Pharmacokinetics Lecture Notes

Introduction

• Pharmacokinetics: Study of what the body does to a drug.
  • Key Processes: Absorption, Distribution, Metabolism, Elimination.

Absorption

• Definition: How a drug enters the bloodstream.
• Routes of Administration:
  • Oral, Parenteral, Topical, Nasal, Rectal.
• Mechanisms:
  • Passive Diffusion: Movement from high to low concentration.
    • Water-soluble: Moves through channels.
    • Lipid-soluble: Passes through membranes easily.
  • Facilitated Diffusion: Uses carrier proteins from high to low concentration.
  • Active Transport: Energy-dependent (ATP to ADP) transport.
  • Endocytosis: Engulfment by cell membrane for large molecules.
• Factors Affecting Absorption:
  • pH, surface area, blood flow.
• Bioavailability: Proportion of a drug that enters circulation when introduced into the body.
  • Influenced by metabolism in gut and liver.

Distribution

• Definition: How a drug spreads through the body.
• Factors Influencing Distribution:
  • Lipophilicity: Lipophilic drugs move through membranes easily.
  • Blood Flow: Organs like the brain receive more blood flow.
  • Capillary Permeability: Varies in different organs (e.g., brain vs. liver).
  • Binding to Proteins and Tissues: Albumin binding slows distribution.
• Volume of Distribution (Vd):
  • Theoretical volume for drug concentration in plasma.
  • High Vd: Drug extensively distributed in tissues (lipophilic, low molecular weight).
  • Low Vd: Drug concentrated in blood (high molecular weight, protein-bound).

Metabolism

• Location: Primarily liver, also other tissues.
• Phases of Metabolism:
  • Phase 1: Making drugs more hydrophilic.
    • Reactions: Oxidation, hydrolysis, reduction.
    • Catalyzed by cytochrome P450 enzymes.
  • Phase 2: Conjugation reactions.
    • Reactions: Glutathione conjugation, acetylation, sulfation, glucuronidation.
    • Produces polar conjugates for elimination.

Elimination

• Definition: Removal of drugs from the body.
• Routes: Hepatic, renal, biliary.
• Kinetics:
  • First Order: Proportional to drug concentration.
  • Zero Order: Constant amount eliminated, independent of concentration.
• Half-life: Time to reduce plasma concentration by half.
• Steady State: Rate of administration equals rate of elimination.
  • Reached in 4-5 half-lives.
  • Maintains therapeutic range.

Cytochrome P450 Enzymes

• Important Enzymes: CYP 3A4/5, 2D6, 2C8/9, 1A2.
• Inducers: Increase enzyme activity (e.g., Phenytoin, Rifampin).
  • Mnemonic: "PCRABS"
• Inhibitors: Decrease enzyme activity (e.g., Grapefruit, Cimetidine).
  • Mnemonic: "GPACMAN"

Conclusion

• Understanding pharmacokinetics is crucial for drug action.
• Helps in predicting the dosing and therapeutic effectiveness of medications.