Barriers, Reservoirs & Volume of Distribution
Why does an anaesthetic put a patient to sleep in one arm–brain circulation, then let them wake up minutes later — even though the drug is still in their body? Why can a single number, sometimes larger than the whole human body, tell you how big a starting dose to give? This is the strange, beautiful logic of barriers, hiding places, and the volume of distribution.
In the operating room, the anaesthetist pushes a dose of thiopental into the vein. Within one circulation — about 30 seconds — the patient is unconscious. But then something curious: minutes later, without any reversal drug, the patient begins to stir. The thiopental has NOT been eliminated; almost all of it is still in the body. So where did it go, and why did the effect end? The answer reveals two of distribution's deepest ideas: redistribution between tissues, and the reservoirs where drugs hide.
Redistribution: the effect ends before the drug leaves
Thiopental is highly lipid-soluble. Because it dissolves in fat so easily, it floods into the brain — which is well-perfused and fatty — almost instantly, producing anaesthesia in one circulation. But the brain holds only a fraction of the body's tissue. As the seconds pass, the drug keeps following the blood into the much larger, slower-filling compartments: first muscle, then fat. This shift pulls thiopental OUT of the brain and back into the blood to be delivered elsewhere. The brain level falls below the threshold for sleep, and the patient wakes — not because the drug is gone, but because it has redistributed away from its site of action.
Redistribution — not elimination — terminates the action of a single dose of a very lipophilic drug. This is why one dose of thiopental is short-acting despite slow elimination, and why REPEATED doses become long-acting: once the fat and muscle reservoirs are saturated, there is nowhere left to redistribute to, so the drug lingers in the brain and the patient stays under far longer.
Barriers: the guarded organs
Not every tissue lets drugs in freely. The blood–brain barrier is a wall of tightly-joined capillary cells, backed by efflux pumps (like P-glycoprotein) that actively spit drugs back out. Only small, lipid-soluble, unionized drugs cross it easily — which is why thiopental reaches the brain in seconds but many other drugs can't touch it at all. This barrier protects the brain but also frustrates treatment: getting antibiotics or chemotherapy into the central nervous system is genuinely hard. The placental barrier, by contrast, is far more permissive — most drugs cross it to some degree, which is why prescribing in pregnancy demands such caution about teratogens.
Some tissues act as long-term reservoirs that hoard drugs. Fat stores lipophilic drugs (and slowly leaks them back out for days). Bone locks up tetracyclines (staining growing teeth) and heavy metals. These stores don't cause an immediate effect, but they prolong a drug's stay in the body and can be a slow-release source long after the last dose.
- Redistribution (not elimination) ends a single lipophilic dose's effect — e.g., thiopental.
- The blood–brain barrier admits only small, lipophilic, unionized drugs (+ efflux pumps).
- The placenta is permissive — most drugs cross; beware teratogens in pregnancy.
- Fat and bone are reservoirs that store drugs and prolong their stay.
Volume of distribution: a number, not a place
Now we can put a single number on all of this: the volume of distribution (Vd). It answers one question — if all the drug in the body were dissolved at the concentration we measure in the plasma, what volume of fluid would it take to hold it? In plain form: Vd = total amount of drug in the body ÷ its plasma concentration. It is called an APPARENT volume because it is a calculated ratio, not a real tank you could point to.
Read it as a hint about WHERE the drug is hiding. A LOW Vd (a few litres, near the blood volume) means the drug mostly stays in the plasma — typically because it is highly protein-bound or too water-soluble to leave the blood (warfarin, heparin). A HIGH Vd (tens to hundreds of litres) means the drug has left the blood and buried itself in tissues, so very little remains in the plasma — digoxin's Vd is around 500 litres, and some drugs run into the thousands. That is how a Vd can exceed total body size: it isn't a real volume, it's a measure of how thoroughly the drug abandons the blood for the tissues.
Vd is not just trivia — it directly sizes the loading dose. To immediately fill the body to a target concentration, you need: loading dose = Vd × target concentration (adjusted for bioavailability). A drug with a big Vd (like digoxin) hides most of a dose in tissue, so you must give a large loading dose up front to get the plasma level you want. A drug with a small Vd needs a much smaller loading dose. We'll build the full dosing maths on this in the Kinetics & Dosing series.
- Believing a single thiopental dose is short because it's eliminated fast. It's redistribution.
- Treating Vd as a real anatomical volume. It's an apparent ratio — it can exceed body size.
- Expecting a high-Vd drug to be cleared well by dialysis. Little of it is in the blood to remove.
- Forgetting that repeated doses of a lipophilic drug become long-acting once reservoirs fill.
A drug has a volume of distribution of 500 L in a 70 kg person. This tells you the drug:
- Redistribution ends a single lipophilic dose's effect before the drug is eliminated.
- The blood–brain barrier is selective; the placenta is permissive; fat & bone are reservoirs.
- Vd = amount in body ÷ plasma concentration — an apparent volume that can exceed body size.
- Low Vd = stays in blood (dialyzable); high Vd = buried in tissue; Vd sets the loading dose.
- Katzung BG. Basic & Clinical Pharmacology — Volume of distribution, redistribution & barriers.
- Brunton LL, et al. Goodman & Gilman's The Pharmacological Basis of Therapeutics — Distribution, blood–brain barrier & Vd.
- Rang HP, Dale MM, et al. Rang & Dale's Pharmacology — Distribution, redistribution & tissue reservoirs.
- Miller RD. Miller's Anesthesia — Thiopental redistribution & duration of action.
- Rowland M, Tozer TN. Clinical Pharmacokinetics & Pharmacodynamics — Volume of distribution & loading dose.
