Source: Health Products Regulatory Authority (IE) Revision Year: 2023 Publisher: KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia
Pharmacotherapeutic group: Antithrombotic agents: platelet aggregation inhibitors excl. Heparin
ATC code: B01AC06
Acetylsalicylic acid inhibits the platelet activation: blocking the platelet cyclooxygenase by acetylation, it inhibits thromboxane A2 synthesis, a physiological activating substance released by the platelets and which would play a role in the complications of the atheromatous lesions.
Inhibition of TXA2-synthesis is irreversible, because thrombocytes, which have no nucleus, are not capable (due to lack of protein synthesis capability) to synthesise new cyclooxygenase, which had been acetylated by acetylsalicylic acid.
The repeated doses from 20 to 325 mg involve an inhibition of the enzymatic activity from 30 to 95%.
Due to the irreversible nature of the binding, the effect persists for the lifespan of a thrombocyte (7-10 days). The inhibiting effect does not exhaust during prolonged treatments and the enzymatic activity gradually begins again upon renewal of the platelets 24 to 48 hours after treatment interruption.
Acetylsalicylic acid extends bleeding time on average by approximately 50 to 100%, but individual variations can be observed.
Experimental data suggest that ibuprofen may inhibit the effect of low dose acetylsalicylic acid on platelet aggregation when they are dosed concomitantly.
In one study, when a single dose of ibuprofen 400 mg was taken within 8 h before or within 30 min after immediate release acetylsalicylic acid dosing (81 mg), a decreased effect of acetylsalicylic acid on the formation of thromboxane or platelet aggregation occurred. However, the limitations of these data and the uncertainties regarding extrapolation of ex vivo data to the clinical situation imply that no firm conclusions can be made for regular ibuprofen use, and no clinically relevant effect is considered to be likely for occasional ibuprofen use.
After oral administration, acetylsalicylic acid is rapidly and completely absorbed from the gastrointestinal tract. The principal site of absorption is the proximal small intestine. However, a significant portion of the dosage is already hydrolysed to salicylic acid in the intestinal wall during the absorption process. The degree of hydrolysis is dependent on the rate of absorption. After intake of Aspirin Krka 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.
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.
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.
Salicylic acid and its metabolites are predominantly excreted via the kidneys.
The preclinical safety profile of acetylsalicylic acid is well documented.
In experimental animal studies, salicylates have shown no other organ injury than renal damage.
In rat studies, fetotoxicity and teratogenic effects were observed with acetylsalicylic acid at maternotoxic doses. Clinical relevance is unknown as the doses used in non-clinical studies are much higher (7 times at least) than the maximal recommended doses in targeted cardiovascular indications.
Acetylsalicylic acid was extensively investigated with regard to mutagenic and carcinogenic effects. The results as a whole show no relevant signs for any mutagenic or carcinogenic effects in mice and rat studies.
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