Pharmacology Test 2: Immunomodulators Lec 36

Front 1

Cyclosporine

Back 1

synth by fungus, has 9-carbon novel amino acid at position 1, where hydrogen bonds are formed.

Front 2

Cyclosporine Mech of action

Back 2

binds cyclophilin. The cyclosporin-cyclophilin complex then binds calcineurin, causing its inactivation, which is not then able to dephosphorylate NFAT, so NFAT can't enter the nucleus and IL-2 gene is not transcribed.

Front 3

So Cyclosporine causes immunosupression how?

Back 3

Since NFAT isn't able to turn on the IL-2 gene, there is low IL-2. IL-2 otherwise would cause CD4 and CD8 T cell proliferation.

So, it INHIBITS activatin and proliferation of T Cells.

Front 4

Cyclosporine Metabolism

Back 4

CYP3A4, largely hepatic. Increased clearance with phenytoin, phenobarbital. Decrease clearance with erythromycin, ketoconazole, amphotericin B or St John's wart.//

VERY narrow TI

Front 5

Cyclosporine Toxicity

Back 5

nephrotox, neurotox (tremor), hypertension, hirsutism, hyperlipidemia, gingival hyperplasia.

Front 6

Tacrolimus (FK506)

Back 6

a lactone-lactam antibiotic, structurally unrelated to cyclosporine, 50-100x more potent than cyclosporine, les nephrotoxicity. Also used topically to treat atopic dermatitis.//

Front 7

Tacrolimus: Mech of action

Back 7

It inactivates calcineurine by forming Tacrolimus-FKBP complex and binding calcineurin, unlike cyclosporine which binds 'cyclophilin'. The rest of the down stream consequence is the same, where then, calcineurin cannot be activated by calmodulin, thus no NFAT dephosphorylation and low IL-2 gene transcription.//

Front 8

Tacrolimus: Pharmacology

Back 8

used as prophylaxis after kidney and liver transplants, also as rescue therapy in pts experiencing graft rejections.//

Metabolized in liver, shorter half life than cyclosporine.//

Front 9

Tacrolimus: Toxicity

Back 9

nephro, neuro (tremor, headache, seizures, insomnia), GI disturbances, hyperglycemia, pancreatic beta cell function inhibition. INCREASED RISK OF malignant lymphomas.//

Front 10

Pimecrolimus

Back 10

similar to tacrolimus, binds FKBP, used for topical treatment of atopic dermatitis. 2nd line b/c skin cancer risk

Front 11

Sirolimus

Back 11

structurally related to tacrolimus. Mech: binds FKBP, which (this complex) then inhibits mTOR > no dephosphorylation and no transcription of IL-2 gene.

Inhibition of mTOR results in lack of response to growth stim. factors AND inhibition of T and B cell proliferation.

Front 12

Sirolimus Pharmacology

Back 12

metabolized by CYP3A4, same as cyclosporine and tacrolimus. Used as part of combo tx for renal transplant, and with islet cell transplantation.//

Has been used with stents in coronary arteries to prevent neointimal proliferation. *NOW WE THINK IT MAY NOT BE A GOOD THING*

Front 13

Sirolimus Tox

Back 13

anemia, thrombocytopenia, hyperlipidemia.

CONTRAINDICATED FOR AFTER LIVER TRANSPLANTATION

Front 14

Mycophenolate mofetil

Back 14

prodrug metabolized by liver to mycophenolic acid (MPA). Useful in pts in combo with cyclosporine or tacrolimus.

Front 15

Mech of action of mycophenolate mofetil

Back 15

once converted to MPA, it inhibits inosine monophosphate dehydrogenase, which is required for de novo PURINE synthesis. For B and T cells, the major source of PURINE is de novo synthesis instead of HPRT mediated salvage.

Front 16

Mycophenolate mofetil pharmacology

Back 16

recom. after renal and heart transplantation.//

Decrease absorption with mg or Al (so don't use these antacids).//

side effects: diarrhea, leakopenia

Front 17

Leflunomide

Back 17

inhibits dihydroorotate dehydrogenase, essential for PYRIMIDINE biosynthesis.

EFFECTIVE in rheumatoid arthritis.

Front 18

Thalidomide

Back 18

used for tx of erythema nodosum leprosum (type 2 leprosy rxn). Side effects: peripheral neuropathy. TERATOGENIC, NEVER use in pregnant women.

Front 19

daclizumab and basiliximab

Back 19

Ab against IL-2 receptor's (CD25) alpha chain > inhibits T cell activation. reduces incidence of acute rejection

Front 20

muromanab

Back 20

Ab against epsilon chain of CD3 on T cell surface, blocks T cell receptor engagement. Indication: reversal of rejection of heart, liver and kidney transplant

Front 21

infliximab

Back 21

Ab against TFNalpha. Tx of Crohn's dz, UC, rheumatoid and psoriatic arthritis, and ankylosing spondylitis.

Side effects: TB REACTIVATION, Hep B reactivatin, malignancies, heptotoxicities. anti-infliximab AB devp

Front 22

etanercept

Back 22

chimeric recombinant of soluble p75-TFN receptor type II and Fc portion of human IgG. Acts by "soaking up" the free TNF.//

Used in RA, ankylosing spondylitis and plaque psoriasis.//

causes increase incidence of demyelinating dzs.

Front 23

natalizumab

Back 23

Ab against alpha4 subunit of Integrin. Inhibits lymphocyte migration to sites of inflamation. Used in Crohn's dz and MS. Use associated with PML.

Front 24

efalizumab

Back 24

Ab against CD11a, a subunit of LFA-1.

For tx of plaque psoriasis, blocks T Cell activation.

Front 25

abatacept

Back 25

binds CD80 and CD86, blocking their binding to CD28 and T Cell activation. Works upstream from infliximab and etanercept.

Front 26

azathioprine

Back 26

purine analog, metabolized to 6-mercaptopurine, disrupts de no purine synthesis, and disrupts transcription when incorporated into DNA.

Used for RA in combo with cyclosporine,/tacrolimus plus prednisone.

Front 27

glatiramir

Back 27

antigenically similar to myelin basic protein, used for tx of remitting-relapsing MS.

Front 28

Immunoglobulins

Back 28

Lymphocyte IGs: Ab to T cell surface Ag, depletes T Cells

Front 29

IFN alpha

Back 29

2a: hep C, KS, CML, hair cell leukemia.

2b: hep B, C and several malignancies.

n1, alfacon-1: Hep C

n3: chondyloma accuminata

Front 30

IFN beta

Back 30

1a, 1b: MS

Front 31

IFN gamma

Back 31

for chronic granulomatous dz and congenital osteopetrosis.

EXACERBATE MS***

Front 32

Imiquimod

Back 32

stim. of cytokine and IFN alpha synthesis. for tx of genital warts and actinic keratosis.