NSAIDs, Analgesics & Antipyretics

A perennial high-yield block in NEET PG pharmacology. The examiner reliably tests COX-1 vs COX-2 selectivity, paracetamol hepatotoxicity and its antidote, aspirin's dose-dependent actions, and the GI/renal/cardiovascular adverse-effect spectrum. Master the mechanisms and the "drug of choice" tables and you bag almost every question.

Definition & classification

Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit cyclo-oxygenase (COX), blocking conversion of arachidonic acid to prostaglandins (PGs), prostacyclin (PGI₂) and thromboxane A₂ (TXA₂). They share four core actions: analgesic, antipyretic, anti-inflammatory and antiplatelet (variable). Paracetamol is grouped here by tradition but is a weak anti-inflammatory.

Arachidonic acid cascade (the master flow):

Membrane phospholipids → (phospholipase A₂) → arachidonic acid → COX-1/COX-2 → PGG₂/PGH₂ → tissue-specific PGs (PGE₂, PGI₂, PGF₂α) and TXA₂.

• Steroids block phospholipase A₂ (via lipocortin/annexin-1) → block BOTH the COX and lipoxygenase (LOX) arms.
• NSAIDs block only COX → arachidonic acid may be shunted to the LOX arm (→ leukotrienes), explaining aspirin-induced asthma.
• Zileuton blocks 5-LOX; montelukast/zafirlukast block leukotriene (CysLT₁) receptors.

High-yield: Corticosteroids inhibit phospholipase A₂; NSAIDs inhibit cyclo-oxygenase. This single distinction is a recurring one-liner.

COX isoenzymes

Feature	COX-1 (constitutive)	COX-2 (inducible)
Expression	Constitutive, "housekeeping"	Induced by inflammation/cytokines
Key sites	Gastric mucosa, platelets, kidney	Inflammatory cells, kidney (macula densa), CNS, endothelium
Main products	Gastroprotective PGE₂/PGI₂, platelet TXA₂	Inflammatory PGs, endothelial PGI₂
Inhibition effect	GI ulceration, antiplatelet	Anti-inflammatory, ↓ pain, fewer GI effects
Also present	—	Constitutive in kidney & brain

High-yield: Platelets express only COX-1 → produce TXA₂ (pro-aggregatory, vasoconstrictor). Endothelium has COX-2 → produces PGI₂ (anti-aggregatory, vasodilator). Selective COX-2 inhibitors leave platelet TXA₂ intact while suppressing protective PGI₂ → prothrombotic imbalance → ↑ cardiovascular events.

Classification by COX selectivity

Class	Examples	Notes
Non-selective (COX-1 = COX-2)	Aspirin, ibuprofen, naproxen, diclofenac, indomethacin, piroxicam, ketorolac	GI toxicity common
Preferential COX-2	Nimesulide, meloxicam, etodolac, nabumetone	Relatively GI-sparing
Selective COX-2 (coxibs)	Celecoxib, etoricoxib, parecoxib	↑ CV risk; rofecoxib/valdecoxib withdrawn
COX-3 / central (poor anti-inflammatory)	Paracetamol	Antipyretic + analgesic

Chemical groups worth recalling: salicylates (aspirin), propionic acids (ibuprofen, naproxen, ketoprofen), acetic acids (diclofenac, indomethacin, ketorolac, etodolac), oxicams (piroxicam, meloxicam), fenamates (mefenamic acid), pyrazolones (phenylbutazone), sulphonanilide (nimesulide), para-aminophenol (paracetamol).

Aspirin (acetylsalicylic acid) — the prototype

Aspirin irreversibly acetylates a serine residue on COX (Ser-530 of COX-1, Ser-516 of COX-2). Because platelets are anucleate and cannot synthesise new enzyme, a single dose inhibits platelet TXA₂ for the platelet's entire 7–10 day lifespan — the basis of low-dose antiplatelet therapy.

High-yield (dose-dependent actions of aspirin):

• 75–150 mg/day → antiplatelet (irreversible COX-1 inhibition in platelets)
• 325–650 mg → analgesic + antipyretic
• 3–6 g/day → anti-inflammatory (anti-rheumatic)
• High doses → uricosuric; low doses → urate retention (biphasic effect on urate).

Kinetics: Aspirin shows zero-order (saturation) kinetics at higher doses — small dose increments cause disproportionate plasma rises and toxicity. Hydrolysed to salicylic acid; ~80% protein bound.

Salicylate toxicity (salicylism)

Classic sequence: tinnitus, deafness, vertigo → hyperventilation → mixed acid-base disorder = respiratory alkalosis (early, central stimulation of respiration) + high-anion-gap metabolic acidosis (late). Children acidose faster.

• Management: gastric lavage/activated charcoal, IV fluids, urinary alkalinisation with sodium bicarbonate (ion-trapping increases salicylate excretion), correct hypokalaemia, haemodialysis in severe cases.

High-yield: Reye syndrome = acute encephalopathy + fatty liver (microvesicular steatosis) in children given aspirin during viral illness (varicella, influenza). Avoid aspirin under 16 years; use paracetamol instead.

Other uses of aspirin: secondary prevention of MI/stroke, acute coronary syndrome (loading 300 mg chewed), Kawasaki disease (one of few paediatric exceptions), colorectal cancer chemoprevention. Contraindicated in peptic ulcer, bleeding disorders, G6PD deficiency (high dose), and before surgery.

Paracetamol (acetaminophen) — the favourite

Centrally acting analgesic-antipyretic; negligible anti-inflammatory and no antiplatelet/GI effect. Acts on a CNS COX variant ("COX-3") and modulates serotonergic/endocannabinoid pathways. Safe in peptic ulcer, asthma, pregnancy, children and the elderly. The antipyretic of choice.

Hepatotoxicity — must-know mechanism

Therapeutic doses are conjugated (glucuronidation + sulphation) and excreted. A small fraction is oxidised by CYP2E1 to the toxic electrophile NAPQI (N-acetyl-p-benzoquinone-imine), normally detoxified by conjugation with glutathione.

Overdose flow:

Large dose → conjugation pathways saturated → more NAPQI formed → hepatic glutathione depleted → NAPQI binds hepatocyte proteins → centrilobular (zone 3) hepatic necrosis.

High-yield: Toxic dose ≈ >150 mg/kg or >10–12 g in adults. Risk ↑ with chronic alcohol use and enzyme inducers (CYP2E1 induction → more NAPQI) and with malnutrition (low glutathione).

Clinical phases of paracetamol poisoning:

Phase	Time	Features
I	0–24 h	Nausea, vomiting, malaise; LFTs normal
II	24–72 h	RUQ pain, rising AST/ALT, ↑ INR
III	72–96 h	Peak hepatotoxicity — fulminant hepatic failure, encephalopathy, AKI
IV	4 days–2 wk	Recovery or death

Antidote — N-acetylcysteine (NAC): replenishes hepatic glutathione (provides cysteine), also acts as a glutathione substitute and antioxidant. Most effective within 8 hours of ingestion. Use the Rumack-Matthew nomogram (plasma level vs time, from 4 h post-ingestion) to decide therapy. Methionine is an oral alternative.

High-yield: NAPQI is the toxic metabolite; NAC (N-acetylcysteine) replenishes glutathione and is the antidote — best given within 8 hours.

Other important individual NSAIDs

• Ibuprofen — safest non-selective NSAID for GI; first-line for mild-moderate pain, PDA closure alternative.
• Indomethacin — most potent; closes patent ductus arteriosus (PDA) in neonates (PGE-mediated patency blocked), gout, ankylosing spondylitis; high CNS toxicity (frontal headache).
• Ketorolac — potent parenteral analgesic for post-operative pain, comparable to opioids; limit to 5 days (GI bleed, renal risk).
• Diclofenac — popular; short half-life, accumulates in synovial fluid; hepatotoxicity risk.
• Naproxen — longest half-life among common NSAIDs; lowest CV risk → preferred when an NSAID is needed in cardiac patients.
• Piroxicam — long half-life (once daily) but high GI ulceration risk.
• Mefenamic acid — dysmenorrhoea; can cause haemolytic anaemia, diarrhoea.
• Nimesulide — preferential COX-2; hepatotoxicity → contraindicated under 12 years in India.
• Celecoxib — sulfonamide-based coxib; GI-sparing, CV risk; least CV risk among coxibs.
• Etoricoxib — long-acting COX-2 inhibitor, popular for arthritis/gout in India.
• Phenylbutazone — agranulocytosis/aplastic anaemia → obsolete.

Adverse effects of NSAIDs (system-wise)

Gastrointestinal

COX-1 inhibition ↓ protective PGE₂/PGI₂ → ↓ mucus/bicarbonate, ↑ acid → erosions, ulcers, bleeding (often painless). Risk highest with piroxicam, ketorolac, indomethacin; lowest with ibuprofen and coxibs.

High-yield: Misoprostol (a PGE₁ analogue) is the specific agent for NSAID-induced peptic ulcer prophylaxis. PPIs are preferred for tolerability; misoprostol causes diarrhoea and is abortifacient (avoid in pregnancy).

Renal

PGs maintain renal blood flow in states of low effective volume. NSAIDs → vasoconstriction → ↓ GFR, sodium/water retention, hyperkalaemia, acute kidney injury, papillary necrosis, and antagonism of antihypertensives/diuretics.

High-yield: Analgesic nephropathy = chronic interstitial nephritis + renal papillary necrosis from long-term combined analgesic abuse (classically phenacetin-containing mixtures). Presents with sterile pyuria, haematuria, ↑ risk of urothelial (transitional cell) carcinoma.

Cardiovascular

COX-2 inhibition → ↓ endothelial PGI₂ with intact platelet TXA₂ → prothrombotic state → ↑ MI/stroke. Rofecoxib and valdecoxib were withdrawn for excess CV events. Coxibs and diclofenac carry the highest CV risk; naproxen the lowest. NSAIDs also raise BP and worsen heart failure.

Other

• Aspirin-exacerbated respiratory disease (Samter's triad) = asthma + nasal polyps + aspirin sensitivity (LOX shunting → ↑ leukotrienes).
• Hypersensitivity, urticaria, angioedema.
• Pregnancy: NSAIDs in third trimester → premature closure of ductus arteriosus, oligohydramnios; avoid.
• Aspirin + warfarin/methotrexate → ↑ toxicity (displacement + reduced clearance).

Drug-of-choice quick map

Indication	Drug of choice
Antipyretic (esp. children)	Paracetamol
Closure of PDA	Indomethacin (or ibuprofen)
Acute gout	NSAID (naproxen/indomethacin) or colchicine
Antiplatelet	Low-dose aspirin
Post-op parenteral analgesia	Ketorolac
Dysmenorrhoea	Mefenamic acid / naproxen
NSAID ulcer prophylaxis	Misoprostol / PPI
NSAID needed in CV-risk patient	Naproxen
Paracetamol overdose	N-acetylcysteine
Aspirin overdose	Urinary alkalinisation + supportive care

Key differentials / comparisons

Aspirin vs Paracetamol — Aspirin: anti-inflammatory, antiplatelet, GI/renal toxic, Reye risk, irreversible COX block. Paracetamol: no anti-inflammatory/antiplatelet action, hepatotoxic in overdose, safe in children/ulcer/asthma.

Reversible vs irreversible inhibitors — Only aspirin is irreversible (acetylation); all other NSAIDs are reversible/competitive. Hence aspirin's antiplatelet effect long outlasts its plasma half-life.

Selective vs non-selective — Coxibs spare GI but raise CV risk; non-selectives cause GI injury but (except diclofenac) are CV-safer.

High-yield: Ibuprofen blunts the antiplatelet effect of aspirin by reversibly occupying the COX-1 site and blocking aspirin's access — give aspirin first, or use a different NSAID.

Mnemonics & named facts

• "GRANS" for NSAID adverse effects: GI bleed, Renal failure, Allergy/Asthma, Na⁺/water retention (oedema, ↑BP), Salicylism/bleeding.
• Samter's triad = aspirin + asthma + nasal polyps (think "ASA-Polyp-Asthma").
• Rumack-Matthew nomogram — paracetamol; Reye — aspirin in kids; NAPQI — toxic metabolite; CYP2E1 — generates it.
• Aspirin's biphasic urate effect: low dose retains urate, high dose uricosuric.

Recently asked / exam angle

• COX-2 selective inhibitor → increased cardiovascular risk: mechanism is suppression of endothelial PGI₂ with preserved platelet TXA₂ (one-liner favourite).
• Toxic metabolite of paracetamol = NAPQI; antidote = N-acetylcysteine (replenishes glutathione) — repeatedly asked.
• Reye syndrome association with aspirin in children + viral fever.
• Analgesic nephropathy → renal papillary necrosis and transitional cell carcinoma risk.
• Aspirin antiplatelet dose (75–150 mg) and the irreversible acetylation mechanism.
• Indomethacin for PDA closure; NSAIDs cause premature ductus closure in 3rd-trimester pregnancy.
• Misoprostol (PGE₁) for NSAID-induced ulcer prophylaxis.
• Steroids inhibit phospholipase A₂ vs NSAIDs inhibit COX.
• Acid-base picture of salicylate poisoning (respiratory alkalosis + metabolic acidosis).
• Naproxen = lowest CV risk NSAID; rofecoxib withdrawn.
• Zero-order kinetics of aspirin at toxic doses.

Rapid revision

1. NSAIDs inhibit COX → ↓ prostaglandins; steroids inhibit phospholipase A₂ → block both COX and LOX arms.
2. Platelets have only COX-1 (TXA₂); endothelium makes PGI₂ — basis of coxib CV risk.
3. Aspirin irreversibly acetylates COX → antiplatelet effect lasts platelet lifespan (7–10 days).
4. Aspirin dose ladder: 75–150 mg antiplatelet, 325–650 mg analgesic/antipyretic, 3–6 g anti-inflammatory.
5. Reye syndrome → avoid aspirin in children <16 with viral illness; Kawasaki is the exception.
6. Salicylate poisoning = respiratory alkalosis + metabolic acidosis; treat with urinary alkalinisation.
7. Paracetamol → toxic metabolite NAPQI via CYP2E1; depletes glutathione → zone-3 hepatic necrosis.
8. Antidote = N-acetylcysteine, best within 8 h; use Rumack-Matthew nomogram; toxic dose >150 mg/kg.
9. Indomethacin closes PDA; NSAIDs cause premature ductus closure in late pregnancy.
10. Misoprostol (PGE₁) prevents NSAID-induced peptic ulcers; PPIs preferred for tolerability.
11. Analgesic nephropathy → renal papillary necrosis + transitional cell carcinoma.
12. Naproxen = safest NSAID for cardiovascular patients; rofecoxib/valdecoxib withdrawn for CV events.