Cardiac Glycosides (Digoxin)
High-yield Verified · Oct 2026One target — the Na⁺/K⁺-ATPase — explains the stronger beat, the slower AV node (with indirect vagal stimulation), the arrhythmias of toxicity and the hyperkalemia of acute overdose.
Nursing view → administration, monitoring and patient teaching
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Drugs
Mechanism
Inhibits the myocardial Na⁺/K⁺-ATPase, raising intracellular sodium and, via the Na⁺/Ca²⁺ exchanger, intracellular calcium — increasing contractility (positive inotropy). Simultaneously increases vagal tone, slowing SA-node firing and AV-node conduction (negative chronotropy/dromotropy).
The sodium pump and the calcium it leaves behind
The Na⁺/K⁺-ATPase pumps 3 Na⁺ out and 2 K⁺ in for each ATP, and its catalytic α subunit carries the ion-binding sites. All of digoxin’s actions are mediated through this pump. Digoxin reversibly inhibits it, so intracellular sodium builds up. The Na⁺/Ca²⁺ exchanger, which normally keeps intracellular calcium low by bringing sodium in, then exchanges less, so calcium rises; SERCA stores it in the sarcoplasmic reticulum, and more calcium for actin–myosin cross-bridges strengthens contraction (positive inotropy).
In the myocardium and conduction system, the extra intracellular calcium also increases automaticity and reduces conduction velocity. At toxic concentrations, cell excitability rises and resting potential falls, and spontaneous cycles of calcium release and uptake cause afterdepolarizations and aftercontractions — which is why almost any arrhythmia can appear.
Vagal and neurohormonal effects
Digoxin indirectly stimulates the parasympathetic nervous system, slowing the SA node and prolonging conduction and refractoriness at the AV node; the extra intracellular calcium also lengthens the AV node’s refractory period. The result is a negative chronotropic effect and slower AV conduction, which controls the ventricular rate in atrial fibrillation — the label limits that indication to the resting rate, and digoxin does not significantly reduce heart rate during exercise.
Digoxin also deactivates neurohormones: it lowers sympathetic and renin–angiotensin activation, sensitizes baroreceptors and reduces catecholamine reuptake at nerve terminals. At higher concentrations the balance flips — sympathetic outflow from the CNS increases and potassium leaks out of cells.
At therapeutic doses the ECG may show a prolonged PR interval and ST depression, and digoxin can cause false-positive ST–T changes on exercise testing; these electrophysiologic effects are not signs of toxicity.
Why the window is narrow: what shifts the response
Electrolytes. Hypokalemia, hypomagnesemia and hypercalcemia predispose to toxicity, and lower potassium raises the risk of adverse reactions at any level; acidosis, alkalosis and hypoxemia add risk. Hypocalcemia can nullify digoxin’s effect, because digoxin acts on contractility and excitability much as calcium does.
Clearance and P-glycoprotein. Digoxin is cleared mainly by the kidneys, and declining renal function is the commonest cause of chronic toxicity. It is a P-glycoprotein substrate in intestinal absorption, renal tubular secretion and biliary-intestinal secretion; in vitro, amiodarone, quinidine, verapamil and macrolides inhibit renal P-glycoprotein transport, which can reduce digoxin clearance. The label lists amiodarone (serum level up 70%), quinidine (100%), verapamil (50–75%) and dronedarone (exposure up 150%) among the larger increases.
Other modifiers. In about 1 patient in 10, gut bacteria degrade 40% or more of an oral dose to inactive dihydrodigoxin, so certain antibiotics can raise the level — in some cases as much as doubling it. Hypothyroidism lowers digoxin requirements, while atrial arrhythmias of hyperthyroid or other hypermetabolic states resist it. In amyloid heart disease, digoxin binds extracellular amyloid fibrils, raising susceptibility to toxicity at therapeutic levels.
Comparing the drugs
Acute versus chronic digoxin toxicity
| Drug | How it arises | Potassium | What predominates and how it is managed |
|---|---|---|---|
| Acute overdose | Ingestion without prior background use, intentional or inadvertent | Hyperkalemia — the major electrolyte complication and a marker of severity | Activated charcoal even late (enterohepatic recirculation); digoxin Fab for life-threatening arrhythmias or hyperkalemia |
| Chronic toxicity | Rising levels from reduced clearance, usually renal insufficiency (the commoner form) | Hypokalemia worsens toxicity and is corrected | Non-specific malaise and weakness may predominate; stop the drug, correct electrolytes and interacting drugs, Fab for symptomatic arrhythmias |
Acute-on-chronic toxicity is an extra bolus in a patient already taking digoxin.
Digoxin and its antidote at a glance
| Drug | Half-life | Elimination | Distribution | Removed by dialysis? |
|---|---|---|---|---|
| Digoxin | 1.5–2 days (3.5–5 days if anuric) | 50–70% unchanged in urine, proportional to creatinine clearance; about 13% metabolized (not by CYP450) | Large, about 475–500 L; about 25% protein-bound | No — most is bound in extravascular tissue |
| Digoxin immune Fab (ovine) | 15–20 h, up to 10-fold longer in renal impairment | Fab–digoxin complexes cleared by the kidney and reticuloendothelial system | Considerable extracellular penetration | No — digoxin–Fab complexes are not removed by hemodialysis |
Pharmacokinetics
- Absorption
- Tablet bioavailability is 60–80%, with peak serum levels at 1–3 hours. Intestinal P-glycoprotein limits absorption; high-bran meals and malabsorption reduce it, and gut-bacterial reduction to dihydrodigoxin can inactivate a large share of a dose in some patients.
- Distribution phase
- A 6–8 hour tissue-distribution phase follows each dose. Early high serum levels do not reflect concentrations at the site of action; post-distribution steady-state levels equilibrate with tissue and correlate with effect — so levels drawn too soon after a dose can be falsely high. In heart failure, levels of about 0.5–0.9 ng/mL have been linked to better prognosis; in a DIG-trial analysis, 1.2 ng/mL or more raised mortality.
- Volume and body size
- The large apparent volume of distribution (about 475–500 L) reflects tissue binding; it correlates with lean, not total, body weight. Digoxin crosses the blood–brain barrier and placenta, and about 25% is protein-bound.
- Renal elimination
- Elimination is first-order and largely renal: 50–70% of an IV dose appears unchanged in urine, proportional to creatinine clearance. The half-life is 1.5–2 days, prolonged to 3.5–5 days in anuria, so a new steady state takes longer to reach in renal impairment.
- Metabolism
- Only about 13% of a dose is metabolized, by hydrolysis, oxidation and conjugation; digoxin does not depend on, induce or inhibit cytochrome P450. Its interactions run through P-glycoprotein and renal function instead.
- Onset
- Tablets act in 0.5–2 hours with peak effect at 2–6 hours; IV digoxin acts in 5–30 minutes with peak at 1–4 hours.
- Assay pitfalls
- Digoxin-like immunoreactive substances, spironolactone and its metabolites, and some traditional herbal substances can interfere with digoxin immunoassays, usually giving falsely high results.
Uses & drug choice
- Heart failure with reduced ejection fraction (symptom control; added when other therapy is insufficient)
- Rate control in atrial fibrillation / atrial flutter (when conventional therapy does not reach the target rate)
Adverse effects
- Bradycardia and AV block
- Indirect vagal stimulation slows the SA node and prolongs AV conduction and refractoriness; digoxin-induced bradycardia and heart block are parasympathetically mediated and respond to atropine.
- Dysrhythmias (PVCs, bigeminy, ventricular arrhythmias)
- Toxic concentrations raise excitability and lower resting potential, and spontaneous calcium release and uptake cause afterdepolarizations. Bidirectional ventricular tachycardia is pathognomonic; bundle-branch patterns are rare because conduction through the His bundle and bundle branches is little affected.
- Hyperkalemia (acute overdose)
- With the pump inhibited, potassium shifts from inside cells to outside; extremely high levels produce hyperkalemia, especially with impaired renal function.
- Toxicity potentiated by low K⁺, low Mg²⁺, high Ca²⁺ and renal impairment
- Digoxin competes with K⁺ for its binding site on the pump, so with low potassium its action is unopposed and adverse reactions become more likely; digoxin also acts on excitability much as calcium does, and reduced renal clearance lets it accumulate.
Toxicity & antidote
Overdose causes nausea, vomiting, anorexia and fatigue in 30–70% of patients, yellow-green color-vision changes, and almost any arrhythmia; characteristic ones include new Mobitz type 1 AV block, accelerated junctional rhythm and non-paroxysmal atrial tachycardia with block. Peak cardiac effects occur 3–6 hours after ingestion. Digoxin is not removed by dialysis because of its large extravascular volume of distribution.
Digoxin immune Fab binds digoxin with an affinity of 10⁹–10¹⁰ M⁻¹ — greater than digoxin’s affinity for the sodium pump — so free digoxin falls and the equilibrium shifts away from the receptor. The Fab–digoxin complexes are cleared by the kidney and reticuloendothelial system.
Two consequences follow. Serum digoxin can no longer be read: the total level may rise precipitously after Fab, but it is almost entirely Fab-bound and inactive, and standard assays stay misleading until the Fab is eliminated — days, or a week or more in severe renal impairment — so the level should be drawn before Fab. And potassium falls: severe toxicity shifts potassium out of cells and can leave hyperkalemia with a whole-body deficit, so when Fab reverses the effect potassium moves back in and hypokalemia can develop rapidly. Withdrawing digoxin’s inotropic support can also worsen heart failure or the ventricular rate in atrial fibrillation.
Interactions
Contraindications
- Ventricular fibrillation — A labeled contraindication; toxic digoxin levels can themselves cause ventricular tachycardia and fibrillation.
- Sinus node disease or AV block (consider a pacemaker first) use caution — Digoxin may cause severe sinus bradycardia or sinoatrial block, and advanced or complete heart block in pre-existing incomplete AV block.
- Hypersensitivity to digoxin or other digitalis — Known hypersensitivity to digoxin or other forms of digitalis is a labeled contraindication.
- Hypokalemia / hypomagnesemia / hypercalcemia use caution — These electrolyte states increase sensitivity to digoxin, so toxicity occurs even at lower levels — correct them before and during therapy.
- Renal impairment (dose reduction) use caution — Digoxin is cleared by the kidneys; impaired clearance lets levels accumulate into the toxic range.
High-yield
- Down — lower potassium raises the risk of digoxin adverse reactions
- Up in overdose — acute toxicity shifts potassium out of cells: hyperkalemia marks severity
- Down again after Fab — reversal moves potassium back in, so watch for rapid hypokalemia
- F — free digoxin falls (Fab binds it more tightly than the pump does)
- A — assays read high: total digoxin includes inactive Fab-bound drug, so draw the level before Fab
- B — be ready for low potassium as it shifts back into cells
Practice questions
Q1A 68-year-old man with HFrEF remains symptomatic on standard therapy, and digoxin is added. His exercise tolerance improves over the next weeks.
Which sequence best explains digoxin’s positive inotropic effect?
- A.β1-receptor stimulation raises cAMP and opens L-type calcium channels
- B.Phosphodiesterase-3 inhibition raises cAMP
- C.Increased vagal tone strengthens ventricular contraction
- D.Direct opening of ryanodine receptors in the sarcoplasmic reticulum
- E.Na⁺/K⁺-ATPase inhibition raises intracellular Na⁺, so the Na⁺/Ca²⁺ exchanger leaves more Ca²⁺ in the cell
Show answer
E. Na⁺/K⁺-ATPase inhibition raises intracellular Na⁺, so the Na⁺/Ca²⁺ exchanger leaves more Ca²⁺ in the cell — All of digoxin’s actions are mediated through the Na⁺/K⁺-ATPase. Reversibly inhibiting it raises intracellular sodium, which reduces exchange through the Na⁺/Ca²⁺ exchanger, so calcium accumulates in the myocyte and increases contractility. The vagal effect slows the SA and AV nodes rather than strengthening contraction.
Q2A 74-year-old woman with digoxin toxicity and complete heart block receives digoxin immune Fab. An hour later her rhythm has improved, yet a repeat serum digoxin is far higher than the pretreatment value.
What best explains the laboratory result?
- A.Fab has displaced digoxin from tissue, worsening toxicity
- B.The assay measures digoxin that is now bound to Fab and inactive
- C.Laboratory error from hemolysis
- D.Renal failure has stopped digoxin elimination
- E.The pretreatment sample was drawn during the distribution phase
Show answer
B. The assay measures digoxin that is now bound to Fab and inactive — After Fab, total serum digoxin may rise precipitously, but it is almost entirely Fab-bound and unable to reach its receptors; standard digoxin assays stay clinically misleading until the Fab is eliminated. That is why the level should be drawn before Fab is given.
Q3An 80-year-old man on long-term digoxin for atrial fibrillation starts amiodarone. Two weeks later he has nausea, yellow-tinted vision and new bigeminy; his digoxin level has risen sharply although his dose and renal function are unchanged.
Which mechanism most likely explains the rise?
- A.Amiodarone inhibits P-glycoprotein, reducing digoxin’s renal tubular secretion
- B.Amiodarone induces CYP3A4 metabolism of digoxin
- C.Amiodarone displaces digoxin from plasma proteins
- D.Amiodarone causes hypercalcemia
- E.Amiodarone increases digoxin absorption by killing gut bacteria
Show answer
A. Amiodarone inhibits P-glycoprotein, reducing digoxin’s renal tubular secretion — Digoxin is a P-glycoprotein substrate in intestinal absorption, renal tubular secretion and biliary secretion; in vitro, amiodarone inhibits renal P-glycoprotein transport, which can reduce digoxin clearance (the label lists a 70% rise in serum digoxin). Digoxin is not metabolized by cytochrome P450 and is only about 25% protein-bound.
Q4A 25-year-old woman ingested her grandmother’s digoxin 4 hours ago. She is vomiting and has second-degree AV block; serum potassium is 6.4 mEq/L.
Why is her potassium elevated?
- A.Vomiting has concentrated her blood
- B.Digoxin blocks renal potassium secretion through the ROMK channel
- C.Inhibition of the Na⁺/K⁺-ATPase shifts potassium out of cells
- D.Digoxin stimulates aldosterone release
- E.Rhabdomyolysis from seizures
Show answer
C. Inhibition of the Na⁺/K⁺-ATPase shifts potassium out of cells — Digoxin causes a shift of potassium from inside to outside the cell, so severe intoxication can produce life-threatening hyperkalemia; it is the major electrolyte complication of acute toxicity and a marker of severity, and hyperkalemia is an indication for digoxin Fab.
Q5A 72-year-old man takes digoxin for chronic atrial fibrillation. His resting ventricular rate is controlled, but it rises steeply whenever he walks briskly.
Which feature of digoxin explains this pattern?
- A.It blocks β1 receptors only at rest
- B.Its effect wears off within a few hours
- C.It shortens the AV-node refractory period
- D.Its AV slowing is largely vagally mediated, and it does not significantly reduce heart rate during exercise
- E.Most of it is metabolized by the liver, which works faster during exercise
Show answer
D. Its AV slowing is largely vagally mediated, and it does not significantly reduce heart rate during exercise — Digoxin slows the AV node through indirect parasympathetic stimulation, and the label limits its atrial fibrillation indication to control of the resting rate, noting that digoxin does not significantly reduce heart rate during exercise. Its half-life is 1.5–2 days, so it does not wear off within hours. All of digoxin’s actions are mediated through the Na-K ATPase, not β1 receptors; it increases the refractory period rather than shortening it; and only about 13% of a dose is metabolized, with 50–70% excreted unchanged in the urine.
Sources
- Digoxin — mechanism, therapeutic range, monitoring — StatPearls (NCBI)
- Cardiac Glycoside / Digoxin Toxicity — hypokalemia, dysrhythmias, immune Fab — StatPearls (NCBI)
- Cardiac Glycosides — nursing considerations (apical pulse, potassium) — Open RN — Nursing Pharmacology
- LANOXIN (digoxin) tablets — prescribing information (contraindications, warnings, counseling) — DailyMed (NLM)
- DIGIFAB (digoxin immune fab) — prescribing information — DailyMed (NLM)
- LANOXIN (digoxin) Injection and Injection Pediatric (Covis) — FDA label — FDA / DailyMed
- General Survey — taking a pulse for a full 60 seconds — Open RN — Nursing Skills
- Cardiovascular and renal system — diuretics and hypokalemia (Ch. 6) — Open RN — Nursing Pharmacology
- Therapeutic Uses of Diuretic Agents — diuretic hypokalemia and digoxin — StatPearls (NCBI)
- High alert medications off the radar: a systematic review (ISMP list, Table 6) — PMC (open access)
- Congenital Heart Defects — cardiac glycosides in infants and children (Ch. 17) — Open RN — Nursing Health Promotion
- Review: failure of current digoxin monitoring — heart-failure serum target, DIG-trial levels — Frontiers in Cardiovascular Medicine (PMC, CC BY 4.0)
- Physiology, Sodium Potassium Pump — 3 Na⁺ out, 2 K⁺ in; α subunit — StatPearls (NCBI)
- Digoxin Immune Fab — indications and monitoring — StatPearls (NCBI)
By LearnDrugs
Educational summary for medical students. Always verify against current prescribing information and guidelines. Not medical advice.