Pravastatin

Indications

Pravastatin is primarily indicated for the prevention of coronary events in hypercholesterolemic patients who do not exhibit clinical symptoms of coronary heart disease. Its use is associated with a reduced risk of myocardial infarction, the need for myocardial revascularization procedures, and cardiovascular mortality. Pravastatin is also employed in the secondary prevention of cardiovascular events for patients with clinically evident coronary heart disease. It is effective in lowering the risk of total mortality by decreasing coronary death, myocardial infarctions, strokes, and transient ischemic attacks while also slowing the progression of coronary atherosclerosis. Additionally, pravastatin acts as adjunctive therapy for patients with primary dysbetalipoproteinemia (type III hyperlipidemia) who do not respond adequately to dietary interventions. Dyslipidemia, characterized by elevated plasma cholesterol and triglycerides or low high-density lipoprotein levels, poses an increased risk for atherosclerosis development.

Pharmacodynamics

Pravastatin works by inhibiting 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase, which leads to an increased expression of hepatic LDL receptors and consequently lowers plasma LDL cholesterol levels. The drug significantly reduces total cholesterol, LDL cholesterol, and apolipoprotein B levels. It also moderately decreases very-low-density lipoproteins (VLDL) cholesterol and triglycerides while increasing high-density lipoprotein (HDL) cholesterol and apolipoprotein A. In clinical studies involving patients with prior myocardial infarction or angina and high total cholesterol, pravastatin treatment resulted in an 18% reduction in total cholesterol, a 27% reduction in LDL cholesterol, a 6% decrease in triglycerides, and a 4% increase in HDL cholesterol. Moreover, it lowered the risk of death from coronary disease by 24%. When taken with cholestyramine, pravastatin can reduce LDL levels by 50% and slow the progression of atherosclerosis, thereby reducing the risk of myocardial infarction and mortality.

Absorption

Following oral administration, pravastatin is absorbed within 60 to 90 minutes. It has a low bioavailability of approximately 17%, which is attributed to its polar nature, leading to significant first-pass metabolism and incomplete absorption. Pravastatin is swiftly absorbed from the upper part of the small intestine through proton-coupled carrier-mediated transport and is then taken up by the liver via the sodium-independent bile acid transporter. The peak serum concentration, ranging from 30 to 55 mcg/L, is generally reached within 1 to 1.5 hours, with an area under the curve (AUC) spanning 60 to 90 mcg.h/L.

Metabolism

After administration, pravastatin undergoes extensive first-pass extraction in the liver. Unlike many drugs, its metabolism does not primarily involve cytochrome P-450 isoenzymes and only occurs to a minor extent in the liver. Consequently, pravastatin is highly available to peripheral tissues. The drug's metabolism is largely governed by glucuronidation reactions, with minimal involvement of CYP3A enzymes. Importantly, pravastatin does not result in active metabolites following its metabolic processes. The primary metabolite generated is the 3-alpha-hydroxy isomer, which has clinically negligible activity.

Mechanism of Action

Pravastatin functions as a precise inhibitor of the human hepatic enzyme HMG-CoA reductase, which plays a crucial role in the biosynthesis of cholesterol. By targeting this enzyme, pravastatin disrupts the early-limiting step of cholesterol production, leading to a notable decrease in its synthesis. This decrease in cholesterol subsequently promotes an increase in the number of LDL receptors on cell surfaces, thus enhancing the receptor-mediated metabolism and clearance of LDL. Furthermore, the inhibition of LDL production by pravastatin results in a reduced synthesis of VLDL in the liver, as LDL serves as a precursor for these molecules.