Other immunosuppressive drugs Flashcards
PK with cyclosporine
- Variable F
- CYP and PGP substrate
- Eliminated via bile
- Factors that affect PK: time-post transplant, high fat meals, bile production, liver disease, gastroparesis, diarrhea, age, other meds, SNPs
More specific side effects of cyclosporine
Neurologic (seizures, headache, tremor), GI, hyperglycemia, liver toxicity but rare, hypomagnesemia, hyperkalemia, HTN
–> most common AE is nephrotoxicity and depends on concentration of cyclosporine
T/F: Cyclosporine interacts w statins
True and is OATP mediated because cyclosporine is an OAT substrate (tacrolimus is not)
T/F: You should take sirolimus 2 hours after cyclosporine
False, it should be at least 4 hours after d/t CYPs
How to monitor cyclosporine
Target trough or peak and therapeutic range should be 100-350 ng/ml
Note: drug monitoring is important since it has a narrow therapeutic range and has multiple toxicities
T/F: Tacrolimus is the most widely used immunosuppressant
True
Tacrolimus PK
- Even more variable F
- CYP and PGP substrate
- Same AEs and interactions seen with cyclosporine
CYP3A5 polymorphisms affecting tacrolimus concentrations and dosing
- Extensive metabolizer has 2 functional alleles & cause lower concentrations of drug (increase dose)
- Intermediate metabolizer has 1 functional allele & cause lower concentrations of drug (increase dose)
- Poor metabolizer has 3 non-functional alleles and does not need a dose change
How to monitor tacrolimus
- Trough or peak concentrations and therapeutic levels are 5-20 ng/ml
Sirolimus & everolimus MOA
Inhibits mTOR1 which is responsible in regulating cell growth and proliferation
Sirolimus PK
- CYP3A4 and PGP substrate
- Highly variable
- Really long t 1/2
What are side effects of sirolimus?
- Delayed wound healing, mouth ulcers, thrombocytopenia, leukopenia, dyslipidemia, proteinuria
- Dose adjustments- within 5-7 days of last dose
- Drug interactions- cyclosporine
Everolimus PK
- CYP3A4 and PGP substrate
- Shorter half life
Note- cyclosporine inhibits everolimus metabolism
What are side effects of everolimus?
Delayed wound healing, leukopenia, hyperlipidemia, proteinuria (no ulcers or thrombocytopenia)
Azathioprine MOA
Inhibits de novo purine synthesis and incorporates into DNA –> inhibits T and B cell proliferation
How does TPMT effect azathioprine dosing?
- Low or deficient= consider alt dosing or extreme dose reduction
- Intermediate TPMT= start at 30-70% target dose
What are side effects of azathioprine?
Bone marrow suppression, myopathy, alopecia, pancreatitis, hepatitis
Note: monitor WBC, Hgb, Hct, Plt
Mycophenolate MOA
Inhibits de novo guanosine synthesis by inhibiting inosine monophosphate dehydrogenase (IMPDH)
Note: specific to lymphocytes
Mycophenolate indication
Maintenance therapy only after organ transplant
Mycophenolate adverse effects + interactions
AE: GI (dose limiting), neutropenia, anemia
Drug interactions are antacids and cholestyramine
Note- enteric coated has decreased GI side effects
Corticosteroids indication
Maintenance or treatment of rejection and are considered broad spectrum
What two drugs block IL-2
Daclizumab and basiliximab
What are specific indications for belatacept (inhibits T cell activation)?
Approved for prevention of acute kidney transplant rejection and used in EBV+ patients but has increased risk of PTLD
Antithymocyte globulin (polyclonal antibody)
MOA: depletes circulating T cells within 24 hours
Indication: induction or treatment of rejection
AEs: cytokine release syndrome, bone marrow suppression, increased risk of CMV and cancers
Bortezomib
MOA: proteasome inhibitor that targets plasma cells and decreases production of donor specific antibodies
Indication: treats antibody-mediated rejection post organ transplant
Eculizumab
MOA: anti-C5 mAB and inhibits complement activation
Indication: treats antibody-mediated rejection post organ transplant
T/F: antibody mediated rejection is easy to treat
False, it is hard to treat because no definitive tx and we need better drugs
