Pharmacokinetics and Pharmacodynamics Lecture Notes

Introduction to Pharmacokinetics

• Definition: Pharmacokinetics refers to what the body does to a drug.
• Key Steps:
  1. Absorption
  2. Distribution
  3. Metabolism
  4. Elimination

Overview of Pharmacokinetics Steps

1. Absorption:
   • Process of drug entering the bloodstream (oral, topical, etc.).
2. Distribution:
   • Movement of the drug throughout the body.
3. Metabolism:
   • Drug modification primarily by the liver to facilitate excretion.
4. Elimination:
   • Excretion of drug and its metabolites (via urine, feces, etc.).

Detailed Breakdown of Pharmacokinetics Steps

Absorption

• Routes of Administration: Parenteral, topical, nasal, rectal, etc.
• Methods of Absorption:
  1. Passive Diffusion:
     • Movement from high to low concentration.
     • Water-soluble drugs use channels; lipid-soluble drugs pass through membranes easily.
  2. Facilitated Diffusion:
     • Larger molecules need carrier proteins.
  3. Active Transport:
     • Energy-dependent process using ATP.
  4. Endocytosis:
     • Engulfment of large drugs by the cell membrane.
• Factors Affecting Absorption: pH, surface area, blood flow.
• Bioavailability:
  • Amount of drug absorbed in unchanged form; measured via AUC (Area Under Curve).
  • Bioavailability formula: (AUC oral / AUC IV) x 100.

Distribution

• Factors Affecting Distribution:
  • Lipophilicity: Lipophilic drugs diffuse easily.
  • Blood Flow: Organs with higher blood flow receive drugs faster (e.g., brain > skin).
  • Capillary Permeability: Varies by tissue (e.g., liver vs. brain).
  • Binding to Plasma Proteins: Some drugs bind to albumin, slowing distribution.
  • Volume of Distribution (Vd):
    • Calculated as amount of drug in the body / concentration in plasma.
    • Higher Vd indicates a larger distribution in tissues.

Elimination

• Routes of Elimination: Hepatic, renal, biliary.
• Clearance: Total body clearance is the sum of individual clearance processes.
• Kinetics of Elimination:
  • First-Order Kinetics: Amount eliminated proportional to concentration.
  • Zero-Order Kinetics: Constant amount eliminated regardless of concentration.
• Half-Life: Time required to reduce drug concentration by half, crucial for predicting duration and steady-state concentrations.
• Steady State: Achieved in about 4-5 half-lives; important for therapeutic range.

Metabolism

• Liver's Role: Transforms lipophilic drugs into hydrophilic substances for excretion.
• Metabolic Reactions:
  1. Phase 1: Involves oxidation, hydrolysis, and reduction. Catalyzed by cytochrome P450 enzymes.
  2. Phase 2: Conjugation reactions (e.g., glucuronidation) produce polar conjugates for easier elimination.
• Key Cytochrome P450 Enzymes: CYP3A4, CYP2D6, CYP2C8, CYP2C9, CYP1A2.
• Drug Interactions:
  • Inducers: Phenytoin, Carbamazepine, Rifampin, Alcohol, Barbiturates, St. John's Wort (Mnemonic: P-Crubs).
  • Inhibitors: Grapefruit, protease inhibitors, azole antifungals, cimetidine, macrolides, amiodarone, calcium channel blockers (Mnemonic: G-PACMAN).

Conclusion

• Understanding pharmacokinetics is essential for drug dosing and therapeutic effectiveness.