Nonnarcotic Analgesics - Aspirin

COX enzymes: COX-1 constitutively expressed in all tissues; functions as a housekeeping enzyme. COX-2 enzymes expressed only in the brain; expression is induced by cytokines and prostaglandins produced by COX-2 are responsible for resetting body temp, sensitization of pain receptors, and vasodilation. Inhibition of COX-2 responsible for therapeutic effects of NSAIDs. Inhibition of COX-1 responsible for side effects of NSAIDs. IC50 is the concentration of an agent that inhibit 50% of enzyme activity.

Salicylates (aspirin) – Analgesic, anti-pyretic, anti-inflammatory, and anti-platelet properties

Chemistry: Weak acid pKa 3.5

Analgesic action: Relieves low to moderate pain from integumental structures. Hollow viscera are less responsive. Peripheral analgesic effect produced by inhibition of the synthesis of prostaglandins and thromboxanes in inflamed tissues. Potent inhibitors of COX-1 and far less potent at COX-2.

Anti-pyretic action: Lowers elevated body temperature. Does not reduce exercise-induced hyperthermia.

Anti-inflammatory effects: Inhibition of prostaglandin and thromboxane synthesis is the mechanism of anti-inflammatory action. Higher doses required. COX-2 plays a bigger role in inflammation than does COX-1. Aspirin does not inhibit the formation of leukotrienes via the lipoxygenase pathway.

Antiplatelet effect: Prolongation of bleeding time. Aspirin covalently acetylates (irreversible) a serine at the active site of platelet cyclooxygenase, thereby reducing formation of thrmoboxane A2. Aspirin should be avoided in patients with severe hepatic damage, hypoprothrmobinemia, vitamin K deficiency, or hemophilia.

Effects on organ systems

• Respiration: Stimulate respiration directly and indirectly. High doses depress respiration and cause respiratory acidosis. Respiratory alkalosis occurs during mild poisoning. Indirect effect due to uncoupling of oxidative phosphorylation.

• Acid-base balance and electrolytes: With severe toxicity respiratory acidosis and metabolic acidosis can occur simultaneously (low pH, low HCO3-, normal PCO2). Dehydration may occur due to sweating and vomiting. Hypokalemia can result from respiratory alkalosis.

• GI tract: Exacerbation of peptic ulcers, GI hemorrhage, and erosive gastritis may occur in patients on high-dose therapy. Involves inhibition of prostaglandin synthesis, which protects gastric mucosa.

• Kidney: Low doses (2 g or less) decrease urate excretion by competing with urate. Decreased renal blood flow due to inhibition of PGE synthesis

• Blood: Antiplatelet

• Metabolism: Uncoupling of oxidative phosphorylation. Pyrexia occurs at toxic doses.

• CNS: In toxic doses, slaicylates produce CNS stimulation followed by depression. Dizziness, tinnitus, high tone deafness.

Pharmacokinetics: Highly bound to plasma proteins (decreased binding with increasing age). Metabolism takes place in liver. Metabolims shows mixed-order kinetics (half-life 3-6 hrs in low doses, 15-30 hrs high doses). Excreted in urine as free and conjugated metabolites. Alkalinization of urine can markedly enhance clearance.

Toxicology: Mild chronic salicylate intoxication (salicylism) causes skin eruptions, hyperthermia, and dehydration. Treatment of acute poisoning must be immediate (gastric lavage, emesis, bicarbonate to promote excretion). Hypersensitivity reactions occur. Contraindicated for long periods during pregnancy due to thrombotic effects and prostaglandin inhibition.

Drug interactions: Due to salicylate-induced displacement from plasma proteins (warfarin) and anticoagulant action (vitamin K, ethanol, anticoagulants).

Usage: Antipyretic (300-600 mg every 4 hrs); analgesic (300-600 mg every 4 hrs, can lead to loss of effectiveness and rebound headache); anti-inflammatory (4 g daily for RA, SLE sx); antiplatelet; closure of patent ductus arteriosus.

Reye’s syndrome: Do not give to children suffering from influenza and chicken pox (fatal hepatic necrosis).

Category: Pharmacology Notes