Singapore Drugs Database

Indication

Unfractionated heparin is indicated for prophylaxis and treatment of venous thrombosis and its extension, prevention of post-operative deep venous thrombosis and pulmonary embolism and prevention of clotting in arterial and cardiac surgery. In cardiology, it is used to prevent embolisms in patients with atrial fibrillation and as an adjunct antithrombin therapy in patients with unstable angina and/or non-Q wave myocardial infarctions (i.e. non-ST elevated acute coronary artery syndrome) who are on platelet glycoprotein (IIb/IIIa) receptor inhibitors. Additionally, it is used to prevent clotting during dialysis and surgical procedures, maintain the patency of intravenous injection devices and prevent in vitro coagulation of blood transfusions and in blood samples drawn for laboratory values.

Mechanism of Action

Under normal circumstances, antithrombin III (ATIII) inactivates thrombin (factor IIa) and factor Xa. This process occurs at a slow rate. Administered heparin binds reversibly to ATIII and leads to almost instantaneous inactivation of factors IIa and Xa The heparin-ATIII complex can also inactivate factors IX, XI, XII and plasmin. The mechanism of action of heparin is ATIII-dependent. It acts mainly by accelerating the rate of the neutralization of certain activated coagulation factors by antithrombin, but other mechanisms may also be involved. The antithrombotic effect of heparin is well correlated to the inhibition of factor Xa. Heparin is not a thrombolytic or fibrinolytic. It prevents progression of existing clots by inhibiting further clotting. The lysis of existing clots relies on endogenous thrombolytics.

Pharmacokinetics

Absorption

Heparin must be given parenterally as it is not absorbed through the gastrointestinal mucosa. It is usually given by iv infusion or deep sc injection. The onset of action is immediate after iv injection but can be delayed 20 to 60 minutes following sc injection. Plasma heparin concentrations may be increased and activated partial thromboplastin times (aPTTs) may be more prolonged in geriatric adults (older than 60 years of age) compared with younger adults.

Distribution

40-70 mL/min (approximately the same as blood volume) Although heparin does not distribute into adipose tissues, clinicians should use actual body weight in obese patients to account for extra vasculature.

Metabolism

Liver and the reticulo-endothelial system are the sites of biotransformation. The metabolic fate of heparin is not well understood.

Elimination

Clearance

Adult Clearance = 0.43 ml/kg/min 25-28 weeks gestation = 1.49 ml/kg/min

Toxicity

In mouse, the median lethal dose is greater than 5000 mg/kg. Another side effect is heparin-induced thrombocytopenia (HIT syndrome). Platelet counts usually do not fall until between days 5 and 12 of heparin therapy. HIT is caused by an immunological reaction that makes platelets form clots within the blood vessels, thereby using up coagulation factors. It can progress to thrombotic complications such as arterial thrombosis, gangrene, stroke, myocardial infarction and disseminated intravascular coagulation. Symptoms of overdose may show excessive prolongation of aPTT or by bleeding, which may be internal or external, major or minor. Therapeutic doses of heparin give for at least 4 months have been associated with osteoporosis and spontaneous vertebral fractures. Osteoporosis may be reversible once heparin is discontinued. Although a causal relationship has not been established, administration of injections preserved with benzyl alcohol has been associated with toxicity in neonates. Toxicity appears to have resulted from administration of large amounts (i.e., about 100–400 mg/kg daily) of benzyl alcohol in these neonates. Its use is principally associated with the use of bacteriostatic 0.9% sodium chloride intravascular flush or endotracheal tube lavage solutions.

Active Ingredient/Synonyms

Calciparine | Eparina | Heparinate | Heparinic acid | Liquaemin | Panheprin | Unfractionated heparin | Heparin |