An understanding of the pharmacokinetics of HMG-CoA reductase inhibitors should help reduce the incidence of serious dru
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An understanding of the pharmacokinetics of HMG-CoA reductase inhibitors should help reduce the incidence of serious drug interactions The HMG-CoA reductase inhibitors (statins) are increasingly used for both the primary and secondary prevention of coronary heart disease. The statins (atorvastatin, fluvastatin, lovastatin, pravastatin and simvastatin) are generally well tolerated. However, raised liver enzymes and skeletal muscle abnormalities, including myopathy and rhabdomyolysis, are rare, but potentially serious, adverse events. These adverse events are frequently associated with drug interactions. The most clinically relevant drug interactions for all the statins apart from pravastatin involve alterations in cytochrome P450 metabolic pathways. In addition, the concurrent use of other lipid-lowering drugs (i.e. fibrates and nicotinic acid) has been associated with an increased risk of skeletal muscle abnormalities. Statins may also alter the concentrations of other drugs (e.g. warfarin and digoxin) leading to an alteration in effect.
Statins effective … The HMG-CoA reductase inhibitors (statins) inhibit cholesterol synthesis and are particularly effective at reducing levels of low-density lipoprotein cholesterol (LDL-C), an important risk factor in coronary heart disease.[1] The use of statins has been shown to reduce coronary heart disease in both primary and secondary prevention studies.[1]
… and serious adverse events rare Although the statins are well tolerated by most patients, they are occasionally associated with potentially more serious adverse events including raised liver enzymes and skeletal muscle abnormalities.[1,2] Elevations in liver enzymes (>3 times upper limit of normal) are usually asymptomatic, and occur in 50% of drugs used in humans.[1] Therefore, it is not surprising that many of the clinically relevant statin-drug interactions outlined in the Differential features table are between the CYP3A4 metabolised statins (i.e. atorvastatin, lovastatin and simvastatin) and CYP3A4 inhibitors (e.g. diltiazem,
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22 Differential features Comparison of selected features of some HMG-CoA reductase inhibitors (statins) and some of their possible drug interactions[1-3] Feature Dose required to achieve 30% reduction in LDL-C levels (mg/day)
Atorvastatin 5
Fluvastatin 60
Lovastatin 20
Pravastatin 30
Simvastatin 10
Relative potencya
12
1
3
2
6
Major metabolic enzyme
CYP3A4
CYP2C9
CYP3A4
Hydroxylase
CYP3A4
Drug or food interaction: alteration of statin metabolism Miscellaneous agents Grapefruit juice
√
√
Azole antifungals
√√
HIV protease inhibitors
√√
√b
√√
Erythromycin
√√
√√
√√
Clarithromycin
√
Telithromycin
√√
√
√√
√√ √b
√√
Antibiotics √√
√√
√√ √√
Antidepressants √√
Nefazodone
√√
Cardiovascular drugs Diltiazem
√√
Verapamil
√
√
Other lipid regulating drugs Fibrates
√√
√√
√√
√√
√√
Nicotinic acid
√√
√√
√√
√√
√√
√√
√√
√√
√√
√√
Immunosuppresssive drugs Ciclosporin
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