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Note: KD Tripathi's Essentials of Medical Pharmacology is not available in this textbook library. The following is a comprehensive NSAID overview drawn from Katzung's Basic and Clinical Pharmacology (16th Ed) and Lippincott Illustrated Reviews: Pharmacology, which cover the same content in the same depth. KD Tripathi's coverage of NSAIDs follows essentially the same framework.

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NSAIDs - Nonsteroidal Anti-Inflammatory Drugs

Definition & Overview

• Katzung's Basic and Clinical Pharmacology, 16th Ed, p. 1004

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Mechanism of Action

• Membrane phospholipids → (phospholipase A2) → Arachidonic acid
• Arachidonic acid → (COX-1 / COX-2) → Cyclic endoperoxides → Prostaglandins (PGE2, PGI2), Thromboxane A2 (TXA2)

• Most NSAIDs are non-selective - they inhibit both COX-1 and COX-2
• Selective COX-2 inhibitors (coxibs like celecoxib) were developed to spare the GI tract

1. Anti-inflammatory - reduce PGE2 and PGI2 at sites of inflammation
2. Analgesic - reduce sensitization of peripheral nociceptors by PGE2
3. Antipyretic - block PGE2 synthesis in the hypothalamus (PGE2 is the mediator that raises the thermoregulatory set-point in fever)
4. Antiplatelet - aspirin irreversibly inhibits COX-1 in platelets, blocking TXA2-mediated aggregation

• Lippincott Illustrated Reviews: Pharmacology, p. 1333-1334

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Classification of NSAIDs

I. Non-Selective COX Inhibitors

• Aspirin (Acetylsalicylic acid) - irreversibly inhibits COX (acetylates it); half-life 15 min (aspirin), 1.9-12 hrs (salicylate); antiplatelet dose 75-325 mg/day; anti-inflammatory dose 1200-1500 mg TID
• Sodium salicylate, Choline magnesium salicylate - non-acetylated; do NOT inhibit platelet aggregation; safer in asthma and bleeding disorders

• Ibuprofen - half-life 2 hrs; 600 mg QID; over-the-counter availability; low GI toxicity
• Naproxen - half-life 12-17 hrs; only NSAID marketed as single enantiomer; twice-daily dosing; more favorable cardiovascular profile than ibuprofen
• Ketoprofen - half-life ~2 hrs; 75 mg TID
• Flurbiprofen - half-life ~4 hrs; 300 mg TID
• Oxaprozin - long half-life 50-60 hrs; once-daily dosing; used in OA and RA

• Indomethacin - half-life 4-5 hrs; 25-50 mg TID; most potent NSAID; high CNS side effects (severe headache, dizziness in 25-50%); used in acute gout, ankylosing spondylitis, closure of patent ductus arteriosus (PDA) in neonates
• Diclofenac - half-life ~2 hrs; 50-75 mg BID; slight COX-2 selectivity; available as topical gel; combined with misoprostol (Arthrotec) for GI protection
• Sulindac - sulfoxide prodrug converted to active sulfide metabolite; half-life ~16 hrs; spares renal prostaglandins (relatively renal-sparing); 150-200 mg BID
• Etodolac - slight COX-2 selectivity; 300-500 mg BID; lower GI ulcer incidence
• Ketorolac - parenteral NSAID; used for short-term acute pain (max 5 days IV/IM); not for chronic use due to GI and renal toxicity; available as ophthalmic drops for conjunctivitis and post-surgical eye inflammation
• Tolmetin - short half-life; used in JIA

• Piroxicam - half-life 50 hrs (due to extensive enterohepatic circulation); once-daily dosing 20 mg; also inhibits leukocyte migration; doses >20 mg/day significantly increase peptic ulcer risk
• Meloxicam - half-life 20 hrs; once-daily dosing; slight COX-2 selectivity at low doses (7.5 mg); 7.5-15 mg/day
• Tenoxicam

• Mefenamic acid - blocks PG synthesis AND antagonizes PG receptors; used for dysmenorrhea; max 7 days use; diarrhea common
• Meclofenamate

• Nabumetone - only NSAID that is a non-acidic prodrug (ketone); metabolized to active acid (6-MNA); half-life 22-30 hrs; lower GI ulcer incidence; once-daily dosing 1000-2000 mg

II. Selective COX-2 Inhibitors (Coxibs)

• COX-2 inhibition blocks PGI2 (prostacyclin) synthesis in vascular endothelium
• PGI2 is vasodilatory and inhibits platelet aggregation
• COX-1 still produces TXA2 → unopposed vasoconstriction and platelet aggregation → thrombotic risk
• Katzung's Basic and Clinical Pharmacology, 16th Ed, p. 1012-1014

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Pharmacokinetics - General Properties

• Almost all NSAIDs are weak organic acids (exception: nabumetone, a ketone prodrug)
• Well absorbed orally
• Highly protein-bound (to albumin)
• Metabolized by liver (CYP enzymes for most)
• Excreted by kidneys
• Cross the blood-brain barrier and placenta
• Alkalinization of urine increases salicylate excretion

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Pharmacological Effects

1. Anti-inflammatory

• Suppress PGE2 and PGI2 at inflammatory sites
• Reduce vasodilation, edema, and pain sensitization
• Do NOT suppress the underlying immune disease process (unlike DMARDs)

2. Analgesic

• Effective for mild-to-moderate pain (headache, dysmenorrhea, dental pain, musculoskeletal pain)
• Peripheral mechanism: reduce PGE2 sensitization of nociceptors
• Central mechanism also contributes (especially for ketorolac, indomethacin)

3. Antipyretic

• Block hypothalamic PGE2 synthesis
• Lower elevated temperature but do NOT affect normal body temperature
• Aspirin is avoided in children with viral infections - risk of Reye syndrome (acute hepatic failure + encephalopathy)

4. Antiplatelet (Aspirin)

• Irreversible acetylation of COX-1 in platelets
• Platelet cannot regenerate COX (anucleate) → effect lasts 8-10 days (platelet lifespan)
• Low-dose aspirin (75-162 mg) used for secondary prevention of MI, stroke, TIA
• All other NSAIDs inhibit platelets reversibly (effect wears off when drug is cleared)

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Clinical Uses

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Adverse Effects

1. Gastrointestinal (Most Common)

• Dyspepsia, nausea, epigastric pain
• Peptic ulcer disease (gastric > duodenal) - due to COX-1 inhibition → reduced PGE2 → reduced mucus and bicarbonate secretion → mucosal damage
• GI bleeding, perforation
• Risk is highest with: piroxicam, indomethacin, ketorolac
• Risk is lowest with: ibuprofen, nabumetone, etodolac, celecoxib
• Prevention: PPI (omeprazole), H2 blocker, or misoprostol (PGE1 analog that restores mucosal protection)

2. Renal

• Reduced renal prostaglandins → decreased GFR, sodium retention, edema
• Acute kidney injury (especially in states of reduced renal perfusion: heart failure, cirrhosis, volume depletion, elderly)
• Hyperkalemia (reduced renin and aldosterone)
• Analgesic nephropathy with chronic use - papillary necrosis
• Sulindac is relatively renal-sparing (prodrug not active in kidney)
• COX-2 inhibitors are NOT renal-sparing

3. Cardiovascular

• All NSAIDs (especially COX-2 selective): increased risk of MI, stroke, hypertension
• Fluid retention → worsening heart failure
• Naproxen has the most favorable CV profile among non-selective NSAIDs
• Avoid NSAIDs (except aspirin) after recent MI

4. Platelet / Bleeding

• Non-selective NSAIDs: reversible platelet inhibition → increased bleeding time
• Aspirin: irreversible platelet inhibition
• Coxibs: NO antiplatelet effect - safer in surgical settings regarding bleeding

5. Pulmonary / Hypersensitivity

• Aspirin-exacerbated respiratory disease (AERD) - "aspirin triad": asthma + nasal polyps + aspirin sensitivity
• Mechanism: COX-1 blockade shunts arachidonic acid toward leukotriene synthesis → bronchoconstriction
• Cross-reaction with other NSAIDs (COX-1 inhibitors)
• Non-acetylated salicylates and coxibs are generally safe in these patients

6. CNS

• Indomethacin: severe headache, dizziness, confusion in 25-50% of patients (most CNS-toxic NSAID)
• Tinnitus, hearing loss with aspirin (salicylism)
• Aseptic meningitis (rare, especially with ibuprofen in SLE patients)

7. Hepatic

• Transient elevation of liver enzymes
• Rare serious hepatotoxicity (diclofenac has highest risk among NSAIDs)
• Contraindicated in severe hepatic impairment

8. Pregnancy

• Avoid in 3rd trimester - premature closure of ductus arteriosus, oligohydramnios
• 1st trimester: possible increased miscarriage risk
• Aspirin (low dose) is used in preeclampsia prevention

9. Uterine

• Delay labor (tocolytic effect) via PG inhibition

10. Reye Syndrome

• Aspirin in children with viral illness (influenza, varicella) → Reye syndrome (hepatic failure + encephalopathy) - avoid aspirin <19 years

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Salicylate Toxicity (Salicylism)

• Gastric lavage / activated charcoal
• IV sodium bicarbonate (alkalinize urine → increases salicylate excretion as ionized form cannot be reabsorbed)
• Dialysis in severe cases

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Drug Interactions

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Contraindications

• Active peptic ulcer disease
• Severe renal or hepatic impairment
• Hypersensitivity to NSAIDs / aspirin
• 3rd trimester pregnancy
• Pre-existing platelet disorders / hemophilia (especially aspirin)
• Aspirin: children with viral infections (Reye syndrome)
• COX-2 inhibitors: ischemic heart disease, stroke (cardiovascular risk)

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Individual Drug Highlights (KD Tripathi Style)

Aspirin

• Irreversible COX inhibitor; antiplatelet for life of platelet (8-10 days)
• Used: MI, stroke prevention, Kawasaki disease, pericarditis
• Reye syndrome in children - AVOID

Indomethacin

• Most potent non-selective NSAID
• Drug of choice for: ankylosing spondylitis, acute gout, PDA closure
• High CNS toxicity - limits use

Ketorolac

• Only parenteral NSAID (also oral, ophthalmic)
• Short-term acute pain only (≤5 days)
• Potent analgesic - comparable to opioids for moderate-severe pain

Mefenamic Acid

• Dual mechanism: COX inhibitor + PG receptor antagonist
• Best for: dysmenorrhea
• Max duration: 7 days

Celecoxib

• Selective COX-2 inhibitor; does not affect platelets
• Preferred in GI-risk patients
• Contains sulfonamide group - avoid in sulfonamide allergy
• CV risk still present - avoid in ischemic heart disease

Paracetamol (Acetaminophen)

• Analgesic and antipyretic - NOT anti-inflammatory (no peripheral COX inhibition at therapeutic doses)
• No GI toxicity, no platelet effect
• Overdose → hepatotoxicity via NAPQI metabolite; antidote: N-acetylcysteine

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Summary Table

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Sources:

• Katzung's Basic and Clinical Pharmacology, 16th Ed - Chapter 36: NSAIDs, Disease-Modifying Antirheumatic Drugs, Nonopioid Analgesics (pp. 1003-1020)
• Lippincott Illustrated Reviews: Pharmacology - Chapter 40: Anti-Inflammatory, Antipyretic, and Analgesic Agents (pp. 1331-1370)

KD Tripathi's Essentials of Medical Pharmacology is not in this textbook library, but Katzung and Lippincott cover NSAIDs in equivalent depth and are used as complementary references globally.