Digoxin Clinical Reference

ACC/AHA 2022 / AHA 2021 Heart Failure Indications

Indication	Class	Evidence	Notes
HFrEF (LVEF ≤40%) symptomatic on optimal GDMT — reduce hospitalization	IIa	B-R	Add after BB, ACEi/ARNi, MRA, SGLT2i optimized
AF + rapid ventricular rate in HFrEF — rate control	IIa	C-LD	Especially when BB poorly tolerated or hemodynamically unsuitable for high-dose BB
AF rate control (no HF, not first-line)	IIb	C	Less effective during exertion; consider in sedentary patients or as add-on
HFpEF	III	—	No mortality benefit; not recommended

Dosing & Therapeutic Targets

Subtherapeutic

Therapeutic

Caution

Toxic risk ↑

0 0.5 0.9 1.2 2.0 ng/mL

Parameter	Detail
Target (HFrEF)	0.5 – 0.9 ng/mL (DIG trial post-hoc; mortality benefit)
Rate control (AF)	0.8 – 1.2 ng/mL acceptable if tolerated
Maintenance	0.125 – 0.25 mg PO OD 0.0625 mg (half-tablet) if elderly / CKD / low lean body mass
Loading (urgent rate control)	IV: 0.25–0.5 mg slow IV → 0.125–0.25 mg q6h PRN (max 1 mg/24h) PO: 0.5–0.75 mg → 0.25 mg q6–8h × 2 doses
Sample timing	≥6 h post-dose (distribution phase complete)
Renal adjustment	50–70% renally cleared; reduce dose proportional to eGFR; monitor in AKI/CKD progression

Note: Higher levels (≥1.2 ng/mL) associated with increased mortality (DIG, 1997). Target lowest effective level; women may be more susceptible at equivalent levels.

Risk Factors for Toxicity

Toxicity can occur even at "therapeutic" levels when predisposing factors are present.

Hypokalemia (<3.5) Hypomagnesemia Renal impairment Hypercalcemia Hypothyroidism Advanced age Low lean body mass Structural HD / Myocarditis Amiodarone Verapamil / Diltiazem Macrolides Hypoalbuminemia

Clinical Features

Cardiac

Any new dysrhythmia
Regularization of AF (junctional takeover)
PAT with 2:1 AV block (classic)
Bidirectional VT (pathognomonic)
Accelerated junctional rhythm
High-degree AV block (2nd / 3rd)
Sinus bradycardia / SA block
PVCs, VF (severe)

GI (early, common)

Nausea, vomiting
Anorexia
Abdominal pain / diarrhea

Neuropsychiatric

Fatigue, weakness
Confusion / delirium
Headache

Visual (highly specific)

Xanthopsia (yellow-green vision)
Halo vision / blurring
Scotomas, photophobia

ECG Findings

Scooped ST depression (effect, not toxicity)
Prolonged PR interval
Shortened QT
PAT + AV block
Bidirectional VT

Key: PAT with 2:1 block and bidirectional VT are the most classic ECG patterns. Regularization of AF = junctional escape — stop digoxin immediately.

Level Interpretation

Serum Level	Interpretation	Action
< 0.5 ng/mL	Subtherapeutic	Consider uptitration if symptomatic
0.5 – 0.9 ng/mL	Therapeutic (HFrEF target)	Continue; reassess symptoms
1.0 – 2.0 ng/mL	High-normal; acceptable for AF rate control	Monitor; check electrolytes; review DDI
> 2.0 ng/mL	Toxic range	Hold digoxin; correct electrolytes; consider Fab
> 10 ng/mL	Severe / potentially fatal	Immediate digoxin-specific Fab

Remember: Clinical toxicity can occur at "normal" levels with hypokalemia or hypomagnesemia. Always interpret level in clinical context.

Acute Digoxin Toxicity — Management Flowchart

Discontinue digoxin

Hold all doses. Do not rechallenge until toxicity fully resolved.

Continuous cardiac monitoring + 12-lead ECG

Identify dysrhythmia type — determines urgency and specific intervention.

Correct electrolytes aggressively

Target K&sup+ 4.0–5.0 mEq/L • Mg²+ ≥1.8 mg/dL • Avoid IV calcium (risk of "stone heart")

KCl IV (if hypokalemia)

10–20 mEq/h IV; continuous ECG monitoring
If K&sup+ > 5.5 mEq/L → avoid (may worsen AV block)

MgSO&sub4; IV

1–2 g IV over 5–20 min; stabilizes membrane, suppresses ectopy
Avoid if severe renal failure

Dysrhythmia-specific management

Bradycardia / AV block

• Atropine 0.5–1 mg IV (may have limited effect; muscarinic override)
• Temporary pacing (transcutaneous → transvenous) if hemodynamically unstable
• DO NOT use isoproterenol (increases automaticity → ventricular arrhythmia)
• Digoxin Fab if unresponsive or severe

Ventricular arrhythmias (PVCs, VT, VF)

• Lidocaine 1–1.5 mg/kg IV bolus → 1–4 mg/min infusion (preferred; no negative chronotropy)
• Phenytoin 100 mg IV q5min up to 1 g — historic; rarely used now
• AVOID DC cardioversion unless life-threatening — may precipitate refractory VF in digitalized myocardium
• If cardioversion required: use lowest effective energy; pretreat with Fab if time permits

Digoxin-Specific Fab — Definitive Antidote

Indications for Fab (Digibind® / DigiFab®)

• Life-threatening arrhythmia (VF, sustained VT, complete AV block)
• Severe bradycardia unresponsive to atropine
• Hyperkalemia K&sup+ > 5.0 from acute toxicity
• Serum digoxin > 10–15 ng/mL (acute) or > 6 ng/mL (chronic) with symptoms
• Hemodynamic instability

Fab Dosing (Digibind® 38 mg/vial; DigiFab® 40 mg/vial)

If amount ingested known:
No. vials = (mg ingested × 0.8) ÷ 0.5

If serum level known:
No. vials = (Serum dig [ng/mL] × weight [kg]) ÷ 100

Empiric (unknown amount/level):
Acute OD: 10–20 vials IV over 30 min (bolus if cardiac arrest)
Chronic toxicity: 3–6 vials; reassess

Post-Fab caution: Serum digoxin levels unreliable for 7–10 days (assay measures bound + free Fab complexes)

GI decontamination (acute oral ingestion <1–2 h)

Activated charcoal 1 g/kg PO if no airway compromise. Cholestyramine may reduce enterohepatic recirculation in chronic toxicity.

Hemodialysis

NOT effective — large Vd (~7 L/kg), tissue-bound. Fab is the only effective removal strategy.

Avoid IV calcium gluconate for hyperkalemia in digoxin toxicity — may worsen cardiac toxicity ("stone heart"). Use sodium bicarbonate, glucose-insulin, or Fab instead.

Major Drug Interactions

Drug	Effect on Dig	Mechanism	Action
Amiodarone	↑ 50–100%	P-gp inhibition + ↓ renal clearance	↓ Dig dose 50%; monitor level
Verapamil / Diltiazem	↑ 40–70%	P-gp inhibition	↓ dose; additive bradycardia risk
Quinidine	↑ ~100%	P-gp + Vd displacement	↓ dose 50%; avoid if possible
Clarithromycin / Erythromycin	↑ significantly	P-gp inhibition + ↓ gut metabolism (Eggerthella lenta)	Monitor level; consider dose reduction
Itraconazole	↑ ~50%	P-gp inhibition	Reduce dose; monitor
Propafenone	↑ 30–60%	P-gp inhibition	Reduce dose; monitor
Spironolactone	↑ (assay interference)	Immunoassay cross-reaction; also ↓ renal clearance	Interpret levels cautiously
Loop / Thiazide diuretics	Level unchanged; ↑ toxicity	Hypokalemia + hypomagnesemia → sensitize myocardium	Aggressive electrolyte monitoring
Cholestyramine / Antacids	↓ absorption	Bind digoxin in GI tract	Separate by ≥2 hours
Rifampicin / St. John's Wort	↓ level 30–50%	P-gp induction	May need dose ↑; monitor

Mechanism: Digoxin is a P-glycoprotein (P-gp / ABCB1) substrate. Most clinically significant interactions involve P-gp inhibitors. Renal function changes also markedly alter exposure.

Absolute Contraindications

Condition	Reason
WPW + AF	Accelerates accessory pathway conduction → VF
2nd / 3rd degree AV block (without pacemaker)	Worsens AV conduction block
Ventricular fibrillation	Proarrhythmic
HOCM with outflow obstruction	Positive inotropy worsens LVOT gradient
Acute MI (early phase with HF)	↑ automaticity in ischemic myocardium; arrhythmia risk