Alcohol (drug)

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Ethanol
Ethanol-2D-skeletal.svg
Ethanol-3D-balls.png Ethanol-3D-vdW.png
Clinical data
Pronunciation /ˈɛθənɒl/
Other namesAbsolute 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 [1]
    Addiction
    liability
    Moderate (10–15%) [2]
    Routes of
    administration
    Common: by mouth, topical
    Uncommon: suppository, inhalation, ocular, insufflation, [3] injection [4]
    Drug class Analgesic; Depressants; Sedatives; Anxiolytics; Euphoriants; GABAA receptor positive modulators
    ATC code
    Legal status
    Legal status
    Pharmacokinetic data
    Bioavailability 80%+ [5] [6]
    Protein binding Weakly or not at all [5] [6]
    Metabolism Liver (90%): [7] [8]
    Alcohol dehydrogenase
    MEOS (CYP2E1)
    Metabolites Acetaldehyde; Acetate; Acetyl-CoA; Carbon dioxide; Water; Ethyl glucuronide; Ethyl sulfate
    Onset of action Peak concentrations: [7] [5]
    • Range: 30–90 minutes
    • Mean: 45–60 minutes
    Fasting: 30 minutes
    Elimination half-life Constant-rate elimination at typical concentrations: [9] [8] [7]
    • 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 [6] [5]
    Duration of action 6–16 hours (amount of time that levels are detectable) [10]
    Excretion • Major: metabolism (into carbon dioxide and water) [5]
    • Minor: urine, breath, sweat (5–10%) [7] [5]
    Identifiers
    CAS Number
    PubChem CID
    IUPHAR/BPS
    DrugBank
    ChemSpider
    UNII
    KEGG
    ChEBI
    ChEMBL
    PDB ligand
    Chemical and physical data
    Formula C2H6O
    Molar mass 46.0684 g/mol g·mol−1
    3D model (JSmol)
    Density 0.7893 g/cm3 (at 20 °C) [11]
    Melting point −114.14 ± 0.03 °C (−173.45 ± 0.05 °F) [11]
    Boiling point 78.24 ± 0.09 °C (172.83 ± 0.16 °F) [11]
    Solubility in water 1000mg/mL (at 25 °C) [12]

    Alcohol, sometimes referred to by the chemical name ethanol, is a psychoactive drug that is the active ingredient in drinks such as beer, wine, and distilled spirits (hard liquor). [13] It is one of the oldest and most common recreational substances, causing the characteristic effects of alcohol intoxication ("drunkenness"). [14] 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 only one of several types of alcohol, but it is the only type of alcohol that is found in alcoholic beverages or commonly used for recreational purposes; other alcohols such as methanol and isopropyl alcohol are toxic. [13]

    Contents

    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, [15] brain damage, [16] and its consumption is the fifth leading cause of cancer. [17] [ failed verification ] 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. [18] 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. [19] This is the major inhibitory neurotransmitter in the brain, and by facilitating its actions, alcohol suppresses the activity of the central nervous system. [19] The substance also directly affects a number of other neurotransmitter systems including those of glutamate, glycine, acetylcholine, and serotonin. [20] [21] The pleasurable effects of alcohol ingestion are the result of increased levels of dopamine and endogenous opioids in the reward pathways of the brain. [22] [23] Alcohol also has toxic and unpleasant actions in the body, many of which are mediated by its byproduct acetaldehyde. [24]

    Alcohol has been produced and consumed by humans for its psychoactive effects for almost 10,000 years. [25] 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. [26] 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. [27] Currently, alcohol is illegal for sale and consumption in a few mostly Middle Eastern countries.

    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 [28] 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, [28] 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. [29] [ better source needed ] 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. [30] [ better source needed ] Also, alcohol dilates blood vessels. Consequently, a person feels warmer, and their skin may flush and appear pink. [29] [ better source needed ]

    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 quantity for servings of 150 ml (5 US fl oz) and 350 ml (12 US fl oz), respectively, but these beverages also contain non-ethanol food energy. 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. [31] Ignoring the non-alcohol contribution of those beverages, the average energy contributions are 48 and 108 cal/day, respectively. Alcoholic beverages are considered empty calorie foods because other than food energy they contribute no essential nutrients.

    Drug harmfulness

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

    Social harm

    A 2010 study ranking various illegal and legal drugs based on statements by drug-harm experts. Alcohol was found to be the overall most dangerous drug, and the only drug that mostly damaged others. HarmCausedByDrugsTable.svg
    A 2010 study ranking various illegal and legal drugs based on statements by drug-harm experts. Alcohol was found to be the overall most dangerous drug, and the only drug that mostly damaged others.

    Alcohol causes considerable societal damage including suppression of psychological inhibitions, which may increase the risk for activities such as impulsive sex, drunk dialing, and alcohol-related crimes such as public intoxication, and drunk driving.

    Alcohol causes a plethora of detrimental effects in society, both to the individual and to others. [27] It is highly associated with automobile accidents, sexual assaults, and both violent and non-violent crime. [27] About one-third of arrests in the United States involve alcohol abuse. [27] Many emergency room visits also involve alcohol use. [27] 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. [27] Heavy drinking is associated with vulnerability to injury, marital discord, and domestic violence. [27] Alcohol use is directly related to considerable morbidity and mortality, for instance due to overdose and alcohol-related health problems. [33]

    Automobile accidents

    A 2002 study found 41% of people fatally injured in traffic accidents were in alcohol-related crashes. [34] Abuse of alcohol is associated with more than 40% of deaths that occur in automobile accidents every year. [27] The risk of a fatal car accident increases exponentially with the level of alcohol in the driver's blood. [35] 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%. [36]

    Sexual assault

    Alcohol is often used to facilitate sexual assault or rape. [37] [38] Over 50% of all rapes involve alcohol.[ clarification needed ] [27] It is the most commonly used date rape drug. [39]

    Violent crime

    Over 40% of all assaults and 40 to 50% of all murders involve alcohol. [27] More than 43% of violent encounters with police involve alcohol. [27] Alcohol is implicated in more than two-thirds of cases of intimate partner violence. [27] In 2002, it was estimated that 1 million violent crimes in the United States were related to alcohol use. [27] Alcohol is more commonly associated with both violent and non-violent crime than are drugs like marijuana. [27]

    Health consequences

    Alcohol abuse and dependence are major problems and many health problems as well as death can result from excessive alcohol use. [27] [33] Alcohol dependence is linked to a lifespan that is reduced by about 12 years relative to the average person. [27] In 2004, it was estimated that 4% of deaths worldwide were attributable to alcohol use. [33] Deaths from alcohol are split about evenly between acute causes (e.g., overdose, accidents) and chronic conditions. [33] The leading chronic alcohol-related condition associated with death is alcoholic liver disease. [33] Alcohol dependence is also associated with cognitive impairment and organic brain damage. [27] Some researchers have found that even one alcoholic drink a day increases an individual's risk of health problems. [40]

    Adverse effects

    Short-term 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. Rational harm assessment of drugs radar plot.svg
    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.

    Central nervous system impairment

    Alcohol causes generalized central nervous system depression and associated cognitive, memory, motor, and sensory impairment. It slows and impairs cognition and reaction time, 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, analgesia, spins, stupor, and unconsciousness result.

    At very high concentrations, anterograde amnesia, markedly decreased heart rate, pulmonary aspiration, positional alcohol nystagmus (PAN), respiratory depression, and death can result due to profound suppression of central nervous system function and consequent dysautonomia.

    Gastrointestinal effects

    Diagram of mucosal layer Stomach mucosal layer labeled.svg
    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. [42] 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. [43] A person who drinks alcohol regularly is strongly advised to reduce their intake to prevent PUD aggravation. [43]

    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. [44]

    Allergic-like reactions

    Ethanol-containing beverages can cause alcohol flush reactions, exacerbations of rhinitis and, more seriously and commonly, bronchoconstriction in patients with a history of asthma, and in some cases, urticarial skin eruptions, and systemic dermatitis. Such reactions can occur within 1–60 minutes of ethanol ingestion, and may be caused by: [45]

    • genetic abnormalities in the metabolism of ethanol, which can cause the ethanol metabolite, acetaldehyde, to accumulate in tissues and trigger the release of histamine, or
    • true allergy reactions to allergens occurring naturally in, or contaminating, alcoholic beverages (particularly wine and beer), and
    • other 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 brain damage, Wernicke's encephalopathy and Alcoholic Korsakoff syndrome (AKS) which frequently occur simultaneously, known as Wernicke–Korsakoff syndrome (WKS). [46] Lesions, or brain abnormalities, are typically located in the diencephalon which result in anterograde and retrograde amnesia, or memory loss. [46]

    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.[ medical citation needed ] According to the U.S. Centers for Disease Control (CDC), alcohol consumption by women who are not using birth control increases the risk of fetal alcohol syndrome. The CDC currently recommends complete abstinence from alcoholic beverages for women of child-bearing age who are pregnant, trying to become pregnant, or are sexually active and not using birth control. [47]

    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." [48]

    Other effects

    Frequent drinking of alcoholic beverages is a major contributing factor in cases of elevated blood levels of triglycerides. [49]

    Reinforcement disorders

    Addiction

    Alcohol addiction is termed alcoholism.

    Two or more consecutive alcohol-free days a week have been recommended to improve health and break dependence. [50] [51] [52]

    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%. [53]

    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% risk 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. [53] It interacts with cocaine in vivo to produce cocaethylene, another psychoactive substance. [54] Ethanol enhances the bioavailability of methylphenidate (elevated plasma dexmethylphenidate). [55] [ irrelevant citation ] In combination with cannabis, ethanol increases plasma tetrahydrocannabinol levels, which suggests that ethanol may increase the absorption of tetrahydrocannabinol. [56]

    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 is between alcohol and metronidazole.

    Metronidazole is an antibacterial agent that kills bacteria by damaging cellular DNA and hence cellular function. [57] 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. [58] [59] 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. [60]

    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. [61] 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. [19] [62] Identifying molecular targets for ethanol has proven unusually difficult, in large part due to its unique biochemical properties. [62] 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. [62] [63] 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. [62] [63] Instead, researchers have had to rely on functional studies to elucidate the actions of ethanol. [62] Moreover, although it has been established that ethanol modulates ion channels to mediate its effects, [21] ion channels are complex proteins, and their interactions and functions are complicated by diverse subunit compositions and regulation by conserved cellular signals (e.g. signaling lipids). [19] [62]

    In spite of the preceding however, much progress has been made in understanding the pharmacodynamics of ethanol over the last few decades. [20] [62] 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. [19] [20] [21] [62] Ethanol has specifically been found in functional assays to enhance or inhibit the activity of a variety of ion channels, including the GABAA receptor, the ionotropic glutamate AMPA, kainate, and NMDA receptors, the glycine receptor, [64] the nicotinic acetylcholine receptors, [65] the serotonin 5-HT3 receptor, voltage-gated calcium channels, and BK channels, among others. [19] [20] [21] [66] [67] 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. [62] In any case, ethanol has long shown a similarity in its effects to positive allosteric modulators of the GABAA receptor like benzodiazepines, barbiturates, and various general anesthetics. [19] [62] Indeed, ethanol has been found to enhance GABAA receptor-mediated currents in functional assays. [19] [62] In accordance, it is theorized and widely believed that the primary mechanism of action is as a GABAA receptor positive allosteric modulator. [19] [62] However, the diverse actions of ethanol on other ion channels may be and indeed likely are involved in its effects as well. [20] [62]

    Recently, a study showed the accumulation of an unnatural lipid phosphatidylethanol (PEth) competes with PIP2 agonists sites on lipid-gated ion channels. [68] . This presents a novel indirect mechanism and suggests that a metabolite, not the ethanol itself, can effect the primary targets of ethanol intoxication. Many of the primary targets of ethanol are known to bind PIP2 including GABAA receptors, [69] but the role of PEth will need to be investigated for each of the primary targets.

    In 2007, it was discovered that ethanol potentiates extrasynaptic δ subunit-containing GABAA receptors at behaviorally relevant (as low as 3 mM) concentrations. [19] [62] [70] This is in contrast to previous functional assays of ethanol on γ subunit-containing GABAA receptors, which it enhances only at far higher concentrations (> 100 mM) that are in excess of recreational concentrations (up to 50 mM). [19] [62] [71] 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. [62] [70] In addition, Ro15-4513 blocked the enhancement of δ subunit-containing GABAA receptor currents by ethanol in vitro. [62] 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. [62] [70] Taken together, these findings suggest a binding site for ethanol on subpopulations of the GABAA receptor with specific subunit compositions via which it interacts with and potentiates the receptor. [19] [62] [70] [72]

    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. [73] 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. [74]

    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). [75] [76] One of ethanol's primary effects is the allosteric inhibition of NMDA receptors and facilitation of GABAA receptors (e.g., enhanced GABAA receptor-mediated chloride flux through allosteric regulation of the receptor). [77] At high doses, ethanol inhibits most ligand-gated ion channels and voltage-gated ion channels in neurons as well. [77]

    With acute alcohol consumption, dopamine is released in the synapses of the mesolimbic pathway, in turn heightening activation of postsynaptic D1 receptors. [75] [76] 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. [75] [76]

    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; [75] [76] an adaptive downregulation of the D1 receptor pathway and CREB function occurs as well. [75] [76] 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. [76] These modifications to CREB function in the mesolimbic pathway induce expression (i.e., increase gene expression) of ΔFosB in the NAcc, [76] 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). [76] [78] [79] [80]

    Relationship between concentrations and effects

    Blood alcohol levels and effects [81]
    mg/dLmM% v/vEffects
    50110.05%Euphoria, talkativeness, relaxation
    100220.1%Central nervous system depression, nausea, possible vomiting, impaired motor and sensory function, impaired cognition
    >14030>0.14%Decreased blood flow to brain
    300650.3%Stupefaction, possible unconsciousness
    400870.4%Possible death
    500109>0.55%Death

    Recreational concentrations of ethanol are typically in the range of 1 to 50 mM. [71] [19] Very low concentrations of 1 to 2 mM ethanol produce zero or undetectable effects except in alcohol-naive individuals. [71] 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. [71] 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. [71] In jurisdictions in the United States, maximum blood alcohol levels for legal driving are about 17 to 22 mM. [82] [83] 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. [71] [82] 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. [71] Concentrations above this range, specifically in the range of 100 to 200 mM, would cause death in all people except alcoholics. [71]

    List of known actions of ethanol

    Ethanol has been reported to possess the following actions in functional assays at varying concentrations: [63]

    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. [63] This seems to be because the effects of ethanol on these channels are a summation of positive and negative allosteric modulatory actions. [63]

    Pharmacokinetics

    Absorption

    Ethanol can be taken orally, by inhalation, rectally, or by injection (e.g., intravenous), [7] [87] though it is typically ingested simply via oral administration. [5] The oral bioavailability of ethanol is around 80% or more. [5] [6] In fasting volunteers, blood levels of ethanol increase proportionally with the dose of ethanol administered. [87] 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. [7] 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. [7] [5]

    Food in the gastrointestinal system and hence gastric emptying is the most important factor that influences the absorption of orally ingested ethanol. [7] [87] The absorption of ethanol is much more rapid on an empty stomach than with a full one. [7] 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. [7] The type of food, whether fat, carbohydrates, or protein, also is of little importance. [87] Not only does food slow the absorption of ethanol, but it also reduces the bioavailability of ethanol, resulting in lower circulating concentrations. [7] People who have fasted overnight have been found to reach peak ethanol concentrations more rapidly, at within 30 minutes of ingestion. [7]

    Distribution

    Upon ingestion, ethanol is rapidly distributed throughout the body. [5] It is distributed most rapidly to tissues with the greatest blood supply. [7] As such, ethanol primarily affects the brain, liver, and kidneys. [5] Other tissues with lower circulation, such as bone, require more time for ethanol to distribute into. [7] Ethanol crosses biological membranes and the blood–brain barrier easily, through a simple process of passive diffusion. [5] [87] The volume of distribution of ethanol is around .55 L/kg (0.53 US pt/lb). [5] It is only weakly or not at all plasma protein bound. [5] [6]

    Metabolism

    Approximately 90% of the metabolism of ethanol occurs in the liver. [7] [8] This occurs predominantly via the enzyme alcohol dehydrogenase, which transforms ethanol into its metabolite acetaldehyde (ethanal). [7] [8] Acetaldehyde is subsequently metabolized by the enzyme aldehyde dehydrogenase into acetate (ethanoate), which in turn is broken down into carbon dioxide and water. [7] Acetate also combines with coenzyme A to form acetyl-CoA, and hence may participate in metabolic pathways. [5] 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. [5] 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. [7] [8] 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. [7] [8] A small amount of ethanol undergoes conjugation to form ethyl glucuronide and ethyl sulfate. [5] There may also be another metabolic pathway that metabolizes as much as 25 to 35% of ethanol at typical concentrations. [6]

    At even low physiological concentrations, ethanol completely saturates alcohol dehydrogenase. [7] 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. [7] For this reason, the metabolism of ethanol follows zero-order kinetics at typical physiological concentrations. [8] 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. [8] [9] 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. [8] [7] At very high concentrations, such as in overdose, it has been found that the rate of elimination of ethanol is increased. [6] 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). [6] [5] This seems to be because other processes, such as the MEOS/CYP2E1, also become involved in the metabolism of ethanol at higher concentrations. [5] However, the MEOS/CYP2E1 alone does not appear sufficient to fully explain the increase in ethanol metabolism rate. [6]

    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. [88] However, those having acquired alcohol tolerance have a greater quantity of these enzymes, and metabolize ethanol more rapidly. [88]

    Elimination

    Ethanol is mainly eliminated from the body via metabolism into carbon dioxide and water. [7] Around 5 to 10% of ethanol that is ingested is eliminated unchanged in urine, breath, and sweat. [5] Ethanol or its metabolites may be detectable in urine for up to 96 hours after ingestion. [5]

    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. [13] 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. [89] In general, higher alcohols are less toxic. [89] 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). [90] [91] However, its vapors can produce eye irritation and inhalation can cause pulmonary edema. [89] 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. [89]

    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. [92] 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. [25] The earliest evidence of winemaking was dated at 6,000 to 5,800 BCE in Georgia in the South Caucasus. [93] Beer was likely brewed from barley as early as the 6th century BCE (600–500 BCE) in Egypt. [94] Pliny the Elder wrote about the golden age of winemaking in Rome, the 2nd century BCE (200–100 BCE), when vineyards were planted. [95]

    Society and culture

    Alcohol is legal in most of the world. [96] 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. [96] In addition, there are strict regulations on alcohol sales and use in many countries throughout the world. [96] 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). [96] Also, many countries have bans on public drinking. [96] Drinking while driving or intoxicated driving is frequently outlawed and it may be illegal to have an open container of alcohol in an automobile. [96]

    See also

    Related Research Articles

    Alcoholism Broad term for when drinking alcohol results in problems

    Alcoholism, also known as alcohol use disorder (AUD), is a broad term for any drinking of alcohol that results in mental or physical health problems. The disorder was previously divided into two types: alcohol abuse and alcohol dependence. In a medical context, alcoholism is said to exist when two or more of the following conditions are present: a person drinks large amounts of alcohol over a long time period, has difficulty cutting down, acquiring and drinking alcohol takes up a great deal of time, alcohol is strongly desired, usage results in not fulfilling responsibilities, usage results in social problems, usage results in health problems, usage results in risky situations, withdrawal occurs when stopping, and alcohol tolerance has occurred with use. Alcohol use can affect all parts of the body, but it particularly affects the brain, heart, liver, pancreas and immune system. Alcoholism can result in mental illness, Wernicke–Korsakoff syndrome, irregular heartbeat, an impaired immune response, liver cirrhosis and increased cancer risk. Drinking during pregnancy can result in fetal alcohol spectrum disorders. Women are generally more sensitive than men to the harmful effects of alcohol.

    Alcohol intoxication Physical effects due to ethanol (alcohol)

    Alcohol intoxication, also known as drunkenness or alcohol poisoning, is the negative behavior and physical effects due to the recent drinking of 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, coma, or death. Complications may include seizures, aspiration pneumonia, injuries including suicide, and low blood sugar. Alcohol intoxication can lead to alcohol-related crime with perpetrators more likely to be intoxicated than victims.

    Disulfiram chemical compound

    Disulfiram is a drug used to support the treatment of chronic alcoholism by producing an acute sensitivity to ethanol. Disulfiram works by inhibiting the enzyme acetaldehyde dehydrogenase, causing many of the effects of a hangover to be felt immediately following alcohol consumption. Disulfiram plus alcohol, even small amounts, produce flushing, throbbing in head and neck, throbbing headache, respiratory difficulty, nausea, copious vomiting, sweating, thirst, chest pain, palpitation, dyspnea, hyperventilation, fast heart rate, low blood pressure, fainting, marked uneasiness, weakness, vertigo, blurred vision, and confusion. In severe reactions there may be respiratory depression, cardiovascular collapse, abnormal heart rhythms, heart attack, acute congestive heart failure, unconsciousness, convulsions, and death.

    Long-term effects of alcohol consumption health effects of drinking alcoholic beverages

    The best available current evidence suggests that consumption of alcohol does not improve health. Previous assertions that low or moderate consumption of alcohol improved health have been deprecated by more careful and complete meta-analysis. Heavy consumption of ethanol can cause severe detrimental effects. Health effects associated with alcohol intake in large amounts include an increased risk of alcoholism, malnutrition, chronic pancreatitis, alcoholic liver disease and cancer. In addition, damage to the central nervous system and peripheral nervous system can occur from chronic alcohol abuse. Even light and moderate alcohol consumption increases risk for certain types of cancer.

    Acetaldehyde dehydrogenase class of enzymes

    Acetaldehyde dehydrogenases are dehydrogenase enzymes which catalyze the conversion of acetaldehyde into acetic acid. The oxidation of acetaldehyde to acetate can be summarized as follows:

    GABA<sub>A</sub> receptor ionotropic receptor and ligand-gated ion channel, with endogenous ligand γ-aminobutyric acid

    The GABAA receptor (GABAAR) is an ionotropic receptor and ligand-gated ion channel. Its endogenous ligand is γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system. Upon activation, the GABAA receptor selectively conducts Cl through its pore. Cl- will flow out of the cell if the internal voltage is less than resting potential and Cl- will flow in if it is more than resting potential. This causes an inhibitory effect on neurotransmission by diminishing the chance of a successful action potential occurring. The reversal potential of the GABAA-mediated inhibitory postsynaptic potential (IPSP) in normal solution is −70 mV, contrasting the GABAB IPSP (-100 mV).

    Neuropharmacology is the study of how drugs affect cellular function in the nervous system, and the neural mechanisms through which they influence behavior. There are two main branches of neuropharmacology: behavioral and molecular. Behavioral neuropharmacology focuses on the study of how drugs affect human behavior (neuropsychopharmacology), including the study of how drug dependence and addiction affect the human brain. Molecular neuropharmacology involves the study of neurons and their neurochemical interactions, with the overall goal of developing drugs that have beneficial effects on neurological function. Both of these fields are closely connected, since both are concerned with the interactions of neurotransmitters, neuropeptides, neurohormones, neuromodulators, enzymes, second messengers, co-transporters, ion channels, and receptor proteins in the central and peripheral nervous systems. Studying these interactions, researchers are developing drugs to treat many different neurological disorders, including pain, neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease, psychological disorders, addiction, and many others.

    Alcohol flush reaction condition in which a person develops flushes or blotches

    Alcohol flush reaction is a condition in which a person develops flushes or blotches associated with erythema on the face, neck, shoulders, and in some cases, the entire body after consuming alcoholic beverages. The reaction is the result of an accumulation of acetaldehyde, a metabolic byproduct of the catabolic metabolism of alcohol, and is caused by an aldehyde dehydrogenase 2 deficiency.

    Fomepizole chemical compound

    Fomepizole, also known as 4-methylpyrazole, is a medication used to treat methanol and ethylene glycol poisoning. It may be used alone or together with hemodialysis. It is given by injection into a vein.

    Alcohol tolerance bodily responses to the functional effects of ethanol in alcoholic beverages

    Alcohol tolerance refers to the bodily responses to the functional effects of ethanol in alcoholic beverages. This includes direct tolerance, speed of recovery from insobriety and resistance to the development of alcoholism.

    Alcohol and health

    Alcohol has a number of effects on health. Short-term effects of alcohol consumption include intoxication and dehydration. Long-term effects of alcohol consumption include changes in the metabolism of the liver and brain and alcoholism. Alcohol intoxication affects the brain, causing slurred speech, clumsiness, and delayed reflexes. Alcohol stimulates insulin production, which speeds up glucose metabolism and can result in low blood sugar, causing irritability and possibly death for diabetics. Even light and moderate alcohol consumption increases cancer risk in individuals. A 2014 World Health Organization report found that harmful alcohol consumption caused about 3.3 million deaths annually worldwide. Negative efforts are related to the amount consumed with no safe lower limit seen. Some nations have introduced alcohol packaging warning messages that inform consumers about alcohol and cancer, as well as foetal alcohol syndrome.

    Acamprosate chemical compound

    Acamprosate, sold under the brand name Campral, is a medication used along with counselling to treat alcohol dependence.

    Ethanol, an alcohol found in nature and in alcoholic drinks, is metabolized through a complex catabolic metabolic pathway. In humans, several enzymes are involved in processing ethanol first into acetaldehyde and further into acetic acid and acetyl-CoA. Once acetyl-CoA is formed, it becomes a substrate for the citric acid cycle ultimately producing cellular energy and releasing water and carbon dioxide. Due to differences in enzyme presence and availability, human adults and fetuses process ethanol through different pathways. Gene variation in these enzymes can lead to variation in catalytic efficiency between individuals. The liver is the major organ that metabolizes ethanol due to its high concentration of these enzymes.

    A drug-related blackout is a phenomenon caused by the intake of any substance or medication in which short-term and long-term memory creation is impaired, therefore causing a complete inability to recall the past. Blackouts are frequently described as having effects similar to that of anterograde amnesia, in which the subject cannot recall any events after the event that caused amnesia.

    Hangover unpleasant physiological and psychological effects following the consumption of ethanol

    A hangover is the experience of various unpleasant physiological and psychological effects following the consumption of alcohol, such as wine, beer and distilled spirits. Hangovers can last for several hours or for more than 24 hours. Typical symptoms of a hangover may include headache, drowsiness, concentration problems, dry mouth, dizziness, fatigue, gastrointestinal distress, absence of hunger, light sensitivity, depression, sweating, nausea, hyper-excitability, irritability and anxiety.

    Alcohol withdrawal syndrome human disease

    Alcohol withdrawal syndrome is a set of symptoms that can occur following a reduction in alcohol use after a period of excessive use. Symptoms typically include anxiety, shakiness, sweating, vomiting, fast heart rate, and a mild fever. More severe symptoms may include seizures, seeing or hearing things that others do not, and delirium tremens (DTs). Symptoms typically begin around six hours following the last drink, are worst at 24 to 72 hours, and improve by seven days.

    Short-term effects of alcohol consumption

    The short-term effects of alcohol consumption – due to drinking beer, wine, distilled spirits or other alcoholic beverages – range from a decrease in anxiety and motor skills and euphoria at lower doses to intoxication (drunkenness), stupor, unconsciousness, anterograde amnesia, and central nervous system depression at higher doses. Cell membranes are highly permeable to alcohol, so once alcohol is in the bloodstream, it can diffuse into nearly every cell in the body.

    Effects of alcohol on memory

    Ethanol is the type of alcohol found in alcoholic beverages. It is a volatile, flammable, colorless liquid that acts as a central nervous system depressant. Ethanol can impair different types of memory.

    Kindling due to substance withdrawal refers to the neurological condition which results from repeated withdrawal episodes from sedative–hypnotic drugs such as alcohol and benzodiazepines.

    While researchers have found that moderate alcohol consumption in older adults is associated with better cognition and well-being than abstinence, excessive alcohol consumption is associated with widespread and significant brain lesions. The effects can manifest much later—mid-life Alcohol Use Disorder has been found to correlate with increased risk of severe cognitive and memory deficits in later life. Alcohol related brain damage is not only due to the direct toxic effects of alcohol; alcohol withdrawal, nutritional deficiency, electrolyte disturbances, and liver damage are also believed to contribute to alcohol-related brain damage.

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    Further reading

    Pathophysiology of ethanol
    Pharmacology of ethanol