterial thrombosis, or thrombocytopenic purpura, has also occurred in a few patients;232 systemic lupus erythematosus has been reported rarely.1
Hypersensitivity pneumonitis,228, 229 pleurisy,234, 235 pulmonary granulomas,234, 235 and pleuropulmonary fibrosis233 have been reported in some patients receiving acebutolol.
Allergic reactions including laryngospasm, respiratory distress, and fever combined with aching and sore throat have occurred in patients receiving other β-blockers.1
Reversible alterations in liver function test results may occur in patients receiving acebutolol therapy; marked elevations of serum AST (SGOT) or ALT (SGPT), moderately elevated alkaline phosphatase, and increased serum LDH and bilirubin have occurred in a small number of patients receiving acebutolol.1, 218 In some patients, fever, malaise, dark urine, anorexia, nausea, and headache also have been reported;1, 218 it has been suggested that hypersensitivity reactions may have been involved in these hepatotoxicity reactions.218 In some patients, adverse hepatic effects recurred after rechallenge with acebutolol, but were reversible following discontinuance of the drug.1
Results of a large prospective cohort study of nondiabetic adults 45-64 years of age indicate that use of β-blockers in hypertensive patients is associated with increased risk (about 28%) of developing type 2 diabetes mellitus compared with other hypertensive patients who were not receiving hypotensive therapy.337, 338 In this study, the number of new cases of diabetes per 1000 person-years was 33.6 or 26.3 in patients receiving a β-blockers or no drug therapy, respectively.337 The association between the risk of developing type 2 diabetes mellitus and use of β-blockers reportedly was not confounded by weight gain, hyperinsulinemia, or differences in heart rate.337, 338 It is not known if the risk of developing diabetes is affected by β-receptor selectivity.337 Further studies are needed to determine whether concomitant use of ACE inhibitors (which may improve insulin sensitivity) would abrogate β-blocker-induced adverse effects related to glucose intolerance.338 Therefore, until results of such studies are available, the proven benefits of β-blockers in reducing cardiovascular events in hypertensive patients must be weighed carefully against the possible risks of developing type 2 diabetes mellitus.337
Hypoglycemia,336 which may result in loss of consciousness, also may occur in nondiabetic patients receiving β-blockers. Patients most at risk for the development of β-blocker-induced hypoglycemia are those undergoing dialysis, prolonged fasting, or severe exercise regimens.336
β-Blockers may mask signs and symptoms of hypoglycemia (e.g., palpitation, tachycardia, tremor) and potentiate insulin-induced hypoglycemia.1, 336 Although it has been suggested that nonselective β-blockers are more likely to induce hypoglycemia than selective β-blockers, such an adverse effect also has been reported with selective β-blockers (e.g., atenolol).336 In addition, selective β-blockers are less likely to mask symptoms of hypoglycemia or delay recovery from insulin-induced hypoglycemia than nonselective β-blockers because of their vascular sparing effects; however, selective β-blockers can decrease insulin sensitivity by approximately 15-30%, which may result in increased insulin requirements.336
Arthralgia and myalgia have occurred in about 2% of patients receiving acebutolol,1, 2 and back or joint pain1, 2, 157, 158 has occurred in up to 2% of patients.1, 2 Increases in serum bilirubin concentration,152 chills,158, 170, 190 shock syndrome,231 and asthenia155, 158, 207 have occurred rarely.
Adverse hematologic reactions (e.g., agranulocytosis, nonthrombocytopenic purpura) have occurred with other β-blockers.1 The possibility that other adverse effects associated with other β-blockers may occur during acebutolol therapy should be considered.1
Precautions and Contraindications
Acebutolol shares the toxic potentials of β-blockers, and the usual precautions associated with these agents should be observed.1, 2, 4, 7, 34, 35, 36
In patients with heart failure, sympathetic stimulation is vital for the support of circulatory function.1 Acebutolol should be used with caution in patients with inadequate cardiac function, since heart failure may be precipitated by blockade of β-adrenergic stimulation when acebutolol therapy is administered.1 In addition, in patients with latent cardiac insufficiency, prolonged β-adrenergic blockade may lead to cardiac failure.1 Although β-blockers should be avoided in patients with overt heart failure, acebutolol may be administered cautiously, if necessary, to patients with well-compensated heart failure (e.g., those controlled with cardiac glycosides and/or diuretics).1 Patients receiving acebutolol therapy should be instructed to consult their physician at the first sign or symptom of impending cardiac failure (including unexplained respiratory symptoms) and should be adequately treated (e.g., with a cardiac glycoside and/or diuretic); if cardiac failure continues, acebutolol should be discontinued, gradually if possible.1 If a cardiac glycoside is used concomitantly with acebutolol, the possibility of combined impairment of AV conduction should be considered.1 (See Drug Interactions: Drugs Affecting Cardiac Conduction.)
Abrupt withdrawal of acebutolol may exacerbate angina symptoms or precipitate myocardial infarction (MI) in patients with coronary artery disease.1 Therefore, patients receiving acebutolol (especially those with ischemic heart disease) should be warned not to interrupt or discontinue therapy without consulting their clinician.1, 276 When discontinuance of acebutolol therapy is planned, particularly in patients with ischemic heart disease, dosage of the drug should be reduced gradually over a period of about 2 weeks.1 When acebutolol therapy is discontinued, patients should be monitored carefully and advised to temporarily limit their physical activity.1, 276 If exacerbation of angina occurs after acebutolol therapy is interrupted, antianginal therapy should be reinstituted promptly, and appropriate measures for the management of unstable angina pectoris should be initiated.1 Because coronary artery disease is common and may be unrecognized,148, 226 it may be prudent not to discontinue acebutolol therapy abruptly, even in patients receiving the drug for conditions other than angina.148, 226, 268, 276, 277
Since β-blockers may reduce cardiac output and precipitate or aggravate the symptoms of arterial insufficiency in patients with peripheral or mesenteric vascular disease, acebutolol should be used with caution in these patients, and the patients should be observed for evidence of progression of arterial insufficiency.1
Acebutolol should be used with caution in patients undergoing major surgery involving general anesthesia.1 The necessity of withdrawing β-adrenergic blocking therapy prior to major surgery is controversial.1, 148, 226, 238 Severe, protracted hypotension and difficulty in restarting or maintaining a heart beat have occurred during surgery in some patients who have received β-blockers.1, 148, 226 As with other β-blockers, the effects of acebutolol can be reversed by administration of β-agonists (e.g., dobutamine, isoproterenol).1 If patients continue to receive acebutolol prior to surgery, particular caution should be employed if anesthetics that depress the myocardium are used, and the lowest possible dosage of acebutolol should be used.1
Since β-blockers may inhibit bronchodilation produced by endogenous catecholamines, the drugs generally should not be used in patients with bronchospastic disease; however, because of its relative β1-selective adrenergic blocking activity, acebutolol may be used with caution in patients with bronchospastic disease who do not respond to or cannot tolerate other hypotensive agents.1 In such patients, the lowest effective dosage of acebutolol should be used; in addition, it would be prudent to administer acebutolol initially in divided doses daily to avoid the higher plasma concentrations associated with once-daily dosing.1 Patients receiving acebutolol should contact their physician if any difficulty in breathing occurs.1 A bronchodilator (e.g., a β2-adrenergic agonist, theophylline) should be available for immediate use if necessary.1
Patients who have a history of anaphylactic reactions to a variety of allergens reportedly may be more reactive to repeated accidental, diagnostic, or therapeutic challenges with such allergens while taking β-blockers, and may be unresponsive to usual doses of epinephrine used to treat anaphylactic reactions.1
Signs of hyperthyroidism (e.g., tachycardia) may be masked by acebutolol, and patients having or suspected of developing thyrotoxicosis should be monitored carefully because abrupt withdrawal of β-adrenergic blockade might precipitate thyroid storm.1 In addition, it is recommended that acebutolol be used with caution in patients with diabetes mellitus (especially those with labile diabetes) since the drug also may mask signs and symptoms of hypoglycemia (e.g., tachycardia, palpitation, blood pressure changes, tremor, feelings of anxiety, but not sweating) and may potentiate insulin-induced hypoglycemia.1 (See Cautions: Endocrine Effects.) However, many clinicians state that patients with diabetes mellitus may be particularly likely to experience a reduction in morbidity and mortality with the use of β-blockers.335 (See Uses: Heart Failure, in Metoprolol 24:24.)
Acebutolol should be used with caution in patients with renal or hepatic impairment, and dosage of the drug should be reduced in those with substantial renal impairment.1 (See Dosage and Administration: Dosage in Renal and Hepatic Impairment.)
Acebutolol is contraindicated in patients with second- or third-degree AV block, severe bradycardia, cardiogenic shock, or overt cardiac failure.1
Safety and efficacy of acebutolol in children younger than 12 years of age have not been established.1, 268 For information on overall principles and expert recommendations for treatment of hypertension in pediatric patients, see Uses: Hypertension in Pediatric Patients, in the Thiazides General Statement 40:28.20.
Mutagenicity and Carcinogenicity
No evidence of acebutolol- or diacetolol-induced mutagenesis was seen in the Ames microbial mutagen test.1 No evidence of carcinogenesis was seen in mice and rats receiving oral acebutolol hydrochloride dosages up to 300 mg/kg daily (about 15 times the maximum recommended human dosage) or in rats receiving oral diacetolol dosages up to 1800 mg/kg daily.1
Pregnancy, Fertility, and Lactation
Reproduction studies in rats and rabbits using acebutolol dosages up to 630 and 135 mg/kg daily (about 31.5 and 6.8 times the maximum recommended daily human dosage), respectively, have not revealed evidence of harm to the fetus.1 However, acebutolol dosages of 135 mg/kg daily in rabbits produced maternal toxicity associated with slight fetal growth retardation, reduced food intake, decreased rate of weight gain, and mortality.1 Reproduction studies in rats and rabbits using diacetolol dosages up to 1800 and 450 mg/kg daily, respectively, have not revealed evidence of harm to the fetus; however, diacetolol dosages of 450 mg/kg daily were associated with increased postimplantation loss and decreased food consumption and weight gain in pregnant rabbits, and diacetolol dosages of 1800 mg/kg daily were associated with a slightly increased incidence of fetal bilateral cataract in rats.1 Acebutolol has been used effectively for the management of hypertension in a limited number of pregnant women and was well tolerated.239, 240, 241 Infants of mothers who received acebutolol for the management of hypertension during pregnancy had lower birthweights, decreased systolic blood pressures and heart rates during the first 72 hours after delivery, and, in one case, transient hypoglycemia.239 It is not known whether use of acebutolol in pregnant women affects the usual course of labor and delivery; in animals, no specific effects have been observed.1 There are no adequate and controlled studies to date using acebutolol in pregnant women, and the drug should be used during pregnancy only when the potential benefits justify the possible risks to the fetus.1
Reproduction studies in two generations of male and female rats using oral acebutolol and diacetolol dosages up to 240 and 1000 mg/kg daily, respectively, have not revealed evidence of impaired reproductive performance or fertility.1
Acebutolol and diacetolol are distributed into milk in higher concentrations than in maternal plasma,1, 2, 105 with acebutolol and diacetolol milk-to-plasma ratios of about 7.1 and 12.2, respectively.1 Further studies are needed, but some data suggest that clinically important amounts of acebutolol and diacetolol may be absorbed by nursing infants.106 The manufacturer recommends that acebutolol not be used in nursing women.1
Diuretics and Hypotensive Agents
When acebutolol is administered with diuretics or other hypotensive agents, the hypotensive effect may be increased.1, 2, 142, 144, 157, 158, 160 This effect usually is used to therapeutic advantage, but careful adjustment of dosage is necessary when these drugs are used concomitantly.1, 2, 144, 157, 158, 160 No substantial pharmacokinetic interactions between acebutolol and hydrochlorothiazide or hydralazine have been observed.1
When acebutolol and a catecholamine-depleting drug (e.g., reserpine) are administered concomitantly, the effects of the drugs may be additive.1 Patients receiving both drugs concurrently should be observed closely for evidence of marked bradycardia or hypotension, which may be manifested as vertigo, presyncope or syncope, or orthostatic changes in blood pressure without compensatory tachycardia.1
The β-adrenergic stimulating effects of sympathomimetic agents are antagonized by acebutolol.1, 2 Acebutolol can antagonize the bronchodilation produced by β-adrenergic agonists in patients with bronchospasm,57, 58, 59, 62 and greater than usual dosages of β-adrenergic agonist bronchodilators may be required in some patients receiving acebutolol.268, 277
Exaggerated hypertensive reactions have been reported in patients receiving β-adrenergic blocking agents (β-blockers) and α-adrenergic agonists (including those contained in nonprescription oral cold preparations and topical nasal decongestants) concomitantly, and patients receiving acebutolol should be warned of this potential hazard.1
Drugs Affecting Cardiac Conduction
Concomitant use of β-blockers and certain other cardiovascular drugs (e.g., cardiac glycosides, nondihydropyridine calcium-channel blocking agents) can have additive negative effects on SA or AV nodal conduction.318, 319 Slowing or complete suppression of SA node activity with development of slow ventricular rates (e.g., 30-40 bpm), often misdiagnosed as complete AV block, has been reported in patients receiving the nondihydropyridine calcium-channel blocking agent mibefradil (no longer commercially available in the US), principally in geriatric patients and in association with concomitant β-adrenergic blocker therapy.318, 319
Acebutolol has decreased the hypoglycemic action of glyburide in type II diabetic patients, presumably by decreasing insulin secretion.244 Nonsteroidal anti-inflammatory agents have blunted the hypotensive effects of β-blockers.1
No substantial interactions between acebutolol and tolbutamide or warfarin have been observed to date, and no substantial pharmacokinetic interactions between acebutolol and digoxin, sulfinpyrazone, or oral contraceptives have been observed to date.1
The acute lethal dose of acebutolol hydrochloride in humans is not known;1, 2, 4 some patients have survived ingestions of up to 7.6 g of the drug alone,243 but death has occurred in other patients ingesting up to 8.6 g of the drug alone.249, 250 The oral LD50 of acebutolol hydrochloride is 3.2 and 5.2 g/kg in male and female rats, respectively, and 2.61 g/kg in female mice.268 The IV LD50 of the drug is 115 and 120 mg/kg in male and female rats, respectively, and 75 and 78 mg/kg in male and female mice, respectively.268 The maximum nonlethal oral and IV doses in dogs are 250 and 45 mg/kg, respectively.268
Limited information is available on the acute toxicity of acebutolol hydrochloride.1, 2, 242, 243, 249, 250 In general, overdosage of acebutolol may be expected to produce effects that are mainly extensions of pharmacologic effects, particularly those involving the cardiovascular system.1, 2, 242, 243, 258, 259, 260 As with other β-blockers, symptomatic bradycardia, advanced AV block, intraventricular conduction defects, hypotension, acute cardiac failure, seizures, and, in susceptible individuals, bronchospasm and hypoglycemia, might occur with acebutolol overdosage.1, 2 Only a few cases of acute overdosage with the drug have been reported.242, 243, 249, 250 A 15-year-old female who ingested 7.6 g of the drug remained conscious and exhibited severe hypotension, first-degree heart block, and severe intraventricular conduction disturbances.243 Plasma acebutolol concentration 1 hour after ingestion of the drug was 15 µg/mL.243 Treatment consisted of gastric lavage, administration of activated charcoal, IV fluids, and IV administration of calcium gluconate to restore blood pressure; the patient recovered completely without sequelae.243 In an adult who was reported to have intentionally ingested acebutolol hydrochloride 9.6 g, labetalol hydrochloride 7.2 g, and trimipramine 625 mg, loss of consciousness, bradycardia, and profound hypotension resulted.242 Treatment consisted of gastric lavage and IV administration of atropine, isoproterenol, dopamine, glucagon, and calcium chloride; the patient recovered completely within 7 days after the ingestion.242 In some patients who died following overdosage of acebutolol, blood concentrations of the drug were 33-78 µg/mL.249, 250
Treatment of acebutolol overdosage generally involves symptomatic and supportive care.1, 2, 4, 242, 243, 257, 258, 259, 260 Following acute ingestion of the drug, the stomach should be emptied immediately by inducing emesis or by gastric lavage.1, 257, 258 If the patient is comatose, having seizures, or lacks the gag reflex, gastric lavage may be performed if an endotracheal tube with cuff inflated is in place to prevent aspiration of gastric contents.257, 258 For symptomatic bradycardia, IV atropine sulfate may be given; if bradycardia persists, IV isoproterenol hydrochloride may be administered cautiously (larger than usual doses may be necessary),1, 2, 258, 259, 260 and in refractory cases, use of a transvenous cardiac pacemaker should be considered.258, 259, 260 A vasopressor may be given for severe hypotension that persists despite correction of bradycardia; blood pressure and pulse rate should be monitored frequently.1, 2, 258, 259, 260 For heart failure, a cardiac glycoside and diuretic may be used.1, 2 Glucagon may also be useful for the management of myocardial depression and hypotension.1, 2, 258, 259, 260 A β-adrenergic agonist and/or a theophylline derivative may be used for bronchospasm.1, 2, 258, 259 For seizures, IV diazepam may be used.258, 259 Since acebutolol and diacetolol are dialyzable, hemodialysis may be useful in enhancing their elimination in severe acebutolol overdosage.1, 2, 4
Acebutolol is a β1-selective adrenergic blocking agent (β-blocker) and has pharmacologic actions similar to those of other β-blockers.1, 2, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 34, 35, 36, 37, 38 At low dosages, acebutolol selectively inhibits response to adrenergic stimuli by competitively blocking cardiac β1-adrenergic receptors,1, 2, 11, 12, 13, 14, 15, 16, 19, 20, 23 while having little effect on the β2-adrenergic receptors of bronchial and vascular smooth muscle.1, 2, 12, 13, 14, 15, 16, 19, 20, 23, 24, 27, 51, 52, 53, 54, 55, 56, 60 At high dosages (e.g., greater than 800 mg daily),268 the selectivity of acebutolol for β1-adrenergic receptors usually diminishes, and the drug will competitively inhibit β1- and β2-adrenergic receptors.4, 24, 35, 178 The β1-selective blocking activity of acebutolol appears to be more pronounced in animals than in humans.17, 51, 52, 57, 58, 59 In vivo studies in animals11, 12, 13 and humans11, 21, 85 indicate that the relative β1-adrenergic blocking activity of acebutolol, on a weight basis, is approximately 10-30% that of propranolol,11, 12, 13, 21, 85 as determined by inhibition of reflex tachycardia in animals11, 12, 13 or inhibition of exercise-85 or tilt-induced21 or reflex11 tachycardia in healthy individuals.
In addition to inhibiting access of physiologic or synthetic catecholamines to β-adrenergic receptors, acebutolol exhibits mild intrinsic sympathomimetic activity (ISA) (partial β-agonist activity).1, 2, 11, 12, 18 Acebutolol also has a membrane-stabilizing effect on the heart, which is similar to that of quinidine1, 2, 11, 12, 22, 44, 45 but occurs only at high plasma concentrations22, 44, 45 and usually is not apparent at dosages used clinically.1, 2, 22, 44, 45
The pharmacologic effects of acebutolol result from both the unchanged drug and its major metabolite, diacetolol.1, 2, 114, 115, 116, 117 Diacetolol is equipotent to acebutolol1, 2, 114, 115, 116, 117 and, in animals, has greater β1-selective adrenergic blocking activity than the parent drug.1, 114 Diacetolol also has weak ISA,114, 115 but does not have substantial membrane-stabilizing activity.114 Diacetolol may contribute substantially to the observed effects of acebutolol, since plasma concentrations of the metabolite are consistently higher than those of the parent drug during acebutolol therapy.2, 90, 91, 94, 122
By inhibiting myocardial β1-adrenergic receptors, acebutolol produces negative chronotropic and inotropic activity.2, 11, 12, 13, 16, 18, 19, 26, 27, 28, 29, 34, 47 Both of these actions are reversed somewhat, but not entirely, by the drug's ISA.1, 2, 12, 18, 26, 40, 60, 154, 155 The negative chronotropic action of acebutolol on the sinoatrial (SA) node results in a decrease in the rate of SA node discharge.40
Exercise-induced heart rate is decreased,1, 2, 4, 11, 12, 13, 23, 24, 25, 27 reflex orthostatic tachycardia is inhibited,1, 2, 4, 11, 12, 13, 23, 24 and cardiac output at rest2, 25, 140, 193 or during exercise1, 28, 29 is decreased1, 2, 25, 28, 29, 140, 193 or remains unchanged during acebutolol therapy.26, 140 Because of acebutolol's ISA, the decrease in resting heart rate produced by the drug is generally slightly less than (by about 3 beats/minute)1 that produced by other β-blockers that do not possess ISA.1, 2, 23, 153, 154, 156, 171
In patients with ischemic heart disease or coronary artery disease who have well-compensated cardiac function, oral acebutolol does not substantially affect left ventricular function.2, 43, 47, 48 Following IV administration of the drug in patients with ischemic heart disease or coronary heart disease,25, 27, 32 cardiac index25, 27 and stroke index25, 32 may be reduced and total peripheral resistance25, 27 and pulmonary resistance index25 may be increased. Hemodynamic effects of acebutolol in patients with impaired autonomic responsiveness appear to be similar to those of patients with normal autonomic function.2, 29 The decrease in myocardial contractility19, 29, 32 and heart rate29 produced by acebutolol leads to a reduction in myocardial oxygen consumption, which accounts for the effectiveness of the drug in chronic stable angina pectoris.35, 48, 216
Acebutolol decreases systolic and diastolic blood pressure at rest1, 2, 13, 19, 23, 56, 57, 139 and during exercise.1, 2, 155, 160, 171 The precise mechanism of acebutolol's hypotensive action has not been determined.7, 22, 26, 34, 35, 139, 178 It has been postulated that β-blockers reduce blood pressure by blocking peripheral (especially cardiac) adrenergic receptors (decreasing cardiac output), by decreasing sympathetic outflow from the CNS, and/or by suppressing renin release.7, 26, 34, 35, 140, 178 Acebutolol does not consistently affect renin release.26, 71, 139, 140, 141, 142, 143, 144 Acebutolol is effective in reducing blood pressure in patients with low renin hypertension,139, 162, 163 but it appears that decreases in mean arterial pressures may be greater in patients with normal or high plasma renin activity (PRA).141, 143β-blockers without ISA may increase peripheral vascular resistance (PVR) initially;25, 26, 27 however, acebutolol generally has no effect on or only minimally increases PVR.2, 4, 23, 26, 31, 32, 167 Acebutolol appears to have a lesser effect on β2-receptors in peripheral vasculature than nonselective β-blockers (e.g., propranolol).1, 2, 23, 24, 31
Antiarrhythmic and Electrophysiologic Effects
Acebutolol exhibits antiarrhythmic activity1, 2, 137, 185, 186, 187, 188, 189, 190, 193, 194, 195, 196, 199, 204 and, like other β-blockers, is considered a class II antiarrhythmic agent.254 The antiarrhythmic and electrophysiologic effects of acebutolol appear to be mediated principally via the drug's β-blocking activity.2, 4, 42 Acebutolol slows conduction in the atrioventricular (AV) node and increases AV node refractoriness1, 2, 4, 41, 42, 45, 46 without substantially affecting sinus node recovery time, atrial or ventricular effective refractory period, or HV conduction time.1, 2, 12, 41, 42, 45, 46 At plasma acebutolol concentrations greater than 1000 ng/mL, the HV interval may be prolonged substantially, possibly as a result of the drug's membrane-stabilizing activity.2, 45
Despite relatively minimal distribution of acebutolol and diacetolol into the CNS,8, 104 acebutolol can produce nervous system effects,1, 2, 4, 6, 150, 152, 154, 158, 170, 198 although limited comparative data suggest that the frequency and/or severity of such effects may be less than those observed with some other β-blockers.152, 154, 156, 262 (See Cautions: Nervous System Effects.) Acebutolol appears to have little effect on psychomotor performance and does not substantially prolong complex reaction time.262 In healthy individuals, the drug did not produce EEG changes263 and did not affect total sleep time or the number or duration of awakenings.264 In patients with hypertension, acebutolol did not affect the state of arousal as assessed by psychological testing, but did reduce the state of anxiety at the beginning of therapy.265
Unlike some β-blockers,147, 148 acebutolol does not consistently suppress plasma renin activity (PRA).26, 71, 139, 140, 141, 142, 143 Correlations between initial PRA, subsequent changes in PRA, and decreases in blood pressure have varied in patients receiving acebutolol.139, 140, 141, 142, 143, 144, 145 Acebutolol therapy does not appear to be associated with a reduction in glomerular filtration rate;146, 150 however, renal blood flow may be decreased in some patients.26 Use of the drug in patients with hypertension and chronic renal failure146, 149 has generally not been associated with deterioration of renal function;146, 149 however, in a small number of patients with severe renal impairment, a reduction in glomerular filtration rate has been observed.146
Because of its β1-receptor selectivity, low1, 51 and usual52, 53, 54, 57, 58, 59, 60, 61, 62, 64, 155, 158 dosages of acebutolol usually have little effect on bronchial airway resistance; however, the drug may increase airway resistance and decrease ventilatory capacity,51, 52, 53, 54, 57, 58, 59, 60, 61, 62, 63, 64, 155, 158 especially in patients with asthma and/or chronic obstructive pulmonary disease (COPD) or when high dosages are used.52, 53, 57, 58, 59, 60, 61, 62, 63, 64, 158, 268 Although an increase in airway resistance as measured by forced expiratory volume in 1 second (FEV1) or by resting and postexercise peak expiratory flow rates was not observed in many studies in patients with55, 65, 77, 157, 190, 191, 192, 200 or without56, 156, 186, 194, 205 asthma or COPD who received acebutolol, evidence of increased airway resistance has occurred in some healthy individuals51, 54 and in some patients with1, 52, 53, 57, 58, 59, 60, 61, 62, 63, 64 or without COPD150, 152, 170 who received the drug. Acebutolol's effect on airway resistance generally appears to be less than that of nonselective β-blockers (e.g., propranolol),1, 2, 51, 52, 54, 64 but generally comparable to57, 59, 60, 61, 62, 64 or greater than1, 52, 54 that of other β1-selective agents. Low dosages of acebutolol (up to 400 mg daily)268 generally do not inhibit β-adrenergic agonist-induced bronchodilation appreciably;2, 52, 53, 54, 55, 64, 66 however, in some patients with asthma57 or COPD,58β-agonist-induced bronchodilation may be substantially57, 59, 62 or completely58 inhibited by the drug.
Endocrine and Metabolic Effects
Acebutolol does not appear to substantially affect glucose metabolism.73, 75 Acebutolol does not affect the rate of recovery of blood glucose concentration following insulin-induced hypoglycemia in healthy individuals2, 68, 70 or in type II diabetic patients managed by diet;2, 74 however, the drug may potentiate insulin-induced hypoglycemia in diabetic patients receiving oral hypoglycemic agents.74 Acebutolol does not appear to affect blood glucose concentrations following exercise-induced hypoglycemia.2, 75 Results of oral glucose tolerance tests have varied following short-71, 72 or long-term69, 71 administration of acebutolol in patients with angina72 or hypertension.69, 71 Acebutolol caused a decrease72 or increase71 in glucose tolerance following short-term administration of the drug.71, 72 Following long-term administration, there was a decrease69 or no change71 in glucose tolerance;69, 71 rates of plasma insulin increases were reduced71 or remained unchanged;69 and fasting blood glucose concentrations were increased slightly.69
Following long-term (6-12 months) administration of acebutolol, the drug does not substantially affect plasma2, 69, 81 or blood2, 79 total cholesterol, low-density lipoprotein (LDL)-cholesterol, very low-density lipoprotein (VLDL)-cholesterol, high-density lipoprotein (HDL)-cholesterol, or triglyceride concentrations in hypertensive patients.2, 69, 79, 81, 292 Serum free fatty acid concentrations appear to decrease after a month of therapy with acebutolol and remain unchanged thereafter.2, 69, 81 Acebutolol slightly inhibits isoproterenol-induced increases in plasma free fatty acid concentrations82 and delays free fatty acid response to insulin-induced hypoglycemia.80
Acebutolol does not appear to substantially alter serum concentrations of thyroid hormones in hyperthyroid patients84 or plasma concentrations of growth hormone, luteinizing hormone, cortisol, or testosterone in healthy male adults,83 but has substantially decreased plasma prolactin and follicle-stimulating hormone concentrations in healthy male adults.83
Acebutolol hydrochloride is well absorbed from the GI tract following oral administration;1, 2, 4, 11, 91, 109 however, the drug undergoes extensive first-pass metabolism in the liver.1, 2, 97, 99, 109, 122, 124 The absolute bioavailability of acebutolol in commercially available acebutolol hydrochloride capsules is approximately 35-50%.1, 4, 94, 97, 102 The rate of absorption of acebutolol and peak plasma concentrations and areas under the plasma concentration-time curves (AUCs) of the drug and its major metabolite (diacetolol) may be slightly decreased by the presence of food, but the extent of absorption of the drug is not substantially affected.1, 2, 101 Since acebutolol undergoes intestinal secretion into the GI tract1, 87, 111 and acebutolol and diacetolol are distributed into bile,92 they may undergo enterohepatic circulation;90, 92 however, diacetolol apparently is not well absorbed from the GI tract.2, 118
Following oral administration, peak plasma acebutolol and diacetolol concentrations occur within 2-2.5 hours (range: 1-4 hours) and 4 hours (range: 2.4-5 hours), respectively, in healthy individuals1, 2, 94, 95, 97, 98, 99, 126, 135 or patients with hypertension91 or arrhythmias.2, 90, 137 Peak plasma concentrations of acebutolol reportedly increase proportionally with single oral doses ranging from 200-400 mg,1, 2, 85, 93 but with higher single doses or following multiple-dose oral administration, the pharmacokinetic profile of the drug deviates somewhat from linearity,1, 2, 9 possibly as a result of saturation of hepatic biotransformation sites.1, 4, 9 There is considerable interindividual and intraindividual variation in plasma concentrations attained with a given dosage.2, 91, 95, 125, 126 Following oral administration of a single 400-mg dose of acebutolol in fasting, healthy individuals2, 94, 98, 102, 122 or hypertensive patients,91 peak plasma acebutolol and diacetolol concentrations of approximately 650-1060 and 700-1080 ng/mL, respectively, are achieved. Peak plasma concentrations and AUCs of acebutolol and diacetolol in geriatric individuals may be approximately twofold those observed in younger individuals,1, 2, 122 possibly as a result of decreased first-pass metabolism and renal function.1, 122 Following oral administration of a single 400-mg dose of acebutolol in geriatric hypertensive patients, peak plasma acebutolol concentrations averaged 1600 ng/mL (range: 1350-1900 ng/mL).122
Following oral administration of an average acebutolol dosage of 350 mg (5 mg/kg) 3 times daily for 3 days in healthy individuals, peak plasma acebutolol and diacetolol concentrations after an individual dose were 1300-1800 and 2000-2800 ng/mL, respectively.2, 94 Following multiple-dose oral administration of acebutolol hydrochloride for 3 days or 1 year, the AUC of acebutolol increased by approximately 50 or 100%, respectively, as compared with single-dose oral administration; the AUC of diacetolol was similarly increased.2, 94 Following oral administration of acebutolol hydrochloride as a single dose,2, 85, 91 as multiple doses (for 3 days),2, 91, 94 or chronically (for 1 year),2, 90 plasma concentrations of diacetolol are approximately 2, 2.6, or 2.7 times higher, respectively, than those of unchanged acebutolol.2, 85, 90, 91, 94
The relationship between plasma acebutolol concentration and pharmacologic effects of the drug has not been clearly established.2, 85, 91, 138, 194 Relationships between pharmacologic effects (e.g., postexercise decrease in blood pressure,2, 85, 91 reflex tachycardia,98 reduction of resting heart rate,1, 85, 96, 138 response of exercise-induced tachycardia)1, 2, 100 and dose1, 2, 85 or plasma acebutolol or diacetolol concentration2, 91, 98, 100 have been reported in some studies following single2, 85, 91, 98, 100 or multiple96, 138 doses, but such relationships were not found in other studies following multiple doses.2, 91, 138, 194 As with other β-adrenergic blocking agents (β-blockers),39, 129, 130 there has been a lack of correlation and wide interindividual variation between plasma acebutolol and/or diacetolol concentration and blood pressure reduction.91
In healthy1, 21, 98, 100 or hypertensive91 individuals, the effect of acebutolol on resting, reflex, or exercise-induced heart rate and systolic blood pressure begins within 1-1.5 hours,1, 3, 21, 91, 100 peaks after 2-8 hours,1, 21, 91, 100 and may persist for up to 24 hours or longer.1, 3, 91, 98, 100 Following oral administration of a single 300-mg dose of acebutolol in patients with ventricular premature complexes (VPCs), suppression of VPCs occurs within about 1 hour, peaks at 4-6 hours, and may persist for up to 10 hours.137 A relationship between the antiarrhythmic activity and plasma concentrations of acebutolol has not been established;2, 194 however, following IV administration in patients with coronary artery disease, plasma acebutolol concentrations greater than 1000 ng/mL were associated with substantial increases in the HV interval.45
Distribution of acebutolol hydrochloride into body tissues and fluids has not been fully characterized.93, 103, 104, 105, 106, 107, 112, 125 Following IV administration in rats, acebutolol is distributed extensively into many tissues, including heart, liver, kidneys, lungs, intestines, stomach, and salivary glands, but only minimally into CSF or testes.11 Following oral administration of acebutolol hydrochloride in healthy individuals, acebutolol and, to a lesser extent, diacetolol, are distributed into saliva and minimally into CSF.104 Following oral administration of a single 300-mg dose of acebutolol, about 3-9% of the dose is distributed into bile within 24 hours, in approximately equivalent amounts as acebutolol and diacetolol.92 Peak biliary concentrations of acebutolol are approximately 60-100 times greater than peak plasma concentrations.92
Following IV administration, acebutolol is rapidly and widely distributed into the extravascular space.93 The apparent volume of distribution of the drug in healthy adults is approximately 1.6-3 L/kg (range: 1-3.8 L/kg) following IV administration.93, 102, 112 In healthy individuals, the volume of distribution in the central compartment (Vc) and at steady state (Vss) averages 0.16-0.22 and approximately 1.2 L/kg, respectively, following IV administration.93, 112 The apparent volume of distribution may be decreased in geriatric patients.122
In vitro, acebutolol and diacetolol are approximately 11-25 and 6-9% bound, respectively, to plasma proteins at plasma acebutolol concentrations of 20-9000 ng/mL.2, 93, 103 Acebutolol is approximately 50% bound to erythrocytes.4, 125
Acebutolol and diacetolol readily cross the placenta1, 2, 105, 106, 107 and can accumulate in the fetus.105, 106, 107 In pregnant women receiving acebutolol, the mean acebutolol and diacetolol ratios of umbilical venous to maternal venous plasma concentrations were 0.8 (range: 0.5-1) and 0.6 (range: 0.3-0.8), respectively.105, 106
Acebutolol and diacetolol are distributed into milk;1, 2, 105, 106 the mean acebutolol and diacetolol milk-to-plasma ratios are approximately 7.1 and 12.2, respectively.1, 106
Plasma concentrations of acebutolol appear to decline in a biphasic manner following oral administration.95, 125 Following a single oral dose in healthy adults, the half-life of acebutolol in the initial distribution phase (t½α) is about 3 hours95 and the half-life in the terminal phase (t½β) has been reported to average 11 hours (range: 6-12 hours).95, 125 The half-lives of the two identified metabolites, diacetolol and acetolol, average 7.5 (range: 7-11 hours) and 3 hours, respectively, following a single oral dose of the drug.101, 108, 125 The half-life of acebutolol tends to be slightly prolonged following multiple rather than single doses.94, 95 Following multiple-dose oral administration of acebutolol in healthy individuals (400 mg twice daily for 56 days), the elimination half-life of acebutolol averaged 13 hours (range: 9-20 hours).95 The elimination half-lives of acebutolol and diacetolol may be slightly increased in geriatric patients.122
In patients with renal impairment, the elimination half-life of acebutolol is not substantially increased;1, 123, 125, 136 however, because diacetolol is eliminated to a greater extent by the kidneys than the parent drug, its elimination half-life is prolonged,1, 86, 123, 125, 136 particularly in those patients with severe renal impairment.123, 125 Following single or multiple oral doses of acebutolol, the elimination half-life of diacetolol reportedly averaged 21.5 hours (range: 11-49 hours) or 32 hours (range: 17-54 hours) in patients with creatinine clearances of 6-56 or less than 5 mL/minute, respectively.124, 125, 126, 127
The plasma elimination half-lives of acebutolol and diacetolol in neonates born to women receiving the drug during pregnancy ranged from 6-14 and from 24-30 hours, respectively, in the first 24 hours after birth; the half-life of diacetolol decreased to 12-16 hours during the second day.105 Neonatal urinary excretion of the drug and diacetolol was maximal during the first 24 hours after birth.105
Acebutolol is rapidly and extensively metabolized in the liver.2, 110, 113 Acebutolol undergoes extensive hydrolysis of the butyramide group to form the desbutyl primary amine, acetolol, which is almost completely converted via N -acetylation to diacetolol.2, 4, 6, 99, 108, 109, 110, 113 The extent of metabolism of acebutolol to diacetolol appears to be independent of the genetic acetylator phenotype of the patient.113 Diacetolol is equipotent to acebutolol and has a similar pharmacologic profile.1, 2, 114, 115, 116, 117 (See Pharmacology.)
Following oral administration, acebutolol and its metabolites are excreted in feces and in urine.1, 87, 92, 109, 111, 123 Acebutolol and diacetolol are excreted in feces via biliary elimination,92 and systemically absorbed acebutolol also undergoes intestinal secretion into the GI tract.1, 87, 111 Although not clearly established, acebutolol and diacetolol may undergo enterohepatic circulation.90, 92 Following a single oral dose of acebutolol in healthy individuals,1, 2, 94, 95, 97, 102, 109, 125, 127 about 50-60% of the dose is excreted in feces,1, 109, 111 in approximately equal amounts as acebutolol and diacetolol,109 and about 10-50% is excreted in urine within 1-4 days,1, 2, 3, 94, 95, 97, 102, 109, 111, 125, 127, 136 10-17% as acebutolol,2, 3, 95, 97, 109, 125, 127 15-26% as diacetolol,2, 3, 95, 97, 109, 125, 127 and 3-9% as acetolol.3, 109 Following IV administration of acebutolol, approximately 40-66% of the dose is excreted in urine within 1-4 days,93, 94, 97, 102, 109 about 30-40% as unchanged drug,93, 97, 109 13-26% as diacetolol,93, 97, 109 and 3% as acetolol;109 approximately 33% is excreted in feces,109 about 16% as acebutolol, 17% as diacetolol, and 0.2% as acetolol.109
The fraction of acebutolol excreted in urine as unchanged drug and diacetolol decreases with decreasing renal function and is reduced markedly in patients with severe renal impairment.2, 124, 125, 136 Following a single 200-mg oral dose of acebutolol in patients with creatinine clearances of 14-56 mL/minute, the fraction excreted in urine within 72 hours as unchanged drug and diacetolol averaged approximately 6% (range: 2-13%) and 19% (range: 11-26%), respectively; in patients with creatinine clearances less than 10 mL/minute, the fraction excreted in urine within 48 hours as unchanged drug and diacetolol averaged approximately 0.4% (range: 0.1-0.6%) and 2% (range: 1.6-3.2%), respectively.125 Urinary excretion of acebutolol appears to be independent of urinary pH.121
Following IV administration of acebutolol in healthy individuals, total plasma clearance of acebutolol averages 7-11 mL/minute per kg;93, 97, 102, 112 renal clearance of the drug is about one-third of total plasma clearance, averaging approximately 3 mL/minute per kg (range: 2.5-4 mL/minute per kg).93, 102, 112 Total plasma clearance may be decreased in geriatric patients, averaging approximately 6 mL/minute per kg (range: 5.3-7 mL/minute per kg).122
The apparent renal clearances of acebutolol and diacetolol are decreased in patients with reduced renal function.125 In patients with creatinine clearances of 6-56 mL/minute, renal clearances of acebutolol and diacetolol averaged 0.32 and 0.35 mL/minute per kg, respectively.125 In patients with renal impairment, renal clearances of acebutolol125, 127 and diacetolol1, 125, 127 are related directly to creatinine clearance.1, 125, 127 It appears that an increase in nonrenal clearance of acebutolol may compensate for decreased renal clearance of the unchanged drug in the presence of renal impairment.125, 127 Limited data suggest that the presence of cirrhosis does not substantially affect the pharmacokinetics of acebutolol or diacetolol.128 The effects of hepatic impairment on the elimination of acebutolol remain to be more fully evaluated.128
Acebutolol and diacetolol are removed by hemodialysis.1, 125, 127 The amount of drug removed by hemodialysis depends on several factors (e.g., type of coil used, dialysis flow rate).131, 132, 133, 134 The hemodialysis clearances of acebutolol and diacetolol reportedly are 43 and 40 mL/minute, respectively.125 In patients with creatinine clearances less than 5 mL/minute, the half-life of diacetolol is decreased to approximately 7 hours (range: 5-12 hours) during hemodialysis.125 It is not known whether acebutolol and diacetolol are removed by peritoneal dialysis.268
Acebutolol hydrochloride is a β1-selective adrenergic blocking agent possessing mild intrinsic sympathomimetic activity.1, 2, 4, 5, 6, 7, 8, 11, 12, 13, 14, 15, 16, 17 Acebutolol is related structurally to atenolol and metoprolol in that the drugs contain substituents in the para position of the benzene ring; however, acebutolol differs from these drugs in that it also contains an acetyl group at position 3 of the benzene ring.21, 36, 178 The presence of large substituents in the para position is believed to account in part for the selective β1-adrenergic blocking effect of these drugs.10, 261 The presence of the oxygen atom in the para position in acebutolol may account in part for its intrinsic sympathomimetic activity.261 The presence of the amide group in acebutolol is associated with decreased lipophilicity of the drug.251
Acebutolol hydrochloride occurs as a white or slightly off-white, crystalline powder1, 3 and has solubilities of 200 mg/mL in water and 70 mg/mL in alcohol3 at room temperature (approximately 25°C).268 The lipophilicity of acebutolol is substantially less than that of labetalol or propranolol but comparable to that of some other currently available β-adrenergic blocking agents (β-blockers) (e.g., metoprolol).252 The apparent pKa of the drug in water is 9.4.3
Acebutolol hydrochloride capsules should be stored in tight containers1, 253 at room temperature (approximately 25°C).1, 2, 3 Commercially available 200- and 400-mg capsules of acebutolol should be protected from light.1, 305 Acebutolol hydrochloride capsules have an expiration date of 3 years following the date of manufacture.3
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Capsules | 200 mg (of acebutolol)* | Acebutolol Hydrochloride Capsules | |
400 mg (of acebutolol)* | Acebutolol Hydrochloride Capsules | |||
Sectral® | Promius |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
1. Wyeth-Ayerst Laboratories. Sectral® (acebutolol hydrochloride) prescribing information. In: Physicians' desk reference. 53rd ed. Montvale, NJ: Medical Economics Company Inc; 1999:3381-3.
2. Ives Laboratories Inc. Sectral® product monograph. New York, NY; 1985 Mar.
3. Ives Laboratories Inc. Sectral® product information form for American Hospital Formulary Service. Philadelphia, PA; 1985 Jan.
4. Singh BN, Thoden WR, Ward A. Acebutolol: a review of its pharmacological properties and therapeutic efficacy in hypertension, angina pectoris and arrhythmia. Drugs . 1985; 29:531-69. [PubMed 3891306]
5. Cowling CGD, Leary WP. Acebutolol: a review. Curr Ther Res . 1981; 30:765-74.
6. De Bono G, Kaye CM, Roland E et al. Acebutolol: ten years of experience. Am Heart J . 1985; 109(5 Part 2):1211-24. [PubMed 2859785]
7. Anon. Acebutolol. Med Lett Drugs Ther . 1985; 27:58-60. [PubMed 3892259]
8. Abernethy DR, Arendt RM, Greenblatt DJ. Pharmacologic properties of acebutolol: relationship of hydrophilicity to central nervous system penetration. Am Heart J . 1985; 109(5 Part 2):1120-5. [PubMed 2859774]
9. Ryan JR. Clinical pharmacology of acebutolol. Am Heart J . 1985; 109(5 Part 2):1131-6. [PubMed 2859776]
10. Mimnaugh MN, Gearien JE. Adrenergic drugs. In: Foye WO, ed. Principles of medicinal chemistry. 2nd ed. Philadelphia: Lea & Febiger; 1981:377-93.
11. Maxwell DR, Collins RF. Acebutolol (Sectral): I—review of the pharmacology and pharmacokinetics. Clin Trials J . 1974; 11(Suppl 3):9-18.
12. Basil B, Jordan R, Loveless AH et al. β-Adrenoceptor blocking properties and cardioselectivity of M & B 17,803A. Br J Pharmacol . 1973; 48:198-211. [PubMed 4147427] [PubMedCentral]
13. Daly MJ, Flook JJ, Levy GP. The selectivity of β-adrenoceptor antagonists on cardiovascular and bronchodilator responses to isoprenaline in the anaesthetized dog. Br J Pharmacol . 1975; 53:173-81. [PubMed 238697][PubMedCentral]
14. Harms HH. Isoproterenol antagonism of cardioselective beta adrenergic receptor blocking agents: a comparative study of human and guinea-pig cardiac and bronchial beta adrenergic receptors. J Pharmacol Exp Ther . 1976; 199:329-35. [PubMed 10427]
15. Baird JRC, Linnell J. The assessment of β-adrenoceptor blocking potency and cardioselectivity in vitro and in vivo. J Pharm Pharmacol . 1972; 24:880-5.
16. Harms HH, Spoelstra AJG. Cardiac and bronchial β-adrenoceptor antagonistic potencies of atenolol, metoprolol, acebutolol, practolol, propranolol and pindolol in the anaesthetized dog. Clin Exp Pharmacol Physiol . 1978; 5:53-9. [PubMed 25152]
17. Briant RH, Dollery CT, George CF. Cardiac and peripheral vascular beta-receptors in the dog and in man: the selectivity of acebutolol (Sectral). Clin Trials J . 1974; 11(Suppl 3):25-8.
18. Bilski A, Robertson HH, Wale JL. A study of the relationship between cardiac β-adrenoceptor blockade and intrinsic sympathomimetic activity in rats depleted of catecholamines. Clin Exp Pharmacol Physiol . 1979; 6:1-9. [PubMed 32980]
19. Levy B. The selective beta receptor blocking properties of DL-1-(2-acetyl-4- n -butyramidophenoxy)-2-hydroxy-3- isopropylaminopropane-HCl (M&B 17803-A) in the anesthetized dog. J Pharmacol Exp Ther . 1973; 186:134-44. [PubMed 4146701]
20. Dreyer AC, Offermeier J. In vitro assessment of the selectivities of various beta-adrenergic blocking agents. Life Sci . 1980; 27:2087-92. [PubMed 6111008]
21. Cuthbert MF, Owusu-Ankomah K. Effect of M & B 17803A, a new β-adrenoceptor blocking agent, on the cardiovascular responses to tilting and to isoprenaline in man. Br J Pharmacol . 1971; 43:639-48. [PubMed 4400530] [PubMedCentral]
22. Giacomini JC, Thoden WR. Ancillary pharmacologic properties of acebutolol: cardioselectivity, partial agonist activity, and membrane-stabilizing activity. Am Heart J . 1985; 109(5 Part 2):1137-44. [PubMed 2859777]
23. Wollam GL, Cody RJ Jr, Tarazi RC et al. Acute hemodynamic effects and cardioselectivity of acebutolol, practolol, and propranolol. Clin Pharmacol Ther . 1979; 25:813-20. [PubMed 445948]
24. Mougeot G, Hugues FC, Julien D et al. Influence of propranolol and acebutolol on isoprenaline-induced changes in heart rate and peripheral blood flow in man. Arch Int Pharmacodyn Ther . 1981; 251:116-25. [PubMed 7259364]
25. Svendsen TL, Trap-Jensen J, C et al. Immediate central hemodynamic effects of five different beta-adrenoceptor-blocking agents, acebutolol, atenolol, pindolol, practolol, and propranolol, in patients with ischemic heart disease. Am Heart J . 1985; 109(5 Part 2):1145-50. [PubMed 2859778]
26. Dreslinski GR, Aristimuno GG, Messerli FH et al. Effects of beta blockade with acebutolol on hypertension, hemodynamics, and fluid volume. Clin Pharmacol Ther . 1979; 26:562-5. [PubMed 498697]
27. Nigri A, Mangieri E, Martuscelli E et al. Acute hemodynamic effects of acebutolol and propranolol. Clin Ther . 1984; 6:693-8. [PubMed 6478471]
28. Dalal JJ, Ross PJ, Wong K et al. Acute effects of acebutolol on cardiovascular function in man. Br J Clin Pharmacol . 1981; 11:265-8. [PubMed 7213527][PubMedCentral]
29. Mason JW, Specter MJ, Ingels NB et al. Haemodynamic effects of acebutolol. Br Heart J . 1978; 40:29-34. [PubMed 341929][PubMedCentral]
30. Lewis BS, Bakst A, Mitha AS et al. Haemodynamic effects of a new beta-blocking agent "Sectral' (M & B 17803A). Br Heart J . 1973; 35:743-51. [PubMed 4146280] [PubMedCentral]
31. Ireland MA, Littler WA. The effects of oral acebutolol and propranolol on forearm blood flow in hypertensive patients. Br J Clin Pharmacol . 1981; 12:363-8. [PubMed 7295466][PubMedCentral]
32. Joye JA, Lee G, DeMaria AN et al. Afterload advantage of cardioselective beta blockade by acebutolol versus propranolol: hemodynamic assessment by cardiac catheterization in coronary patients. Circulation . 1978; 58:153. [PubMed 647879]
33. Ablad B, Brogard M, C et al. β-Adrenergic receptor blocking properties of three allyl-substituted phenoxypropanolamines. Eur J Pharmacol . 1970; 13:59-64. [PubMed 4395676]
34. Prichard BNC. β-Adrenergic receptor blockade in hypertension, past, present and future. Br J Clin Pharmacol . 1978; 5:379-99. [PubMed 26370][PubMedCentral]
35. Thadani U. Beta blockers in hypertension. Am J Cardiol . 1983; 52:10-5D.
36. Conolly ME, Kersting F, Dollery CT. The clinical pharmacology of beta-adrenoceptor-blocking drugs. Prog Cardiovasc Dis . 1976; 19:203-34. [PubMed 10600]
37. Shand DG. State-of-the-art: comparative pharmacology of the β-adrenoceptor blocking drugs. Drugs . 1983; 25(Suppl 2):92-9.
38. Breckenridge A. Which beta blocker? Br Med J . 1983; 286:1085-8. (IDIS 169422)
39. Waal-Manning HHJ. The antihypertensive action of several β-adrenoceptor-blocking drugs. N Z Med J . 1976; 83:223-6. [PubMed 8748]
40. LeClercq JF, Rosengarten MD, Kural S et al. Effects of intrinsic sympathetic activity of beta-blockers on SA and AV nodes in man. Eur J Cardiol . 1981; 12:367-75. [PubMed 6113145]
41. Marrott PK, Ruttley ST, Jenkins PM et al. The electrophysiological evaluation of intravenous acebutolol, a β-blocking drug. Eur J Cardiol . 1977; 6:117-30. [PubMed 913484]
42. Amlie JP, Lessum S, Collins RF et al. Plasma levels and electrophysiological effects of acebutolol (M & B 17.803) in the dog heart in situ. Acta Pharmacol Toxicol . 1977; 40:378-88.
43. Kaul S, Hecht HS, Seidman R et al. Comparative effects of oral acebutolol and propranolol at rest and during exercise in ischemic heart disease: double-blind placebo crossover study utilizing radionuclide ventriculography. Am Heart J . 1984; 108:469-74. [PubMed 6382987]
44. Rochette L, Didier JP, Moreau D et al. Role of beta-adrenoceptor antagonism in the prevention of reperfusion ventricular arrhythmias: effects of acebutolol, atenolol, and d-propranolol on isolated working rat hearts subject to myocardial ischemia and reperfusion. Am Heart J . 1984; 107:1132-41. [PubMed 6144264]
45. Mason JW, Winkle RA, Meffin PJ et al. Electrophysiological effects of acebutolol. Br Heart J . 1978; 40:35-40. [PubMed 341930][PubMedCentral]
46. Touboul P, Huerta F, Porte J et al. Etude des proprietes electrophysiologiques de l'acebutolol chez l'homme. (French; with English abstract.) Therapie . 1975; 30:417-27.
47. Chandraratna PAN, Aronow WS, Laddu A. Effects of acebutolol and propranolol on left ventricular performance assessed by echocardiography. Clin Pharmacol Ther . 1980; 27:460-3. [PubMed 7357803]
48. Katz RJ, DiBianco R, Singh S et al. Acebutolol and left ventricular function: assessment by radionuclide angiography. Clin Pharmacol Ther . 1981; 29:149-54. [PubMed 7460480]
49. Maclagan J, Ney UM. A comparison of the bronchoconstrictor and β-adrenoceptor blocking activity of propranolol and acebutolol. Br J Pharmacol . 1980; 68:196-8. [PubMed 6101978][PubMedCentral]
50. Wood AJJ. Pharmacologic differences between beta blockers. Am Heart J . 1984; 108:1070-7. [PubMed 6148865]
51. Kumana CR, Kaye CM, Leighton M et al. Cardiac and pulmonary effects of acebutolol. Lancet . 1975; 5:89-93.
52. Benson MK, Berrill WT, Cruickshank JM et al. A comparison of four β-adrenoceptor antagonists in patients with asthma. Br J Clin Pharmacol . 1978; 5:415-9. [PubMed 26371][PubMedCentral]
53. Nair S, Maguire WC, Laddu AR. The effect of acebutolol, a beta adrenergic blocking agent, and placebo on pulmonary functions in asthmatics. Int J Clin Pharmacol Ther Toxicol . 1981; 19:519-26.
54. Gribbin HR, Mackay AD, Baldwin CJ et al. Bronchial and cardiac β-adrenoceptor blockade—a comparison of atenolol, acebutolol and labetalol. Br J Clin Pharmacol . 1981; 12:61-5. [PubMed 6264936][PubMedCentral]
55. Mue S, Sasaki T, Ohmi T et al. Influence of acebutolol on the haemodynamic and respiratory function of asthmatic patients. J Pharmacother . 1979; 2:67-71.
56. DiBianco R, Dickie KJ, Singh S et al. Pulmonary effects of acebutolol, a “cardioselective” beta adrenergic blocking agent. Int J Clin Pharmacol Ther Toxicol . 1982; 20:1-7. [PubMed 6120142]
57. Greefhorst APM, van Herwaarden CLA. Ventilatory and haemodynamic effects of terbutaline infusion during beta1-selective blockade with metoprolol and acebutolol in asthmatic patients. Eur J Clin Pharmacol . 1982; 23:203-8. [PubMed 6756931]
58. Whitsett TL, Levin DC, Manion CV. Comparison of the beta1 and beta2 adrenoceptor blocking properties of acebutolol and propranolol. Chest . 1982; 82:668-73. [PubMed 6128186]
59. Greefhorst APM, van Herwaarden CLA. Comparative study of the ventilatory effects of three beta1-selective blocking agents in asthmatic patients. Eur J Clin Pharmacol . 1981; 20:417-21. [PubMed 6116610]
60. Leary WP, Coleman AJ, Asmal AC. Respiratory effects of acebutolol hydrochloride: a new selective beta-adrenergic blocking agent. S Afr Med J . 1973; 47:1245-8. [PubMed 4146466]
61. Skinner C, Palmer KNV, Kerridge DF. Comparison of the effects of acebutolol (Sectral) and practolol (Eraldin) on airways obstruction in asthmatics. Br J Clin Pharmacol . 1975; 2:417-22. [PubMed 786353][PubMedCentral]
62. Skinner C, Palmer KNV. Airways obstruction in asthmatic patients: comparison of the effects of acebutolol, practolol and placebo. Clin Trials J . 1974; 11:29-32.
63. Palmer KNV. Respiratory side effects of beta-blockers. Br Med J . 1977; 1:841.
64. Decalmer PBS, Chatterjee SS, Cruickshank JM et al. Beta-blockers and asthma. Br Heart J . 1978; 40:184-9. [PubMed 25075][PubMedCentral]
65. Freed E. Acebutolol-controlled tachycardia in a depressed asthmatic. Med J Aust . 1980; 1:442.
66. Tattersfield AE, Harrison RN. Effect of β-blocker therapy on airway function. Drugs . 1983; 25(Suppl 2):227-31.
67. Gibbons DO, Lant AF, Ashford A et al. Comparative effects of acebutolol and practolol on the lipolytic response to isoprenaline. Br J Clin Pharmacol . 1976; 3:177-84. [PubMed 973938][PubMedCentral]
68. Newman RJ. Comparison of propranolol, metoprolol, and acebutolol on insulin-induced hypoglycaemia. Br Med J . 1976; 2:447-9. [PubMed 8187][PubMedCentral]
69. Lehtonen A. The effect of acebutolol on plasma lipids, blood glucose and serum insulin levels. Acta Med Scand . 1984; 216:57-60. [PubMed 6385635]
70. Grimaldi A, Bennett P, Delas B et al. β-Blockers and hypoglycaemia (assessment of cardioselective and intrinsic sympathomimetic properties in relation to severity of hypoglycaemia). Curr Ther Res . 1984; 36:361-73.
71. Covi G, Dalla Riva AD, Pomari S et al. Long-term treatment of essential hypertension with acebutolol: an evaluation of clinical and metabolic effects. Curr Ther Res . 1982; 31:1018-25.
72. Birnbaum J, DiBianco R, Becker KL et al. Glucose and lipid metabolism during acebutolol and propranolol therapy of angina in nondiabetic patients. Clin Pharmacol Ther . 1983; 33:294-300. [PubMed 6337762]
73. Frances Y, Luccioni R, Vague P et al. Effects of betaxolol, propranolol, and acebutolol on the glycoregulation after oral glucose tolerance test in hypertensive patients. In: Morselli PL, ed. LERS monograph series. Vol 1. New York: Raven Press; 1983:213-20.
74. Deacon SP, Karunanayake A, Barnett D. Acebutolol, atenolol, and propranolol and metabolic responses to acute hypoglycaemia in diabetics. Br Med J . 1977; 2:1255-7. [PubMed 338101][PubMedCentral]
75. Koch G, Franz IW, Gubba A et al. β-Adrenoceptor blockade and physical activity: cardiovascular and metabolic aspects. Acta Med Scand . 1983; 672(Suppl):55-62.
76. Barnett AH, Leslie D, Watkins PJ. Can insulin-treated diabetics be given beta-adrenergic blocking drugs? Br Med J . 1980; 280:976-8.
77. Leary WP. The cardioselectivity of acebutolol (Sectral) in man. Clin Trials J . 1974; 11(Suppl 3):33-5.
78. James I. The beta-blocker dilemma. Geriatric Med . 1983; 13:429-30.
79. Giuntoli F, Scalabrino A, Galeone F et al. Antihypertensive and metabolic effects of a long-term treatment with acebutolol. Curr Ther Res . 1984; 36:188-94.
80. Newman RJ. Comparison of the antilipolytic effect of metoprolol, acebutolol, and propranolol in man. Br Med J . 1977; 2:601-3. [PubMed 901996][PubMedCentral]
81. Lehtonen A. Effect of beta blockers on blood lipid profile. Am Heart J . 1985; 109(5 Part 2):1192-6. [PubMed 2859784]
82. Harms HH, Gooren L, Spoelstra AJG et al. Blockade of isoprenaline-induced changes in plasma free fatty acids, immunoreactive insulin levels and plasma renin activity in healthy human subjects, by propranolol, pindolol, practolol, atenolol, metoprolol and acebutolol. Br J Clin Pharmacol . 1978; 5:19-26. [PubMed 23133][PubMedCentral]
83. Lewis MJ, Groom GV, Barber R et al. The effects of propranolol and acebutolol on the overnight plasma levels of anterior pituitary and related hormones. Br J Clin Pharmacol . 1981; 12:737-42. [PubMed 6800389][PubMedCentral]
84. Jones MK, John R, Jones GR. The effect of oxprenolol, acebutolol and propranolol on thyroid hormones in hyperthyroid subjects. Clin Endocrinol . 1980; 13:343-7.
85. Collett JT, Hendrickson JA, Chew YC et al. Comparative beta-blocking potencies of acebutolol and propranolol relative to plasma drug levels. Int J Clin Pharmacol Ther Toxicol . 1981; 19:473-8. [PubMed 6117519]
86. de Villiers AS, Folb PI, Pascoe M et al. Pharmacokinetics of acebutolol and its acetyl metabolite, diacetolol, in hypertensive patients and in renal use. S Afr J Sci . 1981; 77:286.
87. George CF, Gruchy BS. Elimination of drugs by active intestinal transport. J Pharm Pharmacol . 1979; 31:643-4. [PubMed 41074]
88. Cockburn JJ. Which beta blocker? Br Med J . 1983; 286:1439. Letter.
89. Feely J, Maclean D. New drugs: beta blockers and sympathomimetics. BMJ . 1983; 286:1972. [PubMed 6407660][PubMedCentral]
90. Winkle RA, Meffin PJ, Ricks WB et al. Acebutolol metabolite plasma concentration during chronic oral therapy. Br J Clin Pharmacol . 1977; 4:519-22. [PubMed 911602][PubMedCentral]
91. Martin MA, Phillips FC, Tucker GT et al. Acebutolol in hypertension: relationships between drug concentration and effects. Eur J Clin Pharmacol . 1978; 14:383-90. [PubMed 367793]
92. Kaye CM. The biliary excretion of acebutolol in man. J Pharm Pharmacol . 1976; 28:449-50. [PubMed 6757]
93. Meffin PJ, Winkle RA, Peters FA et al. Acebutolol disposition after intravenous administration. Clin Pharmacol Ther . 1977; 22:557-67. [PubMed 913023]
94. Meffin PJ, Winkle RA, Peters FA et al. Dose-dependent acebutolol disposition after oral administration. Clin Pharmacol Ther . 1978; 24:542-7. [PubMed 699478]
95. Gulaid AA, James IM, Kaye CM et al. The pharmacokinetics of acebutolol in man, following the oral administration of acebutolol HCl as a single dose (400 mg), and during and after repeated oral dosing (400 mg, b.d.) Biopharm Drug Dispos . 1981; 2:103-14.
96. de Soyza ND, Murphy ML, O'Riley M et al. Correlation of antiarrhythmic activity of acebutolol with blood levels and heart rate. Clin Pharmacol Ther . 1982; 31:217.
97. Roux A, Flouvat B, Fouache Y et al. Systemic bioavailability of acebutolol in man. Biopharm Drug Dispos . 1983; 4:293-7. [PubMed 6626703]
98. Cuthbert MF, Collins RF. Plasma levels and β-adrenoceptor blockade with acebutolol, practolol and propranolol in man. Br J Clin Pharmacol . 1975; 2:49-55. [PubMed 1234486][PubMedCentral]
99. Meffin PJ, Harapat SR, Harrison DC. Quantitation in plasma and urine of acebutolol and a major metabolite with preliminary observations on their disposition kinetics in man. Res Commun Chem Pathol Pharmacol . 1976; 15:31-51. [PubMed 968178]
100. Watson RDS, Littler WA. Onset and duration of β-adrenergic receptor blockade following single oral dose acebutolol hydrochloride (Sectral). Br J Clin Pharmacol . 1979; 7:557-61. [PubMed 37868][PubMedCentral]
101. Zaman R, Wilkins MR, Kendall MJ et al. The effect of food and alcohol on the pharmacokinetics of acebutolol and its metabolite, diacetolol. Biopharm Drug Dispos . 1984; 5:91-5. [PubMed 6704510]
102. Kaye CM, Kumana CR, Leighton M et al. Observations on the pharmacokinetics of acebutolol. Clin Pharmacol Ther . 1976; 19:416-20. [PubMed 1269192]
103. Coombs TJ, Coulson CJ, Smith VJ. Blood plasma binding of acebutolol and diacetolol in man. Br J Clin Pharmacol . 1980; 9:395-7. [PubMed 7378256][PubMedCentral]
104. Zaman R, Jack DB, Kendall MJ. The penetration of acebutolol and its major metabolite, diacetolol, into human cerebrospinal fluid and saliva. Br J Clin Pharmacol . 1981; 12:427-9. [PubMed 7295474][PubMedCentral]
105. Bianchetti G, Boutroy MJ, Dubruc C et al. Placental transfer and pharmacokinetics of acebutolol and N -acetyl acebutolol in the newborn. Br J Pharmacol . 1981; 72:135-6P.
106. Bianchetti G, Dubruc C, Vert P et al. Placental transfer and pharmacokinetics of acebutolol in newborn infants. Clin Pharmacol Ther . 1981; 29:233-4.
107. Daffos F, Freund M, Sarrot G et al. Passage transplacentaire de l'acebutolol et du diacetolol. Nouv Presse Med . 1982; 11:2154-5.
108. Alexander MS, Bianchine JR. Acebutolol kinetics following oral and intravenous administration in man. Clin Pharmacol Ther . 1984; 35:225.
109. Gabriel R, Kaye CM, Sankey MG. Preliminary observations on the excretion of acebutolol and its acetyl metabolite in the urine and faeces of man. J Pharm Pharmacol . 1981; 33:386-7. [PubMed 6115014]
110. Andresen BD, Davis FT. Metabolism of acebutolol-d6 in the rat correlates with the identification of a new metabolite in human urine. Drug Metab Dispos . 1979; 79:360-5.
111. Collins RF, George CF. Studies on the disposition and fate of [14C]-acebutolol in man and dog. Br J Clin Pharmacol . 1976; 3:346-7P.
112. Roux A, Flouvat B, Chau NP et al. Pharmacokinetics of acebutolol after intravenous bolus administration. Br J Clin Pharmacol . 1980; 9:215-7. [PubMed 7356910][PubMedCentral]
113. Gulaid A, James IM, Kaye CM et al. Lack of correlation between acetylator status and the production of the acetyl metabolite of acebutolol in man. Br J Clin Pharmacol . 1978; 5:261-2. [PubMed 656272][PubMedCentral]
114. Basil B, Jordan R. Pharmacological properties of diacetolol (M&B 16,942), a major metabolite of acebutolol. Eur J Pharmacol . 1982; 80:47-56. [PubMed 6124437]
115. Thomas MS, Tattersfield AE. Comparison of beta-adrenoceptor selectivity of acebutolol and its metabolite diacetolol with metoprolol and propranolol in normal man. Eur J Clin Pharmacol . 1986; 29:679-83. [PubMed 2872056]
116. Ohashi K, Warrington SJ, Kaye CM et al. Observations on the clinical pharmacology and plasma concentrations of diacetolol, the major human metabolite of acebutolol. Br J Clin Pharmacol . 1981; 12:561-5. [PubMed 7295489][PubMedCentral]
117. Flouvat B, Roux A, Delhotal B et al. The beta-blocking effect of diacetolol in humans and its relationship to plasma levels. Int J Clin Pharmacol Ther Toxicol . 1982; 20:358-61. [PubMed 6126441]
118. Flouvat B, Roux A, Chau NP et al. Pharmacokinetics and bioavailability of diacetolol, the main metabolite of acebutolol. Eur J Clin Pharmacol . 1981; 19:287-92. [PubMed 7286031]
119. Kaye CM. New drugs: beta blockers and sympathomimetics. BMJ . 1983; 286:1439. [PubMed 6404493][PubMedCentral]
120. Feely J, deVane PJ, Maclean D. Beta-blockers and sympathomimetics. BMJ . 1983; 286:1043-7. [PubMed 6131725][PubMedCentral]
121. Kaye CM, Long AD. The influence of pH on the buccal absorption and plasma and renal elimination of acebutolol. Br J Clin Pharmacol . 1976; 3:196-7. [PubMed 9955][PubMedCentral]
122. Roux A, Henry JF, Fouache Y et al. A pharmacokinetic study of acebutolol in aged subjects as compared to young subjects. Gerontology . 1983; 29:202-8. [PubMed 6852547]
123. Munn S, Bailey RR, Begg E et al. Plasma and urine concentrations of acebutolol and its acetyl metabolite in patients with renal functional impairment. N Z Med J . 1980; 91:289-91. [PubMed 6930006]
124. Kirch W, Kohler H, Berggren G et al. The influence of renal function on plasma levels and urinary excretion of acebutolol and its main N-acetyl metabolite. Clin Nephrol . 1982; 18:88-94. [PubMed 7140021]
125. Roux A, Aubert P, Guedon J et al. Pharmacokinetics of acebutolol in patients with all grades of renal failure. Eur J Clin Pharmacol . 1980; 17:339-48. [PubMed 7418713]
126. Kaye CM, Dufton JF. Preliminary observations on the elimination of acebutolol in severe chronic renal failure. Br J Clin Pharmacol . 1976; 3:198-9. [PubMed 788740][PubMedCentral]
127. Smith RS, Warren DJ, Renwick AG et al. Acebutolol pharmacokinetics in renal failure. Br J Clin Pharmacol . 1983; 16:253-8. [PubMed 6626416][PubMedCentral]
128. Zaman R, Jack DB, Wilkins MR et al. Lack of effect of liver disease on the pharmacokinetics of acebutolol and diacetolol: a single dose study. Biopharm Drug Dispos . 1985; 6:131-7. [PubMed 4005393]
129. Esler M, Zweifler A, Randall O et al. Pathophysiologic and pharmacokinetic determinants of the antihypertensive response to propranolol. Clin Pharmacol Ther . 1978; 22:299-308.
130. Collste P, Haglund K, Frisk-Holmberg M et al. Pharmacokinetics and pharmacodynamics of alprenolol in the treatment of hypertension. Eur J Clin Pharmacol . 1976; 10:89-95. [PubMed 964292]
131. Gibson TP, Matusik E, Nelson LD et al. Artificial kidneys and clearance calculations. Clin Pharmacol Ther . 1976; 20:720-6. [PubMed 991541]
132. Pond S, Rosenberg J, Benowitz NL et al. Pharmacokinetics of haemoperfusion for drug overdose. Clin Pharmacokinet . 1979; 4:329-54. [PubMed 389527]
133. Lee CSC, Marbury TC. Drug therapy in patients undergoing haemodialysis: clinical pharmacokinetic considerations. Clin Pharmacokinet . 1984; 9:42-66. [PubMed 6362952]
134. Pond SM. Renal principles: diuresis, dialysis, and hemoperfusion. In: Goldfrank's toxicologic emergencies. 3rd ed. Norwalk, CT: Appleton-Century-Crofts; 1986:102-15.
135. Jack DB, Quarterman CP, Zaman R et al. Variability of beta-blocker pharmacokinetics in young volunteers. Eur J Clin Pharmacol . 1982; 23:37-42. [PubMed 6127220]
136. Tjandramaga TB. Altered pharmacokinetics of β-adrenoceptor blocking drugs in patients with renal insufficiency. Arch Int Pharmacodyn Ther . 1980; 247(Suppl):38-53.
137. Gradman AH, Winkle RA, Fitzgerald JW et al. Suppression of premature ventricular contractions by acebutolol. Circulation . 1977; 55:785-91. [PubMed 66105]
138. DiBianco R, Singh SN, Shah PM et al. Comparison of the antianginal efficacy of acebutolol and propranolol. Circulation . 1982; 65:119-28.
139. Fournier A, Hardin JM, Alexandre JM et al. Anti-hypertensive effect of acebutolol: its relation to sympathetic nervous system responsiveness and to plasma renin and dopamine-β-hydroxylase activities. Clin Sci Mol Med . 1976; 51:477-80s.
140. Martin MA, Phillips CA, Smith AJ. Acebutolol in hypertension—a double-blind trial against placebo. Br J Clin Pharmacol . 1978; 6:351-6. [PubMed 359018][PubMedCentral]
141. Menard J, Bertagna X, N'Guyen PT et al. Rapid identification of patients with essential hypertension sensitive to acebutolol (a new cardioselective beta-blocker). Am J Med . 1976; 60:886-90. [PubMed 14503]
142. Belleau LJ, Lebel M, Brossard JJ. Merits of adding a beta blocker (acebutolol) to a diuretic (hydrochlorothiazide) in the treatment of hypertension. J Clin Pharmacol . 1982; 22:20-7. [PubMed 7037871]
143. Alhenc-Gelas F, Plouin PF, Ducrocq MB et al. Comparison of the antihypertensive and hormonal effects of a cardioselective beta-blocker, acebutolol, and diuretics in essential hypertension. Am J Med . 1978; 64:1005-12. [PubMed 655186]
144. Gorkin JU, Elijovich F, Dziedzic SW et al. Addition of acebutolol to diuretics in hypertension. Clin Pharmacol Ther . 1981; 30:739-44. [PubMed 6118215]
145. Thibonnier M, Lardoux MD, Corvol P. Comparative trial of labetalol and acebutolol, alone or associated with dihydralazine, in treatment of essential hypertension. Br J Clin Pharmacol . 1980; 9:561-7. [PubMed 6992823][PubMedCentral]
146. Begg E, Munn S, Bailey RR. Acebutolol in the treatment of patients with hypertension and renal functional impairment. N Z Med J . 1979; 89:293-5. [PubMed 286923]
147. Heel RC, Brogden RN, Speight TM et al. Atenolol: a review of its pharmacological properties and therapeutic efficacy in hypertension. Drugs . 1979; 17:425-60. [PubMed 38096]
148. Merck Sharp & Dohme. Blocadren® prescribing information. West Point, PA; 1985 Apr.
149. Gabriel R. Acebutolol in the management of hypertension in patients with renal disease. Br J Clin Pract . 1979; 33:259-62. [PubMed 486303]
150. Wahl J, Singh BN, Thoden WR. Comparative hypotensive effects of acebutolol and hydrochlorothiazide in patients with mild to moderate essential hypertension: a double-blind multicenter evaluation. Am Heart J . 1986; 111:353-62. [PubMed 3511650]
151. Hansson L, Berglund G, Andersson O et al. Controlled trial of acebutolol in hypertension. Eur J Clin Pharmacol . 1977; 12:89-92. [PubMed 336378]
152. Wahl J, Turlapaty P, Singh BN et al. Comparison of acebutolol and propranolol in essential hypertension. Am Heart J . 1985; 109:313-21. [PubMed 3880995]
153. Singh AN, Paul L, Brossard JJ. Double-blind cross-over study of two beta-blocking agents acebutolol and propranolol in essential hypertension. Curr Ther Res . 1980; 28:964-71.
154. Davidov M. Acebutolol in essential hypertension: results of two multicenter studies against placebo and propranolol. Am Heart J . 1985; 109(5 Part 2):1158-67. [PubMed 2859780]
155. Manttari M, Eisalo A. A comparison of two cardioselective beta-blockers with different ancillary properties in the treatment of hypertension. Acta Med Scand . 1982; 668(Suppl):114-7.
156. Turner AS, Brocklehurst JC. Once-daily acebutolol and atenolol in essential hypertension: double-blind crossover comparison. Am Heart J . 1985; 109(5 Part 2):1178-83. [PubMed 3993534]
157. Hua ASP, Kalowski S, Whitworth JA et al. Acebutolol in mild to moderate hypertension. Med J Aust . 1980; 1:226-8. [PubMed 6990216]
158. Baker PG, Goulton J. A multicentre study of a once daily dosage of acebutolol in the treatment of hypertension in general practice. J Int Med Res . 1979; 7:201-14. [PubMed 456733]
159. Nadeau J, Ogilvie RI, Ruedy J et al. Acebutolol and hydrochlorothiazide in essential hypertension. Clin Pharmacol Ther . 1980; 28:296-301. [PubMed 7408389]
160. Franz IW. Differential antihypertensive effect of acebutolol and hydrochlorothiazide/amiloride hydrochloride combination on elevated exercise blood pressures in hypertensive patients. Am J Cardiol . 1980; 46:301-5. [PubMed 6105821]
161. Leary WP, Asmal AC, Williams PC. Aldactone and acebutolol in treatment of hypertension. J Int Med Res . 1979; 7:29-32. [PubMed 369923]
162. Khalil SI, El Zein O, Bella ME. A double-blind, crossover study of acebutolol and hydrochlorothiazide/amiloride diuretic in Sudanese patients with essential hypertension. Curr Med Res Opin . 1982; 8:39-43. [PubMed 7049584]
163. Oli JM. Acebutolol in the management of hypertension in Nigerians. Curr Ther Res . 1981; 30:477-82.
164. MacGregor GA, Banks RA, Markandu ND et al. Lack of effect of beta-blocker on flat dose response to thiazide in hypertension: efficacy of low dose thiazide combined with beta-blocker. BMJ . 1983; 286:1535-8. [PubMed 6405876][PubMedCentral]
165. Nievel JG, Havard CWH. Assessment of the efficacy and acceptability of an acebutolol/hydrochlorothiazide combination in the treatment of mild to moderate essential hypertension. Curr Med Res Opin . 1981; 7:526-35. [PubMed 7030637]
166. Mitenko PA, McKenzie JK, Brossard JJ. Antihypertensive action of acebutolol (Sectral) when used concomitantly with hydrochlorothiazide. Br J Clin Pharmacol . 1982; 13:209-12. [PubMed 7059418][PubMedCentral]
167. Ogilvie RI, Nadeau JH. Cardiovascular effects of acebutolol and hydrochlorothiazide in essential hypertension. Hypertension . 1982; 4:320-4. [PubMed 7040230]
168. Down PF, Rao SK, Braverman AM et al. Treatment of hypertension in the elderly with a low dose combination of a beta-adrenoceptor blocker and a thiazide diuretic: comparison with methyldopa. Br J Clin Pract . 1983; 37:371-4,88. [PubMed 6367793]
169. Fraser DM, Nimmo GR, Poloniecki JD. Acebutolol in the treatment of diabetic patients with hypertension. Curr Med Res Opin . 1986; 10:122-7. [PubMed 3519092]
170. Boyles PW. Effects of age and race on clinical response to acebutolol in essential hypertension. Am Heart J . 1985; 109(5 Part 2):1184-92. [PubMed 2859783]
171. Costa FV, Caldari R, Borghi C et al. Acebutolol, atenolol and nadolol: comparison of their antihypertensive efficacy at rest and during exercise. Curr Ther Res . 1984; 35:961-73.
173. Anon. Drugs for hypertension. Med Lett Drugs Ther . 1984; 26:107-12. [PubMed 6150424]
174. Moser M. Initial treatment of adult patients with essential hypertension. Part I: why conventional stepped-care therapy of hypertension is still indicated. Pharmacotherapy . 1985; 5:189-95. [PubMed 2863806]
175. Kaplan NM. Initial treatment of adult patients with essential hypertension. Part II: alternating monotherapy is the preferred treatment. Pharmacotherapy . 1985; 5:195-200. [PubMed 4034407]
176. World Health Organization/International Society of Hypertension Fourth Mild Hypertension Conference. 1986 guidelines for the treatment of mild hypertension: memorandum from the WHO/ISH. Hypertension . 1986; 8:957-61.
178. Weiner N. Drugs that inhibit adrenergic nerves and block adrenergic receptors. In: Gilman AG, Goodman LS, Rall TW et al, eds. Goodman and Gilman's the pharmacological basis of therapeutics. 7th ed. New York: Macmillan Publishing Company; 1985:181-214.
179. Rudd P, Blaschke TF. Antihypertensive agents and the drug therapy of hypertension. In: Gilman AG, Goodman LS, Rall TW et al, eds. Goodman and Gilman's the pharmacological basis of therapeutics. 7th ed. New York: Macmillan Publishing Company; 1985:784-805.
180. Kaplan NM. Mild hypertension: when and how to treat. Arch Intern Med . 1983; 143:255-9. [PubMed 6130750]
181. Kaplan NM. Non-drug treatment of hypertension. Ann Intern Med . 1985; 102:359-73. [PubMed 3882040]
182. Veterans Administration Cooperative Study Group on Antihypertensive Agents. Return of elevated blood pressure after withdrawal of antihypertensive drugs. Circulation . 1975; 51:1107-13. [PubMed 1093758]
183. Kaplan NM. New choices for the initial drug therapy of hypertension. Am J Cardiol . 1983; 51:1786-8. [PubMed 6134465]
184. Lewis JE. Comparison of acebutolol and hydrochlorothiazide in essential hypertension. Am Heart J . 1985; 109(5 Part 2):1168-74. [PubMed 2859781]
185. de Soyza N, Shapiro W, Chandraratna PAN et al. Acebutolol therapy for ventricular arrhythmia: a randomized, placebo-controlled, double-blind multicenter study. Circulation . 1982; 65:1129-33. [PubMed 7042111]
186. Lui HK, Lee G, Dhurandhar R et al. Reduction of ventricular ectopic beats with oral acebutolol: a double-blind, randomized crossover study. Am Heart J . 1983; 105:722-6. [PubMed 6846115]
187. Burckhardt D, Raeder EA. The effect of acebutolol on cardiac arrhythmias in patients with chronic coronary artery disease. Am Heart J . 1980; 99:443-5. [PubMed 6102434]
188. Peretz DI, McMurtry TJ. Evaluation of the clinical effectiveness of acebutolol, a cardio-specific beta-adrenergic blocking agent, in the suppression of premature ventricular contractions. Curr Ther Res . 1979; 26:557-61.
189. Singh SN, DiBianco R, Davidov ME et al. Comparison of acebutolol and propranolol for treatment of chronic ventricular arrhythimia: a placebo-controlled, double-blind, randomized crossover study. Circulation . 1982; 65:1356-64. [PubMed 6176357]
190. Shapiro W, Park J, Koch GG. Variability of spontaneous and exercise-induced ventricular arrhythmias in the absence and presence of treatment with acebutolol or quinidine. Am J Cardiol . 1982; 49:445-54. [PubMed 6174041]
191. Labram C. Control of cardiac arrhythmias: the use of acebutolol. Clin Trials J . 1974; 3:115-20.
192. Williams DO, Tatelbaum R, Most AS. Effective treatment of supraventricular arrhythmias with acebutolol. Am J Cardiol . 1979; 44:521-5. [PubMed 382821]
193. Ahumada GG, Karlsberg RP, Jaffe AS et al. Reduction of early ventricular arrhythmia by acebutolol in patients with acute myocardial infarction. Br Heart J . 1979; 41:654-9. [PubMed 465240][PubMedCentral]
194. de Soyza N, Kane JJ, Murphy ML et al. The long-term suppression of ventricular arrhythmia by oral acebutolol in patients with coronary artery disease. Am Heart J . 1980; 100:631-8. [PubMed 6778183]
195. de Soyza N. Acebutolol for premature ventricular contractions: short- and long-term effects. Am Heart J . 1985; 109(5 Part 2):1205-9. [PubMed 3993536]
196. Khambatta RB. Clinical tachydysrhythmias: the effect of acebutolol (Sectral) on tachydysrhythmias in general and after myocardial infarction. Clin Trials J . 1971; 11:109-14.
197. Aronow WS, Turbow M, Lurie M et al. Treatment of premature ventricular complexes with acebutolol. Am J Cardiol . 1979; 43:106-8. [PubMed 758758]
198. Chandraratna PAN. Comparison of acebutolol with propranolol, quinidine, and placebo: results of three multicenter arrhythmia trials. Am Heart J . 1985; 109(5 Part 2):1198-204. [PubMed 3993535]
199. Glasser SP, Clark PI, Laddu AR. Comparison of the antiarrhythmic effects of acebutolol and propranolol in the treatment of ventricular arrhythmias. Am J Cardiol . 1983; 52:992-5. [PubMed 6195911]
200. Aronow WS, Van Camp S, Turbow M et al. Acebutolol in supraventricular arrhythmias. Clin Pharmacol Ther . 1979; 25:149-53. [PubMed 365429]
201. Aronow WS, Wong R, Plasencia G et al. Effect of acebutolol and propranolol on premature ventricular complexes. Clin Pharmacol Ther . 1980; 28:28-31. [PubMed 6993085]
202. Letac B. Treatment of cardiac arrhythmias: use of intravenous acebutolol. Clin Trials J . 1974; 11:105-8.
203. Gotsman MS, Lewis BS, Mitha AS. Acebutolol (Sectral) in the treatment of cardiac arrhythmias. Clin Trials J . 1974; 11:121-6.
204. Platia EV, Berdoff R, Stone G et al. Comparison of acebutolol and propranolol therapy for ventricular arrhythmias. J Clin Pharmacol . 1985; 25:130-7. [PubMed 2580866]
205. DiBianco R, Singh S, Singh JB et al. Effects of acebutolol on chronic stable angina pectoris: a placebo-controlled, double-blind, randomized crossover study. Circulation . 1980; 62:1179-87. [PubMed 6777070]
206. Lee G, DeMaria AN, Favrot L et al. Efficacy of acebutolol in chronic stable angina using single-blind and randomized double-blind protocol. J Clin Pharmacol . 1982; 22:371-8. [PubMed 6813360]
207. Tremblay G, Biron P, Proulx A. Acebutolol: efficacy of a single daily dose in angina pectoris. Curr Ther Res . 1979; 25:637-40.
208. Tremblay G, Biron P, Caille G et al. Double-blind crossover trial of single- versus twice-daily doses of acebutolol in angina. Curr Ther Res . 1981; 29:644-50.
209. Rod JL, Admon D, Kimchi A et al. Evaluation of the beta-blocking drug acebutolol in angina pectoris. Am Heart J . 1979; 98:604-12. [PubMed 495406]
210. Macdonald IL, Culbert PS, Robertson JW et al. A comparison study of acebutolol, a cardiospecific β-adrenergic blocker, and propranolol in the treatment of angina pectoris. Curr Ther Res . 1978; 24:470-8.
211. DiBianco R, Singh SN, Shah PM et al. Comparison of the antianginal efficacy of acebutolol and propranolol: a multicenter, randomized, double-blind placebo-controlled study. Circulation . 1982; 65:1119-28. [PubMed 6804109]
212. Ross MB, Levine P. A double-blind cross-over evaluation of acebutolol and propranolol in patients with angina pectoris. Curr Ther Res . 1981; 29:202-7.
213. Biron P, Tremblay G, Proulx A. Double-blind crossover comparison of acebutolol and propranolol in angina. Clin Pharmacol Ther . 1978; 23:109.
214. Rotem CE, Carruthers J, Byrne A. Long-term management of angina pectoris with acebutolol. Curr Ther Res . 1979; 26:562-7.
215. Frishman WH. β-Adrenoceptor antagonists: new drugs and new indications. N Engl J Med . 1981; 305:500-6. [PubMed 6114433]
216. Opie LH. Drugs and the heart. Lancet . 1980; 1:693-8. [PubMed 6103100]
217. Leonard RG, Talbert RL. Calcium-channel blocking agents. Clin Pharm . 1982; 1:17-33. [PubMed 6764159]
218. K.dtdberg RP. Calcium channel blockers for cardiovascular disorders. Arch Intern Med . 1982; 142:452-5.
219. Zelis R. Calcium-blocker therapy for unstable angina pectoris. N Engl J Med . 1982; 306:926-8. [PubMed 6121290]
220. Biron P, Tremblay G. Differential antianginal responsiveness to acebutolol. Eur J Clin Pharmacol . 1975; 8:15-9. [PubMed 786672]
221. Kimchi A, Gotsman MS, Lewis BS. Acebutolol in angina pectoris: objective assessment using graded treadmill testing. Isr J Med Sci . 1978; 14:941-7. [PubMed 363642]
222. Gotsman MS, Lewis BS. The treatment of angina pectoris: an objective assessment of oral acebutolol (Sectral). Clin Trials J . 1974; 11(Suppl 3):80-5.
223. Pfisterer M, Muller-Brand J, Burkart F. Combined acebutolol/nifedipine therapy in patients with chronic coronary artery disease: additional improvement of ischemia-induced left ventricular dysfunction. Am J Cardiol . 1982; 49:1259-66. [PubMed 7064850]
224. Steele P, Gold F. Favorable effects of acebutolol on exercise performance and angina in men with coronary artery disease. Chest . 1982; 82:40-3. [PubMed 7044708]
225. De Ponti C, De Biase AM, Cataldo G et al. Effects of nifedipine, acebutolol, and their association on exercise tolerance in patients with effort angina. Cardiology . 1981; 68(Suppl 2):195-9. [PubMed 7032697]
226. Geigy Pharmaceuticals. Lopressor® prescribing information. In: Huff BB, ed. Physicians' desk reference. 41st ed. Oradell, NJ: Medical Economics Company Inc; 1987:956-60.
227. Booth RJ, Wilson JD, Bullock JY. β-Adrenergic-receptor blockers and antinuclear antibodies in hypertension. Clin Pharmacol Ther . 1982; 31:555-63. [PubMed 6122525]
228. Akoun GM, Herman DP, Mayaud CM et al. Acebutolol-induced hypersensitivity pneumonitis. BMJ . 1983; 286:266-7. [PubMed 6402066][PubMedCentral]
229. Akoun GM, Mayaud CM, Milleron BJ et al. Drug-related pneumonitis and drug-induced hypersensitivity pneumonitis. Lancet . 1984; 1:1362. [PubMed 6145066]
230. Cody RJ Jr, Calabrese LH, Clough JD et al. Development of antinuclear antibodies during acebutolol therapy. Clin Pharmacol Ther . 1979; 25:800-5. [PubMed 87291]
231. Tirlapur VG, Evans PJ, Jones MK. Shock syndrome after acebutolol. Br J Clin Pract . 1986; 40:33-4. [PubMed 3707825]
232. Piette JC, Bourgeois P, Herson S et al. Acebutolol-induced lupus (AIL). Arthritis Rheum . 1985; 28(Suppl 4S):S52.
233. Record NB Jr. Acebutolol-induced pleuropulmonary lupus syndrome. Ann Intern Med . 1981; 95:326-7. [PubMed 6973944]
234. Wood GM, Bolton RP, Muers MF et al. Pleurisy and pulmonary granulomas after treatment with acebutolol. BMJ . 1982; 285:936. [PubMed 6811073][PubMedCentral]
235. Leggett RJE. Pleurisy and pulmonary granulomas after treatment with acebutolol. BMJ . 1982; 285:1425.
236. Lyall MG, Bainbridge JG, Khambatta RB. Ophthalmological monitoring of patients receiving long-term acebutolol. Br J Clin Pharmacol . 1983; 16:574-6. [PubMed 6639845][PubMedCentral]
237. Welsh N, Leary WP, Van Der Byl K. Acebutolol: prolonged administration without ophthalmological complications. Curr Ther Res . 1983; 33:611-5.
238. Martin DE, Kammerer WS. The hypertensive surgical patient: controversies in management. Surg Clin North Am . 1983; 63:1017-33. [PubMed 6138862]
239. Dumez Y, Chobroutsky C, Hornych H et al. Neonatal effects of maternal administration of acebutolol. BMJ . 1981; 283:1077-9. [PubMed 6794766][PubMedCentral]
240. Williams ER, Morrissey JR. A comparison of acebutolol with methyldopa in hypertensive pregnancy. Pharmatherapeutica . 1983; 3:487-91. [PubMed 6669592]
241. Dubois D, Petitcolas J, Temperville B et al. Treatment of hypertension in pregnancy with β-adrenoceptor antagonists. Br J Clin Pharmacol . 1982; 13(Suppl):375-8S. [PubMed 7059437][PubMedCentral]
242. Lewis M, Kallenbach J, Germond C et al. Survival following massive overdose of adrenergic blocking agents (acebutolol and labetalol). Eur Heart J . 1983; 4:328-32. [PubMed 6617679]
243. Sangster B, de Wildt D, van Dijk A. A case of acebutolol intoxication. J Toxicol Clin Toxicol . 1983; 20:69-77. [PubMed 6887301]
244. Zaman R, Kendall MJ. The effect of acebutolol and propranolol on the hypoglycaemic action of glibenclamide. Br J Clin Pharmacol . 1982; 13:507-12. [PubMed 6802160][PubMedCentral]
245. Ashton WL. An open, multicentre study of acebutolol, given as a single daily dose, in the management of hypertension. Curr Med Res Opin . 1977; 5:279-83. [PubMed 162667]
246. Ashton WL. Acebutolol (400 mg) given as a single daily dose to hypertensive patients previously stabilized on 400 mg acebutolol daily in divided doses: an open multicentre study. Curr Med Res Opin . 1978; 5:347-53.
247. Watson RDS, Stallard TJ, Littler WA. Comparison of once and twice daily administration of acebutolol in hypertension. Br J Clin Pharmacol . 1980; 9:209-12. [PubMed 6766731][PubMedCentral]
248. Frick MH, Kala R. Antiarrhythmic significance of dosing intervals in beta receptor blocking therapy of hypertension with acebutolol. Am J Cardiol . 1981; 48:911-6. [PubMed 6118059]
249. Klug E, Schneider V. Todliche Vergiftung mit Acebutolol (Prent). (German; with English abstract.) Z Rechtsmed . 1979; 83:325-30.
250. Beyer H, Blank P, Kelch L et al. Letale Vergiftung mit Acebutolol. (German; with English abstract.) Intensivmed Prax . 1981; 18:83-5.
251. Cruickshank JM. The clinical importance of cardioselectivity and lipophilicity in beta blockers. Am Heart J . 1980; 100:160-78. [PubMed 6105819]
252. Woods PB, Robinson ML. An investigation of the comparative liposolubilities of β-adrenoceptor blocking agents. J Pharm Pharmacol . 1981; 33:172-3. [PubMed 6116760]
253. The United States pharmacopeia, 24th rev, and The national formulary, 19th ed. Rockville, MD: The United States Pharmacopeial Convention, Inc; 2000:15.
254. Bigger JT Jr, Hoffman BF. Antiarrhythmic drugs. In: Gilman AG, Goodman LS, Rall TW et al, eds. Goodman and Gilman's the pharmacological basis of therapeutics. 7th ed. New York: Macmillan Publishing Company; 1985:748-83.
255. Chatterji AN. A randomized crossover comparison of acebutolol and methyldopa in the treatment of mild to moderate essential hypertension. Curr Med Res Opin . 1978; 5:675-81. [PubMed 367712]
256. Anon. Drugs for cardiac arrhythmias. Med Lett Drugs Ther . 1986; 28:111-6. [PubMed 2878351]
257. Gosselin RE, Smith RP, Hodge HC. Clinical toxicology of commercial products. 5th ed. Baltimore: Williams & Wilkins; 1984:I-8.
258. Frishman W, Jacob H, Eisenberg E et al. Clinical pharmacology of the new β-adrenergic blocking drugs. Part 8. Self-poisoning with beta-adrenoceptor blocking agents: recognition and management. Am Heart J . 1979; 98:798-811. [PubMed 40429]
259. Weinstein RS. Recognition and management of poisoning with beta-adrenergic blocking agents. Ann Emerg Med . 1984; 13:1123-31. [PubMed 6150667]
260. Anon. Beta-blocker poisoning. Lancet . 1980; 1:803-4.
261. Machin PJ, Hurst DN, Bradshaw RN et al. β-Selective adrenoceptor antagonists. Part 2: 4-ether-linked phenoxypropanolamines. J Med Chem . 1983; 26:1570-6. [PubMed 6138435]
262. Broadhurst AD. Comparison of effect on psychomotor performance of single doses of propranolol and acebutolol. Curr Med Res Opin . 1980; 7:33-8. [PubMed 7428410]
263. Kayed K, Godtlibsen OB. Central effects of the β-adrenergic blocking agent acebutolol: a quantitative EEG study using normalised slope descriptors. Eur J Clin Pharmacol . 1977; 12:327-31. [PubMed 598404]
264. Kayed K, Godtlibsen OB. Effects of the β-adrenoceptor antagonists acebutolol and metoprolol on sleep pattern in normal subjects. Eur J Clin Pharmacol . 1977; 12:323-6. [PubMed 598403]
265. Lewis MJ, Jones DM, Dart AM et al. The psychological side effects of acebutolol and atenolol. Br J Clin Pharmacol . 1984; 17:364-6. [PubMed 6712870][PubMedCentral]
266. Lewis BS, Mitha AS, Gotsman MS. Acebutolol in cardiac arrhythmias. S Afr Med J . 1974; 4:821-4.
267. Booth RJ, Bullock JY, Wilson JD. Antinuclear antibodies in patients on acebutolol. Br J Clin Pharmacol . 1980; 9:515-7. [PubMed 6104977][PubMedCentral]
268. Wilson FS (Wyeth Laboratories Inc, Philadelphia, PA): Personal communication; 1987.
269. Anon. Choice of a beta-blocker. Med Lett Drugs Ther . 1986; 28:20-2. [PubMed 2869400]
270. Wallin JD, Shah SV. β-Adrenergic blocking agents in the treatment of hypertension: choices based on pharmacological properties and patient characteristics. Arch Intern Med . 1987; 147:654-9. [PubMed 2881524]
271. McDevitt DG. β-Adrenoceptor blocking drugs and partial agonist activity: is it clinically relevant? Drugs . 1983; 25:331-8.
272. McDevitt DG. Clinical significance of cardioselectivity: state-of-the-art. Drugs . 1983; 25(Suppl 2):219-26.
273. Frishman WH. β-Adrenoceptor antagonists: new drugs and new indications. N Engl J Med . 1981; 305:500-6. [PubMed 6114433]
274. Thadani U, Davidson C, Chir B et al. Comparison of the immediate effects of five β-adrenoceptor-blocking drugs with different ancillary properties in angina pectoris. N Engl J Med . 1979; 300:750-5. [PubMed 581782]
275. Lewis RV, McDevitt DG. Adverse reactions and interactions with β-adrenoceptor blocking drugs. Med Toxicol . 1986; 1:343-61. [PubMed 2878346]
276. Bradberry JC. Discontinuing β blockers. Clin Pharm . 1984; 3:457,460.
277. Reviewers' comments (personal observations); 1987.
278. Frishman WH. Clinical differences between beta-adrenergic blocking agents: implications for therapeutic substitution. Am Heart J . 1987; 113:1190-8. [PubMed 2883867]
279. Abengowe CU, Rehan N. Acebutolol in the treatment of hypertension in African patients. Curr Ther Res . 1987; 41:737-45.
280. 1988 Joint National Committee. The 1988 report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med . 1988; 148:1023-38. [PubMed 3365073]
281. Tanner LA, Bosco LA, Zimmerman HJ. Hepatic toxicity after acebutolol therapy. Am Intern Med . 1989; 111:533-4.
282. Webster J. Interactions of NSAIDs with diuretics and β-blockers: mechanisms and clinical implications. Drugs . 1985; 30:32-41. [PubMed 2863124]
283. Radack KL, Deck CC, Bloomfield SS. Ibuprofen interferes with the efficacy of antihypertensive drugs: a randomized, double-blind, placebo-controlled trial of ibuprofen compared with acetaminophen. Ann Intern Med . 1987; 107:628-35. [PubMed 2889416]
284. Watkins J, Abbott EC, Hensby CN et al. Attenuation of hypotensive effects of propranolol and thiazide diuretics by indomethacin. Br Med J . 1980; 281:702-5. [PubMed 7427409][PubMedCentral]
285. Mills EH, Whitworth JA, Andrews J et al. Non-steroidal anti-inflammatory drugs and blood pressure. Aust N Z J Med . 1982; 12:478-82. [PubMed 6758745]
286. Durao V, Prata MM, Goncalves LMP. Modification of antihypertensive effect of β-adrenoreceptor-blocking agents by inhibition of endogenous prostaglandin synthesis. Lancet . 1977; 2:1005-7. [PubMed 72901]
287. Salvetti A, Arzilli F, Pedrinelli R et al. Interaction between oxprenolol and indomethacin on blood pressure in essential hypertensive patients. Eur J Clin Pharmacol . 1982; 22:197-201. [PubMed 7049707]
288. Beta blockers/NSAIDs. In: Tatro DS, Olin BR, eds. Drug interaction facts. St. Louis: JB Lippincott Co; 1989: 154.
289. Boissel JP, Lezorovicz A, Picolet H et al. Efficacy of acebutolol after acute myocardial infarction (the APSI Trial). Am J Cardiol . 1990; 66:24-31C.
290. Boissel JP, Leizorovicz A, Picolet H et al. Secondary prevention after high-risk acute myocardial infarction with low-dose acebutolol. Am J Cardiol . 1990; 66:251-60. [PubMed 2195860]
291. De Backer G. Multicentre study of the efficacy and tolerance of acebutolol versus atenolol in the long term treatment of mild arterial hypertension. Drugs . 1988; 36(Suppl 2):51-6. [PubMed 3063506]
292. Clucas A, Miller N. Effects of acebutolol on the serum lipid profile. Drugs . 1988; 36(Suppl 2):41-50. [PubMed 3063505]
293. Reviewers' comments (personal observations).
294. American College of Cardiology and American Heart Association. ACC/AHA guidelines for the early management of patients with acute myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Assessment of Diagnostic and Therapeutic Cardiovascular Procedures (Subcommittee to Develop Guidelines for the Early Management of Patients with Acute Myocardial Infarction). Circulation . 1990; 82:664-707. [PubMed 2197021]
295. Goldman L, Sia STB, Cook EF et al. Costs and effectiveness of routine therapy with long-term beta-adrenergic antagonists after acute myocardial infarction. N Engl J Med . 1988; 319:152-7. [PubMed 2898733]
296. Yusuf S, Peto R, Lewis J et al. Beta blockade during and after myocardial infarction: an overview of the randomized trials. Prog Cardiovasc Dis . 1985; 27:335-71. [PubMed 2858114]
297. Pedersen TR for the Norwegian Multicenter Study Group. Six-year follow-up of the Norwegian multicenter study on timolol after acute myocardial infarction. N Engl J Med . 1985; 313:1055-8. [PubMed 2864634]
298. Frishman WH, Furberg CD, Friedewald WT. β-Adrenergic blockade for survivors of acute myocardial infarction. N Engl J Med . 1984; 310:830-7. [PubMed 6142420]
299. Furberg CD. Secondary prophylaxis after acute myocardial infarction. Am J Cardiol . 1987; 60:28-32A. [PubMed 3604941]
300. Australian and Swedish Pindolol Study Group. The effect of pindolol on the two years mortality after complicated myocardial infarction. Eur Heart J . 1983; 4:367-75. [PubMed 6617682]
301. Schroder R. Oxprenolol in myocardial infarction survivors: brief review of the European infarction study results in light of other beta-blocker postinfarction trials. Z Kardiol . 1985; 74(Suppl 6):165-72. [PubMed 2869616]
302. European Infarction Study Group. European infarction study (E.I.S.): a secondary prevention study with slow release oxprenolol after myocardial infarction: morbidity and mortality. Eur Heart J . 1984; 5:189-202. [PubMed 6373264]
303. Taylor SH, Silke B, Ebbutt A et al. A long-term prevention study with oxprenolol in coronary heart disease. N Engl J Med . 1982; 307:1293-1301. [PubMed 6752712]
305. Wyeth-Ayerst Laboratories, Radnor, PA: Personal communication.
307. Weber MA, Laragh JH. Hypertension: steps forward and steps backward: the Joint National Committee fifth report. Arch Intern Med . 1993; 153:149-52. [PubMed 8422205]
308. Collins R, Peto R, MacMahon S et al. Blood pressure, stroke, and coronary heart disease. Part 2, short-term reductions in blood pressure: an overview of randomized drug trials in their epidemiological context. Lancet . 1990; 335:827-38. [PubMed 1969567]
309. Alderman MH. Which antihypertensive drugs first—and why! JAMA . 1992; 267:2786-7. Editorial.
310. MacMahon S, Peto R, Cutler J et al. Blood pressure, stroke, and coronary heart disease. Part 1, prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias. Lancet . 1990; 335:765-74. [PubMed 1969518]
311. SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension: final results of the Systolic Hypertension in the Elderly Program (SHEP). JAMA . 1991; 265:3255-64. [PubMed 2046107]
312. Dahlof B, Lindholm LH, Hansson L et al. Morbidity and mortality in the Swedish Trial in Old Patients with Hypertension (STOP-hypertension). Lancet . 1991; 338:1281-5. [PubMed 1682683]
313. MRC Working Party. Medical Research Council trial of treatment of hypertension in older adults: principal results. BMJ . 1992; 304:405-12. [PubMed 1445513][PubMedCentral]
314. National Heart, Lung, and Blood Institute. NHLBI panel reviews safety of calcium channel blockers. Rockville, MD; 1995 Aug 31. Press release.
315. National Heart, Lung, and Blood Institute. New analysis regarding the safety of calcium-channel blockers: a statement for health professionals from the National Heart, Lung, and Blood Institute. Rockville, MD; 1995 Sep 1.
316. Psaty BM, Heckbert SR, Koepsell TD et al. The risk of myocardial infarction associated with antihypertensive drug therapies. JAMA . 1995; 274:620-5. [PubMed 7637142]
317. Yusuf S. Calcium antagonists in coronary artery disease and hypertension: time for reevaluation? Circulation . 1995; 92:1079-82. Editorial.
318. Roche. Posicor® (mibefradil hydrochloride) tablets prescribing information. Nutley, NJ; 1997 Dec.
319. Ellison RH. Dear doctor letter regarding appropriate use of Posicor®. Nutley, NJ: Roche Laboratories; 1997 Dec.
320. Sidmak Laboratories. Verapamil hydrochloride tablets prescribing information. East Hanover, NJ; 1996 Apr.
321. National Heart, Lung, and Blood Institute National High Blood Pressure Education Program. The sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI). Bethesda, MD: National Institutes of Health; 1997 Nov. (NIH publication No. 98-4080.)
322. Kaplan NM. Choice of initial therapy for hypertension. JAMA . 1996; 275:1577-80. [PubMed 8622249]
323. Psaty BM, Smith NL, Siscovich DS et al. Health outcomes associated with antihypertensive therapies used as first-line agents: a systematic review and meta-analysis. JAMA . 1997; 277:739-45. [PubMed 9042847]
324. Whelton PK, Appel LJ, Espeland MA et al. for the TONE Collaborative Research Group. Sodium reduction and weight loss in the treatment of hypertension in older persons: a randomized controlled trial of nonpharmacologic interventions in the elderly (TONE). JAMA . 1998; 279:839-46. [PubMed 9515998]
326. Genuth P. United Kingdom prospective diabetes study results are in. J Fam Pract . 1998; 47:(Suppl 5):S27.
328. Watkins PJ. UKPDS: a message of hope and a need for change. Diabet Med . 1998; 15:895-6. [PubMed 9827842]
329. Bretzel RG, Voit K, Schatz H et al. The United Kingdom Prospective Diabetes Study (UKPDS): implications for the pharmacotherapy of type 2 diabetes mellitus. Exp Clin Endocrinol Diabetes . 1998; 106:369-72. [PubMed 9831300]
330. Tatti P, Pahor M, Byington RP et al. Outcome results of the fosinopril versus amlodipine cardiovascular events randomized trial (FACET) in patients with hypertension and NIDDM. Diabetes Care . 1998; 21:597-603. [PubMed 9571349]
331. American Diabetes Association. The United Kingdom Prospective Diabetes Study (UKPDS) for type 2 diabetes: what you need to know about the results of a long-term study. Washington, DC; 1998 Sep 15 from American Diabetes Association web site. [Web]
332. UK Prospective Diabetes Study Group. Efficacy of atenolol and captopril in reducing risk of macrovascular complications in type 2 diabetes: UKPDS 39. BMJ . 1998; 317:713-20. [PubMed 9732338][PubMedCentral]
333. Davis TME. United Kingdom Prospective Diabetes Study: the end of the beginning? Med J Aust . 1998; 169:511-2.
335. Anon. Consensus recommendations for the management of chronic heart failure. On behalf of the membership of the advisory council to improve outcomes nationwide in heart failure. Part II. Management of heart failure: approaches to the prevention of heart failure. Am J Cardiol . 1999; 83:9A-38A.
336. Lim PO, MacDonald TM. Antianginal and β-adrenergic blocking drugs. In: Dukes MNG, ed. Meyler's side effects of drugs. 13th ed. New York: Elsevier/North Holland Inc; 1996:488-535.
337. Gress TW, Nieto FJ, Shahar E et al. Hypertension and antihypertensive therapy as risk factors for type 2 diabetes mellitus. N Engl J Med . 2000; 342:905-12. [PubMed 10738048]
338. Sowers JR, Bakris GL. Antihypertensive therapy and the risk of type 2 diabetes mellitus. N Engl J Med . 2000; 342:969-70. [PubMed 10738057]
339. Izzo JL, Levy D, Black HR. Importance of systolic blood pressure in older Americans. Hypertension . 2000; 35:1021-4. [PubMed 10818056]
340. Frohlich ED. Recognition of systolic hypertension for hypertension. Hypertension . 2000; 35:1019-20. [PubMed 10818055]
341. Bakris GL, Williams M, Dworkin L et al. Preserving renal function in adults with hypertension and diabetes: a consensus approach. Am J Kidney Dis . 2000; 36:646-61. [PubMed 10977801]
342. Hansson L, Zanchetti A, Carruthers SG et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet . 1998; 351:1755-62. [PubMed 9635947]
345. Fuster V, Ryden LE, Asinger RW et al. ACC/AHA/ESC guidelines for the management of atrial fibrillation. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines and Policy Conferences (Committee to Develop Guidelines for the Management of Patients with Atrial Fibrillation). J Am Coll Cardiol . 2001; 38:1266i-lxx.
347. Ryan TJ, Antman EM, Brooks NH et al. ACC/AHA guidelines for the management of patients with acute myocardial infarction: 1999 update: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction). Circulation . 1999; 100(9):1016-30. [PubMed 10468535]
348. ACC/AHA guidelines for the management of patients with chronic stable angina: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1999 Guidelines for the Management of Chronic Stable Angina). 2002. Available from ACC website. Accessed 2003 Feb 13. [Web]
349. Williams CL, Hayman LL, Daniels SR et al. Cardiovascular health in childhood: a statement for health professional from the Committee on Atherosclerosis, Hypertension, and Obesity in the Young (AHOY) of the Council on Cardiovascular Disease in the Young, American Heart Association. Circulation . 2002; 106:143-60. [PubMed 12093785]
350. Braunwald E, Antman EM, Beasley JW et al. ACC/AHA 2002 guideline update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients with Unstable Angina). Circulation . 2002; 106(14):1893-900. [PubMed 12356647]
352. Appel LJ. The verdict from ALLHAT—thiazide diuretics are the preferred initial therapy for hypertension. JAMA . 2002; 288:3039-60. [PubMed 12479770]
353. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA . 2002; 288:2981-97. [PubMed 12479763]
355. Douglas JG, Bakris GL, Epstein M et al. Management of high blood pressure in African Americans: Consensus statement of the Hypertension in African Americans Working Group of the International Society on Hypertension in Blacks. Arch Intern Med. 2003; 163:525-41.
357. The Guidelines Subcommitee of the WHO/ISH Mild Hypertension Liaison Committee. 1999 guidelines for the management of hypertension. J Hypertension . 1999; 17:392-403.
359. Wright JT, Dunn JK, Cutler JA et al. Outcomes in hypertensive black and nonblack patients treated with chlorthalidone, amlodipine, and lisinopril. JAMA . 2005; 293:1595-607. [PubMed 15811979]
360. Neaton JD, Kuller LH. Diuretics are color blind. JAMA . 2005; 293:1663-6. [PubMed 15811986]
361. Dahlof B, Devereux RB, Kjeldsen SE, et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint Reduction in Hypertension Study (LIFE): a randomised trial against atenolol. Lancet . 2002;359:995-1003. [PubMed 11937178]
500. National Heart, Lung, and Blood Institute National High Blood Pressure Education Program. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7). Bethesda, MD: National Institutes of Health; 2004 Aug. (NIH publication No. 04-5230.)
501. James PA, Oparil S, Carter BL et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA . 2014; 311:507-20. [PubMed 24352797]
502. Mancia G, Fagard R, Narkiewicz K et al. 2013 ESH/ESC Guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens . 2013; 31:1281-357. [PubMed 23817082]
503. Go AS, Bauman MA, Coleman King SM et al. An effective approach to high blood pressure control: a science advisory from the American Heart Association, the American College of Cardiology, and the Centers for Disease Control and Prevention. Hypertension . 2014; 63:878-85. [PubMed 24243703]
504. Weber MA, Schiffrin EL, White WB et al. Clinical practice guidelines for the management of hypertension in the community: a statement by the American Society of Hypertension and the International Society of Hypertension. J Clin Hypertens (Greenwich) . 2014; 16:14-26. [PubMed 24341872]
505. Wright JT, Fine LJ, Lackland DT et al. Evidence supporting a systolic blood pressure goal of less than 150 mm Hg in patients aged 60 years or older: the minority view. Ann Intern Med . 2014; 160:499-503. [PubMed 24424788]
506. Mitka M. Groups spar over new hypertension guidelines. JAMA . 2014; 311:663-4. [PubMed 24549531]
507. Peterson ED, Gaziano JM, Greenland P. Recommendations for treating hypertension: what are the right goals and purposes?. JAMA . 2014; 311:474-6. [PubMed 24352710]
508. Bauchner H, Fontanarosa PB, Golub RM. Updated guidelines for management of high blood pressure: recommendations, review, and responsibility. JAMA . 2014; 311:477-8. [PubMed 24352759]
515. Thomas G, Shishehbor M, Brill D et al. New hypertension guidelines: one size fits most?. Cleve Clin J Med . 2014; 81:178-88. [PubMed 24591473]
523. Fihn SD, Gardin JM, Abrams J et al. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. Circulation . 2012; 126:e354-471.
524. WRITING COMMITTEE MEMBERS, Yancy CW, Jessup M et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation . 2013; 128:e240-327.
526. Kernan WN, Ovbiagele B, Black HR et al. Guidelines for the Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke . 2014; :. [PubMed 24788967]
527. O'Gara PT, Kushner FG, Ascheim DD et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation . 2013; 127:e362-425. [PubMedCentral]
530. Myers MG, Tobe SW. A Canadian perspective on the Eighth Joint National Committee (JNC 8) hypertension guidelines. J Clin Hypertens (Greenwich) . 2014; 16:246-8. [PubMed 24641124]
536. Kidney Disease: Improving Global Outcomes (KDIGO) Blood Pressure Work Group. KDIGO clinical practice guideline for the management of blood pressure in chronic kidney disease. Kidney Int Suppl . 2012: 2: 337-414.
800. Yancy CW, Jessup M, Bozkurt B et al. 2016 ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Heart Failure: An Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. Circulation . 2016; :.
1200. Whelton PK, Carey RM, Aronow WS et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension . 2018; 71:el13-e115. [PubMed 29133356]
1201. Bakris G, Sorrentino M. Redefining hypertension - assessing the new blood-pressure guidelines. N Engl J Med . 2018; 378:497-499. [PubMed 29341841]
1202. Carey RM, Whelton PK, 2017 ACC/AHA Hypertension Guideline Writing Committee. Prevention, detection, evaluation, and management of high blood pressure in adults: synopsis of the 2017 American College of Cardiology/American Heart Association hypertension guideline. Ann Intern Med . 2018; 168:351-358. [PubMed 29357392]
1207. Burnier M, Oparil S, Narkiewicz K et al. New 2017 American Heart Association and American College of Cardiology guideline for hypertension in the adults: major paradigm shifts, but will they help to fight against the hypertension disease burden?. Blood Press . 2018; 27:62-65. [PubMed 29447001]
1209. Qaseem A, Wilt TJ, Rich R et al. Pharmacologic treatment of hypertension in adults aged 60 years or older to higher versus lower blood pressure targets: a clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians. Ann Intern Med . 2017; 166:430-437. [PubMed 28135725]
1210. SPRINT Research Group, Wright JT, Williamson JD et al. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med . 2015; 373:2103-16. [PubMed 26551272]
1216. Taler SJ. Initial treatment of hypertension. N Engl J Med . 2018; 378:636-644. [PubMed 29443671]
1220. Cifu AS, Davis AM. Prevention, detection, evaluation, and management of high blood pressure in adults. JAMA . 2017; 318:2132-2134. [PubMed 29159416]
1222. Bell KJL, Doust J, Glasziou P. Incremental benefits and harms of the 2017 American College of Cardiology/American Heart Association high blood pressure guideline. JAMA Intern Med . 2018; 178:755-7. [PubMed 29710197]
1223. LeFevre M. ACC/AHA hypertension guideline: what is new? what do we do?. Am Fam Physician . 2018; 97(6):372-3. [PubMed 29671534]
1224. Brett AS. New hypertension guideline is released. From NEJM Journal Watch website. Accessed 2018 Jun 18. [Web]
1229. Ioannidis JPA. Diagnosis and treatment of hypertension in the 2017 ACC/AHA guidelines and in the real world. JAMA . 2018; 319(2):115-6. [PubMed 29242891]
1235. Mann SJ. Redefining beta-blocker use in hypertension: selecting the right beta-blocker and the right patient. J Am Soc Hypertens . 2017; 11(1):54-65. [PubMed 28057444]