🧬 Receptor activity
| Target | Action | Affinity | Source | |
|---|---|---|---|---|
| Nicotinate phosphoribosyltransferase | — | Ki 0.5 nM | CHEMBL | TargetNicotinate phosphoribosyltransferase Action— AffinityKi 0.5 nM SourceCHEMBL |
| Prostaglandin G/H synthase 1 | — | Ki 27900 nM | CHEMBL | TargetProstaglandin G/H synthase 1 Action— AffinityKi 27900 nM SourceCHEMBL |
| Prostaglandin G/H synthase 2 | — | Ki 52000 nM | CHEMBL | TargetProstaglandin G/H synthase 2 Action— AffinityKi 52000 nM SourceCHEMBL |
| Carbonic anhydrase 2 | — | Ki 100000 nM | CHEMBL | TargetCarbonic anhydrase 2 Action— AffinityKi 100000 nM SourceCHEMBL |
| Carbonic anhydrase 7 | — | Ki 100000 nM | CHEMBL | TargetCarbonic anhydrase 7 Action— AffinityKi 100000 nM SourceCHEMBL |
| Carbonic anhydrase 9 | — | Ki 100000 nM | CHEMBL | TargetCarbonic anhydrase 9 Action— AffinityKi 100000 nM SourceCHEMBL |
| Carbonic anhydrase 12 | — | Ki 100000 nM | CHEMBL | TargetCarbonic anhydrase 12 Action— AffinityKi 100000 nM SourceCHEMBL |
| Carbonic anhydrase 1 | — | Ki 100000 nM | CHEMBL | TargetCarbonic anhydrase 1 Action— AffinityKi 100000 nM SourceCHEMBL |
| Carbonic anhydrase 4 | — | Ki 100000 nM | CHEMBL | TargetCarbonic anhydrase 4 Action— AffinityKi 100000 nM SourceCHEMBL |
| Solute carrier family 22 member 20 | — | Ki 101000 nM | CHEMBL | TargetSolute carrier family 22 member 20 Action— AffinityKi 101000 nM SourceCHEMBL |
| Fatty acid-binding protein, liver | — | Ki 348000 nM | CHEMBL | TargetFatty acid-binding protein, liver Action— AffinityKi 348000 nM SourceCHEMBL |
| Solute carrier family 22 member 6 | — | Ki 428000 nM | CHEMBL | TargetSolute carrier family 22 member 6 Action— AffinityKi 428000 nM SourceCHEMBL |
| Unchecked | — | Ki 20000000 nM | CHEMBL | TargetUnchecked Action— AffinityKi 20000000 nM SourceCHEMBL |
Mechanism of action
Acetylsalicylic acid (ASA) blocks prostaglandin synthesis. It is non-selective for COX-1 and COX-2 enzymes. Inhibition of COX-1 results in the inhibition of platelet aggregation for about 7-10 days (average platelet lifespan). The acetyl group of acetylsalicylic acid binds with a serine residue of the cyclooxygenase-1 (COX-1) enzyme, leading to irreversible inhibition. This prevents the production of pain-causing prostaglandins. This process also stops the conversion of arachidonic acid to thromboxane A2 (TXA2), which is a potent inducer of platelet aggregation. Platelet aggregation can result in clots and harmful venous and arterial thromboembolism, leading to conditions such as pulmonary embolism and stroke. It is important to note that there is 60% homology between the protein structures of COX-1 and COX-2. ASA binds to serine 516 residue on the active site of COX-2 in the same fashion as its binding to the serine 530 residue located on the active site of COX-1. The active site of COX-2 is, however, slightly larger than the active site of COX-1, so that arachidonic acid (which later becomes prostaglandins) manages to bypass the aspirin molecule inactivating COX-2. ASA, therefore, exerts more action on the COX-1 receptor rather than on the COX-2 receptor. A higher dose of acetylsalicylic acid is required for COX-2 inhibition.
Produce analgesia through a peripheral action by blocking pain impulse generation and via a central action, possibly in the hypothalamus. The peripheral action may predominate and probably involves inhibition of the synthesis or prostaglandins, and possibly inhibition of the synthesis and/or actions of other substances, which sensitize pain receptors to mechanical or chemical stimulation. /Salicylates/
May produce antipyresis by acting centrally on the hypothalamic heat-regulating center to produce peripheral vasodilation resulting in increased cutaneous blood flow, sweating, and heat loss. The central action may involve inhibition of prostaglandin synthesis in the hypothalamus; however, there is some evidence that fevers caused by endogenous pyrogens that do not act via a prostaglandin mechanism may also respond to salicylate therapy. /Salicylates/
CNS ... ESP NUCLEI LOCATED IN HYPOTHALAMUS PLAYS MAJOR ROLE IN REGULATION OF PERIPHERAL MECHANISMS CONCERNED WITH BODY HEAT PRODN & LOSS. WITH SALICYLATES, HEAT PRODN IS NOT INHIBITED, BUT HEAT LOSS IS INCR BY INCR PERIPHERAL BLOOD FLOW & PERSPIRATION. /SALICYLATES/
Aspirin acetylates prostaglandin endoperoxide synthase (prostaglandin G/H-synthase) and irreversibly inhibits its cyclooxygenase (COX) activity. The enzyme catalyzes the conversion of arachidonic acid to PGH2, the first committed step in prostanoid biosynthesis. Two isoforms of prostaglandin endoperoxide synthase exist, PGHS-1 and PGHS-2 (also referred to as COX-1 and COX-2, respectively). PGHS-1 (COX-1) is expressed constitutively in most cell types, including platelets. PGHS-2 (COX-2) is undetectable in most mammalian cells, but its expression can be induced rapidly in response to mitogenic and inflammatory stimuli. Aspirin is a relatively selective inhibitor of platelet PGHS-1 (cyclooxygenase-1, COX-1). The existence of 2 isoenzymes with different aspirin sensitivities, coupled with extremely different recovery rates of their cyclooxygenase (COX) activity following inactivation by aspirin, at least partially explains the different dosage requirements and durations of aspirin effects on platelet function versus the drug's analgesic and anti-inflammatory effects. Human platelets and vascular endothelial cells process PGH2 to produce thromboxane A2 and prostacyclin (epoprostenol, PGI2), respectively. Thromboxane A2 induces platelet aggregation and vasoconstriction, while prostacyclin inhibits platelet aggregation and induces vasodilation. Aspirin is antithrombotic in a wide range of doses inhibiting thromboxane A2 and prostacyclin.
For more Mechanism of Action (Complete) data for ACETYLSALICYLIC ACID (12 total), please visit the HSDB record page.
Pharmacodynamics
**Effects on pain and fever** Acetylsalicylic acid disrupts the production of prostaglandins throughout the body by targeting cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). Prostaglandins are potent, irritating substances that have been shown to cause headaches and pain upon injection into humans. Prostaglandins increase the sensitivity of pain receptors and substances such as histamine and bradykinin. Through the disruption of the production and prevention of release of prostaglandins in inflammation, this drug may stop their action at pain receptors, preventing symptoms of pain. Acetylsalicylic acid is considered an antipyretic agent because of its ability to interfere with the production of brain prostaglandin E1. Prostaglandin E1 is known to be an extremely powerful fever-inducing agent. **Effects on platelet aggregation** The inhibition of platelet aggregation by ASA occurs because of its interference with thromboxane A2 in platelets, caused by COX-1 inhibition. Thromboxane A2 is an important lipid responsible for platelet aggregation, which can lead to clot formation and future risk of heart attack or stroke. **A note on cancer prevention** ASA has been studied in recent years to determine its effect on the prevention of various malignancies. In general, acetylsalicylic acid is involved in the interference of various cancer signaling pathways, sometimes inducing or upregulating tumor suppressor genes. Results of various studies suggest that there are beneficial effects of long-term ASA use in the prevention of several types of cancer, including stomach, colorectal, pancreatic, and liver cancers. Research is ongoing.
Pharmacokinetics
Half-life
The half-life of ASA in the circulation ranges from 13 - 19 minutes. Blood concentrations drop rapidly after complete absorption. The half-life of the salicylate ranges between 3.5 and 4.5 hours.
15 to 20 minutes (for intact molecule); rapidly hydrolyzed to salicylate. In breast milk (as salicylate): 3.8 to 12.5 hours (average 7.1 hours) following a single 650 mg dose of aspirin.
Cats are deficient in glucuronyl transferase and have a prolonged excretion of aspirin (the half-life in cats is 37.5 hr).
Absorption
Absorption is generally rapid and complete following oral administration but absorption may be variable depending on the route, dosage form, and other factors including but not limited to the rate of tablet dissolution, gastric contents, gastric emptying time, and gastric pH. **Detailed absorption information** When ingested orally, acetylsalicylic acid is rapidly absorbed in both the stomach and proximal small intestine. The non-ionized acetylsalicylic acid passes through the stomach lining by passive diffusion. Ideal absorption of salicylate in the stomach occurs in the pH range of 2.15 - 4.10. Intestinal absorption of acetylsalicylic acid occurs at a much faster rate. At least half of the ingested dose is hydrolyzed to salicylic acid in the first-hour post-ingestion by esterases found in the gastrointestinal tract. Peak plasma salicylate concentrations occur between 1-2 hours post-administration.
Excretion of salicylates occurs mainly through the kidney, by the processes of glomerular filtration and tubular excretion, in the form of free salicylic acid, salicyluric acid, and, additionally, phenolic and acyl glucuronides. Salicylate can be found in the urine soon after administration, however, the entire dose takes about 48 hours to be completely eliminated. The rate of salicylate is often variable, ranging from 10% to 85% in the urine, and heavily depends on urinary pH. Acidic urine generally aids in reabsorption of salicylate by the renal tubules, while alkaline urine increases excretion. After the administration of a typical 325mg dose, the elimination of ASA is found to follow first order kinetics in a linear fashion. At high concentrations, the elimination half-life increases.
This drug is distributed to body tissues shortly after administration. It is known to cross the placenta. The plasma contains high levels of salicylate, as well as tissues such as spinal, peritoneal and synovial fluids, saliva and milk. The kidney, liver, heart, and lungs are also found to be rich in salicylate concentration after dosing. Low concentrations of salicylate are usually low, and minimal concentrations are found in feces, bile, and sweat.
The clearance rate of acetylsalicylic acid is extremely variable, depending on several factors. Dosage adjustments may be required in patients with renal impairment. The extended-release tablet should not be administered to patients with eGFR of less than 10 mL/min.
The materno-fetal transfer of salicylic acid and its distribution in the fetal organism was investigated in women of early pregnancy. Acetylsalicylic acid was administered orally in a single dose or in repeated doses at different times before legal interruption. The mean passage rates were about 6-15%. They were independent of the maternal serum concentrations of salicylic acid. The distribution of salicylic acid on the fetal liver, intestine, kidneys, lungs and brain was different. All fetal organs (9th to 15th week of gestation) studied exhibit an acetylsalicylic acid-splitting esterase activity. The esterase activity of the fetal liver was about 30% of the hydrolytic activity of the adult liver. The esterase activity was mainly located in the 105 000 X g-supernatant of cell homogenates.
Approximately 80-100% of an oral dose of aspirin is absorbed from the GI tract. However, the actual bioavailability of the drug as unhydrolyzed aspirin is lower since aspirin is partially hydrolyzed to salicylate in the GI mucosa during absorption and on first pass through the liver. There are relatively few studies of the bioavailability of unhydrolyzed aspirin. In one study in which aspirin was administered IV and as an oral aqueous solution, it was shown that the solution was completely absorbed but only about 70% reached the systemic circulation as unhydrolyzed aspirin. In another study in which aspirin was administered IV and orally as capsules, only about 50% of the oral dose reached the systemic circulation as unhydrolyzed aspirin. There is some evidence that the bioavailability of unhydrolyzed aspirin from slowly absorbed dosage forms (e.g., enteric-coated tablets) may be substantially decreased. Food does not appear to decrease the bioavailability of unhydrolyzed aspirin or salicylate; however, absorption is delayed and peak serum aspirin or salicylate concentration may be decreased. There is some evidence that absorption of salicylate following oral administration may be substantially impaired or is highly variable during the febrile phase of Kawasaki disease.
Metabolism
Acetylsalicylic acid is hydrolyzed in the plasma to salicylic acid. Plasma concentrations of aspirin following after administration of the extended-release form are mostly undetectable 4-8 hours after ingestion of a single dose. Salicylic acid was measured at 24 hours following a single dose of extended-release acetylsalicylic acid. Salicylate is mainly metabolized in the liver, although other tissues may also be involved in this process. The major metabolites of acetylsalicylic acid are salicylic acid, salicyluric acid, the ether or phenolic glucuronide and the ester or acyl glucuronide. A small portion is converted to gentisic acid and other hydroxybenzoic acids.
Acetylsalicylic acid is hydrolyzed in the stomach and in blood to salicylic acid and acetic acid; ... .
MAJOR URINARY METABOLITES OF ASPIRIN INCL SALICYLURONIC ACID ... SALICYL-O-GLUCURONIDE ... & SALICYL ESTER GLUCURONIDE ... & FREE SALICYLIC ACID ... .
A 52 year-old woman ingested approximately 300 tablets (325 mg) of aspirin in a suicide attempt. /Investigators/ analyzed the concentrations of salicylic acid (SA) and salicyluric acid (SUA) in body fluids and organs using a modified previous high-performance liquid chromatographic method. The concentrations of SA in heart and femoral blood were 1.1 mg/mL and 1.3 mg/mL, respectively; the results were far higher than the lethal level. The concentration of SA was 0.3-0.4 mg/g in brain, 0.9-1.4 mg/g in lung, 0.6-0.8 mg/g in liver and 0.9 mg/mL in kidney.
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.
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.
Protein binding
50% to 90% of a normal therapeutic concentration salicylate (a main metabolite of acetylsalicylic acid) binds plasma proteins, particularly albumin, while acetylsalicylic acid itself binds negligibly. Acetylsalicylic acid has the ability to bind to and acetylate many proteins, hormones, DNA, platelets, and hemoglobin.
External links
Fact-sheets from PsychonautWiki. Harm-reduction reference only — not medical advice.