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Year 2 - LCRS - Pharmacology > Alcohol (22.01.2020) > Flashcards

Alcohol (22.01.2020) Flashcards

1
Q

How do you calculate the absolute amount of alcohol?

A

% ABV x 0.78 = g alcohol/100ml

ABV = alcohol by volume

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2
Q

How can you calculate units of alcohol? How much pure alcohol is one unit of alcohol?

A

(% alcohol x volume) / 1000

1 unit is 10 ml or 8 g of alcohol

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3
Q

What is a ‘‘safe level’’ of alcohol consumption?

A

Men & Women; less than or equal to 14 units/week -> low risk

(this is not a safe level but a low risk level)

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4
Q

What is binge drinking defined as?

A

> 8 units in one sitting

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5
Q

Why are heavier people better able to tolerate alcohol?

A
  • The bigger you are the more ability you have to distribute the alcohol.
  • BLOOD LEVELS – 0.01% = 10mg/100ml blood
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6
Q

Administration of alcohol and BA

A
  • 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
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7
Q

Metabolism of alcohol (1st phase)

A
  • 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
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8
Q

Why are women more affected by alcohol?

A

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)

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9
Q

Why do we develop tolerance to alcohol?

A
  • 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.
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10
Q

Why is the speed of drinking important?

A
  • 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.
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11
Q

Metabolism of alcohol (2nd phase)

A

Acetaldehyde -> Acetic acid

vis Aldehyde dehydrogenase

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12
Q

Disulfiram

A
  • 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
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13
Q

Why are some people more sensitive to alcohol?

A
  • 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.
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14
Q

Pharmacodynamics - potency of alcohol

A
  • 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

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15
Q

Pharmacodynamics – Acute effects: CNS

A
  • 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
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16
Q

How does alcohol cause CNS effects?

A
  • 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.

17
Q

Pharmacodynamics of alcohol – Acute effects: Euphoria

A
  • 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
18
Q

Pharmacodynamics of alcohol – Acute effects: CNS

A
  • 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
19
Q

Pharmacodynamics of alcohol – Acute effects: CVS

A

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
20
Q

Pharmacodynamics of alcohol – Acute effects: Endocrine

A
  • interferes with VP
  • ability to retain water is suppressed
  • causes diuresis and polyuria
  • this may be due to acetaldehyde
21
Q

Alcohol: Pharmacodynamics – Chronic effects: CNS

A
  • 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
22
Q

Alcohol: Pharmacodynamics – Chronic effects: Liver

A
  • 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.

23
Q

Pharmacodynamics – Chronic effects: GIT

A
  • damage to gastric mucosa (this is proportional to dose)
  • carcinogenic

-> stomach cancer in chronic alcoholics

24
Q

Pharmacodynamics – Chronic effects: Endocrine system

A
  • increased ACTH secretion (-> cushingoid)

- decreased testosterone secretion

25
Q

What are the key chronic problems with alcohol?

A
  • problems with the brain

- problems with the liver

26
Q

Wernicke-Korsakoff syndrome

A

Wernicke-Korsakoff syndrome (due to thiamine deficiency)

  • Wernicke’s encephalopathy – (hypothalamus/thalamus)
  • Korsakoff’s psychosis – (deep brain e.g. hippocampus)
  • first one is reversible, second one not really and is often followed by death in some time.
27
Q

Wernicke-Korsakoff syndrome

A

Wernicke-Korsakoff syndrome (due to thiamine deficiency)

  • Wernicke’s encephalopathy – (hypothalamus/thalamus)
  • Korsakoff’s psychosis – (deep brain e.g. hippocampus)
  • first one is reversible, second one not really and is often followed by death in some time.
28
Q

Hangover pharmacodynamics:

A
  • Symptoms - Peak as BAC → 0
  • Nausea: Irritant ➡️ Vagus ➡️ Vomiting center
  • Headache: Vasodilation
  • Fatigue: 1. Sleep deprivation, 2. ‘Rebound’
  • Restlessness and muscle tremors ‘Rebound’
  • Polyuria and polydipsia ↓ ADH secretion

Cure:

  • Sleep
  • Water drinking – does it help clear toxins (e.g. acetaldehyde?)
  • Kidney Int 67 : 613 –621, 2005 – 15min water load is largely excreted
  • Water mixed with an easily absorbed sugar is largely excreted
29
Q

How does alcohol affect GABA?

A
  • directly and indirectly
  • has a positive effect on GABA (HOW it does it is less clear cut)
  • binds to GABA R and promotes Cl- influx directly
  • presynaptic: increased release of allopregnenolone (which binds to GABA R and promotes Cl- influx)

-> alcohol potentiates a natural inhibitor

30
Q

acute CNS effects of alcohol

A
  • ENHANCES GABA directly and indirectly
  • NMDA receptors: inhibits (allosteric modulation)
  • interferes with Ca2+ channels and NT efflux
31
Q

What are the effects of alcohol on thiamine?

A
  • reduces thiamine
  • thiamine deficiency because chronic alcoholics get a lot of their calories from alcohol and therefore don’t get enough thiamine
  • thiamine is an important cofactor that drives metabolism in the brain
  • overall there is impaired brain function

Brian regions with high metabolic demand are particularily sensitive
- dementia, cortical atrophy, damaging things such as oxygen species Strat building up, eye problems, confusion, problems in the cerebellum (balance, gait), Wernickes encephalopathy (reversible)

Kosakoffs psychosis is not reversible

32
Q

ROS

A

reactive oxygen species

can build up in the brain in thiamine deficiency and can cause damage in the brain

33
Q

Liver cirrhosis

A
  • fibroblasts - supportive framework
  • decreased hepatocyte regeneration
  • increased fibroblasts
  • decreased amount of active liver tissue

Cirrhotic liver is when you need to think about a transplant.

34
Q

How does alcohol lead to cirrhosis?

A
  • first you get fat buildup because there is not enough NAD+ to metabolise triglycerides etc
  • the fatty buildup comes with inflammation
  • the inflammation causes remodelling of the liver, there are WBC and there is putting down of connective tissue, the hepatocytes don’t regenerate, there are increased fibroblasts instead of active hepatocytes
35
Q

What are the beneficial effects of alcohol?

A
  • low dose alcohol reduces mortality from CAD
  • increased HDL.s
  • increased tPA levels and decreased platelet aggregation

we think that low dose alcohol has a beneficial effect on fat profile

are these effects via polyphenols - it might be a polyphenol (from red wine) effect rather than alcohol

polyphenols are particularily helpful

36
Q

When are hangover symptoms the worst?

A

When alcohol concentration reaches zero.

37
Q

Hangover - fatigue - why?

A
  • really poor quality sleep

- particularily as alcohol concentration reaches 0, you get a rebound excitation

38
Q

How to cure a hangover?

A
  • sleep
  • water -> more fluid leaving the kidneys so the toxins might leave sooner if there is more flow through the kidneys.
  • water with sugar is even better

Year 2 - LCRS - Pharmacology (34 decks)

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