Veral Mechanism of Action

Pharmacotherapeutic group: Calcium channel blockers, selective calcium channel blockers with direct cardiac effects, phenylalkylamine derivatives. ATC code: C08DA01.
Pharmacology: Pharmacodynamics: Verapamil hydrochloride belongs to the group of calcium antagonists. These substances have an inhibitory effect on the calcium influx via muscle cell membranes. Verapamil hydrochloride also acts as a calcium antagonist on smooth musculature, particularly in the area of vessels and gastrointestinal tract. The effect on the smooth vascular muscles is manifested as vasodilation. As a calcium antagonist, verapamil hydrochloride also exerts a marked effect on the myocardium. The effect on the AV nodes is seen in the form of prolonged conduction time.
A negative-inotropic effect can occur on the working myocardium.
In humans, verapamil hydrochloride causes a decrease in total peripheral resistance due to vasodilation; no increase in cardiac output by reflex action occurs. The result is a corresponding fall in blood pressure.
Pharmacokinetics: Verapamil hydrochloride is a racemic mixture consisting of equal portions of the R-enantiomer and the S-enantiomer. Verapamil is extensively metabolised. 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.
Absorption: 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 non-retarded verapamil is 22% and that of retarded verapamil 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 one to two hours after non-retarded administration, and four to five hours after retarded administration. The peak plasma concentration of norverapamil is attained approximately one and five hours after non-retarded or retarded administration, respectively.
The presence of food has no effect on the bioavailability of verapamil.
Distribution: 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%.
Metabolism: Verapamil is extensively metabolised. In vitro metabolic studies indicate that verapamil is metabolised 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 an appreciable pharmacological effect (approximately 20% that of the parent compound), which was observed in a study with dogs.
Elimination: 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).
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 faeces. About 3% to 4% of renally excreted active substance is excreted unchanged. 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).
There are larger inter-individual differences in clearance.
Special populations: Paediatric patients: 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. Steady-state plasma concentrations appear to be somewhat lower in the paediatric population after oral dosing compared to those observed in adults.
Geriatric patients: Aging may affect the pharmacokinetics of verpamil 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.
Renal insufficiency: 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 haemodialysis.
Hepatic insufficiency: The half-life of verapamil is prolonged in patients with impaired liver function owing to lower oral clearance and a higher volume of distribution.
Toxicology: Preclinical safety data: In vitro and in vivo studies gave no evidence that verapamil hydrochloride exerts mutagenic effects.
A long-term study in rats gave no evidence that verapamil hydrochloride has a tumorigenic potential.
Embryotoxicity studies in rabbits and rats gave no evidence of a teratogenic potential employing daily doses of up to 15 mg/kg and 60 mg/kg, respectively. However, in the maternal-toxic range, embryolethality and growth retardation (low birth weight in the offspring) occurred in rats.