Priacin Mechanism of Action

Pharmacotherapeutic Group: HMG-CoA reductase inhibitor. ATC Code: C10A A01.
Pharmacology: Pharmacodynamics: After oral ingestion, simvastatin, which is an inactive lactone, is hydrolyzed in the liver to the corresponding active β-hydroxyacid form which has a potent activity in inhibiting HMG-CoA reductase (3-hydroxy-3-methylglutaryl CoA reductase). This enzyme catalyses the conversion of HMG-CoA to mevalonate, an early and rate-limiting step in the biosynthesis of cholesterol.
Simvastatin has been shown to reduce both normal and elevated low-density lipoprotein cholesterol (LDL-C) concentrations. Low-density lipoprotein (LDL) is formed from very low-density protein (VLDL) and is catabolised predominantly by the high affinity LDL receptor. The mechanism of the LDL-lowering effect of simvastatin may involve both reduction of VLDL-cholesterol (VLDL-C) concentration and induction of the LDL receptor, leading to reduced production and increased catabolism of LDL-C. Apolipoprotein B (apo B) also falls substantially during treatment with simvastatin. In addition, simvastatin moderately increases high-density lipoprotein cholesterol (HDL-C) and reduces plasma triglycerides (TG). As a result of these changes, the ratios of total- to HDL-C and LDL- to HDL-C are reduced.
High Risk or Existing Coronary Heart Disease (CHD): In the heart protection study (HPS), the effects of therapy with Priacin were assessed in 20,536 patients (40-80 years), with or without hyperlipidaemia and with CHD other occlusive arterial disease or diabetes mellitus. In this study, 10,269 patients were treated with simvastatin 40 mg/day and 10,267 patients were treated with placebo for a mean duration of 5 years. At baseline, 6793 patients (33%) had LDL-C levels <116 mg/dL; 5063 patients (25%) had levels between 116 mg/dL and 135 mg/dL and 8680 patients (42%) had levels >135 mg/dL.
Treatment with Priacin 40 mg/day compared with placebo significantly reduced the risk of all cause mortality [1328 (12.9%) for simvastatin-treated patients versus 1507 (14.7%) for patients given with placebo; p=0.0003], due to an 18% reduction in coronary death rate [587 (5.7%) versus 707 (6.9%); p=0.0005; absolute risk reduction of 1.2%]. The reduction in nonvascular deaths did not reach statistical significance. Priacin also decreased the risk of major coronary events [a composite endpoint comprised of nonfatal myocardial infarction (MI) or CHD death] by 27% (p<0.0001). Simvastatin reduced the need for undergoing coronary revascularization procedures (including coronary artery bypass grafting or percutaneous transluminal coronary angioplasty) and peripheral and other noncoronary revascularization procedures by 30% (p<0.0001) and 16% (p=0.006), respectively. Simvastatin reduced the risk of stroke by 25% (p<0.0001), attributable to a 30% reduction in ischemic stroke (p<0.0001). In addition, within the subgroup of patients with diabetes, simvastatin reduced the risk of developing macrovascular complications including peripheral revascularization procedures (surgery or angioplasty), lower limb amputations or leg ulcers by 21% (p=0.0293). The proportional reduction in event rate was similar in each subgroup of patients studies, including those without coronary disease but who had cerebrovascular or peripheral artery disease, men and women those aged either under or >70 years at entry into the study, presence or absence of hypertension and notably those with LDL-C <3 mmol/L at inclusion.
In the Scandinavian simvastatin survival study (4S), the effect of therapy with simvastatin on total mortality was assessed in 4444 patients with CHD and baseline total cholesterol 212-309 mg/dL (5.5-8 mmol/L). In this multicenter, randomized, double-blind, placebo-controlled study, patients with angina or a previous MI were treated with diet, standard care and either simvastatin 20-40 mg/day (n=2221) or placebo (n=2223) for a median duration of 5.4 years. Simvastatin reduced the risk of death by 30% (absolute risk reduction of 3.3%). The risk of CHD death was reduced by 42% (absolute risk reduction on 3.3%). Simvastatin also decreased the risk of having major coronary events (CHD death plus hospital-verified and silent nonfatal MI) by 34%. Furthermore, simvastatin significantly reduced the risk of fatal plus nonfatal cerebrovascular events (stroke and transient ischemic attacks) by 28%. There was no statistically significant difference between groups in noncardiovascular mortality.
Primary Hypercholesterolaemia and Combined Hyperlipidaemia: In studies comparing the efficacy and safety of simvastatin 10, 20, 40 and 80 mg daily in patients with hypercholesterolemia, the mean reductions of LDL-C were 30%, 38%, 41% and 47%, respectively. In studies of patients with combined (mixed) hyperlipidaemia on simvastatin 40 and 80 mg the median reduction in triglycerides were 28% and 33% (Placebo: 2%), respectively and mean increases in HDL-C were 13% and 16% (Placebo: 3%), respectively.
Pharmacokinetics: Simvastatin is an inactive lactone which is readily hydrolyzed in vivo to the corresponding β-hydroxyacid, a potent inhibitor of HMG-CoA reductase. Hydrolysis takes place mainly in the liver; the rate of hydrolysis in human plasma is very slow.
Absorption: In man, simvastatin is well absorbed and undergoes extensive hepatic first-pass extraction. The extraction in the liver is dependent on the hepatic blood flow. The liver is the primary site of action of the active form. The availability of the β-hydroxyacid to the systemic circulation following an oral dose of simvastatin was found to be <5% of the dose. Maximum plasma concentration of active inhibitors is reached approximately 1-2 hrs after administration of simvastatin. Concomitant food intake does not affect the absorption.
The pharmacokinetics of single and multiple doses of simvastatin showed that no accumulation of medicinal product occurred after multiple dosing.
Distribution: Both simvastatin and its β-hydroxyacid metabolite are highly bound (>95%) to human plasma proteins.
Elimination: Simvastatin is a substrate of cytochrome P-450 3A4 (CYP3A4) (see Contraindications and Interactions). The major metabolites of simvastatin present in human plasma are the β-hydroxyacid and 4 additional active metabolites. Following an oral dose of radioactive simvastatin to man, 13% of the radioactivity was excreted in the urine and 60% in the faeces within 96 hrs. The amount recovered in the faeces represents absorbed medicinal product equivalents excreted in bile, as well as unabsorbed medicinal product. Following an IV injection of the β-hydroxyacid metabolite, its t_½ averaged 1.9 hrs. An average of only 0.3% of the IV dose was excreted in urine as inhibitors.
Toxicology: Preclinical Safety Data: Based on conventional animal studies regarding pharmacodynamics, repeated dose toxicity, genotoxicity and carcinogenicity, there are no other risks for the patient than may be expected on account of the pharmacological mechanism. At maximally tolerated doses in both the rat and the rabbit, simvastatin produced no foetal malformations and had no effects on fertility, reproductive function or neonatal development.