L20-21 Immunopharmacology Flashcards
When is the immune system suppressed when preparing for a transplant?
Before the procedure and exposure to the new tissue. A primary response is easier to suppress than a secondary one. Inhibition is more likely the earlier you start.
Side effects of immune suppression
Infections
Increased risk of lymphomas and other malignancies
What part of the immune system is suppressed by Glucocorticoids?
Pretty much the whole immune system
Tacrolimus and Cyclosporine work at what part of the immune system?
T-cell activation and cytokine production
What drug class made organ transplants possible?
T-cell suppressants
Before this all there was was corticosteroids
How are T-cell suppressants used?
Mostly for prevention and not so much for active rejection
What are the 2 main T-cell suppressant drugs and how do they work?
Cyclosporine
Tacrolimus
Work by inhibiting Calcineurin which is involved in the Gq signaling pathway that ultimately produces IL-2 which self-activates and signals proliferation
Cyclosporine
Calcineurin inhibitor inhibiting T-cell proliferation
Used to prevent rejection, maintenance, autoimmune disease, severe asthma
Does not affect the marrow
Decreases IL1/2
Increases TGFbeta–may increase cancer risk
Metabolized by CYP3A4
Narrow therapeutic range
Many drug interactions
No grapefruit juice!
Toxicity: RENAL!, HTN, gingival hyperplasia, hyperglycemia/lipidemia
What are the induces of CYP3A4?
Phenobarbitol, phenytoin, rifampin
What are the inhibitors of CYP3A4?
Erythromycin, ketoconazole, verapamil
Tacrolimus, TK506
Inhibits calcineurin (T-cell specific) Decreases IL2/4 Prevents rejection Can rescue rejection episode Used particularly in liver transplant CYP3A4 metabolism Nephrotoxic, HTN, Hyperglycemia, Neurotoxic–Insomnia and tremor, increased risk of skin cancer
Tacrolimus administration, pharmacokinetics, interactions
Oral absorption affected by food Narrow therapeutic range Metabolized by CYP3A4 Avoid grapefruit Do not combine with aminoglycosides because of nephrotoxicity
Pimecrolimus
Similar to Tacrolimus binding FKBP-12 to inhibit calcineurin
Cream for atopic dermatitis
Betatacept
Inhibits T-cells by blocking CD80 and 86 receptors on APC’s
Used for kidney transplant in EBV positive patients
Sirolimus
Blocks T-cell proliferation in response to IL-2 Attacks mammalian target of Rapamycin Also inhibits B-cell proliferation Causes bone marrow suppression Increases cholesterol and triglycerides
Mycophenolate-Mofetil
Antiproliferative agent
Inhibits monophosphate dehydrogenase–only B and T cells need this for purine synthesis, other cells use HPGRT
Specific for T cell proliferation and antibody production from B cells
Prevent rejection, often combine with tacrolimus
SE: mild, Rash, leukopenia, not used in pregnancy!, sepsis with CMV
Azathioprine
Antiproliferative agent
converted in vivo to 6-mercaptopurine
Inhibits purine synthesis and thereby cell proliferation of lymphocytes
Prevents rejection, treats renal component and glomerulonephritis in lupus, treats severe rheumatoid arthritis
SE: Bone Marrow Suppression!, Teratogenic!, Increased risk of infection–herpes, metabolixed by xanthine oxidase like mercaptopurine–careful with Allopurinol
Cyclophosphamide
Antiproliferative Alkylating agent cross links DNA Direct effect on T and B cells Can destroy T cells Blocks response to new antigens Can inhibit an established immune response! Organ transplant rescue Bone marrow transplant CYP450 activation!
Cyclophosphamide SE
Hemorrhagic cystitis, give MESNA
Teratogenic, Bone marrow suppression
Methotrexate
Antiproliferative
Human dihydrofolate reductase inhibitor decreases lymphocyte and macrophage function
Organ transplants, RA
Causes bone marrow suppression, fetal toxicity
Thalidomide
Antiproliferative Decreases TNFalpha TERATOGENIC! Anti tumor effects Graft vs Host reactions Unknown MOA SE: sedation, neutropenia, neuropathy
Leflunomide
Inhibits Pyrimidine synthesis inhibits T-cell proliferation and decreases b cell AB production
Decreases TNF-alpha used for RA
Lots of SE
Antithymocyte Globulin (ATG)
Horse or rabbit Ab against T-cells
Used during acute rejection but can be used to prevent
Severe reaction because it is a foreign protein–must give with corticosteroids and cytotoxic drugs
Daclizumab/Basilixumab
Binds IL-2 receptor to prevent activation of T-cells
Prophylaxis for kidney transplant
Humanized and chimeric so few SE and no general immunosuppression needed
What drugs are used for induction in transplants?
Daclizumab, Basilixumab
What drugs are used for initial and maintenance in transplant?
Tacrolimus or Cyclosporine, corticosteroids, mycophenylate mofetil, azithioprine
What drugs are used for acute rejection of transplant?
High-dose corticosteroids, anti-lymphocyte Ab’s, cyclophosphamide, tacrolimus, mycophenolate mofetil
What drugs are used for prophylaxis in transplants?
antiviral, antibiotics, antifungal, insulin, BP meds
Ustekinumab (Stelara)
T-cell directed antibody
Blocks IL-12 and 23
Used for plaque psoriasis
Natalizumab (Tysabril)
T-cell directed antibody
Binds integrin
Treats Crohn’s and MS
Vedolizumab (Entyvio)
T-cell directed antibody
Crohn’s
Omalizumab (Xolair)
Anti-IgE blocks binding to mast cells, basophils, used for severe allergic asthma
Adalimumab, infliximab
Bind TNF-alpha
Used in RA
Etanercept
Fusion protein to TNF-alpha
Abatacept
Fusion protein that decreases T cell activation
Toclizumab
Ab to IL-6 which is increased in RA
Bevacizumab (Avastin), Ranibizumab (Lucentis)
Ab to VEGF
Used for macular degeneration to control leaky BV’s
Pegaptanib (Macugen)
Ab to VEGF for macular degeneration
Aflibercept (Eylea)
Fusion protein to VEGF-a for macular degeneration
IL-2 use
Increases proliferation of T-cells and B-cells, macrophages
Used for renal cell carcinoma and malignant melanoma
Toxic: severe hypotension, lots of SE so admin in hospital only
Oprelvekin, rh-IL-11
Recombinant IL-11
Prevents chemo induced thrombocytopenia
Causes fluid retention
GCSF (Filgrastim; Neupogen)
Human recombinant C-CSF to treat neutropenia from stem cell transplant, chemo, HIV treatment, interferon
Bone pain SE
Epoetin alfa (Epogen, Procrit)
Recombinant EPO
Decreases anemia in chemo, HIV, kidney disease
Increased risk of clots, stroke, HTN
Interferons
Alpha (alfa) and beta response to viruses
Gamma activates macrophages
Inflammatory responses
Alfa 2b
Interferon alfa
HepC c ribavirin
hairy cell, other
Multiple Sclerosis Tx
Interferon beta-1b was first drug for this–decreased antigen to myelin
Glatiramer: decoy for myelin basic protein
Natalizumab
Teriflunomide: reduces T-cells
Fingolimod: decreases lymphs in blood and CNS
Dimethyl fumarate:
Classic interferon toxicities
Depression and suicide
Flu-like
Bone marrow suppression
Alopecia
