Alcohol: short vs long term effects and moderate vs excessive doses
Ethanol Metabolism

Author: Ihab Mansour
Date: 07/02/2014


1. Introduction

Ethanol, also called ethyl alcohol, pure alcohol, grain alcohol, or drinking alcohol, is a volatile, flammable, colorless liquid with the structural formula CH3CH2OH, often abbreviated as C2H5OH or C2H6O. Ethanol is a psychoactive drug and is one of the oldest recreational drugs used by humans.

Ethanol can cause alcohol intoxication when consumed. Best known as the type of alcohol found in alcoholic beverages, it is also used in thermometers, as a solvent, and as a fuel.
Ethanol is the principal psychoactive constituent in alcoholic beverages. With depressant effects on the central nervous system, it has a complex mode of action and affects multiple systems in the brain, most notably increasing the activity of GABA receptors. Through positive allosteric modulation, it enhances the activity of naturally produced GABA. Other psychoactives such as benzodiazepines, barbiturates exert their effects by binding to the same receptor complex, thus have similar CNS depressant effects.



In a general population alcohol-dependent, less than 50% people develop any significant withdrawal symptoms that require pharmacologic treatment upon cessation of alcohol intake. Among alcoholists that suffer from alcohol withdrawal syndrome, only 5% of patients progress and develop delirium tremens and withdrawal seizures.
It has been observed that white patients have a higher risk of developing severe alcohol withdrawal, while black patients have a lower risk. Whether or not sex differences exist in the rates of development of severe alcohol withdrawal is not clear and the data collected are not statistically significant. In any particular alcohol-dependent person, symptoms of withdrawal can differ widely among different episodes.
Delirium tremens rarely occurs among pediatric patients, because the physiologic substrate for severe alcohol withdrawal takes time to develop: although they may suffer from severe neurological damage and seizure.
Racial variations in the incidence of severe alcohol withdrawal.

Racial variations in the incidence of severe alcohol withdrawal,2009

3.Pharmacology and metabolism

Ethanol binds to α7-nAChRs as an agonist, GABA receptor (especially the δ subunit) as a positive allosteric modulator, 5-HT3 receptor agonist, NMDA receptor antagonist, AMPA receptor antagonist, Kainate receptor antagonist, glycine receptor agonist and an inhibitor of potassium, sodium and calcium ion channels. It also appears to cause an increase in dopamine through a poorly understood process that may involve inhibiting the enzyme that breaks dopamine down . Ethanol also appears to block the reuptake of adenosine.

The removal of ethanol through oxidation by alcohol dehydrogenase in the liver from the human body is limited. Hence, the removal of a large concentration of alcohol from blood may follow zero-order kinetics. This means that alcohol leaves the body at a constant rate, rather than having an elimination half-life.
Also, the rate-limiting steps for one substance may be in common with other substances. For instance, the blood alcohol concentration can be used to modify the biochemistry of methanol andethylene glycol. Methanol itself is not highly toxic, but its metabolites formaldehyde and formic acid are; therefore, to reduce the concentration of these harmful metabolites, ethanol can be ingested to reduce the rate of methanol metabolism due to shared rate-limiting steps. Ethylene glycol poisoning can be treated in the same way.

Alcohol is metabolized mainly by two pathways oxidative path ways that take place mainly in the liver and non-oxidative pathways that occur mainly in extra-hepatic tissues. Oxidative ethanol metabolism mainly occurs in the liver via a major pathway in which the enzyme cytosolic alcohol-dehydrogenase (ADH) produces acetaldehyde, a highly reactive and toxic molecule. This oxidation is accompanied by the reduction of NAD+ to NADH.

Through this pathway, ethanol oxidation generates a highly reduced cytosolic environment, pre-dominantly in liver cells (i.e., hepatocytes). In addition to ADH, a group of enzymes known as the cytochromeP450 isozymes, including CYP2E1,1A2, and 3A4, also contribute to ethanol oxidation to acetaldehyde in the liver. These enzymes, which are present pre-dominantly in a cell component called the endoplasmic reticulum (ER),become involved particularly after chronic ethanol intake. CYP2E1 is induced by chronic ethanol consumption and assumes an important role in metabolizing ethanol to acetaldehydeat elevated alcohol concentrations. 3Alcohol metabolism by CYP2E1 also produces highly reactive ROS, including hydroxyethyl, superoxide anions, and hydroxyl radicals.

Finally, another enzyme called catalase, which is located in cell components called peroxisomes, also can oxidize ethanol ,however, quantitatively this is considered a minor pathway of ethanol oxidation. All of these oxidative pathways generate acetaldehyde, which then is rapidly metabolized further. This is donemainly by mitochondrial aldehydedehydrogenase (ALDH2) to formacetate and NADH.

The Brain from Top to Bottom – Alcohol,2010
The Clinical Pharmacology of Alcohol,2012
Alcohol Metabolism and Epigenetics Changes

4.Alcohol and Health

Alcohol stimulates insulin production, which speeds up glucose metabolism and can result in low blood sugar, causing irritability and (for diabetics) possible death. Severe alcohol poisoning can be fatal. Alcohol intoxication affects the brain, causing slurred speech, clumsiness, and delayed reflexes. In addition, alcohol is an addictive drug that can greatly cause sleep problems.

4.1.Short-term effects of alcohol

The drug alcohol, to be specific ethanol, is a central nervous system depressant with a range of side-effects. Cell membranes are highly permeable to alcohol, so once alcohol is in the bloodstream it can diffuse into nearly every biological tissue of the body. Short-term effects of alcohol can take on many forms , include intoxication and dehydration.

4.1.1.Moderate doses

Ethanol inhibits the ability of glutamate to open the cation channel associated with the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors. Stimulated areas include the cortex, hippocampus and nucleus accumbens, which are responsible for thinking and pleasure seeking. Another one of alcohol's agreeable effects is body relaxation, possibly caused by neurons transmitting electrical signals in an alpha waves-pattern; such waves are observed (with the aid of EEGs) when the body is relaxed.

Short-term effects of alcohol include the risk of injuries, violence and fetal damage.

Areas of the brain responsible for planning and motor learning can be sharpened. A related effect, caused by even low levels of alcohol, is the tendency for people to become more animated in speech and movement. This is due to increased metabolism in areas of the brain associated with movement, such as the nigrostriatal pathway. This causes reward systems in the brain to become more active, which may induce certain individuals to behave in an uncharacteristically loud and cheerful manner.

Alcohol has been known to mitigate the production of antidiuretic hormone. Alcohol causes the osmoreceptors to signal that there is low osmotic pressure in the blood, which triggers an inhibition of the antidiuretic hormone. As a consequence, one's kidneys are no longer able to reabsorb as much water as they should be absorbing, leading to creation of excessive volumes of urine and the subsequent overall dehydration.

4.1.2.Excessive doses

Acute alcohol intoxication through excessive doses in general causes short- or long-term health effects. NMDA receptors start to become unresponsive, slowing areas of the brain for which they are responsible. Contributing to this effect is the activity that alcohol induces in the gamma-aminobutyric acid(GABA) system. The GABA system is known to inhibit activity in the brain. GABA could also be responsible for the memory impairment that many people experience.

It has been asserted that GABA signals interfere with the registration and consolidation stages of memory formation. As the GABA system is found in the hippocampus (among other areas in the CNS), which is thought to play a large role in memory formation, this is thought to be possible.
Anterograde amnesia, colloquially referred to as "blacking out", is another symptom of heavy drinking. This is the loss of memory during and after an episode of drinking.

Another classic finding of alcohol intoxication is Ataxia which is responsible for the observation that drunk people are clumsy, sway back and forth, and often fall down. It is presumed to be due to alcohol's effect on the cerebellum.

Wikipedia 2014, Short-term effects

4.2.Long-term effects of alcohol

4.2.1.Moderate doses

Different countries recommend different maximum quantities. For most countries, the maximum quantity for men is 140 g–210 g per week. For women, the range is 84 g–140 g per week. Most countries recommend total abstinence whilst pregnant or breastfeeding.
In a 2010 long-term study of an older population, the beneficial effects of moderate drinking were confirmed. Both abstainers and heavy drinkers showed an increased mortality of about 50% over moderate drinkers after adjustment for confounding factors.

Cardiovascular system. Alcohol has been found to have anticoagulant properties. Thrombosis is lower among moderate drinkers than abstainers. A meta-analysis of randomized trials found that alcohol consumption in moderation decreases serum levels of fibrinogen, a protein that promotes clot formation, while it increases levels of tissue type plasminogen activator, an enzyme that helps dissolve clots. These changes were estimated to reduce coronary heart disease risk by about 24%. Also, serum levels of C-reactive protein (CRP), a marker of inflammation and predictor of CHD (coronary heart disease) risk, are lower in moderate drinkers than in those who abstain from alcohol, suggesting that alcohol consumption in moderation might have anti-inflammatory effects. Despite epidemiological evidence, many have cautioned against recommendations for the use of alcohol for health benefits. Nevertheless, a large prospective non-randomized study has shown that moderate alcohol intake in individuals already at low risk based on body mass index, physical activity, smoking, and diet, yields further improvement in cardiovascular risk.

Intermittent claudication. A study found that moderate consumption of alcohol had a protective effect against intermittent claudication. The lowest risk was seen in men who drank 1 to 2 drinks per day and in women who drank half to 1 drink per day.

Heart attack and stroke. Excessive alcohol consumption leads to an increased risk of heart failure. However, Drinking in moderation has been found to help those who have suffered a heart attack survive it, but at present days there are no evidence which proves protective role of low doses of alcohol against heart attacks.

Wikipedia 2014, Long-term effects

4.2.2.Excessive doses

Excessive doses of alcohol consumption causes cirrhosis, hepatitis that can eventually lead to alcoholic liver disease, and cancer. It also increases the risk of chronic gastritis and pancreatitis in both its chronic and acute forms.
Chronic heavy alcohol consumption impairs brain development, causes brain shrinkage, dementia, physical dependence, increases neuropsychiatric and cognitive disorders and causes distortion of the brain chemistry. Chronic consumption of alcohol may result in increased plasma levels of the toxic aminoacid homocysteine; which may explain alcohol withdrawal seizures, alcohol-induced brain atrophy and alcohol-related cognitive disturbances. Alcohol's impact on the nervous system can also include disruptions of memory and learning (see Effects of alcohol on memory), such as resulting in a blackout phenomenon.
Chronic use of alcohol used to induce sleep can lead to insomnia. Frequent moving between sleep stages occurs, with awakenings due to headaches and diaphoresis. Stopping chronic alcohol abuse can also lead to profound disturbances of sleep with vivid dreams. Chronic alcohol abuse is associated with NREM stage 3 and 4 sleep as well as suppression of REM sleep and REM sleep fragmentation. During withdrawal REM sleep is typically exaggerated as part of a rebound effect.

Epigenetics-Relevant Consequences. Oxidative alcohol metabolism can exert epigenetic effects through several mechanisms, including increase in the NADH/NAD+ ratio and the formation of ROS and acetate. The ratio of NADH to NAD+ fluctuates in response to changes in metabolism. Alcohol metabolism produces a significant increase in the hepatic NADH/NAD+ ratio in the cytoplasm and mitochondria of hepatocytes, as evidenced by changes in the levels of several other molecules in those cell compartments. The resulting shift of the redox potential of the hepatocytes causes a marked alteration in various reversible metabolic pathways. As a result, ethanol-oxidation vastly increases the availability of oxidizable NADH to the electron-transport chain in the mitochondria. NAD+ influences many important cellular reactions. NAD+ and NADH mainly are used by enzymes that catalyze substrate oxidation involving energy metabolism, histone deacetylation, and cell death. Increased NADH/NAD+ ratios in both the cytosol and mitochondria of hepatocytes influence the direction of several reversible reactions, leading to alterations in hepatic lipid, carbohydrate, protein, lactate, and uric acid metabolism. The increase in the ratio of NADH/NAD+ also results in derangement of carbohydrate metabolism, cell death, modulation of the mitochondrial permeability transi-tion (MPT) opening, and modulation of gene expression.

The Figure summarizes the epigenetic effects of alcohol metabolism, which include the following:

•Global hypo-methylation resulting from a reduction in SAM levels. SAM levels are reduced as a result of alcohol-induced reduction infolate and the inhibition of methio-nine synthase. At the same time, SAH levels increase, which inhibits DNMT.
•Histone modification that is associated with an increase in NADH levels caused by alcohol metabolism. The increase in NADH affects SIRT1 activity, leading to gene expression and/or silencing.
•Production of ROS, which affect the expression of inflammatory genes, and acetate, which is used in extra-hepatic tissues to produce acetyl-CoA. The latter then is used in histone acetylation by HATs.
These epigenetic changes resulting from chronic alcohol consumption can lead to organ pathology. Understanding the exact nature of the epigenetic changes will help design medication for the treatment or alleviation of alcohol-induced organ damage.

Blackout phenomenon. Alcohol can have a dramatic impact on memory, it disrupts activity in the hippocampus via several routes: directly, through effects on hippocampal circuitry, and indirectly, by interfering with interactions between the hippocampus and other brain regions. A blackout is a phenomenon caused by the intake of alcohol or other substance in which long term memory creation is impaired or there is a complete inability to recall the past. At low doses, the impairments produced by alcohol are often subtle, though they are detectable in controlled conditions. As the amount of alcohol consumed increases, so does the magnitude of the memory impairments. Large quantities of alcohol, particularly if consumed rapidly, can produce a blackout, an interval of time for which the intoxicated person cannot recall key details of events, or even entire events.

Wikipedia 2014, Long-term effects
Alcohol Metabolism and Epigenetics Changes
What Happened? Alcohol, Memory Blackouts, and the Brain, 2004


Despite the moderate intake of alcohol presents long-term benefits, appare clearly severity of effects that result by chronic excessive quantities. The alcohol dependence is a disease which is usually preceded by many years of alcohol abuse, in addition to health problems, physical, psychological and social, the problematic use of alcohol causes enormous costs to society, which in Switzerland are around 2.3 billion francs/year (Jeanrenaud 2005). The consumption of alcohol increases the aggressiveness and is responsible for a very large number of accidents. The consumption of alcohol occupies a prominent place in the statistics on accidents and injuries, in fact alcohol is among the major causes of serious road accidents: 13% of all road accidents with severe outcome and 17% of all accidents with fatal outcome is attributable to alcohol.

Becomes of crucial importance nowadays prevention in the social-health background: the Italian law on alcohol and problems related to it (law no. 125/01) states that in work activities that involve a high risk of injury at work, or for the security, safety or health of third parties are prohibited from hiring and administration of alcoholic beverages and spirits and gives direct responsibility to the competent physician (MC), as well as occupational physicians responsible for the territory of the ASL , the making of alcohol-testing in the workplace. Unfortunately, it is difficult to distinguish between alcohol-related disease and psychiatric illness that may be the causative factor or coexisting alcohol abuse. For this reason, we must not forget, however, that alcoholism is a disease of the personality and involves a regression to a primitive state of development of the person.


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