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Therapeutics in Hepatobiliary Disease Narelle Brown Animal Referral Hospital 30/04/10

Mar 26, 2015

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Therapeutics in Hepatobiliary Disease Narelle Brown Animal Referral Hospital 30/04/10 Slide 2 Slide 3 Section 1 Antibiotic Therapy Slide 4 When To Consider Antibiotic Therapy? Increased risk of infection EHBDO Chronic liver Dz with portal hypertension Compromised hepatic perfusion /bile flow Enteric Bacterial Translocation Bowel Dz Bacterial dysbiosis Splanchnic Hypoperfusion Slide 5 Hepatobiliary Infections Considerations: primary Vs secondary infections innocent Bystander effects on antibiotic metabolism (dose and dosing frequency) bacteria found in bile/liver/GB :enteric origin E Coli, Clostridium, Enterococcus sp anaerobic and gm neg bacteria ideally based on culture and sensitivity Slide 6 Samples for culture Cholecystocentesis Not advised if EHBDO or US changes necrotizing cholecystitis Transhepatic approach Limits bile extravasation Drain as much of the bile as possible Submit sample in culture bottle US guidance (22G spinal needle) Recheck US 24-48hrs later Slide 7 Samples for culture:Liver Abscess Ultrasound guided May be only therapy required if complete drainage Generally better to surgically explore once stable as often associated with necrotic center (neoplasia) or migrating FB Slide 8 Samples for Culture:Liver Biopsy surgically Tru-Cut (ultrasound guided), laproscopy Sample liver tissue for culture (into sterile, sealed container) Assess patients ability to clot BEFORE you do the biopsy Slide 9 General guidelines In the absence of C+S: Cover aerobic and anaerobic enteric orgs B lactamase resistance penicillin OR metronidazole OR clindamycin PLUS Aminoglycoside or fluorinated quinolone Start treatment BEFORE sx if EHBDO or known infection Slide 10 Antibiotics Antibiotics that achieve therapeutic concentrations in liver and bile, renal excretion: Amoxicillin 11-20mg/kg PO,IV,IM BID Cephalexin 15mg/kg PO, SQ, IV BID-TID Ticarcillin 50mg/kg IV TID Enrofloxacin 2.5-5mg/kg PO, SQ BID Slide 11 Metronidazole Dose: 7.5mg/kg PO, IV, rectal BID-TID High bioavailability Wide tissue distribution (bone/bile/CSF,brain/prostate/ascites) Note Liver dose Important action against many urease producers (decrease ammonia production) Immunosuppressive activity Overdose: cerebellar/central vestibular signs/seizures Slide 12 Neomycin Can be used alone or is synergistic with lactulose in effects on gut flora (decrease ammonia production) Not systemically absorbed Beware if concurrent IBD as may be absorbed May improve portal hypertension 22mg/kg Po BID-TID Slide 13 Chloramphenicol ???? If you have to use it use a low dose : 11mg/kg PO, SQ, IV BID Inactivates mixed function oxidases in liver>>>>> adverse drug reactions Anorexia / Erythroid hypoplasia Bone marrow injury in humans Slide 14 Antibiotics to Avoid Tetracyclines Lincomycin Erythromycin Trimethoprim-Sulphonamides Either inactivated by liver, require hepatic metabolism or can injure liver Slide 15 REMEMBER Hepatobilary disease can influence the clearance and volume of distribution of drugs See table in Greenes Infectious diseases Slide 16 Section 2 Detoxification/Removal Intestinal Toxins Slide 17 Lactulose Decrease intestinal ammonia production Decrease ammonia absorption Antiendotoxin effect Indicated for treatment hepatic encephalopathy Works synergistically with neomycin 0.25-1.0 ml PO per 5kg Adjust dose to achieve 2-3 soft stools /day Slide 18 Enemas Perform a mechanical enema first to flush faecal contents from colon Retention enemas for a prolonged effect Lactulose: 5-15ml diluted 1:3 with water: retain 20-30 mins. If faecal pH >6 repeat Activated charcoal Vinegar :dilute 1:10 with water BID-TID Betadine :dilute 1:10 in water :flush out after 10-15 mins :BID-TID Slide 19 Section 3 Gastric Protectants Slide 20 Gastric protectants Animals with chronic major bile duct obstruction at an increased risk gastroduodenal ulceration/perforation H2 Receptor antagonists Cimetidine (??) Suppression cytochrome P450 oxidases Most cases increases pharmacologic effects or toxicity of concomitant drugs 5mg/kg IM, IV, PO BID-TID Famotidine 20-30x more potent than cimetidine 0.4-0.7mg/kg PO, IV (SID if PO, BID if IV) Slide 21 Proton Pump Inhibitors Omeprazole 5-10 fold more potent than cimetidine Inhibits p450 cytochrome oxidases similar to cimetidine 0.7-2mg/kg PO SID (dogs) Limited experience with this drug in cats Slide 22 Gastric Cytoprotection Sucralfate Direct action on mucosal prostoglandin E production Binds to surface mucosal ulcers/protective barrier Inhibits pepsin activity Does NOT require an acid environment to be effective (no need to stagger dose with antacid) ? Will interfere with absorption of drugs orally administered It inactivates fluoroquinolones May promote constipation Slide 23 Sulcralfate DOSE: Large dogs: 1g, PO BID-QID Medium dogs: 0.5gm PO BID-QID Small Dogs/Cats: 0.12-0.25g PO BID-QID May cause oesophageal impaction so best mixed with water and given via syringe Slide 24 Section 4 Antiemetic Therapy Slide 25 Metoclopramide (Maxalon) Impaired hepatic function decreases plasma clearance by 25% Normal dose: 0.2-0.4mg/kg PO TID-QID 1-2mg/kg/24hours CRI 25% reduced dose: 0.13-0.3mg/kg PO TID -QID 0.75-1.5mg/kg/24hours CRI IV Slide 26 Ondansetron (Zofran) Good anti-emetic effect in patients with poor responsive to maxalon $$$$ Dose: 0.1-1.0mg/kg PO q12hours(use low end dose range with liver dz as eliminated by hepatic metabolism) Cats: 0.1-0.5mg/kg PO BID-SID Slide 27 Maropitant (Cerenia) NK1 antagonist Good anti-emetic Dose:1mg/kg s/c SID or 2mg/kg PO SID Slide 28 Section5 Immunosuppressive/Immunomodulatory Therapy Slide 29 Immunosuppressant/Immunomodulatory Therapy Glucocorticoids Azathioprine Ursodeoxycholic Acid Slide 30 Glucocorticoids Indications Antifibrotic (weak) Non septic active inflammation Immunologic Injury Promote bile flow Appetite stimulant Side Effects Sodium/water retention Catabolic Increased susceptibility infection GI ulceration Slide 31 Glucocorticoids If ascites or oedema are a problem-use glucocorticoids that lack mineralocorticoid activity Dexamethasone (try for every three day dosing to avoid excessive suppression P-A axis) Taper dose to lowest effective level Slide 32 Azathioprine Immunosuppression More expensive than prednisolone Steroid sparing Side Effects Bone marrow suppression Hepatopathy Pancreatitis Toxic to humans Slide 33 Ursodeoxycholic Acid (UDCA) Non Toxic hydrophilic bile acid Choleretic Decreases proportion toxic bile acids Reduces the immune response Increased production glutathione (GSH) and metallothionein in hepatocytes Contraindicated EHBDO 15mg/kg/day divided in 2 doses Indicated in cholestatic disorders (not PSS or HL) Slide 34 Section 6 Anti-Oxidant Therapy Slide 35 Anti-Oxidants Vitamin C (can be pro-oxidant) S-Adenosyl-L-Methionine (SAMe) Vitamin E Silymarin N-Acetlcysteine Zinc* UDCA* Slide 36 S-Adenosyl-L-Methione (SAMe) Precursor of cysteine:one of AA that makes up glutathione (GSH) GSH is a defense mechanism against oxidative stress. Depletion GSH:oxidative stress Helps to restore depleted GSH in hepatocytes 20mg/kg PO SID (empty stomach). Do not split tabs 2 isomers:ss and rs (the ss is the active form) Slide 37 Silymarin Extracted from milk thistle Free radical scavenger Increases cellular SOD (main defense against oxidative damage) Choleretic/anti-inflammatory Indicated where main damage to liver is oxidative Amanita mushroom intoxication Paracetamol intoxication 20-50mg/kg/day divided q6-8hr PO No side effects Slide 38 Vitamin E Dose:10-15 IU/kg /day PO Indicated in liver dz associated with oxidative injury Anti-inflammatory Especially important in fat malabsorption (bile duct obstruction) Copper toxicity Paracetamol toxicity No side Effects Slide 39 N-Acetylcysteine Cytoprotective (along with SAMe, UDCA, Silymarin, Vit E) Anti-oxidant (increases GSH) Anti-Inflammatory Improves hepatic circulation Improves tissue O2 delivery 140mg/kg IV once then 70mg/kg IV q6hr Slide 40 AntiFibrotic Drugs Fibrosis end result of chronic inflammation A lot of research into drugs to limit fibrosis/cirrhosis :all experimental at this stage Colchicine: Stimulates collagenase Side Effects HE, BM suppression, renal injury, neuropathy 0.025-0.3mg/kg SID few days then EOD NO evidence that it helps Dont use it (?if fibrosis is primary lesion) Slide 41 Anti Copper Medications Free intracellular copper causes oxidative damage Genetic disease Bedlington Terriers Skye Terriers West Highland White Terriers Dalmatians Labradors Dobermans DNA test (dont need a liver biopsy anymore) Secondary to decreased bile excretion Slide 42 Anti-Copper Medications Chelating Agents Bind free extracellular copper .excreted in urine.movement copper from intracellular space to extracellular spacedecreases intracellular toxic pool D Penacillamine (preferred) Trientine (more potent) 10-15mg/kg BID with food Slide 43 Anti-copper Medications(cont) Zinc (gluconate or acetate) Induces metallothionein in enterocytes-binds cu -sequestered in senescent enterocytes -sloughed..excreted Give 1 hour Before meals Dont use chelators and zinc together 10mg elemental zinc /kg BID Watch for haemolytic anaemia (excess zinc) or iron deficiency Slide 44 Ascites Rare in cats with liver dz Portal hypertension w/o hypoalbuminaemia will only cause ascites RARELY (ie: A-V fistula, complete thrombosis portal vein) Sodium restriction Cage rest Sodium wasting diuretics Slide 45 Ascites with Hepatobiliary Disease Measure BW, abdominal girth, PCV, TS, BUN Spironolactone 0.5-1.0mg/kg PO BID 3-4d Frusemide 1.0mg/kg PO BID -4d If respond :taper drugs to lowest effective dose Slide 46 Ascites With Hepatobiliary Disease If no response:(and PCV/TS/BUN stable) Spironolactone 2mg/kg PO BID 4d If still no response (and PCV etc stable) Frusemide 2mg/kg PO BID Watch: Hypokalemia Dehydation Slide 47 Ascites (cont) :If still no response Colloid Administration Expand the ECF compartment:promo