A39: Antidotes in Depth

INTRODUCTION

Sodium nitrite is an effective cyanide antidote when administered in a timely fashion and followed by sodium thiosulfate, which acts in synergy. 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.¹³ Although the exact mechanism of action of the nitrites is unclear, the production of methemoglobin is both therapeutic in cyanide poisoning and potentially life-threatening if nitrites are administered to a patient with impaired oxygen carrying capacity, from elevated concentrations of carboxyhemoglobin, methemoglobin, or sulfhemoglobin from any cause. In the latter cases, hydroxocobalamin and or sodium thiosulfate can still be administered intravenously without causing harm.

HISTORY

Expanding on earlier work that demonstrated the limited role of methylene blue and the efficacy of sodium nitrite in cyanide poisoned dogs, inhaled amyl nitrite prevented the development of cyanide-induced seizures and muscular rigidity.⁴ Amyl nitrite administered by inhalation protected dogs from up to four minimum lethal doses of sodium cyanide (a total of 24 mg/kg subcutaneously). 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 cyanide. The same authors discovered that intravenous (IV) use of sodium thiosulfate alone protected against three minimum lethal doses of cyanide 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.^3,5

PHARMACOLOGY

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.

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 cyanide, producing cyanomethemoglobin. This drives the reaction toward cyanomethemoglobin and liberates cyanide from cytochrome oxidase. Stroma-free methemoglobin is effective against four minimum lethal doses of cyanide in rats.²⁰ Nitrites oxidize the iron in hemoglobin to produce methemoglobin. Because nitrites are accepted antidotes for cyanide poisoning, for many years methemoglobin formation was assumed to be their sole antidotal mechanism of action.^14,24 Other, faster methemoglobin inducers, such as 4-dimethyaminophenol and hydroxylamine, also are effective as cyanide antidotes.^14,22 The production of methemoglobin by nitrite is slow, but when methylene blue is administered to prevent methemoglobin formation, nitrite remains an effective antidote.^14,24 Reasoning that nitrite-induced vasodilation might be part ...