Drug Use in Chronic Liver Disease

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Drug Use in Chronic Liver Disease

• Dr Ian Coombes
• University of Queensland
• Safe Medication Practice Medication Unit

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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

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Chronic liver disease (CLD)

• Inflammation of the liver for gt than 6 months
• Have permanent structural changes in the liver
• Eventually leads to reduced liver function

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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

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Normal Situation
Systemic Circulation
Urea
Collateral
Splanchnic Circulation
GIT
Bacteria
Protein NH3
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Causes Of Chronic Hepatic Failure

• Viral Hepatitis
• Hepatitis C
• Hepatitis B / D
• Alcohol
• Autoimmune Disease
• Primary Biliary Cirrhosis (PBC)
• Primary Sclerosing Cholangitis (PSC)
• Autoimmune Hepatitis

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• Hereditary Metabolic Disorders
• Haemochromatosis - Iron overload
• Wilsons Disease - Copper accumulation
• Alpha - 1 - antitrypsin deficiency
• Fatty Liver
• Venous Outflow Obstruction (Budd-chiari Syndrome)
• Drugs
• eg methyldopa, isoniazid, nitrofurantoin,
  methotrexate, amiodarone
• Cryptogenic

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Major complications of liver disease

• Portal hypertension
• Ascites
• Bleeding
• Encephalopathy
• Hepato-renal syndrome
• Effects on drug handling and sensitivity

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Complications of ALD Portal hypertension

• Increased resistance to flow through the portal
  system ? blood forced down alternate channels
• Collateral circulation
• Portosystemic shunting

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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)

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Complications of CLD Ascites

• Caused by
• ? albumin
• Portal hypertension
• ? renal perfusion
• Na/water retention
• ? aldosterone
• Treatment
• Diuretics (spironolactone/frusemide)
• Ascitic taps
• shunts

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Starlings Forces control of fluid movement in
CV system
Arteriolar Level Capillary Bed Venule
Albumin
CO2
OPgtBP
BPgtOP
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).
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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

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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

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

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Investigation of CLD

• Signs and symptoms, history
• Liver enzymes
• Plasma protein, coagulation factors, auto
  antibodies
• Imaging ultrasound, cholangiography
  (endoscopic, percutaneous, MR)
• Liver biopsy

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Classification of CLD

• Child-Pugh classification (modified version).
• Point score correlates with survival.

Parameter Number of Points Number of Points Number of Points
1 2 3
Bilirubin (umol/L) lt34 34-51 gt51
Albumin (g/L) gt35 28-35 lt28
Prothrombin time lt3 3-10 gt10
Ascites None Slight Moderate to severe
Encephalopathy None Mild Moderate to severe
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What the points mean!

Class Total points 1 yr mortality
A 5 6 low
B 7 9 20 40
C 10 15 40 60
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Management of CLD

• Treatment of underlying cause if possible
• Adequate nutrition
• Prevention and symptomatic treatment of
  complications
• Liver transplantation

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Drug Use in Chronic Liver Disease

• Disease severity
• Pharmacokinetic response
• absorption
• distribution
• elimination
• hepatic clearance
• Pharmacodynamic response
• Potentially hepatotoxic drugs

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Consider

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

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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

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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 gt60 first pass clearance

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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
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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.

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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

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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.

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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.

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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

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Case 1 continued

• On examination
• 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

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Laboratory Tests

• UEs
• Sodium 130 mmol/L ?
• Potassium 3.9 mmol/L
• Creatinine 130 micromol/L ?
• Glucose 4.3 mmol/L
• Haemotology
• Hb 100 g/L ?
• WCC 16.7 x 109/L ?
• Platelets 256 x 109/L
• INR 1.9 ?

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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 107 U/L
• AST 143 U/L ?

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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

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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?
4. What are the pharmacodynamic changes that occur
   in chronic liver disease that effect drug dosing?
5. What are the potential problems with
   aminoglycoside and analgesic use in this patient?