Class antirheumatoid drugs

1. ANTIRHEUMATOID DRUGS Dr. RAGHU PRASADA M S MBBS,MD ASSISTANT PROFESSOR DEPT. OF PHARMACOLOGY SSIMS & RC.

2. Pathopysiology

3. Antirheumatoid drugs Immunosupressants-leflunomide , methotrexate, cyclosporine, Azathioprine DMARDs- Abetacept , chloroquine , hydroxychloroquine , mycophenolate mofetil , rituximab , Sulfasalazine , tocilizumab Glucocorticoids TNF α blocking agents Etanercept , Infliximab , Adalimumab , certolizumab , etanercept , golimumab , infliximab

4. TNF α blocking agents TNF- α activates the release of nitric oxide which causes vasodil - atation and adhesions are increased  local blood vessel occlusion

5. ETANERCEPT Genetically engineered fusion protein Serves as externally administered soluble TNF- α receptor which prevents TNF- α from binding to membrane bound TNFR It does not discriminate between TNF- α and TNF- β ( lymphotoxin ) TNF- β is important in modulating cellular immune response to infection and tumour .

6. ETANERCEPT Adm -sc 25mg/twice/wk T1/2-112hrs Uses: Rheumatoid athritis , juvenile arthritis and psoriatic arthritis It is used in treating sarcidosis , wageners granulomatosis , scleroderma Etanercept+methotrexate - recent trials ADR-well tolerated, anti etanercept antibodies may appear, drug induced lupus and activation of latent TB

7. INFLIXIMAB It is chimeric monoclonal antibody It cross links with soluble as well as membrane bound TNF α receptors and inhibit activated T-cells and macrophage function IV infusion 3-5mg/kg Uses Trmt of crohns disease Juvenile chronic arthritis, psoriatic arthritis Adverse reactions-URTI, nausea, headache, latent TB activation, Long term use- anti- infliximab antibodies

8. ADALIMUMAB Recombinant human anti-TNF monoclonal Ab Less immunogenic than infliximab Given sc 40mg every other week Plasma t1/2-is 9-14days Combination with methotrexate is beneficial

9. LEFLUNOMIDE Acts through active metabolite A-77 which inhibits DHODH( dihydro - Orotate-Dehydrogenase ) enzyme leading to decrease in ribonucleotide synthesis ( UMP levels) Arrest of stimulated cells in the G1 phase of cell growth inhibits T cell proliferation and production of autoantibodies by B cells 2ATP+co2+glutaminedihyro-orotateorotate  UMP levels arrests the growth of stimulated cells in G1 phase of cell cycle

10. Leflunomide DHODH is therefore upregulated in G1 phase of cell cycle which catalyses formation of oratate from dihydro-orotate in mitochondria T 1/2 -19 days undergoes enterohepatic circulation Clinical efficacy similar to methotrexate ADE- diarrhoea , headache, rashes, hepatic transaminases C/I- pregnancy , lactation D/I- cholestyramine increases its excretion

11. Methotrexate It is a folic acid antogonist with cytotoxic and immunosuppressant activity It has rapid onset of action, acts at much lower doses than those needed in Ca chemotherapy It acts by inhibiting AICAR (Amino Immidazole carboxamide Ribonucleotide ) transformylase and thymidylate synthase This inhibits replication and function of T cells ( and possibly of B-cells)because of selective inhibition of DNA synthesis

12. Methotrexate Uses Juvenile chronic arthritis, psoriasis, wegener’s granulomatosis Adverse reactions Mucosal ulcers, hepatotoxicity, pseudolymphomatous reactions Toxicity : leucovorin can be given after weekly dose of methotrexate

13. Cyclosporine It inhibits IL1 and IL2 receptor production It inhibits macrophage- Tcell interaction and T cell responsiveness Dose 3-5mg/kg/day Adverse drug effects- neprotoxicity , accentuated with NSAIDs Toxicity – hepatotoxicity, hirsuitism , gingival hyperplasia

14. AZATHIOPRINE Is a prodrug of 6-mercaptopurine 6MP 6-thio GTP provides a counterfeit product which gets false incorpoaration into DNA of lymphocyte makes it non-functional prevention of T-cell activation and proliferation USES organ transplant rejection, Rh.arthritis , IBD S/E- BM depression, Leukopenia , thrombocytopenia, Alopecia,

15. MYCOPHENOLATE MOFETIL Semisynthetic fungal antibiotic  mycophenlic acid inhibits proliferation of both T and B lymphocytes and reduces production of cytotoxic T cells by inhibiting cytosine.mono-PO4 dH  denovo purine biosynthesis MMF interferes with leukocyte adhesion to endothelial cells through inhibition of E- selectin and P- selectin orally well absorbed, MMF undergoes enterohepatic circulation and eliminated by kidney. ADR-GIT, haematopoietic and hepatic toxicity

16. Glucocorticoids Symptomatic relief is dramatic Immediate relief in inflammation, can give time for action of DMARDS Severe inflammation- patients with vasculitis or RH.lung Intra- articular TRIAMCINOlONE , HYDROCORTISONE is advocated MOA- effect on immune response and inflammatory mediators inhibit clonal proliferation of TH1 cells through decreasing the transcription of gene for IL2

17. Miscellaneous- gold compounds MOA-they alter a morphology and capability of macrophages Cell mediated immune responses are suppressed Reduction in circulating rheumatoid factors and ESR Prevents joint destruction and induces healing SODIUM AUROTHIOMALATE(IM)-reduces lysosomal enzyme activity, reduces histamine release from mast cells AURANOFIN-oral ADR- exfoliative dermatitis, hepatitis, albiminuria , peripheral neuritis

18. Hydroxychloroquine It is primarily anti malarial drug It traps free radicals, suppresses T lymphocyte responses to mitogens , stabilizes lysosomal enzymes and decreases leukocyte chemotaxis , it is useful in patients of RA It does not retard the progression of bone damage. ADR: rashes, greying of hair, myopathy , and neuropathy

19. Sulfasalazine Primarily used in ulcerative colitis Metabolised to sulfapyridine and 5-aminosalicylic acid in the colon by bacterial action Sulfapyridine absorbed systemically and appears to be active component I treating RA Sulfasalazine decreases rheumatoid factor levels and suppresses the generation of superoxide free radicals and cytokine release by inflammatory cells

20. Sulfasalazine T 1/2 -6-15hrs Uses –juvenile chronic arthritis, RA, ankylosing spondylitis ADR- GIT disturbances, malaise, headache - reversible leukopenia

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