Immunopharmacology

Question 1

What are the mechanisms of corticosteroid producing immunosuppression?

Answer 1

Bind cytosolic receptor, binds GRE as TF causing downregulation of cytokines IL-1,2,6, interferon, inhibit activation of CTLs, inhibit APCs, and induce lymphoid cell apoptosis.

Question 2

Cyclosporine binds to which protein to inhibit calcineurin (what is MOA)?

Answer 2

Cyclosporine forms a complex with cyclophilin (highlighted red), a cytoplasmic receptor protein present in target cells. The complex inhibits calcineurin phosphatase activity. This prevents NFAT dephosphorylation such that NFAT does not enter the nucleus and gene transcription is not activated. Therefore, the T lymphocyte fails to respond to specific antigenic stimulation (decrease cell mediated immunity).

Question 3

Tacrolimus binds to which protein to inhibit calcineurin?

Answer 3

Binds immunophilin and inhibits calcineurin and then rest is same MOA as Cyclosporin.

Question 4

What enzyme does calcineurin inhibitors? What is the final result?

Answer 4

Effective against T-cell-dependent immune mechanisms (e.g. transplant rejection)
Preferentially inhibits antigen-triggered signal transduction in T lymphocytes and blunts expression of many lymphokines including IL-2.

Question 5

What protein does sirolimus bind to and what target does it inhibit (what is MOA)?

Answer 5

Binds to FKBP-12, which inhibits a protein kinase, designated mammalian target of rapamycin (mTOR) (rapamycin = sirolimus). Inhibition of mTOR blocks cell-cycle progression at the G1/ S phase transition because mTOR is a key enzyme in cell-cycle progression. Inhibits T-lymphocyte activation and proliferation downstream of the IL-2.

Question 6

What are the side effects of cyclosporine (used in organ transplant, RA, psoriasis)?

Answer 6

Renal dysfuntion, HTN, hyperlipidemia, hyperglycemia (last two precipitate DM and cardiovascular issues), gum hyperplasia

Question 7

What are the side effects of Tacrolimus (used in prophylaxis of solid-organ allograft rejection)?

Answer 7

All same as Cyclosporine PLUS neurotoxicity and hyperkalemia (must check electrolyte levels bc of this).

Question 8

Can cyclosporine and Tacrolimus be used together?

Answer 8

No! They will enhance renal toxicity.

Question 9

What are the side effects of sirolimus (first line drug to prevent renal transplant rejection)?

Answer 9

Hyperlipidemia and hyperglycemia (precipitate DM) but does NOT cause renal toxicity. Causes LIVER toxicity and bone marrow suppression suppression (neutropenia).

Question 10

What is MOA of mycophenolate and what are its side effects?

Answer 10

Prodrug that is rapidly hydrolyzed to active drug, mycophenolic acid (MPA) selectively and reversibly inhibits of inosine monophosphate dehydrogenase (IMPDH). IMPDH is an important enzyme in the de novo pathway of guanine nucleotide synthesis. B and T lymphocytes are highly dependent on this pathway for cell proliferation.

Question 11

What does muromonab inhibit?

Answer 11

Binds to the CD3 receptor, induces rapid internalization of the T-cell receptor, prevents subsequent antigen recognition

Question 12

What do Dacliximab and basiliximab inhibit?

Answer 12

Bind to CD25 on T cells, which is α subunit of IL-2 receptor, therefore block IL-2 receptor and inhibit IL-2 induced T –cell activation.

Question 13

What drugs are used for preventing rejection of kidney transplantation?

Answer 13

Muromonab, Dacliximab (daclizumab) and basiliximab, Antithymocyte globulin (ATG), sirolimus

Question 14

What do infliximab and adalimumab inhibit?

Answer 14

Anti-TNF-alpha monoclonal antibody blocking TNF

Question 15

What is the application of infliximab, adalimumab, and etanercept?

Answer 15

Rheumatoid arthritis

Crohn’s disease

Question 16

What do you need to check before using infliximab, adalimumab, and etanercept?

Answer 16

Always check for herpes, TB (PPD), and certain fungi bc can reactivate latent infections.

Question 17

What does etanercept inhibit?

Answer 17

fusion protein of TNF receptor with FC region of human IgG1, mimics TNF receptor to bind to free TNF or membrane-bound TNF

Question 18

What cancer does Levamisole treat?

Answer 18

Originally antihelmintic, Its only clinical indication is as adjuvant therapy with 5-fluorouracil after surgical resection in patients with colon cancer .

Question 19

What are the uses of Thalidomide?

Answer 19

Indicated for the treatment of patients with erythema nodosum leprosum and in multiple myeloma.

Question 20

BCG (Bacillus Calmette-Guerin) is used to treat which cancer?

Answer 20

Attenuated, live culture of the bacillus of Calmette and Guerin strain of Mycobacterium bovis. Indicated for treatment and prophylaxis of carcinoma in situ of the urinary bladder (given as instillation into the bladder).

Question 21

When do you use Rho (D) globulin and what disease does it prevent?

Answer 21

Give to Rh - pregnant woman at 28 weeks and right at delivery (within 72 hr.) to prevent hemolytic disease of the newborn (Rhesus disease).

Question 22

What are the side effects of mycophenolate?

Answer 22

HTN, diarrhea / vomiting, and bone marrow suppression suppression (neutropenia) but unlike sirolimus BM supression reversible (if stop giving then immediately stops).

Question 23

What is the MOA of Antithymocyte globulin (ATG) and why can you not give it for a long time (ADR)?

Answer 23

Cause T-cell depletion, last for one year

Can cause cytokine release syndrome (fever, hypotension, rigor).

Question 24

Drugs for ulcerative colitis and Crohn’s disease

Answer 24

1. Sulfasalazine, mesalamine
2. Glucocortisone: Budesonide
3. Immunorepressive drugs: Azathioprine, 6-mercaptopurine, Methotrexate
4. Anti TNF antibody: Infliximab Adalimumab, Certolizumab
5. Anti-integrin antibody: Natalizumab

Question 25

Disease Modifying Anti-Rheumatic Drugs (DMARDs) for rheumatoid arthritis

Answer 25

1. Methotrexate: Dihydrofolate reductase
2. Hydroxychloroquine (can cause visual disturbances)
3. Sulfasalazine
4. Leflunomide: Dihydro-orotic acid dehydrogenase (DHOD) inhibitor. Decreases UMP
5. Azathioprine
6. Etanercept: TNF receptor fused with human IgG1 FC
7. Infliximab; Adalimumab: Antibody to TNF
8. Anakinra: IL-1 receptor antagonist
9. Rituximab: Antibody to CD20 (kills B cell)
10. Abatacept: CTLA-4 fused with human IgG1 FC region, Inhibits T cell activation ( #1 thru 5 = non-biologicals, rest = biologicals).