Zheng - Immunosuppressive Drugs

Question 1

Maintenance therapy

Answer 1

Calcineurin inhibitor, glucocorticoid, mycophenolate

Question 2

What are the calcineurin inhibitors and what are they used for?

Answer 2

Cyclosporine and tacrolimus

• used for prevention of transplant rejection.
• used in conjunction with other things due to its nephrotoxic effects
• tacrolimus is more potent.

Question 3

Mechanism of action of cyclosporine and tacrolimus

Answer 3

The main protein here is NFAT. Usually NFAT is phosphorylated and thus can’t get into the nucleus. When a T cell is activated there is a transient rise in Calcium , binds to calmodulin and activates calcineurin. Calcineurin then de phosphorylates NFAT so it can go into the nucleus and upregulate IL-2.
- the mechanism here is to block the calcineurin enzyme so there is no up regulation of IL2 and thus no up regulation of T-cells.

Question 4

Toxic it’s and drug interactions of the calcineurin inhibitors

Answer 4

Renal toxicity is main concern.
It also interacts with drugs that affect the P450 enzymes.
Don’t take it with sirolimus due to increased renal toxicity.

Question 5

What are the two mTOR inhibitors and what is there MOA?

Answer 5

Sirolimus and everolimus
- the MOA is that IL-2 usually binds to its receptor and causes a downhill cascade through the mTOR pathway to induce transcription and translation and the further proliferation of T cells. These drugs bind to mTOR and inhibit its actions.

Question 6

Toxicities and drug interactions of sirolimus and everolimus

Answer 6

Can cause an increase in cholesterol and triglycerides so we usually give it with statins.
Don’t give it with calcineurin inhibitors because they extend the half life of calcineurin, which is nephrotoxic.

Question 7

Azathioprine is what kind of drugwhat is the mechanism of action?

Answer 7

Cytotoxic drug
- it is activated by glutathione and what it does is that it incorporates itself into DNA/RNA synthesis and de novo purine synthesis.

Question 8

Drug interactions of azathioprine

Answer 8

Don’t take it with allopurinol because allopurinol inhibits xanthine oxidase, which is needed to metabolize azathioprine.

Question 9

Mycophenolate mofetill is what kind of drug and what is its MOA?

Answer 9

Cytotoxic drug

• it blocks the enzyme inosine mono phosphate dehydrogenase (IMPD) which blocks the de novo synthesis pathway.
• – fun fact: B and T cells lack the purine salvage pathway so this drug essentially blocks the lymphocyte proliferation.

Question 10

Daclizumab

Answer 10

Immunosuppressive antibody.

Monoclonal antibody that binds to the IL-2 receptor (CD25)on activated T cells and works via competitive inhibition.

Question 11

Muromonab

Answer 11

Immunosuppressive antibody.
A mouse monoclonal antibody raised against the CD3 subunit of the T cell receptor.
Causes destruction of the CD3 bearing T cells.

Question 12

What is the MOA of glucocorticoids?

Answer 12

They get into the cell and bind to the receptor which is usually bound to heat shock proteins (hsp) and thus are inactive. Binding of the glucocorticoid releases the receptor and allows it to be active. It then dimerizes and enters the nucleus where it binds to the DNA and doesn’t allow for transcription of IL-1 and IL-2.

Question 13

Adverse effects of glucocorticoids

Answer 13

Growth retardation 
Osteoporosis
Increased infections
Ulcers
Obesity
Hyperglycemia
Hypertension
Muscle wasting

Question 14

Induction therapy

Answer 14

You want to suppress the immune system so that you don’t trigger the initial immune response.