Alcohol (22.01.2020) Flashcards
(38 cards)
How do you calculate the absolute amount of alcohol?
% ABV x 0.78 = g alcohol/100ml
ABV = alcohol by volume
How can you calculate units of alcohol? How much pure alcohol is one unit of alcohol?
(% alcohol x volume) / 1000
1 unit is 10 ml or 8 g of alcohol
What is a ‘‘safe level’’ of alcohol consumption?
Men & Women; less than or equal to 14 units/week -> low risk
(this is not a safe level but a low risk level)
What is binge drinking defined as?
> 8 units in one sitting
Why are heavier people better able to tolerate alcohol?
- The bigger you are the more ability you have to distribute the alcohol.
- BLOOD LEVELS – 0.01% = 10mg/100ml blood
Administration of alcohol and BA
- taken orally
- of you drink on an empty stomach any fluid entering just passes through -> it is fast in the place where it is more readily absorbed
- if you drink on a full stomach it mixes in with the food and stays there
- 20% is absorbed
- 80% has to wait to be absorbed (lower down)
- speed of onset is proportional / linked to gastric emptying
Metabolism of alcohol (1st phase)
- 85% via liver: first pass hepatic metabolism
- Alcohol dehydrogenase (75%)
- Mixed function oxidase (25%)
- Alcohol -> Acetaldehyde
- acetaldehyde is quite a toxic compound
- these enzymes are all saturable - not all alcohol will be metabolised and will leak into the systemic circulation
- 15% stomach
- alcohol dehydrogenase in the stomach
- metabolised to acetaldehyde there
- > does not enter the systemic circulation
- women have about 50% less alcohol dehydrogenase in their stomachs
Why are women more affected by alcohol?
a) less capacity to metabolise it (about 50% less alcohol dehydrogenase in the stomach)
b) women have more body fat and less body water compared to men; therefore the alcohol is less well distributed and more concentrated. (50% vs 59% body water)
Why do we develop tolerance to alcohol?
- when drinking alcohol, the liver upregulates the “mixed function oxidases” so that the liver is more effective at metabolising alcohol.
- this is reversible, so when you stop drinking the amount of this enzyme will go down and so will the alcohol tolerance.
Why is the speed of drinking important?
- the liver enzymes that metabolise alcohol to acetaldehyde (ADH and mixed function oxidases) are all saturable - not all alcohol will be metabolised and will leak into the systemic circulation
- if you drink a big dose, the enzymes will be saturated and alcohol will leak into the systemic circulation.
Metabolism of alcohol (2nd phase)
Acetaldehyde -> Acetic acid
vis Aldehyde dehydrogenase
Disulfiram
- blocks aldehyde dehydrogenase
- can be used as alcohol aversion therapy
- causes acetaldehyde to build up and the idea is to have a build-up of acetaldehyde in the blood
Why are some people more sensitive to alcohol?
- There is a common genetic polymophism (commonly associated with Asians, Asian flush thing, makes them more nauseous)
- the enzyme affected is aldehyde dehydrogenase -> the enzyme is not as effective as in other people
- this causes acetaldehyde buildup which makes them more nauseous, flush etc.
Pharmacodynamics - potency of alcohol
- alcohol has LOW potency
- it is a very simple molecule
- it can bind to many different targets but not particularly well
- this means you need to have many interactions in order to have any effect at all.
Can you identify a pharmacological target for alcohol? ➡️ NO
What would you predict regarding the affinity and efficacy for this target? ➡️ Not good
Pharmacodynamics – Acute effects: CNS
- depressant effect (primary effect)
- CNS agitation may occur
- the degree of CNS excitability depends on
a) environment (social vs. non-social setting; social increases CNS activation)
b) personality
How does alcohol cause CNS effects?
- direct and indirect effects on GABA:
- post-synaptic: binds to GABA-R and causes Cl- influx
- pre-synaptic: causes an increase in allopregnenolone release (neuroactive steroid that bind to GABA-R and promotes Cl- influx)
- NMDA-R: binds and decreases their function
- interacts with calcium channels and interferes with Ca2+ influx
The brain is quite complex - we know what the effects of alcohol are but we are not sure exactly what is causing them.
Pharmacodynamics of alcohol – Acute effects: Euphoria
- binds to mu-receptor (the same one that opiates bind to)
- disinhibition of GABA -> like cannabis but a different target
- more firing of neurones from VTA to NAcc and therefore more dopamine release there
Pharmacodynamics of alcohol – Acute effects: CNS
- Corpus Collosum - Passes info from the left brain (rules, logic) to the right brain (impulse, feelings) and vice versa. (-> change in behaviour due to the depressant effect)
- Hypothalamus - Controls appetite, emotions, temperature, and pain sensation. Alcohol can influence all those things.
- Reticular Activating System – Consciousness (this area is usually not very sensitive to drugs)
- Hippocampus - Memory
- Cerebellum - Movement and coordination (-> psychomotor performance)
- Basal Ganglia – Perception of time
Pharmacodynamics of alcohol – Acute effects: CVS
Cutaneous vasodilation:
- Ca2+ entry
- prostaglandins
- This may not be due to alcohol but due to acetaldehyde. It may also have an effect on prostaglandins.
Blood Pressure:
- HR goes up
- alcohol depresses the arterial baroreceptors -> less sympathetic inhibitio
- Centrally mediated decrease in baroreceptor sensitivity leads to an acute increase in heart rate and chronic alcohol may be associated with an increased blood pressure
Pharmacodynamics of alcohol – Acute effects: Endocrine
- interferes with VP
- ability to retain water is suppressed
- causes diuresis and polyuria
- this may be due to acetaldehyde
Alcohol: Pharmacodynamics – Chronic effects: CNS
- thiamine is reduced
- it is not clear cut if it is an alcohol or thiamine problem
- alcoholics get a lot of their calories from alcohol
- because of that they don’t get enough thiamine in their diet and thiamine is an important co-factor that drives metabolism in the brain -> overall impaired brain function
- brain regions with high energy demand are mostly affected
- things like reactive oxygen species building up and causing damage
- chronic alcoholics suffer from dementia, cortical atrophy
- you can get balance, eye, movement, confusion
- encephalopathy followed by cortical psychosis and then death may follow
Alcohol: Pharmacodynamics – Chronic effects: Liver
- alcohol requires NAD+ to be metabolised
- chronic alcohol uses up all NAD+
- other processes (e.g. lipid metabolism, driving pyruvate into the CAC, drive ETC)
- you impair with liver function with chronic alcohol use
- there is lipid build-up
- acidosis and ketosis (because pyruvate cannot get into the CAC it is driven into lactic acid and ketone production) -> high metabolic demand and negative effect on the liver
=> Fatty liver (e.g. after a heavy night out; fat buildup (droplets) because you were metabolising alcohol rather than fat. This is reversible because when you stop drinking it will be metabolised.
=> high inflammatory component to e.g. acidosis and ketosis; you can get inflammatory changes in the liver, hepatitis. Reactive oxygen species cause infiltration of WBCs which also release free radicals and cytokines. This is still reversible BUT:
- if enough WBCs (particularily fibroblasts: start laying down connective tissue which replaces hepatocytes and you go from a fully functional liver to decreasing hepatocyte number, decreased metabolism, toxic buildup in the blood, CIRRHOSIS
You can go from a fully functional liver to a liver that has loss of hepatocytes and you get toxin build up in the blood. At the point of a cirrhotic liver you start thinking of a liver transplant.
Pharmacodynamics – Chronic effects: GIT
- damage to gastric mucosa (this is proportional to dose)
- carcinogenic
-> stomach cancer in chronic alcoholics
Pharmacodynamics – Chronic effects: Endocrine system
- increased ACTH secretion (-> cushingoid)
- decreased testosterone secretion
