Alcohol, Chemistry and You

Effects of Ethyl Alcohol on Organ Function

Dr. Bill Boggan

Brain: Acute and chronic alcohol consumption can have both subtle as well as dramatic effects on the brain and its functioning. The effects of alcohol on the brain can occur by both direct and indirect means. Thus, it is not really necessary that the alcohol actually reach the brain, though it does, for brain function to be modified. For example, damage to the brain can occur through alcohol-induced deficiencies in nutrition, liver disease, and through alterations the function of other bodily systems (e.g. immune, hormonal), which produce substances which end up in the blood and get transported to the brain. In the most extreme case, another person who has been drinking could become violent and injure you, e.g. automobile crashes.

How does ethyl alcohol act in the brain to produce its effects?

Alcohols direct action on the brain is as a depressant. It generally decreases the activity of the nervous system. One could ask how it could be a depressant if after one or two drinks a person tends to talk more and become more active. The answer is that alcohol can cause disinhibition, i.e. inhibits cells and circuits in the brain which themselves are normally inhibitory. To understand how alcohol can effect the brain one needs to know how the brain works. The brain is composed of different regions or areas as shown. Different regions of the brain are primarily involved in different activities. For examples, the cerebellum is involved in coordination of bodily movements; the frontal cortex is primarily involved in cognitive processes; the occipital lobe contains the visual cortex; and a portion of the temporal lobe of the cortex is involved in audition. The list goes on and on.

In order for the parts to communicate with one another to achieve coordination and allow our bodies to function in a reasonable manner, the parts are connected by nerve cells also called neurons. It is estimated that there are 100 billion nerve cells in the brain so one can visualize the complexity of the inner workings of the brain.

Nerve cells communicate with one another via electrical and chemical signals. In essence signals coming from outside the body like light, sound, smells, tastes, and pressure are converted (transduced) into chemical and electrical signals which pass from one part of the body to another and from one part of the brain to another.

Once inside the brain electrical signals and chemical signals continue to be generated to allow communication between the brain parts and regions. Electrical signals generated in one neuron causes of the release of chemicals called neurotransmitters (NTs) from that neuron. These NTs in turn are then available to act at other neurons in close proximity to the first to either excite or inhibit that neurons activity.

NTs act on neurons by attaching (binding) to chemical constituents called receptors of the neuronal membrane. There are a substantial number of different types of receptors for each NT. The binding of the NT to the receptor is the occasion for a number of secondary responses both at the membrane level and within the cell. Though there is usually only one or two NTs released from a particular neuron, numerous NTs bind to each neuron and their collective action determines the overall response of the neuron. The resultant response can be the generation of an electrical signal (action potential) created by changes in ion flow across the nerve cell membrane (sodium, potassium, and chloride are particularly important) or inhibition of cellular electrical activity.

There are a substantial number of NTs in the brain. Four of the most important NTs with respect to alcohol are glutamate, gamma aminobutyric acid (GABA), dopamine (DA), and serotonin. Glutamate is the major excitatory NT in the brain. Ethyl alcohol acts to inhibit a subset (N- methyD-aspartate, NMDA) of glutamate receptors, thus diminishing the excitatory actions of glutamate. GABA is the major inhibitory NT in the brain. Alcohol acts primarily at the GABAa receptor to facilitate its action, thus in essence creating enhanced inhibition. Changes in the number of both NMDA and GABA receptors and ability of these receptors to bind their NTs appear to be involved in the development of tolerance to and dependence on alcohol. The third important NT in alcohol action, Dopamine, is involved in reward processes and thus seems to be responsible for the rewarding aspects of alcohol consumption. Other things that people find rewarding such as food, sex, and other drugs of abuse also act to release DA in the brain. Serotonin also appears to play a role in reward processes and therefore seems to be important in alcohol use and abuse. In addition, serotonin is a prominent player in mood states, compulsive disorders, aggression, and effects of other drugs of abuse like methamphetamine and LSD.

It should be recognized that in addition to the regions or parts of the brain and the billions of neurons in the brain, there are also various systems. Systems often involve numerous parts just like the fuel system in a car involves the fuel tank, the fuel pump, the tubing, the fuel injectors, etc. One important system mentioned above is the reward system, which plays an important role in the rewarding (reinforcing) properties ethyl alcohol and other drugs such as cocaine. A major part of the reward system starts deep within the brain in an area called the ventral tegmental area and projects to the nucleus accumbens and then on to upper parts of the brain such as the cerebral cortex.

Current research supports the idea that initial exposure to alcohol activates the reward pathway releasing DA in the Nucleus accumbens, which in turn sends messages to the cortex to be coded as experiences and perhaps as memories. Once coded, these experiences can influence, i.e. promote, subsequent behavior such further alcohol intake. Since these "memories" of drinking are linked to the environment in which the drinking took place, it is not surprising that the environmental cues can be important in guiding subsequent drinking behavior. Alcohols action on the brain produces of a number of behavioral effects. These effects are dependent upon the 1. amount of alcohol taken in, 2. the time period over which the alcohol is drunk, 3. whether other drugs are being taken at the same time, 4. the previous drinking history of the individual, 5. the physical state of the person doing the drinking, 6. the genetic background of the individual( i.e. ethnicity, gender), 7. the mood and psychological makeup of the individual and 8. the environment when alcohol is taken. 1. Amount of alcohol drunk: Generally small amounts of alcohol [Blood Alcohol Concentrations (BAC) = 0.03 0.12%] produce lowered inhibitions, feelings of relaxation, more self confidence, diminished judgement, reduced attention span, and slight incoordination. BACs of 0.09 to 0.25% induce more incoordination, slower reaction times, loss of balance, blurred vision, exaggerated motions, difficulty in remembering. Higher BACs to 0.3% result in confusion, dizziness, slurred speech, severe intoxication, alterations in mood including withdrawal, aggression, or increased affection, and diminished ability to feel pain. Even higher BACs, to 0.4%, can result in stupor, being incapacitated, having loss of feeling,, being difficult to arouse, and lapses in and out of consciousness. Finally, as the blood level approaches 0.50% the person may die due to a variety of physiological complications such as diminished reflexes, slower heart rate, lower respiration, and decreased body temperature.

I 2. Time over which the alcohol is drunk: Rapid intake of alcohol results in more alcohol in the stomach and small intestine. This produces a larger gradient of alcohol and greater absorption into the blood stream and thus distribution into the tissues including the brain. If alcohol is taken in more rapidly than it is metabolized (1/3 oz to 1/4 oz. per hour in an average person), then the BAC continues to rise. 3. Use of other drugs with alcohol: The utilization of other drugs at the same time that alcohol is being drunk can result in increased effects of the alcohol. This action can occur several ways including enhancing the absorption and distribution of alcohol, action on the same chemical systems in the brain as alcohol, and/or slowing the metabolism of ethanol through competition at the liver for metabolizing enzymes or even damage to the liver so it doesnt work as well. 4. Previous drinking history: The previous drinking history is influential in determining the effects of current alcohol consumption. Often times, dependent upon the amount and timing of prior alcohol consumption, the person will develop a tolerance. Tolerance to alcohol can be loosely defined as needing alcohol to produce the same effect. Therefore, a person who has developed tolerance will need more alcohol to produce some of the same effects. It should be noted that not all systems underlying behavior develop tolerance at the same rate. In addition to tolerance, it is probably that after heavy long-term drinking that damage has been done to the brain and to the liver. In these cases response to alcohol may be different than that originally seen and/or prolonged since the liver cant metabolize the ethanol as rapidly. 5. Physical state: A persons physical state can be an important determinant of their response to alcohol. As mentioned in number four above, if a person has an impaired liver, then the metabolism of ethanol will be impaired thus enhancing and/or prolonging the alcohol action. Further, the nutritional status of the person can be an important determinant of the action. Food in the stomach will compete with ethanol for absorption into the blood stream. It is well known that alcohol competes and influences the processing of nutrients in the body. To the extent that a well nourished body is able to respond to everyday demands of living, the extend of malnourishment may determine the extent and magnitude to which the body can respond to alcohol.

6. Genetic background: The genetic background of an individual is an important determinant in the response to alcohol. There are several important examples of this. A certain portion of the Asian population carries modifications of enzymes responsible for the metabolism of alcohol such that drinking causes these individuals to have facial flushing and become sick or nauseous. Women are generally more responsive than men to the same amount of alcohol because of differences in metabolism and differences in the amount of body water. Children of alcoholics are much more likely to become alcoholic, findings that are not a result of environment. Many strains of animals are more responsive to alcohol than are other strains and animals have been bred to prefer alcohol, sleep longer after ethanol administration, and to have more severe withdrawal from alcohol. 7. Mood and psychological makeup: Use of alcohol tends to potentiate the mood of the user. Thus, if one is sad, alcohol may make you sadder. If you are happy, alcohol may make you happier. The psychologically make-up of an individual becomes important since alcohol may diminish some controls, which keep the person functioning well under usual circumstances. Loss of those controls may lead to difficulties such as aggression and other unwanted behaviors. 8. Environment: The environment in which a person drinks is an important determinant of the effects of alcohol. For example drinking at a festive party will often cause the person to become more festive. A good example of this is the behavior of the thousands of people who attend Mardi Gras in New Orleans each year. This is essentially a huge party that goes on and on and peo ples behavior and energy level is potentiated by the group. In contrast, it would be expected that drinking at sad occasions would result in more sadness. Liver: An association between alcohol consumption and liver disease has been known for over 200 years (Smart and Mann, 1992). In fact, the most common cause of illness and death from liver disease is from long-term alcohol consumption (National Center on Health Statistics, 1994). Since the liver is the primary site of alcohol metabolism, it is not surprising that it is particularly susceptible to alcohol-related injury. The injury to the liver from long-term drinking apparently comes not only from ethanol, but also from the dangerous products generated upon the metabolism of ethanol. These include acetaldehyde and highly reactive molecules called free radicals. (Free radicals are a group of elements or atoms usually passing intact from one compound to another, therefore in an uncombined from. As free, it is usually short lived and highly reactive.)

Since the liver is the largest organ in the body (approx. 3.3lbs) and one of the most important being involved in a number of important processes, it has considerable reserves and is able to regenerate itself. Therefore, limited damage to the liver can go undetected and the insult needs to be quite substantial in order for damage to occur. With respect to alcohol, this means drinking large quantities of alcohol over many years. It has been estimated (Mazey et al., 1988) that in men the dose needed would be 600 kilograms taken chronically. This is equivalent to 72 oz of beer, 1 liter of wine, or 5 or 6 standard drinks (1.5oz) daily for 20 years. For women, the amount needed would be one-fourth of this due to gender differences in the ability to "handle" alcohol.

There are three major categories of liver damage (French et al, 1993) from alcohol ingestion, which are usually thought of as a progression in severity, however this is not always the case. These are:

1. Fatty liver Fatty liver means fat disposition in the liver. This can occur after as single drinking session and after chronic consumption. Fatty liver is reversible and may not lead to more serious liver problems. 2. Alcoholic hepatitis "This disorder is characterized by widespread inflammation and destruction of the liver". The liver may have scar tissue. The symptoms may include fever, jaundice and abdominal pain. The condition may be fatal, but may be reversible if one quits drinking. It occurs in 50% of heavy drinkers.

3. Alcoholic cirrhosis This is the most advanced form of liver disease and is diagnosed in 15 to 30 % of heavy drinkers. Between 40 and 90 percent of the 26,000 annual deaths form cirrhosis are alcohol related. (Dufour et al, 1993). Cirrhosis is characterized by extensive scar tissue (fibrosis) that stiffens blood vessels and distorts the internal structure of the liver. Cirrhosis causes malfunction of other bodily organs such as the brain and kidneys. Kidney: The major functions of the kidneys are to regulate the volume and composition of the fluids and electrolytes in the body. They help in the supply of nutrients to the cells of the body and in clearing cellular waste as well as providing stable conditions for the cells to function. The substances regulated by the kidneys include water, sodium, potassium, calcium, and phosphate in the fluids (extracellular fluids) surrounding the various cells. In addition the kidneys regulate the acid-base balance which is important in maintaining cell structure, permeability, and metabolic activity. Further, the kidneys produce hormones that influence numerous physiological processes. Because of their involvement in all these important bodily processes, alcohol, has the potential to influence and/or compromise these functions of the kidneys and thus has the potential to induce severe consequences for the functioning of the organism. Images below are courtesy Alcohol Health and Research World, Effects of Alcohol on Organ Function, Vol21, #1, 1997. U.S. Department of Health and Human Services

Normal Kidney

How does ethyl alcohol act in the kidney to produce electrolyte Disturbances? As with most organs in the body there are a number of regulatory processes which allow the kidney to function normally and optimally, ethyl alcohol can disturb these controls. The precise effects depend upon the amount of alcohol taken and the time over which it is consumed. Alcohol has been shown to change the structure and function of the kidney and impair their ability to regulate the volume and composition of fluid and electrolytes in the body. Gross and microscopic changes in the kidney include alterations in the structure of the glomerulus (see figure), swelling or enlargement (nephromegaly) of the kidney, and increased number of cells with fat, protein, and water. These effects alter the ability of the kidneys to function normally.

The rate of blood flow through the kidneys is an important determinant of the amount of filtration of the blood and absorption of substances from the blood that can take place. Various effects of alcohol have been reported including both increased and reduced blood flow. These effects seem to be related to whether or not the person also had liver disease and in animal models which species of animal was used. Alcohols on electrolyte balance has major implications for the satisfactory functioning of the cells of the body. As a prime example, the cells of the brain and particularly neurons are highly dependent upon proper amounts of sodium, potassium, chloride, and calcium being available. Disruption in the proper flow and availability of these electrolytes alters the ability of the neurons to function which leads to modifications in behavior and the ability of the brain to regulate other bodily processes.

Effect of Ethyl Alcohol on Electrolytes Problem Major Cause(s) Low sodium level (hyponatremia). Massive intake of solute-free fluid. Low potassium level (hypokalemia). Dietary deficiency, gastric losses, leaky membranes, shifts from extracellular to intracellular. Low phosphorus level (hypophosphatemia). Dietary deficiency, malabsorption, increased cellular uptake. Low magnesium level (hypomagnesemia). Dietary deficiency, malabsorption, phosphorus deficiency. Ethyl alcohol can induce urine flow within 20 minutes. As a result of these fluid losses the concentrations of electrolytes in the blood can changed and can be dramatic, particularly in cases of extreme loss of water. Ethyl alcohol appears to affect a hormone called antidiuretic hormone, which induces the kidney to conserve fluids. This effectively concentrates the urine. Ethyl alcohol decreases the ability of the body to concentrate urine, thus promotes water loss rather than allowing the water to be absorbed back into the body. As a result of this electrolyte levels in the blood also rise due to less water being taken back in. Proper acid-base balance (i.e. hydrogen ion concentration) is crucial to the proper functioning of most of the bodys metabolic reactions. The kidneys play an important role in regulating this acidity, thus the rate at which metabolic processes proceed. Examples of alcohol-related acid-base disturbances include low levels of phosphate, which may result from hyperventilation during withdrawal from alcohol and cases of alkalosis (low acidity) which may be a result of severe vomiting after binge drinking. The latter sickness leads to losses of fluid, salt, and stomach acid.

2003 Kennesaw State University Principal Investigator Laurence Peterson Project Director Matthew Hermes

http://www.chemcases.com/alcohol/alc-07.htm