NSAID's

BASIC SCIENCES- PHARMACOLOGY

1. PREPARED BY: DR. BEENA VIJAYAN PARVATHY Ist YEAR MDS DEPARTMENT OF PERIODONTICS AND IMPLANTOLOGY NSAIDs ALLPPT.com _ Free PowerPoint Templates, Diagrams and Charts

2. CONTENTS • Introduction Definition History Classification Mechanism of Action Prostaglandins and Periodontitis Salicylates Propionic Acid Derivatives Anthranilic Acid Derivatives Aryl-acetic Acid Derivatives Oxicam Derivatives Pyrollo-pyrolle Derivatives

3. • Indole Derivatives Pyrazolone Derivatives Preferential Cox-2 Inhibitors Selective Cox-2 Inhibitors( coxibs ) Para Amino Phenol Derivatives Choice Of NSAID’s NSAID’s As Host Modulatory Agents Risk vs Benefits of NSAIDs for Periodontal Disease Treatment NSAID’s – Enzymes Combinations Commercially Available Combinations NSAID’s And Periodontitis Review Conclusion • References

4. INTRODUCTION The inflammatory response is complex, involving immune system and various endogenous agents like prostaglandins, bradykinin , histamine, chemotactic factors & superoxide free radicals formed by the action of lysosomal enzymes. The NSAIDs have anti-inflammatory, analgesic, and antipyretic properties. Prostaglandins, prostacyclins and TXA2( Thromboxane A 2 ) have been associated with gingivitis, periodontitis and alveolar bone resorption . ( Goodson et al, 1974, Williams, 1990 ).

5. DEFINITION NSAIDs are chemically diverse class of drugs that have anti-inflammatory, analgesic, and antipyretic properties. In 1971, John Vane and co-workers made the landmark observation that aspirin and some NSAIDs blocked prostaglandin generation. This is now considered to be the main mechanism of action of NSAIDs. NSAIDs are used to suppress the symptoms of inflammation associated with rheumatic disease.

6. HISTORY Willow bark (Salix alba) had been used for many centuries. Salicylic acid was prepared by hydrolysis of the bitter glycoside obtained from this plant. Sodium salicylate was used for fever and pain in 1875. Its great success led to the introduction acetylsalicylic acid (aspirin) in 1899 ( Fredrich Bayer & Co). Phenacetine and antipyrine were also introduced. The development of phenylbutazone in 1949 having anti - inflammatory activity almost comparable to corticosteroids.

7. Indomethacin was introduced in 1963. A host of compounds heralded by the propionic acid derivative, ibuprofen have been added since then and cyclooxygenase (COX) inhibition is recognised to be their most important mechanism of action. Some selective COX-2 inhibitors ( rofecoxib , celecoxib ) have also been added.

8. CLASSIFICATION ( KD Tripathi 1 st ed) Non selective COX inhibitors 1. Salicylates : Aspirin 2. Propionic acid deriviatives : Ibuprofen, Naproxen, Ketoprofen , Flurbiprofen . 3. Anthranilic acid deriviatives : Mephenamic acid. 4. Aryl acetic acid derivatives : Diclofenac , Aceclofenac . 5. Oxicam deriviatives : Piroxicam , Tenoxicam . 6. Pyrrolo pyrrole deriviative : Ketorolac . 7. Indole deriviative : Indomethacin . 8. Pyrazolone deriviative : Phenylbutazone . B. Preferential COX – 2 inhibitors Nimesulide , Meloxicam , Nabumetone . C. Selective COX – 2 inhibitors Celecoxib , Etoricoxib , Parecoxib . D. Analgesic – antipyretics with poor antiinflammatory action 1. Paraaminophenol deriviative : Paracetamol . 2. Pyrazolone deriviative : Metamizol . 3. Benzoxazocine deriviative : Nefopam .

9. MECHANISM OF ACTION OF NSAIDs Inflammation occurs when tissue get injured by any cause. Inflammation is defined as the local response of living tissues to injury due to any agent. Due to inflammation various inflammatory mediators are released such as prostaglandin,histamine,bradykinin,IL-1,TNFalpha etc. Prostaglandins 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.

10. A drug that prevents the synthesis of prostaglandin is likely to be effective in relieving pain due to inflammation of any kind. This is done by inhibiting cyclo – oxygenase (COX) enzyme in the pathway for prostaglandin synthesis. COX exists in two isoforms : 1.COX-1-Constitutive (House keeper) Mucus secretion, Haemostasis, renal functions. It is physiologic enzymes. 2.COX-2-Inducible (Inflammatory response) Sites-brain, Juxtaglomerular cells (constitutive). It is pathologic enzymes.

11. Beneficial actions due to Prostaglandin synthesis inhibition  Analgesia  Antipyresis  Anti inflammatory  Anti thrombotic  Closure of ductus arteriosus Shared toxicities due to Prostaglandin 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.

12. Analgesia Prostaglandins induce hyperalgesia by increasing sensitivity of afferent nerve endings to chemical and mechanical stimuli and thus amplify action of other first line inflammatory mediators. Prostaglandins in CNS lowers threshold of central pain circuit. NSAIDs block this pain sensitizing mechanism therefore effective against inflammation associated pain. 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.

13. Antipyresis Fever in infection is produced by pyrogens , TNF, ILs, interferon- induce production of Prostaglandins in hypothalamus-raise its temp. set point. NASIDs block the action of pyrogens (COX2).

14. Anti-inflammatory Inhibition of Prostaglandin 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 granulocyte macrophage-CSF,IL-6,and lymphocyte transformation factors. NSAIDs-Stabilises leucocytes lysosomal membrane, and antagonizes certain action of kinins .

15. Antiplatelet Inhibit synthesis of TXA 2 by acetylating platelet COX irreversibly. Anaphylactoid reaction Aspirin precipitates bronchial asthma, angioneurotic swelling, urticaria or rhinitis in certain individuals. These subjects react similarly to chemically diverse NSAIDs, ruling out immunological basis for the reaction.

16. PROSTAGLANDINS AND PERIODONTITIS Prostaglandins - mediators of the cardinal signs of inflammation: redness, edema , pain, heat, and loss of function. (Weeks et al 1972, Hinman et al 1972, Kuehl et al 1980) . Multiple studies found that in addition to prostaglandins, the prostacyclines and phospholipases also caused bone resorption . ( Raisz et al 1977, Dewhirst et al 1984, Newman et al 1984, Loning et al, 1980; El Attar et al, 1981; Ohm et al, 1984; Yoda et al, 1984; Mendieta et al, 1985; El Attar et al, 1986; Williams et al, 1988; Dewhirst et al, 1983).

17. SALICYLATES ASPIRIN Aspirin is acetyl salicylic acid converted in body to salicylic acid. It was obtained from ‘willow bark’ ( Salicaceae ) but is now synthesizedMethyl salicylate is a volatile liqiud derivate. MOA-aspirin inhibits COX irreversibly by acetylating one of its serine residue. Its one of the oldest analgesic-anti inflammatory drug and is still widely used.

18. PHARMACOLOGICAL ACTIONS ANALGESIC,ANTIPYRETIC,ANTIINFLAMMTORY ACTION :- Aspirin is a weaker analgesic than morphine (600 mg ~codeine 60mg), but effectively relieves, tissue injury related inflammation and integumental pain. Relatively ineffective in severe viceral and ischemic pain. The analgesic action is mainly due to obtunding of peripheral receptors and prevention of prostoglandin -mediated sensitization of nerve endings.

19. • Aspirin resets the hypothalamic thermostat and rapidly reduces fever by promoting heat loss (sweating, cutaneous vasodilatation), but does not decrease heat production. • Anti inflammatory action is exerted at high doses(3-5g/day or 100mg/kg/day) • Signs of inflammation are supressed but progression of underlying disease in Rh arthritis,Rh fever and osteoarthrirtis are not affected.

20. METABOLIC EFFECTS :- Significant only at anti-inflammatory doses. Cellular metabolism is increased, especially in skeletal muscles due to uncoupling of oxidative phosphorylation increased heat production. Increased decrease in blood sugar(specially in diabetics) and liver glycogen is depleted. Hyperglycemia is seen at toxic doses due to central sympathetic stimulation increases release of Adrenal and corticosteroids.

21. ACID BASE AND ELECTROLYTE BALANCE :- Usual analgesic dose(0.3-1.5g) have no effect. Anti-inflammatory doses produce significant change in acid balance. CVS :- No direct effect in therapeutic dose. Larger doses increase cardiac output to meet increased peripheral O 2 demand and cause vasodilatation. Toxic doses depress vasomotor centre. BP may fall.

22. GIT :- Aspirin and released salicylic acid irritates gastric mucosa cause epigastric distress, nausea and vomiting. At high doses it stimulates chemoreceptor trigger zone as well. Aspirin remains unionized in gastric juice but on entering mucosal cell it ionises. This ion trapping enhances gastric toxicity.

23. BLOOD :- Even small doses inhibit TXA2 synthesis irreversibly by platelets this interferes platelet aggregation thus bleeding time prolonged to twice the normal value. This last for 1 week ( turn over time of platelet). Long term intake of aspirin decrease synthesis of clotting factors in liver and predisposes to bleeding ( prevented by prophylactic Vit K therapy).

24. PHARMACOKINETICS Well absorbed from stomach and small intestine. 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. Volume of distribution=0.17L/kg. Slowly enters the brain but freely crosses placenta.

25. 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 with released salicylic acid is 3-5hrs. Metabolic processes get saturated over therapeutic range. t1/2 of anti-inflammatory doses may be 8-12hrs. While that during poisoning may be upto 30hrs. Thus elimination is dose dependant.

26. ADVERSE EFFECTS a) Gastrointestinal :- • Most common side effect that occurs at analgesic dose (0.3-1.5g/day). • Epigastric distress, nausea, vomiting. • Increased occult blood loss in stools. • Gastric mucosal damage and peptic ulcer. b) Hypersensitivity and Idiosyncrasy :- • Though infrequent, these can be serious. • Reactions include; rashes, urticaria , angioedema , rhinorrhoea , asthma and anaphylactoid shock.

27. c) Salicylism :- High doses(at anti-inflammatory doses) or chronic use of aspirin may induce a syndrome characterised by tinnitus, hearing defects, blurring of vision, dizziness, headache, mental confusion, hyperventilation and electrolyte imbalance. Effects are reversible. d) Rey’s syndrome :- • Occurs in infants and children. • Occurs when aspirin given during viral infections( varicella , influenza). • Characterized by liver damage and encephalopathy. • Replaced by acetaminophen in such condition to reduce fever.

28. e) Acute salicylate poisoning :- • 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 Vomiting, dehydration, electrolyte imbalance, acidotic breathing, hyper/ hypoglycemia , petechial hemorrhages , restlessness, delirium, hallucinations, hyperpyrexia, convulsions, coma and death due to respiratory and cardiovascular failure.

29. TREATMENT • Symptomatic and supportive. • Most important is external cooling. • Gastric lavage . • I.V. infusion of Na+ , K+ , HCO3 and glucose(dextrose-5%). • Vitamin K 10mg I.V. • Peritoneal dialysis or hemodialysis .

30. PRECAUTIONS AND CONTRAINDICATIONS • Peptic ulcer. • Sensitive patients. • 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.

31. INTERACTIONS • Aspirin displaces warfarin , naproxen, sulfonylurease & phenytoin from its plasma protein binding sites-toxicity of these drugs may occur • Its anti-platelet action increases risk of bleeding in patients on oral anticoagulant. • Inhibits tubular secretion of uric acid and antagonizes action of uricosuric agents.

32. USES AND DOSES • 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/days- in various infections.

33. VARIOUS PREPERATIONS AVAILABLE • Aspirin 350mg T • Colsprin 100,325,625mg T • Ecospirin 75,150,325mg T • Disprin 350mg T • Loprin 75,162.5mg T • Biosprin : recently available injection prepration (Lysine acetylsalicylate 900mg+Glycine100mg/5ml water)

34. PROPIONIC ACID DERIVATIVES • IBUPROFEN (1969) better tolerated alternative to aspirin • MOA- inhibit PG synthesis • Most potent- naproxen • Others – ketoprofen , flurbiprofen • Anti inflammatory efficacy is rated somewhat lower to that of high dose of aspirin • Inhibit platelet aggregation reversibly and cause short lasting prolongation of bleeding time.

35. ADVERSE EFFECTS • Most common-nausea, gastric discomfort and vomiting (less than aspirin or indomethacin ). • Gastric erosion and occult blood loss-rare. • CNS-headache, dizziness, blurring of vision, tinnitus, depression. • Rashes, itching and other hypersensitivity phenomenon are infrequent. CONTRAINDICATED In pregnant woman and peptic ulcer patient.

36. PHARMACOKINETICS AND INTERACTIONS • Better tolerated orally and the incidences of adverse reactions are low. • Highly bound to plasma proteins (90-99%). • Because they interact with platelet function, SHOULD NEVER BE USED with anticoagulants. • Enter brain, synovial fluid and cross placenta. • Metabolized in liver by hydroxylation and glucuronide conjugation. • Excreted in urine as well as bile.

37. DOSAGE AND PREPARATIONS OF PROPIONIC ACID DERIVATIVES DRUG PLASMA t1/2 DOSAGE PREPERATIONS IBUPROFEN 2 hr 400-600mg (5-10mg/kg) TDS BRUFEN,EMFLAM,IBUSYNTH 200,400,600mg T, IBUGESIC also 1 00mg/5ml suspension NAPROXEN 12-16hr 250mg BD-TDS NAPROSYN,NAXID, ARTAGEN,XENOBID 250mg T,NAPROSYN also 500mg T KETOPROFEN 2-3hr 50-100mg BD-TDS KETOFEN 50,100mg T, OSTOFEN 50mg C,RHOFENID 100mg,200mg SRT,100mg/200ml amp FLURBIPROFEN 4-6hr 50mg BD-QID ARFLUR 50,100mg T,200mg SR T, FLUROFEN 100mg T.

38. USES • Rh arthritis, osteoarthritis , other musculoskeletal disorders specially when pain is more prominent than inflammation. • Soft tissue injury, tooth extraction, fractures, post partum and post op, supress swelling and inflammation-VERY POPULAR IN DENTISTRY. • NAPROXEN is more efficacious and better tolerated in anti inflammatory doses (long acting and BD dose).

39. ANTHRANILIC ACID DERIVATIVE(FENAMATE) MEPHENAMIC ACID It is an analgesic, antipyretic and anti inflammatory agent which inhibits COX as well as antagonises certain actions of PGs. Mephenamic acid exerts peripheral as well as central analgesic action. ADVERSE EFFECTS Diarrhoea is the most important dose related side effect. PHARMACOKINETICS Oral absorption is slow but almost complete. It is highly bound to plasma proteins. Partly metabolized and excreted in urine as well as bile. Plasma t ½ is 2-4 hours.

40. USES It is indicated as analgesic in muscle, joint and soft tissue pain It effective in dysmenorrhoea. It may be useful in cases of rheumatoid and osteoarthritis. DOSE 250-500mg TDS MEDOL 250,500mg T MEFTAL 250,500mg T;100mg/5ml susp . PONSTAN 125,250,500mg T,50mg/ml syrup.

41. ARYL-ACETIC ACID DERIVATIVE DICLOFENAC SODIUM Along with prostaglandin inhibition, it also reduces nuetrophil chemotaxis • Inhibits the lipooxygenase pathways, thus reducing formation of the leukotrienes • May inhibit phospholipase A 2. • Used commonly to treat mild to moderate post-operative or post-traumatic pain, particular when inflammation is also present, and is effective against menstrual pain. Well absorbed orally, plasma half life is ~2hrs. • Good tissue penetrability & concentration in synovial fluid is maintained for three times longer than plasma.

42. Dose: 50mg TDS, then BD oral,75mg deep im VOVERAN, DICLONAC, MOVONAC 50mg enteric coated T,100mg SRT,25mg/ml in 3ml amp for im injection. Diclofenac potassium: VOLTAFLAM 25,50mg T, VOVERAN 1% topical gel. ACECLOFENAC Relatively selective COX2 congener of diclofenac sodium Dose : 100mg BD ACECLO,DOLOKIND 100mg T,200 mg SRT. USES Toothache, Rh and osteoarthritis, bursitis, ankylosing spondylitis , dysmenorrhoea,post traumatic and post op inflammatory conditions affords quick relief of pain and wound oedma .

43. ADVERSE EFFECTS • Epigastric pain • Nausea • Headache • Dizziness • Rashes • Gastric ulceration & bleeding are less common • Reversible increase in serum aminotransferases • Kidney damage is rare.

44. OXICAM DERIVATIVES PIROXICAM Long acting, potent NSAID with good antiinflammatory action. MOA • Reversible inhibitor of COX. • Lowers concentration of prostaglandin in synovial fluid. • Decreases production of IgM Rheumatoid factor. • Chemotaxis of leucocytes is inhibited. PHARMACOKINETICS Well absorbed orally, 99% is plasma bound. • Single daily dose is sufficient. • Used for short and long term antiinflammatory conditions.

45. ADVERSE EFFECTS • Heartburn, nausea, anorexia are common • Better tolerated and less ulcerogenic than indomethacin • Cause less faecal blood loss than aspirin • Rashes and pruritis are seen in < 1 % cases • Edema and reversible azotaemia (abnormally high levels of nitrogen containing compounds in blood) have been observed. USES Short term analgesic and long term anti inflammatory drug in Rh and osteoarthritis, ankylosing spondylitis , acute gout, musculoskeletal injuries and in dentistry.

46. DOSE • 20 mg BD for 2 days followed by 20mg OD • DOLONEX,PIROX 10,20 mg C , 20mg disp T, 20mg/ml inj in 1 and 2 ml amp • PIRICAM 10,20 mg C • TENOXICAM : congener of piroxicam ; TOBITIL 20 mg T, dose 20 mg OD.

47. PYROLLO-PYROLLE 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 ,dental pain 2. Acute musculoskeletal pain (15-30mg IM or IV) 3. Renal colic 4. Migraine 5. Pain due to bony metastasis

48. One of the few NSAIDs that can be used for parenteral administration. • Continous use for more than 5 days is not recommended. • Cause Dizziness, Dyspepsia, Nausea and pain at site of injection • Should not be given to patients on oral anticoagulants. • Not indicated for preaesthetic medication or for obstetric analgesia. • KETOROL, ZOROVON, KETANOV,TOROLAC 10mg T, 30mg in 1 ml amp.

49. INDOLE DERIVATIVES It is a potent analgesic anti-inflammatory & antipyretic It relives only inflammatory or tissue related pain. It is highly potent inhibitor of PG synthesis and suppresses neutrophil motility. PHARMACOKINETICS It is well absorbed orally, rectal absorption is slow but dependable. It is 90% bound to plasma proteins, partly metabolized in liver to inactivate products and excreted by kidney. Plasma t1/2 is 2-5 hours.

50. ADVERSE EFFECTS A high incidence of gastrointestinal and CNS side effects is produced. Increased risk of bleeding due to decreased platelet aggregation. Gastric irritation, nausea, anorexia, gastric bleeding and diarrhoea are prominent Frontal headache(very common), dizziness, ataxia, mental confusion, hallucination ,depression, pschycosis Leucopenia ,rashes and other hypersensitivity reactions are also reported.

51. CONTRAINDICATIONS Machinery operators Drivers Psychiatric patients Epileptics Kidney disease Pregnant women and in children DOSE 25-50 mg BD INDICIN, INDOCAP 25mg C,75mg SR C, ARTICID 25,50mg C, INDOFLAM 25,75mg C,1% eye drop.

52. USES Rheumatoid arthritis Ankylosing spondylitis Acute exacerbations of destructive artropathies Psoriatic arthritis Acute gout Closure of patent ductus arteiosus dose; 0.1-0.2mg/kg

53. PYRAZOLONE DERIVATIVES ANTIPYRINE AND AMIDOPYRINE were introduced in 1884 as antipyretics and analgesics. Their use was associated with agranulocytosis . PHENYLBUTAZONE was introduced in 1949 but are rarely used now due to risk of bone marrow depression. Two other pyrazolone -METAMIZOL and PROPIPHENAZONE. METAMIZOL (DIPYRONE) • It is a derivative of amidopyrine which continues to be widely used. • In contrast to phenylbutazone , it is a potent and promptly acting analgesic. • It can be given orally, I.M. as well as I.V but gastric irritation and pain at injection site occurs.

54. . DOSE 0.5-1.5 g oral/IM/IV ANALGIN 0.5g tab NOVALGIN, BARALGAN 0.5g tab,0.5gm/ml in 2ml and 5ml amps,ULTRAGIN 0.5gm/ml injection in 2ml amp and 30ml vial. PROPIPHENAZONE Another pyrazolone , similar in properties to metamizol ; claimed to be better tolerated. DOSE 300-600 mg TDS, SARIDON,ANAFEBRIN: Propiphenazone 150 mg + Paracetamol 250 mg., DART: propiphenazone 150mg + paracetamol 300mg + caffeine 50mg T.

55. PREFERENTIAL COX-2 INHIBITORS NIMESULIDE • Weak inhibitor of prostaglandin synthesis. • Anti inflammatory action may be exerted by other mechanisms like reduced generation of superoxide by nuetrophils , inhibition of platelet activating factor synthesis & TNF release, free radical scavenging, inhibition of metalloproteinase activity in cartilage. USES Short lasting inflammatory conditions like sports injuries, sinusitis, other ENT disorders, dental surgery, bursitis, low back ache, dysmmenorrhea , post op pain, osteoarthritis and fever.

56. PHARMACOKINETICS • Completely absorbed orally. • 99% plasma protein bound. • Extensively metabolized and excreted mainly in urine. • Plasma t1/2 2-5hrs. ADVERSE EFFECTS • GI- epigastralgia , heart burn, nausea, loose motion • Dermatological- rashes, pruritis • Central- somnolence, dizziness • Haematuria in children. Used in asthmatics who cannot tolerate ASPIRIN.

57. DOSE 100mg BD; NIMULID,NIMEGESIC,NIMODOL,100mg T,50mg/ml susp . MELOXICAM • Newer congener of piroxicam has COX2:COX1 selectivity ratio 10. • Since measurable inhibition of platelet TXA2 occurs at therapeutic dose it has been labelled pref.COX2. DOSE 7.5-15mg OD,MELFLAM,MEL-OD,MUVIK,M-CAM 7.5mg,15mg T

58. NABUMETONE • Prodrug with analgesic, antipyretic and antiinflammatory activity. • Effective in Rh , osteoarthritis and soft tissue injury. DOSE NABUFLAM 500mg T ,1tab OD

59. SELECTIVE COX-2 INHIBITORS(COXIBS) Celecoxib , Etoricoxib , Parecoxib , Rofecoxib , Valdecoxib,Lumiracoxib • Directly targets COX-2. • Reduces the risk of peptic ulceration. • These drugs should be avoided in presence of severe hepatic/renal disease & in those receiving rifampin , warfarin , methotrexate . • Increased risk of myocardial infarction and stroke. DOSE Rofecoxib 12.5-25 mg OD, ROFACT, ROFEGESIC, RIFIBAX, ROFLAM, Celecoxib 100-200 mg BD, CELACT, REVIBRA, COLCIBRA, Etoricoxib 60-120mg OD, ETODY,TOROCOXIA, ETOXIB,NUCOXIA,60,90,120mg T, Parecoxib 40mg oral IM/IV repeated after 6-12hrs, REVALDO,VALTO-P 40mg/vial injection, PAROXIB 40mg T.

60. PARA AMINO PHENOL DERIVATIVES PHENACETIN • Was introduced in 1887. PARACETAMOL • The deethylated active metabolite of phenacetin but came into common use since 1950. • The central analgesic action of paracetamol is like aspirin, it raises pain threshold. • Paracetamol is a good and promptly acting antipyretic, it is a poor inhibitor of PG synthesis in peripheral tissues, but more active on COX in brain (poor ability to inhibit COX in presence of peroxides generated at site of inflammation) • Gastric irritation is insignificant; Mucosal erosion and bleeding occur rarely only in overdose. • It does not affect platelet function or clotting factors.

61. PHARMACOKINETICS • Well absorbed orally; only 1/4th is plasma bound ; uniform distribution in body • T1/2 2-3hrs;effect of an oral dose lasts for 3-5hrs. ADVERSE EFFECTS • Nausea and rashes are occasional. • Leukopenia is rare. • Acetaminophen overdose can cause hepatotoxicity , severe hepatotoxicity has been reported even after therapeutic doses. • ANALGESIC NEUROPATHY: occurs after years of heavy ingestion of analgesics; such persons have some personality defect.

62. ACUTE PARACETAMOL POISONING • Occurs specially in small children who have low hepatic glucuronide conjugating ability. • If large dose is taken (>150mg/kg or >10g in an adult) serious toxicity can occur ; fatality common with>250mg/kg. • Early manifestation : nausea, vomiting, abdominal pain, liver tenderness. • After 12-18hrs: hepatic, renal tubular necrosis, hypoglycemia progressing to coma. • After 2days: jaundice. • Further fulminating hepatic failure and death.

63. TREATMENT • If patient is bought early:vomiting is induced, gastric lavage done, activated charcoal given to prevent further absorption. • ANTIDOTE : N- acetylcysteine infused IV /orally • Paracetamol is not recommended in premature infants for fear of hepatotoxicity . USES • Headache • Musculoskeletal pain • Toothache • Dysmenorrhea • Much safer than aspirin in terms of GI manifestations • Does not prolong bleeding time ; so less chance of post extraction haemorrhage

64. DOSE 0.5- 1gTDS, infants 50mg, children 1-3yrs 80-160mg, 4-8yrs 240-320mg, 9-12yrs 300-600mg, CROCIN 0.5,1.0mg T, METACIN, PARACIN 500mg T 125mg/5ml syrup, 150mg/ml paed.drops , ULTRAGIN, PYRIGESIC, CALPOL 500mgT, 125mg/5ml syrup NEOMOL,FEVASTIN,FEBRINIL 300mg/2 ml injection, CROCIN PAIN RELIEF: paracetamol 650mg+caffeine 50mg T.

65. CHOICE OF NSAIDs 1.Mild to moderate pain with little inflammation paracetamol or low dose ibuprofen. 2. Acute musculoskeletal, osteoarthritic , injury associated inflammation-a propionic acid derivative, diclofenac or rofecoxib . 3. Postextraction or other acute short lasting pain- ketorolac,diclofenac , nimesulide , a propionic acid derivative. 4.Gastric intolerence to conventional NSAIDs- etoricoxib , paracetamol 5. H/O asthma, anaphylactic reaction to aspirin or other NSAIDs- nimesulide,COX2 inhibitor. 6. Pregnancy- paracetamol best preferred, second best low dose aspirin. 7. Paediatric- paracetamol ,aspirin, ibuprofen, naproxen.

66. NSAID’s as HOST MODULATORY AGENTS • Concept of host modulation was 1st introduced by Williams (1990) and Golub et al (1992). • To modify or reduce destructive aspects of host response: so that immune-inflammatory response to plaque is less damaging; host modulation therapies has been developed. • Treatment concept that aims to reduce tissue destruction and stabilize or even regenerate the periodontium by modifying or downregulating destructive aspects of host response and upregulating protective or regenerative responses.( CARRANZA)

67. ACTIONS • Inhibits prostaglandins • Reduce inflammation – Used to treat pain, acute inflammation, and chronic inflammatory conditions. – Inhibits osteoclastic activity in periodontitis (Howell TH in oral bio med 1993) • NSAIDs such as indomethacin ( W illiams RC 1987) flurbiprofen ( J effcoat MK JP 1989) and naproxen(Howell TH 1993) administered daily for up to 3 years, significantly slowed the rate of alveolar bone loss compared with placebo.

68. DISADVANTAGES • Administration for extended periods is necessary for periodontal benefits to become apparent, and are associated with significant side effects: – gastrointestinal problems, – hemorrhage (from decreased platelet aggregation), – and renal and hepatic impairment. • Research shows that the periodontal benefits of taking long-term NSAIDs are lost when patients stop taking the drugs, with a return to or even an acceleration of the rate of bone loss seen before NSAID therapy, often referred to as a “rebound effect.”(William RC j dentres 1991).

69. Inhibition of COX-1 by nonselective NSAIDs causes side effects – gastrointestinal ulceration – and impaired hemostasis • Use of selective COX-2 inhibitors reduce periodontal inflammation without the side effects typically observed after long-term ( nonselective ) NSAID. • Selective COX-2 inhibitors slowed alveolar bone loss in animal models( Bezerra MM J Periodontol 1993) and modified prostaglandin production in human periodontal tissues (Vardar S J Periodontol 2003)

70. Risk vs Benefits of NSAIDs for Periodontal Disease Treatment • NSAIDs - harmful side effects. • Gastrointestinal upset. • Haemorrhage. • Renal and hepatic impairment. • Induction of aseptic meningitis in previously healthy patients. • Ibuprofen in high doses impairs wound healing(Proper et al, 1988). • It is not clear whether NSAIDs promote or hinder the overall mineralization process in contemporary periodontal regenerative therapy (McAllister et al,1995).

71. NSAID’s – Enzymes Combinations • Enzyme combination of NSAIDs helps in reduction of unwanted drug effects while maintaining the anti-inflammatory/analgesic efficacy . • Protease enzymes belonging to family metalloprotease , have been successfully tested for their anti inflammatory properties, which include trypsin , chymotrypsin and serratiopeptidse (Miyata et al., 1971; McQuade and Crewther , 1969; Lyerly and Kreger , 1981; Aiyappa and Harris, 1976; Decedue et al 1979). • Proteolytic enzymes are large protein molecules and they will be absorbed in an active form from GIT. To overcome their destruction in stomach by hydrolysis, these tablets are given in enteric coated dosage form and in combinations.

72. Commercially Available Combinations • Aceclofenac , Paracetamol , Serratiopeptidase- Acecloren , Acekem -SP • Diclofenac Potassium, Serratiopeptidase - Acfast d, Aldase D (50mg) • Diclofenac Sodium, Serratiopeptidase - Actimol S, Alnec -S • Diclofenac Potassium, Chymotrypsin - Alfapsin -D, Alzibit -D • Diclofenac Potassium, Trypsin,Chymotripsin - Chemofast -D , Chymobel Plus

73. NSAID’s And Periodontitis Review According to Anusha Etikala et al, the influence of administration of NSAID drugs on outcomes following periodontal treatments (nine clinical studies) and dental implant placement (four animal studies and two human clinical studies). Conflicting results were found on the effects of NSAIDs during periodontal wound healing. NSAID administration, specifically COX-2 inhibitors could inhibit bone formation around orthopedic implants and concluded within the limitations of this review, NSAIDs negatively affected osseointegration titanium implants. According to Maracella Morro et al in the study they compared the effects of the selective COX-2 inhibitor etoricoxib with those of the classical non-selective NSAID diclofenac on the inflammatory process and alveolar bone loss in an experimental model of periodontitis in rats.

74. CONCLUSION • NSAIDs have an extremely safe profile when used for acute dental pain. • Within a group they tend to have similar characteristics and tolerability. There is little difference in clinical efficacy among the NSAIDs when used at equivalent doses. • Rather, differences among compounds usually relate to dosing regimens (related to the compound's elimination half-life), route of administration, and tolerability profile. • So a clinician should have a thorough knowledge of mechanism of action, pharmacokinetics, pharmacodynamics , dosage and adverse effects of each drug before prescribing the same.

75. REFERENCES Essentials of pharmacology for dentistry K D Tripathi – 2nd edition. Carranza’s Clinical Periodontology - 11 th edition. Periobasics – 2 nd edition . Pharmacology and therapeutics for dentistry John A Yagiela,Enid A Neidle,Frank J Dowd-4th edition. Effects of NSAIDS on Periodontal and Dental Implant Therapy; Compendium- 2019. Host modulation therapy with anti- inflammatory agents Periodontology 2000, Vol. 10 , 2017.