EXAM #4: IMMUNOSUPPRESSANTS Flashcards
What types of grafts will NOT provoke an immune response?
1) Autografts (self)
2) Isografts (identical twins)
What is an allograft?
Transplant between two non genetically identical individuals
What are the two hallmark Calicneurin inhibitors used as immunosuppressants?
Cyclosporine
Tarcolimus
What are the anti-proliferative/ anti-metabolic immunosuppressants?
Azathioprine
Mycophenolate mofetil
Sirolimus
What are the “biological” immunosuppressants?
Antithymocyte globulin
Muromonab-CD3
Anti-TNF-a
What are the two adverse effects associated with immunsuppressants as a drug class?
1) Infection
2) Malignancy
What are the “genomic” effects of glucocorticoids i.e. MOA related to the genome?
1) Bind cytosolic receptor
2) Translocate to nucleus
3) Alter gene expression to decrease pro-inflammatory cytokines
Can also alter transcription factors to decrease production of proinflammatory cytokines
What are the “non-genomic” effects of glucocorticoids?
1) Alter signaling pathways
2) Insertion into cell membrane to alter ion transport
What are the effects of glucocorticoid administration?
1) Decreased peripheral lymphocytes
2) Decreased pro-inflammatory cytokines
3) Inhibition IL-2
4) Reduced neutrophil chemotaxis
*Little effect on humoral immunity
What are the pro-inflammatory cytokines?
IL-1
IL-6
TNF-a
IFN-gamma
What is the function of IL-2?
T-cell proliferation
What are the indications for glucocorticoid administration?
1) Prevent transplant rejection
2) GVHD
3) Autoimmune disease
4) Prevention of initial “cytokine storm” with biological immunosuppressants
What adverse effects are seen with glucocorticoids?
1) Growth retardation
2) Poor wound healing
3) HTN
4) AVN
5) Cataracts
6) Hyperglycemia
7) Adrenal crisis upon discontinuation
What is low dose glucocorticoid therapy?
Less than 7.5 mg prednisone/ predisoe equivalent per day
What is medium dose glucocorticoid therapy?
7.5mg- 30mg prednisone/ prednisoe equivalent per day
What is high dose glucocorticoid therapy?
30-100mg prednisone/ prednisoe equivalent per day
What is very high dose glucocorticoid therapy?
Greater than 100mg prednisone/ prednisoe equivalent per day
What is pulse glucocorticoid therapy?
Greater than 250mg for a day, or a few days prednisone/ prednisoe equivalent per day
What class of drug is Cyclosporine?
Calcineurin inhibitor
What immunity is inhibited by Cyclosporine?
T-cell mediated immunity especially involved in:
1) Transplant rejection (kidney)
2) Autoimmunity
What is the MOA of cyclosporine?
1) Complexes with CYCLOPHILIN in cytoplasm
2) Complex with CALCINEURIN
3) Complex prevents dephosphorylation of NFAT
4) NFAT cannot translocate to nucleus
5) NO IL-2, the T-cell growth factor
What are the clinical indications for Cyclosporine?
1) Prophylaxis for transplantation
2) GVHD
What is the major toxicity associated with Cyclosporine?
Nephrotoxicity
Neurtoxicity
Skin cancer
Hirsutism
What is the interaction between Grapefruit and Cyclosporine?
- Grapefruit juice inhibits cytochrome p450
- Increases blood concentrations of Cyclosporine increasing toxicity
What type of drug is Tacrolimus?
Calcineurin inhibitor (like Cyclosporin)
What is the MOA of Tacrolimus?
1) Complexes with CYCLOPHILIN in cytoplasm
2) Complex with CALCINEURIN
3) Complex prevents dephosphorylation of NFAT (transcription factor in nucleus)
4) NFAT cannot translocate to nucleus
5) NO IL-2, the T-cell growth factor
How does Tacrolimus differ from Cyclosporine?
Easier to measure blood levels with Tacrolimus
What is the major clinical indication for Tacrolimus?
Prophylaxis for transplant rejection
What class of drug is Azathioprine?
Purine antimetabolite
What is the MOA of Azathioprine?
1) Metabolized to 6-mercaptopurine
2) 6-MP is metabolized further
3) Metabolites incorporate into DNA and block de novo purine synthesis
What is unique about lymphocytes that makes Azathioprine specific?
Lymphocytes don’t have a pruine salvage pathway
*Thus, blocking de novo kills lymphocytes
What are the clinical indications for Azathioprine?
1) Prevent transplant rejection
2) Severe RA
3) Glucocorticoid resistant autoimmune disease
What are the adverse effects associated with Azathioprine?
1) Myelosuppression–monitor with CBC
2) Hepatotoxicity–monitor with liver enzymes
What type of drug is Mcyphenolate Mofetil?
Purine antimetabolite
What is the MOA of Mycophenolate Mofetil?
1) Prodrug
2) Metabolized to MPA (active)
3) Inhibits IMP required for de novo synthesis of pruine
*Results in killing lymphocytes
What are the clinical indications for Mycophenolate Mofetil?
1) Prophylaxis for transplant rejection
2) SLE
*Commonly given with glucocortiocoid and calcineurin inhibitor
What adverse effects of Mycophenolate Mofetil?
1) Myelosuppression
2) GI upset
3) CMV infections
4) TERATOGENIC
What class of drug is Sirolimus?
Antimetabolite
What is the MOA of Sirolimus?
mTOR inhibitor
What are the clinical indications for Sirolimus?
1) Transplant prophylaxis
2) Renal transplant that can’t tolerate nephrotoxicity of other drugs
What class of drug is Antithymocyte Globulin?
Biological
What is the MOA of Antithymocyte Globulin?
1) Binds T-cell CD markers
2) Depletes circulating T-cells via:
- Complement activation
- Inhibition of T-cell activation
What are the clinical indications for Antithymocyte Globulin?
1) Induction immunosuppression
2) Treatment of acute transplant rejection
What adverse reaction is highly associated with Antithymocyte Globulin?
1) Cytokine storm (treated with glucocorticoids)
2) Serum sickness
What class of drug is Muromonab-CD3?
Biological
What is the MOA of Muromonab-CD3?
Anti-CD3 antibody (T-cell CD marker)
1) Initiates complement mediated lyisis
2) Prevention T-cell activation
What are the clinical indications for Muromonab-CD3?
Reverse glucocorticoid-resistant organ transplant
What is a drawback to Muromonab-CD3?
Mouse-antibody; body will generate antibodies generated against Muromonab-CD3
Can only be used once
What complications are associated with Muromonab-CD3?
1) Cytokine storm with administration
2) Potentially fatal adverse reactions including anaphylaxis
What are the three anti-TNF-a biologicals?
1) Infliximab
2) Adalimumab
3) Etanercept
What is Infliximab?
Part mouse and part human anti-TNF-a antibody
What is Adalimumab?
Recombinant IgG1 anti-TNF-a antibody
What is Entercept?
TNF-a receptor fused to Fc IgG1
How are the anti-TNF-a biologicals clinically used?
Autoimmune diseases
