Chapter 80 Salicylates
• Salicylate toxicity represents an infrequent yet serious and complex nonsteroidal antiinflammatory drug toxicity.
• Toxicity results when unbound drug in blood and tissue leads to uncoupling of oxidative phosphorylation and disruption of the Krebs cycle, which results in global organ dysfunction.
• The principal treatment for salicylate toxicity involves alkalinization of the urine to increase the rate of drug excretion.
PATHOPHYSIOLOGY OF TOXIC EXPOSURE
Table 80-1 Clinical Signs and Mechanisms of Salicylate-Induced Injury by Organ System7–9
Organ System | Mechanism of Injury | Site of Injury or Clinical Signs |
---|---|---|
Central nervous system | Direct stimulation | Stimulation of respiratory center leads to primary respiratory alkalosis |
Uncoupling of oxidative phosphorylation | Decreased glucose in CSF and brain (independent of plasma glucose) | |
Respiratory or pulmonary | Increased pulmonary capillary permeability (possibly via inhibition of prostacyclin or altered platelet-vessel interactions) | Noncardiogenic pulmonary edema |
Renal | Compensatory response to respiratory alkalosis | Increased renal excretion of sodium, potassium, bicarbonate |
Direct increase in tubular permeability | Additional loss of potassium, imbalance of sodium and water | |
Uncoupling of oxidative phosphorylation | Additional potassium loss due to inhibition of active transport | |
Decreased renal blood flow with or without direct renal injury | Acute renal failure (may be nonoliguric or oliguric) | |
Salicylate-induced inappropriate antidiuretic hormone | Oliguria | |
Hepatic and metabolic | Disruption of Krebs cycle and inhibition of dehydrogenases | Increased production of lactate and pyruvate (important source of metabolic acidosis) |
Increased lipolysis | Increased production and accumulation of ketone bodies | |
Uncoupling of oxidative phosphorylation | Increased systemic metabolism and tissue glycolysis (typical sequelae include: increased body temperature; increased CO2 production; increased O2 consumption; hypoglycemia) | |
Gastrointestinal | Direct injury with or without prostaglandin-mediated injury | Gastric irritation or ulceration, GI hemorrhage, vomiting |
Direct central stimulation of the chemoreceptor trigger zone | Vomiting (contributes to dehydration, loss of potassium) | |
Coagulation | Antagonism of vitamin K (direct effect of salicylate analogous to that of warfarin) | Drug-related coagulopathy with prolongation of prothrombin time |
Irreversible inhibition of platelet function | Decreased platelet aggregation, altered primary hemostasis |
CO2, Carbon dioxide; CSF, cerebrospinal fluid; GI, gastrointestinal; O2, oxygen.
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