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  • 1. Non-steroidal Anti- inflammatory Drugs Dr Alex Dodoo Ph.D. MPSGH, MRPharmS Centre for Tropical Clinical Tropical Pharmacology & Therapeutics, UGMS Accra, GHANA alexooo@yahoo.com OR anododoo@ug.edu.gh
  • 2. Outline  NSAIDs  Indications  Mechanism(s) of Action  Non-specific Cox or Cox-2  Side-effects  Selection Non-Steroidal Anti-Inflammatory Drugs 18th July 2008
  • 3. NSAIDs  Non-steroidal anti-inflammatory drugs  Compare with opoid analgesics (usually required for moderate to severe pain; narcotic; usually addictive) e.g. morphine; codeine  Compare with paracetamol which has very little or no anti-inflammatory activity  Most are organic ACIDS Non-Steroidal Anti-Inflammatory Drugs 18th July 2008
  • 4. NSAIDs Types Salicylates (Salicylic Aspirin acid derivatives) Diflusinal Sodium Salicylate Acetic Acid derivatives Indometacin Sulindac Etodolac Diclofenac Non-Steroidal Anti-Inflammatory Drugs 18th July 2008
  • 5. NSAIDs Types Propionic Acid Ibuprofen Derivatives Naproxen Ketoprofen Flurbiprofen Enolic Acids Piroxicam Phenylbutazone Non-acidic compounds Nabumetone Non-Steroidal Anti-Inflammatory Drugs 18th July 2008
  • 6. Indications  Pain and inflammation in rheumatic diseases  Musculoskeletal disorders  Post-operative analgesia  Acute Gout  Migraine  Dysmenorrhoea  Fever and pain in children (including post-immunization pyrexia)  Pyrexia  Dental pain  Less well-defined conditions of back pain and soft-tissue disorders  Patients NOT responsive to one NSAID may well respond to another – need to tailor treatment to the individual patient. Full analgesic effect may take up to three weeks Non-Steroidal Anti-Inflammatory Drugs 18th July 2008
  • 7. Mechanism(s) of Action  Inhibition of prostaglandin synthesis  Inhibition of Cox-1  Inhibition of Cox-2  Cox-2 is induced 10-80 fold in inflammation  Inhibition of Cox-2 is the main mechanism for the anti- pyretic, analgesic and anti-inflammatory actions  Inhibition of Cox-1 leads to side effects  Most NSAIDS are non-selective but there are “selective” Cox-2 inhibitors Non-Steroidal Anti-Inflammatory Drugs 18th July 2008
  • 8. Non-selective Cox or Cox-2?  Non-selective  Ibuprofen, Diclofenac, Indometacin, naproxen, Piroxicam, ketoprofen, azapropazone  Cox-2  Newer  Provides protection against gastrointestinal side effects of NSAIDS  Celecoxib, Rofecoxib, Etoricoxib, Lumiracoxib, Rofecoxib Parecoxib, Valdecoxib Non-Steroidal Anti-Inflammatory Drugs 18th July 2008
  • 9. Nonselective Cox or Cox-2?  Action of NSAIDs due to inhibition of Cox-2  Side effects usually due to inhibition of Cox-1  Extensive experience with Non-selective Cox Inhibitors  Cox-2 expensive  Evidence for cost-effectiveness of Cox-2  (see www.npc.co.uk) Non-Steroidal Anti-Inflammatory Drugs 18th July 2008
  • 10. CSM Advice on NSAIDS (BNF 53)  All NSAIDs are associated with serious gastrointestinal toxicity  Relative risk higher in the elderly  Among 7 non-selective NSAIDs, Ibuprofen has the lowest side effect profile with Azapropazone having the highest side effect profile  Piroxicam, ketoprofen, indometacin, naproxen and diclofenac intermediate  Selective Cox-2 inhibitors have lower risk of serious upper GI side effects than non-selective NSAIDS Non-Steroidal Anti-Inflammatory Drugs 18th July 2008
  • 11. CSM Advice on NSAIDS (BNF 53)  Ibuprofen generally preferred; start at lowest recommended dose  Not to use more than ONE NSAID at a time  All NSAIDs (including Cox-2 inhibitors) contraindicated in patients with ACTIVE peptic ulceration  Non-selective NSAIDs contraindicated in patients with peptic ulceration  Combination of a NSAID with low dose aspirin may increase GI side effects  Any degree of worsening of asthma may be related to the ingestion of NSAID!!! Non-Steroidal Anti-Inflammatory Drugs 18th July 2008
  • 12. NSAIDS and Cardiovascular events: CSM Advise on selective Cox-2 inhibitors  In the light of emerging concerns abut CV safety, Cox-2 inhibitors should be used in preference to non-selective NSAIDS ONLY when specifically indicated (i.e. for patients who are at particularly high risk of developing gastro duodenal ulcer, perforation or bleeding and after an assessment of CV risk.  CHM advised (October 2006) that the lowest effective dose of NSAID or Cox-2 inhibitor should be prescribed for the shortest period of time to control symptoms and that the need for long- term treatment should be reviewed periodically Non-Steroidal Anti-Inflammatory Drugs 18th July 2008
  • 13. Examples  Ibuprofen  Lowest incidence of side effects  Lowest (?) potency  Maximum daily dose 2.4g  Useful alternative to aspirin in children under 12 (16 years!) – Reye’s syndrome  Sustained-Release preparations e.g. Brufen Retard  Various oral preparations  Combination products with paracetamol (e.g. Parafen), codeine (Nurofen Plus; Codafen Continus)  Topical preparations e.g. Ibugel, Ibuleve, Proflex  Useful in dysmenorrhoea, dentistry  Not strong enough in acute gout Non-Steroidal Anti-Inflammatory Drugs 18th July 2008
  • 14. Examples  Diclofenac  Moderate potency  Useful in acute gout  Moderate side effects (compared to ibuprofen)  Maximum daily dose (by ANY route) is 150mg!!!  Tablets, Suppositories, Gels, Injections  Sustained Release Products  Combination of strengths? E.g. Voltarol Retard 100mg + Voltarol ec 50mg; Naklofen-Duo 75 mg (dual release 25mg immediate release and 50mg m/r) Non-Steroidal Anti-Inflammatory Drugs 18th July 2008
  • 15. Examples  Aspirin  Avoid in under 12 (under 16s) because of Reye’s syndrome  Useful in juvenile arthritis  Irreversible inhibitor of platelet aggregation  Low dose aspirin for prevention of cardiovascular events and DVT?  Combination of low dose aspirin and NSAID not recommended  Dose 300-900mg every 4 to 6 hours  Present in several OTC products – watch out for accidental over dosage (e.g. Alka Seltzer, Anadin etc)  Combination products – with paracetamol, caffeine, codeine etc  No topical preparation Non-Steroidal Anti-Inflammatory Drugs 18th July 2008
  • 16. Side-Effects  Most notorious side effect  adverse gastrointestinal events including gastric or intestinal ulceration  2 mechanisms responsible for GI side effects  Local erosion of orally administered agents  (THEREFORE they are to be taken with or after meals)  Inhibition of biosynthesis of cytoprotective prostaglandins PGI2 and PGE2  Hence NSAIDs still do cause GI side effects despite the ROUTE of administration  Administration of cytoprotectants e.g. misoprostol [AVOID IN PRE- MENOPAUSAL WOMEN] for GI protection  May be given with proton pump inhibitors e.g. omeprazole, esomeprazole, rabeprazole, lansoprazole for GI protection Non-Steroidal Anti-Inflammatory Drugs 18th July 2008
  • 17. Side Effects  Others include:  Nephrotoxicity - possible interactions with ACE Inhibitors  Renal failure may be provoked by NSAIDs especially in patients with pre-existing renal impairment  Hypersensitivity reactions including rashes, urticaria, brochoconstriction  Anaphylaxis (rare)  Hepatotoxicity Non-Steroidal Anti-Inflammatory Drugs 18th July 2008
  • 18. Caution/Contraindication  Avoid ALL NSAIDs in patients with active peptic ulceration  Caution in those with peptic ulceration (risk/benefit)  Asthma – any worsening of asthma should be investigated  Pregnancy; Breastfeeding ; allergic conditions Non-Steroidal Anti-Inflammatory Drugs 18th July 2008
  • 19. Selection  Which NSAID  Combination of optimum strength with least side effects  Which Route  Oral; rectal;  Parenteral reserved for inpatient use  Topical for musculoskeletal pain etc  Wash hands thoroughly after use  Which Patient  Caution in elderly; those requiring chronic care; those with allergies  Fixed Dose Combination products?  Combination with other analgesics? Non-Steroidal Anti-Inflammatory Drugs 18th July 2008
  • 20. Selection  Chronic or acute pain?  Gastroprotection?  Cox-2 inhibitors  Benefits only few patients hence should be given ONLY when benefits are clear  Avoid concomitant use of aspirin as benefit of Cox-2 inhibition is lost  Side effects? (low GI side effects but other side effects notably serious cardiotoxicity exist!): Rofecoxib and Valdecoxib withdrawn due to association with excess cardiac-related mortality following long-term use  Use in patients with cancer  Use post-operatively Non-Steroidal Anti-Inflammatory Drugs 18th July 2008
  • 21. Other Drugs for Inflammation  Gout  NSAIDs for acute gout  Aspirin usually contraindicated as it inhibits excretion of uric acid, even at low doses  Allopurinol  Colchicine Non-Steroidal Anti-Inflammatory Drugs 18th July 2008
  • 22. Other drugs for pain and inflammation  Disease Modifying Anti-rheumatic Drugs (DMARDs)  antimalarials (chloroquine; hydroxychloroquine)  Penicillamine  Sulfasalazine  Immunosuppresants e.g. azathioprine, cyclophosphamide, methotrexate  Gold compounds Non-Steroidal Anti-Inflammatory Drugs 18th July 2008
  • 23. Other drugs for pain and inflammation  Tricyclic antidepressants, e.g. amitriptyline especially for neuropathic pain  Benzodiazepines  Baclofen (a skeletal muscle relaxant)  Anticonvulsants, typically Carbamazepine in trigeminal neuralgia; phenytoin and gabapentin have also been tried. Pregabalin is licensed for trigeminal neuralgia  Transcutaneous electrical nerve stimulation (TENS) Non-Steroidal Anti-Inflammatory Drugs 18th July 2008
  • 24. Rubefacients and topical antirheumatics  Rubefacients act by counter-irritation.  Topical NSAIDs provide slight relief of pain in muscoloskeletal conditions  Examples include:  Ibuprofen  Piroxicam  Ketoprofen  Felbinac  Diclofenac Non-Steroidal Anti-Inflammatory Drugs 18th July 2008