Transcript Ethanol
literally hundreds of types of alcohol ◦ isopropyl - rubbing ◦ methyl alcohol – methanol or wood alcohol ◦ ethanol First written “recipe” for making beer – about 3000 BC (Egyptians) fermenting fruit – sugar dissolved in H20 and exposed to air – microorganisms (yeasts) LOVE it First written “recipe” for making beer – about 3000 BC (Egyptians) fermenting fruit – sugar dissolved in H20 and exposed to air – microorganisms (yeasts) LOVE it ◦ metabolic byproducts of yeast – ethanol and C02 C02 bubbles to the top leaving…… yeasts multiply – alcohol concentration but only to ~ 10 – 15% ◦ implications: 1. limited to fruit going bad – - was there something that we could store to make alcohol anytime? 1. limited to fruit going bad – - was there something that we could store to make alcohol anytime? 2. alcohol content could not reach higher than 10 – 15% - distillation! described in Arabic manuscripts from the 9th century heating fermented mixture vapor condensed and cooled and resulting liquid is higher in alcohol content than earlier fluid (alcohol has lower boiling point than water and so condenses; repeat cycle can reach up to 95% ethanol by this process (although higher than 40% is pretty aversive) By 17th century – distillation techniques used whatever grain was cheap Result: - grain neutral spirits ( tastes only of alcohol) - used in research, added to gasoline, cleaners, solvents and make various beverages. - first beverages made from grain neutral spirits (gin - filtering distillate through juniper berries and diluting it with water) Europe – only fermented beverages were used until 10th century ◦ distilled wine was first spirits of western World (used to treat many illnesses including senility) ◦ aqua vitae - “water of life” ◦ Irish-gaelic equivalent- “whiskey” tricky- it differs in different countries US – alcohol percentage is denoted by volume Other countries – use alcohol expressed by weight (g ethanol/volume) tricky- it differs in different countries US – alcohol percentage is denoted by volume Other countries – use alcohol expressed by weight (g ethanol/volume) Proof – used primarily with distilled spirits 2x the percentage of alcohol by volume ex. 50% alcohol by volume history: past and present – ◦ being paid with alcohol Alcohol equivalencies .05x 12 =.6 .07 x 8.5 =.6 .12 x 5 =.6 .4 x 1.5 = .6 mg% (amount of alcohol in blood by weight) ◦ usually presented as mg of alcohol/100 ml of blood ◦ legal level of intoxication varies across states – KY .075% ◦ LD50 ~ .45 wine glass that can hold at least 750 ml (an entire bottle of wine) tiny molecule, moderately polar, especially soluble in water (and somewhat in fat) readily crosses bbb so blood and brain levels are equal - unique because it requires no digestion before it is absorbed - has a lot of calories but no nutritional value - absorbed mainly through the capillaries in small intestines (although some absorption by the stomach as well) 1. amount of food in the stomach 1a. type of food – milk or high protein seems to slow absorption 2. dietary status malnourished – increases rate of absorption 3. the rate at which the beverage is consumed pyloric valve can constrict….. 3a. Strength of alcohol in drink 4. carbonation 8. mood 5. body fluid 9. previous history 6. body fat 7. gender 10. age 11. weight 12. 13. other drugs that affect gastric emptying exercise 14. congener content 15. carbonation 16. change in body temperature distribution is along a concentration gradient so once you have absorbed alcohol from stomach and intestines – dissolves in all your body water. - - also distributed to all target organs if organ is very vascularized – will reach equilibrium with alcohol in blood more rapidly than poorly vascularized 1. brain 2. liver 3. lungs 4. kidneys - body begins breaking down alcohol almost immediately **approximately 5%-10% leaves the body unchanged in sweat, urine, or breath. - - remaining 95% must be metabolized or chemically altered alcohol oxidation – combined with O2 occurs with aid of two liver enzymes Ethanol metabolism Alcohol alcohol dehydrogenase Acetaldehyde small amount of ADH in stomach (sex differences – likely) flushing response Bosron et. al. 1993 & Crabb 1995 Ethanol metabolism Alcohol alcohol dehydrogenase Acetaldehyde acetaldehyde dehydrogenase Acetic acid CO2 + H2O + energy ethanol is metabolized at a constant rate (regardless of dose) ethanol is metabolized at a constant rate (regardless of dose) ◦ metabolic tolerance (in absence of liver disease) 2ndary metabolism – liver microsomal enzyme system (usually not activated unless chronic etoh) Biphasic Alcohol Effects Scale Stimulant scale Elated Talkative Energized Up Excited Vigorous Stimulated Sedative scale Inactive Sedated Down Slow thoughts Heavy head Sluggish Difficulty concentrating telescoping effect can still be problematic if ◦ ◦ ◦ ◦ drink too quickly health conditions over 65 medical interactions - Injuries ◦ 60% fatal burn injuries, drownings and homicides ◦ 50% severe trauma injuries and sexual assaults ◦ 40% fatal motor vehicle crashes, suicides and fatal falls Health problems ◦ sleep disorders, depression, stroke, STD, etc Alcoholism costs the nation $150 Billion / annum many organ systems are affected including ◦ liver- fatty liver and cirrhosis ◦ ◦ ◦ ◦ pancreas - pancreatitis heart - cardiomyopathy immune function - compromised endocrine function - altered “low-risk” drinking – no more than 4 drinks/day AND no more than 14/week (men) 3 drinks/day and no more than 7/week (women) can still be problematic if ◦ ◦ ◦ ◦ drink too quickly health conditions over 65 medical interactions - like other CNS depressants (sedative hypnotics), it depresses CNS activity messy drug – affects all major neurotransmitter systems, lipid membranes deficits in Wernicke’s encephalopathy ◦ problem solving, short-term memory, visual spatial abilities, balance and postural stability ◦ characterized by confusion, ocular disturbances role of thiamine Korsakoff’s disease ◦ typically considered a more serious (and often permant) memory impairment (both anterograde and retrograde amnesia) and cognitive deficit; characterized by confabulation GABA ◦ GABA A receptor – ◦ indirectly enhances GABA function ◦ RO 15-4513 – reduces sedative effects of ETOH reduces sedative effects of ETOH (shortterm) does nothing to reduce LD 50 increases risk of seizure GABA – GABAA receptor subtype ◦ allosteric effect; ◦ GABA receptor complex How might ETOH work on GABA receptors? Extracellular Ion channel pore ? Cl- Intracellular Cl- Extracellular Ion channel pore barbiturates Ethanol benzodiazepines Cl- Intracellular ? Cl- Ethanol enhancement of responses mediated by GABAA receptors Flunitrazepam Pentobarbital Ethanol GABAA synaptic responses from rat hippocampus are enhanced in magnitude and duration by flunitrazepam (a benzodiazepine), pentobarbital (a barbiturate), and by ethanol. All three drugs share similar pharmacological effects: sedation and CNS depression glutamate receptors ◦ NMDAR function compensatory mechanisms ethanol has multiple other effects on NTs and membranes including ◦ ◦ ◦ ◦ dopamine 5HT norepinephrine adenosine psychological dependence chemical dependence methanol ◦ colorless and little taste if added to other ingredients ◦ sometimes added to bootleg ◦ readily available in solvents, fuels, paint removers, windshield wiper fluid, dry gas, etc. ◦ can produce significant delayed toxicity; optic nerves particularly vulnerable Methanol metabolism Methanol alcohol dehydrogenase Formaldehyde acetaldehyde dehydrogenase Formic Acid CO2 + H2O + energy sweet tasting; found in antifreeze; metabolites toxic to kidneys treatment - alcohol pharmacotherapy ◦ disulfiram (Antabuse) available for ~ 50 years Ethanol metabolism Alcohol alcohol dehydrogenase Acetaldehyde acetaldehyde dehydrogenase Acetic acid blocks breakdown of acetaldehyde (5 – 10 fold CO2 + H2O + energy pharmacotherapy ◦ disulfiram (Antabuse) available for ~ 50 years premise: benefits and disadvantages Symptoms ◦ ◦ ◦ ◦ ◦ ◦ head, neck and chest flushing throbbing headache nausea and vomiting, diarrhea weakness, dizziness, anxiety orthostatic hypotension sweating, palpitations, itching other food stuffs with enough alcohol to produce effect ◦ mouthwash, flavorings, inhibits cytochrome P450 enzyme activity – consequences: potential drug interactions (interfering with other drug metabolism including some BZ, caffeine, some anticonvulsants) naltrexone (Revia) ◦ approved for use in 1995 by FDA ◦ extended release naltrexone (Vivetrol) approved in 2006 – more recently A brief history of acamprosate since its discovery in France 1975 - synthesized as potential GABAmimetic anxiolytic 1979 - first animal studies on alcohol preference 1984 - first positive data in alcoholism from France 1988-96 - positive clinical trials throughout Europe 1997-02 - accepted throughout Europe, Australia (37 countries), etc etc. 2002 - declared non-approvable by the FDA