Pharmacology - chapter 40 - Immunosuppressants

Question 0

The immune activation cascade can be described as a three signal model. Discribe this signal pathway.

Answer 0

1 T cell triggering by CD3 receptor-antigen complex on surface of APC
2 Costimulation when CD80 and CD86 of APC bind T cell CD28.
3 Stimulation of T cell poliferation.

Question 1

Why are several immunosuppressants usually used together in a regime of different drugs, rather than monotheraphy?

Answer 1

Because it’s beneficial to use several drugs at lower doses, rather than one at a higher dose. This is because this group of drugs are associated with severe toxicity when large doses are administered.

Question 2

Three categories of immunosuppressive drugs, based on theri mechanism of action?

Answer 2

1 interfere with cytokine production or action
2 disrupt cell metabolism, preventing lymphocyte proliferation
3 mono-and polyclonal antibodies block T cell surface molecules.

Question 3

• Enhances activity of NK cells.
• Attracts neutrophils and macrophages.

Which cytokine be dis?

Answer 3

IL-1

Question 4

• induces proliferation of antigen-primed T cells
• enhances activity of NK cells.

Which cytokine can this be?

Answer 4

Yes, it is IL-2

Question 5

• enhances activity of NK cells and macrophages.
• increases expression og MHC molecules.
• Enhances production og IgG2a.

Which cytokine?

Answer 5

Iterferon gamma

Question 6

• cytotoxic effect on tumor cells.
• induces cytokine secretion in the inflammatory response.

Cytokine?

Answer 6

TNF-alpha

Question 7

what is the role of IL-2 in immuno suppressive therapy?

Answer 7

it stimulates the proliferation of antigen-primed T helper cells which in turn produce more IL-2, IFN-gamma and TNF-alpha. These cytokines collectively activate NK cells, macrophages, cytotoxic T lymphocytes. Therefore, drugs that interfere with IL-2 production will dampen the immune response.

Question 8

Cyclosporine, mechanism of action?

Answer 8

binds with cyclophilin to form a complex that binds with calcineurin, thus inhibiting the calcineurin pathway that activates NFATc(cytoplasmic Nuclear Factor of Activated T cells). NFATc is a transcription factor that codes for IL-2.

Question 9

Cyclosporine, areas of use?

Answer 9

used to prevent rejection of kidney, liver and cardiac allogeneic transplants.

Question 10

Cyclosporine, metabolism?

Answer 10

Cyclosporine is metabolized by CYP3A4. It is also a substrate for intestinal P-glycoprotein.

Question 11

Cyclosporine, adverse effects?

Answer 11

Nephrotoxicity is the most common and important adverse effect of cyclosporine.

Question 12

Drugs by which coadministration will increase the nephrotoxicity of cyclosporine?

Answer 12

1 drugs that can cause renal dysfunction - e.g. aminoglycoside antibiotyka.
2 Anti-inflammatory such as diclofenac, naproxen or sulindac that potentiate the nephrotoxicity of cyclosporine.

Question 13

One type of diuretics one should not administer along with cyclosporine?

Answer 13

K+ - sparing diuretics, as patients are proned to become hyperkalemic.

Question 14

Tacrolimus, mechanism of action?

Answer 14

Similar to that of cyclosporine, except Tacrolimus binds with FK-binding protein, another component of the calcineurin pathway.

Question 15

Tacrolimus, pharmacokinetics?

Answer 15

Metabolized by CYP3A4/5 and is a substrate for P-glycoprotein.

Question 16

Tcrolimus, adverse effects?

Answer 16

Nephrotoxicity and neurotoxicity. Development of post-transplant insulin dependent diabetes mellitus is a problem, particularily for black and hispanic patients.

Question 17

Sirolimus, areas of use?

Answer 17

Used in kidney transplant, administered together with cyclosporine and corticosteroids.

Sirolimus-coated stents are inserted into cardiac vasculature to inhibit restenosis of blood vessels by reducing proliferation of endothelial cells.

Question 18

Sirolimus, mechanism of action?

Answer 18

Sirolimus bind with mTOR, interfering with signal 3: preventing IL-2 signal to induce T cell proliferation and thereby preventing activated T cell from entering S phase.

Question 19

Sirolimus, pharmacokinetics?

Answer 19

Long half life(57-62 hours)
Metabolized by CYP3A4.
Interacts with the same drugs as do cyclosporine and tacrolimus

Question 20

Everolimus, mechanism of action?

Answer 20

mTOR inhibitor.

Question 21

Azathioprine, mechanism of action?

Answer 21

prodrug that is converted first to 6-mercaptopurine and then to thiosinic acid. Thiosinic acid interfere with de novo synthesis of purine, a pathway that lymphocytes are dependent on, as they do not have a purine salvage pathway.

Question 22

Allopurinol and Azathioprine relationship?

Answer 22

Allopurinol significantly reduce the metabolism of azathioprine(60-70%). Therefore, lowering the dose of azathioprine is required.

Question 23

Lymphocytes and purine synthesis?

Answer 23

Lymphocytes lack the salvage pathway for purine synthesis and is therefore are dependent on de novo synthesis of purines.

Question 24

Antithymocyte globulins?

Answer 24

Antibodies that binds to the surface of ciruclating T lymphocytes, which undergo destruction by complement activation, apoptosis, opsoniation or they are phagocytosed in the liver or spleen.

Question 25

Mauromonab-CD3, mechanism of action?

Answer 25

Bind to CD3 receptors and disrupt the T-lymphocyte function by blocking antigen recognition site. By this mechanism the circulating T cells are depleted.

Question 26

Mauromonab-CD3, pharmacokinetics?

Answer 26

Intial binding to CD3 receptors transiently activates the T cell and results in cytokine release(cytokine storm)

Question 27

Mauromonab-CD3, adverse effects?

Answer 27

Anaphylactoid reactions may occur. Symptoms range from mild flu-like illness to a life threatening shock-like reaction.

Question 28

Basiliximab and Daclizumab, mechanism of action?

Answer 28

IL-2 antagonists. Both compounds are anti-CD25 antibodies and bind to the alpha chain of the IL-2 receptor.

Question 29

Basiliximab & daclizumab, adverse effects?

Answer 29

Their major toxicity is GI.

Question 30

Alemtuzumab. mechanism of action?

Answer 30

anti-CD52 antibody that cause depletion of T cells from the peripheral circulation.

Question 31

Sirolimus, adverse effects?

Answer 31

hyperlipidemia

Question 32

Name five main groups of immunosuppressants

Answer 32

``` 1 Cytotoxic drugs 2 Calcineurin inhibitors 3 Glucocorticosteroids 4 Cytokin inhibitors 5 Antibodies ```

Question 33

Cyclophosphamide, mechanism?

Answer 33

Alkylating agent: adding an alkyle group to DNA preventing replication and cell division.

Question 34

Methotrexate, mechanism?

Answer 34

inhibits dihydrofolate reductase, an enzyme that reduces dihydrofolic acid to tetrahydrofolic acid - a compound that is necessary in the metabolism of nucleic acids.

Question 35

Azathioprine, mechanism?

Answer 35

interferes with purinesynthesis --> metabolized to mercaptopurine --> a purine analogue that inhibits DNA synthesis

Question 36

Leflunomide mechanism?

Answer 36

inhibits pyrimidine synthase

Question 37

Mycophenolate mofetil mechanism?

Answer 37

converted to mycophenolic acid in the body ---> inhibits inosine monophosphate dehydrogenase which prevent proliferation of B & T lymphocytes

Question 38

What is calcineurin?

Answer 38

= protein phoshatase 3 that activates the T cells of the immunesystem by: 1 activating NFAT(Nuclear Factor of Activated T-cells) 2 stimulating IL-2 production 3 stimulating cell proliferation and activating

Question 39

Ciclosporin moa?

Answer 39

inhibits IL-2 production and decreases T-cell proliferation

Question 40

Tacrolimus moa?

Answer 40

Same as ciclosporin, but more potent

Question 41

Glucocorticosteroids mechanism?

Answer 41

1 Inhibits transcription factor AP-1 and NF-KB = inhibits COX 2 Activated lipocortin 1 = inhibition of Phospholipase A2

Question 42

Etanerecept mechanism?

Answer 42

soluble TNF-alpha receptor that prevents TNF-alpha from binding with receptors in the tissues- Like extra non-functional receptors

Question 43

Infliximab and Adalimuab mechanism?

Answer 43

Monoclonal antibodies against TNF-alpha

Question 44

Certolizumab mechanism?

Answer 44

antibody against TNF-alpha. Used in ULC and crohns disease

Question 45

Anakinra mchanism?

Answer 45

IL-1 receptor antagonist. Used in Rheumatid Arthritis

Question 46

2 x immunosuppressive antibodies against adhesive molecules?

Answer 46

Efalizumab - antibody against integrin alpha1 | Alefacept - interfering with CD2 protein(surface protein on NK and T cell)

Question 47

3 x antibodies against lymphocyte antigen?

Answer 47

1 Anti Thymocyte Globulin - decrease nr of circulating T cells 2 Muronomab - antibody against CD3 on T cells 3 Basiliximab & Daclizumab - antibody aginst IL-2 receptor(CD25 antigen)