A40: Antidotes in Depth

INTRODUCTION

Sodium thiosulfate is a safe and effective antidote that detoxifies cyanide by donating a sulfur moiety to form thiocyanate. Thiocyanate is much less toxic than cyanide and is renally eliminated. Sodium thiosulfate works synergistically with nitrites and is probably at least additive to hydroxocobalamin in the detoxification of cyanide. Because sodium thiosulfate does not compromise hemoglobin oxygen saturation, it can be used without nitrites in circumstances where the formation of methemoglobin would be detrimental, as in patients who have elevated levels of carboxyhemoglobin or preexistent methemoglobinemia from smoke inhalation, drug exposure, or congenital dyshemoglobinemias when hydroxocobalamin is unavailable. 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 a swine cyanide model could not show a benefit of sodium thiosulfate as sole therapy or show an added benefit to that offered by hydroxocobalamin.³ Sodium thiosulfate is used prophylactically with nitroprusside to prevent cyanide toxicity. Sodium thiosulfate is also used to treat calcific uremic arteriolopathy (calciphylaxis) theoretically by increasing the solubility of calcium deposits, inducing vasodilation, and acting as a free radical scavenger.^6,24,28,32

HISTORY

In 1933, Chen and colleagues⁸ noted that preexposure treatment with intravenous (IV) sodium thiosulfate protected dogs against three minimum lethal doses of sodium cyanide, and even more remarkable were the synergistic effects obtained by combining sodium thiosulfate with either inhaled amyl nitrite or IV sodium nitrite, which protected the dogs against 10 to 18 minimum lethal doses of cyanide.^7,8

PHARMACOLOGY

Chemistry

The chemical formula of sodium thiosulfate is Na₂S₂O₃. The molecular weight of sodium thiosulfate is 248 Da. It forms a pentahydrate that is highly water soluble.

Mechanism of Action

The sulfur provided by sodium thiosulfate binds to cyanide with the help of rhodanese (cyanide sulfur transferase) and mercaptopyruvate sulfur transferase.^8,36,38 Sulfane sulfur (a divalent sulfur bound to one other sulfur) is the only sulfur that reacts with cyanide to produce thiocyanate, which is minimally toxic and renally eliminated. In several animal models, sodium thiosulfate protects against several minimum lethal doses of cyanide.^16,20 The addition of rhodanese increases the efficacy of sodium thiosulfate, but the use of rhodanese is impractical in the clinical setting.^20,37 The cationic site on rhodanese is crucial to cleaving the sulfur–sulfur bond of thiosulfate and forming a sulfur–rhodanese complex that readily reacts with cyanide.³⁸

Rhodanese is probably not solely responsible for sulfur–sulfur bond cleavage, as rhodanese is largely a mitochondrial enzyme found in the liver and skeletal muscle, and sodium thiosulfate is a divalent ion that poorly crosses membranes.^{12,20,25,36,...}