EXAM #4: IMMUNOSUPPRESSANTS Flashcards by Mohammed Al-Amri

What types of grafts will NOT provoke an immune response?

1) Autografts (self)

2) Isografts (identical twins)

How well did you know this?

Not at all

Perfectly

What is an allograft?

Transplant between two non genetically identical individuals

How well did you know this?

Not at all

Perfectly

What are the two hallmark Calicneurin inhibitors used as immunosuppressants?

Cyclosporine

Tarcolimus

How well did you know this?

Not at all

Perfectly

What are the anti-proliferative/ anti-metabolic immunosuppressants?

Azathioprine
Mycophenolate mofetil
Sirolimus

How well did you know this?

Not at all

Perfectly

What are the “biological” immunosuppressants?

Antithymocyte globulin
Muromonab-CD3
Anti-TNF-a

How well did you know this?

Not at all

Perfectly

What are the two adverse effects associated with immunsuppressants as a drug class?

1) Infection

2) Malignancy

How well did you know this?

Not at all

Perfectly

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

How well did you know this?

Not at all

Perfectly

What are the “non-genomic” effects of glucocorticoids?

1) Alter signaling pathways

2) Insertion into cell membrane to alter ion transport

How well did you know this?

Not at all

Perfectly

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

How well did you know this?

Not at all

Perfectly

What are the pro-inflammatory cytokines?

IL-1
IL-6
TNF-a
IFN-gamma

How well did you know this?

Not at all

Perfectly

What is the function of IL-2?

T-cell proliferation

How well did you know this?

Not at all

Perfectly

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

How well did you know this?

Not at all

Perfectly

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

How well did you know this?

Not at all

Perfectly

What is low dose glucocorticoid therapy?

Less than 7.5 mg prednisone/ predisoe equivalent per day

How well did you know this?

Not at all

Perfectly

What is medium dose glucocorticoid therapy?

7.5mg- 30mg prednisone/ prednisoe equivalent per day

How well did you know this?

Not at all

Perfectly

What is high dose glucocorticoid therapy?

30-100mg prednisone/ prednisoe equivalent per day

How well did you know this?

Not at all

Perfectly

What is very high dose glucocorticoid therapy?

Greater than 100mg prednisone/ prednisoe equivalent per day

How well did you know this?

Not at all

Perfectly

What is pulse glucocorticoid therapy?

Greater than 250mg for a day, or a few days prednisone/ prednisoe equivalent per day

How well did you know this?

Not at all

Perfectly

What class of drug is Cyclosporine?

Calcineurin inhibitor

How well did you know this?

Not at all

Perfectly

What immunity is inhibited by Cyclosporine?

T-cell mediated immunity especially involved in:

1) Transplant rejection (kidney)
2) Autoimmunity

How well did you know this?

Not at all

Perfectly

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

How well did you know this?

Not at all

Perfectly

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