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Getting the right results with pharmacology

iming of tests and the influence of other drugs and illnesses are crucial considerations when monitoring blood drug concentrations. Only a few drugs yield to this investigation: the important ones are listed below.

Target range

Target range (often inaccurately referred to as the 'normal' or 'therapeutic' range) is the range of blood concentrations within which a therapeutic effect is likely to occur and toxic effects are likely to be minimal (see table). Some patients do well with blood concentrations above or below the target range, but it should be the aim in individualising therapy.

Unlike a biochemical reference range, target range can change. If the albumin binding of phenytoin falls, the target range also falls, and toxicity is more likely at concentrations in the high reaches of the usual target range.

When to measure

Individualising therapy

Measure blood concentration:

learly in therapy, when the relation between dosage and blood concentration in the patient is unknown; aim for a concentration in the target range

lafter a change in dosage

lwhen anything changes the relation between dosage and blood concentration or between concentration and effect (see table).

Suspected toxicity

A blood concentration above the target range reinforces a suspicion of toxicity. However, toxicity can occur even when plasma concentration is within the target range. Hypokalaemia sensitises the heart to the action of digoxin, and reduced albumin binding increases the amount of phenytoin available to the brain for a given blood concentration.

Measuring compliance

A drug detectable in the blood is evidence the patient has taken it ­ at least on the day of blood sampling.

Timing

If you measure blood concentration on a day when a steady state has not yet been reached (before about four half-lives of repeated administration) you will underestimate the eventual steady-state concentration. Measuring the concentration too soon after a reduction in dosage will result in an overestimation.

It is important to pick a blood sampling time in relation to the time of dosing (see table). After oral administration the blood concentration rises and falls before tissue distribution is complete. You can therefore be misled if you take a sample at the wrong time during a dosage interval. Patients should take digoxin and lithium late in the evening, so blood can conveniently be sampled the next morning.

Practical points on specific drugs

Phenytoin Plasma concentrations of phenytoin above the target range are quite well related to its acute toxic effects but not to its long-term adverse effects, such as gingival hyperplasia, hirsutism, acne, and folate and vitamin D deficiencies.

Steady state takes several weeks ­ about two weeks at low dosages and up to three weeks or longer at high. Do not change the dosage too often and restrict increments to 25-50mg. When the plasma phenytoin concentration is below 60µmol/l an 50mg increase in the daily dose is acceptable. If it is above 60µmol/l do not increase the daily dose by more than 25mg.

Phenytoin is highly bound to plasma albumin, and reduced albumin binding makes more phenytoin available to the brain for a given plasma concentration. This means the target range falls. Phenytoin plasma albumin binding is reduced in:

lrenal insufficiency, irrespective of albumin depletion

lsevere hypoalbuminaemia (25g/l or less)

lthird trimester of pregnancy (possibly because of hypoalbuminaemia)

ldisplacement by other drugs (eg, salicylates).

So, when you measure the plasma phenytoin concentration, also measure the plasma albumin and creatinine concentrations.

Digoxin During regular maintenance dosage (without a loading dose) steady state occurs after about seven days if renal function is normal or up to 18 days in renal insufficiency.

Factors that alter the link between the plasma concentration of digoxin and its effects make the concentration difficult to interpret.

 · Potassium depletion: hypokalaemia increases the pharmacological effect of a given concentration of digoxin by increasing its tissue binding. Measure the plasma potassium as well as plasma digoxin concentrations. If you suspect digoxin toxicity and there is hypokalaemia, withdraw digoxin on the assumption that toxicity has occurred.

 · Thyroid disease: hyperthyroidism reduces both the plasma digoxin concentration and its pharmacological action. Hypothyroidism does the reverse. There are no guidelines for interpreting plasma digoxin concentrations in thyroid disease.

 · Age: plasma digoxin concentrations are not easily interpreted in children under six months as they have reduced plasma concentrations of digoxin for a given dosage and are more resistant to its effects.

Lithium Serum concentrations of lithium above the target range are well related to its acute toxic effects but not to its long-term adverse effects, such as hypothyroidism.

It takes about three days for a steady state to be reached during regular maintenance therapy, but there is wide variability. In some patients it may take a week.

Serum lithium concentration monitoring is necessary because:

llithium is nephrotoxic and is excreted by the kidneys; toxicity causes renal damage,

further retention of lithium, and further toxicity

lsystemic availability varies from patient to patient, is altered by diarrhoea, and varies from formulation to formulation

lhyponatraemia (eg, in diarrhoea) alters renal lithium excretion.

Theophylline The time to steady state is usually less than a day, but the half-life varies among individuals; in some the time to steady state may be as long as two to three days.

Plasma concentrations of theophylline above the target range are quite well related to its acute toxic effects. Theophylline availability varies from formulation to formulation.

Ciclosporin Ciclosporin is generally measured in whole blood and the result of the assay depends on the measurement technique. Check the target range with your local laboratory. Time to steady state is about two days.

Risk of transplant rejection in the first six months increases when the blood ciclosporin concentration is below the target range, but after the first few months of therapy lower concentrations are compatible with maintained efficacy. Risks of adverse effects, such as nephrotoxicity and hepatotoxicity, are well related to concentrations above the target range.

Interpretation

Always interpret blood concentration in the light of the patient's clinical condition, never in isolation. Target range is a statistical concept based on observations in populations of patients; concentrations below the range's lower or above the upper ends can be associated with a therapeutic response.

If patients respond to treatment, but have a blood concentration below the target range, do not adjust the dose simply to engineer a concentration within target.

With digoxin, a plasma concentration below target range is an indication for withdrawing therapy if, say, the patient's atrial fibrillation is well controlled.

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