Penny North-Lewis
Paediatric Liver Pharmacist
Leeds Teaching Hospitals NHS Trust
July 2013

 To provide an approach to drug usage and dosing decisions in palliative patients with liver dysfunction

 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

 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?

 Introduction to the issues
 Basic hepatology
 How you link this to drug handling
 Workshop

Homeostasis e.g. glucose
Synthesis
(e.g. albumin & clotting factors)
Lipid Metabolism e.g. cholesterol
Bile production and secretion
Metabolism e.g drugs, oestrogens, toxic products such as ammonia
Filtration e.g. antigens

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)
 Chronic
Extended duration – months/years

Some terminology used in liver disease
 Hepatocellular
 Fatty infiltration (steatosis) e.g. alcohol
 Inflammation (hepatitis) e.g. viral
 Cell death (necrosis) e.g. POD
 Cholestasis
 Static bile flow (not specifically bilirubin)

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

Liver Oesophagus
Stomach
Portal Vein
Spleen
Splenic vein
Kidney
Inferior vena cava

Liver conditions seen in palliative care??
 End stage chronic liver disease / cirrhosis
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 Coagulopathy, encephalopathy, ascites, bleeding varices
Cancer – liver primary or mets
 Intra- or extra-hepatic cholestasis, pruritus
 Incidental liver dysfunction or disease
 E.g cardiac failure, prolonged hypoxia
 Liver disease unrelated to palliation

 Introduction to the issues
 Basic hepatology
 How you link this to drug handling
 Liver tests
 Signs of liver disease
 Drug handling
 Workshop

Drug handling in a liver patient first principles
Liver Test Results
Drug
Characteristics e.g. pharmacokinetics and side effects
The patient
Signs of
Liver Disease

 Knowing this helps!
 Liver dysfunction is a continuum – mild to severe – depending on disease and stage.

 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

 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

 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
 Increased in cholestasis
 Increased by enzyme inducing drugs e.g. rifampicin and alcohol
 Useful to determine if isolated raised alkaline phosphatase is liver related

 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)
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Decreased synthesis of clotting factors (cirrhosis)
OR
Vitamin K malabsorption (in cholestasis)
 Elevation > 3 seconds significant
 Prolonged in acute & chronic liver disease
 Useful prognostic indicator of impending liver failure e.g. acute liver failure or decompensated chronic liver disease

 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
Drug
Characteristics e.g. pharmacokinetics and side effects
The patient
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

 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

 Cholestasis
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↑ ↑ Alk Phos, ↑GGT, ↔ to ↑SBr (probably ↑)
 Hepatitis
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↑ to ↑ ↑ ↑ ALT
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↔ to ↑ INR, (↔ to ↑Alk Phos and SBr)
 Cirrhosis
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↔ to ↑ALT, ↔ to ↑INR, ↔ to ↑SBr, ↓Albumin
 Worsening if decompensated

Drug handling in a liver patient first principles
Liver Test Results
Drug
Characteristics e.g. pharmacokinetics and side effects
The patient
Signs of
Liver Disease

 Ascites may impair absorption e.g. diuretics
 Bigger doses or IV
 Cholestasis may impair absorption of fat soluble drugs e.g. fat soluble vitamins
 Bigger doses

 Ascites will increase volume of distribution for water soluble drugs
 Bigger doses per kg
 Low albumin will alter amount of free drug if highly protein bound
 Reduced doses

 Decompensated cirrhosis - reduced number of functioning hepatocytes
 Reduce dose or increase interval
 Portal hypertension - reduced first pass metabolism if highly extracted drug e.g. propranolol, lidocaine
 Reduce dose

 Prodrugs that need to be metabolised to the active form in the liver may need bigger doses! E.g. enalapril

 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?

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

 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

 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

Rules for prescribing in liver disease
 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

 NSAIDs
 Opioids
 Tricyclic antidepressants
 Benzodiazepines
 Antipsychotics
 Antimuscarinics
 Anticholinergics
 Long acting drugs unless carefully titrated and pt stable

 Introduction to the issues
 Basic hepatology
 How you link this to drug handling
 Workshop
 Review of common palliative drugs
 Cases

Review of common palliative drugs
Analgesia
 Paracetamol
 Naproxen
 Codeine
 Tramadol
 Morphine
 Fentanyl
Drug Considerations Drug ….………………
Pharmacokinetics
Absorption
Distribution
Metabolism
Elimination
Considerations
Lipid solubilty
(Absorption affected by ascites)
Water/fat
Protein binding %
Displaced by bilirubin or displaces bilirubin
First pass effect
Hepatocyte dependent
Prodrug
CYPs
Active metabolites
Genetics
Biliary excretion
Alternative mechanisms
Enterohepatic recirculation
(Renal impairment)
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

 Hepatitis
 Mild, normal INR and no chronic liver disease
 Cholestasis
 Normal hepatocyte function
 Cirrhosis
 Compensated but only just – INR 1.3-1.4, albumin 32, known varices, no encephalopathy

 Hepatic metabolism (multiple pathways)
 Need glutathione
– stores may be reduced in the severely malnourished
 Hepatotoxic in overdose oxidation
Paracetamol CYP2E1 NAPQI conjugation with Mercapturic acid/ glutathione Cysteine acid conjugates conjugation conjugation with protein sulfhydryls
Glucuronide Sulphate
Complexes
Hepatotoxicity

 Use in mild hepatitis?
 Yes (caution alcoholics)
 In cholestasis?
 Yes
 In cirrhosis?
 Yes
 Reduce to TDS in severe decompensated cirrhosis

 Protein binding >99%
 Extensively hepatically metabolised
 ?biliary excretion
 Half life 12-15 hrs
 Side effects
 GI ulceration
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Platelet inhibition
Renal toxicity
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Fluid and electrolyte imbalance
Hepatotoxicity

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Use in hepatitis?
 Yes, normal dose. Caution hepatoxicity
In cholestasis?
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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

 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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Use in mild hepatitis?
 Yes – normal dose
In cholestasis?
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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

 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
 Lowers seizure threshold
 Plus usual opiate ADRs

 Use in mild hepatitis?
 Yes, normal dose
 In cholestasis?
 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

 Low protein binding
 Extensive hepatic metabolism, first pass
>50%
 Biliary excretion and enterohepatic recirculation
 Half life 1-5 hrs
 Side effects
 Sedation, respiratory depression
 Constipation
 Pruritus

 Use in mild hepatitis?
 Yes – normal dose
 In cholestasis?
 Possible impaired excretion
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Pruritus, bile duct spasm
Yes – normal dose but monitor and use prn
 In cirrhosis?
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Poor metabolism, accumulation. Varices may affect
1 st pass
Sedation, resp depression – encephalopathy
Caution reduce dose (to 25-50%) and frequency

 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 t ½ = 13 hrs)
 Side effects
 As morphine, caution delayed effects

 Use in mild hepatitis?
 Yes – normal dose
 In cholestasis?
 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

Score
SBr
Albumin
INR
Ascites
Encephalopathy
1
<34
>35
<1.7
None
None
2
34-51
30-35
1.7-2.3
Easily controlled
Minimal
3
>51
<30
>2.3
Poorly controlled
Advanced
A = 5-6 (mild), B = 7-9 (moderate), C ≥ 10 (severe)

 Rhee & Broadbent paper
 Critique – especially look at comments for the drugs we have discussed
 Any other things stand out?

 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%

 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!

 Medicines Q&As on NELM
 Drug PK data – Dollery, micromedex,
SPC
 Drugs and the Liver
 Caution with interpreting references