Lacipil Mechanism of Action

Pharmacology: Pharmacodynamics: Lacidipine is a specific and potent calcium antagonist, with a predominant selectivity for calcium channels in the vascular smooth muscle.
Its main action is to dilate peripheral arterioles, reducing peripheral vascular resistance and lowering blood pressure.
Following the oral administration of 4 mg Lacidipine (Lacipil) to volunteer subjects, a minimal prolongation of QTc interval has been observed.
In the four-year randomised double-blind ELSA (European Lacidipine Study on Atherosclerosis) trial, the primary efficacy parameter for atherosclerosis was the measurement of carotid intima-media thickness (IMT) by ultrasonography. The results in the patients treated with Lacidipine (Lacipil) showed significant effects on IMT variables, consistent with an anti-atherogenic effect.
Pharmacokinetics: Absorption: Lacidipine is rapidly but poorly absorbed from the gastrointestinal tract following oral dosing and undergoes extensive first-pass metabolism in the liver. Absolute bioavailability averages about 10%. Peak plasma concentrations are reached between 30 and 150 min.
Metabolism: There are four principal metabolites which possess little, if any pharmacodynamic activity. The drug is eliminated primarily by hepatic metabolism (involving P450 CYP3A4). There is no evidence that lacidipine causes either induction or inhibition of hepatic enzymes.
Elimination: Approximately 70% of the administered dose is eliminated as metabolites in the faeces and the remainder as metabolites in the urine.
The average terminal half-life of lacidipine ranges from between 13 and 19 h at steady state.
Toxicology: Pre-clinical Safety Data: The only significant toxicological findings with lacidipine were reversible and consistent with the known pharmacological effects of calcium channel antagonists at high doses - decreased myocardial contractility and gingival hyperplasia in rats and dogs, and constipation in rats.
No evidence of developmental toxicity was seen following administration of lacidipine to pregnant rats or rabbits. In a fertility and reproductive study in rats, embryotoxicity was seen at maternally toxic doses and, consistent with the expected pharmacological activity of a calcium channel antagonist on the myometrium, increased duration of gestation and difficulties during parturition were seen at high doses. Calcium channel antagonists are known to interfere pharmacologically with the normal function of the myometrium during parturition, leading to decreased contractility.
Lacidipine was not genotoxic in a battery of in vitro and in vivo tests. There was no evidence of carcinogenic potential in mice. Consistent with other calcium channel antagonists, there was an increase in benign interstitial cell tumours in the testis in a carcinogenicity study in rats. However, the endocrine mechanisms believed to be involved in the production of interstitial cell hyperplasia and adenomas in the rat are not relevant to humans.