pharmacology 16 alcohol

8/2/2019 Pharmacology 16 Alcohol

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Pharmacology & Therapeutics

Alcohol

Chris John


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History of Alcohol

China 9000 B.C.

Egypt 2650-2180 B.C.

Babylon Code of Hammurabi 1750 B.C.


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History of Alcohol

Greece c. 1000 B.C.

Rome Bacchanalia; c. 200 B.C.

Mongolian Still

700 A.D.


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Alcohol consumption per capita in liters of pure ethanol.

Spanagel R Physiol Rev 2009;89:649-705

Alcohol & Medicine


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28,000 hospital admissions/year

33,000 deaths/year

Alcohol related

Cost to NHS; 3bn/year Illness/Injury

1/3 of all A&E attendances

Junior Doctors

50% > advised alcohol units/week

Alcohol & Medicine


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Absolute amount:

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

Units:

%ABV x volume (ml) 1 unit = 10ml or 8g of absolute alcohol1000

No consistency!!

Alcohol - dosing

Safe level?:

Men


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Alcohol - dosing

BLOOD LEVELS

Likelihood ofcar accident

20-40mg/ml (Minimal effects)

Up to 50mg/ml Up to 80mg/ml (Legal driving limit) x 4

Up to 150mg/ml (90% - gross intoxication) x 25

300mg/ml (Coma)

4-500mg/ml (Death)

Minimal effects -

half to one pint of

beer

Very minimal

therapeutic window

when you're referring

to minimal effects to

death. Only ten fold

increase.


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Alcohol - Pharmacokinetics

20%80%

Speed of onset Gastric emptying

Hence told to drink

on a full stomach.

Full stomachs do not

empty quickly.Fluid stimulates

gastric opening.On empty stomach -

alcohol pretty much

goes straight

through.


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Metabolism 90%

Alcohol dehydrogenase (75%)

Mixed function oxidase (25%)

85% - Liver

Alcohol

Acetaldehyde

Ten per cent is

excreted in your

breath. Hence the

breath analyser


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Metabolism 90%

Alcohol dehydrogenase

Mixed function oxidase

85% - Liver

Alcohol

Acetaldehyde

Induction of mixed

function oxidase.THIS IS TOLERANCE


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85% - Liver ; First Pass Hepatic Metabolism


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Metabolism


15% - GIT

Alcohol

Acetaldehyde

< 50%

The twenty percent

that gets absorbed

in the stomach hasits own metabolic

pathway Alcohol

dehydrogenase in

stomach as with

liver. Women have 50% less

alcohol

dehydrogenase in

their stomachs as

compared with men


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Body water: 50%e.g. 60kg woman

65% ICF; ~ 20L

35% ECF; ~ 10L

(incl 2L plasma)

Body water: 59%e.g. 75kg man

65% ICF; ~ 30L

35% ECF; ~ 15L

(incl 3L plasma)

Women moreaffected more

than menNot just less

alcohol

dehydrogenaseWomen are fatter

therefore menhave higher body

water and hence

less concentrated

alcohol. Don't worry an

ICF and ECF


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Less body waterLess ADH

Women


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Acetaldehyde

Aldehyde dehydrogenase

Acetic acid


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Acetaldehyde

Aldehyde dehydrogenase

Acetic acid

Disulfiram

Genetic polymorphism

Drug to treat alcohol.Alcohol dehydrogenase

inhibitorPrevents acetyldehyde

from breaking downs and

hence the buildup of

toxic substances

Hence disulfiram is

used to promote

aversion - you get

sick, you feel terrible

every time you consume

alcohol and hence don't

take it.

Genetic polymorphism -

Chinese and JapaneseAlso creates aversion

like disulfiram


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1. Are you starting to get low marks? Are you skiving offwork?

2. Do you ever try to stop or drink less - and fail?

3. Have you begun to drink in the morning, before school orwork?

4. Do you gulp your drinks as if to satisfy a great thirst ?

5. Do you ever have loss of memory due to your drinking?

6. Do you avoid being honest with others about your drinking

7. Do you ever get into trouble when you are drinking?

8. Do you often get drunk when you drink, even when you do

not mean to?

9. Do you think you're big to be able to hold your drink?

Alcohol test??


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Alcohol test??

2005 30%

2006 15%

2007 10%

2008 Sample Excluded!!

2009 30%

2010 15%

2011 15%


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IMPT. LOW pharmacological potency

Alcohol = Ethanol (C2H5OH)

Nicotine 20ng/ml

Cocaine 200ng/ml

Alcohol 200g/ml

Alcohol - Pharmacodynamics

We do not have an

alcohol receptor.However due to the

simple structure, it

binds to a largenumber of targets,

but not well with

each


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Pre- vs Post-synaptic

Allopregnenolone

Allosteric modulationACUTE EFFECTS; Central Nervous System

NMDA receptors

Neurotransmitters!Ca2+ channels

Increase gaba presynaptically and chloridepostsynaptically

Increase neuro steroids such as

allopregnenolone and which in turn increases

GABA secretion

DECREASED NMDA

INCREASED GABA


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1. CNS is functionally complex

2. Ethanol has low potencylow selectivity


ACUTE EFFECTS; Central Nervous System


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NAccVTA

Dopamine

GABA

Euphoria:

Dopaminetransporter


Remember dose related effect

Alcohol increases

inhibitory GABA and

decreases excitatory NMDA.

Hence reduces stimulation

and increases depressive

effects

However at low doses, it

must be disinhibiting NMDA.

hence stimulation

So it's difficult to

understand the actualmechanisms of alcohol

NMDA receptors are particularly important when they

become overactive during withdrawal from alcohol as

this causes symptoms such as agitation and,

sometimes, epileptiform seizures.


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N-Methyl-D-aspartic acid or N-Methyl-D-aspartate (NMDA) is an amino acid

derivative which acts as a specific agonist at the NMDA receptor mimicking the

action of glutamate, the neurotransmitter which normally acts at that receptor.

Unlike glutamate, NMDA only binds to and regulates the NMDA receptor andhas no effect on other glutamate receptors (such as those for AMPA and

kainate).

NMDA receptors are particularly important when they become overactive during

withdrawal from alcohol as this causes symptoms such as agitation and,

sometimes, epileptiform seizures.


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Certain brain regions appear to be more sensitive;

CORTICAL region

Impairs

(a) Sensory function

(b) Motor function




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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



Alcohol suppresses generation of

memories by inhibiting hippocampus


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Cutaneous vasodilation;

Ca2+ entryprostaglandins

ACETALDEHYDE??


ACUTE EFFECTS; Cardiovascular System

Hence facial

flushing

Actually it could just

as easily be the toxic

metabolite acetyl

aldehyde that causes

the vasodilation


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ACUTE EFFECTS; Cardiovascular System

Suppression of

arterial

baroreceptors.

If they are firing

away they will

stimulate PS and

inhibit sympathetic.

Alcohol therefore

interferes with

baroreceptors and

hence disinhibits

sympathetic

inhibition. Therefore

increase in heart

rate!


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ADH


ACUTE EFFECTS; Endocrine System

Diuresis (polyuria);

K+ entry

ACETALDEHYDE??

Ethanol (alcohol)

reduces the calcium-

dependent secretion of

AVP by blocking

voltage-gated calcium

channels inneurohypophyseal

nerve terminals.[8]

Thereby causing

DIURESIS


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Dementia Cortical atrophy/ volume cerebral white matterAtaxia Cerebellar cortex degeneration

Wernicke-Korsakoff syndrome (due to thiamine deficiency)

Wernickes encephalopathy (3rd ventricle & aqueduct)

Korsakoffs psychosis (dorsomedial thalamus)


CHRONIC EFFECTS;Central Nervous System

Cortical atrophy

Worsened in chronic

alcoholics

Asked to read up more about

this on our own


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CHRONIC EFFECTS;LiverMUST MUST

MUST KNOW

Mostimportant bit

- alcohol

uses up your

NAD stores.

So your

ability to

metabolise

fats and

gluconeogenic

pathways and

divert a lot

of metabolic

pathwaysinappropriate

ly


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CHRONIC EFFECTS;Liver

Fatty LiverHealthy Liver

Glycerol + Hepatocyte

Fatty acids Mitochondria

Blood

Triacylglycerol

Liver

Even with one or two

pints

NAD+ depleted andhence fats and

glycerols are not

broken down. Hence

the fatty liver.


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Blood + Hepatic cytokine changes (e.g. IL-6 and TNF-)Free radicals



Hepatitis

By diverting these metabolic

pathways inappropriately, you

generate inflammationThis is hepatitis. Inflammation of

the liver.Driven by chronic alcohol. Fatty liver progressing to theinflammatory state of hepatitis.Hepatitis still reversible.Structural changes after a long

time of inflammation. Fibroblasts

start to appear.


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Fibroblasts (connective tissue cells) Supportive framework

Hepatocyte regeneration Fibroblasts Active liver tissue



Cirrhosis


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"I would never say to anybody you don't deserve to live, no matter who they are

"I know myself I will never drink again. The only reason I would is because

I want to kill myself or I want to go through this again - and I don't want

either, so there's no reason to drink."


Ethical Dilemma Liver Transplant

Patient 1

Alcohol-induced

liver cirrhosis

July 2002- Liver Transplant

2004 Found guilty of drink driving (2.5 times the legal limit)

George best


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Patient 2

Haemochromotosis

A genetic disease that causes the body to absorb and store too much iron.Hemo" for blood and "chroma" for color (referring to the characteristic bronze

skin tone that iron overload can cause).

Excess iron doesn't leave the body and is stored in major organs such as the liver.Over many years, iron accumulates to toxic levels that can damage the organ.



Head of

haemochromotosis

societyThey need liver

transplants

Al h l Ph d i


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BENEFICIAL EFFECTS

Mortality from coronary artery disease (Men 2-4 units/day);HDLstPA levels/ platelet aggregationPolyphenols??


CHRONIC EFFECTS; Cardiovascular System

They think that

these beneficial

effects are due topoly phenols.

Compounds outside

alcoholSo drink red wine

for CV benefits

because of these


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Damage to gastric mucosa ( dose)Carcinogenic


15% - GIT

Alcohol

Acetaldehyde


CHRONIC EFFECTS; Gastrointestinal tract

Acetyldehyde is

carcinogenic


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CHRONIC EFFECTS;Endocrine System

Testosterone secretion

ACTH secretionAlcohol like

cushings due to

cortisol effects

Al h l Ph d i


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HANGOVER

Symptoms - Peak as BAC 0

Nausea Irritant Vagus Vomiting centerHeadache Vasodilation

Fatigue 1. Sleep deprivation, 2. Rebound

Restlessness and muscle tremors Rebound

Polyuria and polydipsia ADH secretion

CURE??


Symptoms of

hangovers are worseas blood alcohol

concentration

approaches zero

Therefore the cure is to go back to alcohol

Rebound activation is causing the tremors

d h i i

pharmacology 16 alcohol

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