Drug treatment of rheumatoid arthritis

NSAIDs used in rheumatoid arthritis

1- aspirin (2-6g/day) 2- indometacin - used orally or suppository night to relieve nocturnal pain or morning stiffness because of *long duration of action* 3- Piroxicam

Write about Mesalazine

1- inhibits both COX & lipo-oxygenase enzymes 2- scavenge free radicals 3- inhibits production of pro-inflammatory cytokines & immunoglobulins

Mechanism of action of Methotrexate

1- inhibits folate-dependent enzymes - involved in purine biosynthesis - lead to reducing lymphocyte proliferation 2- inhibits 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) transformylase - lead to increase the amount of AICAR that inhibits the degradation of adenosine - increased plasma concentrations of adenosine - mediate many anti-inflammatory effects like TNFα production. - most rapid acting disease modifying drug - therapeutic effect develops in 3-6 weeks - t1/2=6-9h - given orally once weekly & gradually increase the dose as bone marrow & liver function allows. - Parenteral administration possible - mainly used in pediatrics - excreted mainly in urine & 30% in bile

Contraindications of methotrexate

1. Moderate to severe renal impairment 2. Liver disease 3. Pregnancy because it is embryotoxic (both male & female patients should avoid conception for at least 6 months after cessation of methotrexate) 4. Breast feeding 5. Active infection because bone marrow suppression

Using of Steroids

1. To provide in-term relief of inflammatory symptoms during weeks that is taken by DMARDs 2. In severe cases like vasculitis or rheumatoid lung 3. During failure of DMARDs or development of intolerable side effects 4. Intra-articular injection of steroids when one or two joints are involved.

Action of Drugs that used in rheumatoid arthritis

1. relieve pain, inflammation & muscle stiffness with NSAIDs 2. modify course of disease or induce remission

Clinical uses of of methotrexate

1. rheumatoid arthritis 2. as cytotoxic drug (in high doses) 3. psoriatic arthritis 4. less commonly in connective tissue diseases like SLE

Other immunosuppressants used in rheumatoid arthritis

- Azathioprine - ciclosporin - cyclophosphamide used in resistant cases

Interference with cytokine expression or signaling in rheumatoid arthritis

- Cytokines play a central role in immune response & in rheumatoid arthritis - TNF-α appears to be at the heart of inflammatory process.

Cautions & contraindications of Hydroxychloroquine (antimalarial drug)

- Hepatic & renal impairment - G6PD deficiency - breast feeding

Adverse effects of gold salts

- Mouth ulcers - irreversible skin pigmentation - proteinurea - blood dyscrasias - hepatitis - peripheral neuropathy - pulmonary fibrosis.

Adverse effects of mesalazine

- Nausea - Vomiting - headache & rash (common) - hemolytic anemia - methemoglobinemia & SLE like syndrome(rare) - reversible infertility in male & not in female - not teratogenic

Write about Sulfapyridine ( antibiotics)

- active moiety in rheumatoid arthritis - reduces rheumatoid factor titers - inhibits IL-2 induced T-cell proliferation

Write about Adrenal corticosteroids

- considered as DMARD because they reduce disease severity & associated damage - clinical effects are noticeable within 24h. - given orally (Prednisone & Prednisolone)

Write about Gold salts

- decreased as a result of its toxicity - increased use of methotrexate - more recently anti-TNFα biological agents e.g. Sodium aurothiomalate by deep i.m. injection. - Auranofin orally - less effective but has less severe adverse effects

Adverse effects of Leflunomide

- diarrhea is the commonest - allergic reactions - Alopecia - Hypertension - leucopenia - hepatitis

Write about using of NSAIDs in rheumatoid arthritis

- first choice in rheumatoid arthritis - relieve symptoms - not slow disease progression.

Clinical uses of Methotrexate (Rheumatrex)

- first line treatment in rheumatoid arthritis - 60% of patients at lower doses than those needed cancer chemotherapy.

Contraindications of gold salts

- hepatic disease - renal disease - pregnancy & lactation

Write about Leflunomide

- inhibits dihydro-orotate dehydrogenase - mitochondrial enzyme required for synthesis of pyrimidines - arrests proliferation of activated T-cells. - licensed for treatment of rheumatoid arthritis and psoriatic arthritis

Adverse effects of methotrexate

- most serious side effects are 1- bone marrow toxicity 2- hepatic toxicity 3- pneumonitis. - Regular monitoring of full blood count and liver function test are recommended. - Mouth ulcers and nausea are common and can be improved by co-administration of folic acid (5mg)

Disease modifying anti-rheumatic drugs (DMARDs)

- reduce disease activity - prevent radiologically determined disease progression - require 4-6 months of treatment for full response - decrease 1- ESR 2- C-reactive protein 3- RF (rheumatoid factor)

Write about Sulfasalazine

- results from conjugate of mesalazine (5-aminosalicylic acid) to sulfapyridine - poorly absorbed from gut but is cleaved by bacterial azoreductases in colon to release mesalazine & sulfapyridine

Rheumatoid arthritis

- systemic autoimmune inflammatory disorder - characterized by inflammation within synovial joints - causing 1- pain 2- swelling 3- Stiffness - progress to erosion and eventually to joint destruction

Write about Hydroxychloroquine (antimalarial drug)

- used as an adjunct to other disease modifying drugs. - mechanism of action is unclear but in vitro found to reduce production of pro-inflammatory cytokines including TNFα & IL-β - best to be used in mild disease. - relatively nontoxic

Adverse effects of Hydroxychloroquine (antimalarial drug)

- well tolerated - low incidence of side effects like GIT disturbances & rashes. - Retinal toxicity rarely occurs with long term use

Anti-TNFα agents

1 Infliximab - humanized monoclonal IgG1 Abs - causes down regulation of macrophages & T-cell function - given with methotrexate by iv infusion. 2 Etanercept - recombinant molecule - licensed to be used s.c. in rheumatoid arthritis in adults.

One of side effect of methotrexate is mouth ulcer why ?

Due to deficiency of folic acid

How Gastric intolerance & PU reduced when used NSAIDs

by using 1- H2 antagonists or 2- misoprostol or 3- selective COX-2 inhibitors