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Drug Use in Patients with Renal Failure

Arini Setiawati
Dept. of Pharmacology & Therapeutics
Faculty of Medicine, University of Indonesia
Jakarta, Indonesia

In general, dosage adjustment in RF is not required when (a) renal elimination of the drug is <33%, and the metabolites are not active, or (b) GFR
is still > 50 mL/min, and for most antibiotics, when GFR is still > 20 mL/min. For drugs with narrow margin of safety and the main elimination
is by renal excretion (e.g. aminoglycosides, vancomycin, digoxin), dosage adjustment is required in all degrees of RF. Drug dosage in RF can be
estimated from calculation or dosing tables. Drug use in RF should be avoided if too risky (eg. tetracycline) and other safer drugs are available.
The dosage estimation should be refined by titration of efficacy and safety in individual patients. Supplemental dose postHD is required when
HD clearance is at least 30% of total body clearance. Predictably, this is for drugs with MW < 500 D, water soluble, uncharged, minimal protein
binding, and Vd < 1 L/kg. Alteration in pharmacokinetics and pharmacodynamics of drugs in RF causes increased risk of adverse drug reactions.
Multiple medications in patients with RF cause increased drug interactions in these patients.

Key words: renal failure, dosage adjustment, hemodialysis, Cockroft & Gault Formula, Giusti-Hayton correction factor

Umumnya, penyesuaian dosis pada gagal ginjal (GG) tidak diperlukan jika (a) eliminasi obat oleh ginjal <33%, dan metabolitnya tidak aktif, atau
(b) laju filtrasi glomerulus (LFG) masih >50 mL/menit, dan untuk kebanyakan antibiotik, jika LFG masih > 20% mL/menit. Untuk obat-obat de-
ngan batas keamanan yang sempit dan eliminasi utamanya melalui ginjal (misalnya aminoglikosida, vankomisin, digoksin), penyesuaian dosis
diperlukan pada semua derajat gagal ginjal. Dosis obat pada GG dapat diestimasi dari perhitungan atau tabel dosis. Penggunaan obat pada
GG harus dihindarkan jika terlalu berisiko (misalnya tetrasiklin) dan ada obat-obat lain yang lebih aman. Estimasi dosis harus diperhalus dengan
titrasi efikasi dan keamanan pada masing-masing pasien. Dosis pengganti pasca-hemodialisis (HD) diperlukan jika klirens HD sedikitnya 30%
dari klirens tubuh total. Hal ini dapat diprediksi untuk obat dengan berat molekul <500 D, larut air, tidak bermuatan, ikatan protein minimal, dan
Vd <1 L/kg. Perubahan dalam farmakokinetik dan farmakodinamik obat pada GG meningkatkan risiko terjadinya efek samping. Banyaknya obat
yang diberikan pada pasien GG meningkatkan terjadinya interaksi obat pada pasien GG ini. Arini Setiawati. Penggunaan Obat pada Pasien
Gagal Ginjal.

Kata kuci: gagal ginjal, penyesuaian dosis, hemodialisis, formula Cockroft & Gault, faktor koreksi Giusti-Hayton

INTRODUCTION pharmacy and consequently increased drug Distribution & protein binding
Drugs are eliminated by hepatic metabolism interactions. Uremia and increased plasma free fatty acids in
to inactive metabolites and/or by renal ex- patients with renal failure will cause decreased
cretion of parent drug and/or active or toxic PHARMACOKINETICS IN RENAL binding of acidic drugs to albumin, resulting in
metabolites. FAILURE increased free drugs level in plasma, e.g. phe-
nobarbital, phenytoin, salicylic acid, warfarin,
In renal failure, for drugs eliminated complete- Absorption NSAIDs, sulfonamides, theophyllin, etc. Malnu-
ly or partially (more than 33%) by the kidneys, Patients with renal failure experience nau- trition and proteinuria which occur in patients
renally excreted active or toxic metabolites sea, vomiting, diarrhea and/or bowel edema, with renal failure will cause decreased serum
need dosage adjustment. Meanwhile, clinical- which cause drug malabsorption; it is wors- protein, and this will also cause increased free
ly significant removal by hemodialysis need a ened by nonsteroidal anti-inflammatory drugs in plasma. Increased plasma free drugs
supplemental dose. drugs (NSAIDs). Increased salivary urea in pa- level will lead to increased intensity of drug
tients with renal failure, by gastric ureases will effect, extent of drug distribution, and rate of
In renal failure (RF), drug pharmacokinetics be converted to ammonia, which will increase drug elimination, and decreased total plasma
and pharmacodynamics are frequently al- gastric pH and cause decreased absorption concentration.
tered, resulting in increased risks of adverse of iron, ketoconazole, itraconazole and other
drug reactions. Moreover, multiple medical drugs requiring acid medium for their absorp- These effects are due to only free drugs can
problems in patients with RF lead to poly- tion. diffuse out of the capillary blood vessels to

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be distributed to the receptors where they tional nephrons. In renal failure, the functional fusible. Diffusivity decreases as drug molecular
act, and to the organs of elimination where nephron mass decreases, causing a decrease weight increases. Drugs with MW more than
they are eliminated, leading to decreased to- in glomerular filtration. For example, ampicil- 1.000 Dalton (very few drugs) have negligible
tal plasma concentration. Edema or ascites in lin, aminoglycosides, and digoxin are excreted diffusive clearance, while small solutes have
renal failure causes increased volume of distri- mainly by glomerular filtration. Ampicillin has flow-dependent clearance, and larger mol-
bution of water soluble drugs, while volume a large margin of safety, and decreased glom- ecules have decreased diffusion rate. Charged
contraction decreases volume of distribution erular filtration is compensated by increased drugs are less dialyzable because of charged
of aminoglycosides and increases its plasma biliary excretion, therefore a decrease in dos- repulsion at the membrane surface and drug
concentration. Digoxin is accumulated in age is required only when the GFR is less than binding to the membrane.
muscles, therefore muscle wasting in patients 20 mL per minute. On the other hand, amino-
with renal failure causes a decrease in its vol- glycosides and digoxin have low therapeutic Supplemental dose after HD is required if sig-
ume of distribution and an increase in its plas- ratios, and therefore their dosage should be nificant drug removal occurs during HD. Drugs
ma concentration. decreased in all degrees of renal failure. Dys- with MW less than 500 Dalton, that are water
function of tubular secretion will cause a de- soluble and unchanged, having minimal pro-
Metabolism crease in excretion of drugs actively secreted tein binding and volume of distribution less
For drugs that are metabolized completely by by proximal renal tubule. Organic acids, such than 1 L/kg, undergo significant removal.
the liver to inactive metabolites, no dosage as conjugates and free fatty acids, accumulate
adjustment is required in patients with renal in renal failure. They will inhibit secretion of HD clearance is clinically significant if it in-
failure. Phase II metabolism or conjugation other organic acids that are also secreted by creases total body clearance by 30 to 50%.
reactions are normal in renal failure. Among proximal renal tubule because of competition Since dose is plasma concentration times vol-
phase I reactions, the microsomal oxidation is for the same efflux transporter, P-glycoprotein. ume of distribution (Vd), then
normal or accelerated (due to accumulation For example, the renal secretion of penicillins, Supplemental dose
of inducers). Meanwhile, reduction (e.g. corti- cephalosporins, sulfonamides, nitrofurantoin, = (desired concentration concentration postHD) x Vd
sol), peptide hydrolysis (e.g. insulin, glucagon thiazides and furosemide is inhibited. The
and PTH), and ester hydrolysis (e.g. diflunisal competition of organic bases is usually not Peritoneal dialysis (PD) is very inefficient in
and procaine), are slowed due to decreased clinically important. removing drugs, e.g. 1 HD treatment can re-
nonhepatic (especially renal) metabolism. move 2/3 of body stores of aminoglycosides,
Passive tubular reabsorption is only for nonionic while 24-hour CAPD (continuous ambulatory
Excretion lipid soluble drugs. It is affected by urinary flow peritoneal dialysis) removes only 25 30% of
Renal excretion consists of glomerular filtra- rate and urinary pH. In renal failure, the urinary the drug.
tion, active tubular secretion, and active and flow decreases, but the tubular concentrations
passive tubular reabsorption. Examples of of drugs also decrease, and hence the passive Table 2 Drugs requiring supplemental doses after each HD
drugs mainly eliminated by renal excretion can tubular reabsorption is not affected. session
be seen in Table 1. These drugs are excreted Aminoglycosides
by the kidneys in unchanged form, and hence Accumulation of toxic metabolites in renal failure Cephalosporins (most)
they will accumulate in renal failure, causing leads to increased adverse drug reactions, e.g. Penicillins (most)
increased intensity of their pharmacological accumulation of toxic metabolite of meperidine Sulfonamides, TMP
effects and toxicity; therefore their dosage causes seizures, that of nitrofurantion causes Ofloxacin, Ciprofloxacin
should be reduced in renal failure. peripheral neuropathy, while that of morphine Metronidazole
causes excess respiratory depression. Flucytosine
Table 1 Drugs mainly eliminated by renal excretion Ethambutol, INH
Nitrofurantoin End-stage renal disease (ESRD) means glom- Pyrazinamide
Penicillins erular filtration is diminished to almost none. In Aciclovir, Ganciclovir
Cephalosporins this situation, tubular secretion of acidic drugs is Zidovudine, Didanosine
Aminoglicosides much decreased due to competition with high
Diuretics accumulation of organic acids, and therefore di- Dosage Adjustment in Renal Failure
Tetracyclines (Avoid !) alysis is required. Drugs excreted by glomerular Drug elimination by the kidney is assumed to
Sulfonamides filtration, are water soluble and hence at least be directly proportional to GFR (glomerular
ACE inhibitors partially dialyzable, while drugs excreted by tu- filtration rate); and ClCr (creatinine clearance) is
Digoxin bular secretion are or are not dialyzable. traditionally used to approximate GFR. Cock-
Ethambutol roft & Gault formula calculates ClCr from CCr
Atenolol HEMODIALYSIS (HD) (creatinine plasma concentration).
Disopyramide Since dialysate is aqueous, only water soluble
drugs are dialyzable. HD procedure is mostly For men: ClCr (mL/min) =
Only unbound drugs with molecular weight based on diffusion of solutes through mem-
less than 60.000 Dalton are filtered by func- brane pores, and only unbound drugs are dif- For women: 0.85 x ClCr for men

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For acute renal failure, ClCr <10 mL/min should cause some creatinine is secreted via the renal 6. hypermagnesemia, in case the patient
be assumed for drug dosage adjustment. tubule. consumes high dose of Mg-containing ant-
acids, causing somnolence, coma, cardiac ar-
Loading dose (DL) Example of maintenance dose adjustment: rhythmias, or death.
DL is given to achieve therapeutic concentra- Drug A has f =1, meaning that all of the drug
tion directly are excreted unchanged via the kidney (ClR = Other Pharmacologic Problems in Renal
DL = Desired therapeutic conc. (peak) x Vd ClT ). Failure
(mg/kg) (mg/L) (L/kg) 1. Urinary tract infections
Renal failure with GFR = 33 mL/min, normal These require adequate antibiotic concentra-
No adjustment are needed for DL in renal fail- GFR = 100 mL/min. tion in renal parenchyma and urine. Aminogly-
ure, except for digoxin, 50 75% of the usual cosides enter urine only by glomerular filtra-
DL and aminoglycosides, 75 80% of the usual Normal dosage = 7 mg/kg once daily in 60 kg tion, hence they are not effective. Conversely,
DL , because of decreased Vd and narrow mar- patient. penicillins, cephalosporins, sulfonamides and
gin of safety. trimethoprim enter urine by tubular secretion,
G = 1 1 (1 33/100) = 1/3 therefore they are effective. Normal doses of
Maintenance dose (DM) DM in renal failure: these antibiotics are required to produce ad-
Dosage adjustment is required for DM in renal 7 x 60 mg = 420 mg every 1/G = 3 days or equate urine levels.
failure. There are 2 methods for this purpose. 420 mg x G = 420 mg x 1/3 = 140 mg once daily or
The first method is interval extension (I) with 2/3 x 420 mg = 280 mg every 2 x 1 day = 2 days 2. Renal cyst infection
normal DM. This method may produce odd It requires antibiotics that can penetrate cyst
interval and hence causing increased dosing Among these 3 dosages, choose the most walls. Cotrimoxazole, chloramphenicol, fluoro-
errors and decreased compliance. This method convenient one. quinolones can penetrate cyst walls, therefore
is not for drugs with narrow margin of safety they are effective. Penicillins, cephalosporins,
because of large plasma level fluctuation, but Pharmacodynamics in Renal Failure aminoglycosides have poor penetration,
it is encouraged for drugs with concentration- In renal failure, many changes in homeostatic hence they are not effective.
dependent killing (e.g. aminoglycosides). The mechanism occur, resulting in changes in re-
second method is DM reduction (D) with nor- sponses to drugs. 3. Neuromuscular blockers
mal interval. This method is desired for drugs These accumulate in renal failure, producing
with narrow margin of safety (e.g. digitalis, These changes are among others: increased and prolonged effect, and are wors-
antiarrhythmias, tricyclic antidepressants, anti- 1. hyperkalemia, commonly occurs in renal ened by accumulation of aminoglycosides,
convulsants), and is not for drugs which stable failure, will increase myocardial irritability to which also causes neuromuscular block, re-
plasma concentrations are not desired (e.g. due catecholamines which may cause cardiac ar- sulting in respiratory depression.
to toxicity from aminoglycosides). A combina- rhythmias
tion of I and D methods can be used for con- 4. Creatinine is a base
venience, provided efficacy and safety are not 2. hypokalemia, may also occur due to low Therefore it is also actively secreted by renal
jeopardized. The following formula are used for potassium diet, diuretic use or some renal dis- tubule. Basic drugs (e.g. trimethoprim) will
calculation of maintenance dose adjustment: eases, will increase myocardial sensitivity to compete with it for tubular secretion, pro-
G = 1 f (1 GFRF/GFRN) digitalis toxicity ducing decreased creatinine clearance and
f = ClR/ClT increased creatinine serum.
where: 3. uremia will cause:
G = Giusti-Hayton correction factor increased CNS sensitivity to barbiturates 5. Metabolic loads
GFRF = GFR in renal failure and opiates; because uremia itself causes Acid load, e.g. by aspirin, NSAIDs; Alkali load,
GFRN = normal GFR somnolence, malaise, etc e.g. by antacids; Creatinine load, by anabolic
ClR = renal clearance of the drug dysfunction of thrombocytes; impairment and androgenic steroids; Mg load, by antac-
ClT = total clearance of the drug of coagulation will lead to increased sensitiv- ids, laxatives; K load, by K-penicillin, K-sparing
ity to anticoagulants and antiplatelets diuretics, ACE inhibitors; Na load, by ampicillin,
D =D G or 1F = 1N 1/G decreased tissue sensitivity to insulin, and piperacillin, ticarcillin; Ureum load, by gluco-
also peripheral neuropathy corticoids, tetracyclines (antianabolics), hy-
where: peralimentation, protein; H2O load, by NSAIDs,
D = DM in renal failure 4. less responsive to drugs acting directly to carbamazepine.
D = normal DM the kidney, e.g. diuretics, uricosuric
1F = dosing interval in renal failure Drug Use in Renal Failure
1N = normal dosing interval 5. more sensitive to nefrotoxic effects of 1. NSAIDs are nephrotoxic
analgesics, aminoglycosides, cephaloridin, Inhibition of renal prostaglandin by NSAIDs
For small GFR in ESRD (ClCr < 10 mL/min), use cephalothin, amphotericin B, lithium, sulfon- causes renal vasoconstriction, leading to
Clinulin (inulin clearance) or Cliohexol, not ClCr be- amides, tetracyclines, etc. acute renal failure. NSAIDs can also cause drug

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hypersensitivity, resulting in interstitial nephri- anion pump in the renal tubule. In azotemia, d. Antituberculosis drugs
tis. Long-term use of NSAIDs can cause renal organic acids compete for the active transport, Isoniazid, rifampicin and pyrazinamide are giv-
papillary necrosis. therefore the dosage should be increased by en in normal doses in RF. With isoniazid, pyri-
doubling doses every 30 to 60 minutes until doxine should be added to prevent peripheral
Avoid usage in high-risk patients, i.e. elderly or ceiling dose is reached or diuresis occurs. If neuropathy.
compromised renal blood flow and volume this is ineffective, thiazide should be added.
depletion with concomitant urinary tract in- If it is still ineffective, loop diuretics should be Streptomycin and ethambutol should be
fection. If use is necessary, especially for long- given as continuous i.v. infusion. avoided where possible. The major toxicity
term use, close monitoring of ClCr and regular of streptomycin is vestibular, therefore if re-
urinalysis are required. b. Thiazides are generally not effective when quired, a reduced dose should be given 2 or
ClCr is less than 25 mL/min. 3 times weekly for the first 2 months, and the
2. Analgesics plasma levels must be monitored.
Acetaminophen is a safe analgesic, but not c. Ototoxicity. Especially ethacrynic acid, but
always effective. Opiates are used for more se- also furosemide and bumetamide. Ethambutol causes optic neuritis if excessive
vere pain, but retention of active metabolites dosages are used or renal function is im-
causes prolonged analgesia and respiratory 5. Antimicrobial agents (AMs) paired. Therefore the dose should be reduced
depression. Except aminoglycosides and vancomycin, most and given intermittently. If any visual changes
AMs have a wide therapeutic index, hence little develop, the drug should be discontinued
Analgesic nephropathy can be avoided by us- or no dosage adjustment is normally made un- immediately and medical advice must be
ing a single analgesic, not a mixture of more til the GFR is less than 20 mL/min. sought.
than 1 analgesic, especially in combination
with caffeine or codeine. AMs that are removed by dialysis should be e. Amphotericin B
administered after dialysis or a supplemental This drug is nephrotoxic. The drug is used
3. Cardiovascular drugs dose should be given after dialysis. in renal failure only if these is no alternative,
a. Angiotensin converting enzyme (ACE) and plasma levels and renal function must be
inhibitors and angiotensin receptor block- a. Aminoglycosides (AGs) monitored closely. Since binding to lipopro-
ers (ARBs). Use in pre-existing renal disease The bactericidal efficacy correlates with thera- teins decreases in RF, low plasma levels should
due to atherosclerosis (compromised renal peutic peak concentrations, while toxicity cor- be interpreted accordingly.
perfusion), and also pre-existing peripheral, responds to rising trough levels. Therefore, the
cerebral, or coronary vascular diseases associ- dosage adjustment should follow especially f. Antiviral drugs
ated with renal dysfunction, which are usually the interval approach. Peak and trough serum Acyclovir and ganciclovir are eliminated by
reversible on drug withdrawal. Accumulation levels as well as ClCr should be measured to kidney, therefore the dose should be reduced
of these drugs in renal dysfunction requires monitor therapy and avoid toxicity. in RF, because accumulation leads to CNS tox-
dosage reduction. Renal function should be icity and unconsciousness.
checked 3 to 4 days after starting therapy to AGs aggravate pre-existing renal impairment,
ensure no decreased in GFR or increased in but also cause de novo acute renal failure. 6. Antianxiety drugs, Hypnotics and Antipsy-
serum potassium. Nephrotoxicity is usually reversible, but oto- chotics
toxicity may cause irreversible vestibular dam- Patients with advanced RF are particularly
b. Calcium channels blockers (CCBs) age. Concomitant use of loop diuretics, espe- sensitive to CNS depressant effect of these
These drugs are eliminated by hepatic metab- cially ethacrynic acid, greatly increases the risk drugs, therefore therapy should be started
olism, hence they are used in usual dosages of ototoxicity. with a smaller than normal dose.
in RF.
b. Vancomycin 7. Lithium and Antidepressants
c. Digoxin This drug is nephrotoxic and ototoxic; there- Lithium should be avoided if possible or de-
DL and DM should be reduced in RF, and plas- fore its plasma concentrations should be crease the dose with careful monitoring of
ma concentrations should be monitored. monitored. It is not dialyzed, hence after a plasma levels. Tricyclic antidepressants and
single i.v. infusion, therapeutic levels can be newer antidepressants can be prescribed in
d. -blockers maintained for 5 days in patients with end- normal dosages.
The dose of -blockers that is mainly elimi- stage RF on dialysis.
nated by kidney should be reduced. 8. Insulin
c. Tetracyclines In reduced renal function, insulin requirement
4. Diuretics These drugs greatly increase BUN in RF due is also reduced, because it is eliminated by the
a. Loop diuretics are required to avoid vol- to its antianabolic effects and worsen the re- kidney. In uremia, these is insulin resistance
ume overload. These drugs have extensive nal dysfunction. Therefore use of these drugs due to a post-receptor defect; this is corrected
protein binding, therefore are not much fil- should be avoided in RF, except doxycycline by dialysis. The compensatory response to hy-
tered via glomerulus, but secreted by organic and minocycline. poglycemia may also be impaired in uremia.

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9. Oral antidiabetics (OADs) hence the dose should be reduced in severe GI hemorrhage, rashes and renal impairment,
Since chlorpropamide has an extended half- RF. Proton pump inhibitors require no dosage hence the dose should be reduced in RF.
life of > 36 hours, its use in RF should be avoid- adjustment in RF.
ed. Glibenclamide also causes prolonged hy- NOTE
poglycemia in RF due to accumulation of an b. Antacids Calculation of drug dosage in RF is based on
active metabolite which binds tightly to pan- Antacids containing Mg and Al (including various assumptions, i.e. no change and no
creatic -cells. sucralfate) should be avoided in severe RF or interindividual variation in drug absorption,
dialysis patients because of increased risk of distribution, and metabolism; no active/toxic
Metformin is contraindicated in RF because toxicity. metabolites; drug elimination independent
the risk of lactic acidosis. of dose (linear pharmacokinetics); no change
11. Antigout drugs and no interindividual variation in pharma-
Glipizide is the OAD of choice in RF because of Allopurinol is metabolized to oxypurinol. Its cological response; stable renal function;
its short duration of action and its elimination accumulation in renal failure causes rashes (in and renal clearance of drug is proportional
by hepatic metabolism to inactive metabo- severe case, it can cause potentially fatal toxic to ClCr. Therefore dosage adjustment based
lites. epidermolysis), bone marrow depression and on calculation is only for initial estimation. It
GI upset; therefore the daily dose should be should be followed by further adjustments
10. Gastrointestinal drugs reduced in RF. based on the plasma drug level (if available),
a. Antiulcers and the most important on patients clinical
Ranitidine is eliminated by liver and kidney, Colchicine in excessive doses causes diarrhea, response.

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