Non-steroidal anti-inflammatory drugs (NSAIDs) PDF

Part 2: Non-steroidal anti-inflammatory drugs (NSAIDs) Classification Non-selective COX inhibitors (inhibit COX-1 and COX-2): – Salicylic acid derivatives: aspirin, aloxiprine, aminosalicylic acid, diflunisal, methyl salicylate, etc. – A...

Part 2: Non-steroidal anti-inflammatory drugs (NSAIDs) Classification Non-selective COX inhibitors (inhibit COX-1 and COX-2): – Salicylic acid derivatives: aspirin, aloxiprine, aminosalicylic acid, diflunisal, methyl salicylate, etc. – Acetic acid derivatives: – Carboxylic acetic acid: indomethacin, sulindac, etodolac. – Phenyl acetic acid: diclofenac – Propionic acid derivatives: iboprufen, ketoprofen, fenoprufen, naproxen. – Fenamic acid derivatives: mefenamic acid, fulfenamic acid. – Pyrazolone derivatives: phenylbutazone, azapropazone – Oxicams: piroxicam, tinoxicam. Selective COX-2 inhibitors: celecoxib, etoricoxib, meloxicam. ▌Acetylsalicylic acid (Aspirin) Chemistry and pharmacokinetics  Oral absorption is complete; most of absorption occurs from the stomach and upper GIT.  Widely distributed to all tissues including CNS.  Metabolism of salicylates occurs by the hepatic microsomal enzymes. – At low doses, elimination is done by the first-order process. – At high doses, elimination is done by the zero-order process.  Excretion is increased by alkalinization of urine (pH 8) because in alkaline urine, most of aspirin is ionized and less re-absorbable. Mechanism and pharmacological effects Aspirin is non-selective and irreversible COX inhibitor leading to inhibition of both PGs and TXs. This distinguishes it from other NSAIDs, which reversibly inhibit COX enzyme. Analgesic action: for mild to moderate intensity pain (not severe pain). Mechanism: – Peripheral effect: decrease PGs synthesis in the peripheral inflamed tissues. – Central effect: decrease PGs synthesis in the subcortical sites (thalamus and hypothalamus). 122 Antipyretic effect: Aspirin is antipyretic but NOT hypothermic agent i.e. it can lower elevated body temperature but not normal body temperature. Mechanism: – Decrease PGE2 synthesis in the hypothalamus. – Decrease the hypothalamic response to interleukin-1 (endogenous pyrogen). – Cutaneous VD and increase sweating. Anti-inflammatory, anti-immunological and anti-rheumatic effects: Mechanism: By inhibition of COX enzyme, it ↓ synthesis of PGs and TXs, and possibly other inflammatory mediators leading to: – Decrease inflammatory cell activation and chemotaxis. – Decrease capillary permeability. – Decrease hyaluronidase enzyme and inhibits spread of inflammation. – Stabilize lysosomal membranes of inflammatory cells. Respiratory effects: – Low toxic doses: produce metabolic acidosis → compensatory hyperventilation to wash excess CO2 → prolonged respiratory alkalosis. – High toxic doses: produce metabolic acidosis together with inhibition of RC → death from severe acidosis. CVS effects: – Therapeutic doses: no significant effect on the CVS. – Toxic doses: inhibit VMC leading to circulatory failure. GIT effects: salicylates can produce 2 types of gastric ulcer: – Acute gastric ulcer: occurs as a result of acute ingestion of large doses of salicylates. The pathogenesis is related to trapping of salicylate ions inside the gastric mucosal cells leading to acute, painful gastric bleeding. – Chronic gastric ulcer: occurs as a result of chronic ingestion of salicylates. The pathogenesis is related to chronic inhibition of the protective PGE1, PGE2 and PGI2 synthesis leading to chronic ulceration and chronic blood loss. Hepatic effects: salicylates can produce 2 types of hepatic injury: – Mild hepatic injury: it is dose-dependent, reversible and asymptomatic. There may be mild increase in serum transaminases (SGOT and SGPT). 123  – Sevvere hepatic injury: “Reye’s “ syyndrome”:: it is a rare e and fatal condition occurs if a aspirin is used u to conntrol fever of some viral infectio ons (e.g. chicken c poxx, influenzaa, etc.) in children below 12 2 years old.. There is severe fa atty infiltra ation of the liver, panncreas, and kid dney asssociated with enccephalopatthy. The etiologyy is unk known. Man nagement is supporttive. Hemattologic efffects: – Antiplatelet acction: aspirrin inhibit p platelet aggregation by: – Irreverssible inhibition of COOX enzyme e → ↓ TXA2 → ↓ plateleet aggregattion. – Irreverssible acetylation of pla atelet cell membrane m s → ↓ platellet adhesio ons. – Decrea ase plateleet ADP syn nthesis → decrease platelet accuumulation. – Asp gh doses (> 6 gm /day) inhiibits hepatic prothrrombin (fa pirin in hig actor II) synthesis → prrolong blee eding time e. 124 Renal e effects: – Anaalgesic neephropathyy: it is cchronic re enal Aspirin in a dose of 75- failu ure due to chronic abuse o of analgessics, 150mg is not thought to which produc ce chronicc renal ischhemia duee to have a signnificant effe ect on deccrease syntthesis of reenal PGE2 and PGI2. plasma uraate levels - the – Saltt and wateer retentionn: due to d decrease RBF R British Socciety for Rheu- R matology recommen nd it andd increase aldosteron ne should be continued if re- – Antaagonize diuretic d efffect of d diuretics and quired for cardiovas scular antiihypertensive effects s of β-blocckers: due e to prophylaxiss. deccrease syntthesis of PGE P 2. – Uricc acid excrretion: smaall-to-mode erate doses of asppirin can ↓ uric u acid ex xcretion andd thus con ntraindicate ed in patiennts with gouut. Metabo olic effectts: – High doses cause c oupling of oxidative phosphorrylation → tachycard unco dia and hyp perpyrexia. Uterus s: – Prolongation of pregnancy and d delay of labo or due to inhibition of o PGs nec cessary for uterrine contra action during labor. T The use of NSAAIDs after 20 weeks of pregna ancy is not recoommended d. Therap peutic use es of salicy ylates  As analgesicc and anttipyretic: in mild-to-- mooderate paiin e.g. hea adache, art rthritis, etc. It should notn be used rou utinely as s antipyretic be ecause fevver may bee a norma al pro otective meechanism.  As anti-inflam mmatory and a anti-rrheumatic c: in rheumatic c fever, rheumatoid r d arthritis, osteoarthritis, etc.  As antithrom mbotic: see box. 125