ETX 30 Lecture Notes

ETX 30: Chemicals and Drugs of Use and Abuse - Spring 2025

Overview

  • PK/TK PD/TD
  • Caffeine facts
  • Caffeine PK
  • Caffeine PD
  • Caffeine toxicity
  • Group activity: Is the Huberman Lab Podcast claim that you should delay caffeine 90-120 minutes after waking scientifically valid?

Updates

  • PPTs are updated with content from class.
  • Survey 1/Practice Assignments due at 4:40pm on Tuesday 4/15.
  • 24-hour grace period extends the deadline until 4/16 at 4:40pm.

Quiz Recap

  • Group quiz scores increased individual scores by 29%!
Concepts to Clarify
  • Therapeutic Index: TD<em>50/ED</em>50TD<em>{50} / ED</em>{50}
    • The therapeutic index is a ratio comparing the dose that produces toxicity in 50% of the population (TD<em>50TD<em>{50}) to the dose that produces a desired effect in 50% of the population (ED</em>50ED</em>{50}).
    • A larger therapeutic index is better because it indicates a wider margin between effective and toxic doses.
  • ED50: The lower the ED50ED_{50}, the lower the dose needed to achieve a 50% biological response; pink is the most potent.

Half-Life

  • Time for plasma concentration to drop by one half.
  • Drug half-life can range from minutes to hours to days.
  • Half-life determines the duration of action.
  • Dosing frequency depends on half-life (e.g., Ritalin vs. Concerta).

PD/TD: Dynamics

  • Studying a specific interaction of a drug with a specialized area on a target cell.
  • Targets: Receptors, enzymes, transporters, ion channels (ionotropic receptor).

Drugs that Target Receptors

  • Receptors are macromolecules involved in chemical signaling between and within cells, located on the cell membrane or within the cytoplasm.
  • Agonists: A chemical (ligand) that produces an effect by binding to the receptor (e.g., heroin is an opioid receptor agonist).
  • Magnitude of response: Depends on the number of receptors bound.
  • Potency vs. Efficacy: Potency refers to the amount of drug needed to achieve an effect, while efficacy is the maximum effect a drug can produce

Drugs that Target Receptors

  • Antagonists: A chemical that prevents or inhibits the binding of an agonist (e.g., naloxone is an opioid receptor antagonist).

Enzymes

  • Enzymes are proteins that act as biological catalysts, converting a substrate to a product.
  • Inhibitors: Bind to an enzyme and block its activity.
  • Inducers: Bind to an enzyme and induce its activity.
  • Activators: Bind to an enzyme and increase its activity (allosteric).

Transporters

  • Enhancer: Induces chemical transport (e.g., a modulator that acts on a neurotransporter to bring a chemical back into the cell).
  • Inhibitor: Inhibits the action of a transporter (e.g., a modulator that acts on a neurotransporter to stop it from bringing a chemical back into a cell).
  • Releaser: Induces the release of a neurotransmitter from the presynaptic vessel (e.g., amphetamines).

College Students and Caffeine Stats

  • Average caffeine intake: 175 mg.
  • Caffeine content:
    • Soda: 30-40mg
    • Tea: 30-50 mg
    • Coffee: 80-100 mg
    • Energy drinks: 40-250 mg
  • Percentage of college students consuming:
    • Coffee: 72.0%
    • Tea: 61.4%
    • Soda: 68.8%
    • Energy Drinks: 36.4%
    • Other: 12.2%

Caffeine Fast Facts

  • Chemical name: 1,3,7-trimethylxanthine.
  • Purine: A heterocyclic aromatic organic compound that consists of two rings (pyrimidine and imidazole) fused together.
  • Found in >60 plants, primary sources: coffee, kola nuts, tea, and chocolate.
  • Most widely used psychoactive drug in the world.

Caffeine Exposure

  • Oral ingestion in beverages.
  • Caffeine-containing gum (absorbed through oral mucosa).
  • High bioavailability: 99% absorbed within 45 minutes of ingestion.
  • Peak plasma levels: 15-120 minutes.
  • Variable based on rate of gastric emptying and diet.

Caffeine Biodistribution

  • Both hydrophilic and lipophilic.
  • Distributes freely into intracellular tissue water and readily crosses the blood-brain barrier.

Caffeine Metabolism & Elimination

  • Metabolism primarily occurs in the liver by the enzyme CYP1A2.
  • 75-80% of caffeine is converted to a metabolite with low toxicity.
  • Half-life: 1.5-5 hours
  • Interindividual variability of caffeine metabolism.
    • Smoking: increases CYP1A2 activity.
    • Oral contraceptives that inhibit CYP1A2.
    • Genetic variants in CYP1A2 that reduce enzyme activity.
  • Metabolites are excreted in the urine.

Caffeine Mechanism of Action

  • Caffeine is an antagonist to the adenosine receptors A2A and A1.
  • Antagonist: a chemical that prevents or inhibits the binding of an agonist.

Adenosine

  • Adenosine acts as an important regulator of a sleep-wake cycle.
  • Activation of A2A receptors enhances the release of several neurotransmitters (acetylcholine, glutamate, and dopamine) but inhibits GABA release.

Adenosine Regulation

  • Extracellular adenosine is tightly controlled.
    • Enzymes (5′‐ecto‐nucleotidases) degrades ATP>ADP>AMP>adenosine.
    • Enzymes (Adenosine kinase) phosphorylates adenosine to AMP.
    • Enzymes (adenosine deaminase) metabolize adenosine.
    • Transporters (ENTs 1-4) bring adenosine back into cells.

Other Caffeine Effects

  • Adenosine receptor antagonism by coffee also increases respiratory rate and constricts blood vessels, and causes heart palpitations.
  • Most biological responses through A2A and A1 antagonism but can act on other adenosine receptors.
  • Increases neurotransmitter release of monoamines (e.g., dopamine and adrenaline).
  • Acts as a CNS stimulant.

Cortisol

  • Stress hormone that is at its lowest at the initiation of sleep and peaks when you are about to wake up.
  • Caffeine may elevate cortisol, but less of an impact in frequent users.

Caffeine Medical Uses

  • Mild CNS stimulation: ~5-10 μMμM
  • Antiasthmatic effects: 50 μMμM
  • Treats lack of breathing in premature babies.
  • Added to acetaminophen and ibuprofen for pain relief.
  • Second-line treatment for ADHD.

Caffeine Toxicity

  • Recommended <400 mg caffeine/day.
  • Toxic doses ~1200mg of caffeine.
  • Lethal dose ~10 g.
  • Increase urinary output (dehydration).
  • Anxiety, jitteriness, insomnia.
  • Caffeine overdose is rare: mainly supportive care including hydration (i.v.), maintain blood pressure, and treat tachycardia, dialysis.

Group Work and Caffeine

  • Moderate consumption of caffeinated coffee enhances task-relevant participation in group activities.
  • Subjective evaluations of the participation of other group members and oneself are also positively influenced.
  • The positive impact of consuming a moderate amount of caffeinated coffee on the evaluation of participation of other group members and oneself is moderated by a sense of an increased level of alertness.

Levels of Evidence

  • Meta-analysis
  • Systematic Reviews
  • Randomized Controlled Trials
  • Cohort Studies
  • Case Control Studies
  • Case Series & Case Reports
  • Animal Studies/Laboratory Studies

News Critique

  • Science news articles are a great way to learn about new ideas, discoveries, and research. An important skill is to be able to assess the credibility of your sources of information.
  • Evaluate the scientific validity of the Huberman Lab podcast claim that you should delay coffee intake by 90-120 minutes.