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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 Blood supply Liver receives 25% of resting cardiac output Blood enters via hepatic artery (25%) & portal vein (75%) Blood leaves via carries blood from gut rich in absorbed nutrients portal flow increases after meals hepatic vein Also leaving liver hepatic ducts carry bile to gall bladder Normal Situation Urea Systemic Circulation Collateral Splanchnic Circulation Protein Bacteria NH3 GIT Causes Of Chronic Hepatic Failure RISK FACTORS Viral Hepatitis Hepatitis C Hepatitis B / D • IVDU RISK FACTORS • TATTOOS • IVDU • BODY PIERCING • MOTHER TO BABY • BLOOD TRANSFUSION (pre (Vertical) 1989/90) - ASIA • SEXUAL Alcohol Autoimmune Disease Primary Biliary Cirrhosis (PBC) Primary Sclerosing Cholangitis (PSC) Autoimmune Hepatitis 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 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 Decreased clotting factors Oesophageal / Gastric / Rectal varices Variceal bleeding mortality after 1st bleed 50% 60% re-bleed in 1 year 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 Urea Diseased Liver Systemic Circulation Cirrhosis Collateral Splanchnic Circulation Portal Hypertension Protein Portal systemic shunting Bacteria NH3 Drugs GIT Complications of CLDHepatorenal 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 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? What are the side effects? First pass? 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 Social history Alcoholic liver disease/haemochromatosis 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 Potassium Creatinine Glucose 130 mmol/L 3.9 mmol/L 130 micromol/L 4.3 mmol/L 100 g/L 16.7 x 109/L 256 x 109/L 1.9 Haemotology Hb WCC Platelets INR Laboratory Tests LFT/Gastro Total Protein Albumin Bilirubin ALT GGT ALP AST 61 g/L 23 g/L 86 umol/L 63 U/L 96 U/L 107 U/L 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? 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? 4. 5.