PSYCH 265 1st Edition Lecture 16Outline of Last Lecture I. Regulation of wakefulnessII. GABA(a) Chloride Receptor complexIII. Functional neurotransmissionIV. GABA presynaptic inhibitionV. Drug actions on GABAVI. Barbiturates VII. Effects/clinical usesVIII. Synergistic CNS depressionIX. Enzyme induction by barbX. Development of toleranceXI. Selective barb toleranceXII. Barb abuseOutline of Current Lecture I. Barbiturate withdrawal II. Barbiturate vs. benzodiazepinesIII. Withdrawal from benzoIV. Chemical properties of ethanolV. Absorption of ethanolVI. Distribution of ethanolVII. BACVIII. Metabolism of ethanolIX. Metabolism & excretionX. Pharmacogentetics of EthanolThese notes represent a detailed interpretation of the professor’s lecture. GradeBuddy is best used as a supplement to your own notes, not as a substitute.XI. Ethnic Differences in ADHXII. Ethnic Differences in ALDHXIII. DisulfiramCurrent Lecture-Barbiturate withdrawal oSymptoms of withdrawal TremorsDifficulty sleeping Agitation & possible hallucinationsHyperpyrexia SeizuresoPregnant women taking barbiturates can cause their baby to become addicted, & the newborn may have withdrawal symptoms-Barbiturates vs. Benzodiazepines -Withdrawal from benzodiazepines oCan cause a person to experience a range of different symptoms oMost common effect include anxiety & insomnia oLikely to experience more intense symptoms if they abruptly stop taking medication oPhysical withdrawal symptoms can range from stomach & muscle cramps, diarrhea, tremors, and fever to a general feeling of being unwell oDepending on severity of addiction, these symptoms can last 3-10 daysPsychological withdrawal symptoms usually lost longer & include anxiety attacks,irrational & angry outbursts, depression, and lack of sleepALCOHOL ETHANOL-Chemical properties of ethanoloEthanol, U.S.P. =95% EtOHoAnhydrous (absolute) EtOH= 100% EtOHoProof= 2 x %EtOH content oEquivalence 12 oz beer (3-6% ethanol by volume)5 oz wine (10-12%)1.5 oz distilled spirits (40-75%)oEthanol limit for driving (.08%)0.08%=.8g/L=.8mg/mL -Absorption of ethanoloApproximately 75-80% of oral ETOH absorbed from small intestines; remainder absorbedfrom the stomachoIn fasting state, >50% of alcohol absorbed within 15 min Max blood level reached in 20 min 80-90% complete absorption within 30-60 minoPresence of food slows the rate of absorption from stomach -Distribution of ethanoloAlcohol has high affinity for water and is totally distributed in total body water, including body tissues and fluidsoOnce absorption of alcohol is complete, an equilibrium occurs such that blood in all parts of the body contains approximately the same concentration of alcohol oAlcohol crosses the placenta and can affect the fetus-->fetal alcohol syndrome oIn general, women tend to have a higher percentage of body fat and thus a lower percentage of body wateroTotal body water tends to decrease with age, so an older person will also be more affected by the same amount of alcohol Age 18-40Male-61%, female 52%Age over 60Male 51%, female 46% -Blood Alcohol Concentration/Level- BAC Behavioral & Physical Effects.40-.50 Respiratory depression, circulatory collapse, coma, death.30 Stupor, confusion, inability to stay awake.20 Depressed sensory & motor capacity, difficulty keeping eyes open, really slurred speech, double vision.15 Impairment of balance, movement, judgment and perception, blurred vision.10 Slowed reaction time, impaired motor function, slurred speech.05 Lowered alertness, euphoria.03-.04 Relaxed, happy, mild motor impairmement -Metabolism of Ethanol -Regardless of how much a person consumes, the body can only metabolize a certain amountof alcohol every hour (zero-order kinetics) -Metabolism & excretion of EthanoloAlcohol is removed from the bloodstream by a combination of metabolism, excretion, and evaporationTypically about 90-95% is metabolizedAlcohol dehydrogenase (ADH)Cytochrome P450 (CYP) familyCatalase1-3% is excreted in urine1-5% evaporates through the breath<0.5% also excreted in sweat, tears, feces, milk, ect -Metabolism of Ethanol -ADH converts alcohol to acetaldehyde -Acetaldehyde is a toxic by-product of alcohol -ALDH converts acetaldehyde to acetic acid -Acetic acid is broken down to carbon dioxide and water -Pharmacogenetics of Ethanol oADH consists of at least 5 related enzymesoSeveral of these ADH enzymes (ADH1, ADH2) show genetic polymorphism (there are several genetic variants, which differ in their efficiency for ethanol oxidation)ADH2*2 (works faster than usual)ADH2*3 (works faster than usual)ADH3*1 (works faster than usual)-People with ADH2*2 enzyme rapidly converts alcohol to acetaldehyde -Slight accumulation of acetaldehyde can produce vasodilation (flushing or erythema), a sensation of warmth, headache and trembling -Ethnic Differences in ADH-85% Caucasians have ADH2*1 (normal activity)-90% Asians have ADH2*2 (increased activity)-20% Jewish people have ADH2*2 (increased activity)-People with ADH2*2 have lower risk of becoming alcoholic -Another variant of ADH (ADH2*3) occurs in 12-25% of African American's -ADH2*3 protects against alcoholism by metabolizing alcohol to acetaldehyde efficiently, leading to less positive response to alcohol and reduced likelihood of alcoholism -Pharmacogenetics of Ethanol-2nd step of ethanol metabolism is mainly mediated by ALDH, which rapidly converts acetaldehyde to acetate -There is an important genetic polymorphism in human ALDH-ALDH2*2 is virtually inactive & converts acetaldehyde to acetic acid very slowly -Ethnic Differences in ALDHo60% Asians have ALDH2*2 (inactive)oIn a European (ALDH2) with a BAC of 0.05%, blood acetaldehyde level remains under 2.0μmol/L oIn a Japanese with ALDH2*2, this value may reach 35μmol/LoVirtually 0% of Native American Indians have ALDH2*2oCarriers of ALDH2*2 exhibit particularly low rates of alcohol use and alcoholism -Disulfiram (Antabuse)-The identical symptoms are observed for Europeans with active ALDH2 if the enzyme becomes blocked-This effect can be reproduced by disulfiram (antabuse) a drug completely blocks ALDH-Resulting upward jolt in acetaldehyde concentration, with its accompanying serious hangover symptoms, plagues drug addicts in the withdrawal state who are undergoing treatment, after any indulgence in alcohol -Pharmacogenetics of Ethanol-90%