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1. CNS Pharmacology
CNS Depressants II/Drugs of Abuse IV-
Ethanol
Prepared and Presented by:
Marc Imhotep Cray, M.D.
Professor BMS and Pharmacology
Recommended Reading:
Sedative Hypnotic Drugs
Formative Assessment
Practice question
Clinical:
E-Medicine Article
Alcoholism
NIAAA Home

2. Introduction
 The objective of this lecture is to review
the pharmacology and neurobiology of
Alcohol, Alcohol Abuse and Alcoholism
Presentation references and Resources for further research and study of the subject:
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
http://www.alcoholmedicalscholars.org/
2

3. Introduction(2)
 Alcohol is most widely
used drug in the world,
and almost no other
substance has been as
comprehensively studied
as much as alcohol, not
only because it is one of
the most commonly
abused drugs, but also
because of its unique and
interesting pharmacology http://www.uspharmacist.com/index.asp?show=article&page=8_1137.htm
3

4. Introduction (3) Highlighted Focus
 Outline
 The first part of the lecture will review
the pharmacokinetics of alcohol - aspects
of absorption, distribution and metabolism -
and highlight the factors contributing to the
large variability in alcohol pharmacokinetics
4

5. Introduction (4) Highlighted Focus
 The second part of the lecture will review
the pharmacodynamics of alcohol, focusing
on the CNS effects, discuss aspects of alcohol
tolerance, why alcohol is an addictive
substance, what neurotransmitter systems it
affects, and
 Organ Systems Pharmacological Effects /
organo-pathology
5

6. Alcohol Pharmacokinetics
Absorption
 Ethanol is rapidly absorbed from stomach, small
intestine and colon but the rate of absorption from
the stomach is influenced by the food content
 Ethanol evenly distributed throughout all fluids and
tissues, after absorption
 Placental permeability ensures access of ethanol to
the fetus
Also see notes page
6

7. Alcohol Pharmacokinetics
Distribution
 The distribution of alcohol is into total body water
 There are gender differences in body composition,
with women having a lower proportion of total body
water compared to men, even if they have same
weight
 Thus, if a woman and a man, who both have same
weight, consume the same amount of alcohol, the
woman would achieve higher blood alcohol levels
compared to the man
7

8. Alcohol Pharmacokinetics
Metabolism:
 Most ethanol molecules are oxidized, with the
rate of oxidation insensitive to ethanol
concentration (zero-order kinetics).
 Most ethanol oxidation occurs in the liver and
is catalyzed by alcohol dehydrogenase.
 The product is acetaldehyde which is then
converted to acetyl CoA
Also see notes page
8

9. Alcohol Pharmacokinetics
Metabolism(2):
 To a limited extent, in humans, ethanol
is also oxidized by mixed function
oxidases in liver microsomal
membranes
 Genetic polymorphisms occur for both
alcohol and aldehyde dehydrogenase
Also see notes page
9

10. Alcohol Pharmacokinetics
Alcohol Metabolism(3):
 The removal of ethanol (alcohol) through oxidation by
alcohol dehydrogenase in the liver from the human
body is limited
 Hence the removal of a large concentration of alcohol
from blood may follow zero-order kinetics
10

11. Alcohol Pharmacokinetics
Alcohol Metabolism(4):
 Also the rate-limiting steps for eth common with
other substances
 For instance, the blood alcohol concentration can be
used to modify the biochemistry of methanol and
ethylene glycol
 In this way oxidation of methanol to toxic
formaldehyde and formic acid in the human body can
be prevented by giving an appropriate amount of
ethanol to a person who has ingested methanol
 Note that methanol is very toxic and causes
blindness and death
 A person who has ingested ethylene glycol can be
treated in the same way
11

12. Alcohol Pharmacodynamics
 ETOH apparent stimulatory
effects result from depression of
inhibitory control mechanisms in
the brain
 Characteristic responses to
alcohol include euphoria,
impaired thought processes and
decreased mechanical efficiency
Also see notes page for Concentration-
Response relationships
12

13. Alcohol Pharmacodynamics
ETOH Tolerance
Tolerance (definition) also see notes page for significance
 Tolerance can be defined as the phenomenon of decreased effect
with prolonged exposure to a drug.
 When the tolerance occurs within the time course of a single
exposure to the drug it is called acute tolerance.
 Chronic tolerance occurs over repeated uses of the drug.
 Tolerance can be metabolic (or pharmacokinetic) - due to
induction of enzymes - for example, barbiturates
 Tolerance can also be pharmacodynamic - due to physiological
adaptation of the body to the presence of the drug - for
example, most drugs of abuse
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14. ETOH Mechanism of Action
 Ethanol enhances GABA-mediated
synaptic inhibition
 Ethanol inhibits glutamate-
activated ion channels (excitatory)
(predominately the NMDA glutamate
receptors at mild intoxicating ethanol
concentrations.)
14

15. ETOH Mechanism of Action(2)
 Ethanol may also act by
affecting 5-HT3
receptors.
 Activation of these
receptors results in
excitation of inhibitory
interneurons.
 Serotonin's action at
the 5-HT3 receptor
subtype is enhanced
by ethanol
Modified from
http://www.chemcases.com/alcohol/alc-07.htm 15

16. Alcohol Neuropharmacology
and Reinforcement
Current research supports the idea
that initial exposure to alcohol
activates the reward pathway
releasing DA in the Nucleus
accumbens, which in turn sends
messages to the cortex to be coded as
experiences and perhaps as
memories. Once coded, these
experiences can influence, i.e.
promote, subsequent behavior such
further alcohol intake. Since these
"memories" of drinking are linked to
the environment in which the drinking
took place, it is not surprising that the
environmental cues can be important
in guiding subsequent drinking
behavior.
Also see notes page
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17. ETOH Drug-Drug Interactions
 Ethanol enhances CNS depression caused by
other sedative-hypnotics.
 Ethanol interferes with metabolism of drugs that
utilize the same hepatic oxidase system.
 For example the clearance of phenytoin is prolonged
due to competition with ethanol for the same mixed-
function hepatic oxidase system.
 By contrast, with chronic use, ethanol causes induction
of hepatic metabolizing enzymes and can, in this case,
increase clearance of many drugs (e.g. phenytoin
(Dilantin), Tolbutamide (Orinase)).
17

18. ETOH Drug-Drug Interactions(2)
 Chronic consumers of ethanol are
susceptible to acetaminophen
hepatoxicity probably due to
accumulation of toxic metabolites and
glutathione depletion.
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19. ETOH Contraindications
Contraindications for ethanol use:
 Hepatic disease,
 gastrointestinal ulcer,
 cardiac or skeletal myopathy,
 pregnancy,
 individuals previously addicted to
ethanol
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20. ETOH Gross and Histopathology
Webpath Drug Abusr Tutorial Slides
 Normal liver, gross.
 Fatty change of liver, microscopic.
 Micronodular cirrhosis of
liver, gross.
 Micronodular cirrhosis of
liver, microscopic.
 Hepatocellular carcinoma, liver
with micronodular cirrhosis, gross.
 Esophageal varices, gross.
 Wernicke's disease, hemorrhages
in the mammillary bodies, gross.
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21. ETOH Organ Systems: Pharmacological
and Pathological Effects
Central Nervous System
 Acute effects
 Ethanol is a CNS depressant
 Depression of inhibitory CNS systems may be responsible for apparent
stimulation that is observed initially.
 With moderate intoxication, mood swings, outgoing, and expansive
behavior occur
 General impairment of statements function becomes evident with increased
intoxication
 Large amounts of ethanol may lead to severe (even lethal)
respiratory depression
 Chronic effects
 Chronic and excessive ethanol use results in brain
damage, memory loss, sleep disturbances.
 Increased risk of seizures
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22. Ethanol: Chronic CNS Effects
Neuropsychiatric disturbances
including Wernicke's
encephalopathy
 (Wernicke's encephalopathy is due to a
nutritional thiamine deficiency
 Common causes include Alcohol,
chemotherapy-associated prolonged
vomiting with lack of nourishment,
eating disorders, elderly patients who
had been living alone and who have not
been maintaining adequate nutrition
[Wernicke's may be precipitated in the hospital by
glucose administration to patients who is deficient
in thiamine]
" Wernicke-Korsakoff
encephalopathy.
Note pigmentation of gray matter around
third ventricle. Occurs with Vitamin B1
deficiency, most often in chronic
alcoholics.“
image from educational materials (pathology) University
of Texas (Houston)
22

23. ETOH Organ Systems: Pharmacological
and Pathological Effects
 Cardiovascular System
 Acute Effects:
 Ethanol causes a generalized vasodilation (due to both central
effects and effects on the vascular bed)
 Moderate doses, however, can cause a vasoconstrictive effect in
the heart and brain.
 In severe intoxication, cardiovascular depression occurs
secondary to central vasomotor effects and respiratory
depression.
 Chronic Effects:
 With chronic use, significant and irreversible damage to the
myocardium may occur.
 This effect is one of the most important causes of cardiomyopathy.
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24. ETOH Organ Systems: Pharmacological
and Pathological Effects
Gastrointestinal Tract
 Ethanol increases gastric secretions by (a) direct action on
the stomach (may increase gastrin), (b) psychological
mechanism (if the individual likes it), (c) stimulating
sensory endings in the buccal and gastric mucosa
 At high ethanol concentrations (80 proof [40% alcohol]),
direct gastric mucosal irritation occurs resulting in
congestive hyperemia and inflammation.
 These concentrations can result in an erosive gastritis.
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25. ETOH Organ Systems: Pharmacological
and Pathological Effects
Liver
 Chronic use of ethanol
promotes hepatic
cirrhosis and is
associated with an
increased risk of cancer
and drug toxicity
(acetaminophen).
 Acute use probably
does not produce
lasting hepatic changes.
From:
http://library.med.utah.edu/WebPath/TUTORIAL/DRUG/DRUG012.html
Micronodular cirrhosis of liver, gross.
25

26. ETOH Organ Systems: Pharmacological
and Pathological Effects
Teratogenic effects:
 Fetal alcohol syndrome
consists of many dysfunction.
including low IQ, microcephaly,
facial abnormalities
 Ethanol appears to be the most
frequent cause of
teratogenically-caused mental
deficiency in the West.
See: http://www.cdc.gov/ncbddd/fas/
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27. ETOH Organ Systems: Pharmacological
and Pathological Effects
Sexual Functions:
 Inebriation interferes with coitus, decreasing sexual
responsiveness in both men and women.
 Chronic ethanol abuse may lead to impotence, sterility,
testicular atrophy, and gynecomastia.
 Feminization in males is due to both hyperestrogenization
with reduced rate of testosterone production (due to
hepatic damage) and by ethanol's induction of hepatic
metabolizing enzymes, increasing the rate of testosterone
inactivation.
Renal: Increased diuresis due to reduction in ADH and
hence a decrease in tubular water reabsorption.
27

28. ETOH and Disulfiram
 Disulfiram
 Disulfiram (Antabuse) inhibits aldehyde
dehydrogenase which results, following ethanol
ingestion, in an increased acetaldehyde
concentration.
 The resulting "acetaldehyde syndrome" consists
of facial flush, headache, hypotension, marked
uneasiness, confusion, vomiting and other
symptoms.
 These unpleasant effects are the basis of the use of
disulfiram as part of the treatment of chronic alcoholism.
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29. 29

30. Finish-THANK YOU
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31. Drugs and Neurotransmitters & Mental
Disorders Interactive Tutorials and
Animation Learning Tools
 Psychotropic Medications and Neurotransmitters
Wisconsin Online
 Alcohol and the brain from PBS
 The Effect of Drugs and Disease on Snaptic
Transmission Harvard Education
 Nicotine Patch by Nucleus Communications
 GABA Inhibition of Glutamate Bay Area Pain Medical
Associates
 Acute Pain Bay Area Pain Medical Associates
 How Drugs Affect Neurotransmitters INMHA
31

32. Drugs and Neurotransmitters & Mental
Disorders Interactive Tutorials and
Animation Learning Tools
 Schizophrehia UNIVERSITY OF CENTRAL LANCASHIRE
 Epilepsy UNIVERSITY OF CENTRAL LANCASHIRE
 Pharmacologic Action of Meth RnCeus.com
 How is Pain Produced University of Edinburgh
 How Much Alcohol can YOU TAke BBC
 The Brain: Understanding Neurobiology Through the Study of Addiction
National Institutes of Health
 The Science of Addiction University of Utah, Genetic Science Learning
Center
 Stimulants and Antidepressants Dr. Ian Winship of the University of
Alberta
 Tranquilizers and CNS Depressants Dr.Ian Winship of the University of
Alberta
 Genetics of Addiction Genetics Science Learning Center
32

33. eMedicine Articles on Addiction
 Alcohol-Related Psychosis
 Alcoholism
 Amphetamine-Related
Psychiatric Disorders
 Caffeine-Related Psychiatric
Disorders
 Cannabis Compound Abuse
 Cocaine-Related Psychiatric
Disorders
 Hallucinogens
 Inhalant-Related Psychiatric
Disorders
 Injecting Drug Use
 Nicotine Addiction
 Opioid Abuse
 Phencyclidine (PCP)-Related
Psychiatric Disorders
 Sedative, Hypnotic, Anxiolyti
c Use Disorders
 Stimulants
 Substance-Induced Mood
Disorders: Depression and
Mania
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