Immunosuppressants Flashcards
What are the indications for immunosuppressants?
- abnormal inflammation (inflammatory arthropathies, UC/Crohn’s, psoriasis)
- unwanted normal inflammation (solid organ transplants, bone marrow grafts - prevent rejection)
What are the advantages and adverse effects of steroid sparing agents?
Advantages: rapid onset, easy to administer, able to treat variety of inflammatory conditions
Adverse effects: weight gain and fluid retention, glaucoma, osteoporosis, infection, hypertension, hypokalaemia, peptic ulceration and GI bleed, psychological/psychiatric symptoms
Describe the mechanism of action of corticosteroids
- glucocorticoid meets receptor and moves into nucleus of cell
- influences DNA transcription to down regulate inflammatory proteins and increase transcription of anti-inflammatory proteins
List the non-steroid immunosuppressant drugs
- DNA synthesis inhibitors: methotrexate, azathioprine, mycophenolate
- lymphocyte signalling inhibitors: cyclosporin, tacrolimus, sirolimus, leflunomide
Describe the mechanism of action of methotrexate
- interferes with dihydrofolate reductase in folic acid metabolism and thymidylate synthetase
- results in the reduction of thymidine availability and decreased DNA synthesis
- proliferation of cell arrested (S-phase arrest)
List the adverse effects of methotrexate
- GI: nausea, vomiting, diarrhoea, hepatitis, stomatitis
- haematological: leukopenia
- other: frequent infection, pulmonary infection
- can be reduced with administration of folic acid 4 days after methotrexate
Describe the clinical use of methotrexate
- given once a week with folic acid
- given orally (or s/c if not tolerated)
- takes weeks for effect
- regular blood monitoring of patient needed
Describe the mechanism of azathioprine
- purine analogue which is converted within cells into a nucleoside analog which is incorporated into DNA and RNA chains
- results in premature termination of nucleic acid chains
- halts cell growth and metabolism
- favours lymphocytes (other cells have purine salvage pathway)
What are the other actions of azathioprine?
- prevent immune responses through cytotoxic effect
- inhibits T cell co-stimulation through interference with CD28
List the adverse effects of azathioprine
- GI: nausea, vomiting, diarrhoea, hepatitis and cholestasis
- haematological: leukopenia, thrombocytopenia
- other: frequent infection, hair loss
Describe azathioprine metabolism and the importance of screening prior to treatment
- TMPT enzyme vital in reducing active drug levels in cells
- without it can result in accumulation of active metabolites and development of severe toxicity
- importance in checking TMPT activity in patients prior to therapy
What are the indications for azathioprine in clinical practice?
- UC and Crohn’s (IBD)
- myasthenia gravis and eczema (inflammatory conditions)
Describe the clinical use of azathioprine
- given orally on daily basis
- takes weeks for effect
- bloods need monitoring on monthly basis
Describe the mechanism of action of cyclosporin
- small molecule inhibitor of calcineurin
- prevents activation of nuclear factors from activated TCR complex altering the transcription of activating cytokines (IL2)
- inhibition of T cell activation
List the adverse effects of cyclosporin
- nephrotoxicity
- hypertension
- hepatotoxicity
- anorexia and lethargy
- hirsutism
- parenthesis
Describe the mechanism of action of tacrolimus
- different class to cyclosporin but similar mode of action
- more potent than cyclosporin and better tolerated
- combines with other factors to inhibit calcineurin
What are the indications for cyclosporin/tacrolimus?
- solid organ transplant (liver, kidney, heart, lung)
- inflammatory conditions (sometimes)
- topical treatment (skin/eye)
Describe the clinical use of cyclosporin/tacrolimus
- given orally on daily basis
- dose established through therapeutic drug monitoring
- be aware of many drug interactions through cytochrome P450 enzymes
- bloods need regular monitoring
What are the disadvantages of immunosuppressants?
- often insufficient in controlling inflammatory disease with subsequent progression and has a slow rate of onset so not good for acute severe disease
- highly toxic even in low doses (bone marrow suppression, frequent infections)
List the features of biologic therapies
- able to target specifically designated components of the immune system with minimal off-target effects (lower toxicity)
- usually parenteral route with better side effect profile
What are the side effects of biologic therapies?
- hypersensitivity
- infusion reactions
- GI toxicity
- risk of infection (but less of a problem compared to other therapy)
Risk of infection associated with anti-TNF therapy
- increased risk of TB (disseminated)
- screening for latent disease before treatment (IGRA) and treat if required before treatment
- salmonella and listeria
Risk of infection associated with rituxmab therapy
- increased risk of hep B reactivation
- screen and prophylaxis if necessary
Risk of infection associated with abatacept therapy
- increased risk of pneumonia and RTI
- TB
Risk of infection associated with anti-IL-1 therapy
- increased risk of RTI and pneumonia
