Immunosuppressants Flashcards
Use of Immunosuppressants
Autoimmune disorders
Allograft rejection
Inflam disorders
Rule of thumb of organ transplants
Use cocktail therapy
Induction - steroids
Maintenance - CNIs
Acute rejection - Steroids
Most immunosuppresion strategies try to
Reduce or eliminate steroids
Calcineurin inhibitors and mech of action
Cyclosporine, tacrolimus, pimecrolimus
Bind immunophilins
Cyclosporine binds cyclophin A to inhibt calcineurin
Other 2 bind FKBP-12 and inhibit calcineurin
Calcinuein
Is a Ca2 dependent protein phosphatase….ubiquitous expression
Mech of CNIs
inhibit calcineurin and prevent activation of NFAT…inhibits cytokine expression which prevents T and B cell activation…can;t really help with T cells that are alrwady activated
One effect is inhibition of IL-2
CNI most common use, bioavailability, metabolics, adverse effects,
Prophylactic use
Variable bioavailability
Metabolized by CYP3A system in the liver
Extensive adverse effects
CNIs in allograft transplant patients
Good at preventing acute rejection
Given orally at lowest dose that is effective
If dose is too high, then adverse effects
If too low, then risk of acute rejection
Don’t use until renal function stabilizes or improves
Only in maintenance phase
CNIs and atopic dermititis
Topical CNI second line therapy to topical steroids
Used prophylactically
CNIs advantage over topical steroids
CNIs show less absorption into bloodstream so fewer side effects
CNIs DO NOT retard development of mature immune response function
Disadvantage of CNIs over topical steroids
CNIs are newer so no generics
Not a lot known about side efffect
Pimecrolimus vs tracrolimus topical
Pimecrolimus shows less immunosuppression systemically than tacrolimus so preferred to use in young children or mild to moderate symptoms
CNI side effects
Nephrotoxocity
PTDM (treat with insulin to combat)
Hypertension
Nephrotoxicity of CNIs
Acute is most common and is reversible
Chronic can be irreversible
CNI interactions
Durgs that inhibit CYP3A4 increase CNI levels and increased toxicity
Drugs that induce CYP3A4 decrease CNI and increase risk of rejection
Drugs that bind CNI and prevent absorption decrease CNI and increase risk of rejection
Cytotoxic drugs
Azatthiprine and mycopheolate mofetil
Inhibit de novo purine synthesis
AZ
Metabolite inhibits Glutamine PRPP amidotransferase that is rate limiting for converting PRPP to IMP
Also inhibits salvage pathway by methylating IMP
Makes it an antimetabolite
MM
Inhibits IMP dehydrogenase that is rate limiting enzyme for converting IMP to GMP
Prefernetially inhibits IMPDH2 in lymphocytes
Sirloimus
Binds to FKBP-12 and then binds to mTOR that is part of larger protein complex…mTOR normally positively regulate cells cycle so if inhibited, arrested in G1 phase
Cytoxic drugs and allograft
Used during induction (MF preferred)
Maintenance used to lower or eliminate use of steroids or CNIs
Not used during acute rejection
Azatioprine kinetics and metabolism
Incompletely absorbed…50% bioavail…metabolized in liver by XO and TPMT…excreted in urine
MM kinetics and metabolism
Converted to MPA and absored rapidly and lamost completely
94% bioavail
Metabolized to MPAG bu glucuonyl transferase and exreted into urine and bile…Subject to enterohepatic recycling…2nd peak at 6-12 hours
Sirolimus kinetics and metabolism
Similar to cyclosporine and tacrolimus
Incomplete absorption and metabolism by CYP3A4
Adverse effect of Azathioprine
Risk of leukopenia (salvage path)
Mutation of TPMT can cause 6-MP toxicity
