Thomas M Guenthner Ph D Department of Pharmacology E 417 MSA m c 868 996 2558 tmg uic edu PHARMACOLOGY AND TOXICOLOGY OF ETHYL ALCOHOL I EPIDEMIOLOGY Ethyl alcohol Ethanol EtOH is the single most widely used pharmacological agent in the world Most costly abused drug in western world cost to US society is 65 000 lives and 136 billion per year Used regularly by 2 3 of US adults 1 3 of US adults average 2 drinks per day i e are functionally influenced by ethanol on a daily basis 10 of US adults are physically or psychologically addicted Alcohol induced liver disease 4 cause of death among US males Total US consumption is 700 million gallons per year II CHEMICAL PROPERTIES OF ETHANOL AND OTHER ALCOHOLS Hydroxylated alkanes low molecular weight simple chemical structure Low boiling point high vapor pressure Good solvents mix with both water and organic solvents as chain length increases lipophilicity increases Hypnotic and toxic potency generally increases with chain length i e potency of hexanol pentanol butanol propanol ethanol methanol beyond C6 miscibility with water decreases potency decreases Special exceptions methanol is toxic due to formaldehyde and formic acid formation isopropanol is toxic due to acetone formation III AVAILABLE FORMS OF ETHANOL grain alcohol ethanol wood alcohol methanol rubbing alcohol isopropanol USP ethanol 95 ethanol 5 water azeotrope denatured alcohol anhydrous absolute ethanol 100 ethanol beer 3 6 ethanol wine 10 12 ethanol fortified to 20 distilled spirits 4075 ethanol 80 to 150 proof consumable forms pharmacologically equivalent except for absorption kinetics 12 oz beer 4 oz glass of wine 1 oz shot of spirits 1 IV ABSORPTION Small lipophilic molecule easily crosses membranes Readily absorbed from stomach small intestine colon also from lungs More readily absorbed from small intestine than stomach delaying gastric emptying slows absorption see fig 1 Blood Ethanol Conc mg ml 1 0 Empty Stomach 0 5 Full Stomach 0 0 0 1 2 3 4 5 6 Time hours Effect of Food on Ethanol Absorption Blood alcohol in fingertip blood after ingestion of ethanol on an empty stomach upper curve or with a meal lower curve Data from a single human subject More concentrated solutions absorbed more rapidly highest rate with 30 EtOH V DISTRIBUTION Eventually distributed in total body water Initially distributed into highly perfused organs rapidly enters CNS see figure 2 The same blood level is more intoxicating during the rising phase of distribution than in the clearance phase Readily crosses placenta and is excreted in mothers milk VI EXCRETION 2 Over 90 metabolized by oxidation see below 2 8 excreted unchanged via urine Excretion of unchanged ethanol via lung is basis for breath test VII CORRELATION OF BLOOD LEVELS WITH INTOXICATION Blood levels correlated to pharmacological effects Prima facie evidence for intoxication under law 3 ways of expressing blood levels concentration of 1 g ethanol per liter blood a 100 mg dl b 100 mg c 0 1 Table 1 shows symptoms corresponding to given blood level Blood Alcohol Conc BAC Manifestation of effect 50 mg dl 0 05 Increased sociability euphoria 50 100 mg dl 0 05 0 1 Disturbances in gait Lack of concentration Increased reaction time 100 150 mg dl 0 1 0 15 Ataxia Impaired mental and motor skills Impaired short term memory Slurred speech 200 mg dl 0 2 Lack of response to sensory stimuli 250 mg dl 0 25 Coma 500 mg dl 0 5 Respiratory inhibition Death Not absolute some chronic alcoholics tolerate 0 5 quite well In Illinois 0 08 is defined as legal limit for DUI Loading dose of 70 g ethanol 4 12 oz beers produces 0 1 blood level in a 70 kg man this level maintained by consumption of 10 g ethanol 8 10 oz beer hr VII CLEARANCE 3 Figure 3 above shows clearance of ethanol after consumption of various amounts Clearance is linear constant rate and at the same rate for all amounts ZERO ORDER not concentration dependent Rate of elimination is the same at high and low ethanol concentrations about 10 g hr Consumption of more than 10 g hr 8 10 oz beer will cause blood levels to continue to rise A 70 kg man with a blood level of 0 1 will require 6 8 hours for complete elimination Hepatic clearance metabolism is the most important factor in elimination The rate of elimination is essentially the rate of hepatic metabolism Elimination is zero order because metabolism is zero order VII METABOLISM Occurs almost exclusively in the liver Three known pathways for ethanol see figure 4 below Pathway 1 alcohol dehydrogenase ADH the only really significant pathway for ethanol elimination Converts ethanol to acetaldehyde with NAD as cofactor Rate limiting process in ethanol elimination Usual amount of substrate ethanol present greatly exceeds Km Therefore enzyme acting almost always at maximal velocity essentially independent of increased or decreased ethanol concentration Explains zero order kinetics Suggested that increasing regeneration of NAD from NADH could speed ethanol metabolism Fructose Not practical Pathway 2 catalase uses peroxide as oxidative cofactor of very minor importance H3C H2 C OH NAD Slow Step Ethanol H3C H2 C H2 C H3C Catalase OH H2O2 NADH H3C H C O H2O Acetaldehyde CYP2E1 NADPH O2 OH O Acetaldehyde Ethanol H3C H C Alcohol Dehydrogenase MEOS H3C H C O NADP Ethanol Acetaldehyde H3C H C OH C H3C O Aldehyde Dehydrogenase O NAD Rapid Step Acetic acid Acetaldehyde 4 NADH Pathway 3 Cytochrome P 450 also called MEOS microsomal ethanol oxidizing system Not important in overall elimination of ethanol but has important therapeutic implications Specific P 450 CYP2E1 which metabolizes a number of drugs and environmental compounds is induced by ethanol and inhibited by ethanol Naive drinkers will metabolize these compounds phenytoin and tolbutamide are examples more slowly because of the inhibitory effects of ethanol on 2E1 Chronic alcoholics may metabolize these compounds more rapidly because of induction of CYP2E1 by chronic ethanol Metabolic activation of nitrosamines to reactive mutagens is an example 4th reaction aldehyde dehydrogenase actually part of alcohol dehydrogenase pathway Converts acetaldehyde product of ADH to acetate with NAD as cofactor Rapid compared to ADH therefore not rate limiting Ensures little or no buildup of acetaldehyde toxic Genetic defect in this enzyme exists especially frequent in Central and Eastern Asians and genetically related ethnic groups Low aldehyde dehydrogenase levels cause acetaldehyde buildup headache flushing vasodilation
View Full Document
Unlocking...