ANTIRHEUMATOID DRUGS

Dr. RAGHU PRASADA M SMBBS,MDASSISTANT PROFESSOR DEPT. OF PHARMACOLOGYSSIMS & RC.

Pathopysiology

Antirheumatoid drugs

Immunosupressants-leflunomide, methotrexate, cyclosporine, Azathioprine

DMARDs- Abetacept, chloroquine, hydroxychloroquine, mycophenolate mofetil, rituximab, Sulfasalazine, tocilizumab

Glucocorticoids TNFα blocking agentsEtanercept, Infliximab, Adalimumab, certolizumab,

etanercept, golimumab, infliximab

TNFα blocking agents

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

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.

ETANERCEPT

Adm-sc 25mg/twice/wk T1/2-112hrsUses: Rheumatoid athritis, juvenile arthritis and

psoriatic arthritisIt is used in treating sarcidosis, wageners

granulomatosis, sclerodermaEtanercept+methotrexate- recent trials

ADR-well tolerated, anti etanercept antibodies may appear, drug induced lupus and activation of latent TB

INFLIXIMAB

It is chimeric monoclonal antibody It cross links with soluble as well as membrane bound

TNFα receptors and inhibit activated T-cells and macrophage functionIV infusion 3-5mg/kg

UsesTrmt of crohns diseaseJuvenile chronic arthritis, psoriatic arthritisAdverse reactions-URTI, nausea, headache, latent TB

activation, Long term use- anti-infliximab antibodies

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

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 growthinhibits T cell proliferation and production of autoantibodies by B cells

2ATP+co2+glutaminedihyro-orotateorotate UMP levels arrests the growth of stimulated

cells in G1 phase of cell cycle

Leflunomide

DHODH is therefore upregulated in G1 phase of cell cycle which catalyses formation of oratate from dihydro-orotate in mitochondria

T1/2-19 days undergoes enterohepatic circulation Clinical efficacy similar to methotrexate

ADE- diarrhoea, headache, rashes, hepatic transaminases

C/I- pregnancy , lactationD/I- cholestyramine increases its excretion

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

Methotrexate

UsesJuvenile chronic arthritis, psoriasis, wegener’s

granulomatosisAdverse reactionsMucosal ulcers, hepatotoxicity, pseudolymphomatous

reactionsToxicity :leucovorin can be given after weekly dose of

methotrexate

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

AZATHIOPRINE

Is a prodrug of 6-mercaptopurine 6MP6-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

USESorgan transplant rejection, Rh.arthritis, IBD

S/E-BM depression, Leukopenia, thrombocytopenia, Alopecia,

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-selectinorally well absorbed, MMF undergoes enterohepatic circulation and eliminated by kidney.

ADR-GIT, haematopoietic and hepatic toxicity

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

mediatorsinhibit clonal proliferation of TH1 cells through decreasing the transcription of gene for IL2

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

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

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

Sulfasalazine

T1/2-6-15hrsUses –juvenile chronic arthritis, RA, ankylosing

spondylitisADR- GIT disturbances, malaise, headache - reversible leukopenia

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