NSAIDs: Complete Reference

Definition

Mechanism of Action

The Arachidonic Acid Cascade

The Two COX Isoenzymes

"COX-1 is present in all cells and plays an important role in homeostatic functions. COX-2 is induced by injury or inflammation and generates prostaglandins as part of the inflammatory process. Nonselective NSAIDs inhibit both COX-1 and COX-2, resulting in multiple beneficial effects (reduction of inflammation, pain, fever) and some important undesirable effects."

How NSAIDs Block COX

• Aspirin - Transfers an acetyl group irreversibly to a serine residue (Ser530) in the COX active site, permanently inactivating both COX-1 and COX-2. Because platelets cannot synthesize new protein, this antiplatelet effect lasts for the entire platelet lifespan (~10 days).
• Traditional (nonselective) NSAIDs (ibuprofen, naproxen, etc.) - Compete reversibly with arachidonate for the COX active site. Ibuprofen is a rapid, reversible, time-independent inhibitor; indomethacin and diclofenac are time-dependent allosteric inhibitors that bind more slowly but exit the active site only after hours.
• Selective COX-2 inhibitors (coxibs) - Exploit a unique valine substitution at position 523 in COX-2 (vs. isoleucine in COX-1), which opens a hydrophobic side pocket accessible only to bulkier coxib molecules. Celecoxib and etoricoxib occupy this pocket with their sulfur-containing phenyl ring, achieving selective COX-2 inhibition without blocking COX-1.

Three Pharmacological Effects Explained

1. Anti-inflammatory: Reducing prostaglandin synthesis blunts vasodilation, vascular permeability, and sensitization of immune cells at inflammatory sites. NSAIDs suppress inflammation in arthritis but do not arrest disease progression.
2. Analgesic: PGE2 sensitizes peripheral nociceptors to bradykinin and histamine. By decreasing PGE2, NSAIDs raise the pain threshold. This effect is primarily mediated via COX-2 inhibition. All NSAIDs have roughly equivalent analgesic efficacy; ketorolac is an exception as it can address more severe pain (short-term only).
3. Antipyretic: Pyrogens (cytokines from activated WBCs) stimulate PGE2 synthesis in the anterior hypothalamus, raising the thermostat set-point. NSAIDs block this PGE2 synthesis, resetting the thermostat toward normal, increasing peripheral vasodilation and sweating. NSAIDs have no effect on normal body temperature.

Classification

By COX Selectivity (Most Clinically Useful)

1. Nonselective COX-1 and COX-2 Inhibitors (traditional NSAIDs - tNSAIDs)

2. Preferentially COX-2 Selective

• Meloxicam, nimesulide, etodolac, nabumetone

3. Highly Selective COX-2 Inhibitors (Coxibs)

"The prototypical COX-2-selective NSAIDs, celecoxib and rofecoxib, are diaryl compounds containing a sulfonamide (celecoxib) and methylsulfone (rofecoxib). The sulfur-containing phenyl ring of COX-2-selective NSAIDs plays a pivotal role in binding stability by occupying the hydrophobic side pocket characteristic of the COX-2 catalytic site."

Aspirin: A Special Case

Therapeutic Uses

1. Musculoskeletal and Inflammatory Conditions

• Osteoarthritis - first-line for symptomatic pain relief
• Rheumatoid arthritis - symptom relief only (do not modify disease; must be combined with DMARDs)
• Ankylosing spondylitis
• Gout (acute attacks) - indomethacin classically used
• Psoriatic arthritis

2. Pain Management

• Mild-to-moderate pain: headache, myalgia, arthralgia, dental pain
• Dysmenorrhea (menstrual cramps) - very effective
• Postoperative pain - part of multimodal analgesia; opioid-sparing effect
• Ketorolac - parenteral NSAID for moderate-to-severe pain (short-term only, max 5 days)
• Cancer pain - useful combined with opioids for opioid-sparing effect

3. Fever

• Aspirin, ibuprofen, naproxen (avoid aspirin in children under 19 with viral infections - Reye syndrome risk)

4. Cardiovascular

• Low-dose aspirin (75-162 mg/day, typically 81 mg): secondary prevention of MI, TIA, stroke; acute MI management
• Irreversible COX-1 blockade reduces thromboxane A2-mediated platelet aggregation

5. Other Uses

• Tocolysis (preterm labor) - indomethacin (COX inhibitor reduces prostaglandin-driven uterine contractions)
• Ductus arteriosus closure in neonates - indomethacin or ibuprofen IV
• Topical applications: Diclofenac gel (osteoarthritis of knee/hands); ketorolac eye drops (allergic conjunctivitis, post-op ocular inflammation); salicylic acid (acne, warts, corns)
• Colorectal cancer chemoprevention (ongoing research)

Adverse Effects (Side Effects)

1. Gastrointestinal (Most Common)

• 10-60% of chronic users develop GI complaints (dyspepsia, nausea, abdominal pain)
• Peptic ulcer disease, gastric/duodenal erosions, bleeding, perforation - more than 100,000 hospitalizations and ~16,500 deaths/year in the USA
• NSAID enteropathy - small bowel mucosal injury (increased permeability, chronic blood loss, ulceration, diaphragm-like strictures) seen in up to 70% of NSAID users on capsule endoscopy
• Risk reduced (but not eliminated) with selective COX-2 inhibitors (coxibs)
• Prevention: proton pump inhibitors (PPIs) co-prescribed; misoprostol (a prostaglandin analog)

2. Cardiovascular

• Selective COX-2 inhibitors (coxibs) - increased risk of MI, stroke, and thrombotic events
• Nonselective NSAIDs - generally balance out cardiovascular effects (reduced TXA2 and reduced PGI2)
• However, all NSAIDs (except aspirin) may increase cardiovascular risk at higher doses or with prolonged use
• Celecoxib contraindicated perioperatively in CABG patients
• Can increase blood pressure (sodium and water retention)
• Can worsen congestive heart failure

3. Renal

• Acute kidney injury (AKI) - especially in volume-depleted patients, those with heart failure, CKD, or elderly
• Sodium and water retention - edema, hypertension
• Hyperkalemia
• Chronic renal failure with prolonged use
• Analgesic nephropathy with long-term phenacetin combination products

4. Hematological

• Platelet dysfunction / prolonged bleeding time - COX-1 inhibition reduces TXA2-mediated platelet aggregation (especially problematic with aspirin, which is irreversible)
• Thrombocytopenia (less common)
• Increased risk of bleeding, particularly with anticoagulants

5. Respiratory

• Aspirin-exacerbated respiratory disease (AERD) / Samter's Triad: aspirin sensitivity in patients with asthma + nasal polyps. Caused by shunting of arachidonic acid toward leukotrienes (via 5-lipoxygenase) when COX is blocked - leukotrienes are potent bronchoconstrictors
• Can precipitate acute bronchospasm in susceptible asthmatic patients

6. Hepatic

• Elevated liver enzymes (transaminases) - usually dose-dependent and reversible
• Rare: serious hepatotoxicity (more associated with specific agents; lumiracoxib withdrawn for this reason)

7. CNS

• Headache, dizziness, tinnitus (especially salicylate toxicity)
• Salicylate toxicity / salicylism (high-dose aspirin): tinnitus, vertigo, hearing loss, hyperventilation, metabolic acidosis

8. Hypersensitivity

• Urticaria, angioedema, anaphylaxis
• Cross-reactivity among NSAIDs common

9. Fetal/Neonatal (Specific to Pregnancy)

• Premature closure of the ductus arteriosus (prostaglandins E2 and prostacyclin normally maintain ductal patency)
• Oligohydramnios (reduced fetal urine output)
• Neonatal pulmonary hypertension
• Risk is greatest after 30-32 weeks gestation - indomethacin use requires fetal Doppler monitoring

10. Reye Syndrome

• Aspirin in children <19 years old with viral illness (influenza, varicella) - risk of fulminating hepatitis with cerebral edema. Aspirin is therefore contraindicated in children for viral fever.

Key Contraindications Summary

Summary Table

• Lippincott Illustrated Reviews: Pharmacology
• Fischer's Mastery of Surgery, 8e
• Rosen's Emergency Medicine: Concepts and Clinical Practice
• Firestein & Kelley's Textbook of Rheumatology, 2-Volume Set
• Goldman-Cecil Medicine, International Edition
• Sleisenger and Fordtran's Gastrointestinal and Liver Disease
• Harper's Illustrated Biochemistry, 32nd Ed.
• Creasy & Resnik's Maternal-Fetal Medicine: Principles and Practice