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78 Cards in this Set
- Front
- Back
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True or false. You can fix the liver.
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False, you can't fix the liver, but the liver is very good at regenerating if given a chance, generally speaking best approach is to give the liver less work, not more
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In animals with hepatic disease we must always take into consideration the central role of the liver in ________.
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Detoxification of drugs
-Drugs may rely on hepatic activation -Drugs may rely on hepatic detoxification |
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What is the risk of using a drug that has cytochrome inhibition in an animal with a hepatopathy?
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May see increased toxicity, decreased efficacy, either or both
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What are the 5 specific liver drugs?
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1) Ursodeoxycholic acid
2) Silibinin 3) S-Adenosylmethionine 4) Penicillamine 5) Elemental zinc -In content of Cu toxicity |
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What are the 3 drugs groups that are to treat "stuff" happening to livers?
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1) Anti-inflammatories
-Prednisone, azathioprine, others.. 2) Antifibrotics -Colchicine 3) Support for hepatic encephalopathy e.g. lactulose |
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Why does cholestasis cause insult to the liver?
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Bile acids are detergents and is what digests fat so if in contact with hepatocytes it will damage the cell membranes
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Where are bile acids secreted? Where do they accumulate?
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Bile acids are secreted into the bile canaliculi and accumulate in gall bladder
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What is ursodeoxycholic acid?
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A naturally occurring bile acid compound, but usually a minor part of bile
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Ursodeoxycholic acid has a higher _______ in ______ than many of the other bile acids.
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Solubility in water
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True or false. Ursodeoxycholic acid is toxic to hepatocytes and GI mucosa.
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False, not toxic to hepatocytes or GI mucosa bc is water soluble
-Unlike lithocholic acid, which is directly toxic |
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Bile acids are all some form of _____ acids.
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Cholic
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______ Acid is directly toxic to hepatocytes and GI mucosa and is a major trigger for diarrhea in animals with reabsorption in problems that can't reuptake bile acids.
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Lithocholic acid
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How is ursodeoxycholic acid administered?
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Oral administration
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What are the 2 effects of ursodeoxycholic acid on the liver?
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1) Suppresses hepatic synthesis of all bile acids
2) Suppresses hepatic cholesterol synthesis |
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What are the sequelae to decreased cholesterol in bile?
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Allows other cholesterol derived substances to dissolve-->
-Inspissated bile may dissolve -Bile flow improved (by replacing the pool w/ water soluble bile acid makes it so most of bile is water soluble) |
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Will Ursodeoxycholic acid be detected by bile acid assays?
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Yes, because ursodeoxycholic acid is a natural bile acid
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What is a contraindication of ursodeoxycholic acid use?
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Contraindicated if complete biliary obstruction
-Increased risk of biliary rupture--> bile peritonitis=bad -Usually recommend abdominal ultrasound before starting |
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How is Silibinin produced?
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Silibinin is the active ingredient extracted from Milk Thistle
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What is the primary mechanism of action of Silibinin?
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Powerful antioxidant
-other claims more questionable -Experimentally shown benefit in dogs w/ oxidant intoxication |
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What are the 2 therapeutic uses of Silibinin?
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Treatment of choice for:
1) Amanita mushroom 2) Acetaminophen toxicity |
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What is Silibinin often combined with in veterinary patients?
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S-Ame
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S-Ame is an important precursor for _____ and thus ______ synthesis.
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Cysteine and thus glutathione (an important antioxidant)
-Cysteine is limiting amino acid -S-Ame is limiting precursor |
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*What is the most important first line of defense against any free radical mediated damage in hepatocytes?
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Glutathione
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S-Ame is empirically recommended for "liver _____"
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Support
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True or false. S-Ame has had controlled, blind studies that show its efficacy in small animals with liver disease.
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False, not proven, but say it can't hurt...
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What happens to metal metabolism when there's a hepatopathy?
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Liver is responsible for sequestering/recycling metals from circulation so when there's disorders in metal metabolism it results in accumulation in hepatocytes
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What is a clinical sign of iron accumulation?
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Hemochromatosis
-Extremely rare in dogs/cats, due to poorly controlled long term GI bleeding or overtransfused animals |
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What is caused by copper accumulation in the liver?
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Copper-accumulation hpeatopathy
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What is the mechanism of action of D-penicillamine?
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A copper chelating agent, used to reduce hepatocyte copper load to concentrations below toxic
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What is the first stage of therapy in dogs with confirmed excess copper accumulation?
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D-Penicillamine
-Measure copper in a biopsy first! |
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What are 3 side effects of D-penicillamine?
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1) Anorexia
2) Nausea 3) Vomiting |
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How long are animals with copper accumulation treated with D-penicillamine?
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At recommended doses will reduce it by 1000 ppm/ YEAR of treatment
-Only way to know is do biopsy -May need prolonged treatment in bad disease |
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When is elemental zinc used in animals with a hepatopathy?
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Follow up therapy for copper accumulation disorders
-NOT effective in cases where hepatocyte copper concentrations are still too high- use D-Penicillamine first! |
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What is the mechanism of action of Elemental zinc?
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Reduces intestinal copper absorption
-Prevents reaccumulation -Zinc increases expression of metallothionine on apical enterocytes, which binds copper in the meal, apical enterocytes slough & carry copper away |
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Should elemental zinc be given before or after a meal?
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Given ~30 m before a meal
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What are 3 side effects of elemental zinc?
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All are GI:
1) Nausea 2) Inappetence 3) Diarrhea |
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What kind of diet should elemental zinc be used with?
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Ultra-low copper content diet (specifically formulated liver diets)
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What are the only two liver specific drugs that have been tested?
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1) D-Penacillamine
2) Silibinin -All other use is empirical or "traditional" |
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What drug should you use for cholestasis w/o biliary obstruction?
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Ursodeoxycholic acid
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What 2 drugs would you want to use for acute oxidant damage to the liver?
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Silibinin
Denamarin |
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What drugs can be used for chronic liver disease?
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S-Ame/Denamarin, but there is no objective evidence of benefit
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What drug should be used after copper therapy?
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Elemental zinc
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What drug can't be combined with zinc?
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D-penicillamine-it will bind the zinc
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Why does prednisone/prednisolone help with liver hepatopathies?
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Many liver diseases feature inflammation as a central part of pathology
-Ongoing severe inflammation promotes loss of hepatocyte mass and fibrosis Loss of hepatocytes + fibrosis---> end stage liver disease and liver failure |
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How do prednisone and prednisolone differ?
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Prednisone requires hepatic activation
Prednisolone is the active drug -So animals w/ liver failure may not be able to activate prednisone |
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Why should prednisolone be given to cats instead of prednisone?
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Lack glutathionation pathway which is necessary for prednisone activation
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In animals with a hepatopathy prednisone/prednisolone is typically used at _______ doses.
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Immune suppressive doses
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What are the adverse effects of prednisone/prednisolone use in an animal with liver disease?
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At these doses almost guaranteed to see "Cushionoid" side effects:
-Polyuria, polydipsia, polyphagia, tachypnea, anxiety, sleep disturbances |
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Why is it soooooo crucial to taper off of prednisone/prednisolone?
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Acute withdrawl can result in iatrogenic addison's=potentially lethal
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How can the side effects of prednisone/ prednisolone be minimized?
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Can add azathioprine
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What is the mechanism of action of azathioprine?
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Purine analogue--> immune suppressent
-Interferes w/ DNA synthesis -Pro-drug that is metabolized to 6-mercaptopurine which interferes w/ DNA synthesis |
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Why does Azathiprine have a low therapeutic index in cats?
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Potentially lethal myelosuppression
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True or false. Azathioprine is a direct acting agent.
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False, pro-drug that's metabolized to 6-mercaptopurine
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What cells are most susceptible to azathioprine?
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Fast growing cells (particularly lymphocytes)
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What are 2 therapeutic uses of azathioprine?
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1) Common "second line" immune suppressant drug in canine immune mediated diseases
2) Very useful for "pred sparing effect" -used in combo w/ pred to decrease dose and/or frequency |
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Why can't we just use cyclosporin for an animal with a hepatopathy, seeing as it has less myelosppression?
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Hepatotoxic!
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Why does it take some time for azathioprine to reach full efficacy?
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Need time for metabolism and existing cells need to die
-So if need lots of pred for long duration start azathioprine at same time as pred |
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What is the main side effect of azathioprine?
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Ironically: Hepatotoxicity
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When using prednisone in combination with azathioprine how should you stop use of the drugs?
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Taper pred first, then azathioprine
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What animal should azathioprine not be used in?
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CATS!!!! are almost guaranteed to die!
-Severe myelosuppression |
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What are 3 side effects of azathioprine?
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1) Myelosuppression: initially monitor WBCs monthly
2) GI signs: vomiting, diarrhea -Usually transient 3) Hepatotoxicity: monitor chemistry panels, may need early taper |
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What are 3 immunomodulators?
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1) Azathioprine
2) Cyclosporin-hepatotoxic don't recommend 3) Mycophenalate mofetil -Used in autoimmune hepatitis in people, limited experience w/ dogs & cats |
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What is an antifibrotic?
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Colchicine
-Extract from colchicum |
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What are 2 uses of antifibrotics (Colchicine)?
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1) Hepatic amyloidosis
2) Interstitial fibrosis in humans -NO evidence of efficacy in canine chronic hepatitis |
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What is the mechanism of action of colchicine?
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Interferes with microtubules
-This is what leads to tetraploidy in plants |
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Why shouldn't colchicine be used in pregnant animals OR those intended for breeding?
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Teratogenic
-Chromosomal abnormalities, abortions |
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What are 4 side effects of colchicine?
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1) Nausea & vomiting
2) Azoospermia/reduce sperm counts 3) Bone marrow suppression 4) Hypocobalaminemia (low vit B12) |
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Vitamine E is important in recovery from/prevention of ________.
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Oxidative stress
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True or false. There seems to be a liver condition caused by vitamin E deficiency.
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False, NOT really!!! Lack of evidence
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When do you want to use prednisone and azathioprine?
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In BIOPSY PROVEN chronic idiopathic inflammation
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What are the 2 major roles of the liver?
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1) Detoxification of compounds in portal circulation
2) Clearance of bile acids from portal circulation and excretion in bile -Both can be pharmacologically manipulated |
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What is lactulose used for?
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Used as an osmotic laxative
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What is the difference b/w lactulose and lactose?
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Lactose: glucose + galactose
Lactulose: fructose + galactose |
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Why isn't lactulose cleaved until reaching the colon?
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Mammalian digestive enzymes are unable to cleave, but intestinal bacteria can
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What is the mechanism of action of lactulose?
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Cleaved in large intestine into monosaccharides that are fermented to organic acids--> pulls fluid into the large bowel--> laxative effect
-Acidification of gut contents converts ammonia (NH3) to ammonium (NH4+)-lost in feces--> decreased encephalopathic toxins |
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What is the purpose of lactulose use in an animal with a hepatopathy?
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Used to reduce hepatic encephalopathy
-Central part of medical management of portosystemic shunts |
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Lactulose is used in combination what 3 meds in animals with a hepatic encephalopathy?
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1) Metronidazole OR
2) Neomycin OR 3) Ampicillin |
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How is lactulose administered?
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A very viscous and sickly sweet syrup, administered 3 times daily
-WARN about diarrhea |
