Drug abuse 3: Alcohol

Question 1

What is the formulae for absolute amount of alcohol?

Answer 1

% ABV x 0.78 = g alcohol/100ml

ABV = alcohol by volume

Question 2

How do you calculate the number of units?

Answer 2

[%ABV x volume (ml)]/ 1000 = units

1 unit = 10ml or 8g of absolute alcohol

Question 3

What are the safe levels of alcohol?

Answer 3

Men and Women; =< 14 units/week LOW RISK

Binge drinking i.e. > 8 units in one sitting; 18% of 16-24 yrs (> 30%) ↓

Question 4

How does drinking on a full stomach influence your blood alcohol level?

Answer 4

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.

Question 5

Where is alcohol absorbed?

Answer 5

Alcohol is absorbed from the stomach but better in the small intestine.
20% - stomach
80% - small intestine

Question 6

Describe the metabolism of alcohol?

Answer 6

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.

Question 7

Which enzyme increases with chronic use?

Answer 7

Cytochrome p450 increases with chronic use –> you become tolerant.

Question 8

What happens when you drink alcohol very quickly

Answer 8

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.

Question 9

Why can alcohol be absorbed through the stomach?

Answer 9

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

Question 10

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.

Answer 10

Less body water

Less ADH

Question 11

How is acetaldehyde broken down?

Answer 11

Aldehyde dehydrogenase: breaks acetaldehyde (has negative effects) to acetic acid.

(Genetic polymorphism - asian people aldehyde dehydrogenase doesn’t work as effectively)

Question 12

What drug can be effective as alcohol aversion therapy.

Answer 12

Aldehyde dehydrogenase inhibitor = build up of acetalydehyde which has negative effects

Disulfiram

Question 13

Describe the pharmacodynamics of alcohol

Answer 13

Alcohol is a depressant (primary effect)

CNS agitation may occur and it is dependent on various factors.
See diagram

Question 14

Can you identify a pharmacological target for alcohol? What would you predict regarding the affinity and efficacy for this target?

Answer 14

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.

Question 15

How does alcohol have a depressant effect?

Answer 15

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

Question 16

What are the acute effects of alcohol? CNS

Answer 16

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

Question 17

How might alcohol cause euphoria?

Answer 17

Alcohol at a high dose can behave like heroin/morphine. It will bind to the opiate receptors on GABA

Question 18

What are the acute effects of alcohol? CVS?

Answer 18

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

Question 19

What are the acute effects of the alcohol? Endocrine system

Answer 19

Diuresis (polyuria)

Probably due to inhibiting ADH - maybe acetaldehyde.

Question 20

What are the chronic effect of alcohol in the brain?

Answer 20

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

Question 21

Chronic effects in the liver?

Answer 21

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.

Question 22

How do you develop hepatitis?

Answer 22

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.

Question 23

How does cirrhosis develop?

Answer 23

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.

Question 24

What is the order of liver disease?

Answer 24

Fatty liver - very reversible
Hepatitis - reversible
Cirrhosis - irreversible

Question 25

What are the beneficial effects of chronic alcohol?

Answer 25

Decreased mortality from coronary artery disease (Men 2-4 units/day);

Increased HDLs (improves lipid profile)
Increased tPA levels/ decreased platelet aggregation

Question 26

What are the chronic effects on the GIT?

Answer 26

Damage to gastric mucosa (proportional to dose)

Ulceration is common in alcoholics

We are not sure if it is directly carcinogenic

Question 27

What are the chronic effects on the endocrine system?

Answer 27

Increased ACTH

Decreased Testosterone secretion

Question 28

What are the effects of hangover?

Answer 28

Symptoms - peak as rebound excitation

Nausea: Irritant –>Vagus
–>Vomiting center

Headache: Vasodilation

Fatigue:

1) Sleep deprivation,
2) ‘Rebound’

Restlessness and muscle tremors: ‘Rebound’

Polyuria and polydipsia:
↓ ADH secretion

Best thing to do is to sleep