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Microbiology & Pharmacology > Pharmacology - chapter 40 - Immunosuppressants > Flashcards

Pharmacology - chapter 40 - Immunosuppressants Flashcards

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0
Q

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

A

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.

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1
Q

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

A

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.

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2
Q

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

A

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

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3
Q
  • Enhances activity of NK cells.
  • Attracts neutrophils and macrophages.

Which cytokine be dis?

A

IL-1

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4
Q
  • induces proliferation of antigen-primed T cells
  • enhances activity of NK cells.

Which cytokine can this be?

A

Yes, it is IL-2

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5
Q
  • enhances activity of NK cells and macrophages.
  • increases expression og MHC molecules.
  • Enhances production og IgG2a.

Which cytokine?

A

Iterferon gamma

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6
Q
  • cytotoxic effect on tumor cells.
  • induces cytokine secretion in the inflammatory response.

Cytokine?

A

TNF-alpha

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7
Q

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

A

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.

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8
Q

Cyclosporine, mechanism of action?

A

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.

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9
Q

Cyclosporine, areas of use?

A

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

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10
Q

Cyclosporine, metabolism?

A

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

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11
Q

Cyclosporine, adverse effects?

A

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

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12
Q

Drugs by which coadministration will increase the nephrotoxicity of cyclosporine?

A

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.

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13
Q

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

A

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

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14
Q

Tacrolimus, mechanism of action?

A

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

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15
Q

Tacrolimus, pharmacokinetics?

A

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

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16
Q

Tcrolimus, adverse effects?

A

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

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17
Q

Sirolimus, areas of use?

A

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.

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18
Q

Sirolimus, mechanism of action?

A

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.

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19
Q

Sirolimus, pharmacokinetics?

A

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

20
Q

Everolimus, mechanism of action?

A

mTOR inhibitor.

21
Q

Azathioprine, mechanism of action?

A

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.

22
Q

Allopurinol and Azathioprine relationship?

A

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

23
Q

Lymphocytes and purine synthesis?

A

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

24
Q

Antithymocyte globulins?

A

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.

25
Q

Mauromonab-CD3, mechanism of action?

A

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

26
Q

Mauromonab-CD3, pharmacokinetics?

A

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

27
Q

Mauromonab-CD3, adverse effects?

A

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

28
Q

Basiliximab and Daclizumab, mechanism of action?

A

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

29
Q

Basiliximab & daclizumab, adverse effects?

A

Their major toxicity is GI.

30
Q

Alemtuzumab. mechanism of action?

A

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

31
Q

Sirolimus, adverse effects?

A

hyperlipidemia

32
Q

Name five main groups of immunosuppressants

A 
1 Cytotoxic drugs
2 Calcineurin inhibitors
3 Glucocorticosteroids
4 Cytokin inhibitors
5 Antibodies
33
Q

Cyclophosphamide, mechanism?

A

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

34
Q

Methotrexate, mechanism?

A

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

35
Q

Azathioprine, mechanism?

A

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

36
Q

Leflunomide mechanism?

A

inhibits pyrimidine synthase

37
Q

Mycophenolate mofetil mechanism?

A

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

38
Q

What is calcineurin?

A

= 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

39
Q

Ciclosporin moa?

A

inhibits IL-2 production and decreases T-cell proliferation

40
Q

Tacrolimus moa?

A

Same as ciclosporin, but more potent

41
Q

Glucocorticosteroids mechanism?

A

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

42
Q

Etanerecept mechanism?

A

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

43
Q

Infliximab and Adalimuab mechanism?

A

Monoclonal antibodies against TNF-alpha

44
Q

Certolizumab mechanism?

A

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

45
Q

Anakinra mchanism?

A

IL-1 receptor antagonist. Used in Rheumatid Arthritis

46
Q

2 x immunosuppressive antibodies against adhesive molecules?

A

Efalizumab - antibody against integrin alpha1

Alefacept - interfering with CD2 protein(surface protein on NK and T cell)

47
Q

3 x antibodies against lymphocyte antigen?

A

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)

Microbiology & Pharmacology (32 decks)

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