Eicosanoids and Their Applications in Medicine

Lesson 31: Pharmacology of Inflammation

• This lesson covers the pharmacology of inflammation.

Inflammation

• Inflammation is the body's defensive response to pathogen invasion, cellular or tissue damage from trauma or antigenic stimulation.
• Initial damage can be biological, chemical, or physical.
• Inflammation involves the release of various mediators.
• Key mediators include prostaglandins, leukotrienes (eicosanoids), histamine, and serotonin.
• These mediators promote inflammation.
• Key symptoms of inflammation include heat, redness, swelling, pain, and loss of function.

Anti-inflammatory Drugs

• Anti-inflammatory drugs can be categorized into five major groups.
  • Inhibitors of cyclo-oxygenase (COX) enzymes:
    • Non-steroidal anti-inflammatory drugs (NSAIDs)
    • COXibs (COX-2 selective NSAIDs)
  • Disease-modifying antirheumatic drugs (DMARDs)
  • Glucocorticoids
  • Drugs for gout control
  • Antihistamines (for allergic inflammation)

Eicosanoids

• Eicosanoids are signaling molecules produced by oxidizing fatty acids.
• They play a significant role in inflammation.
• They have various effects.
  • Vascular effects:
    • Some eicosanoids induce vasoconstriction (e.g., TXA2).
    • Others cause vasodilation (e.g., PGE2, PGI2).
    • Platelet effects:
      • Certain eicosanoids (e.g., TXA2) promote platelet aggregation.
      • Others (e.g., PGI2) inhibit platelet aggregation.
  • Effects on the body:
    • Pain and fever: PGE2 is involved in pain and fever perception
    • Renal effects: PGE2 and PGI2 have protective effects on the kidneys (renal blood flow).
    • Gastrointestinal tract: PGE2 and PGI2 protect the stomach's lining and decrease acid secretion.
    • Respiratory system: LTC4, LTD4, and LTE4 cause bronchospasms and mucus secretion.
    • Uterus: PGE causes uterine contraction.

Cyclo-Oxygenase Inhibitors (NSAIDs)

• COX-1: A constitutive enzyme found in most tissues (platelets, etc.) responsible for essential physiological functions.
• COX-2: An inducible enzyme, mainly upregulated in inflammatory tissue.
  • COX-1 inhibitors are often linked to adverse effects
  • COX-2 inhibitors are intended to minimize side effects.

Cyclo-Oxygenase Inhibitors (NSAIDs) - Mechanism of Action

• NSAIDs work by inhibiting COX-1 and COX-2 enzymes.
• COX-2 inhibition typically leads to anti-inflammatory effects, while COX-1 inhibition can cause adverse effects.

Common ADRs

• Gastric and intestinal damage (e.g. bleeding, ulceration)
• Adverse cardiovascular effects
• Hypersensitivity reactions
• Renal effects (e.g., papillary necrosis, fluid retention).
• Analgesic-Associated Nephropathy
• Liver disorders, bone marrow depression

Aspirin and Salicylates

• Aspirin irreversibly inhibits COX-1 and COX-2.
• Low doses of aspirin can inhibit platelet aggregation.
• Common side effects include gastric irritation, bleeding, dizziness, tinnitus, and respiratory distress.
• Overdose treatment involves inducing vomiting, administering sodium bicarbonate, and fluids/electrolytes.
• Contraindications: use in children with viral infection (Reye's syndrome), concurrent use with warfarin, and gout.
• Aspirin may reduce the incidence of some cancers.

Ibuprofen, Ketoprofen, and Naproxen

• These are non-selective COX inhibitors.
• Mechanisms of action include analgesic, antipyretic, and anti-inflammatory effects.
• Pharmacokinetics vary; Naproxen has a longer half-life than ibuprofen or ketoprofen.
• Common adverse effects from long-term use include gastric irritation, nausea, dyspepsia, bleeding ( peptic ulcer disease).
• Other adverse effects include hepatotoxicity and renal toxicity.

Indomethacin

• Potent COX inhibitor used for moderate-to-severe inflammatory conditions.
• Used for stimulating the closure of patent ductus arteriosus in newborns.
• Parenteral administration is possible.
• Compared to other drugs, it has less nausea, vomiting, and drowsiness.
• It's used for short-term management of moderate pain like postoperative pain from dental surgery.

Paracetamol

• Classified as an NSAID but lacks anti-inflammatory properties.
• Actions are purely analgesic and antipyretic.
• Peak plasma concentration after 30-60 minutes.
• Extensively metabolized by the liver.
• Metabolic byproducts are excreted through the kidneys.
• Hepatotoxic effects and renal damage are possible with large doses.
• Not associated with Reye's syndrome; can be administered to children.

Clinical Uses of NSAIDs

• Analgesia (headache, dysmenorrhea)
• Anti-inflammatory (rheumatoid arthritis, gout, soft tissue disorders)
• Antithrombotic (for myocardial infarction)
• Anti-pyretic (fever reduction)

Selective COX-2 Inhibitors (COXibs)

• Potent analgesic, anti-inflammatory agents.
• Used for patients at high risk of serious gastrointestinal side effects.
• Cardiovascular risk should be assessed before long-term use.
• Used in osteoarthritis and rheumatoid arthritis.