Medical Pharmacology Topics   

Salicylates

Salicylates like aspirin are used in low to moderate intensity pain but may be superior to opiates in pain from inflammation. They are less toxic than opioids and act mostly in the periphery. They reduce inflammation and pain in arthritis but do not alter the disease. They decrease pain swelling and fever in rheumatic fever but do not alter the progress of the disease. No tolerance develops to the analgesic effects of salicylates. Salicylates are also indicated to reduce fever, and topical application of salicylic acid has keratolytic action used to treat warts.

Salicylates have other pharmacological actions that may lead to unwanted side effects: respiratory stimulation, electrolyte imbalance, major GI irritation, uric acid excretion, platelet inhibition, hepatotoxicity, and acute renal or hepatic insufficiency in sensitive patients. Some persons have hypersensitivity reactions: skin eruptions, asthma, anaphylaxis. They are also Reye's Syndrome. 

Respiration is stimulated directly by stimulating the respiratory center in the medulla, and  indirectly by uncoupling oxidative phosphorylation in skeletal muscle, thus increasing CO2 production. This may result in respiratory alkalosis and increased bicarbonate excretion. Toxic doses, especially in infants, cause central respiratory paralysis and respiratory acidosis.

Respiratory alkalosis results in compensation for the lost bicarbonate (?). Further changes with toxic doses result in both respiratory and metabolic acidosis because of less bicarbonate in the blood, decreased respiration (thus CO2 increases), and accumulation of acid metabolites in blood. Salicylates also increase water loss and K+ and Na+ excretion associated with alterations in acid-base balance.

Gastrointestinal effects of salicylates include epigastric distress, nausea, vomiting, gastric ulceration, hemorrhage, local irritation and abdominal pain. The mechanism seems to be inhibition of GI PGF2alpha and PGE2, which inhibit acid secretion.

Historically, salicylate was used as a uricosuric agent, but the effect is dose dependent. At low doses it decreases urate excretion, antagonizes other uricosurics and worsens gout. At large doses (>5g/d) it increases urate excretion. It is not used as an uricosuric any more.

Aspirin inhibits platelet aggregation and prolongs bleeding, presumably by blocking thromboxane A2 synthesis. Platelets are more sensitive to irreversible COX inhibition since they cannot synthesize the enzyme. Therefore aspirin is contraindicated in patients with severe hepatic damage, vitamin K deficiency, hemophilia and pregnant women near term. Caution is required with patients on anticoagulant therapy. Studies suggest that aspirin reduces the incidence of acute myocardial infarction and death in men with unstable angina and reduces the frequency of ischemic attacks in patients with arteriosclerosis, both of these effects due to its long lasting alteration in platelet function.

Salicylate is absorbed in the stomach and small intestine by passive transport with a peak plasma concentration in 2 hrs. it distributes to total body but has a high plasma protein binding. It is largely biotransformed in the liver, with little salicylate excreted unchanged. At toxic concentrations, excretion may shift from 1st to zero order kinetics.

Aspirin overdose occurs with relatively high frequency, more likely in children. Symptoms include:

• CNS: tinnitus, hearing loss, dimness of vision, headache, hyperthermia, dizziness, drowsiness, mental confusion, delirium, convulsions, coma
• GI: nausea, vomiting
• Acid/base balance: initial respiratory alkalosis, then respiratory and metabolic acidosis
• Dehydratation due to excessive sweating, vomiting, hyperventilation
• In severe intoxication, cardiorespiratory arrest

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