Immunopharmacology

Question 1

What are the 5 classes of immunosuppressant drugs

Answer 1

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

Question 2

Name 2 Calcineurin inhibitors

Answer 2

Ciclosporin, Tacrolimus

Question 3

Ciclosporin mec of action?

Answer 3

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

Question 4

Ciclosporin clinical use

Answer 4

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

Question 5

Ciclosporin side effects

Answer 5

Nephrotoxicity
Neurotoxicity
Hyperglycemia
Hyperlipidemia
Hypertension
Gum hyperplasia

Question 6

Tacrolimus mec of action

Answer 6

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

Question 7

Tacrolimus clinical use

Answer 7

Macrolide antibiotic

Oral/IV/Topical

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

Question 8

Tacrolimus side effects

Answer 8

Nephrotoxicity
Neurotoxicity
Hyperglycemia
Hyperlipidemia
Hypertension

Question 9

Name 1 drug under mTOR inhibitor

Answer 9

Sirolimus (Rapamycin)

Question 10

Sirolimus mec of action

Answer 10

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)

Question 11

Advantage of Sirolimus besides immunosuppressant?

Answer 11

Anti-proliferative, anti-angiogenic.

Use in Sirolimus-eluting coronary stent to prevent arterial restenosis

Question 12

Sirolimus + Ciclosporin effect, and side effect

Answer 12

effect: Additive immunosuppression

side effect: impaired renal function!!!

Question 12

Sirolimus side effect

Answer 12

Hyperglycemia
Hyperlipidemia
Hypertension
Thrombocytopenia (low platelet)

Ciclosporin + Sirolimus = additive immunosuppression but impaired renal function!

Question 13

Name 2 cytotoxic antimetabolites

Answer 13

Azathioprine, mycophenolate

Question 14

Azathioprine mec of action

Answer 14

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

Question 15

Azathioprine clinical uses

Answer 15

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

Question 16

What is the benefit of triple therapy?

Answer 16

calcineurin inhibitor + steroid + cytotoxic antimetabolite:

aim to reduce dose, reduce adverse effect of each

Question 17

Azathioprine side effects

Answer 17

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

Question 18

Mycophenolate mec of action

Answer 18

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

Question 19

Mycophenolate clinical uses

Answer 19

More selective anti-proliferative effects for T/B cells

Suppress Ab formation by B cells

inhibit leukocyte to graft sites (after transplant)

Question 20

Mycophenolate side effects

Answer 20

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

Question 21

What is the full name for S1P recepter?

Answer 21

Sphingosine 1-Phosphate Receptor

Question 22

What is 1 S1P receptor agonist?

Answer 22

Fingolimod

Question 23

Fingolimod mec of action

Answer 23

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

Question 24

Fingolimod side effects

Answer 24

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

Question 25

What are involved in Biologics

Answer 25

Polyclonal antibodies, Monoclonal antibodies

Question 26

Name 1 polyclonal antibody

Answer 26

Rabbit anti-thymocyte globulin

Question 27

Rabbit anti-thymocyte globulin mec of action

Answer 27

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)

Question 28

Rabbit anti-thymocyte globulin side effects

Answer 28

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

Question 29

Name 1 monoclonal Ab

Answer 29

Daclizumab

Question 30

Daclizumab mec of action

Answer 30

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

Question 31

Daclizumab clinical use

Answer 31

Suppress transplant rejection

Question 32

Daclizumab side effects

Answer 32

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

Question 33

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

Answer 33

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

Question 34

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

Answer 34

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

Question 35

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

Answer 35

Tacrolimus

Question 36

Fingolimod clinical use

Answer 36

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