Table of Contents
Page created on June 8, 2019. Last updated on May 23, 2022 at 11:25
Introduction to ethanol
Ethanol (hereafter alcohol) is the most commonly used recreational drug in humans. Overdose can cause death due to respiratory and circulation depression. Ethanol itself is responsible for the “positive” CNS effects of alcohol, like euphoria and decreased inhibition. The “negative” effects like headache and nausea are rather caused by ethanol’s metabolite acetaldehyde.
Pharmacodynamics of alcohol
Alcohol acts on the CNS both as a stimulant and as a depressant. Its depressant actions resemble those of volatile anaesthetics like isoflurane. It increases neuronal activity in some parts of the brain, like the mesolimbic dopaminergic pathway, which is involved in reward. Alcohol affects the CNS by multiple mechanisms:
- By binding to an allosteric site on GABAA receptors, increasing their affinity for GABA
- Alcohol binds to a different allosteric site than benzodiazepines and barbiturates
- By inhibiting the excitatory NMDA receptors
- By enhancing glycine receptors
- By inhibiting voltage gated Ca2+ channels
- By inhibiting adenosine transport
Alcohol enhances the CNS depressant effect of other drugs like benzodiazepines, antidepressants, antipsychotics and opioids.
Behavioural effects:
It’s well-known that alcohol causes generalized CNS depression, which is seen as slurred speech, motor incoordination, poor judgement and increased self-confidence. Stimulation of the reward pathway produces a feeling of euphoria. At higher doses of intoxication aggression can occur.
Neurotoxic effects:
Alcohol doesn’t just cause acute changes in the nervous system but chronic changes as well. This may be due to ethanol itself, its metabolite acetaldehyde or due to dietary deficiencies often seen in alcoholics, like thiamine deficiency. Binge drinking is considered worse than chronic drinking in this aspect, as binge drinking probably allows for higher concentrations of alcohol in the brain.
Heavy drinkers may develop cerebral atrophy with symptoms like convulsions and dementia. Peripheral neuropathy can also occur.
Effects on other systems:
- It induces cutaneous vasodilation.
- This causes a warm feeling but actually increases heat loss.
- It inhibits ADH, causing diuresis
- It stimulates salivary and gastric secretions
- It directly damages the gastric mucosa, causing chronic gastritis
- It damages the liver, causing alcoholic liver disease
- It can cause acute or chronic pancreatitis
- It impairs testosterone synthesis in the testicles and increases testosterone metabolism in the liver
- It is carcinogenic
- It is teratogenic
The effects of alcohol on the liver were described in pathophysiology 2, but a short summary will be included here:
- The NADH/NAD+ ratio increases, inducing a state of pseudohypoxia
- Fats accumulate in the liver
- To decrease the NADH/NAD+ ratio hepatocytes convert pyruvate into lactate, which means that there are no substrates for gluconeogenesis
Pharmacokinetics of alcohol
Absorption:
Alcohol is rapidly absorbed, much of it through the gastric mucosa. A substantial portion of absorbed alcohol is cleared by hepatic first-pass metabolism.
Alcohol is metabolized by the liver with zero-order kinetics rather than first-order kinetics, which means that a constant amount of alcohol is metabolized every minute, regardless of the concentration. This is because the enzymes the liver uses to metabolize alcohol are very quickly saturated. If the alcohol concentration increases the liver can’t increase its rate of clearance (because the enzymes are already saturated), so alcohol accumulates in the body.
When consumed with food alcohol must compete with the food for absorption, meaning that the alcohol is absorbed slowly from the GI tract. This gives the liver more time to metabolize the alcohol. When alcohol is consumed on an empty stomach it will be rapidly absorbed as there is no food to compete with alcohol for absorption. All consumed alcohol will therefore quickly be absorbed and quickly saturate the liver’s capacity for metabolism, causing alcohol to accumulate in the body.
Distribution:
Alcohol is rapidly and evenly distributed throughout the body. It has a Vd = 0.6 L/kg
Elimination:
99% of ingested alcohol is eliminated from the body by biotransformation. The remaining 1% of eliminated alcohol is eliminated unchanged via urine, sweat and breathing.
Biotransformation:
Alcohol is biotransformed by converting it into acetaldehyde by one of three enzymes, CYP2E1, alcohol dehydrogenase (ADH) or catalase. Of these three the first two are most important. In non-alcoholics most consumed alcohol is metabolised by ADH rather than CYP2E1.
The conversion of alcohol into acetaldehyde by ADH requires the cofactor NAD+, which is converted to NADH during the reaction. This is the reason the NADH/NAD+ ratio increases after alcohol ingestion. The reason alcohol elimination follows zero-order kinetics is not because the ADH enzyme itself is saturated, but because NAD+ is quickly depleted. The rate of elimination of alcohol depends on how fast the body can convert NADH back into NAD+.
In alcoholics the chronic alcohol consumption induces CYP2E1, so in this population CYP2E1 plays a more important role in biotransformation than in non-alcoholics.
After alcohol has been converted into acetaldehyde by one of the three aforementioned enzymes the acetaldehyde must be converted into acetic acid (=acetate). This conversion is performed by the enzyme acetaldehyde dehydrogenase (ALDH), which also requires NAD+ as a cofactor, further increasing the NADH/NAD+ ratio.
Differences in biotransformation between populations:
There are regional differences in the genes for the ADH and ALDH enzymes that affects different populations’ response to alcohol. The most important genetic polymorphisms are described in the tables below:
For ADH:
| Allele | ADH1B*1 | ADH1B*2 |
| Phenotype | Slow metabolizer | Rapid metabolizer |
| Carriers | Caucasians, Africans | Asians |
| Rate of ethanol conversion | Slow | Rapid |
| “Positive” CNS depressing effects of alcohol | Long & strong | Short & weak |
For ALDH:
| Allele | ALDH2*1 | ALDH2*2 |
| Phenotype | Rapid metabolizer | Slow metabolizer |
| Carriers | Caucasians, Africans | Asians |
| Rate of acetaldehyde conversion | Rapid | Slow |
| “Negative” symptoms of acetaldehyde | Short, negligible | Heavy |
Caucasians and Africans usually have ADH1B*1 and ALDH2*1. These populations metabolize ethanol to acetaldehyde slowly but acetaldehyde to acetate rapidly. This means that most of their consumed alcohol remains as ethanol, and the ethanol that is converted into the symptom-causing acetaldehyde is rapidly converted into the non-symptom-causing acetate. For this reason, these populations experience more of the “positive” and fewer of the “negative” effects of alcohol consumption, which gives them a high risk of alcohol dependence.
Asians, however, usually have ADH1B*2 and ALDH2*2. This population metabolizes ethanol to acetaldehyde quickly but acetaldehyde to acetate slowly. This means that most of their consumed alcohol remains as acetaldehyde, which gives this population much more negative effects and fewer positive effects after alcohol consumption. This gives them a low risk of alcohol dependence.
Chronic alcoholism
Chronic alcohol consumption causes permanent changes in many proteins and cells in the CNS, leading to tolerance and dependence. After 1 – 3 weeks of continuous alcohol consumption the potency of alcohol is reduced two or three-fold, indicating that tolerance occurs quickly.
Acquired alcohol tolerance:
Acquired alcohol tolerance occurs when neurons in the CNS adapt to the constant presence of ethanol. These changes include a reduction in the number of GABAA receptors and an increase in voltage-gated calcium channels and NMDA receptors. Alcohol tolerance also causes tolerance to commonly used anaesthetics, which makes alcoholics difficult to anaesthetize.
Alcohol dependence:
Alcoholism causes two types of dependence: physical dependence and psychological dependence.
A drug causes physical dependence if the person experiences unpleasant physical withdrawal symptoms after the drug is withdrawn. In the case of alcohol these withdrawal symptoms occur due to the permanent changes in the CNS neurons described above. Common withdrawal symptoms include:
- Sleep disruption
- Hallucinations
- Sympathetic activation
- Tremors
- Seizures
- Delirium tremens
Delirium tremens is a state that occurs approximately three days after alcohol withdrawal and lasts for around three more days. It is characterised by hallucinations, fever, delirium, seizures and possibly death.
A drug causes psychological dependence if the person experiences unpleasant psychological withdrawal symptoms after the drug is withdrawn, like anxiety, stress and dysphoria. Alcohol causes euphoria by activating the reward system, so withdrawal will cause a rebound dysphoria. Fear of the physical withdrawal symptoms can also contribute to psychological dependence.
Pharmacological treatment of alcoholism:
The symptoms of alcohol withdrawal can be treated with benzodiazepines like diazepam. This makes the withdrawal period easier for the patient and also treats psychomotor symptoms and seizures.
To promote alcohol cessation, multiple drugs are helpful:
- Disulfiram – an ALDH inhibitor
- This increases the acetaldehyde levels after alcohol consumption, causing acetaldehyde syndrome, which makes the experience of drinking worse and promotes abstinence
- Naltrexone – an opioid antagonist
- This decreases the euphoric effect caused by drinking, which promotes abstinence
- Acamprosate – an NMDA receptor antagonist
- This decreases the craving for alcohol
Acetaldehyde syndrome is caused by high levels of acetaldehyde in the body, which occurs when a patient who takes disulfiram consumes alcohol. Symptoms include vomiting, tachycardia and hypotension.
Methanol poisoning
Methanol is used as an industrial solvent and as a component of products like windshield fluid. It can also be present together with ethanol in homemade alcohol.
Methanol is converted into formaldehyde acid by alcohol dehydrogenase (ADH) and later to formic acid by acetaldehyde dehydrogenase. Formic acid is toxic and mediates most of the symptoms of methanol poisoning. These include metabolic acidosis, visual disturbances and death. The first symptom of methanol poisoning is often vision loss.
Methanol poisoning is treated with:
- Gastric lavage, to prevent more methanol from being absorbed
- Sodium bicarbonate infusion – for the metabolic acidosis
- Fomepizole or ethanol
- Fomepizole is an ADH inhibitor, which decreases the level of formic acid in the body
- Ethanol competes with methanol for the ADH enzyme and can therefore be used as an antidote
- Folic acid
- Folic acid enhances the elimination of formic acid
- Haemodialysis
Ethylene glycol poisoning
Ethylene glycol is also used as an industrial solvent. It is also found in antifreeze.
Ethylene glycol is converted into glycolaldehyde by alcohol dehydrogenase (ADH) and into glycolic acid by ALDH. Glycolic acid is then converted into other compounds, one of them being oxalic acid. These metabolites are toxic and mediate the symptoms of ethylene glycol poisoning. Glycolic acid causes metabolic acidosis, and oxalic acid causes acute renal failure.
Ethylene glycol poisoning is treated similar as methanol poisoning:
- Gastric lavage, to prevent more ethylene glycol from being absorbed
- Sodium bicarbonate infusion – for the metabolic acidosis
- Fomepizole or ethanol
- Fomepizole is an ADH inhibitor, which decreases the level of toxic metabolites in the body
- Ethanol competes with methanol for the ADH enzyme and can therefore be used as an antidote
- Haemodialysis