NSAIDs: Mechanism & Actions

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

• NSAIDs are classified as COX-1 versus COX-2 inhibitors.
• Non-selective COX-1 and COX-2 inhibitors include aspirin, indomethacin (Indocid®), ibuprofen (Brufen®), ketoprofen (Profenid®, Ketofan®), piroxicam (Feldene®), diclofenac (Voltaren®, Cataflam®).
• Selective COX-2 inhibitors include celecoxib (Celebrex®).

Mechanism of Action

• Aspirin irreversibly acetylates (and thus inactivates) cyclooxygenase enzyme.
• Other NSAIDs are reversible inhibitors of the enzyme.
• This leads to decreased synthesis of PGs and TXA2.

Pharmacological Actions

• Anti-inflammatory effect: Reduced PGs mean reduced inflammation and reduced bradykinin.
• Analgesic effect: Reduced PGs peripherally at the site of inflammation and reduced pain pathways centrally at a subcortical site.
• Antipyretic effect: Decreased PGE2 in the hypothalamic thermoregulatory center resets the thermostat.
• Antiplatelet effect: Aspirin irreversibly inhibits COX in platelets, which lack a nucleus and cannot resynthesize the enzyme.
• In the endothelium, aspirin inhibits PGI2 synthesis, but the endothelium can synthesize new COX and PGI2 due to possessing a nucleus.
• Low doses of aspirin result in massive inhibition of TXA2 synthesis in platelets with little effect on endothelial PGI2 production, leading to reduced platelet aggregation.
• Gastrointestinal effects: Oral and parenteral NSAIDs produce GI adverse effects, ranging from heartburn to gastric and duodenal ulcers.
• This effect can be prevented by misoprostol, proton pump inhibitors (PPIs) such as omeprazole, and selective COX-2 inhibitors.

Renal function

• NSAIDs affect renal function.

Effect on Uric Acid Excretion

• Uric acid filtered in the glomeruli is actively reabsorbed and secreted again in the proximal tubules.
• Aspirin's effect on uric acid excretion is dose-dependent.
• Small doses of aspirin (1-2 g/day) decrease tubular secretion of uric acid, increasing plasma urate concentration.
• High doses of aspirin (> 5 g/day) decrease tubular reabsorption of uric acid, increasing uric acid excretion.
• Moderate doses of aspirin (2-3 g/day) do not alter uric acid excretion.

Clinical Uses of NSAIDs

• Anti-inflammatory use for musculoskeletal disorders like myositis, tendinitis, rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis.
• Examples of dosages include aspirin (3-6 g/day), ketoprofen (200 mg/day), and piroxicam (20 mg/day).
• Analgesic use for low to moderate intensity pain, such as headache, dysmenorrhea, and dental pain.
• Antipyretic use in febrile states.
• Aspirin in low doses (75-325 mg/day) is used for prophylaxis from myocardial infarction and stroke in high-risk patients.

Adverse Effects and Precautions

• GI toxicity, which is not shared with selective COX-2 inhibitors.
• Increased bleeding tendency, especially with aspirin.
• Alteration of renal function in susceptible individuals.
• Hypersensitivity reactions, especially with aspirin (15%).
• Decreased uric acid excretion (increased uric acid in the blood) with low doses of aspirin.
• Reye's syndrome: Avoid using aspirin in viral infections in children.
• Salicylism: Symptoms include vomiting, tinnitus, vertigo, and decreased hearing.

Drug Interactions

• Aspirin enhances the activity of coumarin anticoagulants, sulfonylurea antidiabetic agents, methotrexate, phenytoin, and valproic acid by displacing them from plasma protein binding sites.
• Aspirin and other NSAIDs may reduce the antihypertensive effect of ACE inhibitors by interfering with bradykinin-facilitated PGs synthesis.

Paracetamol (=Acetaminophen)

• Paracetamol inhibits COX-3 in the brain but not at sites of inflammation.
• It is an analgesic and antipyretic without anti-inflammatory activity
• Paracetamol has no antiplatelet or ulcerogenic activity and does not affect uric acid excretion.
• Paracetamol can be safely administered during pregnancy.
• Acute overdosage causes hepatotoxicity.