Drug Usage

in Patients with Renal Failure

Arini Setiawati
Dept. Pharmacology & Therapeutics
Medical Faculty, Uni. o! "ndonesia
#$cretion

Most important organ % &idneys

#$cretion % unchanged !orm & meta'olites

#$cretion o! unchanged & actie !orms %

renal elimination

( processes %
) glomerular !iltration
) actie secretion in pro$imal renal tu'ule
) rea'sorption along the renal tu'ules

Renal !unction %
) mature at the age o! * years
+, * yrs% normal -
cr
, ../ mg0d12
) a!ter the age o! 3. % 45 0 year
6lomerular !iltration
ultra!iltrate +plasma minus protein2
all !ree drugs 7
Actie secretion

From 'loodstream to the lumen o! pro$imal renal

tu'ule

Mem'rane transporters %
) P)gp % !or organic cations & neutral
compounds
) MRP % !or organic anions & con8ugated
meta'olites

-ompetition among organic acids, and

among organic 'ases
#$ample % penicillin 9 pro'enecid !or gonorrhea
Rea'sorption

mostly occurs 'y nonionic passie di!!usion along

the renal tu'ules

the degree o! ionisation depends on the p: o! the

luminal !luid
) acidic drugs % p;a (.. < /.=
) 'asic drugs % p;a >.. < 4*..
#.g. in cases o! pheno'ar'ital or salicylate
to$icity % al&alini?e the tu'ular urine with
@a:-A
(
ionisation e$cretion

mem'rane transporters at distal renal tu'ule %

!or actie rea's. !rom the tu'ular lumen
'ac& into the systemic circulation, o!
compounds reBuired
can 'e a!!ected
'y urinary p:
Renal e$cretion
in renal dys!unction

decrease drug doses or increase interal o!

drug adm.
+-alculation 'ased on creatinine clearance2

Drugs %
) elim. 'y hepatic meta'olism to inactie meta'olites
and 0 or 'y renal e$cretion o! parent drug and 0 or
actie 0 to$ic meta'olites
"n renal !ailure %
) For drugs eliminated completely 0 partially +C ((52
'y the &idneys, renally e$creted actie0to$ic meta)
'olites need dosage ad8ustment
) -linically signi!icant remoal 'y hemodialysis
needs supplemental dose
Renal Failure +RF2 %

Drug pharmaco&inetics & pharmacodynamics

!reBuently altered ris& o! ADR

Multiple medical pro'lems polypharmacy

drug interactions
Drug a'sorption in RF %

@, D, D, 'owel edema drug mala'sorption,

worsened 'y @SA"Ds
gastric
saliary urea ammonia
ureases
gastric p:
a's. o! Fe, &etocona?ole,
itracona?ole, etc.
Plasma protein 'inding in RF

Uremia
FFA

Malnutrition
Proteinuria
!ree drug intensity o! drug e!!ect
e$tent o! drug distri'ution
rate o! elimination
total plasma conc.
protein 'inding !ree drug, esp.
acidic drugs to al'umin
+penic., pheno'ar'., phenytoin, salic.,
war!arin, @SA"Ds, sul!a, theoph.2
serum protein !ree drug
Drug distri'ution in RF
#dema or ascites D
d
o! water)sol. drugs
Dol. contraction D
d
o! aminoglyc.
Muscle wasting D
d
o! digo$in

plasma conc.

Renal e$cretion in RF
Renal clearance +-l
R
2 E
!u F 6FR 9 actie tu'ular secretion
) actie & passie tu'ular rea'sorption
!u E !raction o! un'ound drug +to plasma protein2
Drugs mainly eliminated 'y renal e$cretion

Penicillins F #tham'utol

-ephalosporins F Diuretics

Aminoglycosides F A-# inhi'itors

Tetracyclines +Aoid 72 F Digo$in

Sul!onamides F Atenolol

@itro!urantoin F Disopyramide
These drugs are e$creted 'y the &idneys in
unchanged !orm will accum. in RF

intensity o! pharmacol. e!!ect &
to$icity

dosage
6lomerular !iltration in RF

only unbound drugs with MW < 60.000 are filtered by

functional nephrons

RF functional nephron mass GFR

eg. ampicillin
aminoglycosides
digoin
! ampicillin " large margin of safety
GFR biliary ecretion
dosage only if GFR < #0 m$%min.
! aminoglycosides
digoin
dosage in all degrees of RF
e$creted mainly 'y glom. !iltr.

low therap. ratio

Actie tu'ular secretion in RF

Dys!unction o! tu'ular secretion e$cretion o! drugs

Arganic acids accum. in RF +eg. con8ugates, FFA2

inhi'it secretion o! penicillins, cephalosporins,
sul!a, nitro!urantoin, thia?ides, !urosemide, etc.

Arganic 'ases competition usually not important

clinically.

Passie tu'ular rea'sorption in RF

only !or nonionic lipid solu'le drugs

a!!ected 'y urinary !low rate & urinary p:

in RF % urin. !low 'ut also tu'ular conc. o! drugs

does not a!!ect passie tu'ular rea'sorption
Renal e$cretion o! meta'olites in RF

accum. o! to$ic meta'olites ADR

eg. o! meperidine sei?ures
o! nitro!urantoin periph. neuropathy
o! morphine e$cess respir. depr.
#nd)stage renal disease +#SRD2

#SRD ) glom. !iltration almost none

) tu'ular secretion o! acidic drugs
+competition with accum. organic acids2
reBuires dialysis

Drugs ) e$creted 'y glomerular !iltration G

at least partially dialy?a'le
) e$creted 'y tu'ular secretion G
may 0 may not 'e dialy?a'le
Renal !unction !or drug dosing

Drug elimination 'y the &idney is assumed directly

proportional to 6FR, and
-l
-r
is traditionally used to appro$imate 6FR.

-oc&cro!t & 6ault !ormula %

+43. ) age2 $ ideal HI +&g2
) For men % -l
-r
+ml0min2 E
/* $ -
-r
+mg0dl2
) For women % ..J= $ -l
-r
!or men
) For acute renal !ailure % -l
-r
, 4. m10min should 'e
assumed !or drug dosage ad8ustment
Dosage Ad8ustment % D
1
1oading dose +D
1
2

to achiee therapeutic conc. directly

D
1
E Desired therap. conc. +pea&2 $ D
d
+mg0&g2 +mg0l2 +l0&g2

@o ad8ustment, e$cept %
) digo$in % =.)/= 5 o! usual D
1
) aminoglycosides% /=)J. 5 o! usual D
1
'ecause D
d
& narrow margin o! sa!ety
Dosage Ad8ustment o! D
M
+maint. dose2
* methods %
4. "nteral e$tention + l 2 with normal D
M
) may prod. odd interal dosing errors &
compliance
) not !or drugs with narrow margin o! sa!ety
+large plasma leel !luctuation2
) potentially lead to periods o! su'therapeutic
drug concentrations.
) encouraged !or drugs with conc.)dependent
&illing +eg. aminoglycosides2
Dosage Ad8ustment o! D
M
+*2
*. D
M
reduction +D2 with normal interal
) more constant drug leels
) desired !or drugs with narrow margin o! sa!ety
+digitalis, antiarrhythmics, and anticonulsants2
) ris&s to$icity due to higher trough leels +eg.
aminoglycosides2
(. -om'ination o! " & D G !or conenience,
without 8eopardi?ing e!!icacy & sa!ety
Dosage Ad8ustment o! D
M
+(2
6 E 4 < ! +4 < 6FR
F
0 6FR
@
2
! E -l
R
0 -l
T
6 E 6iusti):ayton
correction !actor
6FR
F
E 6FR in RF
6FR
@
E normal 6FR
-l
R
E renal clearance
o! drug
-l
T
E total clearance
o! drug
Dosage Ad8ustment < e$ample
6entamicin % ! E 4
RF with 6FR E (( ml0min.
@ormal 6FR E 4.. ml0min.
@ormal dosage E / mg0&g od in >. &g patient
to achiee -
ma$
E *. g0ml E 4. $ M"- o! Ps.aerug.
6 = 4 < 4 +4) ((04..2 E 40(
D
M
in RF %
) 3*. mg eery ( $ 4 day E ( days or
) 40( $ 3*. mg E 43. mg once daily or
) *0( $ 3*. mg E *J. mg eery * $ 4 day E * days
+choose the most conenient2 < as an e$ample o! dosage
ad8ustment
'ut !or A6, choose the 4
st
Pharmacodynamics in RF
Uremia %
) -@S sensitiities to 'en?odia?epines and opiates
) pressor e!!ects o! catecholamine
) 'radycardia 'y )'loc&ers
) hypo&alemia arrhythmia 'y digitalis
) hyper&alemia AD 'loc& 'y digitalis, Buinidine,
procainamide, phenothia?ines,
T-ADs
Ather Pharmacologic Pro'lems in RF +42
4. UT"s % reBuire adeB. AH conc. in renal
parenchyma or urine
K A6 < enter urine only 'y glom. !iltration
not e!!ectie
K Penic, -ephalosp.
SA, TMP
K ReBuire normal doses adeB. urin. leels
+modest serum leels < no clin. conseB.2
enter urine 'y tu'. secr.
e!!ectie
Ather Pharmacologic Pro'lems in RF +*2
*. Renal cyst in!ection %
K -otrimo$a?ole
-hloramph, FL
K Penic, -ephalosp,
A6
can penetrate cyst walls
e!!ectie
poor penetration
not e!!ectie
Ather Pharmacologic Pro'lems in RF +(2
(. Muscle paralysis
RF accum. o! @M 'loc&ers
& prolonged e!!ect,
worsened 'y accum. o! A6
respir. dys!unction
3. -reatinine ) a 'ase also actiely secreted
'y renal tu'ule
'asic drugs +cimetidine, TMP2 compete !or
tu'ular secr. -l
cr
& -
cr
Ather Pharmacologic Pro'lems in RF +32
=. Meta'olic loads
Acid Aspirin, aceta?olamide
Al&aline Antacids, car'enicillin
-reatinine Ana'olic & androgenic steroids
Mg Antacids, la$aties
; ;)penic, ;)sparing diuretics, A-#"
@a Ampicillin, piperacillin, ticarcillin
Urea 6lucocorticoids, tetracyclines
+antiana'olics2, hyperalimentation,
protein
:
*
A @SA"Ds, car'ama?epine
Summary +42
4. "n general %
Dosage ad8ustment in RF is not reBuired, when %
a2 renal elimination o! the drug , (( 5, and
the meta'olites are not actie, or
'2 6FR still C =. m10min.
For most anti'iotics % when 6FR still C *. ml0min.
*. For drugs ) with narrow margin o! sa!ety &
) main elimination 'y renal e$cretion
+eg. aminoglycosides, ancomycin, digo$in2
dosage ad8ustment is reBuired in all degrees o! RF.
Summary +*2
(. Supplemental dose post:D %
) :D clearance at least (. 5 o! total 'ody clearance
) Drugs with MI , =.. D, water solu'le, uncharged,
minimal protein 'inding, D
d
, 4 l0&g
3. Alteration in phM&inetics & phMdynamics
ris& o! ADR
=. Multiple medication drug interactions
-onclusions
Drug usage in RF %
4. #stimate dosage !rom calculation or dosing
ta'les
*. Aoid use i! too ris&y and other sa!er drug is
aaila'le
(. Re!ine the dosage estimation 'y titration o!
e!!icacy and sa!ety in indiidual patient
3. Supplemental dose can 'e predicted !rom
MI, water solu'ility, charge, protein 'inding,
and D
d
@ote %
-alculation o! drug dosage in RF is 'ased on
arious assumptions %

no change & no interindiidual ariation in drug

a'sorption, distri'ution, and meta'olism

no actie 0 to$ic meta'olites

drug elimination indep. o! dose +linear phM&inetics2

no change & no interindi. ariation in phMcol. response

sta'le renal !unction

-l
R
o! drug N -l
-r
+!or drugs !iltered 'y glomerulus or
secreted 'y renal tu'ule2
dosage ad8ustment 'ased on the a'oe calculations ))
only !or initial estimation,
should 'e !ollowed 'y !urther ad8ustments
'ased on patientMs clinical response and0or
the plasma drug concentration
&han'
(ou