Pharmacodynamics Lecture Notes

Introduction

• Topic: Pharmacodynamics
• Prerequisite knowledge: Pharmacokinetics (ADME: Absorption, Distribution, Metabolism, Excretion)
• Website resources: Notes, illustrations
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Understanding Pharmacokinetics Recap

• Absorption: Drug crosses cell membranes → blood → hepatic portal system → liver (first-pass effect) → systemic circulation
• Distribution: Drug in vasculature → tissues
• Clearance: Kidneys or liver

Pharmacodynamics Overview

• Concept: What the drug does to the body
• Cellular Interaction: Drug binds to receptors on cells → produce cellular responses (stimulate/inhibit)

Receptor Types

Extracellular Receptors

1. Ligand-Gated Ion Channels
   • Example: GABA A receptors (Lorazepam for seizures)
2. G-Protein Coupled Receptors (GPCRs)
   • Structure: 7-pass receptors
   • Pathways: Gq, Gs, Gi proteins
   • Example: Norepinephrine on heart muscle cells
3. Tyrosine Kinase Receptors
   • Example: Insulin receptors
   • Activation: Phosphorylation of tyrosine residues

Intracellular Receptors

• Characteristics: For hydrophobic, small, non-polar drugs (e.g., steroids, nitric oxide)
• Process: Drug crosses cell membrane → intracellular receptor → nucleus → binds transcription factors → increases protein synthesis
• Time Frame: Slower but longer-lasting effects

Desensitization (Tachyphylaxis) and Tolerance

Desensitization (Tachyphylaxis)

• Rapid response: Due to large initial drug dose
• Mechanisms:
  • Decrease receptor synthesis
  • Receptor inactivation via kinases and arrestin
  • Receptor internalization
• Drug concentration: Increasing does not change response

Tolerance

• Chronic exposure: Over hours to weeks
• Mechanisms:
  • Decrease receptor synthesis and internalization
  • Upregulating metabolic enzymes (e.g., for drugs like alcohol, opioids)
• Overcoming tolerance: Increase drug dose

Dose-Response Relationship

Potency

• Definition: Affinity of drug to receptor
• Measure: EC50 (drug concentration for 50% max effect)
• Graph: Left shift = increased potency, right shift = decreased potency

Efficacy

• Definition: Max effect a drug can produce
• Dependent on:
  • Number of receptors occupied
  • Intrinsic activity of the drug
• Graph: Lower peak = decreased efficacy

Therapeutic Index

• Definition: Measure of drug safety
• Calculation: TD50 (toxic dose) / ED50 (effective dose)
• Implications: Small TI = high risk of side effects, Large TI = safer
• Examples:
  • Small TI: Warfarin, Gentamicin, Lithium
  • Large TI: Penicillin, Corticosteroids

Intrinsic Activity

Types of Agonists

1. Full Agonist: Produces max response (e.g., Norepinephrine)
2. Partial Agonist: Produces sub-maximal response (e.g., Buprenorphine)
3. Inverse Agonist: Decreases response below basal level

Types of Antagonists

1. Competitive Antagonists
   • Mechanism: Compete with agonists for active binding site
   • Effect on graph: Increase EC50 (decrease potency), no change in Emax
2. Non-Competitive Antagonists
   • Mechanism: Bind to allosteric sites
   • Effect on graph: Decrease Emax (decrease efficacy), no change in EC50

Practice Problems Review

• Question Topics: GABA A receptor, dose-response relation, therapeutic index, competitive vs non-competitive antagonists