1. Dr. Eduardo D. Rosas Blum Department of Pharmacology

2. A 33yo female with rheumatoid arthritis is initially treated with ibuprofen but her joint pain and stiffness are worsening. Another drug is prescribed but later she developed side effects like dizziness, blurred vision, “halos” around bright light. Ophthalmologic examination reveals corneal deposits and retinal pigmentation. Which drug was MOST LIKELY prescribed ? A. Cyclophosphamide. B. Hydroxychloroquine. C. Penicillamine. D. Methotrexate. E. Etodolac.

4. Rheumatic Disease ► Immunologic disease. ► Multiple systemic effects. ► Shorten life. ► Reduce mobility and quality of life. ► First line of treatment NSAIDs. ► …… ???

6. Rheumatoid Arthritis ► Systemic chronic inflammation with a progressive arthritis. ► Affects more women, presents in the 20-60s ► Involves an autoimmune reaction, creating antibodies (rheumatoid factor) against autologous IgG leading to immune complexes.

7. Rheumatoid Arthritis ► Morning stiffness with improvement. ► Symmetrical small joints of hands and feet. ► Low-grade fever, malaise, fatigue. ► Joint swelling, redness an warmth. ► X-rays show erosions and osteoporosis. ► Types: Juvenile RA, Ankylosing Spondylitis, Arthritis associated with ulcerative colitis. Psoriatic arthritis.

8. Osteoarthritis ► Degenerative joint disease. ► Increases with age, affects 80% people over 70 at least in one joint. ► Joint stiffness, decrease range of motion, effusions and bony swellings. ► X-rays shows narrowing of the joint space due to loss of cartilage and osteosclerosis. ► Vertebrae, hip, knees and distal interphalangeal joints. ► Treatment: NSAIDs, 1 st line Aspirin.

10. Rheumatic Disease ► Immunologic disease. ► Multiple systemic effects. ► Shorten life. ► Reduce mobility and quality of life. ► First line of treatment NSAIDs. ► Aspirin drug of choice. ► Little effect on bone and cartilage damage.

11. Disease-Modifying Antirheumatic Drugs ► DMARDs. ► Slow acting (6weeks – 6 months) ► 2 nd line of treatment ► Controversy it’s long term efficacy. ► Methotrexate, Chlorambucil, Cyclosphosphamide, Cysclosporine, Azathioprine, etc.

12. Methotrexate ► First DMARDs of choice in Rheumatoid Arthritis (RA). ► 60% patient used it. ► Lower doses than in cancer chemotherapy. ► Inhibits aminoimidazolecarboxamine (AICAR), affecting PMN chemotaxis. ► Some effect of the dihydrofolate, affecting the lymphocyte and macrophages function.

13. Methotrexate ► 70% VO absorption. ► Half-life of 6-9hrs, increase with hydroxychloroquine. ► Excreted in urine (70%), Bile (30%) ► Decreases rate of appearance of new erosions. ► Mild and severe RA and refractory RA. ► Juvenile arthritis, Psoriasis, SLE, etc.

14. Methotrexate ► Adverse Effects: ► Nausea and mucosal ulcer. ► Hepatoxicity. ► “hypersensibility” reaction to the Lung. ► Contraindicated in pregnancy.

15. Cyclophosphamide ► Cross-links DNA, preventing replication. ► Metabolite phosphoramide mustard. ► Prevents replication. ► Suppress T and B cell function (30-40%). ► Indication for RA only in PO presentation (no IV). ► SLE, Vasculitis, Wegeners’s granulomatosis, other sever rheumatic diseases.

16. Cyclophosphamide ► Adverse Effects. ► Hemorrhagic cystitis. ► Bone marrow suppression, alopecia, bladder carcinoma (very rare).

17. Cyclosporine ► Regulates gene transcription. ► Inhibits IL-1 and IL-2 receptor. ► Inhibits macrophage -T cell interaction and T cell responsiveness. ► Erratic absorption, new preparations give up to 20-30% bioavailability. ► Grapefruit increases bioavailability up to 62%. ► Metabolized by CYP3A (many drug interaction).

18. Cyclosporine ► Retards the appearance of new bony erosions. ► Could be use in SLE, Wegener’s granulomatosis, polymyositis, juvenile chronic arthritis. ► Nephrotoxicity. ► Interactions: diltiazem, K-sparing diuretics, other CYP3A inhibitors. ► Other: hypotension, hyperkalemia, hepatotoxicity, hirsutism.

19. Azathioprine ► Suppresses inosiniz acid synthesis, B and T cell function, immunoglobulin productions and IL-2 secretions. ► Fast metabolizers clear drug 4x faster. ► Bimodal metabolism.

20. Azathioprine ► Also used in psoriasis, reactive arthritis, SLE, etc. ► Bone marrow suppression. ► GI disturbances, risk for infections. ► Increase risk for lymphomas. ► Rarely: rash, fever and hepatotoxicity.

21. Chloroquine ► Used in malaria. ► Anti-inflammatory effect unknown. ► Theory: suppression of the T lymphocytes response to mitogens, decrease leukocyte chemotaxis, trapping free radicals. ► Rapidly absorbed, only 50% bound to proteins. ► Extensively tissue bound. ► Deaminated by the liver, half-life up to 45 days.

22. Chloroquine ► Indicated for RA, but not very efficacious. ► Improve symptoms. ► No effect in protecting bone alterations. ► Takes 3 – 6 months to obtain response. ► Other uses: skin manifestation of SLE.

23. Chloroquine ► Adverse effects ► Ocular toxicity (check-ups each 12 months) ► Dyspepsia, nausea, vomiting, abdominal pain, rashes and nightmares. ► Safe in pregnancy.

25. Gold Salts ► Approved in 1960s. ► Aurothiomalate, aurothioglucose (IM), auranofin (PO). ► Today are infrequently used (very toxic). ► IM formulas 50% elemental gold, PO 29%. ► Alters morphology and capabilities of macrophages. ► Inhibits: chrematistic factor-1, IL-8, IL-1B, vascular endothelial growth factor.

26. Gold Salts ► IM: alter lysosomal enzyme activity, inhibits histamine release, inactive 1 st component of complement, suppresses PMN phagocytosis. ► High bioavailability, concentration in synovial membranes, liver, kidney, spleen lymph nodes and bone marrow. ► IM: 75-80% eliminated in one month but total half-life is 1 year.

27. Gold Salts ► Excreted 66% urine, 33% feces. ► Slow radiographic progression in RA. ► Also used in Sjogren’s syndrome, juvenile RA. ► PO: less effect than IM.

28. Gold Salts ► Adverse effects ► Pruritic skin rashes, Stomatitis and metallic taste. ► Trombocytopenia, leukopenia and pancytopenia. ► Aplastic anemia (rare). ► Nephrotic syndrome ► Enterocolitis, cholestatic jaundice, peripheral neuropathy and pulmonary infiltrates.

29. Sulfasalazine ► Salycilate. ► Metabolites treat RA. ► Decreased production of IgA and IgM rheumatoid factor. ► No clear mechanism action related to the efficacy.

30. Sulfasalazine ► PO: 10-20% absorbed. ► Fraction undergoes enterohepatic recirculation and is reduce by colonic bacteria into sulfapyridine and 5- aminosalicylic. ► Sulfapyridine: well absorbed, excreted after hepatic metabolism (RA). ► 5-aminosalicylic: unabsorbed (IBD). ► Half-life 6-17hrs.

31. Sulfasalazine ► Reduces the rate of appearance of new joint damage. ► Juvenile RA, ankylosing spondylitis. ► Adverse effects ► Nausea, vomiting, headache and rash. ► Hemolytic Anemia (rare), Neutropenia, thrombocytopenia (very rare).

32. Penicillamine ► Decreases bone destruction in RA. ► Unknown mechanism of action. ► Severe side effects. ► Rarely used.

34. TNFa Blocking agents. ► TNFa cytokines are the heart of the inflammatory process. ► Has TNF receptor. ► Anti-TNF antibodies, can cross-link the receptor. ► Curative for refractory cases. ► Adalimumab, Infliximab, Etanercept.

35. Adalimumab ► Recombinant human TNF monoclonal antibody. ► Down regulation of macrophages and T cell function. ► Half-life of 9-14 days. Methotrexate decrease clearance. ► Produces antimonoclonal antibodies 12% cases (reduce to 4% with methotrexate)

36. Adalimumab ► Decreases the rate of the formation of new erosions. ► Effective in alone or in combination with methotrexate. ► Tested for SLE, juvenile RA, Psoriasis.

37. Adalimumab ► Adverse Effects ► Increase macrophage-dependent infection. ► Tuberculosis and opportunistic infections. ► Drug-induce lupus is extremely rare. ► Rare: leukopenia, vasculitis.

38. Infliximab ► Chimeric monoclonal antibody (25% mouse, 75% human) ► High affinity for the TNF receptors. ► IV route. ► Half-life 9-12 days. ► Produces antichimeric AB in 62% cases after use.

39. Infliximab ► Effective in RA, ulcerative colitis, Juvenile RA, Psoriasis, etc. ► Used alone or in combination with methotrexate. ► Other DMARDs can be use in combination.

40. Infliximab ► Adverse Effects ► Respiratory tract infections, nausea, headache, sinusitis, rash and cough. ► Associated with TB reactivation. ► Infusion site reaction.

41. Etanercept ► Recombinant fusion proteins of TNF p75 receptors linked to the Fc of the IgG1. ► Binds the TNFa molecules and inhibits lymphotoxin-a. ► Slowly absorbed and half-life is 4.5 days. ► Decreases the rate of new erosions like methotrexate alone. ► Same indications as infliximab.

42. Etanercept ► Adverse effects. ► Lower incidence of TB reactivation. ► Similar incidence of opportunistic infections. ► Most be alert for lymphomas (as other TNF agents). ► Lupus-like syndrome higher incidence. ► 16% can produce antibodies.

43. Leflunomide ► Inhibits dihydroorotate dehydrogenase. ► Leads to inhibition of lymphocyte division and maturation. ► Inhibits T cell proliferation and B cell antibody production. ► Completely absorbed. Half-life of 19 days. ► Cholestyramine enhances clearance by 50%.

44. Leflunomide ► As effective as Methotrexate for RA. ► Inhibition of bony damage. ► Can be combined. ► Diarrhea, loose bowels. ► Elevation of liver enzymes. ► Mild alopecia, weight gain, increase BP. ► Contraindicated in pregnancy.

45. Combinations ► Methotrexate as base. ► Improve: cyclosporine, chloroquine, infliximab, leflunomide, adalimumab and etanercept. ► No effect: rest. ► Combinations does not increase risk of toxicities. ► When monotherapy fails, the rule is to start combination.

48. Gout Hyperuricemia associated with recurrent bouts of acute arthritis. Inborn error of purine metabolism (90%). Over production of uric acid. Asymptomatic period of hyperurecemia followed by inflammatory synovitis. Large toe more typical. Chronic: erosions of bone and cartilage.

49. Gout NSAIDs preferred. Longer time to produce symptomatic improvement. Indomethacin commonly used (naproxen or sulindac). Aspirin inhibits the uricosuric effect of probenecid and sulfinpyrazone. Treatment aimed to relieve the gouty attack and prevent recurrent episodes.

50. Colchicine Isolated from Cholchium Autumnale. Interferes with microtubules, thus preventing the migration of granulocytes to the inflammatory site. Inhibits the formation of LTB4. No uricosuric effect. Readily absorption, peak plasma concentration 2hrs.

51. Colchicine Used for alleviating the inflammation of the acute gouty arthritis. NSAIDs have replace then because of their adverse effects. Now used for preventing recurrent episodes.

52. Colchicine Adverse Effects GI: diarrhea. Nausea, vomiting, abdominal pain. Blood dyscrasias ( aplastic anemia, thrombocytopenia) in long term use. Alopecia, neuropathy, myopathy and hemorrhagic gastroenteritis.

53. Allopurinol Analog of hypoxanthine, that inhibits the conversion of hypoxanthine to uric acid by xanthine oxidase. Lowers both serum and urinary concentration of uric acid. Well absorbed orally. Half-life of 30 hrs.

54. Allopurinol Drug of choice for patients for severe hyperuricemia, in gout or other conditions. If a attacks occurs discontinue the drug. Should be started several days after the gouty attacks, or after colchicine use.

55. Allopurinol Adverse Effects. Exfoliative Dermatitis. Nausea, diarrhea, rash and fever. Rarely blood dyscrasias, hepatotoxicity and peripheral neuropathy. Reduce dose in ARI and increases toxicity of anticoagulants.

56. Probenecid Uricosuric agent. Competes for other acids (including uric acid) at the transport sites in the renal tubule. Low doses causes retention of urate (inhibits tubular secretions). At therapeutic doses their effect is to block uric acid reabsorption in the proximal tubule. Increase rate of uric acid excretion

57. Probenecid Used when allopurinol is not tolerated. During the attack should be continued if the patient is on maintenance therapy (never start). Used to prevent penicillin elimination and raise its serum level.

58. Probenecid Adverse effects GI: nausea, vomiting. Hypersensibility (rash and fever). Renal calculi may occur in patients with high urate excretion. Recommend high-fluid intake to prevent stone formation. Nephrotic syndrome and peptic ulceration. Hemolytic anemia in G6PD.

59. Sulfinpyrazone Derivative of phenylbutazone. 90% excreted in the urine Similar indications than probenecid. Also may inhibit platelet aggregation (inhibits prostaglandins). Same adverse effects. Except on rare instances can produce blood dyscrasias and volume overload. Potenciates the effects of insulin, sulfonyureas and warfarin.

62. High-Yield Slides. Dr. Rosas Blum

63. RA treatments NSAIDs are commonly used (GI bleeding). NSAIDs are commonly used (GI bleeding). COX-2 (AMI). COX-2 (AMI). DMARDs. DMARDs.

64. DMARDs Hydroxychloroquine Hydroxychloroquine Mild arthritis Mild arthritis Methotrexate, infliximab, glucocorticoids, gold. Methotrexate, infliximab, glucocorticoids, gold. Severe disease. Severe disease.

65. Hydroxychloroquine Mechanism unknown. Mechanism unknown. Causes retinopathy. Causes retinopathy. Hemolysis with G6PD deficiency. Hemolysis with G6PD deficiency.

66. Methotrexate Cytotoxic to lymphocytes. Cytotoxic to lymphocytes. Bone marrow toxicity. Bone marrow toxicity. Crystalluria. Crystalluria. Interferes with folic acid antagonist. Interferes with folic acid antagonist. Give Leukovorin as a antidote (“leucovorin rescue”) Give Leukovorin as a antidote (“leucovorin rescue”)

67. Gold Auronofin, Aurothioglucose Auronofin, Aurothioglucose Interferes with monocytes and lymphocytes. Interferes with monocytes and lymphocytes. Cutaneous reactions is common. Cutaneous reactions is common.

68. Penicillamine Suppress T-lymphocytes. Suppress T-lymphocytes. Lupus-like syndrome. Lupus-like syndrome. Proteinuria. Proteinuria. Fast vs slow acetylators. Fast vs slow acetylators.

69. TNFa Infliximab Infliximab Monoclonal antibody against TNFa Monoclonal antibody against TNFa Use also in IBD. Use also in IBD. Etanercept Etanercept TNF receptor fused to human IgG fragments. TNF receptor fused to human IgG fragments. Both are associated with infusion reactions and increase risk for infections. Both are associated with infusion reactions and increase risk for infections.

70. Gout Acute attacks are the result from crystallization of sodium urate in joints and subsequent inflammatory reaction. Acute attacks are the result from crystallization of sodium urate in joints and subsequent inflammatory reaction. Sodium urate is end product of purine metabolism. Sodium urate is end product of purine metabolism.

71. Managements of attacks Colchicine Colchicine Indomethacine or NSAIDs. Indomethacine or NSAIDs. Intraarticular steroids. Intraarticular steroids.

72. Chronic management Goal is to reduce uric acid pool. Goal is to reduce uric acid pool. Allopurinol Allopurinol Uricosuric drugs Uricosuric drugs Diet Modification Diet Modification

73. Colchicine Highly effective for gouty attacks. Highly effective for gouty attacks. Interferes with granulocyte mobilization Interferes with granulocyte mobilization Adverse effects. Adverse effects. Very toxic. Very toxic. Damage to rapidly dividing cells (GI=diarrhea) Damage to rapidly dividing cells (GI=diarrhea) Neurotoxicity. Neurotoxicity.

74. Uricosuric Agents Probenecid, sulfinpyrazone Probenecid, sulfinpyrazone Probenecid is also uses to inhibit penicillin secretion from the renal tubules. Probenecid is also uses to inhibit penicillin secretion from the renal tubules. Increase rate of uric acid excretion. Increase rate of uric acid excretion. Used for chronic management of gout. Used for chronic management of gout. Well tolerated not always effective. Well tolerated not always effective.

75. Allopurinol Inhibits xanthine oxidase. Inhibits xanthine oxidase. Preventing the end stage conversion of purines to uric acid. Preventing the end stage conversion of purines to uric acid. Used for primary hyperurecemia of gout. Used for primary hyperurecemia of gout. Or hyperurecemia secondary to hematologic disorders or chemotherapy treatments. Or hyperurecemia secondary to hematologic disorders or chemotherapy treatments. Adverse effects: severe skin reactions Adverse effects: severe skin reactions “Exfoliative dermatitis” “Exfoliative dermatitis”

76. A 33yo female with rheumatoid arthritis is initially treated with ibuprofen but her joint pain and stiffness are worsening. Another drug is prescribed but later she developed side effects like dizziness, blurred vision, “halos” around bright light. Ophthalmologic examination reveals corneal deposits and retinal pigmentation. Which drug was MOST LIKELY prescribed ? A. Cyclophosphamide. B. Hydroxychloroquine. C. Penicillamine. D. Methotrexate. E. Etodolac.

77. laloblum_md@yahoo.com