Paper
Controlled Release Metoprolol Formulations
Published Mar 1, 1992 · G. Plosker, S. Clissold
Drugs
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Abstract
SummarySynopsisConventional formulations of metoprolol have become well established in cardiovascular medicine and are particularly useful in the management of hypertension and ischaemic heart disease. Recently developed controlled release metoprolol delivery systems (metoprolol CR/ZOK and metoprolol OROS) were designed to overcome the drug delivery problems of matrix-based sustained release forms by releasing the drug at a relatively constant rate over a 24-hour period, and thus producing sustained and consistent metoprolol plasma concentrations and β1-blockade while retaining the convenience of once daily administration. Clinically and statistically significant reductions in blood pressure have been observed with metoprolol CR/ZOK and metoprolol OROS 24 hours after administration in mildly or moderately hypertensive patients. Studies in patients with mild to moderate hypertension have demonstrated that a similar or higher percentage of patients achieved a goal response with metoprolol CR/ZOK compared with matrix-based sustained release formulations of metoprolol, or conventional atenolol or bisoprolol, while metoprolol OROS achieved an equal or greater response rate compared with conventional or matrix-based sustained release metoprolol preparations. In patients with stable effort angina pectoris, once daily administration of metoprolol CR/ZOK provided at least equal antianginal efficacy as conventional metoprolol in divided doses, while metoprolol OROS reduced the mean number of anginal attacks by the same margin as atenolol.Controlled release metoprolol formulations have been well tolerated in clinical trials. Metoprolol CR/ZOK was associated with a similar or lesser degree of adverse effects related to the central nervous system compared with atenolol or long acting propranolol. Metoprolol CR/ZOK also demonstrated less pronounced β2-mediated bronchoconstrictor effects than atenolol in asthmatics, and less general fatigue and leg fatigue in healthy subjects. Metoprolol OROS produced less pronounced bronchoconstrictor effects than atenolol, matrix-based sustained release metoprolol or long acting propranolol in patients with asthma or obstructive airways disease, and healthy volunteers. These results are presumably due to the β1-selectivity of metoprolol in addition to the relatively low plasma concentrations maintained by metoprolol CR/ZOK and metoprolol OROS, and the avoidance of high peak plasma concentrations with these agents. Despite the relative safety of the controlled release forms of metoprolol, the use of all β-adrenoceptor antagonists should be avoided in patients with a history of bronchospasm.Thus, controlled release metoprolol formulations offer the potential to maximise the confirmed benefits of this agent in the management of hypertension and angina, by maintaining clinically effective plasma concentrations within a narrow therapeutic range over a 24-hour dose interval.Pharmacodynamic PropertiesMetoprolol is a selective β1-adrenoceptor antagonist which has no intrinsic sympathomimetic activity or membrane stabilising activity. The failure of matrix-based sustained release metoprolol preparations to provide consistent plasma metoprolol concentrations and β1-blockade throughout a 24-hour dose interval has led to the development of novel controlled release formulations of the reservoir type. Metoprolol CR/ZOK (controlled release/zero order kinetics) and metoprolol OROS (Oral Osmotic System) are 2 such formulations which have recently been developed and which do produce these effects with once daily administration.Pharmacodynamic studies with metoprolol CR/ZOK or metoprolol OROS in once daily doses ranging from 50 to 400 mg/day have demonstrated more uniform reductions in heart rate and blood pressure during exercise testing, relative to comparable regimens of conventional metoprolol or propranolol administered in divided doses, or once daily administration of matrix-based sustained release metoprolol, or conventional atenolol or bisoprolol.In ischaemic heart disease, metoprolol reduces myocardial oxygen demand by reducing systemic arterial pressure, heart rate and contractility, while blood and oxygen supply to poorly perfused areas may be improved due to an extended period of diastole. Although metoprolol can negatively affect the lipid profile by reducing high density lipoprotein cholesterol serum concentrations and increasing triglyceride levels, evidence from animal and human studies indicate that various haemodynamic and biochemical actions may overcome this to provide an overall antiatherogenic effect. Electrophysiological effects of metoprolol include delayed ventricular repolarisation time, slowed conduction velocity through the atrioventricular node, decreased sinoatrial node recovery time and reduced automaticity.Controlled release metoprolol formulations appear to possess minimal β2-adrenoceptor blocking effects compared with other cardioselective and nonselective β-blocker formulations due to the relative β1-selectivity of metoprolol and the avoidance of high peak plasma concentrations produced by the constant rate delivery systems. In patients with reversible obstructive airways disease, the CR/ZOK and OROS formulations produced a lesser degree of β2-mediated bronchoconstrictor effects than atenolol. Metoprolol OROS also produced a lower magnitude of β2-mediated bronchoconstrictor effects than matrix-based sustained release metoprolol in asthmatic patients, while in healthy adults metoprolol OROS was comparable to matrix-based sustained release metoprolol but caused less intense β2-mediated bronchoconstrictor effects than atenolol or long acting propranolol at the approximate time of maximum plasma drug concentrations. Metoprolol CR/ZOK produced less general fatigue and leg fatigue than did atenolol after exercise testing at a time calculated to coincide with highest plasma drug concentrations. The perceived absence of general fatigue and leg fatigue are thought to be due, to some extent, to the absence or reduced blockade of β2-mediated vasodilatation and glycolysis with controlled release metoprolol.Short and long term administration of metoprolol in healthy adults and hypertensive patients is associated with reduced plasma renin activity which is mediated, at least in part, by β1-adrenoceptors of the kidney. In a small group of patients with hypertension, mean plasma renin activity decreased significantly in responders to 1 month’s treatment with conventional metoprolol. A possible correlation between percentage fall in blood pressure and pretreatment levels of plasma renin activity was documented in a separate group of hypertensive patients.β1-Selective agents, such as metoprolol, are preferable to nonselective β-blockers in insulin-dependent diabetic patients, since they appear to be less likely to slow blood glucose recovery and mask warning symptoms of hypoglycaemia. In healthy volunteers, the magnitude of mean elevations in plasma glucose levels induced by terbutaline (a β-agonist) was attenuated to a significantly lesser extent with metoprolol CR/ZOK than with atenolol, and the subsequent maximum fall in potassium levels was significantly reduced with metoprolol CR/ZOK compared with either atenolol or conventional metoprolol, indicating a lower degree of β2-blocking effects with metoprolol CR/ZOK. During insulin-induced hypoglycaemia in healthy subjects, heart rate increased with placebo and metoprolol CR/ZOK, was unchanged with atenolol and decreased with long acting propranolol, while diastolic blood pressure decreased with placebo, was unchanged with metoprolol CR/ZOK and atenolol, and increased with long acting propranolol.Pharmacokinetic PropertiesCompared with identical doses of both conventional metoprolol and matrix-based sustained release preparations, peak plasma concentrations are lower and time to peak concentrations (tmax) longer with the controlled release formulations. Metoprolol CR/ZOK and metoprolol OROS are bioequivalent with respect to area under the concentration-time curve and Cmax, and both agents produce relatively consistent plasma concentrations within the therapeutic range throughout a 24-hour period. Importantly, they avoid the marked peaks and troughs associated with administration of conventional formulations.Although > 95% of an administered dose of conventional metoprolol is absorbed from the gastrointestinal tract, only 50% is available systemically due to extensive first-pass hepatic metabolism. Bioavailability of conventional tablets of metoprolol increases with food and with long term use due to reductions in presystemic clearance. Systemic availability of controlled release metoprolol formulations is about 20 to 30% lower than that of conventional metoprolol, mainly due to enhanced presystemic hepatic clearance because of relatively slow release of drug from these delivery systems. Food has a minimal effect on the bioavailability and rate of absorption of controlled release metoprolol formulations.Metoprolol is extensively metabolised with only 5% of an oral dose eliminated unchanged in the urine. The elimination half-life is usually 3 to 4 hours and does not significantly increase with impaired renal function. Peak plasma concentrations of the active metabolite, α-hydroxymetoprolol, can increase 3- to 4-fold in renal failure, but due to its low β-blocking activity the overall contribution of this metabolite to clinical efficacy or adverse effects is likely minimal. Liver dysfunction can result in increased systemic availability of metoprolol and, if severe, may necessitate a reduction in dosage. About 5 to 10% of Caucasians are poor metabolisers of metoprolol, and extended-release formulations of the drug may not be required in this subgroup because of higher serum concentrations and AUC values, and greater duration or degree of β-blockade.Therapeutic Use in HypertensionConventional metoprolol is an effective antihypertensive agent wh
Non-RCTControlled release metoprolol formulations (metoprolol CR/ZOK and metoprolol OROS) provide effective blood pressure reduction and 1-blockade while maintaining convenience and safety in once daily administration for patients with hypertension and stable angina pectoris.
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