Non-Biological DMARDS

Question 1

*First line DMARD in RA

MOA
>inhibit AICAR transformylase & thymidilate syhnthetase
>AICAR inhibits AMP deaminase
>AMP released and converted to adenosine
*Adenosine potent inhibitor of inflammation

Other MOA
>dihydrofolate reductase : affects lympho and mono function
>stimulates apoptosis of immune inflamm
>inhibit pro inflamm cytokines

PK
70% absorbed at oral
Metabolized to less active hydroxylated metab

Dosage : 15-25mg weekly
Half life : 6-9hrs ** inc in presence of hydroxychloroquine
Excreted in urine; 30% in bile

Indications
RA, Juvenile chronic arthritis, psoriasis, psoriatic arthritis, AS, wegener’s, SLE, vasculitis

Adverse effect 
**nausea and mucosal ulcer most common
Hepatotoxic
**incidence of GI or liver abn can be reduced by use of leucovorin 24 after weekly dose or daily folic acid
**contraindicated in pregnancy

Answer 1

Methotrexate

Question 2

Major metab : 6-thioguanine (suppress inosinic acid synthesis, B and T cell function, Ig prod, and IL2 secretion

PK
**rapid metabolizers clear the drug 4x faster (high risk of myelosuppression)
Dose : 2mg/kg/day

Indications: psoriatic arthritis, reactive arthritis, polymyositis, SLE, Behcet disease

Adverse: myelosuppression, GI disturbance, infection risk

Answer 2

Azathiorpine

Question 3

Suppress T lymphocyte by decreasing leukocyte chemotaxis, stabilizing lysosomal enzyme, inhibiting DNA RNA synthesis, trapping free radicals

Extensively tissue bound esp in melanin containing tissue

Not very efficacious, takes 3-6 months for effect

• *OCULAR TOXICITY
• *optha monitoring every 6-12 months is advised

Answer 3

Chloroquine/Hydroxychloroquine

Question 4

Alkylating agent

crosslinks DNA to prevent replication
Suppress T and B cell function by 30-40%

Adverse: infertility, hemorrhagic cystitis, BM suppression

Answer 4

Cyclophosphamide

Question 5

Antibiotic and non biologic DMARD

Inhibits IL-1 and 2 receptor production
Inhibits macrophage-Tcell interaction/response

**grapefruit enhances bioavailability (metabolic inhibitor)

Adverse: sterility in women, BM suppression

Answer 5

Cyclosporine

Question 6

Inhibits dihydroorotate dehydrogenase leading to decreased RNA synthesis
Inhibits T cell proliferation and B cell autoantibody production

Adverse: diarrhea, inc liver enzyme, weight gain, mild alopecia

Answer 6

Leflunomide

Question 7

Decreased IgM and IgA RF production

PK
sulfapyridine acetylated and excreted in urine
sulfasalazine excreted UNCHANGED in urine

Indications: RA, juvenile arthritis, ankylosing spondylitis

Adverse: nausea vomiting, positive dsDNA, infertility

Answer 7

Sulfasalazine