Alcohol Metabolism Flashcards
Alcohol dehydrogenase pathway
ADH1-6, mainly 1
Low Kmg so high affinity
Ethanol oxidised to acetaldehyde by ADH using NAD+
Acetaldehyde is toxic -> oxidised to acetate (non toxic) by acetaldehyde dehydrogenase (mitochondrial and cytosolic)
Acetate-> activated to acetyl co A in the liver for free fatty acid synthesis
Or activated in blood and transported to other tissues
Metabolism of ethanol
Ethanol-> small lipid and water soluble molecule-> readily absorbed from intestine by passive diffusion
85-95% metabolised in the liver
2-10% excreted via lungs/kidneys
Adult clearance 100mg/dL/h
Enzymes are non specific
Increases toxicity of paracetamol and halothane
Increases clearance of phenytoin and phenbarbituate
Microsomal ethanol oxidising system
MEO’s oxidise ethanol to acetaldehyde
Principal micro enzyme is cytochrome P450-> mixed function oxidase enzyme
Only 10-20% of metabolism
Variations in isoenzymes influence individual alcohol clearance
Requires NADPH
Associated risks of ethanol intoxication
Inhalation of gastric contents Potentiation of other drugs Hypoglycaemia Lactic acidosis Associated injuries Disinhibition Hypothermia
CNS features related to ethanol concentration
talkativeness
50-100-> slurred speech, emotional instability, in coordination
100-300-> blurred vision, loss of sensory perception
300-500-> severe ataxia, coma, convulsions
>500-> coma, hypothermia, resp depression
Ethanol induced hypoglycaemia
Occurs after heavy drinking-> children, undernourished alcoholics, patients with thyrotoxocisis, vitamin deficiency, adrenal insufficiency
-> decreased in hepatic glucose output and decreased peripheral utilisation
Hypoglycaemia occurs when peripheral use exceeds hepatic output
Increased NADH/NAD+ ratio -> accumulate a no negative feedback -> shifts the lactose dehydrogenase equilibrium to lactate production -> pyruvate converted to lactose
No gluconeogensis
Also causes lactate accumulation, increased fatty acid synthesis and increased formation of triglycerides
NAD+ deficiency blocks reactions mediated by lactate, glycerol 3-P and malate
Lactate acidosis, keto acidosis-> actyle coA enters ketone body synthesis
Stages to ethanol induced hypoglycaemia
Increased ACTH, adrenaline and glucagon
- > liver glycogen breakdown
- > hyperglycaemia -> high NADH/NAD ratio also inhibits glycolysis
- > low liver glycogen
- > hypoglycaemia 2-3 hours later
- > coma
Management of ethanol induced hypoglycaemia
Protect the airway if necessary Check BG Check temp Associated injuries Asses acid base status Paracetamol/salicylate levels if appropriate Haemodialysis in severe cases
Other acute effects of ethanol metabolism
Gout from increased uric acid Lactic acidosis Hyperlipideamia -> hepatic stenosis Keto acidosis Interference with drug metabolism Acetate in blood
Methanol poisoning
Used in anti freeze
Methonal oxidised to metaldehyde by ADH-> oxidised to methanoic acid-> toxic products
-> metabolic acidosis-> methanoic and lactate
-> hypoglycaemia
Aim to prevent metabolism of methanol to toxic products-> IV ethanol as competitive inhibitor -> methanol excreted by kidneys
Haemodyalisis
Long term liver damage
Cirrhosis and failure
Intimately becomes enlarged by fat and collagen fibres-> fibrosis with nodules of regenerating hepatocytes
Fibrosis caused by repeated damage and healing
Sclerosis-> degenerative alteration in the composition of matrix components
As liver function decreases live shrinks -> cirrhosis
Stages of cirrhosis
1) kupffer cells become activated by acetaldehyde acting on hepatocytes, activated by products of hepatocyte damage
2) kupffer cells produce TGFb and respiratory bursts
3) these products activate stellate cells
4) stimulated stellate cells produce extracellular matrix, collagen and metsloproteases-> fibrosis
