1. Nonsteroidal Anti- inflammatory Drugs 1. Non selective drugs1. Non selective drugs Salicylates e.g. Aspirin is the prototype drugSalicylates e.g. Aspirin is the prototype drug Mechanisms of actionMechanisms of action 1- Antiinflammatory1- Antiinflammatory A) Inhibit prostaglandines synthesis through irreversible inhibition of cyclo-oxygenase enzymes ( Cox-1 & Cox-2).A) Inhibit prostaglandines synthesis through irreversible inhibition of cyclo-oxygenase enzymes ( Cox-1 & Cox-2). B) Interferes with the chemical mediators of the kallikrein system.B) Interferes with the chemical mediators of the kallikrein system.

2. Mechanisms of action (cont.) B) Inhibits the migration of polymorphonuclear leukocytes to the site of inflammation.B) Inhibits the migration of polymorphonuclear leukocytes to the site of inflammation. C) Anti-oxidant activity.C) Anti-oxidant activity. D) Stabilizing lysosomesD) Stabilizing lysosomes

3. 2- Analgesics 1- For mild & moderate dull aching pain as antiinflammatory1- For mild & moderate dull aching pain as antiinflammatory 2- Inhibits pain stimuli at subcortical site2- Inhibits pain stimuli at subcortical site

4. 3- Antipyretic 1- COX inhibition in the C.N.S.1- COX inhibition in the C.N.S. 2- Inhibition of IL-12- Inhibition of IL-1

5. 4- Antiplatelet Irreversible inhibition of platelet COXIrreversible inhibition of platelet COX Aspirin effect lasts 8-10 days ( life of platelets )Aspirin effect lasts 8-10 days ( life of platelets )

6. Pharmacological actions A) AnalgesicA) Analgesic B) AntipyreticB) Antipyretic C) AntithromboticC) Antithrombotic D)Anti-inflammatoryD)Anti-inflammatory E) Uricosuric ( large dos)E) Uricosuric ( large dos)

7. Clinical uses A) AnalgesicA) Analgesic B) AntipyreticB) Antipyretic C) Anti-inflammatoryC) Anti-inflammatory D) Antithrombotic( cardioprotective)D) Antithrombotic( cardioprotective) E) Chronic gouty arthritisE) Chronic gouty arthritis F)Cancer pain in combination with opioid drugsF)Cancer pain in combination with opioid drugs

8. Adverse effects At therapeutic dosesAt therapeutic doses A) Gastric upset ( intolerance)A) Gastric upset ( intolerance) & gastric or duodenal ulceration& gastric or duodenal ulceration B) Gouty arthritisB) Gouty arthritis C) Asthma, rashesC) Asthma, rashes D) Hepatotoxicity & renal toxicity are less frequent.D) Hepatotoxicity & renal toxicity are less frequent. E) Reye syndromeE) Reye syndrome

9. High doses or Prolonged use of aspirin A) Salicylism( tinnitus,vertigo, decreased hearing).A) Salicylism( tinnitus,vertigo, decreased hearing). B) HyperapneaB) Hyperapnea C)Respiratory alkalosisC)Respiratory alkalosis D) Metabolic acidosesD) Metabolic acidoses E) HyperthermiaE) Hyperthermia F) Gastric & doudenal ulcer & bleedingF) Gastric & doudenal ulcer & bleeding H) Glucose intoleranceH) Glucose intolerance

10. Contraindications A) PregnancyA) Pregnancy B) Haemophilic patientsB) Haemophilic patients C) Hypersensitivity reaction to aspirinC) Hypersensitivity reaction to aspirin D) Viral infections mainly in childrenD) Viral infections mainly in children E) Peptic ulcersE) Peptic ulcers

11. Drug-Drug interactions Potentiates the gastric irritant effect of alcoholPotentiates the gastric irritant effect of alcohol Potentiates the hypoglycaemic effects of oral hypoglycaemic drugsPotentiates the hypoglycaemic effects of oral hypoglycaemic drugs

12. PARACETAMOL Is effective only as analgesic & antipyretic.Is effective only as analgesic & antipyretic. Has no antiinflammatory effect.Has no antiinflammatory effect. Has no platelet effect.Has no platelet effect. Can be used in patients with haemophilia or peptic ulcer or allergic to aspirin.Can be used in patients with haemophilia or peptic ulcer or allergic to aspirin.

13. PARACETAMOL (cont.) Can be used during pregnancy.Can be used during pregnancy. In children with viral infections.In children with viral infections.

14. ADVERSE EFFECTS Mainly on liver due to its active metabolite ( N-acetyl-p- benzoquinone).Mainly on liver due to its active metabolite ( N-acetyl-p- benzoquinone). At therapeutic doses increases hepatic enzymes.At therapeutic doses increases hepatic enzymes. At high doses causes hepatic necrosis & renal necrosis.At high doses causes hepatic necrosis & renal necrosis. Treatment of paracetamol toxicity with N-acetylcystine (SH donor ) as life savingTreatment of paracetamol toxicity with N-acetylcystine (SH donor ) as life saving

15. 2-Propionic acid derivatives 1. Ibuprofen1. Ibuprofen PharmacokineticsPharmacokinetics Rapidly absorbed after oral ingestion.Rapidly absorbed after oral ingestion. Half-life 1-2 hoursHalf-life 1-2 hours Highly bound to plasma proteinsHighly bound to plasma proteins Excreted through kidney as metabolites.Excreted through kidney as metabolites.

16. Ibuprofen The same mechanism & pharmacological actions of aspirin Except that it is reversible inhibitor for COX enzymesThe same mechanism & pharmacological actions of aspirin Except that it is reversible inhibitor for COX enzymes More potent as antiinflammatory than aspirinMore potent as antiinflammatory than aspirin

17. Clinical uses A) AnalgesicA) Analgesic B) AntipyreticB) Antipyretic C) Anti-inflammatoryC) Anti-inflammatory D)Acute gouty arthritisD)Acute gouty arthritis E) Patent ductus arteriosusE) Patent ductus arteriosus

18. Preparations of Ibuprofen Oral preparations.Oral preparations. Topical cream for osteoarthritis.Topical cream for osteoarthritis. A liquid gel for rapid relief of postsurgical dental pain.A liquid gel for rapid relief of postsurgical dental pain. Intravenous route as In patent ductus arteriosusIntravenous route as In patent ductus arteriosus

19. Adverse effects 1. Gastric upset ( less frequent than aspirin ).1. Gastric upset ( less frequent than aspirin ). 2. Fluid retention2. Fluid retention 3.Hypersensetivity reactions3.Hypersensetivity reactions 4. Ocular disturbances4. Ocular disturbances 5. Rare hematologic effects(agranulocytosis & aplastic anaemia ).5. Rare hematologic effects(agranulocytosis & aplastic anaemia ).

20. Contraindications 1. Peptic ulcer1. Peptic ulcer 2. Allergic patients to aspirin2. Allergic patients to aspirin 3. Kidney impairment3. Kidney impairment 4.Liver diseases4.Liver diseases 5.Pregnancy5.Pregnancy 6.Haemophilic patients6.Haemophilic patients The concomitant administration of ibuprofen antagonizes the irrevesible platelet inhibition of aspirin( limit cardioprotective effect of aspirin ).The concomitant administration of ibuprofen antagonizes the irrevesible platelet inhibition of aspirin( limit cardioprotective effect of aspirin ).

21. Oxicam derivatives PiroxicamPiroxicam TenoxicamTenoxicam

22. Piroxicam Mechanism of actionsMechanism of actions A) Non-selective inhibitors to Cox1 & Cox2A) Non-selective inhibitors to Cox1 & Cox2 B) Traps free radicalsB) Traps free radicals C) Inhibits polymorphonuclear leukocytes migrationC) Inhibits polymorphonuclear leukocytes migration D) Inhibits lymphocyte function.D) Inhibits lymphocyte function.

23. Pharmacokinetics Well absorbed orallyWell absorbed orally Half- Life 45 hoursHalf- Life 45 hours Given once dailyGiven once daily

24. Adverse effects Less frequent gastric upset (20%).Less frequent gastric upset (20%). DizzinessDizziness TinnitusTinnitus HeadacheHeadache AllergyAllergy

25. Acetic acid derivatives 1. Diclofenac1. Diclofenac Mechanism of actionMechanism of action A) As aspirin,but non-selective inhibitor to cox1 & Cox2.A) As aspirin,but non-selective inhibitor to cox1 & Cox2. More potent as anti- inflammatory than analgesic and antipyreticsMore potent as anti- inflammatory than analgesic and antipyretics

26. Pharmacokinetics Accumulates in synovial FluidAccumulates in synovial Fluid

27. Clinical uses A) Any inflammatory conditionsA) Any inflammatory conditions B) Musculoskeletal painB) Musculoskeletal pain C) DysmenorrhoeaC) Dysmenorrhoea D)Acute gouty arthritisD)Acute gouty arthritis E) FeverE) Fever F) Locally to prevent or treat post opthalmic inflammationF) Locally to prevent or treat post opthalmic inflammation G) A topical gel for solar keratosesG) A topical gel for solar keratoses

28. Adverse effects Gastric upsetGastric upset Renal impairmentRenal impairment Elevation of serum aminotransferaseElevation of serum aminotransferase Salt & water retentionSalt & water retention

29. Preparations of Diclofenac Diclofenac with misoprostol decreases upper gastrointestinal ulceration,but result in diarrhea.Diclofenac with misoprostol decreases upper gastrointestinal ulceration,but result in diarrhea. Diclofenac with omeprazole to prevent recurrent bleeding.Diclofenac with omeprazole to prevent recurrent bleeding..1% opthalmic preparation for postoperative opthalmic inflammation..1% opthalmic preparation for postoperative opthalmic inflammation. A topical gel 3% for solar keratoses.A topical gel 3% for solar keratoses. Rectal suppository as analgesic or for postoperative nausea.Rectal suppository as analgesic or for postoperative nausea.

30. Preparations of Diclofenac Oral mouth wash.Oral mouth wash. Intramuscular preparations.Intramuscular preparations.

31. Selective Cox2 inhibitors Advantages :Advantages : 1. Highly selective inhibitors to cox2 enzyme.1. Highly selective inhibitors to cox2 enzyme. 2. Potent anti-inflammatory.2. Potent anti-inflammatory. 3. Have analgesic& antipyretic3. Have analgesic& antipyretic 4. Highly bound to plasma proteins.4. Highly bound to plasma proteins.

32. Selective Cox2 inhibitors 5. Lower incidence of gastric upset5. Lower incidence of gastric upset 6. No effect on platelet aggregation (cox1 )6. No effect on platelet aggregation (cox1 ) 7. Renal toxicities ( they are not recommended for patients with severe renal insufficiency)7. Renal toxicities ( they are not recommended for patients with severe renal insufficiency) 8. High incidence of cardiovascular thrombotic events with some of them as rofecoxib.8. High incidence of cardiovascular thrombotic events with some of them as rofecoxib.

33. Selective Cox2 inhibitors 9- They are recommended in postoperative patients undergoing bone repair.9- They are recommended in postoperative patients undergoing bone repair. 10- Also, indicated in primary familial adenomatous polyposis, dysmenorrhea,10- Also, indicated in primary familial adenomatous polyposis, dysmenorrhea, Acute gouty arthritis, acute musculoskeletal pain, ankylosing spondylitis.Acute gouty arthritis, acute musculoskeletal pain, ankylosing spondylitis.

34. Celecoxib Absorption is decreased by food.Absorption is decreased by food. Half-life 11hoursHalf-life 11hours Highly bound to plasma proteinsHighly bound to plasma proteins No effect on platelet aggregationNo effect on platelet aggregation Metabolized in liver by CYP2C9 to in active metabolite.Metabolized in liver by CYP2C9 to in active metabolite. Its clearance is decreased in liver impairment.Its clearance is decreased in liver impairment. Given twice daily.Given twice daily.

35. Clinical uses Rheumatoid arthritisRheumatoid arthritis OsteoarthritisOsteoarthritis

36. Side effects Dyspepsia & heart burn.Dyspepsia & heart burn. edema & renal adverse effects.edema & renal adverse effects. Allergy (skin rash ).Allergy (skin rash ).

37. Drug interactions With warfarrin potentiate its,through interfering with its metabolism. actionsWith warfarrin potentiate its,through interfering with its metabolism. actions

38. Meloxicam Relatively selective Cox2 inhibitors.Relatively selective Cox2 inhibitors. Safer than piroxicam.Safer than piroxicam.

39. Pharmacokinetics Given orally,rectally, I.M.,I.V.Given orally,rectally, I.M.,I.V. Metabolized in liver to inactive metabolites.Metabolized in liver to inactive metabolites. Excreted in urine 50% and in feces 50%.Excreted in urine 50% and in feces 50%. Half-life 20 hours.Half-life 20 hours. Given once daily.Given once daily.

40. Clinical uses AnalgesicAnalgesic Rheumatoid arthritisRheumatoid arthritis Osteoarthritis.Osteoarthritis.

41. Adverse effects Gastric upsetGastric upset Skin rashSkin rash HeadacheHeadache

42. Drug interactions Cholestyramine increases the clearance of the drug.Cholestyramine increases the clearance of the drug.

43. Nabumetone Well absorbed orally.Well absorbed orally. Metabolized in liver to active metabolities.Metabolized in liver to active metabolities. Half-life 26 hours.Half-life 26 hours. Taken once daily.Taken once daily.

44. Clinical uses Rheumatoid arthritisRheumatoid arthritis OsteoarthritisOsteoarthritis

45. Adverse effects Gastric upsetGastric upset Allergy (skin rash ).Allergy (skin rash ). HeadacheHeadache TinnitusTinnitus PseudoporphyriaPseudoporphyria PhotosensitivityPhotosensitivity

46. Slow acting anti-inflammatory drugs(Disease modifying drugs ). 1.Used as a second line in treating arthritis.1.Used as a second line in treating arthritis. 2.When the disease is progressing & causing deformties.2.When the disease is progressing & causing deformties. 3. Can not repair existing damage,but prevent further injury.3. Can not repair existing damage,but prevent further injury.

47. Slow acting anti-inflammatory drugs(Disease modifying drugs ). 4. Have no analgesic effects4. Have no analgesic effects 5. Need weeks or months to act.5. Need weeks or months to act.

48. Hydroxychloroquine Mechanism of actionMechanism of action 1. Suppress T lymphocytes1. Suppress T lymphocytes 2. Decrease leukocytes action2. Decrease leukocytes action 3. Stabilize lysosomal activity3. Stabilize lysosomal activity 4. Inhibits DNA& RNA synthesis4. Inhibits DNA& RNA synthesis 5. Traps free radicals5. Traps free radicals

49. Clinical uses Arthritis used in a large doses & long durationArthritis used in a large doses & long duration

50. Adverse effects 1. Nausea & vomiting1. Nausea & vomiting 2. Cinchonism ( tinnitus.vertigo )2. Cinchonism ( tinnitus.vertigo ) 3. Irreversible retinal damage3. Irreversible retinal damage 4. Ototoxicity4. Ototoxicity 5. Corneal deposits5. Corneal deposits 6. Allergic skin reaction6. Allergic skin reaction 7. Hepatitis7. Hepatitis

51. Methotrexate Mechanism of actionMechanism of action 1. Dihydrofolate reductase inhibitor1. Dihydrofolate reductase inhibitor 2. Immunosuppressive agent2. Immunosuppressive agent

52. Adverse effects 1. Nausea1. Nausea 2. Mucosal ulcers2. Mucosal ulcers 3. Bone marrow depression which can be reversed by leucovorin.3. Bone marrow depression which can be reversed by leucovorin. 4. Hepatotoxicity is dose related.4. Hepatotoxicity is dose related.

53. Anti- TNF-alpha drugs InfliximabInfliximab 1. Is a chimeric(25%mouse &75%human).1. Is a chimeric(25%mouse &75%human). 2. Binds with high affinity to human TNF-alpha.2. Binds with high affinity to human TNF-alpha. 3. Given as I.V. infusion3. Given as I.V. infusion 4. Half-life 8-12 days.4. Half-life 8-12 days. 5. Given at 0,2,6 weeks followed by intervals of rest 4-6 weeks.5. Given at 0,2,6 weeks followed by intervals of rest 4-6 weeks.

54. Infliximab Improvement reaches up to 60%Improvement reaches up to 60% Can be used in combination with methotrexate reduce the prevalence of human antichimeric antibodies.Can be used in combination with methotrexate reduce the prevalence of human antichimeric antibodies.

55. Clinical uses Rheumatoid arthritisRheumatoid arthritis Ulcerative colitisUlcerative colitis PsoriasisPsoriasis Psoriatic arthritisPsoriatic arthritis Giant cell arteritisGiant cell arteritis SarcoidosisSarcoidosis

56. Adverse effects 1. Upper respiratory tract infections.1. Upper respiratory tract infections. 2. Cough.2. Cough. 3. Nausea.3. Nausea. 4. Headache.4. Headache. 5. Rash.5. Rash. 6- Activate latent tuberculosis6- Activate latent tuberculosis 7- Infusion site reaction7- Infusion site reaction

57. Leflunomide 1. Immunosuppressive drug used in the treatment of R.A.1. Immunosuppressive drug used in the treatment of R.A. 2. Undergoes rapid conversion in intestinal mucosa & plasma to active metabolities.2. Undergoes rapid conversion in intestinal mucosa & plasma to active metabolities.

58. Pharmacokinetics Orally effectiveOrally effective Half-life 15 daysHalf-life 15 days Highly bound to plasma proteinsHighly bound to plasma proteins Cholestyramine increases its clearanceCholestyramine increases its clearance

59. Mechanism of action 1. Inhibits dihydroorotate dehydrogenase which lead to inhibition of ribonucleotide synthesis & arrest the stimulated cells in G1 phase.1. Inhibits dihydroorotate dehydrogenase which lead to inhibition of ribonucleotide synthesis & arrest the stimulated cells in G1 phase. 2. Inhibits T cell proliferation & production of autoantibodies by β cells.2. Inhibits T cell proliferation & production of autoantibodies by β cells.

60. Mechanism ( cont.) Increase interleukin 10 receptorIncrease interleukin 10 receptor mRNA.mRNA. Decrease interleukin 8 receptor type A m RNA.Decrease interleukin 8 receptor type A m RNA. Decrease TNF-α- dependent NFkBDecrease TNF-α- dependent NFkB

61. Clinical uses Rheumatoid arthritisRheumatoid arthritis Can be given with methtrxateCan be given with methtrxate

62. Adverse effects DiarrheaDiarrhea Elevated liver enzymesElevated liver enzymes Mild alopeciaMild alopecia Weight gainWeight gain Increased blood pressureIncreased blood pressure Leukopenia & thrombocytopeniaLeukopenia & thrombocytopenia Contraindicated in pregnancyContraindicated in pregnancy

63. SulfASALAZINE MECHANISM OF ACTIONMECHANISM OF ACTION Through its active metabolite sulfapyridine &the parent drug itself.Through its active metabolite sulfapyridine &the parent drug itself. Suppression of T cell.Suppression of T cell. Inhibition of B cell proliferationInhibition of B cell proliferation

64. Pharmacokinetics Only 10-20% of orally administered sulfa is absorbed.Only 10-20% of orally administered sulfa is absorbed. Fraction undergoes enterohepatic circulation into the bowel.Fraction undergoes enterohepatic circulation into the bowel. Reduced by intestinal bacteria to liberate 5-aminosalicylic acidReduced by intestinal bacteria to liberate 5-aminosalicylic acid

65. Pharmacokinetics And sulfapyridine which is well absorbed while 5-aminosalicylic remains unabsorbed.And sulfapyridine which is well absorbed while 5-aminosalicylic remains unabsorbed. Excreted partly unchanged as sulfasalazine in urineExcreted partly unchanged as sulfasalazine in urine Sulfapyridine metabolized in liver by acetylation &hydroxylationSulfapyridine metabolized in liver by acetylation &hydroxylation Half-life 6-17 hours.Half-life 6-17 hours.

66. Clinical uses Rheumatoid arthritis reduce the rate of appearance of new joint damage.Rheumatoid arthritis reduce the rate of appearance of new joint damage. Juvenile chronic arthritisJuvenile chronic arthritis Ankylosing spondylitis.Ankylosing spondylitis.

67. Adverse effects Nausea, vomitingNausea, vomiting HeadacheHeadache Skin rashSkin rash Hemolytic anemiaHemolytic anemia MethemoglobinemiaMethemoglobinemia Reversible infertility in menReversible infertility in men Neutropenia & thrombocytopenia (rare)Neutropenia & thrombocytopenia (rare)