Overview
This lecture covers the distribution phase of pharmacokinetics, focusing on how drugs move from the bloodstream into body tissues, and the factors influencing this process.
Drug Distribution Process
- Distribution is the movement of a drug from the bloodstream into tissues and organs.
- Distribution determines where in the body a drug can exert its effects.
Factors Affecting Drug Distribution
Blood Flow
- Organs with high blood flow (kidneys, liver, brain) receive more drug.
- Low blood flow organs (skin, adipose tissue) receive less drug.
- Shock (septic, cardiogenic, hypovolemic) decreases tissue drug distribution due to reduced blood flow.
Capillary Permeability
- Leaky capillaries (sinusoidal in liver, spleen; fenestrated in kidneys) increase drug distribution.
- Tight capillaries (blood-brain barrier, muscles) decrease distribution; only small, hydrophobic drugs or those with transporters can cross easily.
- Septic shock increases capillary permeability, causing greater tissue distribution and lower plasma drug concentration.
Protein Binding
- High plasma protein (albumin) binding = less free drug, lower tissue distribution, higher plasma concentration.
- Highly protein-bound drugs act as reservoirs, slowly releasing drug.
- Low protein binding = more free drug, higher tissue distribution, greater risk of toxicity.
Clinical Implications of Protein Binding
- Chronic kidney disease and liver failure decrease albumin levels, increasing free drug and tissue distribution.
Drug Solubility
- Small, hydrophobic, nonpolar drugs distribute easily into tissues.
- Large, charged, hydrophilic drugs remain in plasma.
Volume of Distribution (Vd)
- Vd is a theoretical value indicating how extensively a drug disperses into body fluids and tissues.
- Low Vd: Drug remains mostly in plasma (e.g., heavily protein-bound, large, polar drugs).
- Intermediate Vd: Drug occupies plasma and interstitial fluid (e.g., smaller, less protein-bound drugs).
- High Vd: Drug distributes into all compartments, including intracellular fluid (e.g., small, nonpolar, hydrophobic drugs).
Practice Questions
- Drug with high molecular weight, hydrophilic, and heavily protein-bound has a low volume of distribution.
- Vd calculation: Vd = (bioavailability × dose) / plasma concentration.
- Example: For vancomycin, Vd = (1 × 2000 mg) / 28.5 mg/L = ~70.1 L; Vd per kg = 1 L/kg for a 70 kg patient.
Key Terms & Definitions
- Distribution — Movement of a drug from the bloodstream into tissues.
- Capillary permeability — Ease with which substances pass from blood vessels into tissues.
- Plasma protein binding — Degree to which drugs attach to proteins like albumin in the blood.
- Volume of distribution (Vd) — Theoretical volume representing drug dispersion throughout the body.
- Bioavailability — Fraction of an administered dose reaching systemic circulation.
Action Items / Next Steps
- Review protein binding and Vd calculations.
- Prepare for next lecture on drug metabolism.