EvaSoultogianni_Final

=Alcohol and its interactions with prescribed medication and OTC=

Abstract
Alcohol is the most popular beverage for giving euphoria and happiness. However, chemically, alcohol is an organic compound (wikipedia) and participates in chemical reactions in the human body. Alcohol was introduced in ancient years for religious rituals, medical purposes as well as social use for entertainment (wikipedia). Nowadays, alcoholic beverages can be misused and can harmfully act on the brain to change behavior (Valenzuela, 1997). It is even more harmful when alcohol is consumed along with medication either on purpose or accidentally without knowing that these two will interact and this will result in undesirable outcomes (Therapeutic Research Center, 2008).

History of Alcohol
Alcohol is a chemical product that has many and various functions in people’s life from ancient periods. The most popular use of alcohol back then and nowadays is the alcoholic beverages, which have been playing really important role in many religions around the world and worship (Hanson, 1995). Alcoholic beverages have also been considered are rich sources of vital nutrients and have been used medical procedures for their antiseptic and analgesic properties. Nowadays, alcoholic beverages are mostly used to accompany meals to increase the taste and food pleasure and for entertainment and pleasure of quality of life (Hanson, 1995). Historically, the are no sources showing when alcoholic beverages were first used but intentionally fermented beverages were first discovered in the Neolithic period, which is around 10,000 BC, with the discovery of Stone age beer jugs (Hanson, 1995). Wine, on the other hand, is recorded in the Old Testament that a vineyard was planted in an area what is now eastern Turkey and it also appeared in Egypt around 4,000 BC (Hanson, 1995). Both, wine and beer where used for medical purposes around 2,000 BC (Hanson, 1995). In Egypt as well as in ancient Greece, people have worshiped gods for the invention of beer and wine in these countries, respectively (wikipedia, accessed November, 29). In Greece, specifically, believed in Dionysos, who is the god of grape harvest, because it was believed that intoxication brought people closer to gods making their faith stronger (wikipedia, accessed November, 29).

Introduction
Ethyl alcohol is the organic compound used to make all alcoholic beverages (Tarallo-Falk, 2005).



Figure 1: Ethyl alcohol (chemspider).

Alcohol is a legal depressant in the form of liquid (Tarallo-Falk, 2005) that even very young students can have access to. It can give happiness when it is consumed in limited amounts but it can be very harmful when it is consumed in large amounts and even worse when it is combined with medication. When alcohol interacts with medication increases the side effects of the medication (Tartau et al, 2009).The consumption of alcohol along with medication is a huge load for the United States of America and for many other countries as well imposing medical and socioeconomic concerns in the society (Cruz et. al., 2008). Alcohol was introduced in the society thousands of years ago with significant role in religion, medicine and entertainment (Hanson, 1998). A drug interaction is when another drug or any other substance do not allow the drug to perform and have the results expected. Medication and alcohol interactions change the physiological factors such as absorption, distribution, metabolism and elimination of the drug from the system There are two types of interactions between medication and alcohol: 1. pharmacokinetic interactions and 2. pharmacodynamic interactions (Koppisetti et. al., 2011).

Pharmacokinetic Interactions
Pharmacokinetic interaction is when alcohol interferes with the metabolism of the medication. When alcohol enters the system, preferably from the mouth, a small amount is digested in the stomach but most of it is absorbed to the bloodstream from the gastrointestinal tract. An amount of the alcohol in the bloodstream is metabolized in the liver, while the rest of the ingested alcohol leaves the liver and enters the general circulation to be distributed to the body’s tissues. This kind of alcohol metabolism, which happens in the liver first, is called “first-pass metabolism” (Weathermon et al, 1999). The rate of the alcohol metabolism plays a very important role because the faster the alcohol is metabolized, the faster it will exit the system. However, the metabolic rate depends on many factors such as age, body water, hepatic function, racial group, and not only the rate and pattern of consumption (Pagliaro et al, 1992). Moreover, alcohol is not dissolved in fat tissues. Women and older people usually have more fat and less water compared to younger ages and males. As a result, the metabolic rate also depends on gender (Weathermon et al, 1999).



Figure 2: Basal Metabolic Rate in Females and Males (Paulev-Zubieta)

As a result since the metabolic rates are different the absorption and oxidation/elimination of alcohol from the system will also be different as shown in the following diagram:



Figure 3: Oxidation of Alcohol (Paulev-Zubieta)

Furthermore, the elimination of the alcohol from the system also depends on the rate it is broken down during metabolism (Martin et al, 1985). In the “first-pass metabolism” the alcohol in the liver is broken down by ADH and cytochrome P450 enzymes. In the ADH pathway, alcohol is converted to acetaldehyde via oxidation. Acetaldehyde, which is a very toxic substance and highly reactive, is metabolized into acetate by aldehyde dehydrogenase (ALDH) (Seronello, 2010). In this reaction hydrogen is removed from the ethyl alcohol and it is attached to nicotinamide-adenine dinucleotide (NDA), which is the oxidized form of nicotinamide adenine dinucleotide, also known as NADH (Seronello, 2010). Cytochrome P450 consists of two enzymes: the cytochrome P450 reductase and the CYP2E1. This metabolism pathway is also called microsomal ethanol oxidizing system (MEOS) because it is predominantly present in microsomes, and it is located in the Smooth Endoplasmic Reticulum (SER) (Lieber, 2005). For people who consume alcohol only occasionally in small amounts, CYP2E1 metabolizes a small fraction of that alcohol. But for chronic heavy drinkers, the activity of CYP2E1 increases up to tenfold, so much more alcohol is metabolized by the cytochrome P450 pathway rather than the ADH pathway (Weathermon et al, 1999). Most of the prescribed medication is also metabolized primarily by cytochrome P450 enzymes, either by one or more (Lynch, 2007). When cytochrome P450 enzymes cause interactions of the medication with other substances, such as alcohol, medication can be referred to as inhibitors or inducers (Lynch, 2007). The medications that act as inhibitors block the activity of the cytochrome enzymes (Lynch, 2007). The extend to which an inhibitor affects the metabolism of the medication depends on the ability of the inhibitor to bind the enzyme or enzymes (Lynch, 2007). There are two ways how medication can inhibit the activity of cytochrome enzymes but at the same time be metabolized. Either it inhibits and being metabolized by the same enzyme or it can be metabolized by one enzyme and inhibit another (Lynch, 2007). Medication that act as inducers cause the opposite of inhibition which is to increase the activity of the enzymes and combined with chronic heavy drinking that the CYP2E1 activity is increased (Lynch, 2007). In this pathway the alcohol in the system competes with the medication trying to be metabolized by CYP2E1. As a result the metabolic rate of the medication and the break down is much slower causing high concentrations to be in the system for longer time and this may lead to harmful and even lethal overdoses (Weathermon, 1999). In pharmacokinetic pathway, there is another form of interaction between the medication and alcohol. Medication metabolism can be accelerated when alcohol is not present at the same time to compete for the enzyme metabolism and thus the cytochromes’ activity is increased. Therefore the elimination rate of the medication is faster causing the alcohol to remain in the bloodstream for longer time (Weathermon, 1999). Cytochrome P450, specifically CYP2E1, produces reactive oxygen species (ROS) along with superoxide anion and hydroxy radicals that can cause tissue damage (Zakhari, 2006). Moreover, it has really high capacity to convert xenobiotics to very toxic metabolites which causes high vulnerability to alcoholics (Lieber, 2000).

Pharmacodynamic Interactions
Pharmacodynamic interactions between medication and alcohol do not involve enzyme activation or inhibition. It most commonly takes place in the central nervous system (CNS) (Weathermon, 1999), and changes of the medication action occur in the area of the target tirrue (Pleuvry, 2005). In this case the action of the medication alters because of the presence of alcohol at the site of medication action. There are two forms of interactions: additive or synergistic and opposing or antagonistic (Pleuvry, 2005). Additive or synergistic interactions occur when the two substances interacting, in this case the medication and alcohol, have similar properties and are consumed together (Pleuvry, 2005). An example is when ethanol is consumed with sedative drugs, such as benzodiazepines, where alcohol acts on the same molecule inside or on the surface of the targeted cell as the medication does (Weathermon, 1999). Benzodiazepines also have high therapeutic index, which means that overdoses may cause prolonged sedation and may also be fatal (Pleuvry, 2005). The synergistic sedative effects that benzodiazepine-alcohol interactions cause may lead to substantial central nervous system (CNS) impairment (Weathermon, 1999). There are also certain benzodiazepines that use cytochrome P450 enzymes causing alcohol induced changes in their metabolism (Weathermon, 1999). The second type of interactions are the opposing or antagonistic. In this kind of interactions the two substances, medication and alcohol, apply opposite effects on different receptor systems and they oppose each other physiologically (Pleuvry, 2005). This process is call functional antagonis (Pleuvry, 2005). As already mentioned previously, pharmacodynamic interactions between mediacation and alcohol take place in the central nervous system (CNS) (Weathermon, 1999). It very important to see how alcohol works in the brain and how it interacts with gamma-Aminobutiric acid (GABA), which is the most important inhibitory neurotransmitter in the mammalian central nervous system (wikipedia, accessed November, 29). Alcohol’s effect on the brain is to minimize neuronal activity by increasing the inhibitory action of GABA and decreasing the excitatory action of another neurotransmitter called glutamate (Cruz et al, 2008). The are two amino acids in the GABA receptor transmembrane segment which are very important for allosteric modulation of GABA and other receptors when alcohol is consumed (Lobo et al, 2008). When these amino acids are replaces or in general they do not function are they are expected to, there is loss of ethanol potentiation, which shows that alcohol acts upon ion channels to alter their functions (Lobo et al, 2008). Benzodiazepines and anesthetic barbiturates also target and bind GABA receptors and show cross-tolerance and dependence with alcohol (Paul, 2006). Around thirty years ago GABA receptor-mediated Cl- flux was used to show that alcohol potentiates GABA receptor activity at low intoxication levels (Paul, 2006). It was also found that a specific imidazobenzodiazepine blocked the ability of alcohol to enhance the activity of the GABA receptor-mediated Cl- flux. Alcohol effects, on the synaptoneurosomes (where the synapsis takes place) are more common in the extrasynaptic GABA receptors rather than the GABA receptor-mediated Cl- flux (Paul, 2006).

The chance of alcohol and medication interactions in non-heavy drinkers can be different between pharmacokinetic and pharmacodynamic interactions (Weathermon, 1999). The number of potential for pharmacokinetic interactions is larger than that for pharmacokinetic interactions, because there are many medications and in different classes that use cytochrome P450 enzymes to be metabolized (Weathermon, 1999). Pharmacokinetic interactions are usually more common in heavy drinkers, even if scientists have not completely demonstrated yet, however it has been found that pharmacodynamic interactions mostly occur in non-heavy drinker, even after a single episode of drinking (Weathermon, 1999).

Alcohol interactions with different classes of medication
__Antibiotics:__ Usually doctors and the package inserts warn not to consume alcohol along with antibiotics. And this is because most antibiotics tend to interact with alcohol (Weathermon, 1999). For instance, erythromycin is an antibiotic that interacts with alcohol by increasing alcohol absorbance in the intestine by emptying the gastrointestinal tract much faster. Another example is the anti-tuberculosis drug isoniazid, which should not be combined with alcohol because this antibiotic can cause liver damage which might get worse with very often alcohol consumption(Weathermon, 1999). Researchers have found that interactions between alcohol and medication mostly appear in heavy drinkers because large amounts of alcohol can impair the function of specific immune cells and they are more prone to certain infections (Weathermon, 1999). __Antidepressants:__ This is a class of medication that they are different from antibiotics because they target the central nervous system (CNS) and interact with brain chemicals (Weathermon, 1999). Examples of antidepressants are selective serotonin reuptake inhibitors (SSRIs), tricylic antidepressants (TCAs), and monoamine oxidase (MAO) inhibitors (Weathermon, 1999). The most important property of these medications is that they contain sedative and have stimulating activity (Weathermon, 1999). Usually TCAs have higher amount of sedative and as a result along with alcohol this will cause the most sedation (Weathermon, 1999). These sedative effects occur because alcohol increases the pharamcodynamic interactions (Weathemon, 1999). However, there is also effect on pharmacokinetic interactions. What actually happens is that alcohol interferes with the first pass metabolism of the medication resulting in high levels of the medication in the bloodstream (Weathermon, 1999). Moreover, liver diseases that result from extensive alcohol consumption can negatively affect the medication break-down cause high levels of active medication to be present in the blood (Weathermon, 1999). SSRIs are the most widely used antidepressants and do not contain as much sedative as TCAs (Weathermon, 1999). SSRIs are the most safe antidepressant medication compared to the rest, even if it is combined with large amounts of alcohol (Weathermon, 1999). On the other hand, MAO inhibitors have adverse effects, such as very high blood pressure, when they are consumed with alcohol (Weathermon, 1999). __Barbiturates:__ They are medication most commonly used for anesthesia because they cause sedation and sleepiness (Weathermon, 1999). Currently, the most widely used barbiturate in medicine is Phenobarbital and it is also used for seizure treatment (Weathermon, 1999). This medication act in the central nervous system (CNS) and therefore there are pharmacodynamic interactions betweem alcohol and Phenobarbital when they are consumed together (Weathemon, 1999). In this case, the two substances work synergistically to cause sedation (Weathermon, 1999). Moreover, Phenobarbital affects the pharmacokinetic interactions by inhibiting the medication’s break down in the first pass metabolism (Weathermon, 1999). This results in more active medication in the bloodstream and in slower metabolism (Weathermon, 1999). On the other hand, this class of medication increases the activity of cytochrome P450 eznymes in the liver and thus the alcohol is metabolized faster (Weathermon, 1999). __Muscle Relaxants:__ Many muscle relaxants produce a narcotic reaction with alcohol causing adverse effects such as agitation, dizziness, extreme weakness and confusion (Weathermon, 1999). Examples of muscle relaxants are carisoprodol, cyclobenzaprine, and baclofen (Weathermon, 1999). Carisoprodol is a prescribed medication but it is also distributed in the streets illegally (Weathermon, 1999). When it is metabolized in the liver, it generates an anxiety-reducing agent and this is why street abusers usually combine it with alcohol to get into a state of euphoria and happiness (Weathemon, 1999). __Antihistamines:__ They are medications available both with prescriptions and “over the counter” commonly used for treatment of allergies and cold (Weathermon, 1999). Common side effects, which usually appear in older people, are sedation, low blood pressure and drowziness (Weathermon, 1999). When antihistamines are combined with alcohol, they impair these side effects because pharmacodynamic interactions are increased (Weathermon, 1999). People with these side effects are unable to drive or opperate any kind of machinery and they are also in high risk of falling (Weathermon, 1999) and therefore high risk of serious damage and injuries. __Nonsteroidal anti-inflammatory agents__: They are medications used to treat minor aches and pains (Weathermon, 1999). When they are combined with alcohol there is a high risk of gastrointestinal bleeding in elderly people specifically and also it might damage the stomach mucosa (Weathermon, 1999). __Non-narcotic pain medication:__ A widely known pain medication is aspirin and when it is combined with alcohol it can cause extensive bleeding because the function of some blood cells involved in blood clotting is inhibited (Weathermon, 1999). Acetaminophen is also a pain reliever medication. When it is consumed along with alcohol there is a high risk of toxic effects and liver damage (Weathermon, 1999). Acetaminophen is broken down by CYP2E1 (cytochrome P450 enxyme) which generates toxic products leading to life-threatening liver diseases (Weathermon, 1999). However, CYP2E1 activity is enhanced when alcohol is consumed and this in return increases the formation of toxic products produced by acetaminophen (Weathermon, 1999). This also depends on the dose of the medication as well as the amount of alcohol consumed this is why people should not exceed the dose recommended (Weathermon, 1999). Sometimes acetaminophen drugs might contain small amounts of other flu drugs such as aspirin and ibuprofen and therefore the adverse effects when these drugs are combined with alcohol might be even worse (Weathemon, 1999). __Warfarin:__ It is used in patients with irregular heart rhythms in order to prevent blood clotting (Weathermon, 1999). Warfarin has anticoagulant properties which can be altered with alcohol consumption. When the two substances are combined, the anti-clotting effects of warfarin are increased, which can cause bleeding (Weathermon, 1999). In this case, pharmacokinetic interactions are enhanced, where the increased activity of cytochrome P450 enzymes increase warfarin metabolism (Weathermon, 1999). Since the metabolism is increased, it mean that warfarin break-down is increased which requires higher dose of the medication to achieve the desired drug effect (Weathermon, 1999).

Conclusion
In conclusion, alcohol can bring happiness when it is consumed in small amounts but it can be really harmful when it is combined with medications. This is because the metabolism of the one substance is involved in the metabolic pathway of the second. Pharmacokinetic interactions occur in the first pass metabolism, where metabolism takes place first in the liver, and pharmacodynamic interactions mostly occur in the central nervous system (CNS). Different medication depending on how they are metabolized have either pharmacokinetic interactions or pharmacodynamic interactions or both. What actually happens in the system is that either alcohol does not let the medication to be metabolized so there is more active medication in the bloodstream for longer time or the medication is metabolized faster leaving excess amount of alcohol in the blood. Adverse effects of medication-alcohol combination are much worse for heavy drinkers and most common in elderly people. Finally, people should be very careful with the doses because higher doses can impair the side effects.