Toxicity and mechanisms

The fatal adult dose of aspirin is 500 mg/kg (,...1.98..1..), and toxicity may be lifethreatening at plasma levels of over 750 mg/l (5.40 mmol/l) in adults.

Salicylates have a wide variety of actions. In overdose, this leads to a number of physiological and metabolic derangements. The mechanisms which lead to the clinical effects are outlined in Fig 1. Nausea and vomiting are due to prostaglandin effects in the stomach. The most apparent metabolic effect in the early stages is due to stimulation of the respiratory center, causing hyperventilation which leads to a respiratory alkalosis. Later, a raised anion gap metabolic acidosis supervenes due to increased lactate levels, stimulation of lipid metabolism with ketone body production, and inhibition of aminotransferase. The body compensates by excreting bicarbonate, sodium and potassium ions, and water, reducing the body's buffering capacity, and resulting in an anion gap metabolic acidosis which enhances transfer of the salicylate ion across the blood-brain barrier. Salicylates also uncouple oxidative phosphorylation, decreasing ATP production, increasing oxygen utilization and carbon dioxide and lactate production, and contributing to the metabolic acidosis. The energy which should be used to produce ATP is diverted to mitochondrial heat production, leading to compensatory sweating and flushing, with the body temperature usually remaining normal in adults although pyrexia may occur in children. Vomiting, hyperventilation, and sweating all lead to volume depletion which may further complicate electrolyte disturbances. Consciousness is not usually lost, but in severe cases central nervous system toxicity gradually manifests itself as confusion, coma, and convulsions. Indeed, salicylate lethality has been related to central nervous system dysfunction when a 'critical brain salicylate level' is reached ( Hill 1973).

Fig. 1 Mechanisms of toxicity responsible for the clinical effects seen in salicylate poisoning: G6PD, glucose-6-phosphate dehydrogenase.

Aspirin is rapidly converted to salicylic acid which is further metabolized to five main metabolites: salicyluric acid, salicyl phenolic glucuronide, gentisic acid, acyl glucuronide, and gentisuric acid. The pathways for the first two of these involve saturable hepatic enzymes, so that when a large amount of salicylate is ingested these routes quickly become saturated. This results in a change from first-order kinetics (where elimination is proportional to the plasma concentration) to zero-order kinetics (where only a certain amount is eliminated irrespective of the plasma concentration). Thus salicylate may accumulate following mild therapeutic overdoses, particularly in children, and prior therapeutic use of the drug may increase the toxicity of an acute overdose.

Under zero-order kinetics the amount of salicylate excreted unchanged in the urine increases. With very high plasma concentrations, up to 80 per cent of salicylate can be excreted unchanged in the urine. This pathway is sensitive to changes in urine pH; as the pH rises (i.e. the urine becomes more alkaline), excretion of salicylate is enhanced. This is the basis of urinary alkalinization in salicylate overdose.

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