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Hepatic Toxicology (:check: Types of liver damage which may be caused by…
Hepatic Toxicology (
:check: Types of liver damage which may be caused by toxic compound :check:
- Fatty liver (steatosis)
- Cytotoxic damage
- Cholestatic damage
- Cirrhosis
- Liver tumour
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:lollipop: Mechanism and response to cellular injury :lollipop:
- complex sequence of events
- reversible injury or irreversible leading to death of cell
- divide the stage (primary - initial damage) (secondary - cellular change which follow from the initial damage) (tertiary- observable and final change)
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Biotransformation !,
Functional unit of the liver is known as Acinus
- three main zone : Zone1, Zone 2, Zone 3
- zone 1 highest oxygen supply; lowest in zone 3. so mitochondrial fx highest in zone 1
- zone 1 : fatty acid oxidation, gluconeogenesis, ammonia detoxification to urea - high level of GSH in zone 1 and more CYP450 in zone 3
- arterial supply - hepatic artery
- Most of blood supply come from : portal vein
- Blood drains into the terminal hepatic vein
- Specific site for specific toxicity
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Toxicants and the liver
- constantly exposed to foreign chemicals or xenobiotics
- inhibit hepatic transport and synthetic processes
- dysfunction can occur without appreciable cell damage (i.e hypoglycaemia in impaired gluconeogenesis)
- Loss of fx when toxicant kills an appreciable number of hepatocytes
- replacement of cell mass by non functional scar tissue
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Exposure : unavoidable and constant
- Need biotransformation to expel the toxicant material
- they're usually lipophilic so they tend to stay in the body
- liver will convert them to a more water soluble compound in which can be excreted out from the body
- this process is known as biotransformation!
- may alter its biological effects
- terminates the pharmacological effects of a drugs and lessens the toxicity of xenobiotics
- some drugs undergo biotransformation to active metabolites that exert their pharmacodynamic or toxic effect
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Biotransformation depends on type of drug. - - Highly Lipophilic (accumulate in body fat first) and Lipophilic drugs will undergo Phase I Biotransformation into a polar substance and then proceed to the Phase II Biotransformation - become hydrophilic and can undergo extracellular mobilisation (either biliary excretion or plasma circulation and then renal excretion)
- Polar straight to Phase II
- Hydrophilic straight to extracellular mobilisation
- Phase I (Oxidation, reduction, hydrolysis, bioactivation or bioinactivation)
- Phase II (Conjugation and Bioinactivation)
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:pill: BIOTRANSFORMATION OF PARACETAMOL :pill:
- PARACETAMOL ANTIDOTE;
- N-ACETYL CYSTINE: promotes the synthesise of GSH utilised in the conjugation of the reactive metabolite & best result administrated 8-10 hours following overdose
- METHIONINE : required for glutathione synthesis but not as effective as NAC
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PARACETAMOL OVERDOSE Normal dose will produce Paracetamol Mercapturic Acid and undergo phase II biotransformation. For overdose : use the phase I P450 and produce NAPQI (toxic intermediate/ELECTROPHILE) ,
:scorpius: TYPES OF HEPATOBILIARY INJURY :scorpius:
- Fatty liver - alcohol
- Hepatocyte death - paracetamol , etahnol and ectasy
- Immune mediated response - Ethanol and Halothane
- Canalicular cholestatis - Cyclosporin A, Phhalloidin
- Bile duct damage - Amoxicillin
- Sinusoidal disorder - Anabolic steroid
- Fibrosis and cirrhosis - ethanol, vitamin A and vinyl chloride
- Tumours - androgen, aflatoxin and vinyl chloride
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