Drug Usage

in Patients with Renal Failure

Arini Setiawati
Dept. Pharmacology & Therapeutics
Medical Faculty, Univ. of Indonesia
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 drug malabsorption,
worsened by NSAIDs

gastric
salivary urea ammonia
ureases
gastric pH

abs. of Fe, ketoconazole,
itraconazole, etc.
Plasma protein binding in RF
Uremia
FFA



Malnutrition
Proteinuria
Nefrotic syndr.
free drug intensity of drug effect
extent of drug distribution
rate of elimination
total plasma conc.
protein binding free drug, esp.
acidic drugs to albumin
(penic., phenobarb., phenytoin, salic.,
warfarin, NSAIDs, sulfa, theoph.)
serum protein free drug
Drug distribution in RF
Edema or ascites V
d
of water-sol. drugs

Vol. contraction V
d
of aminoglyc.
Muscle wasting V
d
of digoxin

plasma conc.

Drug biotransformation in RF (1)
Drugs metabolized completely by the liver to
inactive metabolites normal dosage

Phase II metabolism = conjugation
(glucuronidation, sulfation, acetylation) :
normal normal dosage

Drug biotransformation in RF (2)
Phase I metabolism :
- microsomal oxidation : normal or
accelerated (accum. of
inducers)
- reduction (cortisol)
- peptide hydrolysis (insulin, glucagon, PTH)
- ester hydrolysis (diflunisal, procaine)
due to nonhepatic (esp. renal) metabolism
slowed
Drug 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 C
cr
< 0.7 mg/dL)
- after the age of 40 : 1% / year
Renal excretion in RF
Renal clearance (Cl
R
) =
fu GFR + active tubular secretion
- active & passive tubular reabsorption
fu = fraction of unbound drug (to plasma protein)

In Renal Failure : renal excretion

drug doses or interval of drug adm.
Drugs mainly eliminated by renal excretion
Penicillins Ethambutol
Cephalosporins Diuretics
Aminoglycosides ACE inhibitors
Tetracyclines (Avoid !) Digoxin
Sulfonamides Atenolol
Nitrofurantoin 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
- ampicillin : large margin of safety
GFR biliary excretion
dosage only if GFR < 20 ml / min.
- aminoglycosides
digoxin
dosage in all degrees of RF
excreted mainly by glom. filtr.

low therap. ratio
Active tubular 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
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.
Tubular reabsorption
mostly occurs by nonionic passive diffusion of
lipid soluble drugs along the renal tubules
the degree of ionisation depends on the pH of the
luminal fluid
- acidic drugs : pKa 3.0 7.5
- basic drugs : pKa 6.0 12.0
E.g. in cases of phenobarbital or salicylate
toxicity : alkalinize the tubular urine with
NaHCO
3
ionisation excretion
membrane transporters at distal renal tubule :
for active reabs. from the tubular lumen
back into the systemic circulation, of
compounds required

can be affected
by urinary pH
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
- V
d
< 1 l/kg
HD clearance is clinically significant if
total body clearance by 30-50 %
Suppl. dose = (desired conc. conc. postHD) x V
d

significant
removal
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
Cl
Cr
is traditionally used to approximate GFR.
Cockcroft & Gault formula :
(140 - age) x ideal BW (kg)
- For men : Cl
Cr
(ml/min) =
72 x C
Cr
(mg/dl)
- For women : 0.85 x Cl
Cr
for men
- For acute renal failure : Cl
Cr
< 10 ml/min should be
assumed for drug dosage adjustment

Dosage Adjustment : D
L
Loading dose (D
L
)
to achieve therapeutic conc. directly
D
L
= Desired therap. conc. (peak) x V
d
(mg/kg) (mg/l) (l/kg)

No adjustment, except :
- digoxin : 50-75 % of usual D
L
- AGs : 75-80 % of usual D
L

bec. V
d
&
narrow margin
of safety

Dosage Adjustment of D
M
(maint. dose)
2 methods :
1. Interval extention ( l ) with normal D
M
- 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 D
M
(2)
2. D
M
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 D
M
(3)
G = 1 f (1 GFR
F
/ GFR
N
)
f = Cl
R
/ Cl
T

G = Giusti-Hayton
correction factor
GFR
F
= GFR in RF
GFR
N
= normal GFR

Cl
R
= renal clearance
of drug
Cl
T
= total clearance
of drug
Dosage Adjustment of D
M
(4)
D
M
F
= D
M
N
x G D
M
F
= D
M
in RF;
I
F
= I
N
x 1/G D
M
N
= normal D
M
I = dosing interval

For small GFR in ESRD (Cl
Cr
< 10 ml/min) :
use Cl
inulin
or Cl
iohexol
not Cl
Cr
(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 C
max
= 20 mg/ml = 10 x MIC of Ps.aerug.

G = 1 1 (1- 33/100) = 1/3
D
M
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 1
st
Pharmacodynamics in RF
Uremia :
- CNS sensitivities to benzodiazepines and opiates
- pressor effects of catecholamine
- bradycardia by b-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
* Require normal doses adeq. urin. levels
(modest serum levels no clin. conseq.)

enter urine by tub. secr.
effective
Other Pharmacologic Problems in RF (2)
2. Renal cyst infection :
* Cotrimoxazole
Chloramph, FQ

* Penic, Cephalosp,
AG
can penetrate cyst walls
effective
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. Cl
cr
& C
cr

Other Pharmacologic Problems in RF (4)
5. Metabolic loads
Acid Aspirin, acetazolamide
Alkaline Antacids
Mg Antacids, laxatives
K K-penic, K-sparing diuretics, ACEI
Na Ampicillin, piperacillin, ticarcillin
Urea Glucocorticoids, tetracyclines
(antianabolics), hyperalimentation,
protein
H
2
O NSAIDs, carbamazepine
Special Drugs & Circumstances
1. NSAIDs nephrotoxic :
- inhib. of renal PG renal vasocontr. ARF
- hypersensitivity interstitial nephritis
- long-term use renal papillary necrosis
* High-risk pts : - elderly
- compromised RBF &
vol. depletion + UTI
avoid use
* If use is necess., esp. contin. use close monit.
of Cl
Cr
& regular urinalysis

2. Analgesics
* acetaminophen safe, but not always effective
* opiates for more severe pain, but
retention of active metabolites
prolonged analgesia & respir. depr.
* analgesic nephropathy avoided by using single
analgesic (not mixture of > 1 analgesic, esp.
combined with caffeine or codeine)
3. Cardiovascular Drugs
ACEI & ARB
* Pre-existing
- renal dis. due to atherosclerosis
(compromized renal perfusion)
- periph., cerebral, coron. vasc. dis.
* Usually revers. on drug withdrawal
* Accum. In renal dysf. dosage
* Check renal function 3-4 days after starting
therapy ensure no GFR or
serum K
renal
dysf.

CCBs elim. by hepatic metabolism
used in usual dosages in RF
Digoxin : maint. dose in RF monitor plasma
conc.
-blockers : dose of -bl mainly elim. by kidney

Diuretics
* Loop diuretics : required to avoid volume overload
* Extensive prot. binding not much glom. filtr.
must be secreted by organic anion pump in
basolateral membr. of renal tubule
* Azotemia : organic acids compete for the active transp.
dosage : double doses every 30-60 min. until
ceiling dose is reached or diuresis occurs
if ineffective + thiazide
if still ineffective contin. iv inf. of loop diur.
* Thiazides : generally not effective if Cl
Cr
< 25 ml/min.
* Ototoxicity : mostly ethacrynic ac., but also furosemide
& bumetanide
4. Antimicrobial Agents (AMs)
Except AG and vancomycin, most AMs have a wide
therapeutic index little or no dosage adjustiment
is normally made until the GFR
< 20 ml/min.
Drugs that are removed by dialysis adm. after
dialysis or a supplemental dose should be given
after dialysis
Aminoglycosides
* Bactericidal efficacy ~ C
max
* Toxicity C
min
* Nephrotoxicity :
- aggravate pre-existing renal dysfunction
- cause de novo ARF
- usually reversible
* Ototoxicity :
- irreversible vestibular damage
- concom. use of loop diuretics, esp. ethacrynic acid
risk of ototoxicity
dosage adjustm. :
esp. interval approach
Vancomycin
* nephrotoxic & ototoxic plasma conc. should be
monitored
* not dialysed after a single iv infusion, therap.
conc. can be maintained for 5 days in pts with
end-stage RF on dialysis

Tetracyclines
BUN in RF (due to its antianabolic effects
worsen the renal dysf.) do not use in RF,
except doxycycline & minocycline


Antituberculosis drugs
INH, rifampicin, pyrazinamide
normal daily doses may be given in renal impairment;
with INH, + pyridoxine to prevent periph. neuropathy
Streptomycin and ethambutol avoided where
possible
Streptomycin : major toxicity is vestibular
if required : dose 2-3 x/week for first 2 mos,
monitor plasma conc.
Ethambutol : cause optic neuritis if excessive
dosages are used or renal function is
impaired dose, give intermittently;
any visual changes discont.
immediately & seek medical advice


Amphotericin - nephrotoxic
use in renal failure only if there is no alternative
plasma conc. & renal function : monitor closely
prot. binding to lipoproteins in RF low plasma
concs interprete accordingly

Antiviral drugs
aciclovir & ganciclovir are elim. by kidney
dose in RF; accum. lead to CNS toxicity &
unconsciousness




5. Antianxiety drugs, Hypnotics and Antipsychotics
Adv. RF : particularly sensitive to CNS depressant
effect of these drugs start T/ with a smaller than
normal dose

6. Li and Antidepressants
Li avoid if possible or dose with careful
monitoring of plasma conc.
TCADs & newer ADs prescribed in normal
dosages




7. Insulin
renal function insulin requirements, bec. elim.
by kidney
RF dosage is required
Uremia : - insulin resistance due to a post-R/ defect,
corrected by dialysis
- response to hypoglycemia also impaired
8. OADs
chlopropamide t
1
/
2
avoid !
glibenclamide prolonged hypoglycemia due to
accumulation of an active metabolite wh. bind tightly
to pancreatic -cells
metformin : C.I. in RF bec. risk of lactic acidosis
glipizide : OAD of choice in RF because of:
- short duration of action
- eliminated by hepatic metab. to inactive
metabolites



9. GI drugs
Antiulcers
- ranitidine : eliminated by liver & kidney
dose in severe RF
- omeprazole : no dosage adjustment
Antacids
- Mg trisilicate mixtures have high Na content
- Al-cont.comp. ( AL(OH)3 or sucralfate) risk of
Al toxicity in severe RF or dialysis pts avoid !
10. Antigout drugs
Allopurinol : metab. to oxypurinol, accum. in RF
causes rashes (if severe potentially fatal
toxic epidermolysis), bone narrow depression and
GI upset daily dose to 100 mg in RF
Colchicine : in excessive doses diarrhea, GI
hemorhage, rashes and renal impairm. in RF




11. Nephrotic syndrome
Albumin is lost in urine bound drug is also lost
- refractory to diuretic therapy
- clofibrate can provoke severe muscle necrosis,
all fibrates used with caution !

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, V
d
< 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 V
d
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
Cl
R
of drug ~ Cl
Cr
(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