Drug Dosing in Renal Insufficiency - Philippine College of Physicians

Drug Dosing in 

Renal Insufficiency 

Coralie Therese D. Dimacali, MD 

College of Medicine 

University of the Philippines 

Manila

Declaration of Conflict of Interest 

•For today’s lecture on Drug 

Dosing in Renal Insufficiency, I 

declare that I have no potential 

conflict of interest.

Objectives 

• Discuss the effects of impaired kidney 

function on drug pharmacokinetics 

• Describe the principles of 

pharmacotherapy in patients with renal 

disease 

• Calculate drug dosages for patients with 

renal insufficiency

Oral 

absorption 

Parenteral drug 

administration 

Bioavailability 

Liver 

First-pass effect 

Systemic 

Circulation 

Protein-bound 

Free 

Elimination 

Kidneys 

Parent drug 

Active / Inactive 

metabolites 

Tissue receptor 

action

Drug Pharmacokinetics 

• Bioavailability 

% of a drug dose that appears in the central 

circulation after oral administration compared 

to the IV route 

• Drug distribution 

• Drug metabolism 

• Renal handling

Bioavailability in Renal Insufficiency 

• Decreased drug absorption 

Nausea and vomiting 

Alkalinizing effect of salivary urea 

Use of PPIs and H 2 -receptor blockers 

Use of phosphate binders 

Gut edema 

Bacterial colonization 

Altered intestinal motility 

• Altered hepatic first-pass metabolism

Bioavailability in CKD 

• Drug absorption 

Absolute bioavailability rarely altered 

There • Reduced: is no quantitative furosemide, pindolol strategy to predict 

changes • Increased: for one Beta drug blockers, based dihydrocodeine, on data from 

dextropropoxyphene 

another in the same class 

Alterations in peak concentration (C max ) and 

time at which peak concentration is attained 

(T max )



• Drug Distribution 

Volume of distribution (V d ) 

• ratio of administered dose to the resulting plasma 

concentration in equilibrium 

V d = 

Dose 

Blood concentration 

• Useful for predicting loading doses 

Plasma protein binding

Volume of distribution (V d ) in CKD 

• Increased V d 

Edema and ascites 

Hypoalbuminemia 

Potentially decrease 

plasma drug levels of 

water-soluble and 

protein-bound drugs 

• Decreased V d 

Muscle wasting 

Volume depletion 

Potentially increase 

plasma drug levels of 

water-soluble drugs

Plasma protein binding in CKD 

• Acidic drugs have reduced plasma protein 

binding due to decreased albumin 

concentration and albumin affinity 

Unbound fractions may increase 

• Increased drug toxicity 

• Increased drug metabolism 

Lower drug plasma concentrations 

• Altered protein binding may decrease T 1/2




• Drug metabolism

Drug metabolism in CKD 

• Slowing down of reduction and hydrolysis 

reactions 

• Normal rates of glucuronidation, sulfation, 

Since there is significant patient variation, no 

conjugation and microsomal oxidation reactions 

prior assumptions will substitute for careful 

• Consider adverse effects of pharmacologically 

clinical evaluation. 

active metabolites 

Seizures from meperidine 

Peripheral neuropathy from nitrofurantoin 

Respiratory depression from morphine




• Drug metabolism 

• Renal handling of drugs

Renal handling of drugs 

• Renal excretion dependent on: 

Glomerular filtration rate (GFR) 

• Molecular size 

• Protein binding 

Tubular secretion 

• May compensate for decreased protein binding 

Tubular reabsoprtion 

• As rate of creatinine clearance (Cl Cr ) decreases, drugs 

dependent on tubular secretion are also excreted more 

slowly. 

• The Cl Cr is a reasonable estimate of GFR and the tubular 

capacity for drug excretion.

Renal handling of drugs in CKD 

• Decreased drug clearance 

• Prolonged plasma half-life of drugs 

• Accumulation of ‘active’ drug metabolites 

• Decreases in renal drug metabolism 

• Changes in drug distribution: protein 

binding

Drug metabolism and drug 

handling in AKI 

• Changes in metabolism 

There are large gaps in knowledge of 

Delayed drug metabolism 

drug Variable metabolism effect on hepatic and metabolic disposition activity in 

patients with multiorgan dysfunction 

• Reduced drug clearance 

syndrome, multisystem organ failure 

Hypoxia 

and Decreased AKI; thus, protein synthesis patients are at risk of 

underdosing and overdosing. 

Competitive inhibition from medications 

Decreased hepatic perfusion

Mathematics of drug elimination 

• Total body drug clearance = Drug dose 

AUC 

• Renal clearance = Total amount of drug in urine 

Plasma drug concentration 

• Renal clearance rate = 

Clearance 

Sample collection time 

• T 1/2 = V d x 0.693 

Drug clearance

Application of Pharmacokinetic Parameters 

Parameter 

Bioavailability (F) 

Volume of distribution (V d ) 

Clearance (C) 

Half-life (T 1/2 ) 

Clinical Application 

Determines amount of drug 

reaching systemic circulation and 

amount at site of action 

Determines size of a loading dose 

Determines maintenance dose 

Determines amount of time 

needed to reach steady-state 

serum concentrations

Approach to adjust drug dosage 

1. Obtain history and relevant clinical 

information. 

2. Estimate GFR. 

3. Review current medications. 

4. Calculate individualized treatment 

regimen. 

5. Monitor. 

6. Revise regimen. 

KDIGO 2011

Assessment of kidney function 

• GFR should be standard measure to 

evaluate kidney function for drug dosing 

purposes 

• Clinicians should use the most accurate 

method/tool to assess kidney function 

for the individual patient 

KDIGO 2011

Estimation of GFR and Creatinine 

Clearance 

• Cockcroft and Gault 

Cl Cr = 

(140 – age) x Wt (kg) 

S Cr (mg/dl) x 72 

x 0.85 (F) 

• MDRD Study Equation 

GFR = 175.6 x SCr -1.154 x Age -0.203 x 1.212 

[black] x 0.742 [female]

Estimation of GFR and Creatinine 

Clearance 

• CKD-EPI formula 

GFR = 141 x min(SCr/κ,1) α x max(SCr/ 

κ,1) -1.209 x 0.993 Age x 1.159 

[black] x 1.018 [female] 

κ = 0.7 [females], 0.9 [males] 

α = -0.329 [females], -0.411 [males] 

Min = minimum of SCr/κ or 1 

Max = maximum of SCr/ κ or 1 

Age = measured in years

Estimation of GFR in AKI 

• No estimating equations can provide an 

accurate estimate of GFR in AKI 

• Timed clearances of creatinine and urea 

may be particularly of value for AKI 

• Measure creatinine clearance with 

incorporation of mean of the beginning 

and ending serum creatinine value as an 

estimate of GFR 

KDIGO 2011

Goals of therapy 

• Maintain efficacy while avoiding drug 

accumulation and associated adverse 

reactions. 

Maintain peak, trough or average 

steady-state drug concentration 

Optimize time above the MIC or ratio of 

AUC to MIC

Prescribing for a patient with renal dysfunction 

Ascertain level of renal function (% normal Cl Cr ) 

Establish integrity of liver metabolism 

Establish loading dose 

Maintenance dose: dose reduction vs interval extension 

Check for drug interactions 

Decide on blood level monitoring

Calculating individualized regimen 

• Loading dose (LD) required if: 

drug has a long half-life 

there is need to rapidly achieve desired 

steady-state concentration 

volume of distribution (VD) is significantly 

increased 

LD P t = Usual LD x 

Vd Pt 

Normal Vd


• Generally no change in LD EXCEPT for digoxin 

(50-75% of usual LD due to reduced Vd in renal 

failure) 

• With volume contraction, lower standard LD of 

aminoglycosides by 20-25% to avoid toxicity 

• In AKI, increased Vd of many drugs, especially 

hydrophilic antibiotics (Beta lactams, 

cephalosporins, penems) necessitates 

administration of aggressive loading doses (25- 

50% greater)


• Maintenance dose 

Prolonging dose interval and maintaining 

same dose results in achievement of similar 

peak and trough concentrations and AUC 

Adjust to patient’s renal function, as reflected 

by the drug’s T 1/2 

Initiate at normal or near-normal dosage 

regiments considering the positive fluid 

balance in early AKI



Changing dosing interval 

Normal Cl Cr 

Dosing interval = 

x Normal interval 

Patient’s Cl Cr 

Reducing dose given at standard intervals 

Dose = 

Patient’s Cl Cr 

Normal Cl Cr 

x Normal dose



Changing dosing interval 

100 

Dosing interval = 

x 8 hours = 40 hrs. 

20 

Reducing dose given at standard intervals 

20 

Dose = 

x 1000 mg = 200 mg 

100

ke = 0.693 / T 1/2 

Dtsch Arztebl Int 2010; 107(37): 647–56


• Dettli’s proportionality rules: 

Rule 1: Dose of a drug must be reduced in 

inverse proportion to the T1/2 

Rule 2: The interval (Tau) between doses 

must be prolonged proportionally to the T1/2 

D D norm 

. 

T1/2 norm 

= 

Tau Tau norm T1/2


• Dettli’s proportionality rules: 

If dosing interval unchanged, AUC same but 

with higher trough values—may prompt 

physician to wrongly lower the dose 

Implies absurdly low doses or wide intervals 

between doses


• Halving rule of Kunin: 

Starting dose should be the same as the 

normal dose, and thereafter half the starting 

dose should be given at intervals equal to one 

half-life. 

If the half-life is shorter than the dosing 

interval, dose adjustment is usually 

unnecessary. 

Achieves effective peak levels but markedly 

higher trough levels more adverse effects.

Dtsch Arztebl Int 2010; 107(37): 647–56


“Start low, go slow” 

vs. 

“Go fast, start high”

Drug dosing considerations for CKD 

• Drug dosing recommendations may be different 

from original pharmacokinetic study due to 

variability in serum creatinine determinations 

• Use the most appropriate tool to assess kidney 

function 

• Drug dosages should be adjusted according to 

FDA or EMA approved product labeling 

KDIGO 2011

Drug dosing considerations for CKD 

• Peer-reviewed literature recommendations 

should be used to guide drug-dosage 

adjustments 

• Obese CKD patients with large variations 

in protein levels should have drug dosage 

individualized based on best available 

evidence. 

KDIGO 2011

Drug level monitoring 

• Ensures therapeutic levels while avoiding toxicity 

• Measurement of serum drug concentrations 

should be done especially for drugs with a 

narrow therapeutic range 

• Drug assays only measure total blood 

concentrations and may underestimate plasma 

levels or the active or free form of the drug 

• If not possible, dosage adjustments should be 

done in the presence of excessive 

pharmacologic effects or toxicity

Drug dosing considerations for HD 

• Dose should be given post-HD. Consider 

supplementary dose in addition to the dose 

adjusted to kidney failure after HD. 

• Supplementary dose derived from studies of 

low-flux membranes should be empirically 

increased by 50% when using hi-flux dialyzers. 

• Extended dialysis regimens with high diffusive 

membranes increase drug clearance and 

supplementary dose may need to be increased. 

KDIGO 2011

Drug dosing considerations for PD 

• Perform antibiotic loading by an extended cycle 

in CAPD and APD 

• Transperitoneal 

For most drugs 

drug 

in clinical 

movement 

use, 

may 

there 

be 

is 

less 

little 

effective in the acute phase of peritoneal 

evidence infection when of significant inflammation-related drug removal capillary during 

hyperperfusion subsides chronic PD. 

• Short dwell times in APD may prevent 

accumulation of antibiotic in the peritoneal 

cavity. 

• Monitoring of drug blood levels is advocated. 

KDIGO 2011

Key points 

• Renal dysfunction may result in altered 

pharmacokinetics and pharmacodynamics of 

individual drugs. 

• The goal of therapy is to maintain efficacy while 

avoiding drug accumulation and associated 

adverse effects. 

• An individualized approach is recommended, 

taking into consideration the integrity of other 

organ systems and potential drug interactions.


• Monitoring drug levels may be necessary 

to ensure therapeutic levels while avoiding 

toxicity. 

• Physicians should be vigilant in 

recognizing adverse events. 

• In the intensive care unit, a “Go fast, start 

high” policy avoids subtherapeutic blood 

levels.


• Consider giving scheduled doses after HD 

sessions OR give supplemental doses 

immediately post HD 

• For most drugs in clinical use, there is little 

evidence of significant drug removal 

during chronic PD.

References 

Am Fam Physician 2007; 75:1487-96

Drug Dosing in Renal Insufficiency - Philippine College of Physicians

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