YOU ARE DOWNLOADING DOCUMENT

Please tick the box to continue:

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

Therapeutics in HepatobiliaryDisease

Narelle BrownAnimal Referral Hospital

30/04/10

Page 2: Therapeutics in Hepatobiliary Disease Narelle Brown Animal Referral Hospital 30/04/10.
Page 3: Therapeutics in Hepatobiliary Disease Narelle Brown Animal Referral Hospital 30/04/10.

Section 1Antibiotic Therapy

Page 4: Therapeutics in Hepatobiliary Disease Narelle Brown Animal Referral Hospital 30/04/10.

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

Page 5: Therapeutics in Hepatobiliary Disease Narelle Brown Animal Referral Hospital 30/04/10.

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

Page 6: Therapeutics in Hepatobiliary Disease Narelle Brown Animal Referral Hospital 30/04/10.

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

Page 7: Therapeutics in Hepatobiliary Disease Narelle Brown Animal Referral Hospital 30/04/10.

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

Page 8: Therapeutics in Hepatobiliary Disease Narelle Brown Animal Referral Hospital 30/04/10.

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

Page 9: Therapeutics in Hepatobiliary Disease Narelle Brown Animal Referral Hospital 30/04/10.

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

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

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

Page 11: Therapeutics in Hepatobiliary Disease Narelle Brown Animal Referral Hospital 30/04/10.

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

Page 12: Therapeutics in Hepatobiliary Disease Narelle Brown Animal Referral Hospital 30/04/10.

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

Page 13: Therapeutics in Hepatobiliary Disease Narelle Brown Animal Referral Hospital 30/04/10.

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

Page 14: Therapeutics in Hepatobiliary Disease Narelle Brown Animal Referral Hospital 30/04/10.

Antibiotics to Avoid

• Tetracyclines• Lincomycin• Erythromycin• Trimethoprim-Sulphonamides• Either inactivated by liver, require hepatic

metabolism or can injure liver

Page 15: Therapeutics in Hepatobiliary Disease Narelle Brown Animal Referral Hospital 30/04/10.

REMEMBER

• Hepatobilary disease can influence the clearance and volume of distribution of drugs

• See table in Greenes Infectious diseases

Page 16: Therapeutics in Hepatobiliary Disease Narelle Brown Animal Referral Hospital 30/04/10.

Section 2Detoxification/Removal Intestinal Toxins

Page 17: Therapeutics in Hepatobiliary Disease Narelle Brown Animal Referral Hospital 30/04/10.

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

Page 18: Therapeutics in Hepatobiliary Disease Narelle Brown Animal Referral Hospital 30/04/10.

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

Page 19: Therapeutics in Hepatobiliary Disease Narelle Brown Animal Referral Hospital 30/04/10.

Section 3Gastric Protectants

Page 20: Therapeutics in Hepatobiliary Disease Narelle Brown Animal Referral Hospital 30/04/10.

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)

Page 21: Therapeutics in Hepatobiliary Disease Narelle Brown Animal Referral Hospital 30/04/10.

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

Page 22: Therapeutics in Hepatobiliary Disease Narelle Brown Animal Referral Hospital 30/04/10.

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

Page 23: Therapeutics in Hepatobiliary Disease Narelle Brown Animal Referral Hospital 30/04/10.

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

Page 24: Therapeutics in Hepatobiliary Disease Narelle Brown Animal Referral Hospital 30/04/10.

Section 4Antiemetic Therapy

Page 25: Therapeutics in Hepatobiliary Disease Narelle Brown Animal Referral Hospital 30/04/10.

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

Page 26: Therapeutics in Hepatobiliary Disease Narelle Brown Animal Referral Hospital 30/04/10.

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

Page 27: Therapeutics in Hepatobiliary Disease Narelle Brown Animal Referral Hospital 30/04/10.

Maropitant (Cerenia)

• NK1 antagonist• Good anti-emetic • Dose:1mg/kg s/c SID or 2mg/kg PO SID

Page 28: Therapeutics in Hepatobiliary Disease Narelle Brown Animal Referral Hospital 30/04/10.

Section5Immunosuppressive/Immunomodulatory Therapy

Page 29: Therapeutics in Hepatobiliary Disease Narelle Brown Animal Referral Hospital 30/04/10.

Immunosuppressant/Immunomodulatory Therapy

• Glucocorticoids• Azathioprine • Ursodeoxycholic Acid

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

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

Page 31: Therapeutics in Hepatobiliary Disease Narelle Brown Animal Referral Hospital 30/04/10.

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

Page 32: Therapeutics in Hepatobiliary Disease Narelle Brown Animal Referral Hospital 30/04/10.

Azathioprine

• Immunosuppression• More expensive than prednisolone• Steroid sparing • Side Effects

– Bone marrow suppression– Hepatopathy– Pancreatitis– Toxic to humans

Page 33: Therapeutics in Hepatobiliary Disease Narelle Brown Animal Referral Hospital 30/04/10.

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)

Page 34: Therapeutics in Hepatobiliary Disease Narelle Brown Animal Referral Hospital 30/04/10.

Section 6Anti-Oxidant Therapy

Page 35: Therapeutics in Hepatobiliary Disease Narelle Brown Animal Referral Hospital 30/04/10.

Anti-Oxidants

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

Page 36: Therapeutics in Hepatobiliary Disease Narelle Brown Animal Referral Hospital 30/04/10.

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)

Page 37: Therapeutics in Hepatobiliary Disease Narelle Brown Animal Referral Hospital 30/04/10.

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

Page 38: Therapeutics in Hepatobiliary Disease Narelle Brown Animal Referral Hospital 30/04/10.

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

Page 39: Therapeutics in Hepatobiliary Disease Narelle Brown Animal Referral Hospital 30/04/10.

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

Page 40: Therapeutics in Hepatobiliary Disease Narelle Brown Animal Referral Hospital 30/04/10.

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)

Page 41: Therapeutics in Hepatobiliary Disease Narelle Brown Animal Referral Hospital 30/04/10.

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

Page 42: Therapeutics in Hepatobiliary Disease Narelle Brown Animal Referral Hospital 30/04/10.

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

Page 43: Therapeutics in Hepatobiliary Disease Narelle Brown Animal Referral Hospital 30/04/10.

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

Page 44: Therapeutics in Hepatobiliary Disease Narelle Brown Animal Referral Hospital 30/04/10.

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

Page 45: Therapeutics in Hepatobiliary Disease Narelle Brown Animal Referral Hospital 30/04/10.

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

Page 46: Therapeutics in Hepatobiliary Disease Narelle Brown Animal Referral Hospital 30/04/10.

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

Page 47: Therapeutics in Hepatobiliary Disease Narelle Brown Animal Referral Hospital 30/04/10.

Ascites (cont) :If still no response

• Colloid Administration– Expand the ECF compartment:promote

diuresis – Plasma preferred ($$$)

Page 48: Therapeutics in Hepatobiliary Disease Narelle Brown Animal Referral Hospital 30/04/10.

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)

Page 49: Therapeutics in Hepatobiliary Disease Narelle Brown Animal Referral Hospital 30/04/10.

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)

Page 50: Therapeutics in Hepatobiliary Disease Narelle Brown Animal Referral Hospital 30/04/10.

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

Page 51: Therapeutics in Hepatobiliary Disease Narelle Brown Animal Referral Hospital 30/04/10.

Summary

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

Page 52: Therapeutics in Hepatobiliary Disease Narelle Brown Animal Referral Hospital 30/04/10.

Summary

• N-Acetylcysteine– Paracetamol Toxicity– Acute Liver Failure

• Ursodeoxycholic Acid– Cholestatic Hepatopathies– Necro-inflammatory Hepatopathies– Metabolic Hepatopathies– Immune-Mediated Hepatopathies

Page 53: Therapeutics in Hepatobiliary Disease Narelle Brown Animal Referral Hospital 30/04/10.

Summary

• Silymarin– Amanita Mushroom Toxicity– Hepatotoxicity– Cholestatic Hepatopathies– Necro-Inflammatory hepatopathies

• Vitamin E– Cholestatic hepatopathies– Necro-Inflammatory Hepatopathies

Page 54: Therapeutics in Hepatobiliary Disease Narelle Brown Animal Referral Hospital 30/04/10.

Case Study

• 13 yr FS Chihuahua• 9 day hx lethargy ,

inappetance• PU/PD• Orange Urine• Vomited once

Page 55: Therapeutics in Hepatobiliary Disease Narelle Brown Animal Referral Hospital 30/04/10.

Clinical Pathology

• CBC: Hct 57% WBC 13 N’phil 9.2 L’cyte 2.6 M’cyte 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

Page 56: Therapeutics in Hepatobiliary Disease Narelle Brown Animal Referral Hospital 30/04/10.

Physical Examination

• Mildly Dehydrated• T 39.3C• Icteric mm• Mild cranial abdominal discomfort,

hepatomegaly• BCS 6/9

Page 57: Therapeutics in Hepatobiliary Disease Narelle Brown Animal Referral Hospital 30/04/10.

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

Page 58: Therapeutics in Hepatobiliary Disease Narelle Brown Animal Referral Hospital 30/04/10.

Thoracic Radiographs

• Unremarkable

Page 59: Therapeutics in Hepatobiliary Disease Narelle Brown Animal Referral Hospital 30/04/10.

Exploratory Laparotomy

• CBD obstructed by choleliths and inflammatory debris

• Flushed CBD via enterotomy • Splenectomy• Intestinal polypoid mass resection

Page 60: Therapeutics in Hepatobiliary Disease Narelle Brown Animal Referral Hospital 30/04/10.

Pathology

• Bile Culture: no growth• Splenic Masses: Nodular

hyperplasia/myelolipomas• Intestinal leimyosarcoma (low

grade:completely resected)• Liver: vacuolar change

Page 61: Therapeutics in Hepatobiliary Disease Narelle Brown Animal Referral Hospital 30/04/10.

Treatment

• Timentin • enrofloxacin• Esomeprazole• Methadone • IV Fluids

Page 62: Therapeutics in Hepatobiliary Disease Narelle Brown Animal Referral Hospital 30/04/10.

Outcome

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

Page 63: Therapeutics in Hepatobiliary Disease Narelle Brown Animal Referral Hospital 30/04/10.


Related Documents