A16: Antidotes in Depth

INTRODUCTION

Protamine is a rapidly acting antidote that is used primarily to reverse the anticoagulant effects of unfractionated heparin (UFH). It neutralizes the anti-IIa activity of low-molecular-weight heparin (LMWH) and incompletely neutralizes the anti-Xa activity of LMWH, which may normalize activated partial thromboplastin time (aPTT) and the thrombin time, but variably resolves clinical bleeding. Protamine has no effect on heparin pentasaccharide fragments or analogs such as fondaparinux.

HISTORY

The antidotal properties of protamine were recognized in the late 1930s, leading to its approval as an antidote for heparin overdose in 1968.⁶⁹ However, the largest body of literature pertaining to protamine originates from its use in neutralizing heparin following cardiopulmonary bypass and dialysis procedures.

PHARMACOLOGY

Chemistry

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 effects.⁷⁶ Commercially available protamine sulfate is derived from the sperm of mature testes of salmon and related species. Upon hydrolysis, protamine yields basic amino acids, particularly arginine, proline, serine, and valine, but not tyrosine and tryptophan.

Related Protamine Variants

In animal studies, synthetic protamine variants, not available for clinical use, were effective in reversing the anticoagulant effects of LMWH and are reported to be less toxic than protamine.^11,41,85,86 The effects of protamine sulfate and protamine chloride appear to be comparable.⁵³

Mechanism of Action

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. Heparin alters the stereochemistry of AT, thereby catalyzing the subsequent inactivation of thrombin and other clotting factors.³² 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.^3,55 LMWH has a reduced ability to inactivate thrombin as a result of lesser AT binding, but the smaller fragments of LMWH inactivate factor Xa almost as well as the larger molecules of UFH, allowing for equivalent efficacy. Immunoelectrophoretic studies demonstrate that because of the net positive charge of protamine, it has a greater affinity for heparin than heparin for AT, producing a dissociation of the heparin–AT complex and favoring a protamine–heparin complex.⁷³ This complex is removed by the reticuloendothelial system.²

PHARMACOKINETICS AND PHARMACODYNAMICS

Normal volunteers, free of cardiovascular disease and heparin-free, received 0.5 mg/kg protamine intravenously over 10 min. In this study, the protamine plasma half-life was 7.4 minutes, and it was undetectable within 20 minutes. Pharmacokinetic modeling did not fit a typical pattern.⁸ The same investigators ...