The number of intoxications with organophosphorus pesticides (OPs) is estimated at some 3,000,000 per year, and the number of deaths and casualties some 300,000 per year. OPs act primarily by inhibiting acetylcholinesterase (AChE), thereby allowing acetylcholine to accumulate at cholinergic synapses, disturbing transmission at parasympathetic nerve endings, sympathetic ganglia, neuromuscular endplates and certain CNS regions. Atropine is the mainstay of treatment of effects mediated by muscarine sensitive receptors; however, atropine is ineffective at the nicotine sensitive synapses. At both receptor types, reactivation of inhibited AChE may improve the clinical picture. The value of oximes, however, is still a matter of controversy. Enthusiastic reports of outstanding antidotal effectiveness, substantiated by laboratory findings of reactivated AChE and improved neuromuscular transmission, contrast with many reports of disappointing results. In vitro studies with human erythrocyte AChE, which is derived from the same single gene as synaptic AChE, revealed marked differences in the potency and efficacy of pralidoxime, obidoxime, HI 6 and HLo 7, the latter two oximes being considered particularly effective in nerve agent poisoning. Moreover, remarkable species differences in the susceptibility to oximes were revealed, requiring caution when animal data are extrapolated to humans. These studies impressively demonstrated that any generalisation regarding an effective oxime concentration is inappropriate. Hence, the 4 mg/L concept should be dismissed. To antagonise the toxic effects of the most frequently used OPs, pralidoxime plasma concentrations of around 80 mumol/L (13.8 mg/L pralidoxime chloride) should be attained while obidoxime plasma concentrations of 10 mumol/L (3.6 mg/L obidoxime chloride) may be sufficient. These concentrations should be maintained as long as circulating poison is expected to be present, which may require oxime therapy for up to 10 days. Various dosage regimens exist to reach this goal. The most appropriate consists of a bolus short infusion followed by a maintenance dosage. For pralidoxime chloride, a 1 g bolus over 30 minutes followed by an infusion of 0.5 g/h appears appropriate to maintain the target concentrtion of about 13 mg/L (70 kg person). For obidoxime chloride, the appropriate dosage is a 0.25 g bolus followed by an infusion of 0.75 g/24 h. These concentrations are well tolerated and keep a good portion of AChE in the active state, thereby retarding the AChE aging rate. AChE aging is particularly rapid with dimethyl phosphoryl compounds and may thwart the effective reactivation by oximes, particularly in suicidal poisoning with excessive doses. In contrast, patients with diethyl OP poisoning may particularly benefit from oxime therapy, even if no improvement is seen during the first days when the poison load is high. The low propensity to aging with diethyl OP poisoning may allow reactivation after several days, when the poison concentration drops. Rigorous testing of the benefits of oximes is only possible in randomised controlled trials with clear stratification according to the class of pesticides involved, time elapsed between exposure and treatment and severity of cholinergic symptoms on admission.

https://link.springer.com/content/pdf/10.2165%2F00139709-200322030-00004.pdf

The role of oximes in the management of organophosphorus pesticide poisoning

Summary SNP remains an effective, reliable, and commonly used drug for the rapid reduction of significant arte- rial hypertension regardless of the etiology, for after- load reduction in the face of low CO when blood volume is normal or increased, and for intraoperative induced hypotension. After establishing indwelling arterial monitoring, an initial infusion rate of 0.3-0.5 pg * kg-’ . min -’ is be f: un with titration as needed up to 2.0 p.g * kg-’ * min- . Higher rates for brief periods of time (10 min) are acceptable. The use of alternative drugs to reduce the dose or shorten the duration of infusion should be considered when the 2.0 pg * kg-’ * mine1 range is exceeded (Table 1). SNP should not be used by individuals unfamiliar with its potency and metabolic pathways, as the many reports of adverse reactions testify. Careful attention to infusion rates, particularly in patients at risk for depleted thiosulfate stores, is mandatory, and the use of other drugs in conjunction with or instead of SNP should always be considered. As with many therapeu- tic interventions, SNP requires careful administration to appropriately selected patients by a clinician who knows its inherent hazards. Despite its toxicity, SNP is popular because it often the most (in some cases, the only) effective drug in some difficult clinical circumstances.

Sodium nitroprusside: twenty years and counting.

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.

Clinical Pharmacokinetics of Nitroprusside, Cyanide, Thiosulphate and Thiocyanate

The combination of sodium thiosulfate and sodium nitrite has been used in the United States since the 1930s as the primary antidote for cyanide intoxication. Although this combination was shown to exhibit much greater efficacy than either ingredient alone, the two compounds could not be used prophylactically because each exhibits a number of side effects. This review discusses the pharmacodynamics, pharmacokinetics, and toxicology of the individual agents, and their combination.

The antidotal action of sodium nitrite and sodium thiosulfate against cyanide poisoning.

Fenoldopam, but not nitroprusside, improves renal function in severely hypertensive patients with impaired renal function☆

Sodium nitroprusside (SNP) as a mono-infusion was administered to 51 patients for periods of a few hours. A further group of 19 patients received SNP for periods of several days as a combination solution of SNP mixed with sodium thiosulphate. The concentrations of cyanide and of thiocyanate in the blood of all patients were measured. In seven of the patients the level of thiosulphate was also measured. Infusion of SNP on its own at levels exceeding 2 microgram/kg/min led to the rising of cyanide levels in the blood being proportional to dosage. Infusion of SNP mixed with thiosulphate showed no such accumulation of cyanide in any patient, irrespective of dosage level and duration. The efficacy at lowering blood pressure was fully maintained in the mixed infusion. The elimination half-life for thiosulphate was 16.5 min. Pharmacokinetic calculation of the rise in cyanide level showed that mono-infusions of 5-10 micrograms SNP/kg/min could within 5-10 h cause a life-threatening cyanide level in the blood. By contrast, mixed infusion of SNP together with thiosulphate, for which light-opaque syringes and tubing must be used, is a procedure free of danger and should become the technique of choice when therapeutically administering SNP in order to lower blood pressure.

J Busse

Papers

Cyanide toxicity of sodium nitroprusside in therapeutic use with and without sodium thiosulphate