Inflammation and NSAIDs Overview

Inflammation and NSAIDs

• Inflammation is a protective response to injury, aiming to remove damaging agents and promote healing.
• COX-1 is a constitutive enzyme found in tissues.
• COX-2 is induced by inflammatory cytokines.
• Prostaglandins (PGs) are not pain initiators, but sensitize pain receptors.
• Prostaglandins have diverse effects, including vasodilation, bronchodilation, and influencing gastric function. Examples include PGE2 and PGF2α.
• Thromboxane A2 (TXA2) induces platelet aggregation and vasoconstriction.
• PGI2 inhibits platelet aggregation and causes vasodilation. A balance between TXA2 and PGI2 is needed.
• Nociceptors convey pain signals to the brain.
• NSAIDs inhibit cyclooxygenases (COX) enzymes, reducing prostaglandin production, thus decreasing pain sensitivity.
• COX-1 has housekeeping functions, and COX-2 expression is triggered by inflammatory factors, such as TNF-α and IL-1.
• NSAIDs can reduce fever (antipyretic action).
• IL-1 is released by activated macrophages, leading to COX-2 induction in the brain and subsequent fever response.

Aspirin (ASA)

• High doses (325 mg) have anti-inflammatory, analgesic, and antipyretic actions.
• Low doses (81 mg) reduce cardiovascular events (MI, stroke) and colon cancer recurrence risk.
• Irreversibly inhibits TXA2 at low doses, prolonging the anti-platelet effect. This effect lasts for the lifespan of the platelet (3-7 days).
• This anticoagulant effect decreases thrombus formation.
• It reduces PGE2 and PGI2 leading to renal vasoconstriction. This can cause kidney damage and is contraindicated for patients with impaired kidney function (<30 GFR).
• Adverse effects include gastric distress, nausea, vomiting, microscopic bleeding, prolonged bleeding time, and potentially respiratory depression at high doses.
• Reye's syndrome risk is associated with aspirin use after viral infections in children, which is fatal.
• Salicylism (mild toxicity) presents with symptoms like nausea, vomiting, hyperventilation, headache, dizziness, and tinnitus.
• Severe toxicity can cause metabolic acidosis, coma, and vascular collapse.
• Contraindicated in pregnancy and breastfeeding due to excretion in breast milk.

Propionic Acid Derivatives (e.g., Ibuprofen)

• Ibuprofen has anti-inflammatory, analgesic, and antipyretic activity.
• It's a reversible COX inhibitor, making it more potent than aspirin as an anti-inflammatory agent.
• Rapid oral absorption and a shorter half-life (1-2 hours).
• Highly bound to plasma proteins, requiring higher doses for effect.
• Excreted via kidneys as metabolites, thus contraindicated for patients with kidney dysfunction.
• Clinical uses include analgesia, antipyrexia, anti-inflammation, and acute gouty arthritis.
• Available as oral preparations, topical creams, liquids, and intravenous formulations.
• Adverse effects include gastric upset, fluid retention, and hypersensitivity reactions.
• Rare hematologic effects (agranulocytosis, aplastic anemia) can occur.

Heteroaryl Acetic Acids (e.g., Diclofenac)

• Diclofenac is a potent anti-inflammatory agent, more potent than some other NSAIDs.
• Clinical applications cover various inflammatory conditions, musculoskeletal pain, dysmenorrhea, and acute gout.
• Available as sodium or potassium salts. Sodium salt can cause fluid retention. Potassium salt is preferable for cardiovascular patients.
• Diclofenac combined with Misoprostol decreases GI ulceration but may cause diarrhea. Combined with Omeprazole can help prevent bleeding.
• Common side effects include gastric upset, renal impairment, and elevated liver enzymes.

Heteroaryl Acetic Acids (e.g., Ketorolac)

• Ketorolac is a potent analgesic and anti-inflammatory agent.
• Primarily used for short-term management of acute pain rather than long-term inflammation.
• Suitable for post-operative care, spine pain, and various inflammatory conditions.
• Oral and ophthalmic forms are available.
• Administration should be limited to <5 days due to side effects.
• Common side effects include nausea, vomiting, diarrhea, stomach pain, and headache.

Acetic Acid Derivatives (e.g., Indomethacin)

• Indomethacin is a potent anti-inflammatory agent.
• Used for chronic musculoskeletal pain, patent ductus arteriosus closure, and ophthalmic conditions.
• Can be used for uveitis.
• High doses can be toxic. Also used for Gout and suppression of uterine contractions.
• Absorbed orally, largely bound to plasma proteins.

Sulindac

• Sulindac is a prodrug, which is metabolized to an active compound, which inhibits COX-1 and COX-2.
• May have fewer GI side effects than other NSAIDs due to enterohepatic circulation.

COX-2 Selective NSAID (e.g., Celecoxib)

• Celecoxib selectively inhibits COX-2.
• Used for osteoarthritis, but not as an analgesic.
• Lowers risks for gastric upset compared to traditional NSAIDs.
• Significant risk in increasing cardiovascular risks, specifically myocardial infarctions and strokes.
• Contraindicated for patients with severe renal insufficiency.

Steroidal Anti-Inflammatory Drugs (SAIDs)

• SAIDs (Corticosteroids) are potent anti-inflammatory agents.
• Used in various conditions, including adrenal insufficiency, arthritis, and allergic reactions.
• Significant side effects include increased susceptibility to infections, delayed healing, osteoporosis, growth retardation, and Cushing syndrome.

Autacoids (Histamine, Antihistamines)

• Autacoids act as local hormones. Include histamine, serotonin, prostaglandins, and vasoactive peptides.
• Histamine mediates allergic and inflammatory reactions, gastric acid secretion, and brain neurotransmission.
• It's stored in mast cells and released by tissue injury or allergic reactions.
• Histamine receptors (H1, H2, H3, H4) mediate diverse effects.
• Histamine antagonists (antihistamines) block histamine receptors to reduce allergic responses.
• First-generation antihistamines often cause sedation and other side effects.
• Second-generation antihistamines are less sedating and have fewer autonomic effects. H2 blockers (e.g., cimetidine) reduce gastric acid production and used for ulcers and GERD. Histamine receptor blockers (H1 and H2) reduce effects of histamine in body.

Explore the key concepts of inflammation and the role of NSAIDs in managing pain. This quiz covers the functions of COX enzymes, the significance of prostaglandins, and how NSAIDs operate to reduce sensitivity to pain. Test your understanding of these critical biological mechanisms!