Immunopharmacology Flashcards
What are the 5 classes of immunosuppressant drugs
- Calcineurin inhibitor
- mTOR inhibitor
- Cytotoxic antimetabolites
- S1P receptor agent
- Biologics (pAb, mAb)
Name 2 Calcineurin inhibitors
Ciclosporin, Tacrolimus
Ciclosporin mec of action?
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
Ciclosporin clinical use
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
Ciclosporin side effects
Nephrotoxicity
Neurotoxicity
Hyperglycemia
Hyperlipidemia
Hypertension
Gum hyperplasia
Tacrolimus mec of action
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
Tacrolimus clinical use
Macrolide antibiotic
Oral/IV/Topical
Second line T cell immunosuppressant, 100X more potent than Ciclosporin, more bone marrow suppression
Tacrolimus side effects
Nephrotoxicity
Neurotoxicity
Hyperglycemia
Hyperlipidemia
Hypertension
Name 1 drug under mTOR inhibitor
Sirolimus (Rapamycin)
Sirolimus mec of action
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)
Advantage of Sirolimus besides immunosuppressant?
Anti-proliferative, anti-angiogenic.
Use in Sirolimus-eluting coronary stent to prevent arterial restenosis
Sirolimus + Ciclosporin effect, and side effect
effect: Additive immunosuppression
side effect: impaired renal function!!!
Sirolimus side effect
Hyperglycemia
Hyperlipidemia
Hypertension
Thrombocytopenia (low platelet)
Ciclosporin + Sirolimus = additive immunosuppression but impaired renal function!
Name 2 cytotoxic antimetabolites
Azathioprine, mycophenolate
Azathioprine mec of action
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
Azathioprine clinical uses
Effective in renal transplant, various autoimmune disorders using triple therapy (calcineurin inhibitor + steroid + azathioprine)
What is the benefit of triple therapy?
calcineurin inhibitor + steroid + cytotoxic antimetabolite:
aim to reduce dose, reduce adverse effect of each
Azathioprine side effects
Bine marrow depression:
leukopenia
anaemia
thrombocytopenia
bleeding
GIT toxicity (fast div)
lymphoma? (lack of WBC)
neoplasia?
Mycophenolate mec of action
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
Mycophenolate clinical uses
More selective anti-proliferative effects for T/B cells
Suppress Ab formation by B cells
inhibit leukocyte to graft sites (after transplant)
Mycophenolate side effects
Less bone marrow suppression than Azathioprine:
Neutropenia (risk of opp infection)
Anaemia
HYpertension
Diarrhoea (less GIT toxicity)
What is the full name for S1P recepter?
Sphingosine 1-Phosphate Receptor
What is 1 S1P receptor agonist?
Fingolimod
Fingolimod mec of action
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
Fingolimod side effects
“first dose” negative cardiac chronotropic effects (lower HR) due to S1P1, S1P3 activation in sinoatrial cells
What are involved in Biologics
Polyclonal antibodies, Monoclonal antibodies
Name 1 polyclonal antibody
Rabbit anti-thymocyte globulin
Rabbit anti-thymocyte globulin mec of action
Non-selective purified IgG against T, B lymphocytes, NK cells, MHC class I,II, Costimulator mlcs…
- opsonisation, complement dependent cytotoxicty
- ADCC
- depletion of T cells
- cross like TCR leading to T cell anergy induction (bind, activate TCR but w/o costimulation)
Rabbit anti-thymocyte globulin side effects
“first dose effect” cytokine release syndrome (fever, chills, hypotension)
leukopenia
thrombocytopenia
serum sickness
dvp of anti-IgG Ab
granulomatous inflammation at site of injection
Name 1 monoclonal Ab
Daclizumab
Daclizumab mec of action
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
Daclizumab clinical use
Suppress transplant rejection
Daclizumab side effects
First dose effect “flu-like” syndrome: fever, headache, cytokine storm
Anaphylaxis and serum sickness
risk of opp infection
How would you treat the px with maintenance dose after renal transplant?
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
Which of the following is common to ciclosporin, tacrolimus and sirolimus?
- All bind to immunophilins (ciclosporin vs FKBP12 vs FKBP12)
- All inhibit T cell proliferation
(inhibit Calcineurin, NFAT vs inhibit mTOR)
Which of the following drugs is MOST potent at preventing nuclear transcription of the IL-2 gene?
Tacrolimus
Fingolimod clinical use
Multiple sclerosis
THINK: MS act on neurones, you don’t want other drugs that have neurotoxicity, or are highly toxic
