Clinical pharmacokinetics of nitroprusside, cyanide, thiosulphate and thiocyanate

Sodium nitroprusside decomposes within a few minutes after intravenous infusion to form metabolites which are pharmacologically inactive but toxicologically important. Free cyanide, which represents 44% w/w of the sodium nitroprusside molar mass, is formed and must be detoxified in the body into thiocyanate using thisulphate as substrate. Nitroprusside penetrates cell membranes slowly. At therapeutic dose levels its distribution is probably mainly extracellular. Contact with the sulfhydryl groups in the cell walls, however, immediately initiates breakdown of the molecule. Sodium nitroprusside taken orally is not absorbed from the gastrointestinal tract to any appreciable extent. Cyanides in the body form prussic acid, which can rapidly penetrate mucous and cell membranes. In the blood, about 99% of the prussic acid binds to the methaemoglobin of erythrocytes. At normal physiological levels, however, the total body methaemoglobin of an adult human can only bind about 10mg of prussic acid; this is a small fraction of the amounts usually infused therapeutically as sodium nitroprusside. The endogenous detoxification of prussic acid exhibits zero-order kinetics. The limiting factor is a sulphur donor, principally thiosulphate, which is available in the body in only limited amounts. The rate of spontaneous detoxification of prussic acid in humans is only about 1 microgram/kg/min, corresponding to a sodium nitroprusside infusion of about 2 microgram/kg/min. This dose limit set by the prussic acid toxicity of sodium nitroprusside can, however, be increased considerably by simultaneous infusion of thiosulphate. A lack of thiosulphate can be detected early by a rise of the prussic acid concentration in the erythrocytes. Thiosulphate taken orally is not absorbed by the body. After intravenous infusion, its serum half-life is about 15 minutes. Most of the thiosulphate is oxidised to sulphate or is incorporated into endogenous sulphur compounds; a small proportion is excreted through the kidneys. Thiocyanate taken orally is completely absorbed by the body. In healthy persons its volume of distribution is approximately 0.25 L/kg and the serum half-life about 3 days; elimination is mainly renal. Thiocyanate toxicity does not represent a serious therapeutic problem with intravenous infusion of sodium nitroprusside.