5.10 Pharm: Immunosuppressants

Question 1

Calcineurin Inhibitors: Cyclosporine

MOA, use, PK (metabolized by) , ADR,

Answer 1

• MOA: Binds to cyclophiloin→Inhibit calcineurin, blocks T-cell activation
• Use: Used alone or in combo
o Human organ transplantation, Graft vs, Host, AI disorder
• PK: Oral, Metabolized by P450 3A
• ADR: Nephrotoxicity, HTN, Hyper glycemia, kalemia, Hirsutism, AMS, Seizures

Question 2

Calcineurin inhibitor: Tacrolimus

MOA,Therapeutic use, PK, ADR

Answer 2

Tacrolimus
• MOA: Binds to FKBP→Inhibit calcineurin blocks T-cell activation
• Therapuetic use: Human and stem cell transplantation, prophylaxis rejection solid-organ therapy, prophylactic agent GVH (Methotrexxate/mycophenolate mofetil)
• PK: Oral and IV, Metabolized by P450
• ADR: Nephrotoxicity, Neurotoxicity, Hyper-Glycemia/Kalemia, HTN, GI complaints

Question 3

Sirolimus 
MOA
Use
PK
ADR

Answer 3

Sirolimus: Signal proliferation inhibitor
• MOA: Binds to FK506-P12→Inhibit mTOR
• Use: Prevent rejection of solid organ allografts
o Dermatologic disorders
o Prophylaxis and therapy in steroid refractory acute and chronic GVH hematopoetic stem cell transplant recipients
• PK: Oral, Metabolixed by Cytochrome P450 3A and glycoprotein
• ADR: Myelosuppression, Hapatotoxicity, Diarrhea, hypertriglyceridemia, pneumonitis, HA

Question 4

Mycophenolate mofetil (MMF)
MOA, Use, PK, ADR

Answer 4

• MOA: Prodrug Mycophenolic acid
o Inhibits denovo synthesis of purines→Inhibits T and B lymphocyte response
• Use: Solid organ transplant (refractory rejection), First line prevent/reduce chronic allograft vasculopathy in cardiac trans patients, prevent/treat GVH in hematopoietic stem cell pts, New: Lupus
• PK: Oral IV
• ADR: GI disturbances, HA, HTN, Reversible myelosuppression

Question 5

Cytotoxic agents: Azathioprine

MOA, Use, ADR, Pharmacogenomics

Answer 5

• Prodrug of mercaptopurine
• MOA: Interfere with purine nucleic acid metabolism→Destruction of stimulated lymphoid cells proliferation
• Use: Renal allografts, transplantation of other tissues
• ADR: BM suppression (Leukopenia), Skin rashes, fever, N/V/D
• Dose has to be reduced if on other drugs that inhibit xanthine oxidase such as Allopurinol
• Pharmacogenomics: Some people are slow metabolizers due to defect with thiopruine methyl transferase

Question 6

Ganciclovir/Valganciclovir (prodrug)

MOA, Use, Pk, ADR

Answer 6

Ganciclovir/Valganciclovir (prodrug)
o MOA: Inhibit viral DNA polymerase
o Use: Drug of voice for CMV infection and prevention/preemptive (transplant setting)
• CMV retinitis in AIDs patients
• Preemtive vs prophylaxis
• Pre-emptive giving to pt with higher risk of getting CMV
• Prophylaxis: Giving to everyone regardless
o PK: Excreted unmodified in urine
• GCV route of admin: Oral, IV (severe), IO CMV retinitis
• VGC oral more bioavail than GCV
o ADR: Myelosuppression

Question 7

Foscarnet

MOA, Use, Pk, ADR

Answer 7

• Foscarnet
o MOA: Inhibit viral DNA polymerase and RNA polymerase
• Doesn’t require phosphorylation for activation→Can be used as alternative to acyclovir
o Use: GCV- resistant CMV in AIDS patients with retinitis
• GCV-resistant transplant recipients
• GCV intolerant
• In addition to GCV for CMV retinitis
o PK: IV
o ADR: Impaired renal function, hypo/hypercalcemia, Hypomagnesemia, Hypo/hyperphosphatemia, hypokalemia

Question 8

Cidofovir

MOA, Use, Pk, ADR, CI

Answer 8

• Cidofovir:
o MOA: Inhibit viral DNA polymerase; Inhibit viral DNA synthesis
• Diphosphate independent of viral enzymes
o Use: CMV retinitis in patients with AIDs; Previous antiviral therapy failures
o PK: IV; must be administered with oral probenecid, most of drug excreted unchanged in urine
o ADR:Dose-dependent tubular nephrotoxicity, Fanconi type syndrome: Proteinuria, glucosuria, and bicarb wasting
o CI: Proteinuria, baseline creatinine >1.5; caution needed in preg women

Question 9

• Brincidofovir: Use

Answer 9

Used to tx ebola