DMARDs Disease-Modifying Anti rheumatic Drugs

DMARDS: They are immune modulators that are believed to restore a more normal immune environment within the joint synovium. Characteristic features: 1- Slow acting(called slow acting anti rhumatic agent (SAARA) (onset 10-14 weeks or even more).

2- Not act by inhibiting COX and 3- Has no or little analgesic activity. 4- Has no or little anti-inflammatory activity. Used for patients with RA if the disease does failed to respond to COX inhibitors (NSAIDs).

Normal joint

arthritis

DMARD act to 1- Slow the course of the disease 2-May induce remission 3-Preventing further destruction of the joints and involved tissues. Drug is stopped when there is no response after 3 months and change to other drug

Other medicines, such as analgesics, NSAIDs(eg, ibuprofen or naproxen), and sometimes, prednisone, are added to: 1-Provide faster relief of symptoms. 2-Reduce the total dose of medication needed 3-Prevent further damage to joints.

The choice of DMARD The choice of DMARD depends on many factors, including: 1- The stage and severity of the joint condition. 2- The balance between possible adverse effects and expected benefits. 3- Patient preference.

Before starting treatment The patients should know: 1-Possible adverse effects and toxicities. 2- Dosing regimen. 3-Monitoring frequency. 4-Expected results.

The most common DMARDs are: 1- Methotrexate. 2- Sulfasalazine. 3- Hydroxychloroquine. 4- Leflunomide.

Less frequently used DMARA include gold salts azathioprine cyclosporine

A-Gold Salts: The available preparations include: gold sodium thiomalate(deep i.m. injection), aurothioglucose (i.m. injection) and auranofin (oral). Mechanism of action It taken up by macrophages and suppress phagocytosis and lysosomal enzyme activity, t1/2 is 22 days.

Side effects: mainly include pruritus, dermatitis, glossitis, stomatitis. dimercaprol is antidote. Contraindication: pregnancy

B-Methotrexate: MOA: An anticancer, acts by competitive inhibition of the enzyme dihydrofolate reductase and enzyme involved in protein synthesis as well as anti-inflammatory and cytokine-modulating effects. It is well absorbed orally t1/2 5 hr. response occur sooner than other. Doses are less than that in cancer therapy(7.5 mg weekly).

Side effects: mucosal ulceration, nausea, liver cirrhosis, acute pneumonia like syndrome. NSAIDs increase its toxicity ( slowing its rate of excretion). Antifolate drugs (trimethoprim) also increase toxicity. It is teratogenic

C-Sulfasalazine: It comprises sulfapyridine and 5-aminosalicylic acid linked by an azo-bond which is split by colonic bacteria. Sulfapyridine has an antifolate action which is believed to benefit RA

D-Azathioprine: is metabolized to 6-mercaptopurine (an inhibitor of purine synthesis). It causes inhibition to cellular immune response. Side effects: nausea, rash, bone marrow suppression, liver toxicity. Allopurinol potentiates its effect

E- D-Penicillamine: an analog of the amino acid cysteine, mode of action is unclear Side effects: GI upset, taste impairment, thrompocytopenia, allergic reaction and proteinuria

F- Hydroxychloroquine and chloroquine: they are antimalarial effects, they exert anti-inflammatory and immune modulating activity(by inhibiting nuclic acid synthesis, stabilize lysosomal membranes and free radicals trap). t1/2 is 18 days. Side effects: cause retinal damage (accumulated in tissue ), so that frequent ophthalmological examination is needed. Skin discoloration, alopecia and GI upset can also occur.

G-Leflunomide: selectively inhibits pyrimidine synthesis and prevents T-cell proliferation. It has faster onset of action than other DMARDs. It decreases pain and inflammation in RA. It is well absorbed orally. Side effects: GI disturbances, mouth ulcers, abdominal cramp, increase blood pressure, headache, abnormal liver function tests, skin complications. It is teratogenic.

H-Biological agents: They are derived from natural substances and chemically altered and they include: Etanercept, Infliximab, Adalimumab and Anakinra

Etanercept: Inhibits the activity of the cytokine(TNF) which predominates in synovium of RA patients and it responsibles for most of its inflammatory reaction. It is given s.c. twice a week. Side effects: injection site reactions, headache, infection, depression, Dyspnea and abdominal cramps

Infliximab: it is a monoclonal antibody composed of human and murine regions. It binds selectively to human TNF-α and neutralizing it. It is given by i.v. infusion Used in RA and Crohn's disease. Side effects: anti-infliximab antibodies formation in prolonged used. Infection and lymphoma .

Adalimumab: is a recombinant monoclonal antibody that binds to human TNF-α receptor sites, thereby interfering with endogenous TNF-α activity. Administered by s.c. injection only. Side effects: headache, nausea and injection site reactions

Anakinra: is an interleukin-1 receptor antagonist Anakinra: is an interleukin-1 receptor antagonist. either used alone or in combination with DMARDs.

drugs are used for patients with sever RA failed to controlled by standard agents of DMARDs. include: cyclophosphamide, cyclosporine, chlorambucil and mycophenolate

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