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INTRODUCTION

Sodium nitrite is an effective cyanide (CN) antidote that acts best when administered in a timely fashion and is followed by sodium thiosulfate. The utility of amyl nitrite, a volatile drug available in ampules that can be broken and administered by inhalation while sodium nitrite is being prepared to administer intravenously, is questioned.39 This combination of sodium nitrite followed by sodium thiosulfate was the only antidote combination available to treat CN toxicity before the US Food and Drug Administration (FDA) approval of hydroxocobalamin in December 2006. Although there has never been a head-to-head study in humans comparing hydroxocobalamin with the combination for the treatment of CN toxicity, the advantages of hydroxocobalamin are that it works quickly and directly to inactivate CN to form cyanocobalamin. In addition, hydroxocobalamin can be administered to patients with impaired oxygen-carrying capacity from elevated concentrations of carboxyhemoglobin (COHb), methemoglobin, or sulfhemoglobin, making it the preferred CN antidote under most circumstances.

HISTORY

In 1895, Lang reported the efficacy of sodium thiosulfate in detoxifying hydrocyanic acid.36 The treatment of patients with CN poisoning with methylene blue led to the understanding of the role of methemoglobin in detoxifying CN and the search for better methemoglobin inducers.22 Experiments in CN-poisoned canines demonstrated the limited role of methylene blue and the efficacy of amyl nitrite, sodium nitrite, and sodium thiosulfate.12-14 Amyl nitrite administered by inhalation protected canines from up to four minimum lethal doses of sodium CN (a total of 24 mg/kg subcutaneously).13 In the regimen used, therapy was started within 5 to 7 minutes of exposure and was continued for several hours. The frequency of inhalation was based on ­clinical response. These experimental results led to the use of inhaled amyl nitrite for patients poisoned by CN. The same authors discovered that intravenous (IV) use of sodium thiosulfate alone protected against three minimum lethal doses of CN in dogs and that the combination of sodium thiosulfate with either inhaled amyl nitrite or IV sodium nitrite protected against 10 to 18 minimum lethal doses, respectively.12,14

PHARMACOLOGY OF THE NITRITES

Chemistry

The chemical formula for sodium nitrite is NaNO2 and for amyl nitrite is C5H11NO2. Sodium nitrite has a molecular weight of 69 Da, and amyl nitrite has a molecular weight of 117 Da. Amyl nitrite is volatile even at low temperatures and is highly flammable.

Mechanism of Action

Cyanide quickly and reversibly binds to the ferric iron in cytochrome oxidase, inhibiting effective energy production throughout the body. The ferric iron in methemoglobin preferentially combines with CN, producing cyanomethemoglobin. This drives the reaction toward cyanomethemoglobin and liberates CN from cytochrome oxidase. Stroma-free methemoglobin is effective against four minimum lethal doses of CN in rats.65 Nitrites oxidize the iron in hemoglobin to produce methemoglobin. ...

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