Acetylsalicylic acid

Acetylsalicylic acid belongs to the group of acidic nonsteroidal anti-inflammatory drugs with analgaesic, antipyretic and anti-inflammatory properties. Its mechanism of action is based on irreversible inhibition of cyclo-oxygenase enzymes involved in prostaglandin synthesis.

Acetylsalicylic acid in oral doses of in general 0.3 to 1.0 g, is used for the relief of pain and in minor febrile conditions, such as colds or influenza, for the reduction of temperature and relief of the joint and muscle pains.

It is also used in acute and chronic inflammatory disorders such as rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis.

Acetylsalicylic acid also inhibits platelet aggregation by blocking thromboxane A₂ synthesis in platelets. Thus, it is used for various vascular indications at doses of in general 75 to 300 mg daily.

Absorption

After oral administration, acetylsalicylic acid is rapidly absorbed from the gastrointestinal tract. However, a significant portion of the dosage is already hydrolysed to salicylic acid in the intestinal wall during the absorption process.

After intake of gastro-resistant tablets the maximum plasma levels of acetylsalicylic acid and salicylic acid are reached after about – 3.5 and 4.5 hours, respectively, following administration in the fasted state. If the tablets are taken with food, maximum plasma levels are reached approximately 3 hours later than in the fasted state.

Distribution

Acetylsalicylic acid as well as the main metabolite salicylic acid, are extensively bound to plasma proteins, primarily albumin, and distributed rapidly into all parts of the body. The degree of protein binding of salicylic acid is strongly dependant of both the salicylic acid and albumin concentration. The volume of distribution of acetylsalicylic acid is ca. 0.16 l/kg of body weight. Salicylic acid slowly diffuses into the synovial fluid, crosses the placental barrier and passes into breast milk.

Biotransformation

Acetylsalicylic acid is rapidly metabolised to salicylic acid, with a half-life of 15-30 minutes. Salicylic acid is subsequently predominantly converted into glycine and glucuronic acid conjugates, and traces of gentisic acid. Elimination kinetics of salicylic acid is dose-dependent, because the metabolism is limited by liver enzyme capacity. Thus, elimination half-time varies and is 2‑3 hours after low doses, 12 hours after usual analgetic doses and 15-30 hours after high therapeutic doses or intoxication.

Elimination

Salicylic acid and its metabolites are predominantly excreted via the kidneys.

The preclinical safety profile of acetylsalicylic acid is well documented.

In animal studies, salicylates caused kidney damage at high dosages but no other organic lesions. Acetylsalicylic acid has been extensively studied in vitro and in vivo for mutagenicity; no relevant evidence of a mutagenic potential was found. The same applies to carcinogenicity studies.

Salicylates have exhibited teratogenic effects in animal studies and a number of different species. Implantation disorders, embryotoxic and foetotoxic effects and impairment of learning ability in the offspring after prenatal exposure have been described.