DISEASE MODIFYING ANTI RHEUMATOID DRUGS

1. DMARDS
MODERATOR: DR. V. K. VERMA
RESIDENT: FARIHA FATIMA

4. 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.

5. 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.

6. 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.

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

10. 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,

12. 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.

13. 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.

14. 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

15. 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.

16. 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.

17. 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.

18. 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.

19. 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.

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

21. 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.

22. 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.

23. 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.

24. 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.

25. 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).

26. 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.

27. 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.