Immunosuppressants

Question 1

What are some of the adverse effects of steroids?

Answer 1

• Weight gain and fluid retention,
• Glaucoma,
• Osteoporosis,
• Infection,
• Hypertension and hypokalaemia,
• Peptic ulceration and GI bleed,
• Psychological/psychiatric symptoms

Question 2

What is the mechanism of action of corticosteroids?

Answer 2

• Down regulation of inflammatory proteins and upregulation of anti-inflammatory proteins

Question 3

What are some examples on immunosuppressants which inhibit DNA synthesis

Answer 3

• Methotrexate,
• Azathioprine,
• Mycophenolate

Question 4

What are some examples of drugs which inhibit lymphocyte signalling?

Answer 4

• Cyclosporin,
• Leflunomide

Question 5

Describe features of methotrexate

Answer 5

• At high doses it’s a cytotoxic chemotherapy agent and at low doses it is an immunosuppressant.
• It causes inhibition of dihydrofolate reductase which reduced the amount of thymine and therefore prevents DNA synthesis. This affects the S phase of the cell cycle.
• It also affects adenosine signalling

Question 6

What are the side effects of methotrexate?

Answer 6

• GI: Nausea, vomiting, diarrhoea, hepatitis and stomatitis.
• Haematological: Leukopenia
• Frequent infections,
• Pulmonary fibrosis

Question 7

How cant he toxicity of methotrexate be reduced?

Answer 7

Give 5mg of folic acid 4 days after methotrexate (mtx on mondays, folic acid on fridays)

Question 8

What are the indications and clinical uses of methotrexate?

Answer 8

• Most commonly used for rheumatological diseases such as RA, psoriasis and psoriatic arthritis and giant cell arthritis.
• It is normally given orally but can be s/c if GI upset. Takes several weeks to become effective and pts require monitoring

Question 9

What is the mechanism of action of azathioprine?

Answer 9

• It is a prodrug of 6-mercaptopurine which gets converted within a cell to a nucleoside analogue. It is then incorporated into DNA/RNA strands leading to chain termination. This halts cell growth and metabolism. Preferentially affects lymphocytes.
• Inhibition of T cell co-stimulation via CD28

Question 10

What are the adverse effects azathioprine

Answer 10

GI: Nausea, vomiting, diarrhoea, hepatitis and cholestasis.
Haematological: Leukopenia and thrombocytopenia
- Hair loss and frequent infections

Question 11

What is an important enzyme to check prior to putting a patient on azathioprine

Answer 11

TPMT - this enzyme metabolises azathioprine but some individuals lack the enzyme so they get a toxic build up of the drug

Question 12

What are the indications and clinical use of azathioprine

Answer 12

Most commonly used for ulcerative colitis and crohns but can be used in myasthenia gravis or eczema,
Given orally on daily basis, takes weeks to become evident and requires monthly monitoring of bloods

Question 13

What is the mechanism of action of cyclosporin?

Answer 13

• Small molecule inhibitor of calcineurin which inhibits transduction from the activated TCR complex. It has profound inhibition of T cell activation and prevents formation of cytokines

Question 14

What are the adverse effects of cyclosporin?

Answer 14

• Nephrotoxicity,
• Hypertension,
• Hepatotoxicity,
• Anorexia and lethargy,
• Hirsutism,
• Paraesthesia,
• Doesn’t cause suppression of the bone marrow

Question 15

Name a drug with a similar action to cyclosporin?

Answer 15

Tacrolimus. It may be slightly better tolerated and has a more potent activity

Question 16

What are the indications and clinical use of cyclosporin?

Answer 16

• Usually given for organ transplantation and sometimes used for inflammatory conditions.
• Given orally on daily basis has many drug interactions due to cytochrome P45 enzymes.

Question 17

What are the disadvantages of immunosuppressants?

Answer 17

• They are often insufficient to control inflammatory disease,
• Slow rate of onset so limited use in acute severe disease,
• Significant toxicities even at low doses and cause bone marrow suppression and frequent infections

Question 18

Describe the benefits of biologic therapies

Answer 18

They can target specific components of the immune system with minimal off target affects. Often need to be delivered parentally.
Can have TNF inhibitor sand anti-interleukins

Question 19

What are the adverse effects and risks of infections with biologic therapies?

Answer 19

• They may cause hypersensitivity reactions, infusion reactions of mild GI toxicity.
• Anti-TNF therapy increases the risk of TB because TNF is involved in formation of granuloma. Must be screened prior to treatment via interferon gamma release assay.
• Rituximab increases risk of hepatitis B reactivation so require screening