Chapter 2  ·  Module 2  ·  Visual Summary

Distribution

Volume of distribution, plasma protein binding, tissue barriers, and compartment models

Volume of Distribution (Vd) — The Clinical Spectrum

Drug Vd (L/kg) Distribution Reason Dialyzable?
Heparin ~0.06 Plasma only Large molecule, cannot leave vasculature Yes
Warfarin ~0.14 Plasma + interstitial ~99% albumin-bound; low tissue penetration Yes (partial)
Gentamicin ~0.25 Extracellular fluid Polar; cannot cross cell membranes Yes
Lithium ~0.8 Total body water Hydrophilic; distributes uniformly Yes
Digoxin ~7 Extensive tissue binding Binds Na/K-ATPase in muscle No
Amiodarone ~60 Extreme tissue accumulation Highly lipophilic; stores in fat, liver, lung No
Half-life relationship: Half-life = (0.693 × Vd) / clearance. Large Vd extends half-life even with normal clearance (amiodarone: weeks to months). Large Vd drugs are NOT effectively removed by dialysis.

Plasma Protein Binding

Albumin — Acidic Drugs

Binds weak acid drugs

  • Warfarin, phenytoin, valproic acid, furosemide, most NSAIDs
  • Normal albumin: 3.5–5.0 g/dL
  • Falls in cirrhosis, nephrotic syndrome, critical illness → increases free fraction
  • Free phenytoin increases in hypoalbuminemia — correct total level or measure free

Alpha-1-acid glycoprotein — Basic Drugs

Binds weak base drugs

  • Lidocaine, propranolol, methadone, tricyclic antidepressants
  • Acute-phase reactant: rises in inflammation, surgery, myocardial infarction
  • Rising alpha-1-acid glycoprotein → increased bound fraction → total level rises without change in free drug effect
  • Falls in hepatic insufficiency and neonates
Free Drug Hypothesis: Only UNBOUND drug is pharmacologically active, crosses membranes, and is eliminated. Standard assays measure TOTAL drug (bound + free). In hypoalbuminemia or renal failure: same total level ≠ same free level ≠ same clinical effect. Always interpret drug levels in the context of the patient’s protein binding status.

Blood-Brain Barrier — Drug Penetration Requirements

Crosses Blood-Brain Barrier

Lipophilic, small, un-ionized

  • Small molecular weight (<400–500 Da)
  • Lipophilic (high log P)
  • Un-ionized at physiological pH
  • Not a P-glycoprotein substrate
  • Examples: diazepam, most general anesthetics, ethanol, fentanyl, morphine

Poor Blood-Brain Barrier Penetration

Hydrophilic or P-glycoprotein substrate

  • Penicillin, vancomycin, gentamicin: excluded under normal conditions
  • Penetrate in meningitis (inflammation opens barrier)
  • Loperamide: potent opioid but excluded by P-glycoprotein → no CNS effects at therapeutic doses
  • Many chemotherapeutic agents excluded by P-glycoprotein

Clinical Applications — Loading Dose and Dialysis

Loading Dose

LD = Target Cp × Vd

  • Large Vd → large loading dose required
  • Fluid overload (sepsis, edema): Vd increases for hydrophilic drugs → higher loading dose
  • Obesity: hydrophilic drugs use lean body weight; lipophilic drugs use total body weight
  • Digoxin: requires multiple IV doses to fill tissue reservoir

Dialyzability

Small Vd = dialyzable

  • Lithium (Vd ~0.8 L/kg): dialyzable — use in toxicity
  • Digoxin (Vd ~7 L/kg): not dialyzable — use digoxin antibody fragments
  • Tricyclics (Vd >20 L/kg): not dialyzable — supportive care only
  • Drug redistributes from tissue back to plasma as soon as dialysis ends

Compartment Models — Distribution Phase and Sampling Timing

One-Compartment

Instant uniform distribution

  • Single exponential decline after IV bolus
  • Single straight line on semi-log plot
  • Plasma level at any post-dose time is interpretable
  • Typical: gentamicin, most hydrophilic drugs

Two-Compartment

Distribution phase then elimination

  • Rapid initial decline (distribution phase) → slower elimination phase
  • Level during distribution phase: falsely elevated
  • Digoxin: wait 6–8 hours after IV dose before sampling
  • Lidocaine: IV bolus then infusion (not repeated boluses)
  • Vancomycin: draw trough before next dose after distribution complete
Pathological state effects on distribution: Edema / ascites → Vd increases for hydrophilic drugs; raise loading doses during fluid overload, reduce as fluid mobilizes. Cirrhosis → low albumin + ascites → altered distribution of both albumin-bound and hydrophilic drugs. Renal failure → endogenous albumin displacers increase free phenytoin fraction; standard total level targets do not apply.