Pharmacodynamics Lecture Notes

Introduction

• Pharmacodynamics: Study of what the drug does to the body.
• Complementary to Pharmacokinetics (ADME: Absorption, Distribution, Metabolism, Excretion).
• Focuses on drug-receptor interactions and resulting effects.

Drug-Receptor Interactions

• Drugs exert effects by binding to receptors.
• Receptors types:
  • Extracellular receptors
    • Ligand-gated ion channels (e.g., GABA_A receptors, Lorazepam)
    • G-protein coupled receptors
    • Tyrosine kinase receptors
  • Intracellular receptors (e.g., Steroids, Nitric Oxide)
• Desensitization: Rapid decrease in receptor response (tachyphylaxis).

Extracellular Receptors

Ligand-Gated Ion Channels

• Drugs open/close ion channels, altering ion flow and cell activity.
• Example: Lorazepam acts on GABA_A receptors to treat seizures by hyperpolarizing neurons.

G-Protein Coupled Receptors

• 7-pass receptors; activate second messengers (e.g., cAMP, Protein Kinase A).
• Example: Norepinephrine on heart muscle increases contraction.

Tyrosine Kinase Receptors

• Involves phosphorylation of tyrosine residues, activating cellular responses.
• Example: Insulin and glucose uptake.

Intracellular Receptors

• For hydrophobic, lipid-soluble drugs.
• Involves transcription factors and DNA transcription.
• Slower but persistent effects.

Tachyphylaxis and Tolerance

Tachyphylaxis

• Rapid desensitization to a drug.
• Mechanisms:
  • Receptor downregulation
  • Phosphorylation and inactivation
  • Internalization
• Does not improve with increased drug concentration.

Tolerance

• Develops over time with chronic drug exposure.
• Involves increased metabolic breakdown of drugs.
• Can be overcome by increasing drug dosage.

Dose-Response Relationship

Potency

• Potency and affinity: Higher affinity, higher potency; requires lower dose to achieve 50% of maximum effect (EC50).

Efficacy

• Maximum effect a drug can produce (Emax).
• Affected by receptor occupancy and intrinsic activity.

Therapeutic Index

• Therapeutic index (TI): Ratio of toxic dose (TD50) to effective dose (ED50).
• Narrow TI indicates higher risk of toxicity (e.g., Warfarin).

Agonists and Antagonists

Agonists

• Full agonists: Maximal response (e.g., Phenylephrine for alpha-1 receptors).
• Partial agonists: Sub-maximal response (e.g., Buprenorphine for opioid receptors).
• Inverse agonists: Reduce activity below baseline.

Antagonists

• Competitive antagonists: Bind to same site as agonist; can be overcome by increasing agonist concentration.
• Non-competitive antagonists: Bind to different site; reduce efficacy, not overcome by increasing agonist.

Practice Questions Review

• Understanding drug-receptor interactions and dose-response curves is crucial for pharmacology exams.
• Recognize ligand-gated ion channels, G-protein coupled receptors, and differences between competitive and non-competitive antagonists.
• Interpret dose-response curves for potency and efficacy.