Immunosuppressant drugs Flashcards
What are the main roles of the immune system?
Defence against infection
Recognising and responding to tissue grafts and newly introduced proteins
defence against tumours
What is innate and adaptive immunity?
Adaptive immunity = specific immunity that adapts to presence of microbial invaders
Innate immunity = natural immunity that is always present
What are T cells/what do they do?
T cells are immune cells that express T cell receptor (TCR)
Interact w/ antigen presenting cells through MHC receptor
Subsets:
- CD4 helper cells
- CD8 cytotoxic/suppressor cells
What are B lymphocytes? (types of immunoglobulin?)
Responsible for antibody production of different immunoglobulin (Ig) classes
Types of immunoglobulin:
- IgG
- IgM
- IgA
- IgE –> immediate hypersensitivity binds to basophils and mast cells
*immunoglobulin are activated by Th
What are the 4 broad types of immunosuppressive drugs? (characterised based on target/action)
Inhibitors of IL-2 production of action
- calcineurin inhibitors: cyclosporine, tacrolimus
Inhibitors of cytokine gene expression
- corticosteroids
Inhibitors of purine or pyrimidine synthesis
- azathioprine, mycophenolate mofetil
Immunosuppressant antibodies
What is the normal mechanism behind T-cell activation?
TCR activate —> inc Ca2+ inside cell –> activation of calmodulin –> activation of calcineurin (phosphatase) –> dephosphorylation of NFAT (nuclear factors of activated T cells) –> moves to nucleus –> regulates gene transcription of cytokines
What is the MAO of calcineurin inhibitors?
Cyclosporine binds to cyclophilin whilst tacrolimus binds to FkBP
Complexes associate w/ calcineurin –> inhibits calcineurin –> inhibition of the nuclear translocation of NFAT –> inhibit gene transcription –> inhibits cytokine production (mainly IL-2)
What is the MOA of cyclosporine?
Inhibit IL-2 synth + dec expression of IL-2 receptor –> dec clonal proliferation and induction of cytotoxic T-cells from CD+8 precursors
What are some notable ADRs of cyclosprine?
Nephrotoxicity = causes vasoconstriction due to removal of NO mediator, dec angiotensin II (vasocon), dec prostaglandins (dec blood to kidney) —> damage kidney
Hepatotoxicity, HTN
Anorexia
Lethargy
Hirsutism
Tremor
Paraesthesia
GI disturbances
What are some drug interactions associated w/ cyclosporine and tacrolimus?
Cimetidine, erythromycin, ketoconazole = inc cyclosporine plasma concentration
Diuretics (amiloride, spironolactone) = inc risk of hyperkalaemia
ACEi = inc hyperkalaemia risk
Statins = inc rhabdomyolysis risk
NSAIDs = potential additive renal tox
What are some notable points about the pk of cyclosporine? (metabolism, excretion, accumulation?, absorption route?)
Poorly absorbed by mouth
metabolised by liver, excreted in bile
Accumulates in most tissue in concentrations 3x - 4x of that seen in plasma
- some drug remains in lymphomyeloid tissue, fat deposits for time after drug ceased
What is the MOA of tacrolimus?
Internal receptor is immunophilin termed FKBP (FK-binding protein)
What are some notable facts about tacrolimus pk? (administration, metabolism, t1/2)
Given orally, IV or ointment
99% metabolised by liver
T1/2 = approx. 7 hrs
What are some notable ADRs for tacrolimus?
More severe ADRs than cyclosporine
Nephrotoxicity and neurotoxicity (worse than above)
Hirsutism (less than cyclosporine)
GI disturbances
Metabolic disturbance (hyperglycaemia)
Thrombocytopenia, hyperlipidaemia
What is the MOA of sirolimus and Everolimus?
Bind FKBP –? complex inhibits activity of mammalian target rapamycin (mTOR) –> inhibits IL-2 mediated signal transduction –> cell cycle arrest in G1-S phase
