Pharmacodynamics Introduction

Pharmacodynamics Intro

• Pharmacodynamics describes the effects of a drug on the body
• It involves how a drug interacts with its target.
• Key processes in pharmacodynamics include: absorption, distribution in the blood, metabolism, elimination.

Principles of Drug Action

• Drug effects arise from altering the normal functions of cells and tissues.
• Drug action occurs through interaction with receptors, enzymes, or by nonspecific chemical/physical interactions.
• Interaction with Receptors: A crucial mechanism for drug action.
  • Ligand-activated ion channels: Drugs bind to these channels, altering their ion permeability.
    • Example of ligand-activated ion channels is ACh nicotinic receptor.
    • Example of a drug is Acetylcholine.
  • G-protein-coupled receptors: The largest class of receptors, involving seven transmembrane segments, intracellular loops, and an intracellular carboxy-terminal tail.
    • Act via interaction with GTP binding proteins (G proteins).
    • Different G protein subtypes exist, like G_α-coupled receptors, where different classes of hormones (e.g. Epinephrine) can cause different actions in the body. Specifics of G protein activation can be seen in the examples provided.
      • This activation frequently involves cAMP and PKA activation or other changes.
  • Receptor-activated tyrosine kinases: These receptors have tyrosine kinase activity and are involved in signal transduction (e.g., insulin receptor triggering cell response)
  • Intracellular nuclear receptors: These receptors are located inside the cell; activated by hormones (e.g. Cortisol) that enter the cells, initiating a nuclear response.

Mechanism of Drug action

• Enzymes: Drugs can affect enzymes by stimulation (increasing activity), direct (changing the activity), by inducing (increasing enzyme synthesis), or by inhibiting (decreasing activity). This inhibition can be competitive (drug and substrate compete for the active site) or non-competitive (drug binds away from the active site, changing enzyme function).
• Receptors: Drugs alter receptor function by acting as agonists, antagonists, full agonist, partial agonists, or inverse agonists.
  • Agonist: Activates a receptor to produce a response similar to that of a biological molecule.
  • Partial agonists: Produce a submaximal effect and can antagonize full agonists.
  • Inverse agonist: Produces an effect opposite to that of an agonist.
  • Antagonist: Prevent action of an agonist on a receptor or subsequent response, which can be competitive or non-competitive.
• Ligands: A ligand is a molecule that attaches to a receptor (e.g., a hormone attaching to a specific site on the receptors).
  • Efficacy: The ability of a drug to initiate a cellular effect.
  • Affinity: The ability of the drug to attach to the receptor

Drug-Receptor Interactions

• Drugs mostly bind via reversible bonds (hydrogen, ionic, hydrophobic).
• Drug-receptor interactions are stereospecific.
• A drug's dissociation constant (K_D) indicates the concentration needed for 50% occupancy.

Receptor Regulation and Drug Tolerance

• Receptors can dynamically change density (down-regulate) and affinity for drugs (desensitization).
• Continuous agonists can desensitize (tachyphylaxis).
• Repeated antagonists can initially increase receptor response (supersensitivity).
• Chronic exposure to antagonists can increase receptor numbers (upregulation).
• Tolerance involves diminishing effect with continued use of a drug, due to receptor changes, as well as other factors (e.g., enzyme).

Dose-response relationships

• Dose-response relationships can be graded, where the response is continuous, or quantal, where the response is an all-or-none phenomenon (e.g., death, or achieving a certain response) -Graded response uses percentages of maximal response
  • Quantal response looks at the cumulative % showing a response, using an ED50 (effective dose for 50% response) or LD50 (lethal dose for 50% of test subjects)

Synergism and Antagonism

• Synergism: The combined effect of drugs is greater than expected from summation (additive or supraadditive).
• Antagonism: The combined effect of drugs is less than expected from summation (additive or supraadditive). A physical antagonism can occur, where substances interfere with action, or chemical antagonism.

Clinical Pharmacokinetics

• Clinical Pharmacokinetics describes how the drug concentration in plasma changes over time.
  • One-compartment model: A simplified representation of drug distribution in the body. The IV dose example demonstrates the concept of this model.
  • Two-compartment model: A more complex model of drug distribution, acknowledging distribution phase followed by an elimination phase. -First-order elimination: The rate of elimination is proportional to drug concentration. -Zero-order elimination: The rate of elimination is constant, regardless of drug concentration.
  • Half-life (t_1/2): The time it takes for plasma drug concentration to decrease by half. Crucial for determining dosage frequency to reach steady-state. Methods of calculations are shown.
  • Steady-state (ss): Concentration of a drug in the plasma will reach a steady-state after repeated administration of doses.
    • Maintenance dose rate (MDR): Rate required to reach steady-state.
    • Loading dose (LD): Dose to rapidly achieve desired concentration.