IPC Kidney: Principles of Drug Dosing in Kidney Diseases (Week 3)

which measure of eGFR is preferred? which is traditionally used for drug dosing?

CKDEPI 2021, cockroft-gault

which 2 measurements of eGFR have 20-30% discordance in dosing recommendations?

CKDEPI 2021 and cockcroft-gault

what are the criteria a drug has to meet to have NO CHANGE in regimen for kidney dysfunction pts?

large therapeutic index, fraction excreted unchanged in urine <=30%, metabolites are inactive (or no metabolites)

which PK factors can be changed?

ADME

for PK, what changes are seen in absorption?

largely unchanged

for PK, what changes are seen in distribution?

can be increased, decreased, or unchanged depending on the drug. consider protein and tissue binding changes/

for PK, what changes are seen in metabolism?

decrease in phase I enzyme capacity (CYP450 system), no change in phase II

phase II metabolites are eliminated by ___

kidney

for PK, what changes are seen in elimination?

decreased kidney elimination

what 2 pharmacodynamic changes can be seen?

increase in BBB permeability which increases CNS effects, decreased platelet aggregation which increases bleeding risk

___ inhibit CYP enzymes and drug transporters in the gut and liver, leading to...

uremic toxins, increased bioavailability and systemic exposure

what are the 2 big changes to hepatic metabolism?

altered 1st pass effect, metabolic processes altered (decreased phase I)

how does altered first pass effect impact hepatic metabolism?

decreased metabolism due to inactive metabolite leads to increased amount of active drug, leading to increased bioavailabilty

changes in PK during hepatic metabolism have a lot of pt variability, therefore...

not useful to predict clinical changes in dosing regimen

when morphine metabolites are not being eliminated by the kidney, what happens?

increased respiratory depression and CNS toxicity

which drugs can have metabolite accumulation?

allopurinol, cefotaxime, meperidine, morphine, primidone, sodium nitroprusside

which drug has a metabolite that has similar pharmacologic effect as the parent drug?

allopurinol

which drug has an inactive metabolite?

cefotaxime

which drugs have neurotoxic metabolites?

meperidine, morphine

which drug has a metabolite that is active drug?

primidone

which drug has a metabolite that causes cellular toxicity?

sodium nitroprusside

the ___ of the metabolite determines the clinical use of drug

effect

for drugs with metabolite accumulation, AVOID...

drugs with toxic metabolites

for drugs with metabolite accumulation, USE CAUTION...

with drugs that have pharmacologically active metabolites

for drugs with metabolite accumulation, MONITOR...

drugs with inactive metabolites

for opioid PK changes, the dose relates to ___

peak concentration which provides maximum pain relief

for opioid PK changes, the interval relates to ___

duration of pain relief

what are some changes in PD seen with opioids?

kidney dysfuntion increases sensitivity to therapeutic and toxic effects, increased opioid receptor sensitivity, increased BBB permeability increases CNS effects

clinical pearls for morphine dosing in kidney dysfunction

use caution in CKD, avoid in kidney failure (accumulation of active/toxic metabolite)

clinical pearls for codeine dosing in kidney dysfunction

case reports of narcosis, respiratory failure; avoid or use low doses in renal failure

clinical pearls for hydrocodone dosing in kidney dysfunction

reduce dose and/or extend interval; accumulation of active/toxic metabolite

clinical pearls for oxycodone dosing in kidney dysfunction

reduce dose and/or extend interval

clinical pearls for hydromorphone dosing in kidney dysfunction

drug of choice, 25% reduction in starting dose

clinical pearls for fentanyl dosing in kidney dysfunction

drug of choice, 25-50% reduction in starting dose

clinical pearls for methadone dosing in kidney dysfunction

reduce starting dose 50%

clinical pearls for meperidine dosing in kidney dysfunction

avoid, accumulation of neurotoxic metabolite

which opioids can you give in pts with kidney dysfunction?

fentanyl, methadone

which opioids can be given with caution in pts with kidney dysfunction?

hydromorphone, oxycodone, hydrocodone

which opioids need to be avoided in pts with kidney dysfunction?

morphine, codeine, meperidine

what changes in PK does renal dysfunction cause?

decrease GFR, decrease protein binding and increased fraction unbound, alteration in reabsorption and secretion processes

in SKI, ___ based assessments are inaccurate

SCr

in AKI dosing is based on...

diagnosis, pt condition and age, relative decline in kidney function, degree to which drug/metabolite eliminated by kidneys

how can urine output help determine an estimate of GFR?

non-oliguric: GFR >30

oliguric: GFR ~15-30

anuric: GFR <10

loading dose =

change in Cp * Vd

___ most affects loading dose

Vd

in general, loading dose for kidney dysfunction =

LD for normal kidney function

what are the 2 drug exceptions that require different loading doses in kidney dysfunction?

digoxin LD decreased by 50% (Vd reduced in kidney failure), hydrophilic antibiotics may need higher LD in volume overload/AKI

what are examples of hydrophilic antibiotics that may need an increased LD in volume overload or AKI?

aminoglycosides, beta lactams, carbapenems, glycopeptides, linezolid, colistin

___ most affects maintenance dose

CL

maintenance dose =

Css desired *(CL x dosing interval) / F

you can estimate maintenance dose by altering...

interval or dose using proportions

what is the interval method for maintenance dose?

(normal crcl/patients crcl) * normal interval

what is the dose method for maintenance dose?

(patients crcl/normal crcl) * normal dose

what are the antimicrobial agents that do not require dose adjustment for kidney dysfunction?

azithromycin, ceftriaxone, clindamycin, doxycycline, linezolid, metronidazole, moxifloxacin

for antibiotics, dose adjustment depends on what factors?

site of infection/antimicrobial tissue penetration, severity of illness, stability of renal function

dose adjustments for antibiotics have a high risk of ___

efficacy failure

for antibiotics, ___ is usually the same or higher in CKD/AKI

volume of distribution

for antibiotics loading doses should not be...

decreased, some should be increased

consider ___ dosing for antibiotics in AKI

24-48h of aggressive

which anticoagulant is a vitamin K antagonist?

warfarin

which anticoagulants are factor Xa inhibitors?

rivaroxaban, apixaban, fondaparinux, edoxaban

which anticoagulants are direct thrombin inhibitors?

dabigatran, bivalirudin, argatroban, lepirudin, desirudin

which anticoagulants are low-molecular weight heparin?

tinzaparin, enoxaparin, dalteparin

what change in PK happens with anticoagulants?

reduced kidney elimination

what change in PD happens with anticoagulants?

increased bleeding risk

how do anticoagulants increase bleeding risk in kidney disease?

kidney disease > uremia > platelet dysfunction > bleeding

what is the % kidney clearance for eliquis?

27%

what is the % kidney clearance for xarelto?

33%

what is the % kidney clearance for savaysa?

50%

what is the % kidney clearance for pradaxa?

80%

which DOACs have the most and least kidney clearance?

most: pradaxa, least: eliquis

what is the % kidney clearance for fondaparinux?

77%

what is the % kidney clearance for enoxaparin?

40-50%

what is the % kidney clearance for desirudin?

40-50%

what is the % kidney clearance for dalteparin?

33%

what is the % kidney clearance for bivalirudin?

20%

what is the % kidney clearance for tinzaparin?

minimal

which parenteral anticoagulants have the most and least kidney clearance?

most: fondaparinux, least: tinzaparin

how does volume of distribution change in edematous state?

increased Vd

how does volume of distribution change with muscle wasting/volume depletion?

decreased Vd

volume of distribution affects drug ___

concentration

protein binding alters ___ of drug

free fraction

how does hypoalbuminia affect free fraction of drug?

decreases protein binding > increased free fraction of drug > toxicity

what are the changes in PK seen for distribution?

Vd affects drug concentration, protein binding affects free fraction of drug, altered tissue binding

altered protein binding due to decreased affinity leads to...

decreased albumin, structural changes, or endogenous inhibitors (uremic toxins)

digoxin Vd decreases with renal disease due to...

decreased myocardial tissue uptake

how do you dose adjust metformin for egfr >45?

no adjustment

how do you dose adjust metformin for egfr 30-45?

consider 50% dose reduction

how do you dose adjust metformin for egfr <30?

contraindicated

what is the risk associated with metformin?

lactic acidosis

which drug must be discontinued 48h prior to IV contrast media?

metformin

which sulfonylurea is preferred in renal dysfunction?

glipizide

which sulfonylurea is bad in renal dysfunction?

glyburide

what is the risk associated with sulfonylureas?

prolonged hypoglycemia with long duration agents

___ provide better control than sulfonylureas but are does BID-TID

meglitinides

what are the 3 DPP4 inhibitors?

sitagliptin, saxagliptin, linagliptin

what is the brand name of sitagliptan?

januvia

what is the brand name of saxagliptan?

onglyza

what is the brand name of linagliptan?

tradjenta

what is the dose for sitagliptin with CrCl 30-50 ml/min?

50 mg once daily