Nsaids

1. NSAIDs N on S teroidal A nti I nflammatory D rug s

2. INFLAMMATION Inflammation ( Latin , inflamatio , to set on fire) is the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. It is a protective attempt by the organism to remove the injurious stimuli as well as initiate the healing process for the tissue.

3. Burns Chemical irritants Frostbite Toxins Infection by pathogens Physical injury Immune reactions due to hypersensitivity Radiation Foreign bodies CAUSES

4. The classic signs and symptoms of acute inflammation English Latin Redness Rubor * Swelling Tumor /Turgor * Heat Calor * Pain Dolor * Loss of function Functio laesa **

5. Process of Inflammation Inflammation can be classified as either acute or chronic . The initial phase of cell injury is known as the acute phase and is mediated by several autacoids like : Histamine 5-HT Bradykinin Prostaglandins When a tissue is injured, from any cause, prostaglandin synthesis in that tissue increases.

6. Synthesis of Prostaglandins Cyclo-oxygenase (COX) pathway Membrane Phospholipids Phospholipase A 2 Arachidonic Acid Prostaglandins Thromboxanes Prostacyclin COX

7. Among the most widely used all therapeutic agents world wide They are frequently prescribed for ‘rheumatic’ musculo -skeletal complaints and are often taken without prescription for minor aches and pains More than 50 different NSAIDs on the market and none of these is ideal in controlling or modifying the signs and symptoms of inflammation NSAIDs

8. Analgesic Antipyretic Anti-inflammatory actions Compared to Morphine: Weaker analgesics Do not depress CNS Do not produce physical dependence No abuse liability NSAIDs Cont..

9. They are also called: Non norcotic Non opioid Aspirin like analgesics They act primarily on peripheral pain mechanisms but also in CNS to raise pain threshold These drugs are chemically diverse, but most are organic acids. NSAIDs Cont..

10. Non of these steroid All are analgesic, antipyretic, anti-inflammatory (expect paracetamol) Do not produce CNS, RS depression. Dose dependent uricosuric action. Act by inhibition of PGs except Nimesulide, Nefopam Common characteristics of all NSAIDs Cont..

11. Classification Non selective COX inhibitors: Salicylates Aspirin , Diflunisal Pyrazolone derivatives Phenylbutazone, Oxyphenbutazone Indole derivatives Indomethacin, Sulindac Propianic acid derivatives Ibuprofen, Naproxen, Ketoprofen, Flurbiprofen Anthranilic acid derivatives Mephenamic acid Aryl-acetic acid derivatives Diclofenac Pyrrolo-pyrrolo derivative ketorolac

12. Preferential COX-2 inhibitors: Nimesulide, Meloxicam, Nabumatone Selective COX-2 inhibitors Celecoxib, Rofecoxib, Valdecoxib Analgesic –Antipyretics with poor Anti inflammatory action Para amino phenol derivatives Paracetamol (Acetaminophen) Pyrazolone derivatives Metamizol (Dypirone), Propifenazone Benzoxazocine derivative Nefopam Classification cont..

13. Non selective COX inhibitors: Salicylates Aspirin , Diflunisal Pyrazolone derivatives Phenylbutazone, Oxyphenbutazone Indole derivatives Indomethacin, Sulindac Propianic acid derivatives Ibuprofen, Naproxen, Ketoprofen, Flurbiprofen Anthranilic acid derivatives Mephenamic acid Aryl-acetic acid derivatives Dicofenac Pyrrolo-pyrrolo derivative ketorolac

14. Mechanism of action When a tissue is injured, from any cause, prostaglandin synthesis in that tissue increases. PGs have TWO major actions : They are mediators of inflammation They also sensitize pain receptors at the nerve endings, lowering their threshold of response to stimuli and allowing the other mediators of inflammation

15. Naturally, a drug that prevents the synthesis of PGs is likely to be effective in relieving pain due to inflammation of any kind In 1971 Vane and coworkers made the landmark observation that aspirin and some NSAIDs blocked PG generation. This is they do by inhibiting cyclo – oxygenase (COX) enzyme in the pathway for PGs synthesis Mechanism of action Cont..

16. Membrane Phospholipids Phospholipase A 2 Arachidonic Acid Prostaglandins Thromboxanes Prostacyclin COX Synthesis of Prostaglandins Cyclo-oxygenase (COX) pathway NSAIDs

17. COX Exists in two isoforms: COX-1 (constitutive) COX-2 (inducible) Oxidative stress Injury Ischemia Neurodegenerative diseases

18. Beneficial actions due to PG synthesis inhibition Analgesia Antipyresis Antiinflammatory Antithrombotic Closure of ductus arteriosus

19. Shared toxicities due to PG synthesis inhibition Gastric mucosal damage Bleeding Limitation of renal blood flow/Na + & water retention Delay/prolongation of labour Asthma and anaphylactoid reactions in susceptible individuals

20. Salicylates - Aspirin Prototype Acetylsalicylic acid It was obtained from ‘willow bark’ ( Salicaceae ) but is now synthesized Methyl salicylate is a volatile liqiud derivate. (Counter irritant) Irreversible inhibitor of COX Nonselective inhibitor of COX

21. Aspirin – Pharmacological actions Antiinflammatory action: Potent Exerted at high doses (3-6g/day or 100mg/kg/day) Signs of inflammation are suppressed Acts mainly by inhibiting PG synthesis

22. Aspirin – Pharmacological actions Analgesic action: Mild analgesic effect ≤ codeine Effective in non -visceral pain Inhibition of peripheral PG synthesis

23. Aspirin – Pharmacological actions Antipyretic action: Reduces body temperature in fever Resets the hypothalamic thermostat Rapidly reduces fever by heat loss But does not decrease heat production Metabolic effects: These are significant at only at antiinflammatory doses ↑ Cellular metabolism increased heat production ↑ Utilization of glucose

24. Respiration: Stimulated at therapeutic doses by peripheral and central actions Hyperventilation is prominent in salicylate poisoning Further raise causes respiratory depression and death due to respiratory failure Acid -base and electrolyte balance: Significant changes at antiinflammatory doses Hypokalemia, Respiratory alkalosis(400µg-500µgstimulation of respiratory centre inc. pO 2) , compensated respiratory alkalosis(most pts), respiratory acidosis(higher doses500µg to 1mg medullary depress,inc.pCO 2 ), uncompensated metabolic acidosis(poisoning) and dehydration(poisoning). Aspirin – Pharmacological actions

25. CVS: No direct effect in therapeutic doses Larger doses increase Cardiac Output (3g) Toxic doses depress VMC GIT: Irritate gastric mucosa and cause epigastric distress, nausea and vomiting Also stimulates CTZ “Ion trapping” Heart burn, dyspepsia, gers.astritis , erosion, Gastric ulcers. Aspirin – Pharmacological actions Asp Asp Acid pH 1.5 pH 7.1 Gastric mucosal cell

26. Effect on platelets/coagulation: TXA 2 enhances platelet aggregation PGI 2 decreases it Low doses(80-100mg/day) An anticoagulant effect with a prolonged BT Aspirin – Pharmacological actions

27. Urate excretion: Dose related effect is seen <2gm/day- urate retention and antagonism of all other uricosuric drugs 2-5gm/day- variable effects, often no change >5gm/day- increased urate excretion Not suitable in chronic gout- high doses are not tolerated Aspirin – Pharmacological actions

28. 9. Local irritant effect: Cause irritating to the skin & mucosa and destroys epithelical cells Keratolytic effects 10. Endocrine effect: Large dose stimulate adrenal cortex by hypothalamus inc adrenocortico steroid production L.Dose dec . thyroid uptake of iron cause goitre . Aspirin – Pharmacological actions

29. Well absorbed Poor water solubility is the limiting factor Solubility is more at higher pH Rapidly deacetylated in the gut wall, liver, plasma and other tissues to salicylic acid 80% bound to proteins Vd=0.17L/kg Slowly enters the brain but freely crosses placenta Aspirin – Pharmacokinetics

30. Conjugated in the liver by glycine and glucuronic acid Excreted by glomerular filtration as well as tubular secretion t1/2 of aspirin as such is 15-20min Together that released salicylic acid is 3-5hrs Metabolic processes get saturated over therapeutic range t1/2 of antiinflammatory doses may be 8-12hrs While that during poisoning may be upto 30hrs Thus elimination is dose dependant Aspirin – Pharmacokinetics

31. Gastrointestinal: Most common Epigastric distress, Nausea, Vomiting Increased occult blood loss in stools Gastric mucosal damage and peptic ulcer Rey’s syndrome Occurs in infants and children Occurs when aspirin given during viral infections Characterized by liver damage and encephalopathy Replaced by acetaminophen in such condition to reduce fever Aspirin – Adverse effects

32. Hypersensitivity: Though infrequent, these can be serious Reactions include; rashes, urticaria, angioedema, rhinorrhoea, asthma and anaphylactoid shock Salicylism High doses(at antiinflammatory doses) or chronic use of aspirin may induce a syndrome characterised by tinnitus, hearing defects, blurring of vision, dizziness, headache and mental confusion Effects are reversible Aspirin – Adverse effects

33. Aspirin – Adverse effects

34. Acute salicylate poisonig: More common in children Fatal dose in adults estimated to be 15-30gm, but considerably low in children Serious toxicities seen at serum levels >50mg/dl Manifestations are: vomiting, dehydration, electrolyte imbalance, acidotic breathing, hyper/hypoglycemia, petecheal hemorrhages, restlessness, delirium, hallucinations, hyperpyrexia, convulsions, coma and death due to respiratory and cardiovascular failure Aspirin – Adverse effects

35. Treatment: Symptomatic and supportive Gastric lavage i.v. infusion of Na + , K + , HCO 3 and glucose(dextrose-5%) Vitamin K 10mg i.v. Peritoneal dialysis or hemodialysis Aspirin – Adverse effects

36. contraindications Peptic ulcer Ulcerative colitis Gout Renal failure Patients hypersensitive to salicylates Hemophilias Aspirin – Contraindications

37. Drug interactions Aspirin – Drug interactions

38. Uses As analgesic As antipyretic Antiinflammatory Acute rheumatic fever Rheumatoid arthritis Osteoarthritis 4. Cardio protective Aspirin – Uses

39. As analgesic and antipyretic: 0.3-0.6gm, 6-8 hourly Acute rheumatic fever: 75-100mg/kg/day in divided doses/4-6 days 50mg/kg/day/2-3wks- maintenance dose Rheumatoid arthritis: 3-5gm/day Cardio protective: 80-100mg/day Aspirin – Doses(oral)

40. Sodium salicylate : Aspirin alternative in rheumatic fever But now is obsolete Methylsalicylate (Topical): Used topically as a counterirritant in muscle and joint pain, in the form of liniments and ointments Systemic absorption can lead to toxicity Salicylic acid (Topical): Used as keratolytic and corn remover Combined with benzoic acid (Whitefield ointment) for local use in epidermophytosis Other clinically used Salicylates

41. These are : Aminopyrine and antipyrine Phenylbutazone and oxyphenbutazone Analgin ( dipyrone ) Phenylbutazone : Potent antiinflammatory drug Poorly tolerated by many patients Causes GI, hepatic, renal and fatal hematologic, agranulocytosis toxic effects Gives rise to various drug interactions Hence now it is rarely used Pyrazolone Derivatives

42. Oxyphenbutazone : Metabolic degradation product of phenylbutazone Less gastric irritation than phenylbutazone It shares all toxic effects of phenylbutazone Analgin ( Dipyrone , Novalgin ): Has potent analgesic antipyretic but no antiinflammatory actions Has no advantage over aspirin Toxic effects are similar to phenylbutazone Pyrazolone Derivatives Cont…

43. Indomethacin : Potent antiinflammatory agent Has antipyretic, analgesic and anti-inflammatory actions Effective in gout , rheumatoid arthritis, ankylosing spondylitis and osteoarthritis. Given orally, absorbed well Mainly metabolized by liver and excreted by kidneys Its action is more prolonged than its t 1 / 2 Headache is the most common adverse effect, followed by giddiness, mental confusion, blurring of vision, depression and psychotic disturbances. Total daily dose is 50-150mg in divided doses ( Indomethacin 25mg cap) after food. Indole Derivatives

44. Tocolytic agent: As effective as MgSo4 It dec . preterm birth significantly by arresting premature uterine contractions Dose; 25mg 2-3 times a day. Sulindac : Fluorinated derivative of indomethacin It is a prodrug and has a longer duration of action Given orally in the dose of 100-200mg twice a day Indole Derivatives Cont..

45. These are : Ibuprofen, naproxen, flurbiprofen and ketoprofen Analgesic, antipyretic and anti-inflammatory properties similar to Aspirin Better tolerated orally Adverse effects are lower than aspirin and indomethacin Highly bound to plasma proteins (92-99%) ADR: cause GI disturbances such as epigastric pain, nausea, sensation of fullness in the stomach and heartburn Less frequently they may cause CNS symptoms Propionic acid Derivatives

46. Mefenamic acid : Useful in chronic and dull aching pains No advantages over other NSAIDs Weaker analgesic than aspirin Adverse reactions include gastric upset, diarrhoea , dizziness, headache, skin rashes, hemolytic anemia Dose is 500mg 2-3 times a day Used in Dysmenorrhoea Anthranilic acid Derivatives (Fenamates )

47. Diclofenac : Probably has greater activity than other NSAIDs Extensively bound to plasma proteins, t 1 / 2 is 1-2hrs Accumulates in the synovial fluid- probably responsible for its longer duration of action than its t 1/ 2 Incidence of adverse reactions is 20% Adverse effects similar to propionic acid derivatives+elevation of liver enzymes Arylacetic acid Derivatives

48. Piroxicam : Structurally different from other NSAIDs Given orally, well absorbed, has long t 1 / 2 (38-45hrs) – administered OD Commonly causes GI and CNS disturbances Has been used to treat rheumatoid arthritis, ankylosing spondylitis, osteoarthritis and acute gout Has no advantages except a longer duration of action Oxicam Derivatives

49. Ketorolac : Has less antiinflammatory activity IM. 20-30mg (single dose) is a moderately effective analgesic in patients with moderate to severe postoperative pain IV ketorolac has been as effective as, and have fewer side effects than morphine in surgical and chronic cancer pain Has longer duration of action (t 1 / 2 5hrs) Metabolised in liver and excreted by kidneys Pyrollo pyrollo Derivatives

50. The commonly used drug is Paracetamol (Acetaminophen) Potent antipyretic and equianalgesic with aspirin in therapeutic doses but devoid of significant antiinflammatory effect Does not produce gastric irritation, acid –base imbalance, electrolyte disturbances nor does it affect blood clotting Hence is preferred to aspirin as an analgesic antipyretic Absorption, fate and excretion: Rapidly absorbed on oral administration Peak plasma levels are reached within ½ an hour to 1hour Para aminophenol Derivatives

51. Metabolised in the liver and excreted in urine as conjugation products of glucuronic and sulfuric acids Poor metabolism in infants- enhanced toxicity Adverse effects : At recommended therapeutic doses (500-1000mg) in healthy subjects is well tolerated Hepatic and renal toxicity : Larger doses (7-10gm) produce extensive hepatocellular damage and renal tubular necrosis, and may cause death Para aminophenol Derivatives Cont..

52. This is a major problem in paracetamol poisoning Liver toxicity is due to N-acetyl-P- benzoquinone imine which normally turns harmless by conjugation with glutathione Early manifestations are just nausea, vomiting, abdominal pain and live tenderness with no impairment of consciousness After 12-18hrs centrilobular hepatic necrosis occurs which may be accompanied by renal tubular necrosis and hypoglycemia that may progress to coma Para aminophenol Derivatives Cont..

53. paracetamol N-acetyl benzoquinone imine Glutathione conjugate of toxic metabolite (non toxic, excreted) Cell proteins get covalently Bound to toxic metabolite →cell death Oxidation of SH group Of hepatic and renal Cell proteins Methionine or N-acetylcysteine Conjugates of toxic metabolite For normal therapeutic doses In toxic doses Treatment Glutathione Glutathione Para aminophenol Derivatives Cont..

54. Treatment : Patient is brought early (within 16hrs of ingestion) Vomiting should be induced or gastric lavage done Activated charcoal is given orally or through tube to prevent further absorption Other supportive measures, as needed, should be taken Specific : N- acetylcysteine 150mg/kg should be infused i.v. over 15min, followed by the same dose i.v. over next 20hrs Para aminophenol Derivatives Cont..

55. Nefopam : Different from other NSAIDs since it has atropin like actions Effective in traumatic and post operative pain, and in musculoskeletal pain not responding to other NSAIDs Atropine like adverse effects Contraindicated in epilepsy Benzoxazocine Derivatives

56. These are : Nimesulide, Meloxicam, Nabumatone Nimesulide : Relative weak PGs inhibitor with COX-2 selective action Other mechanisms implicated are reduced superoxide generation by neutrophils, inhibition of PAF synthesis and free radical scavenging action Gastric and other adverse effects are similar to other NSAIDs Has been reported to cause nephrotoxicity and hepatotoxicity Not licensed in some developed countries And it has been withdrawn from others Use should be avoided especially in children and old persons Pref COX-2 inhibitors

57. Selectively block COX-2 activity more than COX-1 activity Less action on stomach, blood vessels and kidneys This group includes : Celecoxib, Rofecoxib and Valdecoxib Given orally, absorption is complete Established analgesic- antiinflammatory NSAIDs They have to be shown effective in treatment of osteoarthritis and rheumatoid arthritis Their major advantage is that they cause fewer gastric ulcers and do not inhibit platelet aggregation Stomach friendly Selective COX-2 Inhibitors

58. Adverse effects : The most common adverse effects are nausea, vomiting, dyspepsia, abdominal pain, diarrhoea and edema of the lower extremities Share some of the renal adverse effects of non selective COX inhibitors and renal toxicity Hence their use should be restricted to patients who do not tolerate other NSAIDs Selective COX-2 Inhibitors Cont..

59. Recently, the use of rofecoxib and valdecoxib has been reported to be associated with increased incidence of MI and stroke Hence, they have been withdrawn by the original manufacturers Currently all the selective COX -2 inhibitors are under suspicion regarding their long term toxicity They have been described as drugs with “marginal efficacy, heighted risk and excessive cost compared with traditional NSAIDs” Selective COX-2 Inhibitors Cont..

60. Diclofenac 1% gel Ibuprofen 10% gel Naproxen 10% gel Ketoprofen 2.5% gel Flurbiprofen 5% gel Nimesulide 1% gel Piroxicam 0.5% gel Topical NSAIDs

61. Thank you