1. Alcohol An Arabic Word Meaning “Something Subtle”
ETHYL ALCOHOL (ETOH)
Alcohol
An Arabic Word Meaning
“Something Subtle”

2. Alcohol Made from the fermentation of carbohydrates
Fermented in every culture on earth at some point in time
Animals (monkeys and birds) consume fermented fruit

3. Alcohol History Probably the world’s oldest anodyne
Beers & wines since about 6400 BC
Berries, apples and honey
Early use for spiritual ceremonies
First brewery in Egypt 3700 BC
Only natural fermentation until BC
Process of distillation in Arabia

4. Alcohol History
1500s - high alcohol consumption problems (reign of Henry VIII)
first laws against drunkenness passed in England
Gin discovered in 1650 by Dutch physician
From corn mash poured over juniper berries
1700s - gin epidemic - led to decline in British population
tried to regulate use - led to riots
Coffee & Tea & Methodist movement led to decline in alcohol use

5. Alcohol History In the US Was condoned to point of drunkenness
Used as anesthetic in Civil War
18th Amendment (1920)
Illegal to produce alcoholic beverages
Increased number of drinking establishments
Increased strength of organized crime
21st repealed 18th in 1933 – Happy Days are Here Again

6. Alcohol: Forms Proof Naturally Fermented (max 14%) Beer Wine Mead
Distilled (up to 95%)
Whiskey (40%)
Gin (40%)
Vodka (40%)
Tequila (40%)
Everclear (95%)
Proof
British Army used “proof” as a measure of concentration
Poor alcohol on gunpowder and tried to light it

7. Alcohol Prevalence in US
90% Ever drank
65% Current drinkers (gender and age differences). 70% men and 60% women
>40% Temporary problems
10-20% Abuse
5-15% Dependence (Lifetime)
5% point prevalence of dependence

8. Copyright Alcohol Medical Scholars Program
YEARLY COSTS IN US
$300 Billion Overall
$71 Billion Direct Costs
22,000 Deaths + 2,000,000 Injuries
4,600,000 Damaged Vehicles
15% - 25% Healthcare Budget
90% of Liver Disease
72% of Pancreatitis
41% of Seizure Disorders
13% of Breast Cancers
Copyright Alcohol Medical Scholars Program 8

9. Closer to Home – Consequences in College Students
Death: 1,700 college students between the ages of 18 and 24 die each year from alcohol-related unintentional injuries, including motor vehicle crashes .
Injury: 599,000 students between the ages of 18 and 24 are unintentionally injured under the influence of alcohol.
Assault: More than 696,000 students between the ages of 18 and 24 are assaulted by another student who has been drinking.
Sexual Abuse: More than 97,000 students between the ages of 18 and 24 are victims of alcohol-related sexual assault or date rape.
Unsafe Sex: 400,000 students between the ages of 18 and 24 had unprotected sex and more than 100,000 students between the ages of 18 and 24 report having been too intoxicated to know if they consented to having sex.

10. Closer to Home – Consequences in College Students
Academic Problems: About 25 percent of college students report academic consequences of their drinking including missing class, falling behind, doing poorly on exams or papers, and receiving lower grades overall.
Health Problems/Suicide Attempts: More than 150,000 students develop an alcohol-related health problem and between 1.2 and 1.5 percent of students indicate that they tried to commit suicide within the past year due to drinking or drug use.
Drunk Driving: 2.1 million students between the ages of 18 and 24 drove under the influence of alcohol last year. Vandalism: About 11 percent of college student drinkers report that they have damaged property while under the influence of alcohol .

11. Route/Absorption Oral is by far the route of choice
Rapidly absorbed, primarily from small intestine
20% stomach, 80% small intestine
Peak blood alcohol concentration (BAC) depends on:
Amount and alcohol concentration of beverage
Rate of drinking
Food consumption and composition
Gastric emptying and gastric metabolism
Hepatic (liver) first pass
Gender
Alcohol Pharmacokinetics: Absorption
After oral absorption, alcohol is absorbed almost completely from the duodenum. It is rapidly absorbed by diffusion. The rate of absorption is extremely variable depends on several factors:
- volume, type and alcohol concentration of the beverage - less concentrated solutions are absorbed more slowly, however very concentrated solutions can inhibited gastric emptying. Also carbonation can increase the absorption of alcohol
- rate of drinking - the faster you drink, the faster the absorption
- food - food has a major effect on alcohol absorption. The amount, timing and type of food all have an effect. For example, high-fat foods can significantly delay the absorption of alcohol. The effect of food on alcohol is primarily due to the delay in gastric emptying seen after meal consumption.
- gastric metabolism, as well as hepatic first-pass metabolism can significantly decrease the bioavailability of alcohol and thus the amount of alcohol getting into the systemic circulation.

12. Metabolism Metabolism 90-98% metabolized in liver
Alcohol Acetaldehyde Acetate
A constant 0.015% per hr metabolized
Accumulation of acetaldehyde associated with headache, gastritis, nausea, dizziness (hangover)
Those of certain Asian descent lack a gene that codes for ADH (50%)
Alcohol
dehydrogenase
Aldehyde
dehydrogenase
Alcohol Pharmacokinetics: Metabolism
Metabolism of alcohol occurs primarily in the liver, in a 2-step process. In the first step, alcohol is oxidized to acetaldehyde by the enzyme alcohol dehydrogenase or ADH. This enzyme saturates at fairly low blood alcohol concentrations (it has a low Km and follows Michaelis-Menten kinetics). Thus at moderate blood alcohol levels seen after social drinking, it follows apparent zero-order kinetics - this means that the rate of metabolism is at the maximal capacity and has a constant rate of approximately 7-10 grams per hour (equivalent to 1-drink per hour). However, the rate is extremely variable between individuals and even within individuals from day-to-day.

13. Pharmacokinetics: Gender Differences
in absorption
Differences in gastric ADH activity
in volume of distribution
Differences in body composition and total body water (TBW)
in metabolism
Differences in liver volume, ADH activity?
Effect of menstrual cycle on alcohol pharmacokinetics
Effect of sex hormones (OC) on alcohol PK
Gender Differences in pharmacokinetics
As mentioned before, there are gender difference in alcohol pharmacokinetics. There are gender differences in gastric ADH activity resulting in differences in absorption and bioavailability. Differences in distribution of alcohol arise from gender differences in body composition and total body water. Differences in metabolism result in women having higher alcohol elimination rates per kg body weight or lean body mass possibly related to the higher liver volumes per unit lean body mass seen in women, or due to gender differences in alcohol dehydrogenase activity.
The effect of the menstrual cycle on alcohol pharmacokinetics has been studied and overall there does not appear to be any effect, although the response to alcohol may be different in women during the different phases of the cycle.
Also, studies on the effect of oral contraceptives on alcohol pharmacokinetics are conflicting - with some studies showing an effect and some not.

14. Pharmacodynamics: CNS Effects
Alcohol is a CNS depressant
Apparent stimulatory effects result from depression of inhibitory control mechanisms in the brain
Characteristic response: euphoria, impaired thought processes, decreased mechanical efficiency, sedation
Alcohol Pharmacodynamics
Alcohol is a central nervous system depressant. Its 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.

15. Concentration-Effect Relationship
BAC [%]
Effects
Mood elevation. Slight muscle relaxation.
Relaxation and warmth. Increased reaction time. Decreased fine muscle coordination.
Impaired balance, speech, vision, hearing, muscle coordination. Euphoria.
Gross impairment of physical and mental control.
Severely intoxicated. Very little control of mind or body.
Unconscious. Deep coma. Death from respiratory depression
Alcohol Pharmacology: Concentration-Response relationships
This slide shows the characteristic effects of alcohol at progressively increasing blood alcohol levels. Its important to note that this correlation is based on the acute use of alcohol by a socially-drinking, non-abusing individual. At low BACs corresponding to 1-2 drinks ( %), there is mood elevation and slight muscle relaxation. As BACs increase, there is increased relation, warmth, and increases in reaction time. At around the legal limit of intoxication, there is impairment of balance, speech, vision, hearing and muscle coordination, accompanied by feelings of euphoria. At higher BACs, there is progressive intoxication, impairment and loss of physical and mental control, until levels of where the individual is in a deep coma and at risk of death from respiratory depression. It is important to re-emphasize that this is the scenario in non-abusing individuals. Once chronic use and abuse occurs and tolerance develop, the threshold concentrations at which these effects occur are elevated.

16. Alcohol as a Reinforcer
Reinforcer: a substance whose pharmacological effects drive the user to continue to use it
Positive reinforcing effects:
Gain pleasure
Altered consciousness
Conform to behavior of peers
Negative reinforcing effects:
Relief of stress and negative emotions
Relief of withdrawal symptoms
Alcohol as a Reinforcer
It seems self-evident, but nevertheless is worth stating that alcohol would not be a drug of abuse except for its action on the brain. It is important to discuss the mechanism of action of alcohol and why alcohol is so addictive and why its effects are so reinforcing.
A reinforcer in this context can be defined as a substance whose pharmacological effects are rewarding so that it drives the user to continue to use it - in other words, the effect reinforces the use of the drug. In most cases the reward is positive - such as the pleasurable, euphoric effects of drugs, or the altered consciousness following the drug, or to conform to the behavior of peers. If the pharmacological effect reverses an aversive state, it is called negative reinforcement - such as the relief of stress and negative emotions or the relief of withdrawal.

17. Alcohol as a Reinforcer: Neural Systems
Alcohol and a reinforcer: Neural Systems
There has been considerable research into understanding the neural circuits involved in reinforcement. This is the dopamine (DA) system. The DA system originates in the ventral tegmental area (VTA) and connects to the nucleus accumbens, prefrontal cortex as well as hippocampus. This is the mesocorticolimbic system.
Activation of the VTA results in the release of DA in the nucleus accumbens and limbic system and the prefrontal cortex. This is associated with rewarding/reinforcing effects, not only for alcohol but for almost all abused drugs.
Activation of mesocorticolimbic system

18. Alcohol as a Reinforcer: Evidence
Animal models of alcohol preference
Selectively bred animal lines show innate differences in limbic structures and neurotransmitter function
Animal models of self-administration
Animals trained to chronically self-administer alcohol show differences in neurotransmitter levels in the mesolimbic system
Animals will bar-press repeatedly for intra-cranial injections of alcohol into the VTA (ventral tegmental area)
Alcohol as a Reinforcer - Evidence
Two lines of animal evidence exist to indicate the involvement of alcohol in this system. Animal models of alcohol preference: These are animals that have been bred for their preference to alcohol, and these animals consume large amounts of alcohol preferentially, and show innate differences in their limbic structures and neurotransmitter function compared to control animals or those that do not prefer to drink alcohol.
Animal models of self-administration: These are animals that have been trained to chronically self-administer alcohol. These animals show differences in neurotransmitter levels in their mesolimbic system. Also animals with cannulae directly inserted into the VTA will bar-press repeatedly for intra-cranial injections of alcohol directly into the VTA.

19. Reinforcement: Neurochemical systems
Glutamate
Excitatory Input
Enkephalin or
Dynorphin
Inhibitory Neuron
k Opioid
Receptors
Dopamine Receptors
Enkephalin
Inhibitory
Neuron
Dopamine Neuron
GABA
Neuron
m Opioid
Receptors
REWARD
GABA-A Receptors
Alcohol: Neurochemical systems
This is a diagram of a dopamine neuron (in yellow) originating in the VTA and projecting into the nucleus accumbens. These dopamine neurons are regulated by a variety of neurotransmitter systems:
-excitatory NMDA systems (red)
-inhibitory GABA neurons (green)
-opioid neurons and receptors (blue)
Alcohol is postulated to act by facilitating GABA-A function, by interacting with the GABA-A receptor, but at a site different from the GABA binding site or the benzodiazepine binding site. This leads to the activation of the VTA dopamine neuron.
GABA Inhibitory Feedback
GABA
Inhibitory
Neuron
Presynaptic
Opioid
Receptors
(m, d?)
Ventral Tegmental Area
(VTA)
Nucleus Accumbens
(NAc)

20. Neuropharmacology: Summary
Experience Transmitter/Receptor
euphoria/pleasure Dopamine, Opioids
anxiolysis/ataxia  GABA
sedation/amnesia  GABA +  NMDA
nausea 5HT3
neuroadaptation NMDA, 5HT
stress CRF
withdrawal GABA, NMDA ( Ca, Mg)
Alcohol: Neuropharmacology - summary
To summarize, alcohol has effects on most of the neurotransmitter systems in the brain - some directly and some indirectly. The table in this slide shows a list of the neuropharmacological effects or experiences observed following alcohol and the neurotransmitter systems associated with each.

21. Negative Health Effects
Exacerbates ulcers
Can cause cancer (head, neck, oral, GI)
Liver disease
Fatty Liver
Fibrosis
Cirrhosis
CVD
Accidents & Violence

22. Health Benefits Protective against CVD – Increases HDL
Stress inoculation????
Bone mineral density
Men 3 or less/day
Women 2 or less/day
Never more than 5

23. Tolerance: Definitions
Acute Tolerance: during the time-course of a single exposure to drug
Chronic Tolerance: over repeated use of drug
Cross Tolerance: Tolerance to one drug leads to tolerance to other drugs in a class
Benzos
Barbs
General Anesthesia
GHB
Alcohol: Tolerance (definition)
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, while 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.

24. Tolerance: Significance
Why is tolerance to alcohol important?
One of the determinants of increased alcohol consumption
maintains or aggravates alcohol dependence
increases risk of organic complications of alcoholism
Cross-tolerance to other depressant drugs
Genetic determinants exist
Low response predicts alcoholism
Alcohol: Tolerance (significance)
Tolerance is important because it is one of the primary determinants of increased alcohol drinking. When one becomes tolerant, they can no longer feel the effects of the drug, or feel a decreased effect at a given dose and this makes them increase their consumption - this can lead to the development or worsening of alcohol dependence problems. Moreover, the large doses consumed can be toxic to the body and lead to organic complications like cirrhosis etc.
Tolerance is one of the diagnostic criteria for alcoholism per the DSM-IV. Tolerance to alcohol also makes the individual cross-tolerant to other CNS depressant drugs like barbiturates and benzodiazepines. There are genetic determinants of tolerance that might be related to the genetic risk of developing alcohol dependence.
Also, there are studies that show that individuals who have a low response to alcohol early in their drinking careers, which could be due to the development of tolerance, are at a greater risk for developing alcoholism later in life.

25. Withdrawal
Tremors, sweating, anxiety, perspiration, headache, nausea, vomiting
As withdrawal continues, one can have grand mal seizures
DTs – Severe agitation, hallucinations, high fever, delirium
The most likely of all drug withdrawals to be fatal

26. Dependence DSM-IV Disorder
It is the model for all other substance dependence
Public Health Model
Agent Factors
Host Factors
Environment

27. Agent Factors CNS Depressant
Potentiates GABA, Dopamine, Endorphins. Inhibits glutamate
Produces stimulation, sedation, motor incoordination
Withdrawal potential
Toxic to body/brain tissues
Direct Effects
GI/Liver
Heart
Brain

28. Host Factors Genetic Susceptibility Males > Females
Age – College years
Personality/Psychopathology

29. Environmental Factors
Models
Access
Policy
Peers
Media
Social Norms

30. Ultimately There is – Use – Most people who drink
Misuse – College and/or drinking to cope
Abuse – Continued misuse
Dependence – Small percent - BIG TROUBLE

31. Be Careful If Family history Depression Anxiety ADHD
If you can hold your liquor