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Drug Handling in Palliative Patients with Liver Dysfunction OR Do I need to change the dose? Penny North-Lewis Paediatric Liver Pharmacist Leeds Teaching Hospitals NHS Trust July 2013 Aim To provide an approach to drug usage and dosing decisions in palliative patients with liver dysfunction Plan for session Introduction to the issues Basic hepatology How you link this to drug handling Workshop Problems with prescribing in liver dysfunction Poor understanding of liver dysfunction Lack of information in regular sources e.g BNF, SPC (misinformation/lack of data) No easy equation to use Lack of research, small numbers of patients Back to first principles Need to know what type of liver disease your patient has and estimate the extent of liver dysfunction Need to consider what drug factors will affect use in a patient with liver dysfunction e.g pharmacokinetics and side effect profile Need to put the two together and decide Can the drug be used at all? Are there any specific precautions to use? What dose should be given? Plan for session Introduction to the issues Basic hepatology How you link this to drug handling Workshop What does the liver do? Homeostasis e.g. glucose Synthesis Lipid Metabolism (e.g. albumin & clotting factors) e.g. cholesterol Filtration Bile production and secretion e.g. antigens Metabolism e.g drugs, oestrogens, toxic products such as ammonia Some terminology used in liver disease Acute Sudden onset – jaundice to encephalopathy in less than 7 days (hyperacute), 28 days (acute), 6 months (sub-acute) Chronic Extended duration – months/years Some terminology used in liver disease Hepatocellular Fatty infiltration (steatosis) e.g. alcohol Inflammation (hepatitis) e.g. viral Cell death (necrosis) e.g. POD Cholestasis Static bile flow (not specifically bilirubin) Cholestasis Intrahepatic Extrahepatic Some terminology used in liver disease Ongoing damage: Hepatocellular and cholestasis initially Throughout hepatocytes Biliary system Fibrosis An increase in connective tissue in the liver – reversible Some terminology used in liver disease Cirrhosis Widespread disorganised nodules in the liver combined with fibrosis Compensated cirrhosis When a cirrhotic liver continues to function Decompensated cirrhosis When a cirrhotic liver can no longer function adequately – signs eg coagulopathy occur Portal hypertension Liver Portal Vein Oesophagus Stomach Spleen Splenic vein Kidney Inferior vena cava Liver conditions seen in palliative care?? End stage chronic liver disease / cirrhosis Cancer – liver primary or mets Coagulopathy, encephalopathy, ascites, bleeding varices Intra- or extra-hepatic cholestasis, pruritus Incidental liver dysfunction or disease E.g cardiac failure, prolonged hypoxia Liver disease unrelated to palliation Plan for session Introduction to the issues Basic hepatology How you link this to drug handling Liver tests Signs of liver disease Drug handling Workshop Drug handling in a liver patient first principles Liver Test Results The patient Drug Characteristics e.g. pharmacokinetics and side effects Signs of Liver Disease Diagnosis Knowing this helps! Liver dysfunction is a continuum – mild to severe – depending on disease and stage. Transaminases (0-35iu/L) (ALT & AST) Enzyme released from hepatocytes when damaged Markers of hepatocellular injury High elevations in acute injury (in several thousands) Can be normal in severe chronic liver disease (cirrhosis) Also found in heart, muscle and kidney ALT more specific to liver than AST Bilirubin (3-17 micromol/l) Product of erythrocyte breakdown Conjugated in liver to form water soluble version which can be excreted Plasma levels >50micromol/L give jaundice Haem of erythrocytes bilirubin plasma albumin (unconjugated) hepatocyte (conjugated & water soluble) bile faeces Causes of Hyperbilirubinaemia Unconjugated Increased production Decreased uptake Decreased conjugation Conjugated Intrahepatic cholestasis Extrahepatic cholestasis Haem of erythrocytes bilirubin plasma albumin (unconjugated) hepatocyte (conjugated & water soluble) bile faeces Alkaline Phosphatase (normal range varies for age and hospital) Biliary enzyme – raised with bile duct damage Increased in cholestasis Less raised in hepatocellular disease Not specific to the liver also found in bone (eg raised in Paget’s disease/bone metastases) small quantities in the intestine and placenta Gamma glutamyl transferase (GGT) (0-30u/l) Enzyme in biliary tract Increased in cholestasis Increased by enzyme inducing drugs e.g. rifampicin and alcohol Useful to determine if isolated raised alkaline phosphatase is liver related Albumin (37-49g/l) Synthesised in liver Half-life approx 20 days Good indicator of chronic liver disease Low specificity Decreased intake e.g. malnutrition Increased loss e.g. enteropathy Prothrombin Time (~13 secs) or INR (0.9-1.2) Decreased synthesis of clotting factors (cirrhosis) OR Vitamin K malabsorption (in cholestasis) Elevation > 3 seconds significant Prolonged in acute & chronic liver disease Useful prognostic indicator of impending liver failure e.g. acute liver failure or decompensated chronic liver disease Other useful tests Ultrasound – liver texture, dopplers for blood flow in hepatic artery, portal vein Liver biopsy – fibrosis, cirrhosis, intrahepatic cholestasis OGD – varices HIDA – bile flow (cholestasis) Blood glucose, creatinine Drug handling in a liver patient first principles Liver Test Results The patient Drug Characteristics e.g. pharmacokinetics and side effects Signs of Liver Disease Signs of liver disease Jaundice Pale stools/dark urine Palmar erythema White nails Gynaecomastia/testicular atrophy Spider naevi Ascites Bruising and bleeding Splenomegaly Oesphageal and gastric varices Encephalopathy Jaundice “Spiders” Ascites Useful tips on interpreting LFTs Not all LFTs are specific to the liver LFTs alone DO NOT provide a diagnosis As a guide , a significant change = >double upper limit of normal Some values may be within normal ranges in chronic severe liver disease Different hospitals have different ranges Useful tips on interpreting LFTs Cholestasis ↑ ↑ Alk Phos, ↑GGT, ↔ to ↑SBr (probably ↑) Hepatitis ↑ to ↑ ↑ ↑ ALT ↔ to ↑ INR, (↔ to ↑Alk Phos and SBr) Cirrhosis ↔ to ↑ALT, ↔ to ↑INR, ↔ to ↑SBr, ↓Albumin Worsening if decompensated Drug handling in a liver patient first principles Liver Test Results The patient Drug Characteristics e.g. pharmacokinetics and side effects Signs of Liver Disease Absorption Ascites may impair absorption e.g. diuretics Bigger doses or IV Cholestasis may impair absorption of fat soluble drugs e.g. fat soluble vitamins Bigger doses Distribution Ascites will increase volume of distribution for water soluble drugs Bigger doses per kg Low albumin will alter amount of free drug if highly protein bound Reduced doses Metabolism Decompensated cirrhosis - reduced number of functioning hepatocytes Reduce dose or increase interval Portal hypertension - reduced first pass metabolism if highly extracted drug e.g. propranolol, lidocaine Reduce dose Metabolism Prodrugs that need to be metabolised to the active form in the liver may need bigger doses! E.g. enalapril Elimination Cholestasis – biliary cleared drugs may accumulate Caution if active/toxic metabolites are produced, possibly not important if inactive Compensatory pathways e.g. renal if reduced biliary clearance? Side Effect Profile Drugs with the following side effects may need to be avoided/used with caution: GI ulceration – varices, coagulopathy Constipation – cirrhosis, encephalopathy Pruritus - cholestasis Sedation – encephalopathy, cirrhosis Coagulation defects - coagulopathy Effects on electrolytes – cirrhosis, encephalopathy Effects on fluid balance – ascites, cirrhosis Renal toxicity - cirrhosis Hepatotoxicity Dose dependent (intrinsic e.g. paracetamol, methotrexate) Dose independent (idiosyncratic) Usually acute, can be chronic Acute is usually in 5 to 90 days of starting drug Can occur after stopping causative drug Existing liver dysfunction does not increase risk of hepatotoxic reaction When do you need to worry? Decompensated cirrhosis – encephalopathy, coagulopathy Varices – risk of bleeding, effect on first pass metabolism Ascites – Na content, fluid retention Cholestasis – if drug biliary cleared Low albumin – if highly protein bound >90% Drug Handling in liver impairment – in practice Pharmacokinetic changes are not predictable The liver has amazing capacity to continue to carry out functions even when cirrhotic Need to be careful not to under dose patients for essential therapies e.g. chemotherapy and pain relief Rules for prescribing in liver disease Avoid or use certain drugs cautiously Avoid hepatotoxic drugs if possible Use therapeutic levels, where possible Monitor for efficacy eg BP, HR Monitor for toxicity Check renal function Use the smallest effective dose at the greatest interval and titrate according to response Drugs to avoid/use cautiously!! NSAIDs Opioids Tricyclic antidepressants Benzodiazepines Antipsychotics Antimuscarinics Anticholinergics Long acting drugs unless carefully titrated and pt stable Plan for session Introduction to the issues Basic hepatology How you link this to drug handling Workshop Review of common palliative drugs Cases Review of common palliative drugs Drug Considerations Analgesia Paracetamol Naproxen Codeine Tramadol Morphine Fentanyl Drug ….……………… Pharmacokinetics Absorption Considerations Lipid solubilty (Absorption affected by ascites) Distribution Water/fat Protein binding % Displaced by bilirubin or displaces bilirubin Metabolism First pass effect Hepatocyte dependent Prodrug CYPs Active metabolites Genetics Biliary excretion Alternative mechanisms Enterohepatic recirculation (Renal impairment) Elimination Side effects Consider – GI ulceration, sedation, coagulopathy, platelet effects, effects on fluid balance, effect on electrolytes, biliary sludging, renal impairment, constipation Hepatotoxicity - known hepatotoxin/type Published information in specific liver diseases/clinical studies BNF/SPC Effect of drug on liver patient Hepatitis Cholestasis Mild, normal INR and no chronic liver disease Normal hepatocyte function Cirrhosis Compensated but only just – INR 1.3-1.4, albumin 32, known varices, no encephalopathy Paracetamol Hepatic metabolism (multiple pathways) Need glutathione – stores may be reduced in the severely malnourished Hepatotoxic in overdose Paracetamol oxidation CYP2E1 conjugation NAPQI conjugation with glutathione conjugation with protein sulfhydryls Glucuronide Sulphate Complexes Hepatotoxicity Mercapturic acid/ Cysteine acid conjugates Paracetamol Use in mild hepatitis? (caution alcoholics) In cholestasis? Yes Yes In cirrhosis? Yes Reduce to TDS in severe decompensated cirrhosis Naproxen Protein binding >99% Extensively hepatically metabolised ?biliary excretion Half life 12-15 hrs Side effects GI ulceration Platelet inhibition Renal toxicity Fluid and electrolyte imbalance Hepatotoxicity Naproxen Use in hepatitis? In cholestasis? Yes, normal dose. Caution hepatoxicity May displace bilirubin from protein binding sites Caution if deranged clotting from vit K malabsorption Prefer avoid but could use with caution. In cirrhosis? Poor metabolism, accumulation Bleeding risk, renal toxicity, fluid and electrlyte disturbance AVOID Codeine First pass metabolism 50% Some biliary excretion Half life 3-4 hrs Partial prodrug? Converted to morphine Side effects Sedation, respiratory depression Constipation Pruritus Codeine Use in mild hepatitis? In cholestasis? Yes – normal dose Possible impaired excretion Pruritus Yes – normal dose but use prn and monitor In cirrhosis? Poor metabolism, possibly reduced efficacy as not converted to morphine Sedation, respiratory depression High first pass metabolism – caution if varices Reduce dose and frequency and give laxatives Dihydrocodeine may be better as parent drug exerts effect Tramadol Hepatic metabolism, first pass low Active intermediate metabolites No biliary excretion Half life 6 hrs Renal excretion 10%, increases to 30% in cirrhosis Side effects Lowers seizure threshold Plus usual opiate ADRs Tramadol Use in mild hepatitis? In cholestasis? Yes, normal dose Yes, normal dose In cirrhosis? Complex PK – parent partially active and slow metabolism, intermediate active but slow to be formed and slow to clear - ?overall effect? Use very cautiously – start low. Give laxatives Morphine Low protein binding Extensive hepatic metabolism, first pass >50% Biliary excretion and enterohepatic recirculation Half life 1-5 hrs Side effects Sedation, respiratory depression Constipation Pruritus Morphine Use in mild hepatitis? In cholestasis? Yes – normal dose Possible impaired excretion Pruritus, bile duct spasm Yes – normal dose but monitor and use prn In cirrhosis? Poor metabolism, accumulation. Varices may affect 1st pass Sedation, resp depression – encephalopathy Caution reduce dose (to 25-50%) and frequency Fentanyl Protein binding 80% Large Vd – slow redistribution, only small amt of drug available in central compartment Half life not sig different in cirrhosis – long (redistribution t½ = 13 hrs) Side effects As morphine, caution delayed effects Fentanyl Use in mild hepatitis? In cholestasis? Yes – normal dose Yes – normal dose, poss increase pruritus In cirrhosis? Metabolism only mildly impaired Sedation, resp depression – encephalopathy Can use – titrate carefully, caution with delayed effects. Avoid patches – long acting and delayed absorption Child-Pugh score – cirrhosis only Score 1 2 3 SBr <34 34-51 >51 Albumin >35 30-35 <30 INR <1.7 1.7-2.3 >2.3 Ascites None Encephalopathy None Easily controlled Minimal Poorly controlled Advanced A = 5-6 (mild), B = 7-9 (moderate), C ≥ 10 (severe) Problems with literature Rhee & Broadbent paper Critique – especially look at comments for the drugs we have discussed Any other things stand out? Cases Key messages – when to worry Cirrhosis, esp decompensated – encephalopathy, coagulopathy Varices – risk of bleeding, effect on first pass metabolism Ascites – Na content, fluid retention Cholestasis – if drug biliary cleared Low albumin – if highly protein bound >90% Key messages – generic rules Work out what is wrong with your patient’s liver and how bad it is See if the pharmacokinetics of the drug you want to use could be affected Check the drug doesn’t have side effects which could harm the patient Think! Sources of further information Medicines Q&As on NELM Drug PK data – Dollery, micromedex, SPC Drugs and the Liver Caution with interpreting references