Alcohol Pharmacology

1 drink equivalents
0.54 ounces of ethanol are contained in one “shot” (1 oz.) of distilled spirits, a glass of wine (3.5 – 5 oz.) and a 12-ounce beer. Thus, as a general rule, 1 beer = 1 wine glass = 1 shot

pharmacokinetics of alcohol
Ethanol is absorbed rapidly from the GI tract with peak BACs reached within 30 minutes. Most (about 80%) absorption occurs in the small intestine due to its large surface area and enriched vasculature (20% absorption in the stomach). Thus, delayed gastric emptying because of food in the stomach, especially fatty food, will delay alcohol absorption. Carbonated alcoholic beverages, e.g. champagne, tend to be absorbed more rapidly than non-carbonated alcoholic beverages.

kinetics of alcohol metabolism
At the usual blood levels of ethanol, the rate of oxidation is independent of time and concentration, i.e. follows zero-order kinetics. Typically, an adult can metabolize 7 – 10 g of alcohol per hour (about “1 drink” = one 12 ounce beer, 1 oz distilled spirits, or 3.5 – 5 oz wine) with “excess” alcohol remaining in the blood to “accumulate”. Thus, most people who become intoxicated drink, on average, more than one drink per hour. In effect, alcohol is metabolized more slowly than it is absorbed and with zero order kinetics, consumption has to be controlled in order to prevent accumulation/intoxication. About 90% of ethanol is metabolized by the liver and 10% is excreted through the urine and respiration, the latter of which forms the breathalyzer test.

gender differences involving alcohol
In general, for an equivalent oral dose of ethanol, women will have a higher peak alcohol concentration than men. This is likely due to at least 2 factors: (1) women have a lower total body water content and (2) women have lower levels of alcohol dehydrogenase in the stomach than men, which allows more alcohol to pass into the small intestine. As a result, women are more susceptible to hepatoxicity (and heart damage) than men. Women are,however, much less likely to be involved in alcohol-related car crashes.

alcohol and body water content
Ethanol is rapidly distributed to tissues with high water content. In effect, the blood alcohol concentration is “simplistically” the ratio of total body alcohol divided by total body water. Thus, individuals who weigh less will be more affected by a given amount of alcohol than individuals who weigh more. For people of the same weight, however, a well-muscled individual will be less affected than a person with a high body fat content since fat does not contain much water and will not “absorb” alcohol.

usual blood level maximum for conviction of DWI (or DUI)
The usual blood level maximum for conviction of driving under the influence in the U.S. is 80 mg/dL (0.8 g per 100 ml or 0.08%)

BAC 0.10 – 0.20 g/100ml (100 – 200 mg/dL)
– excitement
– emotional/lability, dysphoria, restlessness, impaired motor functions delayed reaction time, wide-based gait (ataxia), slurred speech and impaired judgement/perception

BAC 0.40g/100ml
– coma and death
– no reflexes, hypothermia, bradycardia, hypotension, respiratory depression and arrest, death

metabolism of ethanol related to concentration
Ethanol is typically metabolized by alcohol dehydrogenase to acetaldehyde (the main pathway), generating an NADH from NAD+. The excess NADH contributes to hypoglycemia and lactic acidosis. At higher concentrations of ethanol, ethanol is metabolized to acetaldehyde through the microsomal ethanol oxidizing system (MEOS).

metabolism of methanol
It is methanol that is metabolized by alcohol dehydrogenase to formaldehyde. Methanol is typically consumed by “desperate” alcoholics or by persons who mistake methanol for “alcohol”. Some individuals have drunk methanol (wood alcohol, rubbing alcohol) or ethylene glycol (antifreeze) in suicide attempts. Ethanol has a higher affinity for alcohol dehydrogenase than methanol, which is why it is given intravenously in case of methanol poisoning.

action of disulfiram
Disulfiram (antabuse) inhibits aldehyde dehydrogenase, the enzyme needed to convert acetaldehyde to acetate. Thus, acetaldehyde accumulates after one has drunk ethanol and results in facial flushing, dizziness, headache, nausea, and vomiting – a most unpleasant reaction (“Antabuse reaction”). The drug can be administered to alcoholics as a “deterrent” to drinking.

drugs that cause individuals to have facial flushing, nausea, vomiting, dizziness, and headache when consumed with alcohol
Certain drugs can cause an antabuse -like (disulfiram) reaction because they inhibit aldehyde dehydrogenase and lead to accumulation of acetaldehyde. This brings on symptoms that include a facial flushing, nausea, vomiting dizziness, and headache. Most of these agents are antibiotics including metronidazole, trimethoprim, and certain cephalosporins. Patients prescribed these medications must be warned not to drink at all. Acetaminophen when used with ethanol does not cause an antabuse-like reaction, but can lead to hepatotoxicity.

Asians and alcohol
Some Asians (especially Japanese and Chinese) have a genetic deficiency in the activity of aldehyde dehydrogenase. When they consume even small amounts of ethanol, the ethanol is oxidatively metabolized to acetaldehyde by alcohol dehydrogenase, but cannot be further oxidized to acetate because of the deficit. Thus, acetaldehyde levels rise and these individuals have an antabuse-like reaction.

drugs that have dangerous interactions with alcohol or that can potentiate its effects
One of the most dangerous drug combinations is ethanol with acetaminophen. Drinking three drinks or more per day can result in enhanced P450 mediated conversion of acetaminophen to toxic metabolites. Alcohol can potentiate the effect of sedative hypnotic agents, tricyclic antidepressants and phenothiazines by inhibiting their metabolism.Naltrexone is often used to treat alcohol dependence, but is not likely to have a dangerous interaction if consumed with alcohol.

metabolic derangements often associated with acute alcohol intoxication
Alcohol intoxication, especially when associated with vomiting, can result in a wide range of metabolic derangements that include dehydration (volume loss due to vomiting and alcohol-induced diuresis), metabolic acidosis and ketosis, hypokalemia (vomiting) and hypophosphatemia. In addition, patients may have hypomagnesemia, hypocalcemia, and hypernatremia, the latter of which may in part be due to hyperaldosteronism..

cardiovascular effects of heavy drinking
Heavy drinking is associated with atrial and ventricular arrhythmias. These may be due, in part, to electrolyte abnormalities (potassium and magnesium). Prolonged drinking over many years can lead to ventricular hypertrophy with fibrosis. Ethanol also leads to vasodilation either because of direct central effects or because of direct smooth muscle relaxation due to its acetaldehyde metabolite. This effect may explain the increased risk of hypothermia and death in homeless persons in winter who are drinking heavily. Alcohol is also linked to hypertension independently of other risk factors such as obesity, or salt, coffee, and cigarette consumption.Moderate alcohol consumption may be associated with a lower risk of coronary artery disease by raising serum HDL levels or other mechanisms such as inhibiting clot formation, or protecting against reperfusion injury. Recent interest has focused on resveratrol, an anti-oxidant, found in the skin of red wine grapes as a key factor in cardiovascular risk reduction.

effects of chronic ethanol use
Chronic alcohol use is associated with vitamin deficiencies including folate, which can result in a megaloblastic (large RBCs) anemia. (Alcohol interferes with folate metabolism in the liver resulting in a depletion of folate stores.) Cirrhosis and other types of liver failure can result in gynecomastia and testicular atrophy because the damaged liver cannot breakdown estrogen. Chronic ethanol users also develop a toxic neuropathy probably due to the direct toxic effect of alcohol, exacerbated by vitamin deficiencies. The neuropathy is characterized by numbness, parestheias and atrophy/weakness. In addition, the tendons of the hand shrink causing curled fingers (Dupuytren’s contracture). Alcohol use can cause painless blurring of vision for reasons that are not entirely clear.

neurological effects of alcohol
Alcohol in high doses can cause a wide range of neurological symptoms including anterograde amnesia (“blackouts”) in which people have a loss of memory for events that occurred during and after an episode of drinking, presumably by impairing hippocampal functioning.Alcohol can also result in vertigo/dizziness symptoms. For instance, the alcohol concentration in blood is higher relative to that of the endolymph (endolymph is relatively dense). When alcohol levels fall when drinking stops, the relative alcohol concentration in blood is lower than that of endolymph, resulting in a relatively dilute endolymph. These changes stimulate fluid in the semicircular canals. The “direction” of vertigo may vary depending on the relative increases/decreases in relative blood/endolymph alcohol concentration. Alcohol also has a direct effect on cerebellar pathways, resulting in the typical wide-based (“drunken sailor”) alcoholic gait. Alcohol can also result in analgesia.

GI effects of chronic alcohol use
Chronic alcohol use can cause a wide range of gastrointestinal effects including gastritis and fatty liver. Chronic alcohol use can result in pancreatitis that can be life threatening. Damage to the small intestine can result in diarrhea, with subsequent weight loss and vitamin deficiencies.

deaths linked to alcohol consumption
Although alcohol has been linked to heart disorders, especially arrhythmias, it is less associated with cardiovascular death. It is one of the leading causes of accidents, especially motor vehicle accidents and falls. Alcohol is also involved in a large percentage of deaths involving suicide and homicide. It has been linked with cancers, especially those of the GI tract. Most importantly, alcohol has been linked to deaths from liver disease, especially cirrhosis.

cancers linked to alcohol
Alcohol has been implicated in cancers involving the GI tract including the mouth, pharynx, esophagus, and liver.

fetal alcohol syndrome
Chronic alcohol use during pregnancy can cause mental retardation and various congenital abnormalities including microcephaly, a flattened face and joint abnormalities. Some cases may include congenital heart defects and mental retardation.

CNS effects of alcohol
Ethanol inhibits NMDA receptor activation and enhances the action of GABA at GABA-A receptors. These actions undoubtedly play a major role in its effect on cognition, memory and anxiolysis. It also increases dopamine release in the nucleus accumbens, which in part explains its rewarding effects and a person’s craving for it.

signs and symptoms of alcohol withdrawal
Alcohol withdrawal typically causes anxiety, tremor, sweating, and autonomic arousal including elevated temperature, tachycardia, and hypertension.

time course of alcohol withdrawal in a person tolerant to alcohol
Mild withdrawal symptoms can begin within 6 to 8 hours after discontinuation of alcohol. These syndromes usually end within 1 to 2 days. Delirium tremens typically begins 2 to 7 days following discontinuation of alcohol. Seizures usually begin within 1 to 3 days after cessation of alcohol use.

delirium tremens
Delirium tremens is a serious medico-psychiatric complication that is characterized by autonomic instability (fever, increased blood pressure, increased pulse), disorientation (a hallmark of all types of delirium), agitation and visual hallucinations. The hallucinations can be amusing, pleasant “Lilliputian”, e.g., of small pink elephants or can be vivid, striking and fearsome (almost terrifying) resulting in dramatic behavioral responses, e.g., fleeing a charging elephant, a giant spider, or a raging fire. Patients can also experience hallucinations in other modalities, i.e., tactile (“formication” = bugs crawling on skin) or auditory. Patients can be violently agitated, requiring restraints to prevent self injury or injury to others.

treatment of alcohol withdrawal syndrome in patients without compromised liver function
Drugs that are cross-tolerant with alcohol can be used to treat the alcohol withdrawal syndrome. The most commonly used are in the benzodiazepine class. Longer-acting agents such as diazepam are used in persons without liver disease because they can be given less often than shorter-acting agents such as lorazepam and, in effect, provide a “smoother detox”. Drugs that have a shorter half-life and no active metabolites such as lorazepam or oxazepam are useful in patients with liver failure. Phenobarbital is cross-tolerant with alcohol and was used years ago prior to the widespread use of benzodiazepines, but can cause respiratory depression. It is not widely used now in detoxification. Naltrexone and acamprosate are used to reduce alcohol craving, but are not used in the acute treatment to prevent withdrawal.

Wernick-Korsakoff syndrome
The classic triad of Wernicke-Korsakoff syndrome is confusion, extraocular motor palsies, and ataxia. Confabulation is a type of memory deficit in which a person “invents” details to fill in gaps in memory. It is also very common in Wernicke-Korsakoff syndrome.

All patients suspected of having Wernicke-Korsakoff syndrome should be administered what?
All alcoholic patients should be administered thiamine to prevent Wernicke-Korsakoff syndrome. Patients suspected of having it already should also receive thiamine. Thiamine should always be given prior to or concurrently with intravenous glucose solutions. Glucose oxidation is dependent on thiamine and the last reserve of circulating thiamine (B-1) may be driven intracellularly, serving to further aggravate neurologic damage. Responsiveness to thiamine also requires correction of hypomagnesemia, usually done with parenteral magnesium sulfate.

what is the most dangerous complication of acute alcohol intoxication?
The most dangerous complication of acute alcohol intoxication is respiratory depression, which can be fatal fairly quickly if blood alcohol levels are very high.

what are some drugs used in the treatment of alcoholism?
Naltrexone, a long acting opioid receptor antagonist, is used in the treatment of alcoholism. Acamprosate has many actions, especially as a weak NMDA-receptor antagonist and GABA-A receptor activator, and is more widely used in Europe. Serotonin 5HT3-receptor antagonists (e.g., ondansetron), CB1 receptor antagonists, are also under investigation.

BAC 0.30 – 0.40g/100ml
– stupor
– impaired consciousness, sleep and stupor

BAC 0.0 – 0.03g/100ml
slight buzz

BAC 0.03 – 0.10g/100ml
– euphoria
– relaxation, talkativeness, diminished inhibitions, slow reaction times, beginning motor impairment, mild balance problems, poor concentration and memory

BAC 0.20 – 0.30 g/100ml
– confusion
– disorientation, severe motor impairment, inability to stand or walk, decreased response to stimuli, impaired gag reflex (risk for aspiration), nausea and vomiting, beginning stupor

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