Introduction
Simvastatin is a widely prescribed lipid-lowering medication belonging to the HMG-CoA reductase inhibitor class, commonly known as statins. First approved by the FDA in 1991, simvastatin has become a cornerstone in the management of dyslipidemia and cardiovascular risk reduction. This synthetic derivative of lovastatin works by competitively inhibiting HMG-CoA reductase, the rate-limiting enzyme in cholesterol biosynthesis.
Mechanism of Action
Simvastatin exerts its pharmacological effects through competitive inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme responsible for converting HMG-CoA to mevalonate in the cholesterol biosynthesis pathway. This inhibition results in:
- Decreased hepatic cholesterol synthesis
- Upregulation of hepatic LDL receptors
- Increased clearance of LDL cholesterol from the bloodstream
- Reduction in very low-density lipoprotein (VLDL) and intermediate-density lipoprotein (IDL) particles
Simvastatin is administered as an inactive lactone prodrug that undergoes hydrolysis in the liver to its active β-hydroxyacid form.
Indications
FDA-approved indications include:
- Primary hyperlipidemia (Types IIa and IIb) and mixed dyslipidemia
- Homozygous familial hypercholesterolemia
- Hypertriglyceridemia (Type IV hyperlipidemia)
- Primary dysbetalipoproteinemia (Type III hyperlipidemia)
- Reduction of cardiovascular risk in patients with coronary heart disease (CHD) or at high risk of CHD
Dosage and Administration
Standard dosing: 5-40 mg orally once daily in the evening- Initial dose: 10-20 mg daily
- Maximum dose: 40 mg daily (80 mg dose restricted due to increased myopathy risk)
- Renal impairment: No dosage adjustment necessary
- Hepatic impairment: Contraindicated in active liver disease
- Geriatric patients: No dosage adjustment necessary
- Asian patients: Consider lower starting doses due to increased systemic exposure
Pharmacokinetics
Absorption: ~85% bioavailability; extensive first-pass metabolism Distribution: Protein binding >95%; volume of distribution: 20 L/kg Metabolism: Extensive hepatic metabolism via CYP3A4 isoenzyme; substrate for P-glycoprotein Elimination: Half-life: 2-3 hours; primarily excreted in feces (60%) with 13% renal excretion Active metabolites: Simvastatin acid and several inactive metabolitesContraindications
- Active liver disease or unexplained persistent elevations of serum transaminases
- Pregnancy and breastfeeding
- Hypersensitivity to simvastatin or any component of the formulation
- Concomitant use with strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, HIV protease inhibitors)
- Patients taking cyclosporine, danazol, or gemfibrozil
Warnings and Precautions
Myopathy/Rhabdomyolysis: Risk increases with higher doses, advanced age, renal impairment, and concomitant interacting medications Hepatotoxicity: Monitor liver enzymes before initiation and periodically thereafter Diabetes Mellitus: May increase HbA1c and fasting serum glucose levels Cognitive Effects: Rare reports of cognitive impairment (memory loss, confusion) Avoid in pregnancy: Category X - may cause fetal harmDrug Interactions
Major interactions:- Strong CYP3A4 inhibitors: Increased simvastatin exposure by 3-12 fold (avoid concomitant use)
- Gemfibrozil: Increases risk of myopathy (contraindicated)
- Cyclosporine: Increases AUC by 8-fold (contraindicated)
- Danazol: Increases myopathy risk (contraindicated)
- Amiodarone, verapamil, diltiazem: Dose limitation to 10 mg daily
- Warfarin: May potentiate anticoagulant effect (monitor INR)
Adverse Effects
Common (>1%):- Headache (3.5%)
- Gastrointestinal disturbances (3.0%)
- Myalgia (1.5%)
- Upper respiratory infection (2.1%)
- Rhabdomyolysis (<0.1%)
- Hepatotoxicity (0.5-2.0%)
- Myopathy (0.02-0.2%)
- Pancreatitis (<0.1%)
Monitoring Parameters
Baseline:- Lipid profile (total cholesterol, LDL, HDL, triglycerides)
- Liver function tests (ALT, AST)
- CK levels if symptomatic
- Renal function
- Lipid profile at 4-12 weeks and periodically thereafter
- Liver enzymes periodically (more frequently if elevated)
- CK if patient reports muscle symptoms
- HbA1c in patients with diabetes risk factors
Patient Education
- Take medication as prescribed, typically in the evening
- Report unexplained muscle pain, tenderness, weakness, or brown urine immediately
- Avoid grapefruit and grapefruit juice during therapy
- Maintain regular follow-up appointments for monitoring
- Continue lifestyle modifications (diet, exercise, smoking cessation)
- Inform all healthcare providers about simvastatin use
- Use effective contraception while taking simvastatin
References
1. FDA Prescribing Information: Zocor (simvastatin) tablets 2. Grundy SM, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol. Circulation. 2019;139(25):e1082-e1143 3. Thompson PD, et al. Statin-associated side effects. J Am Coll Cardiol. 2016;67(20):2395-2410 4. Cholesterol Treatment Trialists' Collaboration. Efficacy and safety of statin therapy in older people: a meta-analysis of individual participant data from 28 randomised controlled trials. Lancet. 2019;393(10170):407-415 5. Sirtori CR. The pharmacology of statins. Pharmacol Res. 2014;88:3-11 6. Neuvonen PJ, et al. Simvastatin but not pravastatin is very susceptible to interaction with the CYP3A4 inhibitor itraconazole. Clin Pharmacol Ther. 1998;63(3):332-341