Multi-Systems: Autoimmune Treatments Flashcards
What are the (3) signals req’d for T Lymphocyte activation?
- MHC from APC w/ Antigenic Peptide presented to TCR
- Co-stimulatory binding of APC CD 80/86 to T-cell CD 28
-
Self-Reception of IL-2 on T-cell
- Stimulates activation, proliferation, and Effector function
What are the (2) Calcineurin Inhibitors?
- Cyclosporine
- Cyclosporine –> Cyclophilin –> Calcineurin
- Tacrolimus (FK506)
- Tacrolimus –> FKBP-12 –> Calcineurin
- Calcineurin + Calmodulin + Ca2+ –> dephosphorylates NFAT to activated NFAT
- -> inhibits IL-2 gene transcription
What is the Mechanism of Cyclosprine?
- Inhibits Calcineurin - Protein phosphatase req’d for Transcription of IL-2 (T cell activator)
- Inhibition suppresses Cell-mediated immunity
- Normally, Calcineurin mediates Dephosphorylation of NFAT (Nuclear Factor of Activated T cells) –> NFAT nuclear translocation and IL-2 promoter binding –> Increased IL-2 exspression
- Cyclosprine binds to Cyclophilin, complex blocks Calcineurin activity –> Decreased IL-2 expression
Clinical application of Cyclosporine?
- Immunosuppression
- Organ transplant recipients
- Tx of “Graft vs. Host” Disease in Bone Marrow Transplant recipients
- Can be used as a DMARD
-
CYP3A4 Mediated metabolism
- CYP3A4 inhibitors (Erythromycin or Voriconazole) can dramatically elevate Cyclosporine lvls
- –> Nephrotoxicity risk
SEs of Cyclosporine?
- Nephrotoxicity especially when combined with Erythromycin or Voriconazole
- HTN
- Hirsutism
- Gum Hyperplasia (Gingival Hyperplasia)
- Neurotoxicity
- Hyperlipidemia
Mechanism of Tacrolimus (FK506)?
- Calcineurin Ihibitor for Immunospupression
- 50x - 100x more potent than Cyclosporine
- Less Nephrotoxicity
- Binds to FKBP-12 –> Tacrolimus-FKBP complex –> inhibits Calcineurin and suppresses IL-2 expression
Clinical use of Tacrolimus (FK506)?
- Immunosuppression
- prevents Graft vs Host disease
- Primarily used for Prophylaxis after Kidney (Renal)
and Liver Transplants - Rescue therapy
SEs of Tacrolimus (FK506)?
- Nephrotoxicity (less than Cyclosporine)
- HTN
- Inhibition of Pancreatic Beta-Islet cells
- Increased risk of Lymphoma
- Neurotoxicity
(3) Drugs that are Inhibitors of Cell Proliferation?
- Sirolimus
- Mycophenolate mofetil
- Azathioprine
Mechanism of Sirolimus?
- Like Tacrolimus, binds to FKBP-12 forms complex
- HOWEVER, it does not inhibit Cacineurin, but instead blocks IL-2 responsiveness of T cells by
- *Inhibiting P13-kinase, mTOR kinase** (mammalian target of Rapamycine) which modulates Gene expression
- mTOR dysregulation is a/w Neoplasia
- mTOR inhibitors can be used in the treatment of some types of Malignancy
- Metabolized in the Liver by CYP3A4
Clinical uses of Sirolimus?
- Immunosuppression for Organ Transplant recipients
- Prevention of Cardiac stent Restenosis
- Sirolimus-eluting Coronary artery stents inhibit Neointimal hyperplasia and decrease restenosis rates
-
Kaposi Sarcoma in transplant pts. –> lesion regression
- KS requires mTOR activity for growth
- Tuberous sclerosis - genes mutated in this disorder (TSC1 and TSC2) is to regulate mTOR
- Metabolized in Liver CYP3A4
SEs of Sirolimus?
- Anemia
- Leukopenia
- Thrombocytopenia
- Hyperlipidemia (Increased Cholesterol and Triglycerides)
- Increased risk of Lymphocele in Transplant pts.
- Contraindicated in Liver and Lung pts.
- Diarrhea, Nausea, Constipation
Mechanism of Mycophenolate Mofetil?
- Active metabolite –> Mycophenolic acid
–>Inhibitor ofIMP dehydrogenase, the rate-limigting step in thede novo synthesis of GMP
(Inosine monophoshate dehydrogenase, IMP dehyd.)
–> Inhibition is particulary toxic to B and T lymphocytes which rely on de novo synthesis of Purine biosynthesis - Mycophenolic acid also binds to Type II IMP dehydrogenase isoform expressed in Lymphocytes
–> Impaired Lymphocyte proliferation
–> Immunosuppresion
Clinical use of Mycophenolate Mofetil?
- Immunosuppresion of Solid Organ Transplants
- -> used w/ low dose Cyclosporine/Tacrolimus
- Recommended following Renal and Heart Transplant
- -> Should NOT be administered w/ Antacids (decreased absorption)
- Treats RA, Psoriasis, SLE, Inflammatory Bowel disease
SEs of Mycophenolate Mofetil?
-
Myelosuppression (Bone Marrow Suppression cells)
- Leukopenia (WBCs)
-
GI symptoms
- Nausea
- Cramping
- Diarrhea
Mechanism of Azathioprine?
- Active Metabolite is **6-mercaptopurine (6-MP)
- -> acts as a IMP dehydrogenase inhibitor
- -> Also Inhibits PRPP** an enzyme that catalyses the rate-limiting step in de novo Purine Synthesis
- Purine analog that Disrupts de novo Purine Biosynthesis (Both GMP and AMP)
- -> Inhibits DNA replication
Clincial use of Azathioprine?
- Immunosuppression of Solid Organ Transplantation
- RA, Psoriasis, SLE, IBD
SEs of Azathioprine?
- Leukopenia
- Diarrhea
(6) Disease-Modifying Anti-Rheumatic Drugs (DMARDs)?
“MS CLPT”
- Methotrexate
- Sulfasaline
- Chloroquine
- Leflunamide
- Penicillamine
- Tofacitinib
Mechanism of Methotrexate?
- Folic acid analog –> Antagonist
- Inhibits Dihydrofolate reductase (DHFR) and prevents Folate recycling –> Decreased Synthesis of Purine Nucleotides Metabolism and Adenosine accumulation
- Impaired Nucleic Acid synthesis
- -> Disproportionately affects rapidly dividing cells
Clinical use of Methotrexate?
-
Immunosuppression - First-line therapy
- Sever RA
- Psoriasis
- Ankylosing Spondylitis
- Polymyositis
- Dermatomyositis
- SLE
- Wegener’s Vasculitis
- Antineoplastic - Used in combination w/ Chemotherapy for many Malignancies
- Ectopic Pregnancies