Metoprolol

Abstract

Synopsis: Metoprolol¹ is a β₁-selective adrenoceptor blocking drug. In hypertension, its duration of effect is longer than expected from its half-life and it is suitable for twice daily administration. There is some evidence that once daily administration may be possible in treating hypertension. It is similar in efficacy to other β-adrenoceptor blocking drugs in angina pectoris and essential hypertension, when given in equiactive β-blocking dosages. Metoprolol is well tolerated and side-effects have not proved a problem. It has some pharmacodynamic and pharmacokinetic differences from other β-adrenoceptor blocking drugs and may prove useful in cases where these differences are shown to be clinically important. Animal pharmacology: In animal studies, metoprolol has been shown to possess β-adrenoceptor blocking activity, as evidenced by antagonism of the cardiovascular effects of isoprenaline. Like propranolol, it has no partial agonist activity, but unlike propranolol, only weak membrane stabilising activity. Evidence of the ‘cardioselective’ properties of metoprolol is provided by the finding that metoprolol inhibits the heart rate response to isoprenaline at doses about one-fifteenth of those required to inhibit the vasodilator response. However, there is experimental evidence that metoprolol is somewhat less ‘cardioselective’ than practolol. In these respects, the profile of actions of metoprolol more closely resembles atenolol. In spontaneously hypertensive rats, metoprolol like propranolol largely prevented the increases in arterial blood pressure and structural changes in resistance vessels seen in untreated age-matched controls. Studies in rats and dogs indicate that metoprolol is almost completely absorbed from the gastrointestinal tract. Distribution is typical of that of a moderately lipophilic basic drug. In the dog and rats, as in man, metoprolol is largely metabolised, the metabolites having only slight β-adrenoceptor blocking activity compared with metoprolol itself. Due to presumed differences in hepatic first pass metabolism, the bioavailability in the dog is about 6 to 8 times that in the rat. Human pharmacology: Acute or repeated administration of metoprolol to normal subjects or hypertensive patients results in a reduction in heart rate and cardiac output which appears to be related to the dose and plasma concentration of the drug. Stroke volume is unchanged. Further studies are required to determine the effect of metoprolol on cardiac output relative to that of propranolol. Single oral or intravenous doses of metoprolol rapidly lower systolic, but not diastolic pressure in hypertensive and normal persons, but diastolic blood pressure is reduced by several weeks’ administration. As in animals, propranolol and metoprolol differ considerably in their effect on the haemodynamic response to infused adrenaline or isoprenaline. The difference is considered to result from a much less pronounced effect of metoprolol on adrenergic β₂receptors compared with propranolol. In asthmatic patients, metoprolol causes some reduction in basal forced expiratory volume and vital capacity, but less than that produced by equiactive β-blocking doses of propranolol. Nevertheless, any β-adrenoceptor blocking drug is best avoided in asthma. Unlike propranolol, metoprolol does not significantly inhibit the bronchodilatation induced by inhaled isoprenaline or β₂-adrenoceptor stimulants such as terbutaline or salbutamol. Chronically administered metoprolol, and also single doses, reduces plasma renin activity in hypertensive patients and in normal subjects to a comparable extent as propranolol. Metoprolol is readily and rapidly absorbed after oral administration and is rapidly distributed to body tissues. Plasma levels vary considerably between individuals, due partly to significant hepatic first-pass elimination, which results in 50% of the administered oral dose reaching the systemic circulation. Metoprolol is only 11% bound to human serum albumin, which is reflected in its large volume of distribution. The elimination half-life of metoprolol is about 3 to 4 hours in most patients and is independent of dose and duration of therapy. The drug undergoes extensive biotransformation and is excreted principally via the kidneys; only about 3% of a dose is excreted as unchanged drug after oral administration and about 10% after an intravenous dose. The metabolites have no clinically important activity. Therapeutic trials: Controlled therapeutic trials in patients with angina pectoris or essential hypertension have shown metoprolol to be an effective β-adrenoceptor blocking drug in these diseases. Metoprolol has been superior to placebo in all studies in which they have been compared, and its effects have been statistically indistinguishable from those of equivalent β-blocking doses of propranolol in the prophylaxis of angina pectoris and in lowering blood pressure in mild to moderate hypertension. On the basis of present evidence, it appears that metoprolol is an effective prophylactic treatment in angina pectoris, as evidenced by subjective and objective criteria. Trials comparing several β-adrenoceptor blocking drugs in moderate essential hypertension, have shown that the antihypertensive activity and efficacy of individually titrated doses of metoprolol is similar to that of other β-adrenoceptor blocking drugs at equivalent dosages. Data available to date, suggest that twice daily metoprolol is comparable in efficacy to a thrice daily regimen in reducing blood pressure in patients with mild to moderate hypertension. There is some evidence that once daily dosage is also effective in hypertension. Side-effects: In therapeutic trials in patients with angina pectoris or hypertension, metoprolol has been well tolerated and any side-effects reported have been mild or moderate, similar in frequency to those reported with placebo, and have not generally interfered with normal daily activities. Dizziness, tiredness and gastric upset have been the most frequently reported side-effects, but have seldom been troublesome. Dosage: The initial dosage in hypertension is 50mg night and morning increasing to 100 or 200mg per dose depending on the response. Metoprolol can be given as part of a combined treatment regimen with a diuretic and/or another drug such as a peripheral vasodilator where combined therapy is necessary. In angina pectoris, the usual dosage is 50mg 3 times daily. The 100mg tablets may be given thrice or twice daily to meet individual patient needs, although 3 times daily administration of metoprolol is preferable during the initial period of treatment of angina pectoris.