Infective Liver Disease

Transcription

1 The Role oeofdrugs in Non Infective Liver Disease Peter Tenni Senior Lecturer in Therapeutics, School of Pharmacy University of Tasmania Senior Research Fellow Unit for Medication Outcomes Research and Education University of Tasmania 1 Presentation Outline Normal Liver Function Common Non infective Liver Diseases Use of Liver Function Tests Clinical Consequences of Liver Disease Drugs in the management of Liver disease Drugs as a cause of Liver Disease Adjustment of drug use in Liver disease 2

2 Normal Liver Functions Synthesis (eg. clotting factors, albumin) Metabolism (eg. Vitamin D) Clearance (eg. drugs, aldosterone) Storage (eg. vitamins, glycogen) Secretion (eg. bile salts) Filtration (eg. antigens) Homeostasis (eg. glucose) 3 Common Non Infectious Liver Diseases Alcoholic Liver Disease Almost 150,000 people with ALD in Australia (~1%) Non Alcoholic Steatohepatitis (Fatty Liver) Cholestatic Jaundice Bile Stones Liver Malignancies Secondaries from other primary diseases (esp. bowel cancer, breast cancer) Primary Liver Cancer 4

3 Bilirubin Enzymes Liver Function Tests (LFTs) Alkaline phosphatase Aminotransaminases (AST & ALT) Gamma Glutamyl Transpeptidase (γgt) Other markers (non LFTs) serum albumin serum urea INR and prothrombin time 5 Liver Function Tests Bilirubin Haemoglobin Haem Pre Intra Bilirubin + Glucuronide Post Bilirubin may be increased as a result of prehepatic, intrahepatic or posthepatic causes Bilirubin Bilirubin Glucuronide Urobilinogen Urobilin (Brown) Urobilin (Yellow) 6

4 Liver Function Tests Enzymes 7 Liver Function Tests Enzymes Transaminases (ALT and AST) Contained within hepatocytes Primarily an indicator of liver damage Other sources: muscle, kidney, brain Alkaline Phosphatase Contained within ihi cells lining i bile canaliculi Primarily an indicator of obstruction processes Other sources: bone, placenta, small intestine and kidney Gamma Glutamyl Transpeptidase Hepatocyte microsomal enzyme Widely distributed in the tissues including liver and kidneys Highly sensitive marker of cholestasis Also elevated in metabolic or damage situations 8

5 INR Other LiverFunction Tests Synthesis of clotting factors decreased in severe liver disease Albumin Major plasma protein synthesised and secreted by the liver Long half life ~ 20 days, hence serum albumin falls slowly with decreased synthesis Urea Produced by protein breakdown in the liver and is reduced in liver dysfunction 9 Use of Liver Function Tests LFTs may indicate the type of liver disease (obstructive or damage) g) and may indicate the duration of disease (synthetic indicators) LFTs are not useful to quantify the extent of liver disease indeed lower levels may be associated with more severe damage 10

6 Clinical Consequences of Liver Disease Non Specific fatigue, anorexia, weight loss, vague abdominal discomfort, nausea Signs Jaundice, Spider Naevi, Hepatomegaly, Palmar erythema, Finger clubbing, Gynaecomastia, Asterixis Cirrhosis/Fibrosis Severe Disease Portal Hypertension Ascites/Oedema Varices Encephalopathy Bleeding Abnormalities 11 Jaundice Hepatomagaly Finger Clubbing Spider Naevi 12

7 Cirrhosis Fibrosis i of the liver parenchyma as a result of chronic liver injury causing: Portal hypertension Varices Ascites Reduced metabolic and synthetic functions Encephalopathy Hypoalbuminaemia Bleeding problems Altered handling of drugs Increased risk of liver malignancy 13 Management of Major Complications of Non Infectious Liver Disease Portal Hypertension/Ascites/Varices Reduce fluid retention Dietary salt reduction Fluid restriction Spironolactone (antialdosterone effect Doses of mg daily are common, with a maximum daily dose of 600mg. Monitoring daily weights, urea and electrolytes 14

8 Management of Oesophageal Varices Often the only symptom is GI bleeding Mortality of acute bleed is 20 40% Acute Management Blood volume support (Haemaccel etc.) Emergency endoscopy to confirm diagnosis and to either ligate or sclerose the vessels Replace coagulation factors (usually clotting is defective) Ifbleeding continues Octreotide 25 50mcg/hr or Vasopressin (reduces splanchnic blood flow) 15 Management of Oesophageal Varices Prevention of re bleeding Chances of a re bleed are ~ 60% in first 12 months Can re sclerose every 4 weeks or so and monitor closely Reduce heart rate (aim for 20 25% reduction if possible) with Propranolol 20mg bd ( doses up to 200mg daily may required) Do You Feel Lucky? 16

9 Encephalopathy Relates to excessive concentrations of ammonia in the CNS (breakdown product of protein) Early signs are changes to personality, intellect and emotions as well as sleep disturbances, confusion and disorentation Later progression involves psychotic episodes (Korsakoff s psychosis) 17 Management of Encephalopathy Treatment aims to reduce ammonia production by: Avoiding high intake of protein (low protein diets recommended) Sterilising the gut thereby blocking bacterial digestion of protein. Lowering the gut ph this results is the ammonia bi being ionised i dto ammonium ion (NH 4+ ) which h is not readily absorbed across the gut wall into the general circulation. 18

10 Management of Encephalopathy: Lactulose Is a disaccaride laxative that is converted to lactic and formic acids by colonic bacteria This acidic medium decreases ammonia (nitrogen) absorption and reduces the nitrogen load presented to the liver. As a result of its laxative effects, dose is titrated to produce soft motions, aim for 30 45mL three or four times a day (often not achievable) 19 Management of Encephalopathy: Neomycin decreases the number of ammonia producing bacteria in the gastrointestinal tract. not significantly absorbed and effect contained to the GIT. may cause a problem in patients with renal failure Many adverse effects which include: rashes, malabsorption, superinfection (esp. candidiasis), renal toxicity (and eliminated renally), ototoxicity (esp. in renal failure) 20

11 Drug Induced LiverDisease Predominantly cholestatic or hepatitic picture Depends on relative degrees of elevation of Alkaline phosphatase p and Transaminases For example Alkaline phosphatase 5x N and ALT 2xN Likely cholestatic Alkaline phosphatase 2x N and ALT 5xN Likely intrahepatic ti damage Many drugs cause transient elevation of transaminases (probably not a toxic effect) 21 Drug Induced LiverDisease Intrahepatic damage Alcohol Amiodarone Anti Tb drugs Halothane Methyldopa Carbamazepine Paracetamol Phenytoin Ketoconazole Valproate Cholestasis Phenothiazine Tricyclics Benzodiazepine Macrolides Ketoconazole Augmentin, flucloxacilin Oestrogens Androgens Sulphonylureas l Thioamides 22

12 Drug Induced LiverDisease 23 Drug Metabolism by the Liver Most drugs are metabolised to more lipid soluble compounds which are eliminated renally Metabolism mostly takes place in the liver Phase One metabolism Phase Two metabolism Liver blood flow Other sites of metabolism serum, skin, intestines, kd kidneys 24

13 Perfusion and Liver Metabolism of Drugs 25 LiverDrug Metabolism Phase One Metabolism Phase Two Metabolism 26

14 Phase One Liver Metabolism Oxidative reactions aimed at increasing the polarity of the compounds hydroxylation, oxidation, demethylation Markedly affected by perfusion and also hepatocyte capacity (therefore reduced capacity in moderate liver dysfunction) Metabolites vary in activity it compared to the parent drug, so consequences of liver disease can be an increase or decrease ineffect oranincrease inadverse effects Similarly Active Less Active More Active Amitrityline/nortriptyline Imipramine/ desipramine Diazepam/oxazepam Tramadol Pethidine Most drugs Codeine/morphine Tamoxifen/hydroxytamoxifen Other prodrugs 27 Changes in Blood Flow Through the Liver and/orchangesin Phase One Metabolism Capacity Drug dose (100mg) Drug dose (100mg) Liver removes 85mg Phase One removes 70mg Metabolism Remaining systemic drug dose (15mg) Remaining systemic drug dose (30mg) 28

15 First Pass Liver Metabolism Drugs with iha high h degree of first pass metabolism have a large difference between oral and parenteral doses, Morphine 30 60mg oral = 5 10mg IV Propranolol 40mg orally = 2mg IV or cannot be given orally at all Glyceryl trinitrate not given orally Lignocaine not given orally 29 Perfusion and Liver Clearance of Drugs Drugs with ihhigh h hepatic extraction tend to be cleared well, even in the presence of reduced blood flow to the liver Morphine, propranolol, pethidine, lignocaine, glyceryl trinitrate Bioavailability of drugs with low hepatic extraction will be effected by liver flow (eg. RHF) Diazepam, theophylline, warfarin, paracetamol, tolbutamide 30

16 Phase Two Liver Metabolism For example conjugation with glucuronide Usually metabolite is less active, occasionally has some activity (eg morphine glucuronide) Capacity for phase two metabolism retained until quite severe liver disease is present Therefore preferred drugs in patients with liver disease only require phase two metabolism (eg oxazepam or lorazepam vs diazepam) 31 Dose Adjustment in Liver Disease Check kinetics of the drugs and activity/nature of metabolites (if known) Determine whether an increase in effects, a decrease in effects or an increase in adverse effects is likely Monitor! Minimise use of hepatotoxic drugs in patients with established liver disease 32

17 Presentation Overview Normal Liver Function Common Non infective Liver Diseases Use of Liver Function Tests Clinical Consequences of Liver Disease Drugs in the management of Liver disease Drugs as a cause of Liver Disease Adjustment of drug use in Liver disease 33 The Role oeofdrugs in Non Infective Liver Disease Peter Tenni Senior Lecturer in Therapeutics, School of Pharmacy University of Tasmania Senior Research Fellow Unit for Medication Outcomes Research and Education University of Tasmania 34