Chapter 2 · Module 2 of 5 · Pharmacokinetics

Distribution

Volume of distribution, plasma protein binding, tissue barriers, loading dose calculations, dialyzability, and compartment model timing pitfalls

Volume of distribution (Vd) is an apparent volume relating the amount of drug in the body to its plasma concentration; it ranges from plasma-only drugs (heparin, Vd ~0.06 L/kg) to drugs with extreme tissue accumulation (amiodarone, Vd ~60 L/kg); large Vd extends half-life and makes a drug undialyzable
Only unbound (free) drug is pharmacologically active, crosses membranes, and is eliminated; albumin binds acidic drugs (warfarin, phenytoin, NSAIDs) and falls in cirrhosis, nephrotic syndrome, and critical illness; alpha-1-acid glycoprotein binds basic drugs (lidocaine, propranolol) and rises in acute illness — standard total drug levels can be misleading in both directions
Blood-brain barrier penetration requires small molecular weight (<400–500 Da), lipophilicity, un-ionized state at physiological pH, and absence of P-glycoprotein efflux; inflammation opens the BBB (meningitis allows penicillin/vancomycin penetration); loperamide is excluded by P-gp — potent opioid with no CNS effect at therapeutic doses
Loading dose = target plasma concentration × Vd; large Vd requires large loading doses; fluid overload increases Vd for hydrophilic drugs requiring dose adjustment; only drugs with small Vd are effectively removed by dialysis — digoxin (Vd ~7) and tricyclics (Vd >20) are not dialyzable
Two-compartment drugs show a distribution phase after IV dosing where plasma levels are falsely elevated before equilibration with tissues — digoxin levels drawn within 6–8 hours of IV dosing are uninterpretable; vancomycin troughs must be drawn before the next dose after distribution is complete

Section 1 — Volume of Distribution — The Clinical Spectrum

Section 1

Vd Determines Half-Life Extension and Dialyzability

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: t½ = (0.693 × Vd) ÷ clearance. Large Vd extends half-life even with normal clearance — amiodarone's half-life is weeks to months. Drugs with large Vd are NOT effectively removed by dialysis because most drug resides in tissues, not in the plasma being filtered.

Section 2 — Plasma Protein Binding

Section 2

Albumin, Alpha-1-Acid Glycoprotein, and the Free Drug Hypothesis

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 the measured total level or directly measure free drug

AAG — Basic Drugs

Binds Weak Base Drugs

Lidocaine, propranolol, methadone, tricyclic antidepressants
Acute-phase reactant: rises in inflammation, surgery, myocardial infarction
Rising AAG → 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: the same total level does not equal the same free level and does not produce the same clinical effect. Always interpret drug levels in the context of the patient's protein binding status.

Section 3 — Tissue Barriers to Drug Distribution

Section 3

Blood-Brain Barrier and Placental Transfer

Crosses the BBB

Lipophilic, Small, Un-Ionized

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

Poor BBB Penetration

Hydrophilic or P-gp Substrate

Penicillin, vancomycin, gentamicin: excluded under normal conditions
Penetrate in meningitis — inflammation disrupts tight junctions
Loperamide: potent mu-opioid but excluded by P-gp → no CNS opioid effects at therapeutic doses
Many chemotherapy agents excluded by P-gp (CNS sanctuary)

Placenta as partial barrier: The placenta is not an effective barrier — lipophilic drugs readily cross. Drugs designed to avoid CNS effects (e.g., quaternary ammonium compounds) also avoid fetal exposure. Hydrophilic drugs cross poorly. Fetal drug levels generally approximate maternal levels for lipophilic drugs at equilibrium.

Sections 4 & 5 — Clinical Applications and Pathological States

Sections 4 & 5

Loading Dose, Dialyzability, and Fluid State Effects

Loading Dose

LD = Target Cp × Vd

Large Vd → large loading dose required to fill tissue reservoir
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 before steady state

Dialyzability

Small Vd = Dialyzable

Lithium (Vd ~0.8): dialyzable — first-line treatment in severe toxicity
Digoxin (Vd ~7): not dialyzable — use digoxin-specific antibody fragments
Tricyclics (Vd >20): not dialyzable — supportive care only
Drug redistributes from tissue back to plasma after dialysis ends — rebound toxicity possible

Pathological states and altered distribution: Edema and ascites increase Vd for hydrophilic drugs — raise loading doses during fluid overload, reduce as fluid mobilizes. Cirrhosis: low albumin plus ascites alters distribution of both albumin-bound and hydrophilic drugs simultaneously. Renal failure: endogenous albumin displacers accumulate and increase free phenytoin fraction — standard total level targets do not apply; use free phenytoin levels.

Section 6 — Compartment Models and Sampling Timing

Section 6

Distribution Phase and Drug Level Timing Pitfalls

One-Compartment Model

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 Model

Distribution Phase Then Elimination

Rapid initial decline (distribution) → slower elimination phase
Level during distribution phase: falsely elevated — do not act on it
Digoxin: wait 6–8 hours after IV dose before sampling
Lidocaine: IV bolus then infusion (not repeated boluses during distribution)
Vancomycin: draw trough before next dose after distribution is complete

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Katzung BG, ed.	Basic and Clinical Pharmacology, 15th edition	McGraw-Hill, 2021
Brunton LL, Knollmann BC, eds.	Goodman & Gilman's The Pharmacological Basis of Therapeutics, 14th edition	McGraw-Hill, 2023
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Brunton LL, Hilal-Dandan R, Knollmann BC, eds.	Goodman & Gilman's The Pharmacological Basis of Therapeutics, 13th edition	McGraw-Hill, 2018
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