Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties
Pharmacotherapeutic group

Pharmacotherapeutic group: Beta blocking agents; ATC code: C07AB02
Mechanism of Action
Neobloc is a cardioselective beta-adrenergic blocking agent. It has a relatively greater blocking effect on beta1-receptors (i.e. 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.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties
Absorption
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%.

Distribution
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 blood- brain barrier, the placenta. It is slightly bound to plasma protein. The medicinal product is approx. 5–10% bound to plasma proteins.

Biotransformation
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.

Elimination
The metabolites are excreted in the urine together with only small amounts of unchanged metoprolol. Metoprolol is excreted in breast milk.
Special population
Elderly:
In comparison with administration to younger patients, the pharmacokinetics of metoprolol when administered to older patients shows no significant differences.

Renal impairment:
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.

Hepatic impairment:
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.

Severe angina pectoris
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.

Respiratory impairment
It has not been proven that beta-blockers with ISA give a lower risk for bronchospasm or enhancement of pre-existing bronchospastic complaints.