Atorvastatin
Atorvastatin
Generic Name
Atorvastatin
Mechanism
- Competitive inhibitor of HMG‑CoA reductase, the rate‑limiting enzyme of endogenous cholesterol biosynthesis in the liver.
- Down‑regulates hepatic LDL‑receptor transcription → ↑ LDL‑receptor density → enhanced LDL‑removal from plasma.
- Increases HDL‑cholesterol modestly by reducing hepatic triglyceride synthesis.
- Lowers VLDL production, thereby decreasing triglycerides.
- Secondary pleiotropic effects: improves endothelial function, reduces oxidative stress, stabilizes atherosclerotic plaques.
Pharmacokinetics
| Parameter | Details |
| Absorption | Oral; peak plasma conc. in 1–3 h; food decreases AUC by ~30 % (take on empty stomach preferred). |
| Distribution | Plasma protein bound ~95 % (largely albumin). Strongly lipophilic → tissue penetration, including heart & vascular wall. |
| Metabolism | Predominantly CYP3A4‑mediated (oxidative metabolism) → active metabolite (ortho‑hydroxy) accounts for ~20 % activity. Minor pathways: glucuronidation (UGT1A1). |
| Elimination | Urinary (35 %), fecal (45 %) via bile; terminal half‑life 14 h (active metabolite 20 h). |
| Drug‑Drug Interactions | Strong CYP3A4 inhibitors (ketoconazole, clarithromycin, ritonavir) ↑ AUC → ↑ myopathy risk.
CYP3A4 inducers (rifampin, carbamazepine) ↓ exposure.
∂–glycoprotein inhibitors/inducers minor effect. |
| Special Populations | Renal impairment: use with caution (most metabolites excreted renally).
Hepatic impairment: avoid or lower dose; serum AST/ALT monitored.
Pregnancy/Lactation: Category X – contraindicated. |
Indications
- Primary prevention of atherosclerotic cardiovascular disease (ASCVD) in patients ≥40 y with ≥10 % 10‑yr risk (USPSTF, ACC/AHA).
- Secondary prevention in individuals with established ASCVD or diabetes mellitus.
- Heterozygous familial hypercholesterolemia (FH).
- Dyslipidemia in patients with elevated LDL‑C ≥70 mg/dL or ApoB ≥90 mg/dL.
- Statin‑intolerant patients requiring minimal use (bridging with limited doses).
Contraindications
| Category | Key Points |
| Contraindicated | Pregnancy; lactation; active liver disease (ALT > 3× ULN); concurrent use with strong CYP3A4 inhibitors >two doses per week. |
| Warnings | Myopathy—including rhabdomyolysis (especially with fibrate or niacin combination).
Hepatic injury: monitor ALT/AST 2× ULN; stop if ≥3× ULN or with symptoms.
Diabetes mellitus: may worsen glycemic control (monitor HbA1c). |
| Precautions | Crystalluria (rare); caution in elderly & CKD. |
Dosing
- Initial: 10 mg once daily (usually at night).
- Titration: Increase in increments of 10 mg every 4–6 weeks to target LDL‑C goal.
- Max: 80 mg/day.
- Aspiration: Take on an empty stomach or separate from high‑fat meals to improve absorption.
- Split dosing: Rarely used; if needed for intolerance.
| Setting | Typical Dose | Comment |
| Primary Prevention (age ≥ 40) | 10–20 mg | Start low; titrate but avoid exceeding 20 mg unless high risk. |
| Secondary Prevention | 20–80 mg | Aggressive LDL target (<70 mg/dL for high‑risk). |
| FH | 40–80 mg | Plus lifestyle; consider combination therapy. |
| Diabetes | 10–20 mg | Start low; monitor glucose. |
Adverse Effects
| Category | Adverse Effects |
| Common | Headache, myalgia, abdominal discomfort, mild transaminase ↑, reduced appetite, insomnia. |
| Serious | Rhabdomyolysis (CK > 10× ULN, myalgia + weakness + dark urine), severe hepatic injury (ALT/AST > 3× ULN + symptoms), drug‑induced cutaneous reactions (rare), pregnancy‑related fetal harm. |
Monitoring
- Baseline: Lipid profile, fasting glucose/HbA1c, liver function tests (ALT/AST), creatinine.
- Follow‑up:
- Lipids every 4–12 weeks after dose change.
- LFTs at 4 weeks, then every 3 months in patients ≥65 y or with elevated baseline values.
- CK if myalgia, weakness, or unexplained fatigue.
- Patient Education: Report dark urine, severe muscle pain, unexplained fatigue, jaundice, or new liver‑symptom.
Clinical Pearls
- Asian and African–American patients: Lower starting dose (5 mg) may reduce myopathy risk while still achieving LDL reductions due to lower CYP3A4 activity.
- Drug‑Drug Interaction “Pro-Tip”: Do not co‑administer atorvastatin with nifedipine or other CYP3A4 inhibitors >10 mg daily; consider ezetimibe or PCSK9 inhibitor when intensive lowering is needed.
- Combination Use: When adding ezetimibe, dose‐adjust the statin by 25 % to mitigate liver enzyme elevations.
- Diabetes Point: A modest ↑ in HbA1c (~0.3 %) has been observed over long‑term use; proactive diet & glucose monitoring is advised.
- Compliance Hack: Carb‑free 1 hour before bed is often easier for patients; reminds them to keep it separate from high‑fat dinner.
- Kidney‑Safety: Atorvastatin is relatively safe in CKD stages 3–4; no dose adjustment needed, but monitor CK if decreased muscle function.
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• Key Take‑away: Atorvastatin, a lipophilic HMG‑CoA reductase inhibitor, remains a cornerstone for ASCVD risk reduction. Its potent LDL‑lowering, favorable safety profile at low doses, and clear monitoring guidelines make it the first‑line therapy in both primary and secondary prevention of cardiovascular disease.