Transcript Gastroenterology

Drug Use in Chronic
Liver Disease
Dr Ian Coombes
University of Queensland
Safe Medication Practice Medication Unit
Objectives
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After this session you will be able to:
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Describe the relationship between chronic liver
disease and the development of a number of
complications.
Discuss the strategies commonly used to manage
these complications
Describe the influence of liver disease on the
pharmacokinetics of drugs
Chronic liver disease (CLD)
Inflammation of the liver for > than 6
months
 Have permanent structural changes
in the liver
 Eventually leads to reduced liver
function
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Blood supply
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Liver receives 25% of resting
cardiac output
Blood enters via
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hepatic artery (25%) & portal
vein (75%)
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Blood leaves via
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carries blood from gut
rich in absorbed nutrients
portal flow increases after
meals
hepatic vein
Also leaving liver
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hepatic ducts
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carry bile to gall bladder
Normal Situation
Urea
Systemic Circulation
Collateral
Splanchnic Circulation
Protein
Bacteria
NH3
GIT
Causes Of Chronic Hepatic Failure
RISK FACTORS
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Viral Hepatitis
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Hepatitis C
Hepatitis B / D
• IVDU
RISK FACTORS
• TATTOOS
• IVDU
• BODY
PIERCING
• MOTHER
TO BABY
• BLOOD
TRANSFUSION
(pre (Vertical)
1989/90) - ASIA
• SEXUAL
Alcohol
Autoimmune Disease
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Primary Biliary Cirrhosis (PBC)
Primary Sclerosing Cholangitis (PSC)
Autoimmune Hepatitis
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Hereditary Metabolic Disorders
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Haemochromatosis - Iron overload
Wilson’s Disease - Copper accumulation
Alpha - 1 - antitrypsin deficiency
Fatty Liver
Venous Outflow Obstruction (Budd-chiari
Syndrome)
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Drugs
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eg methyldopa, isoniazid, nitrofurantoin,
methotrexate, amiodarone
Cryptogenic
Major complications of liver disease
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Portal hypertension
Ascites
Bleeding
Encephalopathy
Hepato-renal syndrome
Effects on drug handling and
sensitivity
Complications of ALD –
Portal hypertension
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Increased resistance to
flow through the portal
system  blood forced
down alternate
channels
Collateral circulation
Portosystemic shunting
Consequences of portal
hypertension
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Ascites
Hepatic encephalopathy
Increased risk of spontaneous
bacterial peritonitis
Increased risk of hepatorenal
syndrome
Splenomegaly-mild
panyctopenia
Portacaval anastomoses
(oesophageal varices,
haemorrhoids, caput medusae)
Complications of CLD – Ascites
Caused by:
 ↓ albumin
 Portal hypertension
 ↓ renal perfusion
 Na/water retention
 ↑ aldosterone
Treatment:
 Diuretics (spironolactone/frusemide)
 Ascitic taps
 shunts
Starling’s Forces – control of
fluid movement in CV system
Arteriolar Level
Capillary Bed
Venule
Albumin
CO2
OP>BP
BP>OP
O2 +
Nutrients
Movement of fluid controlled by hydrostatic pressue (BP) and
Oncotic pressure (OP - generated by albumin).
When albumin decreases (due to liver disease– fluid remains in tissue bed –
ascites (as driven by portal hypertension).
Complications of CLD – Bleeding
Caused by:
 Portal hypertension
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Decreased clotting factors
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Oesophageal / Gastric / Rectal varices
Variceal bleeding mortality after 1st bleed 50%
60% re-bleed in 1 year
Liver site of clotting factor production
Increased prothrombin time/INR
Infection can exacerbate bleeding
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Endotoxin mediated
Complications of CLD- Hepatic
encephalopathy
May be precipitated by:
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GI bleeding, constipation, high dietary protein load
Electrolyte disturbances
Infection
Drugs
Renal impairment
Pathogenesis incompletely understood
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Ammonia
Treatment:
 Lactulose/neomycin
 Avoiding sedating agents
Urea
Diseased Liver
Systemic Circulation
Cirrhosis
Collateral
Splanchnic Circulation
Portal
Hypertension
Protein
Portal systemic shunting
Bacteria
NH3
Drugs
GIT
Complications of CLDHepatorenal syndrome
Acute oliguric RF with portal HT & ascites
 Intense vasoconstriction occurs in otherwise
normal kidneys
Caused by:
 Pathogenesis unknown
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Related to altered renocortical blood flow
Treatment:
 Avoid precipitating drugs & treatments
 No effective treatment – poor prognosis
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terlipressin
Investigation of CLD
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Signs and symptoms, history
Liver enzymes
Plasma protein, coagulation factors, auto
antibodies
Imaging – ultrasound, cholangiography
(endoscopic, percutaneous, MR)
Liver biopsy
Classification of CLD
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Child-Pugh classification (modified version).
Point score correlates with survival.
Parameter
Number of Points
1
2
3
Bilirubin (umol/L)
<34
34-51
>51
Albumin (g/L)
>35
28-35
<28
Prothrombin time
<3
3-10
>10
Ascites
None
Slight
Moderate
to severe
Encephalopathy
None
Mild
Moderate
to severe
What the points mean!
Class
Total points
1 yr mortality
A
5–6
low
B
7–9
20 – 40%
C
10 – 15
40 – 60%
Management of CLD
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Treatment of underlying cause if possible
Adequate nutrition
Prevention and symptomatic treatment of
complications
Liver transplantation
Drug Use in Chronic Liver Disease
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Disease severity
Pharmacokinetic response
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absorption
distribution
elimination
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hepatic clearance
Pharmacodynamic response
Potentially hepatotoxic drugs
Consider…
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Is it hepatically cleared?
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What are the side effects?
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First pass?
Constipation
CNS side effects
Renal toxicity
Is it hepatotoxic?
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Idiosyncratic or dose related?
PHARMACOKINETIC CONSIDERATIONS IN
LIVER DISEASE
Five variable will affect the pharmacokinetics of a
drug in liver disease.
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HEPATIC BLOOD FLOW
REDUCTION IN HEPATIC CELL MASS
PORTAL – SYSTEMIC SHUNTING
CHOLESTASIS
DECREASE IN PROTEIN BINDING
1.
HEPATIC BLOOD FLOW
Reduction occurs in:
 cardiac failure
 cirrhosis
 hepatic venous outflow obstruction
 portal vein thrombosis
 Large decrease in blood pressure e.g. shock
HIGH RISK DRUGS
>60% first pass clearance
Hepatic Extraction of drugs
High Extraction
Limited Extraction
Low Extraction
Chlormethiazole
Propranolol
Lignocaine
Verapamil
GTN
Paracetamol
Diazepam *
Chlordiazepoxide*
Theophylline
Oxazepam *
Lorazepam *
Frusemide *
Spironolactone*
Digoxin
Valproic Acid
Tolbutamide
Cimetidine
2.
REDUCED HEPATIC CELL MASS
Associated with both acute and chronic liver disease:
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Decrease first pass metabolism of drugs
with a high hepatic extraction – increase in bioavailability
Decrease elimination of drugs with a low hepatic extraction
i.e. capacity limited drugs – lead to increase in half-life.
3.
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PORTAL SYSTEMIC SHUNTING
80% blood entering liver – portal vein,
Bioavailability of drugs with high extraction can
increase significantly,
Peak plasma concentrations will be increased,
Half-life will be prolonged,
Elimination delayed – may lead to toxicity
4.
CHOLESTASIS
Failure of passage of bile salts to
duodenum. Directly affects hepatocellular
function – drug clearance.
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Lack of bile - reduces absorption of
lipid soluble drugs
Reduced plasma protein binding of
drugs – competition with bile salts.
5.
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REDUCTION IN PROTEIN BINDING
Majority of plasma proteins (PP) synthesised by liver,
Reduction in PP – decrease binding potential – increase in
free drug concentrations e.g. phenytoin
If drug highly extracted – no increase in plasma conc – but
for other drugs will result in increase in free drug plasma
concs.
Competition may also occur for binding sites e.g. bile salts.
Case 1
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48 year old 86 kg man
PC – massive abdominal distension and pain
HPC -  abdominal distension, pain and lethargy,
confusion
PMH includes
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Social history
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Alcoholic liver disease/haemochromatosis
Lives alone
Alcohol abuse
Allergies - NKA
Case 1 continued
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On examination
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HR: 84 reg BP: 115/70 mmHg RR: 18/min
Temp: 37.7C
Ascites+++, abdominal pain
Mild confusion
Medications
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Omeprazole 20mg bd
Lactulose 20mL tds prn
Thiamine 100mg daily
Vitamin K 10mg daily
Spironolactone 100mg daily
Laboratory Tests
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U&Es
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Sodium
Potassium
Creatinine
Glucose
130 mmol/L
3.9 mmol/L
130 micromol/L
4.3 mmol/L
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100 g/L
16.7 x 109/L
256 x 109/L
1.9
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Haemotology
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Hb
WCC
Platelets
INR
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Laboratory Tests
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LFT/Gastro
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Total Protein
Albumin
Bilirubin
ALT
GGT
ALP
AST
61 g/L
23 g/L
86 umol/L
63 U/L
96 U/L
107 U/L
143 U/L
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Diagnosis and Plan
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Decompensated ALD with increasing ascites
and mild encephalopathy
Lactulose 30mL 3-4 times daily
Ascitic tap with albumin cover
Fluid restrict 1.5L/day
Low salt
Weigh daily
Add frusemide 40mg mane
1.
Which lab tests indicate
liver disease? Which tests are used to assess
disease severity?
2.
What are the common complications of chronic
liver disease (seen in this patient + any others) and
describe briefly the main forms of treatment for each
of the complications. Consider current therapy
3.
What pharmacokinetic changes occur in chronic
liver disease that effect drug metabolism?
What are the pharmacodynamic changes that
occur in chronic liver disease that effect drug
dosing?
What are the potential problems with
aminoglycoside and analgesic use in this patient?
4.
5.