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Beta Blocking Agent (Selective).
Pharmacology: Pharmacodynamics: Metoprolol is a beta-adrenergic receptor blocking agent which acts preferentially on beta1 adrenoceptors, mainly located in cardiac muscle. This preferential effect is not absolute since at higher doses metoprolol also inhibits beta2 adrenoceptors, mainly located in the bronchial and vascular musculature. Metoprolol has no partial agonist (intrinsic sympathomimetic) activity and membrane-stabilizing activity is detectable only at doses much greater than required for beta blockade.
Metoprolol's beta-blocking activity is manifested by (1) a decrease in heart rate and cardiac output at rest and upon exercise, (2) decrease in systolic blood pressure upon exercise, (3) inhibition of isoproterenol-induced tachycardia, and (4) decrease in reflex orthostatic tachycardia.
The antihypertensive mechanism of beta-blockers has not been elucidated. Several possible mechanisms have been proposed: (1) competitive antagonism of catecholamines at peripheral (particularly cardiac) adrenergic neuron sites resulting in decreased cardiac output, (2) a central effect leading to decreased sympathetic outflow to the periphery, and (3) suppression of renin activity.
In angina pectoris, metoprolol decreases the frequency and severity of ischemic episodes and increases physical working capacity. These beneficial effects may be due to decreased myocardial oxygen demand as a result of the decreased heart rate and myocardial contractility.
In supraventricular tachycardia, atrial fibrillation, ventricular extrasystoles or other ventricular arrhythmias, metoprolol has a regulating effect on the heart rate. Its anti-arrhythmic effect is due to inhibition of automaticity of pacemaker cells and prolongation of atrioventricular (AV) conduction.
Metoprolol decreased mortality in patients with suspected or confirmed myocardial infarction. This effect is due to a decreased incidence of severe ventricular arrhythmias and limitation of infarct size. Metoprolol has also been shown to decrease the incidence of non-fatal myocardial reinfarction.
Pharmacokinetics: Metoprolol is readily and completely absorbed from the gastrointestinal tract. Peak plasma metoprolol concentrations are achieved 1.5 to 2 hours after dosing. Due to extensive hepatic first-pass metabolism, the bioavailability of a single metoprolol dose is about 50%, increasing to 70% during repeated administration. Ingestion with food may increase the bioavailability of a single oral dose by about 20 to 40%.
Metoprolol is widely distributed, with a volume of distribution of 3.2 to 5.6 L/kg. It crosses the blood-brain barrier and the placenta, and is distributed into breast milk. It is about 10% bound to plasma protein. Metoprolol levels in cerebrospinal fluid are similar to those in plasma in patients with hypertension.
Metoprolol is extensively metabolized in the liver, predominantly by the cytochrome P450 isoenzyme CYP2D6, and undergoes oxidative deamination, O-dealkylation followed by oxidation, and aliphatic hydroxylation. There are marked ethnic differences in the prevalence of poor metabolizers phenotype. About 7% of Caucasians and less than 1% Orientals are poor metabolizers. CYP2D6 poor metabolizers exhibit several-fold higher plasma metoprolol concentrations than extensive metabolizers with normal CYP2D6 activity. However, the CYP2D6 dependent metabolism of metoprolol appears to have little or no effect on its safety or tolerability.
Metoprolol and its inactive metabolites are excreted in urine mainly via glomerular filtration, although tubular secretion and reabsorption may be involved. Metoprolol's average elimination half-life is 3 to 4 hours; it may be 7 to 9 hours in poor metabolizers. About 95% of the dose can be recovered in urine within 72 hours. Less than 5% of an oral metoprolol dose is excreted unchanged in urine.
The excretion of metabolites is decreased in patients with renal impairment. Significant accumulation of metabolites will occur only in patients with creatinine clearance of about 5 mL/min or less, and this accumulation would not influence metoprolol's beta-blocking properties.
Liver cirrhosis may increase the bioavailability of unchanged metoprolol and decrease its total clearance.
Inflammatory disease has no effect on metoprolol's pharmacokinetics. Hyperthyroidism may increase presystemic metoprolol clearance.
