Heparin - Pharmacology

Note: KD Tripathi's "Essentials of Medical Pharmacology" is not in the available textbook library. The following is compiled from Katzung's Basic & Clinical Pharmacology (16th Ed) and Lippincott Illustrated Reviews: Pharmacology, which are the standard references covering the same content taught in Indian pharmacology curricula alongside KD Tripathi. The factual content is equivalent.

Chemistry

Mechanism of Action

Figure: Heparin acts as a cofactor - it binds antithrombin, induces a conformational change, and is then released intact to be reutilized. (Lippincott Pharmacology)

Figure: Unfractionated heparin (UFH) accelerates antithrombin inhibition of BOTH thrombin and factor Xa; LMWH selectively accelerates inhibition of factor Xa only. (Lippincott Pharmacology)

1. Heparin is an indirect anticoagulant - it works via the endogenous inhibitor antithrombin (AT, formerly antithrombin III).
2. Antithrombin is an α-globulin (serine protease inhibitor) that naturally inhibits thrombin (factor IIa), factor IXa, and factor Xa - but does so very slowly in the absence of heparin.
3. When heparin binds to antithrombin via a unique pentasaccharide sequence, it causes a conformational change in antithrombin that accelerates its inhibitory activity ~1,000-fold.
4. The antithrombin-protease complex forms, after which heparin is released intact and can bind more antithrombin molecules - acting as a true catalytic cofactor (not consumed).
5. Only ~one-third of molecules in commercial UFH preparations carry the active pentasaccharide sequence needed for high-affinity antithrombin binding.

UFH vs LMWH - Key Mechanistic Difference

Uses (Clinical Pharmacology / Therapeutic Uses)

1. Treatment of acute venous thromboembolism - DVT and pulmonary embolism (PE)
2. Prophylaxis of postoperative venous thrombosis - patients undergoing major surgery (e.g., hip replacement, general surgery)
3. Acute MI / Unstable angina - prevents further clot formation
4. Arterial thrombosis and embolism
5. Cardiac and arterial surgery - maintenance of anticoagulation during cardiopulmonary bypass, vascular procedures
6. Anticoagulant of choice in pregnancy - heparin does not cross the placenta (due to its large molecular size and strong negative charge); safe for the fetus
7. Disseminated intravascular coagulation (DIC) - to interrupt consumptive coagulopathy
8. Maintenance of IV line patency - in low ("flush") doses
9. Extracorporeal circuits - hemodialysis, heart-lung bypass

Pharmacokinetics

• Route: IV (immediate onset) or subcutaneous (SC); never IM (risk of hematoma)
• Onset: Within minutes of IV administration; 1-2 hours after SC injection
• Half-life: ~1.5 hours (UFH); dose-dependent
• Protein binding: Extensive binding to plasma proteins - causes unpredictable pharmacokinetics
• Metabolism: Taken up by monocyte/macrophage system; undergoes depolymerization and desulfation
• Excretion: Renal (inactive metabolites + some parent drug)
• Monitoring: aPTT (target 1.5-2.5x normal) or anti-Xa levels (0.3-0.7 units/mL)

Adverse Effects

Figure: Three main adverse effects of heparin - Bleeding, Hypersensitivity, and Thrombocytopenia (Lippincott Pharmacology)

1. Bleeding (Most Common/Major)

• Most important and frequent complication
• Risk higher in: elderly women, renal failure patients
• Managed by: stopping heparin, or giving protamine sulfate (antidote)
  • Protamine forms a stable 1:1 ionic complex with heparin, neutralizing it
  • Dose: 1 mg protamine per 100 units of heparin administered
  • Caution: excess protamine is itself a weak anticoagulant

2. Heparin-Induced Thrombocytopenia (HIT)

• Occurs in 1-4% of UFH-treated patients (lower with LMWH)
• Immune-mediated - antibodies form against heparin-PF4 (platelet factor 4) complex
• Paradoxically causes thrombosis (venous > arterial), not just low platelets
• Monitor platelet counts frequently during therapy
• Management: immediately stop heparin + switch to a direct thrombin inhibitor (e.g., argatroban)
• LMWHs are NOT safe substitutes in HIT (cross-sensitivity risk)

3. Osteoporosis

• Seen with long-term heparin therapy
• Can lead to spontaneous fractures

4. Hypersensitivity Reactions

• Heparin is of animal (porcine) origin - antigenic
• Reactions: chills, fever, urticaria, anaphylactic shock

5. Alopecia

• Reversible hair loss reported with prolonged use

6. Hypoaldosteronism / Mineralocorticoid Deficiency

• Long-term use associated with mineralocorticoid deficiency

7. Hypertriglyceridemia

• Heparin causes release of lipoprotein lipase from tissues
• Initially clears postprandial lipemia, but long-term use can be associated with lipid abnormalities

Contraindications

• HIT (history or active)
• Hypersensitivity to heparin
• Active bleeding / hemophilia
• Significant thrombocytopenia / purpura
• Severe hypertension
• Intracranial hemorrhage
• Infective endocarditis
• Active tuberculosis
• GI ulcerative lesions
• Threatened abortion / visceral carcinoma
• Advanced hepatic or renal disease
• Recent surgery of brain, spinal cord, or eye

Antidote