Alcohol: Biochemical and Neurochemical Aspects

Types of alcohol commonly used:

Propanolol --> Desinfection

Methanol --> toxic solvent

Ethanol--> Drug

Alcohol Metabolism

Biochemical Pathways of Alcohol Metabolism

• Alcohol (ethanol) is primarily metabolized in the liver through two main enzymatic steps:

  • Step 1: Ethanol is converted to acetaldehyde by the enzyme alcohol dehydrogenase (ADH).

  • Step 2: Acetaldehyde is further converted to acetic acid (acetate) by aldehyde dehydrogenase (ALDH).

• Overall reaction:

• Acetic acid is then converted to carbon dioxide and water via the citric acid cycle.

• Cytochrome P450 enzymes (especially CYP2E1) also contribute to alcohol metabolism, especially at higher concentrations.

Factors Affecting Alcohol Metabolism

• Food in the stomach slows alcohol absorption by delaying gastric emptying. Food dilutes alcohol, fatty foods help slow absorption greatly.

• Gender differences: Females generally have lower levels of gastric ADH (enzyme), less body water, and more body fat, leading to higher blood alcohol concentrations (BAC) for the same amount consumed.

• Genetic differences in ADH and ALDH activity can affect susceptibility to alcohol's effects and toxicity. More significant effects in women

Alcohol Absorption and Distribution

• Alcohol is absorbed primarily in the small intestine, but also in the stomach.

  20% in stomach (fast), 80% in intestines (slow)

  high concentration causes more irritation due to more absorption

• Distribution is rapid due to alcohol's high water solubility.

• Peak BAC is influenced by rate of consumption, food intake, alcohol concentration and individual metabolism.

  Rate of absorption depends: surface area, vascularization, concentration gradient btwn blood and gut

• Esfinter pirolus: the rate of gastric emptying (how open or closed the pyloric sphincter is) greatly affects how fast alcohol enters the bloodstream, carbonated beverages increase opening

Physiological Effects of Alcohol

Acute Effects

Acetaldehyde accumulation causes toxic effects (emesis, nausea, flushing, headache) --> treated with DISULFIRAM

• CNS depression: Alcohol acts as a central nervous system depressant, impairing motor coordination, judgment, and reaction time.

• Cardiovascular effects: Vasodilation, increased heart rate at low doses, arrhythmias at high doses.

• Respiratory depression: At very high BAC, alcohol can suppress the respiratory centers in the brainstem, leading to death.

• 2-5% is excreted by urine, sweat and breath

• Supresses immune system

• Gatritis

• Hepatic Cirrhosis

Ethnic differences:

50% of asians have inactive mitochondrial ALDH resulting in excessive flushing, palpitations, dizziness, and nausea

(depends on GENOYPE: homozygous active < heterozygous < homozygous inactive)

Isoenzymes of ADH between ethnic groups have varying Km (smallest is caucasian, highest is african american)

Chronic Effects

• Liver damage: Chronic alcohol use can cause fatty liver, alcoholic hepatitis, and cirrhosis.

• Wernicke-Korsakoff syndrome: Thiamine deficiency in alcoholics leads to severe memory impairment and confabulation.

• Fetal Alcohol Syndrome (FAS): Prenatal alcohol exposure can cause growth retardation, neurological problems, and facial abnormalities.

• Alcoholism: Delirium Tremens (convulsions, hallucinations, panic attacks), withdrawal effects acn include: anxiety, high BP, rapid HR, rapid breathing, vomiting, tremors

Tolerance and Dependence

• Metabolic tolerance: Increased enzyme activity (especially CYP2E1) leads to faster alcohol metabolism, functional tolerance caused my changes in GABA receptors.

• Pharmacodynamic tolerance: Neural adaptation reduces alcohol's effects at the same BAC.

• Behavioral tolerance: Learned adaptation to alcohol's effects in specific environments.

• Dependence: changes in Dopamine and Serotonin are long lasting

Neurochemical Effects of Alcohol

ansiolítico-hipnótico

desinhibición

placer (dopamina en nucleus accumbens)

alta dosis: agresión, incapacidad motora)

disminuye deseo sexual

Major Neurotransmitter Systems Affected

Brain areas:

Cerebral cortex, Thalamus, Cerebellum, Nucleus Accumbens, Hypothalamus, Mammillary body, Frontal cortex

• Potentiates GABAA receptors: Alcohol enhances inhibitory GABAergic transmission, leading to CNS depression. (NMDA receptors are inhibited)

• inhibits Glutamate (NMDA receptors) : Alcohol inhibits excitatory glutamatergic transmission, contributing to cognitive impairment and memory loss.

• Dopamine: Alcohol increases dopamine release in the nucleus accumbens, reinforcing its rewarding effects.

• Serotonin: decreased serotonin which causes aggression

• Endogenous opioids (endorphins): Alcohol stimulates the release of endorphins, contributing to its pleasurable effects (reduce pain and can create feelings of pleasure or euphoria).

Neuronal membranes: stimulates Gs protein, modifies gating, disturbs lipid composition, interacts with polar heads of membranes

Withdrawal and Neuroadaptation

• Chronic alcohol use leads to compensatory upregulation of NMDA receptors and downregulation of GABAA receptors.

• Withdrawal is characterized by CNS hyperexcitability, anxiety, tremors, and risk of seizures.

• Cross-tolerance and cross-dependence can occur with other CNS depressants (e.g., benzodiazepines).

Alcohol Use Disorder (AUD)

Genetic and Environmental Factors

• Family, twin, and adoption studies show a genetic predisposition to AUD, 3-7 times more likely if you have alcoholic family members

• Type I (usually femail, later in life) and Type II (usually male, early in life) alcoholism differ in age of onset, genetic influence, and behavioral characteristics.

• Gene-environment interactions play a significant role in risk.

• Wernicke Encefalopahty: Thymine deficiency from stomach irritation, causes confusion, ataxia, double vision, decreases brain glucose

  • CAN BECOME PERMANENT IF NOT TREATED WITH IV B6 (Kosakoff syndrome: anterograde amnesia, apathy)

Diagnosis and Treatment

• Diagnosis: Based on behavioral criteria, tolerance, withdrawal, and continued use despite harm.

• Treatment: Includes behavioral therapy, support groups, and pharmacological agents (e.g., disulfiram, naltrexone, acamprosate).

  Cross Dependence: barbiturates and benzodiazepines can be used for treatment

• RO 15-4513 overcomes motor impairment

• Disulfiram: Inhibits ALDH, causing acetaldehyde accumulation and unpleasant reactions if alcohol is consumed.

• Haloperidol: manejar Delirium Tremens

• Naltrexona: disminuye cravings

Key Tables

Table: Enzymes Involved in Alcohol Metabolism

Table: Acute vs. Chronic Effects of Alcohol

Key Terms and Definitions

• Blood Alcohol Concentration (BAC): The percentage of alcohol in the bloodstream; legal intoxication is typically 0.08% in many countries.

• Hangover: A set of symptoms (headache, nausea, fatigue) following heavy alcohol consumption, partly due to acetaldehyde accumulation and dehydration.

• Binge drinking: Consuming a large amount of alcohol in a short period, often defined as 5+ drinks for males or 4+ for females in two hours.

• Fetal Alcohol Syndrome (FAS): A condition in children resulting from alcohol exposure during pregnancy, characterized by growth deficiencies and neurological problems, fetal reaches BAC of mother quickly

  • low IQ

  • low birth weight

  • characteristical features

  • maladaptive conduct

  • anxiety

  • socislization impairment

Example: Alcohol Metabolism Pathway

When a person consumes alcohol, ethanol is absorbed into the bloodstream and transported to the liver. There, alcohol dehydrogenase converts ethanol to acetaldehyde, a toxic intermediate. Aldehyde dehydrogenase then rapidly converts acetaldehyde to acetic acid, which is further metabolized to carbon dioxide and water. Genetic variations in these enzymes can lead to differences in alcohol tolerance and risk of adverse effects.

Summary

• Alcohol metabolism involves key liver enzymes and produces toxic intermediates.

• Acute and chronic alcohol use have significant biochemical and neurochemical effects.

• Genetic, environmental, and neurochemical factors contribute to the risk of AUD.

• Understanding these mechanisms is essential for the study of biochemistry and pharmacology.