Antidotes in De..

Hydroxocobalamin is a relatively new antidote for cyanide toxicity in the United States. Cyanocobalamin, vitamin B12, is formed when hydroxocobalamin combines with cyanide. 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. Unfortunately, there are no controlled studies comparing sodium thiosulfate with hydroxocobalamin in these circumstances.

The antidotal actions of cobalt as a chelator of cyanide were recognized as early as 1894.12,35Hydroxocobalamin has been used as a cyanide antidote in France for many years, first as a sole agent and then in combination with sodium thiosulfate.19 In the United States, hydroxocobalamin was finally approved by the Food and Drug Administration (FDA) in December 2006 and is available under the trade name Cyanokit.11,13

Hydroxocobalamin subsequently was shown to be successful in protecting against several minimum lethal doses of cyanide as long as an equimolar ratio of hydroxocobalamin to cyanide was used.1,7,28,33

The molecule is porphyrinlike in structure and has a cobalt ion at its core. The only difference between cyanocobalamin (vitamin B12) and hydroxocobalamin (referred to as vitamin B12a) is the replacement of the CN group with an OH group at the active site in the latter.24,30

The cobalt ion in hydroxocobalamin combines with cyanide to form the nontoxic cyanocobalamin.27,28 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.19 An ex vivo study using human skin fibroblasts demonstrates 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, particularly 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.7,16 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.27,35 Use of hydroxocobalamin with sodium thiosulfate is synergistic and comparable to the sequential use of sodium nitrite with sodium thiosulfate.19,33

Under an FDA Investigational New Drug permit, the first pharmacokinetic study of intravenous (IV) hydroxocobalamin was performed in the United States and published in 1993.13,14 Adult volunteers who were heavy smokers were given 5 g hydroxocobalamin (5%) intravenously, obtained from a French manufacturer. The first four patients ...

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