Pharmacodynamics Lecture Notes

Overview

• Pharmacodynamics: Explores what a drug does to the body.
• Opposite of pharmacokinetics, which is the body's action on the drug.

Drug Interaction with Cell Receptors

• Drugs interact with cell receptors to produce a biological effect.
• Example: Signals can inhibit DNA replication.
• Cell receptors have unique responses upon stimulation.

Types of Receptors

1. Ligand-Gated Ion Channels

• Ligand: A molecule/ion.
• Binding opens the channel briefly, allowing ion passage (e.g., sodium, potassium).

2. G Protein-Coupled Receptors (GPCR)

• Structure: 7 transmembrane segments.
• Composed of alpha, beta, gamma subunits.
• Inactive state: Alpha has GDP; upon ligand binding, GTP replaces GDP.
• Subunits Function:
  • Alpha dissociates, interacts with enzymes/proteins.
• Types of G Proteins:
  • Gs: Stimulates adenylyl cyclase to produce cyclic AMP (cAMP).
  • Gi: Inhibits adenylyl cyclase, lowering cAMP.
  • Gq: Activates phospholipases C (PLC), resulting in DAG and IP3.

3. Enzyme-Linked Receptors

• Ligand Type: Hormones or growth factors.
• Action: Activates tyrosine kinase activity.
• Process: Ligand binding causes receptor dimerization and phosphorylation.

4. Intracellular Receptors

• Location: Inside the cell.
• Mechanism: Ligands cross the lipid membrane, bind to receptors, enter the nucleus, and regulate gene expression.

Receptor Lifecycle

• Synthesis: DNA codes for receptor proteins assembled in the cell membrane.
• Regulation:
  • Downregulation: Decreases receptor numbers upon overstimulation.
  • Upregulation: Increases receptors when signals are weak.

Dose-Response Relationships

• Increased drug concentration increases effect until receptors are saturated.
• EC50: Concentration causing 50% maximal effect - indicates potency.
• Emax: Maximum efficacy when all receptors are occupied.

Drug Activity

Intrinsic Activity

• Full Agonist: Produces maximal effect, comparable to endogenous ligands.
• Partial Agonist: Cannot achieve maximal effect.
• Inverse Agonist: Stabilizes receptors in inactive form.
• Antagonist: Blocks receptor activity.
  • Competitive: Shifts dose-response curve right, requires higher concentrations for EC50.
  • Non-Competitive/Irrversible: Reduces Emax, not displaced by agonist.
  • Allosteric: Binds different site, causes conformational change, reducing Emax.

Therapeutic Index

• Definition: Ratio of dose causing toxicity in 50% of the population to the effective dose in 50%.
• ED50: Effective dose for 50% of the population.
• TD50: Toxic dose for 50% of the population.
• Graph: Shows positive therapeutic and negative toxic responses.

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End of lecture notes on pharmacodynamics.