The total amount of drug in the extracellular fluid (ECF
) depends on the balance between that entering and that leaving the compartment; the plasma concentration depends on the volume of fluid through which the retained drug is distributed.
Timing of the sample
Blood samples must be taken at a standard time after ingestion of the drug, the exact time varying with the known differences in the rate of absorption, metabolism and excretion of different drugs (Table 25.1
The following factors may affect the blood concentration of some drugs.
It has been shown that not all patients take a drug exactly as prescribed. The patient may not take the drug at all, take more than the prescribed dose, take the drug intermittently or become confused about the timing and dose, particularly if taking more than one drug.
Therapeutic drug monitoring in adultsa
Major route of elimination
Trough (note long half-life)
Check thyroid function Has active metabolite
May cause hyponatraemia Enzyme-inducing drug
Monitor renal and liver function
Trough (?mainly useful for checking compliance)
Risk of agranulocytosis
Risk of weight gain
Risk of diabetes mellitus
Possible cardiac toxicity
6-8 h post dose
Check plasma potassium Monitor renal function
Peak: 30 min post-i.v., 60 min post-i.m.
12 h post dose
May cause hypothyroidism
Monitor renal function
Undergoes saturable metabolism
Partially metabolized to phenobarbital
Monitor renal and liver function
2 h post dose
Mainly useful to assess compliance or confirm toxicity
i.v., intravenous; i.m., intramuscular.
aTherapeutic ranges are less reliable for patients taking a number of drugs. Sampling times are only a general guide. In some cases, samples taken at other times may be appropriate.
Clinicians should realize that poor compliance might cause a poor clinical response or toxicity. A regular review of therapy and careful explanation to the patient are important. Assay of plasma concentrations is only a crude method of assessing compliance and only tests the situation at the time when blood was taken.
Entry of the drug into, and distribution through, the extracellular fluid
Lipid-soluble drugs can pass through cell membranes more readily, and are therefore absorbed more rapidly, than water-soluble ones; they reach the highest plasma concentrations at between 30 and 60 min after ingestion. The rate of absorption in an individual patient may be affected by:
the timing of ingestion in relation to meals,
the rate of gastric emptying: this must be allowed for, for example during treatment with drugs affecting gut motility or after gastric surgery,
vomiting, diarrhoea or malabsorption syndromes,
the administration of other compounds, such as the bile acid sequestrants which may also bind certain drugs within the intestinal lumen.
Volume of distribution
The final plasma concentration of a drug reached after a standard amount has been absorbed depends on the volume through which it has been distributed. For example, it may be difficult to predict the appropriate dose in oedematous or obese patients who, because they have a larger than normal volume of distribution, may have unexpectedly low plasma concentrations. By contrast, in small children, with a low volume of distribution, there is a danger of overdosage. The patient’s weight or surface area may need to be allowed for when the dose is calculated.
Binding to plasma albumin
Many drugs, like many endogenous substances, are partly inactivated by protein binding, usually albumin. Most drug assays estimate the total concentration of the free plus the protein-bound drug. Biological feedback mechanisms do not control free drug concentrations as they do those of plasma calcium and hormones; therefore, the method of interpretation to allow for altered protein binding is different. Measured plasma concentrations fall little due to a reduction in protein binding; a larger proportion of the measured drug will be in the unbound, free, active form, so that metabolism and excretion will increase. Unless this is realized, dangerously high plasma free concentrations may be interpreted as being within, or even below, the therapeutic range if the plasma albumin concentration is very low.
The bound proportion varies with differing plasma albumin concentrations, and there is no valid correction factor that allows for protein abnormalities. About 90 per cent of phenytoin, 70 per cent of salicylic acid, 50 per cent of phenobarbital and 20 per cent of digoxin is protein bound. However, binding may be affected by the following:
Abnormalities in plasma albumin concentration Blood should be taken without stasis to minimize a possible rise in plasma albumin, and albumin-bound drug, concentrations. Low concentrations, such as those often found in hepatic cirrhosis or the nephrotic syndrome, may reduce the proportion of protein-bound drugs.
Competition for binding sites on protein Many drugs, unconjugated bilirubin fatty acids and hydrogen ions compete with each other for binding sites.
Metabolism and excretion of drugs
The blood concentrations of a drug depend on normal hepatic and renal function as well as on acid-base and electrolyte balance. The time taken for the plasma drug concentration to fall to half its original concentration is called its effective half-life. To maintain a reasonably steady plasma concentration, drugs with a short half-life should be taken more frequently than those with a long one. After starting treatment, a steady state is usually reached after about five times its half-life has elapsed; the first specimen of blood for monitoring should not be taken earlier than this.
The rate at which the plasma drug concentration falls after it has reached peak concentration depends on the rate of distribution through the ECF
(see above), the rate of entry into cells and the rate at which it is metabolized and excreted, whether in urine or bile.
The rate of elimination of most drugs depends on their plasma concentration. A small increase in the dose of some, such as phenytoin, may exceed the capacity of the metabolic or excretory pathways and so cause a disproportionate increase in plasma levels; the plasma concentrations of these drugs should be monitored carefully. The rate at which this occurs is termed saturation kinetics.
Metabolic conversion to active or inactive metabolites
Some drugs are active only after metabolic conversion; others are inactivated, usually by conjugation in the liver. Ideally, a drug assay should measure all the active forms, whether the parent compound or its active metabolite, and none of the inactive forms.
If a number of different drugs are being prescribed, one may affect the plasma concentration of another by altering its binding to plasma proteins, rate of metabolism or excretion. For example, sodium valproate displaces phenytoin from its protein-binding sites and reduces its rate of metabolism.
Some drugs (for example phenytoin) may induce the synthesis of enzymes that inactivate them, and
consequently higher doses than usual may be needed to produce the desired effect. In other cases, reduced receptor sensitivity may require higher doses than normal in order to increase the plasma concentration and to achieve the desired effect.