Alcohol/Ethanol (ethyl alcohol)

NHSDA 2000 Alcohol Use Statistics(National Household Survey on Drug Abuse)

• “Drink” = can or bottle of beer, glass of wine or a wine cooler, shot of liquor, or mixed drink with liquor in it.

• Current use - At least one drink in the past 30 days (includes binge and heavy use).

• Binge use - Five or more drinks on the same occasion at least once in the 30 days prior to survey (includes heavy use).

• Heavy use - Five or more drinks on the same occasion at least five different days in the past 30 days.

12 oz Beer = 4 oz Wine = 1 oz Liquor

What is equal to what?

= =

Calculating BALs

• BALs are given in milligrams (mg) per 100 milliliters (ml) of whole blood

• Convert weight (e.g., 100 lbs) to kilograms by dividing by 2.2 (1 kg = 2.2 lb)

• This weight is adjusted because not all of the body is capable of absorbing alcohol (75% in men and 66% in women)

• Convert alcohol to milligrams• Divide the mg of alcohol/ml of body fluid x 100

• The effects of Alcohol vary depending on many factors

– Previous experience

– Amount consumed in a given time period

– Drinker's size, body build, and metabolism

– Type and amount of food in the stomach

– Gender

Statistics– About half of Americans ages 12 and older report drinking

alcohol.

– About 3 in 10 (30 percent) American adults drink at levels that increase their risk for physical, emotional, and social problems.

– Of these heavy drinkers, about 1 in 4 currently has an alcohol abuse or dependence disorder.

– Alcohol is the leading cause of death among teenagers, because of traffic fatalities

• 16 % of teenagers have had “blackouts”

– Teenagers who start drinking before age 15 are FOUR times as likely to become alcohol dependent as those who begin at age 21

Incidence by Gender and Age

• More men report being current drinkers than do women.

• The rate of alcohol dependence is also lower for women than for men.

• The incidence of heavy alcohol use is highest among young adults between ages 21 and 29.

• The incidence of alcohol problems is lowest among adults ages 65 and older.

Positive Effects of Moderate Doses(1-2 drinks/day)

• Pleasurable

• Anxiolytic (relieves anxiety and depression)

• Increases socialization (“the social lubricant”)

• Lowers mortality rate relative to non-drinkers

– probably due to elevating HDL (“good” cholesterol)

• Increases levels of estrogen (easing postmenopausal symptoms)

Expectancies and Advertisement

• Many “positive” effects of alcohol are expectancy-based

– Sociability

– Attractiveness

– Sexual prowess

– Etc.

• Where do alcohol expectancies come from?

Negative Effects of High-level Consumption

• Reduced sex drive

• Shrinking brain, enlarged ventricles

• High blood pressure

• Cirrhosis of the liver

• Peripheral Neuropathy

• Korsakoff’s Syndrome

• Depression

• Decreased brain glucose metabolism

Negative Effects continued

• Cerebellar degeneration

• Increased risk of stroke

• Muscle inflammation and atrophy

• Men: testicular atrophy, decreased sperm and testosterone production, impotence

• Women: menstrual irregularities

• Addiction

Fetal Alcohol Spectrum Disorders

• The most serious risk during pregnancy is fetal alcohol spectrum disorders (FASD).

• FASD is the leading known cause of mental retardation in the United States.

Fetal Alcohol Spectrum Disorders

A. Magnetic resonance imaging showing the side view of a 14-year-old control subject with a normal corpus callosum; B. 12-year-old with FAS and a thin corpus callosum; C. 14-year-old with FAS and agenesis (absence due to abnormal development) of the corpus callosum.

Source: Mattson, S.N.; Jernigan, T.L.; and Riley, E.P. 1994. MRI and prenatal alcohol exposure: Images provide insight into FAS. Alcohol Health & Research World 18(1):49–52.

Cause of FASD

• The sole cause of FASD is women drinking alcoholic beverages during pregnancy.

• Alcohol is a teratogen (something that interferes with development of fetus)

“Of all the substances of abuse (including cocaine, heroin, and marijuana), alcohol produces by far the most serious neurobehavioral effects in the fetus.”

—IOM Report to Congress, 1996

Acute Cognitive Impairments

• Memory formation

• Attention (divided, selective)

• Reaction time

• Visual search and tracking

• Abstract thinking

• Problem solving/flexibility

• Multi-tasking

• “Alcohol myopia”

• Impaired judgement of abilities

• Flattened P300

White et al., 1998

Normal Alcoholic

Karaaslan et al., 1999

Typical examples of P300

Tapert et al., 2001

18-25 year olds performing a nonverbal working memory test

Non-drinkers Alcoholics

Pharmacokinetics

• Both water soluble and lipid soluble

• Absorbed through lining of digestive tract

• Follows zero-order kinetics for elimination

• 5-15% excreted unmetabolized through exhaled breath, sweat, urine

• 85-95% metabolized in liver

• build up of acetaldehyde leads to “flushing response”

Ethanol Acetaldehyde AcetateAlcohol

DehydrogenaseAldehyde

Dehydrogenase

Pharmacokinetics (cont)

• Another system of alcohol metabolism: microsomal ethanol-oxidizing system (MEOS) – involved in the metabolism of barbiturates.– Alcohol dehydrogenase saturates at low to moderate BACs (Michaelis-

Menten kinetics)

– Apparent zero-order kinetics at moderate BACs

• Alcohol Elimination Rate = 7 g per hr

• Disappearance Rate = 0.015% per hr

• Histamine receptor antagonists (e.g., Tagmet and Zantac), typically used to reduce stomach acidity, also reduce levels of alcohol dehydrogenase, increasing BAL.

• Women have lower levels of alcohol dehydrogenase

• Some Asians have a malfunctioning aldehyde dehydrogenase enzyme

Old Pharmacodynamic View

• Lipid Perturbation Hypothesis (Meyer, 1901)– Alcohol disturbs cell membrane integrity

– Leaky cells allow chemicals in more easily

– Widespread non-specific effects

• Alcohol does do this, but so do things like a slight change in temperature (i.e., fevers)

• More specific effects on receptors…

Acute Pharmacodynamics

• Indirect agonist at GABAa receptor

• Inverse agonist at NMDA receptor

• Facilitates DA, 5-HT neurotransmission

• Increases DA levels in NAc, via some indirect GABAa

effect

Ro15-4513, a GABAa antagonist (indirect for GABA, direct for alcohol) reverses alcohol intoxication

Alcohol and the GABA Receptor

• When alcohol enters the brain, it binds to GABA receptors and amplifies the hyperpolarization effect of GABA.

• The neuron activity is further diminished• This accounts for some

of the sedative affects

of alcohol

science.howstuffworks.com/ alcohol.htm

Alcohol and Dopamine

Alcohol and Nicotine

Chronic Pharmacodynamics(adaptive processes)

• Decreased GABAa receptor function

• Increased density of NMDA receptors

• Decreased DA function

• 5-HT dysfunction

Alcoholics are more sensitive to stress than non-alcoholics

Blocking one receptor that mediates stress, the neurokinin 1 receptor (NK1R) reduces the exaggerated activation in areas of the brain associated with negative emotions.

The blocker also restored activity in the pleasure centers of the brain in response to positive pictures.

Markus Heilig

Tolerance

• Behavior– commonly half the level of behavioral intoxication at same blood

alcohol level of nontolerant individuals

– environment-dependent tolerance

– learned tolerance

• Pharmacokinetic Mechanism– liver increases enzyme levels

– accounts for up to 25% of tolerance

• Pharmacodynamic mechanisms– changes in NMDA and GABAa receptors as per chronic effects

Withdrawal• Excitatory/inhibitory amino acid imbalance

– Hyperexcitability– Seizures

• Delirium Tremens (DTs) - 5% of patients develop it and a 35% mortality rate if untreated– Rapid heart rate - Tremors– Increased body temperature - Hallucinations– Increased blood pressure - Sweating– Psychomotor agitation - Loss of ability to control muscle

movement– Confusion - Increased blood pressure– Cardiovascular collapse and death– Disorientation - altered mental status– Sleep disorders

• Dysfunctional monoamine systems– Depression

Pharmacotherapies

• Benzodiazepines– For acute withdrawal

• Disulfiram (Antabuse)– Interferes with alcohol metabolism

– Causes aversive reaction (like flushing response)

• Naltrexone– Opioid antagonist

– Supposed to decrease craving

– Efficacy still under debate

Pharmacotherapies (cont.)

• Antidepressants– Causal direction between alcoholism and depression unclear

– May treat underlying motivation to drink, or reduce depression as withdrawal symptom

Family History Positive

• FHP: one or more first-degree alcoholic relatives

• 3-7x risk of alcoholism (esp. males)

• Increased response to pleasurable (and reinforcing?) effects, decreased response to impairing effects

– May map onto periods of increasing vs. decreasing blood alcohol level (BAL)

• Decreased cortisol (stress hormone) response

• Smaller decrease in P300 amplitude from acute alcohol