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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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Alcohol - Pharmacokinetics
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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Alcohol - Pharmacokinetics
Metabolism 90%
Alcohol dehydrogenase
Mixed function oxidase
85% - Liver
Alcohol
Acetaldehyde
Induction of mixed
function oxidase.THIS IS TOLERANCE
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Alcohol - Pharmacokinetics
85% - Liver ; First Pass Hepatic Metabolism
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Alcohol - Pharmacokinetics
Metabolism
Alcohol dehydrogenase
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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Alcohol - Pharmacokinetics
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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Alcohol - Pharmacokinetics
Less body waterLess ADH
Women
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Alcohol - Pharmacokinetics
Acetaldehyde
Aldehyde dehydrogenase
Acetic acid
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Alcohol - Pharmacokinetics
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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Alcohol - Pharmacodynamics
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
Alcohol - Pharmacodynamics
ACUTE EFFECTS; Central Nervous System
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Alcohol - Pharmacodynamics
NAccVTA
Dopamine
GABA
Euphoria:
Dopaminetransporter
ACUTE EFFECTS; Central Nervous System
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
Alcohol - Pharmacodynamics
ACUTE EFFECTS; Central Nervous System
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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 - Pharmacodynamics
ACUTE EFFECTS; Central Nervous System
Alcohol suppresses generation of
memories by inhibiting hippocampus
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Cutaneous vasodilation;
Ca2+ entryprostaglandins
ACETALDEHYDE??
Alcohol - Pharmacodynamics
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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Alcohol - Pharmacodynamics
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
Alcohol - Pharmacodynamics
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)
Alcohol - Pharmacodynamics
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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Alcohol - Pharmacodynamics
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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Alcohol - Pharmacodynamics
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
Alcohol - Pharmacodynamics
CHRONIC EFFECTS;Liver
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
Alcohol - Pharmacodynamics
CHRONIC EFFECTS;Liver
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."
Alcohol - Pharmacodynamics
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.
Alcohol - Pharmacodynamics
Ethical Dilemma Liver Transplant
Head of
haemochromotosis
societyThey need liver
transplants
Al h l Ph d i
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Alcohol - Pharmacodynamics
Ethical Dilemma Liver Transplant
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BENEFICIAL EFFECTS
Mortality from coronary artery disease (Men 2-4 units/day);HDLstPA levels/ platelet aggregationPolyphenols??
Alcohol - Pharmacodynamics
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
Alcohol dehydrogenase
15% - GIT
Alcohol
Acetaldehyde
Alcohol - Pharmacodynamics
CHRONIC EFFECTS; Gastrointestinal tract
Acetyldehyde is
carcinogenic
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Alcohol - Pharmacodynamics
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??
Alcohol - Pharmacodynamics
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