Young rat : 10.6 orally
Old rat : 7.06 orally
Imagine yourself going for a couple of drinks after a long day at work.Not very long after finishing your single malt scotch (assuming you're not a heavy drinker) , you notice your state of mind begin to change.You think slower, have a lower reaction time, decreased coordination and slurred speech begins to set in and you begin acting more impulsively.A sense of warmth and mild euphoria is also noticed, and it's this effect that has been sought in the thousands of years since the discovery of fermentation.
But how does this actually happen?Why does alcohol affect people so differently?And why are some people "lightweights" while others can hold their liquor?
The answer to those and other questions can be found in the following sections.
2. WHAT IS ALCOHOL?
There are several alcohols, but I'll only mention the two that are relevant to the discussion: Ethyl alcohol or Ethanol (drinking alcohol) and methyl alcohol or Methanol (wood alcohol).
Ethanol has only two carbon atoms, 5 hydrogens and a hydroxyl group (OH).This is the type of alcohol that is in alcoholic beverages.
Methanol has a simpler molecular structure, with only one C atom instead of two, and is sometimes the by-product of clandestine/improper distillation. It's metabolites include formic acid and formaldehyde, and drinking enough will cause blindness, coma, and death.
To ensure that the methanol is removed, legitimate distillers will throw away the first portion of the distilled product, since methanol has a lower boiling point than ethanol and therefore vaporizes first.
3. ABSORPTION AND METABOLISM OF ALCOHOL
Before going into the more interesting part, you need to understand the ABCs of the absorption, metabolism, and distribution of alcohol.I must admit, it is a complex topic for those unfamiliarized with the subject, but I've made sure to include all necessary information for the understanding of how alcohol works, in a clear, reader-friendly and concise manner.
Ethanol is a pretty small molecule that forms no ions and is insoluble in lipids and yet it's easily absorbed, and readily enters the brain.Due to its rather variable pharmacokinetics, the effects can't be described very accurately based on the amount ingested and so they're measured based on the amount that is in blood alcohol concentration (BAC).
Absorption occurs mainly in the intestine, and in much smaller part in the stomach.It crosses these membranes through a process called passive diffusion, which is the process through which substances flow from the side of the membrane with the highest concentration to the side with the least, which in this case involves the higher concentration of alcohol in the stomach/intestine and the lower concentration in the blood stream as shown bellow:
This means that the more concentrated the drink, and the faster its drank, as common sense would have it, the faster it diffuses into the bloodstream.Food delays the alcohol from getting into the intestine, and milk seems to delay absorption especially well.
Alcohol is metabolized primarily in the liver before being excreted as water and CO2 in the urine (about 95%) with the other 5% being excreted through the lungs.This is why cops can estimate your BAC using a breathalyzer test.
Alcohol metabolism is fairly constant independently of blood levels, and so if a person drinks faster than what can be metabolized, intoxication occurs.There are two enzymes that are extremely important for alcohol metabolism: Alcohol dehydrogenase and acetaldehyde dehydrogenase (ALDH).
First, alcohol dehydrogenase converts alcohol to acetaldehyde, an intermediate metabolite that is in significant part responsible for the hangover experienced after significant alcohol intake.This enzyme is found in the stomach, where it is 60% more active in men than in women, leading to a higher concentration that will have a faster absorption rate in women.
Certain medications such as aspirin and cimetidine can impair gastric metabolism, increasing absorption.
Once metabolized into acetaldehyde, it is quickly modified by the enzyme acetaldehyde dehydrogenase to form acetic acid.Drugs like disulfiram
) inhibit this enzyme, inducing acute alcohol sensitivity, meaning that if someone drinks while taking the drug, they will suffer extreme hangover symptoms within 10min. which include nausea, vomiting, and a wicked headache.For this reason, the drug is often used to manage alcoholism.
This two step metabolic process is shown in this diagram:
Alcohol dehydrogenase ____________ALDH ____________________Oxidation
Alcohol -------------------Acetaldehyde--------------------acetic acid---------------------CO2 and H2O
Other enzymes such as cytochrome P450
also have a role in the metabolism of alcohol and many prescription drugs, which is why so many drugs interact with alcohol.
4. ALCOHOL PHARMACODYNAMICS: HOW DOES ALCOHOL WORK?
We all know what effects alcohol has on our minds. But how does it happen? In this section, I go into what alcohol actually does to get you drunk.Keep in mind that no neurotransmitter system works by itself, and what affects one will indirectly affect others.
Alcohol is different than most drugs because it influences the phospholipid bilayer of neurons.This has a huge impact on the normal functioning of cells and this leads to a change in several neurotransmitter systems.I describe those changes in this chapter.
Glutamate is the main excitatory ("stimulant") neurotransmitter in the brain.Alcohol inhibits a type of glutamate receptors known as the N-methyl-D-asparate (NMDA) receptors which mediate memory and associative learning.They are ligand-gated channels that allow Ca2+ and NA+ through to cause depolarization.Alcohol inhibits these receptors by reducing the effectiveness of glutamate in the receptor.This explains, in part, alcohol's effects of learning and memory.
GABA, as opposed to glutamate, is the main inhibitory neurotransmitter in the brain.GABA stands for Gamma-aminobutyric acid and it's the target of many sedatives
including benzodiazepines like diazepam
).Alcohol opens the Cl- channel in the GABA-A subtype which produces hyperpolarization on the membrane.Repeated agonism of this receptor leads to downregulation, but more on that later.
Pretty much every drug of abuse has a direct or indirect effect on the dopaminergic pathways.It is directly linked to the pleasure centers of the brain, which have always had a very important role as they are behind all of our motivations, no matter how basic or intuitive.For example, dopamine
is what makes you feel good when you have sex, drink water after being thirsty, or win the lottery.It's what makes your favorite food taste good and make you enjoy your favorite tv show, and alcohol, like all recreational drugs, has significant effects on this neurotransmitter.
One interesting fact that confirms it's role in addiction is that when dopamine antagonists (blockers) are injected directly into the mice brain areas associated with pleasure and reward it significantly reduces their consumption of alcohol.
When scientists first discovered the opiate
receptors, they were confused as to why we'd have receptors for morphine
, a substance only found in the opium
poppy, in our brain.After much thinking, the only conclusion that could be drawn was that morphine-like substances must be produced in our bodies that fit the same receptors and have a role in anxiety and pain reduction.These substances were eventually found and named "endorphins" and "enkephalins".
Alcohol induces the release of these endogenous opioids
, which contribute significantly to it's rewarding and pleasurable effects.As to prove this statement, opioid receptor antagonists (blockers) were given to rats along with their alcohol, and this significantly decreased their consumption.
5.ALCOHOL TOLERANCE: HOW DOES IT OCCUR?
Everyone knows that the more and the longer you drink regularly, the more you need to drink to reach the same effect.This has no one single mechanism, and instead, is a combination of different factors that in combination create tolerance to alcohol:
5.1 Metabolic changes
Prolonged consumption of alcohol leads to an increase in alcohol dehydrogenase and other enzymes that contributes to a more rapid metabolism of the drug.
5.2 Receptor regulation
As explained earlier, alcohol has effects on several neurotransmitter systems and their combined regulation is in part, responsible for tolerance to alcohol:
As alcohol inhibits or antagonizes this receptor, the expected response is upregulation.This means that NMDA receptors increase in number over chronic exposure to alcohol, making it less effective in its action.
As explained earlier, alcohol acutely increases the Cl- influx at the GABA-A receptor, but chronic exposure to the drug has the opposite effect.Normal Cl- influx decreases at this receptor, making it less sensitive to the effects of alcohol.
Opposite to acute effects, animals that have been chronically exposed alcohol show severely reduced dopaminergic firing in the ventral tegmental area and nucleus accumbens, both areas being strongly involved in reward and pleasure.
ENDOGENOUS OPIOID SYSTEMS:
Chronic alcohol consumption reduces gene expression responsible for endorphin and enkephalin release from the pituitary gland, causing chronic dysphoria and further tolerance tot he drug.
5.3 BEHAVIORAL TOLERANCE
We've all met or heard about the office drunk who is completely smashed 24/7 and yet acts pretty normal, even getting their work done.How can they do this? The answer is behavioral tolerance.
An interesting experiment was done on mice that were chronically fed alcohol and then made to run on a treadmill.They were pretty unsuccessful in the beginning, but surely enough they soon began running on the treadmill almost as well as rats that were given alcohol after running on the treadmill (as to eliminate other alcohol-related factors).
6. DIFFERENCES IN PHYSIOLOGICAL RESPONSE: WHY AM I A LIGHTWEIGHT?
We've all met someone who can outdrink the best of us, and now that we understand the basics, we can begin to understand why people react so differently to alcohol, and why sex, age, race and genetic makeup matter so much.
Although most certainly a factor, lack of tolerance to alcohol is not always the reason some people get smashed on two cans of beer, while others can drink pint after pint without puking all over your floor.In this section, I'll explain how people are different when it comes to tolerating booze.
It would not surprise the reader to hear that women have a lesser tolerance to the effects of alcohol than men.But what the reader may not know is that alcohol dehydrogenase is 60% less active in the gastric fluid of a woman than in that of a man.This obviously leads to a faster absorption, and therefore a higher peak alcohol concentration.
Racial differences in alcohol metabolism are somewhat harder to explain, but put simply, involve differences in the acetyldehyde dehydrogenase (ALDH) gene.As discussed earlier, when this enzyme is blocked by the drug disulfram, alcohol consumption produces an instant severe hangover accompanied by flushing.
Everyone has a pair of chromosomes with the ALDH gene, one from the mother and one from the father.The two chromosomes can either be formed by the same pair of the same gene (alleles) or two different alleles.
These alleles, individually, can be either active or inactive.This means that someone with two active alleles have normal metabolism of acetaldehyde and will tolerate alcohol well, while someone with two inactive alleles will experience severe flushing, nausea, and vomiting with amounts of alcohol that would be perfectly tolerable to most people as they are unable to properly metabolize acetaldehyde.Alternatively, someone may have one active and one inactive ALDH allele which produces a response to alcohol somewhere in between the previous two cases.
Most people of Asian descent inherit genes that encode only the inactive form of the enzyme, or only one active form, making them either very susceptible to alcohol's effects (in the first case) or otherwise more susceptible than most people.The latter can have a lower vulnerability to alcoholism.
Alcohols are oxidized in the body to their corresponding aldehydes or ketones by the enzyme alcohol oxidase. This enzyme oxidizes ethanol into acetaldehyde, which is responsible for many of the negative side-effects of alcohol consumption. Acetaldehyde is readily converted into acetic acid (the same acid found in vinegar) upon reaction with water from the body. Failure to stay hydrated while drinking alcohol prevents the conversion of acetaldehyde to acetic acid and causes a number of negative side-effects attributable to both dehydration and acetaldehyde intoxication. These can include headaches, sensitivity, lethargy, dysphoria, thirst, mild depression, and anxiety. Acetaldehyde intoxication can often be noted by a mildly fruity odor on one's breath.
Acetic acid formed via ethanol metabolism increases the acidity of the stomach often causing a sour stomach feeling and, in high enough amounts, can cause nausea and vomiting as well as diarrhea and other negative effects.