Immunosuppressants Flashcards
1
Q
Uses of immunosuppressants (4)
A
- Solid organ/tissue transplantation rejection
- Graft vs Host Disease
- Autoimmune Diseases (RA, SLE, MS, CD)
- Inflammatory Diseases
2
Q
Classes of immunosuppressants & examples (7)
A
- Calcineurin inhibitors (Cyclosporin A, Tacrolimus (FK506) )
- mTOR inhibitors (Sirolimus (Rapamycin) )
Cytotoxic agents
- Azathioprine
- Mycophenolate mofetil (MMF), mycophenolate sodium (MPS)
- Polyclonal antibodies (Atgam, thymoglobulin)
- Monoclonal antibodies & fusion proteins (Muromonab-CD3 (OKT3) )
- Rho (D) immune globulin
3
Q
Mechanism of action of calcineurin inhibitors
A
T cell-selective immunosuppressants
- CSA binds to ubiquitous cytosolic cyclophilin - CSA:cyclophilin complex binds & inhibits calcineurin
- Prevents translocation of transcription factor NF-AT - remains phosphorylated, cannot enter nucleus
- Inhibits cytokine gene transcription & synthesis
- Inhibits primarily T cell proliferation, but also B cell & CTL
- FK506 binds to ubiquitous cytosolic immunophilin (FKBP)
4
Q
Uses of calcineurin inhibitors (5)
A
- Transplants - kidney, pancreas, liver, cardiac
- Uveitis
- Rheumatoid Arthritis
- Psoriasis
- Asthma
5
Q
Toxicity of calcineurin inhibitors (7)
A
- Nephrotoxicity
- Hyperglycemia
- Hyperlipidemia
- Increased cancer risk
- Hypertension (CSA)
- Gum hyperplasia (CSA)
- Neurotoxicity (tacrolimus)
6
Q
Mechanism of action of mTOR inhibitors
A
- Sirolimus binds to FKBP-12 in the cytoplasm - Sirolimus:FKBP complex - binds & inhibits mTOR (Ser/Thr kinase)
- Inhibits activity of 70 kDa S6 kinase, activity of 4E-BP1, growth arrest from GI to S phase
- Inhibits cytokine-mediated proliferation of T & B cells
7
Q
Uses of mTOR inhibitors (2)
A
- Anti-proliferative & anti-angiogenesis activities
2. Eluting coronary stents to prevent restenosis
8
Q
Toxicity of mTOR inhibitors (4)
A
- Hyperlipidemia
- Thrombocytopenia
- Delayed wound healing
- Mouth ulcers
9
Q
Mechanism of action of azathioprine
A
- Converted to 6-mercaptopurine (6-MP) and then to active metabolite 6-thioguanine (6TG)
- Can integrate into DNA
(A) Structural analog/antimetabolite - impedes DNA synthesis
(B) formation of thioinosinic acid - inhibits de novo purine synthesis - decreased lymphocyte proliferation
10
Q
Uses of azathioprine (1)
A
- Renal transplant/other autoimmune disorders
- Triple therapy: Steroid + calcineurin inhibitor + azathioprine
11
Q
Toxicity of azathioprine (2)
A
- Bone marrow depression (leukopenia, anemia, thrombocytopenia, bleeding)
- Drug interactions: allopurinol inhibits xanthine oxidase which metabolizes 6-MP to an inactive metabolite - accumulation of azathioprine/6-MP - toxicity
12
Q
Mechanism of action & uses of MMF/MPS
A
- Converted to active metabolite mycophenolic acid
- Inhibits de novo pathway of purine synthesis by inhibiting inosine 5’-monophosphate dehydrogenase (IMPDH) - preferentially inhibits type II (inducible) over type I (resting)
- more selective anti-proliferative effects for T/B cells
- suppresses antibody formation by B cells
- inhibits recruitment of leukocytes to graft sites
13
Q
Toxicity of MMF/MPS (4)
A
- Diarrhea
- Neutropenia
- Anemia
- Hypertension
less bone marrow depression & GI toxicity than azathioprine
14
Q
Mechanism of action of polyclonal antibodies
A
- Non-selective purified IgG targeted at T & B lymphocytes, NK cells, MHC class I & II antigens, co-stimulatory molecules
- Opsonisation & complement dependent cytotoxicity, ADCC, depletion of T-lymphocytes, cross linking of TCR to induce anergy
15
Q
Uses of polyclonal antibodies
A
- Immune globulin intravenous (IGIV) - normalize patients immune network in autoimmune disorders, AIDS, bone marrow transplants
