Clopidogrel
Clopidogrel
Generic Name
Clopidogrel
Mechanism
- Pro‑drug activation: Hepatic CYP2C19 converts clopidogrel to its 2‑oxo‑acid metabolite.
- P2Y12 receptor blockade: The active metabolite irreversibly inhibits the ADP‑dependent P2Y12 platelet receptor.
- Resulting effect: Inhibits platelet aggregation and thrombus formation without affecting bleeding time dramatically in most patients.
- Synergy: Often combined with aspirin (dual antiplatelet therapy, DAPT) to maximize antithrombotic efficacy.
Pharmacokinetics
| Parameter | Typical Value | Notes |
| Bioavailability | ~27 % (after oral dose) | Dependent on entero‑hepatic activation |
| Metabolism | Hepatic CYP2C19, plus CYP1A2, CYP2B6 | Pro‑drug; major site of genetic variability |
| Active metabolite half‑life | ~6 h (rapid hepatic metabolism) | Irreversible binding to P2Y12; functional effect lasts 7–10 days |
| Cmax | ~200 pmol/L (peak 1–2 h post‑dose) | Variable due to first‑pass metabolism |
| Elimination | Renal (>40 %) and fecal | No dose adjustment for mild‑moderate CKD |
| Drug interactions | Strong CYP2C19 inhibitors (e.g., fluconazole, omeprazole) → ↓ activation; strong CYP2C19 inducers (rifampin) → ↑ clearance | Concomitant antiplatelet agents (tirofiban) can potentiate bleeding risk |
Indications
- Acute coronary syndrome (ACS): PCI or CABG patients requiring DAPT.
- ST‑segment elevation myocardial infarction (STEMI) and non‑STEMI.
- Stable coronary artery disease (CAD) post‑PCI.
- Ischemic stroke/TIA: secondary prevention, often in combination with aspirin.
- Peripheral arterial disease (PAD): post‑angioplasty or for primary prevention of acute limb events.
- Atrial fibrillation with CAD: when warfarin is contraindicated or as an adjunct to warfarin.
Contraindications
- Known hypersensitivity to clopidogrel or any excipients.
- Active pathological bleeding (e.g., peptic ulcer, intracranial hemorrhage).
- Platelet count < 100 × 10⁹/L or significant thrombocytopenia.
- Severe hepatic impairment (Child‑Pugh C).
- Use of potent CYP2C19 inhibitors in patients who do not have the *CYP2C19* loss‑of‑function allele.
- Concurrent use with potent antiplatelet agents (e.g., ticagrelor) increases bleeding risk; consider only if clinical necessity outweighs risk.
Warnings
• Bleeding: Monitor for signs of major bleeding; consider reversal agents (platelet transfusion) in life‑threatening bleeding events.
• Drug interactions: Avoid or monitor when co‑administered with drugs that alter CYP2C19 activity.
• Genetic variability: *CYP2C19* loss‑of‑function alleles (*/*) reduce activation; consider alternative agents (ticagrelor, prasugrel) or pharmacogenomic testing.
Dosing
| Indication | Initial/Daily Dose | Route | Notes |
| ACS / DAPT | 75 mg once daily (pre‑PCI loading 300–600 mg may be given IV/PO) | Oral | Loading dose often 300 mg PO; 600 mg IV for high‑risk ACS patients |
| Acute Stroke/TIA | 75 mg once daily | Oral | Same as CAD; add aspirin if indicated |
| Stable CAD | 75 mg once daily | Oral | Continue indefinitely as part of DAPT or monotherapy |
| PAD | 75 mg once daily | Oral | Often combined with aspirin |
• Take with food to improve absorption.
• Maintain dose consistency; do not substitute with generic unless same formulation.
Adverse Effects
Common (≤10 %)
• Bleeding events (gastrointestinal, epistaxis).
• Headache.
• Diarrhea.
• Rash (rare hypersensitivity).
Serious (≤1 %)
• Major hemorrhage (intracranial, GI).
• Severe thrombocytopenia (immune mediated).
• Severe allergic reactions (anaphylaxis).
• Unexplained bruising, petechiae.
Rare
• Hypersensitivity pneumonitis.
• Acute thrombotic events in *CYP2C19* poor metabolizers.
Monitoring
- Platelet function tests (optional): Verify P2Y12 inhibition (e.g., VerifyNow P2Y12 assay).
- Hemoglobin/hematocrit: Baseline and periodically if bleeding is suspected.
- CBC: Monitor platelets if abnormal.
- Renal & hepatic function: At baseline and anytime there is clinical suspicion of organ dysfunction.
- Co‑administration review: Check for new CYP2C19 inhibitors or potent antiplatelet agents.
Clinical Pearls
1. Genotype matters – Patients with *CYP2C19* loss‑of‑function alleles have ≤30 % of normal antiplatelet effect; consider ticagrelor or prasugrel in ACS.
2. Loading dose nuance – IV 600 mg is preferred in emergent PCI; PO 300 mg can be given a few hours before intervention if IV option is unavailable.
3. DAPT duration – 12 months post‑stent; shorten to 6 months for drug‑eluting stents in high bleeding risk patients.
4. Drug‑drug interactions – Proton‑pump inhibitors (PPIs) should be chosen wisely; pantoprazole is the least potent CYP2C19 inhibitor.
5. Stop before surgery – Discontinue 5–7 days prior to high‑bleed risk procedures; resume 24–48 h after hemostasis.
6. Platelet transfusion – Only for life‑threatening bleeding; it can neutralize active drug but not the irreversible receptor blockade.
7. Alternative strategy – In patients with significant bleeding risk or poor metabolizers, consider antiplatelet monotherapy (e.g., aspirin) or a switch to a reversible P2Y12 inhibitor if the clinical scenario allows.
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• Key Take‑away: Clopidogrel remains a cornerstone antiplatelet agent, but its efficacy hinges on metabolic activation and genetic variability. Optimizing dose, monitoring bleeding, and being vigilant about drug interactions are essential for safe and effective use.