Chemical formula: C₂₇H₃₈N₂O₄ Molecular mass: 454.602 g/mol PubChem compound: 2520
Verapamil is a calcium antagonist which blocks the inward movement of calcium ions in cardiac muscle cells, in smooth muscle cells of the coronary and systemic arteries and in cells of the intracardiac conduction system. Because of its effect on the movement of calcium in the intracardiac conduction system, verapamil reduces automaticity, decreases conduction velocity and increases the refractory period.
Verapamil, a phenylalkylamine calcium antagonist, has a balanced profile of cardiac and peripheral effects. It lowers heart rate, increases myocardial perfusion and reduces coronary spasm. In a clinical study in patients after myocardial infarction, verapamil reduced total mortality, sudden cardiac death and reinfarction rate.
Verapamil reduces total peripheral resistance and lowers high blood pressure by vasodilation, without reflex tachycardia. Because of its use-dependent action on the voltage-operated calcium channel, the effects of verapamil are more pronounced on high than on normal blood pressure.
As early as day one of treatment, blood pressure falls; the effect is found to persist also in long-term therapy. Verapamil is suitable for the treatment of all types of hypertension: for monotherapy in mild to moderate hypertension; combined with other antihypertensives (in particular with diuretics and, according to more recent findings, with ACE inhibitors) in more severe types of hypertension. In hypertensive diabetic patients with nephropathy, verapamil in combination with ACE inhibitors led to a marked reduction of albuminuria and to an improvement of creatinine clearance.
Verapamil hydrochloride is a racemic mixture consisting of equal portions of the R-enantiomer and the S-enantiomer. Verapamil is extensively metabolized. Norverapamil is one of 12 metabolites identified in urine, has 10 to 20% of the pharmacologic activity of verapamil and accounts for 6% of excreted drug. The steady-state plasma concentrations of norverapamil and verapamil are similar.
Steady state after multiple once daily dosing is reached after three to four days.
Greater than 90% of verapamil is rapidly absorbed from the small intestine after oral administration. Mean systemic availability of the unchanged compound after a single dose of verapamil is approximately 33%, owing to an extensive hepatic first-pass metabolism. Bioavailability is about two times higher with repeated administration. Peak verapamil plasma levels are reached four to five hours after oral administration. The peak plasma concentration of norverapamil is attained approximately five hours after oral administration. The presence of food has no effect on the bioavailability of verapamil.
Verapamil acts within 1-2 hours after oral administration with a peak plasma concentration after 1-2 hours. There is considerable interindividual variation in plasma concentrations.
Verapamil is widely distributed throughout the body tissues, the volume of distribution ranging from 1.8–6.8 L/kg in healthy subjects. Plasma protein binding of verapamil is approximately 90%.
Verapamil is extensively metabolized. In vitro metabolic studies indicate that verapamil is metabolized by cytochrome P450 CYP3A4, CYP1A2, CYP2C8, CYP2C9 and CYP2C18. 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.
Following oral administration, the elimination half-life is three to seven hours. Approximately 50% of an administered dose is eliminated renally within 24 hours, 70% within five days. Up to 16% of a dose is excreted in the feces. About 3% to 4% of renally excreted drug is excreted as unchanged drug. The total clearance of verapamil is nearly as high as the hepatic blood flow, approximately 1 L/h/kg (range: 0.7-1.3 L/h/kg).
Following intravenous infusion, verapamil is eliminated bi-exponentially, with a rapid early distribution phase (half-life about four minutes) and a slower terminal elimination phase (half-life two to five hours).
Limited information on the pharmacokinetics in the paediatric population is available. After intravenous dosing, the mean half-life of verapamil was 9.17 hours and the mean clearance was 30 L/h, whereas it is around 70 L/h for a 70-kg adult.
Aging may affect the pharmacokinetics of verapamil given to hypertensive patients. Elimination half-life may be prolonged in the elderly. The antihypertensive effect of verapamil was found not to be age-related.
Impaired renal function has no effect on verapamil pharmacokinetics, as shown by comparative studies in patients with end-stage renal failure and subjects with healthy kidneys. Verapamil and norverapamil are not significantly removed by hemodialysis.
The half-life of verapamil is prolonged in patients with impaired liver function owing to lower oral clearance and a higher volume of distribution.
Verapamil hydrochloride, administered intravenously, has been shown to be rapidly metabolized.
Verapamil crosses the placenta and is excreted in breast milk.
Reproduction studies have been performed in rabbits and rats at oral verapamil doses up to 0.6 and 1.2 times respectively the maximum recommended human oral daily dose based on a body surface area comparison (mg/m²) and have revealed no evidence of teratogenicity. In the rat, however, a dose similar to the clinical dose was embryocidal and retarded fetal growth and development. These effects occurred in the presence of maternal toxicity (reflected by reduced food consumption and reduced weight gain of dams). This oral dose has also been shown to cause hypotension in rats.
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