Transcript Cholestasis - Yorkshire and the Humber Deanery

Drug Handling in Palliative
Patients with Liver Dysfunction
OR
Do I need to change the dose?
Penny North-Lewis
Paediatric Liver Pharmacist
Leeds Teaching Hospitals NHS Trust
July 2013
Aim

To provide an approach to drug usage
and dosing decisions in palliative
patients with liver dysfunction
Plan for session
Introduction to the issues
 Basic hepatology
 How you link this to drug handling
 Workshop

Problems with prescribing in liver
dysfunction
Poor understanding of liver dysfunction
 Lack of information in regular sources
e.g BNF, SPC (misinformation/lack of data)
 No easy equation to use
 Lack of research, small numbers of
patients

Back to first principles
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Need to know what type of liver disease
your patient has and estimate the extent of
liver dysfunction

Need to consider what drug factors will
affect use in a patient with liver dysfunction
e.g pharmacokinetics and side effect profile

Need to put the two together and decide
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Can the drug be used at all?
Are there any specific precautions to use?
What dose should be given?
Plan for session
Introduction to the issues
 Basic hepatology
 How you link this to drug handling
 Workshop

What does the liver do?
Homeostasis
e.g. glucose
Synthesis
Lipid Metabolism
(e.g. albumin &
clotting factors)
e.g. cholesterol
Filtration
Bile production
and secretion
e.g. antigens
Metabolism e.g drugs,
oestrogens, toxic products
such as ammonia
Some terminology used in liver
disease
Acute
Sudden onset – jaundice to
encephalopathy in less than 7 days
(hyperacute), 28 days (acute), 6 months
(sub-acute)
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Chronic
Extended duration – months/years
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Some terminology used in liver
disease

Hepatocellular
Fatty infiltration (steatosis) e.g. alcohol
 Inflammation (hepatitis) e.g. viral
 Cell death (necrosis) e.g. POD
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Cholestasis

Static bile flow (not specifically bilirubin)
Cholestasis
Intrahepatic
Extrahepatic
Some terminology used in liver
disease
Ongoing damage:
Hepatocellular and cholestasis
initially
Throughout hepatocytes

Biliary system
Fibrosis
An increase in connective tissue in the liver – reversible
Some terminology used in liver
disease

Cirrhosis
Widespread disorganised nodules in the liver
combined with fibrosis
Compensated cirrhosis
When a cirrhotic liver continues to function

Decompensated cirrhosis
When a cirrhotic liver can no longer function
adequately – signs eg coagulopathy occur

Portal hypertension
Liver
Portal Vein
Oesophagus
Stomach
Spleen
Splenic vein
Kidney
Inferior vena cava
Liver conditions seen in palliative
care??

End stage chronic liver disease /
cirrhosis
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Cancer – liver primary or mets
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Coagulopathy, encephalopathy, ascites,
bleeding varices
Intra- or extra-hepatic cholestasis, pruritus
Incidental liver dysfunction or disease
E.g cardiac failure, prolonged hypoxia
 Liver disease unrelated to palliation

Plan for session
Introduction to the issues
 Basic hepatology
 How you link this to drug handling
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Liver tests
 Signs of liver disease
 Drug handling
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Workshop
Drug handling in a liver patient first principles
Liver Test Results
The
patient
Drug
Characteristics
e.g. pharmacokinetics
and side effects
Signs of
Liver Disease
Diagnosis
Knowing this helps!
 Liver dysfunction is a continuum – mild
to severe – depending on disease and
stage.

Transaminases (0-35iu/L)
(ALT & AST)
Enzyme released from hepatocytes
when damaged
 Markers of hepatocellular injury

High elevations in acute injury (in several
thousands)
 Can be normal in severe chronic liver
disease (cirrhosis)

Also found in heart, muscle and kidney
 ALT more specific to liver than AST
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Bilirubin (3-17 micromol/l)
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Product of
erythrocyte
breakdown
Conjugated in liver to
form water soluble
version which can be
excreted
Plasma levels
>50micromol/L give
jaundice
Haem of erythrocytes
bilirubin
plasma
albumin (unconjugated)
hepatocyte (conjugated & water
soluble)
bile
faeces
Causes of Hyperbilirubinaemia


Unconjugated
 Increased production
 Decreased uptake
 Decreased
conjugation
Conjugated
 Intrahepatic
cholestasis
 Extrahepatic
cholestasis
Haem of erythrocytes
bilirubin
plasma
albumin (unconjugated)
hepatocyte (conjugated & water
soluble)
bile
faeces
Alkaline Phosphatase
(normal range varies for age and hospital)

Biliary enzyme – raised with bile duct
damage

Increased in cholestasis
Less raised in hepatocellular disease
 Not specific to the liver

also found in bone (eg raised in Paget’s
disease/bone metastases)
 small quantities in the intestine and placenta

Gamma glutamyl transferase (GGT)
(0-30u/l)

Enzyme in biliary tract
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Increased in cholestasis
Increased by enzyme inducing drugs
e.g. rifampicin and alcohol

Useful to determine if isolated raised
alkaline phosphatase is liver related
Albumin (37-49g/l)

Synthesised in liver

Half-life approx 20 days

Good indicator of chronic liver disease

Low specificity

Decreased intake e.g. malnutrition

Increased loss e.g. enteropathy
Prothrombin Time (~13 secs)
or INR (0.9-1.2)

Decreased synthesis of clotting factors (cirrhosis)
OR

Vitamin K malabsorption (in cholestasis)

Elevation > 3 seconds significant

Prolonged in acute & chronic liver disease
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Useful prognostic indicator of impending liver
failure e.g. acute liver failure or decompensated
chronic liver disease
Other useful tests
Ultrasound – liver texture, dopplers for
blood flow in hepatic artery, portal vein
 Liver biopsy – fibrosis, cirrhosis,
intrahepatic cholestasis
 OGD – varices
 HIDA – bile flow (cholestasis)
 Blood glucose, creatinine

Drug handling in a liver patient first principles
Liver Test Results
The
patient
Drug
Characteristics
e.g. pharmacokinetics
and side effects
Signs of
Liver Disease
Signs of liver disease

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Jaundice
Pale stools/dark urine
Palmar erythema
White nails
Gynaecomastia/testicular
atrophy
Spider naevi
Ascites
Bruising and bleeding
Splenomegaly
Oesphageal and gastric varices
Encephalopathy
Jaundice
“Spiders”
Ascites
Useful tips on interpreting LFTs
Not all LFTs are specific to the liver
 LFTs alone DO NOT provide a diagnosis
 As a guide , a significant change =
>double upper limit of normal
 Some values may be within normal
ranges in chronic severe liver disease
 Different hospitals have different ranges
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Useful tips on interpreting LFTs
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Cholestasis
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↑ ↑ Alk Phos, ↑GGT, ↔ to ↑SBr (probably ↑)
Hepatitis
↑ to ↑ ↑ ↑ ALT
 ↔ to ↑ INR, (↔ to ↑Alk Phos and SBr)
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Cirrhosis
↔ to ↑ALT, ↔ to ↑INR, ↔ to ↑SBr, ↓Albumin
 Worsening if decompensated
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Drug handling in a liver patient first principles
Liver Test Results
The
patient
Drug
Characteristics
e.g. pharmacokinetics
and side effects
Signs of
Liver Disease
Absorption

Ascites may impair absorption e.g.
diuretics

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Bigger doses or IV
Cholestasis may impair absorption of
fat soluble drugs e.g. fat soluble
vitamins

Bigger doses
Distribution
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Ascites will increase volume of
distribution for water soluble drugs

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Bigger doses per kg
Low albumin will alter amount of free
drug if highly protein bound
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Reduced doses
Metabolism
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Decompensated cirrhosis - reduced
number of functioning hepatocytes
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Reduce dose or increase interval
Portal hypertension - reduced first
pass metabolism if highly extracted
drug e.g. propranolol, lidocaine
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Reduce dose
Metabolism
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Prodrugs that need to be metabolised to
the active form in the liver may need
bigger doses! E.g. enalapril
Elimination
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Cholestasis – biliary cleared drugs may
accumulate
Caution if active/toxic metabolites are
produced, possibly not important if inactive
 Compensatory pathways e.g. renal if
reduced biliary clearance?
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Side Effect Profile
Drugs with the following side effects may need to be
avoided/used with caution:
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GI ulceration – varices, coagulopathy
Constipation – cirrhosis, encephalopathy
Pruritus - cholestasis
Sedation – encephalopathy, cirrhosis
Coagulation defects - coagulopathy
Effects on electrolytes – cirrhosis, encephalopathy
Effects on fluid balance – ascites, cirrhosis
Renal toxicity - cirrhosis
Hepatotoxicity
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Dose dependent (intrinsic e.g. paracetamol,
methotrexate)
Dose independent (idiosyncratic)
Usually acute, can be chronic
Acute is usually in 5 to 90 days of starting drug
Can occur after stopping causative drug
Existing liver dysfunction does not increase
risk of hepatotoxic reaction
When do you need to worry?
Decompensated cirrhosis –
encephalopathy, coagulopathy
 Varices – risk of bleeding, effect on first
pass metabolism
 Ascites – Na content, fluid retention
 Cholestasis – if drug biliary cleared
 Low albumin – if highly protein bound
>90%

Drug Handling in liver impairment –
in practice
Pharmacokinetic changes are not
predictable
 The liver has amazing capacity to
continue to carry out functions even
when cirrhotic
 Need to be careful not to under dose
patients for essential therapies e.g.
chemotherapy and pain relief
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Rules for prescribing in liver disease
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Avoid or use certain drugs cautiously
Avoid hepatotoxic drugs if possible
Use therapeutic levels, where possible
Monitor for efficacy eg BP, HR
Monitor for toxicity
Check renal function
Use the smallest effective dose at the greatest
interval and titrate according to response
Drugs to avoid/use cautiously!!
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NSAIDs
Opioids
Tricyclic antidepressants
Benzodiazepines
Antipsychotics
Antimuscarinics
Anticholinergics
Long acting drugs unless carefully titrated and
pt stable
Plan for session
Introduction to the issues
 Basic hepatology
 How you link this to drug handling
 Workshop

Review of common palliative drugs
 Cases
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Review of common palliative drugs
Drug Considerations
Analgesia
 Paracetamol
 Naproxen
 Codeine
 Tramadol
 Morphine
 Fentanyl
Drug ….………………
Pharmacokinetics
Absorption
Considerations
Lipid solubilty
(Absorption affected by
ascites)
Distribution
Water/fat
Protein binding %
Displaced by bilirubin or
displaces bilirubin
Metabolism
First pass effect
Hepatocyte dependent
Prodrug
CYPs
Active metabolites
Genetics
Biliary excretion
Alternative mechanisms
Enterohepatic recirculation
(Renal impairment)
Elimination
Side effects
Consider – GI ulceration, sedation, coagulopathy, platelet effects, effects on fluid balance, effect
on electrolytes, biliary sludging, renal impairment, constipation
Hepatotoxicity - known hepatotoxin/type
Published information in specific liver diseases/clinical studies
BNF/SPC
Effect of drug on liver patient
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Hepatitis
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Cholestasis
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Mild, normal INR and no chronic liver
disease
Normal hepatocyte function
Cirrhosis
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Compensated but only just – INR 1.3-1.4,
albumin 32, known varices, no
encephalopathy
Paracetamol
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Hepatic metabolism (multiple pathways)
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Need glutathione – stores may be reduced in the
severely malnourished
Hepatotoxic in overdose
Paracetamol
oxidation
CYP2E1
conjugation
NAPQI
conjugation with
glutathione
conjugation with protein
sulfhydryls
Glucuronide
Sulphate
Complexes
Hepatotoxicity
Mercapturic acid/
Cysteine acid conjugates
Paracetamol

Use in mild hepatitis?
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(caution alcoholics)
In cholestasis?
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Yes
Yes
In cirrhosis?
Yes
 Reduce to TDS in severe decompensated
cirrhosis
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Naproxen
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Protein binding >99%
Extensively hepatically metabolised
?biliary excretion
Half life 12-15 hrs
Side effects
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GI ulceration
Platelet inhibition
Renal toxicity
Fluid and electrolyte imbalance
Hepatotoxicity
Naproxen
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Use in hepatitis?
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In cholestasis?
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Yes, normal dose. Caution hepatoxicity
May displace bilirubin from protein binding sites
Caution if deranged clotting from vit K
malabsorption
Prefer avoid but could use with caution.
In cirrhosis?
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Poor metabolism, accumulation
Bleeding risk, renal toxicity, fluid and electrlyte
disturbance
AVOID
Codeine
First pass metabolism 50%
 Some biliary excretion
 Half life 3-4 hrs
 Partial prodrug? Converted to morphine
 Side effects

Sedation, respiratory depression
 Constipation
 Pruritus
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Codeine
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Use in mild hepatitis?
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In cholestasis?
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Yes – normal dose
Possible impaired excretion
Pruritus
Yes – normal dose but use prn and monitor
In cirrhosis?
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Poor metabolism, possibly reduced efficacy as not
converted to morphine
Sedation, respiratory depression
High first pass metabolism – caution if varices
Reduce dose and frequency and give laxatives
Dihydrocodeine may be better as parent drug exerts effect
Tramadol
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Hepatic metabolism, first pass low
Active intermediate metabolites
No biliary excretion
Half life 6 hrs
Renal excretion 10%, increases to 30% in
cirrhosis
Side effects
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Lowers seizure threshold
Plus usual opiate ADRs
Tramadol
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Use in mild hepatitis?
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In cholestasis?
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Yes, normal dose
Yes, normal dose
In cirrhosis?
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Complex PK – parent partially active and slow
metabolism, intermediate active but slow to be
formed and slow to clear - ?overall effect?
Use very cautiously – start low. Give laxatives
Morphine
Low protein binding
 Extensive hepatic metabolism, first pass
>50%
 Biliary excretion and enterohepatic
recirculation
 Half life 1-5 hrs
 Side effects
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Sedation, respiratory depression
 Constipation
 Pruritus
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Morphine
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Use in mild hepatitis?
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In cholestasis?
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Yes – normal dose
Possible impaired excretion
Pruritus, bile duct spasm
Yes – normal dose but monitor and use prn
In cirrhosis?
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Poor metabolism, accumulation. Varices may affect
1st pass
Sedation, resp depression – encephalopathy
Caution reduce dose (to 25-50%) and frequency
Fentanyl
Protein binding 80%
 Large Vd – slow redistribution, only small
amt of drug available in central
compartment
 Half life not sig different in cirrhosis –
long (redistribution t½ = 13 hrs)
 Side effects
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As morphine, caution delayed effects
Fentanyl
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Use in mild hepatitis?
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In cholestasis?
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Yes – normal dose
Yes – normal dose, poss increase pruritus
In cirrhosis?
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Metabolism only mildly impaired
Sedation, resp depression – encephalopathy
Can use – titrate carefully, caution with delayed
effects.
Avoid patches – long acting and delayed absorption
Child-Pugh score – cirrhosis only
Score
1
2
3
SBr
<34
34-51
>51
Albumin
>35
30-35
<30
INR
<1.7
1.7-2.3
>2.3
Ascites
None
Encephalopathy
None
Easily
controlled
Minimal
Poorly
controlled
Advanced
A = 5-6 (mild),
B = 7-9 (moderate),
C ≥ 10 (severe)
Problems with literature

Rhee & Broadbent paper
Critique – especially look at comments for
the drugs we have discussed
 Any other things stand out?

Cases
Key messages – when to worry
Cirrhosis, esp decompensated –
encephalopathy, coagulopathy
 Varices – risk of bleeding, effect on first
pass metabolism
 Ascites – Na content, fluid retention
 Cholestasis – if drug biliary cleared
 Low albumin – if highly protein bound
>90%

Key messages – generic rules
Work out what is wrong with your
patient’s liver and how bad it is
 See if the pharmacokinetics of the drug
you want to use could be affected
 Check the drug doesn’t have side effects
which could harm the patient
 Think!
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Sources of further information
Medicines Q&As on NELM
 Drug PK data – Dollery, micromedex,
SPC
 Drugs and the Liver
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Caution with interpreting references