Immunosuppressants 3: 17-34

Question 1

What is the difference between Basiliximab and Daclizumab?

Answer 1

Basiliximab is from chimeric mouse; not used much

Daclizumab is humanized

Question 2

What do IL-2 receptor antagonists work against?

Answer 2

Antibodies against IL-2 CD25 receptors on activated T-cells

Prevent activated T-cell killing but does NOT deplete T-cells, mechanism is not completely understood

Question 3

What are the IL-2 receptor antagonists?

Answer 3

Basiliximab and Daclizumab

Question 4

What are IL-2 receptor antagonists used for?

Answer 4

Prophylaxis of acute rejection, maintenance immunosuppression

Question 5

Adverse effects of IL-2 receptor antagonists?

Answer 5

Hematological, infections, anaphylactic reactions

Usually well tolerated

Question 6

What are the Calcineurin inhibitors?

Answer 6

Cyclosporine (IV and Oral)

Tacrolimus (preferred) (IV and Oral)

Question 7

What is cyclosporine used for?

Answer 7

Liver, heart, kidney and other transplants
Rheumatoid arthritis and psoriasis
Also maintenance suppression

Question 8

How does Cyclosporine work?

Answer 8

Calcineurin inhibitor; inhibits mRNA transcription of IL-2, binds cyclophilin to inhibit calcineurin
Prevents NF-AT from stimulating IL-2 transcription

Question 9

Adverse effects of cyclosporine?

Answer 9

Constriction of afferent artery at glomerulus, renal dysfunction (majority of pts)
P-glycoprotein transport in BBB can cause tremor
Hypertension (50% of renal patients, all heart transplants)
Diabetogenic esp with glucocorticoids
CYP3A interactions (increase or decrease levels)

Question 10

How does Tacrolimus work?

Answer 10

Binds FK binding protein to inhibit actions of Calcineurin, prevents NF-AT activating IL-2 transcription

Question 11

How is Tacrolimus administered?

Answer 11

Oral and IV

Food decreases absorption!

Protein bound

Question 12

What is Tacrolimus used for?

Answer 12

Maintenance suppression and rescue in acute rejection

Question 13

Adverse effects of Tacrolimus?

Answer 13

Nephrotoxicity
Neurotoxicity (tremor, headache, seizures)
GI
Hypertension
Hyperglycemia
Tumors
Secondary infections

Damages pancreatic beta cells –> diabetes

CYP3A4 metabolism affected

Question 14

Between CyA and Tac, which one has the highest nephrotoxicity?

Answer 14

Same (+++)

Question 15

Between CyA and Tac, which one has the highest hyperglycemia?

Answer 15

Tac

CyA is ++, Tac is +++

Question 16

Between CyA and Tac, which one has the highest metabolic complications?

Answer 16

Same (+++)

Question 17

Between CyA and Tac, which one has the highest hypertension?

Answer 17

Same (+++)

Question 18

Between CyA and Tac, which one has the highest neurotoxicity - CNS tremors?

Answer 18

Same (++)

Question 19

Between CyA and Tac, which one has the highest neurotoxicity - Disorientation?

Answer 19

Tac (+++)

CyA is ++

Question 20

Between CyA and Tac, which one has the highest Hirsutism?

Answer 20

CyA (++)

Tac has none!

Question 21

Between CyA and Tac, which one has the highest Alopecia?

Answer 21

Tac (++)

CyA has none

Question 22

What agents target Rapamycin (mTOR) inhibitors?

Answer 22

Sirolimus

Everolimus

Question 23

How does Sirolimus work?

Answer 23

Binds to FKB-12 and inhibits mTOR stimulated cell proliferation at G1-S phase transition

Question 24

How is Sirolimus metabolized?

Answer 24

CYP3A4 metabolism, there are 7 major metabolites

Question 25

How is Sirolimus administered?

Answer 25

Oral only

Question 26

When is Sirolimus used?

Answer 26

For Acute RENAL transplants only (not used in liver and lung transplants because of bronchial and hepatic artery stenosis)

Prophylaxis - used to limit use of calcineurin inhibitors

Heart stents to prevent proliferation effects (prevent cells growing on the stent)

Question 27

Adverse effects of Sirolimus?

Answer 27

Dyslipidemia - cholesterol and TG’s treat
Thrombocytopenia
Wound healing - use lymphoceles, wait 1 month after transplant to start therapy
Interstitial pneumonitis, pulmonary infections
Lymphoma
Bone marrow suppression

Question 28

How does Everolimus compare to Sirolimus?

Answer 28

Approved for renal transplants and liver transplants
Chemically related
SHORTER half life
Shorter time to steady state
Actions are very similar

Both used together increase renal toxicity but also decrease rejection (usually not used together though)

Question 29

What agents are used Pre-operatively?

Answer 29

Antibodies

Question 30

What agents are used intra-operatively?

Answer 30

Methylprednisolone

Question 31

What agents are used post-operatively?

Answer 31

Calcineurin inhibitor (Cyclosporine or Tacrolimus) + Glucocorticoid + Anti-metabolite (Mycophenolate mofentil or Azathioprine)

Sirolimus is also used to delay use of calcineurin inhibitors

Question 32

What options do we have if a patient has rejection?

Answer 32

Alter maintenance regimen
Methotrexate
Plasmapheresis (for vascular rejection)
Total lymphoid irradiation
Re-transplantation

Question 33

How can we alter maintenance regimen if rejection occurs?

Answer 33

Change cyclosporine to tacrolimus
Change mycophenolate mofentil to azathioprine
Change Azathioprine to cyclophosphamide