15 - Alcohol Flashcards
Where in the world is alcohol consumption highest?
Western Europe
How do you calculate absolute amount of alcohol in a drink?
% ABV x 0.78 = g alcohol/100ml
ABV = alcohol by volume
How do you calculate units of alcohol?
UNITS
[% ABV x volume (ml)]/1000
1 unit = 10ml or 8g of absolute alcohol
What is the safe level (low risk) of units of alcohol for men and women in a week?
Men & Women
- 14 units/week
- low risk
What counts as binge drinking in terms of units?
BINGE DRINKING
More than 8 units in one sitting
Define levels of alcohol in the blood as:
- Only Safe Driving Limit
- Driving Skills Impaired
- Legally Intoxicated
Blood Levels
- 0.01% = 10mg/100ml in blood
How does drinking on a full stomach influence your blood alcohol level?
The speed of onset is directly proportional to gastric emptying
Eating food reduces the rate of gastric emptying and, as a result, reduces the speed of alcohol onset
Outline the metabolism of alcohol
85% in Liver
Of this 85%:
- 75% by alcohol dehydrogenase
- 25% by mixed function oxidase (CYP450)
- can be upregulated to allow for better alcohol tolerance
- this upregulation can be reversed
15% in GIT
Of this 15%
- 100% by alcohol dehydrogenase
Alcohol is really water-soluble and therefore, you wouldn’t expect it to diffuse across lipid membranes well. However, it is also a very small molecule and so it able to diffuse across the stomach/gut.
Alcohol is metabolised to acetaldehyde
- this metabolite has many toxic effects
- want this cleared ASAP
How can the speed with which alcohol is drunk impact upon its effect?
In this graph alcohol is either administered:
- all at once
- in 4 separate doses
The dose administered all at once has much greater effects and lasted longer
This shows that the liver enzyme system can be saturated
- if you flood the system with alcohol, the enzymes become saturated
- lots of alcohol then won’t be metabolised on the first pass and escapes into the systemic circulation
What is the difference in alcohol metabolism in the stomach between men and women?
The ability of women to metabolise alcohol in the stomach is less than 50% of that of men because women have less alcohol dehydrogenase in their stomachs
How does alcohol distribute itself in the body?
ALCOHOL IS VERY WATER SOLUBLE
MEN
- Body water = 59%
- e.g. 75kg man
- 65% ICF; ~ 30L
- 35% ECF; ~ 15L
- (incl. 3L plasma)
WOMEN
- Body water = 50%
- e.g. 60kg woman
- 65% ICF; ~ 20L
- 35% ECF; ~ 10L
- (incl. 2L plasma)
As men have a higher % of body water, alcohol is more diluted in males than in females.
A man and a woman of similar height and weight share a bottle of wine. Explain why the blood alcohol levels in the woman are likely to be higher.
- Men have a higher % of body water and therefore, because alcohol is water-soluble, it is more diluted in them
- Women have less alcohol metabolism occur in their stomach due to a lower amount of alcohol dehydrogenase being present in their GIT
How is the main metabolite of alcohol (acetaldehyde) dealt with by the body?
Acetaldehyde is toxic
Aldehyde dehydrogenase, present in the liver and the stomach, converts it to acetic acid
Acetic acid is inert
What is important to remember about aldehyde dehydrogenase?
There is a genetic polymorphism of the gene that encodes aldehyde dehydrogenase
- makes the enzyme less effective
- acetaldehyde builds up
- particularly common in Asian populations
People with this alternate version of the gene feel the negative effects of acetaldehyde more
Explain why disulfiram can be effective as alcohol aversion therapy.
Disulfiram is an aldehyde dehydrogenase inhibitor
Cause acetaldehyde to build up
People feel more negative effects when they drink alcohol due to the acetaldehyde build up
How pharmacologically potent is alcohol?
Alcohol has low pharmacological potency
Dose needed to have a significant effect:
Nicotine 20ng/ml
Cocaine 200ng/ml
Alcohol 200mg/ml
What is the other name for alcohol?
Ethanol (C2H5OH)
Other than a depressant effect, what can alcohol do to the CNS?
CNS agitation may occur but this is dependent on:
- Degree of CNS Excitability
- Environment
- Non-social setting
- Social setting
- Personality
- Environment
VERY DEPENDENT ON ENVIRONMENT
This is at low levels of alcohol (at high levels, all effects on CNS are depressant)
Certain brain functions at a low level of alcohol in certain settings, you may get disinhibition. For example, may manifest as more self-confidence.
How can alcohol cause euphoria?
At high doses, alcohol binds to the opiate receptor (μ-receptor)
This turns off GABA
GABA is normally inhibitory on the reward pathway
Reward pathway is therefore able to fire and cause feelings of euphoria
Where in the CNS, other than in the reward pathway, does alcohol have acute effects?
HIGH DOSE ALCOHOL
Corpus Collosum
- Passes info from the left brain (rules, logic) to the right brain (impulse, feelings) and vice versa.
- Slight disconnect caused
- Sensible and emotional parts of brain not connected properly
Hypothalamus
- Appetite
- Emotions
- Temperature
- Pain sensation.
Reticular Activating System (RAS)
- Consciousness
Hippocampus
- Memory
Cerebellum
- Movement
- Coordination
Basal Ganglia
- Perception of time
What acute effects does alcohol have on the CVS in terms of the heart?
Centrally mediated decrease in baroreceptor sensitivity leads to an acute increase in heart rate
- baroreceptors signal to heart to slow down
- if blood pressure is high, baroreceptor signalling is high
- if alcohol gets into baroreceptors, it decreases their sensitivity
- less inhibition of sympathetic nerves
Chronic alcohol may be associated with an increased blood pressure.
What chronic effects on the CNS can be caused by alcohol?
Largely believed to be due to thiamine deficiency
Thiamine essential for metabolism
Thiamine needs are increased in chronic alcoholics
- not just due to the alcohol
- also due to poor diet as too many calories are coming from alcohol
Brain regions with high metabolic demand will therefore have:
- impaired metabolism
- mitochondrial impairment
- NMDA excitotoxicity
- ROS (Reactive Oxygen Species) leak into system
- If this occurs for long enough, ROS cause mitochondrial damage
- Precipitates apoptosis
Dementia
- Cortical atrophy/volume cerebral white matter confusion (encephalopathy)
- oculomotor symptoms
Ataxia
- Cerebellar cortex degeneration
- gait
Wernicke-Korsakoff syndrome
- due to thiamine deficiency
Wernicke’s encephalopathy
- hypothalamus/thalamus
Korsakoff’s psychosis
- deep brain e.g. hippocampus
What is the key role of thiamine in metabolism?
Thiamine essential for metabolism
- low thiamine decreases the activity of many enzymes which play key roles in metabolism
- thiamine acts as an essential coenzyme to the TCA cycle and the pentose phosphate shunt.
What are the effects of chronic alcohol use on the liver?
Alcohol metabolized by cytosolic alcohol dehydrogenase (ADH) to acetaldehyde
Further metabolized to acetate by mitochondrial aldehyde dehydrogenase (ALDH2).
Both enzymes use NAD+as a cofactor, producing a reducing equivalent NADH in both steps.
Increased production of NADH was implicated in the disruption of many dehydrogenase-related reactions in the cytoplasm and mitochondria [i.e. the tricarboxylicacid cycle (TCA) and β-oxidation of fatty acids], thereby suppressing energy supply and fatty acid oxidation, which in turn results in alcoholic fatty liver.
Cytochrome P450 2E1 (part of the microsomal ethanol oxidising system) leaks oxygen radicals as part of its operation and when they exceed the cellular defense systems they result in oxidative stress with its pathologic consequences. This is true when excess alcohol has to be metabolized, as in alcoholic steatohepatitis, or when CYP2E1 is confronted by an excess of ketones and fatty acids associated with diabetes, obesity, or both, resulting in nonalcoholicsteatohepatitis.
Alcohol related problems for Glycolysis – Glucose to pyruvate (requires 2 x NAD+), pyruvate into acetyl coA(requires 2 x NAD+), acetyl coAinto Krebs Cycle (requires 6 x NAD+). With alcohol using up NAD+, then pyruvate must be converted to lactate to generate NAD+ for glycolysis. Acetyl coAunable to enter citric acid cycle are transformed to ketones.
SIMPLE TERMS:
Alcohol metabolism uses NAD+
Depleted stores of NAD+
Beta-oxidation of fats also requires NAD+
This cannot occur due to depleted stores
Therefore, fat builds up in the liver
TCA cycle cannot also not occur because it needs NAD+
Pyruvate, Acetyl CoA etc. cannot cycle in the TCA
Ketones, lactic acid etc. start to be formed
Things like acidosis begin to happen
What would be the initial impact of high quantities of alcohol consumption on the liver?
Impaired beta-oxidation of fats due to lots of NAD+ being used to metabolise alcohol
Glycerol and fatty acids aren’t metabolised and so are stored as triacylglycerol in the liver (fat droplets)
THIS PROCESS IS REVERSIBLE
At what point does fatty liver become hepatitis?
Consistent intake of high quantities of alcohol
- consistently depleting the liver of NAD+
- deranged metabolic processes leak free radicals as a result
- these free radicals are pro-inflammatory and can cause tissue damage
- constantly exposing the liver to acetaldehyde
- damaging to liver tissue
- causes hepatitis to occur
COMPLICATED EXPLANATION:
The oxidative stress caused by CYP2E1 induction and mitochondrial injury results in lipid peroxidation and membrane damage. In addition, the acetaldehyde produced by the oxidation of ethanol has toxic effects, decreasing the activity of key enzymes, and markedly reducing oxygen use in mitochondria damaged by long-term ethanol consumption. The impaired oxidation capacity of the mitochondria may, in turn, interfere with the oxidation of acetaldehyde leading to a vicious circle of progressive acetaldehyde accumulation and greater mitochondrial injury. Moreover, acetaldehyde promotes cell death by depleting the concentration of reduced glutathione (GSH), inducing lipid peroxidation, and increasing the toxic effect of free radicals. Oxidative stress promotes inflammation, which is aggravated by an increase of the proinflammatory cytokine tumornecrosis factor-alpha (TNF-α) in the Kupffercells. Kupffercells are a major source of cytokines.
Acetaldehyde, the first metabolite of ethanol, can upregulatetranscription of collagen I directly as well as indirectly by upregulatingthe synthesis of transforming growth factor-beta 1 (TGF-beta1).
At what point does fatty liver become irreversible?
FATTY LIVER > HEPATITIS > CIRRHOSIS (irreversible)
Consistent inflammatory profile leads to fibroblast infiltration of the liver
Fibroblasts begin to lay down connective tissue to replace active metabolic hepatocytes, causing cirrhosis
There is decreased active liver tissue, causing build up of toxins
