Renal Disease Flashcards
Ideal marker of GFR
-freely filtered, no clearance due to tubular secretion/reabsorption
-not metabolized by renal tissues
-no effect on renal function
Assessment of kidney function
-measuring GFR is gold standard (insulin, cystatin, markers)
-measure ClCr based on measured urinary clearance (urine collection)
-estimated ClCr or eGFR based on SeCr is widely used clinically
CG
-estimates creatine clearance, mL/min
CKD-EPI
-estimates GFR, mL/min/1.73m2
Estimated renal function
-CG (crcl ml/min)
-CKD-EPI (GFR, mL/min/1.73m2
-MDRD
-dif in units due to BSA
Cockcroft and Gault
-ClCr
-modified ClCr (adjusts for weight)
-formula sheet
Estimation of renal function
-eGFR most reliable (CKD-EPI methods)
FDA guidance on estimation of renal clearance
-eGFR corrected to BSA and reported as mL/min for use in drug dosing
-CG ClCr with IBW or AdjBW in overweight BMI>25
-prob gonna suggest eGFR in future and may even provide incentives to manufacturers
Limitations
-SeCr generated from muscle mass and diet
-amputees, body builders, vegans
-tubular secretion of SeCr (overstimulation of GFR esp at low ClCr)
-SeCr MUST be stable
Bottome line for estimation of renal function
-perform two estimates
-if estimates are dif selection of dose should be targeted risk/benefit
-TDM or conservative dose is narrow therapuetic index drug
-aggressive for wide therapuetic index
-actual measure of CrCl may be needed
Chronic kidney disease
-urine-albumin-creatine ration >30mg/g
-GFR <60mL/min for > 3 months
CKD staging
- GFR >90 ml/min/1.73m2
- 60-89
3a.45-59
3b. 30-44 - 15-29
- failure <15
CKD effect on Absorption
-no good data to suggest changes
-D-xylose absorption slowed
-likely reduced absorption and gastric emptying due to neuropathy
-reduced bioavailability due to gut wall edema, furosemide
-reduced due to drug interactions
-maybe reduced due to changes inc gas pH
Floroquinolone antibiotics-when admin with divalent cations
-when admin with divalent cations
-mg, ca
-form insoluble salts and reduce absorption
CKD effect on bioavailability
-alt metabolism/transport
-inc bioavailability of CYP
-dialysis may negate these effects
-suggesting uremic toxins may be responsible
CkD effect on distrivution
Vss=Vp + VT (fu/fu,t)
-any changes in those variables
-Vp and Vss change due to fluid overload
-see Di Piro for additional examples of Vd and protein binding changes
Alterations in plasma volume (Vp) drug distribution
-fluctuations in volume
-inc fluid admin
-hydrophilic drugs (aminoglycosides, cephalosporins)
Alterations in tissue binding (fu,t)
-dec tissue binding
-digoxin volume reduced in CKD stage 5 and HD pt
-actual dec due to dec tissue binding, acidosis or presence of DLIS
Drug distribution: protein binding
-inc binding of BASIC drugs to AAG
-CKD pt have more AAG
-dec binding of ACIDIC drugs to albumin
dec binding of drugs to albumin
-changes to albumin-binding sites
-accumulation of endogenous inhibitors of binding
-HYPOalbuminemia
-accumulation of competing metabolites
Phenytoin (anti-seizure)
-CKD alters relationship between total [DPH] and therapeutic and toxic effects
-narrow therapeutic index drug w non-linear or capacity limited PK
<10 mcg/mL
Phenytoin healthy vs CKD
-normal fu=0.08
-CKD fu=0.16
-Cl int is same
Clinical considerations for protein binding
-measure of unbound concentrations are desired in CKD pt
-highly protein bound drugs
-some have sut point of fu<0.2
-narrow therapeutic index drugs
-marked variation in fu
CKD effect on elimination and metabolism
-ClT = ClR + ClNR +Cl…
-reduction in ClR obv
-what happens to ClNR?
-most drugs are metabolized prior to excretion
-acute vs chronic
-hepatic and non-hepatic metabolism may be altered
-complex
As renal impairment increases, enzyme function
decreases
Metabolism in CKD
-CYP3A allegedly lower
-reduced Cl of CYP3A substrates
-likely reduction in ClNR in numerous enzymes
drug transport in CKD
-impaired
-OATP, P-glycoprotein reduced
-Fexofenadine
Metabolism and transport bottome line
-impact of given drug is difficult to guess
-no strategy for making predictions even in the same drug class
-qualitative strats may be employed by knowing the enzyme or transporter involved
CKD effect on metabolite accumulation
-inc side effects
-esp morphine, allopurinol, propoxyphene, procainamide, meperidine
-esp polar coumpunds in kidney
Renal clearance
-ClR = [GFR*fu] + [Clsecretion - Cl reabsorption]
-assume all renal drug elimination processes decline in parallel
Renal excretion graphs
-no ClR = straight line at 100% Cl
-no Cl NR = goes all the way down to zero
Grouping based on ClCr
-as CrCl inc, ClT inc
-ClT = slope + b(ClCR)
Relationship between Cl and renal function
-ClT = ClCR
-ClT = ClR + ClNR
-linear
too much H2 blocker (cimetidine) in elderly
-dementia side effect
Drug dosage adjustment in CKD
-collect
-assess
-plan
-monitor follow uppp
Drugs that require special consideration
-antibiotics
-lithium and digoxin
-cyclophosphamide
-metformin
-DOACs
Antibiotic special consideration in CKD
-aminoglycosides, vancomysin (NTI drugs)
-beta-lactam (penicillins, cephalosporins, etc)
Lithium and digoxin special considerations in CKD
-NTIs
-extensively removed renally
-significant toxcities
Cyclophosphamide special considerations in CKD
-active metabolites may accumulate
Metformin special considerations in CKD
-associated w development of lactic acidosis, if doses not adjusted in CKD
DOACs (direct oral anticoagulants)
-surpassed warfarin as ACs used most commonly
-variable renal excretion
-significant toxicities
Individualization of drug therapy
-determine dose adj factor (Q)
-determine dose and/or interval change (dec dose, inc interval)
-low Q = greater change in regimen
If fe is 1
-all drug eliminated by kidney
If fe is 0
-all drug is metabolized
low Q =
greater change in regimen
Dose pt =
-Q * normal dose
-dec dose
Interval pt =
-interval normal/Q
-inc interval
Renal dosage adj assumptions
-ClCr is good assessment and declines linearly w ClCr
-drug does NOT follow linear PKs
-unaltered drug absorption, protein binding and ClNR
Cefazolin ex
-has own equation for ClCR estimating
Limitations
-nonlinear assumptions
-NTI drugs should use TDM and estimation of Cmax and Cmin
Narrow Therapeutic Index drugs
-akikacin
-gentamicin
-tobramycin
-vacnomycin
-digoxin
-phenytoin
