Lecture on Pharmacokinetics

Introduction

• Understanding pharmacokinetics and pharmacodynamics is crucial before studying drug mechanisms of action.
• Pharmacokinetics: Describes what the body does to the drug.

Key Steps in Pharmacokinetics

1. Absorption

   • Drug is absorbed into the bloodstream after administration.
   • Routes include oral, topical, nasal, rectal, etc., but must cross a membrane unless given intravenously (IV).

2. Distribution

   • Drug moves from bloodstream into fluids inside and outside cells.
   • Influenced by lipophilicity, blood flow to organs, capillary permeability, and binding to plasma proteins.

3. Metabolism

   • Drug is modified for easier excretion, primarily by the liver.

4. Elimination

   • Final removal of drug and metabolites, mainly through bile, urine, and feces.
   • Total body clearance is the sum of individual clearance processes.

Absorption Details

• Can occur via:

  • Passive Diffusion: Movement from high to low concentration; water-soluble drugs pass through channels, lipid-soluble pass through membranes.
  • Facilitated Diffusion: Similar to passive but requires carrier proteins.
  • Active Transport: Energy-dependent, utilizing ATP.
  • Endocytosis: Engulfment by cell membrane for large drugs.

• Bioavailability: The proportion of drug absorbed into systemic circulation, influenced by metabolism in gut and liver.

  • Measured by Area Under Curve (AUC).

Distribution Factors

• Lipophilicity: Lipid-soluble drugs pass membranes easier than water-soluble.

• Blood Flow: Organs like the brain receive more blood flow.

• Capillary Permeability: Varies by organ (e.g., liver vs. brain).

• Binding to Proteins/Tissues: Certain drugs bind to plasma proteins like albumin, affecting distribution.

• Volume of Distribution (Vd): Theoretical volume needed to achieve blood concentration.

  • High Vd indicates extensive tissue distribution.

Elimination Processes

• Kinetics:

  • First-order kinetics: Elimination rate proportional to drug concentration.
  • Zero-order kinetics: Constant elimination rate (e.g., Aspirin).

• Half-life: Time to reduce drug concentration by half; aids in understanding duration of action and steady state.

• Steady state: Achieved when drug administration equals elimination, typically after 4-5 half-lives.

• Loading Dose: Used in emergencies to quickly achieve desired concentration.

Metabolic Reactions

• Phase 1 Reactions: Introduce/unmask polar groups to make drugs more hydrophilic.

  • Examples: Oxidation, hydrolysis, reduction.
  • Catalyzed by Cytochrome P450 enzymes.

• Phase 2 Reactions: Conjugation to make drugs more water-soluble for excretion.

  • Examples: Glutathione conjugation, acetylation, sulfation, glucuronidation.

Cytochrome P450 and Drug Interactions

• Important Enzymes: CYP 3A4/5, CYP 2D6, CYP 2C8/9, CYP 1A2.
• Inducers: Phenytoin, Carbamazepine, Rifampin, chronic alcohol use, barbiturates, St. John's Wort. Mnemonic: "PCRABS".
• Inhibitors: Grapefruit, protease inhibitors, azole antifungals, Cimetidine, macrolides (except Azithromycin), Amiodarone, nondihydropyridine calcium channel blockers. Mnemonic: "GPACMAN".

Conclusion

• A thorough understanding of pharmacokinetics is essential for drug administration and therapeutic effectiveness.
• Important to monitor drug concentration and interactions to avoid toxicity and ensure efficacy.