ALCOHOL

PROF. DR. SHAH MURAD

shahmurad65@gmail.com

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Social
problem

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Legal issue

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TEMPERANCE

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Accept

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Not accept

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Intellectual
STIGMA !!!!
!

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Should take

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Should not !!!!

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SIN

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WORSHIP

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Increase IQ

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DECREASE IQ !!!

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Mind Depressant

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Mind Stimulant !!!

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WHERE IS THE TRUTH
about ALCOHOL
then ???????????

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 Same conflicts in
MEDICAL SCIENCES
about ALCOHOL

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• Ethanol (alcohol, ethyl
alcohol) is the world's most
commonly used recreational
drug, yet, despite many
years of research, ethanol's
exact pharmacological
mechanism remains
somewhat elusive.

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• Ethanol has been shown to
affect a member of nearly every
type of ion channel in the body,
but often at concentrations far
above those found in
recreational users.

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• In order to make sense of the huge
amount of research into the effects of
ethanol on neurons, one must gauge it
against the threshold plasma
concentration of ethanol needed to
produce an effect and a rough
estimation of the fatal concentration
in humans, i.e. the range of ethanol's
concentration found during
recreational usage
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• It is estimated that the plasma
concentration necessary to cause
threshold effects in humans is 5mM
(40mg/100mL) while in a review of 808
fatal alcohol poisonings, the mean
plasma concentration was 72mM.
• To put blood concentrations further in
context, the blood-alcohol limit in
most states in the US is 17.4 mM.

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GABA-A receptors

• Because of ethanol's depressive

effects, there has been
constant speculation that its
site of action is the GABA-A
receptor (the major inhibitory
receptor in the brain, the same
receptor enhanced by
benzodiazepines and
barbiturates).
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• Many experiments have looked
into this possibility, and they
broadly fit into two categories:
ones that found no effect and
ones that found a relatively high
potency effect, well within
recreational concentrations.

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• Exactly why there is this stark
dichotomy is unclear, though it
may have something to do with
more recently discovered facts
about the distribution of
"subunits" of GABA-A receptors.

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NMDA receptors
• Inhibition of NMDA receptors by
ethanol is another theme that has
received a lot of attention, because of
the similar anaesthetic nature of
ethanol and the classical NMDA
receptor antagonists, >>>>>>>>>>>
the dissociative anaesthetics
(ketamine).

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• The NMDA receptor is a compelling site
for explaining ethanol's actions, as the
concentrations of ethanol that start to
cause a significant inhibition of the
NMDA receptor are the same
concentrations at which the effects of
ethanol are beginning to be registered
in humans (~5mM).
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• NMDA receptor antagonists are
classically known for their ability
to block the formation of
memories, an effect that larger
amounts of ethanol are renowned
for.
• However, one problem with this
theory is the lack of similarity
between alcohol's intoxication
state and that induced by ketamine
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Nicotinic Acetylcholine
Receptors
• The nicotinic acetylcholine receptor
is another interesting target of
ethanol.

• Ethanol potentiates the alpha7

subtype of the nicotinic
acetylcholine receptor at
concentrations that overlap the
concentration needed to intoxicate.
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• The alpha7 subtype is one of the
most common nicotinic acetylcholine
receptor subtypes in the brain, the
other common subtype, the alpha-4-
beta-2 subtype, is not affected by
ethanol.

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• It is almost certain that ethanol's
classical "depressant" effects are not
mediated by this receptor, as the
classical nicotinic acetylcholine
receptor agonist nicotine is not
depressant.

• However, one effect that nicotine and

ethanol share is their addictive
nature. 30
• It has been demonstrated that
nicotinic acetylcholine receptor
antagonists inhibit the increase
in dopamine release in the brain
caused by ethanol and the
rewarding effects in humans

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Voltage-Gated Sodium
Channels
• Ethanol has been shown to
inhibit voltage-gated sodium
channels (the same channel
local anesthetics inhibit), but
only at very high concentrations

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 Potassium Channels and
GIRKS
• ethanol modulates potassium
channels.
• Potassium channels are very
important in reducing neuronal
excitability.

• The G-protein coupled inward rectifying

(GIRK) channel is a channel modulated by
CB1-cannabinoid and Mu-opioid receptors
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(as well as many others).
• Ethanol has been shown to directly open
(or at least potentiate the opening of)
this channel at concentrations starting
at ~20-75mM.

• While this puts the GIRK channel outside

the range for mediating ethanol's
recreational effects, it could be
responsible for some of the effects of
ethanol seen at higher doses, such as
analgesia. 34
• In mice lacking a functional GIRK
channel, ethanol had severely
reduced potency as an analgesic.
• Ethanol has also been shown to
enhance the activity of calcium-
activated potassium channels.
• These channels become active when
a neuron fires repetitively, slowing
and eventually stopping the neuron
from firing. 35
• Ethanol activates these receptors
in the high range of ethanol blood
concentrations, and so may be
responsible for some of the
depressant effects of ethanol at
high concentrations.

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Glycine Receptor

• The glycine receptor is an inhibitory

receptor distributed largely in the spinal
cord and brainstem.

• Ethanol potentiates this receptor at

concentrations directly overlaying its
recreational plasma concentrations.
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• This could cause a variety of
effects like inhibition of signaling
from the brain to the body, and
might also be responsible for
respiratory depression at high
doses, but is unlikely to mediate
the classical cognitive effect of
ethanol
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Voltage-Gated Calcium
Channels
• The effect of ethanol on voltage-gated calcium
channels is one effect that has received a lot of
press.

• Ethanol inhibits these channels at

concentrations very similar to its recreational
plasma concentration and has an IC50 in the39
middle of the recreational range.
• The opening of voltage-gated calcium
channels is responsible for the release
of neurotransmitters throughout the
body and, by inhibiting this, ethanol will
decrease neurotransmitter release.

• This inhibition causes a decrease in

both excitatory and inhibitory synaptic
transmission
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Serotonin 5-HT3
Activation
• Ethanol has also been shown to
potentiate the serotonin 5-HT3
receptor.

• This receptor is somewhat

enigmatic, but is believed to
modulate excitation in some parts
of the brain, and to facilitate
vomiting.
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• The ethanol concentrations that
are needed to potentiate the 5-
HT3 receptor are outside the
range reached during
recreational usage

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• Despite ethyl alcohol being one of
the most widely used psychoactives,
the pharmacology of its altering
effects is still not yet fully
understood.

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• There are many systems that it
is known to affect, but many of
the documented neuro-
physiological effects only occur
at plasma concentrations
outside the range that ethanol
is used in humans.

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• Its effects on GABA-A receptors
seem tantalizing, but generally
unlikely, due to either a far too high
or too low potency, depending on the
subunit makeup.

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• Ethanol's inhibition of NMDA
receptors seems likely to be a
contributor to its effects.

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 Is alcohol a Poison?

• A poison is any substance that is

capable of causing injury, illness or
death to an organism.

• Salt, water and oxygen are all poisons because

in high enough quantities they can harm people.
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• Too much salt in a diet can
cause serious health problems,
hyper hydration can kill
athletes, and too much oxygen
given to a premature infant can
cause permanent blindness.

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• Toxicologists emphasize that “the
dosage makes the poison.”

• Although salt, water, oxygen, aspirin,

alcohol beverages, and many other
substances can cause poisoning in
excessive amounts, it makes no sense to
call them poisons.
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ETHYL ALCOHOL IS A
POISON

• “ETHYL ALCOHOL IS A POISON.

• >>>>>>>>>>>> ‘No intelligent

person knowingly ingests poison
unless they want to die
prematurely’
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• So why do so many groups and
organizations insist on calling
alcohol a poison?

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• Apparently to stigmatize
alcoholic beverages and
frighten people into alcohol
abstinence.

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• The tactic was first used effectively by
the Anti-Saloon League, the Women’s
Christian Temperance Union, the KKK
and other anti-alcohol groups. The
technique is still widely used today.

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• Governmental efforts to
promote the belief that alcohol
beverages are harmful and to
censor any evidence to the
contrary have continued for
many decades, often under
pressure from special interest
groups.
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"When news leaked that the two scientists'
report contained language to the effect that
moderate drinking was unharmful,
temperance organizations in the state
immediately rallied and deluged the
legislature and the governor's office with
cries of objection."

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• The National Institutes of Health much
later funded a study that found
moderate drinkers to be less likely to
suffer heart disease, but refused to
allow the Harvard researchers to
publish the results because it
considered them "socially undesirable."

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