To outline the liver’s role in

the following processes:

• Protein handling
• Carbohydrate handling
• Lipid handling
• Bile and bilirubin handling
• Hormone inactivation
• Drug metabolism
• Immunological function
• HOW TO ASSESS THE LIVER
FUNCTION ?
•
• PLEASE ANSWER
•
Principles of drug use in liver
disease
• Pharmacokinetics and
pharmacodynamics
• Adverse effects
• Interactions
Can you use paracetamol in
a patient with liver
disease?
• YES OR NO?
•
• Many people would answer no,
perhaps because of the worries
about paracetamol hepatotoxicity.
• The answer, however, is most likely
to be
• yes, but in actual fact you cannot
answer it without knowing more
about the patient.
 CASE STUDIES
• Patient 1 – Mild hepatitis without
cirrhosis
• Non-alcoholic steatohepatitis
• The synthetic and metabolic capacity
of this patient’s liver is unlikely to
be affected by the isolated rise in
ALT and drug handling is unlikely to
be altered.
• It is important to ensure that the
patient has no signs of cirrhosis, as
many diseases that present with
LET’S TALK ABOUT CHOICE OF
ANALGESIC
Paracetamol
• Paracetamol can safely be given to this

patient in normal therapeutic doses.

• If this patient was alcoholic or malnourished it

might raise additional concerns. Information

regarding the therapeutic use of paracetamol
in alcoholics is limited and conflicting.
Considering the evidence available, current
practice is not to reduce the dose of
paracetamol in alcoholics. However, if the
patient were malnourished a dose reduction
might be considered.
• If the patient had acute viral hepatitis with

significantly raised transaminases and a raised

PT, an increase in the dosage interval of
paracetamol should be considered as the
clearance of paracetamol has beenshown to
• Non-steroidal anti-inflammatory
drugs (NSAIDs)
• • NSAIDs can be used in this patient at
normal therapeutic doses.
• • Given the rare but potential
hepatotoxic risk with NSAIDs, patients
should be instructed to be aware of
the symptoms of hepatotoxicity and
• to report fatigue, malaise, anorexia,
nausea and vomiting.
•
Opioids
• Opioids can be used in this patient at

normal therapeutic doses.

• If the patient had acute viral

hepatitis with significantly raised

transaminases, an increase in the
dosage interval of pethidine should
be considered as the clearance of
pethidine has been shown to be
reduced by approximately 50% in
these types of patients.
HOW ABOUT LIPID
LOWERING
DRUGS?
Statins
• Although the ALT is slightly higher than
three times ULN, a statin could be used
with great caution.
• However, as statins can cause raised ALT
and AST, their use may make it difficult
to distinguish between iatrogenic
elevation of ALT and AST and worsening
hepatitis.
• The statin should be started at a low dose
and increased according to clinical
response.
• There is no specific recommendation in
relation to which statin should be used.
Bile acid sequestrants


• Colestyramine and colestipol could

be used in this patient provided
they are not constipated.
• The INR should be routinely
monitored in case vitamin K
absorption is inhibited.
Fibrates


• Fibrates occasionally cause deranged

LFTs: elevated ALT/AST, altered ALP
and GGT.
• Use of a fibrate may make it difficult
to distinguish between iatrogenic
elevation of ALT and AST and
worsening hepatitis.
• Ezetimibe
• Ezetimibe has caused elevations in
transaminases when used with
simvastatin,
• with which it is usually combined.
Inhibitors of fasting-induced


lipolysis
• Acipimox is not associated with liver
adverse drug reactions and should
be safe to use.
• Niacin (nicotinic acid) has been
reported to cause transient
elevation in transaminases at high
doses, as well as more serious
hepatic reactions.
• The SR form could be used with
caution.
 Patient 2 – Cholestasis
Primary sclerosing cholangitis
• The synthetic and metabolic capacity of
this patient’s liver is unlikely to be
affected by cholestasis.
• However, consideration needs to be
given to
• protein binding (the patient has
hyperbilirubinaemia); excretion of the
drug or metabolites in bile (the
patient has cholestasis); and
• The lipophilicity of the drug (some
lipophilic drugs require bile salts for
absorption, and these would be
reduced in cholestasis).
P a ra ce ta m o l

Pa ra ce ta m o lca n b e sa fe ly
a d m in iste re d to th is p a tie n t in
n o rm a lth e ra p e u tic
d o se s.
NSAIDs
• Many centres prefer to avoid using
NSAIDs
• However, if the liver disorder is
purely cholestatic in origin and the
disease has not progressed to
cirrhosis and portal hypertension,
NSAIDs may be an option.
•
• other types of patients who are
chronically cholestatic may have
impaired absorption of vitamin K
and a raised INR. In these types of
patients there is an increased risk
of bleeding, and NSAIDs should
therefore be avoided.
•
• WHY ?
•
• PLEASE ANSWER
• Cholestasis may reduce the absorption
of the highly lipophilic ibuprofen.
• All NSAIDs are highly protein bound and

increased levels of free drug may occur

in the presence of a raised bilirubin,
because it can displace the bound drug
from albumin.
• The metabolism of NSAIDs is unlikely to

be affected in this patient.

• Cholestasis may reduce the elimination

of certain NSAIDs that are excreted via

the biliary tract (e.g. sulindac,
indometacin).
• Ibuprofen is associated with the lowest

risk of GI bleeding compared toother

NSAIDs.
Why again ?
• Taking into account
pharmacokinetics, adverse effects
and clinical studies,
• ibuprofen may be considered the
best choice in this patient, for the
following reasons:
• • Short half-life
• • No biliary excretion of active forms
• • Possibly the lowest risk of
hepatotoxicity
• • Lowest risk of bleeding when used
at doses <1600 mg/day.
O p io id s
O p io id s ca n b e u se d w ith ca u tio n a s
m e ta b o lism is n o t a ffe cte d in th is p a tie n t. C a re
m u st b e ta k e n to a v o id co n stip a tio n .
 M o st o p io id s h a v e lo w lip id so lu b ility a n d a re
w e ll a b so rb e d o ra lly in ch o le sta sis .
 M o st o p io id s h a v e lo w p ro te in b in d in g , so
a lte ra tio n s in a lb u m in a n d b iliru b in a re u n lik e ly
to a lte r fre e d ru g le v e ls .
 C h o le sta sis m a y re d u ce th e e lim in a tio n o f
m o rp h in e a n d p o ssib ly co d e in e , a s th e y
u n d e rg o so m e b ilia ry e x cre tio n .
 M o rp h in e ca n re d u ce b ilia ry se cre tio n s a n d
ca n ca u se b ile d u ct sp a sm , w h ich co u ld ca u se
re d u ce d b ilia ry flo w , p o te n tia lly e x a ce rb a tin g
th is p a tie n t’ s p ro b le m s .
üIn p ra ctice th is d o e s n o t a p p e a r to b e
clin ica lly sig n ifica n t.
• It is important to note that the patient
could rapidly deteriorate into a state of
decompensation where liver function
would be markedly affected.


• Other things to consider are the

– raised INR and
– low platelet count (avoid drugs that affect
coagulation or cause bleeding), the risk
of
• encephalopathy if the liver function
decompensates (caution with any
drugs causing sedation, constipation,
fluid or electrolyte disturbances) and
the
• risk of hepatorenal syndrome (avoid
Statins


• In 2006 the National Lipid Association’s

Statin Safety Assessment Task Force
concluded that chronic liver disease and
stable, compensated liver disease are
not contraindications to the use of
statins [2, 3].
• However, statins should be used with
caution in this patient for two reasons:
• • They are highly excreted in bile and
their pharmacodynamic disposition in
obstructive cholestasis is unknown.
• • They are highly protein bound, and
hyperbilirubinaemia may result in
increased blood levels of free drug and
metabolites through displacement from
Bile acid sequestrants


• Colestyramine and colestipol could

be used in this patient provided
there is no constipation.
• The INR should be routinely
monitored in case vitamin K
absorption is inhibited.
• These drugs might have a beneficial
effect on the pruritus.
Fibrates


• The fibrates are very lipophilic & highly protein

bound.
• Hyperbilirubinaemia may cause displacement
from plasma proteins, leading to increased free
drug concentrations.
• Fenofibrate and bezafibrate are excreted almost
entirely in the urine and are more appropriate
than gemfibrozil in obstructive jaundice.
• Gemfibrozil is significantly excreted in bile and
undergoes enterohepatic recycling, to which
part of its activity is due; this would be reduced
by obstructive jaundice.
• All fibrates can cause an increase in the
cholesterol saturation of bile. An increase in
gallstone formation has been reported. This is a
class effect.
• The fibrates may cause altered LFTs, including
Ezetimibe


• Ezetimibe is highly lipid soluble but it is

not clear whether it requires bile salts
for absorption.
• Part of its activity is due to enterohepatic
recycling, which may be reduced by
obstructive jaundice.
• This may lead to a reduction in, or the
elimination of, any secondary peaks.
• It is highly plasma protein bound:
hyperbilirubinaemia may cause
displacement from plasma proteins,
leading to increased free drug
concentrations.
• It has not been reported to cause
cholestasis. However, it is generally
used with simvastatin which would not
Inhibitors of fasting-induced


lipolysis
• As acipimox and niacin are not highly
protein bound and are not
lipophilic,
• cholestasis should not affect their
disposition.
• They are largely excreted in the
urine. Neither has been reported to
cause cholestasis.
• Both may cause pruritus, from which
this patient suffers.
Drug interactions


• Fluvastatin has been reported to

interact with rifampicin, causing
increased clearance of the statin.
• Rifampicin is an inducer of the CYP
450 3A4 isoenzyme and may
increase the rate of clearance of
statins that are substrates for 3A4.
 Patient 3 – Compensated
cirrhosis
Cryptogenic cirrhosis
• Despite cirrhosis, this patient is
maintaining good hepatocyte function
• (normal albumin, mildly raised INR,
normal bilirubin) and the metabolic and
excretory capacity of the liver should
not be significantly reduced.
• The patient has portal hypertension, so
blood flow to the liver will be impaired,
which will reduce first-pass metabolism
of highly extracted drugs (extraction
ratio >0.7).
• This will result in greater bioavailability of
oral doses of these drugs.
P a ra ce ta m o l
 Pa ra ce ta m o l ca n sa fe ly b e a d m in iste re d in n o rm a l
th e ra p e u tic d o se s in th is p a tie n t.
 C a u tio n sh o u ld b e u se d in p a tie n ts su sce p tib le to
h e p a tic e n zym e in d u ctio n
( e . g . chronic alcoholics and patients taking enzyme -
in d u cin g d ru g s).
E n zym e in d u ctio n m a y th e o re tica lly e n h a n ce th e
p ro d u ctio n o f toxic
m e ta b o lite s, b u t cu rre n tly th e re is n o cle a r e vid e n ce
th a t th e se in te ra ctio n s a re clin ica lly sig n ifica n t.
 C u rre n t e vid e n ce su g g e sts th a t ch ro n ic a lco h o lic
p a tie n ts ca n b e g ive n p a ra ce ta m o lin n o rm a l
th e ra p e u tic d o se s, a s u n le ss th e y h a ve o th e r risk
fa cto rs su ch a s m a ln u tritio n , th e ir risk o f d e ve lo p in g
se ve re h e p a to toxicity is n o g re a te r th a n th a t o f th e
g e n e ra l p o p u la tio n .
 C a u tio n sh o u ld b e u se d in p a tie n ts w ith re d u ce d
a b ility to e lim in a te th e toxic m e ta b o lite d u e to
NSAIDs


• NSAIDs should be avoided in this

patient, or indeed any patient with
cirrhosis, because of their
unfavourable side-effect profile:
üIncreased risk of bruising/bleeding
üIncreased risk of renal dysfunction
and hepatorenal syndrome
üIncreased risk of gastrointestinal
ulceration (especially if taken
concomitantly with alcohol)
üDisturbance of electrolytes and fluid
balance.
Opioids


• Ideally opioids should be avoided in

this patient as most are
metabolised by the liver and have a
high first-pass effect (exceptions
include tramadol).
• Strong opioids
• These should only be considered in
severe pain, preferably after
discussion with a liver unit.
Tramadol
Should not be considered first line in cirrhotic patients
for the following
reasons:
 Tramadol itself acts on the neurotransmitters
norepinephrine and serotonin, whereas the active
intermediate metabolite acts on opioid receptors and has a
much higher affinity for these than tramadol.

 If metabolism is reduced the analgesic effect provided by

the active
metabolite would be expected to decrease.
 The half-life of tramadol and its active metabolite will
be increased
(owing to reduced clearance) so the overall effect on
tramadol activity is
not known.

 Tramadol can lower the seizure threshold, which could

precipitate
seizures in susceptible individuals, e.g. alcoholics.
Statin
• compensated liver disease are not
contraindications to the use of statins, but
• contraindicated in decompensated disease
or liver failure
• As the patient has portal hypertension,
blood flow through the liver is reduced
and the first-pass effect is likely to be
lessened, increasing the amount of all
statins reaching the systemic circulation.
• a statin is necessary, the drug of choice
would be pravastatin which undergoes
less first-pass extraction and is only partly
cleared by the liver
• should be started at a low dose, e.g. 10 mg
• Bile acid sequestrants
• Colestyramine and colestipol could
be used provided the patient is not
constipated.
• Fibrates can cause derangements of
LFTs, both cholestatic (GGT and ALP)
and hepatitic (AST, ALT).
• This may be difficult to distinguish from
an endogenous change in the patient’s
liver picture.
• The fibrates have been reported to cause
a reduction in haemoglobin, which
might be - significant in this patient, as
she has thrombocytopenia and one
varix:
• Fenofibrate can also reduce fibrinogen
levels. Fibrates should therefore be
avoided in this patient.
Ezetimibe


• Ezetimibe is only partly metabolised

by the liver and should be safe to
use alone.
Inhibitors of fasting-induced lipolysis


• Acipimox is only partly metabolised and

should be safe in this patient.
• Niacin undergoes extensive first-pass
metabolism, which would be reduced
due to the decrease in liver blood flow
caused by the patient’s cirrhosis.
• Both drugs are gastric irritants and should
probably be avoided in patients with
varices or a history of variceal bleeding
or coagulopathy, or a risk thereof.
• Niacin can also cause thrombocytopenia.
• This patient has a varix and would be at
 Patient 4 – Decompensated
cirrhosis
• Alcoholic liver disease
This patient has decompensated liver disease with
significantly impaired synthetic, metabolic and
excretory function (low albumin, raised INR,
hyperbilirubinaemia, encephalopathy).
• The reduction in hepatocyte mass and function will
significantly reduce the metabolism of low extraction
ratio drugs (hepatocyte dependent).
• The patient also has severe portal hypertension, which
will reduce first-pass metabolism, increasing the
bioavailability of high extraction ratio drugs.
• The ascites may alter the absorption and distribution of
some drugs.
• Highly protein-bound drugs may be affected by
hypoalbuminaemia and hyperbilirubinaemia, resulting
in increased levels of free drug.
• Other things to consider are the
raised INR (avoid drugs that
• affect coagulation or cause
bleeding), encephalopathy (avoid
any drugs
• causing sedation and other CNS side
effects, constipation, fluid or
• electrolyte disturbances) and
impaired renal function (adjust
doses
• accordingly and avoid renally toxic
drugs).
• Paracetamol
• The half-life has been shown to be
prolonged in some single-dose
• studies, but no accumulation or
hepatotoxicity has been shown
after
• repeated dosing, therefore normal
doses and frequency can be used.
• Further advice as for Patient 3 with
compensated cirrhosis.
• NSAIDs
• NSAIDs should be avoided in
decompensated cirrhotic patients
because
• of the potential for impaired
metabolism and increases in the level
of
• unbound drug due to low albumin and
high bilirubin, but more importantly
• NSAIDs should be avoided because of
their unfavourable sideeffect
• profile (see details in Patient 3).
Opioids analgesic


• Ideally opioids should be avoided in

this patient, as most are
metabolisedn by the liver
• so there is a risk of accumulation in
hepatic cirrhosis and portal
hypertension.
For Lipid lowering drugs
• Hyperlipidaemia rarely occurs in
cirrhotic patients.
• Patients with decompensated disease
should not be given medical
treatment for hyperlipidaemia:
• medications should be withheld during
the period of decompensation
• reinitiated according to the principles
outlined when the patient’s synthetic
function recovers.
• Note that chronic alcohol use can
induce CYP450 enzymes: drugs which
are metabolised by this system may
 Patient 5 – Acute liver
failure
Paracetamol overdose
• This patient has markedly impaired hepatocyte function
and hence reduced metabolic and excretory capacity
(raised INR, hyperbilirubinaemia,encephalopathy).
Low extraction drugs (hepatocyte dependent) are
likely to accumulate and should be used cautiously.
• The distribution of highly protein-bound drugs may be
affected by hyperbilirubinaemia, increasing the
unbound fraction. Biliary excretion may be impaired.
• Other things to consider are the
• raised INR (avoid drugs that affect coagulation or cause
bleeding), encephalopathy (avoid any drugs causing
sedation, constipation, fluid or electrolyte
disturbances) and impaired renal function.
• Paracetamol could be considered in a
patient with acute liver failure
caused by something other than a
paracetamol overdose.
• Normal therapeutic doses of
paracetamol can be used,
• but it may be prudent to extend the
dosing interval in all patients with
acute liver failure because
• a reduced clearance has been
demonstrated in patients with
acute viral hepatitis and a
prolonged PT.
• NSAIDs
• NSAIDs should be avoided in any
patient with acute liver failure
• because of their unfavourable side-
effect profile.
• • Increased risk of bruising/bleeding
• • Increased risk of renal dysfunction
and hepatorenal syndrome
• • Increased risk of gastrointestinal
ulceration
• • Disturbance of electrolytes and fluid
balance.
• Opioids
• In practice, the metabolism of opioids
appears to be well preserved
during periods of acute liver
dysfunction, but the drugs are likely
to accumulate in prolonged
disease.
• this patient has
• grade III encephalopathy the use of
any opioid should be avoided if
possible unless the patient is
ventilated.
 Lipid Lowering Drugs.
• Patient 5 – Acute liver failure
• Unnecessary medications should be
withheld until the patient’s liver
• function normalises and their
pharmaceutical needs are
reassessed.
BEST OF LUCK IN FINAL
EXAM
WISHING YOU TO BE LUCKY
 WITH

 LIVER CASE

 IN

 COMING PROFESSIONAL III

EXAM