Immunosuppressant Pharmacology Flashcards
What are the calcineurin inhibitors and how do they work in general?
- Tacrolimus
- 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.
What are the drug targets of tacrolimus and cyclosporin A?
Tacrolimus - FK-binding proteins
Cyclosporin - “cyclo”philins
What is the primary toxicity of concern with the calcineurin inhibitors and how can the risk of this toxicity be increased?
Nephrotoxic - obliterative vasculopathy.
Risk increased with other nephrotoxic drugs, or CYP3A4 inhibitors (these drugs are metabolized by CYP).
What are the more specific toxicities of cyclosporin?
- Gingival hyperplasia
- Hirsutism
Also:
Hypertension - secondary to renal arteriolar vasoconstriction #6678
Hyperlipidemia, neurotoxicity.
What are the more specific toxicities of tacrolimus?
- Increased risk of diabetes + neurotoxicity as compared to cyclosporin
- NO gingival hyperplasia or hirsutism (vs cyclosporin)
Rest of side effects are the same.
What is the non-calcineurin-inhibiting immunophilin and how does it work?
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.
What are the important toxicities and non-toxicities of Sirolimus?
Kidney Sir-vives = NOT nephrotoxic! Good for transplant prophylaxis. Can be used with cyclosporin for this reason.
Toxic = Pan-Sir-topenia -> pancytopenia
What other biologic drug is used for kidney transplant prophylaxis other than calcineurin inhibitors / sirolimus?
Basiliximab - Inhibits IL-2R
What is one really specific indication for mycophenolate mofetil in lupus? Mechanism of action?
Used for the treatment of Lupus nephritis
-> inhibits IMP dehydrogenase
Give another cancer other than renal cell carcinoma which IL-2 is used to treat?
Metastatic melanoma
What is epoetin alfa? Use?
Erythropoietin
Treatment of anemia, especially in renal failure
What is Filgrastim?
G-CSF - granulocyte stimulation (Fil”gra”stim)
What is Sargramostim?
GM-CSF - granulocyte and monocyte stimulation (Sar”GraM”ostim)
What are the treatment uses of IFNalpha?
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
What is Romiplostim?
Thrombopoietin analog
What is Eltrombopag?
trombo -> thrombopoietin receptor agonist
What is Oprelvekin and what is it used for?
IL-11, used for treatment of thrombocytopenia (stimulates megakaryocytes)
What is the mechanism of daclizumab? Usage?
Anti-CD25 (IL-2 receptor component, also expressed on Treg cells)
Treatment of relapsing multiple sclerosis
What is the mechanism of Eculizumab and usage?
Anti-complement C5
Paroxysmal nocturnal hemoglobinuria
What is the mechanism of Natalizumab and the usage? Risk?
anti alpha4-integrin (needed in WBC adhesion), Multiple sclerosis
Increased risk of PML in patients with JC virus
What is the mechanism of Vedolizumab and usage?
anti-alpha4-integrin - used in Crohn’s disease, does not cross BBB so no increased risk of PML
What is the inhibitor of RSV fusion protein used for prophylaxis in high risk infants?
Palivizumab
What are the two drugs which can be used in treatment of diabetic retinopathy / wet macular degeneration?
anti-VEGF’s:
Ranibizumab
Bevacizumab
What effect do glucocorticoids have on hepatic glycogen stores?
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
Which drugs which affect IL-2 will decrease transcription of IL-2 vs decrease response to IL-2?
Transcription - Cyclosporine, Tacrolimus
Response - Sirolimus, Daclizumab (relapsing MS), Basiliximab
Which drugs work FB binding proteins?
-limus drugs, tacrolimus and sirolimus
What’s the mechanism of sirolimus derivatives in drug-eluting coronary stents?
Block the mTOR pathway -> prevent smooth muscle cell proliferation, “neointimal hyperplasia” which results in restenosis
