Pharmacodynamics and Drug-Target Interactions

Introduction to Pharmacology - Lecture 5

• Topic: Physiology of Receptors
• Date: January 21st, 2025
• Readings: Chapters 1 (Pharmacodynamics only) and 2 of Katzung's book.

This Week's Schedule

• Tuesday, January 21st: Lecture 5 - Pharmacodynamic I
• Thursday, January 23rd: Lecture 6 - Pharmacodynamic II
• Friday, January 23rd: Tutorial 3 - Drug Discovery

Pharmacology

• Pharmacodynamics: Describes what the drug does to the body.
  • Classification is determined with this aspect.
  • Useful in deciding if the drug is best used to treat a specific disease.
• Pharmacokinetics: Describes what the body does to the drug.
  • Explains how the drug is absorbed, distributed, metabolized, and eliminated in the body.
  • Important for choosing the right type of drug and administration method.

Pharmacodynamics Principles

• Drug interacts with a target (receptor).
• Receptors: Include proteins, DNA, or other structures within a cell affected by the interaction with the drug.
• Effector Mechanism: A drug changes cell communication. An effector plays a role in this, communicating how the drug-target interaction affects the cell.
• Orphan Receptors: Unknown ligands. A potential area for drug discovery.

Types of Effector Systems

• Regulatory Proteins: Drugs bind and impact hormone receptor interactions.
• Enzymes: Drugs bind to the active site of enzymes affecting substrate binding and catalytic function.
• Structural Proteins: Drugs modify cell structure.
• Transport Proteins: Drugs impact how other substances are transported, affecting their movements throughout the organism.
• This includes both carrier proteins and channel proteins.

Drug-Target/Receptor Interactions

• Drug binding: Causes a conformational change in the protein target, affecting shape and function.
• Direct effect: Can happen immediately.
• Indirect effect: Response occurs through a series of intermediary steps.
• Selectivity: Receptors have their own mechanisms to determine what a drug does.
• Duration: Depends on bond types between drug and target.

Model of Drug-Target Interactions

• Protein targets: Bind to ligands.
• Ligands: Can stimulate or not stimulate the target pathway.
• Constitutive Activity: States that even in absence of ligands, targets are always in equilibrium between their active and inactive states.
• Inert Binding Sites: Binding to non-regulatory targets doesn't affect biology. It can, however, change how the drug circulates in the body.

Drug-Target Interactions (Quantitative)

• Effect increases with higher drug concentrations.
• Emax: Highest effect the drug can produce.
• EC50: Drug concentration producing 50% of the maximum response.

Drug-Target Interactions (Mass Action Law and Affinity)

• Fraction of free receptors: Decreases with increasing drug concentration until saturated (Bmax).
• Kd (equilibrium dissociation constant): Drug concentration where 50% of the receptors are bound.
• Kd values: Low Kd: Higher affinity. High Kd: Low affinity.

Drug-Target Interactions (Logarithmic scale)

• Plotted as response versus log of the drug concentration.
• It expands the scale of the concentration axis at low concentrations, enabling faster changes to be shown.

Drug-Target/Receptor Interactions (Coupling)

• Two major types: Direct (Ion channels) and Indirect (Enzymes).

Occupancy-Response Relationship

• Maximum response: May occur without maximum receptor occupancy.
• Kd and EC50: Are not always equivalent.
• Useful in determining how to properly dose the drug.

Agonists

• Agonist: Molecule that looks like, binds like, and acts like an endogenous ligand, activating a given target.
  • Full agonist: Activates all the target receptors.
  • Partial agonist: Activates some of the target receptors.
  • Inverse agonist: Decreases constitutive activity.

Special Type of Agonists

• Some agonists don't mimic the structure of an endogenous ligand.
  • They activate a target pathway by inhibiting negative regulators of the endogenous pathway in that specific target system.
• Acetylcholinesterase (ACE): Example that inhibits negative pathway regulators.

Antagonists

• Antagonist: Molecule that looks like and binds to a receptor, but does not activate it.
  • It prevents the activity of an endogenous ligand.
• Competitive antagonist: Competes with endogenous ligands for binding to the receptor.
• Non-competitive antagonist: Binds to the receptor in a different location than the receptor's binding site and deactivates it.
  • May be irreversible (binds tightly or covalently).

Allosteric Regulators

• Allosteric regulator: Binds to a different pocket on the receptor.
  • Can enhance or inhibit the receptor's response to agonist.