Paracetamol Nimesulide

“ Humanity has but three great enemies; Fever, Famine and War. Of these by far the most terrible, is fever.” ( Sir William Osler )

Pathogenesis of fever Infectious agents or toxin ( Endo/Exo) Mediators of inflammation Monocyte/Macrophages Endothelial cells and other cell type Corticosteroid Pyogenic cytokines IL –1 alpha and beta TNF,IL_6, IFNS Enhanced immunity Archidonic Acid PGF2 COX2 Antipyretic Anterior hypothalamus Elevation of Thermoregulatory Set point Increased heat production Increased heat conservation Fever

MODE OF ACTION Tissue damage, release of pyrogens and phospholipids from cell membrane Archidonic acid NSAID block COX –1*and COX –2 in periphery and CNS Paracetamol blocks COX –2 and COX –3 ? in CNS PG 3 Fever and Pain COX –1* is critical to maintain the integrity of platelets,renal function and gastric mucosa.

Choice of antipyretic is highly debatable Which should the choice Safety. Wide therapeutic window. Short duration of action. Side effect: Over dosing either intentional or accidental.

Choice of antipyretic According to WHO paracetamol is the drug of first choice*. Ibuprofen is a useful 2 nd line drug. No other NSAID including Nimesulide should be prescribed for children with high grade fever and used with caution has been cleared by US FDA for using as antipyretic. * WHO 1990

PCM was first used clinically by Von Mering in Marketed in US in UK Well tolerated. Rarely produce side effects of any kind when administered in recommended doses.

Paracetamol approved FDA (USA) OTC – status since Consider safer in asthmatic patients.

Pharmacokinetics: PCM bio availability above 80%. Peak plasma concentration occur between 15 mins and 2 hours after ingestion. It has few Pharmacokinetics drug interaction.

Adverse effects. Excellent safety records at therapeutic doses. Excellent safety in patient of all age. PCM no associated risk of major upper GI bleed or mucosal damage.

Side Effect Haemostasis Meth- haemoglobinaemia. Thrombocytopenia. Anaemia. Agranulocytosis. Hepatotoxicity. Nephrotoxicity

Contraindication and precaution Apart from hypersensitivity, No absolute contraindication. Suitable in all areas with a wide range of medical conditions  Children  Elderly  Patients with mild to moderate liver disease, renal disease,GI problems.  Asthmatics

PCM overdose Excellent safety and tolerability. Effective antidote for PCM available. Therapeutic overdose is rare. Acute toxic dose – 150 mg/kg or 10 times the recommended dose. Over dose is usually suicidal and appropriate over a period of time.

Nimesulide :- Long duration of action. Small therapeutic window. Easy Overdosing – negligence or ignorance. Serious infection may be missed. May cause hypotension occasionally. Many countries have withdrawn

Nimesulide NSAID with selective COX 2 inhibitory action. Peak 1 – 4hrs after intake. Marginal better than paracetamol. Patient in long term use must be monitored for side effect.

Side effects of Antipyretic Adverse effectPCMNSAID GI side effectRare + + Skin RashRare + + RO bleedingNil + + Bronchial hyper-reactivityNil + Hepato-toxicity ( overdose) ( Overdose) Nephrotoxicity National Kidney foundation USA, PCM – Safe. SeizureNil + HypothermiaNil + PregnancySafeunsafe < 6 month RecommendedNot recommended