Pharmacokinetics: Distribution and Volume of Distribution

Vocabulary-style flashcards covering absorption, distribution, capillary permeability, protein binding, solubility, volume of distribution, and related clinical considerations from the pharmacokinetics lecture.

Absorption

Process by which a drug moves from the site of administration into the systemic circulation; applies to all routes except IV and is influenced by bioavailability and first-pass metabolism.

Bioavailability

Fraction of an administered drug that reaches systemic circulation; IV administration has 100% bioavailability (F = 1).

First-pass metabolism

Metabolism of a drug before it reaches systemic circulation, often in the liver and gut, reducing the amount of active drug reaching the bloodstream.

Distribution

Movement of a drug from the bloodstream into tissues; influenced by blood flow, capillary permeability, protein binding, and solubility; determines volume of distribution.

Blood flow (distribution factor)

Tissue blood flow affects how much drug is delivered to a tissue; higher flow (e.g., kidneys, liver, brain) can increase distribution; lower flow can decrease it.

Capillary permeability

Ease with which a drug moves from blood to tissue; leaky capillaries (sinusoidal, fenestrated) increase distribution; continuous capillaries with tight junctions reduce it.

Sinusoidal capillaries

Leaky capillaries in liver, bone marrow, and spleen with large gaps that allow easy drug leakage into tissues; increases distribution.

Fenestrated capillaries

Capillaries with large fenestrations (e.g., kidneys, glands) and fewer tight junctions; permit easier leakage of drugs into tissues.

Continuous capillaries

Capillaries with tight junctions and no fenestrations (e.g., muscle, brain); restrict movement of drugs unless facilitated by transporters or if the drug is very lipophilic.

Transporters

Membrane proteins that facilitate movement of drugs across capillary walls when passive diffusion is insufficient.

Protein binding

Drugs binding to plasma or tissue proteins (notably albumin); only the unbound (free) drug distributes to tissues; high binding reduces distribution and can prolong plasma residence (reservoir).

Albumin

Major liver-produced plasma protein; binds many drugs; high binding reduces free drug; can act as a reservoir releasing drug over time.

Effects of CKD on distribution

Chronic kidney disease lowers albumin levels and causes albumin loss in urine, increasing free drug and distribution; risk of toxicity rises.

Effects of cirrhosis on distribution

Liver disease reduces albumin production, increasing free drug and distribution; higher risk of toxicity due to more drug available to tissues.

Solubility

Drug solubility and lipophilicity determine membrane crossing; high nonpolar, small, hydrophobic drugs diffuse more readily and distribute more widely.

Volume of distribution (Vd)

Theoretical volume that would be required to contain the total amount of drug at the same concentration as in plasma; reflects distribution across compartments (plasma, interstitial, intracellular).

Low volume of distribution

Drug largely confined to plasma; often highly protein-bound and of high molecular weight; example: warfarin (VD ≈ 8 L).

High volume of distribution

Drug widely distributed into tissues; typically low protein binding and highly lipophilic; example: chloroquine (VD can be very large, e.g., ~150,000 L).

Warfarin example

Warfarin has a low Vd (~8 L) and is highly protein-bound, tending to stay in plasma where it exerts its anticoagulant effect.

Chloroquine example

Chloroquine has an extremely high Vd (very high tissue distribution) due to being highly lipophilic and poorly protein-bound, distributing widely beyond plasma.

Vancomycin Vd calculation

Apparent Vd can be calculated with Vd = F × Dose / Cmax; for IV F = 1; example: Dose = 2000 mg, Cmax = 28.5 mg/L → Vd ≈ 70 L (≈1 L/kg for a 70 kg patient).

Capillary leak in septic shock

Septic shock causes increased capillary permeability, increasing drug distribution into tissues and lowering serum drug concentrations; sometimes necessitates higher antibiotic dosing.

Brain distribution and blood-brain barrier

Brain capillaries have tight junctions (continuous capillaries) limiting diffusion; drugs must be very small and lipophilic or use transporters to cross into the brain.