Immunopharmacology Flashcards
What are 6 types of immune suppressants?
1) Calcineurin inhibitors
2) mTOR inhibitors
3) Cytotoxic antimetabolites
4) S1P Receptor agonists
5) pAbs
6) mAbs
What are 2 calcineurin inhibitors?
Ciclosporin
Tacrolimus
What are the differences between ciclosporin and tacrolimus?
- Calcineurin binds to cyclophilin to inhibit calcineurin, Tacrolimus binds to FKBP12
- Tacrolimus is 10-100x>potent than Ciclosporin
- Both can be given Oral/IV Calcineurin can be given as ophthalmic solution, tacrolimus can be given topical
- Ciclosporin can cause gum hyperplasia
How do calcineurin inhibitors like ciclosporin and tacrolimus lead to immune suppression?
By binding to other molecules and inhibiting calcineurin, they prevent the dephosphorylation (activation) and nuclear translocation of NFAT (transcription factor of activated T cells).
→ inhibit cytokine gene transcription (eg. IL-2/3/4/6, TNFα, IFNy)
→ inhibits primary T cell proliferation
What are some clinical indications of calcineurin inhibitors?
1) Kidney, pancreas, liver, cardiac transplants
2) Uveitis
3) RA
4) Psoriasis
What are some adverse effects of calcineurin inhibitors?
1) Hyperglycemia
2) Hyperlipidemia
3) Hypertension
4) Neurotoxicity
5) Nephrotoxicity
6) Gum hyperplasia (Ciclosporin only)
Give an example of a mTOR inhibitor
Sirolimus (Rapamycin)
How does an mTOR inhibitor like sirolimus lead to immune suppression?
It binds to FKBP12 and inhibits mTOR
→ maintains the repressor activity of 4E-BP1
→ growth arrest from G1 to S
→ inhibit cytokine-mediated proliferation of T and B cells
What is a drug commonly used with sirolimus?
ciclosporin (useful but ↓renal f(x))
Why are Sirolimus-eluting coronary stent used?
Sirolimus inhibits T/B cell proliferation and has anti-proliferative and anti-angiogenic properties → prevent arterial stenosis/re-narrowing of artery
What are some clinical indications of mTOR inhibitors?
Sirolimus-eluting coronary stents
What are some adverse effects of mTOR inhibitors?
1) Hyperlipidemia
2) Hyperglycemia
3) Hypertension
4) Thrombocytopenia
Give 2 examples of cytotoxic metabolites.
Azathioprine, Mycophenolate
also Cyclophosphamide (alkylating agent), methotrexate (DHR inhibitor)
How do anti-metabolites lead to immune suppression?
They misincorporate into DNA and impede lymphocyte proliferation
What is the MOA of Azathioprine?
1) 6-MP→ 6-TG (guanine analogue) → impedes DNA synthesis → ↓lymphocyte proliferation
What is the triple therapy used with Azathioprine and when is it clinically indicated?
Calcineurin inhibitor + Corticosteroid + Azathioprine
- for renal transplant and autoimmune disorders
What are some adverse effects of Azathioprine
1) Bone marrow suppression
2) Bleeding
3) GI toxicity
4) Lymphoma
5) Neoplasia
What is the MOA of Mycophenolate?
1) MMF/MPS converted to → MPA (mycophenolic acid) (active metabolite)
2) MPA inhibits IMPDH → inhibits purine synthesis
- preferentially inhibits Type 2 (inducible) > 1 (resting) IMPDH
3) impedes DNA synthesis → ↓lymphocyte proliferation
What are the differences between Mycophenolate and Azathioprine?
Mycophenolate
- > anti-proliferative effects
- < bone marrow depressions and GI toxicity
- but results in neutropenia (↑risk of opportunistic viral/fungal infections) and Hypertension
What is an example of a S1P Receptor agonist?
Fingolimod
What is the MOA of Fingolimod?
1) Phosphorylated to Fingolimod-P (analogue of S1P)
2) competitively inhibits S1PR and activates it
3) Functional antagonist (likely through desensitizing S1P receptors or disrupting S1P signalling gradients)
4) prevents lymphocyte egress from lymph nodes and chemokine-gradient-mediated homing
5) ↓ circulating lymphocytes
When is fingolimod clinically indicated?
Multiple sclerosis
What is the main adverse effect of fingolimod?
1st dose negative cardiac chronotropic effects
(due to S1P1/3 activation in sinoatrial cells)
What is the half life of fingolimod?
T1/2~8hrs
