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(Phase 1) Pharmacology remaining topics > Immunopharmacology > Flashcards

Immunopharmacology Flashcards

1
Q

What are the 5 classes of immunosuppressant drugs

A
  1. Calcineurin inhibitor
  2. mTOR inhibitor
  3. Cytotoxic antimetabolites
  4. S1P receptor agent
  5. Biologics (pAb, mAb)
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2
Q

Name 2 Calcineurin inhibitors

A

Ciclosporin, Tacrolimus

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3
Q

Ciclosporin mec of action?

A

Ciclosporin bind cyclophilin

Cyclophilin is a peptidyl-prolyl cis-trans isomerase PPIase, but function as chaperone

Ciclosporin: cyclophilin complex inhibit Calcineurin

prevent calcineurin dephosphorylation and nuclear translocation of NFAT (nuclear factor of activated T cell)

Inhibit cytokine synthesis (IL-2, TNFα, IFNγ)

Inhibit T cell proliferation, differentiation

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4
Q

Ciclosporin clinical use

A

polypeptide antibiotic

Oral/IV/Ophthalmic

first line T cell immunosuppressant, since Little bone marrow suppression unlike cytotoxic antimetabolite

Uses: after transplants, uveitis, rheumatoid arthritis, psoriasis

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5
Q

Ciclosporin side effects

A

Nephrotoxicity
Neurotoxicity
Hyperglycemia
Hyperlipidemia
Hypertension
Gum hyperplasia

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6
Q

Tacrolimus mec of action

A

Tacrolimus bind FKBP12

FKBP12 is also peptidyl-prolyl cis-trans isomerase PPIase, yet function as chaperone

Tacrolimus:FKBP12 complex inhibit Calcineurin

Prevent Dephosphorylation, nuclear translocation of NFAT

Inhibit cytokine syntheiss (IL‐2, TNFα, IFNγ)

Inhibit T cell proliferation, differentiation

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7
Q

Tacrolimus clinical use

A

Macrolide antibiotic

Oral/IV/Topical

Second line T cell immunosuppressant, 100X more potent than Ciclosporin, more bone marrow suppression

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8
Q

Tacrolimus side effects

A

Nephrotoxicity
Neurotoxicity
Hyperglycemia
Hyperlipidemia
Hypertension

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9
Q

Name 1 drug under mTOR inhibitor

A

Sirolimus (Rapamycin)

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10
Q

Sirolimus mec of action

A

Sirolimus bind to FKBP12

Sirolimus:FKBP12 complex bind, inhibit mTOR (mammalian Target of Rapamycin)

prevent kinase activity, growth arrest from G1 to S phase

Inhibit cytokine-mediated T, B proliferation (no IL-2)

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11
Q

Advantage of Sirolimus besides immunosuppressant?

A

Anti-proliferative, anti-angiogenic.

Use in Sirolimus-eluting coronary stent to prevent arterial restenosis

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12
Q

Sirolimus + Ciclosporin effect, and side effect

A

effect: Additive immunosuppression

side effect: impaired renal function!!!

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12
Q

Sirolimus side effect

A

Hyperglycemia
Hyperlipidemia
Hypertension
Thrombocytopenia (low platelet)

Ciclosporin + Sirolimus = additive immunosuppression but impaired renal function!

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13
Q

Name 2 cytotoxic antimetabolites

A

Azathioprine, mycophenolate

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14
Q

Azathioprine mec of action

A

Azathioprine is converted –> 6-mercaptopurine –> 6-thioguanine

6-thioguanine is a structural analog/antimetabolite, impede DNA synthesis

Also Inhibit de novo purine synthesis

reduce lymphocyte proliferation

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15
Q

Azathioprine clinical uses

A

Effective in renal transplant, various autoimmune disorders using triple therapy (calcineurin inhibitor + steroid + azathioprine)

16
Q

What is the benefit of triple therapy?

A

calcineurin inhibitor + steroid + cytotoxic antimetabolite:

aim to reduce dose, reduce adverse effect of each

17
Q

Azathioprine side effects

A

Bine marrow depression:
leukopenia
anaemia
thrombocytopenia
bleeding
GIT toxicity (fast div)
lymphoma? (lack of WBC)
neoplasia?

18
Q

Mycophenolate mec of action

A

Mycophenolate Mofetil (MMF), Mycophenolate Sodium (MPS) are converted to Mycophenolic acid

inhibit de novo purine synthesis pathway

more selective anti-proliferative effects for T/B cells

19
Q

Mycophenolate clinical uses

A

More selective anti-proliferative effects for T/B cells

Suppress Ab formation by B cells

inhibit leukocyte to graft sites (after transplant)

20
Q

Mycophenolate side effects

A

Less bone marrow suppression than Azathioprine:
Neutropenia (risk of opp infection)
Anaemia
HYpertension
Diarrhoea (less GIT toxicity)

21
Q

What is the full name for S1P recepter?

A

Sphingosine 1-Phosphate Receptor

22
Q

What is 1 S1P receptor agonist?

A

Fingolimod

23
Q

Fingolimod mec of action

A

Fingolimod: phosphorylated into active metabolite: Fingolimod-P

Fingolimod-P is structurally similar to S1P, a strong agonist at S1P1,2,3,5 receptors.

Although Fingolimod-P is a strong agonist, it act as a functional antagonist:
1. preventing Lymphocyte Egress from lymph nodes and
2. prevent chemokine gradient-mediated lymphocyte homing (means lower no of circulating lymphocytes).

Long T 1/2 = 8 days

24
Q

Fingolimod side effects

A

“first dose” negative cardiac chronotropic effects (lower HR) due to S1P1, S1P3 activation in sinoatrial cells

25
Q

What are involved in Biologics

A

Polyclonal antibodies, Monoclonal antibodies

26
Q

Name 1 polyclonal antibody

A

Rabbit anti-thymocyte globulin

27
Q

Rabbit anti-thymocyte globulin mec of action

A

Non-selective purified IgG against T, B lymphocytes, NK cells, MHC class I,II, Costimulator mlcs…

  1. opsonisation, complement dependent cytotoxicty
  2. ADCC
  3. depletion of T cells
  4. cross like TCR leading to T cell anergy induction (bind, activate TCR but w/o costimulation)
28
Q

Rabbit anti-thymocyte globulin side effects

A

“first dose effect” cytokine release syndrome (fever, chills, hypotension)
leukopenia
thrombocytopenia
serum sickness
dvp of anti-IgG Ab
granulomatous inflammation at site of injection

29
Q

Name 1 monoclonal Ab

A

Daclizumab

30
Q

Daclizumab mec of action

A

monoclonal Ab targeting IL-2 receptor alpha unit

Prevent IL-2 from binding, prevent signalling pathway, prevent T cell proliferation

Humanized mAb reduced risks on continuous use

31
Q

Daclizumab clinical use

A

Suppress transplant rejection

32
Q

Daclizumab side effects

A

First dose effect “flu-like” syndrome: fever, headache, cytokine storm
Anaphylaxis and serum sickness
risk of opp infection

33
Q

How would you treat the px with maintenance dose after renal transplant?

A

TRIPLE THERAPY
(calcineurin inhibitor +
corticosteroids +
cytotoxic antimetabolite)

THINK: maintenance dose don’t need to be so strong, choose ciclosporin+ prednisolone + Mycophenolate over Azathioprine for less bone marrow suppression

34
Q

Which of the following is common to ciclosporin, tacrolimus and sirolimus?

A
  1. All bind to immunophilins (ciclosporin vs FKBP12 vs FKBP12)
  2. All inhibit T cell proliferation
    (inhibit Calcineurin, NFAT vs inhibit mTOR)
35
Q

Which of the following drugs is MOST potent at preventing nuclear transcription of the IL-2 gene?

A

Tacrolimus

36
Q

Fingolimod clinical use

A

Multiple sclerosis

THINK: MS act on neurones, you don’t want other drugs that have neurotoxicity, or are highly toxic

(Phase 1) Pharmacology remaining topics (4 decks)

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