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Key points
- Digoxin: cardiac glycoside from the foxglove plant; used in HFREF and AF/flutter; narrow therapeutic range (0.5-0.9 µg/L).
- Mechanism: inhibits Na+/K+/ATPase, increasing intracellular calcium (↑contractility) and vagal tone (↓AV node conduction).
- Toxicity: occurs at >1.5 µg/L; common causes include overdose, CKD, drug interactions (e.g. amiodarone, verapamil), or electrolyte imbalance.
- Risk factors: age >55, CKD, PGP inhibitors, hypokalaemia, hypomagnesaemia, hypercalcaemia, hypothyroidism, intercurrent illness.
- Features: cardiac (arrhythmias, bradycardia), GI (nausea, vomiting), neuro (confusion, weakness), ocular (xanthopsia, blurred vision).
- Investigations: ECG (bradyarrhythmias, PVCs), serum digoxin, U&Es, magnesium, calcium, serial ECG monitoring for arrhythmias.
- Management: withhold digoxin, correct electrolytes, cardiac monitoring; Fab fragments for life-threatening arrhythmias, cardiac arrest, or hyperkalaemia >5.5 mmol/L.
- Complications: life-threatening arrhythmias, cardiac arrest, rebound toxicity post-Fab fragments, hypokalaemia.
Introduction
Digoxin is a cardiac glycoside originating from the Digitalis lanata genus of the foxglove plant family. It is one of the oldest medications in cardiology and is frequently used in managing heart failure and cardiac arrhythmia.1
Digoxin toxicity arises when serum concentrations reach supratherapeutic levels. It is associated with numerous systemic manifestations and may be fatal without prompt treatment. It is relatively common and was the fourth most common toxin reported to the UK National Poisons Information Service in 2022-2023.2
Aetiology
Digoxin is indicated for managing heart failure with reduced ejection fraction (HFREF). It is also used for rate control in supraventricular tachyarrhythmias such as atrial fibrillation (AF) and atrial flutter.3-4
Digoxin requires initial loading doses followed by a daily maintenance dose once a steady state is achieved. Dose reductions are required in the elderly and patients with renal impairment.3
Clinical pharmacology
Pharmacodynamics
Digoxin exerts positive inotropic and negative chronotropic effects.
Positive inotropic activity
Digoxin reversibly inhibits the Na+/K+/ATPase enzyme, which increases the concentration of intracellular sodium within cardiac myocytes, resulting in decreased calcium expulsion via the sodium-calcium exchanger.5-6
The increase in calcium within the sarcoplasmic reticulum enhances the binding of actin and myosin within the cardiac myofibrils, yielding increased myocardial contractility.6-8 This increases stroke volume and cardiac output, making digoxin a useful agent in HFREF.
Negative chronotropic activity
At lower doses, digoxin exerts parasympathomimetic effects via the vagus nerve. This decreases the automaticity of the sinoatrial node and slows conduction through the AV node, slowing the ventricular response. Digoxin-induced parasympathetic stimulation partially mediates the increased noradrenaline levels associated with heart failure, decreasing sympathetic drive.5-6, 9
Monitoring
Digoxin has a narrow therapeutic window and requires strict monitoring.
Excretion is primarily renal, so renal function must be routinely monitored. Electrolytes should also be closely monitored as imbalances can precipitate toxicity.3-5
Regular monitoring of serum digoxin during maintenance treatment is not required unless clinically indicated (i.e. suspected toxicity, poor adherence, renal impairment, concomitant use of drugs with known interactions).3-4, 10-11
Digoxin toxicity
The safe therapeutic range of digoxin is 0.5-0.9 micrograms/L.2
Toxicity may develop when serum digoxin levels reach 1.5-3.0 micrograms/L and becomes highly likely over this range. Illness severity does not necessarily correlate with serum levels.2, 11
Acute digoxin toxicity occurs when serum digoxin levels rise sharply within a short timeframe. This most commonly arises in cases of overdose (intentional or accidental).2, 10-11
Chronic digoxin toxicity arises over a longer period and may be caused by:2, 10-11
- Chronic overmedication
- Chronic kidney disease (decreased renal clearance)
- Electrolyte abnormalities
- Drug interactions (e.g. antimicrobial therapy or p-glycoprotein (PGP) inhibition)
- Displacement of digoxin from protein binding sites (drug interactions)
P-glycoprotein inhibition
PGPs are a group of ATP-dependent transmembrane efflux transporters that are heavily expressed in the intestinal epithelium, hepatocytes, renal proximal tubule, and blood-brain barrier.
PGP function is closely linked to digoxin absorption in the gut and clearance via the renal and hepatic routes. Therefore, drugs which inhibit PGP function may increase intestinal absorption and reduce the clearance of digoxin, precipitating toxicity.2, 12
Common examples of PGP inhibitors include:12
- Verapamil
- Diltiazem
- Amiodarone
- Ketoconazole
- Quinidine
- Clarithromycin and erythromycin
Similarly, PGP inducers may result in subtherapeutic digoxin levels. Examples include rifampicin, phenytoin, carbamazepine and St John’s wort.
PGP function is different from that of the CYP450 system.
Risk factors
Risk factors for digoxin toxicity include:2
- Over 55 year olds
- Chronic kidney disease
- Concomitant use of PGP inhibitors
- Electrolyte derangement
- Hypothyroidism
- Low body mass
- Volume depletion
- Myocardial ischaemia
- Hypoxaemia
- Intercurrent illness, e.g. sepsis, acute kidney injury
Electrolyte derangement and digoxin toxicity
Hyperkalaemia is common in digoxin toxicity and is a predictor of mortality. Digoxin-mediated inhibition of Na+/K+/ATPase prevents potassium influx, resulting in higher serum levels and increased risk of fatal cardiac arrhythmia.2, 13-14
Hypokalaemia potentiates the effects of digoxin. Potassium and digoxin bind to the ATPase pump at the same site. Hence, lower potassium enables increased binding of digoxin at the target site.2, 6, 13
Hypomagnesaemia may potentiate digoxin toxicity as normal Na+/K+/ATPase function is magnesium dependent. Furthermore, hypomagnesaemia is often accompanied by hypokalaemia.15
Hypercalcaemia also potentiates the effects of digoxin. Excessive calcium levels, in tandem with digoxin administration, overload intracellular calcium stores. This may result in delayed after-depolarisations, increased automaticity and dysrhythmias.
The role of calcium in managing digoxin-associated hyperkalaemia is controversial (the stone heart theory). Generally, calcium is considered safe, however, there is ongoing debate as to whether it is necessary as digitoxic patients are likely to be sufficiently intracellularly loaded with calcium. Always consult local guidelines.2, 6, 13
Clinical features
The features of digoxin toxicity may be non-specific and depend on the acuity of the illness. Constitutional symptoms such as fatigue, malaise, headache and generalised weakness are common.
Systemic manifestations may include:2, 13, 16
- Cardiac: palpitations, syncope, chest pain, dysrhythmias, hypotension, bradycardia
- Gastrointestinal: anorexia, nausea, vomiting, diarrhoea, abdominal pain
- Neurological: confusion, delirium, weakness, CNS depression
- Ocular: xanthopsia, blurred vision, diplopia, photophobia, photopsia
Cardiac manifestations are the most concerning features in both acute and chronic toxicity as they may rapidly deteriorate into fatal arrhythmias.
Xanthopsia
Xanthopsia is a form of chromatopsia which manifests as a yellow discolouration in vision and a yellow halo around lights. It is a known side effect of digoxin and is often present in toxicity.13
Acute toxicity
Following acute ingestion, patients will likely remain asymptomatic for 1-2 hours, after which they may deteriorate rapidly. Acute toxicity usually presents with GI symptoms (i.e. nausea, vomiting), with neurological and cardiac involvement manifesting over the following 6-12 hours as tissue deposition of digoxin progresses.2, 13
Chronic toxicity
Chronic digoxin toxicity is more common and most frequently occurs in elderly patients with multiple risk factors. It follows a more insidious course over days-weeks. Neurological features are more prominent and GI involvement is also common, but are less pronounced than in acute toxicity.2, 13
Differential diagnoses
In cases of suspected digoxin toxicity, important differentials to consider include:2, 13
- Beta-blocker toxicity
- Calcium channel blocker toxicity
- Alpha-agonist toxicity
- Ischaemic heart disease
- Hypothyroidism
Investigations
Bedside investigations
Relevant bedside investigations include:
- Basic observations: to assess for bradycardia, hypotension, fever and altered mental status
- Blood glucose
- 12-lead ECG: serial ECGs to monitor for dysrhythmia
ECG
Digoxin toxicity can produce virtually any arrhythmia except for atrial tachyarrhythmias with rapid ventricular response due to its atrioventricular (AV) nodal effects. Classic ECG findings are supraventricular tachycardia (due to increased automaticity) with a slow ventricular response (due to decreased AV conduction), but premature ventricular complexes (PVC) are the most common abnormality.17
Acute toxicity most commonly produces significant bradycardia with prolongation of the PR interval and QRS complex. Chronic toxicity is mostly associated with bradyarrhythmias.
In patients with pacemakers, digitoxic effects may be masked by a paced rhythm.
Digitalis effect
The digitalis effect refers to characteristic ECG changes observed with regular digoxin use. This includes:
- Mild PR interval prolongation
- ST depression in a downsloping reverse tick pattern
- Flattened, inverted or biphasic T waves
- QT interval shortening
This is normal with digoxin use and not a sign of toxicity.
Laboratory investigations
Relevant laboratory investigations include:2, 13
- Full blood count: may be normal in acute toxicity, raised white cells may indicate infection as a trigger for chronic toxicity
- Urea and electrolytes: to measure sodium, potassium and renal function
- Bone profile: may show hypercalcaemia
- Serum magnesium: may show hypomagnesaemia
- Serum glucose: to assess for hypoglycaemia
- Serum digoxin level: immediately in chronic toxicity, or 6 hours post acute overdose
- Venous blood gas: point of care measurement of electrolytes, pH, bicarbonate, lactate
In cases of acute overdose, consider testing for other common poisons such as paracetamol or salicylates. A pregnancy test should also be considered in young women.
Diagnosis
Digoxin toxicity is a clinical diagnosis based upon confirmed or suspected exposure to digoxin and suggestive clinical features. An elevated serum digoxin level helps confirm the diagnosis but is not solely diagnostic, as not all patients with elevated levels will develop toxicity.13
Toxicity should be suspected in all patients with typical features who are taking long-term digoxin, particularly if there is a history of renal disease or intercurrent illnesses.2
Management
All patients with suspected digoxin toxicity should be managed using a thorough ABCDE approach, in combination with TOXBASE.
Initial management
The initial management of digoxin toxicity includes:2
- Activated charcoal: if within 2 hours of acute ingestion
- Withold digoxin and potentiating medications
- Cardiac telemetry
- Anti-emetics: to manage nausea or vomiting
- Intravenous fluids: for volume repletion or electrolyte replacement
- Correction of electrolyte disturbance
- Digoxin binding therapy
Any patients with haemodynamic instability or cardiac arrhythmia should be escalated to a senior clinician immediately.
Digoxin binding therapy
Digoxin binding therapy with digoxin-specific antibody (Fab) fragments is indicated in confirmed digoxin toxicity and any of the following:2, 13
- Life-threatening or haemodynamically unstable arrhythmia
- Cardiac arrest
- Severe hyperkalaemia > 5.5 mmol/L
Fab fragments bind free digoxin in the plasma, forming complexes excreted in the urine. The reduction in free circulating digoxin generates a concentration gradient which facilitates dissociation between digoxin and Na+/K+/ATPase, mitigating toxicity.20
It is highly effective; improvement can be expected within 15-30 minutes. There is a small risk of rebound toxicity for up to 24 hours following administration, and dissociation between digoxin and Na+/K+/ATPase may produce a paradoxical rise in serum digoxin levels, despite a clinical improvement.2 Therefore, serum digoxin levels are unreliable following the administration of fab fragments.
Electrolytes should be closely monitored as a return to normal Na+/K+/ATPase function results in an intracellular shift of potassium and may precipitate profound hypokalaemia.2
Ongoing management
The ongoing management of digoxin toxicity includes:
- Management of the underlying cause(s): e.g. acute kidney injury, sepsis
- Psychological support: with the involvement of the psychiatry liaison team, if an acute overdose
Cardiotoxicity
Acute cardiac manifestations in a digitoxic patient (e.g. brady or tachyarrhythmia) indicates severe toxicity and may herald impending cardiac arrest.
This should be managed as per the Resuscitation Council UK advanced life support (ALS) guidelines.19
Management to address digoxin toxicity and underlying causes should take place in tandem with ALS interventions.
Complications
Noteworthy complications of digoxin toxicity include:2
- Life-threatening arrhythmia
- Cardiac arrest
- CNS depression
- GI disturbance
Complications of treatment include:2
- Anaphylaxis to fab fragments
- Hypokalaemia
- Recurrence of previous arrhythmia (e.g. AF, flutter)
Reviewer
Dr Laura Castle
Emergency Medicine Consultant
Editor
Dr Jamie Scriven
References
- David MNV, Shetty M. Digoxin. StatPearls. 2023. Available from: [LINK].
- BMJ Best Practice. Digoxin Toxicity. 2024. Available from: [LINK].
- BNF. Digoxin. 2024. Available from: [LINK].
- Giardina EGV. Treatment with digoxin: Initial dosing, monitoring, and dose modification. UpToDate. 2023. Available from: [LINK].
- Drugbank. Digoxin. 2024. Available from: [LINK].
- Buttner R. Pharm101: Digoxin. LITFL. 2020. Available from: [LINK].
- Gash MC, Kandle PF, Murray IV, et al. Physiology, Muscle Contraction. StatPearls. 2023. Available from: [LINK].
- Ottolia M, Torres N, Bridge J, et al. Na/Ca exchange and contraction of the heart. Journal of Molecular and Cellular Cardiology. 2013. Available from: [LINK].
- Gheorghiade M, Adams K, Colucci W. Digoxin in the management of cardiovascular disorders. Circulation. 2004. Available from: [LINK].
- Rehman R, Hai O. Digitalis Toxicity. StatPearls. 2023. Available from: [LINK].
- NICE CKS. Atrial Fibrillation: Digoxin. 2024. Available from: [LINK].
- Medsafe. Medicines interactions: the role of P-glycoprotein. 2011. Available from: [LINK].
- Levine MD, O’Connor AD. Digitalis (cardiac glycoside) poisoning. UpToDate. 2024. Available from: [LINK].
- Bismuth C, Gaultier M, Conso F, et al. Hyperkalemia in Acute Digitalis Poisoning: Prognostic Significance and Therapeutic implications. Clinical Toxicology. 1973. Available from: [LINK].
- Negru A, Pastorcici A, Crisan S, et al. The Role of Hypomagnesemia in Cardiac Arrhythmias: A Clinical Perspective. Biomedicines. 2022. Available from: [LINK].
- Pincus M. Management of digoxin toxicity. Australian Prescriber. 2016. Available from: [LINK].
- Burns E, Buttner R. Digoxin Toxicity. LIFTL. 2024. Available from: [LINK].
- Burns E. Digoxin Effect. LIFTL. 2024. Available from: [LINK].
- Resuscitation Council UK. Adult advanced life support Guidelines. 2021. Available from: [LINK].
- Levine MD, O’Connor AD. Dosing regimen for digoxin-specific antibody (Fab) fragments in patients with cardiac glycoside (digoxin) toxicity. UpToDate. 2024. Available from: [LINK].
Image references
- Figure 1. Burns E, Buttner R. Digoxin toxicity – PVCs. Available from: [LINK]. License: [CC BY-NC-SA 4.0].
- Figure 2. Burns E, Buttner R. Digoxin toxicity – Atrial tachyarrhythmia with AV block. Available from: [LINK]. License: [CC BY-NC-SA 4.0].
- Figure 3. Burns E, Buttner R. Digoxin toxicity – Atrial flutter with high-grade AV block. Available from: [LINK]. License: [CC BY-NC-SA 4.0].
- Figure 4. Burns E, Buttner R. Digoxin toxicity – Bidirectional ventricular tachycardia. Available from: [LINK]. License: [CC BY-NC-SA 4.0].
- Figure 5. Popfossa. Digitalis effect. Available from: [LINK]. License: [CC BY-NC 2.0].
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