The pattern of distribution from plasma to other body fluids and tissues is a characteristic of each
14 But TDS may have an unexpected outcome for, not only may the sticking plaster drop off unnoticed, it may find its way onto another person. A hypertensive father rose one morning and noticed that his clonidine plaster was missing from his upper arm. He could not find it and applied a new plaster. His nine-month-old child, who had been taken into the paternal bed during the night because he needed comforting, spent an irritable and hypoactive day, refused food but drank and passed more urine than usual. The missing clonidine patch was discovered on his back when he was being prepared for his bath. No doubt this was accidental, but children also enjoy stick-on decoration and the possibility of poisoning from misused, discarded or new (e.g. strong opioid, used in palliative care) drug plasters means that these should be kept and disposed of as carefully as oral formulations (Reed M T et al 1986 New England Journal of Medicine 314:1120).
The distribution volume of a drug is the volume in which it appears to distribute (or which it would require) if the concentration throughout the bod/ were equal to that in plasma, i.e. as if the bod/ were a single compartment.
drug that enters the circulation and it varies between drugs. Precise information on the concentration of drug attained in various tissues and fluids requires biopsy samples and for understandable reasons this is usually not available for humans (although positive emission tomography offers a prospect of obtaining similar information).15 What can be sampled readily in humans is blood plasma, the drug concentration in which, taking account of the dose, is a measure of whether a drug tends to remain in the circulation or to distribute from the plasma into the tissues. If a drug remains mostly in the plasma, its distribution volume will be small; if it is present mainly in other tissues the distribution volume will be large.
Such information is clinically useful. Consider drug overdose. Removing a drug by haemodialysis is likely to be a beneficial exercise only if a major proportion of the total body load is in the plasma, e.g. with salicylate which has a small distribution volume; but haemodialysis is an inappropriate treatment for overdose with dothiepin which has a large distribution volume. These, however, are generalisations and if the knowledge of distribution volume is to be of practical value it must be quantified more precisely.
The principle for establishing the distribution volume is essentially that of using a dye to find the volume of a container filled with liquid. The weight of dye that is added divided by the concentration of dye once mixing is complete gives the distribution volume of the dye, which is the volume of the container. Similarly, the distribution volume of a drug in the body may be determined after a single
15 With positron emission tomography (PET), a positron emitting isotope, e.g. lsO, is substituted for a stable atom without altering the chemical behaviour of the molecule. The radiation dose is very low but can be imaged tomographically using photomultiplier-scintillator detectors. PET can be used to monitor effects of drugs on metabolism in the brain, e.g. 'on' and 'off' phases in parkinsonism. There are many other applications.
intravenous bolus dose by dividing the dose given by the concentration achieved in plasma.16
The result of this calculation, the distribution volume, in fact only rarely corresponds with a physiological body space such as extracellular water or total body water, for it is a measure of the volume a drug would apparently occupy knowing the dose given and the plasma concentration achieved and assuming the entire volume is at that concentration. For this reason, it is often referred to as the apparent distribution volume. Indeed, for some drugs that bind extensively to extravascular tissues, the apparent distribution volume, which is based on the resulting low plasma concentration, is many times total body volume.
Distribution volume is the volume of fluid in which the drug appears to distribute with a concentration equal to that in plasma.
The list in Table 7.2 illustrates a range of apparent distribution volumes. The names of those substances that distribute within (and have been used to measure) physiological spaces are printed in italics.
Selective distribution within the body occurs because of special affinity between particular drugs and particular body constituents. Many drugs bind to proteins in the plasma; phenothiazines and chloro-quine bind to melartin-containing tissues, including the retina, which may explain the occurrence of retinopathy. Drugs may also concentrate selectively in a particular tissue because of specialised transport mechanisms, e.g. iodine in the thyroid.
16 Clearly a problem arises in that the plasma concentration is not constant but falls after the bolus has been injected. To get round this, use is made of the fact that the relation between the logarithm of plasma concentration and the time after a single intravenous dose is a straight line. The log concentration-time line extended back to zero time gives the theoretical plasma concentration at the time the drug was given. In effect, the assumption is made that drug distributes instantaneously and uniformly through a single compartment, the distribution volume. This mechanism, although seeming artificial, does usefully characterise drugs according to the extent to which they remain in or distribute out from the circulation.
TABLE 7.2 Apparent distribution volume of some
drugs (Figures are in litres for a 70 kg person who
ace about 70 I)17
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