Digoxin monitoring and toxicity

management
Digoxin is used to treat a variety of cardiovascular conditions; its
toxicity can cause significant morbidity and mortality if not
recognised early enough. This article provides an overview of the
initiation of digoxin and toxicity management.
Cardiovascular diseases

An electrocardiogram showing bradycardia, which can be

caused by digoxin overdose
After reading this article, you should be able to:
 Understand the mechanism of action and indications for
digoxin;
 Understand common interactions with the use of digoxin;
 Recognise when monitoring of digoxin is indicated;
 Understand the management of digoxin toxicity.
Digoxin is a chemical derived from the plant Digitalis purpurea, more
commonly known as foxglove, and belongs to the class of medicines known
as cardiac glycosides[1]. Digoxin is used to treat a variety of cardiovascular
conditions and provides inotropic activity (i.e. alters the force or energy of
the heart muscle’s contractions) in the management of heart failure, and
negative chronotropic effect (i.e. slows the heart rate) in treating abnormal
heart rhythms, such as atrial flutter and atrial fibrillation[2].

Around 3 million prescriptions are generated for digoxin in England each

year and around 1% of patients will develop toxicity — a risk that increases
with age[3,4]. The use of digoxin in the treatment of heart failure has
declined in recent years owing to findings from observational studies
showing safety concerns linked with increased mortality rates with its use
[2,5,6]. However, the DIG trial — the largest randomised controlled trial of
digoxin in patients with heart failure (n= 3,397) — showed digoxin did not
reduce overall mortality, but reduced the rate of hospitalisation both
overall and for worsening heart failure. These findings more precisely
define the role of digoxin in the management of chronic heart failure[2].

Digoxin toxicity is often accidental and occurs because of inappropriate

dosing, lack of appropriate serum digoxin monitoring, and lack of
recognition of signs/symptoms of digoxin toxicity by both the patient and
healthcare professionals[7]. Pharmacists therefore need to be aware of
digoxin use and signs/symptoms of toxicity when treating patients with
cardiovascular conditions.

Mechanism of action

The main action of digoxin is the inhibition of the sodium–potassium

(Na+ K+) pump by inhibiting the Na+ K+-ATPase enzyme present in the
membrane of cardiac cells (see Figure)[1–3]. Owing to the interplay
between these electrolytes, there may be a considerable increase in
potency when the extracellular potassium concentration is low, as opposed
to hyperkalaemia having the opposite effect[1–3].

Digoxin has a direct action on conduction through increased vagal tone,

resulting in reduced sympathetic tone and diminished impulse conduction
rate through the atria and atrioventricular (AV) node; therefore, the major
effect of digoxin is reduction of ventricular rate[1–3].

Digoxin exhibits its toxic effects by poisoning the Na/K ATPase pathway
that results in an increase in intracellular sodium, leading to increased
intracellular calcium through decreasing calcium expulsion within the
sodium–calcium cation exchanger[7,8].

Figure 1: Mechanism of action of digoxin

Inhibiting the Na/K ATPase enzyme results in a reduction of intracellular
potassium, increase in intracellular sodium and a corresponding
augmented calcium ion influx and thus an increase in the availability of
calcium at the time of excitation-contraction coupling

Initiation

Patients with atrial fibrillation and flutter are usually given higher doses of
digoxin to rapidly control heart rhythm followed by lower maintenance
doses (see Table 1)[3,4]. The primary effect of digoxin is to slow down AV
conduction, leading to a reduction in ventricular response. Patients with
heart failure who are maximised on prognostic therapies (e.g. beta
blockers, angiotensin-converting enzyme inhibitors) and remain
symptomatic with reduced ejection fraction may have digoxin added. In
heart failure, digoxin slows AV conduction to allow for increased
ventricular filling time and to strengthen the force of ventricular
contraction.

Administration of intravenous digoxin produces pharmacological effects

within 5–30 minutes, while oral administration produces an onset of effect
within 30 minutes to 2 hours[1–3].

Dose reduction is managed based on patients’ renal function, interacting

medicines either started or stopped, digoxin serum levels if available or
lack of response. Lower doses are then restarted and titrated based on
therapeutic action.

Monitoring
Digoxin has a narrow therapeutic window, meaning there is a small margin
between the benefit of its effects and toxicity; therefore, monitoring is an
important part of its use. Testing serum digoxin levels can indicate whether
patients are compliant, as very low levels of serum digoxin could indicate
that patients are not taking digoxin as prescribed.

Serum digoxin levels should be measured in newly initiated patients after

seven days, as this is normally when steady state is reached. Monitoring of
serum digoxin is usually carried out after any dose changes, suspected
signs and symptoms of toxicity, or changes in therapy (i.e. concomitant
therapy, such as the antiarrhythmic drugs amiodarone and verapamil,
which can interact with digoxin therapy and affect plasma concentration of
digoxin)[9]. Routine monitoring is not usually recommended in patients
who are therapeutically stable and there is no evidence from randomised
controlled trials to suggest routine monitoring provides better outcomes
for patients[10].

Monitoring is usually indicated in patients with poor renal function, and

very unwell patients (e.g. those with an acute infection, who are older or
have comorbidities) with electrolyte disturbances or suspected overdose
[9].

If toxicity is suspected, serum digoxin radioimmunoassay can be performed

to assess digoxin levels in the blood. Blood should be taken 6 hours or more
after the last dose of digoxin was administered, but ideally 8–12 hours
afterwards[10]. This is usually how long it takes to achieve equilibrium of
serum concentration with the myocardium and plasma to exert digoxin’s
effects[7]. Most data suggest that typical digoxin serum ranges from 0.7
nanograms/mL to 2.0nanograms/mL depending on the indication as this
balances the beneficial effects of the drug with lower risk of toxic
symptoms[10]. Above this range there is an increased risk of developing
signs and symptoms likely of digoxin toxicity[10].

Side effects

Patients reporting side effects should be carefully assessed and referred for
further investigations when required. This would involve taking a thorough
 clinical history and, where possible, a blood test to check urea, electrolytes
and serum digoxin levels. Patients may present to local community
pharmacies with symptoms (see below); when digoxin toxicity is
suspected, patients should be referred to A&E. This is especially important
in older people, owing to the likelihood of additional comorbidities, such
as chronic obstructive pulmonary disease, increasing the risk of toxicity
and making management more difficult[8–10].

The following symptoms could suggest toxicity and patients should be

promptly referred for further assessment:

 Visual disturbances (e.g. blurred vision, changes in how colours look, seeing
spots);
 Confusion;
 Nausea, vomiting and diarrhoea;
 Tachycardia;
 Fatigue and weakness[3,4].
The summary of product characteristics should be consulted for a full list of
side effects reported with the administration of digoxin[8].

General features reported with digoxin toxicity (e.g. nausea, vomiting,

diarrhoea, and general malaise) can develop within 1–2 hours of acute
overdose[7,11]. The cardiac adverse effects may take more than 12 hours
to fully develop[8,11].
Onset of toxicity from chronic therapy can be variable but is often preceded
by dehydration from other causes/drug interactions[7,11]. Serum digoxin
concentrations less than 1.5 nanograms/mL in the absence of
hypokalaemia usually indicate that digoxin toxicity is very unlikely[7].
Serum digoxin concentrations greater than 3 nanograms/mL is suggestive
of toxicity[7,11].

Contraindications

In the management of rate control in atrial fibrillation, there are several

agents that should be used first line, prior to digoxin, depending on
 individual patient clinical needs. These agents commonly include beta
blockers and calcium channel blockers. Digoxin is added only if adequate
rate control is not achieved[12].

As digoxin can affect heart rate and force of contraction, it is

contraindicated in patients with abnormal rhythms, such as intermittent
complete heart block or second-degree AV block, and supraventricular
arrythmias (e.g. Wolff-Parkinson-White syndrome)[8].

Digoxin is contraindicated for use in patients with known hypertrophic

obstructive cardiomyopathy owing to its effect on the force of contraction
and heart rate. Hypersensitivity to the active substance, other digitalis
glycosides or any excipients used to formulate the drug are also
contraindications for its use[8].

Interactions

There are several food and drug interactions that can lead to changes in
digoxin serum concentrations. Patients taking medicines that interact with
digoxin should have doses adjusted according to response and levels
monitored to ensure appropriate dose adjustments are made.

Some common medicines that interfere with digoxin are:

1. Aminoglycosides (e.g. amikacin, gentamicin), which can increase the

serum digoxin level owing to their effect on renal function;
2. Antiarrhythmics (e.g. amiodarone and verapamil). Amiodarone can
double the serum concentration of digoxin, and synergistic effects on heart
rate and AV node conduction can occur. Verapamil can increase serum
digoxin levels. It is recommended to reduce the dose of digoxin by 30–50%
and closely monitor serum digoxin levels to determine effects;
3. Macrolides (e.g. azithromycin, clarithromycin and erythromycin) have
been reported to increase serum digoxin levels. Patients should be
monitored for signs/symptoms of digoxin toxicity;
4. Rifampicin reduces digoxin levels by up to 80%. Patients should be
monitored closely for under digitalisation and serum digoxin levels should
be monitored with dose adjustments as appropriate[8,11,13].
A detailed list of all the interactions and their mechanisms can be found
on MedicinesComplete[11].

Large quantities of fibre have been shown to reduce digoxin bioavailability

by around 20%. Patients should be advised to eat small amounts of fibre-
rich meals while taking digoxin or to consider alternate timing when taking
the medicine[8,11].

Management of digoxin toxicity

Toxicity can be more severe in patients who are taking cardiotoxic

substances (e.g. beta blockers and rate-limiting calcium channel blockers)
[7,13]. The extent of severity can be made worse owing to poor renal
function and increasing age. Prompt treatment of digoxin toxicity is vital;
death can occur because of complications such as ventricular arrhythmias,
conduction impairment or heart failure[7,11].

All patients presenting with suspected digoxin toxicity should have a 12-
lead echocardiogram (ECG) performed. Overdose usually causes a marked
bradycardia with ECG changes, such as PR and QRS prolongation
(representing atrial and ventricular depolarisation respectively), see Figure
2[14]. Sinus arrest, varying degrees of AV with dissociation or escape
rhythms may occur, including paroxysmal atrial tachycardia with AV block,
junctional tachycardia, frequent ventricular ectopics and bigeminy
(alternation between a regular heartbeat and an extra, skipped heartbeat)
[8,11,15]. In serious cases of toxicity, ventricular tachycardia and
ventricular fibrillation may occur. Adverse arrythmias are most common in
patients if there is pre-existing heart disease or in electrolyte disturbances,
such as hypokalaemia[8,11,15].
 Figure 2: Heart excitation and representing atrial depolarisation and
ventricular depolarisation as observed during digoxin toxicity (adapted
from Safa et al.)
Discussion with intensivists is required for patients who are symptomatic
and/or have an abnormal ECG. Rapid fluid resuscitation may be required in
patients with hypovolaemia (i.e. decreased blood volume), being cautious
in those with a history of left ventricular dysfunction. Hypovolaemia caused
by dehydration can be a result of persistent nausea, vomiting and
diarrhoea, and a result of excessive diuresis in patients with heart failure
[10]. Where appropriate, fluid resuscitation will aid in reducing plasma
digoxin concentrations. A blood sample should be obtained from the
patient to assess digoxin concentration in view of suspected toxicity[10].

The information in the Box can support pharmacists to make informed

decisions when managing patients taking digoxin and assessing whether
toxicity is suspected.
Box: Warning signs of digoxin toxicity

 Presence of any of the previously outlined symptoms (visual

disturbance, e.g. green/yellow tinge, nausea/vomiting-
associated, confusion/disorientation);
 Heart rate: is the heart rate <60 beats per minute? Measure to
assess and make a clinical decision to refer for further medical
input;
 Concomitant medicines taken by the patient that can alter the
heart rate or serum potassium levels (e.g. amikacin,
gentamicin, amiodarone and verapamil);
 Assess and check serum potassium levels where possible. Has
the patient had a recent blood test? What serum potassium
level was reported?[8]
Management of digoxin toxicity usually involves correction of electrolytes,
such as in hyperkalaemia. Severe cases will require insulin and dextrose for
the management of hyperkalaemia. Local policies may vary, but an example
would be to administer 10 units of short acting insulin with 100mL of 20%
dextrose intravenously over 5 minutes. If hyperkalaemia is not improving,
these doses can be repeated as clinically indicated[8]. To stabilise the
cardiac membrane excitability, slow, intravenous injection of 10mL of 10%
calcium chloride (6.8mmol) with continuous cardiac monitoring is
required. Alternatively, 10mL of 10% calcium gluconate (2.3mmol) can be
administered by slow intravenous injection. The dose can be repeated in 5–
10 minutes if there are no improvements in the ECG up to a maximum of
30mL (6.8mmol)[8].

If the patient is found to have toxic levels of digoxin (>3 nanograms/mL),

digoxin-specific antibody FAB fragments (DigiFab; Veriton Pharma
Limited) can be administered as an intravenous bolus dose (see Table 2)
[16]. DigiFab can also be used when patients present with poisoning from
digoxin associated with severe bradyarrythmia or severe hyperkalaemia
(e.g. serum potassium levels greater than 6.5mmol/L), which is resistant to
adequate rehydration and conventional treatments[16]. DigiFab rapidly
reduces serum-free digoxin to undetectable levels within 30 minutes[17].
Serum samples for digoxin concentration should be obtained before
DigiFab administration. The above are administered in view of digoxin
causing a shift of potassium from the inside to the outside of the cell[16].
When the toxic effects of digoxin are reversed by DigiFab, potassium shifts
back into the cell, resulting in a decline in serum potassium concentration.
Therefore, serum potassium concentration should be monitored closely,
especially during the first few hours after DigiFab administration[16].
 Each vial should be reconstituted with 4mL of sterile water by gentle
mixing prior to administration[16].

The incidence of digoxin toxicity can be reduced through appropriate

patient education and counselling. Pharmacists should ensure that patients
understand and are counselled on the following:

 The correct dose and regimen of digoxin that should be taken — this can be
achieved by providing patients with instruction sheets or including digoxin
as part of dosette boxes to prevent overdosage/dose omissions.
Community pharmacists can assess this through active and regular
medicines use reviews;
 Recognising the potential side effects;
 The signs of toxicity and what action should be taken in the event of
suspected toxicity. Patients may report their suspected toxicity to their
local community pharmacy or GP for further information/review and, in
severe cases, should be educated to attend their nearest A&E department.