129 - Alcohol Metabolism Flashcards
Effect of ethanol on the brain
Disrupts lipid membranes in the brain.
This disrupts permeability of membrane.
Proportion of US population thought to be dependent on alcohol
~4%
Alcohol dependence definition by NHMRC
Severe Dependence exists when withdrawal causes tremors, anxiety, sweating
or vomiting.
Dependence is a continuum from mild to severe. It is more likely when family or
social groups exhibit high drinking patterns. People who cannot stop drinking,
when they realise that they should, are dependent
NH&MRC recommendations for alcohol dependence
The NH&MRC recommend complete abstinence from alcohol when dependence is evident.
Number of people with alcohol-related brain damage
~2 billion
Estimated cost of alcohol-related medical care, deaths, crime and lost productivity per year in Australia
~8 billion
Name for condition from alcohol neurotoxicity
Wernicke Korsakoff syndrome
Symptoms of Wernicke Korsakoff syndrome
Eyes uncoordinated (nystagmus), wide step, confusion, hypothermia, amnesia and confabulation.
Aetiology of Wernicke Korsakoff syndrome
Thiamine deficiency. Thiamine needed for energy supply of neurone.
Depleted through poor nutrition, alcohol metabolism destroys thiamine.
Proportion of alcohol metabolised in the liver
~90%
Signs of alcoholism 1 2 3 4 5 6 7 8 9 10 11 12
1) Neurological disturbances
2) Jaundice
3) Altered breath
4) Oesophageal varices
5) Feminisation (altered sex hormones)
6) Extensively-scarred live)
7) Portal hypertension
8) Ascites
9) Hand tremors
10) Hypogonadism
11) Easy bruisability
12) Oedema
Types of alcohol-induced liver damage
1
2
3
1) Fatty liver
2) Alcoholic hepatitis
3) Alcoholic cirrhosis
How does alcoholic hepatitis come about?
Damage of hepatocytes attracts immune system, causes inflammation.
Proportion of heavy drinkers with alcoholic hepatitis
Up to 50%
Mortality rate of alcoholic hepatitis
15-20%
Proportion of heavy drinkers with liver cirrhosis
15-30%
Proportion of hepatocytes required for normal liver functionality
At least 40%
Serum albumin concentration with liver damage
Remains quite normal until cirrhosis
Alcohol metabolism in the stomach
Alcohol dehydrogenase present in the stomach.
In caucasian males can metabolise ~1 standard drink
Proportion of alcohol absorbed in the intestine into the blood
~70%
Blood alcohol % at which brainstem stops working
~0.4%
Alcohol oxidation in the liver
1
2
3
- Alcohol dehydrogenase (ADH) in cytosol produces NADH. High NADH represses gluconeogenesis and can lead to hypoglycaemia (the faintness of drinking on an empty stomach). Acetyl-CoA produces energy via the TCA cycle or supports fat synthesis.
- MEOS is the Microsomal Ethanol Oxidising System. Chronic ingestion of alcohol induces CYP 2E1 up to four fold. In liver CYP2E1 consumes NADPH so less energy is produced (alcoholics are rarely as obese as their energy consumption predicts). MEOS rarely exceeds 10%. CYP4A1 is also elevated.
- Catalase in liver peroxisomes uses H2O2 as the oxidant.
Alcohol dehydrogenase pathway
• Alcohol dehydrogenase (ADH) in cytosol produces NADH. High NADH represses gluconeogenesis and can lead to hypoglycaemia (the faintness of drinking on an empty stomach). Acetyl-CoA produces energy via the TCA cycle or supports fat synthesis.
MEOS pathway
•MEOS is the Microsomal Ethanol Oxidising System. Chronic ingestion of alcohol induces CYP 2E1 up to four fold. In liver CYP2E1 consumes NADPH so less energy is produced (alcoholics are rarely as obese as their energy consumption predicts). MEOS rarely exceeds 10%. CYP4A1 is also elevated.
Difference in ability to metabolise alcohol between teetotallers and heavy drinkers
Alcohol dehydrogenase is constitutively produced.
MEOS is inducible.
Why do people go faint when drinking on an empty stomach?
Alcohol dehydrogenase (ADH) in cytosol produces NADH. High NADH represses gluconeogenesis and can lead to hypoglycaemia (the faintness of drinking on an empty stomach)
Why does alcohol affect women more than men?
Alcohol doesn’t distribute in fat, and women typically have a higher body fat %
Amount of blood alcohol that can be cleared each hour
About 0.015% per hour (typical human).
About an hour per standard drink
When does alcohol dehydrogenase work at Vmax?
After 2 drinks (is saturated with substrate)
Why can some alcoholics have less alcohol dehydrogenase than non-heavy drinkers?
Because of liver damage, ADH is non-inducible.
Do breath tests for alcohol estimate blood alcohol % accurately?
Yes, but tend to underestimate blood %.
Effect of alcohol on CYP system and drug metabolism
1
2
Alcohol has two alternate effects on drugs:
- Prevents drug clearance when alcohol is present.
- Promotes drug clearance by elevated CYP 2E1 when alcohol is not present.
Drugs affected by alcohol consumption
Warfarin, metronidazole, paracetamol, acetominophen,
benzodiazapines, barbiturates, phenothiazines, tricyclic
antidepressants, chlormethiazole, hypoglycaemics, MAOIs,
meprobamate and vitamin-D.
CYP450 elevated by alcohol
CYP 2E1
Effect of alcohol on warfarin
Increases warfarin destruction
Liver damage by alcohol vitamin depletion
Chronic alcohol consumption plus dietary neglect
diminishes the intake of antioxidants including
vitamins A, E and C.
Liver damage by alcohol impairment of glutathione
Alcohol interferes with the transport of glutathione
through membranes, leading to depletion of
glutathione from mitochondria. Mitochondria
continuously produce free radicals during electron
transport and these are scavenged in a glutathione
dependent system.
Liver damage by alcohol generation of ROS
1
2
1) Alcohol metabolised by the MEOS pathway
(CYP2E1) loads cells with free radicals.
2) Alcohol in the gut promotes absorption of iron which
becomes a catalyst for free radical production.
Acetaldehyde toxicity
Acetaldehyde reacts with proteins, and all other
amines, to form Schiffs bases and compromise
function.
Ways that alcohol can damage liver
1
2 a, b, c, d
1) Immune system detects cell stress in liver, destroys stressed cells
2) Cells stressed by:
a) Vitamin depletion
b) Glutathione impairment
c) ROS generation
d) Acetaldehyde toxicity
Hormonal effects of alcohol
Sex hormones are affected by chronic alcohol consumption, probably by stimulating microsomal modification or destruction of steroids. In men low testosterone results in : •testicular atrophy •gynaecomastia • loss of libido •feminisation of hair patterns. In women libido is lowered and breast cancer risk increases.
Acetaldehyde metabolism
Aldehyde dehydrogenase metabolises acetaldehyde to acetate.
Isoforms of aldehyde dehydrogenase
ALDH1 and 2. 2 (mitochondrial form) is more important.
Antabuse
Disulfiram (antabuse) 250mg once daily
Irreversible inhibitor of aldehyde dehydrogenase
Ingestion of alcohol → acetaldehyde accumulation causing
tachycardia, flushing, dyspnoea, nausea & vomiting.
Brain system that can lead to alcoholism
D2 dopamine system
Naltrexone
Opioid receptor antagonist
Blocks alcohol induced release of dopamine in Nucleus Accumbens.
Diminishes pleasurable effects and craving for alcohol.
The most clinically successful drug when used with the Sinclair method.
Nalmefene
µ and α opioid receptor antagonist – less hepatotoxic than naltrexone.
Liver toxicity tests for alcoholism
1
2
3
1) GGT (Gamma-glutamyltranspeptidase) elevated
2) ALT (Alanine aminotransferase) elevated
3) CDT
Why is GGT not a perfect test for alcoholism?
GGT can be elevated in other ways.
GGT is induced by many drugs, including alcohol, and its serum activity may be increased in heavy drinkers even in the absence of liver damage or inflammation.
Why is ALT not a perfect test for alcoholism?
Alanine aminotransferase (ALT) is elevated in all types of hepatitis (viral, alcoholic, drug-induced, etc.) due to hepatocyte damage.
Dehydration from alcohol
Production of antidiuretic hormone by the brain (pituitary) signals the kidney to take water back from the urine.
Alcohol interferes with pituitary function. Low antidiuretic
hormone levels result in more body water passing into the
urine. Despite high fluid intake with the alcoholic drinks even more is lost. The body becomes dehydrated.
Times at which foetus is most at risk of foetal alcohol syndrome
At all times, particularly in the first trimester.
Foetal alcohol syndrome effects
Children with FAS typically have small heads, small eyes and certain facial malformations.
Children with foetal alcohol effect are not so easy to recognize, but they have the same behaviors that make getting along in the world extremely challenging. Alcohol-affected children have trouble with abstract concepts like time and money. They have difficulty generalizing, concentrating or learning from example.
