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Non-Steroidal Anti-inflammatory Drugs ( NSAIDs) PART I PROF SATYA 2019

This is an interesting and novel PPT on the Pharmacology of NSAIDs, mainly that of ASPIRIN illustrated with beautiful pictures and flowcharts....!!

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Non-Steroidal Anti-inflammatory Drugs ( NSAIDs) PART I PROF SATYA 2019

  1. 1. Dr.V.Sathyanarayanan M.B.B.S., M.D., ACME Professor of pharmacology
  2. 2. NSAIDs Non Steroidal Anti-inflammatory Drugs Non narcotic, Non opioid Aspirin like Act primarily on peripheral pain mechanisms More commonly employed Many are over-the-counter drugs
  3. 3. NSAIDs IN CONTRAST TO MORPHINE: Do not depress CNS Do not produce physical dependence No abuse liability Particularly effective in inflammatory pain
  4. 4. HISTORY Willow bark – used for many centuries 1899 – Aspirin was introduced 1949 – phenylbutazone 1963 - indomethacin
  5. 5. CHEMICAL NATURE Diverse but  all are weak organic acids or their active metabolites are organic acids
  6. 6. NONSTEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs) Common therapeutic indications Common adverse effects Different pharmacokinetics and potency Different chemical families Common mechanism of action (cyclooxygenase inhibition) Different selectivities to COX I and II Similarities more striking than Differences..!!
  7. 7. COMMON PHARMACOLOGICAL ACTIONS Analgesic (CNS and peripheral effect) may involve non-PG related effects Antipyretic (CNS effect) Anti-inflammatory (except acetaminophen) due mainly to PG inhibition. Some shown to inhibit activation, aggregation, adhesion of neutrophils & release of lysosomal enzymes Some are Uricosuric
  8. 8. COMMON ADVERSE EFFECTS Platelet Dysfunction Gastritis and peptic ulceration with bleeding (inhibition of PG + other effects) Acute Renal Failure in susceptible Sodium+ water retention and edema Analgesic nephropathy Prolongation of gestation and inhibition of labor. Hypersensitivity (not immunologic but due to PG inhibition)
  9. 9. CLASSIFICATION
  10. 10. COX-2 inhibitors • Selective (coxibs) • Preferential COX-3 inhibitors •Antipyretic analgesics Nonselective COX-1/COX-2 inhibitors NSAIDsNSAIDs COX inhibitors
  11. 11. Nonselective COX-1/COX-2 inhibitors (Classical NSAIDs) •Salicylates •Phenylacetates •Indolacetates •Enolates •Fenamates •Propionates •Butylpyrazolidindiones •Pyrazolones De rivatives of acid
  12. 12. MECHANISM OF ACTION Inhibit cycloxygenase (COX ) enzyme – prostaglandin synthesis is inhibited COX1, COX2 COX1 – housekeeping COX2 – mediate inflammation
  13. 13. CYCLOOXYGENASES • COX-1 – constitutive – prostanoids involved in physiological processes (gastroprotective effects, platelet activities) • COX-2 – inducible– activity enhanced by proinflammatory factors(IL-1, IL-2, TNF-α, oncogenes,..) – prostanoids ⇒ inflammation, fever, pain • COX-3 – central mechanism of analgesic and antipyretic effect (localization: heart + CNS)
  14. 14. PROTOTYPE - ASPIRIN Acetylsalicylic acid Rapidly converted to salicylic acid  produces most of the actions Oldest analgesic-antiinflammatory drug
  15. 15. ASPIRIN - PHARMACOLOGICAL ACTIONS
  16. 16. ANALGESIA ANALGESIC IN THE DOSE OF 300 – 900 mg Weaker than morphine Effective in pain associated with inflammation, mild to moderate musculoskeletal pain Ineffective in severe visceral pain and ischaemic pain Emotional component not affected No sedation, subjective effects No tolerance, dependence
  17. 17. ANTIPYRESIS Reduce body temperature in fever by resetting the thermostat of hypothalamus Rapidly reduces fever by promoting heat loss ( sweating, cutaneous vasodilatation ) Does not decrease heat production Not in normal people
  18. 18. ANTI INFLAMMATORY Seen in high doses – 3-6 g/day Because of COX-2 mediated PG inhibition Does not affect other mediators –(LTs, PAF, Cytokines) Suppress signs of inflammation Does not affect progression of the underlying disease
  19. 19. ANTI PLATELET EFFECT Irreversibly Inhibits TxA2 synthesis by platelets Inhibit platelet aggregation  prevent thrombus formation Prolongs bleeding time – twice the normal value Lasts about a week Increased risk of surgical bleeding and anticoagulant associated bleeding Long-term intake of large dose  decreases synthesis of clotting factors predisposes to bleeding
  20. 20. Arachidonic acid Cyclooxygenase (COX) Endoperoxides PGs TxA2 (−) Aspirin Thromboxane A2 synthase (−) 100 mg/24 h >1 g/24 h
  21. 21. GATROINTESTINAL EFFECTS Inhibit gastro protective PGs Irritate gastric mucosa  epigastric pain, nausea , vomiting Ion trapping worsens gastric toxicity Aspirin particle coming in contact with gastric mucosa  promotes local back diffusion of acid  focal necrosis of mucosal cells and capillaries Cause erosive Gastritis, acute ulcers, occult blood loss Soluble aspirin  less gastric irritation At high doses  stimulates CTZ Vomiting
  22. 22. Mechanisms by which NSAIDs may induce mucosal injury Lüllmann, Color Atlas of Pharmacology – 2nd Ed. (2000) Lüllmann, Color Atlas of Pharmacology – 2nd Ed. (2000)
  23. 23. RENAL EFFECTS Decrease blood flow  sodium , water retention  edema Cause papillary necrosis  renal failure in high risk individuals Worsen renal insufficiency Significant in those with CHF, hypovolaemia, hepatic cirrhosis, renal disease
  24. 24. METABOLIC EFFECTS Seen in high doses Increase cellular metabolism  increase glucose utilization  hypoglycemia Negative nitrogen balance Decrease plasma fatty acids Stimulate respiration  respiratory alkalosis Still higher doses  respiratory acidosis Uncompensated Metabolic acidosis Na+, K+, HCO3 loss Dehydration
  25. 25. CVS No direct effect Doses that Enhance metabolic rate indirectly increases cardiac output Toxic doses depress vasomotor centre  fall in BP  CHF may be precipitated in cardiac reserve is low
  26. 26. OTHER ACTIONS Delay labor Closure of ductus arteriosus < 2g/day – urate retention , antagonize uricosurics > 5g/day – urate excretion
  27. 27. PHARMACOKINETICS Absorbed from stomach and small intestines Poorly soluble in water, micro fining and inclusion of an alkali increase absorption Deacetylated in liver  release salicylic acid 80% protein bound Entry into brain is slow Freely crosses placenta Conjugated with glycine in liver to form salicyluric acid Eliminated by kidney , it is dose dependent
  28. 28. DOSE 300 – 900 mg – analgesia 75 - 150 mg – prevent thrombosis 3oo mg - MI
  29. 29. ADVERSE EFFECTS – SIDE EFFECTS Occurs In Analgesic Dose (0.5 g to 2 g /day) GI Effects – nausea, vomiting, epigastric pain, occult blood loss, gastric mucosal damage and peptic ulcer Hypersensitivity- ( infrequent but serious ) – rashes, urticaria, fixed drug eruption, rhinorrhoea, asthma , angioedema Rarely profuse gastric bleeding Idiosyncratic reactions
  30. 30. ADVERSE EFFECTS Antiinflammatory doses –( 3-5 g /day ) salicylism – characterized by Dizziness, tinnitus, vertigo Reversible impairment of hearing and vision  headache, confusion, hyperventilation Long term treatment  hepatic injury, Na & water retention Children  liver damage ( rise in transaminases ) Reye’s syndrome in children having viral infection – a rare form of hepatic encephalopathy
  31. 31. Lüllmann, Color Atlas of Pharmacology – 2nd Ed. (2000) Lüllmann, Color Atlas of Pharmacology – 2nd Ed. (2000)
  32. 32. PRECAUTIONS Bronchial asthma Diabetes mellitus Elective Surgery – stop 1 week before Pregnancy – low birth wt babies, delayed labor, greater postpartum blood loss, premature closure of ductus arteriosus Breast feeding mothers Low cardiac reserve – precipitates CHF
  33. 33. CONTRAINDICATIONS Sensitivity to aspirin Peptic ulcer Bleeding tendencies Children with viral infection Chronic liver disease G-6-PD deficiency
  34. 34. INTERACTIONS Displacement reactions – with warfarin, sulfonylureas, phenytoin, methotrexate  overdose symptoms Diuretics – action is blunted Antihypertensives - effect is lessened Quinolones – increased CNS toxicity (convulsions) Lithium – excretion is delayed – toxicity Analgesic doses  inhibits tubular secretion of uric acid antagonizes uricosuric action of probenacid
  35. 35. Drugs Result Diuretics Decrease diuresis Beta-blockers Decrease antihypertensive effect ACE inhibitors Decrease antihypertensive effect Anticoagulants Increase of GI bleeding Sulfonylurea Increase hypoglycemic risk Cyclosporine Increase nephrotoxicity GCS Increase of GI bleeding Alcohol Increase of GI bleeding Drug interactions with NSAIDs
  36. 36. THERAPEUTIC USES AS ANALGESIC – 0.3 – 0.6 g 6-8 hourly Headache, Backache, toothache Myalgia, joint pain, pulled muscle Neuralgias Dysmenorrhoea Analgesic effect is maximal at 1000 mg ( single dose )
  37. 37. THERAPEUTIC USES AS ANTIPYRETIC Fever of any origin  aspirin is effective Dose is same as for analgesia  Paracetamol  being safer  is preferred generally
  38. 38. THERAPEUTIC USES ACUTE RHEUMATIC FEVER  –Aspirin - first drug to be used in all cases – 4-5 g/day  marked symptomatic relief in 1-3 days When it fails or in severe cases  other drugs Gradual withdrawal
  39. 39. THERAPEUTIC USES RHEUMATOID ARTHRITIS  – 3-5 g/day  afford symptomatic relief ( reduces pain, swelling and morning stiffness) But , Progress of the disease not affected Poorly tolerated  Now newer NSAIDs are preferred
  40. 40. THERAPEUTIC USES OSTEOARTHRITIS Affords symptomatic relief But infrequently used now Paracetamol is the first choice analgesic
  41. 41. THERAPEUTIC USES POST MYOCARDIAL INFARCTION PATIENTS Routinely prescribed for post infarct patients 75 - 150 mg/ day  inhibit platelet aggregation  lowers the incidence of reinfarction and MI New onset angina, sudden worsening angina  associated with high infarction rate  reduced to half by 100- 150 mg of aspirin / day for 12 weeks
  42. 42. THERAPEUTIC USES POST STROKE PATIENTS Reduces Transient Ischaemic Attacks  lowers the incidence of stroke in patients with TIAs
  43. 43. OTHER USES Pregnancy induced hypertension – 80-100 mg/day from 12th week of gestation till child birth  reduce the risk of preeclampsia in pregnant women with diabetes, chronic kidney disease and other predisposing conditions PDA Prevention of colon cancer Familial colonic polyposis – aspirin suppress polyp formation  afford symptomatic relief
  44. 44. ACUTE SALICYLATE POISONING More common in children Fatal dose  15-30 g in adults 500 – 750 mg/l – tinnitus, loss of hearing, vomiting, restlessness, hyperventilation, hypokalemia > 750 mg/l – pulmonary edema, convulsions, dehydration, ketosis Severe poisoning – metabolic acidosis Other manifestations  hyper/hypoglycemia, petechial hemorrhages, delirium, hallucinations, hyperpyrexia Coma and death due to respiratory failure and cardiovascular collapse Do Serial measurements of plasma salicylates
  45. 45. TREATMENT SYMPTOMATIC and SUPPORTIVE External cooling I.V fluids with Na+, K+, HCO3 and glucose according to the need determined by repeated monitoring If bleeding occurs  blood transfusion and Vitamin K Activated charcoal Alkalinize urine with NaHCO3 Hemodialysis – if renal failure develops
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This is an interesting and novel PPT on the Pharmacology of NSAIDs, mainly that of ASPIRIN illustrated with beautiful pictures and flowcharts....!!

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