In therapeutic doses, aspirin is absorbed rapidly from the upper small intestine. With overdosage, however, absorption may occur more slowly. Thus, blood salicylate concentrations can continue to increase for as long as 24 hours after ingestion. Salicylates are distributed unevenly throughout the body fluids and tissues. The low apparent volume of distribution suggests that salicylate remains largely in the central compartment. At therapeutic doses, salicylate is significantly bound to plasma proteins (possibly as high as 80% to 90%). Albumin is the major protein responsible for the extensive protein binding. The degree of protein binding is dependent on both the concentration of salicylic acid and the amount of albumin. As protein-binding sites become saturated in overdosed patients, the amount of non–protein-bound salicylic acid increases, which increases the potential for significant toxicity. Conditions that deplete albumin and other proteins predispose the patient to a disproportionate risk of severe salicylism at a given plasma concentration.

If acid–base status is normal, salicylates are highly ionized. Thus, diffusion of salicylates across the blood–brain barrier and into the central nervous system (CNS) are reduced. Patients with salicylism may develop metabolic acidosis, which increases the fraction of nonionized salicylate. A higher nonionized fraction results in a greater CNS penetration, increased CNS concentration, and elevated cerebral spinal fluid (CSF) concentration. High CSF concentrations are associated with CNS toxicity and greater morbidity.

Initially, the hydrolysis of salicylate salt or aspirin results in the formation of salicylic acid. Salicylic acid undergoes further biotransformation and elimination via first-order processes. As higher doses of salicylate are ingested, biotransformation pathways become saturated, and elimination converts from a dose-dependent first-order process (rate proportional to the dose) to a zero-order process (i.e., a fixed amount of salicylic acid is metabolized per unit of time, regardless of the dose). These toxicokinetics of salicylic acid account for the prolonged elimination half-life, which approximates 20 to 30 hours. In contrast, no reduction occurs in the initial hydrolysis of acetylsalicylic acid (aspirin) to salicylic acid.

Renal clearance accounts for most of the elimination of salicylates and is enhanced from 2% to more than 80% as pH and ionization increase. The kidneys eliminate salicylate by both glomerular filtration and tubule secretion. Salicylate also is reabsorbed, however, in the renal tubule. Reabsorption is affected by urinary pH and urine flow rate. Only nonionized molecules are reabsorbed. Because salicylate is a weak acid (pKa 3.5), the nonionized fraction increases as pH level decreases. Under normal conditions, that is, in the presence of an acidic urine, reabsorption is favored. However, as the urine becomes more alkaline, the amount of ionized salicylate increases, and the proportion that is reabsorbed by the renal tubule decreases.

Neonates absorb salicylate as rapidly as any other age group, but they metabolize it more slowly. Renal elimination is slower in children than in adults, and they have reduced albumin concentrations, which increases plasma salicylate concentrations. The volume of distribution increases in proportion to the dose, suggesting that children may have higher tissue concentrations than are inferred by the plasma concentration.

The toxic effects of salicylate are complex and multifactorial. The acute ingestion of large quantities, particularly in children, may produce nausea and vomiting as a result of local gastric irritation and the stimulation of chemoreceptor trigger zones; this results in dehydration. Table 120.1 summarizes the mechanisms, metabolic consequences, and clinical pathophysiology of acute aspirin toxicity. The primary effects of toxic levels of salicylate include the direct stimulation of the CNS respiratory center and is independent of increased oxygen consumption or carbon dioxide production. Metabolic acidosis is the result of the collective effects of elevated lactic acid and pyruvic acid secondary to Krebs cycle enzyme inhibition, increased ketone body formation from accelerated lipid metabolism, and amino acidemia from inhibition of aminotransferases. In younger children, in chronic salicylate toxicity, and in large-dose poisoning in older children, metabolic acidosis appears early and clinically predominates. Older children with moderate or small-dose poisoning and most adults are able to compensate the metabolic acidosis by hyperventilation, resulting in respiratory alkalosis. Hypoglycemia is uncommon but quite severe when it occurs. Hyperglycemia is more common. Significant CNS hypoglycemia can occur with normal blood glucose levels.

Severe fluid and electrolyte loss can occur with salicylate toxicity. Increased heat production, because of the uncoupling of oxidative phosphorylation, hyperpnea, and tachypnea, all lead to an increase in insensible water loss. Decreased oral intake and vomiting, and the increase in obligatory water and electrolyte loss necessitated by the enhanced renal solute load of organic acids, further aggravates the water, sodium, and potassium loss. The renal excretion of bicarbonate is increased, contributing to the metabolic acidosis.