Pharm 101: Heparin

Class

Anticoagulant

Pharmacodynamics

• Indirect thrombin inhibitor that acts as a co-factor for the antithrombin-protease reaction:
  • Antithrombin III (ATIII) normally inhibits clotting factor proteases, especially IIa (thrombin), IXa, and Xa, by forming equimolar stable complexes with them
  • Heparin binds to and causes a conformational change of ATIII, exposing its active site for more rapid interaction with proteases and accelerating inhibition reactions 1000-fold
• Requires the presence of ATIII
• Acts as a co-factor without being consumed

Pharmacokinetics

• Hepatic metabolism
• Half-life 1.5 hours
• Renal clearance

Clinical uses

• Different methods of administration:
  • IV or SC
  • Continuous (following bolus) or intermittent
  • Therapeutic or prophylactic
  • Close monitoring of aPTT is necessary in patients receiving UFH infusions
• Reversal:
  • Cease drug
  • Administration of antagonist protamine sulfate
  • For every 100 units of heparin remaining in patient, administer 1mg protamine IV
  • Excess protamine must be avoided as it also has an anticoagulant effect

Adverse effects

• Heparin Induced Thrombocytopenia (see below)
• Bleeding (risk increased in elderly women and renal failure)
• Alopecia
• Release of lipoprotein lipase from tissues, accelerating clearing of post-prandial lipaemia
• Drug interactions:
  • Warfarin: increased INR due to changes in pharmacodynamics of warfarin
• Long-term:
  • Osteoporosis
  • Mineralocorticoid deficiency

Precautions/contraindications

• Severe hypertension
• Advanced hepatic or renal disease

Heparin Induced Thrombocytopenia

• 1-5% of patients receiving heparin
• Can still occur with LMWH use
• Type I:
  • Rapidly after drug administration
  • Due to direct platelet-aggregating effect of heparin
  • Little clinical significance, self-resolves
• Type II:
  • Less common
  • 5-14 days after treatment
  • Due to auto-antibodies against complex of heparin and platelet factor 4. This activates platelets and causes thrombi, even in the setting of thrombocytopaenia

Further Reading

• Nickson C. Heparin Induced Thrombotic Thrombocytopaenia Syndrome
• Nickson C. Protamine
• Nickson C. VTE Prophylaxis