Alimentary Pharmacology and Therapeutics
Review article: prescribing medications in patients with
cirrhosis a practical guide
J. H. Lewis & J. G. Stine
Division of Gastroenterology and
Hepatology, Department of Medicine,
Georgetown University Medical
Center, Washington, DC, USA.
Correspondence to:
Dr J. H. Lewis, Division of
Gastroenterology and Hepatology,
Department of Medicine, Georgetown
University Medical Center,
Washington, DC 20007, USA.
E-mail: lewisjh@gunet.georgetown.edu
Publication data
Submitted 6 November 2012
First decision 30 November 2012
Resubmitted 4 April 2013
Accepted 8 April 2013
EV Pub Online 3 May 2013
This uncommissioned review article was
subject to full peer-review.
1132
SUMMARY
Background
Most drugs have not been well studied in cirrhosis; recommendations on
safe use are based largely on experience and/or expert opinion, with dosing
recommendations often based on pharmacokinetic (PK) changes.
Aim
To provide a practical approach to prescribing medications for cirrhotic
patients.
Methods
An indexed MEDLINE search was conducted using keywords cirrhosis,
drug-induced liver injury, pharmacodynamics (PDs), PKs, drug disposition
and adverse drug reactions. Unpublished information from the Food and
Drug Administration and industry was also reviewed.
Results
Most medications have not been adequately studied in cirrhosis, and spe-
cic prescribing information is often lacking. Lower doses are generally rec-
ommended based on PK changes, but data are limited in terms of
correlating PD effects with the degree of liver impairment. Very few drugs
have been documented to have their hepatotoxicity potential enhanced by
cirrhosis; most of these involve antituberculosis or antiretroviral agents used
for HIV or viral hepatitis. Paracetamol can be used safely when prescribed
in relatively small doses (23 g or less/day) for short durations, and is rec-
ommended as rst-line treatment of pain. In contrast, NSAIDs should be
used cautiously (or not at all) in advanced cirrhosis. Proton pump inhibi-
tors have been linked to an increased risk of spontaneous bacterial peritoni-
tis (SBP) in cirrhosis and should be used with care.
Conclusions
Most drugs can be used safely in cirrhosis, including those that are potentially
hepatotoxic, but lower doses or reduced dosing frequency is often recom-
mended, due to altered PKs. Drugs that can precipitate renal failure, gastroin-
testinal bleeding, SBP and encephalopathy should be identied and avoided.
Aliment Pharmacol Ther 2013; 37: 11321156
2013 John Wiley & Sons Ltd
doi:10.1111/apt.12324
 Review: prescribing medications in patients with cirrhosis
BACKGROUND
The use of medications in patients with cirrhosis fre-
quently raises several concerns, especially for gastroente-
rologists and hepatologists who are often asked for their
opinion regarding the safety of drugs in this setting.13
The chance that acute drug-induced liver injury (DILI)
might develop and worsen the underlying liver disease is
one of the most common fears of prescribing prescrip-
tion as well as over-the-counter (OTC) agents.4 How-
ever, the risks of precipitating or worsening renal failure,
inducing gastrointestinal (GI) bleeding, and provoking
hepatic encephalopathy (HE) are, in fact, more likely
scenarios in the cirrhotic patient. The changes that may
occur in drug disposition, metabolism, excretion and
elimination as a result of cirrhosis, the presence of asci-
tes or the inuence of transjugular intrahepatic portosys-
temic shunts (TIPS) or other factors on hepatic blood
ow, present unique challenges in determining how best
to prescribe the multitude of agents that are used to treat
both hepatic and nonhepatic-related disorders in this
population, as will be discussed.
Frequently encountered situations where drugs are
used to manage the various complications of cirrhosis
include the use of diuretics, beta blockers, medications
for the treatment of insomnia and sleep reversal, alcohol
withdrawal, acute and chronic pain relief, and the use of
sedatives and anaesthetics for endoscopic and surgical
procedures, in addition to the routine use of medications
to treat a variety of other comorbid medical conditions,
including short- and long-term use of acid-suppressive
medications, and various antimicrobial agents. Herbal
and other complementary and alternative medications
are commonly used by patients with chronic liver disease
(CLD), including those with advanced cirrhosis, and may
be associated with unanticipated adverse effects.
Among the many drugs that may be used in cirrhosis,
there are a number of potentially hepatotoxic medica-
tions that are often of particular concern in patients with
end-stage liver disease.3 Chief among them are paraceta-
mol (acetaminophen) and other OTC pain relievers.46
Years ago, Zimmerman, the father of modern day drug-
induced hepatotoxicity, opined that most patients with
pre-existing liver disease were not more likely than oth-
ers to experience hepatic injury on exposure to drugs
that can cause idiosyncratic liver damage.1 However, he
reminded us that despite the lack of data suggesting that
most hepatotoxic drugs were harmful in the setting of
CLD, should a DILI reaction occur, the consequences
could be more dire in patients with impaired hepatic
function.1 A similar view was also voiced by Andreasen
Aliment Pharmacol Ther 2013; 37: 1132-1156
2013 John Wiley & Sons Ltd
who noted that while nonpredictable hepatotoxic reac-
tions did not appear to occur more frequently in patients
with liver disease than in others, hepatotoxicity could
still be masked by the underlying liver disease or the
effects of alcohol.2
As a result, many clinicians and patients avoid the use
of drugs, such as paracetamol for headaches or other
pain relief,4 as well as the use of statins for treating
hypercholesterolaemia in patients with cirrhosis, and
oftentimes in patients with lesser degrees of hepatic
impairment.7 The reality, however, is that the number of
agents actually reported to increase the risk of hepato-
toxicity in CLD remains relatively small3 (Table 1).
In particular, the use of antituberculosis drugs (ATDs)
and highly active antiretroviral therapies (HAARTs) in
patients with chronic viral hepatitis are among the most
commonly cited as having an increased risk of acute
DILI.8, 9 There are rare instances and case reports of
other agents causing injury in this setting, but in general,
most drugs can be and are used safely.3 In contrast, sev-
eral clinical examples exist where the treatment of an
underlying liver disease is safely conducted with drugs
that have the potential for hepatic injury. This includes
methotrexate in patients with primary biliary cirrhosis,10
the use of the glitazones in the management of non-alco-
holic steatohepatitis11 and statins, which are being
increasingly used in a number of CLD settings with ben-
ecial effects,12 among more recent examples. While
increased vigilance on the part of prescribers should be
conducted whenever drugs are used in CLD, the risk of
decompensation or hospitalisation among cirrhotics tak-
ing over-the-counter analgesics (OTCAs) was not shown
to be increased in two recent studies.13, 14
In this review, we summarise the potential risks asso-
ciated with the use of various medications and drug
classes used in cirrhosis based on potential changes in
drug metabolism and disposition. In addition, the rec-
Table 1 | Drugs reported (or predicted) to have an
increased risk of hepatotoxicity in patients with liver
disease with adequate evidence6, 8, 10, 13
Antituberculosis drugs (e.g. isoniazid, pyrazinamide, rifampicin)
HAART (e.g. nevirapine)
Methimazole
Methotrexate
Nefazodone
Propoxyphene
Valproate
Vitamin A
HAART, highly active antiretroviral therapy.
1133
J. H. Lewis and J. G. Stine

ommendations for the safe use of some of the most

Table 2 | Potential changes in drug handling in
commonly prescribed agents, as made by several authors
cirrhosis15, 2026
and research groups, will be offered. Although metabolic
changes have been studied for many drugs in patients Pathophysiological factor Clinical consequence
with cirrhosis going back several decades,1 the recom- Reduced hepatic blood Higher bioavailability/serum levels
mendations for safe use in this setting in early reviews ow/lower rst-pass
mainly involved dose reduction15 along with monitoring extraction and portosy
stemic shunting
of plasma concentrations16 and liver function testing.17
Hypoalbuminaemia Less protein binding (increased
Not until more recently, however, have formal guidelines serum concentrations)
for the evaluation of pharmacokinetics (PKs) and dosing Ascites/oedema Increased volume of distribution
adjustments in patients with hepatic impairment been for hydrophilic drugs
proposed by both the Food and Drug Administration Portal gastropathy Altered (increased or decreased)
drug absorption
(FDA)18 as well as the European Medicines Agency Loss of CYP metabolic Reduced rst-pass metabolism/
(EMEA).19 Their recommendations are based largely on activity clearance
the Child-Pugh classication to categorise the degree of Reduced glutathione Increased toxicity
liver dysfunction in cirrhosis. In the case of the FDA stores
Impaired biliary Increased serum concentrations
guidance, hepatic impairment PK studies are recom- excretion
mended if hepatic metabolism and/or drug excretion Impaired renal Increased serum concentrations
accounts for 20% or more of the absorbed drug, or if the excretion
drug has a narrow therapeutic range.18 PD endpoint
CYP, cytochrome P450 enzymes.
assessments should also be completed in such cases; the
type and nature of which need to be selected and dis-
cussed with FDA staff. Dose reductions are usually
required if there is a twofold or greater increase in area Table 3 | Effects of cirrhosis on therapeutic drug
under the curve (AUC) in hepatic impairment studies. response20, 21, 25
The EMEA makes similar recommendations in their Enhanced pharmacodynamic effects
guidance document,19 although relatively few agents have Precipitate Opioid analgesics, anxiolytics, sedatives
encephalopathy
been studied adequately in patients with advanced
Precipitate renal NSAIDs
decompensated cirrhosis (e.g. Child-Pugh class C). As a failure
result, expert opinion based on anticipated pharmacolog- Worsen or NSAIDs
ical changes often remains the mainstay of current clini- precipitate GI
cal recommendations. bleeding
Decreased therapeutic response seen with
Beta adrenoreceptor antagonists
RESULTS Diuretics (furosemide, triamterene,
bumetamie)
Effects of cirrhosis on drug metabolism Codeine
PK and pharmacodynamic changes. As summarised by NSAIDs, nonsteroidal anti-inammatory drugs.
Delco et al.,20 Verbeeck21 and others who have studied
the disposition of drugs in CLD,15, 2226 a number of sig-
nicant PK changes are known to occur in patients with Hypoalbuminaemia. Hypoalbuminaemia must also be
cirrhosis that often require dose adjustments to use those taken into consideration, in particular for drugs that
medications safely (Table 2). have a high binding prole, dened as a drug that exists
As a result of modied PKs due to reduced drug in circulation in bound form >90% of the time. Hypoal-
clearance, upregulation of drug receptors and changes buminaemia can result in important variations in the
in receptor sensitivity, a number of agents may pro- amount of drug circulating in an unbound form, which
duce adverse clinical effects due to higher plasma drug would be responsible for drug efcacy and potential toxi-
concentrations in cirrhotic patients and should be used city.20, 21, 24, 27 Reduced protein binding seen with hypo-
with caution21 (Table 3). These and other specic albuminaemia leads to an increased volume of
factors affecting drug disposition will be discussed distribution (Vd).27 It follows that the larger the fraction
below. of unbound drug, the larger the Vd, implying that the

1134 Aliment Pharmacol Ther 2013; 37: 1132-1156

2013 John Wiley & Sons Ltd
 Review: prescribing medications in patients with cirrhosis

patients with cirrhosis (with or without renal impair-

Table 4 | Child-PughTurcotte classication
ment) have been the general rule dating back more than
Assessment Degree of abnormality Score three decades.1517, 2024
Encephalopathy None 1
Moderate 2 Drug disposition in patients with ascites. Cirrhosis can
Severe 3 have effects on drug absorption, distribution,
Ascites Absent 1 bioavailability, cytochrome P450 (CYP) metabolism and
Slight 2
Moderate 3
hepatic and renal clearance mechanisms, resulting in
Bilirubin (mg/dL) <2 1 pharmacodynamic (PD) consequences.224, 26 Drug
2.13 2 absorption of orally administered agents may be altered
>3 3 by impaired or increased permeability in the presence of
Albumin (g/dL) >3.5 1
mucosal inammation and oedema seen in portal hyper-
2.83.5 2
<2.8 3 tensive gastropathy, or by delays in gastric emptying.20
Prothrombin time 03.9 1 The presence of ascites and oedema can affect the Vd
(s > control) and as a result, both bioavailability and elimination
4.06.0 2 half-life may be affected.21, 32 The use of serial large vol-
>6.0 3
Total score group severity 56 A Mild = MELD 110 ume paracenteses should also be kept in mind when
79 B Moderate = MELD 1120 considering dose adjustment of drugs based on ascites
1015 C Severe = MELD >20 and Vd.32
There is a rather limited body of information on drug
chronic changes seen with cirrhosis will lead to increased disposition in ascites. Antineoplastic agents that accumu-
Vd for hydrophilic drugs.27 This is of particular concern late in ascites (e.g. doxorubicin) have been shown to be
when prescribing drugs that are only found in the extra- cleared much more slowly and have a prolonged half-
cellular compartment (e.g. antimicrobial agents, includ- life.33 On the other hand, gemcitabine is not distributed
ing Beta-lactams, certain aminoglycosides and both in ascitic uid and its PKs appear unchanged in the
glycol- and lipopeptides).27 It is unclear if compensatory presence of ascites.34
mechanisms can fully counteract the increased levels of Other drugs also remain unaffected by ascites and a
the drug (i.e. theoretically the higher drug concentration larger Vd, despite being active predominantly in the
could be rapidly distributed and eliminated to obtain a extracellular compartment. The half-life of amikacin is
new equilibrium). Acidic drugs (Table 4) have an afnity similar in both cirrhotic and noncirrhotic patients with
for albumin and are more likely to be affected by hypo- normal renal function, despite the presence of ascites.35
albuminaemia.27, 28 Temperature and pH are also known Importantly, multiple reports suggest that the effects of
to affect protein binding in vitro, although the clinical ascites on tacrolimus disposition is negligible21, 21; only
effects of these variables remain undetermined27 for most 0.010.09% of the dose administered is found in
drugs. ascites.36
As most drugs that cause hepatotoxicity do so unpre- Diuretic therapy is commonly used to treat decompen-
dictably via idiosyncratic mechanisms, higher blood lev- sated cirrhotics with ascites. Furosemide and torasemide
els are not expected to increase the risk of DILI for most are two such loop diuretics, both of which have altered
agents.3 It is of interest, however, that even so-called idi- PK and PD proles in cirrhosis.37 When given intrave-
osyncratic agents may have a dose relationship.29 nously, both drugs had a reduced elimination rate
Indeed, Lammert et al. found that drugs given in a daily through both renal and nonrenal routes37 in addition to
dose of 50 mg or greater were more likely to be hepato- having a Vd and t1/2 twice normal at steady state 38 and
toxic than those given in daily doses of 10 mg or less.30 when compared with healthy subjects.37 More impor-
Similarly, those agents undergoing extensive (>50%) tantly, the natriuretic potency of both furosemide and
hepatic metabolism were more likely to be hepatotoxic torasemide is markedly reduced in the cirrhotic.37 A poor
compared with agents undergoing lesser degrees of hepa- response to natriuresis appears to be related to altered
tic metabolism.31 Extrapolating these ndings to patients furosemide kinetics due to decreased delivery of drug to
with CLD, the changes in metabolism and drug clearance the renal site of action.38 The concurrent administration
that occur in cirrhosis could theoretically affect a drugs of midodrine to enhance the loss in natriuretic response
risk of causing DILI; as a result, dose reductions in had no measurable clinical effect in one study.39

Aliment Pharmacol Ther 2013; 37: 1132-1156 1135

2013 John Wiley & Sons Ltd
J. H. Lewis and J. G. Stine

In contrast to loop diuretics, data from Dao and Ville-

Table 5 | CYP3A4 substrates, inducers and inhibitors53
neuve suggest that for triamterene, a potassium-sparing
diuretic, despite having markedly elevated plasma levels Substrates Inducers Inhibitors
in cirrhotics with ascites as compared with healthy vol- Carbamazepine Carbamazepine Allopurinol
unteers, there was no difference in the magnitude of its Ehtosuximide Corticosteroids Amiodarone
diuretic response.40 Phenobarbital Efavirenz Atazanavir
Phenytoin Modanil Chloramphenicol
Nevirapine Cimetidine
Effects of cirrhosis on P-glycoprotein and membrane Omperazole Clarithromycin
transporters. P-glycoprotein (P-gp) is a transmembrane Oxcarbazepine Ciclosporin
transporter encoded by the ABCB1 multidrug resistance Phenytoin Daronivir
gene (MDR1) found on the apical surface of epithelial Rifabutin Delviradine
Riampin Diltiazem
cells of several tissues, including the small intestine, bile
St Johns Wort Erythryomycin
canaliculi and renal tubular cells as well as the luminal Fluconazole
surface of endothelial cells of capillaries in the brain and Flucoxetine
testes. It has many functions, including the absorption Grapefruit juice
and excretion of multiple drugs, and when its activity is Imatinib
Indinavir
altered due to induction or inhibition, there are wide- Isoniazid
ranging PK and PD effects that have been seen, as well Itraconazole
as drugdrug interactions (DDIs).4147 Statins and angio- Ketocoazole
tensin-II receptor blockers (ARBs) have been among the Nelnivir
Nifedipine
most widely studied agents in this regard,43, 4851 Quonolones
although studies on P-gp specically performed in cir- Ritonavir
rhotic patients are lacking to our knowledge. Neverthe- Tamoxifen
less, it might be assumed that this transporter would be Valproic acid
Verapamil
impaired in cirrhosis in concert with reduced activity of
CYP3A4,42 or in patients with extrahepatic cholestasis,47
leading to changes in drug disposition. Strong inhibitors none-imine metabolite (NAPQI) by a number of CYP
of CYP3A and P-gp have the potential to increase the P450 enzymes, including 3A4, 2E1 and 2D6, and which
concentration of certainly concomitantly administered serves as the basis for recommendations to avoid its use
drugs, such as statins (as seen with certain protease in cirrhosis,4 Benson et al. point out that not only is CYP-
inhibitors used to treat chronic hepatitis C,52 and should 450 activity not increased in severe liver disease patients,
be used cautiously, if at all, to avoid potentially serious but several studies have demonstrated that CYP-450 con-
DDIs, particularly in cirrhosis tent is either unchanged or is reduced,56 therefore, poten-
Table 5 provides a complete list of relevant CYP3A4 tially leading to a lesser degree of NAPQI formation.4
drug substrates, inducers and inhibitors.53 Similarly, the concentration of hepatic glutathione has
important consequences for preventing hepatocellular
Dose adjustments in cirrhosis injury to agents such as paracetamol, and concern has
Decreased renal elimination in cirrhosis has been been raised that glutathione depletion in cirrhosis could
reported for uconazole, ooxacin and lithium, among place patients at an increased risk of injury, especially
others, and dose adjustments are warranted.20, 21, 24 Sim- with concomitant chronic alcohol ingestion.57, 58 How-
ilarly, the anti-viral agents used to treat or as prophylaxis ever, not all studies have demonstrated decreased gluta-
in chronic HBV (entecavir, tenofovir, etc.), are given in thione concentrations in this setting. Moreover, Benson
reduced dosage (as decreased frequency) for patients et al. note that signicant reductions on the order of
with impaired renal function.54 30% or greater would be needed before covalent binding
The issue of whether CYP enzymes are altered in con- of NAPQI or other toxins to hepatocytes would occur.
centration or impaired in function in cirrhosis is impor- As a result, they opine that concerns about having to
tant in terms of phase 1 metabolism of many drugs, avoid therapeutic doses of paracetamol in the setting of
especially acetaminophen and various opioid cirrhosis are often misplaced.4
analgesics.4, 25, 55 With respect to acetaminophen (parac- Drugs with a normally high rate of rst-pass extrac-
etamol), which is metabolised to its reactive benzoqui- tion by the liver will typically have lower bioavailability.

1136 Aliment Pharmacol Ther 2013; 37: 1132-1156

2013 John Wiley & Sons Ltd
 Review: prescribing medications in patients with cirrhosis
However, as a result of decreased hepatic blood ow,
and the presence of portosystemic shunts in cirrhosis,
such drugs have increased bioavailability and serum con-
centrations, and often require dose reductions [e.g. beta
adrenergic blockers, calcium channel antagonists, cisa-
pride and other prokinetic agents, antipyschotics, anti-
anxiety and sedative agents, antiparkinson drugs,
antidepressants, sumatriptan, certain statins (uvastatin,
lovastatin), morphine].21
For intravenously administered agents, it is suggested
that a normal initial dose can be given, but subsequent
doses should be reduced according to hepatic clear-
ance.21 However, caution must be exercised with bolus
parenteral administration as the initial unbound drug
concentrations can be disproportionately high in the set-
ting of hypoalbuminaemia for highly protein-bound
drugs as it takes time for plasma binding proteins to
exert their effect and re-establish a state of equilibrium.27
Delco et al. proposed using Doppler ow measurements
of portal and hepatic vessels or measuring serum bile
acid levels to help gauge the extent of portosystemic
shunting and the degree of dose reduction although
this remains only a rough estimation.20
For drugs that undergo low rst-pass hepatic extrac-
tion (<30%), bioavailability is generally not affected in
cirrhosis, but clearance may be reduced in the setting of
hypoalbuminaemia for those agents undergoing high
protein binding, and dose reductions may be needed.21
For drugs undergoing intermediate rst-pass extraction
[e.g. codeine, amiodarone, ciprooxacin, erythromycin,
itraconazole, atorvastatin, pravastatin, simvastatin, tricy-
clic antidepressants (TCAs), omeprazole], the inuence
of portosystemic shunting in cirrhosis is less than that
seen with high extraction agents. As a result, treatment
can be initiated with a low normal dose, but mainte-
nance dosing should be adjusted downwards.20, 21
For antimicrobial agents affected by a larger Vd due
to changes in protein binding and ascites, larger initial
doses are suggested in the rst 2448 h, especially in the
critically ill patient.27 Ertapenem and daptomycin are
examples of antibiotics where higher initial dosing may
be needed.27 After the initial phase, dosing should be
guided by antibiotic clearance, with close attention paid
to changes in the GFR of cirrhotic patients.27
Potential DDIs in cirrhosis
Franz et al. 59 recently examined the potential DDIs and
adverse effects from polypharmacy in hospitalised
patients with advanced liver disease in Switzerland. They
retrospectively studied 400 patients with cirrhosis (more
Aliment Pharmacol Ther 2013; 37: 1132-1156
2013 John Wiley & Sons Ltd
than two-thirds of whom were alcoholic), each with a
mean of six comorbid conditions. They were taking a
median number of ve medications (range 018), of
which a median of 3 (range 016) were hepatically elimi-
nated. Among their results, 28% of these patients had
one or more adverse drug reactions (ADRs); most of
which involved diuretics or NSAIDs, and 21.5% had one
or more DDIs, some of which caused severe reactions
and/or the need for hospitalisation. The most common
ADRs due to DDIs were hyperkalaemia (18.2%), hypo-
glycaemia (17.4%), an increased bleeding risk (12.9%),
respiratory depression (7.6%), increased risk of nephro-
toxicity (6.8%) and increased risk of cardiac toxicity
(6.8%). Nearly 13% of all potential DDIs resulted in an
ADR, and most ADRs occurred in patients with the
most advanced cirrhosis (Child-Pugh C), often with
renal impairment. Eight per cent of all ADRs directly
resulted in hospitalisation. The most commonly respon-
sible drugs were spironolactone, torasemide, furosemide
and ibuprofen. Examples of the most common DDIs
included potassium-sparing diuretics with ACE inhibi-
tors; beta blockers with insulin; benzodiazepines (BZDs)
with opiates and potassium-sparing diuretics with NSA-
IDs. Their study is a cautionary tale that emphasises the
complexities that commonly affect pharmacotherapy and
drug handling in the cirrhotic population as previously
noted by others.23, 24 For convenience, Table 10 is pro-
vided to show the conversion between Child-Pugh classi-
cation and MELD.
Effects of TIPS and other portosystemic shunts on
drug metabolism and QTc prolongation
Transjugular intrahepatic portosystemic shunts and other
surgical shunts (e.g. Denver shunt) are performed to man-
age complications from portal hypertension. Patients who
have undergone TIPS appear to have changes in drug
metabolism. As shown by Chalasani et al.,60 there was a
loss in rst-pass metabolism of midazolam due to reduced
intestinal CYP3A concentrations, which is typically respon-
sible for up to 40% CYP3A activity, leading to increased
bioavailability of this medication. Similar ndings were
found with nifedipine and isradipine, emphasising the need
for possible dose adjustments in such patients.
Cirrhotic patients are frequently found to have base-
line QTc interval prolongation, likely reecting an
altered ventricular repolarization due to the portosystem-
ic shunting of splanchnic-derived cardioactive substances
into the systemic circulation.61 In their cohort study,
Trevisani et al. measured QTc intervals in 19 cirrhotic
patients at baseline, 13 months and 69 months after
1137
J. H. Lewis and J. G. Stine
TIPS and compared them to 10 noncirrhotic portal
hypertensive patients. The authors found statistically
similar baseline QTc intervals (453  8 ms vs.
465  6 ms); however, 13 months after TIPS, the QTc
interval increased to 484  7 ms (P = 0.042) and to
480  6 ms (P = 0.03) at 69 months, despite relative
preservation in liver synthetic function, plasma electro-
lytes and haemoglobin concentrations.61 Similarly, Vup-
palanchi et al.62 described a cohort of eight cirrhotic
patients with TIPS and six cirrhotics who had not
undergone TIPS and observed that baseline QTc inter-
vals were higher in both the TIPS (418 ms) and non-
TIPS cirrhotics (431 ms) as compared with nine healthy
controls. After a 7-day course of erythromycin (a known
QTc interval prolonging medicine metabolised by
CYP3A), cirrhotics with a TIPS developed a signicantly
greater prolongation in their QTc interval
(180  68 ms) compared with both the cirrhotics with-
out TIPS (31  10 ms) and with the healthy controls
(38  3 ms) (P = 0.03).62 These ndings should prompt
caution when prescribing any medications known to
prolong QTc in cirrhotic patients who have undergone a
TIPS procedure, especially those patients who are being
prescribed a uoroquinolone for SBP treatment or pro-
phylaxis to best prevent potentially fatal ventricular ar-
rhythmias.
Use of specic drug classes in cirrhosis
Many drugs are prescribed in cirrhosis for nonliver-
related comorbidities,59 although how often they are used
is less well studied. Lucena et al. from the Spanish Col-
laborative Study Group on Therapeutic Management in
liver diseases63 have described the prescribing patterns
along with the most commonly used medications. For
those common conditions requiring treatment among
568 cirrhotic patients from 25 hospitals, medications
were given most often for diabetes mellitus in 30%, vari-
ous infections in 24%, cardiovascular disorders in 20%
and for active alcoholism in 15%. Accordingly, the most
commonly prescribed medications were sulfonylureas
(such as gliblenclamide) for diabetes, uoroquinolones
and amoxicillin-clavulanate for infections, ACE and
angiotensin-II receptor inhibitors and calcium channel
blockers for hypertension, and lorazepam, chlormethiaz-
ole and tiapride (a dopamine receptor antagonist) for
alcohol withdrawal symptoms. Most drugs (other than
calcium channel blockers) were administered in a
reduced daily dose (about two-thirds of normal) to
reect the potential changes in drug disposition in these
patients, 82% of whom were Child-Pugh class B or C,
1138
with nearly half having ascites. In particular, NSAIDs,
antidepressants and anxiolytics were all prescribed less at
the time of discharge as compared with on admission,
reecting the treating physicians concern about these
classes in cirrhosis over the long term.
These authors noted some interesting prescribing pat-
terns in cirrhosis, namely that certain drugs, ACE inhibi-
tors and ARBs in particular, were frequently used despite
being not recommended for patients with cirrhosis and
ascites.64 They noted that amoxicillin-clavulanate was
commonly prescribed, despite being the leading cause of
antibiotic DILI in general, and with few data to guide its
use in cirrhosis. Paracetamol, which undergoes glucuron-
idation and is considered safe to use in cirrhosis, was
prescribed to 30% of patients, including those with alco-
holic liver disease, where the risk of DILI is potentially
increased. However, it was prescribed in an average dose
of not more than 3 g/day as needed.63
The following sections describe the disposition of sev-
eral classes of drugs in cirrhosis as found in the pub-
lished literature, supplemented, in some cases, by the
information describing PK changes seen in patients with
hepatic impairment as described in product labelling.
The list is not intended to be exhaustive and for specic
drugs not addressed in this or other reviews, the inter-
ested reader is encouraged to consult the individual pre-
scribing information contained in the Physicians Desk
Reference65 as well as the FDA website for possible label-
ling and other safety alerts.66
Anaesthetics and sedation for surgery and endos-
copy. The effects of anaesthetics and sedatives on the
recovery period and mental status of patients with cir-
rhosis after endoscopy and surgery is a common clinical
concern. The use of propofol for endoscopy has been rel-
atively well studied and is not thought to precipitate
HE.67, 68 Given it has a short half-life and rapid action,
it appears to be quite safe to use in cirrhosis. Indeed, it
is preferable to the use of BZDs, which may lead to pro-
longed somnolence, encephalopathy and recovery, espe-
cially in decompensated cirrhotics.67, 68 Indeed, the
group from Indianapolis found that propofol sedation,
even administered by registered nurses with adequate
patient monitoring, was well tolerated in patients with
cirrhosis undergoing upper endoscopy to screen for
oesophageal varices.69 They noted that patients were
more satised with the quality of the sedation, and had a
quicker return to baseline function compared with
patients receiving conscious sedation midazolam with
meperidine.69 While propofol is therefore preferred, care-
Aliment Pharmacol Ther 2013; 37: 1132-1156
2013 John Wiley & Sons Ltd
 Review: prescribing medications in patients with cirrhosis
ful attention should be paid to potential adverse reac-
tions, such as hypotension, tachycardia, hypoventilation
and QTc prolongation that can be associated with its
administration.6870
Surgery performed in a cirrhotic patient, especially
transplant procedures, has a unique set of challenges for
the surgical team, as well as the anaesthesiologist.
Among the choices for anaesthetics for liver transplant
patients and those undergoing TIPS, factors such as the
effects on hepatic blood ow gure prominently in the
decision-making process. In a study of 10 patients who
rst received propofol then desurane, and a group of
another 10 patients receiving desurane then propofol,
Meierhenrich et al.71 found that propofol anaesthesia
was associated with signicantly greater preservation of
hepatic blood ow compared with desurane.
In a study of 21 patients with hepatitis C, free and
hepatic venous wedge pressures measured using either
propofol or desurane were studied by Mandell et al.72
Desurane was found to reduce blood pressure differ-
ences between the portal and systemic circulations, lead-
ing to errors in the measurements and assessment of the
success of treatment for portal hypertension. Propofol
had less of an effect on the difference and may be pre-
ferred in this setting. Their ndings have important
implications for patients undergoing TIPS procedure,
especially where portal gradients need to be accurately
assessed. Desurane, however, is not metabolised by the
liver and would still be preferred to other volatile anaes-
thetic agents or halothane.70
Alonso Menarguez et al.73 found that there was no
higher incidence of acute renal failure using sevourane
among transplant recipients, although the drug is renally
excreted. They suggest that in liver transplant anaesthe-
sia, sevourane is as safe as propofol with respect to
renal and hepatic function.
With regard to living donors undergoing partial hepatec-
tomy, Ko et al. studied 64 adult donors and compared des-
urane with isourane anaesthesia.74 They found better
post-operative and renal function tests with isourane com-
pared with desurane at equivalent doses, suggesting that
isourane may in fact be safer in the donor population,
which has important implications for patient and graft sur-
vival in the recipients. At our own institution, the preferred
agent for liver transplant recipients is isourane as well.
Statins. There continues to be a controversy over the use
of HMG Co-A reductase inhibitors (statins) in patients
with CLD and cirrhosis, mostly due to a concern of caus-
ing acute-on-chronic liver injury.12 Although the US
Aliment Pharmacol Ther 2013; 37: 1132-1156
2013 John Wiley & Sons Ltd
FDA currently considers serious statin-related liver injury
to be a rare and unpredictable event,75 it nevertheless
remains an important consideration among physicians
and patients alike. The FDA has reviewed postmarketing
data, cases from US registries of DILI as well as ALF, and
other sources of information on statin-related hepatotox-
icity, and has concluded that the risk of serious liver
injury from all currently marketed statins is very low
(including a risk of less than or equal to just 2 per 1 mil-
lion patient-years in the Adverse Event Reporting System
database).75 However, the risk of adverse hepatic events
from statins receives renewed (but often undeserved)
emphasis with each new case series that appears in the
literature.12 Indeed, the proportion of patients, including
those with cirrhosis, who are not being prescribed statins
because of the potential for adverse hepatic events, but
who might otherwise benet from their cardioprotective
effects, is substantial.7
Several recent retrospective and two prospective trials
all suggest that patients with compensated liver disease
are not at signicantly increased risk of statin-induced
hepatotoxicity.12, 7678 In a large randomised, prospec-
tive, placebo-controlled trial with high-dose pravastatin
(which, in particular, does not undergo P450 metabo-
lism) in hypercholesterolaemic patients with compen-
sated liver disease due to mostly non-alcoholic
steatohepatitis or HCV, the cumulative risk of doubling
an elevated baseline ALT value over 36 weeks was in fact
lower in the pravastatin-treated group compared with
untreated controls (7.5% vs. 12.5%).76 In a post hoc anal-
ysis of the prospective, randomised GREACE trial, sta-
tins were found to be cardioprotective in 123 of those
patients with moderately abnormal liver tests (mostly
from non-alcoholic fatty liver disease).78 Cardiovascular
events occurred in just 10% of the subjects with abnor-
mal LFTs who received statins, compared to 30% of
those with abnormal liver tests not receiving a statin
(68% relative risk reduction). Moreover, de novo eleva-
tions in ALT values were seen infrequently in the study,
and those receiving atorvastatin had substantial
improvement in abnormal baseline LFTs compared with
those not treated with the statin.78
Thus, the use of statins appears safe in CLD12 and
may in fact have a benecial effect on fatty liver and
viral hepatitis.12, 76, 7884 Indeed, in both animal and
human models, statins signicantly lowered portal hyper-
tension pressure and did not cause any untoward hemo-
dynamic effects, thus improving hepatic perfusion.
Moreover, when combined with nonselective beta block-
ers, the effects of statins were additive.85, 86 The role of
1139
J. H. Lewis and J. G. Stine
statins in preventing angiogenesis and inducing apoptosis
has also been studied recently, perhaps presenting an
opportunity for reducing the development of hepatocel-
lular carcinoma.8791
While patients with normal liver tests without under-
lying liver disease no longer require routine liver test
monitoring with statins,12, 75 it is still considered pru-
dent to monitor ALT when statins are to be started in
the setting of advanced brosis or cirrhosis.12 Whether
one statin is safer than another in cirrhosis has not been
formally studied although pravastatin, in contrast to
the others, does not undergo metabolism by the CYP-
450 mixed function oxidase system,92 which may be
impaired in severe hepatic disease.
Regardless of their apparent safety, statins remain lar-
gely underprescribed in cirrhotic patients. Franz et al.
reported that fewer than 10% of their cohort of 400
patients were being treated with statin therapy,59 but of
those cirrhotics taking a statin, none suffered an ADR.
Herbal products in cirrhosis. The safe use of herbal
agents is an important area of concern among patients
with cirrhosis and other CLDs, especially given the fre-
quency of their use9395 and the potential risk of hepato-
toxicity described for many of these products9698
Studies by Seeff et al.99 in cirrhotic patients who were
enrolled into the HALT-C trial have provided updated
information on the frequency of use of herbal agents in
this population. A total of 60 herbal compounds were
reported as being used by the 1145 study participants, of
whom 23% were currently using them, 21% had taken
herbals in the past and 56% reported that they had never
used herbals. Silymarin (milk thistle) accounted for
nearly three-quarters of all herbal therapy usage (17% of
patients), despite no benecial effects being found on
ALT or HCV levels in the study. However, improve-
ments in fatigue, anorexia, nausea and general health
were found to be signicant among users compared with
non-users. No other herbal products accounted for more
than 3% of usage, including green tea, garlic, ginseng,
Echinacea, grape seed, melatonin, St Johns wort, saw
palmetto and kava kava. The study was not designed to
identify whether further hepatotoxicity developed in any
of the herbal therapy users, but relatively few individuals
took agents that have been implicated in DILI (e.g. kava
kava, valerian).96, 97 And it should be noted that despite
a case series suggesting that green tea may be hepato-
toxic,100 others have questioned the analysis,101, 102. The
adequacy of the causality assessment process has also
been called into question for other herbals, including
1140
kava and black cohosh.103, 104 Bunchorntavakul and Red-
dy98 remind us that herbal formulations are often poorly
dened in terms of individual constituents, and may
contain harmful contaminants, such as lead, mercury,
arsenic or other heavy metals105 that can further con-
found the issue.
In a further analysis of the HALT-C dataset, Freed-
man et al.106 found that silymarin was associated with
reduced progression from brosis and cirrhosis, although
viral outcomes were unaffected. Nevertheless, it appears
to be safe in cirrhosis. The herbal agent, glycyrrhizic
acid, which is used in the treatment of chronic HCV, is
best avoided in cirrhosis because of the risk of hyper-
mineralocorticoid effects producing sodium retention,
oedema, hypertension and potassium loss, which may
worsen the clinical course of patients who may be receiv-
ing diuretics.107 The traditional Chinese herbal medicine
Sho-saiko-to is a mixture of seven herbal preparations
that has long been used in the treatment of CLD for its
possible antibrotic effects108 and appears to protect
against the development of hepatocellular carcinoma in
cirrhotic patients, perhaps through a reduction in hepa-
tocyte necrosis via inhibiting the activation of stellate
cells.109 Unfortunately, use may be limited by an
increased risk of interstitial pneumonia and acute respi-
ratory failure, which can be compounded when given
concomitantly with pegylated interferon,109 and instances
of hepatotoxicity have been reported.110
Posadzki et al.111 reviewed the literature for potential
interactions that can occur between various herbal agents
and medications used for a multitude of disorders. While
most herbals were not found to be associated with clini-
cally serious consequences, they did note a number of
circumstances where interactions with herbals, such as St
Johns wort (Hypericum perforatum) and mistletoe (Vi-
scum album), resulted in transplant rejection, delayed
emergence from anaesthesia, renal and hepatic toxicity
and a number of cardiovascular insults. St Johns wort,
in particular, is a strong inhibitor of CYP3A4, and as
such is contraindicated in patients receiving a variety of
agents, including the new protease inhibitors for the
treatment of chronic hepatitis C.
Moderately severe interactions were found for several
other herbal agents, including ginko biloba, Ginseng,
kava (Piper methysticum), saw palmetto (Seronoa repens)
and green tea (Camellia sinensis). They also mention that
most of the interactions occurred when antiplatelet and
anticoagulant drugs are given concomitantly. Echinacea
has been described in multiple reports to have been con-
sumed in large quantities in liver transplant recipients
Aliment Pharmacol Ther 2013; 37: 1132-1156
2013 John Wiley & Sons Ltd
 Review: prescribing medications in patients with cirrhosis
who subsequently presented with episodes of acute rejec-
tion, and in a patient with primary biliary cirrhosis who
presented with worsening of her liver-associated enzymes
and jaundice.112 The question of hepatotoxicity when
Echinacea is combined with methotrexate was recently
raised; however, no specic mention is made as to
whether the cirrhotic patient is at similar or higher
risk.98 The role of Echinacea as an individual hepatotox-
in remains poorly established at this time. As most
reports of herbal-related toxicity and drug interactions
are of poor quality, it is difcult to draw rm conclu-
sions about such potential interactions.111 As a result,
the clinician (and patient) should always identify all
medications, including herbals, that are being taken in
the setting of cirrhosis.
Cardiovascular system drugs. Beta blockers: Both
reversible and fatal cases of DILI from labetalol have been
reported.113, 114 Labetalol is metabolised predominantly by
glucuronosyl transferase, and PK data in rats suggest that
in NASH, CYP P450 induction leads to increased hepatic
removal of labetalol and other cationic beta blockers (e.g.
propranolol, metoprolol and atenolol) leading to lower
hepatic content of the drug.115 However, once the liver is
cirrhotic, NASH-induced brosis and steatohepatitis lead
to decreased hepatocyte permeability and increased hepa-
tic sequestration of labetalol.115 On the other hand, oral
administration of labetalol in CLD leads to higher plasma
concentrations secondary to decreased rst-pass metabo-
lism.116 Bioavailability also correlates inversely with serum
albumin levels leading to clinical implications, including
greater falls in heart rate and supine blood pressure.116 As
all beta blockers undergo rst-pass metabolism, it can be
inferred that CLD may lead to increased plasma concen-
trations of this class of medications and dose reduction
should be considered. In general, labatolol should be used
only when there are no other alternative therapies avail-
able due to the risk of particularly severe hepatotoxicity,
and monitored frequently.70
Not surprisingly, cirrhotic patients appear to be more
widely prescribed beta blockers than most other classes
of drugs with roughly 40% of patients on this type of
medication.59 In their cohort, Franz et al. reported that
of the 146 patients taking beta blockers, 7 patients suf-
fered an ADR (with possible causality), one of which
was due to a DDI.59 Only one patient was hospitalised
as a result. However, in the series by Lucena et al. 63
only 7 of 568 patients were prescribed cardioselective
beta blockers. The authors did not discuss non cardiose-
lective beta blockers used for portal hypertension.
Aliment Pharmacol Ther 2013; 37: 1132-1156
2013 John Wiley & Sons Ltd
ACE inhibitors: Eriksson et al.117 found small, but signif-
icant reductions in arterial blood pressure after the
administration of captopril in patients with cirrhosis.
Aldosterone concentrations decreased, while renin activ-
ity increased after captopril. They concluded that while
captopril inhibits the reninangiotensin system in
patients with cirrhosis, it fails to signicantly decrease
portal venous pressure, and was therefore unlikely to
protect against variceal bleeding in this population. Ena-
lapril was found to have its bioactivation to enalaprilat
signicantly impaired in cirrhosis, but its PD effects were
unaffected.118 Similarly, lisinopril had higher serum con-
centrations in cirrhosis, possibly due to increased drug
absorption, and time to peak concentration was longer
than for enalapril.119 The PD effects of these two agents,
however, have not been well studied.
As a class, ACE inhibitors appear to be relatively well
tolerated in cirrhosis.59, 63 ADRs are rare. Five per cent
of these are mostly due to hyperkalaemia (especially
when combined with potassium-sparing diuretics such as
spironolactone), urinary system disorders, including kid-
ney injury and worsening liver function.59 ACE inhibi-
tors accounted for nearly 1/3 of all antihypertensive
medications prescribed to cirrhotics in the series by Luc-
ena et al.63
Antiarrhythmic agents: Klotz120 has reviewed the metab-
olism and PK changes of several antiarrythmics and rec-
ommendations for their use in cirrhosis are presented in
Table 6. CYP-mediated phase 1 pathways are affected by
several agents and require dose reductions as they often
have narrow therapeutic indices. PK changes of other
agents suggest that the half-life of ecanide is prolonged
in cirrhosis, leading to possible accumulation and there-
fore its use requires dose reduction.121 In contrast, while
the elimination of encainide was seen in cirrhosis,
plasma levels of its active metabolites were largely unaf-
fected.122
Disease modifying antirheumatic drugs. While there is a
well-described risk of HBV reactivation with both bio-
logic and nonbiologic DMARD use,123, 124 much less is
known about the safety of these medications in cirrhosis
as these patients are generally excluded from clinical tri-
als. Thus, we are left with expert opinion to best guide
our therapeutic decisions.125, 126 For nonbiologic disease
modifying antirheumatic drugs (DMARDs), the 2008
American College of Rheumatology (ACR) guidelines
advised that despite patients receiving treatment with
anti-viral agents for HBV, leunomide and methrotrex-
1141
J. H. Lewis and J. G. Stine

Table 6 | Pharmacokinetic changes and dose adjustments for some antiarrythymic agents in patients with hepatic
impairment

Drug Metabolic changes Recommendations for dosing in cirrhosis

Lidocaine Prolonged elimination half-life Reduce IV dose by factor of 2 or 3
(Reversible changes after recovery from acute
viral hepatitis)
Quinidine Half-life increased by 50%, oral clearance unchanged Reduced dose may be necessary
Propafenone Bioavailability triples Reduce dose two to threefold
Metoprolol Increased AUC and half-life Reduce dose based on clinical response
Carvedilol Clearance reduced, half-life prolonged by threefold; Start at 20% of usual dose
bioavailability by fourfold
Satolol No rst-pass effect; normal elimination No dose adjustment needed
Amiodarone Normal half-life is 2553 days and is predicted to Dose based on clinical response
be prolonged in cirrhosis
Dronedarone Limited clinical experience in cirrhosis No dose adjustment needed in CP A or B
Diltiazem Half-life prolonged by >50% May need lower dose
Verapamil Extensively metabolised, clearance reduced two to Reduce dose by 50%
threefold, bioavailability doubled; half-life prolonged
fourfold
Flecanide Fourfold increase in half-life Reduce dose to avoid accumulation
Encainide Fourfold decrease in oral clearance, increased Dose based on clinical effect
bioavailability of parent, but no change in active
metabolites
Enalapril Increased Cmax and AUC, but no appreciable Dose based on clinical effect
difference in inhibition of ACE activity vs. controls
Lisinopril Less effect on serum concentration than reduced Dose based on clinical effect
dose in renal failure with enalapril
Propranolol Steady state clearance decreased Dose based on clinical effect
Nadolol Not metabolised by the liver Dose adjustment for renal impairment

IV, intravenous; AUC, area under the curve; CP, Child-PughTurcotte class; Cmax, maximum concentration.

ate were contraindicated for all Child-Pugh classica-
tions, and minocycline and sulfasalazine were contraindi-
cated for Child-Pugh Class C.127 In treatment-nave
hepatitis B patients, the ACR recommended against
using hydroxychloroquine in advanced cirrhosis (Child-
Pugh Class C), although no specics were provided.128
While the ACR acknowledged that TNF-alpha blockade
has been used when antihepatitis B therapy has been
given prophylactically, they still recommended against
the use of any biologics in treated or untreated chronic
hepatitis B or hepatitis C patients or those with Child-
Pugh class B or C cirrhosis of any aetiology. The
updated 2012 ACR guidelines are silent on how to man-
age rheumatoid arthritis RA patients with hepatitis B
receiving nonbiologic DMARDs, and still advise against
the use of any biologic agent for RA patients with
untreated chronic HBV (due to what they list as contra-
indications to treatment or intolerable side effects) and
in RA patients with treated hepatitis B if there is evi-
dence of advanced cirrhosis (Child-Pugh class B or
C).128 These guidelines do not address the issue of
whether or not RA patients who are receiving concomi-
tant anti-viral therapy for hepatitis B could be treated
with biologics, or whether patients with a history of hep-
atitis B and a positive hepatitis B core antibody would
be candidates for biologics. In contrast, the revised
guidelines do recommend the use of etanercept for
patients with hepatitis C (although there is no mention
of the degree of hepatic impairment that might be pres-
ent).128 Patients with underlying hepatitis B undergoing
cancer chemotherapy (especially those with lymphoma
receiving rituximab) should receive prophylactic therapy
using one of the nucleoside or nucleotide analogues dur-
ing and after the course of chemotherapy to prevent
reactivation and symptomatic aring of the hepati-
tis.129, 130 Clearly not all societal recommendations are
consistent when it comes to these patients with chronic
viral hepatitis or cirrhosis, and we await consensus
guidelines to be agreed upon.
Oral hypoglycaemics. Historically, biguanides, such as
metformin, and other oral hypoglycaemic agents, includ-
ing the sulfonylureas were often avoided in CLD due to
the risk of acute DILI,1, 113, 131 presenting a conundrum

1142 Aliment Pharmacol Ther 2013; 37: 1132-1156

2013 John Wiley & Sons Ltd
 Review: prescribing medications in patients with cirrhosis

to physicians treating diabetic patients with comorbid
liver disease, including NAFLD, which is commonly
found in this population. Contrary to what was previ-
ously thought, Brackett132 has opined that metformin is
not associated with exacerbation of liver injury or was a
signicant cause of DILI, and in fact, may be benecial
in the treatment of steatohepatitis and may protect
against the development of hepatocellular carcinoma, as
reported by others.133, 134
Brackett notes that reports of lactic acidosis in cirrho-
tics are rare, with lactic acidosis being much more likely
due to the effects of encephalopathy or hypoxaemia.
Furthermore, most of the case reports occurred in cir-
rhotics using alcohol, there is no reason to withhold
metformin from patients with liver disease, and that
routine monitoring of liver-associated enzymes during
its use is not supported by published evidence.132 As a
case in point, a report of possible hepatotoxicity associ-
ated with metformin,135 involved a 61-year-old obese
male who presented with jaundice, nausea, fatigue and
weight loss 2 weeks after beginning metformin. Amino-
transferase values were elevated in a range of 1015
times the upper limit of normal. The patient was also
receiving an extended release niacin formulation as well
as simvastatin, and all medications were discontinued.
His symptoms and signs resolved with liver tests return-
ing to normal approximately 2 months later. No rechal-
lenge was performed. While metformin was listed as the
possible causative agent, extended release niacin and the
statins, certainly could have contributed and remain
confounders.
Antidepressants, anticonvulsants and other psychotropic
and central nervous system agents. The PK and PD
effects of agents in these classes have been studied
to varying degrees in patients with cirrhosis.136, 137
Tables 79 summarise the effects of hepatic impairment
on the use of these drugs; much of the information on
their metabolism and recommendations for dosing can
be found in the individual drug labels and patient
medication guides that detail prescribing information,
either directly from the manufacturers65 or accessed via
the FDA website.66 While valproic acid is contraindi-
cated in patients with liver dysfunction, all of the other
agents listed in Tables 79 can be used with caution in
cirrhosis.

Table 7 | Disposition and dosing adjustments for psychotropic and other CNS agents in patients with cirrhosis

Class/agent Clearance Dose adjustment

Antidepressants
Fluoxetine (SSRI) Reduced clearance of parent and active noruoxetine metabolite; Lower doses or reduced frequency in
prolonged half-life cirrhosis
Duloxetine 85% reduction in clearance in CP class B cirrhotics; threefold Current label advises it should not be
(SNRI) increase in half-life; vefold increase in mean exposure prescribed to patients with substantial
alcohol use or evidence of chronic
liver disease
Escitalopram Clearance reduced 37%, half-life doubled with increased plasma Do not exceed 10 mg/day
(SSRI) concentration
Venlafaxine Half-life prolonged by 30%; clearance reduced 4050% in CP Reduce dose by 50%
(Effexor) A and B and up to 90% in CP class C
(SNRI)
Tricyclics
Amitriptyline Increased sedative effect in cirrhotics with portocaval shunts Reduce dose accordingly
MAOIs Half-life may be prolonged Should not be used in patients with
Tranylcypromine abnormal LFTs or history of liver disease
(Parnate)
Bupropion Half-life 50% longer in alcoholics; PKs unchanged in CP class Use with extreme caution in severe
(Wellbutrin) A and B, but altered threefold in class C cirrhotics cirrhosis; use lower doses (not to
exceed 75 mg/day) and reduced
frequency
Mirtazapine Clearance reduced by 30% Reduced dose may be necessary
(Remeron)

CP, Child-Pugh score; SSRI, selective serotonin reuptake inhibitor; SNRI, serotonin-norepinephrine reuptake inhibitor; MAOI,
monoamine oxidase inhibitor; LFT, liver function test; PK, pharmacokinetic.

Aliment Pharmacol Ther 2013; 37: 1132-1156 1143

2013 John Wiley & Sons Ltd
J. H. Lewis and J. G. Stine

Table 8 | Disposition and dose adjustment for anticonvulsants

Anticonvulsants
Lamotrigine Half-life increased 50% in CP class A and No dose adjustment in CP A, reduce by 25% for CP
B and by 300% in CP class C B and C without ascites, reduce by 50% in CP class
C with ascites
Phenytoin (Dilantin) Hypoalbuminaemia increases plasma Avoid with alcohol
concentrationChronic alcohol use causes Adjust dose based on serum albumin concentration
reduced serum levels; acute alcohol causes and monitored blood levels
increased serum levels
Carbamazepine Not well studied, but primarily metabolised Dose based on monitored blood levels; periodic CBCs
(Tegretol) in the liver recommended;
HLA-B*1502 typing recommended in Asians to predict
risk of serious skin reactions
Valproic acid (Depakote) Hyperammonemia may confound hepatic Contraindicated in patients with liver disease or
encephalopathy; may also cause signicant hepatic dysfunction
thrombocytopenia
Levetiracetam (Keppra) PKs unaffected may cause somnolence, Use with caution in patients with prior history of liver
fatigue disease; discontinue immediately for signicant
hepatic dysfunction
No dose adjustments for use in liver disease
CP, Child-Pugh score; CBC, complete blood count; HLA, human leucocyte antigen.

Table 9 | Disposition and dose adjustments for antipsychotics and sedatives

Antipsychotics
Haloperidol PKs unaffected Jaundice reported, avoid alcohol due to additive effects
(butyrophenone) No specic dose adjustment recommended
Lithium Reduced clearance Toxicity does not include hepatic dysfunction; no specic
dosing recommendations for liver disease
Sedatives
Diazepam (Valium) Half-life increased two to vefold Use with caution
(up to 500 h); clearance decreased by 50%
Zolpidem (Ambien) Half-life increased twofold Use lowest dose possible

Selective serotonin reuptake inhibitors (SSRIs), neuro-
leptics and antiepileptics are prescribed in up to 10% of
cirrhotics,63 and ADRs are not uncommon59 and typi-
cally occur when these medications are prescribed in
combination with other potentially harmful agents. For
example, aspirin and venlafaxine use together have been
reported to cause GI bleeding in cirrhotics; amitriptyline
and bactrim prolong the QTc interval and are potentially
pro-arrhythmic; imipramine and venlafaxine were
reported to also cause QTc prolongation.59 The combi-
nation of SSRIs plus a neuroleptic or antiepileptic also
predisposes to serotonin syndrome in the cirrhotic (4
out of 132 DDIs in Katz et al. cohort).59
Benzodizepines and alcohol withdrawal syndrome man-
agement. The management of alcohol withdrawal syn-
drome (AWS) is commonly required in the in-patient
setting.138 Benzodiazepines (BZDs) are the cornerstone
of therapy; however, the impaired metabolism of BZDs
in cirrhotics is problematic as their oxidation is reduced.
MacGilchrist et al. demonstrated signicant impairment
of midazolam metabolism with just a single dose with
resultant greater sedation observed 6 h after intravenous
administration.139 The impairment was independent of
albumin or serum bilirubin and the authors did not dis-
tinguish between compensated and decompensated cir-
rhotics. Flumazenil may be administered for BZD-
induced encephalopathy, however, its use carries an
independent risk of inducing seizure activity.70
In their cohort study, Franz et al. found that BZDs
and related drugs were prescribed in more than 25% of
cirrhotics (clorazepam 7%, oxazepam 3.5%, diazepam
3.3%).59 Similar use was reported by Lucena et al. for a
number of these psychotropic drugs.63 In their multicen-

1144 Aliment Pharmacol Ther 2013; 37: 1132-1156

2013 John Wiley & Sons Ltd
 Review: prescribing medications in patients with cirrhosis
tre observational series of 568 hospitalised cirrhotics,
44% (n = 248) were patients with alcoholic cirrhosis;63
however, only 18 patients were hospitalised for alcohol
withdrawal. Thirteen of these patients were discharged
home on medication for alcohol deprivation syndrome,
the majority of patients (81%) received chlormethiazole,
an alternative to neuroleptic BZDs. BZDs were however
being taken for other indications, including insomnia
amongst others. Lorzepam accounted for one-third of
the 26 different BZD prescriptions; clorazepate (10%),
diazepam (7%) and oxazepam (7%). At discharge, pre-
scribing practices were a little different and reected a
switch to BZDs with short or intermediate half-lives; lo-
razepam accounted for half of the discharge prescrip-
tions. Other BZDs prescribed included oxacepam,
bromazepam, chlorazepam and lormetazepam (8%) each.
The authors attribute this change in prescribing to a
growing awareness of anxiolytics (such as BZDs) having
a risk of precipitating encephalopathy.
Cirrhotics who were prescribed BZDs at discharge
were given low doses in accordance with recommenda-
tions that if BZDs are to be used, only those agents not
metabolised by the liver (lorazepam and oxazepam) with
short to intermediate half-lives should be used, in the
lowest dose possible. However, regardless of how they
are metabolised, BZDs may be associated with an
increased risk of excessive sedation, memory decits,
respiratory depression in patients with liver impairment,
and abuse and dependence liability.138 Not surprisingly,
the majority of DDIs and ADRs reported by Franz et al.
were related to respiratory depression when used in
combination with opiates, and to CNS depression/
encephalopathy when used as monotherapy.35
Recent data in decompensated cirrhotic patients sug-
gest a potential role for gamma hydroxyl butyrate
(GHB), a short-chain fatty acid that exerts an ethanol-
mimicking effect on the central nervous system by acting
on its own receptors and on the GABAB receptors which
moderate AWS.138 However, further study is necessary
before recommendations can be made regarding this par-
ticular treatment. Of note, GHB is metabolised by the
liver, although the relatively short half-life of 46 h sug-
gests that it may be well tolerated, even in decompensat-
ed cirrhosis.138
Maintaining alcohol abstinence is particularly chal-
lenging, especially in the cirrhotic. Disulram has long
been the mainstay of therapy; however, multiple case
reports of fulminant hepatitis, some of which described
the need for liver transplantation in patients with alco-
holic cirrhosis, have been published.140143 Such reports
Aliment Pharmacol Ther 2013; 37: 1132-1156
2013 John Wiley & Sons Ltd
suggest that disulram should be used very cautiously if
at all in cirrhosis. Newer data144 from Italy point to a
potential role for baclofen in the maintenance of alcohol
abstinence. A muscle relaxant and GABA inhibitor,
baclofen is metabolized to only a limited extent (15%) by
the liver. In a randomised double-blind placebo-con-
trolled study of 84 alcohol-dependent cirrhotics, Addol-
orato et al. found that of the 42 patients allocated to
receive baclofen, 71% achieved and maintained absti-
nence at 12 weeks compared to 29% in the placebo arm.
Moreover, the duration of cumulative abstinence was
twofold greater for the baclofen group. No adverse hepa-
tic events were reported, and the authors suggest a role
for baclofen in this setting.
Antineoplastic and immunomodulating agents. The
effects of hepatic impairment on the disposition of anti-
neoplastic agents have been studied to a variable
extent.145, 146 While the metabolism of many classes of
anticancer drugs is altered in cirrhosis, it has been noted
that for many compounds, dose reductions are not
needed when only moderate impairment is present (i.e.
Child-Pugh class A and B cirrhosis). For certain agents,
such as vincristine, vinblastine, paclitaxel and docetaxel,
lower doses are recommended to prevent excessive neu-
tropenia and neurotoxicity.146 Antineoplastic and immu-
nomodulating agents were prescribed to 15% of cirrhotic
patients in one cohort.59
Antimicrobials and antiretrovirals. The effects of cirrho-
sis on the metabolism of various antibiotics, antiretrovi-
rals and ATDs vary according to drug class, and even
within medicinal classes. For drugs such as ampicillin,
PK parameters are unchanged in cirrhosis, but dose
reductions are recommended for patients with renal
impairment.147 Fluoroquinolones are among the most
commonly used antibiotics in cirrhosis, especially to treat
and prevent spontaneous bacterial peritonitis (SBP). No
signicant changes in plasma levels or half-life were seen
with ciprooxacin, and no dosing adjustments are neces-
sary in cirrhosis.148 Ooxacin metabolism is altered by
renal dysfunction in patients with ascites,149 although the
penetration of ooxacin and peoxacin into ascitic uid
is excellent, achieving therapeutic levels.149, 150 However,
uroquinolones may prolong QTc intervals in patients
who have undergone TIPS62 and appropriate care should
be taken.
Macrolide antibiotics, including erythromycin, azithro-
mycin, clindamycin and chloramphenicol should be
avoided in cirrhotic patients (Table 10).70 Tetracycline
1145
J. H. Lewis and J. G. Stine
Table 10 | Antibiotics and antifungals to be avoided or
used with caution in end-stage liver disease or liver
failure70
Azithromycin
Cefoperazone
Ceftazidime
Ceftriaxone
Chloramphenicol
Erythromycin
Gatioxacin
Griseofulvin
Ketoconazole
Metronidazole
Nalidixic acid
Nitrofuantoin (chronic use)
Peoxacin
Piperacillin
Roxithromycin
Telithromycin
Tetracycline
has a prolonged half-life, which corresponds to dose-
related hepatotoxicity and should also be avoided.70
Beta-lactam antibiotics should be used with caution,
given their propensity for leucopenia as cirrhotics are
predisposed to infection from impaired reticular endo-
thelial cell function and phagocytosis leading to ineffec-
tive hepatic destruction of bacteria.70 Aminoglycosides
and vancomycin are generally contraindicated given their
relatively high risk of inducing renal failure.70
The recommendations for use of anti-TB drugs in
cirrhosis are based largely on the known risk of hepato-
toxicity in patients with CLD.151 Rifampicin is eliminated
in the bile and can cause elevations in bilirubin due to
competitive inhibition of excretory pathways. As a result,
it can potentially worsen jaundice in a cirrhotic, and its
risk of hepatotoxicity is increased when used concomi-
tantly with isoniazid (INH).3 Therefore, caution is
advised in the patient with hepatic impairment. In
patients with CLD, ooxacin has been used safely as a
substitute for rifampicin and may be less hepatotoxic
when combined with pyrazinmide compared with rifam-
pin and pyrazinamide.152 INH has an increased risk of
DILI, especially in slow acetylators (slow inactivators)
among other genetic polymorphisms, attributed to
increased blood levels in cirrhosis.153, 154 An excess inci-
dence of elevated LFTs has been recorded in patients with
hepatitis B and hepatitis C,155, 156 and while it is gener-
ally contraindicated in severe liver disease (PDR), it has
been used safely with frequent (every 24 weeks) liver
enzyme monitoring in cirrhotic patients awaiting liver
transplant.157 Concomitant chronic alcohol use appears
1146
to increase the risk of hepatotoxicity.158 Importantly,
INH has been successfully used to treat posttransplant
tuberculosis.159, 160 Pyrazinamide is not recommended
for treatment of latent TB in nonhepatically impaired
patients,161 and given the increased half-life seen in
hepatic impairment,65 and the known increase in hepato-
toxicity in CLD,158 it should be monitored very closely in
cirrhosis. As noted, when combined with oaxacin, its
risk of liver injury is less compared with rifampin and
pyrazinamide.152 Current recommendations suggest that
the Child-Pugh Class A cirrhotics be treated in the same
manner as noncirrhotic patients, however, pyrazinamide
should be avoided in Class B disease.70 Ethambutol, a
urouquinolone and a second-line agent from the RIPE
regimen, may be used in Child Class C disease.70
Antifungal agents, including ketoconazole, miconazole,
fulocnazole and itraconazole should be used with caution
in cirrhosis, largely due to variable effects on CYP
enzyme activity.70 Voriconazole must be dose-reduced
for Child-Pugh Class A and B disease; however, it has
not been studied in Class C patients.
HAART agents have historically been associated with
a higher risk of DILI in patients with chronic hepatitis B
or C,9, 162164 and a correlation between the degree of
hepatic brosis and hepatotoxicity has been found.165
While not all investigators have found chronic viral hep-
atitis to be associated with a higher risk of DILI with
certain ARTs (e.g. tipranavir plus ritonavir;166 or from
atazanavir/ritonavir167), it has been shown that the dis-
position of several ARTs is signicantly altered in CLD
or cirrhosis.168170 Given that higher serum concentra-
tions of NNRTIs (nevirapine, efavirenz, etc.) seen in cir-
rhosis are associated with adverse effects, including
hepatotoxicity, drug level monitoring has been recom-
mended as a means of preventing injury.171174
Among anti-virals used to treat chronic hepatitis B, the
nucleotide and nucleoside analogs are safe for use, includ-
ing in patients with decompensated cirrhosis, in whom
chronic therapy is advised to prevent disease progres-
sion.175 A reduced frequency of dosing is recommended
for all of these agents in renally impaired patients.54 How-
ever, hepatic impairment does not alter the PKs of lami-
vudine176 or any of the newer nucleoside and nucleotide
analogs for chronic hepatitis B as discussed in the drug
labels of adefovir, entecavir, telbivudine or tenofovir.66 In
contrast, it is generally advised not to treat patients with
advanced cirrhosis from hepatitis C infection with inter-
feron therapy due to the risk of hepatic decompensa-
tion177 (although clinical trials are currently underway in
patients who are awaiting liver transplant178).
Aliment Pharmacol Ther 2013; 37: 1132-1156
2013 John Wiley & Sons Ltd
 Review: prescribing medications in patients with cirrhosis
Acid-suppressive medications. Acid-suppressant medica-
tions are prescribed quite frequently in patients with cir-
rhosis. Indeed, PPIs were the most frequently prescribed
class of medication prescribed to cirrhotics (given to
approximately 40% of 400 patients) as reported by Franz
et al.59 Lucena et al. reported that nearly one-fourth of
the 568 patients in their series were prescribed these
medications on admission and 35% on discharge.179
Ulcer-healing drugs accounted for 12% (n = 2377) of all
medications prescribed,179 with both proton pump inhib-
itors (PPIs) and H2 blockers being utilised chronically.
Acid-suppressive therapy, including H2-blockers and
PPIs, appears to be a potential risk factor for both spon-
taneous bacterial peritonitis (SBP),180183 infection with
Clostridium difcile184 and other serious infections in
patients with cirrhosis.185 The odds ratios for the various
infectious associations range from about 1.5 to 3 for PPIs
and somewhat less for H2 blockers.181, 182, 185 While the
precise mechanism by which acid suppression increases
the risk of infection in this setting is uncertain, these
agents are known to facilitate enteric bacterial coloniza-
tion, overgrowth and gut translocation183, 184, possibly
through changes in intestinal permeability.186 The stu-
dies on which these associations of an increased risk of
SBP, etc are based, have been retrospective and observa-
tional in nature,180185 and also have been criticized for
other methodological reasons,187 including the large
number of SBP patients excluded or invalidated, and the
fact that many SBP patients were already receiving anti-
biotics when admitted,182 making the analysis even more
challenging. For example, in the study by Goel et al.
from the Cleveland Clinic182, Terg notes that only about
10% of more than 1309 patients were eligible for analy-
sis, most of whom had inadequate records and medica-
tions to lists to review. Moreover, the risk was apparent
only for those patients taking PPIs in the previous 7 days
, and why the investigators included patients already on
antibiotics was not clearly stated.187 Terg also mentions
that the data on the association of PPIs and bacterial
overgrowth have been conicting.187
Although daily uoroquinolone use has been shown
to substantially reduce the risk of SBP when given as pri-
mary prophylaxis to high-risk patients with cirrhosis as
reported in various meta-analyses,188, 189 it is unknown
whether or not the use of a uoroquinolone (or other
antibiotic) in this setting would mitigate the SBP risk
associated with acid suppression in the same population.
Since about two-thirds of cirrhotics were found to have
no documented indication for the use of a PPI,182 we
join the recommendation by Terg187 that acid-suppres-
Aliment Pharmacol Ther 2013; 37: 1132-1156
2013 John Wiley & Sons Ltd
sive medications be used only when clinically indicated
in the cirrhotic patient at high risk for SBP and other
infections (especially those with ascites). While the risk
of SPB was signicantly lower in those taking PPIs for
more than 90 days,182 the risk may not be completely
eliminated in such patients, and the safety of chronic use
of PPIs and H2 blockers in cirrhosis deserves additional
study, both in terms of design and duration.
Miscellaneous drugs in cirrhosis. Elthrombopag is an
oral thrombopoeitin-receptor agonist that has been in
use for management of idiopathic thrombocytopenic
purpura (and which was recently approved to allow
patients with chronic hepatitis C to receive pegylated
interferon-containing anti-viral treatment regimens. It
has also demonstrated efcacy in reducing the need for
platelet transfusions in patients with cirrhosis and
thrombocytopenia who are undergoing invasive surgical
and endoscopic procedures.190 Preapproval PK studies in
patients with cirrhosis receiving a single 50 mg dose
demonstrated an increased plasma concentration (AUC)
and prolongation of half-life with increasing degrees of
hepatic impairment.191 Compared with healthy controls,
patients with moderate-to-severe cirrhosis (Child class B
or C) had a 93% increase in AUC and more than a dou-
bling (to 114%) of half-life measurements. In contrast,
Cmax values decreased with worsening hepatic function,
but there was high PK variability between subjects. It is
recommended that the initial dose be reduced to 25 mg/
day for those with Child class B or C cirrhosis, but that
no dose adjustment is needed for renally impaired
patients.191
Pain management in the cirrhotic patient
Use of OTCAs in cirrhosis. Paracetamol (acetaminophen)
is probably the single most feared drug by patients and
nonhepatologists alike with respect to its use in patients
with liver disease.4 A study of physician recommenda-
tions on the use of OTCAs by Rossi et al.192 suggested
that when used in low doses (2 g or less), it is safe in
cirrhosis. While it has been demonstrated that doses of
4 g daily over the course of 2 weeks in healthy volun-
teers can lead to marked, but clinically silent, elevations
in ALT and AST,193 other groups have not shown signif-
icant ALT elevations with doses up to 4 g daily, includ-
ing in patients who have used alcohol 194 when used for
shorter periods. The issue of therapeutic misadventure,
a termed coined by Maddrey and Zimmerman in the
mid-1990s,195 is still a cautionary tale, in that unsuspect-
ing chronic alcohol users (which can include cirrhotics)
1147
J. H. Lewis and J. G. Stine
may experience an inadvertent overdose from paraceta-
mol (in doses far lower than the traditional 10 g impli-
cated in most intentional overdoses) leading to acute on
chronic liver failure. However, no instances of acute liver
failure were seen with daily doses less than 2.5 g.195 As a
result, most clinicians suggest that their patients not use
more than 2 g of paracetamol in a 24-h period and to
limit the overall duration of treatment.3, 4, 192 In the survey
conducted by Lucena et al. in Spain, paracetamol was
safely used when doses in general were kept to 3 g/day,
even in those with alcoholic cirrhosis.63
The work of a number of investigators has helped
clarify the usage patterns of a number of OTCAs,
including paracetamol and various NSAIDs, with
respect to their safety in cirrhotics. Khalid et al.13 found
that among noncirrhotic control patients in their liver
clinic, 70% used paracetamol or NSAIDs. In their
patients with compensated cirrhosis, over half men-
tioned the use of OTCAs with 25% using paracetamol
and 31% using NSAIDs. Among those with decompen-
sated cirrhosis who ended up hospitalised for a number
of common causes of hepatic decompensation, only
35% mentioned the use of OTCAs with 19% saying
they used acetaminophen and 16% using NSAIDs.13 Of
interest was the fact that hospitalisation rates were not
increased among cirrhotics using OTCAs as reported by
Fenkel et al.14
Physicians attitudes about prescribing OTCAs in cirrho-
sis. Data suggest that paracetamol is prescribed rather
sparingly in cirrhosis. Franz et al. reported its use in
only 6% of cirrhotic patients,59 and its use was even less
in another series.63 A study of physicians attitudes
regarding the use of OTCAs in CLD was undertaken by
Rossi et al.192 The results of their web-based question-
naire survey found that internists and family physicians
were signicantly more likely not to recommend the use
of acetaminophen in patients with compensated cirrhosis
compared with gastroenterologists who felt that paraceta-
mol (acetaminophen) would be safe. In patients with de-
compensated cirrhosis, 95% of family physicians and
70% of internists would not recommend the use of par-
acetamol compared to just 22% of gastroenterologists.
Even among patients with mild chronic hepatitis without
cirrhosis, 1520% of general practitioners would not rec-
ommend paracetamol. In contrast, none of the gast-
roenterologists questioned in this survey would avoid
paracetamol in that setting. Overall, the recommendation
against the use of NSAIDs was signicantly less common
than recommendations against the use of paracetamol in
1148
both compensated and decompensated cirrhosis. Nongast-
roenterologists were more likely to recommend NSAIDs
compared with gastroenterologists, who in turn, were
more likely to recommend the use of paracetamol.192
Given the very real possibility that ibuprofen and
other NSAIDs might lead to or worsen GI haemorrhage
in patients with underlying gastropathy and coagulopa-
thy,196 the occasional use of paracetamol is in fact pre-
ferred over NSAIDs. In addition, ibuprofen has been
associated with hepatotoxicity among patients with
chronic hepatitis C, suggesting that it might not be safe
in this setting,197 although others have challenged this
notion.198 In a recent survey exploring the attitudes and
preferences of medical students, residents and gastroen-
terology fellows regarding the use of paracetamol (acet-
aminophen) and NSAIDs in CLD patients with various
degrees of hepatic impairment, paracetamol doses less
than 2 g/day were preferred, although only the GI fel-
lows thought it was safe to use paracetamol in patients
with decompensated cirrhosis.199, 200 These ndings
among medical students and residents were very similar
to those of Rossi et al. that compared primary care phy-
sicians to practising gastroenterologists.192 Reasons for
their preferences given by the trainees, who were worried
about using paracetamol, reected their concerns about
worsening underlying liver disease, producing an inad-
vertent overdose, and the overall lack of evidence-based
information on which to justify clinical decisions in this
setting.201 Both surveys illustrate that a signicant vari-
ability exists among health care providers regarding their
recommendations for the use of OTCAs and affords
another opportunity for physician as well as patient edu-
cation on medication use in CLD.
Narcotic analgesic and other pain relievers in cirrho-
sis. The management of acute and chronic pain in cir-
rhosis often raises the fear of precipitating hepatic
decompensation, worsening encephalopathy or creating
addiction, especially in patients with a history of alcohol-
ism or other addictive behaviours. In addition, the PKs
of analgesics, in general, have been poorly studied in
patients with the most severe degrees of hepatic impair-
ment.25, 202 Indeed, opioids were rarely prescribed
among cirrhotics in Spain.63 The need for signicant
reductions in the dose or dosing frequency of a number
of narcotic agents has been recommended since initial
studies on morphine were conducted more than 50 years
ago.203 For example, dose reductions have been recom-
mended for many agents, including, hydromorphone,
methadone, morphine, oxycodone, tramadol amitripty-
Aliment Pharmacol Ther 2013; 37: 1132-1156
2013 John Wiley & Sons Ltd
 Review: prescribing medications in patients with cirrhosis

line, bupivacaine, clonidine and gabapentin, especially in
the presence of renal failure, and it is recommended that
aspirin, dextropropoxyphene, NSAIDs and demerol be
avoided in the presence of concomitant chronic renal
failure.202 Murphy also suggests avoiding amitriptyline,
methadone, carbamazepine and valproic acid, due to a
potentially higher risk of acute liver failure occurring in
cirrhosis.202
Several comprehensive reviews of the PK and PD
effects of opioids, antidepressants and other classes used
to treat pain in the setting of cirrhosis are avail-
able6, 25, 55, 202 and recommendations for their safe use
have been recently summarised.204 Table 11 provides the
important changes in metabolism that have been
observed with the more commonly prescribed opioid
and other classes of analgesics, which underlie the rec-
ommendations for their use in cirrhosis.6, 25, 55, 202, 204
As reviewed by Tegeder et al.25 and Smith,55 a num-
ber of opioids require hepatic biotransformation to
active metabolites, which in the setting of impaired
hepatic function can lead to disparate clinical effects.
For example, a reduced analgesic effect has been seen
with codeine, rendering it less useful as an analgesic in
this setting. In contrast, due to a reduced rst-pass
effect, the bioavailability of meperidine is increased by
as much as 80%, which can result in the accumulation
of its neurotoxic norpethidine metabolite.25 Tramadol
also requires metabolism to an active metabolite and its
analgesic properties may not be fully effective in cirrho-
sis. Moreover, tramadol is known to lower seizure
thresholds in epilepsy and is associated with serotonin
syndrome when combined with SSRIs, TCAs, anticon-
vulsants or morphine.204, 205 All opioids can aggravate
or precipitate HE and should be used with caution.6, 204
Fentanyl, methadone and hydromorphone often require
reduced dosing, but do not have toxic metabolites and
may be better tolerated.25, 55, 204 While methadone
appears to be safe in CLD patients with narcotic addic-
tion, it is best avoided in alcoholics as ethanol interferes
with its metabolism (and raises plasma concentra-
tions).204
Chandok and Watt204 have offered useful recommen-
dations to treat acute and chronic visceral and neuro-
pathic pain in patients with hepatic impairment, based

Table 11 | Metabolic changes of narcotic and other analgesics in patients with cirrhosis and recommendations for
use*

Active
metabolite Bioavailability in
Drug Potency formed cirrhosis Dose adjustment
Morphine 19 Yes Increased 100% Reduce dose and frequency by half
Fentanyl 751259 No Unchanged (CP A or B) Usually none for single dose
Sufentanil 50010009 ? Unchanged Normal dosing
Remifentanil 2509 ? Unchanged Normal dosing
Meperidine (pethidine) 0.19 Yes Increased up to 80% Generally avoid using, or reduced dose and
avoid chronic use
Codeine (methylmorphine) 0.1 9 Yes Reduced Poor analgesic effect and should be avoided
Methadone 19 No Largely unaffected None needed in compensated cirrhosis
Oxymorphone 79 No Increased 1.612.2 fold Reduce dose to prevent accumulation
Oxycodone 19 Yes Increased 5095% Reduce dose to prevent accumulation
Hydromorphone 6109 Yes Limited data Limited data
Dextropropoxyphene <1 9 ? Increased Avoid in cirrhosis**
Tramadol 0.1 9 Yes Increased two to threefold Consider alternative agents

CP, Child-Pugh score.

* After references.6, 25, 55, 201, 204

Relative to parenteral morphine (potency = 1).

May be dependent on hepatic blood ow.
Accumulation may cause seizures from norpethidine metabolite.
Accumulation may occur in severe hepatic impairment.
** Produces sedation and has caused severe hepatotoxicity in cirrhotics.
Can lower seizure thresholds in epilepsy; associated with serotonin syndrome when combined with SSRIs, TCAs, anticonvul-
sants or morphine.

Aliment Pharmacol Ther 2013; 37: 1132-1156 1149

2013 John Wiley & Sons Ltd
J. H. Lewis and J. G. Stine
Table 12 | Approach to prescribing analgesics in
cirrhosis method of Chandok and Watt204
Type of pain Sequence of medications recommended
Visceral/ Acetaminophen <23 g/day or Tramadol
musculoskeletal 25 mg orally q8h
For intractable Hydromorphone 1 mg orally q4h or
pain* Fentanyl 12.5 mg topically q72h
Neuropathic Nortriptyline 10 mg orally at night or
Desipramine 10 mg orally at night or
Gabapentin 300 mg orally/day or
Pregabalin 150 mg orally twice daily and
Acetaminophen <23 g/day
* Do not combine narcotics with tramadol.
in part on expert opinion as well as the known or
expected changes in the metabolism and clearance of
paracetamol, NSAIDs, opioids analgesics and TCAs.
Table 12 provides the algorithmic approach they suggest
to treat pain in cirrhotics who do not have renal impair-
ment or active alcohol or substance abuse. Their recom-
mendations include the use of acetaminophen
(paracetamol) in a maximum dose of 23 g/day in cir-
rhotics as the rst-line agent for the treatment of visceral
or musculoskeletal pain, although they acknowledge that
the safe maximal duration (>14 days) has not been
determined. Paracetamol has a half-life in cirrhosis that
is double that in healthy subjects, but CYP enzyme activ-
ity and glutathione levels do not appear to be signi-
cantly depleted with these sub-therapeutic doses in the
non-alcoholic as previously discussed.4, 56 Even among
alcoholics, they note that small doses of paracetamol
(<2 g) appear to be well tolerated when used for a short
duration.193 In addition, the absence of GI or renal tox-
icity and its lack of an effect on platelets makes paraceta-
mol preferable to NSAIDs as an analgesic/
antipyretic.6, 204 Tramadol is suggested as a second-line
agent, with the caveats listed above, including not com-
bining it with fentanyl or hydromorphone, which are
listed as third-line agents for intractable pain. These
authors recommend the use of TCAs in small doses or
certain anticonvulsants (e.g. gabapentin, pregabalin)
along with acetaminophen as rst-line treatment for neu-
ropathic pain, mindful of the sedation and anticholiner-
gic side effects that they can cause.204, 206
NSAIDs such as ibuprofen, naproxen and sulindac are
excreted predominantly via the kidneys, are heavily pro-
tein-bound and metabolised by CYP-450 enzymes. As
mentioned previously, they are not recommended in cir-
rhosis due to the risk of renal failure (from inhibition of
1150
prostaglandins leading to a decrease in renal blood ow,
and sodium retention),6, 207, 208 and GI mucosal bleeding
(from underlying portal gastropathy or colopathy in the
setting of coagulopathy).6, 196 In addition, the hypoalbu-
minaemia of cirrhosis can alter their PKs with reduced
protein binding.20, 21 Moreover, some NSAIDs (e.g. dic-
lofenac) have a signicant hepatotoxic potential.209 The
selective COX-2 inhibitors have not been well studied in
cirrhosis and agents such as celecoxib, while potentially
safer (as they do not affect platelet or renal function),
should nevertheless be used with caution.
Ultimately the choice of an analgesic regimen should
be based on an individualised approach taking into
account all aspects of cirrhosis, including nutritional sta-
tus, renal function, the potential for DDIs and aetiology
of cirrhosis.204
CONCLUSIONS
The safe use of medications in patients with CLD is an
ongoing challenge for prescribers and patients alike. This
becomes especially true in patients with cirrhosis, in
whom signicant changes can occur in the metabolism
and handling of various agents, specically those medica-
tions which undergo rst-pass metabolism or are metab-
olised by the CYP3A enzymatic pathway. The presence
of portosystemic shunts, including TIPS, may lead to
increased bioavailability of drugs leading to QTc prolon-
gation in cirrhotics, which may precipitate potentially
fatal ventricular arrhythmias.
Very few drugs have been shown to have their hepa-
totoxicity potential enhanced by CLD with or without
cirrhosis; nearly all of these involve antituberculosis
agents given in the setting of chronic hepatitis B or C
and among HIV/AIDS patients. Statins, in particular,
appear to be benecial in chronic hepatitis C and other
causes of cirrhosis and may prevent progression to
HCC.
Lower doses are recommended for the use of several
drugs in cirrhosis, although in many cases, the rationale
for this is based mostly on reduced clearance mecha-
nisms rather than any known excess risk of hepatotoxic-
ity or other adverse PD effects. NSAIDs, in general,
should be used cautiously (or not at all) in cirrhotics due
to their risk of precipitating renal failure and inducing
or worsening GI bleeding. Nevertheless, OTCAs are
widely prescribed, although they do not appear to
increase the risk of hospitalisation. Paracetamol (acet-
aminophen) is safe in patients with CLD, including
cirrhosis when used in small (23 g or less/day) doses
for short durations, and is recommended as rst-line
Aliment Pharmacol Ther 2013; 37: 1132-1156
2013 John Wiley & Sons Ltd
 Review: prescribing medications in patients with cirrhosis

treatment of visceral or musculoskeletal pain. Most nar-
cotics and BZDs are best avoided as their half-lives can
be prolonged in cirrhosis and may precipitate or worsen
encephalopathy. Propofol (without BZDs or narcotics) is
well tolerated among cirrhotic patients undergoing endo-
scopic procedures and isourane is a preferred inhala-
tional anaesthetic for cirrhotics undergoing liver
transplant. Many patients with CLD use herbal remedies,
and clinicians need to be mindful that some can be hep-
atotoxic, making it essential to obtain a complete drug
use history, including all prescription and OTC medi-
cines and supplements.
Proton pump inhibitors and other acid-suppressive
agents have been linked to a greater risk of SBP in cir-
rhotics and should be used with caution or avoided
entirely. When required, shorter duration therapy should
be considered, along with the use of prophylactic antibi-
otics to prevent bacteremia in patients with variceal or
other GI bleeding undergoing endoscopy or other inva-
sive procedures. Antibiotics are also recommended to
prevent recurrent SBP in patients who have been suc-
cessfully treated for a prior episode; whether or not this
will reduce the risk of SBP from acid-suppressive agents
has not been formally studied, but is likely a prudent
recommendation.
AUTHORSHIP
Guarantor of the article: James H. Lewis.
Author contributions: Dr Lewis was responsible for the
concept and design of the article and both Dr. Lewis and
Stine performed the research, collected and analysed the
data and wrote the paper. Both authors approved the
nal version of the manuscript.
ACKNOWLEDGEMENT
Declaration of personal and funding interests: None.

REFERENCES
1. Zimmerman HJ. Hepatotoxicity: The
Adverse Effects of Drugs and Other
Chemicals on the Liver. 2nd ed.
Philadelphia: Lippincott Williams &
Wilkins, 1999; 430.
2. Andreasen PB. Hepatotoxicity in
patients with liver disease. Arch
Toxicol Suppl 1978; 1: 1316.
3. Gupta NK, Lewis JH. Review article:
the use of potentially hepatotoxic
drugs in patients with liver disease.
Aliment Pharmacol Ther 2008; 28:
102141.
4. Benson GD, Koff RS, Tolman KG.
The therapeutic use of acetaminophen
in patients with liver disease. Am J
Ther 2005; 12: 13341.
5. Jones A. Over-the-counter analgesics:
a toxicologic perspective. Am J Ther
2002; 9: 24557.
6. Bosilkovska M, Walder B, Besson M,
et al. Analgesics in patients with
hepatic impairment: pharmacology
and clinical implications. Drugs 2012;
72: 164569.
7. Rzouq FS, Volk ML, Hatoum HH,
et al. Hepatotoxicity fears contribute
to underutilization of statin
medications by primary care
physicians. Am J Med Sci 2010; 340:
8993.
8. Saukkonen JJ, Cohn DL, Jasmer JM,
et al. An ofcial ATS statement:
hepatotoxicity of anti-tuberculosis
therapy. Am J Respir Crit Care Med
2006; 174: 93552.
9. Sulkowski MS, Thomas DL, Mehta
SH, et al. Hepatotoxicity associated
with nevirapine or efavirenz-
containing antiretroviral therapy: role
of hepatitis C and B infections.
Hepatology 2002; 35: 1829.
10. Kaplan MM, Bonder A, Ruthazer R,
et al. Methotrexate in patients with
primary biliary cirrhosis who
respond incompletely to
treatment with ursodeoxycholic
acid. Dig Dis Sci 2010; 55:
320717.
11. Ratzui V, Charlotte F, Bernhardt C,
et al. Long-term efcacy of
rosiglitazone in nonalcoholic
steatohepatitis: results of the fatty
liver improvement by
rosiglitazone therapy (FLIRT 2)
extension trial. Hepatology 2010; 51:
44553.
12. Lewis JH. Clinical perspective: statins
and the liverharmful or helpful. Dig
Dis Sci 2012; 57: 175463.
13. Khalid SK, Lane J, Navarro V, et al.
Use of over-the-counter analgesics is
not associated with acute
decompensation in patients with
cirrhosis. Clin Gastroenterol Hepatol
2009; 7: 9949.
14. Fenkel JM, Coron RN, Daskalakis C,
et al. Over-the-counter analgesics in
cirrhotic patients: a case-control study
examining the risk of hospitalization
for liver-associated events. Scand J
Gastroenterol 2010; 45: 11019.
15. Morgan DJ, McLean AJ. Clinical
pharmacokinetic and
pharmacodynamic considerations in
patients with liver disease: an update.
Clin Pharmacokinet 1995; 29: 37091.
16. Williams RL, Mamelok RD. Hepatic
disease and drug pharmacokinetics.
Clin Pharmacokinet 1980; 5: 52847.
17. Roberts RK, Desmond PV, Schenker
S. Drug prescribing in hepatobiliary
disease. Drugs 1979; 17: 198212.
18. Food and Drug Administration.
Guidance for industry: pharmacokinetics
in patients with impaired hepatic
function: study design, data analysis,
and impact on dosing and labeling.
Available at: fda.gov/downloads/Drugs/
GuidanceCompliance Regulatory-
Information/Guidances/ucm072123.
pdf. Accessed April 4, 2013.
19. European Medicines Agency
Committee for Medical Products for
Human Use. Guideline on the
evaluation of the pharmacokinetics of
medical products in patients with
impaired hepatic function. 17 February
2005. Available at: www.ema.europa.eu/
doc/en_GB/document_library/Scientic_
guideline/2009/09/WC500003122.pdf.
Accessed April 4, 2013.
20. Delco F, Tchambaz L, Schlienger R,
et al. Dose adjustment in patients
with liver disease. Drug Saf 2005; 28:
52945.
21. Verbeeck RK. Pharmacokinetics and
dosage adjustment in patients with

Aliment Pharmacol Ther 2013; 37: 1132-1156 1151

2013 John Wiley & Sons Ltd
J. H. Lewis and J. G. Stine
hepatic dysfunction. Eur J Clin
Pharmacol 2008; 64: 114761.
22. Rodighiero V. Effects of liver disease
on pharmacokinetics: an update.
Clin Pharmacokinet 1999; 37: 399
431.
23. Wesphal JF, Brogard JM. Clinical
pharmacokinetics of newer
antibacterial agents in liver disease.
Clin Pharmacokinet 1993; 24: 4658.
24. Westphal JF, Brogard JM. Drug
administration in chronic liver
disease. Drug Saf 1997; 17: 4773.
25. Tegeder I, Lotsch J, Geisslinger G.
Pharmacokinetics of opioids in liver
disease. Clin Pharmacokinet 1999; 37:
1740.
26. Elbekai RH, Korashy HM, El-Kadi
AO. The effect of liver cirrhosis on
the regulation and expression of drug
metabolizing enzymes. Curr Drug
Metab 2004; 5: 15767.
27. Roberts JA, Pea F, Lipman J. The
clinical relevance of plasma protein
binding changes. Clin Pharmacokinet
2013; 52: 18.
28. Ulldemolins M, Roberts JA, Rello J,
Paterson DL, Lipman J. The effects of
hypoalbuminaemia on optimizing
antibacterial dosing in critical ill
patients. Clin Pharmacokinet 2011;
50: 99110.
29. Uetrecht J. Immunoallergic drug-
induced liver injury in humans.
Semin Liver Dis 2009; 29: 38392.
30. Lammert C, Einarsson S, Saha C,
et al. Relationship between daily dose
of oral medications and idiosyncratic
drug-induced liver injury: search for
signals. Hepatology 2008; 47: 20039.
31. Lammert C, Bjornsson E, Niklasson
A, et al. Oral medications with
signicant hepatic metabolism at
higher risk for hepatic adverse effects.
Hepatology 2010; 51: 61520.
32. Mauss S, Berger F, Filmann N, et al.
Effect of HBV polymerase inhibitors
on renal function in patients with
chronic hepatitis B. J Hepatol 2011;
55: 123540.
33. Gines P, Arroyo V, Rodes J.
Pharmacotherapy of ascites associated
with cirrhosis. Drugs 1992; 43: 31632.
34. Gotlieb WH, Bruchim I, Ben-Baruch
G. Doxorubicin levels in the serum
and ascites of patients with ovarian
cancer. EJSO 2007; 33: 2135.
35. Delauter BJ, Ramanathan RK, Egorin
MJ, et al. Pharmacokinetics of
gemcitabine and 2,2-diuorode-
oxyuridine in a patient with ascites.
Pharmacotherapy 2000; 20: 12047.
36. Lanao JM, Dominguez-Gil A, Macias
JC, et al. The inuence of ascites on
the pharmacokinetics of amikacin. Int
J Clin Pharmacol Ther Toxicol 1980;
18: 5761.
1152
37. Itagaki F, Hori T, Tomita T, et al.
Effect of ascites on tacrolimus
disposition in a liver transplant
recipient. Ther Drug Monit 2001; 23:
6446.
38. Gentilini P, LaVilla G, Marra F, et al.
Pharmacokinetics and
pharmacodynamics of torasemide and
furosemide in patients with diuretic
resistant ascites. J Hepatol 1996; 25:
48190.
39. Fuller R, Hoppel C, Ingalis ST.
Furosemide kinetics in patients with
hepatic cirrhosis and ascites. Clin
Pharmacol Ther 1981; 30: 4617.
40. Misra VL, Vuppalanchi R, Jones D.,
et al. The effects of midodrine on
the natriuretic response to
furosemide in cirrhotics with ascites.
Aliment Pharmacol Ther 2010; 32:
104450.
41. Dao MT, Villenueve JP. Kinetics and
dynamics of triamterene at steady-
state in patients with cirrhosis. Clin
Invest Med 1988; 11: 69.
42. Fromm MF. Importance of P-
glycoprotein for drug disposition in
humans. Eur J Clin Invest 2003; 33
(Suppl. 2): 69.
43. Lin JH, Yamazaki M. Clinical
relevance of P-glycoprotein in drug
therapy. Drug Metab Rev 2003; 35:
41754.
44. Kushuara H, Sugiyama Y. In vitro-in
vivo extrapolation of transporter-
mediated clearance in the liver and
kidney. Drug Metab Pharmacokinet
2009; 24: 3752.
45. Zhou SF. Structure, function and
regulation of P-glycoprotein and its
clinical relevance in drug disposition.
Xenobiotica 2008; 38: 80232.
46. Ieri I, Higuchi S, Sugiyama Y. Genetic
polymorphisms of uptake (OATP1B1,
1B3) and efux (MRP2, BCRP)
transporters: implications for inter-
individual differences in the pharma-
cokinetics and pharmacodynamics of
statins and other clinically relevant
drugs. Expert Opin Drug Metab Toxicol
2009; 5: 70329.
47. Yu M, Zhang W, Qin L, et al.
Enhancement of P-glycoprotein
expression by hepatocyte transplan-
tation in carbon tetrachloride-induced
rat liver. Anat Rec 2010; 293: 1167
74.
48. Brandoni A, Hazelhoff MH, Bulacio
RP, et al. Expression and function of
renal and hepatic organic anion
transporters in extrahepatic
cholestasis. World J Gastroenterol
2012; 18: 638797.
49. Kivisto KT. Comments on Multiple
transporters affect the disposition of
atorvastatin and its two active
hydroxy metabolites: application of in
vitro and ex situ systems. J
Pharmacol Exp Ther 2006; 316: 1386.
50. Heiskanen T, Backman JT,
Neuvonen M, et al. Itraconazole, a
potent inhibitor of P-glycoprotein,
moderately increases plasma
concentrations of oral morphine. Act
Anaesthesiol Scand 2008; 52: 1319
26.
51. Yamada S, Yasui-Furukori N,
Akamine Y, et al. Effects of
P-glycoprotein inducer carbamaze-
pine on fexofenadine pharmaco-
kinetics. Ther Drug Monit 2009; 31:
7648.
52. Yamashiro T, Watanable N,
Yokoyama KK, et al. Requirements of
expression of P-glycoprotein on
human natural killer leukemia cells
for cell-mediated cytotoxicity.
Biochem Pharmacol 1998; 55: 1385
90.
53. Kiser JJ, Burton JR, Anderson PL,
et al. Review and management of
drug interactions with boceprevir and
telaprevir. Hepatology 2012; 55: 1620
8.
54. Gish RG, Clark MD, Kane SD, Shaw
RE, Mangahas MF, Baqai S. Similar
risk of renal events among patients
treated with tenofovir or entecavir for
chronic hepatitis B. Clin Gastroenterol
Hepatol 2012; 10: 9416.
55. Smith HS. Opioid metabolism. Mayo
Clin Proc 2009; 84: 61324.
56. Guengerich FP, Turvey CG.
Comparison of levels of several
human microsomal cytochrome P-
450 enzymes and epoxide hydrolase
in normal and disease states using
immunochemical analysis of surgical
liver samples. J Pharmacol Exp Ther
1991; 256: 118994.
57. Jewell SA, Di Monte D, Gentile A,
et al. Decreased hepatic glutathione
in chronic alcoholic patients. J
Hepatol 1986; 3: 16.
58. Burgunder J-M, Lauterburg BH.
Decreased production of glutathione
in patients with cirrhosis. Eur J Clin
Invest 1987; 17: 40814.
59. Franz CC, Egger S, Born C, et al.
Potential drug-drug interactions and
adverse drug reactions in patients
with liver cirrhosis. Eur J Clin
Pharmacol 2012; 68: 17988.
60. Chalasani N, Gorski JC, Patel NH,
et al. Hepatic and intestinal
cytochrome P450 3A activity in
cirrhosis: effects of transjugular
intrahepatic portosystemic shunts.
Hepatology 2001; 34: 11038.
61. Trevisani F, Merli M, Savelli F, et al.
QT interval in patients with non-
cirrhotic portal hypertension and in
cirrhotic patients treated with
transjugular intrahepatic porto-
Aliment Pharmacol Ther 2013; 37: 1132-1156
2013 John Wiley & Sons Ltd

systemic shunt. J Hepatol 2003; 38:
4617.
62. Vuppalanchi R, Juluri R, Ghabril M,
et al. Drug-induced QT prolongation
in cirrhotic patients with transjugular
intrahepatic portosystemic shunt. J
Clin Gastroenterol 2011; 45: 63842.
63. Lucena MI, Andrade RJ, Tognoni G,
et al. Drug use for non-hepatic
associated conditions in patients with
liver cirrhosis. Eur J Clin Pharmacol
2003; 59: 716.
64. Sokol SI, Cheng A, Frishman WH,
et al. Cardiovascular drug therapy in
patients with hepatic diseases and
patients with congestive heart
failure. J Clin Pharmacol 2000; 40:
1130.
65. Montvale NJ. PDR Network.
Physicians Desk Reference. Available
at: http://www.PDR.net. Accessed
April 4, 2013.
66. Food and Drug Administration. Drug
section. Available at: www.fda.gov/
Drugs/default.htm. Accessed April 4,
2013.
67. Bamji N, Cohen LB. Endoscopic
sedation of patient with chronic liver
disease. Clin Liver Dis 2010; 14: 185
94.
68. Amoros A, Aparicio JR, Garmendia
M, et al. Deep sedation with propofol
does not precipitate hepatic
encephalopathy during elective upper
endoscopy. Gastrointest Endosc 2009;
70: 2628.
69. Weston BR, Chadalawada V,
Chalasani N, et al. Nurse-
administered propofol versus
midazolam and meperidine for upper
endoscopy in cirrhotic patients. Am J
Gastroenterol 2003; 98: 24407.
70. Amarapurkar DN. Prescribing
medications in patients with
decompensated liver cirrhosis. Int J
Hepatol 2011; : 15.
71. Meierhenrich R, Gauss A, Muhling B,
et al. The effect of propofol and
desurane anesthesia on human
hepatic blood ow: a pilot study.
Anesthesia 2010; 65: 108593.
72. Mandell MS, Durham J, Kumpe D,
et al. The effects of desurane and
propofol on portosystemic pressure in
patients with hypertension. Anesth
Analg 2003; 97: 15737.
73. Alonso Menarguez B, Gajate Martin
L, Garcia Suarez J, et al. Retrospective
comparative study between
sevourane and propofol in
maintaining anesthesia during liver
transplant: effects on kidney and liver
function. Rev Esp Anestesiol Reanim.
2012; 59: 23743.
74. Ko JS, Kim G, Shin YH, et al. The
effects of desurane and isourane on
hepatic and renal functions after right
Aliment Pharmacol Ther 2013; 37: 1132-1156
2013 John Wiley & Sons Ltd
Review: prescribing medications in patients with cirrhosis
hepatectomy in living donors.
Transplant Proc 2012; 44: 4424.
75. FDA Drug Safety Communication.
Important safety label changes to
cholesterol-lowering statin drugs.
Available at: www.fda.gov/Drugs/
DrugSafety/ucm293101.htm. Accessed
February 28, 2012.
76. Lewis JH, Mortensen ME, Zweig S,
et al. Efcacy and safety of high-dose
pravastatin in hypercholesterolemic
patients with well-compensated
chronic liver disease: results of a
prospective, randomized, double-
blind, placebo-controlled, multicenter
trial. Hepatology 2007; 46: 145363.
77. Vuppalanchi R, Teal E, Chalasani N.
Patients with elevated baseline liver
enzymes do not have higher
frequency of hepatotoxicity from
lovastatin than those with normal
baseline liver enzymes. Am J Med Sci
2005; 32: 625.
78. Athyros VG, Tziomalos K, Gossios T,
et al. Safety and efcacy of long-term
statin treatment for cardiovascular
events in patients with coronary heart
disease and abnormal liver tests; in
the Greek atorvastatin and coronary
heart disease evaluation (GREACE)
study: a post hoc analysis. Lancet
2010; 376: 191622.
79. Delang L, Paeshuvse J, Vliegen I,
et al. Statins potentiate the in vitro
anti-hepatitis C virus activity of
selective hepatitis C virus inhibitors
and delay or prevent resistance
development. Hepatology 2009; 50: 6
16.
80. Bader T, Fazili J, Madhoun M, et al.
Fluvastatin inhibits hepatitis C
replication in humans. Am J
Gastroenterol 2008; 103: 13839.
81. Segarra-Newnham M, Parra D,
Martin-Cooper EM. Effectiveness and
hepatotoxicity of statins in men
seropositive for hepatitis C virus.
Pharmacotherapy 2007; 27: 84551.
82. Henderson LM, Patel S, Giordano TP,
Green L, El-Serag HB. Statin therapy
and serum transaminases among a
cohort of HCV-infected veterans. Dig
Dis Sci 2010; 55: 1905.
83. Madhoun MF, Bader T. Statins
improve ALT values in chronic
hepatitis C patients with abnormal
values. Dig Dis Sci 2010; 55: 8701.
84. Bader T, Korba B. Simvastatin
potentiates the anti-hepatitis B virus
activity of FDA-approved nucleoside
analogue inhibitors in vitro. Antiviral
Res 2010; 86: 2415.
85. Chang CC, Wang SS, Huang HC,
et al. Pravastatin administration does
not induce detrimental effects on
hemodynamics and collaterals of
portal hypertensive rats. J
Gastroenterol Hepatol 2010; 25: 1394
400.
86. Abraldes JG, Albillos A, Banares R,
et al. Simvastatin lowers portal
pressure in patients with cirrhosis
and portal hypertension: a random-
ized controlled trial. Gastroenterology
2009; 136: 16518.
87. El-Serag HB, Johnson ML, Hachem
C, et al. Statins are associated with a
reduced risk of hepatocellular
carcinoma in a large cohort of
patients with diabetes.
Gastroenterology 2009; 136: 16018.
88. Tsan YT, Lee CH, Wang JD, Chen
PC. Statins and the risk of
hepatocellular carcinoma in patients
with hepatitis B infection. J Clin
Oncol 2012; 30: 62330.
89. Zhang W, Wu J, Zhou L, Xie HY,
Zheng SS. Fluvastatin, a lipophilic
statin, induces apoptosis in human
hepatocellular carcinoma cells
through mitochondria-operated
pathway. Indian J Exp Biol 2010; 48:
116774.
90. Relja B, Meder F, Wilhelm K,
Henrich D, Marzi I, Lehnert M.
Simvastatin inhibits cell growth and
induces apoptosis and G0/G1 cell
cycle arrest in hepatic cancer cells. Int
J Mol Med 2010; 26: 73541.
91. Pradelli D, Soranna D, Scotti L, et al.
Statins and primary liver cancer: a
meta-analysis of observational
studies. Eur J Cancer Prev 2013; 22:
22934.
92. Williams D, Feely J.
Pharmacokinetic-pharmacodynamic
drug interactions with HMG-CoA
reductase inhibitors. Clin
Pharmacokinet 2002; 41: 34370.
93. Levy C, Seeff LB, Lindor KD. Use of
herbal supplements for chronic liver
disease. Clin Gastroenterol Hepatol
2004; 2: 94756.
94. Stickel F, Schuppan D. Herbal
medicine in the treatment of liver
diseases. Dig Liver Dis 2007; 39: 293
304.
95. Ferrucci LM, Bell BP, Dhotre KB,
et al. Complementary and alternative
medicine use in chronic liver disease
patients. J Clin Gastroenterol 2010;
44: e405.
96. Stickel F, Patsenker E, Schuppan D.
Herbal hepatotoxicity. J Hepatol 2005;
43: 90110.
97. Lewis JH. Liver disease caused by
anesthetics, toxins and herbal
preparations. In: Feldman M,
Friedman LS, Brandt LJ, eds.
Sleisenger and Fordtrans
Gastrointestinal and Liver Disease:
Pathophysiology/Diagnosis/
Management, 9th edn. Philadelphia:
Saunders/Elsevier 2010; 144759.
1153
J. H. Lewis and J. G. Stine
98. Bunchorntavakul C, Reddy KR.
Review article: herbal and dietary
supplement hepatotoxicity. Aliment
Pharm Ther 2013; 37: 317.
99. Seeff LB, Curto TM, Szabo G, et al.
Herbal product use by persons
enrolled in the hepatitis C antiviral
long-term treatment against cirrhosis
(HALT-C) trial. Hepatology 2008; 47:
60512.
100. Sarma DN, Barrett ML, Chavez ML,
et al. Safety of green tea extracts: a
systematic review by the US
Pharmacopeia. Drug Saf 2008; 31:
46984.
101. Liss G, Lewis JH. Drug-induced liver
injury: what was new in 2008? Expert
Opin Drug Metab Toxicol 2009; 5: 1
18.
102. Teschke R, Schulze J. Suspected
herbal hepatotoxicity: requirements
for appropriate causality assessment
by the US pharmacopeia. Drug Saf
2012; 35: 10917.
103. Teschke R, Sarris J, Lebot V.
Contaminant hepatotoxins as
culprits for kava hepatotoxicity fact
or ction? Phytother Res 2013; 27:
4724.
104. Teschke R. Black cohosh and
suspected hepatotoxicity:
inconsistencies, confounding
variables, and prospective use of a
diagnostic causality algorithm: a
critical review. Menopause 2010; 17:
42640.
105. Saper RB, Phillips RS, Sehgal A, et al.
Lead, mercury, and arsenic in US-
and Indian-manufactured ayurvedic
medicines sold via the internet. JAMA
2008; 300: 91523.
106. Freedman ND, Curto TM, Morishima
C, et al. Silymarin use and liver
disease progression in hepatitis C
antiviral long-term treatment against
cirrhosis trial. Aliment Pharmacol
Ther 2011; 33: 12737.
107. Sontia B, Monney J, Gaudet L, et al.
Pseudohyperaldosteronism, liquorice,
and hypertension. J Clin Hypertens
(Greenwich) 2008; 10: 1537.
108. Stickel F, Brinkhaus B, Krahmer N,
et al. Antibrotic properties of
botanicals in chronic liver disease.
Hepatogastroenterology 2002; 49:
11028.
109. Lee JK, Kim KH, Shin HK.
Therapeutic effects of the oriental
herbal medicine Sho-saiko-to on liver
cirrhosis and carcinoma. Hepatol Res
2011; 41: 82537.
110. Chiturri S, Farrell GC. Hepatotoxic
slimming aids and other herbal
hepatotoxins. J Gastroenterol Hepatol
2008; 23: 36673.
111. Posadzki P, Watson L, Ernst E.
Herb-drug interactions: an overview
1154
of systemic reviews. Br J Clin
Pharmacol 2013; 75: 60318.
112. Neff GW, OBrien C, Montalbano M.
Consumption of dietary supplements
in a liver transplant population. Liver
Transpl 2004; 10: 8815.
113. Chiturri S, George J. Hepatotoxicity
of commonly used drugs:
nonsteroidal anti-inammatory drugs,
antihypertensives, antidiabetic agents,
anticonvulsants, lipid-lowering agents,
psychotropic drugs. Semin Liver Dis
2002; 22: 16983.
114. Li P, Robertson TA, Zhang Q, et al.
Hepatocellular necrosis, brosis and
microsomal activity determine the
hepatic pharmacokinetics of basic
drugs in right-heart-failure-induced
liver damage. Pharm Res 2012; 29:
165869.
115. Homeida M, Jackson L, Roberts CJ.
Decreased rst-pass metabolism of
labetalol in chronic liver disease. BMJ
1978; 2: 104850.
116. Marinella MA. Labetolol-induced
hepatitis in a patient with chronic
hepatitis B infection. J Clin Hypertens
2002; 4: 1201.
117. Eriksson LS, Kagedal B, Wahren J.
Effects of captopril on hepatic venous
pressure and blood ow in patients
with liver cirrhosis. Am J Med 1984;
76: 6670.
118. Ohnishi A, Tsuboi Y, Ishizaki T,
et al. Kinetics and dynamics of
enalapril in patients with liver
cirrhosis. Clin Pharmacol Ther 1989;
45: 65765.
119. Hayes PC, Plevris JN, Bouchier IA.
Pharmacokinetics of enalapril and
lisinopril in subjects with normal and
impaired hepatic function. J Hum
Hypertens 1989; 3: 1538.
120. Klotz U. Anti-arrhythmics:
elimination and dosage
considerations in hepatic
impairment. Clin Pharmacokinet
2007; 46: 98596.
121. Mcquinn RL, Pentikainen PJ, Chang
SF, et al. Pharmacokinetics of
ecanide in patients with cirrhosis of
the liver. Clin Pharmacol Ther 1988;
44: 56672.
122. Wensing G, Monig H, Ohnhaus EE,
et al. Pharmacokinetics of encainide
in patients with cirrhosis. Cardiovasc
Drugs Ther 1991; 5: 7339.
123. Stine JG, Khokhar OS,
Charalambopoulos J, et al.
Rheumatologists awareness of
screening practices for hepatitis B
virus infection prior to initiating
immunomodulatory therapy. Arthritis
Care Res 2010; 62: 70411.
124. Stine JG, Bass M, Ibrahim D, et al.
Dermatologists awareness of and
screening practices for hepatitis B
virus infection before initiating tumor
necrosis factor-alpha inhibitor therapy.
South Med J 2011; 104: 7818.
125. Yazdany J, Calabrese L. Preventing
hepatitis B reactivation in
immunosuppressed patients: is it time
to revisit the guidelines? Arthritis
Care Res (Hoboken) 2010; 62: 5859.
126. Cabrera Villabla SR, Victoria
Hernandez Miguel M, Sanmarti Sala
R. How does one manage patients
with rheumatoid arthritis and positive
serology to hepatitis B, hepatitis C,
human immunodeciency virus?
Reumatol Clin 2011; 7: 2037.
127. Saag KG, Teng GG, Parkar NM, et al.
American College of Rheumatology
2008 recommendations for the use of
nonbiologic and biologic disease-
modifying antirheumatic drugs in
rheumatoid arthritis. Arthritis Rheum
2008; 59: 76284.
128. Singh JA, Furst DE, Bharat A, et al.
2012 update of the 2008 American
College of Rheumatology
recommendations for the use of
disease-modifying antirheumatic
drugs and biologic agents in the
treatment of rheumatoid arthritis.
Arthritis Care Res 2012; 64: 62539.
129. Charbel H, Lewis JH. Hepatitis B
reactivation during chemotherapy and
other immunosuppression. In: Shetty
K, Wu G, eds. Chronic Viral Hepatitis
Diagnosis and Therapeutics, 2nd edn.
New York, NY: Humana Press, Inc.,
2009; 30736.
130. Lubel B, Angus PW. Hepatitis B
reactivation in patients receiving
cytotoxic chemotherapy: diagnosis
and management. J Gastroenterol
Hepatol 2010; 25: 86471.
131. Jick SS, Stender M, Myers MW.
Frequency of liver disease in type 2
diabetic patients treated with oral
antidiabetic agents. Diabetes Care
1999; 22: 206771.
132. Brackett CC. Clarifying metformins
role and risks in liver dysfunction.
J Am Pharm Assoc 2010; 50: 40710.
133. Donadon V, Balbi M, Mas MD, et al.
Metformin and reduced risk of
hepatocellular carcinoma in diabetic
patients with chronic liver disease.
Liver Int 2010; 30: 7508.
134. Nkontchou G, Cosson E, Aout M,
et al. Impact of metformin on the
prognosis of cirrhosis induced by
viral hepatitis C in diabetic patients. J
Clin Endocrinol Metab 2011; 96:
26018.
135. Cone CJ, Bachyrycz AM, Murata GH.
Hepatotoxicity associated with
metformin therapy in treatment of
type 2 diabetes mellitus with
nonalcoholic fatty liver disease. Ann
Pharmacother 2010; 44: 16559.
Aliment Pharmacol Ther 2013; 37: 1132-1156
2013 John Wiley & Sons Ltd

136. Schlatter C, Egger SS, Tchambaz L,
Krahenbuhl S. Pharmacokinetic
changes of psychotropic drugs in
patients with liver disease:
implications for dose adaptation.
Drug Saf 2009; 32: 56178.
137. Roberts RK, Wilkinson GR, Branch
RA, et al. Effect of age and
parenchymal liver disease on the
disposition and elimination of
chlordiazepoxide (Librium).
Gastroenterology 1978; 75: 47985.
138. Caputo F, Bernardi M, Zoli G.
Efcacy and safety of gamma-
hydroxybutyrate in treating alcohol
withdrawal syndrome in an alcohol-
dependent inpatient with
decompensated liver cirrhosis: a case
report. J Clin Psychopharmacol 2011;
31: 1401.
139. MacGilchrist AJ, Birnie GG, Cook A,
et al. Pharmacokinetics and
pharmacodynamics of intravenous
midazolam in patients with severe
alcoholic cirrhosis. Gut 1986; 2: 1905.
140. Zala G, Schmid M, Buhler H.
Fulminant hepatitis caused by
disulfarim. Dtsch Med Wochenschr
1993; 118: 135560.
141. Vanjak D, Samuel D, Gossert F, et al.
Fulminant hepatitis induced by
disulfarim in a patient with alcoholic
cirrhosis. Survival after
transplantation. Gastroenterol Clin
Biol 1989; 2: 10758.
142. Mohanty SR, LaBrecque DR, Mitos
FA, et al. Liver transplantation for
disulfarim-induced fulminant hepatic
failure. J Clin Gastroenterol 2004; 38:
2925.
143. Rabkin JM, Corless CL, Orloff SL,
et al. Liver transplantation for
disulfarim induced hepatic
failure. Am J Gastroenterol 1998; 93:
8301.
144. Addolorato G, Leggio L, Ferrulli A,
et al. Effectiveness and safety of
baclofen for maintenance of alcohol
abstinence in alcohol-dependent
patients with liver cirrhosis:
randomised, double-blind
controlled study. Lancet 2007; 370:
191522.
145. Koren G, Beatty K, Seto A, et al. The
effects of impaired liver function on
the elimination of antineoplastic
agents. Ann Pharmacother 1992; 26:
36371.
146. Donelli MG, Zucchetti M, Munzone
E, et al. Pharmacokinetics of
anticancer agents in patients with
impaired liver function. Eur J Cancer
1998; 34: 3346.
147. Lewis GP, Jusko WJ.
Pharmacokinetics of ampicillin in
cirrhosis. Clin Pharmacol Ther 1975;
18: 47584.
Aliment Pharmacol Ther 2013; 37: 1132-1156
2013 John Wiley & Sons Ltd
Review: prescribing medications in patients with cirrhosis
148. Dixit RK, Satapathy SK, Kumar R,
et al. Pharmacokinetics of ciproox-
acin in patients with liver cirrhosis.
Indian J Gastroenterol 2002; 21: 623.
149. Montay G, Gaillot J.
Pharmacokinetics of uroquinolones
in hepatic failure. J Antimicrob
Chemother 1990; 26: 617.
150. Sambatakou H, Giamarellos-
Bourboulis EJ, Galanakis N, et al.
Phramacokinetics of uoroquinolones
in uncompensated cirrhosis: the
signicance of penetration in the
ascetic uid. Int J Antimicrob Agents
2001; 18: 4414.
151. Cho YJ, Lee SM, Yoo CG, et al.
Clinical characteristics of tuberculosis
in patients with liver cirrhosis.
Respirology 2007; 12: 4015.
152. Saigal S, Agrawal SR, Nandeesh HP,
et al. Safety of an ooxacin-based
antitubercular regimen for the
treatment of tuberculosis in patients
with underlying chronic liver disease:
a preliminary report. J Gastroenterol
Hepatol 2001; 16: 102832.
153. Saito A, Nagayama N, Yagi O, et al.
Tuberculosis complicated with liver
cirrhosis. Kekkaku 2006; 81: 45765.
154. Hawkins MT, Lewis JH. Latest
advances in predicting DILI in
humans: focus on biomarkers. Expert
Opin Drug Metab Toxicol 2012; 8:
152130.
155. Lee BH, Koh WJ, Choi MS, et al.
Inactive hepatitis B surface antigen
carrier state and hepatotoxicity
during antituberculosis chemotherapy.
Chest 2005; 127: 130411.
156. Kwon YS, Koh WJ, Suh GY, et al.
Hepatitis C virus infection and
hepatotoxicity during antituberculosis
chemotherapy. Chest 2007; 131: 8038.
157. Jahng AW, Tran T, Bui L, et al.
Safety of treatment of latent
tuberculosis infection in compensated
cirrhotic patients during transplant
candidacy period. Transplantation
2007; 83: 155762.
158. Kaneko Y, Nagayama N, Kawabe Y,
et al. Drug-induced hepatotoxicity
caused by anti-tuberculosis drugs in
tuberculosis patients complicated with
chronic hepatitis. Kekkaku 2008; 83:
139.
159. Holty JE, Gould MK, Meinke L, et al.
Tuberculosis in liver transplant
recipients: a systematic review and
meta-analysis of individual patient
data. Liver Transpl 2009; 15: 894906.
160. Jafri SM, Singal AG, Kaul D, et al.
Detection and management of latent
tuberculosis in liver transplant
patients. Liver Transpl 2011; 17: 306
14.
161. Jasmer RM, Daley CL. Rifampin and
pyrazinamide for treatment of latent
tuberculosis infection: is it safe? Am J
Respir Crit Care Med 2003; 167: 80910.
162. Salmon-Ceron D, Sogni P, Spiridon
G, et al. Antiretroviral agents in
HIV-infected patients with cirrhosis.
Presse Med 2005; 34: 1S4552.
163. Maida I, Nunez M, Rios MJ, et al.
Severe liver disease associated with
prolonged exposure to antiretroviral
drugs. J Acquir Immune Dec Syndr
2006; 42: 17782.
164. Labarga P, Soriano V, Vispo ME,
et al. Hepatotoxicity of antiretroviral
drugs is reduced after successful
treatment of chronic hepatitis C in
HIV-infected patients. J Infect Dis
2007; 196: 6706.
165. Aranzabal L, Casado JL, Moya J,
et al. Inuence of liver brosis on
highly active antiretroviral therapy-
associated hepatotoxicity in patients
with HIV and hepatitis C virus
coinfection. Clin Infect Dis 2005; 40:
58893.
166. Macias J, Orihuela F, Rivero A, et al.
Hepatic safety of tipranavir plus
ritonavir (TPV/r)-based antiretroviral
combinations: effect of hepatitis virus
co-infection and pre-existing brosis.
J Antimicrob Chemother 2009; 63:
17883.
167. Pineda JA, Santos J, Rivero A, et al.
Liver toxicity of antiretroviral
combinations including atazanavir/
ritonavir in patients co-infected with
HIV and hepatitis viruses: impact of
pre-existing liver brosis. J Antimicrob
Chemother 2008; 61: 92532.
168. Wyles DL, Gerber JG. Antiretroviral
drug pharmacokinetics in hepatitis
with hepatic dysfunction. Clin Infect
Dis 2005; 40: 17481.
169. Yuen GJ, Weller S, Pakes GE. A
review of the pharmacokinetics of
abacavir. Clin Pharmacokinet 2008;
47: 35171.
170. Barreiro P, Rodriguez-Novoa S,
Labarga P, et al. Inuence of liver
brosis stage on plasma levels of
antiretroviral drugs in HIV-infected
patients with chronic hepatitis C. J
Infect Dis 2007; 195: 9739.
171. Dominguez S, Ghosn J, Peytavin G,
et al. Impact of hepatitis C and liver
brosis on antiretroviral plasma drug
concentrations in HIV-HCV co-
infected patients: the HEPADOSE
study. J Antimicrob Chemother 2010;
65: 24459.
172. Meynard JL, Lacombe K, Poirier JM,
et al. Inuence of liver brosis stage
on plasma levels of efavirenz in HIV-
infected patients with chronic
hepatitis B or C. J Antimicrob
Chemother 2009; 63: 57984.
173. Dahri K, Ensom MH. Efavirenz and
nevirapine in HIV-1 infection: is
1155
J. H. Lewis and J. G. Stine
there a role for clinical
pharmacokinetic monitoring? Clin
Pharmacokinet 2007; 46: 10932.
174. Robertson SM, Scarsi KK, Posteinick
MJ, et al. Elevated plasma
concentrations of protease inhibitors
and nonnucleoside reverse
transcriptase inhibitors in patients
coinfected with human
immunodeciency virus and hepatitis B
or C: case series and literature review.
Pharmacotherapy 2005; 25: 106872.
175. Lok ASF, McMahon BJ. AASLD
practice guidelines. Chronic hepatitis
B: update 2009. Hepatology 2009; 50:
136.
176. Johnson MA, Moore KH, Yuen GJ,
et al. Clinical pharmacokinetics of
lamivudine. Clin Pharmacokinet 1999;
36: 4166.
177. Ghany MG, Nelson DR, Strader DB,
et al. An update on treatment of
genotype 1 chronic hepatitis C virus
infection: 2011 practice guideline by
the American Association for the
Study of Liver Diseases. Hepatology
2011; 54: 143344.
178. Saxena V, Terrault N. Hepatitis C
virus treatment and liver
transplantation in the era of new
antiviral therapies. Curr Opin Organ
Transplant 2012; 17: 21624.
179. Lucena MI, Andrade RJ, Tognoni G,
et al. Multicenter hospital study on
prescribing patterns for prophylaxis
and treatment of complications
of cirrhosis. Eur J Clin Pharmacol
2002; 58: 43540.
180. Dial S, Alrasadi K, Manoukian C,
et al. Risk of Clostridium difcile
diarrhea among hospital inpatients
prescribed proton pump inhibitors:
cohort and case-control studies.
CMAJ 2004; 171: 338.
181. Deshpande A, Pasupuleti V, Thota P,
et al. Acid suppressive therapy
associated with spontaneous bacterial
peritonitis in cirrhotic patients a
meta-analysis. J Gastroenterol Hepatol
2013; 28: 23542.
182. Goel GA, Deshpande A, Loper R,
et al. Increased rate of spontaneous
bacterial peritonitis among cirrhotic
patients receiving pharmacologic acid
suppression. Clin Gastroenterol
Hepatol 2012; 10: 4227.
183. Trikudanathan G, Israel J, Cappa J,
et al. Association between proton
pump inhibitors and spontaneous
bacterial peritonitis in cirrhotic
patients: a systematic review and
meta-analysis. Int J Clin Pract 2011;
65: 6748.
184. Deshpande A, Pant C, Pasupuleti V,
et al. Association between proton
pump inhibitor therapy and
Clostridium difcile infection in a
1156
meta-analysis. Clin Gastroenterol
Hepatol 2012; 10: 22533.
185. Bajaj JS, Ratliff SM, Heuman DM,
et al. Proton pump inhibitors are
associated with a high rate of serious
infection in veterans with
decompensated cirrhosis. Aliment
Pharmacol Ther 2012; 36: 86674.
186. van Vlerken LG, Huisman EJ,
vanHoek B, et al. Bacterial infections
in cirrhosis: role of proton pump
inhibitors and intestinal permeability.
Eur J Clin Invest 2012; 42: 7607.
187. Terg R. Comment. Spontaneous
bacterial peritonitis and
pharmacologic acid suppression in
patients with cirrhosis. Hepatology
2013; 57: 4113.
188. Loomba R, Wesley R, Bain A, Csako
G, Pucino F. Role of uoroquinolones
in the primary prophylaxis of
spontaneous bacterial peritonitis:
meta-analysis. Clin Gastroenterol
Hepatol 2009; 7: 48793.
189. Saab S, Hernandez JC, Chi AC, Tong
MJ. Oral antibiotic prophylaxis
reduces spontaneous bacterial
peritonitis occurrence and improves
short-term survival in cirrhosis: a
meta-analysis. Am J Gastroenterol
2009; 104: 9931001.
190. Afdhal NH, Giannini EG, Tayyab G,
et al. Eltrombopag before procedures
in patients with cirrhosis and
thrombocytopenia. N Engl J Med
2012; 367: 71624.
191. Bauman JW, Vincent CT, Peng B,
et al. Effect of hepatic or renal
impairment on eltrombopag
pharmacokinetics. J Clin Pharmacol
2011; 51: 73950.
192. Rossi S, Assis DN, Awsare M, et al.
Use of over-the-counter analgesics in
patients with chronic liver disease:
physicians recommendations. Drug
Saf 2008; 31: 26170.
193. Watkins PB, Kaplowitz N, Slattery JT,
et al. Aminotransferase elevations in
healthy adults receiving 4 grams of
acetaminophen daily: a randomized
controlled trial. JAMA 2006; 296: 8793.
194. Heard K, Green JL, Bailey JE, et al. A
randomized trial to determine the
change in alanine aminotransferase
during 10 days of paracetamol
(acetaminophen) administration in
subjects who consume moderate
amounts of alcohol. Aliment
Pharmacol Ther 2007; 26: 28390.
195. Zimmerman HJ, Maddrey WC.
Acetaminophen (paracetamol)
hepatotoxicity with regular intake of
alcohol: analysis of instances of
therapeutic misadventure. Hepatology
1995; 22: 76773.
196. Lee YC, Chang CH, Lin JW, et al.
Non-steroidal anti-inammatory
drugs use and risk of upper
gastrointestinal adverse events in
cirrhotic patients. Liver Int 2012; 32:
85966.
197. Riley TR III, Smith JP. Ibuprofen-
induced hepatotoxicity in patients
with chronic hepatitis C: a case series.
Am J Gastroenterol 1998; 93:
15635.
198. Andrade RJ, Lucena MI, Garcia-
Cortes M, et al. Chronic hepatitis C,
ibuprofen, and liver damage. Am J
Gastroenterol 2002; 97: 18545.
199. Banerjee N, Nguyen D, Rivas C, et al.
Trainees attitudes towards the use of
NSAIDs and acetaminophen in
chronic liver disease patients. Am J
Gastroenterol 2012; 107: S164.
200. Banerjee N, Nguyen D, Rivas CA,
et al. Acetaminophen (APAP) dose
preferences of trainees for patients
with chronic liver disease (CLD).
Hepatology 2012; 56: 599600A.
201. Nguyen D, Banerjee N, Rivas C, et al.
Reasons given by trainees for not
recommending acetaminophen or
NSAIDs to patients with chronic liver
disease. Am J Gastroenterol 2012;
107: S164-5.
202. Murphy EJ. Acute pain management
pharmacology for the patient with
concurrent renal or hepatic disease.
Anesth Intensive Care 2005; 33: 31122.
203. Laidlaw J, Read AE, Sherlock S.
Morphine tolerance in hepatic
cirrhosis. Gastroenterology 1961; 40:
38996.
204. Chandok N, Watt KD. Pain
management in the cirrhotic patient:
the clinical challenge. Mayo Clin Proc
2010; 85: 4518.
205. Tashakori A, Afshari R. Tramadol
overdose as a cause of serotonin
syndrome: a case series. Clin Toxicol
(Phila) 2010; 48: 33741.
206. Guaiana G, Barbui C, Hotopf M.
Amitriptyline versus other types of
pharmacotherapy for depression.
Cochrane Database Syst Rev 2003; 2:
CD004186.
207. Dunn MJ. Nonsteroidal anti-
inammatory drugs and renal
function. Annu Rev Med 1984; 35:
41128.
208. Laf G, La Villa G, Pinzani M, et al.
Arachidonic acid derivatives and
renal function in liver cirrhosis.
Semin Nephrol 1997; 17:
53048.
209. Lewis JH. Nonsteroidal anti-
inammatory drugs and leukotriene
antagonists: pathology and clinical
presentation of hepatotoxicity. In:
Kaplowitz N, DeLeve LD, eds. Drug-
Induced Liver Disease. 2nd ed. New
York: Informa Healthcare, 2007; 439
64.
Aliment Pharmacol Ther 2013; 37: 1132-1156
2013 John Wiley & Sons Ltd