| vdl of ethanol | volume of distribution is equivalent to that of total body water (0.5–0.7 L/kg). Two enzyme systems metabolize ethanol to acetaldehyde adh and meos |
| 1. Alcohol dehydrogenase (ADH)— | This family of cytosolic, NAD+-dependent enzymes, found mainly in the liver and gut, accounts for the metabolism of low to moderate doses of ethanol.Gastrointestinal metabolism of ethanol is lower in women than in men. |
| genetic variation in adh | Genetic variation in ADH affects the rate of ethanol metabolism and vulnerability to alcohol-use disorders. |
| order kinetics adh- | Because of the limited supply of the coenzyme NAD+, the reaction has zero-order kinetics, resulting in a fixed capacity for ethanol metabolism of 7–10 g/h. |
| 2. Microsomal ethanol-oxidizing system (MEOS)— | At blood ethanol levels higher than 100 mg/dL, the liver microsomal mixed function oxidase system that catalyzes most phase I drug metabolizing reactions contributes significantly to ethanol metabolism. |
| chronic ethanol metabolism | Chronic ethanol consumption induces cytochrome P450 enzyme synthesis and MEOS activity; this is partially responsible for the development of tolerance to ethanol. The primary isoform of cytochrome P450 induced by ethanol—2E1 converts acetaminophen to a hepatotoxic metabolite. |
| acetaldehyde metabolism | Acetaldehyde formed from the oxidation of ethanol by either ADH or MEOS is rapidly metabolized to acetate by aldehyde dehydrogenase, a mitochondrial enzyme found in the liver and many other tissues. |
| adh inhibition | Aldehyde dehydrogenase is inhibited by disulfiram and other drugs, including metronidazole, oral hypoglycemics, and some cephalosporins. |
| genetic defeciency | Some individuals, primarily of Asian descent, have genetic deficiency of aldehyde dehydrogenase. After consumption of even small quantities of ethanol, these individuals experience nausea and a flushing reaction from accumulation of acetaldehyde. |
| cns affects alcohol | The major acute effects of ethanol on the CNS are sedation, loss of inhibition, impaired judgment, slurred speech, and ataxia. |
| alcohol limits | In nontolerant persons, impairment of driving ability is thought to occur at ethanol blood levels between 60 and 80 mg/dL. Blood levels of 120 to 160 mg/dL are usually associated with gross drunkenness. Levels greater than 300 mg/dL may lead to loss of consciousness, anesthesia, and coma sometimes with fatal respiratory and cardiovascular depression. Blood levels higher than 500 mg/dL are usually lethal. Individuals with alcohol dependence who are tolerant to the effects of ethanol can function almost normally at much higher blood concentrations than occasional drinkers. |
| Additive CNS depression | Additive CNS depression occurs with concomitant ingestion of ethanol and a wide variety of CNS depressants, including sedative-hypnotics, opioid agonists, and many drugs that block muscarinic and H1 histamine receptors. |
| ethanol mechanis, | ethanol facilitates the action of GABA at GABAA receptors, inhibits the ability of glutamate to activate NMDA (N-methyl-d-aspartate) receptors, and modifies the activities of adenylyl cyclase, phospholipase C, and ion channels. |
| other organ system effects alcohol | Ethanol, even at relatively low blood concentrations, significantly depresses the heart. Vascular smooth muscle is relaxed, which leads to vasodilation, sometimes with marked hypothermia. |
| 1. Tolerance and dependenc ethanol | Tolerance occurs mainly as a result of CNS adaptation and to a lesser extent by an increased rate of ethanol metabolism. There is cross-tolerance to sedative hypnotic drugs that facilitate GABA activity (eg, benzodiazepines and barbiturates). Both psychological and physical dependence are marked. |
| 2. Liver effect ethanol | Liver disease is the most common medical complication of chronic alcohol abuse. Progressive loss of liver function occurs with reversible fatty liver progressing to irreversible hepatitis, cirrhosis, and liver failure. Hepatic dysfunction is often more severe in women than in men and in both men and women infected with hepatitis B or C virus. |
| 3. Gastrointestinal system effect ethanol | Irritation, inflammation, bleeding, and scarring of the gut wall occur after chronic heavy use of ethanol and may cause absorption defects and exacerbate nutritional deficiencies. Chronic alcohol abuse greatly increases the risk of pancreatitis. |
| 4. CNS effects ethanol | Peripheral neuropathy is the most common neurologic abnormality in alcohol abuse. More rarely, thiamine deficiency, along with alcohol abuse, leads to Wernicke-Korsakoff syndrome, which is characterized by ataxia, confusion, and paralysis of the extraocular muscles. Prompt treatment with parenteral thiamine is essential to prevent a permanent memory disorder known as Korsakoff’s psychosis. |
| 5. Endocrine system ethanol | Gynecomastia, testicular atrophy, and salt retention can occur, partly because of altered steroid metabolism in the cirrhotic liver. |
| 6. Cardiovascular system effect ethanol | Excessive chronic ethanol use is associated with an increased incidence of hypertension, anemia, and dilated cardiomyopathy. Acute drinking for several days (“binge” drinking) can cause arrhythmias. However, the ingestion of modest quantities of ethanol (10–15 g/day) raises serum levels of high-density lipoprotein (HDL) cholesterol and may protect against coronary heart disease. |
| 7. Fetal alcohol syndrome— | Ethanol use in pregnancy is associated with teratogenic effects that include mental retardation (most common), growth deficiencies, microcephaly, and a characteristic underdevelopment of the midface region. |
| 8. Neoplasia ethanol | Ethanol is not a primary carcinogen, but its chronic use is associated with an increased incidence of neoplastic diseases in the git and a small increase in the risk of breast cancer. |
| 9. Immune system effect ethanol | Chronic alcohol abuse has complex effects on immune functions because it enhances inflammation in the liver and pancreas and inhibits immune function in other tissues. Heavy use predisposes to infectious pneumonia. |
| 1. Excessive CNS depression prevention and treatment | Acute ethanol intoxication is managed by maintenance of vital signs and prevention of aspiration after vomiting. Intravenous dextrose is standard. Thiamine administration is used to protect against Wernicke-Korsakoff syndrome, and correction of electrolyte imbalance may be required. |
| 2. Alcohol withdrawal syndrome | In individuals physically dependent on ethanol, discontinuance can lead to a withdrawal syndrome characterized by insomnia, tremor, anxiety, and, in severe cases, life-threatening seizures and delirium tremens (DTs). Peripheral effects include nausea, vomiting, diarrhea, and arrhythmias. |
| Alcohol withdrawal syndrome prevention management | The withdrawal syndrome is managed by correction of electrolyte imbalance and administration of thiamine and a sedative-hypnotic. A long-acting benzodiazepine (eg, diazepam, chlordiazepoxide) is preferred unless the patient has compromised liver function, in which case a short-acting benzodiazepine with less complex metabolism (eg, lorazepam) is preferred. |
| alcoholism | Alcoholism is a complex sociomedical problem, characterized by a high relapse rate. Several CNS neurotransmitter systems appear to be targets for drugs that reduce the craving for alcohol. |
| alcoholism treatment | The opioid receptor antagonist naltrexone has proved to be useful in some patients, presumably through its ability to decrease the effects of endogenous opioid peptides in the brain. Acamprosate, an NMDA glutamate receptor antagonist, is also FDA approved for treatment of alcoholism. The aldehyde dehydrogenase inhibitor disulfiram is used adjunctively in some treatment programs. If ethanol is consumed by a patient who has taken disulfiram, acetaldehyde accumulation leads to nausea, headache, flushing, and hypotension |
| A. Methanol | Methanol (wood alcohol), a constituent of windshield cleaners and “canned heat,” is sometimes ingested intentionally. |
| methanol intoxication | Intoxication causes visual dysfunction, gastrointestinal distress, shortness of breath, loss of consciousness, and coma. |
| methanol metabolism | Methanol is metabolized to formaldehyde and formic acid, which causes severe acidosis, retinal damage, and blindness. |
| formaldehyde reduction | The formation of formaldehyde is reduced by prompt intravenous administration of fomepizole, an inhibitor of alcohol dehydrogenase, or ethanol, which competitively inhibits alcohol dehydrogenase oxidation of methanol |
| ethylene glycol treatment | Prompt treatment with intravenous fomepizole or ethanol may slow or prevent formation of oxalic acid |
| Ethylene Glycol | Industrial exposure to ethylene glycol (by inhalation or skin absorption) or self-administration (eg, by drinking antifreeze products) leads to severe acidosis and renal damage from the metabolism of ethylene glycol to oxalic acid. |
