Atenolol: A Review of its Pharmacological Properties and Therapeutic Efficacy in Angina Pectoris and Hypertension

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Synopsis: Atenolol1is a β1-selective (cardioselective) adrenoceptor blocking drug without partial agonist or membrane stabilising activity. Its profile of action most closely resembles that of metoprolol which differs only in that it has some membrane stabilising activity. Atenolol has been well studied and is effective in the treatment of hypertension and in the prophylactic management of angina. Its narrow dose response range obviates the need for highly individualised dose titration. In patients with angina its long duration of β-blocking activity allows once daily dosage, whereas other β-blockers, unless in sustained release dosage forms, need to be given in divided doses. Other β-blockers can be given once daily in hypertension, but at present the evidence for effective control with a once daily regimen is more convincing with atenolol. Further studies are needed to clarify any important differences in blood pressure control between the various β-blocking drugs, both in conventional or sustained release dosage forms. As with metoprolol, atenolol is preferable to non-selective β-blockers in patients with asthma or diabetes mellitus. Atenolol has been well tolerated in most patients, its profile of adverse reactions generally resembling that of other β-blocking drugs, although its low lipid solubility and limited penetration into the brain results in a lower incidence of central nervous system effects than seen with propranolol. Atenolol is eliminated virtually entirely as unchanged drug in the urine and dosage needs to be reduced in patients with moderate to severely impaired renal function (glomerular filtration rate less than 30ml/min). There is no need for modification of dosage of atenolol in liver disease.

Pharmacodynamic Studies: Atenolol is a β-adrenoceptor blocking drug without partial agonist (sympathomimetic) or membrane stabilising properties. It appears to be relatively selective for cardiac β1-receptors, although some deterioration in airway function can occur in patients with asthma receiving atenolol, as with other cardioselective β-blockers. However, such changes are clearly less severe than those seen with non-selective β-blockers, such as propranolol, and in some studies atenolol had a lesser effect than the other cardioselective β-blockers. Atenolol can be cautiously administered to patients with obstructive airways disease provided the patient also receives treatment with optimal doses of a β2-adrenoceptor agonist bronchodilator drug.

When administered to hypertensive patients (usually with mild to moderate essential hypertension) in studies which were essentially pharmacodynamic investigations, atenolol reduced both systolic and diastolic blood pressures by about 15%. The dose-response curve in such studies was relatively flat, suggesting that the use of a fixed dose may be justifiable in most patients. The maximum effect usually occurred with a dose of 100 or 200mg, most of the antihypertensive effect occurring by the third day of treatment. As with other β-blockers, the reduction in blood pressure with atenolol is consistently accompanied by a reduction in heart rate (about 15 to 25%) and cardiac output (usually about 20%).

In patients with coronary artery disease, atenolol produces changes in myocardial blood flow which resemble those seen with other β-blockers, regional myocardial blood flow being decreased in both normal and poststenotic areas but to a slightly greater extent in poststenotic areas. Resting myocardial oxygen consumption is also reduced in such patients, as is seen with other β-blockers. As is expected with a β-blocking drug lacking partial agonist activity, atenolol increases AV conduction time (by about 15%). Sinus cycle length, sinus node recovery time and atrial refractoriness are also similarly increased.

Atenolol, in common with other β-blockers, appears to markedly decrease resting and standing-stimulated plasma renin activity, although in 1 study atenolol did not significantly inhibit isoprenaline induced stimulation of plasma renin activity in contrast to other β-blocking drugs tested.

Pharmacokinetic Studies: Atenolol is rapidly but incompletely absorbed from the gastro-intestinal tract, the oral bioavailability being about 50 to 60%. It is not significantly bound to plasma proteins. Atenolol is widely distributed throughout the body, but in man only a small proportion of an administered dose reaches the brain. In healthy subjects the apparent volume of distribution is about 50 to 75L. In pregnancy, atenolol probably readily crosses the placenta, the umbilical and maternal serum levels being approximately equal at birth. Most of the absorbed portion of atenolol is excreted in the urine unchanged, the elimination half-life and total body clearance being 6 to 7 hours and about 100ml/minute/1.73m2, respectively, in patients with normal renal function. In renal dysfunction, however, elimination of atenolol is prolonged, being closely related to the glomerular filtration rate. Accumulation may occur in patients with a glomerular filtration rate less than 30ml/minute if the dosage is not reduced appropriately. In patients with severely impaired renal function, metoprolol, which is excreted in essentially inactive form, can be used without modification of usual dosage.

As is the case with other β-blocking drugs, there is little correlation between plasma levels of atenolol and its hypotensive effect.

Therapeutic Trials: Atenolol has been studied primarily in controlled trials in patients with exercise-related angina pectoris or hypertension. Most of these controlled studies have been reasonably well designed and executed, but all have involved only small groups of patients which were probably too small to have detected any small differences in effectiveness, if they existed, between atenolol and other similarly effective drugs.

In patients with angina pectoris, atenolol (50 to 400mg daily) was clearly superior to a placebo in reducing the frequency or severity of anginal attacks and decreasing the need for glyceryl trinitrate. In most such studies, it also significantly improved other evaluation criteria such as changes in exercise capability and of ST segment depression. In small comparative studies, atenolol was at least as effective as propranolol (240mg daily) or practolol (200 to 800mg daily). No marked differences were seen in these small patient groups between the efficacy of ‘higher’ and ‘lower’ doses of atenolol or of once and twice daily regimens.

In hypertension studies, most patients treated have had uncomplicated mild to moderate essential hypertension. In placebo controlled studies in such patients, atenolol reduced lying, standing or exercise systolic and diastolic blood pressures by about 15 to 20%. As in studies in angina, 100 to 200mg daily was as effective as higher doses in most patients, and no differences were observed between a single or a divided daily dose. Few statistically significant differences between atenolol and other β-blockers have emerged in comparative studies in patients with hypertension, although there was frequently a tendency for atenolol to produce a greater reduction in blood pressure than the comparison drugs, particularly in diastolic pressure, as compared with nonselective β-blockers. The lack of statistical significance in such findings may be related to the small numbers of patients usually studied; well designed studies in larger patient groups would help to establish whether atenolol has a significantly greater hypotensive effect than other β-blocking drugs, and whether it provides better control of blood pressure than other cardioselective agents also administered in a once daily dosage regimen.

In other comparative studies, atenolol (usually 200mg daily) was at least as effective, or in some cases more effective than moderate doses (750 to 1500mg daily) of methyldopa (and was better tolerated than the larger dose), and was more effective than bendrofluazide (usually 10mg daily) given alone. In more severely hypertensive patients, as might be expected, combinations of atenolol and a diuretic, or methyldopa, hydrallazine or prazosin produced a greater hypotensive response than that seen with a single agent. Long term treatment with atenolol in several hundred patients has not shown any reduction of effect over periods of up to several years.

Side Effects: Atenolol has been well tolerated by most patients. It's overall profile of adverse effects generally resembles that of propranolol, although a smaller proportion of patients has discontinued treatment with atenolol (2.2% versus 9.7%). The most common side effects are cold extremities, fatigue and diarrhoea (about 2 to 3% each). As with propranolol, vivid dreams have occasionally been reported with atenolol, but occur less frequently than with propranolol. Hallucinations have not occurred with atenolol. Bronchospasm has occurred in some patients. Atenolol can however, be given with caution to those with obstructive airways disease, provided full doses of a β2-agonist bronchodilator are given at the same time. Although a single case of retroperitoneal fibrosis has been reported in a patient receiving atenolol, a causal relationship was not clearly established.

Dosage and Administration: In angina prophylaxis, 100mg of atenolol daily may be given as a single or divided dose. Higher doses are unlikely to provide further benefit. In hypertension, treatment is usually begun with 100mg daily (single or divided dose). Additional antihypertensive agents such as a diuretic or vasodilating drug may be added to the treatment regimen if necessary. In patients with impaired renal function, dosage should be based in accordance with creatinine clearance, although important accumulation is only likely to occur if the glomerular filtration rate is less than 30ml/minute. Atenolol should not be discontinued abruptly in patients with severe coronary artery disease, as with other β-blockers.

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