Pharmacokinetics Salicylic acid is a simple organic acid with a pKa of 3.0.Aspirin(acetylsalicylic acid; ASA)has a pKa of 3.5.Sodium salicylate and aspirin (Figure 36-2)are equally effective anti-inflammatory drugs,though aspirin may be more effective as an analgesic.The salicylates are rapidly absorbed from the stomach and upper small intestine,yielding a peak plasma salicylate level within 1-2 hours.Aspirin is absorbed as such and is rapidly hydrolyzed (serum half-life 15 minutes)to acetic acid and salicylate by esterases in tissue and blood.Salicylate is bound to albumin,but the binding and metabolism of salicylates are saturable so that the unbound fraction increases as total concentration increases.Beyond a total body load of 600 mg, increases in salicylate dosage increase salicylate concentration disproportionately.As doses of aspirin increase,salicylate elimination half-life increases from 3-5 hours(for 600 mg/d dosage)to 12-16 hours (dosage 3.6 g/d).Alkalinization of the urine increases the rate of excretion of free salicylate and its water-soluble conjugates. 0-Na CH OH Aspirin 0 Sodium salicylate -0 HO-C-CH3 OH Acetic acid Salicylate Conjugation with Conjugation glucuronic acid Oxidation with glycine H 0 Ester and ether -N-CH2-COOH Free HO -0H glucuronides salicylate OH OH Salicyluric acid Gentisic acid (1%) Figure 36-2.Structure and metabolism of the salicylates.(Modified and reproduced, with permission,from Meyers FH,Jawetz E,Goldfien A:Review of Medical Pharmacology,7th ed.McGraw-Hill,1980.) Mechanisms of Action A.ANTI-INFLAMMATORY EFFECTS Aspirin is a nonselective inhibitor of both COX isoforms(Figure 36-3),but salicylate is much less effective in inhibiting either isoform.Nonacetylated salicylates may work as oxygen radical scavengers.Aspirin irreversibly inhibits COX and inhibits platelet aggregation,while nonacetylated salicylates do not.Pharmacokinetics Salicylic acid is a simple organic acid with a pKa of 3.0. Aspirin (acetylsalicylic acid; ASA) has a pKa of 3.5. Sodium salicylate and aspirin (Figure 36-2) are equally effective anti-inflammatory drugs, though aspirin may be more effective as an analgesic. The salicylates are rapidly absorbed from the stomach and upper small intestine, yielding a peak plasma salicylate level within 1-2 hours. Aspirin is absorbed as such and is rapidly hydrolyzed (serum half-life 15 minutes) to acetic acid and salicylate by esterases in tissue and blood. Salicylate is bound to albumin, but the binding and metabolism of salicylates are saturable so that the unbound fraction increases as total concentration increases. Beyond a total body load of 600 mg, increases in salicylate dosage increase salicylate concentration disproportionately. As doses of aspirin increase, salicylate elimination half-life increases from 3-5 hours (for 600 mg/d dosage) to 12-16 hours (dosage > 3.6 g/d). Alkalinization of the urine increases the rate of excretion of free salicylate and its water-soluble conjugates. Figure 36-2. Structure and metabolism of the salicylates. (Modified and reproduced, with permission, from Meyers FH, Jawetz E, Goldfien A: Review of Medical Pharmacology, 7th ed. McGraw-Hill, 1980.) Mechanisms of Action A. ANTI-INFLAMMATORY EFFECTS Aspirin is a nonselective inhibitor of both COX isoforms (Figure 36-3), but salicylate is much less effective in inhibiting either isoform. Nonacetylated salicylates may work as oxygen radical scavengers. Aspirin irreversibly inhibits COX and inhibits platelet aggregation, while nonacetylated salicylates do not