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NSAIDs Pathophysiology
Nonsteroidal anti-inflammatory drugs (NSAIDs) work by inhibiting cyclooxygenase (COX) enzymes and subsequent prostaglandin production. This reduces pain, fever, and inflammation. NSAIDs inhibit both COX-1 and COX-2, with COX-1 inhibition causing side effects like gastric ulceration, while selective COX-2 inhibitors have fewer side effects but higher costs. The mechanisms of analgesia, antipyresis, and anti-inflammation by NSAIDs are through inhibition of prostaglandin biosynthesis in both the central and peripheral nervous systems.
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NSAIDs Pathophysiology
- 2. Non Steroidal Anti-InflammatoryDrugs -All drugs grouped in this class have analgesic, antipyretic and anti-inflammatory actions in different measures. Do not depress CNS Do not produce physical dependence Have no Abuse Liability Weaker Analgesia (except- Inflammatory pain, they are more useful)
- 3. 1. Willow Barkâ Salix Alba â Salicylic Acid was obtained 2. 1875 â Sodium Salicylate â Fever and Pain 3. 1899 â Aspirin â Acetylsalicylic Acid 4. 1899 â Phenacetin & Antipyrine 5. 1949 â Phenylbutazone (Almost comparable to corticosteroids) 6. 1963 â Indomethacin 7. Propionic acid derivative â Ibuprofen â Recognition of COX inhibition 8. Addition of Selective COX-2 inhibitors
- 5. Membrane phospholipids Arachidonic acid LeukotrienesProstaglandins Thromboxane Prostacyclin Prostanoids COX Phospholipase Non Steroidal Anti-Inflammatory Drugs (NSAIDs) mainly produce their effects by inhibiting the biosynthesis of Prostanoids.
- 6. In 1971, Vaneand co-workers made the observation that aspirin and some NSAIDs blocked Prostaglandins generation. This is the major mechanism of action of NSAIDs.
- 7. COX-1 âą Physiologically expressed âąMaintains the normal (house keeping) function. âą Expressed in .. â Platelets â GIT COX-2 âą Induced in pathological states (mostly) âą Physiologically expressed in Kidney, Brain & Foetus. Most of the NSAIDs inhibit COX-1 and COX-2 non-selectively, But now some selective COX-2 inhibitors have been produced. Cyclo-oxygenase enzyme that plays major role in synthesis of PROSTANOIDS.
- 8. Action COX-1/COX-2 Inhibitors COX-2 Inhibitors Analgesic ++ Antipyretic + + Antiinflammatory + + Antiplatelet aggregatory + - Gastric Mucosal Damage + - Renal salt/water retention + + Delay/Prolongation of labour + + Ductus Arteriosus Closure + ?? Aspirin Sensitive Asthma Precipitation + -
- 9. ⹠How pain/hyperalgesiais produced??? PGs, by affecting transducing property of free nerve endings induce hyperalgesia. So that, stimuli that was not eliciting pain first, can elicit now. ⹠How analgesia is produced??? NSAIDs inhibit synthesis of PGs (also in spinal dorsal horn neurones as well as in brain) Also blocks pain sensitizing mechanisms by -TNFα -Bradykinin -Interleukins
- 12. âą How Feveris Produced? However, Fever can also be produced by NON-PG mechanisms.
- 13. âą How antipyresisis Produced? In Normal Individuals, There is no Hypothermia.
- 14. âą How Inflammationtakes place? Increased Capillary Permeability Activation Of Kininogens Infiltration of leucocytes Vasoconstriction in Capillaries Vasodilation in some vascular beds Leukotrienes PAF Cytokines
- 15. Increased Capillary Permeability ActivationOf Kininogens Infiltration of leucocytes Vasoconstriction in Capillaries Vasodilation in some vascular beds Leukotrienes PAF Cytokines âą Majorly NSAIDs exhibit anti-inflammatory action by inhibition of COX-2 enzyme but in initial stages of inflammation there is also inhibition of COX-1 enzyme. Inhibits synthesis
- 16. ANTI-INFLAMMATORY POTENCY αCOX INHIBITORY PROPERTY âą Certain NSAIDs may act by additional mechanisms like⊠1) Inhibition of chemotaxis - by inhibiting expression of adhesion molecules on activated endothelial cells. - by inhibiting expression of selectins and integrins on inflammatory cells. 2) Generation of superoxide/free radicals. 3) Growth Factors, Lymphocyte transformation factors and TNFα may also be affected. e.g. Nimesulide is potent Anti-inflammatory but weak COX Inhibitor. This is due to additional actions âą MajorlyâŠ
- 17. PGs(PGF2α)cause dysmenorrhoea.Dysmenorrhoea âą NSAIDslower levels of Uterine PGs and can relieve in 60- 70%. PGs can trigger labour and also facilitate progression.Parturition âą NSAIDs have potential to retard or delay labour. PGE2 can keep ductus arteriosus patent. Ductus arteriosus closure âą NSAIDs can cause closure of ductus arteriosus if it fails naturally⊠⹠(NSAIDs in pregnancy can cause premature closure though⊠⹠So NSAIDs prescription near term should be avoidedâŠ)
- 18. PGI2 Predominantly - Inhibition ofplatelet aggregation - Bleeding time is prolonged TXA2 *Risk of Post-Partum Haemorrhage is increased in pregnancy* *Risk of surgical bleeding and anti-coagulant associated bleeding is increased*
- 19. ⹠Gastric MucosalDamage:- This is due to inhibition of COX-1 mediated synthesis of gastroprotective PGs (PGE2 & PGI2). Gastric Pain, Mucosal Erosion & NSAIDs induced Gastric Ulcers are common considerations. Relative gastric damage is the parameter for choice of NSAIDs. ⹠Anaphylactoid Reactions:- Can occur to sensitive persons. e.g. Precipitation of Asthma, Angioneurotic swellings, Urticaria⊠Inhibition of COX leads to consequent diversion of Arachidonic acid to Leukotrienes which may be the reason for this, however there is no proof.
- 20. âą Role ofRenal PGsâŠ. Hypovolaemia Decreased Renal Perfusion Sodium Loss Induces PG Synthesis ADH action oppose Vasodilatation Chloride Reabsorption Inhibition âą Role of NSAIDsâŠ. COX-1 dependant impairment of blood flow and GFR reduction Inhibition of Juxtaglomerular COX-2 dependant Sodium and water reabsorption Can cause papillary necrosis Can cause analgesic nephropathy âą Contra-Indicated in⊠CHF Hypovolaemia Hepatic Cirrhosis In Patients receiving diuretics and antihypertensives, Sodium Retention and oedema can occur; diuretic and antihypertensive effects are blunted.