Apo-Pravastatin Mechanism of Action

Pharmacotherapeutic Group: Lipid Metabolism Regulator.
Pharmacology: Pharmacodynamics: Pravastatin sodium is one of a new class of lipid-lowering compounds, the HMG-CoA reductase inhibitors (statins) that reduce cholesterol biosynthesis. These agents are competitive inhibitors of 3-hydroxy-3-methylglutaryl-co-enzyme A (HMG-CoA) reductase, the enzyme catalyzing the early rate-limiting step in cholesterol biosynthesis, conversion of HMG-CoA to mevalonate. Pravastatin is isolated from a strain of Penicillium citrinum. The active drug substance is the hydroxyacid form.
Pravastatin produces its lipid-lowering effect in two ways. First, as a consequence of its reversible inhibition of HMG-CoA reductase activity, it effects modest reductions in intracellular pools of cholesterol. This results in an increase in the number of Low Density Lipoproteins (LDL)-receptors on cell surfaces and enhanced receptor-mediated catabolism and clearance of circulating LDL. Second, pravastatin inhibits LDL production by inhibiting hepatic synthesis of Very Low Density Lipoproteins (VLDL), the LDL precursor.
Epidemiologic and clinical studies have associated the risk of coronary artery disease (CAD) with elevated levels of Total-C, LDL-C and decreased levels of HDL-C. These abnormalities of lipoprotein metabolism are considered as major contributors to the development of the disease. Other factors, e.g., interactions between lipids/lipoproteins and endothelium, platelets and macrophages, have also been incriminated in the development of human atherosclerosis and of its complications.
In long-term, prospective clinical trials, effective treatment of hypercholesterolemia/dyslipidemia has consistently been associated with a reduction in the risk of CAD.
Treatment with pravastatin has been shown to reduce circulating Total-C, LDL-C, and apolipoprotein B, modestly reduce VLDL-C and triglycerides (TG) while producing increases of variable magnitude in HDL-C and apolipoprotein A. Clinical trials suggest that pravastatin's effect on reducing clinical events appears to incorporate both cholesterol modification and some ancillary mechanism.
Pravastatin has complex pharmacokinetic characteristics.
Clinical Studies: In the West of Scotland Study (WOS), the effect of pravastatin treatment on fatal and non-fatal coronary heart disease (CHD) was assessed in 6,595 patients (aged 45 to 66 years) without a previous myocardial infarction, but with elevated LDL-C levels between 4-6.7 mmol/L (156-254 mg/dL). The patients were followed for a median of 4.8 years.
Pravastatin significantly reduced the rate of first coronary events (either CHD death or non-fatal MI) by 31% [248 events in the placebo group (CHD death=44, non-fatal MI=204) vs 174 events in the pravastatin group (CHD death=31, non-fatal MI=143), p=0.0001]. The effect of these cumulative cardiovascular event rates was evident after 6 months of treatment. The risk reduction with pravastatin was similar and significant throughout the entire range of baseline LDL cholesterol levels. This reduction was also similar and significant across the age range studied with a 40% risk reduction for patients younger than 55 years and a 27% risk reduction for patients 55 years and older.
Pravastatin also significantly decreased the risk for undergoing myocardial revascularization procedures [coronary artery bypass graft surgery by 37% (80 vs 51 patients, p=0.009) and coronary angiography by 31% (128 vs 90, p=0.007)]. Cardiovascular deaths were decreased by 32% (73 vs 50, p=0.03), and there was no increase in deaths from non-cardiovascular causes.
In the Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) study, the effect of pravastatin 40 mg daily was assessed in 9014 men and women with normal to elevated serum cholesterol levels [baseline Total-C=155-271 mg/dL (4.0-7.0 mmol/L); median Total-C=218 mg/dL (5.66 mmol/L); median LDL-C=150 mg/dL (3.88 mmol/L)], and who had experienced either a myocardial infarction or had been hospitalized for unstable angina pectoris in the preceeding 3 to 36 months.
Treatment with pravastatin significantly reduced the risk for CHD death by 24% (p=0.0004). The risk for coronary events (either CHD death or non-fatal MI) was significantly reduced by 24% (p<0.0001) in the pravastatin treated patients. The risk for fatal or non-fatal myocardial infarction was reduced by 29% (p<0.0001). Pravastatin reduced both the risk for total mortality by 23% (p<0.0001) and cardiovascular mortality by 25% (p<0.0001). The risk for undergoing myocardial revascularization procedures (coronary artery bypass grafting or percutaneous transluminal coronary angioplasty) was significantly reduced by 20% (p<0.0001) in the pravastatin treated patients. Pravastatin also significantly reduced the risk for stroke by 19% (p=0.0477). Treatment with pravastatin significantly reduced the number of days of hospitalization per 100 person-years of follow-up by 15% (p<0.001). The effect of pravastatin on reducing CHD events was consistent regardless of age, gender, or diabetic status.
In the Cholesterol and Recurrent Events (CARE) study, the effect of pravastatin 40 mg daily on coronary heart disease death and non-fatal MI was assessed in 4,159 men and women with normal serum cholesterol levels [baseline mean Total-C=209 mg/dL (5.4 mmol/L)], and who had experienced a myocardial infarction in the preceeding 3-20 months. Treatment with pravastatin significantly reduced the rate of a recurrent coronary event (either CHD death or non-fatal MI) by 24% [274 patients with events (13.3%) in the placebo group vs 212 patients (10.4%) in the pravastatin group, p=0.003]. The reduction in risk for this combined endpoint was significant for both men and women; in women, the reduction in risk was 43% (p=0.033). The risk of undergoing revascularization procedures (coronary artery bypass grafting or percutaneous transluminal coronary angioplasty) was significantly reduced by 27% (p<0.001) in the pravastatin treated patients (391 [19.6%] vs 294 [14.2%] patients). Pravastatin also significantly reduced the risk for stroke by 32% (p=0.032), and stroke or transient ischemic attack (TIA) combined by 26% [124 (6.3%) vs 93 (4.7%) patients, p=0.025].
Pravastatin monotherapy was effective in reducing both the progression of atherosclerosis and cardiovascular event rates in two controlled trials among patients with moderate hypercholesterolemia and atherosclerotic cardiovascular disease. In these two trials including this type of patient¹ (i.e. in a secondary prevention intervention), pravastatin monotherapy was shown to reduce the rate of progression of atherosclerosis as evaluated by quantitative angiography and B-mode ultrasound. This effect may be associated with an improvement in the coronary endpoints (fatal or non-fatal myocardial infarction). In these trials, however, no effect was observed in all cause mortality.