Summary
Synopsis: During the intervening years since metoprolol1 was first reviewed in the Journal (1977), it has become widely used in the treatment of mild to moderate hypertension and angina pectoris. Although much data have accumulated, its precise mechanisms of action in these diseases remain largely uncertain.
Optimum treatment of hypertension and angina pectoris with metoprolol is achieved through dose titration within the therapeutic range. It has been clearly demonstrated that metoprolol is at least as effective as other β-blockers, diuretics and certain calcium antagonists in the majority of patients. Although a twice daily dosage regimen is normally used, satisfactory control can be maintained in many patients with single daily doses of conventional or, more frequently, slow release formulations. Addition of a diuretic may improve the overall response rate in hypertension.
Several controlled trials have studied the effects of metoprolol administered during the acute phase and after myocardial infarction. In early intervention trials a reduction in total mortality was achieved in one moderately large trial of prolonged treatment, but in another, which excluded patients already being treated with β-blockers or certain calcium antagonists and where treatment was only short term, mortality was significantly reduced only in ‘high risk’ patients. Overall results with metoprolol have not demonstrated that early intervention treatment in all patients produces clinically important improvement in short term mortality. Thus, the use of metoprolol during the early stages of myocardial infarction is controversial, largely because of the requirement to treat all patients to save a small number at ‘high risk’. This blanket coverage approach to treatment may be more justified during the post-infarction follow-up phase since it has been shown that metoprolol slightly, but significantly, reduces the mortality rate for periods of up to 3 years.
Metoprolol is generally well tolerated and its β1-selectivity may facilitate its administration to certain patients (e.g. asthmatics and diabetics) in whom non-selective β-blockers are contraindicated. Temporary fatigue, dizziness and headache are among the most frequently reported side effects.
After a decade of use, metoprolol is well established as a first choice drug in mild to moderate hypertension and stable angina, and is beneficial in post-infarction patients. Further study is needed in less well established areas of treatment such as cardiac arrhythmias, idiopathic dilated cardiomyopathy and hypertensive cardiomegaly.
Pharmacodynamic Studies: Metoprolol is an established β1-selective adrenoceptor antagonist which lacks intrinsic sympathomimetic activity. Thus, compared with propranolol, it has a weak inhibiting effect on isoprenaline (isoproterenol)-mediated tachycardia, and reduces exercise heart rate to a greater extent than β-blockers with intrinsic sympathomimetic activity. In hypertensive subjects metoprolol rapidly reduces systolic blood pressure, but a maximal reduction of diastolic pressure requires several weeks’ treatment. Factors predictive of the magnitude of the antihypertensive effect, and the nature of long term haemodynamic changes, are the subject of dispute. Reduction of myocardial oxygen demand, through reduced heart work, is an important effect in ischaemic heart disease. Intravenous administration to patients causes dose-related reductions in blood pressure, heart rate and cardiac output at rest and during exercise. In patients with anterior wall hypokinesia metoprolol (but not pindolol) reduced the ejection fraction. Both drugs increased hypokinetic segment shortening, but only metoprolol decreased shortening of contralateral non-hypokinetic segments. The mechanism of action of metoprolol in myocardial infarction is only partly understood. Some animal studies have reported that metoprolol reduces the evolution of hypoperfused myocardium to necrotic tissue. Animal and human electrophysiological studies have shown that metoprolol increases myocardial refractoriness. In patients with paroxysmal tachycardia a bolus injection of metoprolol increased sinus node recovery time and cycle length, right atrium to bundle of His conduction time, and A-V node refractoriness.
The effects of metoprolol in patients with obstructive pulmonary disease appear at least partially dependent on the disease type and status. When compared with atenolol single doses of both drugs equally depressed FEV1 and the terbutaline-induced increase in FEV1 in asthmatics.
The effects of metoprolol on plasma catecholamine concentrations are inconsistent and, therefore, of uncertain significance. In contrast, metoprolol reduces plasma renin activity to a similar extent as propranolol in healthy or hypertensive subjects. Blood glucose homeostasis appears largely unaffected by metoprolol. A delayed late phase of recovery from insulin-induced hypoglycaemia has been observed after single-dose metoprolol in healthy subjects, but continuous metoprolol infusion had no effect. In insulin-dependent diabetics recovery was also delayed but the extent of hypoglycaemia after insulin was not affected. The nature and significance of the long term effects of metoprolol on plasma lipids requires further study. Some authors have reported reduced plasma concentrations of high density lipoprotein cholesterol and a tendency for low density lipoproteins to increase following 3 months’ metoprolol treatment.
Metoprolol does not appear to affect renal or hepatic blood flow in normal subjects. Portal hypertension is reduced, but to a lesser extent than after propranolol which reduces hepatic blood flow. Evidence that metoprolol inhibits platelet aggregation as well as erythrocyte viscosity and adherence to endothelial tissue is accumulating. Detrimental effects on physical performance in terms of subjective effort and capacity occur to a lesser extent after metoprolol than propranolol.
Pharmacokinetic Studies: Orally administered metoprolol is almost completely absorbed, although first-pass metabolism reduces its systemic availability by about 50%. The slow release formulations of metoprolol maintain effective plasma concentrations for 24 hours during once daily administration. However, studies in patients are required to assess any clinical advantage of this preparation. Lipophilicity and a low degree of binding to plasma proteins facilitate extensive distribution, and penetration into the central nervous system. After extensive hepatic metabolism metoprolol is excreted primarily as inactive metabolites. After oral or intravenous administratioin, about 95% of a dose is recovered in the urine within 72 hours (approximately 3% as unchanged drug). Total body clearance ranges between 43.2 and 92.4 L/h and the elimination half-life is usually 3 to 4 hours. Many studies have found evidence of polymorphic oxidation of metoprolol. On the other hand, some have shown a variable but unimodal pattern of metabolism. At present, there is no evidence that an increased incidence of adverse effects occurs in poor metabolisers of metoprolol.
Age appears to have little influence on metoprolol pharmacokinetics, but during pregnancy clearance after oral administration may increase. Like atenolol, metoprolol freely penetrates into breast milk but the estimated consumption is unlikely to affect the infant.
Unchanged metoprolol does not significantly accumulate during renal insufficiency, and it is unlikely that any increase in plasma concentrations of active metabolites contributes to pharmacological activity. In contrast, systemic availability increases during cirrhosis in association with a corresponding trend for half-life to increase and total body clearance to decrease.
The pharmacological and therapeutic effects of metoprolol are generally dose-related. However, although it is possible to relate plasma concentrations with β-blocking effects (e.g. reduction of exercise heart rate), attempts to demonstrate relationships between plasma metoprolol concentrations and therapeutic effects have generally failed.
Therapeutic Studies: Many short and several long term studies have confirmed the therapeutic efficacy and good tolerability of metoprolol in mild to moderate hypertension. Satisfactory blood pressure control is usually achieved with single or divided daily dosages of 100 to 200mg. The conventional and slow release formulations compare favourably with each other and with atenolol. Other recent comparative studies have reported that fixed or titrated regimens of metoprolol are at least as effective as treatment with several other β-blockers, labetalol, diltiazem, nifedipine or chlorthalidone. However, enalapril was superior in one study. Additional daily treatment with 25mg hydrochlorothiazide improved control of diastolic pressure. In large numbers of patients blood pressure control was well maintained for up to 1 year with metoprolol and, if required, additional diuretic treatment. Further studies are required to establish the role of metoprolol in treating elderly and pregnant hypertensives. Metoprolol is preferable to a nonselective β-blocker for treating hypertension in patients with asthma or diabetes. However, it should be realised that although the risk of bronchospasm is reduced, it is not absent when metoprolol is administered to patients with hypertension and asthma.
Clinical studies in patients with stable exertional angina have confirmed the short term efficacy of metoprolol as assessed by decreases in anginal frequency and glyceryl trinitrate (nitroglycerin) consumption, and improvements in objective parameters such as work performance and time to onset of anginal pain during exercise. A slow release formulation of metoprolol has been introduced and once-daily administration of 200mg has been shown to be of comparable efficacy to a conventional preparation of metoprolol 100mg twice daily. Other comparative studies in patients with exertional angina pectoris have clearly demonstrated that metoprolol is superior to placebo and as effective as equivalent β-blocking doses of drugs such as propranolol, oxprenolol, practolol and tolamolol. Preliminary trials have shown metoprolol to be at least as effective as the calcium antagonists verapamil and nifedipine in stable exertional angina, while an open study found the β-blocker to be effective in some patients with unstable angina pectoris.
Metoprolol has been evaluated in large numbers of patients during the course of an evolving myocardial infarction and in patients who have suffered an acute ischaemic episode. Early intervention with β-blockers is a contentious therapeutic approach to the management of patients with a suspected impending myocardial infarction. Studies with metoprolol have not demonstrated conclusively that acute intravenous administration with this cardioselective β-blocker produces clinically important improvement in short term mortality, except for certain ‘high-risk’ groups of patients who may be difficult to identify when first treated. However, metoprolol has been well tolerated and produces definite therapeutic benefit in terms of reduction of chest pain and need for analgesic relief, decreased incidence of some tachyarrhythmias, and reduction in the number of patients in whom a threatened infarction developed into an acute event. There was also indirect evidence that it limited infarct size. If some means of identifying those patients likely to respond to immediate intervention with a β1-selective adrenoceptor antagonist can be found, then metoprolol will be a rational choice and may have an important role to play in the therapeutic management of a difficult-to-treat group of patients. In post-infarction patients metoprolol administered orally reduced total mortality. During a 3-year follow-up total mortality was 21.1% in the placebo group and 16.2% in the metoprolol group. Additionally, metoprolol significantly reduced the incidence of sudden cardiac death, the number of patients with angina pectoris or needing coronary artery bypass surgery, the incidence and complexity of chronic ventricular arrhythmias, time spent in hospital, and the number of patients who developed non-fatal reinfarctions. After 3 years some patients had their metoprolol treatment withdrawn over a period of 1 week and 31% needed reinstitution of a β-blocker to alleviate symptoms, while 21% reported improved fitness. Heart rate was increased during the first 3 weeks after withdrawal, which suggests that a rebound effect may occur and, if β-blockade is to be discontinued, it seems preferable to gradually reduce the dosage over a longer period.
Clinical evaluations of metoprolol in other therapeutic areas such as cardiac arrhythmias (treatment and prevention), idiopathic dilated cardiomyopathy, hypotensive cardiomegaly, heart failure with associated tachycardia, and as an adjunct to sodium nitroprusside for inducing controlled hypotension during surgery have been of a preliminary nature, generally in uncontrolled clinical trials including small numbers of patients. Firm conclusions regarding its relative efficacy await further research, although some encouraging results have been reported.
Side Effects: In the majority of patients with mild to moderate hypertension or ischaemic heart disease metoprolol is a safe, well tolerated treatment. Over the course of 1 year the overall incidence of metoprolol-related side effects was 27% in more than 400 patients with hypertension. This compares favourably with the incidence of side effects associated with diuretics. Fatigue (6.2%), dizziness (3.8%) and headache (3.6%) occurred most frequently. Side effects are usually transient and necessitated withdrawal of treatment in only about 7% of patients. Slow release metoprolol does not appear to decrease the incidence or severity of side effects. The incidence of central nervous system-related side effects associated with metoprolol is similar to that with atenolol.
During 90 days of treatment with intravenous and oral metoprolol in patients with suspected myocardial infarction. 9.8 and 5.2% of patients withdrew from the metoprolol and placebo treatment groups, respectively, because of adverse cardiovascular effects. Most of these withdrawals took place during the first 11 days’ treatment and comprised hypotension (metoprolol 3.7% vs placebo 1.4%), bradycardia (2.3 vs 0.7%), atrioventricular block (2.2 vs 1.4%) and congestive heart failure (0.6 vs 1.0%). Although there was a non-significant difference in the overall withdrawal rates because of atrioventricular block, the incidence of first degree atrioventricular block was significantly greater in metoprolol-treated patients.
Some studies have demonstrated rebound cardiac chronotropic effects following sudden termination of metoprolol treatment suggesting that a gradual withdrawal over several weeks might be preferable.
Dosage and Administration: Most patients with hypertension or angina respond satisfactorily to between 100 and 200mg metoprolol daily. Dosage should be titrated for optimum individual response and may be divided or taken as a once-daily slow release formulation. For acute treatment of arrhythmias and suspected myocardial infarction, metoprolol 15mg should be administered as three 5mg intravenous doses at intervals of 5 or 2 minutes, respectively. Treatment should continue with follow-up oral administration of 100 to 200mg metoprolol daily, as divided doses. Patients who do not respond satisfactorily to metoprolol alone may benefit from additional treatment with a different class of antihypertensive, antianginal or antiarrhythmic drug. Metoprolol should be withheld from patients with impaired cardiac function. In patients with obstructive lung disease, unstable diabetes mellitus, peripheral vascular disease and in general anaesthesia metoprolol should be administered with caution, and possibly at a lower dosage.
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Various sections of the manuscript reviewed by: J.L. Anderson, Division of Cardiology, Latter Day Saints Hospital, Salt Lake City, Utah, USA; W. Bernauer, Department of Pharmacology, University of Freiburg, Freiburg, E. Germany; K.J. Broadley, Division of Pharmacology, Welsh School of Pharmacy, University of Wales, Institute of Science and Technology, Cardiff, UK; N.M. Kaplan, Department of Internal Medicine, University of Texas Health Science Center, Dallas, Texas, USA; M.S. Lennard, University Department of Therapeutics, Royal Hallamshire Hospital, Sheffield, UK; D.G. McDevitt, Department of Pharmacology and Clinical Pharmacology, University of Dundee, Dundee, UK; R.M. Norris, Coronary Care Unit, Green Lane Hospital, Auckland, New Zealand; G. Olsson, Department of Medicine, Danderyd Hospital, Danderyd, Sweden; A.J.J. Wood, Department of Pharmacology, Vanderbilt University, Nashville, Tennessee, USA; S. Yusuf, Clinical Trials Section, National Heart, Lung and Blood Institute, Bethesda, Maryland, USA; A. Zanchetti, Centro di Fisiologica Clinica e Ipertensione, Instituto di Clinica Medica IV, Universita di Milano, Milan, Italy.
‘Betaloc’, ‘Beloc’, ‘Seloken’ (Astra); ‘Lopressor’ (Ciba-Geigy); ‘Selopral’ (Hässle); ‘Seloken’ (Bracco, Fujisawa, Searle).
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Benfield, P., Clissold, S.P. & Brogden, R.N. Metoprolol. Drugs 31, 376–429 (1986). https://doi.org/10.2165/00003495-198631050-00002
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DOI: https://doi.org/10.2165/00003495-198631050-00002