HEPARIN

  • Know PD and toxicity of heparin
Structure/class
  1. Indirect thrombin inhibitor
Pharmacodynamics
  1. Heparin binds to endothelial cells and plasma proteins
  2. Its activity depends on the natural anticoagulant antithrombin III.
    • Antithrombin III inhibits clotting factor proteases, especially thrombin (IIa), IXa and Xa. In the absence of heparin, these reactions are slow, but they are accelerated ~1000x in the presence of heparin.
    • Active heparin molecules bind to AT III, causing a conformation change in AT III. This exposes its active site, allowing for more rapid interaction with proteases.
    • Binding of heparin with AT III will increase the degradation of factors IIa and Xa especially.
  3. A side note about LMWH (enoxaparin)
    • LMWH works by inhibiting Factor Xa (and not factor IIa and IXa).
    • If LMWH is used weight based, it has predictable pharmacokinetics and plasma levels in patients with normal renal function. Therefore, LMWH levels are not commonly measured except in the setting of obesity, renal insufficiency or pregnancy.
Absorption/administration
  1. IV or SC.
    • May be given either by intermittent dosing or by continuous infusion.
  2. NOT IM – risk of haematoma.
Distribution  
Metabolism  
Excretion  
Indications
  1. Clotting states –DVT/PE
  2. Post-surgical/in-hospital prophylaxis.
Contraindications
  1. Patients with a chance of life-threatening bleeding/active bleeding
    • Severe thrombocytopaenia, GI ulcer, intracranial hypertension, severe hypertension, advanced renal and hepatic disease.
  2. Patients with known allergic reaction (HIT)
Special precautions
  1. Elderly patient
  2. Renal failure
Interactions  
Adverse effects
  1. Bleeding
  2. HIT
    • This is a systemic hypercoagulable state, occurring in 1-4% of people receiving heparin for a minimum of seven days.
    • Surgical patients are at greatest risk.
    • Mortality and morbidity is due to thrombotic events (and not to bleeding). Venous thrombus usually occurs, but can be arterial.
    • Hence, perform platelet counts – be suspicious if patients on heparin develop new thrombus.
    • HIT should be treated by stopping heparin and commencing a direct thrombin inhibitor (e.g. dabigatran)
  3. Idiosyncratic reactions
    • Allergy, alopecia, osteoporosis and mineralocorticoid deficiency.

 
Dosing/administration
  1. Monitor with APTT.
  2. Measuring factor Xa levels may be helpful
Toxicology
  1. If major bleeding –cease drug. Specific antidote: protamine.
    • Protamine is a very basic, positive charged ion that binds to the negative charge of heparin and inactivates it (chemical antagonist). The stable heparin-protamine complex has no anti-coagulant activity.
    • 1mg of protamine inactivates 100IU of heparin. Important to avoid excess protamine – itself acts as an anti-coagulant.
Withdrawal syndrome