indication

For use in the temporary relief of various forms of pain, inflammation associated with various conditions (including rheumatoid arthritis, juvenile rheumatoid arthritis, systemic lupus erythematosus, osteoarthritis, and ankylosing spondylitis), and is also used to reduce the risk of death and/or nonfatal myocardial infarction in patients with a previous infarction or unstable angina pectoris.

pharmacology

Acetylsalicylic acid is an analgesic, antipyretic, antirheumatic, and anti-inflammatory agent. Acetylsalicylic acid's mode of action as an antiinflammatory and antirheumatic agent may be due to inhibition of synthesis and release of prostaglandins. Acetylsalicylic acid appears to produce analgesia by virtue of both a peripheral and CNS effect. Peripherally, acetylsalicylic acid acts by inhibiting the synthesis and release of prostaglandins. Acting centrally, it would appear to produce analgesia at a hypothalamic site in the brain, although the mode of action is not known. Acetylsalicylic acid also acts on the hypothalamus to produce antipyresis; heat dissipation is increased as a result of vasodilation and increased peripheral blood flow. Acetylsalicylic acid's antipyretic activity may also be related to inhibition of synthesis and release of prostaglandins.

mechanism of action

The analgesic, antipyretic, and anti-inflammatory effects of acetylsalicylic acid are due to actions by both the acetyl and the salicylate portions of the intact molecule as well as by the active salicylate metabolite. Acetylsalicylic acid directly and irreversibly inhibits the activity of both types of cyclooxygenase (COX-1 and COX-2) to decrease the formation of precursors of prostaglandins and thromboxanes from arachidonic acid. This makes acetylsalicylic acid different from other NSAIDS (such as diclofenac and ibuprofen) which are reversible inhibitors. Salicylate may competitively inhibit prostaglandin formation. Acetylsalicylic acid's antirheumatic (nonsteroidal anti-inflammatory) actions are a result of its analgesic and anti-inflammatory mechanisms; the therapeutic effects are not due to pituitary-adrenal stimulation. The platelet aggregation-inhibiting effect of acetylsalicylic acid specifically involves the compound's ability to act as an acetyl donor to cyclooxygenase; the nonacetylated salicylates have no clinically significant effect on platelet aggregation. Irreversible acetylation renders cyclooxygenase inactive, thereby preventing the formation of the aggregating agent thromboxane A2 in platelets. Since platelets lack the ability to synthesize new proteins, the effects persist for the life of the exposed platelets (7-10 days). Acetylsalicylic acid may also inhibit production of the platelet aggregation inhibitor, prostacyclin (prostaglandin I2), by blood vessel endothelial cells; however, inhibition prostacyclin production is not permanent as endothelial cells can produce more cyclooxygenase to replace the non-functional enzyme.

toxicity

Oral, mouse: LD₅₀ = 250 mg/kg; Oral, rabbit: LD₅₀ = 1010 mg/kg; Oral, rat: LD₅₀ = 200 mg/kg. Effects of overdose include: tinnitus, abdominal pain, hypokalemia, hypoglycemia, pyrexia, hyperventilation, dysrhythmia, hypotension, hallucination, renal failure, confusion, seizure, coma, and death.

biotransformation

Acetylsalicylic acid is rapidly hydrolyzed primarily in the liver to salicylic acid, which is conjugated with glycine (forming salicyluric acid) and glucuronic acid and excreted largely in the urine.

absorption

Absorption is generally rapid and complete following oral administration but may vary according to specific salicylate used, dosage form, and other factors such as tablet dissolution rate and gastric or intraluminal pH.

half life

The plasma half-life is approximately 15 minutes; that for salicylate lengthens as the dose increases: doses of 300 to 650 mg have a half-life of 3.1 to 3.2 hours; with doses of 1 gram, the half-life is increased to 5 hours and with 2 grams it is increased to about 9 hours.

drug interactions

Acenocoumarol: Acetylsalicylic acid increases the effect of the anticoagulant, acenocoumarol.

Acetazolamide: Acetylsalicylic acid at high dose increases the effect of the carbonic anhydrase inhibitor, acetazolamide.

Acetohexamide: Acetylsalicylic acid increases the effect of sulfonylurea, acetohexamide.

Anisindione: Acetylsalicylic acid increases effect of the anticoagulant, anisindione.

Betamethasone: The corticosteroid, betamethasone, may decrease the effect of the salicylate, acetylsalicylic acid.

Chlorpropamide: Acetylsalicylic acid may increase the effect of the sulfonylurea, chlorpropamide.

Cortisone acetate: The corticosteroid, cortisone acetate, may decrease the effect of the salicylate, acetylsalicylic acid.

Dexamethasone: The corticosteroid, dexamethasone, may decrease the effect of the salicylate, acetylsalicylic acid.

Dichlorphenamide: Acetylsalicylic acid at high dose increases the effect of the carbonic anhydrase inhibitor, dichlorphenamide.

Dicumarol: Acetylsalicylic acid increases effect of the anticoagulant, dicumarol.

Fludrocortisone: The corticosteroid, fludrocortisone, may decrease the effect of the salicylate, acetylsalicylic acid.

Ginkgo biloba: Additive anticoagulant/antiplatelet effects may increase bleed risk. Concomitant therapy should be avoided.

Gliclazide: Acetylsalicylic acid increases the effect of the sulfonylurea, gliclazide.

Glipizide: Acetylsalicylic acid increases the effect of the sulfonylurea, glipizide.

Glisoxepide: Acetylsalicylic acid increases the effect of the sulfonylurea, glisoxepide.

Glyburide: Acetylsalicylic acid increases the effect of the sulfonylurea, glibenclamide.

Glycodiazine: Acetylsalicylic acid increases the effect of sulfonylurea, glycodiazine.

Griseofulvin: Griseofulvin may decrease the efficacy of acetylsalicylic acid.

Heparin: Increased risk of bleeding.

Hydrocortisone: The corticosteroid, hydrocortisone, may decrease the effect of the salicylate, acetylsalicylic acid.

Ibuprofen: Concomitant therapy of the NSAID, ketoprofen, and acetylsalicylic acid may result in additive adverse/toxic effects (e.g. GI bleeding). The NSAID may also limit the cardioprotective effect of acetylsalicylic acid. Occasional concomitant use may not cause clinically significant problems, but regular, frequent concomitant therapy is not recommended.

Ketoprofen: Concomitant therapy of the NSAID, ketoprofen, and acetylsalicylic acid may result in additive adverse/toxic effects (e.g. GI bleeding). The NSAID may also limit the cardioprotective effect of acetylsalicylic acid. Occasional concomitant use may not cause clinically significant problems, but regular, frequent concomitant therapy is not recommended.

Ketorolac: Acetylsalicylic acid may increase the adverse GI effects ketorolac.

Methazolamide: Acetylsalicylic acid at high dose increases the effect of the carbonic anhydrase inhibitor, methazolamide.

Methotrexate: Acetylsalicylic acid increases the effect and toxicity of methotrexate.

Methylprednisolone: The corticosteroid, methylprednisolone, may decrease the effect of the salicylate, acetylsalicylic acid.

Paramethasone: The corticosteroid, paramethasone, may decrease the effect of the salicylate, acetylsalicylic acid.

Prednisolone: The corticosteroid, prednisolone, may decrease the effect of the salicylate, acetylsalicylic acid.

Prednisone: The corticosteroid, prednisone, may decrease the effect of the salicylate, acetylsalicylic acid.

Probenecid: Acetylsalicylic acid decreases the uricosuric effect of probenecid.

Sulindac: Risk of additive toxicity (e.g. bleed risk). Acetylsalicylic acid may decrease the serum concentration of sulindac. Sulindac may counteract the cardioprotective effects of acetylsalicylic acid. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of both agents if the interacting agent is initiated, discontinued or dose changed.

Telmisartan: Concomitant use of Telmisartan and Acetylsalicylic acid may increase the risk of acute renal failure and hyperkalemia. Monitor renal function at the beginning and during treatment.

Tiaprofenic acid: Increased risk of gastrointestinal bleeding.

Ticlopidine: Increased effect of ticlopidine

Tolazamide: Acetylsalicylic acid increases the effect of the sulfonylurea, tolazamide.

Tolbutamide: Acetylsalicylic acid increases the effect of the sulfonylurea, tolbutamide.

Tolmetin: Additive adverse effects increase the risk of gastrointestinal bleeding. Possible decrease in the cardioprotective effect of acetylsalicylic acid. Monitor for increased bleeding risk during concomitant therapy.

Trandolapril: Acetylsalicylic acid may reduce the efficacy of Trandolapril. Monitor for changes in Trandolapril efficacy if Acetylsalicylic acid is initiated, discontinued or dose changed.

Treprostinil: The prostacyclin analogue, Treprostinil, increases the risk of bleeding when combined with the antiplatelet agent, Acetylsalicylic acid. Monitor for increased bleeding during concomitant thearpy.

Triamcinolone: The corticosteroid, triamcinolone, may decrease the effect of the salicylate, acetylsalicylic acid.

Valproic Acid: Acetylsalicylic acid increases the effect of valproic acid.

Warfarin: The antiplatelet effects of acetylsalicylic acid may increase the bleed risk associated with warfarin.