Q2 LONG ANSWER 10M ★ High-yield

Describe the synthesis of eicosanoids. Compare COX-1 and COX-2 and classify the NSAIDs with their actions and adverse effects.

Pharmacology · 2nd Professional — Para-Clinical

Eicosanoid Synthesis

Membrane phospholipids → phospholipase A2 — inhibited by corticosteroids (through lipocortin/annexin-1) → arachidonic acid → Two pathways diverge → cyclo-oxygenase (COX) — inhibited by NSAIDs → prostaglandins, prostacyclin and thromboxane A2 → 5-lipoxygenase — inhibited by zileuton → leukotrienes (LTB4, and the cysteinyl leukotrienes C4, D4, E4 — the old "SRS-A") → Cysteinyl leukotriene receptors are blocked by montelukast and zafirlukast

Corticosteroids act above the branch point, so they suppress both prostaglandins and leukotrienes; NSAIDs act below it and suppress only the cyclo-oxygenase arm. This single fact explains why steroids are far more powerful anti-inflammatory agents — and why NSAIDs can divert arachidonic acid into the leukotriene pathway and precipitate asthma

Cox-1 and Cox-2

Feature	COX-1	COX-2
Expression	Constitutive — present all the time	Inducible by cytokines at sites of inflammation; also constitutive in kidney, brain and endothelium
Chief sites	Gastric mucosa, platelets, kidney, vascular endothelium	Inflamed tissue, macrophages; kidney and endothelium
Products and role	"housekeeping" — gastric cytoprotection (PGE2), platelet thromboxane A2, renal blood flow	Prostaglandins of inflammation, pain and fever; endothelial prostacyclin
Consequence of inhibition	Gastric ulceration; antiplatelet effect; renal impairment	Anti-inflammatory, analgesic and antipyretic benefit — but also loss of prostacyclin, hence prothrombotic risk

CLINICAL PEARL

The COX-2 story is a lesson in why a clean hypothesis can still be wrong. The reasoning was clean: block only the inducible enzyme and get anti-inflammatory benefit without gastric harm. It worked for the stomach. But COX-2 also makes endothelial prostacyclin, which opposes platelet thromboxane. Blocking it alone left thromboxane unopposed — and rofecoxib was withdrawn for myocardial infarction. The enzyme was never as "inducible-only" as the hypothesis assumed.

Classification of Nsaids

Chemical class	Drugs	Notes
Salicylates	Aspirin, diflunisal	Aspirin is irreversible; all others are reversible
Propionic acid derivatives	Ibuprofen, naproxen, ketoprofen, flurbiprofen	Best gastric tolerance; ibuprofen is the safest of the older NSAIDs
Acetic acid derivatives	Indomethacin, diclofenac, ketorolac, aceclofenac	Potent; indomethacin has marked CNS effects (frontal headache) and is used to close a patent ductus arteriosus
Enolic acid (oxicams)	Piroxicam, tenoxicam, meloxicam	Long half-life, once daily; piroxicam has a high ulcer risk
Fenamates	Mefenamic acid	Dysmenorrhoea; causes diarrhoea and haemolytic anaemia
Selective COX-2 inhibitors (coxibs)	Celecoxib, etoricoxib, parecoxib	Less gastric toxicity, more cardiovascular risk
Preferential COX-2	Nimesulide, meloxicam	Nimesulide is hepatotoxic and banned for children in India
Analgesic-antipyretic, weak anti-inflammatory	Paracetamol, metamizole	Central action; no significant peripheral anti-inflammatory effect

Pharmacological Actions

Action	Mechanism
Analgesic	Chiefly peripheral — prostaglandins sensitise nociceptors to bradykinin and histamine, so removing them raises the pain threshold; effective for inflammatory and musculoskeletal pain but not for visceral or severe pain
Antipyretic	Pyrogens raise hypothalamic PGE2, resetting the thermostat upward; NSAIDs block this and allow it to reset. They lower a raised temperature but not a normal one
Anti-inflammatory	Reduced prostaglandin-mediated vasodilatation, oedema and pain; they do not affect the underlying disease process
Antiplatelet	Reduced platelet thromboxane A2; clinically useful only with aspirin, whose effect is irreversible
Closure of the ductus arteriosus	Patency depends on PGE2; indomethacin or ibuprofen closes a persistent ductus, while a prostaglandin infusion keeps it open in duct-dependent congenital heart disease

Adverse Effects

Gastrointestinal — the commonest: dyspepsia, erosions, ulceration, bleeding and perforation. Caused both by loss of mucosal prostaglandins (a systemic effect, so it occurs with parenteral and rectal routes too) and by local irritation
Renal — prostaglandins maintain renal blood flow when it is threatened, so NSAIDs precipitate acute kidney injury in hypovolaemia, cardiac failure, cirrhosis and old age; also sodium and water retention, hyperkalaemia, and analgesic nephropathy with chronic use
Cardiovascular — increased risk of infarction and stroke (greatest with coxibs and diclofenac, least with naproxen); worsening of hypertension and cardiac failure
Respiratory — aspirin-sensitive asthma, part of the triad with nasal polyps and rhinitis; caused by diversion of arachidonate to leukotrienes, so it is a class effect, not an allergy
Hepatic — raised transaminases; nimesulide and diclofenac are the chief offenders
Haematological — bleeding; rarely agranulocytosis and aplastic anaemia (phenylbutazone, metamizole)
Skin — rashes; rarely Stevens–Johnson syndrome

Choosing Between Nsaids

Consideration	Preferred agent
Lowest gastrointestinal risk (non-selective)	Ibuprofen at low dose
Lowest cardiovascular risk	Naproxen
Highest gastrointestinal risk	Piroxicam, ketorolac, indomethacin — avoid for routine use
Highest cardiovascular risk	Coxibs and diclofenac
Potency for severe inflammation	Indomethacin, diclofenac, naproxen
Once-daily convenience	Piroxicam, meloxicam, naproxen
Localised joint pain	Topical NSAID — systemic absorption is a small fraction of the oral dose
Fever and simple pain	Paracetamol — no NSAID needed at all

The choice is a balance of two opposing risks, and there is no NSAID that is best on both counts — which is why the patient’s own risk profile, not the drug’s reputation, should decide

Applied Aspects

Use the lowest effective dose for the shortest time, and reassess rather than continuing indefinitely; most NSAID harm comes from prolonged use for chronic pain
Co-prescribe a proton pump inhibitor for patients over 65, those with previous ulcer, and those on steroids, anticoagulants or antiplatelets
Avoid NSAIDs in renal impairment, cardiac failure, cirrhosis and dehydration; the combination of an NSAID, an ACE inhibitor and a diuretic is a well-recognised cause of acute kidney injury
Paracetamol first for simple pain and fever, particularly in children and the elderly
Aspirin is avoided in children under 16 because of REYE syndrome
NSAIDs are sold freely over the counter in India, and patients rarely report them; asking directly is essential in anyone with dyspepsia, renal impairment or unexplained anaemia
Never combine two NSAIDs — toxicity is additive and efficacy is not; this includes overlooking low-dose aspirin already being taken
Avoid NSAIDs in the third trimester, where they may close the ductus arteriosus prematurely and cause oligohydramnios
Reassess the indication at every review — most long-term NSAID use began as a short course that was never stopped

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