Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: selective calcium channel blockers, calcium blockers with direct cardiac effects, phenylalkylamines, ATC code CO8DA01.
Verapamil hydrochloride blocks the trans-membrane influx of calcium ions into myocardial cells and smooth muscle vessels. It decreases myocardial oxygen demand by directly intervening in metabolic processes that consume myocardial energy and indirectly by reducing cardiac load. The blocking effect of calcium channels on the smooth muscles of the coronary arteries increases the irrigation of the myocardium, even in the areas of post- stenosis and relieves coronary spasm. The antihypertensive action of verapamil is based on the decrease of peripheral vascular resistance, without reflex tachycardia.
Verapamil hydrochloride has a marked antiarrhythmic effect, especially in supraventricular arrhythmias. It delays conduction in the atrioventricular node. The result, depending on the type of arrhythmia, is the restoration of sinus heart rate and/or normalization of ventricular rate. The normal frequency of heart contractions is not affected, or is slightly decreased.

Pharmacokinetic Properties

5.2 Pharmacokinetic properties
Verapamil hydrochloride is rapidly absorbed in the small intestine. Absorption is 90-92%.
Peak plasma concentrations of verapamil are reached 1-2 hours after administration of the prolonged-release form. The plasma half-life is 3-7 hours. Verapamil is approximately 90% bound to plasma proteins.
The mean systemic bioavailability of verapamil after a single dose is approximately 22% due to extensive hepatic metabolism on first pass. Bioavailability is 1.5 to 2 times higher with repeated administration. In patients with cirrhosis of the liver, a considerable increase in systemic bioavailability is expected.
The substance is metabolized to a large extent. In humans, a large number of metabolites were identified, of which 12 were identified.
Verapamil is extensively metabolized. In healthy men, orally administered verapamil hydrochloride undergoes extensive metabolism in the liver, with 12 metabolites having been identified, most in only trace amounts. The major metabolites have been identified as various N and O‐dealkylated products of verapamil. Of these metabolites, only norverapamil has any appreciable pharmacological effect (approximately 20% that of the parent compound), which was observed in a study with dogs.
Verapamil and its metabolites are mainly eliminated by the kidney. Only 3-4% of the dose is eliminated unchanged. A proportion of 50% of the dose is eliminated by the kidneys in 24 hours and 70% in 5 days. Up to 16% of the dose is excreted in the faeces. Renal dysfunction has no effect on the pharmacokinetics of verapamil, as shown in comparative studies that included patients with end-stage renal disease and subjects with healthy kidneys. The elimination half-life is prolonged in patients with cirrhosis of the liver due to low oral clearance and higher volume of distribution.