NSAIDS (Nonsteroidal Anti-Inflammatory Drugs) PDF

NONSTEROIDAL ANTI- INFLAMMATORY DRUGS (NSAIDS) 1 Oumer Fuad  NONSTEROIDAL ANTI- INFLAMMATORY DRUGS  The term "nonsteroidal" is used to(NSAIDS) distinguish these drugs from steroids, whic...

NONSTEROIDAL ANTI- INFLAMMATORY DRUGS (NSAIDS) 1 Oumer Fuad  NONSTEROIDAL ANTI- INFLAMMATORY DRUGS  The term "nonsteroidal" is used to(NSAIDS) distinguish these drugs from steroids, which have a similar eicosanoid-depressing, anti- inflammatory action.  NSAIDs are non-narcotic, non-opioid, aspirin- like analgesics.  Most currently available NSAIDs act by inhibiting the prostaglandin (PG) synthase enzymes.  Most NSAIDs are competitive, reversible, active site inhibitors of the COX enzymes. Aspirin inhibits them  CLASSIFICATION Nonselective COX inhibitors (traditional NSAIDs) Salicylate Propionic Fenamat Enolic Acetic Pyrazolon s acid e acid acid e derivative derivative derivative derivative s s s s Aspirin Ibuprofen, Mephena Piroxicam Ketorolac, Phenylbut Naproxen, - , Indometha - azone, Ketoprofen mic acid. Tenoxica - cin, Oxyphenb , m Nabumeto - utazone Flurbiprof- - ne en Preferentia Selectiv Analgesic-antipyretics with l COX-2 e COX-2 poor Antiinflammatory inhibitors inhibito action Nimesulide rs Celecoxib 1.Paraaminophenol derivative: , , Paracetamol(Acetaminophen). Diclofenac, Etoricoxib 2.Pyrazolone derivatives: 3 Aceclofena , Metamizol (Dipyrone), c, Parecoxib Propiphenazone. Meloxicam,. 3. Benzoxazocine derivative:  MECHANISM OF ACTIONInhibition Cyclooxygenase (MOA) Aspirin and NSAIDs inhibit the COX enzymes and PG production. There are two forms of COX, COX-1 and COX-2.  COX-1, expressed constitutively in most cells, is the dominant source of prostanoids for housekeeping functions.  COX-2 is the more important source of prostanoid formation in inflammation. 5  COX1 COX2 *Expressed in all tissues *Selectively expressed in renal, brain *constitutive & endothelium, fetus *COX-1 products (PGE2, PGI2) COX-2 products (PG) are are involved in normal induced by various mediators cellular processes in of inflammation, interleukin, stomach, platelets and superoxide radicals, kidney cytokines and endotoxins mainly in inflammed areas and cause more pain and inflammation Constitutive in brain and kidney Inducible in macula densa in response to salt restriction *Does not affect platelet  MOA CONTD… Irreversible Cyclooxygenase Inhibition by Aspirin  Aspirin covalently modifies COX-1 and COX-2, irreversibly inhibiting COX activity.  The duration of aspirin’s effects is related to the turnover rate of COXs in different target tissues.  The importance of enzyme turnover in recovery  Platelets being anucleate have a markedly from aspirin limited capacity for protein synthesis. action is most notable in platelets. Inhibition of platelet COX-1–dependent TxA2 7 formation is cumulative with repeated doses of aspirin.  MOA CONTD… Selective Inhibition of Cyclooxygenase-2  Constitutively expressed COX-1 is the predominant source of cytoprotective PGs formed by the GI epithelium.  COX-2 is source of PG formation in inflammation and cancer.  Selective inhibitors of COX-2 were developed based on the hypothesis 8 they would afford efficacy similar to tNSAIDs with better GI  Features of nonselective COX inhibitors and selective COX-2 inhibitors Action Nonselective COX Selective/COX-2 inhibitors inhibitors 1. Analgesic + + 2. Antipyretic + + 3. Antiinflammatory + + 4. Antiplatelet aggregatory – + 5. Gastric mucosal damage – + 6. Renal salt/water retention + + 7. Delay/prolongation of labour + + 9 8. Ductus arteriosus closure ? +  MOA CONTD… An anti-inflammatory action: the decrease in prostaglandin E2 and prostacyclin reduces vasodilatation and, indirectly, oedema. An analgesic action: decreased prostaglandin generation means less sensitisation of nociceptive nerve endings to inflammatory mediators such as bradykinin and 5-hydroxytryptamine. An antipyretic action: endogenous pyrogens elevate the hypothalamic set point for temperature causing fever. 10  THERAPEUTIC USES Three main therapeutic effects of all NSAIDs, including selective COX-2 inhibitors are:  anti-inflammatory effect: modification of the inflammatory reaction Acetaminophen, which is antipyretic and analgesic is largely devoid of anti-inflammatory activity.  analgesic effect: reduction of certain types of (especially inflammatory) pain  antipyretic effect: lowering of body temperature when this is raised in disease 1 1 (i.e. fever).  THERAPEUTIC USES  Fetal Circulatory System: Indomethacin and ibuprofen have been used in neonates to close the inappropriately patent ductus arteriosus.  Cardioprotection: Aspirin reduces the risk of serious vascular events in high risk patients. Irreversible acetylation of platelet COX → inhibition of platelet function until sufficient numbers of newplatelets are released. Permanent and complete suppression of platelet COX-1– dependent TxA2 formation →  INDICATIONS  Pyrexia FOR NSAIDS  Mild to moderate pain  Rheumatoid arthritis  Osteoarthritis  Inflammatory arthropathies (ankylosing spondylitis, psoriatic arthritis, Reiter’s syndrome)  Acute gout  Dysmenorrhoea  Metastatic bone pain  Headache & Migraine  Postoperative pain 13  Injury  PDA (Patent Ductus Arteriosus)  OTHER CLINICAL USES  Systemic Mastocytosis: ⚫ In patients with systemic mastocytosis, PGD2, released from mast cells in large amounts is the major mediator of severe episodes of flushing, vasodilation, and hypotension. ⚫ This PGD2 effect is resistant to antihistamines. ⚫ The addition of aspirin or ketoprofen provides relief.  Niacin Intolerability: Aspin inhibits PGD2 mediated flushing by niacin.  Bartter Syndrome: ⚫ Caused by mutations in a Na+-K+-2Cl− co- 14 transporter. ⚫ Treatment with indomethacin, combined with  ADVERSE EFFECTS OF NSAIDS Gastrointestinal:  Abdominal pain  Nausea  Diarrhea  Anorexia  Gastric erosions/ulcers  Anemia  GI hemorrhage Platelets:  Inhibited platelet activation  Propensity for bruising 15  Increased risk of hemorrhage  ADVERSE EFFECTS Renal: OF NSAIDS  Salt and water retention  Edema, worsening of renal function in renal/cardiac and cirrhotic patients  Decreased effectiveness of antihypertensive medications  Decreased effectiveness of diuretic medications  Decreased urate excretion (especially with aspirin)  Myocardial  Hyperkalemia * With the infarction* exception Cardiovascular:  Stroke* of low-dose 16  Closure of ductus arteriosus aspirin  Thrombosis*  ADVERSE EFFECTS CNS: OF NSAIDS Headache  Vertigo  Dizziness  Confusion  Hyperventilation (salicylates) Uterus:  Prolongation of gestation  Inhibition of labuor 17  ADVERSE EFFECTS OF NSAIDS Hypersensitivity:  Vasomotor rhinitis  Angioneurotic edema  Asthma  Urticaria  Flushing  Hypotension  Shock 18  ASPRIN & SOME OTHER IMPORTANT 19 NSAIDS  ASPIRIN Actions- ⚫ reduces inflammation ⚫ antiinflammatory action is exerted at high doses (3–6 g/day or 100 mg/kg/ day). ⚫ analgesic(0.3–1.5 g/day) for inflammatory pain ⚫ antipyretic (i.e. reduces raised temperature) ⚫ At low doses (40-325mg) it acts as antiplatelet drug MOA- Irreversibly inactivating both cyclo- oxygenase (COX-1 Abs/Distrb/Elim- Given orally. Half-life only 30min and COX-2). – rapid hydrolysis to salicylate but effects 20 last longer because the COX has been inactivated and new enzyme must be produced.  USES 1. As analgesic 2. As antipyretic 3. Acute rheumatic fever 4. Rheumatoid arthritis 5. Osteoarthritis 21  USES 6.By inhibiting platelet aggregation aspirin lowers the incidence of reinfarction in Postmyocardial infarction and poststroke patients.  Aspirin 6–1000 mg/day reduces the incidence of myocardial infarction (MI)  ‘New onset’ or ‘sudden worsening’ angina is associated with high infarction rate & can be reduced to half by 100–150 mg aspirin per day for 12 weeks.  Aspirin reduces ‘transient ischaemic attacks’ 22 and lowers incidence of stroke in such patients  ADVERSE EFFECTS Gastrointestinal disturbances, especially gastric bleeding.  In high dosage can cause ‘salicylism’ (tinnitus, vertigo, reduced hearing); allergic reactions occasionally; renal toxicity rarely.  Can cause the potentially fatal Reye’s syndrome (encephalopathy & liver disorder) in children after a viral infection.  Prolongs bleeding 23  At therapeutic dose it can cause time. hyperuricemia.  PRECAUTIONS AND CONTRAINDICATIONS  Aspirin is C/I in patients who are sensitive to it and in peptic ulcer, bleeding tendencies, in children suffering from chicken pox or influenza.  Liver disease: can cause hepatic necrosis.  It should be avoided in diabetics, in those with low cardiac reserve or frank CHF and in juvenile rheumatoid arthritis. Aspirin should be stopped 1 week before elective surgery. 24  G-6PD deficiency  ASPIRIN TOXICITY - TREATMENT  Decrease absorption - activated charcoal, emetics, gastric lavage  Enhance excretion - alkalinize urine, forced diuresis, hemodialysis  Supportive measures - fluids, decrease temperature, bicarbonate, electrolytes, glucose, etc… 25  PARACETA Actions: MOL Paracetamol has potent analgesic and antipyretic actions but rather weaker anti inflammatory effects than other NSAIDs. MOA: Inhibition of COX-1, COX-2 and also the recently identified COX-3 which occurs predominantly in the CNS. Absorption/Metabolism: It is given orally and metabolised in the liver (half-life 26 2-4 hours)..  DICLOFE NAC  Diclofenac reduces inflammation , acts as an analgesic, reducing pain in conditions such as arthritis or acute injury.  The action of one single dose is much longer (6 to 8 hours) than the very short half-life that the drug indicates.  This could be partly because it persists for over 11 hours in synovial fluids. 28  Diclofenac is used for: musculoskeletal complaints: arthritis rheumatoid arthritis polymyositis, osteoarthritis, dental pain ankylosing spondylitis gout attacks  Pain management in kidney stones and gallstones.  Is effective against: menstrual pain and Additional indication is: acute migraines. endometriosis.  Usedcommonly to treat : mild to moderate post-operative or post- traumatic pain, particularly when inflammation 29 is also present. Propionic acid derivatives Naproxen, fenoprofen, ketoprofen, flurbiprofen and oxaprozin. Mechanism of action: These drugs are reversible inhibitors of the cyclooxygenases, and thus, inhibit the synthesis of prostaglandins. Uses: All these drugs possess anti-inflammatory, analgesic, and antipyretic activity. Used in the chronic treatment of rheumatoid 29 arthritis and osteoarthritis, because their gastrointestinal effects are generally less intense than that of aspirin.  IBUPRO FEN It is used for relief of symptoms of Arthritis Primary dysmenorrhea, Fever As an analgesic, especially where there is an inflammatory component. 30  MEFENAMIC  Used to treatACID pain, including menstrual pain.  Decreases inflammation (swelling) and uterine contractions by inhibiting prostaglandin synthesis.  Contraindication with liver condition. patients suffering from renal conditions 31  INDOMETHACI N  Indomethacin, is a potent nonselective COX inhibitor  Probenecid prolongs indomethacin's half-life by inhibiting both renal and biliary clearance. Clinical Uses:  Gout and ankylosing spondylitis. In addition, it has been used to treat patent ductus arteriosus. 32 Clinical Uses:  An ophthalmic preparation for conjunctival inflammation to reduce pain after traumatic corneal abrasion.  Gingival inflammation is reduced after administration of indomethacin oral rinse.  Epidural injections produce a degree of pain relief similar to that achieved with methylprednisolone in post laminectomy syndrome. 33  KETOR OLAC  Ketorolac is an NSAID promoted for systemic use mainly as an analgesic, not as an antiinflammatory drug (though it has typical NSAID properties). 37  PIROXI CAM  Piroxicam, an oxicam is a nonselective COX inhibitor but at high concentrations also inhibits polymorphonuclear leukocyte migration, decreases IgM rheumatoid factor and inhibits lymphocyte function.  Suitable for use as long-term antiinflammatorydrug in rheumatoid and osteo-arthritis, ankylosing spondylitis.  Toxicity includes gastrointestinal symptoms (20% of patients),  When piroxicam is used in dosages higher than dizziness, 20 mg/d, an tinnitus,increased headache, and rash. incidence of peptic ulcer and bleeding is encountered. 39  COX-2 SELECTIVE INHIBITORS  These drugs have advantage of very little GI toxicity.  Renal toxicity is similar to traditional NSAIDs and chances of thrombosis (acute MI and stroke) are increased on prolonged use.  Celecoxib, rofecoxib and valdecoxib are sulphonamide derivatives (can cause hypersensitivity reactions)  Etoricoxib is longest acting and requires hepatic function 41  Lumiracoxib is a newer cox 2 inhibitor monitoring during its use.  COX-2 SELECTIVE INHIBITORS  COX-2 inhibitors have been recommended mainly for treatment of osteoarthritis and rheumatoid arthritis.  Other indications include primary familial adenomatous polyposis, dysmenorrhea, acute gouty arthritis & acute musculoskeletal pain.  Currently, 3 selective COX-2 inhibitors (also called coxibs) Celecoxib, Etoricoxib and Parecoxib are available in India. 37  Rofecoxib and valdecoxib were withdrawn THANK YOU 38