Lecture 31+32 Flashcards
metabolism of drugs occur in the liver in two phases?
phase I: involves cytochrome P450
Phase II: makes the molecules more polar
some drugs dont need phase I
Role of CYP3A4 and CYP2E1
CYP3A4 = acts on drugs
CYP2E1 = acts on ethanol metabolism
examples of things that interfere with CYP activity
ethanol induces CYP2E1
grapefruit juice inhibits CYP3A4 in the intestinal epithelial cells
Degradation of Acetaminophen
major pathway:
degrade into Acetaminophen glucuronate and/or Acetaminophen sulfate
minor pathway involves CYP2E1:
converted to NAPQI
high alcohol intake on acetaminophen metabolism
high alcohol intake induces CYP2E1, thus more drug will be broken down by this minor pathway
this will lead to a high NAPQI level, which leads to hepatic damage
Acetadote (N-acetyl cysteine)
A drug that can be injected to prevent haptic damage in those who consumed a high amount of acetaminophen
metabolism of a low amount of ethanol
ethanol is converted to acetaldehyde by alcohol dehydrogenase (needs NAD)
acetaldehyde is taken to the mito where it is converted to acetate by acetaldehyde DH2 (uses NAD)
acetate is released into the blood
what can happen to the acetate released into the blood?
the skeletal muscles and heart have an enzyme acetyl CoA synthetase which uses acetate for the TCA cycle
MEOS in hepatocytes
bound to the ER membrane and uses ethanol and NADPH to form acetaldehyde
larger Km but lower affinity
has CYP2E1 and CYP3A4
chronic alcohol consumption induces MEOS
Mitochondrial aldehyde DH-2 VS Cytosolic aldehyde DH-1
1:
has a low affinity
acts when cytosolic acetaldehyde accumulates
2:
has a high affinity and catalyzes most acetaldehyde oxidation
high levels of ethanol metabolism
MEOS and alcohol DH forms a large amount of acetaldehyde and a lower amount of acetate
Asian flush syndrome
Hereditary deficiency of mitochondrial ALDH-2
thus decreases breakdown of acetaldehyde and thus it accumulates even if ethanol levels are low
flushing, elevated HR, nausea, vomiting
high ethanol levels and fasting
Reduced gluconeogenesis due to high NADH/NAD ratio
have high lactate levels due to alanine being converted to lactate and pyruvate cant go into the TCA cycle so it is converted to lactate due to high NADH levels
glutamine is converted to malate
mild hypoglycemia and lactic acidemia
hepatic steatosis
an early and common finding in those that chronically drink alcohol
this results due to acetaldehyde toxicity
the release of VLDL is inhibited and lipids accumulate in the liver
toxicity of acetaldehyde
tubulins are damaged by this compound, thus VLDL and proteins are not able to leave the hepatocytes
thus proteins and lipid accumulate
lack of blood clotting factors
Disulfiram (antabuse)
this drug inhibits aldehyde dehydrogenase
thus ingestion of ethanol increases the amount of acetaldehyde since it cannot be broken down
methanol toxicity
methanol is converted to formaldehyde and then formic acid
highly toxic; blindness and death and metabolic acidosis
converted by alcohol dehydrogenase
treatment:
competitive inhibition by ethanol or fomepizole
Ethylene glycol toxicity
ethylene glycol is converted to glycolaldehyde by alcohol dehydrogenase and then to glycolic acid and oxalic acid
toxic: renal damage, death, metabolic acidosis
treatment:
competitive inhibition by ethanol or fomepizole
acute/ chronic liver disease labs
elevated total, conjugated, and unconjugated bilirubin
conjugated bilirubin in the urine
extrahepatic cholestasis labs
serum conjugated bilirubin is high
will be in urine
hard to distinguish between hepatocellular and cholestatic disorder
Isolated hyperbilirubinemia
inherited
normal enzyme levels (ALT,AST, ALP)
acute liver disease
High ALT levels (cytosolic enzyme)
Long-standing chronic alcoholic cirrhosis
High AST levels (2:1)
mitochondrial enzyme
ALP
secreted by biliary canaliculi
elevated in intra and extra hepatic cholestasis.. but much higher levels in extra-hepatic
can be elevated during pregnancy, growth, or bone disease
GGT
secreted by biliary ducts
induced by alcohol
marker for alcohol consumption
ALP and GGT are VERY high in extra-hepatic cholestasis (dilation of biliary tree)
albumin and liver function
chronic liver disease will show a decrease in albumin levels
responsible for ascites and pedal edema
also impacts proteins carried by albumin
cirrhosis
will show the beta-gamma bridge
liver damage and prothrombin time
increased prothrombin time
reduced clotting factor synthesis and impaired modification of vitamin K dependent clotting factors
prothrombin time and cholestasis
reduced bile salt thus less fat and less fat soluble vitamin uptake (Vit K)
impairs post-translational carboxylation of vit K dependent factors
chronic liver disease and glucose?
can alter plasma glucose levels
can have either hypo or hyperglycemia
advanced liver disease and ammonia
impaired urea formation and an increase in blood ammonia levels
can have hepatic encephalopathy and coma
due to neurotransmitter imbalance and depletion of alpha ketoglutarate
GI bleeding can lead to the encephalopathy
fatty liver
excessive TAG deposits in liver cells
due to decreased beta oxidation (high NADH)
increased FA and TAG synthesis
decreased VLDL secretion
