Chemical formula: C₁₅H₂₅NO₃ Molecular mass: 267.364 g/mol PubChem compound: 4171
Metoprolol is a cardioselective beta-adrenergic blocking agent. It has a relatively greater blocking effect on beta1-receptors (ie those mediating adrenergic stimulation of heart rate and contractility and release of free fatty acids from fat stores) than on beta2-receptors, which are chiefly involved in broncho and vasodilation.
Metoprolol is readily and completely absorbed from the gastrointestinal tract. Metoprolol is absorbed fully after oral administration. Within the therapeutic dosage range, the plasma concentrations increase in a linear manner in relation to dosage. Peak plasma levels are achieved after approx. 1.5–2 hours. Even though the plasma profile displays a broader interindividual variability, this appears to be easily reproducible on an individual basis. Due to the extensive first-pass effect, bioavailability after a single oral dose is approx. 50%. After repeated administration, the systemic availability of the dose increases to approx. 70%. After oral intake with food, the systemic availability of an oral dose increases by [SIC] approx. 30–40%.
Peak plasma concentrations occur about 1½ hours after a single oral dose. Peak plasma metoprolol concentrations at steady state with usual doses have been reported as 20-340ng/ ml. Metoprolol is widely distributed, it crosses the bloodbrain barrier, the placenta. It is slightly bound to plasma protein. The medicinal product is approx. 5–10% bound to plasma proteins.
Metoprolol is metabolised through oxidation in the liver mainly by the CYP2D6 isoenzyme. Even though three main metabolites have been identified, none of them has a clinically significant beta-blocking effect. Generally, 95% of an oral dose is found in the urine. Only 5% of the dose is excreted unmodified via the kidneys; in isolated cases, this figure can reach as high as 30%. The elimination half-life of metoprolol averages 3.5 hours (with extremes of 1 and 9 hours). Total clearance is approx. 1 litre/minute. It is extensively metabolised in the liver; O-dealkylation followed by oxidation and aliphatic hydroxylation. The rate of hydroxylation to alpha-hydroxymetoprolol is reported to be determined by genetic polymorphism; the half-life of metoprolol in fast hydroxylators is stated to be 3-4 hours, whereas in poor hydroxylators it is about 7 hours.
The metabolites are excreted in the urine together with only small amounts of unchanged metoprolol. Metoprolol is excreted in breast milk.
In comparison with administration to younger patients, the pharmacokinetics of metoprolol when administered to older patients shows no significant differences.
Renal dysfunction has barely any effect on the bioavailability of metoprolol. However, the excretion of metabolites is reduced. In patients with a glomerular filtration rate of less than 5 ml/minute, a significant accumulation of metabolites has been observed. This accumulation of metabolites, however, produces no increase in the beta blockade.
The pharmacokinetics of metoprolol are influenced only minimally by reduced hepatic function. However, in patients with serious hepatic cirrhosis and a portacaval shunt, the bioavailability of metoprolol can increase, and the total clearance can be reduced. Patients with portacaval anastomosis had a total clearance of approx. 0.3 litres/minute and AUC values that were 6 times higher than those found in healthy persons.
Intrinsic sympathomimetic activity (ISA) may be a disadvantage for the patient with severe angina pectoris. There are however no indications that the efficacy in hypertensives is influenced by this characteristic. In exceptional cases, however, very high dosages can cause the ISA to predominate over the beta-adrenergic blocking capacity so that restriction of the maximum dosage is indicated.
It has not been proven that beta-blockers with ISA give a lower risk for bronchospasm or enhancement of preexisting bronchospastic complaints.
There are no preclinical data.
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