Nonsteroidal Anti-inflammatory 2023.pptx

Basics of Non Steroidal Anti Inflammatory Drugs

1. NON STEROIDAL ANTI-INFLAMMATORY DRUGS POST GRADUATE STUDENT DEPARTMENT OF PERIODONTOLOGY

2. CONTENTS Introduction History Classification Mechanism of action Common properties of all NSAIDs Individual drugs Choice of NSAIDS NSAIDS in periodontics Conclusion References

3. PAIN Definition: An unpleasant emotional experience usually initiated by a noxious stimulus and transmitted over a specialized neural network to the central nervous system where it is interpreted as such- ( Monheims )

4. PAIN CONTROL ANALGESICS:  A drug that selectively relieves pain by acting in CNS or on peripheral pain mechanism, without significantly altering consciousness. ANALGESICS Opioid analgesics Non opioid analgesics

5. COMPARED TO OPIODs, NSAIDS ARE : Weaker analgesics (except for inflammatory pain) Don’t depress CNS Don’t produce physical dependence No abuse liability

6. Preferential COX-2 inhibitors Nimesulide , Meloxicam, Etodolac . Selective COX-2 inhibitors Celecoxib , Etoricoxib , Parecoxib .

7. ANALGESIC-ANTIPYRETICS WITH POOR ANTI INFLAMMATORY ACTION Paraaminophenol derivative: Paracetamol Pyrazolone derivatives: Metamizol , Benzoxazocine derivative: Nefopam.

8. MECHANISM OF ACTION NSAIDs – inhibits COX-1 and COX-2 isoforms Decrease in PG and Thromboxane synthesis Antiinflammatory – reversible inhibition of COX-2 Aspirin- irreversible inhibition of COX

9. SALICYLATES Aspirin is acetyl salicylic acid , the prototype converted in the body to salicylic acid – oldest analgesic . Other important salicylates – Sulfasalazine , Diflunisal Natural sources – fruits , vegetables, herbs , spices, nuts and tea

10. PHARMACOLOGICAL ACTIONS Analgesic action Antipyretic Anti inflammatory Antiplatelet GIT CVS

11. PHARMACOKINETICS Salicylates – rapidly absorbed from upper GI tract Distributed throughout the tissues and body fluids Metabolized – liver- glycine and glucuronide conjugation Low doses elimination First order kinetics High doses elimination Zero order kinetics

12. CONTRA INDICATIONS In patients with peptic ulcer, bleeding tendencies, in children sufffering from chicken pox or influenza. In chronic liver disease: cases of hepatic necrosis have been reported. Should be avoided in those with low cardiac reserve or frank CHF and in juvenile RA. To be avoided in pregnant and breast feeding women.

13. PROPIONIC ACID DERIVATIVES Ibuprofen was the first member of this class to be introduced in 1969. Moderate anti-inflammatory effect. Better tolerated than Aspirin. Can be used in children (doesn’t cause Reye’s syndrome) Naproxen being most potent.

14. The plasma t1/2 of Ibuprofen is 2hrs . Dosage is 400-600mg TDS. The plasma t1/2 of Naproxen is 12-16hrs. Dosage:- 250mg BD-TDS. CONTRAINDICATIONS:- Not to be prescribed to pregnant women and peptic ulcer patients

15. ANTHRANILIC ACID DERIVATIVE (FENAMATE) Mephenamic acid : An analgesic, antipyretic and anti-inflammatory drug, known from 1950s, but has not gained popularity because of lower efficacy. Mephanamic acid exerts central as well as peripheral analgesic actions.

16. Pharmacokinetics : Oral absorption is slow but almost complete. Highly bound to plasma proteins . plasma t ½ is 2-4 hours. Dose: 250-500mg TDS Uses : Analgesic in muscle, joint and soft tissue pain, dsymenorrohea , rheumatoid and osteoarthritis. Antipyretic Weak anti-inflammatory effect

17. Adverse effects : Epigastric distress, skin rashes, dizziness and other CNS manifestations. Haemolytic anaemia is rare but serious complication.

18. ARYL-ACETIC ACID DERIVATIVES DICLOFENAC SODIUM: Potent atnti -inflammatory effect Gets concentrated in synovial fluid, hence preferred in inflammatory conditions of joint Incidence of hepatotoxicity is more Diclofenac + misoprostol – reduces GI irritation and peptic ulcer

19. USES:- Diclofenac is the most extensively used NSAID; employed in Rheumatoid and Osteo Arthritis, toothache, ankylosing spondylitis, dysmenorrhoea , post traumatic and post inflammatory conditions-affords quick relief of pain and wound edema. Dosage:- 50mg BD, 1OOmg OD

20. Pharmacokinetics It is well absorbed orally, 99% protein bound, metabolized and excreted both in urine and bile. The plasma t1⁄2 is ~2 hours. Due to good tissue penetrability, concentration in joints and other sites of inflammation is maintained for longer period extending the therapeutic effect Adverse effects : Epigastric pain, nausea, headache, dizziness, rashes. Gastric ulceration and bleeding are less common.

21. OXICAM DERIVATIVE PIROXICAM It is long lasting action with potent anti inflammatory and good analgesic action. It is a reversible inhibitor of COX, lowers PG synthesis and inhibits platelet aggregation. In addition, it decreases the production of IgM Rheumatoid Factor and reduces leucocyte chemotaxis-thus inhibits inflammation in diverse ways. It is 99%plasma protein bound , plasma t1/2 is nearly 2 days. Dose is 20mg BD for two days followed by 20 mg OD.

22. Uses:- Short term analgesic as well as long term anti inflammatory in Rheumatoid and OsteoArthritis , Ankylosing Spondylitis, Acute Gout, musculoskeletal injuries and in dentistry. Adverse effects:- Heart burn Rashes Nausea Edema

23. PYRROLE DERIVATIVE KETOROLAC: This NSAID has potent analgesic , efficacy almost equal to morphoine Relieves pain without causing respiratory depression, hypotension and drug dependence. Used in renal colic, postoperative and metastatic cancer pain

24. Pharmacokinetics: Ketorolac is rapidly absorbed after oral and i.m. administration. It is highly plasma protein bound and 60% excreted unchanged in urine. plasma t1⁄2 is 5–7 hours.

25. Adverse effects : Nausea, abdominal pain, ulceration, loose stools, drowsiness, headache, dizziness, nervousness, pruritus, pain at injection site, rise in serum transaminase and fluid retention have been noted. Uses: Ketorolac is frequently used in postoperative, dental and acute musculoskeletal pain: 15– 30 mg i.m. or i.v. every 4–6 hours (max. 90 mg/ day). It may also be used for renal colic, migraine and pain due to bony metastasis.

26. INDOLE DERIVATIVE: Indomethacin:- This indole acetic acid derivative is a potent anti inflammatory drug with prompt antipyretic action. Very effective in ankylosing spondylitis and psoriatic arthritis Side effects- GI, CNS Contraindicated in epileptic, psychiatric patients and drivers.

27. Pharmacokinetics: Indomethacin is well absorbed orally. It is 90% bound to plasma proteins, partly metabolized in liver to inactive products and excreted by kidney. Plasma t1⁄2 is 2–5 hours. Adverse effects: A high incidence (up to 50%) of gastrointestinal and CNS side effect is produced. Gastric irritation, nausea, anorexia, gastric bleeding and diarrhoea are prominent. Frontal headache (very common), dizziness, ataxia, mental confusion, hallucination, depression and psychosis can occur. Leukopenia, rashes and other hypersensitivity reactions are also reported. Increased risk of bleeding due to decreased platelet aggregability.

28. Uses: Indomethacin is used as a reserve drug in conditions requiring potent anti inflammatory action like ankylosing spondylitis, , psoriatic arthritis and acute gout or rheumatoid arthritis that are not responding to better tolerated NSAIDs. Malignancy associated fever. medical closure of patent ductus arteriosus.

29. PYRAZOLONES Antipyrine (phenazone) and amidopyrine (aminopyrine) were introduced in 1884 as antipyretic and analgesic. Phenylbutazone was introduced in 1949 and soon its active metabolite oxyphenbutazone was also marketed. These two are potent anti inflammatory drugs, inhibit COX, but have slow onset, weak analgesic and antipyretic action.

30. PREFERENTIAL COX-2 INHIBITORS NIMESULIDE: It is a week inhibitor of PG synthesis and indicate relative cox 2 selectively. Used in sports injury , sinusitis, dental surgery, post op pain , fever. Absorbed orally,99% plasma protein bound. T1/2 of 2-5hrs

31. SELECTIVE COX-2 INHIBITORS ( Coxibs ) The theoretical advantage of inhibiting COX-2 without affecting COX-1 function, some highly selective COX-2 inhibitors are introduced. They cause less gastric mucosal damage; occurrence of peptic ulcer and ulcer bleeds is clearly lower than with traditional NSAIDs. They do not depress TXA2 production by platelets (COX-1 dependent); do not inhibit platelet aggregation or prolong bleeding time, but reduce PGI2 production by vascular endothelium.

32. Currently, 3 selective COX-2 inhibitors (also called coxibs ) Celecoxib, Etoricoxib and Parecoxib are available in India. Rofecoxib and Valdecoxib were withdrawn within few years of marketing for increasing cardiovascular (CV) risk. It has been concluded that selective COX-2 inhibitors should be used only in patients at high risk of peptic ulcer, perforation or bleeds. If selected, they should be administered in the lowest dose for the shortest period of time.

33. CELECOXIB: It exerts anti inflammatory, analgesic and antipyretic actions with low ulcerogenic potential. Comparative trials in rheumatoid arthritis have found it to be as effective as naproxen or diclofenac, without affecting COX-1 activity in gastro duodenal mucosa. Pharmacokinetics: Celecoxib is slowly absorbed, 97% plasma protein bound . t1⁄2 of ~10 hours. Dose: It is approved for use in osteo- and rheumatoid arthritis in a dose of 100–200 mg BD.

34. Analgesic –antipyretics with poor anti-inflammatory effect PARACETAMOL: (Acetaminophen) the de ethylated active metabolite of phenacetin, was introduced in 1950. ACTIONS: The central analgesic action of paracetamol is like aspirin, i.e. it raises pain threshold, but has weak peripheral anti inflammatory component. Analgesic action of aspirin and paracetamol is additive. Paracetamol is a good and promptly acting antipyretic. Paracetamol has negligible anti inflammatory action. It is a poor inhibitor of PG synthesis in peripheral tissues, but more active on COX in the brain.

35. PHARMACOKINETICS: Paracetamol is well absorbed orally, only about 1/4th is protein bound in plasma and it is uniformly distributed in the body. Metabolism occurs mainly by conjugation with glucuronic acid and sulfate: conjugates are excreted rapidly in urine. Plasma t1⁄2 is 2–3 hours. Effects after an oral dose last for 3–5 hours. USES Paracetamol is one of the most commonly used ‘over-the-counter’ analgesic for headache, mild migraine, musculoskeletal pain, dysmenorrhoea , etc. but is relatively ineffective when inflammation is prominent as in rheumatoid arthritis. Paracetamol is recommended as first choice analgesic for osteoarthritis by many professional bodies. In contrast to Aspirin, Paracetamol does not stimulate respiration or affect acid-base balance; does not increase cellular metabolism. It has no effects on CVS, platelet function , gastric mucosa.

36. PARACETAMOL TOXICITY Acute paracetamol poisoning- hepatotoxicity Symptoms- nausea, vomiting , diaeehoea , abdominal pain, hypoglycemia, hypotension. Death- heaptic necrosis

37. MECHANISM OF TOXICITY AND TREATMENT Toxic metabolite – detoxified by conjugation with glutathione and gets eliminated High doses- depletion of glutathione Toxic metabolites- proteins- liver and kidney- necrosis Alcoholics and premature infants – hepatotoxicity Oral methionine replenishes glutathione store of liver and protects the liver Activated charcoal – decrease the absorption of paracetamol from gut

38. GUIDELINES FOR USAGE OF NSAIDS Mild-to-moderate pain with little inflammation: paracetamol or low-dose ibuprofen. Postoperative or similar acute but short- lasting pain: ketorolac, a propionic acid derivative. Exacerbation of rheumatoid arthritis, ankylosing spondylitis, acute gout, acute rheumatic fever: naproxen, piroxicam, indomethacin, high dose aspirin. Gastric intolerance to traditional NSAIDs or predisposed patients: a selective COX-2 inhibitor or paracetamol. Patients with history of asthma or anaphylactoid reaction to Aspirin or other NSAIDs: Nimesulide , COX-2 inhibitor. Paediatric patients: only paracetamol, aspirin, ibuprofen and naproxen have been adequately evaluated in children — should be preferred in them. Due to risk of Reye’s syndrome, aspirin should be avoided.

39. HOST MODULATION BY NSAIDS Goldhaber and coworkers examined whether prostaglandins might be responsible in part for the gingival-tissue extract mediated bone resorption. They were studying by adding indomethacin to the culture media, as an inhibitor of cyclooxygenase. The prostaglandin production blocked by indomethacin decreased the bone resorption in tissue culture by up to 50% . Free arachidonic acid (AA) is produced in the hosts when phospholipase A2 acts on the phospholipids present in plasma membranes of the cells which can then be metabolized to produce prostaglandins via the cyclooxygenase (COX) pathway as well as leukotrienes via the lipoxygenase (LOX) pathway.

40. Non‐steroidal anti‐inflammatory (NSAIDs) drugs block the activity of both cyclooxygenase isozymes (COX- 1 and -2) and many authors have demonstrated the role of NSAIDs like flurbiprofen, indomethacin, and naproxen, in inhibiting gingivitis and progression of periodontitis Since NSAIDs are lipophilic and are well absorbed into gingival tissues, its topical application is possible. NSAIDs that have been evaluated for topical administration include ketorolac, tromethamine rinse and S-ketoprofen dentifrice, piroxicam and meclofenamic acid in inhibiting gingivitis and progression of periodontitis.

41. Waite et al (1981) demonstrated that subjects taking several types of NSAIDs, which included phenylbutazone, indomethacin, aspirin, a combination of phenylbutazone and indomethacin, as well as other medications, had less gingival inflammation and shallower pocket depths than a control population not taking medications. In studying the NSAID ibuprofen and its effect on periodontal disease, Williams et al. (1988) demonstrated that high (4 mg/kg) and low (0.4 mg/kg) doses of ibuprofen in both sustained release and normal release formulations resulted in reduction in the rate of bone loss. THE EFFECT OF NSAIDS ON PERIODONTAL DISEASE

42. CONCLUSION

43. REFERENCES Tara V Shanbhag , Pharmacology for dentistry Tripati KD. Non steroidal anti inflammatory drugs. In: Essentials of medical pharmacology: 7, Jaypee publishers; 2013: 192-205. General physiology book sembulingam . Caranza text book .8th edition. Tripati KD. Prostaglandins, leukotrienes and platelet activating factor. In: Essentials of medical pharmacology: 7, Jaypee publishers; 2013: 181-191. Sembulingam for physiologyDewhirst . F. E.: 6-Keto-Prostaglandin El Stimulated Bone Resorption in Organ Culture. Calcif . Tissue Int. 1984; 36:380-383. Heasman, P. A. and R. A. Seymour. The Effect of a Systemically-administered Nonsteroidal Anti inflammatory Drug (Flurbiprofen) on Experimental Gingivitis in Humans. J Clin.Periodontol 1989; 16:551- 556.