PSYC 181 Lecture 3

Pharmacology Overview: Pharmacokinetics vs. Pharmacodynamics

Pharmacology is divided into two primary branches:
- Pharmacokinetics: Focuses on the movement of a drug through the body. This process is heavily influenced by a drug's lipid solubility, which allows it to pass through cell membranes. The charge of a drug, relative to the pH of its environment, also affects its lipid solubility and ease of movement.
- Pharmacodynamics: Focuses on the biochemical effects of a drug and its mechanism of action. It examines how drugs impart biological effects once they reach target sites.

Fundamentals of Drug-Receptor Interactions

Receptor Definition: Receptors serve as the initial site of action for biologically active agents, including drugs. They are protein structures that drugs interact with to initiate biological effects.
Conceptual vs. Physical Structure:
- Textbook Representation: Often depicted using a "lock and key" analogy where a particular abstract shape (the ligand) fits into a specific receptor site.
- Physical Reality: Receptors actually resemble jumbled messes of protein. A drug or agent fits inside this protein complex.
The Active Complex:
- A drug and a receptor do not produce effects in isolation; the combination of a drug binding to a receptor results in an effect known as an active complex.
- This distinction is necessary because the same drug may cause different effects depending on which receptor it binds to, and the same receptor may produce different responses depending on the ligand.
Properties of Binding: Drug-receptor interactions typically involve weak, non-covalent, and reversible actions. Binding is not permanent; a drug imparts effects while bound and stops once it dissociates from the receptor.
Anatomic Location: Receptors are located throughout the body, not exclusively on neurons. Some are even located directly on DNA molecules, where drugs can initiate DNA or protein transcription.

The Law of Mass Action and Cellular Modification

Definition: The cellular response occurs in proportion to the fraction of receptors occupied by a drug.
Relationship of Magnitude: The magnitude of a drug effect is proportional to the number of receptors occupied.
- Example: Binding one morphine molecule to one opioid receptor produces a weak analgesic effect. Binding three molecules to three receptors increases the effect. If ten molecules bind to ten receptors, the effect is even stronger.
Maximum Possible Effect: Because bodies have a finite number of receptors, there is a maximum plateau for drug effects. Once all receptors are occupied, increasing the dose will not increase the biological response.
Drug Functionality: Drugs do not produce novel or unique cellular responses. They merely modify the rate of naturally occurring, ongoing cellular events.
- Analgesia Example: The body naturally mitigates pain through adrenaline and the endogenous opioid system. Painkillers simply modify the rate of these existing processes.
- Hallucination Example: Hallucinations can occur naturally during sleep paralysis, severe dehydration, or extreme hunger. Psychedelic drugs modify the rates of existing systems rather than creating a sensation that is biologically impossible without the drug.

Dose-Response Curves and Pharmacological Metrics

Structure of the Curve: The relationship between drug dose and effect is depicted via a dose-response or dose-effect curve. These are typically logarithmic or sigmoidal rather than linear due to diminishing returns and the maximum effect plateau.
Y-Axis: Represents the percentage of participants experiencing a drug effect. The definition of a "drug effect" is arbitrarily set by the researcher (e.g., a five-point reduction on a ten-point pain scale).
X-Axis: Represents the dose of the drug, typically plotted as the natural log ( $\ln(\text{dose})$ ).
Effective Dose 50 ( $ED_{50}$ ): The dose at which a drug shows half of its maximal effect, or the dose where $50\%$ of participants experience the defined drug effect. This is often considered the "Goldilocks zone" for safe and effective dosing.

Mechanisms of Action: Agonism and Antagonism

Agonism: A drug is an agonist if it activates a receptor upon binding. This activation triggers a biological response.
Antagonism: A drug is an antagonist if it dampens or hinders a biological response by blocking a receptor.
- An antagonist does not produce an opposite effect (which is the role of an inverse agonist); it simply prevents an agonist from binding and activating the receptor.
- Painkiller Comparison: An agonist might trigger the release of endogenous opioids, while an antagonist might block pain signals. Both result in analgesia but via different mechanisms.
General Classifications:
- Stimulants ("Uppers"): Generally act as agonists to stimulate neural activity.
- Depressants: Generally act as antagonists to dampen neural activity.

Comparative Potency and Drug Efficacy

Potency: Refers to the relative location of a drug's dose-response curve along the x-axis. A curve shifted to the left indicates higher potency; a lower dose is required to produce a specific effect.
Factors Influencing Potency:
- Accessibility: How easily a drug reaches receptors based on its pharmacokinetics and bioavailability.
- Affinity: The strength of attraction between a ligand and a receptor.
- Efficacy: The ability of the ligand to activate the receptor once bound (Note: Antagonists lack efficacy metrics because they do not activate receptors).
Maximum Effect: Positioning along the y-axis. Two drugs can have the same maximum effect but different potencies.
- Opioid Examples: Heroin is $2$ to $4$ times faster/more potent than morphine due to its lipid solubility. Fentanyl is $100$ to $1,000$ times faster than morphine.

Therapeutic Indices, Safety Margins, and Drug Specificity

Lethal Dose 50 ( $LD_{50}$ ): The dose at which $50\%$ of participants would die.
Therapeutic Index / Margin of Safety: The separation between the $ED_{50}$ and the $LD_{50}$ . It is quantified by the formula: \t\text{Therapeutic Index} = \frac{LD_{50}}{ED_{50}}
Clinical Goal: Researchers aim for the largest possible separation between these two numbers to prevent the same dose from being effective for some while lethal for others.
Drug "Dirtiness":
- Specificity: How exclusively a drug binds to one receptor type versus many.
- Dose Effects: Higher doses increase the likelihood of a drug binding to non-target receptors, leading to side effects (unwanted/undesirable actions).

Detailed Classification of Antagonists

Competitive Antagonists:
- Bind to the same receptor site as agonists, "competing" for the space.
- Shift the dose-response curve to the right, meaning the drug becomes less potent and requires a higher dose to achieve the same effect.
- Example: Narcan (Naloxone) competes for opioid receptors to prevent or reverse overdoses.
Noncompetitive Antagonists:
- Not only shift the curve to the right but also reduce the maximum possible effect. The agonist cannot overcome this even with higher doses.
- Irreversible Subtype: Forms long-lasting, permanent bonds with the receptor. New receptors must be synthesized by the body to restore function.
  - Examples: Pesticides, poisons, and animal venoms. If these bind to receptors for critical functions like respiration, the organism may die before new receptors are produced.
- Reversible Subtype: Prevents agonist-receptor coupling through different sites (not permanent), but still reduces maximum effect.

Pharmacodynamic Tolerance, Sensitization, and Withdrawal

Functional (Pharmacodynamic) Tolerance: Occurs when receptor availability is altered. Repeated administration leads to a decreased response, shifting the dose-response curve to the right.
- Example: The first nicotine use of the day feels more intense because agonists have fallen off receptors during sleep, making more receptors available.
Sensitization: An increased response with repeated administration, shifting the curve to the right. This is often linked to reward systems.
Cross-Tolerance/Sensitization: Developing a response to one drug in a class (e.g., Fentanyl) creates a similar tolerance level for others in that class (e.g., Morphine).
Upregulation and Downregulation:
- Downregulation: A decrease in the number of available receptors, usually occurring when receptors have been saturated by a drug for an extended period.
- Upregulation: An increase in the number of available receptors.
Withdrawal and Opponent Process Theory:
- Withdrawal symptoms are physiological changes occurring when drug use stops. Alcohol withdrawal is uniquely dangerous as it can be lethal on its own.
- Opponent Process Theory: The body seeks equilibrium. If a drug causes a pleasant euphoric state, the body initiates an unpleasant compensatory state. When the drug wears off, the body swings past equilibrium into a dysphoric or depressed state.
- Toxic effects vs. Withdrawal: Toxic effects of alcohol include dehydration and stomach rot. Withdrawal/Hangover effects include hypersensitivity to light and sound because alcohol (a depressant) originally suppressed those senses.

Structural Neurobiology and the Synapse

The Synapse: The gap between neurons and the site of action for most psychoactive drugs.
- Most cells have $10$ to $15$ synapses, but pyramidal neurons in the hippocampus can have up to $100,000$ synapses.
Neuron Components:
- Dendrites: The input zone that receives signals and collects information via receptors.
- Soma (Cell Body): The integration zone where signals are processed and "read."
- Axon: The conduction zone where action potentials are transmitted.
- Axon Terminals (Nerve Endings): The output zone that sends signals to other cells.
Synaptic Subsets:
- Presynapse: The axon terminal of the sending neuron.
- Synaptic Cleft: The physical gap ( $20$ to $50$ nanometers).
- Postsynapse: The dendrite of the receiving neuron.
Alternative Junctions:
- Tight Junctions: Membranes of adjacent cells are fused together.
- Gap Junctions: Very small spaces ( $2$ to $4\,nm$ ) connected by connections (protein channels).
Connectivity Types:
- Axodendritic: Axon to dendrite ( $80\%$ of brain synapses).
- Axosomatic: Axon to cell body.
- Axoaxonic: Axon to axon.

The Six Stages of Neurotransmission and Inactivation

Synthesis: Neurotransmitters are created from dietary precursors or coded in DNA.
Transport: Microtubules move neurotransmitters from the soma to the axon terminal.
Storage: Neurotransmitters are packaged into vesicles (storage containers).
Release (Exocytosis): Triggered by an action potential. Depolarization opens calcium channels; the influx of $Ca^{2+}$ signals vesicles to fuse with the membrane and spill contents into the cleft.
Binding: Ligands bind to receptors on the postsynaptic dendrite.
Inactivation: Essential to prevent overtaxing the system. Methods include:
- Reuptake: Transporters pull neurotransmitters back into the presynaptic cell.
- Degradation: Enzymes metabolize neurotransmitters into inactive metabolites.
- Diffusion: Ligands drift away from the synaptic cleft.

Classification of Neurotransmitters: Classical and Neuropeptides

Classical Neurotransmitters: Synthesized from amino acids or dietary precursors (e.g., Tryptamine in turkey becomes Serotonin).
- Categories: Amino acids, Monoamines (phenethylamines and endolamines), and Acetylcholine.
- Key Classical Agents:
  - GABA: The primary inhibitory neurotransmitter.
  - Glutamate: The primary excitatory neurotransmitter.
- Nomenclature: Cells are named by the chemistry they release followed by "-ergic" (e.g., dopaminergic, serotonergic/ $5-HT$ ergic).
Neuropeptides: Large chains made via protein synthesis (coded by genes). Examples include endorphins and oxytocin.

Receptor Subtypes, Locations, and Transduction Mechanisms

Receptor Subtypes: One neurotransmitter (key) can fit multiple receptor subtypes (locks), which are located in different brain regions and produce different effects (e.g., $5-HT_{1A}$ , $5-HT_{2A}$ , $5-HT_{2B}$ ).
Autoreceptors: Located on the presynaptic axon terminal. They act as a "thermostat" to detect neurotransmitter levels in the synapse and modulate synthesis/release.
Transduction and Amplification: Receptors can amplify tiny amounts of a drug (e.g., $10\,mg$ in a multi-hundred-pound organism) into large biological responses.
Ionotropic Receptors (Ligand-Gated Channels):
- Coupled directly to an ion channel. Fast-acting but short-lived.
- Opening channels for positive ions excites the cell; opening channels for negative ions (like chloride) inhibits the cell.
- Examples: Nicotinic acetylcholine receptors (neuromuscular junctions) and sedative-hypnotics.
Metabotropic Receptors (G-Protein Coupled Receptors):
- The most common receptor type. Coupled to G-proteins that act as switches.
- They work via second messengers (downstream cascading effects) and can synthesize new proteins or alter gene expression.
- These are slower-acting but have much longer-lasting effects on mood, hunger, and alertness.

Questions & Discussion

Question: Can the same drug act as an agonist at one receptor but an antagonist at a different receptor?
Response: Yes. Effects are determined by the specific combination of the ligand and a particular receptor (the active complex).
Question: When people take noncompetitive drugs that stop bodily functions, is that when all receptors are bound?
Response: Not necessarily. For critical functions like respiration, you don't need every single receptor occupied to cause death; you only need to compromise the system enough to stop breathing.
Question: Are irreversible antagonists associated with overdosing?
Response: While you can overdose on any drug, irreversible noncompetitive antagonists are most commonly associated with pesticides, poisons, and venoms designed to kill.
Question: What are immediate early genes (IEGs)?
Response: These are transcription factors turned on in the first phase of second messenger signaling. They don't alter cellular function themselves but initiate the second phase, which changes cellular expression and long-term function.