Lecture Notes: Pharmacology of NSAIDs and Prostaglandin Analogs

Inflammatory Response

• Tissue injury or irritation releases phospholipase A2
  • Converts phospholipids in the cell membrane into arachidonic acid
• Arachidonic acid is a substrate for:
  • Cyclooxygenase (COX)
  • 5-lipoxygenase (5-LOX)
• Focus on COX Pathway

COX Enzymes

• COX-1
  • Expressed constantly throughout the body
  • Produces thromboxane and prostaglandins
    • Stimulates secretion of protective gastric mucus
    • Controls gastric acid
    • Promotes platelet aggregation
    • Maintains renal blood flow
• COX-2
  • Induced at sites of inflammation
  • Produces prostaglandins that mediate:
    • Inflammation
    • Pain
    • Fever

Mechanism of NSAIDs

• Inhibit COX enzymes → decreased prostaglandin production
• Effects:
  • Anti-inflammatory
  • Antipyretic
  • Analgesic
• Categories based on COX selectivity:
  1. Selective COX-1 Inhibitors
     • Ketorolac, Flurbiprofen, Ketoprofen, Indomethacin, Low-dose Aspirin
  2. Relatively Non-Selective COX Inhibitors
     • Naproxen, Ibuprofen, Piroxicam, Diflunisal
  3. Selective COX-2 Inhibitors
     • Meloxicam, Diclofenac, Celecoxib, Etodolac

Adverse Effects of NSAIDs

Gastrointestinal (GI) Tract

• Inhibit COX-1 → decreased PGE2 and PGI2
  • Risk: GI bleeding, Peptic ulcers

Platelets

• Inhibit COX-1 → decreased thromboxane-A2 (TXA2)
  • Risk: Increased bleeding
  • Aspirin: Irreversible COX-1 inhibition, prolonged effect due to lack of nuclei in platelets

Kidneys

• Decrease renal prostaglandins (E2 and I2)
  • Risk: Kidney injury in susceptible patients (heart failure, old age)

Cardiovascular System

• COX-1 Selective Agents (e.g., Aspirin)
  • Protective effect due to antiplatelet properties
• COX-2 Selective Agents
  • Risk: Increased cardiovascular events (e.g., myocardial infarction, stroke)
  • Mechanism: Imbalance in prostacyclin (vasodilation & inhibition of platelet activation) and thromboxane-A2 (vasoconstriction & promotion of platelet aggregation)

Prostaglandin Analogs

• Designed to mimic endogenous prostaglandins
• Interact with G-protein coupled prostaglandin receptors (≥9 subtypes)

Prostaglandin-E1 Analogs

• Alprostadil
  • Uses: Erectile dysfunction, Neonates with congenital heart defects
  • Mechanism: Stimulates cAMP pathway, leading to relaxation of smooth muscle and vasodilation
• Lubiprostone
  • Use: Chronic constipation
  • Mechanism: Activates type-2 chloride channels, increasing intestinal fluid secretion and motility
• Misoprostol
  • Uses: Prevent/treat stomach ulcers, induce labor
  • Mechanism: Decreases acid secretion, increases bicarbonate and mucus production, softens cervix, and induces uterine contractions

Prostaglandin-F2alpha Analogs

• Bimatoprost, Latanoprost, Travoprost
  • Use: Open-angle glaucoma
  • Mechanism: Increase outflow of aqueous fluid, lowering intraocular pressure
  • Unique Side Effect (Bimatoprost): Elongation and darkening of eyelashes (useful for eyelash hypotrichosis)

Prostacyclin Analogs

• Iloprost, Treprostinil
  • Use: Pulmonary arterial hypertension
  • Mechanism: Increase cAMP, causing vasodilation and reduced pulmonary vascular resistance

Conclusion

• NSAIDs and prostaglandin analogs have significant therapeutic roles
• Understanding their mechanisms and adverse effects is crucial for safe and effective use