Drugs of abuse 3 -Alcohol

Question 1

Where was alcohol first believed to be used

Answer 1

China – 9000 B.C.

Question 2

What is the first known distilling technique for alcohol

Answer 2

Mongolian Still’ – 700 A.D

Question 3

Summarise the epidemiology of alcohol consumption

Answer 3

 Epidemiology – high alcohol consumption especially in Europe, Greenland and Russia.

Question 4

How can we calculate the absolute amount of alcohol

Answer 4

% ABV x 0.78 = g alcohol/100ml (ABV = alcohol by volume)

Question 5

How can we calculate the number of units in a given volume of alcohol

Answer 5

ABV% x volume (ml)/1000

1 unit = 10ml or 8g of absolute alcohol

Question 6

What is the recommended weekly allowance of alcohol for men and women

Answer 6

Men & Women;  14 units/week LOW RISK

Question 7

Define binge drinking

Answer 7

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

Question 8

What is 0.01% of alcohol in the blood equal to

Answer 8

BLOOD LEVELS – 0.01% = 10mg/100ml blood

Question 9

Describe the link between alcohol consumption and drink driving

Answer 9

Levels of alcohol in blood (for the same number of drinks) depends on your gender and body weight.
Legal driving limit is below 80 mg/100 ml- i.e 0.08% alcohol.
Subtract 0.01% for wach 40 minutes of drinking.
1 drink = 1.50z 80 proof spirit
12Oz 5% beer
5Oz 12% wine

Question 10

Where is alcohol absorbed

Answer 10

20% - stomach

80% - small intestine

Question 11

What is the speed of alcohol intoxication proportional to and why

Answer 11

 Speed of onset of intoxication >proportional> to gastric emptying.
o Post-prandial, the stomach does not empty often as it needs to break down food thus alcohol is not absorbed very well – i.e. eating a meal decreases speed of onset.

On an empty stomach- fluid will just hit stomach lining and will leave the stomach stragiht away.

Question 12

What percentage of the alcohol absorbed is metabolised

Answer 12

Metabolism – only 90% is metabolised, 10% breathed off

Question 13

Where is alcohol metabolised

Answer 13

 85% of metabolism occurs in the liver, 15% occurs in the GIT.

Question 14

Describe the metabolism of alcohol in the liver

Answer 14

o Alcohol  acetaldehyde (toxic) via:
 75% - Alcohol dehydrogenase.
 25% - Mixed function oxidase.
• MFO is most significantly upregulated in chronic alcoholics (only 25% in naïve drinkers).- this is the reason for alcohol tolerance.

Question 15

Describe the metabolism of alcohol in the gut

Answer 15

The stomach contains alcohol dehydrogenase, which is responsible for 15% of alcohol metabolism
Women have 50% less alcohol dehydrogenase in their stomachs than men

Question 16

Why would one large dose of alcohol give a larger plasma concentration than several smaller doses

Answer 16

The liver enzymes that are responsible for metabolising alcohol are saturable
o One high-dose alcohol bolus will saturate the enzymatic system and lead to a higher intoxication as opposed to the same absolute amount of alcohol over say 4 separate doses.

Question 17

Describe the typical composition of a female

Answer 17

Body water: 50%
e.g. 60kg woman
65% ICF; ~ 20L 
35% ECF; ~ 10L
	(incl 2L plasma)

Question 18

Describe the typical composition of a male

Answer 18

Body water: 59%
e.g. 75kg man
65% ICF; ~ 30L 
35% ECF; ~ 15L
	(incl 3L plasma)

Question 19

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 19

 Men have a greater volume of body water (and women have more adipose tissue) which allows alcohol to be more widely distributed in men so at a lower concentration. Alcohol is water soluble adn so will distribute more in the blood.
 Men have more ADH as well so more ability to metabolise.

Question 20

Describe the metabolism of acetaldehyde in the gut and liver

Answer 20

 Liver and GIT metabolism:
o Acetaldehyde  Acetic acid via:
 Aldehyde dehydrogenase.
• Polymorphisms can be found in this enzyme leading to Asian flush.

Question 21

What drug can be used as an alcohol aversion therapy

Answer 21

Disulfiram – it is an aldehyde dehydrogenase inhibitor so it promotes the build up of acetaldehyde, which is responsible for most of the negative feelings associated with drinking

Question 22

Why do asians tend to tolerate alcohol poorly

Answer 22

There is a common genetic polymorphism in the aldehyde dehydrogenase gene meaning that some people (particularly Asians) can’t convert acetaldehyde to acetic acid as efficiently so acetaldehyde builds up and makes them feel bad

Question 23

Why does alcohol have a low pharmacological potency

Answer 23

 Alcohol has a LOW potency (it is a very general molecule).
o Influences a lot of receptors due to its uncomplicated shape however doesn’t fit a lot of the receptors very well so not a lot of efficacy.

Question 24

Compare the potency of alcohol to nicotine and cocaine

Answer 24

Amounts to produce an effect:
Nicotine 20ng/ml

Cocaine 200ng/ml

Alcohol 200g/ml

Question 25

What is the primary effect of alcohol

Answer 25

Depressant

Question 26

Describe how low dose alcohol may cause CNS agitation

Answer 26

Depends on degree of CNS excitability:
This in turn depends on your personality and environment (i.e whether you are in a social or un-social setting)
Low dose alcohol is morel likely to cause CNS agitation in low dose settings, and thus give feelings of increased confidence etd
However, the depressant effects will soon kick in as the dose is increased.

Initial stimulatory effects result from depression of inhibitory control pathways

Question 27

Describe the 3 major CNS targets of alcohol

Answer 27

NMDA – alcohol decreases NMDA receptor function (allosteric modulation) - NMDA is excitatory for the brain

Ca2+ channels – alcohol reduces Ca2+ channel function meaning that there is less calcium influx, which negatively affects neurotransmitter exocytosis

GABA:
Post-synpatically- alcohol can bind to GABA receptor- leading to chloride ion influx and thus hyperpolarisation
Pre-synpatically- increase release of allopregenolone- which is a neural steroid and has efficacy for the GABA receptor.

Question 28

What may be the consequences of the action of alcohol on each of the CNS targets

Answer 28

Enhancement of GABA-mediated inhibition (?? Sedative/anxiolytic effects)
Inhibition of calcium entry through voltage gated calcium channels
Inhibition of NMDA receptor function (?? Loss of memory)

Question 29

What is important to remember about the acute CNS effects of alcohol

Answer 29

Important – CNS is functionally more complex than any other system in the body relationship between behaviour of individual cells and that of the organ as a whole is often unclear
This is worsened by alcohol’s low potency and selectivity.

Question 30

Describe how alcohol may cause euphoria

Answer 30

§ Alcohol binds to the m-receptor to inhibit GABA release.
§ Less inhibitory GABA means less inhibition on DA release by the VTA DA neurones into the NAcc.

Opiates may also bind to this receptor

Question 31

Describe how alcohol can impair both sensory and motor function

Answer 31

Sensory function i.e. Mood Changes e.g. self confidence, euphoria (highly labile at higher concentrations) Memory Loss Powers of discrimination and concentration
Motor function i.e. Slurred speech Prolonged reaction time Loss of coordination

Question 32

Describe the effects of alcohol on the different parts of the CNS

Answer 32

Depresses all of these functions:
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

Question 33

Describe how alcohol can cause cutaneous vasodilation (flushing)

Answer 33

Alcohol causes vasodilation (this is thought to be due to acetaldehyde) - acts on pre-capillary sphincters of cutaneous vessels.
It causes decrease calcium influx and increased prostaglandins à vasodilation

Question 34

Describe how alcohol may cause tachycardia and hypertension

Answer 34

Alcohol decreases the sensitivity of baroreceptors
This means decreased baroreceptor firing à decreased parasympathetic firing + decreased inhibition of sympathetic firing à INCREASED HEART RATE

Question 35

Describe normal baroreceptor control of BP

Answer 35

Increased firing rate – stimulates PSNS neurone- which projects to the heart to decrease HR. Also stimulates inhibitory interneurone which is linked to the SNS neurone- therefore we have less vasoconstriction and decreased HR.

Question 36

Describe how alcohol may cause diuresis

Answer 36

Alcohol inhibits vasopressin release from the neurohypophysis
This means that alcohol is a powerful diuretic

This may be due to acetaldehyde
Remember -vasopressin helps you to retain water.

Question 37

What is the role of thiamine in the body

Answer 37

The thiamine requirement for healthy individuals is related to their carbohydrate intake and is between 1–2mg per day: this requirement increases with alcohol misuse. The body can only store between 30–50 mg of thiamine, thus body stores of individuals on a thiamine deficient diet are likely to be depleted in four-to-six weeks. Further thiamine deprivation causes a significant decrease in the activity of many enzymes which play a key role in metabolism. Thiamine acts as an essential coenzyme to the TCA cycle and the pentose phosphate shunt.

Question 38

Describe the effects of chronic alcoholism on the CNS

Answer 38

Most of calories come from alcohol- can lead to thiamine deficiency
Thiamine is an important cofactor for the enzymes involved in energy metabolism and thus is important for cerebral energy utilisation.

A deficiency in thiamine can therefore lead to:
Brain regions with high metabolic demand – impaired metabolism, NMDA excitotoxicity, ROS.

Question 39

Describe the effects of impaired metabolism, NMDA excitotoxicity and ROS on different regions of the CNS

Answer 39

Chronic alcohol caused cortical atrophy and a loss of cerebral white matter à dementia
Confusion (encephalopathy)
oculomotor symptoms
Ataxia – Cerebellar cortex degeneration - gait

Question 40

Summarise Wernicke-Korsakoff syndrome

Answer 40

Wernicke’s encephalopathy (WE) is an acute neuropsychiatric condition due to an initially reversible biochemical brain lesion caused by overwhelming metabolic demands on brain cells that have depleted intracellular thiamine (vitamin B1). This imbalance leads to a cellular energy deficit, focal acidosis, regional increase in glutamate, and ultimately cell death. Classically, Wernicke’s encephalopathy is characterised by the triad ophthalmoplegia (paralysis of muscles surrounding the eye), ataxia, and confusion. However, only 10% of patients exhibit all three features, and other symptoms may also be present. The primary neurological-related injury caused by thiamine deficiency in WE is three-fold: oxidative damage, mitochondrial injury leading to apoptosis, and directly stimulating a pro-apoptotic pathway.

Question 41

Describe and explain how chronic alcoholism can cause Wernicke-Korsakoff syndrome

Answer 41

Wernicke-Korsakoff syndrome is caused by thiamine (vitamin B1) deficiency
Chronic alcoholics tend to have a bad diet
Thiamine is an important cofactor in the generation of ATP within cells
The lack of thiamine impairs the Krebs’ cycle and leads to the build up of oxidative stress within the cells
The oxidative stress can cause mitochondrial damage and apoptosis
Wenicke’s Encephalopathy – caused by mitochondrial injury (thalamus/hypothalamus)- affects the 3rd ventricle and aqueduct.- reversible
Korsakoff’s Psychosis – cell apoptosis in the brain – this is irreversible and the patient will probably die - deep brain structures hippocampus

Question 42

Describe a typical presentation of Korsakoff’s Psychosis

Answer 42

Korsakoffs psychosis is associated with polyneuritis, and is characterized by an impaired ability to acquire new information and by a substantial, but irregular memory loss for which the patient often attempts to compensate through confabulation. Irreversible – neuronal cell death.