User:Mathnerd314159/sandbox/Pharmacology of ethanol

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The pharmacology of ethanol involves both pharmacodynamics (how it affects the body) and pharmacokinetics (how the body processes it). In the body, ethanol primarily affects the central nervous system, acting as a depressant and causing sedation, relaxation, and decreased anxiety. The exact mechanism remains elusive, but ethanol has been shown to affect ligand-gated ion channels, particularly the GABAA receptor.

After oral ingestion, ethanol is absorbed via the stomach and intestines into the bloodstream. Ethanol is highly water-soluble and diffuses passively throughout the entire body, including the brain. Soon after ingestion, it begins to be metabolized, 90% or more by the liver. One standard drink is sufficient to almost completely saturate the liver's capacity to metabolize alcohol. The main metabolite is acetaldehyde, a toxic carcinogen. Acetaldehyde is then further metabolized into ionic acetate by the enzyme aldehyde dehydrogenase (ALDH). Acetate is not carcinogenic and has low toxicity,[1] but has been implicated in causing hangovers.[2][3] Acetate is further broken down into carbon dioxide and water and eventually eliminated from the body through urine and breath. 5 to 10% of ethanol is excreted unchanged in the breath, urine, and sweat.

History

Stage Three of the Five stages of inebriation, c. 1863–1868, by Charles Percy Pickering

Beginning with the Gin Craze, excessive drinking and drunkenness developed into a major problem for public health.[4][5] In 1874, Francis E. Anstie's experiments showed that the amounts of alcohol eliminated unchanged in breath, urine, sweat, and feces were negligible compared to the amount ingested, suggesting it was oxidized within the body.[6] In 1902, Atwater and Benedict estimated that alcohol yielded 7.1 kcal of energy per gram consumed and 98% was metabolized.[7] In 1922, Widmark published his method for analyzing the alcohol content of fingertip samples of blood.[8] Through the 1930s, Widmark conducted numerous studies and formulated the basic principles of ethanol pharmacokinetics for forensic purposes,

total body water instead of body weight.[10] The TBW equations have been found to be significantly more accurate due to rising levels of obesity worldwide.[11]

Pharmacodynamics

In the past, alcohol was believed to be a non-specific pharmacological agent affecting many neurotransmitter systems in the brain.[12] 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:

nicotinic acetylcholine receptors.[15]

Among those that are inhibited are:

G-protein-activated inwardly rectifying K+ channels.[17]

Alcohol is also converted into phosphatidylethanol (a lipid metabolite) by phospholipase D2, and this metabolite has been shown to directly bind to and regulate ion channels.[18][19] 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.[12]

The order in which different types of alcoholic beverages are consumed ("Grape or grain but never the twain" and "Beer before wine and you'll feel fine; wine before beer and you'll feel queer") does not have any effect.[20]

The principal

millimolar mM) concentrations.[22][23] 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.[22][23] Instead, researchers have had to rely on functional studies to elucidate the actions of ethanol.[22] Moreover, although it has been established that ethanol modulates ion channels to mediate its effects,[24] 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).[21][22]

Much progress has been made in understanding the pharmacodynamics of ethanol over the last few decades.

general anesthetics.[21][22] Indeed, ethanol has been found to enhance GABAA receptor-mediated currents in functional assays.[21][22] In accordance, it is theorized and widely believed that the primary mechanism of action is as a GABAA receptor positive allosteric modulator.[21][22] However, the diverse actions of ethanol on other ion channels may be and indeed likely are involved in its effects as well.[25][22]

In 2007, it was discovered that ethanol potentiates

extrasynaptic δ subunit-containing GABAA receptors at behaviorally relevant (as low as 3 mM) concentrations.[21][22][30] 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).[21][22][31] 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.[22][30] In addition, Ro15-4513 blocked the enhancement of δ subunit-containing GABAA receptor currents by ethanol in vitro.[22] 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.[22][30] 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.[21][22][30][32]

A 2019 study showed the accumulation of an unnatural lipid phosphatidylethanol (PEth) competes with PIP2 agonist sites on lipid-gated ion channels.[33] This presents a novel indirect mechanism and suggests that a metabolite, not the ethanol itself, can affect the primary targets of ethanol intoxication. Many of the primary targets of ethanol are known to bind PIP2 including GABAA receptors,[34] but the role of PEth will need to be investigated for each of the primary targets.

GABAA receptors

See also:
GABAA § Ligands
Ethanol binding to GABAA receptor

Many of the effects of activating

GABAA 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.[35] This correlation between activating GABAA receptors and the effects of ethanol consumption have led to the study of ethanol and its effects on GABAA receptors. It has been shown that ethanol does in fact exhibit positive allosteric binding properties to GABAA receptors. However, its effects are limited to pentamers containing the δ-subunit rather than the γ-subunit.[36]

GABAA 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.[35] The δ-subunit has been shown to be able to form the allosteric binding site which makes GABAA receptors containing the δ-subunit more sensitive to ethanol concentrations, even to moderate social ethanol consumption levels (30mM).[37] While it has been shown by Santhakumar et al. that GABAA receptors containing the δ-subunit are sensitive to ethanol modulation, depending on subunit combinations receptors could be more or less sensitive to ethanol.[38] It has been shown that GABAA receptors that contain both δ and β3-subunits display increased sensitivity to ethanol.[36] One such receptor that exhibits ethanol insensitivity is α3-β6-δ GABAA.[38] It has also been shown that subunit combination is not the only thing that contributes to ethanol sensitivity. Location of GABAA receptors within the synapse may also contribute to ethanol sensitivity.[35]

Calcium channel blocking

See also: Calcium channel blocker § Ethanol
Ethanol blocks voltage-gated calcium channel

Research indicates

secondary messenger system.[40] Vasopressin levels are reduced after the ingestion of alcohol.[41] The lower levels of vasopressin from the consumption of alcohol have been linked to ethanol acting as an antagonist to voltage-gated calcium channels (VGCCs). Studies conducted by Treistman et al. in the aplysia confirm inhibition of VGCC by ethanol. Voltage clamp recordings have been done on the aplysia neuron. VGCCs were isolated and calcium current was recorded using patch clamp technique having ethanol as a treatment. Recordings were replicated at varying concentrations (0, 10, 25, 50, and 100 mM) at a voltage clamp of +30 mV. Results showed calcium current decreased as concentration of ethanol increased.[42] Similar results have shown to be true in single-channel recordings from isolated nerve terminal of rats that ethanol does in fact block VGCCs.[43]

Studies done by Katsura et al. in 2006 on mouse cerebral cortical neurons, show the effects of prolonged ethanol exposure. Neurons were exposed to sustained ethanol concentrations of 50 mM for 3 days in vitro. Western blot and protein analysis were conducted to determine the relative amounts of VGCC subunit expression. α1C, α1D, and α2/δ1 subunits showed an increase of expression after sustained ethanol exposure. However, the β4 subunit showed a decrease. Furthermore, α1A, α1B, and α1F subunits did not alter in their relative expression. Thus, sustained ethanol exposure may participate in the development of ethanol dependence in neurons.[44]

Other experiments done by Malysz et al. have looked into ethanol effects on voltage-gated calcium channels on

detrusor smooth muscle cells in guinea pigs. Perforated patch clamp technique was used having intracellular fluid inside the pipette and extracellular fluid in the bath with added 0.3% vol/vol (about 50-mM) ethanol. Ethanol decreased the Ca2+
 current in DSM cells and induced muscle relaxation. Ethanol inhibits VGCCs and is involved in alcohol-induced relaxation of the urinary bladder.[45]

Rewarding and reinforcing actions

Chemical structures of selective dopamine receptor D1 receptor agonists[46][47]

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.[48] 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.[49]

Ethanol's rewarding and reinforcing (i.e., addictive) properties are mediated through its effects on

mesolimbic reward pathway, which connects the ventral tegmental area to the nucleus accumbens (NAcc).[50][51] 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).[52] At high doses, ethanol inhibits most ligand-gated ion channels and voltage-gated ion channels in neurons as well.[52]

With acute alcohol consumption, dopamine is released in the

cAMP response element binding protein (CREB), inducing CREB-mediated changes in gene expression.[50][51]

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;

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).[51][53][54][55]

Relationship between concentrations and effects

Blood alcohol levels and effects[56]
mg/dL mM % v/v Effects
50 11 0.05% Euphoria, talkativeness, relaxation, happiness, gladness, pleasure, joyfulness.
100 22 0.1% Central nervous system depression, anxiety suppression, stress suppression, sedation, nausea, possible vomiting. Impaired motor, memory, cognition and sensory function.
>140 30 >0.14% Decreased blood flow to brain, slurred speech, double or blurry vision.
300 65 0.3% Stupefaction, confusion, numbness, dizziness, loss of consciousness.
400 87 0.4% Ethylic intoxication, drunkenness, inebriation, alcohol poisoning or possible death.
500 109 >0.55% Unconsciousness, coma and death.

Recreational concentrations of ethanol are typically in the range of 1 to 50 mM.[31][21] Very low concentrations of 1 to 2 mM ethanol produce zero or undetectable effects except in alcohol-naive individuals.[31] 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.[31] 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.[31] In jurisdictions in the U.S., maximum blood alcohol levels for legal driving are about 17 to 22 mM.[57][58] 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.[31][57] 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.[31] Concentrations above this range, specifically in the range of 100 to 200 mM, would cause death in all people except alcoholics.[31]

As drinking increases, people become sleepy or fall into a stupor. After a very high level of consumption[vague], 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 coordination along with poor judgment increase 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.[59]

In addition to respiratory failure and accidents caused by its 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 kidney injury
. Metabolic acidosis is compounded by respiratory failure. Patients may also present with hypothermia.

List of known actions in the central nervous system

Ethanol has been reported to possess the following actions in functional assays at varying concentrations:[23]

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.[23] This seems to be because the effects of ethanol on these channels are a summation of positive and negative allosteric modulatory actions.[23]

Pharmacokinetics

The

total body water, speed of drinking, the drink's nutritional content, and the contents of the stomach all influence the profile of blood alcohol content (BAC) over time. Breath alcohol content (BrAC) and BAC have similar profile shapes, so most forensic pharmacokinetic calculations can be done with either. Relatively few studies directly compare BrAC and BAC within subjects and characterize the difference in pharmacokinetic parameters. Comparing arterial and venous BAC, arterial BAC is higher during the absorption phase and lower in the postabsorptive declining phase.[5]

Endogenous production

Further information: Auto-brewery syndrome
Ethanol fermentation cycle

All organisms produce alcohol in small amounts by several pathways, primarily through

bile acid biosynthesis pathways.[66]
Fermentation is a biochemical process during which yeast and certain bacteria convert sugars to ethanol, carbon dioxide, as well as other metabolic byproducts.[67][68] The average human digestive system produces approximately 3 g of ethanol per day through fermentation of its contents.[69] Such production generally does not have any forensic significance because the ethanol is broken down before significant intoxication ensues. These trace amounts of alcohol range from 0.1 to 0.3 μg/mL in the blood of healthy humans, with some measurements as high as 1.6 μg/mL (0.002 g/L).[70]

Auto-brewery syndrome is a condition characterized by significant fermentation of ingested carbohydrates within the body. In rare cases, intoxicating quantities of ethanol may be produced, especially after eating meals. Claims of endogenous fermentation have been attempted as a defense against drunk driving charges, some of which have been successful, but the condition is under-researched.[71]

Absorption

Ethanol is most commonly ingested by mouth,

Gastric emptying is therefore an important consideration when estimating the overall rate of absorption in most scenarios;[5] the presence of a meal in the stomach delays gastric emptying,[73][74] and absorption of ethanol into the blood is consequently slower.[78] Due to irregular gastric emptying patterns, the rate of absorption of ethanol is unpredictable, varying significantly even between drinking occasions.[5] In experiments, aqueous ethanol solutions have been given intravenously or rectally to avoid this variation.[5] 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.[73] The type of food, whether fat, carbohydrates, or protein, also is of little importance.[74] Not only does food slow the absorption of ethanol, but it also reduces the bioavailability of ethanol, resulting in lower circulating concentrations.[73]

Regarding inhalation, early experiments with animals showed that it was possible to produce significant BAC levels comparable to those obtained by injection, by forcing the animal to breathe alcohol vapor.[79] In humans, concentrations of ethanol in air above 10 mg/L caused initial coughing and smarting of the eyes and nose, which went away after adaptation. 20 mg/L was just barely tolerable. Concentrations above 30 mg/L caused continuous coughing and tears, and concentrations above 40 mg/L were described as intolerable, suffocating, and impossible to bear for even short periods. Breathing air with concentration of 15 mg/L ethanol for 3 hours resulted in BACs from 0.2 to 4.5 g/L, depending on breathing rate.[80] It is not a particularly efficient or enjoyable method of becoming intoxicated.[73]

Ethanol is not absorbed significantly through intact skin. The steady state flux is 0.08 μmol/cm2/hr.[81] Applying a 70% ethanol solution to a skin area of 1000 cm2 for 1 hr would result in approximately 0.1 g of ethanol being absorbed.[82] The substantially increased levels of ethanol in the blood reported for some experiments are likely due to inadvertent inhalation.[73] A study that did not prevent respiratory uptake found that applying 200 mL of hand disinfectant containing 95% w/w ethanol (150 g ethanol total) over the course of 80 minutes in a 3-minutes-on 5-minutes-off pattern resulted in the median BAC among volunteers peaking 30 minutes after the last application at 17.5 mg/L (0.00175%). This BAC roughly corresponds to drinking one gram of pure ethanol.[83] Ethanol is rapidly absorbed through cut or damaged skin, with reports of ethanol intoxication and fatal poisoning.[84]

Distribution

After absorption, the alcohol goes through the

bone, require more time for ethanol to distribute into.[73][5] In rats, it takes around 10-15 minutes for tissue and venous blood to reach equilibrium.[86]

The volume of distribution Vd contributes about 15% of the uncertainty to Widmark's equation[87] and has been the subject of much research. Widmark originally used units of mass (g/kg) for EBAC, thus he calculated the apparent mass of distribution Md or mass of blood in kilograms. He fitted an equation of the body weight W in kg, finding an average rho-factor of 0.68 for men and 0.55 for women. This ρm has units of dose per body weight (g/kg) divided by concentration (g/kg) and is therefore dimensionless. However, modern calculations use weight/volume concentrations (g/L) for EBAC, so Widmark's rho-factors must be adjusted for the density of blood, 1.055 g/mL. This has units of dose per body weight (g/kg) divided by concentration (g/L blood) - calculation gives values of 0.64 L/kg for men and 0.52 L/kg for women, lower than the original.

total body water (TBW) - experiments have confirmed that alcohol distributes almost exactly in proportion to TBW within the Widmark model.[90] TBW may be calculated using body composition
analysis or estimated using anthropometric formulas based on age, height, and weight. Vd is then given by , where is the water content of blood, approximately 0.825 w/v for men and 0.838 w/v for women.[91]

These calculations assume Widmark's zero-order model for the effects of metabolization, and assume that TBW is almost exactly the volume of distribution of ethanol. Using a more complex model that accounts for non-linear metabolism, Norberg found that Vd was only 84-87% of TBW.[92] This finding was not reproduced in a newer study which found volumes of distribution similar to those in the literature.[76]

Metabolism

Alcohol dehydrogenase

Several metabolic pathways exist:

Detailed ADH pathway

Energy calculation

The reaction from ethanol to carbon dioxide and water is a complex one that proceeds in at least 11 steps in humans. The first three steps of the reaction pathways lead from ethanol to acetaldehyde to acetic acid to acetyl-CoA. Once acetyl-CoA is formed, it is free to enter directly into the citric acid cycle. Below, the Gibbs free energy of formation for each step is shown with ΔGf values given in the CRC.[95]

Complete reaction:
C2H6O(ethanol) → C2H4O(acetaldehyde) → C2H4O2(acetic acid) → acetyl-CoA → 3H2O + 2CO2.
ΔGf = Σ ΔGfp − ΔGfo

C2H6O(ethanol) +

NADH
+ H+
Ethanol: −174.8 kJ/mol
Acetaldehyde: −127.6 kJ/mol
ΔGf1 = −127.6 kJ/mol + 174.8 kJ/mol = 47.2 kJ/mol (endergonic)
ΣΔGf = 47.2 kJ/mol (endergonic, but this does not take into consideration the simultaneous reduction of NAD+.)

C2H4O(acetaldehyde) +

NADH
+ H+
Acetaldehyde: −127.6 kJ/mol
Acetic acid: −389.9 kJ/mol
ΔGf2 = −389.9 kJ/mol + 127.6 kJ/mol = −262.3 kJ/mol (exergonic)
ΣΔGf = −262.3 kJ/mol + 47.2 kJ/mol = −215.1 kJ/mol (exergonic, but again this does not take into consideration the reduction of
NAD
+.)

C2H4O2(acetic acid) + CoA + ATP → Acetyl-CoA + AMP + PPi

ΔGf3 = −46.8 kJ/mol[96]

After this the acetyl-CoA enters the TCA cycle and is converted to 2 CO2 molecules in 8 reactions.

Because the Gibbs energy is a state function, we can ignore all of these, and indeed can ignore even the above 3 reactions. Overall, the free energy is simply calculated from the free energy of formation of the product and reactants.

For the oxidation of acetic acid we have:
Acetic acid: −389.9 kJ/mol
3H2O + 2CO2: −1500.1 kJ/mol
ΔGf4 = −1500 kJ/mol + 389.6 kJ/mol = −1110.5 kJ/mol (exergonic)
ΣΔGf = −1110.5 kJ/mol − 215.1 kJ/mol = −1325.6 kJ/mol (exergonic)

If catabolism of alcohol goes all the way to completion, then we have a very exothermic event yielding some 1325 kJ/mol of energy. If the reaction stops part way through the metabolic pathways, which happens because acetic acid is excreted in the urine after drinking, then not nearly as much energy can be derived from alcohol, indeed, only 215.1 kJ/mol. At the very least, the theoretical limits on energy yield are determined to be −215.1 kJ/mol to −1325.6 kJ/mol. Step 1 on this reaction is endothermic, requiring 47.2 kJ/mol of alcohol, or about 3 molecules of adenosine triphosphate (ATP) per molecule of ethanol.


Variation

Further information: Alcohol flush reaction

Variations in genes influence alcohol metabolism and drinking behavior.[97] Certain amino acid sequences in the enzymes used to oxidize ethanol are conserved (unchanged) going back to the last common ancestor over 3.5 bya.[98] Evidence suggests that humans evolved the ability to metabolize dietary ethanol between 7 and 21 million years ago, in a common ancestor shared with chimpanzees and gorillas but not orangutans.[99] Gene variation in these enzymes can lead to variation in catalytic efficiency between individuals. Some individuals have less effective metabolizing enzymes of ethanol, and can experience more marked symptoms from ethanol consumption than others.[100] However, those having acquired alcohol tolerance have a greater quantity of these enzymes, and metabolize ethanol more rapidly. Specifically, ethanol has been observed to be cleared more quickly by regular drinkers than non-drinkers.[100]

Falsely high BAC readings may be seen in patients with kidney or liver disease or failure. Such persons also have impaired acetaldehyde dehydrogenase, which causes acetaldehyde levels to peak higher, producing more severe

heavy metals, and some pyrazole compounds. Also suspected of having this effect are cimetidine, ranitidine, and acetaminophen (paracetamol).[citation needed
]

First-pass metabolism

During a typical drinking session, approximately 90% of the metabolism of ethanol occurs in the liver,[73][93] where alcohol dehydrogenase and aldehyde dehydrogenase are present at their highest concentrations (in liver mitochondria).[94] But these enzymes are widely expressed throughout the body, such as in the stomach and small intestine.[72] Some alcohol undergoes a first pass of metabolism in these areas, before it ever enters the bloodstream.[101]

catabolic metabolic pathway
.


Much higher concentrations of enzymes required for the oxidation reactions are found in the liver,[102] which is the primary site for alcohol catabolism.


Quantification

Unlike most physiologically active materials, alcohol is removed from the bloodstream at an approximately constant rate (linear decay or

first-order kinetics, with an elimination half-life of about 4 or 4.5 hours (which implies a clearance rate of approximately 6 L/hour/70 kg).[75][72]

An "abnormal" liver with conditions such as

gall bladder disease, and cancer is likely to result in a slower rate of metabolism. People under 25 and women may process alcohol more slowly.[105] In addition, food such as fructose can increase the rate of alcohol metabolism. The effect can vary significantly from person to person, but a 100 g dose of fructose has been shown to increase alcohol metabolism by an average of 80%. In people with proteinuria and hematuria, fructose can cause falsely high BAC readings, due to kidney-liver metabolism.[106]

In alcoholics

Under alcoholic conditions, the citric acid cycle is stalled by the oversupply of NADH derived from ethanol oxidation. The resulting backup of acetate shifts the reaction equilibrium for acetaldehyde dehydrogenase back towards acetaldehyde. Acetaldehyde subsequently accumulates and begins to form covalent bonds with cellular macromolecules, forming toxic adducts that, eventually, lead to death of the cell. This same excess of NADH from ethanol oxidation causes the liver to move away from fatty acid oxidation, which produces NADH, towards fatty acid synthesis, which consumes NADH. This consequent

alcoholic fatty liver disease
.

In human fetuses

In human embryos and fetuses, ethanol is not metabolized via ADH as ADH enzymes are not yet expressed to any significant quantity in human fetal liver (the induction of ADH only starts after birth, and requires years to reach adult levels).[107] Accordingly, the fetal liver cannot metabolize ethanol or other low molecular weight xenobiotics. In fetuses, ethanol is instead metabolized at much slower rates by different enzymes from the cytochrome P-450 superfamily (CYP), in particular by CYP2E1. The low fetal rate of ethanol clearance is responsible for the important observation that the fetal compartment retains high levels of ethanol long after ethanol has been cleared from the maternal circulation by the adult ADH activity in the maternal liver.[108] CYP2E1 expression and activity have been detected in various human fetal tissues after the onset of organogenesis (ca 50 days of gestation).[109] Exposure to ethanol is known to promote further induction of this enzyme in fetal and adult tissues. CYP2E1 is a major contributor to the so-called Microsomal Ethanol Oxidizing System (MEOS)[110] and its activity in fetal tissues is thought to contribute significantly to the toxicity of maternal ethanol consumption.[107][111] In presence of ethanol and oxygen, CYP2E1 is known[by whom?] to release superoxide radicals and induce the oxidation of polyunsaturated fatty acids to toxic aldehyde products like 4-hydroxynonenal (HNE).[citation needed]

The concentration of alcohol in breast milk produced during lactation is closely correlated to the individual's blood alcohol content.[112]

Elimination

Alcohol is removed from the bloodstream by a combination of metabolism, excretion, and evaporation. 90-98% of ingested ethanol is metabolized into carbon dioxide and water.

sweat.[72] Transdermal alcohol that diffuses through the skin as insensible perspiration or is exuded as sweat (sensible perspiration) can be detected using wearable sensor technology[113] such as SCRAM ankle bracelet[114] or the more discreet ION Wearable.[115] Ethanol or its metabolites may be detectable in urine for up to 96 hours (3–5 days) after ingestion.[72]

The elimination rate is described well by Michaelis–Menten kinetics. M-M kinetics are approximately zero-order above a BAC of 0.15-0.20 g/L, but below this value alcohol is eliminated more slowly and the elimination rate more closely follows first-order kinetics. This change in behavior was not noticed by Widmark because he could not analyze low BAC levels.[88] Eating food in proximity to drinking increases elimination rate significantly.[76]

The elimination rate from the blood is statistically significant between sexes, but the difference is small compared to the overall uncertainty.[116] Explanations for the gender difference are quite varied and include liver size, secondary effects of the volume of distribution, and sex-specific hormones.[117] A 2023 study using a more complex two-compartment model with M-M elimination kinetics, with data from 60 men and 12 women, found statistically small effects of gender on maximal elimination rate and excluded them from the final model. Eating food in proximity to drinking increases elimination rate significantly.[76]

Modeling

Swedish professor Erik Widmark developed a model of alcohol pharmacokinetics in the 1920s.

zero-order kinetics for elimination. The model is most accurate when used to estimate BAC a few hours after drinking a single dose of alcohol in a fasted state, and can be within 20% CV of the true value.[119][120] It is less accurate for BAC levels below 0.2 g/L (alcohol is not eliminated as quickly as predicted) and consumption with food (overestimating the peak BAC and time to return to zero).[121][88]

Onset

People drinking spritzers at a festival in Hungary. Carbonated alcoholic drinks seem to have a shorter onset.

In fasting volunteers, blood levels of ethanol increase proportionally with the dose of ethanol administered.

body weight of the individual and correcting for water dilution.[73]

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.[73][72] People who have fasted overnight have been found to reach peak ethanol concentrations more rapidly, at within 30 minutes of ingestion.[73]

The onset varies depends on the type of alcoholic drink:[122]

  • Vodka tonic: 36 ± 10 minutes
  • Wine: 54 ± 14 minutes
  • Beer: 62 ± 23 minutes

Also, carbonated alcoholic drinks seem to have a shorter onset compare to flat drinks in the same volume. One theory is that carbon dioxide in the bubbles somehow speeds the flow of alcohol into the intestines.[123]

The peak of blood alcohol level (or concentration of alcohol) is reduced after a large meal.[78]

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