Pharmacokinetics · Short notes

Distribution and Protein Binding: Short Notes & Cheat Sheet

Volume of distribution, loading doses, barriers to distribution, plasma protein binding and displacement, and compartment models.

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Short notes

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How widely drugs distribute

Vd is apparent: above about 40 L the drug must be concentrated in tissues rather than dissolved in body water.

Volume of distribution

Vd = amount of drug in the body ÷ plasma concentration. It is an apparent volume and can far exceed total body water.
Small Vd (drug stays in plasma): heparin, warfarin. About extracellular fluid: aminoglycosides. About total body water: ethanol.
Very large Vd (heavy tissue binding): digoxin, amiodarone, chloroquine, tricyclic antidepressants.
Loading dose = target concentration × Vd ÷ F. Drugs with a large Vd are poorly removed by dialysis.

Barriers and redistribution

The blood–brain barrier (tight junctions and P-glycoprotein) keeps out polar and ionised drugs. Inflamed meninges let penicillins through.
Lipid-soluble drugs cross the placenta easily.
Redistribution ends the action of thiopental: it moves from brain to muscle and fat.
Two-compartment drugs show a fast distribution (α) phase followed by a slower elimination (β) phase.

Protein binding

Only the free (unbound) drug is active, distributes into tissues and is metabolised and excreted.
Albumin mainly binds acidic drugs (warfarin, phenytoin, valproate, NSAIDs, sulfonamides). α1-acid glycoprotein binds basic drugs (lidocaine, propranolol, quinidine); it rises in inflammation and after MI.
Low albumin (liver disease, nephrotic syndrome, malnutrition, old age) raises the free fraction of highly bound drugs.
Displacement matters mostly for drugs that are highly bound (over 90%), have a small Vd and a narrow therapeutic index.
In newborns, sulfonamides displace bilirubin from albumin and can cause kernicterus.

Cheat sheet

High-yield facts in one place. Cover the right-hand column and test yourself.

Vd examples

Vd size	Examples
≈ plasma (3–5 L)	Heparin; warfarin is low (≈ 8 L)
≈ extracellular fluid (12–15 L)	Aminoglycosides
≈ total body water (≈ 40 L)	Ethanol
Very large (hundreds of L)	Digoxin, amiodarone, chloroquine, TCAs

Binding proteins

Protein	Binds
Albumin	Acidic drugs: warfarin, phenytoin, NSAIDs, sulfonamides
α1-acid glycoprotein	Basic drugs: lidocaine, propranolol, quinidine
Lipoproteins	Very lipophilic drugs, e.g. ciclosporin

Memory aids

Albumin for Acids, α1-AGP for bAses: Albumin binds acidic drugs; α1-acid glycoprotein binds basic drugs.

Exam traps

A large Vd does not mean the drug is in a large amount of fluid; it means the drug is concentrated in tissues.
Displacement from protein usually raises free drug only briefly, because clearance of free drug also rises.
Phenytoin total levels mislead in hypoalbuminaemia; the free level matters.
Drugs with a very large Vd are hard to remove by haemodialysis.

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