Chapter 10, Alcohol Flashcards
Alcohol Metabolism
CYP enzymes are used in the metabolization of various drugs, including alcohol and benzodiazepines. CYPs can convert alcohol to acetaldehyde.
Alcohol can compete with other drugs for CYP enzymes, leading to reduced metabolism of the drug / greater concentrations of the drug in the blood
What type of drug is Alcohol?
Depressant
Route of Administration of Alcohol
Oral
Duration of Effects of Alcohol
Moderate
What are the Neurotransmitters that Alcohol impacts?
- GABA
- Glutamate
- Dopamine
- Opioids
What is the tolerance level for Alcohol?
Moderate
What is the physical dependence on Alcohol like?
Intense
What is the psychological dependence on Alcohol like?
Moderate
Withdrawal symptoms of Alcohol
- Cramps
- Delirium
- Vomiting
- Sweating
- Hallicinations
- Seizures
- Delirium tremens (DTs)
“The Noble Experiment”
1900-1920s Prohibition
Alcohol use in Canada
Canadians consume an average of about 8.2L of pure ethanol per year (that’s ~1.3 standard drinks per day!)
Brain-Volume Deficits in Alcoholism
Increased ventricle size and sulci, indicating atrophy
Forms of Alcohol
- Ethyl alcohol (ethanol) is the form used in beverages - Ethanol is produced by the fermentation of sugars by yeasts
- Naturally, fermented beverages do not exceed 15% alcohol
Absorption of Alcohol
- Ethanol is easily absorbed from the GI tract and diffuses through the body
- Passive diffusion from GI tract to blood – the greater the concentration of alcohol consumed, the more rapid the movement
- Food in the stomach slows absorption (especially fatty foods)
Factors that impact the absorption of alcohol
- Carbonation (faster absorption)
- Stress, anxiety, fear
- Illness
- Hydration levels
- Estrogen levels?
General Properties of Depressants
Side effects
* Lethargy
* Drowsiness
* Impaired coordination
* Impaired mental function
* Emotional swings
* Dejection
Desired effects
* Euphoria
* Relaxation
* Anxiety reduction
* Reduced inhibitions
Distribution of Alcohol
- Blood alcohol concentration (BAC) expressed as a percentage in grams/100 mL
- Alcohol is less distributed in fatty tissues, therefore a lean person will have a lower BAC
- Other factors play a role in how alcohol affects people (genetics, age, rate of consumption etc.)* Evenly distributed throughout the body
- Freely crosses BBB to affect multiple brain areas
- Freely crosses the placenta
- Fetal BAC is the same as in drinking mother
Metabolism of Alcohol
- Alcohol is mostly metabolized slowly in the liver
- Enzymes in the cytochrome P450 family metabolize alcohol (and many other drugs)
- Enzyme induction is possible
- If alcohol is consumed with other drugs, they may compete for enzymes
Alcohol –> Acetaldehyde –>Acetic acid –> Alcohol dehydrogenase –> Aldehyde dehydrogenase –> Acetate - Zero-order kinetics (constant rate; approx. 10mL of pure ethanol/hour)
- Prolonged heavy use of alcohol can cause liver damage
- Irreversible, but cessation of drinking will slow the rate of damage
Elimination of Alcohol
- ~90% of alcohol is eliminated by breaking down into metabolites
- ~2-10% excreted unchanged
- Ex. In breath, sweat, or urine
Other factors that affect metabolism:
* Gender
* Experience
* Timing
* Food in the stomach
* Other medications
Factors that DO NOT affect metabolism or elimination rates:
* Caffeine
* Cold showers
* Exercise
* Sleep
Physiological Effects of Alcohol
- Peripheral circulation; Dilation of peripheral blood vessels = loss of body heat
- Fluid balance; Diuretic effects
- Hormonal effects in chronic users
- Suppression of REM sleep
Behavioural Effects
Behavioural effects depend on BAC
* Effects are greater when BAC is rising
* Perception of the effects also greater when BAC is rising
Expectations are important
* Culture
* Environment (e.g., alone vs. in a group; with friends vs. with parents, etc.)
* Studies with placebos
How does Alcohol impact the Frontal Lobe?
When alcohol reaches this part of the brain, a person can lose judgment and lower
his or her inhibitions. Alcohol here also affects how the brain gets information from
the senses, which might cause blurry vision and difficulty in smelling, tasting, and
hearing.
How does Alcohol impact the Hippocampus?
Drinking a lot of alcohol in a short period can cause a blackout, when a person
cannot remember entire events. Long-term alcohol use can cause permanent
memory and learning damage in this part of the brain.
How does Alcohol impact the Cerebellum?
This part of the brain helps a person with thinking, coordination, balance, and being aware of everything around them.
Alcohol causes a loss of balance and coordination.
How does Alcohol impact the Hypothalamus?
When alcohol reaches this brain area, it can cause increased blood pressure,
increased hunger and thirst, decreased body temperature, and a decreased heart
rate.
How does Alcohol impact the Medulla?
Drinking alcohol interferes with this part of the brain’s ability to maintain the body’s
normal temperature. Alcohol can also cause slower breathing and heart rate. If a lot
of alcohol is used over a short period of time, it can even cause a person to go into a
coma when this part of the brain shuts down.
Types of Tolerance to Alcohol
- Acute tolerance
- Metabolic tolerance
- Pharmacodynamic tolerance
- Behavioral tolerance
- Cross-tolerance with other depressants
Physical Dependence on Alcohol
- Intensity and duration of withdrawal signs depend on the amount
and duration of drug taking - Hangovers may be evidence of withdrawal (acute toxicity?)
- Hangovers are not
completely understood, but
the symptoms are generally
consistent: Headache, fatigue, upset
stomach, thirst, general malaise - Acetaldehyde or acetate
accumulation - Reactions to congeners
Alcohol Withdrawal
- Alcohol withdrawal can be very dangerous for chronic, heavy drinkers
Acute symptoms occur in the hours since the last dose:
* Shaking hands and feet
* Sweating
* Nausea and vomiting
* Diarrhea
* Tightness in the chest
* Elevated BP; Rapid heartbeat
* Irregular heart rhythms
* Increased body temperature
- Some people experience delirium tremens (DTs) and/or seizures
- Medical supervision and/or pharmacological treatment is necessary for these individuals
- Withdrawal symptoms tend to decrease within 5-7 days but can last for several weeks
Mechanism of Action of Alcohol
- Alcohol primarily facilitates the action of GABA at the GABAA receptor
- Hyperpolarization; Increased inhibition
- Repeated exposure to ethanol reduces GABAA-mediated Cl–flux; may contribute to tolerance and withdrawal
- Alcohol also impacts metabotropic GABAB receptors
- Recall metabotropic receptors have slower, more complex effects
- GABAB receptors are located pre-synaptically and postsynaptically, and at both GABAergic and Glutamatergic cells
- Alcohol affects glutamate by acting as an antagonist at NMDA receptors
- Reduced excitation
- Repeated use leads to upregulation of NMDA receptors (pharmacodynamic tolerance)
- During withdrawal, glutamate release increases causing CNS hyperexcitability (and sometimes seizures)
- During withdrawal, glutamate release
increases after approx. 10 hrs. Timing correlated with hyperexcitability
and seizures are seen in severe alcohol
withdrawal
Role of the Dopamine System
- Alcohol activates dopaminergic cells in the
VTA, causing the release of DA in the NAcc, which is involved in positive reinforcement - In rodents, withdrawal after chronic alcohol use reduces the firing rate of mesolimbic neurons and decreases DA release in the Nacc
Role of the Opioid System
- Alcohol administration increases opioid production and release
- Chronic administration will reduce the production à dysphoria?
- Blocking opioid receptors reduces self-administration in animal models
- A person’s baseline levels of endorphins may influence their susceptibility to AUD
- Opioids probably play a role in alcohol craving
- Naltrexone is an opioid receptor antagonist used in the treatment of alcohol use disorder
- Reduces alcohol consumption and craving
- Improves abstinence rates, but… results are inconsistent; It is greatly beneficial for some and has limited benefit for others
The way Alcohol acts with different neurotransmitters
- GABA usually has an inhibitory effect on DA
- GABA signalling is modified by glutamate and opioids
- Alcohol inhibits glutamate, stimulates the release of endorphins, and reduces GABA’s inhibitory effects, thus increasing DA release in the VTA/NAcc
Alcohol Use Disorder (AUD)
- No specific cause has been identified, but there are some factors that lead to increased risk:
- Anxiety disorders
- Genetics
- Age at initiation
- Stress
- Personality factors
- Culture
Heavy drinking accelerates brain atrophy
* Loss of white matter (connectivity), rather than loss of neurons
Treatment of AUD
- The first step is detoxification
* Medication may be used to control dangerous withdrawal symptoms (e.g., benzodiazepines reduce the likelihood of seizures and can prevent anxiety, insomnia, and muscle spasms)
* Detoxification length depends on the severity of AUD, but initial detox is usually 1 week - The next step is preventing relapse
* One pharmacotherapeutic strategy is to make drinking unpleasant by
using disulfiram - The next step is preventing relapse
* One pharmacotherpeautic strategy is to make drinking unpleasant by
using disulfiram
* Another strategy is to use an opioid receptor antagonist (naltrexone)
to reduce the “high” by blocking endorphin release - The next step is preventing relapse
* One pharmacotherpeautic strategy is to make drinking unpleasant by
using disulfiram
* Another strategy is to use an opioid receptor antagonist (naltrexone)
to reduce the “high” by blocking endorphin release
* Some individuals find individual or group therapy to be helpful in
maintaining their abstinence
Competition and Alcohol Metabolism
Alcohol can compete with other drugs for CYP enzymes, leading to reduced metabolism of the drug / greater concentrations of the drug in the blood
