Digoxin

Class: Cardiotonic Agents
VA Class: CV050
CAS Number: 20830-75-5
Brands: Digitek, Lanoxicaps, Lanoxin

Introduction

Digoxin is a cardiac glycoside with positive inotropic effects.^b

Uses for Digoxin

Used for digitalization and maintenance therapy.^a

Used IV for rapid digitalization in emergency situations.^a

Used principally in the prophylactic management and treatment of CHF and to control the ventricular rate in supraventricular tachyarrhythmias (e.g., atrial fibrillation or flutter).^{a 397}

Digoxin is the only remaining cardiac glycoside in the US, primarily because it can be administered by various routes, it has an intermediate duration of action, and its pharmacokinetics in patients with or without renal insufficiency have been extensively studied.^a

CHF

Used in conjunction with ACE inhibitors, diuretics, and/or β-adrenergic blocking agents in the management of symptomatic CHF associated with left ventricular systolic dysfunction.³⁹⁵

Therapy may be initiated in the early development of heart failure in patients who have started but not yet responded symptomatically to an ACE inhibitor or a β-adrenergic blocking agent;³⁹⁵ alternatively, digoxin may be withheld until the patient’s symptomatic response to the ACE inhibitor or β-blocker has been defined³⁹⁵ and then used only in those patients who remain symptomatic while receiving an ACE inhibitor or β-adrenergic blocking agent.³⁹⁵

In CHF patients receiving digoxin without an ACE inhibitor or β-blocker, digoxin should not be withdrawn, but appropriate therapy with an ACE inhibitor and/or a β-blocker should be initiated.³⁹⁵

Alleviates symptoms and improves clinical status.³⁹⁵ Beneficial effects are additive with those of ACE inhibitors and/or diuretics.^{384 388 389 390 391}

Increases cardiac output resulting in diuresis and symptomatic relief of right-sided heart failure caused by systemic venous congestion (e.g., peripheral edema) and of left-sided heart failure caused by pulmonary congestion (e.g., dyspnea, orthopnea, and paroxysmal nocturnal dyspnea).^a

Increases left ventricular ejection fraction and improves symptoms of heart failure (as evidenced by exercise capacity, heart failure-related hospitalizations and emergency care), while having no apparent effect on overall mortality.^{379 384 386 387 390 391 392}

Generally, most effective in the management of low-output failure secondary to hypertension, coronary artery or atherosclerotic heart disease, primary myocardial disease, nonobstructive cardiomyopathies, and valvular heart disease.^a

Not recommended for patients with asymptomatic left ventricular systolic dysfunction (NYHA heart failure functional class I) since only treatment to prevent progression of heart failure is indicated in these patients and digoxin has not been shown to have a demonstrable effect on such progression.³⁹⁵

Worsens outflow obstruction as a result of its inotropic effects in patients with idiopathic hypertrophic subaortic stenosis.^a

Patients with certain disorders involving heart failure associated with preserved left ventricular ejection fraction (e.g., restrictive cardiomyopathy, constrictive pericarditis, amyloid heart disease, acute cor pulmonale) may be particularly susceptible to digoxin toxicity.^{379 385}

Atrial Fibrillation and Flutter

Management depends on the clinical situation and the patient’s condition and ventricular rate.^a

Other antiarrhythmics (e.g., β-adrenergic blocking agents, diltiazem, magnesium) are first-line therapy for atrial fibrillation and a rapid ventricular response.³⁹⁷

Because conversion of atrial fibrillation to normal sinus rhythm may be associated with embolism, adequate anticoagulation is recommended before administration of digoxin when atrial fibrillation is of >48 hours’ duration.^{396 397}

Atrial arrhythmias associated with hypermetabolic states are particularly resistant to digoxin treatment, and care must to taken to avoid toxicity.^a

In patients with atrial arrhythmias and hypothyroidism, the requirement for digoxin is reduced.^a

Sinus Tachycardia

Used to slow the heart rate when sinus tachycardia is caused by CHF.^a

Ventricular or atrial premature complexes caused by CHF may remit when failure is treated with digoxin, but the drug should not be used to treat premature complexes without heart failure.^a

Generally ineffective and not indicated for sinus tachycardia without heart failure, such as that caused by fever, anemia, blood loss, or hyperthyroidism.^a

Paroxysmal Supraventricular Tachycardias

Used for prevention and treatment of paroxysmal supraventricular tachycardias (PSVTs) such as paroxysmal atrial tachycardia, paroxysmal AV junctional rhythm, or paroxysmal atrial fibrillation/flutter.^a

Treatments of choice for paroxysmal atrial tachycardia include measures to increase vagal tone (such as carotid sinus massage, Valsalva maneuver, and/or gagging) or administration of adenosine.^{a 397}

May be useful in the prophylactic management and treatment of regular supraventricular (reciprocating) tachycardia associated with Wolff-Parkinson-White (W-P-W) syndrome, but generally not alone since it may enhance conduction via the accessory pathway and, in the presence of atrial fibrillation or flutter, result in extremely rapid ventricular rates and even ventricular fibrillation.^{a 397}

Generally not used in the treatment of tachyarrhythmias, especially atrial fibrillation or flutter, when anomalous AV conduction is present.^{a 397}

MI

Use in acute MI is controversial.^{386 387 388 389 390}

Mild left ventricular dysfunction after acute MI usually is treated with modest diuresis and afterload and preload reduction (e.g., with parenteral nitroglycerin); institution of ACE inhibitor therapy also may be appropriate.³⁸⁶

Equivocal results with digoxin in terms of mortality, and concern about increased mortality associated with long-term milrinone therapy has prompted reexamination of digoxin use.^{386 387}

Can be used selectively during acute MI recovery, but generally reserved for supraventricular arrhythmias and for systolic left ventricular heart failure that is refractory to first-line agents.³⁸⁶

Effective for persistent supraventricular tachyarrhythmias in acute MI.^a

Rapid digitalization can slow a rapid ventricular response and improve left ventricular function in supraventricular tachyarrhythmias, especially atrial fibrillation.³⁸⁶

May be particularly useful for slowing a rapid ventricular response in coexisting left ventricular dysfunction.³⁸⁶

Cardiogenic Shock

Value in the treatment of cardiogenic shock has not been established, but occasionally used, especially when pulmonary edema is present.^a

Used to improve left ventricular function in cardiogenic shock and atrial fibrillation or flutter with rapid ventricular rate.^a

Angina Pectoris

May be useful, especially in conjunction with a β-adrenergic blocking agent, in the treatment of angina pectoris when cardiomegaly and CHF are present.^a

Not beneficial alone in the treatment of angina pectoris without cardiomegaly and CHF.^a

Arrhythmia and CHF Prophylaxis during Stress in Heart Disease without Failure

Has been used prophylactically to prevent arrhythmias and CHF in heart disease without failure during certain stressful situations (e.g., surgery, severe illness, pregnancy).

Obesity

Do not use alone or in combination with other drugs as an anorexiant for the treatment of obesity, since anorexia caused by digoxin is a symptom of toxicity, and potentially fatal arrhythmias may occur.³⁸⁰

Digoxin Dosage and Administration

General

• 
  

  Low therapeutic index; therefore, cautious dosage determination is essential.^b

  
  


• 
  

  Usual dosages are averages that may require considerable modification as determined by individual requirements and response; the general condition, cardiovascular status, and renal function of the patient; lean (i.e., ideal body) weight and age of the patient; concomitant disease states, drugs, or other factors likely to alter the pharmacokinetics or pharmacodynamics of digoxin; and plasma digoxin concentrations.^{b 398 399 400 401 402 403}

  
  

Switching Dosage Forms

• 
  

  Consider differences in the bioavailability of IV, oral, and IM preparations when patients are switched from one route of administration to another.^{b 398 399 400 401 402 403}

  
  


• 
  

  When switching from oral (tablets or elixir) or IM to IV therapy, must reduce digoxin dosage by about 20–25%.^b

  
  


• 
  

  When switching from tablets, elixir, or IM therapy to liquid-filled capsules, must reduce digoxin dosage by about 20%.^{b 398 399 400 401 402 403}

  
  


• 
  

  Liquid-filled capsules are 90–100% absorbed; therefore, dosage with the capsules is equivalent to IV dosage.^{b 399}

  
  

Considerations for ECG Monitoring and Dosage Reduction

• 
  

  Perform ECG monitoring of cardiac function during therapy, especially during IV therapy or when given orally for prolonged periods or to patients with increased risk of adverse reactions (e.g., those with severe heart or renal disease).^b

  
  


• 
  

  Reduce dosage in hypokalemia, hypothyroidism, extensive myocardial damage, or conduction disorders, and in geriatric patients, especially those with CAD.^b

  
  


• 
  

  Carefully individualize dosage during concomitant quinidine therapy, since clearance and volume of distribution of digoxin may be decreased.^b

  
  

Administration

Oral Administration

Usually administer orally as a single daily dose.^b

Divided daily dosing generally recommended in infants and young children (<10 years of age).^{b c 398 399 401 402 403}

Divided daily dosing generally recommended for liquid-filled capsules for:

• 
  

  Infants and children <10 years of age.^{b 399}

  
  


• 
  

  Patients requiring a daily dose of ≥300 mcg.^{b 399}

  
  


• 
  

  Patients with a history of cardiac glycoside toxicity or those considered likely to become toxic.^{b 399}

  
  


• 
  

  Patients in whom compliance is not a problem; when compliance is considered a problem, once daily dosing may be appropriate.^{b 399}

  
  

IV Injection

Used when oral therapy is not feasible or when rapid therapeutic effect is necessary; oral therapy should replace IV administration as soon as possible^{b 398 399 400 401 402 403}

Possibility of inadvertent overdosage when a tuberculin syringe is used to measure very small doses; exercise caution.^{b 400 401}

Do not flush the syringe with the parenteral solution following IV administration.^{b 400 401}

Do not mix with other drugs in the same container nor administer simultaneously in the same IV line.^{b 400 401}

Inject IV cautiously in hypertensive patients because IV administration can increase blood pressure transiently.^a

Dilution

Inject IV either undiluted over ≥5 minutes or diluted with ≥4-fold volume of sterile water for injection, 5% dextrose injection, or 0.9% sodium chloride injection and give over ≥5 minutes; use of <4-fold volume of diluent may result in precipitation of digoxin.^{b 400 401}

Use diluted IV solutions of digoxin immediately.^{b 400 401}

Rate of Administration

Slow IV infusion is preferred to rapid (i.e., bolus) IV administration.^{400 401} Rapid IV infusion may cause systemic and coronary arteriolar constriction, which may be clinically undesirable; exercise caution.^{400 401}

Administer over ≥5 minutes.^{400 401}

IM Injection

Rarely justified because of frequent severe local irritation and pain, and unpredictable and/or slow onset relative to IV injection;^{b 400 401} IV injection is preferred to IM injection.^{400 401} IM injection offers no advantages unless other routes of administration are contraindicated.^{400 401}

Inject deep into the muscle, followed by massage of the injection site; inject ≤2 mL at any one site.^{b 400 401}

Replace IM with oral administration as soon as possible.^b

Dosage

Dosage guidelines provided are based upon average patient response and substantial patient variation can be expected.^{398 399 400 401 402 403} Ultimate dosage selection must be based upon clinical assessment of the patient.^{398 399 400 401 402 403}

Pediatric Patients

Titrate dosage carefully in neonates, especially premature infants, because renal clearance of digoxin is reduced.^{b 398 399 401 402 403}

Infants and young children (up to 10 years of age) generally require proportionally larger doses than children older than 10 years of age and adults when calculated on the basis of lean or ideal body weight or body surface area.^{b 398 399 401 402 403}

Children >10 years of age require adult dosages in proportion to the child’s body weight.^{398 399 401 402 403}

Liquid-filled capsules may not be the formulation of choice in infants and young children (<10 years of age) where dosage adjustment is frequent and outside of the fixed dosages provided by the capsules.³⁹⁹

CHF

Digitalization may be accomplished by one of two approaches (i.e., rapid digitalization or slow digitalization) that vary in dosage and frequency of administration, but achieve the same total amount of digoxin accumulated in the body.^{398 401 402}

Rapid digitalization (if considered medically appropriate): Administer a loading dose based upon projected peak digoxin body stores.^{401 402} Daily maintenance dose (calculated as a percentage of the loading dose) will follow loading dose.^{401 402}

Peak body digoxin stores of 8–12 mcg/kg generally provide therapeutic effect with minimum risk of toxicity in most patients with CHF, normal sinus rhythm, and normal renal function.^{b 401 402}

Slow digitalization: Initiate therapy with an appropriate daily maintenance dose, which allows digoxin body stores to accumulate slowly.^{b 401 402} Steady-state serum digoxin concentrations will be achieved in about 5 half-lives of the drug for the individual patient; depending on the patient’s renal function, this may take 1–3 weeks.^{b 401 402}

Digitalizing (i.e., Loading) and Maintenance Dosages

Total digitalizing (i.e., loading) doses and maintenance dosages in pediatric patients (depending on the dosage form administered) are given in the tables that follow,^{b 398 399 401 402 403} and should provide therapeutic effect with minimum risk of toxicity in most patients with CHF, normal sinus rhythm, and normal renal function.^{398 399 401 402 403}

Administer the loading dose in divided doses, with about 50% of the total dose given as the first (i.e., initial) dose; additional fractions (generally 25%) are administered at 4- to 8-hour intervals IV or 6- to 8-hour intervals orally or IM, with careful assessment of the patient’s clinical response before each additional dose is administered.^{b 401 402} If the patient’s clinical response requires a change from the calculated loading dose, then calculation of the maintenance dose is based upon the amount (i.e., total loading dose) actually administered.^{401 402}

Oral

Divided daily dosing is generally recommended in infants and young children (<10 years of age).^{b c 398 403}

Table 1. Usual Pediatric Maintenance Dosages for Digoxin Tablets (normal renal function, based on lean body weight)b398403

Age	Oral Maintenance Dosage (mcg/kg daily)
2–5 years of age	10–15
5–10 years of age	7–10
>10 years of age	3–5

IV digitalizing doses are 80% of oral digitalizing doses of digoxin tablets or elixir.^{401 402}

Divided daily dosing is generally recommended in infants and young children (<10 years of age).^{b c 402}

Estimated or actual digitalizing dose that provides desired clinical response.^{b 402}

Table 2. Usual Pediatric Digitalizing and Maintenance Dosages for Digoxin Elixir (normal renal function, based on lean body weight)b402

Age	Oral Digitalizing (Loading) Dose (mcg/kg)	Oral Maintenance Dosage (mcg/kg daily)
Premature neonates	20–30	20–30% of oral loading dose
Full-term neonates	25–35	25–35% of oral loading dose
1–24 months	35–60	25–35% of oral loading dose
2–5 years of age	30–40	25–35% of oral loading dose
5–10 years of age	20–35	25–35% of oral loading dose
>10 years of age	10–15	25–35% of oral loading dose

IV digitalizing doses are the same as oral digitalizing doses of liquid-filled capsules.³⁹⁹

Divided daily dosing is generally recommended in infants and young children (<10 years of age).^{b c 399}

Estimated or actual digitalizing dose that provides desired clinical response.^{b 399}

Table 3. Usual Pediatric Digitalizing and Maintenance Dosages for Digoxin Liquid-Filled Capsules (normal renal function, based on lean body weight)b399

Age	Oral Digitalizing (Loading) Dose (mcg/kg)	Oral Maintenance Dosage (mcg/kg daily)
2–5 years of age	25–35	25–35% of oral or IV loading dose
5–10 years of age	15–30	25–35% of oral or IV loading dose
>10 years of age	8–12	25–35% of oral or IV loading dose

IV

IV digitalizing doses are 80% of oral digitalizing doses of digoxin tablets or elixir.^{401 402}

Divided daily dosing is generally recommended in infants and young children (<10 years of age).^{b c 401}

Estimated or actual digitalizing dose that provides desired clinical response.^{b 401}

Table 4. Usual Pediatric Digitalizing and Maintenance Dosages for IV Digoxin (normal renal function, based on lean body weight)b401

Age	IV Digitalizing (Loading) Dose (mcg/kg)	IV Maintenance Dosage (mcg/kg daily)
Premature neonates	15–25	20–30% of IV loading dose
Full-term neonates	20–30	25–35% of IV loading dose
1–24 months	30–50	25–35% of IV loading dose
2–5 years of age	25–35	25–35% of IV loading dose
5–10 years of age	15–30	25–35% of IV loading dose
>10 years of age	8–12	25–35% of IV loading dose

Atrial Fibrillation

Peak digoxin body stores exceeding the 8–12 mcg/kg required for most patients with CHF and normal sinus rhythm have been used for control of ventricular rate in patients with atrial fibrillation.^{b 401 402} In the treatment of chronic atrial fibrillation, titrate dosage to the minimum dosage that achieves the desired ventricular rate control without causing undesirable adverse effects.^{401 402} Appropriate target resting or exercising rates have not been established.^{401 402}

Adults

CHF

Digitalization may be accomplished by one of two approaches (i.e., rapid digitalization or slow digitalization) that vary in dosage and frequency of administration, but achieve the same total amount of digoxin accumulated in the body.^{398 399 400 403}

Rapid digitalization (if considered medically appropriate): Administer a loading dose based upon projected peak digoxin body stores.^{398 399 400 403} Daily maintenance dose (calculated as a percentage of the loading dose) will follow loading dose.^{398 399 400 403} Peak digoxin body stores of 8–12 mcg/kg generally provide therapeutic effect with minimum risk of toxicity in most patients with CHF, normal sinus rhythm, and normal renal function.^{b 398 399 400 403}

Slow digitalization: Initiate therapy with an appropriate daily maintenance dose, which allows digoxin body stores to accumulate slowly.^{b 398 399 400 403} Steady-state serum digoxin concentrations will be achieved in about 5 half-lives of the drug for the individual patient; depending on the patient’s renal function, this may take 1–3 weeks.^{b 398 399 400 403}

Loading Dose (for rapid digitalization)

Administer the loading dose in divided doses, with about 50% of the total dose given as the first (i.e., initial) dose; additional fractions (generally 25%) are administered at 6- to 8-hour intervals orally, IM, or IV, with careful assessment of the patient’s clinical response before each additional dose is administered.^{b 398 399 400 403} If the patient’s clinical response requires a change from the calculated loading dose, then calculation of the maintenance dose is based upon the amount (i.e., total loading dose) actually administered.^{398 399 400 403}

Oral

Usually, a single initial dose of 500–750 mcg (0.5–0.75 mg) of digoxin tablets^{398 403} or 400–600 mcg (0.4–0.6 mg) of digoxin liquid-filled capsules³⁹⁹ produces a detectable effect in 0.5–2 hours that becomes maximal in 2–6 hours.^{398 399 403}

Cautiously administer additional doses of 125–375 mcg (0.125–0.375 mg) of digoxin tablets or 100–300 mcg (0.1–0.3 mg) of digoxin liquid-filled capsules at 6- to 8-hour intervals until clinical evidence of an adequate response is achieved.^{398 399 403}

Usual amount (i.e., total loading dose) of digoxin tablets or liquid-filled capsules that a 70-kg patient requires to achieve 8–12 mcg/kg peak body stores is 750–1250 mcg (0.75–1.25 mg) or 600–1000 mcg (0.6–1 mg), respectively.^{398 399 403}

IV

Usually, a single initial dose of 400–600 mcg (0.4–0.6 mg) IV produces a detectable effect in 5–30 minutes that becomes maximal in 1–4 hours.⁴⁰⁰

Cautiously administer additional doses of 100–300 mcg (0.1–0.3 mg) IV at 6- to 8-hour intervals until clinical evidence of an adequate response is achieved.⁴⁰⁰

Usual amount (i.e., total loading dose) of digoxin IV that a 70-kg patient requires to achieve 8–12 mcg/kg peak body stores is 600–1000 mcg (0.6–1 mg).⁴⁰⁰

Maintenance Dosage

Daily maintenance dosage is a replacement of daily digoxin loss from the body and can be estimated by multiplying the daily percentage loss by the peak body stores (i.e., loading dose).^{b 398 399 400 403}

About 30% of total digoxin in the body is eliminated daily in patients with normal renal function; anuric patients eliminate approximately 14% of the total digoxin stores daily.^b The % of digoxin eliminated from the body daily can be estimated by the following equation:^{b 398 399 400 403}

daily % loss = 14 + [creatinine clearance (in mL/min) / 5]

Use this method with caution, since Cl_cr does not accurately measure renal or total body clearance of digoxin.^b

Oral

Tablets: Usually, 125–500 mcg (0.125–0.5 mg) once daily; titrate according to the patient’s age, lean body weight, and renal function.^{398 399 403} Generally, initiate at 250 mcg (0.25 mg) once daily in patients <70 years of age with normal renal function; may increase dosage every 2 weeks according to clinical response.^{398 399 403}

Capsules (liquid-filled): Usually, 150–350 mcg (0.15–0.35 mg) daily in patients with Cl_cr of ≥50 mL/minute.³⁹⁹

IV

Usually, 125–350 mcg (0.125–0.35 mg) once daily in patients with Cl_cr of ≥50 mL/minute.⁴⁰⁰

Atrial Fibrillation

Peak digoxin body stores exceeding the 8–12 mcg/kg required for most patients with CHF and normal sinus rhythm have been used for control of ventricular rate in patients with atrial fibrillation.^{b 398 399 400 403}

In the treatment of chronic atrial fibrillation, titrate dosage to the minimum dosage that achieves the desired ventricular rate control without causing undesirable adverse effects.^{398 399 400 403} Appropriate target resting or exercising rates have not been established.^{398 399 400 403}

Special Populations

Hepatic Impairment

No dosage adjustment is necessary in liver disease if renal function is normal.^b

Renal Impairment

Loading doses (based upon projected peak digoxin body stores) in patients with renal insufficiency (particularly those with Cl_cr <10 mL/minute) should be conservative (i.e., based upon peak digoxin body stores of 6–10 mcg/kg) because of altered digoxin distribution and elimination.^{b 398 399 400 401 402 403}

Pediatric Patients: Cautiously adjust dosage based on clinical response.^{398 399 401 402 403}

Adults: For maintenance dosage, generally initiate at 125 mcg once daily orally (digoxin tablets) in patients with impaired renal function or at 62.5 mcg once daily orally (digoxin tablets) in patients with marked renal impairment; may increase dosage every 2 weeks according to clinical response.^{398 399 400 403}

Geriatric Patients

Reduce dosage, especially in those with CAD.^b

Advanced age may be an indicator of decreased renal function even in patients with normal S_cr (i.e., <1.5 mg/dL).^{398 399 400 401 402 403} (See Renal Impairment under Dosage and Administration.)

Geriatric Patients ≥70 years of age: For maintenance dosage, generally initiate at 125 mcg once daily orally (digoxin tablets).^{398 399 400 403}

Cautions for Digoxin

Contraindications

• 
  

  Ventricular fibrillation^{379 380 c}

  
  


• 
  

  Known hypersensitivity to digoxin or other digitalis preparations^{379 380 c}

  
  

Warnings/Precautions

Warnings

Sinus Node Disease and AV Block

Administer with caution in patients with incomplete AV block, especially in those with Adams-Stokes attacks, since digoxin may induce advanced or complete AV block.^{380 395}

If digoxin is used, a pacemaker should be inserted.^c

May be used in patients with severe bradycardia or complete, stable AV block who have CHF, if the block has not been induced by cardiac glycosides.^a

Accessory AV pathway (Wolff-Parkinson-White Syndrome) and Anomalous AV Conduction

Generally, should not be used alone in the management of W-P-W syndrome since it may enhance conduction via the accessory pathway and, in the presence of atrial fibrillation or flutter, result in extremely rapid ventricular rates and even ventricular fibrillation.^a

Generally, not used in the treatment of tachyarrhythmias, especially atrial fibrillation or flutter, in patients with anomalous AV conduction unless it has been shown that digoxin will not result in an increased ventricular rate via an effect on anomalous AV pathway conduction.^a

Patients with Preserved Left Ventricular Systolic Function

Certain disorders involving heart failure associated with preserved left ventricular ejection fraction (e.g., restrictive cardiomyopathy, constrictive pericarditis, amyloid heart disease, acute cor pulmonale) may be associated with particular susceptibility to digoxin toxicity.^{379 385}

Idiopathic Hypertrophic Subaortic Stenosis

Worsening of outflow obstruction as a result of the inotropic effects of digoxin in idiopathic hypertrophic subaortic stenosis.^a

Major Toxicities

Pathogenesis

Widespread use and the very narrow margin between effective therapeutic and toxic dosages contribute to the high incidence of toxicity and the relatively high associated mortality rate.^{250 251 257 258 259 260 270 295}

Toxic effects are mainly GI, CNS, biochemical, and cardiac in origin.^{46 107 257 261 262 263 264 265 266}

Minimum toxic and lethal doses are not well established.^{258 267}

Infants and children appear to be more tolerant to therapeutic and toxic actions;^{51 258 267 270 277 278 283 285} children without underlying cardiac problems usually can tolerate an acute dose of several mg of digoxin without potentially life-threatening cardiac toxicity.²⁶⁷

Serum digoxin concentrations are useful in confirming the diagnosis of intoxication; however, clinical diagnosis and management should not be based on serum concentrations alone but should always be interpreted in the overall clinical context with all other relevant information.^{232 257 265 270 274 277 395}

At least 6–10 hours usually are necessary for digoxin to equilibrate between plasma and tissue; plasma specimens drawn prior to this time may show glycoside concentrations greater than those present after equilibration.^{248 275 295 360 361}

Use in conjunction with diuretics is a frequent cause of chronic toxicity.^{270 277}

Failure to individualize dosage is another contributing factor in many cases of toxicity.^{258 266 272}

Manifestations

Overdosage is manifested by a wide variety of signs and symptoms that are difficult to distinguish from effects associated with cardiac disease (e.g., adverse GI effects, arrhythmias).^{12 262 263 266 270 273 274 275 276 278}

Before additional doses are administered, attempts should be made to determine whether the manifestations are digoxin induced.^{262 263 266 276 277}

If intoxication cannot be excluded, withhold digoxin therapy temporarily, if clinical situation permits.³⁸⁰

Extracardiac Effects

Extracardiac manifestations of intoxication are similar in both acute and chronic intoxication.^{261 274}

GI effects and, to a lesser extent, CNS and visual disturbances may be more pronounced following acute overdosage.^{261 274}

Acute toxicity may cause hyperkalemia, whereas chronic toxicity may be associated with hypokalemia or normokalemia.^{261 274}

Pediatric patients: Drowsiness^{52 258 269} and vomiting^{51 269} are most prominent extracardiac effects;²⁸¹ life-threatening cardiac arrhythmias have developed suddenly without evidence of any extracardiac signs of intoxication.^{269 282}

GI Effects

Anorexia,^{46 260 262 263 265} nausea,^{46 260 262 263 265 267} and vomiting^{46 260 262 263 265 267} are common early signs of toxicity and may precede or follow evidence of cardiotoxicity.^{50 262 263 277 380}

Large doses may produce emesis by direct GI irritation.^{258 270} Episodes of nausea and vomiting may start and stop abruptly.²⁷⁰

Nervous System Effects

Headache,^{38 46 48 66 261 262 265 266 267 268 270} fatigue,^{46 48 66 261 266 270 276} malaise,^{46 48 261 266 270 276} drowsiness,^{38 46 48 52 125 261 265 266 269 270}