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!
