Cellular Suppression

Question 1

Cyclosporine

Answer 1

1. Class/MOA: Calcineurin inhibitors: prevent transcription of IL-2 leading to decreased T cell activation (binds cyclophilin –> NFAT not dephosphorylated –> no transcription)
2. Kinetics: Poor and variable bioavailability, narrow therapeutic range, metabolized by CYP3A4
3. SE: Renal toxicity, HTN, hyperglycemia/hyperlipidemia, CNS tremor, gingival hyperplasia
4. CI: watch out with CYP inducers and inhibitors!
5. Uses: prevent rejection and maintenance after transplant, AI diseases

Question 2

Tacrolimus

Answer 2

1. MOA: calcineurin inhibitor, prevents transcription of IL-2 leading to decreased T cell activation (binds FKBP)
2. Kinetics: IV/Oral/topical. Must be taken on empty stomach as food interferes w/absorption. Narrow therapeutic range, metabolized by CYP3A4.
3. SE: more tolerable than cyclosporine, SE are the same just lessened: Renal toxicity, HTN, hyperglycemia, CNS effects, insomnia
4. CI: watch out for CYP inducers/inhibitors. Caution with ACE/ARBs, don’t combine with aminoglycosides
5. Uses: Prevent rejection especially with liver, kidney, and heart. Cream for atopic dermatitis.
6. Other: long term use increases opportunistic infections and neoplasms (esp skin cancer)

Question 3

Pimecrolimus

Answer 3

1. Like tacrolimus, binds FKBP-12
2. Cream for atopic dermatitis, does not thin skin/cause atrophy like steroids
3. SE: skin irritation or burning

Question 4

Belatacept

Answer 4

1. MOA: Blocks costimulatory molecules of APCs –> prevents T-cell stimulation and proliferation.
2. Injection only, must be combined with mycophenolate mofetil
3. SE: better CV profile and less risk of diabetes than cyclosporine. GI and infusion related SE are most common.
4. Used in kidney transplants only if EBV positive

Question 5

Sirolimus

Answer 5

1. MOA: blocks response of T-cells to IL-2, inhibits B cell proliferation
2. Oral absorption (significantly reduced by food), CYP3A4 metabolism
3. SE: no renal toxicity, increases cholesterol and triglycerides, profound myelosuppression (anemia/leukopenia), impair wound healing, possible hepatotoxicity.
4. Uses: Kidney transplant, prevent graft v. host in stem cell.

Question 6

Mycophenolate Mofetil

Answer 6

1. MOA: inhibits inosine monophosphate dehydrogenase –> prevents de novo purine synthesis (specific to T/B cells since other cells have salvage), suppresses lymphocyte proliferation and ab production by B cells.
2. Kinetics: well absorbed orally, 90% renal excretion, prodrug that is converted to mycophenolic acid in vivo
3. SE: GI most common, often causes a rash (limits use)
4. CI: PREGNANCY!!! women of child bearing age must use contraception
5. Uses: combined with cyclosporine/tacrolimus and glucocorticoids to prevent rejection.

Question 7

Azathiprine

Answer 7

1. MOA: converted to 6-mercaptopurine in vivo, inhibits de novo purine synthesis, blocks transcription and cell proliferation. Many lymphocyte actions inhibited, inhibits delayed hypersensitivity and cellular cytotoxicity after transplant.
2. Kinetics: metabolized by xanthine oxidase
3. SE: Bone marrow suppression, inc infections (esp herpes), N/V/D, liver toxicity (elevated enzymes), teratogenic, alopecia, skin rashes
4. Uses: Used as adjunct with tacrolimus/cyclosporine and prednisone to prevent transplant rejection, tx glomerulonephritis of SLE, severe RA
5. CI: Pregnancy, must reduce dose greatly if pt is on allopurinol (xanthine oxidase inhibitor).

Question 8

Leflonimide

Answer 8

1. MOA: Inhibits dihydroorotate dehydrogenase –> dec de novo pyrimidine synthesis –> decreased lymphocyte activation
2. SE: Liver and renal toxicity, teratogenic
3. CI: pregnancy
4. Uses: RA

Question 9

Cyclophosphamide

Answer 9

1. MOA: direct effect on T and B lymphocytes, especially those which have undergone antigenic differentiation and division.
2. Kinetics: CYP450 activation
3. SE: Hemorrhagic cystitis (prevent w/ hydration and MESNA), N/V, BM suppression, bladder fibrosis and carcinoma, alopecia, teratogenic
4. CI: Pregnancy
5. Uses: Organ transplant (can inhibit established immune response, good for rescue). Severe MS, RA, SLE. BM transplants, anti-neoplastic.

Question 10

Prednisone

Answer 10

1. Steroid, used for general immunosuppression
2. depress macrophage response, lysis of lymphocytes, decreases cytokine production and responses, inhibits T-cell proliferation, anti-inflammatory
3. SE: Cushings syndrome, immunosuppression, osteoporosis, suppress HPA axis
4. Uses: minimize allergic responses to anti-lymphocytic globulin/monoclonal ab. Transplants both to prevent and treat acute rejection, immunosuppressive for all allergies

Question 11

Methotrexate

Answer 11

1. MOA: inhibits dihydrofolate reductase inhibitor –> T-cell and macrophage inhibition (inhibits folate-dependent steps in purine syn).
2. Kinetics: well absorbed orally, renal excreted.
3. SE: BM suppression, alopecia, hepatotoxicity, teratogenic
4. CI: Pregnancy
5. Uses: immunosuppression in organ transplants, psoriasis, RA

Question 12

Thalidomide

Answer 12

1. MOA: Decreases TNF-alpha and IL-6 –> shifts T-cell response to TH2 subset, decreases activity of neutrophils, enhances cell mediated immunity by T cells
2. Kinetics: Oral admin
3. SE: TERATOGENIC!!!!!!!, inc risk of DVT, sedation, neutropenia
4. CI: PREGNANCY!!!!!
5. Uses: Prevents graft v host, acute myelogenous leukemia. Tx of multiple myeloma, leprosy, some cancers and causes weight gain in AIDS wasting.