Drug abuse 3: Alcohol Flashcards
What is the formulae for absolute amount of alcohol?
% ABV x 0.78 = g alcohol/100ml
ABV = alcohol by volume
How do you calculate the number of units?
[%ABV x volume (ml)]/ 1000 = units
1 unit = 10ml or 8g of absolute alcohol
What are the safe levels of alcohol?
Men and Women; =< 14 units/week LOW RISK
Binge drinking i.e. > 8 units in one sitting; 18% of 16-24 yrs (> 30%) ↓
How does drinking on a full stomach influence your blood alcohol level?
Oral administrated
Speed of onset is directly proportional to gastric emptying.
When you eat the stomach will remained closed off for a while while it digests the food. This means the alcohol remains in the stomach when you drink on a full stomach = slower release of alcohol into the blood stream.
Where is alcohol absorbed?
Alcohol is absorbed from the stomach but better in the small intestine.
20% - stomach
80% - small intestine
Describe the metabolism of alcohol?
90% of the alcohol is metabolised, 10% is secreted unchanged.
85% is metabolised in the liver:
- Alcohol dehydrogenase (metabolises 75% of the alcohol)
- Mixed function oxidase (cytochrome p450) (metabolises 25% of the alcohol)
The metabolite is acetaldehyde
15% is metabolised in the GIT:
- Absorbs through the stomach the lining - it can break down alcohol with alcohol dehydrogenase
- Women have 50% less Alcohol dehydrogenase int he stomach wall compared to men.
Which enzyme increases with chronic use?
Cytochrome p450 increases with chronic use –> you become tolerant.
What happens when you drink alcohol very quickly
If you flood the liver with alcohol the enzymes in the liver can become saturated.
When it is saturated it can get into the systemic circulation.
Why can alcohol be absorbed through the stomach?
Alcohol is very water soluble - so you don’t expect it to diffuse through membranes very well.
However it is very small –> It can diffuse across lipid membranes because its so small.
Broken down by alcohol dehydrogenase
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.
Less body water
Less ADH
How is acetaldehyde broken down?
Aldehyde dehydrogenase: breaks acetaldehyde (has negative effects) to acetic acid.
(Genetic polymorphism - asian people aldehyde dehydrogenase doesn’t work as effectively)
What drug can be effective as alcohol aversion therapy.
Aldehyde dehydrogenase inhibitor = build up of acetalydehyde which has negative effects
Disulfiram
Describe the pharmacodynamics of alcohol
Alcohol is a depressant (primary effect)
CNS agitation may occur and it is dependent on various factors.
See diagram
Can you identify a pharmacological target for alcohol? What would you predict regarding the affinity and efficacy for this target?
Not really - very simple molecule.
It can bind to a lot of receptors but not really have any effects. Low affinity and efficacy.
The idea is to take a high dose so that the overall effect is higher.
High enough dose literally everything becomes a depressant.
How does alcohol have a depressant effect?
Enhance GABA receptor activation - positively modualtes.
Increases presynaptic effects. Allopregnenole is a neuro active steroid. Alcohol increases its production which has a positive effect on the GABA receptor
NMDA receptors - binds and decreases its activity. Decreases an excitatory receptor
Ca2+ channels - decreases calcium channel opening
What are the acute effects of alcohol? CNS
1) CNS is functionally complex - alcohol binds to lots of receptors
- Corpus Collosum - Passes info from the left brain (rules, logic)
to the right brain (impulse, feelings) and vice versa. - Hypothalamus - Controls appetite, emotions, temperature,
and pain sensation. - Reticular Activating System – Consciousness
- Hippocampus - Memory
- Cerebellum - Movement
and coordination - Basal Ganglia –
Perception of time
2) Ethanol has low potency = low selectivity
How might alcohol cause euphoria?
Alcohol at a high dose can behave like heroin/morphine. It will bind to the opiate receptors on GABA
What are the acute effects of alcohol? CVS?
Cutaneous vasodilation - Asian flush
- Decrease Ca2+ entry
- Increase prostaglandins
We think it is acetaldehyde - link back to the genetic polymorphism
Acute tachycardia - a depressant effect on the baroreceptor. It decreases the sensitivity of the baroreceptor = less parasympathetic innervation and less inhibition of the sympathetic –> tachycardia
What are the acute effects of the alcohol? Endocrine system
Diuresis (polyuria)
Probably due to inhibiting ADH - maybe acetaldehyde.
What are the chronic effect of alcohol in the brain?
Thiamine deficiency. Thiamine is cofactor for several enzymes that are involved in energy metabolism –> cerebral energy utilisation
If you have a deficiency it diminishes brain activity.
Brain regions with high metabolic demand are the most affected – impaired metabolism, NMDA excitotoxicity, Reactive Oxygen Species.
Dementia – Cortical atrophy/decrease in 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) Reversible
- Korsakoff’s psychosis – (deep brain e.g. hippocampus) Irreversible, essentially regions of the brain are dying
SEE THIS SLIDE LOOK AT THE BLACK HIGHLIGHTS - associated with Wernicke’s
Chronic effects in the liver?
Alcohol is using NAD+ in the liver.
beta oxidation of fats needs NAD+ –> build up of fat in the liver if the alcohol is using it all up. The glycerol and fatty acids are converted to triacylglycerol leading to a fatty liver
TCA cycle needs NAD+ means pyruvate and acetyl CoA can’t be recycled. This leads to ketones and lactic acid build up.
How do you develop hepatitis?
Oxygen free radicals.
Chronic drinking means you get a constant depletion of NAD+ and exposure to acetaldehyde.
- Lack of NAD+ means oxygen free radicals are released. These can damage tissue and cause inflammation
- Acetaldehyde is also proinflammatory and causes tissue damage.
- Deranged metabolism; pyruvate and acetyl CoA can’t be recycled. Ketone and lactic acid build up
Together you get hepatitis.
How does cirrhosis develop?
For the same reasons which causes hepatitis. If it continues for a long time you get fibroblast infiltration.
These fibroblasts will then lay down connective tissue and replace active hepatocytes.
They are essentially replacing the metabolic tissue.
What is the order of liver disease?
Fatty liver - very reversible
Hepatitis - reversible
Cirrhosis - irreversible
