Drug distribution and protein binding

Drug Distribution - Where'd That Drug Go?

• Volume of Distribution (Vd): Theoretical fluid volume that would be required to contain the amount of drug present in the body at the same concentration as in the plasma.
  • Formula: $Vd = \frac{\text{Amount of drug in body}}{\text{Plasma drug concentration}}$
  • Low Vd: Drug is confined to plasma (large, charged, protein-bound).
  • High Vd: Drug is widely distributed in tissues (small, lipophilic, unbound).

• Plasma Protein Binding:
  • Primarily to albumin.
  • Bound drug is inactive; only free drug exerts effects.

⭐ In states of hypoalbuminemia (e.g., liver disease, nephrotic syndrome), decreased protein binding leads to higher levels of free drug, increasing the risk of toxicity.

Plasma Protein Binding - The Clingy Molecules

• Drugs exist in two forms in plasma: bound and unbound. This binding is reversible.
• Only the unbound (free) fraction is pharmacologically active, can cross membranes, be distributed to tissues, get metabolized, and be excreted.

-   **Albumin:** Binds acidic drugs (e.g., Warfarin, NSAIDs).
-   **α₁-acid glycoprotein:** Binds basic drugs (e.g., Lidocaine, Propranolol).

⭐ Drug Displacement: When two drugs compete for the same binding site, one can displace the other. A highly bound drug like Warfarin can be displaced by sulfonamides, ↑ its free concentration and leading to bleeding risk.

• High protein binding restricts the drug to the vascular compartment, resulting in a low apparent Volume of Distribution ($V_d$).

Volume of Distribution (Vd) - High vs. Low Stakes

• Definition: The theoretical fluid volume required to contain the total amount of administered drug at the same concentration that it is in the plasma.
• Formula: $Vd = \frac{\text{Amount of drug in body}}{\text{Plasma drug concentration}}$

Special Barriers - No Entry Zones

• Blood-Brain Barrier (BBB): Restricts CNS entry.

  • Formed by endothelial tight junctions & astrocyte feet.
  • Permeable to lipid-soluble, non-ionized, small drugs.
  • P-glycoprotein (MDR1) efflux pumps actively remove drugs.
  • Inflammation (e.g., meningitis) can ↑ BBB permeability.

• Placental Barrier:

  • Semi-permeable; most drugs cross to some extent, posing fetal risk (teratogenicity).
  • Lipid-soluble drugs cross more readily.

⭐ Some brain areas lack a BBB (circumventricular organs), like the area postrema (chemoreceptor trigger zone) & posterior pituitary. This allows for monitoring of systemic signals.

High-Yield Points - ⚡ Biggest Takeaways

• Volume of distribution (Vd): High Vd indicates extensive tissue distribution; low Vd suggests confinement to plasma.
• Only unbound (free) drug is pharmacologically active, can be metabolized, and can be excreted.
• Acidic drugs primarily bind to albumin; basic drugs bind to α1-acid glycoprotein.
• Displacement of highly protein-bound drugs (e.g., warfarin) ↑ free drug levels, risking toxicity.
• Lipid solubility is a key determinant for crossing the blood-brain barrier and placenta.
• Redistribution terminates the action of lipophilic drugs like propofol.