Non Steroidal Anti-Inflammatory Drugs (NSAIDs)

Non Steroidal Anti-Inflammatory Drugs (NSAIDs)

Prepared by

Prof.Abdulkader El Daibani


Non steroidal anti-inflammatory drugs (NSAIDs)

Aspirin like drugs and used in treatment of:1) inflammation (anti-inflammatory).2) Fever (antipyretic).3) Pain (analgesic). In addition aspirin (used as antithrombotic

by inhibiting platelets aggregation. Paracetamol is a weak anti-inflammatory agent.


Classification Heterogeneous compounds and can be classified into three

groups:A) Non selective COX-inhibitiors (inhibit COX-1 and COX-2):1) salicylates aspirin (acetyl salicylic acid –ASA), sodium salicylate,

diflunisal.2) Indomethacin,sulindac.3) Diclofenac, tolmetin.4) Ibuprofen, naproxen, ketoprofen.5) Mefenamic acid.6) Piroxicam, tenoxicam.7) Nabumetone.


B) Selective COX-2 inhibitors e.g. celecoxib.C) Selective COX-3 inhibitorsIt has been suggested that paracetamol act by inhibiting

COX-3.

Pharmacokinetics1) all NSAIDs are weak acids except Nabumetone

(prodrug) and metabolized to acidic active metabolite -most are well absorbed from GIT.

2) Most are metabolized by phase I and phase II.3) most are highly bound to plasma albumin (98%).4) Some accumulate in synovial fluid e.g. diclofenac and

this prolong duration of action.


Mode of action:1) Inhibition of COX-1 and Cox-2 (major mechanism).2) Chemotaxis effect.3) ↓ synthesis of interlukin-1.4) ↓ production of free radicals.5) Interfere with intracellular Ca++.Side effect:1) GIT bleeding and ulceration.2) Inhibit platelet aggregation.3)↓ uterine motility.4)Nephrotoxicity.


Aspirin (acetyl salicylic acid ASA) Rarely used now as anti-inflammatory but still used as

analgesic, antipyretic and widely used as antithrombotic in small dose (75-100 mg) once daily.

Pharmacokinetics:1) Rapidly absorbed from stomach and S.I with Cmax

after 1.5 hr.2) Hydrolyzed by tissue and plasma esterases to acetic

acid and salicylate. Salicylate is metabolized by phase I oxidation and

phase II conjugation in liver to form inactive metabolites.


Mode of action: Irreversible and non specific inhibition of COX1 and COX-2

by acetylation of isoenzymes (COX-1 and COX-2).A) Anti-inflammatory effect1) Due to inhibition of COX 2, this is the major mechanism.2) Inhibition of polymorphonuclear neutrophils (PMN).B) Analgesic effect1) effective in mild and moderate somatic pain but not very

effective in visceral pain due to inflammation in periphery.2) Central effect by inhibiting pain stimuli due to ↓ PGE1 and

PGE2

C) antipyretic may be due to inhibition of COX-1 and COX2 in C.N.S.

through inhibition of interleukin-1 leading to ↓ PGE in hypothalamus.


Side effect Some are due to inhibition of COX1.1)GIT Epigastric pain , nausea, gastric erosion leading to

bleeding due to direct effect and inhibition of PGE1 and PGE2 .

2) ↑ bleeding time due to inhibition of TXA2 in platelet formed by COX1.

3) Tinnitus and hearing loss in high dose .4) Uricosuric effect (1-2 g/day) ↓ uric acid tubular secretion in the kidney →↑ plasma

uric acid → gout,so aspirin may aggrevate gout.


5) Kidney↓ PGI2 and PGE2 → decreas blood flow → nephropathy

especially in patients with cardiovascular diseases. 6) Metabolic effectInhibits oxidative phosphorylation in high dose leading to

↓ ATP.7) Drug interactionsHighly bound to plasma protein and may displaces other

drugs bound to plasma albumin e.g. Warfarin.8) Reye's syndrome Rare but sever complication due to encephalopathic

disorder and hepatic fatty degradation after viral infection especially influenza or chicken pox. The syndrome may be due to mitochondrial damage.


Aspirin Toxicity (10-30g)Characterized by:1) hyperventilation leading to respiratory alkalosis.2) metabolic acidosis.3) Hyperthermia.4) Dehydration. If untreated coma and respiratory depression leads to

death.Treatment:1) gastric lavage.2) I/V infusion of NaHCO3 to correct pH and ↑ excretion.

Non Steroidal Anti-Inflammatory Drugs (NSAIDs)

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