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Drugs

, Volume 53, Issue 2, pp 299–336 | Cite as

Pravastatin

A Reappraisal of its Pharmacological Properties and Clinical Effectiveness in the Management of Coronary Heart Disease
  • Malini Haria
  • Donna McTavish
Adis Drug Evaluation

Summary

Synopsis

Pravastatin is an HMG-CoA reductase inhibitor which lowers plasma cholesterol levels by inhibiting de novo cholesterol synthesis.

Pravastatin produces consistent dose-dependent reductions in both total and low density lipoprotein (LDL)-cholesterol levels in patients with primary hyper-cholesterolaemia. Favourable changes in other parameters such as total triglyceride and high density lipoprotein (HDL)-cholesterol levels are generally modest. Combination therapy with other antihyperlipidaemic agents such as cholestyramine further enhances the efficacy of pravastatin in patients with severe dyslipidaemias.

Available data suggest that pravastatin is effective in elderly patients and in patients with hypercholesterolaemia secondary to diabetes mellitus or renal disease.

The benefit of cholesterol-lowering in terms of patient outcomes is currently an area of considerable interest. Recently completed regression studies (PLAC I, PLACII, KAPS and REGRESS) show that pravastatin slows progression of atherosclerosis and lowers the incidence of coronary events in patients with mild to moderately severe hypercholesterolaemia and known coronary heart disease. Large scale primary (WOSCOPS) and secondary (CARE) prevention studies, moreover, demonstrate that pravastatin has beneficial effects on coronary morbidity and mortality. In WOSCOPS, all-cause mortality was reduced by 22%.

Pravastatin is generally well tolerated by most patients (including the elderly), as evidenced by data from studies of up to 5 years in duration. As with other HMG-CoA reductase inhibitors, myopathy occurs rarely (<0.1% of patients treated with pravastatin); approximately 1 to 2% of patients may present with raised serum levels of hepatic transaminases.

Thus, with its favourable effects on cardiovascular morbidity/mortality and total mortality, pravastatin should be considered a first-line agent in patients with elevated cholesterol levels, multiple risk factors or coronary heart disease who are at high risk of cardiovascular morbidity.

Pharmacodynamic Properties

Pravastatin inhibits HMG-CoA reductase, the enzyme which catalyses the rate-limiting step within the cholesterol biosynthetic pathway. By inhibiting de novo cholesterol production and reducing intracellular cholesterol stores, pravastatin stimulates the synthesis and activity of low density lipoprotein (LDL) receptors, thereby enhancing the clearance of atherogenic LDL-cholesterol. In vitro and in vivo data indicate that pravastatin exhibits hepatocellular tissue selectivity, with greatest inhibition of cholesterol synthesis occurring in the liver.

In hypercholesterolaemic patients, pravastatin produces consistent changes in total cholesterol, LDL-cholesterol, high density lipoprotein (HDL)-cholesterol and triglyceride levels; its effects on lipoprotein(a) are, however, variable.

Hypercholesterolaemic patients treated with pravastatin 10 to 20 mg/day also show decreases in apolipoprotein B (the major component of LDL) of 12 to 30%. Other major proteins found in HDL (apolipoprotein AI and AII) increase by 12 to 16%, while apolipoproteins CII, CIII and E [mainly found in chylomicrons and very low density lipoprotein (VLDL)-cholesterol] are reduced by 4 to 8%.

Pravastatin slows the progression of atherosclerosis in humans and may have beneficial effects in stabilising plaques, improving endothelial dysfunction, decreasing platelet thrombus formation, improving fibrinolytic activity and reducing the incidence of transient myocardial ischaemia. The drug appears to have no effect on adrenal and gonadal hormone production, gallstone formation or sleep patterns.

Pharmacokinetic Properties

Pravastatin is administered orally as the sodium salt of the active compound. It is rapidly absorbed with mean peak plasma concentrations (Cmax) occurring between 0.9 and 1.6 hours after single- or multiple-dose administration in hypercholesterolaemic patients. Dose-proportional increases in both Cmax and area under the plasma concentration-time curve were also observed. The drug has an oral bioavailability of 17%.

In healthy volunteers given intravenous pravastatin 10mg, the volume of distribution averaged 0.46 L/kg at steady-state. Approximately 50% of the drug is bound to plasma proteins. Tissue distribution studies in animals have demonstrated that pravastatin is selectively taken up by hepatic cells; negligible distribution into human breast milk has been reported.

The major metabolite of pravastatin, a 3α-hydroxy isomeric compound (SQ 31 906), has approximately one-tenth to one-fortieth of the HMG-CoA reductase inhibitory activity of pravastatin; 75% of the total inhibitory activity of pravastatin is attributable to the parent drug. Pravastatin undergoes extensive first-pass extraction in the liver (extraction ratio 0.66). It is rapidly excreted and has a terminal plasma elimination half-life of 1.3 to 2.6 hours. Approximately 70 and 20% of an oral dose is eliminated in faeces and urine, respectively, over 96 hours. In patients with renal or hepatic insufficiency, these dual routes of elimination may provide compensatory pathways for the excretion of pravastatin.

Clinical Effectiveness

The lipid-lowering efficacy of pravastatin has been well established in several large, controlled clinical trials evaluating patients with primary or secondary hypercholesterolaemia. Recent research has focused on assessing what benefits this has for normo- or hypercholesterolaemic patients with, or at risk of, coronary heart disease (CHD).

Recently completed regression studies (PLAC I, PLAC II, KAPS, REGRESS) show that pravastatin slows the progression of atherosclerosis and lowers the incidence of coronary events in patients with mild to moderately severe hypercholesterolaemia and evident CHD. Long term primary intervention data from WOSCOPS, moreover, demonstrate that pravastatin has beneficial effects on coronary morbidity and mortality, without associated increases in non-cardiovascular mortality. Combined primary end-points of nonfatal myocardial infarction or death from CHD were significantly reduced by 31%; all-cause mortality was lowered by 22%. The risk of recurrent nonfatal myocardial infarctions or death from CHD was also significantly reduced by 24% in patients receiving pravastatin in the CARE study (a secondary intervention trial). Relative reductions in risk were unaffected by age, presence of hypertension or diabetes, gender or smoking status. At present, pravastatin is the only HMG-CoA reductase inhibitor for which primary and secondary prevention data are available.

Combination therapy with other lipid-lowering agents such as cholestyramine, ω-3 fatty acids, gemfibrozil, nicotinic acid (niacin) or probucol enhances the efficacy of pravastatin; coadministration with cholestyramine may, however, negate the beneficial effects on triglycéride levels achieved with pravastatin monotherapy. Although concomitant use of gemfibrozil or nicotinic acid with pravastatin promotes further beneficial changes in both triglyceride and HDL-cholesterol levels, this combination should be used cautiously because of the potential increased risk of myopathy.

The lipid-lowering efficacy of pravastatin in elderly patients appears similar to that observed in younger individuals. Pravastatin has been successfully used in patients with hypercholesterolaemia secondary to other disease states such as diabetes mellitus or renal disease, in patients with hypertension, and in heart and kidney transplant recipients.

Like other HMG-CoA reductase inhibitors, pravastatin is likely to be more cost effective in secondary than in primary prevention, and in higher than in lower risk patient groups. Available pharmacoeconomic data are, however, inconclusive regarding the relative cost-effectiveness of agents within this class of drugs because of the lack of long term clinical outcomes data. Analysis of WOSCOPS and CARE will address some of these issues.

Tolerability

Data from various short and long term (5-year) studies suggest that pravastatin is generally well tolerated by most patients, including the elderly. Commonly reported events include gastrointestinal disturbances and skin rashes.

As with other HMG-CoA reductase inhibitors, myopathy occurs rarely (in <0.1% of patients treated with pravastatin). Concomitant therapy with cyclosporin, gemfibrozil, erythromycin or nicotinic acid may enhance the risk of myopathy in patients receiving HMG-CoA reductase inhibitors. Increases in hepatic transaminases occur in 1 to 2% of patients, and routine monitoring of liver function is indicated. Cataract development and sleep disturbances have not been associated with pravastatin.

The bioavailability of pravastatin was unaffected by concomitant administration with aspirin, antacids (given 1 hour before pravastatin), cimetidine, cholestyramine (given 1 hour after or 4 hours before pravastatin), colestipol (given 1 hour after pravastatin), digoxin, warfarin, probucol or nicotinic acid. Increases in plasma pravastatin concentrations have been observed with concurrent cyclosporin therapy; reductions in pravastatin clearance have also been noted in combination with gemfibrozil.

Dosage and Administration

The recommended adult dosage of pravastatin is generally 10 to 40mg taken once daily at bedtime (or divided into two daily doses). Dosages are usually initiated at 10 to 20 mg/day; in some European countries, starting dosages of 5 mg/day are also advocated. Pravastatin should be titrated according to response at intervals of not less than 4 weeks. Lower dosages may be required in patients with a history of significant renal or hepatic dysfunction, in the elderly or in patients taking concomitant cyclosporin or gemfibrozil. Pravastatin is contraindicated in patients with active liver disease or unexplained increases in hepatic transaminase levels. There are insufficient clinical data to recommend the use of pravastatin in children.

Keywords

Pravastatin Probucol Familial Combine Hyperlipidaemia Hypercholesterolaemic Patient Pravastatin Sodium 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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© Adis International Limited 1997

Authors and Affiliations

  1. 1.Adis International LimitedMairangi Bay, Auckland 10New Zealand

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