3 Pharmacodynamics (Ligands)

Pharmacodynamics Overview

  • Pharmacodynamics: The study of drug effects on the body, specifically how drugs exert their therapeutic effects through mechanisms involving ligands and receptors.

Lecture Structure

  • Lecture 3 is divided into the following sections:

    • 3.1 Agonists: Substances that activate receptors to produce biological responses.

    • 3.2 Antagonists: Substances that inhibit biological responses by blocking receptors.

    • 3.3 Binding Versus Efficacy: Exploring the relationship between drug binding and its effects.

Learning Objectives

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

    • Define drug potency and efficacy.

    • Classify agonists and antagonists based on dose-response curves.

    • Describe types of antagonists (competitive, non-competitive).

    • Define allostery and differentiate between drug affinity and efficacy.

    • Identify receptor reserve from competitive dose-response curves.

Receptor Ligands

  • Ligands: Substances/drugs that bind to receptors influencing their activity.

    • Can be classified as:

      • Agonists: Activate receptors.

      • Antagonists: Block receptor activity.

Agonists

  • Definition: Substances that bind to and activate receptors, resulting in a biological response.

  • Graphical Representation: Concentration-response curves depict efficacy and potency of agonists.

    • Key terms:

      • EC50: Effective Concentration for 50% of maximal effect.

      • Emax: Maximal biological effect observed.

Efficacy vs. Potency

  • Efficacy: Maximum effect a drug can produce (Emax).

  • Potency: Concentration dependence of drug effect (related to EC50).

    • Implication: Strong potency indicates a low EC50; weak potency implies a high EC50.

Variability of Agonists

  • Agonists can vary in:

    • Efficacy: Full, partial, or inverse agonists.

      • Full agonists: Produce maximal effect.

      • Partial agonists: Generate submaximal effects regardless of dose.

      • Inverse agonists: Suppress basal activity of receptors.

Antagonists

  • Definition: Substances that block or inhibit biological responses by binding to receptors without activating them.

  • Types of antagonists:

    • Competitive antagonists: Compete with agonists for the same binding site; effects are surmountable at high agonist concentrations.

    • Non-competitive antagonists: Bind irreversibly or at different sites, reducing agonist efficacy.

Mechanisms of Antagonism

  • Competitive Antagonism: Requires higher concentrations of agonists to overcome antagonist effects, indicated by a dose ratio.

  • Schild Plot: A method for evaluating the interaction between agonists and competitive antagonists based on dose ratios.

Partial Agonists as Antagonists

  • Partial agonists can act as antagonists by competing with full agonists, leading to reduced responses.

  • This results in a rightward shift (increased EC50) for the full agonist but maintains maximum efficacy (same Emax).

Receptor Reserve

  • Definition: The availability of receptors beyond what is needed for a maximal biological effect.

  • In cases of receptor reserve, irreversible antagonists may not reduce maximal biological responses unless concentrations are extreme.

Summary Points

  • Understanding drug properties requires distinguishing between affinity (how well a drug binds), efficacy (how well it activates), and potency (concentration at which the drug yields effects).

  • Affinity: Governed by electrochemical properties; high affinity correlates with low KD (equilibrium dissociation constant).

  • Efficacy: Independent of affinity; measures how well a drug activates its receptor.

  • The relationship between binding and effect (biological response) is complex.

Next Steps

  • Prepare for the following lecture on Pharmacokinetics (Part 1).

  • Contact for questions: Anna Taylor, ataylor1@ualberta.ca.