110414 renal pharm Flashcards
high incidence of acute kidney injury occurs in what cases?
in pts receiving antibiotics, chemo, or radiocontrast dyes
common complication also of thoracic surgery
mechanism of acute kidney injury
arterial occlusion, hypotension, shock
renal ischemia-reperfusion
microvascular dysfxn excess vasoconstriction inflam, oxidative stress endothelial injury endothelial-leukocyte interactions
mismatch btwn O2 consumption and O2 supply
renal tissue hypoxia
tubular necrosis and apoptosis
most common causes of chronic kidney disease
diabetic nephropathy
HTN
tx for chronic kidney disease
inhibitors of renin angiotensin system
effect of renin angiotensin inhibitors in CKD
decrease progression of albuminuria
decrease progression of GFR decline
decrease risk of ESRD
the beneficial effects of them are independent of BP and blood glucose control
what do you want to avoid with tx for CKD?
NSAIDs-they damage the kidneys further. may interact with ACEi and ARBs
CKD mainly causes hypo or hypercalcemia?
hypo, but can have hypo or hypercalcemia
plasma calcium is regulated by
PTH, calcitonin, calcitriol (active vit D)
kidney failure-what happens to phosphate and calcitriol?
decreased GFR leads to decreased renal excretion of phosphate and diminished production of calcitriol, both leading to decreased Ca in blood and increased PTH
what leads to increase in PTH in secondary hyperparathyroidism in kidney disease?
decreased production of vit D3 (calcitriol)
decreased serum Ca
increased serum phosphorous
the above 3 are due to decrease in kidney fxn associated w chronic kidney dis
MOA of calcitriol and vit D analogs
enhance absorption of Ca and PO4 from intestine (by increasing synthesis of Ca ch and a carrier calcium binding protein)
calcitriol also enhances recruitment and differentiation of osteoclast precursor for remodeling–resorption of Ca and PO4 from bone
also enhances tubular reabsorption of Ca
adverse effect of calcitriol and vit D analogs
excessive dosing leads to hypercalcemia
phosphate binders
react with phosphate in GI tract and form an insoluble compound
when can hypercalcemia occur?
with prolonged kidney disease
renal transplant pts can have parathyroid hyperplasia and then, restoration of renal fxn and calcitriol production can lead to hypercalcemia
what can be used to treat hypercalcemia?
bisphosphonates
bisphosphonates MOA
pyrophosphate analogues that bind to hydroxyapatite crystals in bone matrix to inhibit bone resorption
calcitonin MOA
lowers plasma Ca by limiting bone resorption
increases phosphate excretion in urine
side effects of calcitonin
facial flushing
headache, dizziness
GI
taste disturbance
rasburicase
I.V.
recombinant version of enzyme urate oxidase
primarily used as PROPHYLAXIS during chemo (can be used in CKD)
calcitonin effect on kidney
increases Ca and PO4 excretion
PTH effect on kidney
increases calcitriol and increases Ca reabsoprtion
calcineurin inhibitors ex
cyclosporine
tacrolimus
MOA of calcineurin inhibitors
bind to cytosolic receptor proteins
cyclophilin (cyclosporine)
FKBP12 (tacrolimus)
complex binds to and inhibits action of calcineurin
inhibits transcription of cytokines such as IL-2 that are essential for T cell activation and proliferation
cyclosporine
binds cyclophilin, calcineurin inhibitor
oral or IV
side effects of cyclosporine
nephrotoxic
hirsutism
HTN and fluid retention
others
drug interactions of cyclosporine
nephrotoxic-NSAIDs, aminoglycosides
CYP3A4 inducers
CYP450 inhibitors
tacrolimus
bind FKBP12, calcineurin inhibitor
oral or IV
doesn’t stimulate TGFbeta (doesn’t have excessive vasoconstriction) like cyclosporine does
side effects of tacrolimus
pleural and pericardial effusions
cardiomyopathy in children
glucose intolerance
monitoring calcineurin inhibitor side effects
hepatotoxicity–liver fxn should be monitored regularly
cardiovascular (HTN, hypercholesterolemia)–fewer tacrolimus treated pts need antiHTN meds, and tacrolimus’ effect on lipid levels is less than that seen with cyclosporine
glucose intolerance
neurotoxicity (more often w tacrolimus)
calcineurin inhibitor drugs interactions
nephrotoxic agents (NSAIDs, some antibiotics)–monitor renal fxn
K sparing diuretics (hyperkalemia has been seen)
antacids (may inhibit absorption of calcineurin inhibitors)
statins (increased risk of rhabdomyolysis, bone marrow suppression)
use of calcineurin inhibitors has been more in favor of
tacrolimus, b/c of cyclosporine’s side effects
sirolimus MOA
binds to FKBP12 (different site than tacromlimus). the complex binds and modulates the activity of mTOR. inhibits cytokine/IL2-induced cell cycle progression from G1 to S phase
sirolimus route of administration
oral
sirolimus side effects
edema, ascites, tachycardia, HTN
hyperlipidemia
bone marrow suppression
others
drug interactions–drugs that induce cyp3A4, drugs that inhibit CYP450
benefits of mTOR inhibitor sirolimus
potent prophylaxis against acute cellular rejection
less vasoconstriction (than cyclosporine)
not associated w acute or chronic renal insufficiency (tacrolimus and sirolimus can cause decline in kidney fxn)
mycophenolate mofetil
competitive, reversible inhibition of IMPDH, a critical rate limiting enzyme in de novo purine synthesis. lymphocytes are dependent on de novo pathway vs. salavage pathway utilized by other cell types.
inhibits proliferation of B and T lymphocytes
oral or IV
side effects of mycophenolate mofetil
leucopenia, thrombocytopenia, anemia
opportunitistic infec
others
azathioprine
purine analogue
metabolized in liver to 6-mercaptupurine and then to thiosinosine monophosphate (TIMP)
TMP decreases synthesis of DNA precursors and also incorporates into DNA
more non-specific effects than mycophenolate mofetil
blocks CD28 co stimulation of T cells
oral
side effects of azathioprine
bone marrow suppression, leukopenia, thrombocytopenia
comparison of side effects of azathioprine and mycophenolate mofetil
both need to monitor complete blood counts.
GI side effects are more common in mycophenolate mofetil
IL-2 receptor antibodies
basiliximab
daclizumab
alemtuzumab
all are antiCD52-IL2 receptor antibodies
basiliximab
IV
given immediately prior to surgery and 4 days following
belatacept
IV
fusion protein binds CD80 and CD 86 mkolecules. blocks costimulatory action with CD28 on T cell activation
used for renal transplantation in pts SEROPOSITIVE FOR EBSTEIN BARR VIRUS
prednisolone
oral
inhibits pro inflammatory transcription factors such as NFkB. other mechanisms too.
induction agents ex
monoclonal or polycloncal antibodies given IV immediately after surgery
muromonab antithymocyte globulin basiliximab daclizumab alemtuzumab FTY720
