Download Alcohol Metabolism

Alcohol Metabolism
Week 30 LO’s
1. Outline the biochemical pathways by which alcohol is absorbed and metabolised in the body.
3. Explain the pharmacokinetics of alcohol, including why alcohol has simple kinetics with a
constant rate of metabolism per hour.
Absorption
 rapidly absorbed primarily from duodenum
 peak blood alcohol concentration (BAC) depends on:
o amount and [alcohol] of beverage
o rate of drinking
o food consumption and composition e.g. high lipid content → ↓EtOH absorption
o gastric emptying and gastric metabolism
 carbonation ↓ gastric emptying time (more rapid absorption e.g.
champagne)
o hepatic first pass metabolism
Metabolism
 ethanol metabolism occurs almost entirely in the liver (90-98%)
 mainly by a pathway involving successive oxidations to produce acetaldehyde and then acetic
acid
 1st step – oxidation by alcohol dehydrogenase – rate-limiting and zero-order (constant
amount/unit time)
 EtOH oxidation requires NAD+ and its availability:
o is rate-limiting factor (limits EtOH metabolism to about 8g/h)
o leads to competition between EtOH and other metabolic substrates for available NAD+,
which may be factor in EtOH-induced liver damage
 accumulation of acetaldehyde (intermediate metabolite) contributes to hepatotoxicity and is
associated with headache, gastritis, nausea, dizziness (hangover)
 alcohol dehydrogenase:
o oxidizes EtOH → acetaldehyde
o reduces NAD+ → NADH
 mixed function oxidase system also metabolises EtOH → acetaldehyde (see slide 26 of lecture)
 usually this pathway only accounts for a small proportion of EtOH metabolism but it is up
regulated in alcoholics
 EtOH can affect the metabolism of other drugs that are metabolized by the mixed function
oxidase system (e.g. phenobarbitone, warfarin and steroids)
 nearly all acetaldehyde produced → acetate by acetaldehyde dehdrogenase
Excretion
 Kidney – since most Etoh is metabolized, very little is excreted by kidney (can’t hasten exctretion
with diuretucs)
 Lungs – constant % of blood alcohol levels are excreted – tiny amount but basis of breathalyzer
test
Ethanol Metabolism shows saturation or zero-order kinetics:
 disappearance of the drug from the plasma is linear i.e. EtOh is removed at a constant rate
independent of [Plasma]

the reason for this is that the rate of oxidation by alcohol dehydrogenase reaches a maximum at
low EtOH concentrations due to the limited availability of NAD+
2. Describe the effects of alcohol on other biochemical pathways, including fat, carbohydrate and
energy metabolism.
o
o
>70g of alcohol places a large load upon liver leading to metabolic abnormalities
Some biochemical effects of alcohol are attributed to cofactors used in its metabolism, which
limit the availability for other pathways.
Glucose metabolism:
 Gluconeogenesis is decreased due to the decrease in NAD+ levels as a result of alcohol
metabolism
o pyruvate is converted to lactate to increase the availability of TCA intermediates
(Pryuvate + NADH → lactate + NAD+)
o results in hyperlacticacidaemia and lactic acidosis
 acute intoxication can lead to severe hypoglycaemia and sudden death due to ↓ in TCA
intermediates (e.g. OOA)
 ↑ Synthesis and ↑ lactate utilization leads to acidosis which leads to ↓ renal excretion of uric
acid (from purine degradation) – hyperuricaemia
Protein metabolism:
 Protein synthesis is decreased due to an unknown mechanism.
Fat metabolism:
 decrease in TCA activity → Fatty acid oxidation inhibited
 metabolic purpose of FA oxidation – produce NADH for ATP synthesis by oxidative
phosphorylation
 BUT in alcohol metabolism – NADH is produced – thus FA oxidation is ↓
 excess NADH signals for Fatty acid synthesis to ↑
 impaired assembly and secretion of lipoproteins
 All of these lead to steatosis or fatty liver .
Anaerobic metabolism:
 ↑lactate production from pyruvate due to an ↑ in NADH:NAD+.
 Utilisation of lactate decreases leading to hyperlactacidemia, acidosis, and hyperuricaemia.
Other:
 Inhibition of oxidation steps involved in testosterone synthesis  gynecomastia and testicular
atrophy.