Question 12

Define “volume of distribution” and describe the factors that influence it.

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College Answer

A definition was required that included reference to plasma concentration, total body content / 
dose, and the theoretical nature of the volume which can exceed the physical volume of the 
A broad answer listing patient and drug-related factors was required. Patient factors could 
include age, gender, muscle mass, fat mass and abnormal fluid distribution (oedema, ascites,

pleural effusion). The drug factors would include tissue binding, plasma protein binding and 
physicochemical properties of drug (size, charge, pKa, lipid solubility, water solubility). 


A definition which meets the college criteria would be something like this:

Volume of distribution (Vd) is the apparent volume into which a drug disperses in order to produce the observed plasma concentration.  It is a purely theoretical volume which does not correspond to any physiological compartment space, and can substantially exceed the total body volume.

The major determinants of Vd are drug properties which affect protein binding and tissue binding. These consist of molecule size, charge, pKa, and the lipid/water partition coefficient. Patient factors which affect Vd include age, gender, body muscle/fat proportion, level of hydration, water distribution (oedema, effusions, ascites, pregnancy) and extracorporeal sites of distribution (circuit, filters, oxygenator etc). However, a truly "broad" answer can be concocted out of these, and presented in the form of a table:

Factors which Influence the Volume of Distribution
Measurement and pharmacokinetic modelling of Vd
Timing of measurements Depending on when the measurements are taken, the Vd will be different (i.e. it will correspond to Vinitial if the measurements are taken too early, and Vextrap if they are taken during the elimination phase). 
Pharmacokinetic model Vinitial, Vextrap, Varea and Vss are various ways to estimate the Vd of a drug from empirical measurements. All of these methods will yield slightly different results - or, occasionally completely different results.
Free vs. total drug levels In highly protein bound drugs, the calculated volume of distribution for the "total" drug levels will be totally different to the Vd calculated for the free drug. Total Vd will correspond to the Vd of the binding protein rather than the drug itself.
Properties of the drug  
Molecule size The larger the molecule, the harder it will be for it to passively diffuse out of the central compartment, and therefore the smaller the Vd.
Molecule charge Highly ionised charged molecules will have higher water solubility, and may even be trapped in the central compartment by electrostatic factors which keep them bound to proteins with corresponding charge.
pKa pKa determines the degree of ionisation and therefore influences lipid solubility
Lipid solubility Lipid solubility is one of the major determinants of Vd; highly lipid-soluble drugs will have the highest Vd values because of the low fat content of the bloodstream. 
Water solubility Highly water-soluble drugs will have difficulty penetrating lipid bilayer membranes and generally tent do have smaller volumes of distribution, essentially being limited to extracellular water.
Properties of the patient's body fluids
pH pH interactes with the drug's pKa to influence the degree of lipid solubility. pH also influences the degree of protein binding (a good exmaple of this is ionised calcium)
Body water volume Dehydrated patients will have drug levels concentrated in the plasma just as all dissolved substances are concentrated by loss of water. 
Protein levels For highly protein-bound drugs, lower serum protein levels will result in a higher free (unbound) drug fraction. This may have little effect on the Vd as calculated from total drug concentration, but if you are measuring free drug levels it will make the Vd appear smaller.
Displacement Drugs may be displaced from their protein and tissue binding sites by the effects of pH or by competition from other drugs/substances (eg. urea). Displaced drugs mayl redistribute into plasma, decreasing the calculated Vd.
Effects of physiology and pathological states
Age As an old professor of mine had put it, babies are grapes and the elderly are raisins. As you age, body water content decreases, shrinking the Vd of water-soluble drugs. Muscle mass also decreases, and so tissue binding diminishes.
Gender Female Vds tend to be lower than male Vds due to the generally lower  body water content (Soldin & Mattison, 2009)
Pregnancy Both the body water and the body fat content increases, and therefore the Vd increases for most drugs. Not to speak of the possible distribution into amniotic fluid and foetus.
Oedema Oedema represents increased body water and this influences water-soluble substances; Vd for these will increase
Ascites / effusions Just as in oedema, large fluid collections may sequester water soluble drugs and act as reservoirs. 
Effects of apparatus
Adsorption on to apparatus Dialysis filters and ECMO circuits tend to adsorb drugs in an unpredictable fashion, resulting in an apparent increase in the volume of distribution.
Volume expansion In the context of bypass circuits and other large extracorporeal machinery, there may be 2000-2500ml of additional extracorporeal fluid, which will change the volume of distribution (particularly for drugs which are largely confined to the central compartment)


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