Immunosuppressants and Biologics Flashcards
What are the indications for immunosuppressant use?
After/before transplant to reduce risk of rejection Autoimmune diseases - RA - psoriasis/psoriatic arthritis - lupus - autoimmune haemolytic anaemia
Name some classes of immunosuppressants.
Glucocorticoids (steroids)
Anti-metabolic agents
Calcineurin inhibitors
Biologic therapy
What is azathioprine?
An antimetabolite (purine synthesis inhibitor and purine analgoue)
What is azathioprine mostly used in?
Transplant
Vasculitis - inflammation of blood vessels (can kill you - irreversible in the lungs and kidneys)
Describe the mechanism of action of azathioprine.
Purine synthesis inhibitor blocks an important enzyme in purine production Purine analogue (TGTP) is incorporated into the DNA - causes chain termination and cytotoxicity
What are the side affects and risks of Azathioprine?
Side effects
Lecucopenia - not therapeutic like some drugs (this indicates the dose is too high and they are at risk of infection)
A lot of the drugs are hepatotoxic
Risks
Allopurinol - inhibits XO which forces active azathioprine down an over productive pathway (dangerously low WCC)
Sun exposure - transplant patients have higher risks of melanoma
What is mycophenolate mofetil?
Inhibits purine biosynthesis - inosine monophasphate dehydrogenase
Less nephrotoxic and bone marrow toxic than azathioprine (more commonly used)
Can cause GI toxicity
When is mycophenolate mofetil used?
For transplant and vasculitis
Describe the mechanism of action of mycophenolate mofetil.
In lymphocytes, the de novo synthesis of purines is less active
The drug is an inhibitor of inosine monophosphate dehydrogenase
B and T cells therefore can’t proliferate as they can’t acquire the appropriate DNA within the lympocyte
What is the mechanism of action of Methotrexate?
Inhibits the action of the enzyme dihydrofolate reducatase (DHFR)
- can’t make or use folic acid, which is needed for synthesis of thymidine, meaning that DNA synthesis is impaired
- also inhibits GART and AlCARTF
- targets T-cell activation by an accumulation of adenosine
Methotrexate is brought into a cell by transporters, where it is polygutamated (attaching a large insoluble molecule to the soluble methotrexate to keep it in the cell)
What is methotrexate?
An anti-metabolite of the antifolate type
- inhibits synthesis of DNA
- inhibition of T cell activation and suppression of intracellular adhesion molecule expression produced by T cells
- selective down regulation of B cells
What are the side effects of methotrexate?
GI - nausea and vomiting Leucopenia Thrombocytopenia Liver (enzyme and cirrhosis) Pulmonary fibrosis - RA carries risk of interstitial lung disease anyway Pneumonitis
What is ciclosporin used for?
Transplants
Psoriasis
RA
Describe the mechanism of action of ciclosporin.
Binds to ciclophillin and forms a complex that inhibits calcineurin
- calcineurin then dephosphorylates nuclear factor of activation of T cells (NFATC)
- this goes into the cell nucleus and increases IL-2 expression (a regulator of T-cell proliferation)
- leads to T-cell cytokine expression
What are the complications of using ciclosporin?
Drug interactions (increases or decrease ciclosporin levels within the body)
Hypertension
Tremor
Hisutism
Preparation brand - each brand is slightly different and giving a patient a different one can affect bioavailability of the drug
