Pharmacodynamics

PHARMACODYNAMICS

Definition

  • Pharmacodynamics focuses on what happens to the body while a drug is present. It specifically deals with the interaction of drug molecules at the target sites.

Relationship to Pharmacokinetics

  • Pharmacokinetics pertains to how a drug is absorbed, distributed, and eliminated from the body.

  • In contrast, pharmacodynamics examines the effects and mechanisms of action of the drug on the body.

TARGET SITES FOR PSYCHOACTIVE DRUGS

Primary Target

  • Psychoactive drugs typically target membrane receptors in the nervous system.

Clark’s Occupancy Theory

  • Clark’s Occupancy Theory explains the drug-receptor relationship through several steps:

    1. Formation of Drug-Receptor Complex:

    • The drug (D) and receptor (R) bind reversibly to form a drug-receptor complex (D-R).

    1. Magnitude of Response:

    • The magnitude or intensity of the response (E) is directly proportional to the concentration of the D-R complex.

    1. Maximum Response (Emax):

    • The maximum possible response (Emax) occurs when all receptors (RT or Rtotal) are occupied by the D-R complex.

  • Formulations:

    1. D + R ↔ D-R → E

    2. E α D-R

    3. If D-R = Rtotal then Emax

Implications of Receptor Occupancy

  • The number of receptors occupied is crucial to understanding drug effects.

  • Increasing drug concentration at the receptor site logically increases receptor occupancy, thereby affecting the dose-response relationship.

MECHANISM OF ACTION

Serotonin and Anti-emetics

  • After chemotherapy, released serotonin stimulates sensory signals to the area postrema and the emetic center, inducing nausea and vomiting.

  • 5-HT3 antagonists work by competitively inhibiting serotonin binding at 5-HT3 receptors, leading to antiemetic effects.

Dosing and Receptor Occupancy Study

  • A study analyzed the relationships between standard doses and plasma unbound drug concentrations at steady-state (ssf) with complete vomiting inhibition rates, finding no significant positive correlations.

  • However, a positive correlation was found between average receptor occupancy (FB) and complete vomiting inhibition rates for prevention and cure methods after intravenous and oral administration of 5-HT3 antagonists (Yamada et al., 2004).

TYPES OF RECEPTOR INTERACTIONS

Receptor Types

  • Drug-receptor interactions can be classified into the following types:

    1. Ionotropic Receptors:

    • Often referred to as “first message” ligand-gated channels for ions, which create excitatory postsynaptic potentials (EPSPs) or inhibitory postsynaptic potentials (IPSPs).

    • Dendritic ionotropic receptors receive neurotransmitters during normal signal generation.

    1. Metabotropic Receptors:

    • Known as “second message” receptors, which cause G protein activation that modifies neuronal metabolism.

    1. Autoreceptors:

    • A presynaptic binding site that regulates neurotransmitter release from the terminal.

    1. Reuptake Carrier Proteins:

    • Activated when neurotransmitters or drugs enter the synapse, moving ligands across the cell membrane.

    1. Synaptic Enzymes:

    • Act as non-membrane drug-protein interactions where the neurotransmitter or drug binds to an enzyme that degrades them.

ACTION VERSUS EFFECT

Definitions

  • Drug Action:

    • The specific interaction between a drug and a receptor.

  • Drug Effect:

    • The functional change that results from action (e.g., amphetamines stimulate dopamine release, leading to increased alertness, exhilaration, reduced fatigue, and a sense of well-being).

Example

  • Amphetamines affect ionotropic receptors to stimulate NT release by opening calcium channels and impact carrier proteins by preventing NT reuptake.

MEASURING RECEPTOR BINDING

General Principle

  • Occupancy theory assumes that neurotransmitters (NTs) or drugs bind to receptors at action sites.

  • Key Questions:

    • How can we demonstrate the binding of a ligand?

    • Can we find and identify that ligand post-binding?

Radioactive Labeling

  • Radioactive labeling techniques can be used to visualize binding of ligands to receptors.

RADIOLIGAND STUDIES

Global Distribution of Drugs

  • Radiolabeled drug molecules exhibit green fluorescence when introduced, illuminating distribution to receptor sites in brain tissues.

Importance of Binding Studies

  • Radioligand studies focus solely on receptor site binding.

  • Essential elements for interpretable data include:

    1. Specificity

    2. Saturability

    3. Reversibility

    4. Relevance

TESTING SPECIFICITY IN RADIOLIGAND STUDIES

Procedure

  • Introduce varying amounts of radiolabeled ligand into a tissue sample and measure excess remaining as radioactive signal after rinsing.

  • Some nonspecific binding (depot binding) is expected.

  • To differentiate, a non-labeled ligand is introduced to displace the bound labeled ligand from specific sites, leaving remaining bonds in nonspecific sites.

ANALYZING BINDING CURVES

Hypothetical Curves

  • When different concentrations of radioligand are added to tissues, three binding types can be plotted:

    1. Total Binding Curve (A):

    2. Non-specific Binding (B): determined by unlabeled compound displacing the radioligand.

    3. Specific Binding (C): is the difference between total and nonspecific bindings.

TESTING SATURABILITY

Definition

  • The binding curve demonstrates a limit to how much ligand can bind, shown at the flat portion of the curve (C).

TESTING REVERSIBILITY

Critical Factor

  • I.e., a ligand should dissociate from binding sites.

  • The introduction of a competitor should ideally change the binding concentration, moving forward predictions about drug effects.

BINDING STUDIES IN BIOLOGICAL RELEVANCE

Validation Criteria

  • For a ligand to be biologically relevant it must meet three requirements:

    1. The nervous system structure activated by the ligand must possess appropriate proteins for binding.

    2. Increased binding must correlate with increased membrane proteins present.

    3. Increased binding must correspond with measurable biological responses.

DOSE-RESPONSE FUNCTIONS

Fundamental Premise

  • The pharmacological effect correlates with the number of receptors activated, reflecting occupancy theory.

  • The effect size can be modified by adjusting the drug dose.

Experimental Example

  • Experimental data can reflect responses such as lever presses as related to drug dosage (e.g., amphetamine doses).

PRIMARY AND SECONDARY EFFECTS

Definitions

  • Primary Effect: The intended therapeutic effect of a drug.

  • Secondary Effect: Additional effects that occur, which may alter with successive doses.

Key Metrics

  • ED50: The dose effective for 50% of subjects.

  • LD50: The fatal dose for 50% of subjects.

  • Therapeutic Margin: ( TM = LD50 - ED50 )

    • A larger therapeutic margin indicates a safer drug.

Comparative Example

  • Drug A: ED50 = 30 mg/kg, LD50 = 60 mg/kg

  • Drug B: ED50 = 300 mg/kg, LD50 = 450 mg/kg

    • Evaluation of safety based on these metrics.

TOLERANCE IMPACT ON ED AND LD VALUES

Understanding Tolerance

  • Tolerance occurs when the body adapts to a drug, affecting efficacy at different sites.

Case Examples

  • Chlordiazepoxide (Librium): Exhibits minimal tolerance in anxiety but significant sedation.

  • Barbiturates: Show limited tolerance for respiratory depression but significant sedation.

    • Resulting in safety concerns (e.g. chlordiazepoxide being safer, barbiturates being riskier).

CROSS TOLERANCE

Definition

  • Cross tolerance indicates that tolerance to one drug may lead to tolerance of another with similar effects, such as morphine, oxycodone, and fentanyl.