Week 6.2 Alcohol and CNS Depressants: Biological and Psychosocial Factors in Addictions

Different Drugs, Different Effects: Alcohol and CNS Depressants

This lecture is part of the Pharm 3101 course: Biological and Psychosocial Factors in Addictions, delivered by Abdallah Salem from the Discipline of Pharmacology.

Lecture Objectives

By the end of this lecture, students should be able to:

• Describe common alcohol effects in relation to blood alcohol concentration (BAC).

• Describe the factors that affect BAC.

• Describe the acute and chronic effects of alcohol on the central nervous system (CNS).

• Explain treatment goals for alcohol physical dependence.

Recap: CNS Signaling - Amino Acids

Amino acids play critical roles in neurotransmission within the CNS. They are categorized into excitatory and inhibitory pathways.

Excitatory Amino Acids

• Glutamate and Aspartate are the primary excitatory neurotransmitters.

• They are essential for physiological processes such as memory and learning.

• Neurotoxicity: High concentrations of these excitatory amino acids can lead to neurotoxicity, which is associated with neurodegenerative disorders, brain disorders, and stroke.

• Antagonists to these receptors are used as treatments for various CNS diseases.

Inhibitory Amino Acids

• GABA (Gamma-Aminobutyric Acid): This is the primary inhibitory neurotransmitter in the CNS. It is synthesized from glutamate via the enzyme glutamic acid decarboxylase.

• GABA Receptors:

  • $GABAA$: This is a post-synaptic, ligand-gated ion channel specific to chloride ions ($Cl^-$). It serves as the site of action for benzodiazepines and CNS depressants, including alcohol.

GABA Pathways and the $GABAA$ Receptor Complex

GABA Pathways

Inhibition by GABA is observed across all levels of the CNS. Key areas involved in GABA pathways include:

• Nucleus accumbens

• Frontal cortex

• Cerebral cortex

• Cerebellum

• Amygdaloid body

• Olfactory bulb

• Hippocampus

The $GABAA$ Receptor

The function of $GABAA$ receptors can be modulated through multiple drug binding sites, which act as regulatory sites on the receptor. These receptors are involved in several physiological and pathological states:

• Epilepsy

• Anxiety

• Learning and memory

• Drug addiction

Ligand-Gated Channel Mechanism

Stimulation of $GABAA$ receptors results in:

1. An influx of chloride ions ($Cl^-$) into the cell.

2. Hyperpolarization of the cell membrane, reducing neuronal excitability.

CNS Depressants and Sedative-Hypnotics

Definition

The term "CNS depressant" describes the pharmacological effect on the central nervous system (slowing down activity) rather than a change in the user's mood. These substances are also known as sedative-hypnotics.

Common CNS Depressants

• Benzodiazepines (e.g., diazepam, nitrazepam).

• Barbiturates (e.g., pentobarbitone, phenobarbitone).

• Gamma-hydroxybutyric acid (GHB).

• Alcohol.

Effects of Sedative-Hypnotics

These compounds are characterized by their ability to induce sleep and relieve insomnia. They reduce nervousness and excitability by inducing a calming effect. The effect is generally dose-dependent:

• Smaller doses: Produce sedative effects (calming).

• Larger doses: Produce hypnotic effects (sleep-inducing).

Alcohol: Pharmacokinetics (Absorption and Distribution)

Absorption

• Ethanol is a small, highly water-soluble molecule.

• It crosses biological membranes easily via passive diffusion.

• Absorption is rapid, with the fastest absorption occurring in the small intestine.

Distribution

• Once in the systemic circulation, alcohol is distributed rapidly to body tissues.

• It readily crosses both the blood-brain barrier and the placental barrier.

Acute Effects of Alcohol and BAC

The magnitude of alcohol's effects depends on the Blood Alcohol Concentration (BAC). The emotional and psychological response shifts depending on whether the BAC is rising or falling:

• Rising BAC Curve: Associated with positive feelings and euphoria (if the dose is high enough). Anxiolytic (anxiety-reducing) properties are most apparent when the baseline anxiety is high, the dose is moderate, and the BAC is on the rising part of the curve.

• Falling BAC Curve: Generally associated with negative feelings.

• Individual Differences: Some individuals may experience sedation during the rising part of the curve, while others experience stimulation, which may drive them to continue drinking.

Common Alcohol Effects in Relation to BAC

National Drug Strategy Household Survey (NDSHS) 2019: Alcohol Findings

• Giving up alcohol: The proportion of ex-drinkers increased from $7.6\%$ in 2016 to $8.9\%$ in 2019.

• Risky drinking: People drinking at risky levels on a single occasion ($25\%$) and exceeding lifetime risk guidelines ($16.8\%$) remained stable since 2016, though both have decreased since the 2009 NHMRC guidelines.

• Age demographics: Reductions in risky drinking are driven by younger groups; levels among older Australians have remained stable or increased since 2001.

• Dependence: Approximately $1$ in $10$ recent drinkers ($9.9\%$) are likely to meet criteria for alcohol dependence.

• Action taken: $52\%$ of Australians took action to reduce drinking in 2019, compared to $48\%$ in 2016.

• Policy support: Support for policies aimed at reducing excessive alcohol use declined since 2016, while opposition increased.

• Heavy consumption: Adults consuming $11$ or more standard drinks at least once a month declined from $7.4\%$ to $6.7\%$ between 2016 and 2019.

Factors Affecting BAC

Several variables determine an individual's BAC after consumption:

• Body Weight: Generally, higher weight results in lower BAC for the same amount of alcohol.

• Body Composition: Alcohol dissolves well in body water but not in fat.

• Gender: Women typically reach higher BACs than men after consuming equal amounts of alcohol due to differences in percentage of body water:

  • Females: Approximate body water is $53\%$.

  • Males: Approximate body water is $62\%$.

• Rate of Metabolism.

Alcohol Metabolism

The major route of metabolism occurs in the liver through the following pathway:

1. Ethanol is converted to Acetaldehyde by the enzyme Alcohol Dehydrogenase (ADH).

2. Acetaldehyde is converted to Acetic acid by the enzyme Aldehyde Dehydrogenase (ALDH).

Genetic Variation: Differences in the rate of acetaldehyde metabolism exist (e.g., in some Asian subjects). Higher blood acetaldehyde concentrations following a standard dose cause unpleasant symptoms such as flushing, headache, nausea, and dysphoria, which often results in lower alcohol consumption.

Chronic Alcohol Use: Negative Consequences

Sustained high levels of alcohol use increase the risk of several health issues:

• Cardiovascular disease: including hypertension and strokes.

• Liver cirrhosis.

• Cancers.

• Pancreatitis.

• Cognitive problems and dementia.

• Sexual dysfunction.

• Impaired fetal development.

Acute CNS Effects of Alcohol

Alcohol impacts the CNS through several molecular mechanisms:

1. Inhibition of Calcium Channels: It inhibits the opening of voltage-sensitive $Ca^{2+}$ channels, which in turn inhibits neurotransmitter release.

2. Enhancement of $GABAA$ activity: Most $GABAA$ receptors are sensitive to alcohol; this enhancement mediates the sedative and anxiolytic effects of alcohol.

3. Inhibition of NMDA Receptors: It inhibits N-methyl-D-aspartate (NMDA) receptor activity. The NMDA receptor is a subtype of excitatory amino acid receptor for which glutamate is the endogenous agonist.

4. Opioid Systems: Ethanol increases the release of endogenous opioids and dopamine in the brain reward system. This contributes to the reinforcing effects of ethanol.

   • Cross-tolerance: Exists between opioids and alcohol.

   • Animal Studies: Self-administration of alcohol is increased by low doses of opioids and decreased by opioid receptor antagonists.

Dopamine and Neurotransmission

Dopamine is the key neurotransmitter in addiction. Drugs of dependence directly or indirectly activate brain reward pathways by either increasing dopamine release or inhibiting dopamine reuptake.

Tolerance and Physical Dependence

Tolerance to Acute CNS Effects

The brain undergoes cellular adaptation to the presence of alcohol to maintain homeostasis:

• Increase in activity of $Ca^{2+}$ channels.

• Decrease in activity of GABA.

• Increase in activity of glutamate (NMDA).

• Reduction in the release of endorphins and dopamine.

Physical Dependence and Withdrawal

Physical dependence occurs when alcohol is withdrawn, leading to an over-excitability of neurons because the adaptive changes listed above are no longer counteracted by alcohol.

• Alcohol Withdrawal Syndrome: The result of this neuronal over-excitability. A "hangover" is considered a mild withdrawal syndrome following acute intoxication.

• Negative Reinforcement: Users may engage in self-treatment with alcohol to relieve withdrawal symptoms.

• Clinical Significance: Significant withdrawal may occur with regular consumption exceeding $80\,g/day$.

• Symptoms: Sleep disturbance, anxiety, and tremulousness. Severe cases may include seizures and hallucinations.

• Treatment: Most signs and symptoms of withdrawal respond to the administration of benzodiazepines.

Treatment Goals for Physical Dependence

Relapse Prevention (Harm-Reduction Model)

Pharmacotherapies aim to:

• Increase the number of days of abstinence.

• Reduce the amount of alcohol used on drinking days.

• Reduce craving discomfort and protracted withdrawal.

Long-term Goals

• Improvement of social functioning.

• Optimizing physical and mental health.

Australian Alcohol Guidelines (2020)

The National Health and Medical Research Council (NHMRC) provides the following guidelines to reduce health risks:

• Guideline 1: To reduce risk of harm from disease or injury, healthy men and women (aged $18$ and over) should drink no more than $10$ standard drinks per week and no more than $4$ standard drinks on any one day.

• Guideline 2: Children and people under $18$ years of age should not drink alcohol.

• Guideline 3A: Women who are pregnant or planning pregnancy should not drink alcohol to prevent harm to the unborn child.

• Guideline 3B: For breastfeeding women, not drinking alcohol is the safest option for the baby.

Quantifying Alcohol Use

In Australia, alcohol use is quantified by the "Standard Drink."

• $1$ Standard Drink = approximately $10\,g$ of alcohol.

• This is equivalent to $12.5\,mL$ of pure alcohol.

Recommended Reading

• The Biological Basis of Mental Health, 3rd Edition, Chapter 8.