Chapter A41: Hydroxocobalamin

INTRODUCTION

Cyanocobalamin, vitamin B₁₂, is formed when hydroxocobalamin combines with cyanide (CN), quickly dropping CN concentrations and improving hemodynamics. Nitrites and sodium thiosulfate were traditionally used to treat patients with CN toxicity. Nitrites have the disadvantage of purposefully inducing methemoglobin, which is dangerous in a patient with coexistent elevated carboxyhemoglobin (COHb) concentrations, such as in fire victims suspected of having CN toxicity. Based on the mechanism of action of sodium thiosulfate, particularly when used alone, sodium thiosulfate is less effective and works less rapidly than hydroxocobalamin. A study in swine did not show a benefit to sodium thiosulfate as sole therapy or show an added benefit to hydroxocobalamin in a model of intravenous (IV) CN toxicity.⁷ Separately, hydroxocobalamin is under investigation for the treatment of hemorrhagic shock.^8,9,12

HISTORY

The antidotal actions of cobalt as a chelator of CN were recognized as early as 1894.^22,61 Hydroxocobalamin was used as a CN antidote in France for many years, first as a sole agent and then in combination with sodium thiosulfate.³³ Hydroxocobalamin was approved for use in the United States by the Food and Drug Administration (FDA) in December 2006 and is available under the trade name Cyanokit.^21,23

PHARMACOLOGY

Chemistry

The hydroxocobalamin molecule shares structural similarity with porphyrin, with a cobalt ion at its core. The difference between cyanocobalamin (­vitamin B₁₂) and hydroxocobalamin (vitamin B_12a) is the replacement of the CN group with an OH group at the active site in the latter.^40,48

MECHANISM OF ACTION

In experimental models, hydroxocobalamin is successful in protecting against several minimum lethal doses of CN when an equimolar ratio of hydroxocobalamin to CN was used.^1,16,46,56 The cobalt ion in hydroxocobalamin combines with CN in an equimolar fashion to form ­nontoxic cyanocobalamin—one mole of hydroxocobalamin binds one mole of CN.^45,46 Thus, given the molecular weights of each, 52 g of hydroxocobalamin is needed to bind 1 g of CN.³³ So, a standard 5 g of hydroxocobalamin would be expected to bind 96 mg of CN. Doing a theoretical calculation and assuming a CN simian volume of distribution of 0.25 L/kg, this would mean, in an 80-kg man, 4.8 mg/L or 4.8 mcg/mL.

An ex vivo study using human skin fibroblasts demonstrated that hydroxocobalamin penetrates intracellularly to form cyanocobalamin.² In the setting of CN poisoning, hydroxocobalamin removes CN from the mitochondrial electron transport chain, allowing oxidative metabolism to proceed. Hydroxocobalamin also binds structurally similar nitric oxide (NO), a vasodilator, causing vasoconstriction both in the presence and in the absence of CN. This property contributes to its beneficial effects by increasing systolic and ...