1	Metabolism and Pharmacology of Ethanol Prof. David W. Craig Dept. of Chemistry Hobart and William Smith Colleges
2	Behavioral Manifestations of Alcohol Ingestion With 1 to 2 drinks (.01-.05 g/dL BAC) -- euphoria and perceived reduction in anxiety With 3 to 5 drinks (.06-.10 g/dL BAC) -- judgement and motor coordination impaired, sometimes increased aggression With 10 to 13 drinks (.20-.25 g/dL BAC) -- sedation With 0.30 g/dL BAC -- memory impairment and loss of consciousness With 0.40 to .50 g/dL BAC -- depressed respiration , coma, death
3	What Factors Determine a Person’s Blood Alcohol Concentration (BAC in g/dL)? Number of Drinks Consumed Body Size and Build Sex Time Past Drinking Experiences Is Stomach Empty or Full?
4	Alcohol
5	Time – How rapidly can ethanol be absorbed? Rate of absorption is dependent on: concentration gradient between gut and blood surface area of contact degree of vascularization Effect of Food on Absorption food dilutes alcohol in the digestive system fatty foods are slow to digest and slow to move from the stomach to the small intestine
6	Time – How rapidly can ethanol removed? Ethanol clearance is zero order … the rate of clearance is independent of the ethanol concentration Average ethanol clearance rates For moderate drinkers - .017 g/dL/hr Drinkers consuming >60 drinks/month - .020 g/dL/hr 80% of adult population > .012 g/dL/hr
7	Estimation of BAC
8	What if we were to continue for five drinks?
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10	BAC distribution of HWS students returning home late at night
11	BAC distribution of HWS students returning home late at night
12	BAC distribution of HWS students returning home late at night
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14	Metabolic Differences Between Men and Women Women are smaller than men Women have lower total body water content (49%) than men (58%) of comparable size Gastric ADH lower in women virtually nonexistent in alcoholic women declines in men over 50 Fluctuations in gonadal hormone levels during the menstrual cycle may affect the rate of alcohol metabolism
15	Metabolic Differences Between Ethnic Groups Isoenzymes in Alcohol DH (ADH) Beta1 in Caucasian has Km 0.00023 g/dL Beta2 in Asian has Km 0.0043 g/dL Beta3 in 15% African Amer. has Km .165 g/dL 50% Chinese and Japanese Asians have inactive mito. Aldehyde DH (ALDH) resulting in facial flushing, palpitations, dizziness, and nausea
16	Effect of Chronic Use Metabolic Tolerance But….This is not the whole story….more to come
17	Alcohol on the Brain
18	Behavioral Manifestations of Alcohol Ingestion With 1 to 2 drinks (.01-.05 g/dL BAC) -- euphoria and perceived reduction in anxiety With 3 to 5 drinks (.06-.10 g/dL BAC) -- judgement and motor coordination impaired, sometimes increased aggression With 10 to 13 drinks (.20-.25 g/dL BAC) -- sedation With 0.30 g/dL BAC -- memory impairment and loss of consciousness With 0.40 to .50 g/dL BAC -- depressed respiration , coma, death
19	The Brain’s Division of Labor
20	Reward/Pleasure Center
21	Neurons
22	Synapse
23	How the Synapse Functions
24	Regulatory Synapses and Psychoactive Drugs
25	Alcohol Affects Neuro-transmitter Function in the Brain Potentiates GABA receptor function Inhibits Glutamate receptor function Increases Dopamine concentration Increases Seratonin release Stimulates Opiate Neuropeptide Release
26	Affect on Dopamine, Serotonin, and Endogenous Opiates (BAC ~ .01--.05 g/dL) Dopamine stimulates pleasure centers and functions in positive reinforcement alcohol increases Dopamine concentrations in nucleus acumbens and other reward centers Serotonin functions in mood, sleep and positive reinforcement alcoholics and thrill seekers have low serotonin levels and alcohol consumption ( and thrill activities) brings theses levels up to normal. Serotonergic drugs have reduced alcohol consumption by alcoholics. Endorphins and Enkephalins are natural neural peptides that bind to opiate receptors and produce euphoric effects. Endorphins and Enkephalins are released by the brain when exposed to alcohol Euphoria seems to stimulate further drinking
27	Affect on GABA function (BAC >=.06 g/dL) GABA is major inhibitory neurotransmitter controlling “arousal state” and sensory and motor activity Alcohol Potentiates GABA receptor function GABA receptor is site of action of sedative/anesthetic barbiturate, pentobarbitol sedative/anxiolytic benzodiazipines RO 15-4513 overcomes motor impairment
28	Affect on Glutamate Function (BAC ~.02--.2 g/dL) Glutamate is major excitatory neurotransmitter Alcohol inhibits NMDA glutamate receptor function Impaired NMDA Glutamate Receptor Function Causes: cognitive impairment and amnesia inability to learn new information Alcohol parallels action of PCP or “angel dust”
29	Effect of Chronic Use Tolerance changes in number and types of GABA receptors Increase in number of glutamate receptors Withdrawal increased Anxiety within hours -- GABA seizures -- Glutamate Dependence changes in Dopamine and Seratonin function appear to be long lasting
30	What Causes a Hangover? Pounding Headache Caused by reduced blood pressure in cranial vessels General Lethargy Caused by buildup of lactic acid and acidosis by release of acetic acid Hypersensitivity to Light and Sound Alcohol withdrawal leads to increased excitability, depressed mood, and sensitivity to stimuli Queasy Stomach Empty stomach, overly acidic Also due to withdrawal What about taking a drink to relieve hangover symptoms?
31	Alcohol and Sex Physiological responses Erections slower to rise and quicker to fall Reduction in vaginal lubrication Psychological Perceptions 45% of men and 68% if women say alcohol enhances sexual enjoyment Rutgers study (2-3 standard drinks) Subjects who thought they drank alcohol were most highly aroused (those that did not actually get alcohol were slightly less aroused) Subjects who expected tonic but actually got alcohol were less aroused than those that expected alcohol but did not.
32	Important Metabolic Interactions and Health Concerns
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34	Interaction with other Drugs Ethyl ester of Cocaine potentiates cocaine “high” Aspirin and Cimetidine Inhibits Gastric ADH Liver Drug Detoxification Impaired Depleted NAD impairs livers ability to clear other drugs
35	Metabolic Fates of Excess Ethanol and Acetaldehyde Ethyl esters of Fatty Acids and Cholesterol may cause heart damage, impair energy metabolism, disrupt cell membranes Protein Modification by Acetaldehyde enzymes inactivated by imine adducts Ethanol can also be oxidized by MEOS/Cytochrome P450 MEOS oxidation produces harmful free radicals
36	Other Metabolic Processes Affected by Alcohol Metabolism High NADH/NAD ratio: Impaired Energy Metabolism and increased production of lactic acid Inhibits Lipid Degredation in Liver Stimulation of fat synthesis and increases in LDL and HDL levels Inhibition of oxidative steps in testosterone synthesis
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38	Alcohol-Induced Liver Damage Risk becomes significant when alcohol consumption exceeds 6.2oz/day for men 1.55oz/day for women Caused by Free radical rx in fatty liver Cytokine stimulated differentiation of Ito cells into collagen myofibroblasts Increased levels of Acetaldehyde due to lower levels of Aldehyde dehydrogenase
39	Alcohol-Induced Immune System Impairment Suppresses proliferation of lymphocytes in blood, spleen, and thymus Reduced B cell antibody production Natural Killer (NK) cells have reduced activity
40	Alcohol-Induced Changes in the Cardiovascular System Reduced risk of CAD with <=2 drinks/day increased HDL, inhibition of platelet activity Reduction in Cerebral Vascular Disease (Stroke) reduced platelet activity 50% greater risk of hypertension with 3-4 drinks/day Cardiomyopathy (weakened heart muscle) impaired protein metabolism, free radicals Arrhythmias caused by alcohol effect on sinoatrial node