Viva B(iii)

This viva is relevant to Section B(iii) of the 2017 CICM Primary Syllabus, which expects the exam candidate to "Describe factors influencing the distribution of drugs".

Define the term "volume of distribution".

Volume of distribution is ".not a "real volume"... It is the parameter relating the concentration of a drug in the plasma to the total amount of the drug in the body" (Birkett, 2009)

Alternatively:

"(Vd) is defined as the apparent volume into which a drug disperses in order to produce the observed plasma concentration" (Peck & Hill)

How do you calculate the volume of distribution?

volume of distribution - Vd equation

How does the timing of measurement influence the volume of distribution?
  • Drug concentration in the body will vary over time due to clearance and redistribution
  • Taking measurements at different points in time will yield different volumes of distribution, which will depend on the dominant influences on drug distribution at the measurement time.
What is the initial volume of distribution (Vinitial)?
  • This is the Vd of the drug in the central compartment
  •  It is possible to calculate this soon after a drug is administered intravenously, by extrapolating an imaginary line from plasma concentration measurements, extended to time zero.
  • You can use this relationship to estimate the volume of the central compartment
  • For therapeutic purposes, it can be used to estimate high peak plasma concentrations so that - if need be- you can divide your loading dose to avoid toxicity.

v(initial) volume of distribution graph

What is the extrapolated volume of distribution?
  • Extrapolated volume of distribution (Vextrap) is the Vd of tissue distribution.
  • This method .extrapolates a line of best fit from the terminal elimination phase.
  • This will cause an overestimation of Vd for drugs which distribute extensively into the tissues.

v(extrap) volume of distribution graph.JPG

What is meant by the term "non-compartmenal volume of distribution"?
  • Non-compartmental Vd (Varea) is an extrapolated Vd which uses the area under the concentration/time curve.

v(area) volume of distribution graph

Define the term "steady state volume of distribution"
  • Vss describes the volume of distribution during steady state conditions, i.e. when there is a stable drug concentration.
  • Of all the volumes of distribution, Vss is probably the most useful for calculating the loading dose

V(ss) equation

V(ss) steady state volume of distribution

Which factors influence the volume of distribution?
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 higher than male Vds due to the generally higher body water content
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)

References

Gibaldi, M., and P. J. McNamara. "Apparent volumes of distribution and drug binding to plasma proteins and tissues." European journal of clinical pharmacology 13.5 (1978): 373-378.

Toutain, Pierre-Louis, and Alain BOUSQUET‐MÉLOU. "Volumes of distribution." Journal of veterinary pharmacology and therapeutics 27.6 (2004): 441-453.

Riegelman, S., J. Loo, and M. Rowland. "Concept of a volume of distribution and possible errors in evaluation of this parameter." Journal of Pharmaceutical Sciences 57.1 (1968): 128-133.

Krishna, Sanjeev, and Nicholas J. White. "Pharmacokinetics of quinine, chloroquine and amodiaquine." Clinical pharmacokinetics30.4 (1996): 263-299.

Wagner, John G. "Significance of ratios of different volumes of distribution in pharmacokinetics." Biopharmaceutics & drug disposition 4.3 (1983): 263-270.