Module 3: Pathophysiology of Salicylate Toxicity

3.1 Salicylate Metabolism and Pharmacokinetics

Salicylates are weak acids with pKa around 3, making them predictably absorbed in the acidic environment of the stomach. Following oral ingestion, acetylsalicylic acid is rapidly hydrolyzed to salicylic acid in the gut and liver. Peak concentrations typically occur within 30 minutes to 2 hours after therapeutic doses. Salicylates have a small volume of distribution of approximately 150-200 mL/kg, indicating limited tissue distribution. They are highly protein bound to albumin, with 90-95% binding at normal therapeutic concentrations.

In overdose situations, absorption becomes erratic and prolonged due to pylorospasm, pharmacobezoar formation, and enteric coating retarding dissolution. The volume of distribution may increase to 300-500 mL/kg as protein binding sites become saturated. At toxic concentrations, protein binding can decrease to as low as 75%. The unbound fraction has higher lipid solubility allowing increased penetration into tissues and organs including the central nervous system (CNS).

Salicylates are primarily metabolized in the liver through conjugation with glycine and glucuronide to form salicyluric acid and phenolic glucuronides. A small portion is metabolized by cytochrome P450 to gentisic acid. At normal doses, first-order elimination kinetics predominate with a half-life around 2-4 hours. However, with increasing concentrations, enzymatic pathways become saturated. This impairs hepatic clearance and prolongs the half-life up to 15-30 hours.

Salicylates and their metabolites are primarily cleared through the kidneys by glomerular filtration and tubular secretion. Impaired renal blood flow or glomerular filtration will substantially delay excretion. Volume depletion or medications altering renal function can also reduce renal clearance. At highly toxic concentrations, the elimination profile again resembles first-order kinetics as a larger percentage is directly cleared unchanged in the urine.

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3.2 Mechanism of Salicylate Toxicity at Cellular and System Level

The fundamental mechanism of salicylate toxicity involves uncoupling of oxidative phosphorylation in the mitochondria. This impairs synthesis of ATP and causes electrons to be discharged as heat instead of being utilized to generate ATP. As a result, increased oxygen consumption occurs to compensate for the inefficient ATP production.

With sudden decreased ATP availability, cells switch to anaerobic metabolism pathways to meet their high energy demands. This leads to accumulation of lactic acid, pyruvic acid, and other organic acids. Simultaneously, lipid metabolism is enhanced to generate ketone bodies including β-hydroxybutyrate and acetoacetate. The combined effect is the generation of a high anion gap metabolic acidosis.

The non-ionized form of salicylic acid easily penetrates the lipid cellular membrane. However, the charged ionized form at physiologic pH cannot cross the membrane. As acidemia develops, an increased portion of salicylate converts to the non-ionized state. This allows rapid distribution into tissues and exertion of toxic effects on organs throughout the body.

Critically, the non-ionized form readily crosses the blood-brain barrier. Neurotoxicity manifests as cerebral edema, seizures, coma and death. Other organs impacted include the lungs causing pulmonary edema and respiratory distress, kidneys resulting in acute tubular necrosis, skeletal muscle leading to rhabdomyolysis and the liver resulting in centrilobular necrosis.

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3.3 Metabolic and Respiratory Effects

Salicylates have a direct stimulatory effect on the respiratory center in the medulla oblongata. Initial effects of toxicity include hyperventilation and resulting respiratory alkalosis. As serum pH rises, more salicylate remains ionized reducing distribution into the CNS. Eventually, the respiratory system tires and compensatory respiratory acidosis sets in.

The metabolic acidosis stems from multiple factors. Anaerobic metabolism leads to increased lactic acid. Impaired oxidative phosphorylation reduces ATP synthesis worsening acidemia. Salicylates increase free fatty acids, generating ketoacids. Loss of bicarbonate and other electrolytes in urine and vomiting depletes buffering capacity.

Hypokalemia results from intracellular shift to buffer protons, vomiting losses and renal wasting. Hypocalcemia occurs due to albumin binding, impaired protein binding and bicarbonate chelation. Dehydration concentrates the acidic metabolites. Impaired renal acidification prevents excretion of accumulated organic acids.

Hyperglycemia may initially result from catecholamine release, glycogenolysis and impaired insulin response. Prolonged toxicity can precipitate hypoglycemia by depleting glycogen stores, inhibiting gluconeogenesis and increasing glucose consumption. Decreased CSF glucose despite normal serum concentrations likely contributes to CNS toxicity.