Immunosuppressants

Question 1

What are DMARDs

Answer 1

Disease modifying anti-rheumatic drugs

they take 3 months to work and have a small therapeutic index. they inhibit the immune system. have no analgesic effects - only slow course of the disease

Question 2

Methotrexate

Answer 2

a dihydrofolate reductase inhibitor. weekly dosing.

Dihydrofolate reductase converts dihydrofolate (DHF) into tetrahydrofolate (THF). This then produces methylene THF.

The conversion of methylene THF back into DHF occurs by thymidylate synthase which reacts deoxyuridine monophosphate with methylene THF. this produces deoxythymidine monophosphate which then is turned into thymine - necessary for DNA transcription.

Ultimately, methotrexate inhibits the synthesis of thymine upstream.

Causes nausea, post dose “flu”, hepatotoxicity, pulmonary fibrosis, teratogenicity, GIT side effects, nephrotoxicity, and blood disorders.

Folic acid consumption sees reduced side effects. Here it does not prevent the anti-inflammatory effects of methotrexate, suggesting that there is likely other mechanisms through which it exerts its DMARD effects

Question 3

Azathioprine

Answer 3

Inhibits purine synthesis and thus DNA - reduces inflammatory cell proliferation. it is a prodrug for mercaptopurine which then forms 6-TIMP via HPRT or 6-MMP via TPMT. TPMT also then metabolises the active 6-TIMP.

6-TIMP inhibits amidophosphoribosyltransferase to inhibit purine synthesis - active metabolite. it is cytotoxic

TPMT activity is highly variable between patients (11% have low activity and 0.3% have no activity). This may lead to heightened levels of 6-TIMP which may cause toxicity. alternatively, high levels of TPMT can lead to resistance to mercaptopurine.

Mercaptopurine is also used directly instead of given azathioprine

Question 4

Fluorouracil

Answer 4

acts by inhibiting the formation of deoxyuridine monophosphate (dUMP), which is needed for downstream formation of thymine.

same pathway as methotrexate, but different route of inhibition.

Question 5

Leflunomide

Answer 5

inhibits the clonal expansion of T-cells.

a prodrug for teriflunomide - inhibits dihydroorotate dehydrogenase. dihydroorotate is metabolised into rotate which then forms pyrimidines for DNA synthesis

Causes diarrhoea (20%), nausea, rash, alopecia (10% for these 3), abnormal liver function (5%) and teratogenicity.

Question 6

Aminosalicylates

Answer 6

5-aminosalicylate - mesalazine.

Increases PPARy activation. this reduces the synthesis of inflammatory mediators - nuclear receptor.

Sulfasalazine is a prodrug for mesalazine. used in RA and UC. bacteria in the colon convert sulfasalazine into mesalazine and sulfapyridine

Question 7

Calcineurin targetting drugs

Answer 7

cyclosporin is a calcineurin inhibitor - a calcium-dependent phosphatase

Calcineurin dephosporylates the nuclear factor of activated T-cells (NFATc) - this leads to activation.

NFATc is a transcription factor that increases IL-2. IL-2 activates T-cells

Cyclosporin acts by binding to cyclophilin. this complex then inhibits calcineurin.

used in UC, RA, psoriasis, and organ transplant rejection

Tacrolimus is a calcineurin inhibitor used for organ transplants

binds to FKBP (FK506 binding proteins) that inhibit calcineurin

Question 8

Sirolimus/rapamycin

Answer 8

AKA rapamycin.

Inhibits mTOR (mammalian target of rapamycin), a protein kinase involved in protein synthesis. inhibition of mTOR promotes tolerance throughout its effects on regulatory T-cells, promoting their expansion.

the regulatory T-cells prevent autoimmunity by prevent T-cell responses