Immunopharmacology Flashcards
(45 cards)
What are the classes of drugs used for immune suppression in transplantation?
- Glucocorticoids (steroids)
- Calcineurin inhibitors
- Antimetabolites
- IL-2 receptor monoclonal antibodies (“mabs”)
- m-TOR (target of rapamycin) inhibitors
Which branch of the immune system is most affected by glucocorticoids?
Cell-mediated immunity
How do glucocorticoids function in immune suppression?
- Inhibit genes that code for cytokines, most importantly IL-2
- IL-2 is a proliferation signal for T cells, so its inhibition reduces T cell proliferation
- Glucocorticoids also suppress B cell expression of IL-2 and IL-2 receptors
- Anti-inflammatory effects (upregulates expression of lipocortin)
What are the side effects of glucocorticoids?
- Immunodeficiency
- Adrenal gland suppression (if used for over 21 days)
- Hyperglycemia and fat redistribution (characteristic moon face)
- Growth failure and delayed puberty
- Excitatory effects on CNS (euphoria, psychosis)
- Osteoporosis
- Cataracts
- Gastric ulcers (prevented with concurrent administration of omeprazole, misoprostol)
What are the calcineurin inhibitors?
- Cyclosporine
- Tacrolimus
What is the mechanism of action of the calcineurin inhibitors?
- Inhibit calcineurin, which phosphorylates and activates NF-AT
- NF-AT is a transcription factor involved in the synthesis of interleukins (e.g. IL-2) by activated T cells
- Therefore, the drugs decrease levels of IL-2 synthesis
What are the indications of calcineurin inhibitors?
- Human organ transplantation
- GVHD after hematopoietic stem cell transplantation
- Select autoimmune disorders
How are calcineurin inhibitors metabolized?
By P450 3A in the liver, with many drug–drug interactions
What are the adverse effects of calcineurin inhibitors?
- Very narrow therapeutic window
- If levels are too high: toxicities, e.g. nephrotoxicity, confusion, hyperglycemia (especially with tacrolimus), hypertension
- If levels are too low, transplant rejection may occur
- Increased risk of lymphoma and other cancers, e.g. Kaposi sarcoma, skin cancer, has been reported with cyclosporine (though recent evidence suggests this isn’t true)
What are the parameters that must be monitored while taking cyclosporine?
- Trough levels
- Serum electrolytes
- Kidney function
- Liver function
- Blood pressure
- Serum cholesterol
What are the indications of cyclosporine specifically?
- Ophthalmic solution is available for severe dry eye syndrome and ocular GVHD
- Cyclosporine is combined with methotrexate to prevent GVHD after allogeneic stem cell transplantation
- Used in a variety of autoimmune disorders, including uveitis, rheumatoid arthritis, psoriasis, and asthma
What are the indications of tacrolimus specifically?
Topical preparation is available for dermatologic diseases, e.g. atopic dermatitis, psoriasis
What is an example of an m-TOR inhibitor?
Sirolimus (rapamune)
What are the adverse effects of sirolimus?
- Narrow therapeutic window
- If levels are too high: toxicities, e.g. confusion, nephrotoxicity
- If levels are too low, transplant rejection may occur
What is the difference between the use of antimetabolites in anticancer chemotherapy and in immune suppression?
In immune suppression, the dose is lower
What cells do antimetabolites affect?
B cells and T cells
What are examples of antimetabolites?
- Methotrexate
- Azathioprine
- Mercaptopurine
- Mycophenolate
What is methotrexate?
A folic acid analogue that binds dihydrofolate reductase and prevents synthesis of tetrahydrofolate
What are the indications of methotrexate?
- Treatment of autoimmune diseases (e.g. rheumatoid arthritis, Behçet’s disease)
- Transplantations
What are the indications of azathioprine and mercaptopurine?
Transplant and rejection reactions
What is mycophenolate?
A reversible inhibitor of the enzyme inosine monophosphate dehydrogenase (IMPDH), leading to depletion of guanosine nucleotides
What are the indications of mycophenolate?
- More effective than azathioprine in preventing acute rejection
- Used in combination with cyclosporine and prednisolone
- Mycophenolate mofetil is used in solid organ transplant patients for refractory rejection
- Mycophenolate mofetil is combined with prednisonse as an alternative to cyclosporine or tacrolimus in patients who do not tolerate these drugs
- In renal transplants, it is used with low-dose cyclosporine to reduce cyclosporine-induced nephrotoxicity
What are the components of tacrolimus-led triple therapy?
- Tacrolimus (0.1 mg/kg/day) twice daily (every 12 hours)
- Prednisolone
- Azathioprine (1–2 mg/kg) once daily
What organ is tacrolimus-led triple therapy used for?
Kidney transplants
