Drugs

, Volume 42, Issue 3, pp 468–510 | Cite as

Atenolol

A Reappraisal of its Pharmacological Properties and Therapeutic Use in Cardiovascular Disorders
  • Alison N. Wadworth
  • David Murdoch
  • Rex N. Brogden
Drug Evaluation

Summary

Synopsis

Atenolol is a selective β1-adrenoceptor antagonist with a duration of activity of at least 24 hours. The scope of therapeutic use of the drug has been expanded and become better defined since it was first reviewed in the Journal in 1979.

Atenolol is effective and generally well tolerated in patients with all grades of hypertension. Data from comparative studies show that when administered orally, atenolol reduces blood pressure to a similar extent, and in a similar proportion of patients, as usual therapeutic doses of other β- adrenoceptor antagonists (such as acebutolol, celiprolol, betaxolol, indenolol, metoprolol, nadolol, pindolol, propranolol, tertatolol), angiotensin converting enzyme (ACE) inhibitors (e.g. captopril, enalapril and lisinopril), calcium antagonists (e.g. amlodipine, diltiazem, felodipine, isradipine, nitrendipine, nifedipine, verapamil), doxazosin, ketanserin and α-methyldopa. Atenolol effectively lowers blood pressure in elderly patients with hypertension and in women with hypertension associated with pregnancy, and improves objective and subjective indices in patients with stable angina pectoris. Oral atenolol is used for preventing recurrence of supraventricular arrhythmias once control is achieved by intravenous administration of atenolol. Early intervention with intravenous atenolol followed by oral maintenance therapy reduces infarct recurrence and cardiovascular mortality in patients with known or suspected myocardial infarction. There is also encouraging evidence of reduced mortality from cardiovascular disease during long term therapy with atenolol in patients with hypertension.

Atenolol is well tolerated in most patients. Increases in plasma levels of both total triglycerides and very low density lipoprotein (VLDL) triglycerides have accompanied atenolol therapy although the clinical relevance, if any, of longer term metabolic effects has yet to be determined. Its low lipid solubility and limited brain penetration results in a lower incidence of central nervous system effects than that associated with propranolol.

After many years of clinical usage atenolol is a well established treatment option in several areas of cardiovascular medicine such as mild to moderate hypertension and stable angina pectoris. Furthermore, it has also shown potential in the treatment of some cardiac arrhythmias and has been associated with reduced cardiovascular mortality in patients with hypertension and in patients with myocardial infarction.

Pharmacodynamic Properties

Atenolol is a selective and long acting β1-adrenoceptor antagonist. In patients with hypertension, oral administration of atenolol significantly reduces resting systolic and diastolic blood pressures and attenuates the blood pressure increase induced by exercise. In some studies, long term administration of atenolol 50 to 100mg daily improved left ventricular hypertrophy when present before treatment. In patients with coronary artery disease the antihypertensive effects of atenolol are accompanied by reductions in heart rate (8 to 34%) and rate-pressure product (9 to 40%). Atenolol improves indices of oxygen consumption in patients with acute myocardial infarction. Short or long term administration of atenolol 50 to 100mg daily reduces blood pressure in pregnant women.

Although impaired glucose tolerance and increased insulin resistance have been reported in some patients treated with atenolol, improved glucose tolerance has been reported in others. Increases in plasma total triglycerides and very low density lipoprotein triglycerides, and decreases in high density lipoprotein cholesterol generally occur after several months’ treatment with atenolol, but these changes are less pronounced than those associated with propranolol and a trend towards a reduction in effect has been noted during long term administration.

Atenolol 50 to 125mg impairs respiratory function in asthmatic patients, following single or multiple doses, to a lesser extent than propranolol, and does not significantly decrease the bronchodilatation effect of inhaled salbutamol during short or long term treatment.

Pharmacokinetic Properties

Following oral administration, about 50 to 60% of an atenolol dose is absorbed with maximum plasma concentrations reached within 2 to 4 hours. Atenolol is widely distributed in the body (although only a small proportion of an administered dose reaches the brain), and readily crosses the placenta. In adult patients with normal renal function the elimination half-life is about 5 to 7 hours and total clearance is about 6 L/h (100 ml/min) per 1.73m2. A shorter elimination half-life (4.5 hours) has been observed in children. However, there are wide intra- and interindividual differences in the pharmacokinetic properties of atenolol. Most absorbed atenolol is excreted unchanged in the urine. Accumulation into breast milk has been reported but plasma concentrations are negligible in infants. In patients with renal dysfunction the elimination rate is decreased and is related to glomerular filtration rate.

Therapeutic Efficacy

During long term follow-up trials with atenolol, generally 50 to 100mg once daily alone or in combination with a diuretic, goal blood pressures are achieved in about two-thirds of all patients with mild to moderate hypertension. The greatest reductions in blood pressure occur in the first 2 weeks of treatment, and blood pressure remains within normal limits during extended therapy without major adjustment of dosage.

Atenolol 50 to lOOmg daily is clearly more effective than placebo in reducing blood pressure, and in comparative trials it reduced blood pressure in a similar proportion of patients, and to a similar extent, as usual therapeutic doses of other β-adrenoceptor antagonists (acebutolol, celiprolol, betaxolol, indenolol, SR metoprolol, nadolol, SR pindolol, SR propranolol, tertatolol), ACE inhibitors [captopril (100mg), enalapril (20 to 40mg) and lisinopril (20 to 80mg)], calcium antagonists [amlodipine (2.5 to 10mg), diltiazem (240 to 360mg), felodipine (10 to 20mg), isradipine (5 to 20mg), SR nifedipine (20 to 40mg), SR verapamil (240mg) and nitrendipine (20 to 40mg)], doxazosin 1 to 16mg, ketanserin 40 to 80mg and α-methyldopa 1500mg daily. Elderly patients and women with hypertension associated with pregnancy respond well to treatment with atenolol 50 and 50 to 200mg daily, respectively.

In patients with stable angina pectoris, oral atenolol 100mg daily was superior to placebo and at least as effective as usual therapeutic doses of other antianginal agents in reducing the severity and frequency of anginal attacks, reducing glyceryl trinitrate consumption, improving exercise duration, and extending time to lmm ST-segment depression. Atenolol appears to eliminate the morning ischaemic episode peak in patients with silent ischaemia.

In patients with hypertension, with or without evidence of ischaemia, long term atenolol therapy reduced the mortality from myocardial infarction or stroke. In addition, early initiation of atenolol therapy reduced the incidence of both vascular mortality and the occurrence of non-fatal cardiac arrests and reinfarction in patients with suspected myocardial infarction.

Preliminary investigation in patients with paroxysmal supraventricular tachycardia revealed that atenolol reduced the occurrence of supraventricular tachycardia in up to 70% of patients. This benefit was maintained during long term follow-up and atenolol improved the clinical course of patients with sustained paroxysmal reciprocating supraventricular tachycardia. Following coronary artery surgery, orally administered atenolol was significantly superior to placebo in reducing the incidence of supraventricular arrhythmias and atrial fibrillation. Control of ventricular arrhythmias has also been achieved using oral atenolol therapy.

Tolerability

The most frequently reported adverse effects experienced during oral atenolol therapy for hypertension, angina pectoris and arrhythmias are bradycardia (0.6 to 10%), cold extremities/ Raynaud’s phenomenon (2 to 35%), gastrointestinal symptoms (0.5 to 32%), fatigue/weakness (1 to 51%), nightmares/sleep disturbances (6 to 26%), headache (1 to 18%), and sexual disturbances (1 to 14%). In general these effects were mild, occurred more frequently during baseline phases, usually become less frequent with continued therapy and, in most studies, necessitated withdrawal of treatment from only 3 to 6% of patients. Data from comparative studies suggest that the tolerability profile of atenolol is similar to that of other antihypertensive agents although the pattern of effects differed between drug classes. Both hypotension and bradycardia have been observed after intravenous administration of atenolol in patients with myocardial infarction. Atenolol therapy has not been associated with ophthalmological changes or clinically significant changes in haematological or biochemical indices.

Dosage and Administration

Most patients with hypertension respond to once daily oral administration of atenolol 50 to 100mg. The full effect is usually established within 2 weeks. If an optimal response is not achieved an additional antihypertensive agent such as a diuretic, calcium antagonist or ACE inhibitor could be added. It is unlikely that increasing the atenolol dose above 100 mg/day will result in additional benefit for patients receiving monotherapy or combination therapy. The majority of patients with angina pectoris will respond to 100mg daily given orally. For patients with arrhythmias a suitable initial dose is 2.5 to 5mg injected intravenously (1mg/min). This may be repeated at 5-minute intervals until a response is observed, up to a maximum dosage of 10mg. If atenolol is administered by infusion the initial dose should be 0.15 mg/kg over 20 minutes. If required, the injection or infusion may be repeated every 12 hours. Once arrhythmias have been controlled a suitable maintenance dose is 50 to 100mg once daily.

For patients with suspected myocardial infarction, presenting within 12 hours of the onset of chest pain, intravenous atenolol (5mg infused over 5 minutes) should be administered immediately. A second 5mg dose may be given 10 minutes later. 15 minutes after the final infusion an oral 50mg dose should be administered. A second oral 50mg dose should be given after 12 hours and after a further 12 hours maintenance treatment with 100mg once daily should be initiated.

Dosage adjustment is required in patients with severe renal impairment (creatinine clearance < 35 ml/min/ 1.73m2). Patients undergoing dialysis should be given an oral 50mg dose after each dialysis. Atenolol is not recommended for children, patients with overt heart failure or as first therapy in patients with asthma. Atenolol should be administered with caution in patients receiving concomitant class I antiarrhythmic agents or verapamil as these drugs have similar electrophysiological effects. Care must also be taken when administering atenolol to patients whose cardiac reserve is poor.

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© Adis International Limited 1991

Authors and Affiliations

  • Alison N. Wadworth
    • 1
  • David Murdoch
    • 1
  • Rex N. Brogden
    • 1
  1. 1.Adis International LimitedMairangi Bay, Auckland 10New Zealand

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