Drug Use in Chronic Liver

DiseaseDr Ian Coombes

University of Queensland

Safe Medication Practice Medication Unit

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

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

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

Protein NH3

Bacteria

Systemic Circulation

Collateral

Splanchnic Circulation

UreaNormal Situation

GIT

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

RISK FACTORS

• IVDU

• TATTOOS

• BODY PIERCING

• BLOOD TRANSFUSION (pre 1989/90)

RISK FACTORS

• IVDU

• MOTHER TO BABY (Vertical) - ASIA

• SEXUAL

Hereditary Metabolic Disorders Haemochromatosis - Iron overload Wilson’s Disease - Copper accumulation Alpha - 1 - antitrypsin deficiency

Fatty Liver Venous Outflow Obstruction (Budd-chiari

Syndrome) Drugs

eg methyldopa, isoniazid, nitrofurantoin, methotrexate, amiodarone

Cryptogenic

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

sensitivity

Complications of ALD –Portal hypertension

Increased resistance to flow through the portal system blood forced down alternate channels

Collateral circulation Portosystemic shunting

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)

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

O2 + Nutrients

CO2

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).

BP>OP OP>BP

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

Complications of CLD- Hepatic encephalopathyMay 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

Protein NH3

Bacteria

Systemic Circulation

Collateral

Splanchnic Circulation

Urea Diseased Liver

Cirrhosis

PortalHypertension

DrugsPortal systemic shunting

GIT

Complications of CLD- Hepatorenal syndrome Acute oliguric RF with portal HT & ascites Intense vasoconstriction occurs in otherwise

normal kidneysCaused by: Pathogenesis unknown

Related to altered renocortical blood flow

Treatment: Avoid precipitating drugs & treatments No effective treatment – poor prognosis

terlipressin

Investigation of CLD

Signs and symptoms, history Liver enzymes Plasma protein, coagulation factors, auto

antibodies Imaging – ultrasound, cholangiography

(endoscopic, percutaneous, MR) Liver biopsy

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 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

Treatment of underlying cause if possible Adequate nutrition Prevention and symptomatic treatment of

complications Liver transplantation

Drug Use in Chronic Liver Disease Disease severity Pharmacokinetic response

absorption distribution elimination

hepatic clearance

Pharmacodynamic response Potentially hepatotoxic drugs

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?

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

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

High Extraction Limited Extraction Low Extraction

ChlormethiazolePropranololLignocaineVerapamilGTN

ParacetamolDiazepam *Chlordiazepoxide*Theophylline

Oxazepam *Lorazepam *Frusemide *Spironolactone*DigoxinValproic AcidTolbutamideCimetidine

Hepatic Extraction of drugs

2. REDUCED HEPATIC CELL MASS

Associated with both acute and chronic liver disease:

Decrease first pass metabolism of drugswith 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. 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.

Lack of bile - reduces absorption of lipid soluble drugs

Reduced plasma protein binding of drugs – competition with bile salts.

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.

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

Case 1 continued On examination

HR: 84 reg BP: 115/70 mmHg RR: 18/min Temp: 37.7C Ascites+++, abdominal pain Mild confusion

Medications Omeprazole 20mg bd Lactulose 20mL tds prn Thiamine 100mg daily Vitamin K 10mg daily Spironolactone 100mg daily

Laboratory Tests

U&Es 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

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

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

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?