Immunosuppressant Pharmacology

Question 1

What are the calcineurin inhibitors and how do they work in general?

Answer 1

1. Tacrolimus
2. Cyclosporin

They work by having their protein - drug complex bind and inhibit calcineurin, a phosphatase which is required to activate NF-AT.

NF-AT is responsible for increasing translation of IL-2 and other cytokines for T-cell proliferation.

Question 2

What are the drug targets of tacrolimus and cyclosporin A?

Answer 2

Tacrolimus - FK-binding proteins

Cyclosporin - “cyclo”philins

Question 3

What is the primary toxicity of concern with the calcineurin inhibitors and how can the risk of this toxicity be increased?

Answer 3

Nephrotoxic - obliterative vasculopathy.

Risk increased with other nephrotoxic drugs, or CYP3A4 inhibitors (these drugs are metabolized by CYP).

Question 4

What are the more specific toxicities of cyclosporin?

Answer 4

1. Gingival hyperplasia
2. Hirsutism

Also:
Hypertension - secondary to renal arteriolar vasoconstriction #6678
Hyperlipidemia, neurotoxicity.

Question 5

What are the more specific toxicities of tacrolimus?

Answer 5

1. Increased risk of diabetes + neurotoxicity as compared to cyclosporin
2. NO gingival hyperplasia or hirsutism (vs cyclosporin)

Rest of side effects are the same.

Question 6

What is the non-calcineurin-inhibiting immunophilin and how does it work?

Answer 6

Sirolimus (rapamycin) - binds FKBP12 (similar to tacrolimus) but rather inhibits mTOR (mammalian target of rapamycin), a protein responsible for downstream signalling of IL-2. This will keep the cell arrested at G1 phase.

Question 7

What are the important toxicities and non-toxicities of Sirolimus?

Answer 7

Kidney Sir-vives = NOT nephrotoxic! Good for transplant prophylaxis. Can be used with cyclosporin for this reason.

Toxic = Pan-Sir-topenia -> pancytopenia

Question 8

What other biologic drug is used for kidney transplant prophylaxis other than calcineurin inhibitors / sirolimus?

Answer 8

Basiliximab - Inhibits IL-2R

Question 9

What is one really specific indication for mycophenolate mofetil in lupus? Mechanism of action?

Answer 9

Used for the treatment of Lupus nephritis

-> inhibits IMP dehydrogenase

Question 10

Give another cancer other than renal cell carcinoma which IL-2 is used to treat?

Answer 10

Metastatic melanoma

Question 11

What is epoetin alfa? Use?

Answer 11

Erythropoietin

Treatment of anemia, especially in renal failure

Question 12

What is Filgrastim?

Answer 12

G-CSF - granulocyte stimulation (Fil”gra”stim)

Question 13

What is Sargramostim?

Answer 13

GM-CSF - granulocyte and monocyte stimulation (Sar”GraM”ostim)

Question 14

What are the treatment uses of IFNalpha?

Answer 14

Chronic hepatitis B/C - Hippo pacman
Kaposi sarcoma - roses on the side
Malignant melanoma - melanotic ghost
Hairy cell leukemia - Hairy creature
Condyloma acuminata - accumulated tokens
Renal cell carcinoma - Cancer crab in the kidney machine

Question 15

What is Romiplostim?

Answer 15

Thrombopoietin analog

Question 16

What is Eltrombopag?

Answer 16

trombo -> thrombopoietin receptor agonist

Question 17

What is Oprelvekin and what is it used for?

Answer 17

IL-11, used for treatment of thrombocytopenia (stimulates megakaryocytes)

Question 18

What is the mechanism of daclizumab? Usage?

Answer 18

Anti-CD25 (IL-2 receptor component, also expressed on Treg cells)

Treatment of relapsing multiple sclerosis

Question 19

What is the mechanism of Eculizumab and usage?

Answer 19

Anti-complement C5

Paroxysmal nocturnal hemoglobinuria

Question 20

What is the mechanism of Natalizumab and the usage? Risk?

Answer 20

anti alpha4-integrin (needed in WBC adhesion), Multiple sclerosis

Increased risk of PML in patients with JC virus

Question 21

What is the mechanism of Vedolizumab and usage?

Answer 21

anti-alpha4-integrin - used in Crohn’s disease, does not cross BBB so no increased risk of PML

Question 22

What is the inhibitor of RSV fusion protein used for prophylaxis in high risk infants?

Answer 22

Palivizumab

Question 23

What are the two drugs which can be used in treatment of diabetic retinopathy / wet macular degeneration?

Answer 23

anti-VEGF’s:

Ranibizumab
Bevacizumab

Question 24

What effect do glucocorticoids have on hepatic glycogen stores?

Answer 24

Glucocorticoids upregulate gluconeogenesis AND glycogenesis -> increase hepatic glucose stores for times of stress (like insulin)
-> however, they also reduce peripheral insulin sensitivity and raise blood glucose levels, and thus act somewhat like glucagon

Question 25

Which drugs which affect IL-2 will decrease transcription of IL-2 vs decrease response to IL-2?

Answer 25

Transcription - Cyclosporine, Tacrolimus

Response - Sirolimus, Daclizumab (relapsing MS), Basiliximab

Question 26

Which drugs work FB binding proteins?

Answer 26

-limus drugs, tacrolimus and sirolimus

Question 27

What’s the mechanism of sirolimus derivatives in drug-eluting coronary stents?

Answer 27

Block the mTOR pathway -> prevent smooth muscle cell proliferation, “neointimal hyperplasia” which results in restenosis