1. Sedatives: Anxiolytics & Alcohol
Lesson 19

2. Sedative/Anxiolytic Drugs
GABAA agonists (Cl- channels)
Barbiturates
e.g., phenobarbitol, secobarbitol
Benzodiazepines
e.g., valium, librium
Alcohol
ethanol (ETOH)
Buspirone (Buspar)
5HT1A partial agonist ~

3. ALCOHOL Family of structurally similar substances Methyl: Methanol
Isopropyl: Isopropanol (rubbing)
Ethyl: Ethanol (ETOH); beverage
Ethanol Synthesis
Starch + Sugar + YeastCO2 + ETOH
Self-limiting concentration: 12-14%
No accepted medical use
high abuse potential ~

4. Pharmacokinetics Routes: All routes effective
Inhalation - effective but risky
P.O. most common route ~
Solubility
highly water soluble
somewhat lipid soluble
Small & un-ionized
crosses all membrane barriers
Distributes to all tissues ~

5. Pharmacokinetics: Metabolism
Per os absorption
20% stomach / 80% small intestine
Metabolized in liver (90-98%)
Rate slow, fixed: 1/2 oz./hr
Regardless Blood Alcohol Level (BAL)
also coffee, cold shower, etc.
BAL reduced by time or dialysis only
No antidote for overdose ~

6. Ethanol Metabolism ETOH CO2 H2O Energy Acetaldehyde Acetate Alcohol
Dehydrogenase
Aldehyde
Dehydrogenase
Acetyl
CoA
CO2
H2O
Energy
ETOH
Acetaldehyde
Acetate

7. Metabolism: Sex Differences
Same dose  greater effects in females
Weight
Muscle / Fat
New evidence: enzymes
males: ETOH dehydrogenase in stomach
higher 1st pass metabolism ~

8. Alcohol Dose Response Chart
BAL Effect Bottles of beer in 1 hr
M F
.05 euphoria, disinhibition, ¯ coordination
.10 *legally drunk, ¯ coordination, ­ drowsiness
.15 significantly ¯ reaction time
.25 “smashed”, staggering, severe motor ¯
.35 surgical anesthesia, possible death 5-10 hrs
.4-.6 lethal dose
1 quart whiskey
.08

9. Undesirable Effects General Depression Interferes with REM sleep
Withdrawal & Seizures
Blackouts
Wernicke-Korsakoff Syndrome
Severe memory loss
Thiamine deficiency
Fetal Alcohol Syndrome
morphological & cognitive effects ~

10. Effects on Liver Fatty Liver free fatty acids enlarged reversible
Normal
Fatty Liver
free fatty acids
enlarged
reversible
Hepatitis
cell damage
regeneration w/ abstinence
Cirrhosis: irreversible
cell death
fibrous scar tissue
decreased metabolism  toxicity ~
Fatty
Cirrhosis

11. Other Effects Effects on Muscle cells Impairment Degeneration
Depressed immune function
increased probability of sickness
Reproductive function
males  decreased testosterone
sperm
females  disrupts ovarian cycling ~

12. High Dependence Liability
Alcohol Dependence
High Dependence Liability
Positive & Negative Reinforcer
Aversive Aftereffects
Available/Inexpensive
Socially Acceptable
Easily Administered
Rapid Onset of Effects ~

13. Dependence: Genetic Component
Sons of Male Alcoholics at > risk P3
R. Cloniger (1989) Statistical Evaluation
Type I - Environmental
Late developing - Age = 20-30
Type II - Genetic
Early onset (teens & younger)
Impulsive risk takers/Suicidal
Violent/Agressive/Crime ~

14. Liquor-loving Mice Knockout mice delete single gene
Increased ETOH appetite
Drank twice as much ETOH
fewer motor effects
5-HT1B receptor
autoreceptor ~

15. Treatment No best program Success rates: Higher rates:
1 year: up to 50%
2 years: 25%
Higher rates:
select populations & short follow-up
Treatment approaches
12-step programs
Behavioral-Cognitive
Pharmacological ~

16. Antabuse Disulfiram Aversive therapy Interferes with ETOH metabolism
inhibits aldehyde dehydrogenase
Acetaldehyde  toxic ~

17. Antabuse nausea cramps sweating ~ ETOH Disulfiram (Antabuse)
Alcohol
Dehydrogenase
Aldehyde
Dehydrogenase
nausea
cramps
sweating ~
ETOH
Acetaldehyde

18. New Treatments Naltrexone (opioid antagonist) Blocks rewarding effects
Relapse prevention
binge after slipping:  50%
Acamprosate (Campral)
Blocks withdrawal effects
NMDA antagonist / GABA agonist
Naltrexone + Acamprosate?
under investigation ~