NSAIDs

Learning Outcomes

  • Recognise the signs of inflammation

  • Identify the enzymes in the arachidonic acid pathway inhibited by steroids and NSAIDs

  • Explain why COX-1 inhibition by non-selective NSAIDs leads to gastrointestinal ulcers and slows blood clotting

  • Name 3 COX-2 selective drugs and describe their advantages along with the problems that emerged

Inflammation as a Response to Harmful Stimuli

  • Inflammation is defined as the body's response to harmful stimuli or cell damage.

    • Signs of Inflammation:

    • Calor (heat)

    • Dolor (pain)

    • Rubor (reddening)

    • Tumor (swelling)

  • Increased blood flow results in redness and heat.

  • Extra fluid brings immune cells resulting in swelling.

  • Hormones are released which may trigger pain from incidents like a bee sting, stubbed toe, or burnt finger.

Mnemonics for Signs of Inflammation

  • Mnemonics to memorize the signs include:

    • Calor Rubor Tumor

    • Tumor Dolor Rubor

Inflammatory Disorders and Their Implications

  • Various diseases characterized by inflammation (often ending in 'itis') include:

    • Rheumatoid arthritis: inflamed joints

    • Asthma: inflamed bronchial tubes

    • Crohn's disease: inflamed lining of the digestive system

    • Ankylosing spondylitis: inflamed spinal joints

  • Chronic inflammatory disorders are long-lasting and considerably debilitating.

The Arachidonic Acid Pathway and Inflammation

  • The arachidonic acid pathway mediates inflammation.

    1. Arachidonate is released from membrane phospholipids.

    2. Phospholipase A2 (PLA2) hydrolyzes membrane phospholipids when cells are injured, releasing arachidonic acid.

    3. Cyclooxygenase (COX) converts arachidonic acid into Prostaglandin H2 (PGH2).

  • Glucocorticoids reduce inflammation by indirectly inhibiting PLA2 synthesis through activating genes that promote lipocortin I, a PLA2 inhibitor.

Role of PLA2 and COX Enzymes in Inflammation

  • PLA2 Enzymes:

    • Found in snake venom, these enzymes can cause inflammation, pain, and edema by activating the arachidonic acid pathway.

  • COX-1 and COX-2 Isoforms:

    • Both COX-1 and COX-2 are involved in the synthesis of Prostaglandin H2. However, COX-2 is induced mainly in response to cell injury as part of the inflammatory response.

Effects of COX Inhibition

  • Inhibition of COX-1 by traditional non-selective NSAIDs can lead to gastrointestinal injuries, including ulcers, as COX-1 is necessary for producing prostacyclin (PGI2), which protects the gastric mucosa.

  • COX-2 inhibitors provide pain relief and inhibit inflammation but are sometimes associated with increased cardiovascular risks.

Traditional NSAIDs Effects

  • Traditional NSAIDs such as:

    • Aspirin (1899)

    • Ibuprofen (1969)

    • Naproxen (1976)

    • Indomethacin (1965)

    • Ketoprofen (1986)

    • Flurbiprofen (1987)

    • All carry the risk of inducing gastrointestinal ulcers.

  • Ibuprofen and Aspirin have varying risks associated with gastrointestinal ulcers, with Ibuprofen posing a lower risk.

Gastrointestinal and Cardiovascular Risks

  • PGH2 synthesized by COX-1 is essential for normal blood clotting, being converted into Thromboxane A2 (TXA2), which promotes platelet aggregation and clot formation.

  • Aspirin inhibits COX-1 irreversibly, leading to slower clot formation which can protect against cardiovascular issues but risks bleeding.

Aspirin Mechanism and COX-2 Selectivity

  • Aspirin: an irreversible inhibitor of COX enzymes, leads to acetylation of serine residues at the active site, blocking thromboxane synthesis.

  • COX-2 selective drugs or coxibs like Celecoxib (1998) and Rofecoxib (1999) have been developed to mitigate the gastrointestinal risks associated with traditional NSAIDs.

  • Coxibs are intended to relieve inflammation without GI risks due to better selectivity for COX-2.

Cardiovascular Implications of COX-2 Inhibitors

  • Despite being designed to be safer, coxibs may increase heart attack and stroke risks.

  • The company Merck concealed high cardiovascular risks associated with Rofecoxib, which led to its withdrawal after significant cases of severe heart issues were reported.

  • Etoricoxib, another coxib, was noted to raise systolic blood pressure significantly.

Paracetamol: A Non-NSAID Analgesic

  • Paracetamol: acts centrally and is not classified as an NSAID; it selectively inhibits COX-2 and is considered a prodrug activated by metabolism.

    • May activate TRPV1 receptor in the brain, impacting pain sensation and body temperature.

    • Concerns are emerging around its renal and cardiovascular safety.

Points to Remember About NSAIDs

  • NSAIDs can lead to severe adverse effects such as anaphylaxis and ulcers, especially in asthmatics.

  • Co-administration of NSAIDs with gastroprotective drugs (like misoprostol or PPI) can prevent ulcers.

  • While COX-2 selective NSAIDs are less likely to cause stomach issues, they are associated with varying cardiovascular risks.

  • Aspirin can trigger recurrent gout by increasing urate reabsorption. In such patients, blocking COX-1 can shift from producing anti-inflammatory to pro-inflammatory mediators.

Further Reading

  • Suggested readings include:

    • Foye's Principles of Medicinal Chemistry

    • Studies on COX-2 selective NSAIDs and their implications in ischemic stroke and protective gastric behavior.