Pharmacokinetics and Pharmacodynamics Lecture Notes

Introduction

• Focus on pharmacokinetics
• Pharmacokinetics: what the body does to a drug

Key Processes in Pharmacokinetics

1. Absorption

   • Drug enters the bloodstream after administration.
   • Routes include oral, topical, nasal, rectal, and parenteral.
   • Types of absorption:
     • Passive Diffusion: Movement from high to low concentration (water-soluble through channels, lipid-soluble through membranes).
     • Facilitated Diffusion: Requires carrier proteins.
     • Active Transport: Requires energy from ATP.
     • Endocytosis: For large molecules via cell membrane engulfment.
   • Factors affecting absorption: pH, surface area, and blood flow.
   • Bioavailability: The proportion of drug absorbed unchanged; influenced by first-pass metabolism.

2. Distribution

   • Drug moves from bloodstream to tissues.
   • Influenced by:
     • Lipophilicity: Lipophilic drugs pass through membranes easily.
     • Blood Flow: High in organs like the brain vs. skin.
     • Capillary Permeability: Varied by organ (e.g., liver vs. brain).
     • Plasma Protein Binding: Affects distribution speed.
     • Volume of Distribution (Vd): Theoretical volume the drug would need to occupy to provide the same concentration as in the blood.
       • High molecular weight drugs have lower Vd.
       • Lipophilic, low molecular weight drugs have higher Vd.

3. Metabolism

   • Drug modification for elimination, mainly in the liver.
   • Phase 1 Reactions: Oxidation, reduction, hydrolysis (cytochrome P450 enzymes involved).
   • Phase 2 Reactions: Conjugation reactions (e.g., glutathione conjugation, acetylation).

4. Elimination

   • Removal of drug from the body mainly via urine, bile, and feces.
   • Clearance: Sum of all elimination processes.
   • First-order Kinetics: Proportional drug elimination.
   • Zero-order Kinetics: Constant rate elimination (e.g., Aspirin).
   • Half-life: Time to reduce plasma drug concentration by half.
   • Steady State: Achieved when administration rate equals elimination rate.

Key Concepts

• Bioavailability: AUC (Area Under Curve) for oral vs. IV drugs.
• Volume of Distribution helps predict blood vs. tissue concentration.
• Steady State and Half-life: Important for drug dosing and achieving therapeutic effects.
• Loading Dose: Used to rapidly achieve therapeutic concentration.

Cytochrome P450 Enzymes

• Important for phase 1 reactions.
• Key Enzymes: CYP 3A4/5, CYP 2D6, CYP 2C8/9, CYP 1A2.
• Inducers: Phenytoin, Carbamazepine, Rifampin, Alcohol, Barbiturates, St. John's Wort (mnemonic: "PCRABS").
• Inhibitors: Grapefruit, Protease inhibitors, Azole antifungals, Cimetidine, Macrolides (except Azithromycin), Amiodarone, Non-dihydropyridine calcium channel blockers (mnemonic: "GPACMAN").

Conclusion

• Understanding pharmacokinetics is crucial for effective drug use and dosing.
• Bioavailability and drug metabolism are significant factors in the drug's effectiveness and proper use.