Immunosuppressants Flashcards
(37 cards)
What are the side effects of steroids?
- Weight gain and fluid retention
- Glaucoma
- Osteoporosis
- Infection
- Hypertension and hypokalaemia
- Peptic ulceration and GI bleed
- Psychological/psychiatric symptoms
Describe the mechanism of action of corticosteroids
- Glucocorticoid enters the cell and encounters the steroid receptor
- Once joined moves in to the nucleus and becomes associated with the DNA, altering transcription (up regulates anti-inflammatory protein gene and inflammatory protein gene)
Name two classes of non steroid immunosuppressant drugs
- Inhibitors of DNA synthesis
* Lymphocyte signalling inhibitor
Name the inhibitors of DNA synthesis
- Methotrexate
* Azathioprine
Name the lymphocyte signalling inhibitors
•Cyclosporin
What is methotrexate?
- Inhibits DNA synthesis
- At high dose: kills rapidly dividing cells, causing neutropenia, cytotoxic chemo agent
- Low dose: immunosuppressant
What is the mechanism of action of methotrexate?
- Inhibits a variety of enzymes involved in metabolism which is linked to nucleotide synthesis and leads to a reduction in DNA synthesis
- Inhibits DHFR (dihydrofolate reductase), TYMS (Thymidylate synthetase) and ATIC
What stage of the cell cycle do cells get stuck in with methotrexate?
S phase arrest
What are the actions of methotrexate
- Folate antagonism
- Adenosine signalling (anti-inflammatory)
- Methyl donors
- Eicosanoids and MMPs
- Cytokines
- Adhesion molecules
What are the adverse effects of methotrexate?
•Gastrointestinal: - nausea and vomiting - hepatitis - stomatitis •Haematological: - leukopenia •Other: - frequent infection - pulmonary fibrosis (methotrexate lung)
What can be given to reduce methotrexate toxicity?
•folic acid - 5mg given 4 days after methotrexate
How often is methotrexate given?
Once a week
What is azathioprine?
- Inhibitor of DNA synthesis
* Prodrug of 6-mercaptopurine which is an adjunct of hypoxanthine (a precursor of adenosine monophosphate)
What is the mechanism of action of azathioprine?
- Converted within cells into a nucleoside analogue (6-mercaptopurine)
- Incorporated into DNA and RNA chains leading to the termination of nucleic acid strands
- Cell growth and metabolism halts
- Preferential action of lymphocytes as other cells have purine salvage pathway
What are the adverse effects of azathioprine?
•Gastrointestinal
- nausea, vomiting, diarrhoea
- hepatitis, cholestasis
•Haematological
- leukopenia
- thrombocytopenia
•Other
- frequent infection
- hair loss
Explain the metabolism of azathioprine
- TPMT enzyme
- 0.2-0.6% of individuals lack this enzyme so you need to check TPMT activity prior to treatment
- Without it there is an accumulation of the most active metabolites of azathioprine within cells and development of severe toxicity
What are the clinical indications for azathioprine?
•Most commonly used for inflammatory bowel disease
- ulcerative colitis
- Chrons
•Other severe autoimmune diseases:
- myasthenia gravis
- eczema
Describe the clinical use of azathioprine
- Orally on a daily basis
- Effects take several weeks to become evident
- need to monitor bloods on a monthly basis
What is cyclosporin?
- Lymphocyte signalling inhibitor
* Small molecule inhibitor of calcineurin
What is the mechanism of action of cyclosporin?
- Small molecule inhibitor of calcineurin
- Effect of inhibiting signal transduction from the activated TCR complex
- Profound inhibition of T cell activation
What are the adverse effects of cyclosporin?
- Nephrotoxicity
- Hypertension
- Hepatotoxicity
- Anorexia and lethargy
- Hirsutism
- Paraesthesia
What is tacrolimus?
- Different classes drug to cyclosporin but similar mechanism of action
- More potent activity
- Similar use to cyclosporin but may be a little better tolerated
What are the indications of cyclosporin?
- organ transplantation
- Sometimes used for inflammatory conditions
- can be used topically
Describe the clinical use of cyclosporin
- Given orally on a daily basis
- Dose established using therapeutic drug monitoring
- Main drug interactions through cytochrome P450 enzymes
- Need to monitor blood tests regularly
