1. Drug Use in Chronic Liver Disease
Dr Ian Coombes
University of Queensland
Safe Medication Practice Medication Unit

2. Objectives After this session you will be able to:
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

3. 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 3

4. Blood supply Liver receives 25% of resting cardiac output
Blood enters via
hepatic artery (25%) & portal vein (75%)
carries blood from gut
rich in absorbed nutrients
portal flow increases after meals
Blood leaves via
hepatic vein
Also leaving liver
hepatic ducts
carry bile to gall bladder

5. GIT Normal Situation Urea Systemic Circulation Bacteria Protein NH3
Collateral
Splanchnic Circulation
GIT
Bacteria
Protein NH3

6. Causes Of Chronic Hepatic Failure
RISK FACTORS
IVDU
TATTOOS
BODY PIERCING
BLOOD TRANSFUSION (pre 1989/90)
Viral Hepatitis
Hepatitis C
Hepatitis B / D
Alcohol
Autoimmune Disease
Primary Biliary Cirrhosis (PBC)
Primary Sclerosing Cholangitis (PSC)
Autoimmune Hepatitis
RISK FACTORS
IVDU
MOTHER TO BABY (Vertical) - ASIA
SEXUAL

7. Hereditary Metabolic Disorders
Haemochromatosis - Iron overload
Wilson’s Disease - Copper accumulation
Alpha antitrypsin deficiency
Fatty Liver
Venous Outflow Obstruction (Budd-chiari Syndrome)
Drugs
eg methyldopa, isoniazid, nitrofurantoin, methotrexate, amiodarone
Cryptogenic
Haemochromatosis-hereditary disorder with deficient iron metabolism leading to overload (mixed genetic and environmental factors). Liver cirrhosis (with an increased risk of hepatocellular carcinoma, affecting up to a third of all homozygotes) - this is often preceded by a period of a painfully enlarged liver.
Wilson's disease or hepatolenticular degeneration is an autosomal recessive disorder, with a male preponderance. Its main feature is accumulation of copper in tissues, which manifests itself with neurological symptoms and liver disease.
The estimated heterozygous carrier rate is about 1 in 100, meaning that 1 in 100 people are unaffected carriers of this mutation. The main features are liver and neuropsychiatric problems. Chronic active hepatitis, culminating in cirrhosis is the most common hepatic presentation, but some patients present with fulminant liver failure (which is characterised by remarkably low alkaline phosphatase and often high bilirubin levels compared to similar disease states[1]) and a surprisingly rare incidence of hepatocellular carcinoma. Neuropsychiatric phenomena are early dementia, mood disorders or psychosis and signs of asterixis (a flapping tremor of the hands) and parkinsonism (including ataxia, dyskinesia, and rigidity).
Alpha 1-antitrypsin deficiency (α1-antitrypsin deficiency, A1AD or Alpha-1) is a genetic disorder caused by defective production of alpha 1-antitrypsin (A1AT), leading to decreased A1AT activity in the blood and lungs, and deposition of excessive abnormal A1AT protein in liver cells.[1] There are several forms and degrees of deficiency. Severe A1A deficiency causes emphysema and/or COPD in adult life in nearly all people with the condition, as well as various liver diseases in a minority of children and adults, and occasionally more unusual problems.[2
Budd-Chiari syndrome is the clinical picture caused by occlusion of the hepatic vein or inferior vena cava. Its presents with the classical triad of abdominal pain, ascites and hepatomegaly. Examples of occlusion include thrombosis of hepatic veins and membranous webs in the inferior vena cava. The syndrome can be fulminant, acute, chronic, or asymptomatic. It occurs in 1 out of 100,000 individuals and is more common in females. Some 10-20% also have obstruction of the portal vein 7

8. Major complications of liver disease
Portal hypertension
Ascites
Bleeding
Encephalopathy
Hepato-renal syndrome
Effects on drug handling and sensitivity

9. Complications of ALD – Portal hypertension
Increased resistance to flow through the portal system  blood forced down alternate channels
Collateral circulation
Portosystemic shunting
Portosystemic = connecting hepatic portal system and venous part of circulation
Varices = abnormally lengthened vessel
Collateral circulation = circulation of blood established thru enlargement of minor vessels & anastomosis of vessels with those of adjacent parts when a major vein/artery is functionally impaired
Portal hypertension responsible for many complications of CLD – bleeding varices, ascites, encephalopathy and splenomegaly 9

10. Consequences of portal hypertension
Ascites
Hepatic encephalopathy
Increased risk of spontaneous bacterial peritonitis
Increased risk of hepatorenal syndrome
Splenomegaly-mild panyctopenia
Portacaval anastomoses (oesophageal varices, haemorrhoids, caput medusae)
Caput medusae-appearance of engorged umbilical veins 10

11. Complications of CLD – Ascites
Caused by:
↓ albumin
Portal hypertension
↓ renal perfusion
Na/water retention
↑ aldosterone
Treatment:
Diuretics (spironolactone/frusemide)
Ascitic taps
shunts

12. 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).

13. Complications of CLD – Bleeding
Caused by:
Portal hypertension
Oesophageal / Gastric / Rectal varices
Variceal bleeding mortality after 1st bleed 50%
60% re-bleed in 1 year
Decreased clotting factors
Liver site of clotting factor production
Increased prothrombin time/INR
Infection can exacerbate bleeding
Endotoxin mediated

14. Complications of CLD- Hepatic encephalopathy
May be precipitated by:
GI bleeding, constipation, high dietary protein load
Electrolyte disturbances
Infection
Drugs
Renal impairment
Pathogenesis incompletely understood
Ammonia
Treatment:
Lactulose/neomycin
Avoiding sedating agents
Likely to be associated with hi blood levels of gut derived toxins which enter CNS after by passing normal metabolic processes in liver due to portosystemic shunting of blood 14

15. GIT Diseased Liver Urea Systemic Circulation Cirrhosis Portal
Collateral
Splanchnic Circulation
Portal
Hypertension
GIT
Bacteria
Protein NH3
Drugs
Portal systemic shunting

16. Complications of CLD- Hepatorenal syndrome
Acute oliguric RF with portal HT & ascites
Intense vasoconstriction occurs in otherwise normal kidneys
Caused by:
Pathogenesis unknown
Related to altered renocortical blood flow
Treatment:
Avoid precipitating drugs & treatments
No effective treatment – poor prognosis
terlipressin
Avoid excessive diuresis or paracentesis in pts at risk 16

17. Investigation of CLD Signs and symptoms, history Liver enzymes
Plasma protein, coagulation factors, auto antibodies
Imaging – ultrasound, cholangiography (endoscopic, percutaneous, MR)
Liver biopsy

18. Classification of CLD 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
Mild

19. What the points mean! Class Total points 1 yr mortality A 5 – 6 low B
7 – 9
20 – 40% C
10 – 15
40 – 60%

20. Management of CLD Treatment of underlying cause if possible
Adequate nutrition
Prevention and symptomatic treatment of complications
Liver transplantation

21. Drug Use in Chronic Liver Disease
Disease severity
Pharmacokinetic response
absorption
distribution
elimination
hepatic clearance
Pharmacodynamic response
Potentially hepatotoxic drugs

22. Consider… Is it hepatically cleared? What are the side effects?
First pass?
What are the side effects?
Constipation
CNS side effects
Renal toxicity
Is it hepatotoxic?
Idiosyncratic or dose related?

23. PHARMACOKINETIC CONSIDERATIONS IN LIVER DISEASE
Five variable will affect the pharmacokinetics of a
drug in liver disease.
HEPATIC BLOOD FLOW
REDUCTION IN HEPATIC CELL MASS
PORTAL – SYSTEMIC SHUNTING
CHOLESTASIS
DECREASE IN PROTEIN BINDING

24. 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

25. 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

26. 2. REDUCED HEPATIC CELL MASS
Associated with both acute and chronic liver disease:
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.

27. 3. 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

28. 4. CHOLESTASIS Failure of passage of bile salts to
duodenum. Directly affects hepatocellular
function – drug clearance.
Lack of bile - reduces absorption of lipid soluble drugs
Reduced plasma protein binding of drugs – competition with bile salts.

29. 5. 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.

30. Case 1
48 year old 86 kg man
PC – massive abdominal distension and pain
HPC -  abdominal distension, pain and lethargy, confusion
PMH includes
Alcoholic liver disease/haemochromatosis
Social history
Lives alone
Alcohol abuse
Allergies - NKA

31. Case 1 continued On examination Medications
HR: 84 reg BP: 115/70 mmHg RR: 18/min
Temp: 37.7C
Ascites+++, abdominal pain
Mild confusion
Medications
Omeprazole 20mg bd
Lactulose 20mL tds prn
Thiamine 100mg daily
Vitamin K 10mg daily
Spironolactone 100mg daily

32. Laboratory Tests U&Es Haemotology Sodium 130 mmol/L 
Potassium 3.9 mmol/L
Creatinine 130 micromol/L 
Glucose 4.3 mmol/L
Haemotology
Hb 100 g/L 
WCC x 109/L 
Platelets 256 x 109/L
INR 
Low sodium levels likely dilutional hyponatraemia.
Portal hypertension activates renin-angiotensin system causing ADH release and fluid and salt retention.
Hb normal male g/L
TSH elevated ( mU/L)
T4 down ( pmol/L) 32

33. Laboratory Tests LFT/Gastro Total Protein 61 g/L Albumin 23 g/L 
Bilirubin 86 umol/L 
ALT 63 U/L 
GGT 96 U/L 
ALP U/L
AST U/L 

34. Diagnosis and Plan
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
Compensated ALD-remaining undamaged liver can still perform normal functions although LFTs may be abnormal
Decompensated-liver capacity not sufficient to carry out normal functions and body’s metabolism becomes affected-symptoms such as jaundice, ascites, varices etc. 34

35. Which lab tests indicate liver disease
Which lab tests indicate liver disease? Which tests are used to assess disease severity?
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
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?