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

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

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 800-900 BC Process of distillation in Arabia

Alcohol History 1500s - high alcohol consumption problems (reign of Henry VIII) 1608 - 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

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to produce alcoholic beverages Increased number of drinking establishments Increased strength of organized crime 21st repealed 18th in 1933 – Happy Days are Here Again

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

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

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

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.

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 .

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.

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.

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.

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.

Concentration-Effect Relationship BAC [%] Effects 0.02-0.03 Mood elevation. Slight muscle relaxation. 0.05-0.06 Relaxation and warmth. Increased reaction time. Decreased fine muscle coordination. 0.08-0.09 Impaired balance, speech, vision, hearing, muscle coordination. Euphoria. 0.14-0.15 Gross impairment of physical and mental control. 0.20-0.30 Severely intoxicated. Very little control of mind or body. 0.40-0.50 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 (0.02-0.03%), 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 0.04-0.05 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.

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.

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

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.

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)

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.

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

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

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.

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.

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

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

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

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

Environmental Factors Models Access Policy Peers Media Social Norms

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

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