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  • pyrexia of unknown (PUO)
  • Arnaud Chiolero et al., 2002
  • NSAIDs (VK)

    2. 2. Antiinflammatory drugs  Steroid- Glucocorticoids  Nonsteroidal-Aspirin like
    3. 3. INTRODUCTION  ANALGESIC  ANTIINFLAMMATORY  ANTIPYRETIC They are also called “Nonnarcotics,Nonopiodids,or Aspirin like analgesics”
    4. 4. Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) 1. Overview Definition: NSAIDs are chemically diverse class of drugs (>70 NSAIDs in use) that have anti-inflammatory, analgesic, and antipyretic properties. Among the most frequently prescribed drugs -worldwide: 70 million people/day prescribed NSAIDs 230 million people/day take OTC NSAIDs -USA: 80 billion aspirin tablets consumed/year constitute 4% of all prescriptions
    5. 5. CLASSIFICATION  A) Nonselective Cox inhibitors 1.Salicylates2.Pyrazolone derivatives- Aspirin Phenylbutazone, oxyphenbutazone 3.Indole derivatives- Indomethacin, Sulindac 4.Propionic acid derivatives- Ibuprofen, Naproxen, Ketoprofen 5.Anthranilic acid derivatives- Mephenaimic acid 6.Aryl-acetic acid derivatives- Diclofenac sodium 7.Oxicam derivatives- Piroxicam, Tenoxicam 8.Pyrrole derivatives- Ketorolac
    6. 6. B) Preferential cox-2 inhibitor Nimesulide, Meloxicam. C) selective cox- 2 inhibitorsCelecoxib, Rofecoxib,Valdecoxib D) Analgesics- Antipyretics- Paracetamol, Metamizol, Nefopam (non opiod analgesic which donot inhibit PG synthesis)
    7. 7. NSAIDs and Prostaglandins  PGs, Prostacyclins,TXA2-Arachidonic acid  Cyclooxygenase Cox-1-Constitutive (House keeper), Mucus secretion, Haemostasis, renal functions Cox-2 InducibleInflammatory response Sites-brain, JG cells (constitutive)
    8. 8. COX-2 Hypothesis (1990s) Normal Tissue Arachidonic Acid COX-1 Constitutive Inflammation Site Cytokines + Growth factors ILs,TNF COX-2 Inducible COX-2 Inhibitors NSAIDs Physiolgical Prostaglandin Production Normal Functions Pathological Prostaglandin Production Inflammation, pain, fever
    9. 9. Properties of Prostaglandins
    10. 10. Properties of Prostaglandins •Physiological Functions of Prostaglandins Pain: PGI2 and PGE2 sensitize nerve endings to bradykinin, Histamine and substance P Inflammation: PGI2, PGD2 and PGE2 are vasodilators (edema, erythema) Protection of the gastric mucosa: PGI2 Maintenance of renal blood flow: PGE2 Fever: PGE2 Platelets: PGI2 and PGD2 inhibit platelet aggregation TXA2 stimulates platelet aggregation Uterus: PGD2 contracts uterus
    11. 11. Analgesia  PGs---induce hyperalgesia by increasing sensitivity of afferent nerve endings to chemical and mechanical stimuli and thus amplify action of other algesics-bradykinins, histamine, TNF-alpha, ILs.  PGs in CNS lowers threshold of central pain circuit.  NSAIDS block this pain sensitizing mechanism therefore effective against inflammation asso. Pain
    12. 12.  The opioids are the drugs of choice for the treatment of moderate-to-severe pain, the NSAIDs are most frequently used for mild-to-moderate pain.  Prostaglandins by themselves do not cause pain but lower the threshold of the C fiber nociceptors.  As a result, lower concentrations of bradykinin and histamine are required to activate the nociceptor.
    13. 13. Antipyresis  Fever in infection is produced by pyrogens, TNF, ILs, interferon-induce production of PGs in hypothalamus-raise its temp. set point.  NASIDs block the action of pyrogens.(cox-2).  Fever also can occur through non PG mediated mech.—incomplete explanation ???
    14. 14. Anti-inflammatory  Inhibition of PG synthesis at the site of injury.  Anti-inflammatory action of each drug corresponds with their potency to inhibit COX.  NSAIDs -also inhibit expression/ activity of adhesion molecules, growth factors like GMCSF,IL-6,and lymphocyte transformation factorsaffected.  NSAIDs-Stabilises leucocytes lysosomal membrane, and antagonizes certain act.. Of kinkins
    15. 15. Dysmenorrhea  Increase levels of PGs in menstrual blood flow, endometrial biopsies, and their metabolites is seen in dysmennorhic women.—myometrial ischaemia –menstrual cramps.  NSAIDs-lowers uterine PGs--relief
    16. 16. Antiplatelet  Inhibit synthesis of TXA2 by acetylating platelet COX irreversibly.
    17. 17. Ductus arteriosus closure  PGE2, PGI2- responsible for maintaining patency in foetal circulation.
    18. 18. Parturition  Sudden increase in PG synthesis by uterus triggers labour and facilitate progression.  NSAIDs –delay and retard labour
    19. 19. Gastric mucosal damage  Inhibition of synthesis of gastro protective PGS (E2,I2)- decrease in mucus,HCO3,increases acid secretion, may promote mucosal ischemia.  Ion trapping with NSAIDs also play role.
    20. 20. Renal effects  Conditions like hypovoleumia, decrease renal perfusion, and Na+ loss- induce renal PG synthesis –leading to vasodilatation, inhibition of cl - reabsorption…  NSAIDs- 1. Cox dependent impair renal bl.flow.—decrease in gfrrenal insufficiency. 2. JG Cox 2 dependent Na and water retention. 3. Rare ability to cause papillary necrosis on habitual intake. Renal effects more marked in pts of CHF, Hypovolemia, hepatic cirrhosis renal disease, pts on diuretics and antihypertensive----edema
    21. 21. Anaphylactoid reaction  Aspirin precipitates Bronchial asthma, angioneurotic swelling…
    22. 22. Aspirin  Aspirin is acetyl salicylic acid converted in body to salicylic acid.  MOA-aspirin inhibits COX irreversibly by acetylating one of its serine residue.
    23. 23. Pharmacological actions 1.Analgesic- relives pain related to inflammation, tissue injury, connective tissue etc. MOA: -obtunding peripheral receptors -prevents PGs mediated nerve ending sensitization. -raises threshold for pain perception in central sub cortical regions. 2.Antipyretic- resets the hypothalamic thermostat. 3.Antiinflammatorysigns of inflammation like pain, tenderness, swelling, vasodilatation and leukocyte infiltration are suppressed.
    24. 24.  Metabolic effects: At anti-inflammatory doses: 1.↑ heat loss 2.↓ blood sugar  Respiration: At anti-inflammatory doses - increased respiratory rate. In salicylate poisoning- resp.depression  Acid base balance and electrolyte balance -Initially Increased Co2 production and its washout resp.alkalosis. -Later Co2 retention –resp. acidosis (high doses) -Followed by metabolic acidosis. -dehydration occurs in poisoning.  CVS: At toxic doses –depresses VMC, BP falls, CHF may precipitate  Urate excretion: Dose related effect….
    25. 25.  Blood TXA2 inhibition.  GITEpigastric distress, nausea and vomiting Ion trapping Back diffusion of H+ ions Focal necrosis of mucosal cells Acute ulcers
    26. 26. Adverse effects  Side effects Nausea, vomiting ,gi distress Gastric mucosal damage, peptic ulceration.  Hypersensitivity  Anti-inflammatory doses- Salicylism-(3-6g/day) Dizziness, tinnitus, vertigo, reversible impairment in hearing and vision, excitement ,mental confusion, hyperventilation, electrolyte imbalance. In children- Liver damage Reye’s syndrome-hepatic encephalopathy esp. in children having viral infection.  Acute salicylate poisoningMore common in childrens, fatal dose for adults 15-16g
    27. 27. Precautions and contraindications Peptic ulcer Sensitive pts Children suffering from influenza, chickenpox Chronic liver diseases Diabetics CHF, lower cardiac reserve Pregnancy Delayed labor, more postpartum bleed, premature closure of ductus arteiosus  G6PD deficiency       
    28. 28. Interactions  Aspirin displaces warrfarin, naproxen,sulfonylurese, phenytoin from its pp binding sites-toxicity of these agents.  Inhibits tubular secretion of uric acid and antagonizes action of uricosuric agents.  Blunts action of diuretics
    29. 29. Pharmacological actions  Analgesia  Antipyretic  Antiinflammatory  Dysmenorrhea  Antiplatelet  Ductus arteriosus closure  Parturition
    30. 30. 1. As Uses of aspirin analgesic-condn. Aspirin 300mg-600mg 6-8.hlly 2. As antipyretic- in various infections, PUO 3. Acute rheumatic fever4. Rheumatoid arthritis5. Osteoarthitiis6. Postmyocardial infraction & poststroke patients. Aspirin 60-100mg/day 7. Otherpregnancy induced hypertension preeclamcia to delay labour to close patent ductus arteriosus
    31. 31. Indole derivatives- Indomethacin • • • Potent anti-inflammatory, antipyretic, analgesic. Inhibit neutrophil motility. High incidences of GIT and CNS side effects. • Uses: 1. 2. 3. 4. 5. 6. 7. RA not responding to Aspirin. Ankylosing spondilytis. Acute exacerbation of destructive orthopathies. Psoriatic arthritis Malignancy asso. refractory fever. DOC- PDA- dose:0.1-0.2mg/ kg12 hourly Bartter’s syndrome.
    32. 32. Ibuprofen, Naproxen, Ketoprofen Propionic acid derivatives-  Analgesic Antipyretics Antiiflammatory  Inhibit PG synthesis (Nonselective COX in.)  Naproxen being most potent & better tolerated anti- inflammatory drug.  Longer acting twice dosing require.  They inhibit platelet aggregation & prolong bleeding time.
    33. 33. Pharmacokinetics Ibuprofen 400-800mg TDS  Naproxen 250mg BD…(Gout)  Ketoprofen 50-100mg BD  Flubiprofen- ocular anti inflammatory - Better tolerated orally and the incidences of adverse reactions are low. - Highly protein bound drugs like aspirin can displace warrfarin, sulfonylurese, phenytoin from its pp binding sites…..toxicity of these agents.
    34. 34. Adverse effects Better tolerated than aspirin  Gastric discomfort  Gastric erosion  N&V  Dizziness  Blurring of vision  Tinnitus & depression  Rashes & hypersensitivity reaction
    35. 35. uses          Simple analgesics and antipyretic (as low dose aspirin) Dysmenorrhea as inhibit PGs OTC RA, ankylosing spondilytis OA Musculoskeletal pain Soft tissue injuries Fractures Tooth extraction Postpartum & postoperatively
    36. 36. Anthranyllic acid derivatives- Mephenaimic acid  Analgesic, antipyretic, anti-inflammatory. inhibit COX antagonizes certain actions of PGs.  M.A. : exerts peripheral as well as central analgesic action.  S/E- diarrhea epigastric distress skin rash, dizziness  Uses-  Dose- analgesic, effective in dysmenorrhea 250-500mg TDS
    37. 37. Aryl acetic acid derivative- Diclofenac sodium  Similar in efficacy to Naproxen.  Anti inflammatory action- reduces neutrophil chemotaxis and superoxide production.  Dose:50mg BDUses-same as Ibuprofen.
    38. 38. Oxicam derivatives- Piroxicam, Tenoxicam  Long acting potent NSAIDs similar to Indomethacin.  Decreases production of IgM rheumatoid factor.  Reduces leucocytes proliferation and ratio of T -helper cells to T- suppressor cells.  Meloxicam new congener of Piroxicam is selective for COX II 10 times more than COX I.
    39. 39. Pyrrole derivatives  Ketorolac Novel analgesic, modest anti inflammatory drug. In post operative pain it has equaled efficacy of Morphine but do not have morphine like side effects. Uses: 1. Post operative pains 2. Acute musculoskeletal pain 3. Renal colic 4. Migraine 5. Pain due to metastasis. Dose-10-20mg 6hrly
    40. 40. preferential cox2 inhibitor Nimesulide  Used mainly short lasting painful conditions- sport injuries, sinusitis, ear nose disorders, dental surgery, bursitis, low backache, dysmenorrhea, po. pain, o.a.  S/E - fulminant hepatitis bronchospasm  Dose-100mg.
    41. 41. Cox-1 vs. Cox-2 The reality. Arachidonic acid COX-1 “Constitutive” Prostaglandins • GI cytoprotection • Platelet activity • Renal function COX-2 “Inducible” Prostaglandins Pathological • Inflammation • Pain • Fever Physiological • Renal function • Vascular • Tissue repair
    42. 42. Thromboxane A2 vs. Prostacyclin ARACHIDONIC ACID COX -1 Platelet TXA2 Vasoconstriction Platelet Aggregation COX -2 Endothelial PGI2 (Prostacyclin) Vasodilation Anti-Platelet Aggregation
    43. 43. Why do Cox-2 inhibitors increase risk for heart disease? #1. Because they adversely effect the ratio of thromboxane to prostacyclin Aspirin COX-1 COX-2 inhibitors Prostacyclin Thromboxane Thromboxane Decreased CV events COX-2 Prostacyclin Increased CV events
    44. 44. Selective COX2 inhibitors  Celecoxib 100-200mgBD  Rofecoxib 12.5-25mg OD  Valdecoxib 20mg BD  Low ulcerogenic potential -TXA2 level were not reduced -Other Side effects are low  Pedal edema & rise in B.P occurs as a result of salt and water retention due to inhibition of constitutive COX II in JG cells. This may precipitate CHF.  COX II inhibition –inhibits PGI2 –prothrombotic influence….increased cardiovascular events. QT changes in ECG  Use- for long term use as analgesic in chronic pain.
    45. 45. Paracetmol  Acetaminophen  Good & promptly acting antipyretic.  Analgesic- central action peripheral action  Negligible anti-inflammatory action.  Poor inhibitor of PG synthesis in peripheral tissues  More active on COX in brain
    46. 46.  In contrast to aspirin- does not stimulate respiration does not affect acid base balance. or cellular metabolism.  No effect on CVS. platelets.  GIT-insignificant effects P/K- metabolism by glucuronic acid conjugation. S/E- safe drug at antipyretic dose. Analgesic nephropathy (at toxic doses) Papillary necrosis Tubular atrophy Renal fibrosis Renal failure
    47. 47.  Acute paracetmol poisoning- small children - having low hepatic glucuronide conjugating ability. - if large doses >250mg/kg Manifestations• Nausea , vomiting. • Abdominal pain • Liver impairment- hepatic necrosis • Impaired consciousness • Renal tubular necrosis RxGastric lavage, activated charcoal N-acetylcysteine 150mg/kg i.v over 15 mins followed by same dose over 20 hrs.
    48. 48. Choice of NSAIDs  Mild to moderate pain with inflammationParacetmol, Low dose Ibuprofen  Acute musculosketal, OA, injury associated with inflammationDiclfenac, Rofecoxib.  Postoperative- Ketorolac.  Gastric intolerance – Cox2 inhibitors.  Pt. with allergy to aspirin & other NSAIDs - Nimesulide.
    49. 49. Non-Opioid Analgesics 1. A suggested treatment algorithm (American Journal of Medicine 105, 53S-60S, 1998) Moderate-to-severe pain Moderate pain Mild-to-moderate pain Opioids or Tramadol NSAIDs or Tramadol Acetaminophen or Ibuprofen