Antidotes in De..

Protamine is a rapidly acting antidote that is used primarily to reverse the anticoagulant effects of unfractionated heparin (UFH). It also can partially reverse the effects of low-molecular-weight heparin (LMWH).

The antidotal property of protamine was recognized in the late 1930s, leading to its approval as an antidote for heparin overdose in 1968.57 However, the largest body of literature pertaining to protamine originates from its use in neutralizing heparin following cardiopulmonary bypass and dialysis procedures.

The protamines are a group of simple basic cationic proteins found in fish sperm that bind to heparin to form a stable neutral salt, rapidly inactivating heparin and reversing its anticoagulant effect.62 Commercially available protamine sulfate is derived from the sperm of mature testes of salmon and related species. On hydrolysis, it yields basic amino acids, particularly arginine, proline, serine, and valine, but not tyrosine and tryptophan. The effects of protamine sulfate and protamine chloride appear to be comparable.43 The molecular weight of heparins ranges from 3000 to 30,000 daltons and is composed of approximately 45 monosaccharide chains. One milligram of protamine will neutralize approximately 100 U (1 mg) of standard UFH (mean molecular weight [MW]~12,000 daltons).

In contrast to the case of heparin there is no proven method for neutralizing LMWH. Protamine neutralizes the anti-IIa activity of LMWH and a variable portion of the anti-Xa activity of LMWH.28 Because the interaction of protamine and heparin is dependent on the MW of heparin, LMWH (mean MW 4500 daltons) has reduced protamine binding. The protamine-resistant fraction in LMWH is an ultralow-molecular-weight fraction with low sulfide charge.15 It is suggested that 1 mg of enoxaparin equals approximately 100 antifactor-Xa units. To reverse the antithrombotic effects of LMWH within the first 8 hours following administration, the recommendation is to administer 1 mg protamine per 100 antifactor-Xa units of LMWH followed by administration of a second dose of 0.5 mg protamine per 100 anti factor-Xa units if bleeding continues.28

No human studies offer convincing evidence either demonstrating or disputing a beneficial effect of protamine as treatment for hemorrhage following LMWH use.28 Case studies demonstrating both failure and success exist.10,50,52,80 In animal studies, synthetic protamine variants were effective in reversing the anticoagulant effects of LMWH and are reported to be less toxic than protamine. These xenobiotics are not available for clinical use.5,28,33,71,72

Heparins are large electronegative xenobiotics that are rapidly complexed by the electropositive protamine, forming an inactive salt. Heparin is an indirect anticoagulant, requiring a cofactor. This cofactor, AT, was formerly called antithrombin III.28 Heparin alters the stereochemistry of AT, thereby catalyzing the subsequent inactivation of thrombin and other clotting factors.24 Only about one-third of an administered dose of unfractionated heparin binds to AT, and this fraction is responsible for most of its anticoagulant effect.3,45LMWH has a reduced ability ...

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