This chapter is concerned with how laboratory measurement of drug concentration in blood helps in determining correct drug dose. Such an approach is either unnecessary or unsuitable for most drug therapies, but for a limited number of drugs including lithium, digoxin and theophylline, measurement of serum or plasma concentration is the preferred method of optimising dosage and preventing dangerous side effects (toxicity). Measuring drug concentration also provides a means of confirming patient compliance. Other drug therapies, not discussed in this chapter, in which therapeutic drug monitoring is useful, include the anticonvulsant drugs ­carbamazepine, valproate and phenytoin; some drugs used to treat disturbances of cardiac rhythm (e.g. procainamide, quinidine) and a few antibiotics (e.g. ­gentamicin, vancomycin).

Lithium

Pharmacological action and clinical use

Lithium has proven neuroprotective properties but the precise mechanism of its therapeutic value in psychiatric medicine as a mood stabiliser still remains unclear, 50 years after it was first prescribed. Lithium use is largely confined to the ­treatment of bipolar disorder¹. This common long-term mental illness sometimes called ­manic-depression or affective disorder affects around 1.5–2% of the population and is ­characterised by cyclic episodes of severe depression followed by elation (mania). Normal mood is in the middle of a continuum, which runs from ­depression at one extreme to mania at the other. Depression is associated with a lack of energy, diminished interest and ability to experience pleasure, along with feelings of despair and pessimism. During the manic phase of bipolar disease however, symptoms are those of an abnormally expansive mood with increased mental and physical energy. Affected patients are hyperactive and have difficulty sleeping. Inflated self-esteem and false optimism are accompanied by flights of fancy and impulsive behaviour. In its most severe form, mania results in thinking that can race so fast that it becomes fragmented. Speech is fast and may be incoherent. Psychotic symptoms, including hallucination, grandiose delusion and illusion, may be a feature of severe acute mania.

Lithium is an anti-manic drug. Although used to treat acute mania and its less severe form, hypomania, among patients presenting with symptoms, the most important use of lithium is to prevent both manic and depressive episodes in patients with bipolar disorder; the result is a marked reduction in mood swings. Patients may need to take lithium for many years in order to remain well. Unfortunately, for unknown reasons, some patients with bipolar disease do not respond to lithium therapy. Lithium may also be used in conjunction with anti-depressant drugs to treat severe depression not associated with bipolar disease (unipolar depression) that does not respond to anti-depressant drugs alone.

Adverse side effects

All drugs have unwanted side effects and lithium is no exception. Lithium can affect kidney function, causing a condition known as nephrogenic diabetes insipidus, which is characterised by increased urine flow (polyuria) and resulting increased thirst (polydipsia). The thyroid gland of patients on long-term lithium therapy may become under active, with resulting symptoms of hypothyroidism (Chapter 10). This may contribute to the weight gain that is often associated with lithium use. Patients on long-term lithium therapy should have regular (six monthly) thyroid function tests, and serum creatinine estimation to assess renal function. Special caution should be taken in prescribing lithium during pregnancy, as there is increased risk of congenital malformation of the developing foetus associated with lithium use, particularly during the first three months of pregnancy. Lithium is eliminated from the body almost entirely by the kidneys in urine. For this reason the potential for lithium toxicity is greater in older patients, whose renal function is reduced, and patients with kidney disease. To avoid adverse effects, such patients may need a lower dose of lithium than those with normally functioning kidneys.

Why and when to measure serum lithium

The lithium dose required for treatment or prevention of manic symptoms (called the therapeutic dose) is very close to that which results in toxicity. In common with all three drugs discussed in this chapter, lithium is said to have a low ‘therapeutic index’ or narrow ‘therapeutic window’. Fortunately there is a well-defined therapeutic range for serum lithium, providing a means of checking that sufficient drug is being administered for maximum therapeutic effect, consistent with minimum risk of toxic side effects. Serum lithium is checked initially after five to seven days on initial prescription dose. If serum concentration is below the therapeutic range, dose is increased, and if higher than therapeutic range, dose is decreased. Once a safe and effective maintenance dose has been established, serum lithium should be checked every week for four weeks and then every three months. Urgent blood testing is however necessary if any signs or symptoms of toxicity arise and in cases of deliberate overdose (parasuicide).

Patients suffering bipolar disease may be reluctant to take their lithium regularly once initial symptoms of mania have subsided; they may falsely believe that they do not require lithium, and stop taking tablets without consultation with their doctor. Measuring serum lithium provides a means of confirming that patients are continuing with their medication.

Digoxin

Principle pharmacological action and clinical use

Digoxin, which is derived from digitalis, a compound extracted from the leaves of the foxglove plant (digitalis lanata) is used in the treatment of heart disease. Digoxin inhibits the enzyme (ATPase) required for action of the sodium-potassium pump, present in the membrane of all cells, which maintains the distribution of sodium and potassium between cells and surrounding extracellular fluid (Chapter 3). The net effect of reduced sodium-potassium pump activity (and therefore digoxin administration) is an increase in sodium and calcium concentration within cells and a decrease in concentration of cellular potassium. It is the increase in calcium concentration within the muscle cells of the heart that accounts for the positive inotropic (increased force of cardiac muscle cell contraction) effects of digoxin. Apart from its positive inotropic effects, digoxin also indirectly affects (via vagal stimulation) the pacemaker cells of the sino-atrial (SA) and atrio-ventricular (AV) nodes in the heart that propagate electrical signals necessary for normal heart rate and rhythm.

For many years digoxin – in combination with diuretics – was the mainstay drug prescribed for all patients with chronic heart failure, a common condition among the elderly that is discussed in Chapter 9. With the introduction of a more effective drug regime (ACE inhibitors and β-blockers plus diuretic), digoxin is now used more selectively. It is used for that sub-set of patients, around a third, whose heart failure is complicated by co-exisiting atrial fibrillation, the most common cardiac arrhythmia. Digoxin is also used for heart failure patients whose symptoms are worsening or not improving despite optimal dose of ACE inhibitor, β-blocker and diuretic. In patients without heart failure, digoxin use is confined to those with atrial fibrillation.

Toxic (unwanted) side effects

Symptoms of digoxin toxicity include nausea, vomiting, diarrhoea and loss of appetite. Abnormal cardiac rhythms, which may result in either slowing of the heart rate (bradycardia) or increased heart rate (tachycardia), are common; in severe overdose these may be life threatening. Disturbances of normal vision, including blurring of vision and loss of ability to distinguish some colour combinations, may occur. Mental effects include confusion and restlessness; rarely digoxin toxicity can precipitate acute psychoses. The primary effect of digoxin on the sodium-potassium pump determines that digoxin toxicity may be accompanied by raised serum potassium.

Most digoxin is normally eliminated from the body unchanged, by the kidneys, in urine. Patients with diminished kidney function (the elderly and those with renal disease) cannot eliminate digoxin as efficiently as those with normal kidney function and are therefore at greater risk of digoxin toxicity. Abnormally low concentration of serum potassium (hypokalaemia), often the result of diuretic therapy, potentiates digoxin toxicity. A low serum magnesium and raised serum calcium has a similar effect.

Why and when measure serum digoxin

Routine monitoring of serum digoxin levels for all patients receiving digoxin is not considered necessary. However the test is useful in certain clinical situations. Like lithium, digoxin has a low therapeutic index. The serum level required for therapeutic effect is close to that which results in toxic symptoms so that digoxin toxicity is relatively common. Unfortunately many of the signs and symptoms of mild to moderate toxicity are non-specific and may even be due to the underlying disease, which digoxin is being used to treat. The only sure way of making or excluding the diagnosis of digoxin toxicity is to measure serum digoxin concentration. A request for blood digoxin level may be made following a poor clinical response to a ­standard digoxin dose. If the result is below the therapeutic range an increased dose may be safely prescribed. Finally the test can be used to assess patient compliance.

Theophylline

Principle pharmacological action and clinical use

Theophylline is a naturally occurring substance related to caffeine, which is found in the leaves of the tea plant. Although the mechanism of its action is poorly understood, theophylline has three important pharmacological effects: stimulation of cardiac muscle, relaxation of smooth muscle (notably respiratory muscles) and stimulation of the central nervous system. It also has anti-inflammatory effect. The principal clinical use of theophylline, which is derived from its effect on smooth muscle in the lung, is as a bronchodilator and anti-inflammatory agent in the ­treatment of asthma and chronic obstructive pulmonary disease (COPD).

Asthma is a very common condition of the lungs that affects close to 10% of all children and adults in the UK. It is characterised by episodic attacks of airway constriction. Between attacks patients are usually quite well but during attacks, which may be triggered by any number of factors including respiratory infection, environmental irritants (chemical fumes, smoke etc), exercise and even in some cases laughter, the bronchial airways constrict, become inflamed and produce abnormal amounts of mucus. These result in the common symptoms associated with an asthma attack: cough, wheeze and increased breathlessness. In its most severe manifestation, an asthma attack can cause respiratory failure in which normal gas exchange of oxygen and carbon dioxide is sufficiently compromised to threaten life. Although prompt hospital admission and treatment can be life saving, asthma is the cause of around 1000 premature deaths each year in the UK.

Theophylline may be given orally as part of the ongoing drug treatment of chronic asthma to prevent attacks, and is also administered intravenously in the form of aminophylline (a salt of theophylline) for the emergency treatment of acute asthma attacks. Theophylline acts directly to relax the smooth muscles of the bronchi effectively dilating or ‘opening’ the airway. The bronchodilator effect of theophylline is more pronounced if the airway is already constricted, as it is in patients with asthma.

Apart from asthma theophylline is also used in the treatment of chronic ­obstructive pulmonary disease. A quite separate property of theophylline, the ability to stimulate the respiratory centres in the central nervous system, is thought to be the reason for its effectiveness in the treatment of apnoea of prematurity. Affected premature babies suddenly stop breathing for 20 seconds or more, threatening brain function with risk of permanent brain damage. Both the frequency and duration of these so-called apnoea attacks are reduced with theophylline treatment.

Toxic (unwanted) side effects

Many patients experience minor adverse effects of theophylline therapy, and for this reason the drug is usually only prescribed for the prevention of asthma attacks, after other anti-asthma drugs have failed. Nausea, vomiting and loss of appetite are the most common signs of mild toxicity. Headache, insomnia, nervousness and increased irritability reflect the effect of theophylline on the central nervous system (CNS). Whilst many patients may experience both gastrointestinal and CNS effects when they first take theophylline, a tolerance is usually acquired and symptoms disappear. Theophylline is a gastrointestinal irritant that can reactivate peptic ulcers. In ­addition to the gastrointestinal and CNS symptoms, marked toxicity may result in palpitations, increased heart rate and abnormal heart rhythms (usually sinus tachychardia). Cardiac arrest can occur in patients given a single large dose of theophylline (­aminophylline) to control an acute asthma attack. Convulsions and loss of consciousness can occur during marked toxicity. Although rare, severe toxicity can be fatal.

Certain diseases (e.g. liver disease, chronic heart failure and any condition associated with persistent fever) cause a decrease in the rate that theophylline can be eliminated from the body and a consequent increase in serum theophylline to a concentration normally associated with toxic symptoms. Asthmatic patients with these additional problems require a lower dose than normal and careful monitoring if they are to avoid the effects of theophylline toxicity. Conversely smokers ­eliminate theophylline more efficiently than non-smokers so require a higher dose to achieve the same therapeutic effect. Toxicity may arise after quitting smoking if dose is not reduced. Many drugs, including alcohol and some antibiotics, reduce theophylline elimination, thereby increasing toxicity at a given dosage. A full drug history must be taken into account when prescribing theophylline.

Why and when to measure serum theophylline

Theophylline has a low therapeutic index: the serum concentration required for ­therapeutic effect is close to that which results in toxic symptoms. Although the serum level for therapeutic effect has been established, the dose required to attain this therapeutic level varies, so that all patients should have their serum concentration checked during initiation of therapy. Typically dose is increased in small ­increments until serum concentration is within the therapeutic range. Once an ­effective and safe dosing regime has been established, serum concentration need only be checked at six monthly or yearly intervals. More frequent monitoring may be considered in the ­following types of patients whose ability to eliminate theophylline might be ­diminishing. All these patient types have an increased risk of theophylline toxicity:

• Elderly patients.
  
• Patients with concurrent liver disease (cirrhosis, hepatitis).
  
• Patients with concurrent congestive heart failure.
  
• Acutely ill patients (e.g. those receiving intensive care).
  
• Those patients being prescribed some additional drugs.

All patients presenting with signs of toxicity should have serum concentration checked to decide whether a reduction in dose or even temporary withdrawal of the drug is warranted.

Patients who seem to be failing to respond to theophylline might require a larger dose. If serum concentration is below the therapeutic range an increase in dose may be warranted.

Laboratory measurement of serum lithium, digoxin or theophylline

Patient preparation

No particular patient preparation is necessary.

Sample requirements

Around 5 ml of venous blood is required. This should be collected into a plain glass (without additives) tube.

Timing of sample

The concentration of any drug in blood varies in relation to the time of the last dose, so that timing of sample collection is vital for accurate interpretation of routine therapeutic drug monitoring results.

• Blood for lithium should be sampled at 12 hours after the last dose.
  
• Blood for digoxin should be sampled at six hours after the last dose
  
• Blood for theophylline should be sampled at one to two hours after the last dose.

If a patient is exhibiting signs of toxicity or a deliberate overdose is suspected, an urgent test result may be required. In these circumstances it is clearly not appropriate to wait before sampling blood, but it is important to record the time that the sample was taken and the time of the last dose or overdose, if known.

Interpretation of results

Serum lithium

Therapeutic range for those with symptoms of acute mania – 0.8–1.5 mmol/L.

Therapeutic range for maintenance dose to prevent symptoms – 0.5–1.0 mmol/L.

The objective is to maintain serum concentration within the therapeutic range. Patients actually suffering symptoms of acute mania can tolerate slightly higher doses of lithium than those without symptoms; hence the different therapeutic ranges. Once acute symptoms have passed and the patient is stabilised, a maintenance dose must be prescribed which results in a serum concentration within the lower therapeutic range.

Symptoms of mild toxicity (vomiting, diarrhoea, nausea and coarse tremor) ­usually arise as serum concentration rises above 1.5 mmol/L, although a minority of patients may experience these symptoms of lithium toxicity when serum concentration is less than 1.5 mmol/L. More symptoms including confusion, dizziness, tinnitus, irregular heart rate and blurred vision are associated with serum levels above 2.0 mmol/L. Loss of consciousness and fatality can occur in severe overdose (serum lithium >2.5 mmol/L) if treatment to eliminate lithium is not urgently initiated.

Serum digoxin

Therapeutic range – 0.8–2.0 µg/L (1.0–2.6 nmol/L).

Symptoms of toxicity are usually associated with serum digoxin concentration greater than 2.3 µg/L (3.0 nmol/L). However some patients (e.g. those with hypokalaemia, hypomagnesaemia, hypercalcaemia and thyroid disease) have increased sensitivity to the effects of digoxin and symptoms of toxicity might be present at concentration below 2.3 µg/L, and may even occur at concentration within the therapeutic range. So long as causes of increased sensitivity can be excluded, then serum digoxin level within the therapeutic range indicates that any symptoms suggestive of digoxin toxicity are unlikely to be due to digoxin; another cause must be sought and there is no real justification for reducing dose. Conversely the finding of a serum digoxin concentration below the therapeutic range in a patient who is not responding clinically as expected provides objective evidence that the patient is not receiving a sufficiently high dose.

Serum theophylline

Therapeutic range for asthma/COPD treatment – 10–20 mg/L (55–110 µmol/L).

Therapeutic range for apnoea of prematurity – 8–20 mg/L (28–44 µmol/L).

The objective is to maintain serum concentration within the therapeutic range. A serum concentration below the therapeutic range indicates current dose is unlikely to be effective and a serum concentration above the therapeutic range results in unwanted side effects (toxicity). Mild to moderate toxicity is associated with serum concentration in the range (i.e. 20–30 mg/L). Severe toxicity with seizures and life-threatening cardiac arrhythmias do not usually occur until serum concentration is in excess of 165 mmol/L (i.e. 30 mg/L).

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