Source: Medicines and Medical Devices Safety Authority (NZ) Revision Year: 2020 Publisher: Novartis New Zealand Limited, PO Box 99102, Newmarket, Auckland 1149, Telephone: 0800 354 335
Pharmacotherapeutic group: Cardioselective beta-blocker
ATC code: C07AB02
Metoprolol is a cardioselective beta-blocker; it blocks beta1-adrenergic receptors (which are mainly located in the heart) at lower doses than those needed to block beta2-receptors, which are mainly located in the bronchi and peripheral vessels. It has no membrane-stabilising effect nor partial agonist (intrinsic sympathomimetic) activity.
The stimulant effect of catecholamines on the heart is reduced or inhibited by metoprolol. This leads to a decrease in heart rate, cardiac contractility, and cardiac output.
Metoprolol lowers elevated blood pressure in the standing and lying position. It also reduces the rise in blood pressure occurring in response to exercise. Treatment results in an initial increase in peripheral vascular resistance, which during long-term administration is normalised or, in some cases, reduced. As with all beta-blockers, the precise mechanism of the antihypertensive effect of metoprolol is not fully understood. However, the long-term reduction blood pressure seen with metoprolol appears to parallel this gradual decrease in total peripheral resistance.
In patients with angina pectoris, metoprolol reduces the frequency and severity of ischaemic episodes and increases physical working capacity. These beneficial effects may be due to decreased myocardial oxygen demand as a result of the reduced heart rate and myocardial contractility.
In patients with supraventricular tachycardia, atrial fibrillation, or ventricular extrasystoles or other ventricular arrhythmias, metoprolol has a regulating effect on the heart rate. Its anti-arrhythmic action is due primarily to inhibition of the automaticity of pacemaker cells and to prolongation of atrioventricular conduction.
In patients with a suspected or confirmed myocardial infarction, metoprolol lowers mortality. This effect may possibly be attributable to a decrease in the incidence of severe ventricular arrhythmias, as well as to limitation of infarct size. Metoprolol has also been shown to reduce the incidence of non-fatal myocardial reinfarction.
Through its beta-blocking effect, metoprolol is suitable for the treatment of functional heart disorders with palpitation, for the prevention of migraine, and adjunctive treatment of hyperthyroidism.
Long-term treatment with metoprolol may reduce insulin sensitivity. However, metoprolol interferes with insulin release and carbohydrate metabolism less than non-selective beta-blockers.
In short-term studies it has been shown that metoprolol may alter the blood lipid profile. It may cause an increase in triglycerides and a decrease in free fatty acids; in some cases, a small decrease in the highdensity lipoprotein (HDL) fraction has been observed, although to a lesser extent than with non-selective beta-blockers. In one long-term study lasting several years, cholesterol levels were found to be reduced.
Pharmacokinetic and pharmacodynamic studies indicate that 30% of maximum beta-1-adrenoreceptor antagonistic activity is essential for minimum pharmacodynamic effect which is observed with about 45 nmol/L metoprolol in plasma.
Following oral administration of conventional tablet, metoprolol is rapidly and almost completely absorbed from the gastrointestinal tract. The drug is absorbed evenly throughout gastrointestinal tract .Absorption of metoprolol from with Slow Lopresor or Slow Lopresor tablets, absorption is slower, but the availability of metoprolol is similar compared with conventional tablets. Peak plasma concentrations are attained after approximately 1.5 to 2 hours with conventional metoprolol tablets, and after approximately 4 to 5 hours with sustained-release tablets. Plasma concentrations of metoprolol increase approximately in proportion with the dose in the 50-mg to 200-mg dose range. Owing to extensive hepatic first-pass metabolism, approximately 50% of a single oral dose of metoprolol reaches the systemic circulation. The extent of presystemic elimination differs between individuals because of genetic differences in oxidative metabolism. Although the plasma profiles exhibit wide intersubject variability, they are reproducible within an individual. Following repeated administration, the percentage of the dose systemically available is approximately 40% higher than after a single dose (that is, approximately 70%). This may be due to partial saturation of the first-pass metabolism, or reduced clearance as a result of reduced hepatic blood flow. Ingestion with food may increase the systemic availability of a single oral dose by approximately 20% to 40%.
After intravenous injection metoprolol is very rapidly distributed with a half-life of 5 to 15 min. Within the dose range of 10 to 20 mg, the plasma concentrations rise linearly in relation to the size of the dose. Metoprolol exhibits stereo-specific pharmacokinetics.
Metoprolol is extensively and rapidly distributed, with a reported volume of distribution of 3.2 to 5.6 L/kg. The apparent volume of distribution at steady-state (Vss) in extensive metabolizers (4.84 L/kg) is relatively higher than poor metabolizers (2.83 L/kg). The half-life is not dose-dependent and does not change on repeated dosing. Approximately 10% of metoprolol in plasma is protein bound. Metoprolol crosses the placenta, and is found in breast milk (see Section 4.6 Fertility, pregnancy and lactation). In patients with hypertension, metoprolol concentrations in cerebrospinal fluid are similar to those in plasma. Metoprolol is not a significant P-glycoprotein substrates indicating that inter-individual variability in pharmacokinetics of metoprolol can be majorly due to CYP2D6 metabolism.
Metoprolol is extensively metabolised by enzymes of the cytochrome P450 system in the liver. The main metabolic pathways of metoprolol are alpha-hydroxylation, O-demethylation, and oxidative deamination. Alpha-hydroxylation of metoprolol is stereo-selective. The oxidative metabolism of metoprolol is under genetic control with a major contribution of the polymorphic cytochrome P450 isoform 2D6 (CYP2D6). However, the cytochrome P450 2D6 dependent metabolism of metoprolol seems to have little or no effect on safety or tolerability of the drug. None of the metabolites of metoprolol contribute significantly to its beta-blocking effect.
The average elimination half-life of metoprolol is 3 to 4 hours; in poor metabolisers the half-life may be 7 to 9 hours. Following single oral administration of 100 mg metoprolol the median clearance were 31, 168, and 367 L/h in poor metabolizers, extensive metabolizers, and ultra-rapid metabolizers, respectively. The renal clearance of the stereo-isomers does not exhibit stereo-selectivity in renal excretion. Approximately 95% of the dose can be recovered in urine. In most subjects (extensive metabolisers), less than 5% of an oral dose, and less than 10% of an intravenous dose, is excreted as unchanged drug. In poor metabolisers, up to 30% or 40% of oral or intravenous doses, respectively, may be excreted unchanged. The total plasma clearance of metoprolol after intravenous administration is approximately 1 L/min.
Metoprolol exhibits saturable pre-systemic metabolism leading to non-proportionate increase in the exposure with increased dose. However, a dose propionate pharmacokinetics is expected with extended release formulations.
Food appeared to increase the rate of absorption of metoprolol leading to a slightly higher maximum plasma concentration at earlier time. However, it does not impact significantly on the clearance or the time at which the maximum peak concentration is observed (Tmax).
In order to minimize the effect-variations within the individual, it is recommended that Lopresor should always be taken in standardized relation with food: If physician ask the patient to take Lopresor either before the breakfast or with the breakfast then the patient should continue taking Lopresor with same schedule during the course of therapy.
Slow Lopresor can be taken with or without meals preferably in the morning.
The geriatric population may show slightly higher plasma concentrations of metoprolol as a combined result of a decreased metabolism of the drug in elderly population and a decreased hepatic blood flow. However, this increase is not clinically significant or therapeutically relevant. Metoprolol does not accumulate on repeated administration and there is no necessity of dosage adjustment in elderly population.
Pharmacokinetics of metoprolol is not impacted in patient with renal impairment. However, there is a possibility of accumulation of one of its less active metabolite in patients with a creatinine clearance below 5 mL/min, and this accumulation would not influence the beta-blocking properties of metoprolol. Patients with renal impairment may usually be treated with normal dose.
Since the drug is primarily eliminated by hepatic metabolism, hepatic impairment may impact the pharmacokinetics of metoprolol. The elimination half-life of metoprolol is considerably prolonged, depending on severity (up to 7.2 h), in patients with liver impairment. Patients with a portacaval anastomosis.
Patients with a portacaval anastomosis had a systemic clearance of an intravenous dose of approximately 0.3 L/min and area under concentration-time curve (AUC) values up to 6-fold higher than those in healthy subjects.
Inflammatory disease has no effect on the pharmacokinetics of metoprolol.
Hyperthyroidism may increase the presystemic clearance of metoprolol.
The oxidative metabolism of metoprolol is under genetic control with a major contribution of the polymorphic cytochrome P450 isoform 2D6 (CYP2D6). There are marked ethnic differences in the prevalence of the poor metabolizer phenotype. Approximately 7% of Caucasians and less than 1% Orientals are poor metabolizers. CYP2D6 poor metabolizers exhibit several-fold higher plasma concentrations of metoprolol than extensive metabolizer with normal CYP2D6 activity.
Reproduction toxicity studies in mice, rats and rabbits did not indicate teratogenic potential for metoprolol tartrate. High doses were associated with some maternal toxicity, and growth delay of the offspring both in utero and after birth. There was no evidence of impaired fertility in rats at oral doses up to 500 mg/kg.
Metoprolol tartrate was devoid of mutagenic/genotoxic potential in the bacterial cell system (Ames) test and in vivo assays involving mammalian somatic cells or germinal cells of male mice.
Metoprolol tartrate was not carcinogenic in mice and rats after oral administration of doses up to 800 mg/kg for 21 to 24 months.
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