Aspirin and other salicylic acid derivatives

Aspirin and other salicylic acid derivatives

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Last Updated on September 3, 2020 by Sagar Aryal

What are Aspirins?

Aspirin is the precursor of traditional Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) and is the most commonly used salicylic acid derivative. Aspirin is considered as a standard to compare other anti-inflammatory agents.

NSAIDs are a group of different chemical agents, that show differences in their antipyretic, analgesic, and anti-inflammatory activities. The mechanism of action of NSAIDs includes the inhibition of the cyclooxygenase enzymes (involved in catalyzation of the first step in prostanoid biosynthesis).  As a result, the decrease in prostaglandin synthesis can cause both beneficial and unwanted effects.

Aspirin and other salicylic acid derivatives

Image Source: Wikipedia.

Mechanism of Action

Aspirin is a weak organic acid and can cause irreversible acetylation of cyclooxygenase. This irreversible acetylation then leads to the inactivation of cyclooxygenase. Other NSAIDs, including salicylate, cause reversible inhibition of cyclooxygenase rather than irreversible inhibition(as caused by aspirin). Esterases in the body rapidly deacetylate aspirin and thereby produce salicylate, which has antipyretic, anti-inflammatory, and analgesic effects.

  • Anti-inflammatory actions: Aspirin inhibits cyclooxygenase activity and thus blocks prostaglandins formation. As a result, aspirin modulates prostaglandins mediated inflammation aspects. Aspirin can also be used in arthritis for inhibition of inflammation.
  • Analgesic action: Aspirin and other NSAIDS represses sensation of pain by decreasing PGE2 synthesis. PGE2 is involved in the sensitization of nerve endings to the action of histamine, bradykinin, and other chemical mediators released locally by inflammation. The pain of low to moderate intensity arising from musculoskeletal disorders can be managed by salicylates. NSAIDs (in combination with opioids) are effective in treating pain caused by malignancy.
  • Antipyretic action: PGE2 elevates the set-point of the anterior hypothalamic thermoregulatory center and causes fever. PGE2 synthesis is stimulated when endogenous pyrogens (fever producing agents), like cytokines (released by WBCs due to infection), malignancy, hypersensitivity, or inflammation. The PGE2 synthesis and release are blocked by salicylates through lowering body temperature in patients suffering from fever.  The rapid decrease in body temperature of those patients that are having a fever is achieved by increasing the release of heat through peripheral vasodilation and sweating. However, Aspirin does not affect normal body temperature.
  • Respiratory actions: As salicylates uncouple oxidative phosphorylation, that causes an elevated level of CO2 and an increased rate of respiration. Thus, when aspirin is administered in therapeutic doses, it increases alveolar ventilation. However, administered aspirin in higher doses acts directly on the respiratory center in the medulla, causing hyperventilation and respiratory alkalosis that is usually sufficiently compensated by the kidney. Aspirin in toxic dosage causes central respiratory paralysis and respiratory acidosis due to the continued formation of CO2.
  • Gastrointestinal effects: Aspirin inhibits the formation of those prostanoids that are normally involved in the inhibition of gastric acid secretion, prostacyclin (PGI2), and in the stimulation of protective mucus synthesis in the stomach and small intestine,   PGE2, and PGF2α. The resulting adverse effects may include ulceration, epigastric distress, hemorrhage, and iron-deficiency anemia. To prevent gastric and/ or duodenal ulcers,  the PGE1-derivative misoprostol and the proton-pump inhibitors (PPIs) can be used. Furthermore, NSAID-induced ulcer can also be treated by PPIs
  • Effect on platelets:  TXA2 increases platelet aggregation while PGI2 decreases it. Low doses of aspirin are able to irreversibly block thromboxane production in platelets, by acetylation of cyclooxygenase. As platelets do not have nuclei so they are unable to synthesize new enzyme, and the thromboxane absence remain persists for the platelets lifetime( 3–7 days).This results  reduction in platelet aggregation and thus causing prolonged bleeding time. Aspirin also inhibits cyclooxygenase in endothelial cells thus causing a reduction in  PGI2 formation. However, cyclooxygenase can be re-synthesized by endothelial cells, as they possess nuclei.
  • Actions on the kidney: In the presence of circulating vasoconstrictors, cyclooxygenase inhibitors inhibit PGE2 and PGI2 synthesis, however, these prostaglandins maintain the renal blood flow. Thus, the reduction in prostaglandin synthesis may lead to sodium and water retention and can cause hyperkalemia and edema in some patients. All NSAIDs have the potential risk to cause Interstitial nephritis.

Therapeutic Uses

  • Anti-inflammatory, analgesic, and antipyretic uses: For the treatment of gout, rheumatic fever, osteoarthritis, and rheumatoid arthritis; salicylic acid derivatives can be used. Conditions requiring analgesia (arthralgia, headache, and myalgia) can also be treated by salicylic acid derivatives.
  • External applications: The treatment of acne, corns, calluses, and warts can be done by using salicylic acid topically. Methyl salicylate (“oil of wintergreen”) is applied externally as a cutaneous counterirritant in liniments.
  • Cardiovascular applications: Aspirin prevents platelet aggregation. In low doses, aspirin can be used prophylactically to decrease the risk of recurrent Transient Ischemic Attacks (TIAs), to decrease death risk in patients having an acute myocardial infarction, and to minimize the risk of myocardial infarction in patients having chronic stable angina pectoris.

Pharmacokinetics

  • Administration and distribution: By oral route of administration, the un-ionized salicylates are partly absorbed passively from the stomach and mainly from the upper region of the small intestine, as dissolution of the drug is facilitated by higher pH of the gut. The absorption of salicylates is slow and not reliable through rectal absorption. Salicylates must not be administered in children and teenagers that are having viral infections, such as influenza or varicella (chickenpox), to prevent the occurrence of Reye syndrome. Most of the salicylates can cross both the placenta and the blood-brain barrier and can be absorbed through intact skin (particularly methyl salicylate).
  • Dosage: At low doses, salicylates show analgesic activity. Whereas, at higher doses, these drugs exhibit anti-inflammatory activity. For acute myocardial infarction, 162 to 325 mg non-enteric-coated aspirin was given to be chewed and swallowed immediately; so the rapid response can occur.
  • Fate: At low doses of aspirin, esterases hydrolyze the aspirin to salicylate and acetic acid in blood and tissues. The liver converts the salicylate to water-soluble conjugates that are rapidly eliminated by the kidney and have a serum half-life of 3.5 hours. At higher anti-inflammatory dosages, the liver metabolic pathway becomes saturated, a drug having a half-life of 15 hours or more.

Salicylate is an organic acid, secreted into the urine. Excretion of uric acid can also be affected by salicylate, such as uric acid secretion is reduced when aspirin is administered at low doses whereas uric acid secretion is enhanced when aspirin is administered at high doses. Thus, aspirin should be not be given to patients that are suffering from gout. Aspirin should not be administered in chronic kidney disease patients.

Side Effects

  • Gastrointestinal: salicylates show some adverse Gastrointestinal (GI) effects that include nausea, vomiting, epigastric distress, and microscopic GI bleeding.
  • Blood: salicylates can irreversibly acetylate the platelet cyclooxygenase and thus show a reduction in platelet TXA2 level. This can inhibit platelet aggregation and can cause prolonged bleeding time.
  • Respiration: a combination of uncompensated respiratory and metabolic acidosis and respiratory depression can occur when salicylate is given in toxic doses.
  • Metabolic processes: salicylates at higher doses cause uncouple oxidative phosphorylation. The energy required for adenosine triphosphate (ATP) production is lost as heat, thus hyperthermia is caused by salicylates when administered in toxic doses.
  • Hypersensitivity: salicylates can cause hypersensitivity reactions, causing bronchoconstriction, urticaria, and angioedema.
  • Reye syndrome: Reye syndrome is fatal fulminating hepatitis with cerebral edema caused by the administration of salicylates during viral infections. Children are often affected by this syndrome.

Reference

Lippincott’s Illustrated Reviews, Pharmacology,5th edition

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