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A. General Pharmacology > 3. Immunosuppressants > Flashcards

3. Immunosuppressants Flashcards

1
Q

Types of immunosuppressants

A
  1. Calcineurin inhibitors: ciclosporin, tacrolimus
  2. mTOR inhibitors: sirolimus
  3. Cytotoxic antimetabolites: azathioprine, mycophenolate
  4. SLP receptor agent: fingolimod
  5. Biologics
    - Polyclonal antibodies: rabbit anti-thymocyte globulin
    - Monoclonal anti-cytokine signalling antibodies: anti-IL-2R mAb (Daclizumab)
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2
Q

MOA of ciclosporin

A
  1. ciclosporin binds to cyclophilin
  2. ciclosporin:cyclophilin complex binds & inhibits calcineurin
  3. prevents dephosphorylation and nuclear translocation of transcription factors: NF-AT (nuclear factor of activated T cells)
  4. inhibits cytokine gene transcription & synthesis (e.g. IL2, TNF-alpha, INF-gamma)
  5. inhibits primarily T cell proliferation, and B cells & CTL proliferation
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3
Q

Side effects of ciclosporin

A

nephrotoxicity, hyperglycaemia, gum hyperplasia, hyperlipidemia, hypertension, neurotoxicity

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4
Q

MOA of tacrolimus

A
  1. tacrolimus binds to FKBP12
  2. tacrolimus:FKBP12 complex binds & inhibits calcineurin
  3. prevents dephosphorylation and nuclear translocation of transcription factors: NF-AT (nuclear factor of activated T cells)
  4. inhibits cytokine gene transcription & synthesis (e.g. IL2, TNF-alpha, INF-gamma)
  5. inhibits primarily T cell proliferation, and B cells & CTL proliferation
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5
Q

is tacrolimus or ciclosporin more potent?

A

tacrolimus is 10x to 100x more potent than ciclosporin

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6
Q

Side effects of tacrolimus

A

nephrotoxicity, neurotoxicity, hyperglycaemia, hyperlipidemia, hypertension

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7
Q

MOA of sirolimus

A
  1. sirolimus:FKBP complex
  2. sirolimus:FKBP complex binds & inhibits mTOR
  3. ternary complex:
    - inhibits activity of 70kDa S6 kinase
    - maintain repressor activity of 4E-BP1
    - growth arrest from G1 to S phase
  4. inhibits cytokine-mediated proliferation of T & B cells
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8
Q

Advantages of sirolimus

A
  1. anti-proliferative & anti-angiogenic activities

2. sirolimus-eluting coronary stents to prevent arterial restenosis

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9
Q

Side effects of sirolimus

A

hyperlipidemia, thrombocytopenia, hyperglycemia, hypertension

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10
Q

MOA of azathioprine

A
  1. Azathioprine is converted to 6-mercaptopurine (6-MP) which is then converted to 6-thioguanine (6TG)
  2. Immunosuppresive actions of azathioprine:
    - structural analog / antimetabolite: 6TG impedes DNA synthesis
    - inhibits de novo purine synthesis → decrease proliferation of lymphocytes
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11
Q

Side effects of azathioprine

A

bone marrow depression: leukopenia, anemia, thrombocytopenia, bleeding, GI toxicity, lymphoma, neoplasia

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12
Q

Triple therapy effective in renal transplant and various autoimmune disorders

A

calcineurin inhibitor + steroid + azathioprine

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13
Q

MOA of mycophenolate mofetil (MMF), mycophenolate sodium (MPS)

A
  1. MMF and MPS is converted to mycophenolic acid (MPA)
  2. inhibitor of de novo pathway of purine synthesis, inhibition of inosine 5’-monophosphate dehydrogenase (IMPDH)
    - MPA preferentially inhibits type II more than type I IMPDH
  3. more selective anti-proliferative effects for T/B cells
  4. less bone marrow depression and GI toxicity than azathioprine
  5. suppresses antibody formation by B cells
  6. inhibits recruitment of leukocytes to graft sites
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14
Q

Side effects of mycophenolate

A

diarrhoea, neutropenia (risk of opportunistic viral/fungal infections), anemia, hypertension

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15
Q

MOA of fingolimod

A
  1. fingolimod is phosphorylated to fingolimod-P
  2. fingolimod-P targets at sphingosine 1-phosphate (S1P) receptor, activates S1P1, 3, 4 & 5
  3. S1P1 and S1P4 promotes egress of lymphocytes from lymph nodes and chemokine gradient-mediated lymphocyte homing
  4. fingolimod-P is a highly potent agonist at S1P receptors acts as a functional antagonist preventing lymphocyte egress from lymph nodes and reducing circulating lymphocyte
  5. long t1/2 life - 8 days
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16
Q

Side effects of fingolimod

A

“first-dose” negative cardiac chronotropic effects due to S1P1 and S1P3 activation in sinoatrial cells

17
Q

MOA of rabbit anti-thymocyte globulin

A

Non-selective purified IgG targeting T and B lymphocytes, NK cells, and MHC class I and II antigens, co-stimulator molecules, etc

MOA:

  1. opsonisation and complement-dependent cytotoxicity
  2. antibody-dependent cell-mediated cytotoxicity
  3. depletion of T-lymphocytes
  4. cross-link TCR leading to T cell anergy induction
18
Q

Side effects of rabbit anti-thymocyte globulin

A
  1. first dose effect: cytokine release syndrome (fever, chill, hypotension)
  2. thrombocytopenia/leukopenia/serum sickness
  3. development of anti-foreign IgG antibodies
  4. histiocytic lymphoma at the site of injection
19
Q

MOA of daclizumab

A

Anti-IL2-Ralpha mAb

20
Q

Side effects of daclizumab

A
  1. anaphylaxis and serum sickness
  2. first dose “flu-like” syndrome: fever, headache, cytokine storm
  3. increase risk of infection / malignancies

A. General Pharmacology (7 decks)

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