Immunomodulation II
Cytotoxic agents
Alkylating agents:
Cyclophosphamide, ifosfamide
MOA:
add an alkyl group to guanine in DNA, preventing DNA
replication → stops proliferation of rapidly dividing cells (for
example, B and T lymphocytes)
Use:
Helpful in lymphoma (uncontrolled division of cancerous
lymphocytes)
Toxicities:
All come from the fact that they act at any and all cells that are
rapidly dividing
Hair loss, nausea/vomiting, bone marrow suppression
Cyclophosphamide specifically has a unique side effect:
hemorrhagic cystitis via its formation of acrolein
Acrolein can be neutralized by Mesna (our antidote!)
Anti-metabolites - Shutting down ability to make building blocks of DNA
Azathioprine:
MOA:
converted to 6-MP which inhibits purine synthesis → without
purines, cell cannot synthesize DNA and the cell is forced to
undergo apoptosis → stops lymphoid cell proliferation
Use:
Used in inflammatory bowel disease (IBD), rheumatoid arthritis
(RA), and leukemias/lymphomas.
Toxicities:
Same GI toxicity and bone marrow suppression as
cyclophosphamide
TPMT:
TPMT is a detoxifying enzyme that metabolizes 6-MP through an
alternative pathway (ends up inactivating 6-MP)
Individuals with two inactive TPMT alleles (homozygous
deficient) are unable to metabolize 6-MP to an inactive form, so
they have way higher levels of the active, toxic metabolite
have extremely severe bone marrow suppression unless
their dose of azathioprine is reduced
Genetic testing for TPMT before prescribing azathioprine!!!
Mycophenolate mofetil:
MOA:
inhibits an enzyme called IMDPH which results in inhibition of
guanine synthesis → B and T cells can’t replicate
Toxicities:
Same side effects as others
Metabolism
Metabolized to active form by tissue and plasma esterases
Renal excretion
Methotrexate:
MOA:
competitively inhibits DHF reductase and thymidylate synthetase
which prevents cell from regenerating folate which is required for
DNA synthesis
also inhibits AICAR transformylase which leads to an increase in
adenosine levels which is thought to cause immune suppression
Toxicities:
Same side effects as others (bone marrow, GI, mucositis)
Unique effect of ulcerative stomatitis & liver function
abnormalities (regularly monitor LFTs)
Methotrexate enters the cell through folate receptors, is pumped out by
efflux pumps
While in the cell, methotrexate is polyglutamated (a bulky chain of
glutamates is added) → can no longer be pumped out by efflux
pumps
Heavily depends on renal elimination (dose adjust for CKD)
Teratogenic
Lymphocyte signaling inhibitors
Cyclosporine:
MOA:
inhibits calcineurin which ends up preventing production of IL-2
and other pro-inflammatory cytokines
Very wide range of bioavailability b/c dependent on bile → need to
monitor drug levels in patient
Metabolized by CYP3A4 → adjust dosing in liver failure
Toxicities:
nephrotoxicity (from afferent arteriolar constriction)
hypertension (from above)
hyperlipidemia
gingival hypertrophy, hirsutism
neurotoxicity (tremor, headache, seizure)
Tacrolimus:
MOA
Calcineurin inhibitor like cyclosporine
More potent than cyclosporine & more predictive bioavailability (not bile
dependent)
Toxicities:
Same side effects as tacrolimus minus the hypertension and
hyperlipidemia
Glucose intolerance
Sirolimus:
MOA
inhibits mTOR which prevents T cell and B cell proliferation
Toxicities
less nephrotoxic than calcineurin inhibitors
but, synergistic nephrotoxicity with cyclosporin
hyperlipidemia and thrombocytopenia are very common
impaired wound healing
