Drug Use in Chronic Liver Disease Dr 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 3

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

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

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

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 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

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 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

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

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 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 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

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

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

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 Mild

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? 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?

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

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: 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. 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 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

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 16.7 x 109/L  Platelets 256 x 109/L INR 1.9  Low sodium levels likely dilutional hyponatraemia. Portal hypertension activates renin-angiotensin system causing ADH release and fluid and salt retention. Hb normal male 130-170g/L TSH elevated (0.4-4.7mU/L) T4 down (9.1-23.8pmol/L) 32

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 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

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?