Heparin pharmacokinetics and pharmacodynamics

Heparin was discovered approximately 75 years ago and has been used extensively for the last 50 years to treat thromboembolic disorders. An endogenous glycosaminoglycan, heparin is found largely in the liver, lung and intestine. It is available for exogenous administration both as unfractionated and low molecular weight heparin. Unfractionated heparin is a heterogenous mixture of polysaccharide chains of varying length resulting in a range of molecular weights from 3000 to 30,000D while low molecular weight heparin ranges from 3000 to 6000D. Heparin produces its antithrombotic effect by binding to antithrombin III and this complex then binds to thrombin. In order to accomplish this a total of 18 to 22 monosaccharide units is necessary including a specific pentasaccharide binding site for antithrombin III. After either subcutaneous or intravenous injection heparin is distributed primarily within the intravascular space. A short distribution phase is seen which is thought to correspond to endothelial cell binding and internalisation. The disposition curve for unfractionated heparin has a unique concave-convex shape which is the result of combined saturable and nonsaturable elimination mechanisms. The nonsaturable elimination mechanism is renal and is the primary route of elimination for low molecular weight heparins. For this reason, the concave-convex pattern is not seen with low molecular weight preparations. Both forms of heparin are useful antithrombotic agents; however, the correlation between the antithrombotic effect and an in vitro laboratory test for either type still needs further clarification.