Alcohol intoxication

From Wikipedia, the free encyclopedia

Alcohol intoxication
Synonyms	Drunkenness, alcohol poisoning, ethanol intoxication, acute alcohol intoxication
The Drunkenness of Noah by Michelangelo
Specialty	Toxicology, psychiatry
Symptoms	Mild: Mild sedation, decreased coordination Moderate:Slurred speech, trouble walking, vomiting Severe: Decreased effort to breathe, coma
Complications	Seizures, aspiration pneumonia, injuries, low blood sugar
Usual onset	Over minutes to hours
Duration	Several hours
Causes	Ethanol (alcohol)
Risk factors	Social environment, impulsivity
Diagnostic method	Typically based on history of events and physical examination
Differential diagnosis	Hepatic encephalopathy, Wernicke encephalopathy, methanol toxicity, meningitis, traumatic brain injury
Treatment	Supportive care
Frequency	Very common (especially in the Western world)
Deaths	c. 2,200 per year (USA)

Alcohol intoxication, also known as drunkenness or alcohol poisoning, is negative behavior and physical effects due to the recent drinking of ethanol (alcohol). Symptoms at lower doses may include mild sedation and poor coordination. At higher doses, there may be slurred speech, trouble walking, and vomiting. Extreme doses may result in a decreased effort to breathe (respiratory depression), coma, or death. Complications may include seizures, aspiration pneumonia, injuries including suicide, and low blood sugar.

Alcohol intoxication typically begins after two or more alcoholic drinks. Risk factors include a social situation where heavy drinking is common and a person having an impulsive personality. Diagnosis is usually based on the history of events and physical examination. Verification of events by the people a person was with may be useful. Legally, alcohol intoxication is often defined as a blood alcohol concentration (BAC) of greater than 5.4-17.4 mmol/L (25–80 mg/dL or 0.025-0.080%). This can be measured by blood or breath testing. Alcohol is then broken down at a rate of about 3.3 mmol/L (15 mg/dL) per hour.

Management of alcohol intoxication involves supportive care. Typically this includes putting the person in the recovery position, keeping them warm, and making sure they are breathing sufficiently. Gastric lavage and activated charcoal have not been found to be useful. Repeated assessments may be required to rule out other potential causes of a person's symptoms.

Alcohol intoxication is very common, especially in the Western world. Most people who drink alcohol have at some time been intoxicated. In the United States acute intoxication directly results in about 2,200 deaths per year, and indirectly more than 30,000 deaths per year. Acute intoxication has been documented throughout history and alcohol remains one of the world's most widespread recreational drugs. Some religions consider alcohol intoxication to be a sin.

Signs and symptoms

Wine is a Mocker by Jan Steen c. 1663

Alcohol intoxication is the negative health effects due to the recent drinking of ethanol (alcohol). When severe it may become a medical emergency. Some effects of alcohol intoxication, such as euphoria and lowered social inhibition, are central to alcohol's desirability.

The signs and symptoms of acute alcohol poisoning include:

• severe confusion, unpredictable behavior and stupor
• sudden lapses into and out of unconsciousness or semi-consciousness (with later alcoholic amnesia)
• vomiting while unconscious or semi-conscious
• seizures
• respiratory depression (fewer than eight breaths a minute)
• pale, bluish, cold and clammy skin due to insufficient oxygen

Pathophysiology

Alcohol is metabolized by a normal liver at the rate of about 8 grams of pure ethanol per hour. 8 grams or 10 ml (0.34 US fl oz) is one British standard unit. An "abnormal" liver with conditions such as hepatitis, cirrhosis, gall bladder disease, and cancer is likely to result in a slower rate of metabolism.

Ethanol is metabolised to acetaldehyde by alcohol dehydrogenase (ADH), which is found in many tissues, including the gastric mucosa. Acetaldehyde is metabolised to acetate by acetaldehyde dehydrogenase (ALDH), which is found predominantly in liver mitochondria. Acetate is used by the muscle cells to produce acetyl-CoA using the enzyme acetyl-CoA synthetase, and the acetyl-CoA is then used in the citric acid cycle.

Ethanol's acute effects are due largely to its nature as a central nervous system depressant, and are dependent on blood alcohol concentrations:

• 20–79 mg/dL: Impaired coordination and euphoria
• 80–199 mg/dL – Binge drinking: Ataxia, poor judgement, labile mood. The National Institute on Alcohol Abuse and Alcoholism (NIAAA) defines the term "binge drinking" as a pattern of drinking that brings a person's blood alcohol concentration (BAC) to 0.08 g/dL or above
• 200–299 mg/dL: Marked ataxia, slurred speech, poor judgement, labile mood, nausea and vomiting
• 300–399 mg/dL: Stage 1 anaesthesia ("blackout"), memory lapse, labile mood
• 400+ mg/dL: Respiratory failure, coma

As drinking increases, people become sleepy, or fall into a stupor. After a very high level of consumption, the respiratory system becomes depressed and the person will stop breathing. Comatose patients may aspirate their vomit (resulting in vomitus in the lungs, which may cause "drowning" and later pneumonia if survived). CNS depression and impaired motor co-ordination along with poor judgment increases the likelihood of accidental injury occurring. It is estimated that about one-third of alcohol-related deaths are due to accidents and another 14% are from intentional injury.

In addition to respiratory failure and accidents caused by effects on the central nervous system, alcohol causes significant metabolic derangements. Hypoglycaemia occurs due to ethanol's inhibition of gluconeogenesis, especially in children, and may cause lactic acidosis, ketoacidosis, and acute renal failure. Metabolic acidosis is compounded by respiratory failure. Patients may also present with hypothermia.

Mechanism

In the past, alcohol was believed to be a non-specific pharmacological agent affecting many neurotransmitter systems in the brain. However, molecular pharmacology studies have shown that alcohol has only a few primary targets. In some systems, these effects are facilitatory and in others inhibitory.

Among the neurotransmitter systems with enhanced functions are: GABA_A, 5-HT₃ receptor agonism (responsible for GABAergic (GABA_A receptor PAM), glycinergic, and cholinergic effects), nicotinic acetylcholine receptors.

Among those that are inhibited are: NMDA, dihydropyridine-sensitive L-type Ca2+ channels and G-protein-activated inwardly rectifying K+ channels.

The result of these direct effects is a wave of further indirect effects involving a variety of other neurotransmitter and neuropeptide systems, leading finally to the behavioural or symptomatic effects of alcohol intoxication.

GABA_A receptors

Ethanol binding to GABA_A receptor

Many of the effects of activating GABA_A receptors have the same effects as that of ethanol consumption. Some of these effects include anxiolytic, anticonvulsant, sedative, and hypnotic effects, cognitive impairment, and motor incoordination. This correlation between activating GABA_A receptors and the effects of ethanol consumption has led to the study of ethanol and its effects on GABA_A receptors. It has been shown that ethanol does in fact exhibit positive allosteric binding properties to GABA_A receptors. However, binding is only limited to pentamers containing the δ-subunit rather than the γ-subunit. GABA_A receptors containing the δ-subunit have been shown to be located exterior to the synapse and are involved with tonic inhibition rather than its γ-subunit counterpart, which is involved in phasic inhibition. The δ-subunit has been shown to be able to form the allosteric binding site which makes GABA_A receptors containing the δ-subunit more sensitive to ethanol concentrations, even to moderate social ethanol consumption levels (30mM). While it has been shown by Santhakumar et al. that GABA_A receptors containing the δ-subunit are sensitive to ethanol modulation, depending on subunit combinations receptors, could be more or less sensitive to ethanol. It has been shown that GABA_A receptors that contain both δ and β3-subunits display increased sensitivity to ethanol. One such receptor that exhibits ethanol insensitivity is α3-β6-δ GABA_A. It has also been shown that subunit combination is not the only thing that contributes to ethanol sensitivity. Location of GABA_A receptors within the synapse may also contribute to ethanol sensitivity.

Diagnosis

Definitive diagnosis relies on a blood test for alcohol, usually performed as part of a toxicology screen. Law enforcement officers in the United States and other countries often use breathalyzer units and field sobriety tests as more convenient and rapid alternatives to blood tests. There are also various models of breathalyzer units that are available for consumer use. Because these may have varying reliability and may produce different results than the tests used for law-enforcement purposes, the results from such devices should be conservatively interpreted.

Many informal intoxication tests exist, which, in general, are unreliable and not recommended as deterrents to excessive intoxication or as indicators of the safety of activities such as motor vehicle driving, heavy equipment operation, machine tool use, etc.

For determining whether someone is intoxicated by alcohol by some means other than a blood-alcohol test, it is necessary to rule out other conditions such as hypoglycemia, stroke, usage of other intoxicants, mental health issues, and so on. It is best if his / her behavior has been observed while the subject is sober to establish a baseline. Several well-known criteria can be used to establish a probable diagnosis. For a physician in the acute-treatment setting, acute alcohol intoxication can mimic other acute neurological disorders, or is frequently combined with other recreational drugs that complicate diagnosis and treatment.

Management

Acute alcohol poisoning is a medical emergency due to the risk of death from respiratory depression or aspiration of vomit if vomiting occurs while the person is unresponsive. Emergency treatment strives to stabilize and maintain an open airway and sufficient breathing, while waiting for the alcohol to metabolize. This can be done by removal of any vomitus or, if the person is unconscious or has impaired gag reflex, intubation of the trachea.

Other measures may include

• Treat low blood sugar, with intravenous sugar solutions as ethanol induced low blood sugar unresponsive to glucagon.
• Administer the vitamin thiamine to prevent Wernicke-Korsakoff syndrome, which can cause a seizure (more usually a treatment for chronic alcoholism, but in the acute context usually co-administered to ensure maximal benefit).
• Apply hemodialysis if the blood concentration is dangerously high (>400 mg/dL), and especially if there is metabolic acidosis.
• Provide oxygen therapy as needed via nasal cannula or non-rebreather mask.
• While the medication metadoxine may speed the breakdown of alcohol, use in alcohol intoxication requires further study as of 2017. It is approved in a number of countries in Europe, as well as India and Brazil.

Additional medication may be indicated for treatment of nausea, tremor, and anxiety.

Prognosis

A normal liver detoxifies the blood of alcohol over a period of time that depends on the initial level and the patient's overall physical condition. An abnormal liver will take longer but still succeeds, provided the alcohol does not cause liver failure.

People having drunk heavily for several days or weeks may have withdrawal symptoms after the acute intoxication has subsided.

A person consuming a dangerous amount of alcohol persistently can develop memory blackouts and idiosyncratic intoxication or pathological drunkenness symptoms.

Long-term persistent consumption of excessive amounts of alcohol can cause liver damage and have other deleterious health effects.

Society and culture

A 1936 anti-drinking poster

Alcohol intoxication is a risk factor in some cases of catastrophic injury, in particular for unsupervised recreational activity. A study in the province of Ontario based on epidemiological data from 1986, 1989, 1992, and 1995 states that 79.2% of the 2,154 catastrophic injuries recorded for the study were preventable, of which 346 involved alcohol consumption. The activities most commonly associated with alcohol-related catastrophic injury were snowmobiling (124), fishing (41), diving (40), boating (31) and canoeing (7), swimming (31), riding an all-terrain vehicle (24), and cycling (23). These events are often associated with unsupervised young males, often inexperienced in the activity, and many result in drowning. Alcohol use is also associated with unsafe sex.

Legal issues

A drunk-driving simulator in Montreal

Laws on drunkenness vary. In the United States, it is a criminal offense for a person to be drunk while driving a motorized vehicle, except in Wisconsin, where it is only a fine for the first offense. It is also a criminal offense to fly an aircraft or (in some American states) to assemble or operate an amusement park ride while drunk. Similar laws also exist in the United Kingdom and most other countries.

In some countries, it is also an offense to serve alcohol to an already-intoxicated person, and, often, alcohol can be sold only by persons qualified to serve responsibly through alcohol server training.

The blood alcohol content (BAC) for legal operation of a vehicle is typically measured as a percentage of a unit volume of blood. This percentage ranges from 0.00% in Romania and the United Arab Emirates; to 0.05% in Australia, South Africa, Germany, Scotland and New Zealand (but 0.00% for under 20 year olds); to 0.08% in England and Wales, the United States and Canada.

The United States Federal Aviation Administration prohibits crew members from performing their duties within eight hours of consuming an alcoholic beverage, while under the influence of alcohol, or with a BAC greater than 0.04%.

In the United States, the United Kingdom, and Australia, public intoxication is a crime (also known as "being drunk and disorderly" or "being drunk and incapable").

In some countries, there are special facilities, sometimes known as "drunk tanks", for the temporary detention of persons found to be drunk.

Religious views

Some religious groups permit the consumption of alcohol. Some permit consumption but prohibit intoxication, while others prohibit alcohol consumption altogether. Many Christian denominations such as Catholic, Orthodox, and Lutheran use wine as a part of the Eucharist and permit the drinking of alcohol but consider it sinful to become intoxicated.

In the Bible, the book of Proverbs contains several chapters dealing with the bad effects of drunkenness and warning to stay away from intoxicating beverages. The book of Leviticus tells of Nadab and Abihu, Aaron the Priest's eldest sons, who were killed for serving in the temple after drinking wine, presumably while intoxicated. The book continues to discuss monasticism where drinking wine is prohibited. The story of Samson in the Book of Judges tells of a monk from the tribe of Dan who is prohibited from cutting his hair and drinking wine. Romans 13:13–14, 1 Corinthians 6:9–11, Galatians 5:19–21, and Ephesians 5:18 are among a number of other Bible passages that speak against drunkenness. While Proverbs 31:4, warns against kings and rulers drinking wine and strong drink, Proverbs 31:6–7 promotes giving strong drink to the perishing and wine to those whose lives are bitter, to forget their poverty and troubles.

Some Protestant Christian denominations prohibit the drinking of alcohol based upon Biblical passages that condemn drunkenness, but others allow moderate use of alcohol. In some Christian groups, a small amount of wine is part of the rite of communion.

In the Church of Jesus Christ of Latter-day Saints, alcohol consumption is forbidden, and teetotalism has become a distinguishing feature of its members. Jehovah's Witnesses allow moderate alcohol consumption among its members.

In the Qur'an, there is a prohibition on the consumption of grape-based alcoholic beverages, and intoxication is considered as an abomination in the Hadith. Islamic schools of law (Madh'hab) have interpreted this as a strict prohibition of the consumption of all types of alcohol and declared it to be haraam ("forbidden"), although other uses may be permitted.

In Buddhism, in general, the consumption of intoxicants is discouraged for both monastics and lay followers. Many followers of Buddhism observe a code of conduct known as the five precepts, of which the fifth precept is an undertaking to refrain from the consumption of intoxicating substances (except for medical reasons). In the bodhisattva vows of the Brahma Net Sūtra, observed by Mahāyāna Buddhist communities, distribution of intoxicants is likewise discouraged, as well as consumption.

In the branch of Hinduism known as Gaudiya Vaishnavism, one of the four regulative principles forbids the taking of intoxicants, including alcohol.

In Judaism, in accordance with the biblical stance against drinking, wine drinking was not permitted for priests and monks. The biblical command to sanctify the Sabbath day and other holidays has been interpreted as having three ceremonial meals which include drinking of wine, the Kiddush. The Jewish marriage ceremony ends with the bride and groom drinking a shared cup of wine after reciting seven blessings, and according to western "Ashkenazi" traditions, after a fast day. But it has been customary and in many cases even mandated to drink moderately so as to stay sober, and only after the prayers are over.

During the Seder night on Passover (Pesach) there is an obligation to drink 4 ceremonial cups of wine, while reciting the Haggadah. It has been assumed as the source for the wine drinking ritual at the communion in some Christian groups. During Purim there is an obligation to become intoxicated, although, as with many other decrees, in many communities this has been avoided, by allowing sleep during the day to replace it.

In the 1920s due to the new beverages law, a rabbi from the Reform Judaism movement proposed using grape-juice for the ritual instead of wine. Although refuted at first, the practice became widely accepted by orthodox Jews as well.

At the Cave of the Patriarchs in Hebron—the Ibrahimi Mosque as it is called by the Muslims, the Jewish wine drinking rituals during weddings, the Sabbath day and holidays, are a cause for tension with the Muslims who unwillingly share the site under Israeli authority.

Other animals

In the movie Animals are Beautiful People, an entire section was dedicated to showing many different animals including monkeys, elephants, hogs, giraffes, and ostriches, eating over-ripe marula tree fruit causing them to sway and lose their footing in a manner similar to human drunkenness. Birds may become intoxicated with fermented berries and some die colliding with hard objects when flying under the influence.

In elephant warfare, practiced by the Greeks during the Maccabean revolt and by Hannibal during the Punic wars, it has been recorded that the elephants would be given wine before the attack, and only then would they charge forward after being agitated by their driver.

It is a regular practice to give small amounts of beer to race horses in Ireland. Ruminant farm animals have natural fermentation occurring in their stomach, and adding alcoholic beverages in small amounts to their drink will generally do them no harm, and will not cause them to become drunk.

Alcohol (drug)

From Wikipedia, the free encyclopedia

Ethanol

Clinical data
Pronunciation	/ˈɛθənɒl/
Synonyms	Absolute alcohol; Alcohol (USP); Cologne spirit; Drinking alcohol; Ethanol (JAN); Ethylic alcohol; EtOH; Ethyl alcohol; Ethyl hydrate; Ethyl hydroxide; Ethylol; Grain alcohol; Hydroxyethane; Methylcarbinol
Pregnancy category	US: C (Risk not ruled out)
Dependence liability	Moderate
Addiction liability	Moderate (10–15%)
Routes of administration	Common: by mouth, topical Uncommon: suppository, inhalation, ocular, insufflation, injection
Drug class	Central depressants; Sedatives; Anxiolytics; Euphoriants; GABAA receptor positive modulators
Pharmacokinetic data
Bioavailability	80%+
Protein binding	Weakly or not at all
Metabolism	Liver (90%):• Alcohol dehydrogenase • MEOS (CYP2E1)
Metabolites	Acetaldehyde; Acetate; Acetyl-CoA; Carbon dioxide; Water; Ethyl glucuronide; Ethyl sulfate
Onset of action	Peak concentrations: • Range: 30–90 minutes • Mean: 45–60 minutes • Fasting: 30 minutes
Elimination half-life	Constant-rate elimination at typical concentrations: • Range: 10–34 mg/dL/hour • Mean (men): 15 mg/dL/hour • Mean (women): 18 mg/dL/hr At very high concentrations (t1/2): 4.0–4.5 hours
Duration of action	6–16 hours (amount of time that levels are detectable)
Excretion	• Major: metabolism (into carbon dioxide and water) • Minor: urine, breath, sweat (5–10%)
Chemical and physical data
Formula	C2H6O
Molar mass	46.0684 g/mol
Density	0.7893 g/cm3 (at 20 °C)
Melting point	−114.14 ± 0.03 °C (−173.45 ± 0.05 °F)
Boiling point	78.24 ± 0.09 °C (172.83 ± 0.16 °F)
Solubility in water	1000mg/mL (at 25 °C)

Alcohol, also known by its chemical name ethanol, is a psychoactive substance that is the active ingredient in drinks such as beer, wine, and distilled spirits (hard liquor). It is one of the oldest and most common recreational substances, causing the characteristic effects of alcohol intoxication ("drunkenness"). Among other effects, alcohol produces a mood lift and euphoria, decreased anxiety, increased sociability, sedation, impairment of cognitive, memory, motor, and sensory function, and generalized depression of central nervous system function. Ethanol is a type of chemical compound known as an alcohol, and is the only type of alcohol that is found in alcoholic beverages or is commonly used for recreational purposes; other alcohols such as methanol and isopropyl alcohol are toxic.

Alcohol has a variety of short-term and long-term adverse effects. Short-term adverse effects include generalized impairment of neurocognitive function, dizziness, nausea, vomiting, and hangover-like symptoms. Alcohol can be addictive to humans, as in alcoholism, and can result in dependence and withdrawal. It can have a variety of long-term adverse effects on health, for instance liver damage, brain damage, and increased risk of cancer. The adverse effects of alcohol on health are most important when it is used in excessive quantities or with heavy frequency. However, some of them, such as increased risk of certain cancers, may occur even with light or moderate alcohol consumption. In high amounts, alcohol may cause loss of consciousness or, in severe cases, death.

Alcohol works in the brain primarily by increasing the effects of a neurotransmitter called γ-aminobutyric acid, or GABA. This is the major inhibitory neurotransmitter in the brain, and by facilitating its actions, alcohol suppresses the activity of the central nervous system. The substance also directly affects a number of other neurotransmitter systems including those of glutamate, glycine, acetylcholine, and serotonin. The pleasurable effects of alcohol ingestion are the result of increased levels of dopamine and endogenous opioids in the reward pathways of the brain.Alcohol also has toxic and unpleasant actions in the body, many of which are mediated by its byproduct acetaldehyde.

Alcohol has been produced and consumed by humans for its psychoactive effects for almost 10,000 years. Drinking alcohol is generally socially acceptable and is legal in most countries, unlike with many other recreational substances. However, there are often restrictions on alcohol sale and use, for instance a minimum age for drinking and laws against public drinking and drinking and driving. Alcohol has considerable societal and cultural significance and has important social roles in much of the world. Drinking establishments, such as bars and nightclubs, revolve primarily around the sale and consumption of alcoholic beverages, and parties, festivals, and social gatherings commonly feature alcohol consumption as well. Alcohol use is also related to various societal problems, including driving accidents and fatalities, accidental injuries, sexual assaults, domestic abuse, and violent crime. Currently, alcohol is illegal for sale and consumption in Iran, Libya, Sudan, Saudi Arabia, Kuwait, Afghanistan, Somalia, Yemen, and Bangladesh.

Use and effects

Ethanol is typically consumed as a recreational substance by mouth in the form of alcoholic beverages such as beer, wine, and spirits. It is commonly used in social settings due to its capacity to enhance sociability.

The amount of ethanol in the body is typically quantified by blood alcohol content (BAC); weight of ethanol per unit volume of blood. Small doses of ethanol, in general, are stimulant-like and produce euphoria and relaxation; people experiencing these symptoms tend to become talkative and less inhibited, and may exhibit poor judgement. At higher dosages (BAC > 1 g/L), ethanol acts as a central nervous system depressant, producing at progressively higher dosages, impaired sensory and motor function, slowed cognition, stupefaction, unconsciousness, and possible death. Ethanol is commonly consumed as a recreational substance, especially while socializing, due to its psychoactive effects.

Ethanol, alcohol increases levels of high-density lipoproteins (HDLs), which carry cholesterol through the blood. Alcohol is known to make blood less likely to clot, reducing risk of heart attack and stroke. This could be the reason that alcohol produces health benefits when consumed in moderate amounts. Also, alcohol dilates blood vessels. Consequently, a person feels warmer, and their skin may flush and appear pink.

Caloric content

Ethanol is a source of energy and pure ethanol provides 7 calories per gram. For distilled spirits, a standard serving in the United States is 44 ml (1.5 US fl oz), which at 40% ethanol (80 proof), would be 14 grams and 98 calories. Wine and beer contain a similar range of ethanol for servings of 150 ml (5 US fl oz) and 350 ml (12 US fl oz), respectively, but these beverages also contain non-ethanol calories. A 150 ml serving of wine contains 100 to 130 calories. A 350 ml serving of beer contains 95 to 200 calories. According to the U.S. Department of Agriculture, based on NHANES 2013–2014 surveys, women in the US ages 20 and up consume on average 6.8 grams/day and men consume on average 15.5 grams/day. Ignoring the non-alcohol contribution of those beverages, the average ethanol calorie contributions are 48 and 108 cal/day, respectively. Alcoholic beverages are considered empty calorie foods because other than calories, these contribute no essential nutrients.

Adverse effects

Addiction experts in psychiatry, chemistry, pharmacology, forensic science, epidemiology, and the police and legal services engaged in delphic analysis regarding 20 popular recreational substances. Alcohol was ranked 6th in dependence, 11th in physical harm, and 2nd in social harm.

Alcohol has a variety of short-term and long-term adverse effects. It also has reinforcement-related adverse effects, including addiction, dependence, and withdrawal.

Short-term effects

Central depression

Alcohol causes generalized central nervous system depression and associated cognitive, memory, motor, and sensory impairment. It slows and impairs cognition and reaction time, reduces inhibition and impairs judgement, interferes with motor function resulting in motor incoordination, loss of balance, and slurred speech, impairs memory formation, and causes sensory impairment. At high concentrations, amnesia, stupor, and unconsciousness result.

At very high concentrations, markedly decreased heart rate, respiratory depression, and death can result due to profound suppression of central nervous system function and consequent shutdown of vegetative functions.

Gastrointestinal effects

Diagram of mucosal layer

Alcohol can cause nausea and vomiting in sufficiently high amounts (varies by person).

Alcohol stimulates gastric juice production, even when food is not present, and as a result, its consumption stimulates acidic secretions normally intended to digest protein molecules. Consequently, the excess acidity may harm the inner lining of the stomach. The stomach lining is normally protected by a mucosal layer that prevents the stomach from, essentially, digesting itself. However, in patients who have a peptic ulcer disease (PUD), this mucosal layer is broken down. PUD is commonly associated with the bacteria H. pylori. H. pylori secrete a toxin that weakens the mucosal wall, which as a result lead to acid and protein enzymes penetrating the weakened barrier. Because alcohol stimulates a person's stomach to secrete acid, a person with PUD should avoid drinking alcohol on an empty stomach. Drinking alcohol causes more acid release, which further damages the already-weakened stomach wall. Complications of this disease could include a burning pain in the abdomen, bloating and in severe cases, the presence of dark black stools indicate internal bleeding. A person who drinks alcohol regularly is strongly advised to reduce their intake to prevent PUD aggravation.

Ingestion of alcohol can initiate systemic pro-inflammatory changes through two intestinal routes: (1) altering intestinal microbiota composition (dysbiosis), which increases lipopolysaccharide (LPS) release, and (2) degrading intestinal mucosal barrier integrity – thus allowing this (LPS) to enter the circulatory system. The major portion of the blood supply to the liver is provided by the portal vein. Therefore, while the liver is continuously fed nutrients from the intestine, it is also exposed to any bacteria and/or bacterial derivatives that breach the intestinal mucosal barrier. Consequently, LPS levels increase in the portal vein, liver and systemic circulation after alcohol intake. Immune cells in the liver respond to LPS with the production of reactive oxygen species (ROS), leukotrienes, chemokines and cytokines. These factors promote tissue inflammation and contribute to organ pathology.

Allergic-like reactions

Ethanol-containing beverages can cause urticarial skin eruptions, systemic dermatitis, alcohol flush reactions, exacerbations of rhinitis and, more seriously and commonly, bronchoconstriction in patients with a history of asthma. These reactions occur within 1–60 minutes of ethanol ingestion and are due to: 1) genetic abnormalities in the metabolism of ethanol, which cause the ethanol metabolite, acetaldehyde, to accumulate in tissues and trigger the release of histamine, the evoker of these symptoms; 2) true allergy reactions to allergens occurring naturally in, or contaminating, alcoholic beverages, particularly wines and beers, and 3) unknown causes.

Long-term effects

Prolonged heavy consumption of alcohol can cause significant permanent damage to the brain and other organs.

Brain damage

Alcohol can cause permanent brain damage. An extreme example is Wernicke–Korsakoff syndrome.

Liver disease

During the metabolism of alcohol via the respective dehydrogenases, NAD (nicotinamide adenine dinucleotide) is converted into reduced NAD. Normally, NAD is used to metabolize fats in the liver, and as such alcohol competes with these fats for the use of NAD. Prolonged exposure to alcohol means that fats accumulate in the liver, leading to the term 'fatty liver'. Continued consumption (such as in alcoholism) then leads to cell death in the hepatocytes as the fat stores reduce the function of the cell to the point of death. These cells are then replaced with scar tissue, leading to the condition called cirrhosis.

Birth defects

Ethanol is classified as a teratogen. According to the CDC, alcohol consumption by women of child-bearing age who are not using birth control increases the risk of fetal alcohol syndrome. The CDC currently recommends complete abstinence from alcoholic beverages.

Cancer

IARC list ethanol in alcoholic beverages as Group 1 carcinogens and argues that "There is sufficient evidence for the carcinogenicity of acetaldehyde (the major metabolite of ethanol) in experimental animals."

Other effects

Frequent drinking of alcoholic beverages is a major contributing factor in cases of elevated blood levels of triglycerides.

Reinforcement disorders

Addiction

Alcohol consumption is rewarding and reinforcing and can result in addiction to alcohol, which is termed alcoholism.

Dependence and withdrawal

Discontinuation of alcohol after extended heavy use and associated tolerance development (resulting in dependence) can result in withdrawal. Alcohol withdrawal can cause confusion, anxiety, insomnia, agitation, tremors, fever, nausea, vomiting, autonomic dysfunction, seizures, and hallucinations. In severe cases, death can result. Delirium tremens is a condition that requires people with a long history of heavy drinking to undertake an alcohol detoxification regimen.

Overdose

Death from ethanol consumption is possible when blood alcohol levels reach 0.4%. A blood level of 0.5% or more is commonly fatal. Levels of even less than 0.1% can cause intoxication, with unconsciousness often occurring at 0.3–0.4%.

The oral median lethal dose (LD₅₀) of ethanol in rats is 5,628 mg/kg. Directly translated to human beings, this would mean that if a person who weighs 70 kg (150 lb) drank a 500 mL (17 US fl oz) glass of pure ethanol, they would theoretically have a 50% chance of dying. Symptoms of ethanol overdose may include nausea, vomiting, central nervous system depression, coma, acute respiratory failure, or death.

Interactions

Alcohol can intensify the sedation caused by other central nervous system depressants such as barbiturates, benzodiazepines, opioids, nonbenzodiazepines/Z-drugs (such as zolpidem and zopiclone), antipsychotics, sedative antihistamines, and certain antidepressants. It interacts with cocaine in vivo to produce cocaethylene, another psychoactive substance. Ethanol enhances the bioavailability of methylphenidate (elevated plasma dexmethylphenidate). In combination with cannabis, ethanol increases plasma tetrahydrocannabinol levels, which suggests that ethanol may increase the absorption of tetrahydrocannabinol.

Disulfiram-like drugs

Disulfiram

Disulfiram inhibits the enzyme acetaldehyde dehydrogenase, which in turn results in buildup of acetaldehyde, a toxic metabolite of ethanol with unpleasant effects. The medication is used to treat alcoholism, and results in immediate hangover-like symptoms upon consumption of alcohol.

Metronidazole

One of the most important drug/food interactions that should be noted is between alcohol and metronidazole.

Metronidazole is an antibacterial agent that kills bacteria by damaging cellular DNA and hence cellular function. Metronidazole is usually given to people who have diarrhea caused by Clostridium difficile bacteria. C. difficile is one of the most common microorganisms that cause diarrhea and can lead to complications such as colon inflammation and even more severely, death.

Patients who are taking metronidazole are strongly advised to avoid alcohol, even after 1 hour following the last dose. The reason is that alcohol and metronidazole can lead to side effects such as flushing, headache, nausea, vomiting, abdominal cramps, and sweating. These symptoms are often called the disulfiram-like reaction. The proposed mechanism of action for this interaction is that metronidazole can bind to an enzyme that normally metabolizes alcohol. Binding to this enzyme may impair the liver's ability to process alcohol for proper excretion.

Methanol and ethylene glycol

The rate-limiting steps for the elimination of ethanol are in common with certain other substances. As a result, the blood alcohol concentration can be used to modify the rate of metabolism of methanol and ethylene glycol. Methanol itself is not highly toxic, but its metabolites formaldehyde and formic acid are; therefore, to reduce the rate of production and concentration of these harmful metabolites, ethanol can be ingested. Ethylene glycol poisoning can be treated in the same way.

Pharmacology

Pharmacodynamics

Despite extensive research, the precise mechanism of action of ethanol has proven elusive and remains not fully understood. Identifying molecular targets for ethanol has proven unusually difficult, in large part due to its unique biochemical properties. Specifically, ethanol is a very low molecular weight compound and is of exceptionally low potency in its actions, causing effects only at very high (millimolar (mM)) concentrations. For these reasons, unlike with most drugs, it has not yet been possible to employ traditional biochemical techniques to directly assess the binding of ethanol to receptors or ion channels. Instead, researchers have had to rely on functional studies to elucidate the actions of ethanol. Moreover, although it has been established that ethanol modulates ion channels to mediate its effects, ion channels are complex proteins, and their interactions and functions are complicated by diverse subunit compositions.

In spite of the preceding however, much progress has been made in understanding the pharmacodynamics of ethanol over the last few decades. While no binding sites have been identified and established unambiguously for ethanol at present, it appears that it affects ion channels, in particular ligand-gated ion channels, to mediate its effects in the central nervous system. Ethanol has specifically been found in functional assays to enhance or inhibit the activity of a variety of ion channels, including the GABA_A receptor, the ionotropic glutamate AMPA, kainate, and NMDA receptors, the glycine receptor, the nicotinic acetylcholine receptors, the serotonin 5-HT₃ receptor, voltage-gated calcium channels, and BK channels, among others. However, many of these actions have been found to occur only at very high concentrations that may not be pharmacologically significant at recreational doses of ethanol, and it is unclear how or to what extent each of the individual actions is involved in the effects of ethanol. In any case, ethanol has long shown a similarity in its effects to positive allosteric modulators of the GABA_A receptor like benzodiazepines, barbiturates, and various general anesthetics. Indeed, ethanol has been found to enhance GABA_A receptor-mediated currents in functional assays. In accordance, it is theorized and widely believed that the primary mechanism of action is as a GABA_A receptor positive allosteric modulator. However, the diverse actions of ethanol on other ion channels may be and indeed likely are involved in its effects as well.

In 2007, it was discovered that ethanol directly binds to and potentiates extrasynaptic δ subunit-containing GABA_A receptors at behaviorally relevant (as low as 3 mM) concentrations. This is in contrast to previous functional assays of ethanol on γ subunit-containing GABA_A receptors, which it enhances only at far higher concentrations (> 100 mM) that are in excess of recreational concentrations (up to 50 mM). Ro15-4513, a close analogue of the benzodiazepine antagonist flumazenil (Ro15-1788), has been found to bind to the same site as ethanol and to competitively displace it in a saturable manner. In addition, Ro15-4513 blocked the enhancement of δ subunit-containing GABA_A receptor currents by ethanol in vitro. In accordance, the drug has been found to reverse many of the behavioral effects of low-to-moderate doses of ethanol in rodents, including its effects on anxiety, memory, motor behavior, and self-administration. Taken together, these findings suggest a binding site for ethanol on subpopulations of the GABA_A receptor with specific subunit compositions via which it interacts with and potentiates the receptor.

Rewarding and reinforcing actions

The reinforcing effects of alcohol consumption are mediated by acetaldehyde generated by catalase and other oxidizing enzymes such as cytochrome P-4502E1 in the brain. Although acetaldehyde has been associated with some of the adverse and toxic effects of ethanol, it appears to play a central role in the activation of the mesolimbic dopamine system.

Ethanol's rewarding and reinforcing (i.e., addictive) properties are mediated through its effects on dopamine neurons in the mesolimbic reward pathway, which connects the ventral tegmental area to the nucleus accumbens (NAcc). One of ethanol's primary effects is the allosteric inhibition of NMDA receptors and facilitation of GABA_A receptors (e.g., enhanced GABA_A receptor-mediated chloride flux through allosteric regulation of the receptor). At high doses, ethanol inhibits most ligand-gated ion channels and voltage-gated ion channels in neurons as well.

With acute alcohol consumption, dopamine is released in the synapses of the mesolimbic pathway, in turn heightening activation of postsynaptic D₁ receptors. The activation of these receptors triggers postsynaptic internal signaling events through protein kinase A, which ultimately phosphorylate cAMP response element binding protein (CREB), inducing CREB-mediated changes in gene expression.

With chronic alcohol intake, consumption of ethanol similarly induces CREB phosphorylation through the D₁ receptor pathway, but it also alters NMDA receptor function through phosphorylation mechanisms; an adaptive downregulation of the D₁ receptor pathway and CREB function occurs as well. Chronic consumption is also associated with an effect on CREB phosphorylation and function via postsynaptic NMDA receptor signaling cascades through a MAPK/ERK pathway and CAMK-mediated pathway. These modifications to CREB function in the mesolimbic pathway induce expression (i.e., increase gene expression) of ΔFosB in the NAcc, where ΔFosB is the "master control protein" that, when overexpressed in the NAcc, is necessary and sufficient for the development and maintenance of an addictive state (i.e., its overexpression in the nucleus accumbens produces and then directly modulates compulsive alcohol consumption).

Relationship between concentrations and effects

Blood alcohol levels and effects

mg/dL	mM	% v/v	Effects
50	11	0.05%	Euphoria, talkativeness, relaxation
100	22	0.1%	Central nervous system depression, nausea, possible vomiting, impaired motor and sensory function, impaired cognition
>140	30	>0.14%	Decreased blood flow to brain
300	65	0.3%	Stupefaction, possible unconsciousness
400	87	0.4%	Possible death
500	109	>0.55%	Death

Recreational concentrations of ethanol are typically in the range of 1 to 50 mM. Very low concentrations of 1 to 2 mM ethanol produce zero or undetectable effects except in alcohol-naive individuals. Slightly higher levels of 5 to 10 mM, which are associated with light social drinking, produce measurable effects including changes in visual acuity, decreased anxiety, and modest behavioral disinhibition. Further higher levels of 15 to 20 mM result in a degree of sedation and motor incoordination that is contraindicated with the operation of motor vehicles. In jurisdictions in the United States, maximum blood alcohol levels for legal driving are about 17 to 22 mM. In the upper range of recreational ethanol concentrations of 20 to 50 mM, depression of the central nervous system is more marked, with effects including complete drunkenness, profound sedation, amnesia, emesis, hypnosis, and eventually unconsciousness. Levels of ethanol above 50 mM are not typically experienced by normal individuals and hence are not usually physiologically relevant; however, such levels – ranging from 50 to 100 mM – may be experienced by alcoholics with high tolerance to ethanol. Concentrations above this range, specifically in the range of 100 to 200 mM, would cause death in all people except alcoholics.

List of known actions of ethanol

Ethanol has been reported to possess the following actions in functional assays at varying concentrations:

• GABA_A receptor positive allosteric modulator (primarily of δ subunit-containing receptors)
• NMDA receptor negative allosteric modulator
• Increased levels of dopamine and endogenous opioids in the mesolimbic pathway, secondary to other actions
• AMPA receptor negative allosteric modulator
• Kainate receptor negative allosteric modulator
• Glycine receptor positive allosteric modulator
• Nicotinic acetylcholine receptor positive allosteric modulator
• 5-HT₃ receptor positive allosteric modulator
• Glycine reuptake inhibitor
• Adenosine reuptake inhibitor
• L-type calcium channel blocker
• GIRK channel opener

Some of the actions of ethanol on ligand-gated ion channels, specifically the nicotinic acetylcholine receptors and the glycine receptor, are dose-dependent, with potentiation or inhibition occurring dependent on ethanol concentration. This seems to be because the effects of ethanol on these channels are a summation of positive and negative allosteric modulatory actions.

Pharmacokinetics

Absorption

Ethanol can be taken orally, by inhalation, rectally, or by injection (e.g., intravenous), though it is typically ingested simply via oral administration. The oral bioavailability of ethanol is around 80% or more. In fasting volunteers, blood levels of ethanol increase proportionally with the dose of ethanol administered. Blood alcohol concentrations may be estimated by dividing the amount of ethanol ingested by the body weight of the individual and correcting for water dilution. Peak circulating levels of ethanol are usually reached within a range of 30 to 90 minutes of ingestion, with an average of 45 to 60 minutes.

Food in the gastrointestinal system and hence gastric emptying is the most important factor that influences the absorption of orally ingested ethanol. The absorption of ethanol is much more rapid on an empty stomach than with a full one. The delay in ethanol absorption caused by food is similar regardless of whether food is consumed just before, at the same time, or just after ingestion of ethanol. The type of food, whether fat, carbohydrates, or protein, also is of little importance. Not only does food slow the absorption of ethanol, but it also reduces the bioavailability of ethanol, resulting in lower circulating concentrations. People who have fasted overnight have been found to reach peak ethanol concentrations more rapidly, at within 30 minutes of ingestion.

Distribution

Upon ingestion, ethanol is rapidly distributed throughout the body. It is distributed most rapidly to tissues with the greatest blood supply. As such, ethanol primarily affects the brain, liver, and kidneys. Other tissues with lower circulation, such as bone, require more time for ethanol to distribute into. Ethanol crosses biological membranes and the blood–brain barrier easily, through a simple process of passive diffusion. The volume of distribution of ethanol is around .55 L/kg (0.53 US pt/lb). It is only weakly or not at all plasma protein bound.

Metabolism

Approximately 90% of the metabolism of ethanol occurs in the liver. This occurs predominantly via the enzyme alcohol dehydrogenase, which transforms ethanol into its metabolite acetaldehyde (ethanal). Acetaldehyde is subsequently metabolized by the enzyme aldehyde dehydrogenase into acetate (ethanoate), which in turn is broken down into carbon dioxide and water. Acetate also combines with coenzyme A to form acetyl-CoA, and hence may participate in metabolic pathways. Alcohol dehydrogenase and aldehyde dehydrogenase are present at their highest concentrations in the liver, but are widely expressed throughout the body, and alcohol dehydrogenase may also be present in the stomach and small intestine. Aside from alcohol dehydrogenase, the microsomal ethanol-oxidizing system (MEOS), specifically mediated by the cytochrome P450 enzyme CYP2E1, is the other major route of ethanol metabolism. CYP2E1 is inducible by ethanol, so while alcohol dehydrogenase handles acute or low concentrations of ethanol, MEOS is predominant with higher concentrations or with repeated/chronic use. A small amount of ethanol undergoes conjugation to form ethyl glucuronide and ethyl sulfate. There may also be another metabolic pathway that metabolizes as much as 25 to 35% of ethanol at typical concentrations.

At even low physiological concentrations, ethanol completely saturates alcohol dehydrogenase. This is because ethanol has high affinity for the enzyme and very high concentrations of ethanol occur when it is used as a recreational substance. For this reason, the metabolism of ethanol follows zero-order kinetics at typical physiological concentrations. That is, ethanol does not have an elimination half-life (i.e., is not metabolized at an exponential rate), and instead, is eliminated from the circulation at a constant rate. The mean elimination rates for ethanol are 15 mg/dL per hour for men and 18 mg/dL per hour for women, with a range of 10 to 34 mg/dL per hour. At very high concentrations, such as in overdose, it has been found that the rate of elimination of ethanol is increased. In addition, ethanol metabolism follows first-order kinetics at very high concentrations, with an elimination half-life of about 4 or 4.5 hours (which implies a clearance rate of approximately 6 L/hour/70 kg). This seems to be because other processes, such as the MEOS/CYP2E1, also become involved in the metabolism of ethanol at higher concentrations. However, the MEOS/CYP2E1 alone does not appear sufficient to fully explain the increase in ethanol metabolism rate.

Some individuals have less effective forms of one or both of the metabolizing enzymes of ethanol, and can experience more marked symptoms from ethanol consumption than others. However, those having acquired alcohol tolerance have a greater quantity of these enzymes, and metabolize ethanol more rapidly.

Elimination

Ethanol is mainly eliminated from the body via metabolism into carbon dioxide and water. Around 5 to 10% of ethanol that is ingested is eliminated unchanged in urine, breath, and sweat. Ethanol or its metabolites may be detectable in urine for up to 96 hours after ingestion.

Chemistry

Ethanol is also known chemically as alcohol, ethyl alcohol, or drinking alcohol. It is a simple alcohol with a molecular formula of C₂H₆O and a molecular weight of 46.0684 g/mol. The molecular formula of ethanol may also be written as CH₃−CH₂−OH or as C₂H₅−OH. The latter can also be thought of as an ethyl group linked to a hydroxyl (alcohol) group and can be abbreviated as EtOH. Ethanol is a volatile, flammable, colorless liquid with a slight characteristic odor. Aside from its use as a psychoactive and recreational substance, ethanol is also commonly used as an antiseptic and disinfectant, a chemical and medicinal solvent, and a fuel.

Production

Ethanol is produced naturally as a byproduct of the metabolic processes of yeast and hence is present in any yeast habitat, including even endogenously in humans. It is manufactured as a petrochemical through hydration of ethylene or by brewing via fermentation of sugars with yeast (most commonly Saccharomyces cerevisiae). In the case of the latter, the sugars are commonly obtained from sources like steeped cereal grains (e.g., barley), grape juice, and sugarcane products (e.g., molasses, sugarcane juice). Petrochemical and yeast manufacturing routes both produce an ethanol–water mixture which can be further purified via distillation.

Analogues

Ethanol has a variety of analogues, many of which have similar actions and effects. Methanol (methyl alcohol) and isopropyl alcohol are toxic and are not safe for human consumption. Methanol is the most toxic alcohol; the toxicity of isopropyl alcohol lies between that of ethanol and methanol, and is about twice that of ethanol. In general, higher alcohols are less toxic. n-Butanol is reported to produce similar effects to those of ethanol and relatively low toxicity (one-sixth of that of ethanol in one rat study). However, its vapors can produce eye irritation and inhalation can cause pulmonary edema. Acetone (propanone) is a ketone rather than an alcohol, and is reported to produce similar toxic effects; it can be extremely damaging to the cornea.

The tertiary alcohol tert-amyl alcohol (TAA), also known as 2-methylbutan-2-ol (2M2B), has a history of use as a hypnotic and anesthetic, as do other tertiary alcohols such as methylpentynol, ethchlorvynol, and chloralodol. Unlike primary alcohols like ethanol, these tertiary alcohols cannot be oxidized into aldehyde or carboxylic acid metabolites, which are often toxic, and for this reason, these compounds are safer in comparison. Other relatives of ethanol with similar effects include chloral hydrate, paraldehyde, and many volatile and inhalational anesthetics (e.g., chloroform, diethyl ether, and isoflurane).

History

Alcohol was brewed as early as 7,000 to 6,650 BCE in northern China. The earliest evidence of winemaking was dated at 6,000 to 5,800 BCE in Georgia in the South Caucasus. Beer was likely brewed from barley as early as the 6th century BCE (600–500 BCE) in Egypt. Pliny the Elder wrote about the golden age of winemaking in Rome, the 2nd century BCE (200–100 BCE), when vineyards were planted.

Society and culture

Legal status

Alcohol is legal in most of the world. However, laws banning alcohol are found in the Middle East and some Indian states as well as some Native American reservations in the United States. In addition, there are strict regulations on alcohol sales and use in many countries throughout the world. For instance, most countries have a minimum legal age for purchase and consumption of alcohol (e.g., 21 years of age in the United States). Also, many countries have bans on public drinking. Drinking while driving or intoxicated driving is frequently outlawed and it may be illegal to have an open container of alcohol in an automobile.

Societal problems

Alcohol causes a plethora of detrimental effects in society, both to the individual and to others. It is highly associated with automobile accidents, sexual assaults, and both violent and non-violent crime. About one-third of arrests in the United States involve alcohol abuse. Many emergency room visits also involve alcohol use. As many as 15% of employees show problematic alcohol-related behaviors in the workplace, such as drinking before going to work or even drinking on the job. Heavy drinking is associated with vulnerability to injury, marital discord, and domestic violence. Alcohol use is directly related to considerable morbidity and mortality, for instance due to overdose and alcohol-related health problems.

Automobile accidents

A 2002 study found 41% of people fatally injured in traffic accidents were in alcohol-related crashes. Abuse of alcohol is associated with more than 40% of deaths that occur in automobile accidents every year. The risk of a fatal car accident increases exponentially with the level of alcohol in the driver's blood. Most drunk driving laws in the United States governing the acceptable levels in the blood while driving or operating heavy machinery set typical upper limits of legal blood alcohol content (BAC) at 0.08%.

Sexual assault

Alcohol is often used to facilitate sexual assault or rape. Over 50% of all rapes involve alcohol. It is the most commonly used date rape drug.

Violent crime

Over 40% of all assaults and 40 to 50% of all murders involve alcohol. More than 43% of violent encounters with police involve alcohol. Alcohol is implicated in more than two-thirds of cases of intimate partner violence. In 2002, it was estimated that 1 million violent crimes in the United States were related to alcohol use. Alcohol is more commonly associated with both violent and non-violent crime than are drugs like marijuana.

Health consequences

Alcohol abuse and dependence are major problems and many health problems as well as death can result from excessive alcohol use. Alcohol dependence is linked to a lifespan that is reduced by about 12 years relative to the average person. In 2004, it was estimated that 4% of deaths worldwide were attributable to alcohol use. Deaths from alcohol are split about evenly between acute causes (e.g., overdose, accidents) and chronic conditions. The leading chronic alcohol-related condition associated with death is alcoholic liver disease. Alcohol dependence is also associated with cognitive impairment and organic brain damage. Some researchers have found that even one alcoholic drink a day increases an individual's risk of health problems.