Drug therapy in patient with hepatic impairment Arzneimitteltherapie bei Leberinsuffizienz Dominik Wilke 03/04 Mai 2018 43. ADKA-Kongress, Stuttgart
Functions of the Liver I Metabolism (Carbohydrates, Proteins, Fat, Insulin, Bilirubin, Xenobiotics) I Excretion (Bilirubin, Bile, Xenobiotics) I Synthesis (Amino acids, Proteins, Clotting factors, Fibrinogen, Cholesterol, Gluconeogenesis, Hormones, Ferritin) I Storage (Fat soluble vitamins, Folic acid, Glycogen) I Immunological (Kupffer cells, synthesis of factors of the complement system and acute phase proteins) 2
Causes of Liver Disease (samples) Modifed from Knapstein J et al. 2013 Hepatocellular Disease Cholestatic Disease Vascular Disease Tumor Metabolic: Alcohol, Fatty liver disease, Drug Cholestasis (e.g. Gall Stones) Artery: Obstructions, Ischaemia Haemangioma, Adenoma etc. Infection: Virus (Hepatitis A-E, Herpes, EBV, CMV etc.) Primary biliary cholangitis, Primary sclerosing cholangitis Hepatic vein: Congestive heart failure, Budd Chiari syndrome Primary hepatic cancer, Liver metastasis, Klatskin tumor Genetic: Hemochromatosis, M. Wilson, α1-antitrypsin Deficiency Caroli disease Portal vein: Thrombosis with portal hypertension Abscess Autoimmune: Autoimmune Hepatitis 3 Secondary causes (posttraumatic etc.) Parasites (Echinococcosis etc.)
Statistisches Bundesamt. 2015 4
Development of Hepatocellular Disease Fatty liver Cholestasis Physiological Liver Function Fibrosis Cirrhosis Hepatocellular Carcinoma Hepatitis Acute liver failure 5 Sometimes overlapping symptoms!
Liver Function Tests (LFT) Enzyms I Alanine aminotransferase (ALAT or GPT) Liver specific, only in cytoplasm I Aspartate aminotransferase (ASAT or GOT) Very sensitive, less specific (heart, pancreas, kidneys etc.), located in cytoplasm and mitochondria Both elevated in Hepatitis, Ischaemia I Alkaline phosphatase (AP) Not liver specific (also in bone, kidneys and placenta) Elevated in Cholestasis, infiltrative liver disease, damage to biliary tree I γ-glutamyltransferase (γ-gt) Sensitiv, not specific enough Elevated in Cholestasis, CYP P450 inducers, GIT carcinoma 6
Liver Function Tests (LFT) Bilirubin, Albumin, INR I Bilirubin Transported to the liver in the serum attached to albumin Transformed into a water-soluble conjugate which is excreted via the bile into the intestine enterohepatic circulation Elevated in Haemolysis, Hepatocellular damage and Cholestasis I Albumin Long half-life (about 20 days) chronic liver disease Also decreased in patients with malnutrition, chronic inflammatory bowel disease, nephrotic syndrome I International Normalized Ratio (INR) Short half-life (Hours-Days) acute and chronic liver disease, severe cholestasis 7
Child-Pugh Score (use only for patients with underlying liver cirrhosis) Criteria 1 point 2 points 3 points Ascites in sonography Absent Mild-Moderate Severe Grade of hepatic encephalopathy 0 (none) I/II (slight) III/IV (mod-severe) Bilirubin (total) in µmol/l < 35 35-50 > 50 Albumin in g/l > 35 28-35 < 28 INR < 1,7 1,7 2,2 > 2,2 Child-Pugh A 5 6 points Compensated liver function Child-Pugh B 7 9 points Reduced liver function Child-Pugh C 10 15 points Decompensated liver function 8
Summary Liver Function Tests (LFT) I LFTs are fairly non-specific I Albumin, INR/PT and Bilirubin are considered the best predictors I But markers of hepatic dysfunction correlate poorly with hepatic clearing capacity I LFT 2x ULN considered abnormal I If liver dysfunction usually at least 2 will be deranged I Trends not isolation I Check reference ranges and units I LFTs are not always abnormal even in patients with cirrhosis I Abnormal LFTs are not necessarily because of Liver dysfunction 9
Signs/Symptoms of Liver Disease I Jaundice I Pruritus I Pale stools and dark urine I Fatty stools I Gastroesophageal varices I Bleeding I Hepatorenal syndrome I Ascites I Hepatic encephalopathy I Fatigue I (Seizures) I (Infections) 10
Adverse drug reaction Ulcerations in gastrointestinal tract Decreased coagulation Sedation Constipation Decreased seizure threshold Nephrotoxicity Hypoglycaemia Pruritus 11 Drug class (example) Acetylsalicyl acid, NSAIDs, Glucocorticoids, Bisphosphonate NSAIDs, Clopidogrel, Anticoagulants, Heparine, SSRI, Methotrexate Sedatives, Benzodiazepines, Neuroleptics, Opioids, Tricyclic Antidepressants (TCA) Opioids, TCA, Neuroleptics, Calcium canal blocker, Anticholinergics Tramadol, Pethidine, Ciprofloxacin NSAID, Aminoglycosides, Glycopeptide, Diuretics, Iodinecontaining contrast agents Antidiabetics, ACE-inhibitors Opioids
Drug Induced Liver Injury (DILI) I Liver damage varies from transient increase of LFT to acute liver failure I Most common cause of withdrawal of drugs I Prevalence about 19 cases per 100,000 inhabitants I Broad spectrum of drugs with hepatotoxic reactions I Diagnosis of exclusion I Patients with pre-existing liver disease do not have an increased Temple RJ. 2002 Bjornsson ES 2013 susceptibility, but the outcome could be more severe (exceptions e.g. Methotrexate, Sodium Valporate, certain Cytotoxics) I Pathomechanism mostly unknown; direct hepatotoxic damage oder immunological triggered I No linear dose dependency, but higher incidences in high dose regimes Smith and Obach 2005; Uetrecht 1999 12
Pharmacokinetic Considerations I Absorption: Mostly unchanged, exception cholestasis I Distribution: Ascites - Vd water soluble drugs Cachectic Vd highly lipophilic drugs Decreased albumin = decreased protein binding increase in free drug available I Metabolism: Dependent from liver blood flow (high extraction drugs) and/or functioning cell mass (low extraction drugs) Metabolism phases affected in different degrees (CYP P450 > glucuronidation) Caution: Prodrugs I Biliary excretion: Decreased in cholestasis (Enterohepatic circulation!) 13
Thank you very much for your attention and interest! Address: Universitätsklinikum Carl Gustav Carus an der TU Dresden AöR Klinik Apotheke Fetscherstraße 74, 01307 Dresden Contact: Dominik Wilke Telefon: 0351 458-19432 E-Mail: dominik.wilke@uniklinikum-dresden.de