Nsaids

Non steroid anti inflammatory drugs

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2. Parveen.SK 1 st MDS Public health dentistry NSAIDS

3. CONTENTS: Introduction Classification Various Forms of Delivery of NSAIDs Uses of NSAIDs Adverse Effects Mechanism of Action Contraindications Individual drug groups in detail Selection of NSAIDs Conclusion References

4. 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.

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

6. The classic signs and symptoms of acute inflammation English Latin Redness Rubor Swelling Tumor Heat Calor Pain Dolor Loss of Function Functio laesa √ √ √ √

7. PAIN An unpleasant sensory and emotional experience associated with actual or potential tissue damage. There are three type of Pain : Somatic Pain Visceral Pain Referred Pain

8. Analgesic is a drug that selectively relieves pain by acting in the CNS or peripheral pain mechanisms, without significantly altering consciousness. Analgesics relieve pain as a symptom without affecting its cause Analgesic

9. Analgesics are divided into two groups : Opioid / Narcotic / Morphine like analgesic Non Opioid / Non-Narcotic / Non Steroidal Anti inflammatory Drugs

10. w NSAIDS NSAIDS

11. INTRODUCTION NSAIDS are most widely used therapeutic agents world wide. They are frequently prescribed for ‘rheumatic’ musculo-skeletal complaints and are often taken without prescription for minor aches and pains. They have Analgesic, Antipyretic & Anti-inflammatory actions. They act primarily on peripheral pain mechanisms but also in CNS to raise the pain threshold .

12. They are also called: N on narcotic N on opoid analgesics A spirin type or antipyretic analgesic Compared to morphine they are: Weaker analgesics Do not depress CNS Do not produce physical dependence and Have no abuse liability.

13. CLASSIFICATION Non Selective COX inhibitors Salicylates Aspirin, Sodium salicylate Diflunisal Pyrazolone derivatives Phenylbutazone, Oxyphenbutazone Indole derivatives Indomethacin, Sulindac Propionic acid derivatives Ibuprofen, Naproxen, Ketoprofen Anthranilic acid derivatives Mephenamic acid, Flufenamic acid Aryl-acetic acid derivatives Diclofenac, Aceclofenac Pyrrolo-pyrrole derivative Ketorolac Oxicam derivatives Piroxicam , Tenoxicam

14. 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 ), Propiphenazone Benzoxazocine derivative Nefopam

15. Routes of analgesic administration: Oral Intramuscular Injection Intravenous Injection PCA : patient controlled analgesia Epidural Administration Transdermal , Creams, gels and foams. Suppositories PCA

16. Mechanism of action of NSAIDs: 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

17. x Leukotrienes

18. 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 C yclo – oxygenase ( COX) enzyme in the pathway for PGs synthesis

19. COX COX e xists in two isoforms : COX-1 (constitutive) COX-2 (inducible ) COX-1: Present as part of everyday physiological function. Involved in the homeostasis of the entire organism. Protects the stomach by limiting acid secretion. Improves the distribution of blood flow in the kidney . Helps platelets limit bleeding by increasing their adhesiveness . COX-2: Its expression is induced by various stimuli such as the inflammation or at the site of the injury

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21. A ctions due to PG synthesis inhibition Benificial Actions Non beneficial Actions Analgesia: prevention of pain nerve ending sensitization Gastric mucosal damage Antipyresis Bleeding: inhibition of platelet function Anti inflammatory Asthma and anaphylactoid reactions in susceptible individuals Anti thrombotic Delay/prolongation of labour

22. NSAIDS - Adverse effects Gastrointestinal: Gastric irritation, erosions, peptic ulceration, gastric bleeding/ perforation, oesophagitis Renal: C hronic renal failure, interstitial nephritis, papillary necrosis (rare) Hepatic: Raised transaminases, hepatic failure (rare) CNS: Headache, mental confusion, behavioural disturbances , seizure precipitation. Haematological : Bleeding , thrombocytopenia, haemolytic anaemia , agranulocytosis Others: Asthma exacerbation, nasal polyposis, skin rashes, pruritus, angioedema

23. NSAIDS - Contraindications NSAIDs should usually be avoided by people with the following conditions : Peptic ulcer or stomach bleeding Uncontrolled   hypertension Kidney disease People who suffer with Inflammatory Bowel Disease ( Crohn's Disease or Ulcerative Colitis ) Past   stroke  (excluding   aspirin ) Past   myocardial infarction   (excluding   aspirin ) Coronary artery disease  (excluding   aspirin ) Taking aspirin for heart In third trimester of pregnancy Past   transient ischemic attack (excluding   aspirin ) Persons who have a history of allergy to Nsaids (allergic- typeNSAID ) or hypersensitivity reactions , e.g.   aspirin-induced asthma https ://en.wikipedia.org/wiki/Nonsteroidal_anti-inflammatory_drug#Contraindications

24. Non Selective COX inhibitors

25. Salicylate derivatives Aspirin Acetylsalicylic acid It was obtained from ‘willow bark’ (Salicaceae) but is now synthesized. Irreversible COX inhibitor Dose : 300-600mg tid .

26. Aspirin – Pharmacological actions: Anti inflammatory action: Exerted at high doses (3-6g/day or 100mg/kg/day) Signs of inflammation are suppressed Acts mainly by inhibiting PG synthesis Analgesic action : Mild analgesic effect ≤ codeine Effective in non -visceral pain Inhibition of peripheral PG synthesis

27. Antipyretic action: Reduces body temperature in fever. Rapidly reduces fever by heat loss. But does not decrease heat production. Respiration: Stimulated at therapeutic doses by peripheral and central actions. Hyperventilation is prominent in salicylate poisoning. Further raise of dose causes respiratory depression and death due to respiratory failure.

28. CVS : No direct effect in therapeutic doses Larger doses increase Cardiac Output Toxic doses depress vasomotor center. GIT: Irritate gastric mucosa and cause epigastric distress, nausea and vomiting Also stimulates CTZ Heart burn, dyspepsia, gastritis, erosion, gastric ulcers.

29. Effect on platelets/coagulation: It inhibits TXA 2 synthesis thus interferes with platelet aggregation and prolongs bleeding time Local irritant effect : Cause irritating to the skin & mucosa and destroys epithelial cells. Keratolytic effects. Aspirin burn

30. Aspirin – Adverse effects: Side effects – N ausea, vomiting, epigastric distress and occult blood in stools. Hypersensitivity and idiosyncracy – R ashes, urticaria, rhinorrhea, asthma, angioedema and anaphylactoid reactions. Anti-inflammatory doses – produces a syndrome called S alicylism – dizziness, tinnitus, vertigo, reversible impairment of hearing and vision, excitement and mental confusion. Reye’s syndrome - Reye's syndrome tends to occur in previously healthy children about a week after common viral infections such as influenza or chickenpox. The precise reason is unknown, but using aspirin to treat a viral illness or infection may trigger the condition in children .

31. Acute salicylate poisoning : Fatal dose in adults is estimated to be 15-30 gm . Serious salicylate toxicity ( Salicylism ) is seen at serum salicylate levels of  50 mg/dl. Manifestations are: Vomiting, dehydration ,electrolyte imbalance. Acidotic breathing. Hyper / hypoglycemia. Petechial hemorrhage's. Restlessness, delirium, hallucinations, convulsions. Hyperpyrexia. Coma and death due to respiratory faliure and cardiovascular collapse.

32. Aspirin – Contraindications: Peptic ulcer Ulcerative colitis Gout Renal failure Patients hypersensitive to salicylates Hemophilias Aspirin – Uses: As analgesic – headache, backache, myalgia, joint pain, toothache, neuralgias and dysmenorrhea . As antipyretic Acute rheumatic fever Rheumatoid arthritis Osteoarthritis Post myocardial infarction and post-stroke patients

33. Pyrazolone derivatives Phenylbutazone : Potent anti-inflammatory drug. Poor analgesic & antipyretic activity Pharmacokinetics: Absorption- 98 % bound to plasma proteins . Metabolism- Liver. Excretion- Urine. DOSE: 100-200 mg Bid.

34. Adverse effects : More toxic than aspirin. Nausea, vomiting, epigastric distress and peptic ulceration . Diarrhea Edema Hypersensitivity : rashes, serum sickness, hepatitis and stomatitis . Bone marrow depression, agranulocytosis and stevens-johnson syndrome . Goiter and hypothyroidism on long term use .

35. Uses: Because of the serious side effects, these drugs should be used only in severe cases not responding to any other NSAIDs. Rheumatoid arthritis and ankylosing spondylitis: for short periods of 1-2 weeks during an acute exacerbation. In Acute gout.

36. Indole derivatives Indomethacin: Potent anti inflammatory & antipyretic & good analgesic . Pharmacokinetics : Absorption- 90% bound to plasma proteins . Metabolism- Liver. Excretion- Urine . DOSE : 25-50 mg bid.

37. Adverse effects: Gastric irritation, nausea, anorexia, gastric bleeding and diarrhea are prominent. Frontal headache (very common), dizziness, ataxia, mental confusion, hallucination, depression and psychosis. R ashes and other hypersensitivity reactions can also occur. Increased risk of bleeding due to decreased platelet aggregation. Contraindications: In machinery operators, drivers, psychiatric patients, epileptics, in kidney diseases, pregnant women and in children .

38. Uses: Indicated in rheumatoid arthritis not controlled by aspirin. It is particularly efficacious in ankylosing spondylitis, acute exacerbations of destructive arthropathies and psoriatic arthritis. It acts rapidly in acute gout. Malignancy associated fever refractory to other antipyretics may respond to indomethacin. It has been the most common drug used for medical closure of patent ductus arteriosus . Bartter's syndrome responds dramatically, as it does to other PG synthesis inhibitors.

39. PROPIONIC ACID DERIVATIVES Ibuprofen , naproxen, flurbiprofen and ketoprofen : All have similar pharmacodynamic properties but differ considerably in potency and to some extent duration of action . The analgesic, antipyretic and anti-inflammatory activity is rated lower than high dose of the aspirin . All inhibit PG synthesis naproxen being most potent . They inhibit platelet aggregation and prolong bleeding time. Dose: Ibuprofen- 400-800mg tid (BRUFEN) Ibuprofen + paracetamol (COMBIFLAM)

40. Adverse effects: Ibuprofen is better tolerated than aspirin. Side effects are milder and their incidence is lower. Gastric discomfort, nausea and vomiting, less than aspirin or indomethacin, are still most common side effects . CNS side effects include headache, blurring of vision, tinnitus and depression . Precipitates aspirin induced asthma . Fluid retention is less marked . They are not to be prescribed to pregnant women and should be avoided in peptic ulcer patients.

41. Pharmacokinetics and interactions: All are absorbed orally, highly bound to plasma proteins (90-99%), but displacement interactions are not clinically significant. Because they inhibit platelet function, use with anticoagulants should, be avoided. They are likely to decrease diuretic and antihypertensive action of thiazides, furosemide and - blockers. All propionic acid derivatives enter brain, , synovial fluid and cross placenta. They are largely metabolized in liver by hydroxylation and , glucornide conjugation and excreted in urine well as bile .

42. Uses : Ibuprofen is used as a simple analgesic and antipyretic. Ibuprofen and its congeners are widely used in rheumatoid arthritis, osteoarthritis and other musculoskeletal disorders, specially where pain is more prominent than inflammation . They are indicated in the soft tissue injuries, fractures, vasectomy , tooth extraction, postpartum and post-operatively. Ibuprofen is rated as the safest NSAID by the spontaneous adverse drug reaction reporting system in the U.K.

43. ANTHRANILICACIDDERIVATIVE(FENAMATE ) Mephenamic acid: An analgesic, antipyretic and anti-inflammatory drug, which inhibits COX as well as antagonises certain actions of PGs. Mephenamic acid exerts peripheral as well as central analgesic action. Dose : 250-500mg tid . Adverse effects : Diarrhea is the most important dose related side effect. Epigastric distress is complained, but gut bleeding is not significant . Skin rashes, dizziness and other CNS manifestations have occurred . Haemolytic anaemia is rare but serious complication.

44. Uses: Mephenamic acid is indicated primarily as analgesic in muscle, joint and soft tissue pain where strong anti-inflammatory action is not needed. It is quite effective in dysmenorrhoea . It may be useful in some cases of rheumatoid and osteoarthritis but has no distinct advantage.

45. ARYL-ACETICACID DERIVATIVE Diclofenac sodium : An analgesic-antipyretic, anti-inflammatory drug, similar in efficacy to naproxen . It inhibits PG synthesis and has short lasting Antiplatelet action. Neutrophil chemotaxis and superoxide production at the inflammatory site are reduced. It is well absorbed orally, 99%protein bound, metabolized and excreted both in urine and bile . Dose: 50mg bid- tid .

46. The plasma t ½ is approximately 2 hours. It has good tissue penetrability and concentration in synovial fluid is maintained for 3 times longer period than in plasma, exerting extended therapeutic action in joints. Adverse effects : Diclofenac have generally mild adverse effects Epigastric pain Nausea Headache Dizziness Rashes. Gastric ulceration and bleeding are less common Reversible elevation of serum aminotransferases can occur; kidney damage is rare .

47. Uses: Diclofenac is among the most extensively used NSAID Employed in rheumatoid and osteoarthritis Bursitis Ankylosing spondylitis Dysmenorrhea Post-traumatic and postoperative inflammatory Conditions - affords quick relief of pain and wound edema.

48. OXICAM DERIVATIVES Piroxicam : It is a long acting potent NSAID with anti-inflammatory potency similar to indomethacin and good analgesic-antiplatelet action. It is a reversible inhibitor of COX; lowers PG concentration in synovial fluid and inhibits the platelet aggregation-prolonging bleeding time . Thus , it can inhibit inflammation in diverse ways. Dose : 20mg od - orally

49. Pharmacokinetics : It is rapidly and completed absorbed: 99% plasma protein bound ; it is metabolized in liver by hydroxylation and glucoronide conjugation It is excreted in urine and enterohepatic cycling occurs . Uses : It is suitable for use as short term analgesic as well as long term anti-inflammatory drug Rheumatoid and osteo-arthritis Ankylosing spondylitis , Acute gout, Musculoskeletal injuries , In Dentistry

50. Adverse effects : Common side effects are - burn, nausea and anorexia, but it is tolerated and less ulcerogenic than indomethacin ;causes less faecal blood than aspirin. Rashes and pruritus are seen in < 1% patients. Edema and reversible azotemia, have been observed.

51. Pyrollo pyrolle Derivatives Ketorolac : A NSAID with potent analgesic and modest anti-inflammatory activity. In postoperative pain it has equaled the efficacy of morphine. It inhibits PG synthesis and is believed to relieve pain by a peripheral mechanism . Dose: 10mg tid (orally) 30mg/dl qid (IV)

52. Pharmacokinetics: ketorolac is rapidly absorbed after oral and i.m . administration. It is highly plasma protein bound and 60% excreted unchanged in urine . Adverse effects: Nausea, abdominal pain, dyspepsia, ulceration, loose stools, drowsiness, headache, dizziness, nervousness, pruritus, pain at injection site. Rise in serum transaminases and fluid retention have been noted.

53. Contra-indications: It should not be given to patients on the anti-coagulants. Uses : Ketorolac is frequently used in post-operative and acute musculoskeletal pain: 15-30 mg every 4-6 hours (max. 90 mg/ day). It can also be used for renal colic, migraine and pain due to due to bony metastasis. It is used in a dose of 10-20 mg 6 hourly short term management of moderate pain. Use for more than 5 days is not recommended. It should not be used for obstetric purposes.

54. PREFERENTIAL COX-2 INHIBITORS 54

55. Nimesulide: Sulfonamide derivative Selective inhibitor of PG synthesis and there is some relative COX-2 selectivity. Pharmacokinetics : Absorption- 99%Plasma bound Metabolism-Liver Excretion- Urine DOSE- 50- 100mg bid , Children-5mg/kg/day

56. Adverse effects Epigastralgia , heart burn, nausea, loose motions Dermatological rash, pruritus Somnolence , dizziness USES : Short lasting painful inflammatory conditions like sports injuries, sinusitis and other ear-nose-throat disorders, dental surgery, bursitis, low backache, dysmenorrhea. Postop pain, osteoarthritis & for fever

57. Nabumetone : Anti-inflammatory agent. It possesses less analgesic, antipyretic activities; effective in the treatment of rheumatoid and osteoarthritis as well as soft tissue injury . Nabumetone has caused a lower incidence of gastric erosions, ulcers and bleeding, probably because the active COX inhibitor is produced in tissues after absorption. Pharmacokinetics : Absorption-Gut Metabolism-Liver Excretion- Urine

58. Dose- 1-2g od. Not recommended in children Adverse effects : GI bleeding, Gastritis, Stomatitis, Anemia, Dizziness, Headache, Nausea, Abdominal pain, diarrhea, Flatulence, Dyspepsia

59. SELECTIVE COX-2 INHIBITORS 59

60. COX-2 selective inhibitor are Celecoxib , Rofecoxib , Valdecoxib It is a form of (NSAID) that directly targets COX-2 which is produced at the site of inflammation . Selectivity for COX-2 can halve the risk of peptic ulceration. Cox-2-selectivity does not seem to affect other side-effects of NSAIDs (most notably an increased risk of renal failure), and there might be an increase in the risk for heart attack, thrombosis and stroke by a relative increase in thromboxane .

61. Pharmacokinetics: Absorption- Plasma bounded. Metabolism-Liver Excretion- Urine Uses of COX2 inhibtiors : Osteoarthritis. Rheumatoid Arthritis. Ankylosing Spondylitis. For the management of acute pain in adults. Dysmenorrhea . Dose : Celecoxib - 100-200mg bid Rofecoxib - 12.5-50mg od Valdecoxib - 20 mg bid

62. Adverse effects: Celecoxib : Abdominal pain, dyspepsia, dizziness, head ache, peripheral edema, insomnia, mild diarrhea. Rofecoxib : It can decrease prostaglandin production in endothelial cells and lead to an inefficiency in declumping and vasorelaxation. Diarrhea, nausea, hypertension, dyspepsia, heart burn, URI, UTI, epigastric discomfort . Valdecoxib : Cardiovascular Hypertension , Peripheral edema. Dizziness, Headache Nausea, Abdominal fullness, Abdominal pain, diarrhea, Flatulence, Dyspepsia

63. TOPICAL NSAIDS

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

65. SELECTION OF NSAID

66. Lactation Ibuprofen,Indomethacin,Naproxen

67. Moderate to severe Pain Moderate Pain Mild to Moderate Pain Opiods or Tramadol NSAIDS or Tramadol Acetaminophen or Ibuprofen A SUGGESTED TREATMENT ALOGRITHM. AMERICAN JOURNAL OF MEDICINE 105, 535_605,1998 . Management of pain in patients with multiple health problems: a guide for the  practicing physician. Ruoff G, The American Journal Of Medicine [Am J Med], ISSN: 0002-9343, 1998 Jul 27; Vol. 105 (1B), pp. 53S-60S

68. Name Available as Dose / Frequency Salicylates Aspirin 300-350 mg t.i.d Ibuprofen Brufen 400-600mg t.i.d Naproxen Naprosyn 250-500mg b.i.d Diclofenac voveran 50mg b.i.d Piroxicam pirox 10-20mg o.d Paracetamol Crocin 300-500mg t.i.d Indomethacin Indocid 25-50mg t.id

69. 70 CONCLUSION

70. NSAID is a safe therapeutic alternative for young healthy patients, but should be used with caution in the elderly . Ulcer complications associated with the use of NSAIDs, in high-risk patients, are often caused by a failure to identify patients risk factors, concomitant use of aspirin or multiple NSAIDs, and under utilization of gastroprotective agents. COX2 inhibitors & some nonselective NSAIDs increase the risk of myocardial infarction . Physicians must, therefore, take into account both the gastrointestinal and the cardiovascular risks of individual patients when prescribing NSAIDs. In patients with a low cardiovascular risk, NSAIDs can be prescribed according to the level of gastrointestinal risk. Patients with a moderate gastrointestinal risk (one or two risk factors) should receive a COX2 inhibitor or an NSAID plus a Proton pump inhibitors (PPI) or Misoprostol .

71. Patients with more than two gastrointestinal risk factors or prior ulcer complications require the combination of a COX2 inhibitor & PPI . Patients with a high cardiovascular risk (e.g. coronary heart disease or an estimated 10-year cardiovascular risk greater than 10%) should receive prophylactic aspirin & combination therapy with a PPI or Misoprostol irrespective of the presence of gastrointestinal risk factors . Naproxen is the preferred NSAID because it is not associated with excess cardiovascular risk.

72. References K D Tripathi , Essentials of medical pharmacology, J aypee brothers medical publishers(P)Ltd, 6 th edition (2008 ). Padmaja udaykumar , Text book of Pharmacology for dental and allied health sciences , Jaypee brothers medical publishers(P)Ltd, 2 nd edition (2007). Management  of pain in patients with multiple health problems: a guide for the practicing physician. Ruoff G, The American Journal Of Medicine [Am J Med], ISSN: 0002-9343, 1998 Jul 27; Vol. 105 (1B), pp. 53S-60S https:// en.wikipedia.org/wiki/Nonsteroidal_antiinflammatory_drug# Contraindications. AMANDA RISSER et al, NSAID Prescribing Precautions, American Family Physician, December 15, 2009.Volume 80, Number 12

73. 75 T hank you