Immunomodulators Flashcards
Glucocorticoids: MOA
Activates the glucocorticoid receptor transcription factor Modifies expression of cytokine and other immunoregulatory genes Suppresses active immune responses
Glucocorticoids: Indications
Immunosuppression To Prevent graft rejection To prevent GvHD Treatment of Cytokine-release Syndrome Treatment of a wide variety of autoimmune and inflammatory diseases
Glucocorticoids: adv.
Many Adverse effects Hyperglycemia Hypertension Hyperlipidemia Obesity Diabetes Poor wound healing Mania & Psychosis Inc. Risk infections
How to discontinue GC’s
Glucocorticoid dose must be gradually reduced to minimize adverse effects
Azathioprine: MOA
Prodrug Converted to 6-MP by HGPRT Inhibits de novo purine synthesis Incorporated into DNA & causes SSB base mispairing, leading to apoptosis Inhibits CD28 co-stimulation
Indications for azathioprine, mycophenolate
mofetil, and calcineurin inhibitors
Immunosuppression To Prevent graft rejection To prevent GvHD Treatment of autoimmune diseases
Azathioprine: adverse effects
Leukopenia/thrombocytopenia
Hepatotoxicity
Inc. Risk infections and malignancy
Notable interactions for azathioprine
Interacts with anti-gout drugs (Allopurinol &; Febuxostat), leading to Azathioprine toxicity, because inhibiting xanthine oxidase leads to increased levels of 6-mercaptopurine as well
Mycophenolate Mofetil: MOA
Prodrug
Converted to mycophenolic acid
Inhibits inosine monophosphate
dehydrogenase II (IMPDH2
- selectively expressed in lymphocytes, leading to Inhibition of purine nucleotide synthesis
- no salvage pathway in lymphocytes
Mycophenolate Mofetil: adv effects
Leukopenia/anemia
Teratogenic for both male and female
Inc. Risk infections, malignancy
***RARE- Risk of Progressive multifocal leukoencepalopathy (PML), a fatal viral disease caused by reactivation of JC virus
Mycophenolate Mofetil: counterindications
Men and women who wish to become parents
Calcineurin inhibitors: tacrolimus and cyclosporine, MOA
Cyclosporin and tacrolimus bind
cyclophilin and FKBP, respectively
to form inhibitory complexes
Cyclophilin/cyclosporin and
FKBP/tacrolimis complexes inhibit the
calcium-regulated phosphatase, calcineurin
Inhibition of calcineurin inhibits the activation
of the NFAT transcription factor, which is involved
in regulating the expression of IL-2 and multiple
other immunoregulatory genes
Potently inhibit the T cell immune response by
inhibiting Signal 1
Calcineurin inhibitors: adverse effects
Nephrotoxicity****
Hypertension***
Calcineurin inhibitors: Interactions
Metabolized by CYP3A4
3A4 inhibitors inc. risk of toxicity
3A4 inducers inc. risk of risk graft rejection
mTor inhibitors: sirolimus, everolimus, MOA
Drugs form complex with FBKP
FKBP/drug complexs inhibits:
IL-2 mediated activation of mTor kinase
(T cell signal 2)
IL-2 stimulated protein synthesis,
Cell proliferation and survival
mTor inhibitors: indication
Immunosuppression To prevent graft rejection - NOT LUNG - NOT LIVER To prevent GvHD Included in arterial stents to inhibit re-stenosis
mTor inhibitors: adv.
Hypertriglyceridemia Hypercholesterolemia Inc. Lung disease Inc. Risk of diabetes Anemia, thrombocytopenia, & leukopenia Dec. Wound healing Teratogenic Inc. Risk infections, malignancy
mTor inhibitors: Contraindications
Contraindicated in Pregnancy
NOT RECOMMENDED
- Lung transplantation (risk anastomotic dehiscence)
- Liver transplantation (risk hepatic artery thrombosis)
mTor inhibitors: Interactions
CYP 3A4!!!
Ipilimumab MOA
Antibody specific for CTLA4
Antagonizes the negative regulatory CTLA4 protein
responsible for downregulating activated T cells
Enhances T cell responses
Immune checkpoint inhibitors (Ipilimumab and Pembrolizumab/Nivolumab) adverse effects
Potential for RARE
Autoimmune response
(can be fatal)
Immune checkpoint inhibitors (Ipilimumab and Pembrolizumab/Nivolumab) adverse effects
Potential for RARE Autoimmune response (can be fatal)
Ipili: Inflammation of Skin, GI tract, liver, nerves and adrenal glands
Pem/Niv: e.g. lung, liver, colon, kidney, skin, pituitary, thyroid & pancreas
Pembrolizumab/Nivolumab MOA
Antibody specific for the PD1 protein, which is a negative regulatory receptor expressed on activated T cells that is responsible for downregulating T cell responses
The PD1 ligand PD-L1 is expressed on tumor cells, so they can avoid the immune response
Antibody drugs block PD1/PD1-L1 interactions, blocking the inhibitory signal and leading to enhanced tumor immune responses
Counterindications for immune checkpoint inhibitors
PREGNANCY
Which drugs treat relapsing/remitting MS?
Fingolimod
Natalizumab
IFN-beta
Glatiramer Acetate
Adverse effects of natalizumab
Increased risk of progressive multifocal leukoencephalopathy - especially if:
- prior use of immunosuppression - seropositive for JC virus - chronic treatment
Adverse effects of fingolimod
Bradyarrhythmia
Atrioventricular block
Chickenpox infection
Malignancy
Anti-thymocyte globuline, Alemtuzumab adverse effects
Cytokine release syndrome
IVIG - MOA, indications
Pooled Ig from healthy individuals
Provides patient with Ig from healthy
immunized donors to provide immunity
to common pathogens
Rhogam - when is it given
Given to Rh- mother at 28 weeks & 72 hr
post pregnancy to deplete any fetal RBC in
maternal blood
Glatiramer acetate - MOA
Promotes production of specific suppressor T cells that migrate to the brain and produce bystander suppression at sites of inflammation
Indications of Induction agents (Rabbit Anti-thymoycyte Globulins (rTAG), Alemtuzumab, Basiliximab)
Lymphocyte depletion intra-operatively and 3-7 days post-op
MOA of rTAG
Reacts with proteins expressed on lymphocyte surface- CD2, CD3, CD4, CD8, CD11a etc
Actively depletes lymphocytes from the blood and lymphoid organs
- Fc receptor-mediated/complement-dependent lysis and opsonization
After injection recovery of immune system takes several months
Best tolerated lymphocyte depletion induction therapy?
Well tolerated, although more rejection than with depleting agents
Maintentance therapy?
Glucocorticoid + either cyclosporin or tacrolimus + an anti-proliferative drug
- Sirolimus/everolimus are sometimes used in place of either cyclosporin/tacrolimus or the anti-proliferative drug