Dmards

DISEASE MODIFYING ANTI RHEUMATOID DRUGS

1. DMARDS Moderator: dr. v. k. verma RESIDENT : FARIHA FATIMA

2. Pharmacological management The drugs most frequently used in initial therapy are the 'disease-modifying antirheumatic drugs' (DMARD) and the NSAIDS. Unlike the NSAIDS , which reduce the symptoms but not the progress of the disease, the former group may halt or reverse the underlying disease itself.

3. The term 'DMARD' is a latex concept that can be stretched to cover a heterologous group of agents with unrelated chemical structures and different mechanisms of action. Included in this category are methotrexate , sulfasalazine , gold compounds, penicillamine and chloroquine and other antimalarials and various immunosuppressant drugs.

4. The DMARD were often referred to as second-line drugs , with the implication that they were only resorted to when other therapies ( eg .NSAIDS ) failed. Today, however, DMARD therapy may be initiated as soon as a definite diagnosis has been reached. Their clinical effects are usually slow (months) in onset, and it is usual to provide NSAID 'cover' during this induction phase.

5. If therapy is successful, concomitant NSAID (or glucocorticoid) therapy can generally be dramatically reduced.

6. METHOTREXATE Methotrexate is a folic acid antagonist with cytotoxic and immunosuppressant activity and potent antirheumatoid action. It is a common first-choice drug. It has a more rapid onset of action than other Dmards ,

7. Pharmacokinetics: Methotrexate is usually given orally but can also be given intramuscularly, intravenously or intrathecally . The drug has low lipid solubility and thus does not readily cross the blood-brain barrier. Dose : 15 – 25 mg weekly,orally .

8. Indications: Methotrexate is also used as an immunosuppressant drug to treat rheumatoid arthritis and other autoimmune conditions. Side effects: Depression of the bone marrow and damage to the epithelium of the gastrointestinal tract. Pneumonitis can occur. Blood dyscrasias . Liver cirrhosis.

9. sulfasalazine Sulfasalazine, a common first-choice DMARD , It produces remission in active rheumatoid arthritis and is also used for chronic inflammatory bowel disease . It may act by scavenging the toxic oxygen metabolites produced by neutrophils. Side Effects : gastrointestinal disturbances, malaise, headache leucopenia decreased sperm count

10. Pharmacokinetic profile: Half life of the drug is 6 – 15 hrs Dose = 500 mg daily for 7 days orally and increased by 500 mg every week to a maximum of 3g/day in 2 to 3 divided doses.

11. PENICILLAMINE Penicillamine is dimethylcysteine ; it is produced by hydrolysis of penicillin . The d -isomer is used in the therapy of rheumatoid disease. About 75% of patients with rheumatoid arthritis respond to penicillamine . Mechanism of Action: Penicillamine is thought to modify rheumatoid disease partly by decreasing the immune response, IL-1 generation and/or partly by an effect on collagen synthesis, preventing the maturation of newly synthesised collagen.

12. However, the precise mechanism of action is still a matter of conjecture. Pharmacokinetic profile: Penicillamine is given orally, and only half the dose administered is absorbed. It reaches peak plasma concentrations in 1-2 h and is excreted in the urine. Dosage is started low and increased only gradually to minimise unwanted effects. Side Effects: Rashes and stomatitis are the most common unwanted effects but may resolve if the dosage is lowered.

13. Anorexia, fever, nausea and vomiting, and disturbances of taste (the last related to the chelation of zinc) are seen, but often disappear with continued treatment. Proteinuria occurs in 20% of patients and should be monitored.

14. GOLD COMPOUNDS Gold is administered in the form of organic complexes; sodium aurothiomalate and auranofin are the two most common preparations. The effect of gold compounds develops slowly over 3-4 months. Pain and joint swelling subside, and the progression of bone and joint damage diminishes.

15. The mechanism of action is not clear, but auranofin , although not aurothiomalate , inhibits the induction of IL-1 and TNF-alpha.

16. Pharmacokinetics: Sodium aurothiomalate is given by deep intramuscular injection; auranofin is given orally. The half-life is 7 days initially but increases with treatment, so the drug is usually given first at weekly, then at monthly intervals. Unwanted effects with auranofin are less frequent and less severe. Important unwanted effects include skin rashes , mouth ulcers, proteinuria, thrombocytopenia and blood dyscrasias .

17. Encephalopathy, peripheral neuropathy and hepatitis can occur. If therapy is stopped when the early symptoms appear, the incidence of serious toxic effects is relatively low.

18. Hydroxychloroquine and chloroquine Chloroquine is usually reserved for cases where other treatments have failed. The antirheumatic effects do not appear until a month or more after the drug is started, and only about half the patients treated respond .

19. The mechanism of the anti-inflammatory action : unclear. The following mechanisms have been proposed: suppression of t-lymphocyte responses to Mitogens, decreased leukocyte chemotaxis , stabilization of lysosomal Enzymes, inhibition of DNA and RNA synthesis, and the Trapping of free radicals.

20. IMMUNOSUPPRESSANT DRUGS They can be roughly characterised as: Drugs that inhibit IL-2 production or action ( eg . Ciclosporin , tacrolimus ) Drugs that inhibit cytokine gene expression ( eg . corticosteroids ) Drugs that inhibit purine or pyrimidine synthesis ( eg . Azathioprine ).

21. To slow the progress of rheumatoid and other arthritic diseases including psoriatic arthritis, ankylosis spondylitis, juvenile arthritis: disease-modifying anti-rheumatic drugs ( DMARDS ), eg . Methotrexate , leflunomide , ciclosporin ; cytokine modulators ( eg . Adalimumab , etanercept , infliximab ) are used when the response to methotrexate or other DMARDS has been inadequate.

22. Leflunomide Leflunomide has a relatively specific inhibitory effect on activated T cells It is orally active and well absorbed from the gastrointestinal tract. It has a long plasma half-life. Unwanted effects include diarrhoea, alopecia, raised liver enzymes and indeed a risk of hepatic failure.