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| Journal of the New Zealand Medical Association,
12-December-2003, Vol 116 No 1187
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The practice of digoxin therapeutic drug monitoring
Murray Barclay and Evan Begg
Digoxin continues to have an important role in the control
of ventricular rate with atrial fibrillation, and as a positive inotropic agent
in heart failure. Therapeutic drug monitoring (TDM) for digoxin was introduced
more than 30 years ago, and resulted in a marked reduction in the incidence of
digoxin toxicity. However, despite a long experience of TDM with this drug, the
way in which TDM is performed is often inappropriate, as highlighted in the
article by Sidwell et al in this
issue.1
In publications from other countries in the past 15 years,
similar conclusions have been drawn, and show that inappropriate use of TDM with
digoxin is quite common and not restricted to New Zealand. There is often no
clear indication for monitoring,2,3 the sample
is taken at the wrong time resulting in a falsely high or low
concentration,3–5 or an inappropriate
clinical action or inaction is taken after the result is
received.2,3 These problems most likely relate
to a lack of knowledge about the practice of digoxin TDM, in particular amongst
the junior doctors who are most likely to request digoxin concentration
measurement. In this editorial we review the most relevant aspects of the
practice of TDM for digoxin, and specifically the indications for monitoring,
timing of blood samples and interpretation of the results.
Indications for digoxin concentration measurement (Table 1)Confirmation
of toxicity The need to measure digoxin concentrations for confirmation
of toxicity is related to the low therapeutic index of digoxin. The recommended
therapeutic range (1.0 to 2.5 nmol/l) reflects the significant increase in risk
of toxicity that occurs with serum concentrations over 2.6 nmol/l, and which is
almost invariable once the concentration exceeds 3.8
nmol/l.6 Symptoms of toxicity
include nausea, vomiting, diarrhoea,
abdominal pain, confusion, dizziness, agitation, arrhythmias, heart block and
various visual symptoms. Toxicity is generally a clinical diagnosis supported by
an elevated digoxin concentration.
It is also apparent that clinical suspicion of toxicity
correlates poorly with high concentrations. In the study by Sidwell et al, in
those requests in which the indication for TDM was confirmation of toxicity,
only 19% were associated with a high digoxin
concentration.1 This result is not necessarily
surprising given that many of the symptoms of digoxin toxicity are non-specific
and are frequently present in acutely ill patients in general.
Table 1. Indications for therapeutic drug
monitoring
Assessing the effect of
factors altering the pharmacokinetics of digoxin A number of different
factors influence the pharmacokinetics of digoxin in an individual, but renal
function is by far the major contributor. Maintenance dose estimation based on
calculation of the patient’s creatinine clearance, using a formula such as
the Cockcroft and Gault equation, will usually result in an appropriate dose in
most patients. However, renal function alone does not explain all the variance
in serum digoxin concentrations. A computer programme that included renal
function as a variable to predict an appropriate digoxin dose for individual
patients performed only marginally better than physician
attempts.7
Some of the unpredictable relationship between dose and serum
concentration of digoxin may be explained by genetic polymorphism of the
p-glycoprotein gene. P-glycoprotein is involved in the transport of digoxin into
the body in the gastrointestinal tract, and out of the body in the renal
tubules. Mutations within this gene have been shown to alter the bioavailability
and renal clearance of digoxin.8 Drug
interactions (Table 2) also affect serum concentrations of digoxin, usually
through competitive inhibition of p-glycoprotein activity. Because sources of
variability other than renal function are less predictable or measurable,
adjusting an individual’s maintenance dose on the basis of their
creatinine clearance remains the best starting point for dose
individualisation.
Table 2. Drug interactions for digoxin
Therapeutic failure
Digoxin TDM is also considered to be indicated in situations of apparent
therapeutic failure, although the validity of the therapeutic range in terms of
efficacy is unclear. In terms of improving rate control in chronic atrial
fibrillation, a review of the literature found only a weak correlation between
digoxin concentration and ventricular rate.9
This is not surprising given the number of other influences on the
atrio-ventricular node, such as altered sympathetic drive with other
comorbidities (eg, sepsis, hypoxia). However, TDM for individual patients may be
useful to detect patients with a low digoxin concentration and who may benefit
from an increase in digoxin dose, as opposed to those with higher concentrations
who are likely to develop toxicity symptoms only from an increase in
dose.
In congestive cardiac failure there is increasing evidence
that concentrations lower than the currently recommended limit of the
therapeutic range (<1.0 nmol/l) may be as efficacious as higher
concentrations. Results from the PROVED and RADIANCE trials, and their
subsequent re-analysis,10 suggest that digoxin
concentrations between 0.6 and 1.2 nmol/l may be as efficacious, and less
pro-arrythmic, than higher concentrations in patients with heart failure. These
trials suggest that for heart failure at least, the lower end of the therapeutic
range could be lowered to 0.6 nmol/l.
Appropriate sampling timeDigoxin concentrations should be
measured at least eight hours following an oral dose of digoxin and ideally when
concentrations have reached steady-state. Understanding of the reasons behind
these recommendations requires an understanding of the pharmacokinetic profile
of digoxin. Digoxin is well absorbed, with peak serum concentrations occurring
within one hour. A large volume of distribution (4–7 l/kg) reflects that
digoxin concentrates in the tissues, with the active site being within
myocardial and other cells. Redistribution from serum to tissue takes at least
eight hours (Figure 1). Samples taken within eight hours of a dose will falsely
imply elevated tissue concentrations, and inappropriate dose reduction may
result. Our department has been consulted in a number of dramatic cases where an
apparently very high digoxin concentration was an artifact of early
sampling.
Figure 1. Digoxin concentration profile following an
oral dose
 Digoxin elimination is predominantly renal in nature (the
fraction excreted unchanged in the urine is 0.6 to 0.9) and is dependent upon
glomerular filtration and p-glycoprotein-mediated active tubular secretion. A
long half-life of at least 30 h (in normal renal function) results in
steady-state concentrations taking at least five days to be achieved (it takes
four half-lives to achieve >90% of steady-state concentrations). In the
elderly and in patients with renal impairment, elimination is diminished and the
half-life prolonged. In these cases, steady-state may take several weeks to
achieve. Measurement of concentrations before steady-state is reached results in
a falsely low estimate of the steady-state concentration, and inappropriate dose
increases may result.
Dose adjustmentSerum digoxin concentrations should
be interpreted within the clinical context. It is generally accepted that when
the concentration is above the therapeutic range, the dose should be reduced
even in the absence of obvious toxicity. This is because the patient is at risk
of arrhythmia and there is probably no additional efficacy associated with a
high concentration. On the other hand, toxicity can occur with concentrations
within the therapeutic range. This may result from several known factors (Table
3) that change tissue sensitivity to digoxin and alter the therapeutic
index.
Table 3. Factors altering digoxin sensitivity and the
likelihood of toxicity
The period of time that digoxin should be withheld following
an episode of toxicity depends upon how high the concentration is, and the
half-life of digoxin in that patient. In a patient with normal renal function
(half-life approximately 30 h) and a concentration of 3.0 nmol/l, the digoxin
should be withheld for 1–2 days before restarting at the appropriately
altered dose, as this will allow the concentration to drop to within the
therapeutic range. In renal impairment with a prolonged digoxin half-life, doses
may need to be withheld for several days.
When the measured digoxin concentration is low, options
include stopping treatment, increasing the dose or making no change. If the
indication for therapy is rate control, and the current ventricular rate is
appropriate in the presence of low digoxin concentrations, a trial without
digoxin may be appropriate. If ventricular rate is not controlled, a dose
increase is usually indicated. However, poor rate control may be related to
other acute illness processes, and treatment of the underlying condition may be
all that is required. If the concentration is above 0.6 nmol/l and the
indication is heart failure that is now controlled, the dose may not need to be
adjusted for reasons already discussed.
Dose adjustment for apparent therapeutic failure should
ideally only be performed following a digoxin concentration measured at
steady-state. A change in dose will normally result in a proportional change in
digoxin concentration, eg, doubling the dose will double the digoxin
concentration, and halving the dose will halve the concentration (assuming
stable renal function and no new drug interactions). In situations where there
is changing renal function, the adjustment can be estimated by calculating the
change in creatine clearance using the Cockcroft and Gault
formula.11 For example, a halving of the
patient’s renal function from baseline means that only half of the initial
maintenance dose will be required to maintain the same steady-state
concentration.
Digoxin remains a classical drug for which therapeutic drug
monitoring may be useful. It has a narrow therapeutic index, complex
pharmacokinetics, and a dose-response relationship, at least for toxicity.
However, therapeutic drug monitoring is only useful if performed correctly.
Particular attention needs to be paid to the timing of sampling with respect to
dosing, the presence or otherwise of steady-state conditions, and the half-life
and its consequences for dosing in the individual patient.
Author information:
Murray L Barclay, Clinical Pharmacologist; Evan J Begg, Clinical Pharmacologist,
Department of Clinical Pharmacology, Christchurch Hospital,
Christchurch
Correspondence: Dr
Murray Barclay, Department of Clinical Pharmacology, Christchurch Hospital,
Private Bag 4710, Christchurch. Fax: (03) 364 1003; email: MurrayB@cdhb.govt.nz
References:
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