Download Ethanol


literally hundreds of types of alcohol
◦ isopropyl
- rubbing
◦ methyl alcohol – methanol or wood alcohol
◦ ethanol


First written “recipe” for making beer – about
3000 BC (Egyptians)
fermenting fruit – sugar dissolved in H20 and
exposed to air – microorganisms (yeasts)
LOVE it


First written “recipe” for making beer – about
3000 BC (Egyptians)
fermenting fruit – sugar dissolved in H20 and
exposed to air – microorganisms (yeasts)
LOVE it
◦ metabolic byproducts of yeast – ethanol and C02


C02 bubbles to the top leaving……
yeasts multiply – alcohol concentration
but only to ~ 10 – 15%
◦ implications:
1.
limited to fruit going bad –
- was there something that we could store to
make alcohol anytime?
1.
limited to fruit going bad –
- was there something that we could store to
make alcohol anytime?
2.
alcohol content could not reach higher than
10 – 15%
- distillation!

described in Arabic manuscripts from the 9th
century

heating fermented mixture


vapor condensed and cooled and resulting
liquid is higher in alcohol content than earlier
fluid (alcohol has lower boiling point than
water and so condenses; repeat cycle
can reach up to 95% ethanol by this process
(although higher than 40% is pretty aversive)


By 17th century – distillation techniques used
whatever grain was cheap
Result:
- grain neutral spirits ( tastes only of alcohol)
- used in research, added to gasoline,
cleaners, solvents and make various
beverages.
- first beverages made from grain neutral
spirits
(gin - filtering distillate through juniper
berries and diluting it with water)

Europe – only fermented beverages were used
until 10th century
◦ distilled wine was first spirits of western World
(used to treat many illnesses including senility)
◦ aqua vitae - “water of life”
◦ Irish-gaelic equivalent- “whiskey”

tricky- it differs in different countries
US – alcohol percentage is denoted by volume
Other countries – use alcohol expressed by
weight (g ethanol/volume)

tricky- it differs in different countries
US – alcohol percentage is denoted by
volume
Other countries – use alcohol expressed by
weight (g ethanol/volume)
Proof – used primarily with distilled
spirits
2x the percentage of alcohol by
volume
ex. 50% alcohol by volume

history: past and present –
◦ being paid with alcohol
Alcohol equivalencies
.05x 12 =.6
.07 x 8.5 =.6
.12 x 5 =.6
.4 x 1.5 = .6

mg% (amount of alcohol in blood by
weight)
◦ usually presented as mg of alcohol/100
ml of blood
◦ legal level of intoxication varies across
states – KY .075%
◦ LD50 ~ .45
wine glass that can hold at
least 750 ml (an entire bottle
of wine)


tiny molecule, moderately polar, especially
soluble in water (and somewhat in fat)
readily crosses bbb so blood and brain levels
are equal
- unique because it requires no digestion
before it is absorbed
- has a lot of calories but no nutritional
value
- absorbed mainly through the
capillaries in small intestines (although
some absorption by the stomach as well)
1.
amount of food in the stomach
1a. type of food – milk or high protein seems to
slow absorption
2. dietary status
malnourished – increases rate of absorption
3.
the rate at which the beverage is consumed
pyloric valve can constrict…..
3a. Strength of alcohol in drink
4.
carbonation
8. mood
5.
body fluid
9. previous history
6.
body fat
7.
gender
10. age
11. weight
12.
13.
other drugs that affect gastric emptying
exercise
14. congener content
15.
carbonation
16.
change in body temperature
distribution is along a concentration gradient
so once you have absorbed alcohol from
stomach and intestines – dissolves in all your
body water.
-
-
also distributed to all target organs
if organ is very vascularized – will reach
equilibrium with alcohol in blood more rapidly
than poorly vascularized
1. brain
2. liver
3. lungs
4. kidneys
-
body begins breaking down alcohol almost
immediately
**approximately 5%-10% leaves the
body
unchanged in sweat, urine, or breath.
-
-
remaining 95% must be metabolized or
chemically altered
alcohol oxidation – combined with O2
occurs with aid of two liver enzymes
Ethanol metabolism
Alcohol
alcohol dehydrogenase
Acetaldehyde


small amount of ADH in stomach (sex
differences – likely)
flushing response
Bosron et. al. 1993 & Crabb 1995
Ethanol metabolism
Alcohol
alcohol dehydrogenase
Acetaldehyde
acetaldehyde dehydrogenase
Acetic acid
CO2 + H2O + energy

ethanol is metabolized at a constant rate
(regardless of dose)

ethanol is metabolized at a constant rate
(regardless of dose)
◦ metabolic tolerance (in absence of liver disease)

2ndary metabolism – liver microsomal
enzyme system (usually not activated unless
chronic etoh)
Biphasic Alcohol Effects Scale
Stimulant scale
Elated
Talkative
Energized Up
Excited
Vigorous
Stimulated
Sedative scale
Inactive
Sedated
Down
Slow thoughts
Heavy head
Sluggish
Difficulty concentrating
telescoping effect

can still be problematic if
◦
◦
◦
◦
drink too quickly
health conditions
over 65
medical interactions -

Injuries
◦ 60% fatal burn injuries, drownings and homicides
◦ 50% severe trauma injuries and sexual assaults
◦ 40% fatal motor vehicle crashes, suicides and fatal
falls

Health problems
◦ sleep disorders, depression, stroke, STD, etc

Alcoholism costs the nation $150 Billion / annum

many organ systems are affected including
◦ liver- fatty liver and cirrhosis
◦
◦
◦
◦
pancreas - pancreatitis
heart - cardiomyopathy
immune function - compromised
endocrine function - altered



“low-risk” drinking – no more than 4
drinks/day AND no more than 14/week (men)
3 drinks/day and no more than 7/week
(women)
can still be problematic if
◦
◦
◦
◦
drink too quickly
health conditions
over 65
medical interactions -


like other CNS depressants (sedative
hypnotics), it depresses CNS activity
messy drug – affects all major
neurotransmitter systems, lipid membranes

deficits in

Wernicke’s encephalopathy
◦ problem solving, short-term memory, visual
spatial abilities, balance and postural stability
◦ characterized by confusion, ocular disturbances
 role of thiamine

Korsakoff’s disease
◦ typically considered a more serious (and often
permant) memory impairment (both anterograde
and retrograde amnesia) and cognitive deficit;
characterized by confabulation

GABA
◦ GABA A receptor –
◦ indirectly enhances GABA function
◦ RO 15-4513 –
 reduces sedative effects of ETOH

reduces sedative effects of ETOH (shortterm)

does nothing to reduce LD 50

increases risk of seizure

GABA – GABAA receptor subtype
◦ allosteric effect;
◦ GABA receptor complex
How might ETOH work on GABA receptors?
Extracellular
Ion channel pore
?
Cl-
Intracellular
Cl-
Extracellular
Ion channel pore
barbiturates
Ethanol
benzodiazepines
Cl-
Intracellular
?
Cl-
Ethanol enhancement of responses mediated
by GABAA receptors
Flunitrazepam
Pentobarbital
Ethanol
GABAA synaptic responses
from rat hippocampus are
enhanced in magnitude and
duration by flunitrazepam (a
benzodiazepine), pentobarbital (a barbiturate), and
by ethanol.
All three drugs share similar
pharmacological effects:
sedation and CNS
depression

glutamate receptors
◦ NMDAR function

compensatory mechanisms

ethanol has multiple other effects on NTs and
membranes including
◦
◦
◦
◦
dopamine
5HT
norepinephrine
adenosine

psychological dependence

chemical dependence

methanol
◦ colorless and little taste if added to other
ingredients
◦ sometimes added to bootleg
◦ readily available in solvents, fuels, paint removers,
windshield wiper fluid, dry gas, etc.
◦ can produce significant delayed toxicity; optic
nerves particularly vulnerable
Methanol metabolism
Methanol
alcohol dehydrogenase
Formaldehyde
acetaldehyde dehydrogenase
Formic Acid
CO2 + H2O + energy

sweet tasting;
found in antifreeze;
metabolites toxic to kidneys

treatment - alcohol



pharmacotherapy
◦ disulfiram (Antabuse)
 available for ~ 50 years
Ethanol metabolism
Alcohol
alcohol dehydrogenase
Acetaldehyde
acetaldehyde dehydrogenase
Acetic acid
blocks breakdown of
acetaldehyde (5 – 10 fold
CO2 + H2O + energy

pharmacotherapy
◦ disulfiram (Antabuse)
 available for ~ 50 years
 premise:
 benefits and disadvantages

Symptoms
◦
◦
◦
◦
◦
◦
head, neck and chest flushing
throbbing headache
nausea and vomiting, diarrhea
weakness, dizziness, anxiety
orthostatic hypotension
sweating, palpitations, itching

other food stuffs with enough alcohol to
produce effect
◦ mouthwash, flavorings,

inhibits cytochrome P450 enzyme activity –
consequences: potential drug interactions
(interfering with other drug metabolism
including some BZ, caffeine, some
anticonvulsants)

naltrexone (Revia)
◦ approved for use in 1995 by FDA
◦ extended release naltrexone (Vivetrol)
 approved in 2006 –
 more recently
A brief history of acamprosate
since its discovery in France
1975 - synthesized as potential GABAmimetic anxiolytic
1979 - first animal studies on alcohol preference
1984 - first positive data in alcoholism from France
1988-96 - positive clinical trials throughout Europe
1997-02 - accepted throughout Europe, Australia
(37 countries), etc etc.
2002 - declared non-approvable by the FDA