Drug Use in Chronic Liver Disease

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

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

6. 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

7. 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

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

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)

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

15. Diseased Liver Systemic Circulation Urea Cirrhosis 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

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.

19. What the points mean!

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? 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

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 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 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 

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 107 U/L AST 143 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

35. 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?