Simvastatin is a competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme in cholesterol biosynthesis. By blocking this enzyme, it:

1. Reduces Hepatic Cholesterol Synthesis: Lowers intracellular cholesterol levels in the liver.
2. Upregulates LDL Receptors: Increases hepatic uptake of low-density lipoprotein (LDL) cholesterol from the bloodstream.
3. Improves Lipid Profile:
   • Lowers LDL cholesterol by 30–50%.
   • Modestly reduces triglycerides and raises high-density lipoprotein (HDL) cholesterol (Lippincott Textbook of Pharmacology).

1. Primary Hypercholesterolemia and Mixed Dyslipidemia:
   • Management of elevated LDL cholesterol and triglycerides.
2. Cardiovascular Risk Reduction:
   • Primary Prevention: Reduces cardiovascular events in high-risk patients (e.g., diabetes, hypertension).
   • Secondary Prevention: Post-myocardial infarction (MI) or stroke to prevent recurrence (BNF).
3. Familial Hypercholesterolemia:
   • Adjunctive therapy in genetic lipid disorders (Lange Basic & Clinical Pharmacology).

• Adults:
  • Initial Dose: 10–20 mg once daily, taken in the evening.
  • Maintenance Dose: 20–40 mg daily (max 40 mg/day; 80 mg is not recommended due to myopathy risk).
• Special Populations:
  • Renal Impairment: Use lower doses (e.g., 10 mg) if eGFR <30 mL/min/1.73m².
  • Hepatic Impairment: Contraindicated in active liver disease.
• Key Interactions:
  • With CYP3A4 inhibitors (e.g., amiodarone), max dose is 20 mg/day (BNF).

• Common (≥1%):
  • Myalgia (muscle pain), headache, gastrointestinal disturbances (nausea, constipation).
  • Asymptomatic transaminase elevation (1–3% of patients).
• Serious (Rare):
  • Rhabdomyolysis: Severe muscle breakdown (risk <0.1%).
  • Hepatotoxicity: Discontinue if ALT/AST >3× upper limit of normal (ULN).
  • New-Onset Diabetes: Slight increased risk with long-term use (Lange Basic & Clinical Pharmacology).

• Contraindications:
  • Active liver disease or unexplained transaminase elevation.
  • Pregnancy and lactation (risk of fetal harm).
• Monitoring:
  • Baseline liver function tests (LFTs) and lipid profile.
  • Repeat LFTs at 3 months and annually.
  • Check creatine kinase (CK) if myalgia occurs.
• Patient Counseling:
  • Report unexplained muscle pain, tenderness, or dark urine promptly.
  • Avoid excessive grapefruit juice (>1 L/day).

Simvastatin is metabolized by CYP3A4; interactions include:

1. CYP3A4 Inhibitors:
   • Macrolides (e.g., erythromycin), azole antifungals (e.g., ketoconazole): ↑ Simvastatin levels (↑ toxicity risk).
2. Gemfibrozil: ↑ Risk of myopathy (avoid combination).
3. Warfarin: Monitor INR (simvastatin may ↑ anticoagulant effect).
4. Cyclosporine: Contraindicated (↑ simvastatin exposure 10-fold) (BNF).

• Generic Name: Simvastatin.
• Brand Names: Zocor (original), Simvor, Lodales, and generics.