Alcohol
Barbiturates
Steroids
GABA
Benzodiazepines
Ethanol
GABA receptor is a pentamer made up five subunits
(a, b and g) arranged around a ion channel.
Chemical structures of three commonly
used forms of alcohol
Alcohol history
CNS effects
Alcohol metabolism
Behavioral effect
Complications
Beneficial effects
Alcohol History
Alcoholic beverages date back to the very early part of man's
history. Many archaeologists believe that beer made from grains
and wines made from grapes have existed for more than 10,000
years
Throughout its history, alcohol has been used socially for
many diverse purposes, such as calming feuds, giving
courage in battle, celebrating festivals, and seducing lovers.
The Celts, Ancient Greeks, the Norse, Egyptians, and
Babylonians all have records of production and consumption
of alcoholic drinks
The ancient Egyptians have
passages within their texts
referring to the social problems
associated with drunkenness,
and a 1600 BCE Egyptian text
contains 100 medical
prescriptions calling for the use
of alcohol
The first documented distillation of alcohol was the conversion
of wine into brandy during the Middle Ages at a medical school
in Salerno, Italy. The new beverage became known in Latin as
Aqua vitae “the water of life”. Brandy became the primary
distilled liquor in Europe until the middle of the seventeenth
century. At that time the Dutch perfected the process of distilling
liquor and flavoring it with juniper berries. A new alcoholic
beverage was born: gin.
Gin became popular in Europe especially in the poor class
of people because it was easily produced, cheaper than brandy
and fasting acting than wine. By the mid-1700s, alcohol abuse
was the major social problem.
In 1620 alcohol played a pivotal role in the earliest days of settling
The American Colonies.
During the 1700s the social focus for the American communities
was the tavern which was regularly attended as the local church.
In the nineteenth century the average alcohol consumption per
capita was 5 drinks a day and it was common to take “whiskey
breaks” at 11 a.m. and 4 p.m.
In 1830 a new movement, the “Temperance movement” grew
across the nation. Its goals originally focused on the moderation,
not the prohibition, of alcohol. Over time the moderation
Shifted to a total prohibition and in 1851 the first prohibition law
was passed in Maine and other 12 states.
Alcohol history
CNS effects
Alcohol metabolism
Behavioral effect
Complications
Beneficial effects
CNS Effects
Alcohol depresses the CNS. In the
19th century it was used as an anesthetic.
Problems: Duration too long, could not be
controlled. The effective dose for surgical
analgesia is closed to the lethal dose.
MECHANISM OF ACTION:
ACTS ON GABA RECEPTORS: enhances GABA function and Cl- ion flow.
-
What are the consequences of Cl influx?
Cl- influx causes an hyperpolarization
of the membrane
Hyperpolarization is a state in which
the neuron has a more negative
voltage than the resting potential.
The hyperpolarization causes inhibition
By inhibiting the inhibitory input on a neuron, ethanol
may increase the activity on the neuron.
For example ethanol increases the activity of cerebellar
Purkinje cells; this leads to impaired coordination.
ATAXIA IS SEEN.
No balance between inhibitory and excitatory input.
The cerebellum regulates the timing of
movements and integrates sensory and
motor function to provide smooth,
coordinated body movements
Impaired Cerebellar Function
Errors of trajectory, e.g. dysmetria (inability to control the
range of movement of muscular acts) and ataxia (loss of the
ability to coordinate muscular movement)
Inacurate movements resulting in oscillations and tremor (an
unintentional rhythmical alternating movement of muscles)
Decreased resistance to passive movement
Dysarthria, difficulty with speaking, nystagmus
Impaired Cerebellar Function
Nystagmus
Rotation-induced lateral
nystagmus
Alcohol acts also on NMDA receptors and on glutamate release.
Inhibits the NMDA receptors and reduces the release of
glutamate in brain areas like hippocampus, that leads to the
amnesia that occurs for events that take place during intoxication
(e.g. blackout).
All rewarding things activate the
forebrain dopamine system
Main effect of alcohol (A), fearful facial emotion (B), and the interaction between them (C)
on regional brain activation
Subjective feeling of
being intoxicated
correlates best with
activity in the ventral
striatum.
Lessens the limbic
(emotional) response
to threatening faces
which may contribute
to risky decision
making during
intoxication
Copyright ©2008 Society for Neuroscience
Gilman, J. M. et al. J. Neurosci. 2008;28:4583-4591
This effect occur at blood alcohol concentrations as low
as 0.03%, (social drinkers).
In alcohol-dependent rats, glutamate release is
dramatically increased at about 10 h after withdrawal of
alcohol.
The time course of the CNS hyperexcitability and the
seizures that are typical of the alcohol abstinence
syndrome matches the pattern of increased
glutamate release during withdrawal.
Alcohol history
CNS effects
Alcohol metabolism
Behavioral effect
Complications
Beneficial effects
Alcohol intake is self-regulated
Absorption
20 % of ingested alcohol absorbed in the stomach
80% absorbed in the upper small intestine
Absorption is most rapid when the stomach is empty.
Accelerated gastric emptying also accelerates the rate of
alcohol absorption due to rapid passage of alcohol into the
small intestine where the absorption is more rapid
Gastric emptying is decreased by food in stomach.
The presence of food in the stomach slows absorption of alcohol
And prevents the sharp peak in blood level.
Absorption is by passive diffusion and proceeds as long as
the alcohol concentration in intestine exceeds that in the
blood.
Absorption is more rapid from carbonated drinks (champagne).
If alcohol is taken slowly it can be metabolized as fast as is
being absorbed.
Absorption is generally complete in 1-2 hours.
High concentration drinks (greater than 30%) e.g. whiskies and
brandies, retards the absorption because they are direct
stomach irritants and slow stomach emptying.
This irritating effect is often experienced as acute alcoholic or
“morning after” gastritis and is synergistic with aspirin and
Ibuprofen in this action on stomach.
Patients treated for arthritis need to be especially careful of this.
Also taking an aspirin the morning after for the hangover could
Make things worse due to prior stomach irritation.
Some people take an aspirin prior to drink to prevent the
hangover.
Aspirin actually inhibits an enzyme in the intestine that
metabolizes some of the alcohol prior to absorption.
Therefore taking aspirin prior to drinking has been shown to
increase blood alcohol concentration faster and higher.
This effect is even more pronounced in females
Distribution
Alcohol dissolves in the blood and is distributed by the blood stream to
the tissues
Alcohol becomes distributed in the blood and water of the body. Tissues
rich in water (muscle) take up more alcohol from the blood than those
rich in fat.
A lean person has a greater muscle bulk which provides a larger volume
of distribution for the alcohol than an obese counterpart of similar
weight.
Women normally have smaller body mass than man and they have a
higher proportion of body fat. As a result of these two factors women
have lesser volume of water in the body into which the alcohol can
distribute. That is why women usually achieve a higher Blood Alcohol
Concentration (BAC) after drinking the same amount
of alcohol.
Elimination
5% is excreted in the breath
5%
5% is excreted in the urine
90% is broken down by the liver enzymes
Alcohol
Alcohol
Dehydrogenase
CH3CH2OH
Breath
Acetaldehyde
CH3CHO
Acetaldehyde
dehydrogenase
Acetic acid
CH3COOH
Oxidation
reaction
Carbon dioxide
CO2 + H2O +
energy
Henry’s Law: the concentration of a gas in the air
immediately above a liquid is proportional to its
concentration in the liquid. In the lungs there is an
exchange between the alcohol in the blood and the alcohol
in the air within the lungs.
In the 'deep lung' region there is an equilibrium, situation
where the concentration of alcohol in the lung air is
proportional to the concentration in the blood. This breath
to blood ratio used in breath test analyses states that 2100
milliliters of breath will contain the same weight of alcohol
as does 1 milliliter of blood.
Alcohol history
CNS effects
Alcohol metabolism
Behavioral effect
Complications
Beneficial effects
The behavioral effects of consuming alcohol in more than
very moderated quantity, range from the relatively harmless
effects of excitement, slurred speech, to behaviors that have
the potential for causing great harm: uncoordinated
movement, sensorimotor difficulties etc..
Alcohol is a CNS depressant and at low doses has a double –
negative effect; releases the cerebral cortex from its inhibitory
control over subcortical system in the brain. The result is an
illusion of stimulation.
Double-negative effect:
The cortex controls behavior by GABA receptor-dependent
inhibition.
At low doses alcohol inhibits the neural systems that maintain
your ability to control of behaviors that you would prefer not to
exhibit, i.e. punished behaviors.
At high doses more areas of the brain are inhibited,
thus more behaviors are released from inhibition
Blood Alcohol Concentration, BAC:
BEHAVIOR RELATIONSHIP
0.03% DULL AND DIGNIFIED
0.05% DASHING AND DEBONAIR
0.1% DANGEROUS AND DEVILISH
0.2% DIZZY AND DISTRUBING
0.25% DISGUSTING AND DISHEVELED
0.3% DELIRIOUS AND DISORIENTED
0.35% DEAD DRUNK
0.4% DEAD
Death is due to respiratory failure due to depressed medulla.
Vomiting center activated at blood alcohol concentration
(BAC) of 0.12% can be overcome with slow, steady drinking.
If the vomiting center is depressed a person can then drink up
to the lethal concentration.
TOLERANCE AND WITHDRAWAL
Chronic alcohol abuse leads to both tolerance and physical
dependence.
The effects of alcohol are significantly reduced when the drug is
administered repeatedly.
Chronic alcohol use increases the number of liver enzymes that
metabolize the drug.
Neurons also adapt to the continued presence of alcohol by
making compensatory changes in cell function.
Behavioral tolerance, you learn to adjust your behavior under
the influence of alcohol.
In the absence of alcohol (left), GABA opens the Cl- channels and produces an IPSP.
Alcohol enhances the effect of GABA (middle), allowing more Cl- to flow into the cell and
producing more inhibition.
In alcohol dependence (right), both GABA and alcohol have smaller effects on GABA receptors.
This results in less Cl- influx and less inhibition. Therefore, throughout the brain there is more
activation of neurons that may lead to anxiety and seizure susceptibility.
After three doses of
Alcohol (a,b,c),
signs of intoxication
(incoordination in
the balance beam
test) appeared
during the rising
phase of blood
Alcohol levels at
about 0.20%. As
blood alcohol was
declining the
subject felt “sober”
at higher
concentration
(about 0.25%)
showing acute
tolerance.
Test dose given at time
zero BEFORE and
AFTER 7 days of
drinking.
Pharmacological
tolerance starts
quickly.
Repeated alcohol
consumption leads to a
rapid decrease in the
blood alcohol
concentration
Withdrawal is a sign of physical dependence.
The intensity and duration of abstinence signs are dependent on
the amount and duration of drug taking.
Withdrawal from repeated heavy drinking over months or years
produces an intense abstinence syndrome that develops within
a few hours after drinking, stops and may continue over 2 to 4
days.
WITH CHRONIC USE: Tremors, hallucinations, seizures
and delirium.
HANGOVER: is due to reversible toxic effects of ethanol on
the brain, gastro-intestinal tract and liver.
The clinical features are headache, tremor
and nausea.
Alcohol history
CNS effects
Alcohol metabolism
Behavioral effect
Complications
Beneficial effects
Nutritional complications
.
Neurological diseases caused by nutritional
changes due to alcohol consumption.
PELLAGRA: is due to deficiency of niacin
(vitamin B3), low tryptophan, comes with maize
diets, is characterized by
diarrhea, dermatitis and
dementia .
EXCESSIVE ALCOHOL CONSUMPTION is associated with
vitamin B1 (Thiamine) deficiency. Leads to degeneration of
mammilary bodies and anterior nucleus of the thalamus.
KORSAKOFF’S SYNDROME: is a chronic, irreversible
neurological disorder.
Results from the poor diet of the chronic alcoholic rather than
directly from the drug itself. The alcohol provides so many
calories that the alcoholic fails to eat foods that provide a
sufficient supply of vitamin B1. The deficiency is at least partly
responsible for the brain damage and amnesia caused by cell
loss in the medial thalamus and the mammillary bodies of the
hypothalamus.
Clinical features: impairments of short term memory, inability to
learn new information.
Physical complications
GASTRO INTESTINAL TRACT: alcohol as a direct irritant to
the mucosa of the
esophagus, stomach and
small intestine and impairs
the absorption of many vital
nutrients.
Causes gastritis, duodenitis,
peptic ulcer.
CARDIOVASCULAR SYSTEM: hypertension, cardiomyopathy
(increase in the size of heart muscle)
LIVER: causes fatty liver,
alcoholic hepatitis, alcoholic
cirrhosis.
The fatty liver is caused by the
accumulation of triglycerides
inside the liver. When alcohol is
present is metabolized first
leaving the fat for storage. The
condition is reversible as soon as
you stop drinking.
Alcoholic cirrhosis is caused by
death of liver cells that stimulates the
formation of scar tissue. When the
scar tissue develops, blood vessels
carrying oxygen are cut off, that
leads to cell death.
Alcohol is a peripheral dilator, because of its metabolite
acetaldehyde, so the vessels near the skin surface enlarge,
and you feel warmer. In fact, there is a heat loss.
E.g. red nose
Jeronimus Bosch (1450-1516
Hertogenbosch) Copy of the
Bacchus singers
Elimination
5% is excreted in the breath
5% is excreted in the urine
90% is broken down by the liver enzymes
Alcohol
Alcohol
Dehydrogenase
Acetaldehyde
Acetaldehyde
dehydrogenase
CH3CH2OH
CH3CHO
Breath
Vasodilation
Acetic acid
CH3COOH
Oxidation
reaction
Carbon dioxide
CO2 + H2O +
energy
Alcohol inhibit the
Antidiuretic Hormone
(ADH) which acts
to reabsorb water in the
kidneys prior to
elimination in the
urine. As a result urine is
more diluted and more
copious.
At the peak of blood
alcohol concentration
water is retained
resulting in swollen
fingers, hands and feet.
Genetic component?
Tolerance and dependence have been show to be
independently controlled by specific and different
genes.
Rats bred for alcohol preference show a relative
serotonin deficiency.
Rats showing some spontaneous alcoholic preference
can be bred to produce off spring in which this
preference will progressively increase over several
generations until rats will ingest ethanol with unlimited
access in the sufficient quantities to produce physical
dependence.
Alcohol and pregnancy
A woman who drinks during pregnancy runs the
risk that her child will be born with the FETAL
ALCOHOL SYNDROME (FAS)
FAS= Retarded growth that begins
before and continues after birth.
Pattern of facial abnormalities as
short palpebral fissures,short nose,
flat face,thin upper lip.
Impairment of the CNS such as
mental retardation, motor
abnormalities, tremor or
hyperactivity.
Is correlated with the amount of alcohol consumed
The minimal amount of alcohol necessary for inducing the
syndrome has not been determined, but most of the evidence
suggest that it can occur when over than one ounce of ethanol
is consumed per day.
Animal studies indicate that the timing of alcohol consumption is
also relevant, with the fetus being more susceptible to the
teratogenic effects of alcohol early in gestation.
Human studies, however, show a susceptibility of infants to
maternal alcohol consumption during the third trimester due to
the fact that this is the time the brain is growing.
Family problems: contributes to
33% of divorces
33% of child abuse
“Divorce” by Fuad Kapidzic
In USA alcohol is the third largest
health problem and reduces life expectancy by 12 years.
Is associated with: 65% of serious head injuries
50% murders
40% road traffic accidents
30% fatal accidents
30% domestic accidents
Adverse effects
There is a strong correlation between heavy drinking in humans
and cancer of mouth, throat and esophagus. May be synergistic
with tobacco smoking.
The risk is doubled with alcohol use, 15X with alcohol/cigarettes
together.
Myocardial infarcts are associated with heavy drinkers who
suddenly stop.
3 or 4 drinks/day correlates with high systolic and diastolic blood
pressure.
Alcohol and drug interactions
Drug
Antidepressants
(ex: Elavil)
Prescribed Purpose
Used to treat
depression and
other forms of
mental illness
Antihistamines
(ex: Benadryl)
Used to treat allergic
symptoms and
insomnia
Antipsychotic
medications
(ex: Thorazine)
Used to diminish
psychotic
symptoms such as
delusions and
hallucinations
Interaction
- increased sedative effects
- may decrease
effectiveness of antidepressant
- potential for dangerous
rise in blood pressure
- intensified sedation
- excessive dizziness
- intensified sedation
- impaired coordination
- potentially fatal
breathing difficulties
Drug
Narcotic pain
relievers
(morphine,
codeine, Darvon,
Demerol)
Sedatives and
hypnotics
(Valium,
Dalmane, Ativan,
sleeping pills)
Prescribed purpose
Interaction
Used to alleviate
moderate to
severe pain
- intensified sedation
- increased possibility of
a fatal overdose
Used to alleviate
anxiety and
insomnia
- severe drowsiness
- depressed cardiac and
respiratory functions
- increased risk of coma
or fatality
Alcohol and birth control
Studies have shown that taking the birth control pill affects the
way women's bodies process alcohol, leading to higher blood
alcohol concentrations (BAC) and intensifying the effects of
intoxication.
Drinking alcohol can indirectly decrease the pill's by accelerating
its metabolism.
Alcohol and sleep
The quality of the sleep is
fragmented during the second half
of the sleep period.
“The nightmare”
by Henry Fuseli
Alcohol increases the number of times you awaken in
the later half of the night when the alcohol’s relaxing
effect wears off.
Prevents you from getting the deep sleep and REM
sleep.
Alcohol history
CNS effects
Alcohol metabolism
Behavioral effect
Complications
Beneficial effects
Less risk of coronary heart disease due to the alcohol
ability to increase blood levels of high density lipoprotein,
resulting in a lower level of low density, more dangerous
lipoprotein.
Low level consumption may reduce cholesterol levels.
Appetite stimulant and an effective therapy for anorexia
nervosa. Alzheimer’s disease.
Red wine (white helps a little) tends to inactivate viruses
causing polio, herpes simplex, and some gastrointestinal
disorders.
AGED: “the milk of old age”. Facilitates social interactions
of elderly. It also anesthetizes some of their aches and
pain.
Prolongs life? Moderate drinkers have longest lifespan
of both heavy drinkers and abstainers.
• Shorter stay = more drinks/hr
• Drinking alone = more drinks/hr
• Rhythm that equals the heart
rate = more drinking
• Lyrics: sad songs = more
drinking
• More men than women = more
drinking
• Live band = more drinking
• Action photography =
more drinking
Summary
Alcohol acts as a depressant
in the brain via GABA
receptors
Alcohol causes changes in the
normal behavior
Heavy drinking causes
neuronal, fetal and
physiological diseases
“Bacco” by Caravaggio