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Alcohol Barbiturates Steroids GABA Benzodiazepines Ethanol GABA receptor is a pentamer made up five subunits (a, b and g) arranged around a ion channel. Chemical structures of three commonly used forms of alcohol Alcohol history CNS effects Alcohol metabolism Behavioral effect Complications Beneficial effects Alcohol History Alcoholic beverages date back to the very early part of man's history. Many archaeologists believe that beer made from grains and wines made from grapes have existed for more than 10,000 years Throughout its history, alcohol has been used socially for many diverse purposes, such as calming feuds, giving courage in battle, celebrating festivals, and seducing lovers. The Celts, Ancient Greeks, the Norse, Egyptians, and Babylonians all have records of production and consumption of alcoholic drinks The ancient Egyptians have passages within their texts referring to the social problems associated with drunkenness, and a 1600 BCE Egyptian text contains 100 medical prescriptions calling for the use of alcohol The first documented distillation of alcohol was the conversion of wine into brandy during the Middle Ages at a medical school in Salerno, Italy. The new beverage became known in Latin as Aqua vitae “the water of life”. Brandy became the primary distilled liquor in Europe until the middle of the seventeenth century. At that time the Dutch perfected the process of distilling liquor and flavoring it with juniper berries. A new alcoholic beverage was born: gin. Gin became popular in Europe especially in the poor class of people because it was easily produced, cheaper than brandy and fasting acting than wine. By the mid-1700s, alcohol abuse was the major social problem. In 1620 alcohol played a pivotal role in the earliest days of settling The American Colonies. During the 1700s the social focus for the American communities was the tavern which was regularly attended as the local church. In the nineteenth century the average alcohol consumption per capita was 5 drinks a day and it was common to take “whiskey breaks” at 11 a.m. and 4 p.m. In 1830 a new movement, the “Temperance movement” grew across the nation. Its goals originally focused on the moderation, not the prohibition, of alcohol. Over time the moderation Shifted to a total prohibition and in 1851 the first prohibition law was passed in Maine and other 12 states. Alcohol history CNS effects Alcohol metabolism Behavioral effect Complications Beneficial effects CNS Effects Alcohol depresses the CNS. In the 19th century it was used as an anesthetic. Problems: Duration too long, could not be controlled. The effective dose for surgical analgesia is closed to the lethal dose. MECHANISM OF ACTION: ACTS ON GABA RECEPTORS: enhances GABA function and Cl- ion flow. - What are the consequences of Cl influx? Cl- influx causes an hyperpolarization of the membrane Hyperpolarization is a state in which the neuron has a more negative voltage than the resting potential. The hyperpolarization causes inhibition By inhibiting the inhibitory input on a neuron, ethanol may increase the activity on the neuron. For example ethanol increases the activity of cerebellar Purkinje cells; this leads to impaired coordination. ATAXIA IS SEEN. No balance between inhibitory and excitatory input. The cerebellum regulates the timing of movements and integrates sensory and motor function to provide smooth, coordinated body movements Impaired Cerebellar Function Errors of trajectory, e.g. dysmetria (inability to control the range of movement of muscular acts) and ataxia (loss of the ability to coordinate muscular movement) Inacurate movements resulting in oscillations and tremor (an unintentional rhythmical alternating movement of muscles) Decreased resistance to passive movement Dysarthria, difficulty with speaking, nystagmus Impaired Cerebellar Function Nystagmus Rotation-induced lateral nystagmus Alcohol acts also on NMDA receptors and on glutamate release. Inhibits the NMDA receptors and reduces the release of glutamate in brain areas like hippocampus, that leads to the amnesia that occurs for events that take place during intoxication (e.g. blackout). All rewarding things activate the forebrain dopamine system Main effect of alcohol (A), fearful facial emotion (B), and the interaction between them (C) on regional brain activation Subjective feeling of being intoxicated correlates best with activity in the ventral striatum. Lessens the limbic (emotional) response to threatening faces which may contribute to risky decision making during intoxication Copyright ©2008 Society for Neuroscience Gilman, J. M. et al. J. Neurosci. 2008;28:4583-4591 This effect occur at blood alcohol concentrations as low as 0.03%, (social drinkers). In alcohol-dependent rats, glutamate release is dramatically increased at about 10 h after withdrawal of alcohol. The time course of the CNS hyperexcitability and the seizures that are typical of the alcohol abstinence syndrome matches the pattern of increased glutamate release during withdrawal. Alcohol history CNS effects Alcohol metabolism Behavioral effect Complications Beneficial effects Alcohol intake is self-regulated Absorption 20 % of ingested alcohol absorbed in the stomach 80% absorbed in the upper small intestine Absorption is most rapid when the stomach is empty. Accelerated gastric emptying also accelerates the rate of alcohol absorption due to rapid passage of alcohol into the small intestine where the absorption is more rapid Gastric emptying is decreased by food in stomach. The presence of food in the stomach slows absorption of alcohol And prevents the sharp peak in blood level. Absorption is by passive diffusion and proceeds as long as the alcohol concentration in intestine exceeds that in the blood. Absorption is more rapid from carbonated drinks (champagne). If alcohol is taken slowly it can be metabolized as fast as is being absorbed. Absorption is generally complete in 1-2 hours. High concentration drinks (greater than 30%) e.g. whiskies and brandies, retards the absorption because they are direct stomach irritants and slow stomach emptying. This irritating effect is often experienced as acute alcoholic or “morning after” gastritis and is synergistic with aspirin and Ibuprofen in this action on stomach. Patients treated for arthritis need to be especially careful of this. Also taking an aspirin the morning after for the hangover could Make things worse due to prior stomach irritation. Some people take an aspirin prior to drink to prevent the hangover. Aspirin actually inhibits an enzyme in the intestine that metabolizes some of the alcohol prior to absorption. Therefore taking aspirin prior to drinking has been shown to increase blood alcohol concentration faster and higher. This effect is even more pronounced in females Distribution Alcohol dissolves in the blood and is distributed by the blood stream to the tissues Alcohol becomes distributed in the blood and water of the body. Tissues rich in water (muscle) take up more alcohol from the blood than those rich in fat. A lean person has a greater muscle bulk which provides a larger volume of distribution for the alcohol than an obese counterpart of similar weight. Women normally have smaller body mass than man and they have a higher proportion of body fat. As a result of these two factors women have lesser volume of water in the body into which the alcohol can distribute. That is why women usually achieve a higher Blood Alcohol Concentration (BAC) after drinking the same amount of alcohol. Elimination 5% is excreted in the breath 5% 5% is excreted in the urine 90% is broken down by the liver enzymes Alcohol Alcohol Dehydrogenase CH3CH2OH Breath Acetaldehyde CH3CHO Acetaldehyde dehydrogenase Acetic acid CH3COOH Oxidation reaction Carbon dioxide CO2 + H2O + energy Henry’s Law: the concentration of a gas in the air immediately above a liquid is proportional to its concentration in the liquid. In the lungs there is an exchange between the alcohol in the blood and the alcohol in the air within the lungs. In the 'deep lung' region there is an equilibrium, situation where the concentration of alcohol in the lung air is proportional to the concentration in the blood. This breath to blood ratio used in breath test analyses states that 2100 milliliters of breath will contain the same weight of alcohol as does 1 milliliter of blood. Alcohol history CNS effects Alcohol metabolism Behavioral effect Complications Beneficial effects The behavioral effects of consuming alcohol in more than very moderated quantity, range from the relatively harmless effects of excitement, slurred speech, to behaviors that have the potential for causing great harm: uncoordinated movement, sensorimotor difficulties etc.. Alcohol is a CNS depressant and at low doses has a double – negative effect; releases the cerebral cortex from its inhibitory control over subcortical system in the brain. The result is an illusion of stimulation. Double-negative effect: The cortex controls behavior by GABA receptor-dependent inhibition. At low doses alcohol inhibits the neural systems that maintain your ability to control of behaviors that you would prefer not to exhibit, i.e. punished behaviors. At high doses more areas of the brain are inhibited, thus more behaviors are released from inhibition Blood Alcohol Concentration, BAC: BEHAVIOR RELATIONSHIP 0.03% DULL AND DIGNIFIED 0.05% DASHING AND DEBONAIR 0.1% DANGEROUS AND DEVILISH 0.2% DIZZY AND DISTRUBING 0.25% DISGUSTING AND DISHEVELED 0.3% DELIRIOUS AND DISORIENTED 0.35% DEAD DRUNK 0.4% DEAD Death is due to respiratory failure due to depressed medulla. Vomiting center activated at blood alcohol concentration (BAC) of 0.12% can be overcome with slow, steady drinking. If the vomiting center is depressed a person can then drink up to the lethal concentration. TOLERANCE AND WITHDRAWAL Chronic alcohol abuse leads to both tolerance and physical dependence. The effects of alcohol are significantly reduced when the drug is administered repeatedly. Chronic alcohol use increases the number of liver enzymes that metabolize the drug. Neurons also adapt to the continued presence of alcohol by making compensatory changes in cell function. Behavioral tolerance, you learn to adjust your behavior under the influence of alcohol. In the absence of alcohol (left), GABA opens the Cl- channels and produces an IPSP. Alcohol enhances the effect of GABA (middle), allowing more Cl- to flow into the cell and producing more inhibition. In alcohol dependence (right), both GABA and alcohol have smaller effects on GABA receptors. This results in less Cl- influx and less inhibition. Therefore, throughout the brain there is more activation of neurons that may lead to anxiety and seizure susceptibility. After three doses of Alcohol (a,b,c), signs of intoxication (incoordination in the balance beam test) appeared during the rising phase of blood Alcohol levels at about 0.20%. As blood alcohol was declining the subject felt “sober” at higher concentration (about 0.25%) showing acute tolerance. Test dose given at time zero BEFORE and AFTER 7 days of drinking. Pharmacological tolerance starts quickly. Repeated alcohol consumption leads to a rapid decrease in the blood alcohol concentration Withdrawal is a sign of physical dependence. The intensity and duration of abstinence signs are dependent on the amount and duration of drug taking. Withdrawal from repeated heavy drinking over months or years produces an intense abstinence syndrome that develops within a few hours after drinking, stops and may continue over 2 to 4 days. WITH CHRONIC USE: Tremors, hallucinations, seizures and delirium. HANGOVER: is due to reversible toxic effects of ethanol on the brain, gastro-intestinal tract and liver. The clinical features are headache, tremor and nausea. Alcohol history CNS effects Alcohol metabolism Behavioral effect Complications Beneficial effects Nutritional complications . Neurological diseases caused by nutritional changes due to alcohol consumption. PELLAGRA: is due to deficiency of niacin (vitamin B3), low tryptophan, comes with maize diets, is characterized by diarrhea, dermatitis and dementia . EXCESSIVE ALCOHOL CONSUMPTION is associated with vitamin B1 (Thiamine) deficiency. Leads to degeneration of mammilary bodies and anterior nucleus of the thalamus. KORSAKOFF’S SYNDROME: is a chronic, irreversible neurological disorder. Results from the poor diet of the chronic alcoholic rather than directly from the drug itself. The alcohol provides so many calories that the alcoholic fails to eat foods that provide a sufficient supply of vitamin B1. The deficiency is at least partly responsible for the brain damage and amnesia caused by cell loss in the medial thalamus and the mammillary bodies of the hypothalamus. Clinical features: impairments of short term memory, inability to learn new information. Physical complications GASTRO INTESTINAL TRACT: alcohol as a direct irritant to the mucosa of the esophagus, stomach and small intestine and impairs the absorption of many vital nutrients. Causes gastritis, duodenitis, peptic ulcer. CARDIOVASCULAR SYSTEM: hypertension, cardiomyopathy (increase in the size of heart muscle) LIVER: causes fatty liver, alcoholic hepatitis, alcoholic cirrhosis. The fatty liver is caused by the accumulation of triglycerides inside the liver. When alcohol is present is metabolized first leaving the fat for storage. The condition is reversible as soon as you stop drinking. Alcoholic cirrhosis is caused by death of liver cells that stimulates the formation of scar tissue. When the scar tissue develops, blood vessels carrying oxygen are cut off, that leads to cell death. Alcohol is a peripheral dilator, because of its metabolite acetaldehyde, so the vessels near the skin surface enlarge, and you feel warmer. In fact, there is a heat loss. E.g. red nose Jeronimus Bosch (1450-1516 Hertogenbosch) Copy of the Bacchus singers Elimination 5% is excreted in the breath 5% is excreted in the urine 90% is broken down by the liver enzymes Alcohol Alcohol Dehydrogenase Acetaldehyde Acetaldehyde dehydrogenase CH3CH2OH CH3CHO Breath Vasodilation Acetic acid CH3COOH Oxidation reaction Carbon dioxide CO2 + H2O + energy Alcohol inhibit the Antidiuretic Hormone (ADH) which acts to reabsorb water in the kidneys prior to elimination in the urine. As a result urine is more diluted and more copious. At the peak of blood alcohol concentration water is retained resulting in swollen fingers, hands and feet. Genetic component? Tolerance and dependence have been show to be independently controlled by specific and different genes. Rats bred for alcohol preference show a relative serotonin deficiency. Rats showing some spontaneous alcoholic preference can be bred to produce off spring in which this preference will progressively increase over several generations until rats will ingest ethanol with unlimited access in the sufficient quantities to produce physical dependence. Alcohol and pregnancy A woman who drinks during pregnancy runs the risk that her child will be born with the FETAL ALCOHOL SYNDROME (FAS) FAS= Retarded growth that begins before and continues after birth. Pattern of facial abnormalities as short palpebral fissures,short nose, flat face,thin upper lip. Impairment of the CNS such as mental retardation, motor abnormalities, tremor or hyperactivity. Is correlated with the amount of alcohol consumed The minimal amount of alcohol necessary for inducing the syndrome has not been determined, but most of the evidence suggest that it can occur when over than one ounce of ethanol is consumed per day. Animal studies indicate that the timing of alcohol consumption is also relevant, with the fetus being more susceptible to the teratogenic effects of alcohol early in gestation. Human studies, however, show a susceptibility of infants to maternal alcohol consumption during the third trimester due to the fact that this is the time the brain is growing. Family problems: contributes to 33% of divorces 33% of child abuse “Divorce” by Fuad Kapidzic In USA alcohol is the third largest health problem and reduces life expectancy by 12 years. Is associated with: 65% of serious head injuries 50% murders 40% road traffic accidents 30% fatal accidents 30% domestic accidents Adverse effects There is a strong correlation between heavy drinking in humans and cancer of mouth, throat and esophagus. May be synergistic with tobacco smoking. The risk is doubled with alcohol use, 15X with alcohol/cigarettes together. Myocardial infarcts are associated with heavy drinkers who suddenly stop. 3 or 4 drinks/day correlates with high systolic and diastolic blood pressure. Alcohol and drug interactions Drug Antidepressants (ex: Elavil) Prescribed Purpose Used to treat depression and other forms of mental illness Antihistamines (ex: Benadryl) Used to treat allergic symptoms and insomnia Antipsychotic medications (ex: Thorazine) Used to diminish psychotic symptoms such as delusions and hallucinations Interaction - increased sedative effects - may decrease effectiveness of antidepressant - potential for dangerous rise in blood pressure - intensified sedation - excessive dizziness - intensified sedation - impaired coordination - potentially fatal breathing difficulties Drug Narcotic pain relievers (morphine, codeine, Darvon, Demerol) Sedatives and hypnotics (Valium, Dalmane, Ativan, sleeping pills) Prescribed purpose Interaction Used to alleviate moderate to severe pain - intensified sedation - increased possibility of a fatal overdose Used to alleviate anxiety and insomnia - severe drowsiness - depressed cardiac and respiratory functions - increased risk of coma or fatality Alcohol and birth control Studies have shown that taking the birth control pill affects the way women's bodies process alcohol, leading to higher blood alcohol concentrations (BAC) and intensifying the effects of intoxication. Drinking alcohol can indirectly decrease the pill's by accelerating its metabolism. Alcohol and sleep The quality of the sleep is fragmented during the second half of the sleep period. “The nightmare” by Henry Fuseli Alcohol increases the number of times you awaken in the later half of the night when the alcohol’s relaxing effect wears off. Prevents you from getting the deep sleep and REM sleep. Alcohol history CNS effects Alcohol metabolism Behavioral effect Complications Beneficial effects Less risk of coronary heart disease due to the alcohol ability to increase blood levels of high density lipoprotein, resulting in a lower level of low density, more dangerous lipoprotein. Low level consumption may reduce cholesterol levels. Appetite stimulant and an effective therapy for anorexia nervosa. Alzheimer’s disease. Red wine (white helps a little) tends to inactivate viruses causing polio, herpes simplex, and some gastrointestinal disorders. AGED: “the milk of old age”. Facilitates social interactions of elderly. It also anesthetizes some of their aches and pain. Prolongs life? Moderate drinkers have longest lifespan of both heavy drinkers and abstainers. • Shorter stay = more drinks/hr • Drinking alone = more drinks/hr • Rhythm that equals the heart rate = more drinking • Lyrics: sad songs = more drinking • More men than women = more drinking • Live band = more drinking • Action photography = more drinking Summary Alcohol acts as a depressant in the brain via GABA receptors Alcohol causes changes in the normal behavior Heavy drinking causes neuronal, fetal and physiological diseases “Bacco” by Caravaggio