Immunosuppressants 2: 1-16 (up to nonselective)

Question 1

What are the targets of immunosuppressant therapy?

Answer 1

Either prevent B-cell function (not especially useful; works by inhibiting formation of B cells by myelosuppression)

Or preventing T-cell function (Inhibit T-cell formation, T-cell activation, or drugs that interfere with T-cell function)

Question 2

What are nonselective immunosuppressant classes?

Answer 2

Steroids (regulate gene transcription): Prednisone (PO) and methylprednisolone (IV)

Antiproliferative agents (Inhibit DNA synthesis): Azathioprine, Mycophenolate mofetil

Immunoglobulins (Deplete circulating T cells): Anti-lymphocyte antibodies

Question 3

What options do we have for selective immunosuppression?

Answer 3

Calcineurin inhibitors: Cyclosporine, tacrolimus

IL-2 receptor antagonists: Basiliximab, Daclizumab

Target of Rapamycin (mTOR) inhibitors: Sirolimus

Question 4

How do corticosteroids work?

Answer 4

Prevent T-cell activation by blocking cytokine production; they inhibit macrophages, block antigen recognition, and redistribute lymphocytes

Question 5

What are corticosteroids used for?

Answer 5

Maintenance immunosuppression

Question 6

Adverse effects of corticosteroids?

Answer 6

Cushin’s syndrome, osteoporosis, myopathy, cataracts, glucose intolerance, hypercholesterolemia

Question 7

Counseling points for corticosteroids?

Answer 7

Do not withdraw abruptly; taper slowly

Question 8

How does Azathioprine work?

Answer 8

Metabolized into 6-mercaptopurine; disrupts purine incorporation into DNA and prevents proliferation of T-cells

Question 9

How does Azathioprine leave the body?

Answer 9

Metabolites are excreted in the urine

Question 10

What is Azathioprine used for?

Answer 10

Maintenance immunosuppression

Lower doses also used in Rheumatoid arthritis

Question 11

Adverse effects of Azathioprine?

Answer 11

Bone marrow suppression, hematological effects, infections, pancreatitis, hepatitis, cholestatic jaundice, interstitial pneumonitis, increased risk of neoplasia

Question 12

Drug interactions with Azathioprine?

Answer 12

Allopurinol increases drug levels, causing increased neutropenia

Question 13

How does Mycophenolate mofentil work

Answer 13

Inhibits inosine monophosphate dehydrogenase in guanine synthesis
This inhibits DNA synthesis in T and B cells

Question 14

How is Mycophenolate mofentil metabolized?

Answer 14

Hydrolized in the GI system to mycophenolic acid, rapidly absorbed, glucoronidated, and excrteed in the urine

Question 15

What is Mycophenolate mofentil used for?

Answer 15

Maintenance immunosuppression

Question 16

Adverse effects of Mycophenolate mofentil?

Answer 16

Nausea, vomiting, diarrhea
Infections (cytomegalovirus)
Sepsis
Leukopenia
Lymphoma
TERATOGENIC

Question 17

Drug interactions with Mycophenolate mofentil?

Answer 17

Antacids, cholestyramine, increased acyclovir levels (?)

Question 18

Between Mycophenolate and Azathioprine, which has higher GI toxicity?

Answer 18

Mycophenolate

Question 19

Between Mycophenolate and Azathioprine, which has higher bone marrow suppression?

Answer 19

Same

Question 20

Between Mycophenolate and Azathioprine, which has higher liver toxicity (from vein blockage)?

Answer 20

Azathioprine

Mycophenolate has none!

Question 21

What polyclonal antibodies are available?

Answer 21

Lymphocyte immune globulin (Horse)
Antithymocyte globulin ATG (Rabbit)
Muromonab-CD3

Question 22

What does lymphocute immune globulin work against?

Answer 22

Against human T-cell antigens CD2, CD3, CD4, CD8, CD11a, and CD18

Binds peripheral T-cells

Question 23

When is Lymphocyte immune globulin used?

Answer 23

Before transplant and in early rejection

Question 24

Adverse effects of lymphocyte immune globulin?

Answer 24

Leukopenia, thrombocytopenia, fever, muscle pain, serum sickness

Question 25

What does Antithymocyte globulin ATG work against?

Answer 25

CD2, CD3, CD4, CD8, CD11a, CD18, CD25, CD44, CD45, HLA class I and II antigens (more than lymphocyte immune globulin) Depletes circulating T-cells by 80-90%

Question 26

When is Antithymocyte globulin ATG used?

Answer 26

Before renal transplants and in early rejection

Question 27

Adverse effects of Antithymocyte globulin ATG?

Answer 27

``` Leukopenia Thrombocytopenia Fever Muscle pain Serum sickness ```

Question 28

What is Muromonab-CD3 effective against?

Answer 28

Murine IgG2a antibody works against CD3 on T-cells Inhibits signal transduction of antigen recognition, causes internalization of T-cell receptors, preventing recognition of antigens, circulating T-cells decrease rapidly after injection

Question 29

When is Muromonab-CD3 used?

Answer 29

Acute rejection

Question 30

Adverse effects of Muromonab-CD3?

Answer 30

First dose reaction can cause cytokine release to cause massive TNF-alpha, IL-2, and IL-6 release which can result in severe Flu-like symptoms (high fever, chills, tremor, myalgia) Can also cause pulmonary edema (monitor plasma volume)

Question 31

How can you prevent side effects from Murominab-CD3?

Answer 31

Give glucocorticoids beforehand to reduce cytokine release

Question 32

Counseling points for Murominab-CD3?

Answer 32

Give glucocorticoids beforehand to reduce cytokine release Monitor plasma volume to prevent pulmonary edema Avoid in pts with history of seizure Newer humanized mouse form has less anti-antibody effects