Drug Usage

in Patients with Renal Failure

Arini Setiawati
Dept. Pharmacology & Therapeutics
Medical Faculty, Univ. of Indonesia

Excretion
Most important organ : kidneys
Excretion : unchanged form & metabolites
Excretion of unchanged & active forms :
renal elimination
3 processes :
- glomerular filtration
- active secretion in proximal renal tubule
- reabsorption along the renal tubules
Renal function :
- mature at the age of 2 years
(< 2 yrs: normal Ccr < 0.7 mg/dL)
- after the age of 40 : 1% / year

Glomerular filtration
ultrafiltrate (plasma minus protein)
all free drugs !

Active secretion
From bloodstream to the lumen of proximal renal
tubule
Membrane transporters :
- P-gp : for organic cations & neutral compounds
- MRP : for organic anions & conjugated metabolites
Competition among organic acids, and
among organic bases
Example : penicillin + probenecid for gonorrhea

Reabsorption
mostly occurs by nonionic passive diffusion along
the renal tubules
the degree of ionisation depends on the pH of the
luminal fluid
can be affected
- acidic drugs : pKa 3.0 7.5
- basic drugs : pKa 6.0 12.0 by urinary pH
E.g. in cases of phenobarbital or salicylate
toxicity : alkalinize the tubular urine with
NaHCO3 ionisation excretion
membrane transporters at distal renal tubule :
for active reabs. from the tubular lumen
back into the systemic circulation, of
compounds required

Renal excretion
in renal dysfunction

drug doses or interval of drug adm.

(Calculation based on creatinine clearance)

 Drugs :
- elim. by hepatic metabolism to inactive metabolites
and / or by renal excretion of parent drug and / or
active / toxic metabolites

In renal failure :
- For drugs eliminated completely / partially (> 33%)
by the kidneys, and
renally excreted active/toxic metabolites
need dosage adjustment
- Clinically significant removal by hemodialysis
need supplemental dose

Renal Failure (RF) :

Drug pharmacokinetics & pharmacodynamics
frequently altered risk of ADR
Multiple medical problems polypharmacy
drug interactions

Drug absorption in RF :
N, V, D, bowel edema

salivary urea

drug malabsorption,
worsened by NSAIDs

gastric
ureases

ammonia
gastric pH

abs. of Fe, ketoconazole,

itraconazole, etc.

Plasma protein binding in RF

Uremia
FFA

protein binding free drug, esp.

acidic drugs to albumin
(penic., phenobarb., phenytoin, salic.,
warfarin, NSAIDs, sulfa, theoph.)

Malnutrition
Proteinuria
Nefrotic syndr.
free drug

serum protein free drug

intensity of drug effect
extent of drug distribution
rate of elimination
total plasma conc.

Drug distribution in RF
Edema or ascites Vd of water-sol. drugs
Vol. contraction Vd of aminoglyc.
Muscle wasting Vd of digoxin

plasma conc.

Renal excretion in RF
Renal clearance (ClR) =
fu GFR + active tubular secretion
- active & passive tubular reabsorption
fu = fraction of unbound drug (to plasma protein)

Drugs mainly eliminated by renal excretion

Penicillins
Cephalosporins
Aminoglycosides
Tetracyclines (Avoid !)
Sulfonamides
Nitrofurantoin

Ethambutol
Diuretics
ACE inhibitors
Digoxin
Atenolol
Disopyramide

These drugs are excreted by the kidneys in unchanged

form will accum. in RF

intensity of pharmacol. effect &

toxicity

dosage

Glomerular filtration in RF
only unbound drugs with MW < 60.000 are filtered by
functional nephrons
RF functional nephron mass GFR
eg. ampicillin
aminoglycosides
digoxin

excreted mainly by glom. filtr.

- ampicillin : large margin of safety

GFR biliary excretion

dosage only if GFR < 20 ml / min.
- aminoglycosides
digoxin

low therap. ratio

dosage in all degrees of RF

Active tubular secretion in RF

Dysfunction of tubular secretion excretion of drugs
Organic acids accum. in RF (eg. conjugates, FFA)
inhibit secretion of penicillins, cephalosporins,
sulfa, nitrofurantoin,
thiazides, furosemide, etc.
Organic bases competition usually not important
clinically.

Passive tubular reabsorption in RF

only for nonionic lipid soluble drugs
affected by urinary flow rate & urinary pH
in RF : urin. flow but also tubular conc. of drugs
not affect passive tubular reabsorption

Renal excretion of metabolites in RF

accum. of toxic metabolites ADR
eg. of meperidine seizures
of nitrofurantoin periph. neuropathy
of morphine excess respir. depr.

End-stage renal disease (ESRD)

ESRD - glom. filtration almost none
- tubular secretion of acidic drugs
(competition with accum. organic acids)
requires dialysis
Drugs - excreted by glomerular filtration
at least partially dialyzable
- excreted by tubular secretion
may / may not be dialyzable

Drug removal during Hemodialysis (HD)

Dialysate is aqueous only water soluble drugs are
dialyzable
Mostly by diffusion through membrane pores
Only unbound drug is diffusible
Diffusivity as MW
- MW > 1000 Daltons (very few drugs) :
negligible diffusive clearance
- Small solutes : flow-dep. clearance
- Larger mols. : diffusion rate
Charged drugs are less dialyzable, because :
- charged repulsion at the membrane surface
- drug binding to the membrane

Supplemental dose after HD

Required if signif. drug removal occurs during HD
Drugs : - MW < 500 Daltons
- water soluble, uncharged
- minimal protein binding
- Vd < 1 l/kg

significant
removal

HD clearance is clinically significant if

total body clearance by 30-50 %
Suppl. dose = (desired conc. conc. postHD) x Vd

 Peritoneal Dialysis (PD) :

- very inefficient in removing drugs little evidence
of significant drug removal during chronic PD
- eg. 1 HD treatment removes ~ 2/3 of body stores of
aminoglycosides
24-hours CAPD removes only 25-30 % of the drug.

Drugs requiring supplemental doses after

each HD session
Aminoglycosides

Metronidazole

Cephalosporins (most)

Flucytosine

Penicillins (most)

Ethambutol, INH

Vancomycin

Pyrazinamide

Sulfonamides, TMP

Aciclovir, Ganciclovir

Ofloxacin, ciprofloxacin

Zidovudine, Didanosine

Renal function for drug dosing

Drug elimination by the kidney is assumed directly
proportional to GFR, and
ClCr is traditionally used to approximate GFR.
Cockcroft & Gault formula :
(140 - age) x ideal BW (kg)
- For men : ClCr (ml/min) =
72 x CCr (mg/dl)
- For women : 0.85 x ClCr for men
- For acute renal failure : ClCr < 10 ml/min should be
assumed for drug dosage adjustment

Dosage Adjustment : DL
Loading dose (DL)
to achieve therapeutic conc. directly
DL = Desired therap. conc. (peak) x Vd
(mg/kg)

(mg/l)

No adjustment, except :
- digoxin : 50-75 % of usual DL
- AGs

: 75-80 % of usual DL

(l/kg)

bec. Vd &
narrow margin
of safety

Dosage Adjustment of DM (maint. dose)

2 methods :
1.

Interval extention ( l ) with normal DM

- may prod. odd interval dosing errors &
compliance
- not for drugs with narrow margin of safety
(large plasma level fluctuation)
- potentially lead to periods of subtherapeutic
drug concs.
- encouraged for drugs with conc.-dependent
killing (eg. AG)

Dosage Adjustment of DM (2)

2. DM reduction (D) with normal interval
- more constant drug levels
- desired for drugs with narrow margin of safety
(digitalis, antiarrhythmias, and anticonvulsants)
- risks toxicity due to higher trough levels (eg. AG)
3. Combination of I & D for convenience,
without jeopardizing efficacy & safety

Dosage Adjustment of DM (3)

G = 1 f (1 GFRF / GFRN)
f = ClR / ClT

G = Giusti-Hayton
correction factor
GFRF = GFR in RF
GFRN = normal GFR

ClR = renal clearance

of drug
ClT = total clearance
of drug

Dosage Adjustment of DM (4)

D MF = D MN x G

DMF = DM in RF;

IF = IN x 1/G

DMN = normal DM
I

= dosing interval

For small GFR in ESRD (ClCr < 10 ml/min) :

use Clinulin or Cliohexol
not ClCr (some Cr tub.secr.)

Dosage Adjustment example

Gentamicin : f = 1
RF with GFR = 33 ml/min.
Normal GFR = 100 ml/min.
Normal dosage = 7 mg/kg od in 60 kg patient
to achieve Cmax = 20 g/ml = 10 x MIC of Ps.aerug.
G = 1 1 (1- 33/100) = 1/3
DM in RF :
- 420 mg every 3 x 1 day = 3 days or
- 1/3 x 420 mg = 140 mg once daily or
- 2/3 x 420 mg = 280 mg every 2 x 1 day = 2 days
(choose the most convenient) as an example of dosage
adjustment
but for AG, choose the 1st

Pharmacodynamics in RF
Uremia :
- CNS sensitivities to benzodiazepines and opiates
- pressor effects of catecholamine
- bradycardia by -blockers
- hypokalemia arrhythmia by digitalis
- hyperkalemia AV block by digitalis, quinidine,
procainamide, phenothiazines,
TCADs

Other Pharmacologic Problems in RF (1)

1. UTIs : require adeq. AB conc. in renal
parenchyma or urine
* AG enter urine only by glom. filtration
not effective
* Penic, Cephalosp.
SA, TMP

enter urine by tub. secr.

effective

* Require normal doses adeq. urin. levels

(modest serum levels no clin. conseq.)

Other Pharmacologic Problems in RF (2)

2. Renal cyst infection :
* Cotrimoxazole
Chloramph, FQ

can penetrate cyst walls

effective

* Penic, Cephalosp,
AG

poor penetration
not effective

Other Pharmacologic Problems in RF (3)

3. Muscle paralysis
RF accum. of NM blockers
& prolonged effect,
worsened by accum. of AG
respir. dysfunction

4. Creatinine - a base also actively secreted

by renal tubule

basic drugs (cimetidine, TMP) compete for

tubular secr. Clcr & Ccr

Other Pharmacologic Problems in RF (4)

5. Metabolic loads
Acid

Aspirin, acetazolamide

Alkaline

Antacids, carbenicillin

Creatinine

Anabolic & androgenic steroids

Mg

Antacids, laxatives

K-penic, K-sparing diuretics, ACEI

Na

Ampicillin, piperacillin, ticarcillin

Urea
Glucocorticoids, tetracyclines
(antianabolics), hyperalimentation, protein
H 2O

NSAIDs, carbamazepine

Summary (1)
1. In general :
Dosage adjustment in RF is not required, when :
a) renal elimination of the drug < 33 %, and
the metabolites are not active, or
b) GFR still > 50 ml/min.
For most antibiotics : when GFR still > 20 ml/min.
2. For drugs - with narrow margin of safety &
- main elimination by renal excretion
(eg. aminoglycosides, vancomycin, digoxin)
dosage adjustment is required in all degrees of RF.

Summary (2)
3. Supplemental dose postHD :

- HD clearance at least 30 % of total body clearance

- Drugs with MW < 500 D, water soluble, uncharged,
minimal protein binding, Vd < 1 l/kg
4. Alteration in phkinetics & phdynamics
risk of ADR
5. Multiple medication drug interactions

Conclusions
Drug usage in RF :
1.

Estimate dosage from calculation or dosing

tables

2.

Avoid use if too risky and other safer drug is

available

3.

Refine the dosage estimation by titration of

efficacy and safety in individual patient

4.

Supplemental dose can be predicted from

MW, water solubility, charge, protein binding,
and Vd

Note :
Calculation of drug dosage in RF is based on
various assumptions :
no change & no interindividual variation in drug
absorption, distribution, and metabolism
no active / toxic metabolites
drug elimination indep. of dose (linear phkinetics)
no change & no interindiv. variation in phcol. response
stable renal function
ClR of drug ~ ClCr (for drugs filtered by glomerulus or
secreted by renal tubule)
dosage adjustment based on the above calculations -only for initial estimation,
should be followed by further adjustments
based on patients clinical response and/or
the plasma drug concentration

Thank
You