MDG5204 Chap.2 Drug Distribution and the Volume of Distribution
Drug Distribution and the Volume of Distribution
From the blood into the body
Distribution is what happens after absorption: the drug leaves the plasma and moves into interstitial fluid, into cells and into tissues. The lecture defines it through a volume, the volume of body fluid the drug appears to spread through, and the chapter is built around the difference between that apparent volume and the real body compartments.
Total body water is about 42 litres in an adult, split between intracellular and extracellular fluid, with only a few litres of plasma.
What moves a drug, and what holds it back
Four factors dominate. Lipid solubility decides whether a drug can enter cells at all; lipid-insoluble drugs stay in plasma and interstitial fluid, lipid-soluble ones reach every compartment and can accumulate in fat.
Blood flow decides the order in which tissues receive drug, with brain, liver and kidney first and fat and bone last, and it explains redistribution, in which a drug such as thiopentone acts quickly in the brain and then loses its effect as it moves on into muscle and fat.
Plasma protein binding and tissue binding decide how much of the drug is free to act.
The apparent volume and the loading dose
The apparent volume of distribution is the amount of drug in the body divided by the plasma concentration. It should not be read as a physical volume: a value many times larger than total body water simply means that most of the drug has left the plasma for tissue.
Its main use is practical, because the amount needed to reach a chosen plasma concentration is that concentration multiplied by the volume, corrected for bioavailability when the dose is not intravenous.
That product is the loading dose.
Binding, interactions and barriers
Acidic drugs bind mainly to albumin and basic drugs to alpha-1 acid glycoprotein, and only the unbound fraction acts, is metabolised and is excreted. Heavily bound drugs such as warfarin are long acting and vulnerable to displacement by another drug at the same site, and they become dangerous when albumin falls in malnutrition or cirrhosis.
The chapter closes with the two barriers that lipid-soluble drugs cross: the placenta, which is incomplete and exposes the fetus, and the blood-brain barrier, which is near complete and must be crossed by any drug meant to act in the brain.
What this chapter covers
- 01
Distribution defined through the apparent volume a drug seems to occupy
- 02
Total body water, intracellular and extracellular fluid and plasma as reference volumes
- 03
Lipid solubility, blood flow and redistribution to muscle and fat
- 04
Apparent volume of distribution calculated from an intravenous dose
- 05
Loading dose from target concentration, volume and bioavailability
- 06
Plasma protein binding, displacement interactions and tissue binding
Worked example · free
Reading three volumes of distribution
- 2Interpret 4 L against plasma volume.
- 2Interpret 15 L against extracellular water.
- 2Interpret 350 L against total body water.
Key terms
- Apparent Volume of Distribution
- The volume that would hold the whole body content of a drug at its plasma concentration.
- Redistribution
- Movement of a drug from highly perfused organs into muscle and fat, which can end its action.
- Plasma Protein Binding
- Reversible attachment of drug to albumin or alpha-1 acid glycoprotein, leaving only the free fraction active.
- Tissue Binding
- Reversible binding of drug to tissue components, which lowers plasma concentration and raises the apparent volume.
- Loading Dose
- A dose given at the start of treatment to reach the target concentration at once, equal to target concentration times volume over bioavailability.
- Compartment Model
- A mathematical description of the body as one or more spaces in which drug is assumed to be uniform.
Drug Distribution and the Volume of Distribution FAQ
Why can the volume of distribution be larger than the whole body?
Because it is calculated rather than measured. When a drug binds strongly to tissue, very little remains in plasma, and dividing the amount in the body by that small concentration produces a large number. It signals extensive tissue uptake, not a body of that size.
Why do highly protein-bound drugs cause interactions?
Two drugs that bind the same site on albumin compete for it. Adding the second drug displaces some of the first, raising its free fraction even though the total level barely changes, and only the free drug produces an effect. With warfarin that means a higher bleeding risk.
How does obesity change the behaviour of a lipid-soluble anaesthetic?
Fat acts as a reservoir. A lipid-soluble anaesthetic moves into adipose tissue, is stored there and is released back into the circulation slowly, so the apparent volume is large and recovery after the anaesthetic is stopped can be delayed.
Exam move
Memorise the three reference volumes and practise placing any calculated volume against them. Then write the loading dose equation from memory with and without bioavailability, and check it on a dose you invent yourself.
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