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LSM3211 > Immunosuppressants > Flashcards

Immunosuppressants Flashcards

1
Q

List the Clinical use of Immunosupressants

A

(1)Organ Transplant Rejection
kidney, liver, pancreas, heart, ……
(2) Graft-versus-Host Disease
bone marrow transplant
(3) Autoimmune Disorders
rheumatoid arthritis :: systemic lupus erythematosus
multiple sclerosis :: Crohn’s disease :: psoriasis
idiopathic thrombocytopenic purpura
hemolytic anemia
(4) Recalcitrant Inflammatory Diseases
severe asthma :: severe atopic dermatitis

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2
Q

Mechanism of Organ Trasplant Rejection

A

When there is antigen presenting cell in the graf, their antigens are presented and the CD4 helpert T cells and CD8 cytokine t cell read them

after that, they undergo clonal expansion and releave a lot cytokines.
Cytokines would then attract the B lymphocytes and attract the macrophages, which would all attack the transplanted organ,

this results in the organ rejection

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3
Q

List the Immunosupressant Drugs

A

Corticosteroids(Immunosuppressants in Clinical Use)
Cortisone
Antilymphocyte Ab
Azathioprine
Ciclosporin
OKT3 mAbs
Sirolimus
Mycophenolic Acid
Antithymocyte Ab
Fingolimod

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4
Q

Calcineurin Inhibitors: T Cell-Selective Immunosuppressants

A

Ciclosporin

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5
Q

mechannism of action of Calcineurine inhibitors

A

normally,
foreign antigen binds
ca2+ increase
ca activate calmodulin
calmodulinform complex with calclineurine and dephosphorylate nuclear factor of activated t cells
dephospohorylated NFTAC formed heterodimer with NFTAN and activate DNA

however when the drug binds to the CYCLOPHILIN,

Cyclophilin is a peptidyl-prolyl cis-trans isomerase (PPIase) but functions as a
Chaperone in immunosuppression

Cyclophilin complex binds & inhibits Calcineurin, a Ca++/Calmodulin-
dependent Ser/Thr phosphatase (PP2B)

Prevent dephosphorylation and nuclear translocation of transcription Factors:
NF-AT (Nuclear Factor of Activated T Cells)
 Inhibits cytokine gene transcription & synthesis (e.g. IL-2, 3, 4, 6, TNFα, IFNγ)
 Inhibits primarily T Cell proliferation, and B cells & CTL proliferation as well

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6
Q

what is ciclosporin

A

polypeptide antibiotic
(Beauveria nivea)

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7
Q

Efficacy of Ciclosporin

A

Efficacy: First T-cell selective immunosuppressant
↓ Rate of acute rejection and ↑ allograft survival
Little bone marrow suppression

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8
Q

Uses of ciclosporin

A

Uses: kidney, pancreas, liver and cardiac transplants
uveitis, rheumatoid arthritis, psoriasis

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9
Q

Side effect of cuclosporine

A

SE: Nephrotoxicity / Hyperglycemia/ Gum hyperplasia
Hyperlipidemia / Hypertension / Neurotoxicity

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10
Q

What is a mTOR Inhibitors

A

Sirolimus (Rapamycin)

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11
Q

Mechanism of action of Sirolimus

A

Sirolimus:FKBP Complex
 Sirolimus:FKBP Complex binds & inhibits mTOR (mammalian Target of Rapamycin), a
Ser/Thr kinase

this cokmplex :
(1) inhibits activity of 70 kDa S6 kinase (p70S6K)
(2) activates repressor activity of 4E-BP1
(3) growth Arrest from G1 phase
 Inhibits IL-2 cytokine-mediated proliferation of T & B cells

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12
Q

advantages of Sirolimus

A

Anti-proliferative & anti-angiogenic activities

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13
Q

what happens when Sirolimus + Ciclosporine

A

Sirolimus + Ciclosporine : useful combination but may impair renal function

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14
Q

Side effects of sirolimus

A

Hyperlipidemia / thrombocytopenia / hyperglycemia/ hypertension

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15
Q

What are the Cytotoxic Immunosuppressant

A

Azathioprine
Mycophenolate Mofetil (MMF)

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16
Q

conversion of drug Azathioprine

A

Azathioprine is converted to 6-mercaptopurine (6-MP)
 6-MP → 6-methyl-MP → 6-thioguanine (6TG)

17
Q

Immunosuppressive actions of azathioprine:

A

(1) Structural analog/antimetabolite: 6TG impedes DNA and RNA synthesis
(2) Inhibits de novo purine synthesis → ↓proliferation of lymphocytes

18
Q

Side effects of azathioprine

A

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

19
Q

What else is it effective for

A

Effective in renal transplant and various autoimmune disorders using triple therapy
(e.g. calcineurin inhibitor + steroid + azathioprine)

20
Q

What is the conversion of Mycophenolate Mofetil (MMF)

A

MMF is converted to mycophenolic acid, the active metabolite

21
Q

what does MMF inhibit

A

Inhibitor of de novo pathway of purine (guanosine nucleotide) synthesis
MOA: inhibition of inosine 5’-monophosphate dehydrogenase (IMPDH)
MPA preferentially inhibits type II (inducible) more than type I (resting) of IMPDH

 More selective anti-proliferative effects for T /B cells
 Less bone marrow depression and GI toxicity than azathioprine
 Suppresses antibody formation by B cells
 Inhibits recruitment of leukocytes to graft sites

22
Q

Side effects of MMF

A

diarrhea / neutropenia (viral/fungal infections) / anemia / hypertension

23
Q

What is Fingolimod

A

Sphingosine 1-Phosphate Receptor Agonist
indiacated for multiple sclerosis

24
Q

what is Fingolimod converted

A

phosphorylated to active metabolite FTY720-P

25
Q

Mechanism of action of Fingolimod

A

Five S1PR on lymphoid tissues: FTY720-P activates S1P1, 3, 4 & 5R
 S1P1R activation leads to receptor downregulation to prevent lymphocyte egress from lymph
nodes, and decreases circulating auto-aggressive lymphocytes infiltration into the CNS
 Long T1/2: ~ 8 days
 Newer S1P receptor agonists: Siponimod and Ozanimod – selective for S1P1 & 5R

26
Q

Side effects of Fingolimod

A

first-dose” bradycardia/heart block effects due to S1P1 activation in sinoatrial cells,
hypertension, increased liver enzymes, GI upset

27
Q

what is polyclonal antibodies

A

Antibodies raised against human lymphocytes or thymocytes
 Non-selective purified IgG targeting T and B lymphocytes, NK cells, and MHC class I and II
antigens, co-stimulator molecules, etc.

28
Q

Polyclonal antibodies drugs

A

Lymphocyte Immune Globulin, Anti-Thymocyte Globulin

29
Q

mechanism of actions of polyclonal antibodies

A

(1) opsonization 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

30
Q

side effect of Polyclonal antibodies

A

first dose effect: cytokine storm (fever, chill, hypotension)
thrombocytopenia / leukopenia / serum sickness / development of anti-IgG antibodies

31
Q

MOnoclonal Antibodies what are they

A

Muromonab-CD3 (OKT3, Ortho-Kung-T cells-clone 3)
Murine monoclonal antibody
Directed against CD3-TCR complex
First Most selective for T lymphocytes marketed in 1986
T cell depletion / ↓ T cell activity

32
Q

Side effect of Monoclonal Antibodies

A

Development of HAMA: preclude continuous use
Anaphylaxis and serum sickness
First dose “flu-like” syndrome: fever, headache, cytokine storm
↑ Risk of infection / malignancies

LSM3211 (14 decks)

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