Drug Dosing in Kidney Diseases

what qualifies a drug to have no change in regimen for kidney dysfunction patients?

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

how is absorption changed in patients with kidney dysfunction?

largely unchanged

how is distribution changed in patients with kidney dysfunction?

can be increased, decreased, or unchanged depending on drug (consider protin and tissue binding changes)

how is ametabolism changed in patients with kidney dysfunction?

decreased phase 1 enzyme capacity (CYP450 system), no change in phase II .

how is elimination changed in patients with kidney dysfunction?

decreased kidney elimination

what are some pharmacodynamic changes faced by patients with kidney dysfunction?

increased BBB permeability which increases CNS effects, and decreased platelet aggregation which increases bleed risk

clinical pearls for dosing morphine in kidney dysfunction:

use cation in CKD, avoid in kidney failure due to accumulation of active/toxic metabolite

clinical pearls for dosing codeine in kidney dysfunction:

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

clinical pearls for dosing hydrocodone in kidney dysfunction:

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

clinical pearls for dosing oxycodone in kidney dysfunction:

reduce dose and/or extend interval

clinical pearls for dosing fentanyl in kidney dysfunction:

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

clinical pearls for dosing hydromorphone in kidney dysfunction:

drug of choice, 25% reduction in starting dose

clinical pearls for dosing methadone in kidney dysfunction:

reduce starting dose by 50%

clinical pearls for dosing meperidine in kidney dysfunction:

AVOID - accumulation of neurotoxic metabolites

how does renal dysfunction affect elimination?

decreased GFR, decreased protein binding (increased Fu), and alterations in reabsorption and secretion processes (drug transporters)

what factor most affects loading dose?

Vd

T/F: in general LD for kidney dysfunction equals the LD for normal kidney function

true

what are some drug exceptions to loading dose of kidney dysfunction patients = normal kidney function LD?

digoxin (Vd is reduced in kidney failure therefore the LD if decreased by ~50%), and hydrophilic antibiotics may require higher loading doses in volume overload/AKI (aminoglycosides, beta lactams, carbenems, glycopeptides, linezolid, and colistin)

what factor most affects maintenance dose?

Clearance

which antimicrobial agents DO NOT require dose adjustments for kidney dysfunction?

Azithromycin, Ceftriaxone, Clindamycin, Doxycycline, Linezolid, Metronidazole, and Moxifloxacin

clinical pearls of antibiotics in kidney dysfunction

dose adjustments are dependent upon multiple factors (site of infection/antimicrobial tissue penetration, severity of illness, stability of renal function, and high risk of efficacy failure) and volume of distribution is usually the same or higher in CKD/AKI (LD should not be reduced and consider 24-48 hours of aggressive dosing of antibiotics in AKI)

how does kidney dysfunction affect anticoagulant use

reduced kidney elimination and increased bleed risk

why do kidney dysfunction patients have a higher bleed risk on anticoagulants?

kidney disease causes uremia which leads to platelet dysfunction and ultimately bleeding

which anticoagulant has the lowest percent of kidney clearance?

apixaban

brand of apixaban

Eliquis

brand of rivaroxaban

Xarelto

brand of edoxaban

Savaysa

brand of dabigatran

Pradaxa

afib dosing of apixaban

if SCr >= 1.5 mg/dL and age >= 80 years or BW <= 60 kg —→ Max 2.5mg BID

ESRD dosing of apixaban

5 mg BID or 2.5 mg BID if aged >=8 80 years or BW <= 60 kg

when is rivaroxaban contraindicated ?

CrCl < 15 mL/min

Afib dosing of rivaroxaban if CrCl 15 - 50ml/min

15 mg once daily

when is edoxaban CI?

if CrCl > 95 ml/min

dosing of edoxaban for CrCl 15-50 ml/min?

30 mg once daily

dabigatran dosing for CrCl 30-50 ml/min

75 mg BID

dabigatran dosing for CrCl 15-30 ml/min

75 mg BID (if also on Pgp inhibitor AVOID use)

when is dabigatran CI?

CrCl < 15 ml/min

renal dose adjustments for fondaparinux if CrCl 30-50 ml/min

50% reduction

when is fondaparinux CI?

CrCl < 30 ml/min

T/F: you should avoid enoxaparin use in dialysis patients

true

desirudin dosing when CrCl is 30-60 ml/min/1.73m2

5 mg Q12H

desurudin dosing when CrCl < 30 ml/min/1.73m2

1.7 mg Q12H

renal adjustments for dalteparin

CrCl < 30 ml/min use with caution and monitor anti-Xa levels

renal adjustments for bivalirudin when CrCl is 10-30 ml/min

reduce infusion to 1 mg/kg/hr

dialysis renal adjustments for bivalirudin

reduce infusion to 0.25 mg/kg/hr

when to avoid tinzaparin

CrCl < 30 ml/min

how does Vd change with edematous states?

increases

how does Vd change with muscle wasting/volume depletion?

decreases

what changes in distribution occur in kidney dysfunction?

hypoalbuminemia which leads to decreased protein binding and increased free fraction of drug which leads to toxicity, accumulation of endogenous (BUN) or exogenous (drug metabolites) inhibitors of binding, altered tissue binding

what eGFR is CI for metformin due to increased risk of lactic acidosis?

< 30 ml/min/1.73m2

renal dysfunction considerations for metformin if eGFR is 30-45?

consider 50% dose reduction

renal dysfunction considerations for metformin if eGFR is > 45?

no adjustments

which sulfonylurea is preferred in renal dysfunction?

glipizide

what are the risks associated with sulfonylureas in renal dysfunction?

risk of prolonged hypoglycemia with long duration agents

sitagliptin dosing for CrCl 30-50?

50 mg once a day

sitagliptin dosing for CrCl < 30?

25 mg once daily

saxagliptin dosing for CrCl <= 50

2.5 mg once daily

renal adjustments for linagliptin

no adjustments necessary

what are the risks associated with DPP-4 inhibitors in patients with renal dysfunction?

increased risk of hypoglycemia and pancreatitis

what CrCl should you avoid diuretic use in?

CrCl < 30 ml/min

renal adjustments for diuretics if CrCl is 25-50 ml/min?

~2x normal dose

renal adjustments for diuretics if CrCl is < 25 ml/min?

~4x normal dose

T/F: NSAIDs should be avoided in non-dialysis CKD?

true

why should NSAIDs be used cautiously in kidney failure?

increased risk of GI bleed and increased risk of CV events

what is the preferred analgesic in kidney disease patients?

acetaminophen <3333333

when to avoid duloxetine

CrCl < 30 ml/min (exposure ~ 2 fold higher)

renal dosing for tricyclic antidepressants

no renal dosing, may cause altered mental status

renal dosing for anticonvulsants

no kidney dosing but drug interactions and side effect potential

renal dysfunction effect on gabapentin/pregabalin

increased risk of falls and altered mentation