A41: Antidotes in Depth

INTRODUCTION

Cyanocobalamin, vitamin B₁₂, is formed when hydroxocobalamin combines with cyanide, quickly dropping cyanide concentrations and improving hemodynamics. Nitrites and sodium thiosulfate have traditionally been used to treat patients with cyanide toxicity. Nitrites have the disadvantage of producing methemoglobin, which is dangerous in a patient with coexistent elevated carboxyhemoglobin concentrations, such as would be found in fire victims suspected of having cyanide toxicity. Based on the mechanism of action of sodium thiosulfate, particularly when used alone, it is unlikely to be as effective as hydroxocobalamin, or work as quickly. A recent 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 cyanide toxicity.⁷

HISTORY

The antidotal actions of cobalt as a chelator of cyanide were recognized as early as 1894.^15,47 Hydroxocobalamin has been used as a cyanide antidote in France for many years, first as a sole agent and then in combination with sodium thiosulfate.²⁵ Hydroxocobalamin was finally approved by the Food and Drug Administration (FDA) in December 2006 and is available under the trade name Cyanokit.^14,16

In experimental models, hydroxocobalamin was successful in protecting against several ­minimum lethal doses of cyanide when an equimolar ratio of hydroxocobalamin to cyanide was used.^1,10,36,43

PHARMACOLOGY

Chemistry

The molecule is porphyrinlike in structure and has a cobalt ion at its core. The only 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.^31,38

Mechanism of Action

The cobalt ion in hydroxocobalamin combines with cyanide to form the nontoxic cyanocobalamin.^35,36 One mole of hydroxocobalamin binds 1 mole of CN. Given the molecular weights of each, 52 g of hydroxocobalamin are needed to bind 1 g of cyanide.²⁵ An ex vivo study using human skin fibroblasts demonstrated that hydroxocobalamin penetrates intracellularly to form cyanocobalamin.² In the setting of cyanide poisoning, hydroxocobalamin removes cyanide from the mitochondrial electron transport chain, allowing oxidative metabolism to proceed. Hydroxocobalamin also binds nitric oxide, a vasodilator, causing vasoconstriction both in the presence and in the absence of cyanide. This same property potentially contributes to its beneficial effects by increasing systolic and diastolic blood pressure and improving the hemodynamic status of cyanide poisoned patients.^10,21 Other cobalt chelators, such as dicobalt ethylenediaminetetraacetic acid (EDTA), have been used both experimentally and clinically in other countries, but their therapeutic index is narrow, especially in the absence of cyanide. ­Additionally, idiosyncratic adverse effects make these compounds less advantageous.^35,47 In France, hydroxocobalamin is used with ...