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indicationFor the treatment of hypercholesterolemia and to reduce the risk of cardiovascular disease.
pharmacologyThe primary cause of cardiovascular (CV) disease is atherosclerotic plaque formation and sustained elevation of cholesterol in the blood increases the risk of CV disease. Pravastatin lowers hepatic production of cholesterol by competitively inhibiting HMG-CoA reductase, the enzyme that catalyzes the rate-limiting step in the cholesterol biosynthesis pathway via the mevalonic acid pathway. Decreased hepatic cholesterol levels causes increased uptake of low density lipoprotein (LDL) cholesterol and reduces cholesterol levels in the circulation. Pravastatin also inhibits hepatic synthesis if VLDL. At therapeutic doses, pravastatin lowers LDL cholesterol by 20-30%, increase high density lipoprotein (HDL) cholesterol by 3-10%, and decrease plasma triglycerides by 19-34%. HDL cholesterol is thought to confer protective effects against CV disease, whereas high LDL and triglyceride levels are associated with higher risk of disease.
mechanism of actionPravastatin is structurally similar to the HMG, a substituent of the endogenous substrate of HMG-CoA reductase. Unlike its parent compound, mevastatin, and statins such as lovastatin and simvastatin, pravastatin does not need to be activated in vivo. Its hydrolyzed lactone ring mimics the tetrahedral intermediate produced by the reductase allowing the agent to bind with a much greater affinity than its natural substrate. The bicyclic portion of pravastatin binds to the coenzyme A portion of the active site.
toxicitySide effects include diarrhea, nausea, constipation, gas abdominal pain, myopathy, myositis, rhabdomyolysis, and hepatotoxicity. LD50=mg/kg (orally in rat)
biotransformationHepatic, there is a small amount of metabolism by P450 enzymes, but this effect is so minimal that inhibitory pharmacokinetic drug interactions have no real effect on its overall activity and elimination. An in vitro study which found moderate affinity for P450 2C9 (major), 2D6 and 3A4.
absorptionAverage oral absorption of pravastatin is 34% and absolute bioavailability is 17%.
half life77 hours
route of eliminationApproximately 20% of a radiolabeled oral dose is excreted in urine and 70% in the feces.
drug interactionsBezafibrate: Increased risk of myopathy/rhabdomyolysis
Colchicine: Increased risk of rhabdomyolysis with this combination
Colesevelam: Bile Acid Sequestrants may decrease the serum concentration of Pravastatin. Administer pravastatin at least 1 hour before or 4 hours after administration of bile-acid resins (eg, cholestyramine, colestipol, colesevelam) to minimize the risk for any significant interaction.
Cyclosporine: Possible myopathy and rhabdomyolysis
Fenofibrate: Increased risk of myopathy/rhabdomyolysis
Gemfibrozil: Increased risk of myopathy/rhabdomyolysis
Tipranavir: Tipranavir may increase the plasma concentration of Pravastatin. Consider alternate therapy.