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Therapeutics in Hepatobiliary

Therapeutics in Hepatobiliary. Disease. Narelle Brown. Animal Referral Hospital. 30/04/10. Section 1. Antibiotic Therapy. When To Consider Antibiotic Therapy?. Increased risk of infection EHBDO Chronic liver Dz with portal hypertension Compromised hepatic perfusion /bile flow

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Therapeutics in Hepatobiliary

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

  2. Section 1 Antibiotic Therapy

  3. 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

  4. 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

  5. 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

  6. 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

  7. 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

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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

  13. Antibiotics to Avoid • Tetracyclines • Lincomycin • Erythromycin • Trimethoprim-Sulphonamides • Either inactivated by liver, require hepatic metabolism or can injure liver

  14. REMEMBER • Hepatobilary disease can influence the clearance and volume of distribution of drugs • See table in Greenes Infectious diseases

  15. Section 2 Detoxification/Removal Intestinal Toxins

  16. 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

  17. 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

  18. Section 3 Gastric Protectants

  19. 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)

  20. 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

  21. 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

  22. 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

  23. Section 4 Antiemetic Therapy

  24. 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

  25. 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

  26. Maropitant (Cerenia) • NK1 antagonist • Good anti-emetic • Dose:1mg/kg s/c SID or 2mg/kg PO SID

  27. Section5 Immunosuppressive/Immunomodulatory Therapy

  28. Immunosuppressant/Immunomodulatory Therapy • Glucocorticoids • Azathioprine • Ursodeoxycholic Acid

  29. 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 Glucocorticoids

  30. 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

  31. Azathioprine • Immunosuppression • More expensive than prednisolone • Steroid sparing • Side Effects • Bone marrow suppression • Hepatopathy • Pancreatitis • Toxic to humans

  32. 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)

  33. Section 6 Anti-Oxidant Therapy

  34. Anti-Oxidants • Vitamin C (can be pro-oxidant) • S-Adenosyl-L-Methionine (SAMe) • Vitamin E • Silymarin • N-Acetlcysteine • Zinc* • UDCA*

  35. 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)

  36. 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

  37. 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

  38. 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

  39. 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 • Don’t use it (?if fibrosis is primary lesion)

  40. Anti Copper Medications • Free intracellular copper causes oxidative damage • Genetic disease • Bedlington Terriers • Skye Terriers • West Highland White Terriers • Dalmatians • Labradors • Dobermans • DNA test (don’t need a liver biopsy anymore) • Secondary to decreased bile excretion

  41. Anti-Copper Medications • Chelating Agents • Bind free extracellular copper ….excreted in urine….movement copper from intracellular space to extracellular space…decreases intracellular toxic pool • D Penacillamine (preferred) • Trientine (more potent) • 10-15mg/kg BID with food

  42. 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 • Don’t use chelators and zinc together • 10mg elemental zinc /kg BID • Watch for haemolytic anaemia (excess zinc) or iron deficiency

  43. 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

  44. 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

  45. 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

  46. Ascites (cont) :If still no response • Colloid Administration • Expand the ECF compartment:promote diuresis • Plasma preferred ($$$)

  47. Therapeutic Abdominocentesis • 18 or 16g catheter or open ended tom cat catheter through 14g teflon catheter • Remove over 1 hour • Can improve efficiency of diuretics • Risks: • Infection • Bleeding • Continued seroma formation at puncture site (lateral body wall) • Loss albumin • Hypotension (unlikely)

  48. Vitamin K • Deficiency possible with reduced hepatic function or cholestasis • Major Bile Duct Obstruction • 5-15mg (sm-lg dog) IM x3 doses q 12hours • OR • 0.5-1.5mg/kg IM 3 doses q 12 hrs • Then every 7-28d as needed (PIVKA test, PT, PTT) • Don’t give it IV (anaphylactic reactions)

  49. Vitamin K • CATS: • 5mg or 0.5-1.5mg/kg IM -3 doses q12 hours then 1-2x weekly PO until recovery • Watch for heinz body hemolytic anaemia • Monitor PCV/RBC morphology

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