Pharmacology · Short notes

Autacoids and NSAIDs: Short Notes & Cheat Sheet

Histamine and antihistamines, serotonin and migraine drugs, eicosanoids, NSAIDs, paracetamol, gout and DMARDs.

Short notes

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The arachidonic acid cascade

Corticosteroids act at the top, so they reduce both prostaglandins and leukotrienes. NSAIDs block only the COX branch, which can shift arachidonic acid towards leukotrienes (aspirin-sensitive asthma).

Histamine and antihistamines

Histamine is made from histidine and stored in mast cells.
Histamine receptors: H1 (Gq) causes bronchoconstriction, vasodilation, increased permeability and itch. H2 (Gs) stimulates gastric acid. H3 is presynaptic in the CNS.
First-generation H1 blockers (chlorpheniramine, diphenhydramine, promethazine) enter the CNS, so they sedate and have anticholinergic effects. They also treat motion sickness.
Second-generation H1 blockers (cetirizine, loratadine, fexofenadine) sedate little. Fexofenadine is the active metabolite of terfenadine, which was withdrawn for QT prolongation.
Cyproheptadine also blocks 5-HT2. It stimulates appetite and treats serotonin syndrome. Betahistine is used for Ménière's disease.

Serotonin and migraine

Serotonin (5-HT) is made from tryptophan, and about 90% of it is in enterochromaffin cells. Carcinoid syndrome raises urinary 5-HIAA.
Triptans (sumatriptan, 5-HT1B/1D agonists) treat acute migraine. They are contraindicated in coronary artery disease.
Ergotamine also treats acute migraine but is contraindicated in pregnancy and with CYP3A4 inhibitors (risk of ergotism).
Migraine prevention: propranolol, topiramate, amitriptyline, valproate, flunarizine.

Eicosanoids

Phospholipase A2 releases arachidonic acid (glucocorticoids inhibit this step). COX enzymes then make prostaglandins and thromboxane; 5-LOX makes leukotrienes.
COX-1 is constitutive: it protects the stomach and produces platelet TXA2 and renal prostaglandins. COX-2 is induced during inflammation.
TXA2 aggregates platelets and constricts vessels. PGI2 (prostacyclin, epoprostenol) inhibits platelets and dilates vessels, and is used in pulmonary hypertension.
Alprostadil (PGE1) keeps the ductus arteriosus open and treats erectile dysfunction. Dinoprostone (PGE2) ripens the cervix. Carboprost (PGF2α) treats PPH. Latanoprost treats glaucoma but darkens the iris.
Indomethacin, ibuprofen or paracetamol close a patent ductus arteriosus.

NSAIDs and paracetamol

Aspirin irreversibly acetylates COX. At a low dose (75–150 mg) it is antiplatelet, and the effect lasts the platelet's lifespan of 7–10 days.
Aspirin toxicity: GI bleeding, Reye's syndrome in children (avoid under 16), salicylism (tinnitus). Overdose causes respiratory alkalosis, then metabolic acidosis, and is treated by alkalinising the urine with sodium bicarbonate.
Other NSAIDs: ibuprofen, naproxen and diclofenac (reversible); indomethacin (gout, PDA closure); ketorolac (strong painkiller, 5 days maximum); mefenamic acid (period pain).
Selective COX-2 inhibitors (celecoxib, etoricoxib) cause less GI damage but carry more cardiovascular risk.
NSAID adverse effects: peptic ulcer, acute kidney injury (especially the 'triple whammy' with an ACE inhibitor and a diuretic), fluid retention and raised blood pressure. They also raise lithium and methotrexate levels.
Paracetamol reduces pain and fever but not inflammation; the adult maximum is 4 g a day. In overdose its metabolite NAPQI uses up glutathione and destroys the liver. The antidote is N-acetylcysteine, guided by the nomogram from 4 hours after ingestion.

Gout and rheumatoid arthritis

Acute gout: an NSAID (not aspirin), colchicine (blocks microtubules and neutrophil migration; causes diarrhoea) or a corticosteroid.
Long-term urate lowering: allopurinol (xanthine oxidase inhibitor; SJS risk with HLA-B*5801; cut the dose of azathioprine or 6-mercaptopurine) or febuxostat.
Uricosurics such as probenecid block URAT1 and are avoided in patients with kidney stones. Rasburicase prevents tumour lysis syndrome.
Rheumatoid arthritis: methotrexate is the anchor drug. It is given once weekly with folic acid, and is hepatotoxic, myelosuppressive and teratogenic.
Other DMARDs: hydroxychloroquine (retinopathy), sulfasalazine, leflunomide, and biologics (anti-TNF, rituximab, tocilizumab).

Cheat sheet

High-yield facts in one place. Cover the right-hand column and test yourself.

Prostaglandin drugs

Drug (type)	Use
Misoprostol (PGE1)	NSAID ulcer prevention; abortion with mifepristone
Alprostadil (PGE1)	Keep PDA open; erectile dysfunction
Dinoprostone (PGE2)	Cervical ripening, labour induction
Carboprost (PGF2α)	Postpartum haemorrhage
Latanoprost (PGF2α)	Open-angle glaucoma
Epoprostenol (PGI2)	Pulmonary arterial hypertension

Quick answers

Question	Answer
Paracetamol antidote	N-acetylcysteine
Toxic metabolite of paracetamol	NAPQI
Aspirin overdose treatment	Urinary alkalinisation (NaHCO3)
Avoid aspirin in children because of	Reye's syndrome
Close a PDA	Indomethacin / ibuprofen
Acute migraine	Triptan
Acute gout	NSAID / colchicine / steroid
Chronic gout	Allopurinol / febuxostat
Allopurinol + azathioprine	Reduce azathioprine dose by ~75%
Methotrexate is given	Once weekly, with folic acid

Memory aids

Aspirin: alkalosis first, acidosis later: Salicylate overdose stimulates respiration (respiratory alkalosis), then causes metabolic acidosis.
Triple whammy: NSAID + ACE inhibitor/ARB + diuretic together can cause acute kidney injury.

Exam traps

Paracetamol is not anti-inflammatory; it is not an NSAID in the usual sense.
Low-dose aspirin raises serum uric acid, so avoid it in acute gout.
Celecoxib has a sulfonamide group; be careful in patients with sulfonamide allergy.
Methotrexate taken daily instead of weekly is a classic, sometimes fatal, dispensing error.
Fexofenadine, not terfenadine, is the one still in use.

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