Pharmacokinetics: Salicylic acid is a simple organic acid with a pKa of 3.0. Aspirin (acetylsalicylic acid; ASA) has a pKa of 3.5 (see Table 1–3). 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 (Figure 36–3). Salicylate is nonlinearly bound to albumin. Alkalinization of the urine increases the rate of excretion of free salicylate and its water-soluble conjugates.
2.
Mechanisms of Action: Aspirin irreversibly inhibits platelet COX so that aspirin’s antiplatelet effect lasts 8–10 days (the life of the platelet). In other tissues, synthesis of new COX replaces the inactivated enzyme so that ordinary doses have a duration of action of 6–12 hours.
3.
Clinical Uses: Aspirin decreases the incidence of transient ischemic attacks, unstable angina, coronary artery thrombosis with myocardial infarction, and thrombosis after coronary artery bypass grafting (see Chapter 34).
4.
Epidemiologic studies suggest that long-term use of aspirin at low dosage is associated with a lower incidence of colon cancer, possibly related to its COX-inhibiting effects.
5.
Adverse Effects: In addition to the common side effects listed above, aspirin’s main adverse effects at antithrombotic doses are gastric upset (intolerance) and gastric and duodenal ulcers. Hepatotoxicity, asthma, rashes, GI bleeding, and renal toxicity rarely if ever occur at antithrombotic doses.
6.
The antiplatelet action of aspirin contraindicates its use by patients with hemophilia. Although previously not recommended during pregnancy, aspirin may be valuable in treating preeclampsia-eclampsia.
These drugs include magnesium choline salicylate, sodium salicylate, and salicyl salicylate. All nonacetylated salicylates are effective anti-inflammatory drugs, and they do not inhibit platelet aggregation. They may be preferable when COX inhibition is undesirable such as in patients with asthma, those with bleeding tendencies, and even (under close supervision) those with renal dysfunction.
The nonacetylated salicylates are administered in doses up to 3–4 g of salicylate a day and can be monitored using serum salicylate measurements.
COX-2 selective inhibitors, or coxibs, were developed in an attempt to inhibit prostaglandin synthesis by the COX-2 isozyme induced at sites of inflammation without affecting the action of the constitutively active “housekeeping” COX-1 isozyme found in the GI tract, kidneys, and platelets. COX-2 inhibitors at usual doses have no impact on platelet aggregation, which is mediated by thromboxane produced by the COX-1 isozyme. In contrast, they do inhibit COX-2-mediated prostacyclin synthesis in the vascular endothelium. As a result, COX-2 inhibitors do not offer –––––Disturbance of cell membranes Stimulus Phospholipids Arachidonic acid PhospholipaseLipoxygenaseLeukotrienes LTC4/D4/E4 Alteration of vascular permeability, bronchial constriction, increased secretion Bronchospasm, congestion, mucous plugging LTB4 Phagocyte attraction, activation Inflammation Prostaglandins Thromboxane Prostacyclin CyclooxygenaseLeukocyte modulation Inflammation Phospholipase inhibitors Corticosteroids Fatty acid substitution (diet) Lipoxygenase inhibitors Receptor antagonists Colchicine NSAID, ASA