PHARMACOLOGY AND TOXICOLOGY OF ETHYL ALCOHOL. - Ethyl alcohol (Ethanol, EtOH) is the single most widely used pharmacological agent in the world

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1 I. "EPIDEMIOLOGY" PHARMACOLOGY AND TOXICOLOGY OF ETHYL ALCOHOL Thomas M. Guenthner, Ph.D. Department of Pharmacology E-417 MSA, m.c 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 % ethanol - beer - 3-6% ethanol; wine % ethanol (fortified to 20%); distilled spirits % 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

2 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) 1.0 Blood Ethanol Conc. (mg/ml) 0.5 Empty Stomach Full Stomach 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

3 - 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 mg/dl ( %) Disturbances in gait Lack of concentration Increased reaction time mg/dl ( %) 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

4 - 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 C H 2 H 3 C OH Ethanol Alcohol Dehydrogenase C H + NAD + + NADH C O (Slow Step) H 3 Acetaldehyde Catalase C H 2 C H H 3 C OH + H 2 O + H 2 C O 2 O H 3 Ethanol Acetaldehyde C H 2 H 3 C OH + NADPH + O 2 CYP2E1 (MEOS) C H 3 C H O + NADP + Ethanol Acetaldehyde C H 3 C H O Aldehyde Dehydrogenase + NAD + C + NADH (Rapid Step) C O H 3 OH Acetaldehyde Acetic acid 4

5 - 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 - Mimicked by disulfiram (Antabuse). Used as "aversion therapy" for chronic alcoholics. - Other drugs inhibit this enzyme, including metronidazole, tolbutamide, and several cephalosporins (potential drug interaction with ethanol) VIII. BIOCHEMICAL IMPLICATIONS OF ETOH METABOLISM - Acetate produced by aldehyde dehydrogenase can be further oxidized to CO 2 by Krebs cycle, or contribute to fatty acid synthesis (SEE BELOW) - Net conversion of 1 mole of ethanol to 1 mole of acetate, 2 moles of NAD+ to 2 moles of NADH - Massive amounts of NADH produced; 100 ml ethanol produces 1.5 kg NADH. This deranges normal cell function in the liver - NADH converted to ATP; ethanol provides 7 KCal/gm - Very high NADH/NAD+ ratio greatly affects glucose metabolism (see fig 5) 5

6 - NADH favors lactate formation from pyruvate - Formation of Acetyl CoA from pyruvate inhibited - Citrate synthase inhibited (by ATP), thereby further inhibiting function of Citric Acid cycle NET RESULT: pyruvate shunted towards lactate and away from Citric Acid cycle (mimics anaerobic, rather than aerobic, metabolism); Lactic acid accumulates - Pyruvate shunted toward lactate and away from oxaloacetate and malate - Malic dehydrogenase inhibited NET RESULT: Inhibition of gluconeogenesis, drop in blood sugar Consequences of these effects of ethanol on glucose metabolism: 1) Lactate acidosis; low blood ph, lowered excretion of urate 2) Hypoglycemia due to inhibition of gluconeogenesis; main reason why diabetics must avoid ethanol; can also affect body temperature (hypothermia) by inhibition of central thermoregulatory processes. 3) Large amounts of acetate produced by ethanol oxidation cannot be processed through citric acid cycle; therefore fatty acid synthesis increases, producing fatty liver. IX. TOXIC EFFECTS OF ETHANOL ON THE LIVER A) Fatty Liver - Relatively benign condition, seen after exposure to single moderate dose of ethanol - Accumulation of large lipid droplets in hepatocytes - Minor liver enlargement - Causes: Increased fatty acid synthesis due to Acetyl CoA accumulation, also stressinduced hormone-dependent triglyceride mobilization B) Alcoholic hepatitis - More dangerous and debilitating condition - Seen after long periods of chronic exposure - Hepatic necrosis, major hepatomegaly (due to increased hepatocyte size), inflammatory response. - Anorexia, fever, jaundice, pain - due to direct ethanol toxicity, rather than malnutrition - Liver hypoxia may play a role (centrilobular regions of liver hypoxic due to increased rate of oxidative phosphorylation) C) Hepatic Cirrhosis - Terminal stage of alcoholic liver disease, often fatal - Shrunken, lumpy liver (contrast to above 2 conditions) - Loss of lobular structure and function, scar tissue and fibrotic inclusions - Shunting and stenosis produces severe portal hypertension and intestinal varicosities and hemorrhage - Death occurs due to liver disfunction and/or internal bleeding 6

7 - Liver damage irreversible, but can be stabilized by avoidance of further ethanol - Not all alcoholics develop cirrhosis (about 10% do); factors that trigger this disease poorly understood X. TOXICITY OF ETHANOL TO THE G.I. TRACT - Ethanol directly toxic to epithelium; esophagitis, gastritis, ulcers. - Heavy drinkers have higher incidence of oral and esophageal cancer (smoking related?) - Ethanol stimulates secretion of gastric acid and pancreatic enzymes, exacerbating its direct toxicity - Acute and chronic pancreatitis - GI toxicity interferes with vitamin absorption; may contribute to malnourishment in alcoholics XI. MYOTOXICITY - Direct toxic effects on skeletal and cardiac muscle A) Skeletal Myopathy - Observed in 40-60% of alcoholics - Muscle wasting and degeneration - Can produce hyperkalemia, myoglobinemia, renal failure B) Cardiomyopathy - Degeneration of myocardium - Weakness, congestive heart failure, pulmonary congestion, arrhythmias - Some benefit of moderate ethanol consumption due to increased HDL, decreased LDL levels, possibly other effects of tannins in red wine XII. FETOTOXICITY A) Chronic exposure to large amounts of ethanol produces Fetal Alcohol Syndrome (FAS) - Growth deficiency, microencephaly, motor disfunction, distinctive facial features - Mental deficiency - IQ levels from Associated only with massive chronic ethanol consumption (> 1 pint of whiskey/day throughout pregnancy); smallest consumption associated with FAS was 3 drinks per day daily B) Effects of exposure to small amounts controversial - Some suggest that any exposure will produce small effects; no hard evidence for this - Best counsel seems to be abstinence during pregnancy, but not to panic over inadvertent or minor exposure XIII. EFFECTS ON CENTRAL NERVOUS SYSTEM - CNS depressant; stabilizes excitable membranes and inhibits signal transmission A) General effects - Overall depressant effect; "stimulation" seen in moderately intoxicated individuals due to inhibition of behavioral inhibitions - CNS effects correlated with blood levels (table I); highly integrated functions 7

8 (behavior, fine motor skills) are inhibited first, followed by larger muscle control, eventually respiration - Death following acute overdose due to inhibition of respiration, often accompanied by hypothermia. B) Peripheral effects - Anesthetic properties; historically used as general anesthetic; very small T.I. precludes this use - Local anesthetic properties; injection next to nerve will alleviate pain (also kills neuron) C) Molecular mechanisms - "Drug without a receptor"; non-specific effects on all excitable membranes - Inhibition of signal transmission due to general biophysical action on membrane -- fluidization and disorganization, producing disruption of function (signal transmission) - Some specific effects observed - Neurons in cerebral cortex, cerebellum and hypothalamus affected at lower concentration than medulla or brain stem neurons - Some receptor specific effects observed (but no specific antagonist available) - Ethanol interacts with GABA receptor; enhances ability of GABA to open Clion channels, thus increasing ion flux and lowering excitability of membrane - Partially explains inhibition of signal transmission - Also partially explains additive effects and cross tolerance between ethanol and barbiturates or benzodiazepines - Some benzodiazepine antagonists partially block ethanol activity in mice, but no practical "antidote" available - At higher doses, inhibition of Na+ and Ca+ flux and neurotransmitter release seen All effects of ethanol are inhibitory. It is not a stimulant. D) Toxicity to peripheral and CNS - Peripheral neuropathies in chronic users - Loss of sensation & reflexes, muscular atrophy - Central effects - Degeneration of cerebellar nerves can also result in ataxia (improved by thiamine administration) - "Alcoholic dementia"; Wernicke's encephalopathy and Korsakoff's psychosis -- confusion, ataxia, amnesia; often reversible by thiamine (nutritional deficiencies E) Tolerance, addiction, and withdrawal occurs - Tolerance has behavioral, metabolic, and biochemical components - Withdrawal symptoms seen after acute moderate exposure (part of hangover symptoms), but can be life-threatening in alcohol addict 8

9 - Delirium tremens (DT's) can include hyperthermia, seizures, respiratory collapse XIV. ENDOCRINOLOGICAL EFFECTS - Diuresis due to inhibition of ADH release from pituitary - Inhibition of oxytocin secretion; tocolytic activity of ethanol due to both direct action on uterine muscle and inhibition of oxytocin release - Acute stress response due to release of epinephrine and corticosteroids; transient hyperglycemia, breakdown of lipids and mobilization of fatty acids from adipose tissue - Inhibition of luteinizing hormone secretion produces lower circulating testosterone levels in chronic alcoholics - Symptoms are testicular atrophy, decreased facial and body hair, enlarged breasts - Lower estradiol and progesterone levels in female alcoholics; atrophy of ovaries, uterus and vagina seen XV. TREATMENT OF ETHANOL INTOXICATION AND OVERDOSE - No specific antidote or ethanol antagonist - Intoxication only reversed by clearance of ethanol - In acute overdose, supportive therapy required (fluids, respiratory support); hemodialysis can be used to speed clearance - Central stimulants not useful (can provoke seizures) - Depressants like barbiturates, phenothiazine, or benzodiazepines should never be used to pacify a "raging" drunk; because of additivity, fatal overdose can easily occur Hangover treatment - Symptoms caused by mild ethanol withdrawal, dehydration, hypoglycemia, lactate acidosis, REM sleep deprivation, vasodilation (headache), increased pain perception, G.I. irritation (direct, and also stimulation of acid secretion) - No "quick cure"; best treatment is replenishment of blood sugar and fluids, analgesics, and sleep XVI. LEGITIMATE THERAPEUTIC USES OF ETHANOL - Topical disinfectant (70% solution most effective) - Other topical uses - coolant for fever, dehydrating and hardening skin to prevent bedsores (isopropanol also used) - Some analgesic properties, but too dangerous to use as general anesthetic - Antidote for methanol toxicity (blocks its conversion to formaldehyde & formic acid) 9

10 - Has been used to halt premature labor; dangerous due to depression of fetal respiration - Useful in geriatric medicine; improves appetite, aid to socialization and psychological well-being in nursing homes XVII. "NONLEGITIMATE" MEDICAL USES OF ETHANOL - Not useful as hypnotic to fight insomnia; produces sleep but actually inhibits REM sleep - Not useful to maintain or bring up body temperature in cold weather. Peripheral vasodilation causes loss of heat, as does hypoglycemia. Body feels warmer due to peripheral vasodilation, but shivering is inhibited and core temperature drops - Not useful as "tonic" to stimulate work output. Some immediate catecholamine release due to stress response, also some quick calories, but eventual hypoglycemia decreases work output. Perception may be due to analgesic effect. - Administering ethanol to someone who is cold and exhausted is a very bad idea 10