Drug Distribution and Protein Binding

Drug Distribution Fundamentals - Getting Around Town

• Process: Reversible transfer of drug from blood to interstitial/intracellular fluids.
• Key Determinants:
  • Drug Properties: Lipophilicity (↑ = ↑ distribution), ionization (unionized form crosses membranes), molecular size (↓ size = ↑ distribution).
  • Body Factors: Blood flow (high perfusion organs like brain, liver, kidney get more drug faster), capillary permeability (e.g., Blood-Brain Barrier vs. liver sinusoids), plasma protein binding (only free, unbound drug is active & distributes), tissue binding (can create reservoirs).
• Special Barriers:
  • Blood-Brain Barrier (BBB): Tight junctions, P-glycoprotein (P-gp) efflux pumps limit entry of many drugs.
  • Placental Barrier: Not absolute; lipid-soluble drugs cross more readily.

⭐ Highly lipid-soluble drugs (e.g., thiopental) rapidly enter the CNS due to high blood flow and lipophilicity, then redistribute to adipose tissue, leading to a short duration of CNS action but potential for accumulation with repeated doses.

Volume of Distribution (Vd) - How Far It Roams

• Apparent volume a drug occupies to match its plasma concentration ($C_0$). Not a true physiological volume.
• Formula: $V_d = \frac{\text{Dose}}{C_0}$
• Interpretation:
  • Low Vd (< 5 L): Drug mainly in plasma. E.g., Heparin, Warfarin.
  • High Vd (> 15 L, often much higher): Drug widely distributed in tissues. E.g., Chloroquine, Digoxin.
• Factors ↑ Vd: High lipid solubility, high tissue binding, low plasma protein binding.
• Factors ↓ Vd: Low lipid solubility, low tissue binding, high plasma protein binding, large molecular size.
• Clinical Use: Calculate Loading Dose (LD): $\text{LD} = V_d \times C_{target}$

⭐ Drugs with very high Vd (e.g., Chloroquine) are poorly removed by hemodialysis because most drug is in tissues.

Protein Binding - The Drug's Chaperone

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Special Barriers & Redistribution - Restricted Access & Quick Moves

• Special Barriers: Restrict drug access to CNS, fetus, testes.
  • Blood-Brain Barrier (BBB):
    • Tight junctions, ↓fenestrae, P-gp efflux.
    • Favors small, lipophilic, non-ionized drugs.
    • Inflammation/immaturity ↑ permeability.
    • 
  • Placental Barrier:
    • Lipophilic drugs cross; P-gp/BCRP efflux.
    • Risk of fetal exposure/teratogenicity.
  • Blood-Testis Barrier:
    • Protects gametes via Sertoli cell junctions.
• Redistribution:
  • Drug moves from high-flow organs to other tissues.
  • Key for highly lipophilic drugs (IV).
  • Path: Brain/heart (high-flow) → fat/muscle (low-flow, high-volume).
  • Effect: ↓ conc. at action site, shortens effect.
  • E.g., Thiopental: rapid induction, short action via redistribution.

⭐ Thiopental: Brief anesthesia due to redistribution from brain to fat/muscle, not fast metabolism.

High‑Yield Points - ⚡ Biggest Takeaways

• Vd (Volume of distribution) reflects tissue distribution; ↑Vd = more drug in tissues, less in plasma.
• Acidic drugs (e.g., NSAIDs, warfarin) bind albumin; basic drugs (e.g., lidocaine) bind α1-acid glycoprotein (AAG).
• Only unbound (free) drug is pharmacologically active, can be metabolized, and excreted.
• High protein binding acts as a drug reservoir, prolonging duration, but ↓ free drug fraction.
• Displacement interactions are critical for highly bound drugs with a narrow therapeutic index (e.g., warfarin, phenytoin).
• ↑Lipid solubility and ↑tissue binding lead to ↑Vd; ionization generally ↓Vd across membranes.
• Loading dose depends on Vd; maintenance dose on clearance (CL).