1. Dr.B.V.Venkataraman Professor in Pharmacology International Medical School Faculti Perubatan, New BEL Rd Bangalore - 560054 Venkataraman_bv@yahoo.com Drugs Used in Arthritis

2. Immune System Foreign bodies Own cells Eradicated Failed No infection Infection Auto immune Diseases

3. What is rheumatoid arthritis? It is an auto immune disease Affects the lining of the joints, causing pain, swelling, and stiffness. Left untreated, joints may be damaged badly Most common in young-adult to middle-age women.

5. What is osteoarthritis? Osteoarthritis results from wear and tear on the joints.

6. What are the drugs used in RA? 1. Anti inflammatory drugs: NSAIDs 2. Corticosteroids: Prednisolone 3. Disease modifying antirheumatic drug (DMARDS) Non biologic Biologic

8. DMARDS (Non biologic) Target immune cells usually by unknown mechanism a.Immunosuppressants: Methotrexate, leflunomide, azathioprine, cyclosporine etc b.Antimalarials: Hydroxy Chloroquine c.Gold salts: aurothiomalate, aurothioglucose d.Miscellaneous Sulphasalazine

9. DMARDS (biologic) Target specific parts of inflammatory cascade Specific Examples: Anakinra, inflixima,TNFα inhibitors and IL-1 antagonist etc.

10. What is the mechanism of action of NSAIDS? Mechanism Inhibit the synthesis of prostaglandins and reduce cause of pain and inflammation. Main drugs Diclofenac, ibuprofen, indomethacin, piroxicam etc. Long term side effects Allergy, peptic ulcer, bleeding disorders, renal function impairment etc.

11. What is the mechanism of action of NSAIDs? NSAIDs

12. Interactions Bleeding tendency with oral anticoagulants Fluid retention decreases the efficacy of diuretics and antihypertensives. Protein binding increases the risk by displacement principle COX-2 INHIBITORS Less gastric irritation No anti platelet action; no protection against heart attack or stroke

13. How does corticosteroid act on inflammation? Steroids

14. Glucocorticoid How does corticosteroid act on immunity?

15. Corticosteroids Prednisone, methyl prednisolone and hydrocortisone Inflammation, suppress the immunity Side effects: bone loss, weight gain, acne, high blood pressure, mood swings, and infection Topical. Intra articular administration also possible

16. DMARDS (Non biologic) Heterogenous class without common property Symptomatic improvement Slow progress Most of them were developed for other disorder – cancer, immunosuppression Toxicity and inadequate response limit the use Combined with biologic DMARDs

17. METHOTREXATE Inhibition of folic metabolism – for anti cancer activity Proposed Mechanism: Inhibit T-cell proliferation to inhibit transmethylation reactions required for T- cell cytotoxicity to promote the release of adenosine, an endogenous anti-inflammatory mediator to interfere with glutathione metabolism, and alter the recruitment of monocytes to the inflamed joint

18. Azathioprine Methotrexate Mechanism of immunosuppressants drugs

19. METHOTREXATE (Contd) Useful in patients refractory to other drugs Given with folic or folinic acid (Leucovorin) to decrease mouth ulcer, anaemia etc Liver function test Low dose (not anticancer dose) given weekly

20. LEFLUNOMIDE Alternative to Methotrexate Given to patients who can not tolerate methotrexate Inhibits dihydro orotate dehydrogenase (dihydro folatereductase) – anticancer activity Inhibit proliferation (similar to methotrexate) Dose is daily (methotrexate weekly) Liver function test

21. Hydroxy chloroquine Interfering with tumor necrosis factor (TNF) released from macrophages, or Diminishing the presentation of antigens to CD4+ T cells. Slow progress – used in mild disease Well tolerated Retinal toxicity – ophthalmic examination required

22. Sulfasalazine ( Salicylazosulfapyridine ) Sulfasalazine 5-Aminosalicylic acidSulfapyridine Coliform bacteria Local antiinflammatory Immunomodulating Systemic side effect (Carrier) Mechanism not clear; also used in other auto immune conditions Not used in sulpha sensitivity

23. MESALAMINE 5-Aminosalicylic acid Coliform bacteria Local antiinflammatory Immunomodulating No systemic effect (Carrier) Ethylcellulose/pH sensitive resin

24. GOLD SALTS Organic complexes: sodium aurothiomalate, auranolin. Mechanism: poorly understood Very slow progress Oral & parenteral preparations available Toxic symptoms: Proteinuria, thrombocytopenia, and neutropenia – decreased WBCs and kidney damage

25. ANTI-TNF AGENTS Infliximab Adalimumab Etanercept All useful in mild to moderate RA Infliximab (iv) other two (sc) Risk of infection such as tuberculosis Risk of Malignancy

26. Mechanism Anti-TNF monoclonal antibody Binds to TNF-  TNF-  fails to bind to receptor cell surface Side effects breathlessness, hypotension, headache. INFLIXIMAB

27. ADALIMUMAB Mechanism Similar to Infliximab ETANERCEPT Mechanism fusion protein composed of 2 recombinant soluble TNF receptors binds to TNF-α, and lymphotoxin-α

28. ANAKINRA Interleukin-1 β Decrease WBC count, risk of infection (TB) and malignancy - similar to anti-TNF agent. Dramatic relief similar to anti-TNF agent.