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

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Presentation on theme: "Therapeutics in Hepatobiliary Disease Narelle Brown Animal Referral Hospital 30/04/10."— Presentation transcript:

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


3 Section 1 Antibiotic Therapy

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

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

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

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

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

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

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

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

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

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

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

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

16 Section 2 Detoxification/Removal Intestinal Toxins

17 Lactulose –Decrease intestinal ammonia production –Decrease ammonia absorption –Antiendotoxin effect –Indicated for treatment hepatic encephalopathy –Works synergistically with neomycin – ml PO per 5kg –Adjust dose to achieve 2-3 soft stools /day

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 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 mins :BID-TID

19 Section 3 Gastric Protectants

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 mg/kg PO, IV (SID if PO, BID if IV)

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

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

23 Sulcralfate DOSE: Large dogs: 1g, PO BID-QID Medium dogs: 0.5gm PO BID-QID Small Dogs/Cats: g PO BID-QID May cause oesophageal impaction so best mixed with water and given via syringe

24 Section 4 Antiemetic Therapy

25 Metoclopramide (Maxalon) –Impaired hepatic function decreases plasma clearance by 25% –Normal dose: mg/kg PO TID-QID 1-2mg/kg/24hours CRI –25% reduced dose: mg/kg PO TID -QID mg/kg/24hours CRI IV

26 Ondansetron (Zofran) Good anti-emetic effect in patients with poor responsive to maxalon $$$$ Dose: mg/kg PO q12hours(use low end dose range with liver dz as eliminated by hepatic metabolism) Cats: mg/kg PO BID-SID

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

28 Section5 Immunosuppressive/Immunomodulatory Therapy

29 Immunosuppressant/Immunomodulatory Therapy Glucocorticoids Azathioprine Ursodeoxycholic Acid

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

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

32 Azathioprine Immunosuppression More expensive than prednisolone Steroid sparing Side Effects –Bone marrow suppression –Hepatopathy –Pancreatitis –Toxic to humans

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)

34 Section 6 Anti-Oxidant Therapy

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

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)

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

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

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

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 – mg/kg SID few days then EOD –NO evidence that it helps –Dont use it (?if fibrosis is primary lesion)

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

42 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

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

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

45 Ascites with Hepatobiliary Disease Measure BW, abdominal girth, PCV, TS, BUN Spironolactone mg/kg PO BID 3-4d Frusemide 1.0mg/kg PO BID -4d If respond :taper drugs to lowest effective dose

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

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

48 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)

49 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 – mg/kg IM 3 doses q 12 hrs –Then every 7-28d as needed (PIVKA test, PT, PTT) –Dont give it IV (anaphylactic reactions)

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

51 Summary SAMe: –Necroinflammatory hepatopathies –Metabolic Hepatopathies (FHL) –Cholestatic Hepatopathies –Paracetamol Toxicity

52 Summary N-Acetylcysteine –Paracetamol Toxicity –Acute Liver Failure Ursodeoxycholic Acid –Cholestatic Hepatopathies –Necro-inflammatory Hepatopathies –Metabolic Hepatopathies –Immune-Mediated Hepatopathies

53 Summary Silymarin –Amanita Mushroom Toxicity –Hepatotoxicity –Cholestatic Hepatopathies –Necro-Inflammatory hepatopathies Vitamin E –Cholestatic hepatopathies –Necro-Inflammatory Hepatopathies

54 Case Study 13 yr FS Chihuahua 9 day hx lethargy, inappetance PU/PD Orange Urine Vomited once

55 Clinical Pathology CBC: Hct 57% WBC 13 Nphil 9.2 Lcyte 2.6 Mcyte 1.0 Plt 318 Chemistry:Alt 4359 Alkp 6320 Tbil 288 Chol 19.1 Alb 38 Glu 2.8 BUN 6.1 Treated Amoxyclav 4 days

56 Physical Examination Mildly Dehydrated T 39.3C Icteric mm Mild cranial abdominal discomfort, hepatomegaly BCS 6/9

57 Ultrasound Findings Intrahepatic bile ducts markedly distended Common Bile duct distended (1.7cm) Gall bladder distended R Adrenal Mass L Adrenal Mass Multiple Splenic Masses Consistent with EHBDO

58 Thoracic Radiographs Unremarkable

59 Exploratory Laparotomy CBD obstructed by choleliths and inflammatory debris Flushed CBD via enterotomy Splenectomy Intestinal polypoid mass resection

60 Pathology Bile Culture: no growth Splenic Masses: Nodular hyperplasia/myelolipomas Intestinal leimyosarcoma (low grade:completely resected) Liver: vacuolar change

61 Treatment Timentin enrofloxacin Esomeprazole Methadone IV Fluids

62 Outcome Bright, eating, resolution of icterus Treatment with Clavulox/Baytril for 6 weeks Ursodeoxycholic Acid indefinitely Bilateral adrenalectomy??


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