Digoxin Immune Therapy

Digoxin immune Fab (Digibind) is an immunoglobulin fragment that binds with digoxin. It is
currently considered first-line treatment for significant dysrhythmias (eg, severe
bradyarrhythmia, second- or third-degree heart block, ventricular tachycardia or fibrillation)
from digitalis toxicity. This agent should be promptly administered if digoxin toxicity is
suspected as the cause of such arrhythmias.
[17, 22, 23]

Other indications for immunotherapy with digoxin Fab fragment include the following:
Ingestion of massive quantities of digitalis (in children, 4 mg or 0.1 mg/kg; in adults, 10 mg)
Serum digoxin level greater than 10 ng/mL in adults at steady state (ie, 6-8 hours after acute
ingestion or at baseline in chronic toxicity)
Hyperkalemia (serum potassium level greater than 5 mEq/L)
Altered mental status attributed to digoxin toxicity
Rapidly progressive signs and symptoms of toxicity
Digoxin immune Fab is packaged in a 40-mg vial and must be reconstituted with 4 mL of sterile
water for IV injection, furnishing an iso-osmotic solution. For small infants, this preparation can
be diluted further with sterile isotonic saline. Once the product is reconstituted, it should be used
immediately or, if refrigerated, used within 4 hours. It is administered IV over 30 minutes via a
0.22-m membrane filter. In an unstable clinical situation, this agent is administered by IV bolus.
A loading dose of Fab followed by a maintenance infusion is beneficial to the optimization of
binding to Fab. The loading dose immediately captures digoxin already in the vascular space,
and the maintenance dose provides enough Fab to continue to draw digoxin from the tissue into
the serum to be bound. In acute, intentional overdose, administration of 4-6 vials as a loading
dose, followed by 0.5 mg/min for 8 hours and then 0.1 mg/min for about 6 hours, appears to be
safe and effective.
Initially administering half doses is the best approach in patients with chronic toxicity who are
dependent on digoxin. This avoids completely reversing the clinical effects of digoxin and
precipitating complications. Depending on the patient's status, additional doses may be
administered later.
A response is typically observed within 20-30 minutes after infusion. The elimination half-life of
the drug-antibody complex is about 16 hours (range, 20-30 h). Affinity for digitoxin is 10 times
less than for digoxin. In a case series that included pediatric patients, there was a 90-93%
response rate within minutes or hours, with complete resolution within 180 minutes in as many
as 79% of patients. The mean time to the initial response was 19 minutes; complete resolution of
symptoms occurred in 88 minutes.
Digoxin levels drawn after administration of Fab fragments may be exponentially higher because
many assays for measuring digoxin measure total digoxin (including digoxin bound to Fab
fragments). This may be misinterpreted as a therapeutic failure and worsening toxicity.
Conventional digoxin assays remain unreliable for 1-2 weeks after the therapy. Assays that
measure only free digoxin are accurate and should reflect true posttreatment levels, but these
assays are not available at most hospitals.
Complications
In a long-term digoxin user who requires Fab treatment for digitalis toxicity, administration can
precipitate worsening heart failure by removing the beneficial inotropic activity of digoxin,
causing hypokalemia and atrial arrhythmia with rapid ventricular response.
Hypokalemia has occurred in patients who were treated with standard therapy, as well as with
Fab fragments. Clinically adverse phenomena have occurred in fewer than 10% of patients
treated with immunotherapy.
Other untoward effects of Fab include anaphylaxis and serum sickness, because it is a sheep
protein; these reactions are uncommon. Allergy to Fab fragments tends to occur in patients who
have multiple allergies.
The elimination half-life of the digoxin-Fab complex is 20-30 hours, although clearance is
related directly to the glomerular filtration rate and consequently is prolonged in renal
insufficiency. Recrudescence of digoxin toxicity is possible within 7-14 days, because the Fab
complex is eliminated more rapidly than digoxin is released from tissue-binding sites.
Plasmapheresis may be performed or the agent readministered in such situations.
Management of Dysrhythmias
Management of dysrhythmias varies, depending on the following factors:
Presence or absence of hemodynamic instability
Nature of the dysrhythmia
Presence or absence of electrolyte disturbances
Preferences of toxicology and/or cardiology consultants
In hemodynamically stable patients, bradyarrhythmias and supraventricular arrhythmias may be
treated with observation and supportive care. Discontinue the drug and ensure proper hydration
to optimize renal clearance of excess drug. Gastrointestinal (GI) binding agents (eg, activated
charcoal, cholestyramine) may be used to bind enterohepatically recycled digitalis. For patients
with rate-related ischemia or hemodynamic instability, digoxin Fab fragments is the treatment of
choice.
Short-acting beta blockers (eg, esmolol) may be helpful for supraventricular tachyarrhythmias
with rapid ventricular rates, but these agents may precipitate advanced or complete
atrioventricular (AV) block in patients with sinoatrial or AV node depression. Calcium channel
blockers are contraindicated because they may increase digoxin levels.
Premature ventricular contractions (PVCs), bigeminy, or trigeminy may require only observation
unless the patient is hemodynamically unstable, in which case lidocaine may be effective.
Ventricular tachycardia responds best to digoxin immune therapy, but phenytoin and lidocaine
are useful if immune therapy is ineffective or unavailable.
[24]
These drugs depress the enhanced
ventricular automaticity without significantly slowing AV conduction; indeed, phenytoin may
reverse digitalis-induced prolongation of AV nodal conduction.
Phenytoin has been shown to dissociate the inotropic and dysrhythmic action of digitalis, thus
suppressing digitalis-induced tachydysrhythmias without diminishing the contractile effects. In
addition, phenytoin can terminate supraventricular dysrhythmias induced by digitalis, whereas
lidocaine has not been as effective.
Lidocaine may be given in boluses of 100 mg, according to advanced cardiac life support
(ACLS) guidelines. If this is successful, begin a maintenance infusion at 1-4 mg/min. Phenytoin
has been administered in boluses of 100 mg every 5-10 minutes, up to a loading dose of 15
mg/kg.
Atropine may be useful in blocking digoxin-induced effects of enhanced vagal tone on the
sinoatrial (SA) and AV nodes. It has proved helpful in reversing severe sinus bradycardia.
Magnesium sulfate, 2 g IV over 5 minutes, has been shown to terminate dysrhythmias in
digoxin-toxic patients with and without overt cardiac disease. After the initial bolus, a
maintenance infusion at 1-2 g/h is initiated. Monitor magnesium levels approximately every 2
hours. The therapeutic goal is a level between 4 and 5 mEq/L. Serial monitoring of serum
magnesium levels, telemetry, respiratory rate, deep tendon reflexes, and blood pressure is
appropriate.
Magnesium is contraindicated in the setting of bradycardia or AV block and should be used
cautiously in patients with renal failure. It is unclear how well magnesium levels correlate with
digitalis toxicity.
[24]

Asystole and ventricular fibrillation are very ominous findings. Digoxin immune therapy is
indicated in such cases; however, its effect is limited by poor cardiac blood flow. Nevertheless,
the use of immune therapy has been associated with a 50% survival rate in isolated case reports.
Quinidine and procainamide are contraindicated. These agents worsen SA, AV, and His-Purkinje
conductivity. Additionally, quinidine reduces digoxin tissue binding and renal clearance, thereby
increasing digoxin levels. Bretylium, which is no longer available in the United States, is also
contraindicated, as it can precipitate ventricular dysrhythmia.
[24]

Electrical cardioversion and pacing
Cardioversion for severe dysrhythmias due to digitalis is hazardous; it can precipitate ventricular
fibrillation and asystole. However, if the patient is hemodynamically unstable and has a wide,
complex tachycardia and if fascicular tachycardia has been ruled out, cardioversion will need to
be used early.
If the history is consistent with digitalis intoxication, a minimal effective dose is best. Some
clinicians have suggested using 10-25 joules initially in ventricular tachycardia or fibrillation,
but most clinicians suggest starting at 50-100 joules for a wide, complex ventricular tachycardia,
rather than at the 200 joules recommended in ACLS protocols.
With the availability of digoxin-specific Fab, pacemaker use now has limited value. In one study,
the main reason for Fab failure was pacing-induced arrhythmias and delayed or insufficient
administration of Fab. This study also demonstrated a 36% complication rate with pacing.
Hospital Admission
Admission criteria include the following:
New cardiac dysrhythmias
Severe bradyarrhythmias
Advanced AV block
Acute prolongation of the QRS interval
Severe electrolyte abnormalities, especially hypokalemia or hyperkalemia
Dehydration
Inability to care for self
Suicidal ideation
Admit patients with cardiac abnormalities to a monitored bed. Intensive care unit (ICU)
admission criteria include the following:
Hemodynamic instability
Refractory dysrhythmias
Hyperkalemia
Renal failure
Admit patients receiving digoxin immune Fab to the ICU or critical care unit (CCU). Any patient
receiving Fab fragments requires observation in an intensive care setting for at least 24 hours.
Patients who have had an unintentional exposure but exhibit no signs or symptoms of toxicity
after 12 hours can be discharged from the hospital.
Transfer may be indicated if patient is unstable and the hospital has no ICU or CCU capabilities
or no appropriate consultants (eg, toxicologist, cardiologist, intensivist) or when digoxin immune
therapy (if indicated) is not available. Treatment is best discussed with the regional poison
control center and the patient's primary care provider.
Prevention
Digoxin toxicity may develop in patients with dehydration, worsening renal function, or new
electrolyte disturbances. Drug interactions are an important causative factor. Careful patient
monitoring, including drug levels, is required in these clinical settings.
Advanced age decreases the volume of distribution and renal clearance. Elderly patients and
those with chronic renal failure require lower maintenance doses.
Consultations
The following consultations may be employed:
Cardiologists
Nephrologists
Regional poison control centers
Medical toxicologists
Long-Term Monitoring
Patients with accidental exposure and no sign of toxicity after 12 hours can be discharged home with
appropriate follow-up. Observe patients for at least 6 hours on a cardiac monitor. In the absence of
cardiac dysrhythmias, toxic digoxin levels, or hyperkalemia, patients may be discharged with appropriate
follow-up care.
Patients with chronic toxicity and noncardiac symptoms may be discharged if factors that led to the
toxicity have been corrected (eg, electrolyte disorders, dehydration, drug-drug interactions) and proper
care can be ensured. Discontinue use of the drug. Arrange follow-up care in the next 24 hours with a
primary care provider. Patients who have taken an intentional overdose should be cleared by a psychiatry
consult before discharge.
GENERIC NAME: furosemide
BRAND NAME: Lasix
DRUG CLASS AND MECHANISM: Furosemide is a potent diuretic (water pill) that is used to
eliminate water and salt from the body. In the kidneys, salt (composed of sodium and chloride),
water, and other small molecules normally are filtered out of the blood and into the tubules of the
kidney. The filtered fluid ultimately becomes urine. Most of the sodium, chloride and water that is
filtered out of the blood is reabsorbed into the blood before the filtered fluid becomes urine and is
eliminated from the body. Furosemide works by blocking the absorption of sodium, chloride, and
water from the filtered fluid in the kidney tubules, causing a profound increase in the output of urine
(diuresis). The onset of action after oral administration is within one hour, and the diuresis lasts
about 6-8 hours. The onset of action after injection is five minutes and the duration of diuresis is two
hours. The diuretic effect of furosemide can cause depletion of sodium, chloride, body water and
other minerals. Therefore, careful medical supervision is necessary during treatment. The FDA
approved furosemide in July 1982.
PRESCRIPTION: Yes
GENERIC AVAILABLE: Yes
PREPARATIONS: Tablets: 20, 40, and 80mg. Oral solution: 10 mg/ml, 40 mg/5 ml. Injection: 10
mg/ml
STORAGE: Furosemide should be stored at room temperature in a light resistant container.
PRESCRIBED FOR: Furosemide is a powerful diuretic that is used to treat excessive accumulation
of fluid and/or swelling (edema) of the body caused by heart failure, cirrhosis, chronic kidney failure,
and the nephrotic syndrome. It is sometimes used alone or in conjunction with other blood pressure
pills to treat high blood pressure.
DOSING: The usual starting oral dose for treatment of edema in adults is 20-80 mg as a single
dose. The same dose or an increased dose may be administered 6-8 hours later. Doses may be
increased 20-40 mg every 6-8 hours until the desired effect occurs. The effective dose may be
administered once or twice daily. Some patients may require 600 mg daily. The starting oral dose for
children is 2 mg/kg. The starting dose may be increased by 1-2 mg/kg every 6 hours until the desired
effect is achieved. Doses greater than 6 mg/kg are not recommended. The recommended dose for
treating hypertension is 40 mg twice daily.
DRUG INTERACTIONS: Administration of furosemide with aminoglycoside antibiotics (for example,
gentamicin) or [ethacrynic acid (Edecrin) - another diuretic] may cause hearing damage. Furosemide
competes with aspirin for elimination in the urine by the kidneys. Concomitant use of furosemide and
aspirin may, therefore, lead to high blood levels of aspirin and aspirin toxicity. Furosemide also may
reduce excretion of lithium (Eskalith, Lithobid) by the kidneys, causing increased blood levels of
lithium and possible side effects from lithium. Sucralfate (Carafate) reduces the action of furosemide
by binding furosemide in the intestine and preventing its absorption into the body. Ingestion of
furosemide and sucralfate should be separated by two hours.
PREGNANCY: There are no adequate studies of furosemide in pregnant women.
NURSING MOTHERS: Furosemide is secreted in breast milk. Nursing mothers should
avoid breastfeeding while taking furosemide.
SIDE EFFECTS: Common side effects of furosemide include low blood
pressure, dehydration and electrolyte depletion (for example, sodium, potassium). Less common
side effects include jaundice, ringing in the ears (tinnitus), sensitivity to light
(photophobia), rash, pancreatitis, nausea,diarrhea, abdominal pain, and dizziness. Increased blood
sugar and uric acid levels also may occur

GENERIC NAME: lisinopril
BRAND NAME: Zestril, Prinivil
DRUG CLASS AND MECHANISM: Lisinopril is an angiotensin converting enzyme (ACE) inhibitor
used for treating high blood pressure, heart failureand for preventing kidney failure due to high blood
pressure and diabetes. Other ACE inhibitors
include enalapril (Vasotec), quinapril (Accupril),captopril (Capoten), fosinopril
(Monopril), benazepril (Lotensin), ramipril(Altace), moexipril (Univasc) and trandolapril (Mavik).
ACE is important because it is an enzyme responsible for producing the chemical, angiotensin II.
Angiotensin II causes muscles in most arteries, including the arteries of the heart, to contract,
thereby narrowing the arteries and elevating blood pressure. ACE inhibitors such as lisinopril lower
blood pressure by reducing the production of angiotensin II, thereby relaxing arterial muscle and
enlarging arteries. When the blood pressure is lower, the heart - including the failing heart - does not
have to work as hard to pump blood. The arteries supplying the heart with blood also enlarge during
treatment with ACE inhibitors. This increases the flow of blood and oxygen to the heart, further
improving the ability of the heart to pump blood.
The effects of ACE inhibitors are particularly beneficial to people withcongestive heart failure. In the
kidneys, the narrowing of the arteries by angiotensin II decreases blood flow and damages the
kidneys. ACE inhibitors enlarge and reduce the blood pressure in the arteries going to the kidney.
This reduces damage to the kidneys caused by the high blood pressure. The FDA approved lisinopril
in December 1987.
PRESCRIPTION: Yes
GENERIC AVAILABLE: Yes
PREPARATIONS: Tablet: 2.5, 5, 10, 20, 30 and 40 mg
STORAGE: Lisinopril should be stored in a dry place at 15-30 C (59-86 F).
PRESCRIBED FOR: Lisinopril is used to treat elevated blood pressure, heart failure and to improve
survival after a heart attack (myocardial infarction). Like other ACE inhibitors it is also used for
preventing kidney failure due to high blood pressure or diabetes even though it is not FDA approved
for this use.
DOSING: The starting dose of lisinopril is 5 mg daily, and the effective dose range for treating heart
failure is 5-20 mg daily. The dose can be increased by 10 mg every 2 weeks to achieve the
maximum effect.
The starting dose of lisinopril for treating high blood pressure is 10 mg daily. The usual dose range is
20-40 mg daily. A dose of 80 mg is not much more effective than 40 mg.
Treatment of heart attack (myocardial infarction) is started with individual doses of 5 mg followed by
5 mg after 24 hours, 10 mg after 48 hours and then 10 mg daily. Treatment is continued for 6 weeks.
DRUG INTERACTIONS: In general, lisinopril should not be taken with potassium supplements or
diuretics that conserve potassium, for example, hydrochlorothiazide/triamterene (Dyazide), since
blood potassium levels may rise to dangerous levels.
There have been reports of increased lithium (Eskalith, Lithobid) levels when lithium is used in
combination with ACE inhibitors. The reason for this interaction is not known.
There have been reports that aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDS) such
as ibuprofen (Advil, Children's Advil/Motrin, Medipren, Motrin, Nuprin, PediaCare Fever, and many
others),indomethacin (Indocin, Indocin-SR), and naproxen (Anaprox, Naprelan, Naprosyn, Aleve)
may reduce the effects of ACE inhibitors.
Nitritoid reactions (symptoms of facial flushing, nausea, vomiting andhypotension) may occur when
injectable gold (sodium aurothiomalate), used in the treatment of rheumatoid arthritis, is combined
with ACE inhibitors, including lisinopril.
PREGNANCY: Lisinopril should not be taken during pregnancy because fetuses and neonates have
died when lisinopril was administered during pregnancy.
NURSING MOTHERS: It is not known whether lisinopril is excreted in breast milk.
SIDE EFFECTS: First doses of lisinopril can cause dizziness due to a drop in blood pressure.
Lisinopril can cause nausea, headaches, anxiety,insomnia, drowsiness, nasal congestion, and
sexual dysfunction. Like all ACE inhibitors, lisinopril may cause a nonproductive cough that resolves
when the drug is discontinued. Lisinopril should be stopped if there are symptoms or signs of an
allergic reaction including feelings of swelling of the face, lips, tongue or throat. Severe allergic
reactions (anaphylaxis) andhives occasionally occur. Rarely, lisinopril may cause a decrease in red
blood cells (anemia), white blood cells (leukopenia), and platelets (thrombocytopenia).

WARNING: This drug can cause serious (possibly fatal) harm to an unborn baby if used
during pregnancy. Therefore, it is important to prevent pregnancy while taking this medication.
Consult your doctor for more details and to discuss the use of reliable forms of birth control while
taking this medication. If you are planning pregnancy, become pregnant, or think you may be
pregnant, contact your doctor immediately.
GENERIC NAME: digoxin
BRAND NAME: Lanoxin
DRUG CLASS AND MECHANISM: Digoxin increases the strength and vigor of heart contractions,
and is useful in the treatment of heart failure. It is extracted from the leaves of a plant called digitalis
lanata. Digoxin increases the force of contraction of the muscle of the heart by inhibiting the activity
of an enzyme (ATPase) that controls movement of calcium, sodium andpotassium into heart muscle.
Calcium controls the force of contraction. Inhibiting ATPase increases calcium in heart muscle and
therefore increases the force of heart contractions. Digoxin also slows electrical conduction between
the atria and the ventricles of the heart and is useful in treating abnormally rapid atrial rhythms such
as atrial fibrillation, atrial flutter, and atrial tachycardia. (Abnormally rapid atrial rhythms can be
caused by heart attacks, excessive thyroid hormones, alcoholism, infections, and many other
conditions.) During rapid atrial rhythms, electrical signals from the atria cause rapid contractions of
the ventricles. Rapid ventricular contractions are inefficient in pumping blood containing oxygen and
nutrients to the body, causing symptoms of weakness, shortness of breath, dizziness, and
even chest pain. Digoxin alleviates these symptoms by blocking the electrical conduction between
the atria and ventricles, thus slowing ventricular contractions. The FDA approved digoxin in 1975.
PRESCRIPTION: Yes
GENERIC AVAILABLE: Yes
PREPARATIONS: Tablets: 0.125, and 0.25 mg; Elixir: 0.05, 0.25, and 0.1 mg/ml.
STORAGE: Digoxin should be stored at room temperature, 59-86 F (15-30 C) and protected from
light.
PRESCRIBED FOR: Digoxin is used for mild to moderate congestive heart failure and for treating
an abnormal heart rhythm called atrial fibrillation.
DOSING: Digoxin may be taken with or without food. Digoxin is primarily eliminated by the kidneys;
therefore, the dose of digoxin should be reduced in patients with kidney dysfunction. Digoxin blood
levels are used for adjusting doses in order to avoid toxicity. The usual starting dose is 0.0625-0.25
mg daily depending on age and kidney function. The dose may be increased every two weeks to
achieve the desired response.
DRUG INTERACTIONS: Drugs such as verapamil (Calan, Verelan, Verelan PM, Isoptin, Isoptin SR,
Covera-HS), quinidine (Quinaglute, Quinide),amiodarone (Cordarone), indomethacin (Indocin,
Indocin-SR), alprazolam(Xanax, Xanax XR, Niravam), spironolactone (Aldactone),
and itraconazole(Sporanox) can increase digoxin levels and the risk of toxicity. The co-
administration of digoxin and beta-blockers [for example propranolol(Inderal, Inderal LA) or calcium
channel blockers (for example, verapamil), which also reduces heart rate, can cause serious slowing
of the heart rate.
SIDE EFFECTS: Common side effects include nausea, vomiting, headache, dizziness, skin rash,
and mental changes. Many digoxin side effects are dose dependent and happen when blood levels
are over the narrow therapeutic range. Therefore, digoxin side effects can be avoided by keeping
blood levels within the therapeutic level. Serious side effects associated with digoxin include heart
block, rapid heartbeat, and slow heart rate. Digoxin has also been associated with visual disturbance
(blurred or yellow vision), abdominal pain, and breast enlargement. Patients with low blood
potassium levels can develop digoxin toxicity even when digoxin levels are not considered elevated.
Similarly, high calcium and low magnesium blood levels can increase digoxin toxicity and produce
serious disturbances in heart rhythm.

USES: Digoxin is used to treat heart failure, usually along with other medications. It is also used to
treat a certain type of irregular heartbeat (chronic atrial fibrillation). Treating heart failure may help
maintain your ability to walk and exercise and may improve the strength of your heart. Treating an
irregular heartbeat can decrease the risk for blood clots, an effect that may reduce your risk for
a heart attack or stroke.Digoxin belongs to a class of medications called cardiac glycosides. It works
by affecting certain minerals (sodium and potassium) inside heart cells. This reduces strain on the
heart and helps it maintain a normal, steady, and strong heartbeat.

INTRODUCTION Cardiac glycosides have important positive inotropic, neurohormonal, and
electrophysiologic actions, which are the basis for its use in two clinical situations: heart failure due to
systolic dysfunction, and in certain supraventricular tachyarrhythmias. The ability of digoxin to reduce
sympathetic activation has also been recognized. For maximal early benefits, digoxin requires loading
doses, which can be administered intravenously or orally. (See "Use of digoxin in heart failure due to
systolic dysfunction", section on 'Mechanism of action' and "Control of ventricular rate in atrial fibrillation:
Pharmacologic therapy", section on 'Digoxin'.)
While two cardiac glycosides (digoxin and digitoxin) were previously used, digitoxin has not been widely
available since the 1980s. As digoxin is now the only cardiac glycoside available in most countries, the
method of initiating therapy with digoxin is presented here. Recommendations regarding the use of
digoxin in the management of heart failure or arrhythmias are discussed separately. (See "Use of digoxin
in heart failure due to systolic dysfunction" and "Control of ventricular rate in atrial fibrillation:
Pharmacologic therapy", section on 'Digoxin'.)
INITIATION OF THERAPY The electrolyte and renal status of each patient should be ascertained prior
to initiating treatment and periodically thereafter. Hypokalemia or hypomagnesemia, for example, may
promote the development of digoxin-induced arrhythmias, while impaired renal function may result in
higher than anticipated serum drug levels. (See 'Dose adjustments' below.)
The initiation of digoxin therapy has been divided into rapid and slow digitalization followed by the
maintenance digoxin dose, and the proposed regimens vary considerably. The following principles should
be viewed as a general guide to the use of digoxin for its inotropic or electrophysiologic effects, which
must be modified according to clinical circumstances. Patients receiving digoxin for ventricular rate control
in atrial fibrillation or flutter will usually require more rapid loading and higher maintenance doses than
those treated with digoxin for heart failure, in whom a loading dose is typically not required. Doses used
are smaller and blood levels are lower than those needed for the inotropic effect but are generally
sufficient to reduce the sympathetic activation associated with heart failure, the primary mechanism of
benefit in heart failure patients.
Rapid digoxin loading Rapid intravenous and oral digitalization is often used to control the ventricular
response in atrial fibrillation and flutter. However, other drugs may be more effective and/or have a more
rapid onset of action on the ventricular response in these arrhythmias; therefore, rapid digitalization is
rarely needed unless alternative drugs are contraindicated or have not been effective. (See "Control of
ventricular rate in atrial fibrillation: Pharmacologic therapy", section on 'Pharmacologic
treatment' and"Control of ventricular rate in atrial flutter", section on 'Rate control with drugs'.)
The total loading dose with digoxin varies from patient to patient but is usually between 0.75 to 1.5 mg
with intravenous administration and 1 to 1.5 mg with oral administration. (See 'Dose adjustment in renal
disease' below and 'Patients with low body weight' below.)
Intravenous loading For ventricular rate control in atrial fibrillation and flutter, the most rapid
means of digitalization is the intravenous route. An initial intravenous dose of 0.25 to 0.5 mg
of digoxin is given over several minutes, followed by 0.25 mg every 6 hours for a total loading
dose of 0.75 to 1.5 mg (10 to 12 mcg/kg lean body weight) (calculator 1 and calculator 2).
Intravenous digoxin begins to act in 15 to 30 minutes with a peak effect in 1 to 5 hours.
Oral loading Rapid oral digitalization can be accomplished by giving 0.5 mg initially followed by
0.25 mg every six hours for a total loading dose of 0.75 to 1.5 mg.
Slow digoxin loading Slow oral digitalization can be achieved by starting a maintenance dose of
0.125 to 0.25 mg daily. A steady state will be achieved after five cycles of the drug half-life (T1/2), which
is approximately 7 to 10 days in the average subject.
Loading dose adjustments Patients who are hypokalemic, hypomagnesemic, hypercalcemic,
hypoxic, or with hypothyroidism are more sensitive to the effects ofdigoxin. If these issues persist at the
time of digoxin loading, an initial loading dose in the lower range (eg, 0.75 mg or less) should be
considered.
Digoxin distributes widely to skeletal muscle, cardiac, and other lean tissue and has a large volume of
distribution (ie, 4 to 7 L/kg) in normal subjects, which is decreased in patients who are older, have low
skeletal muscle mass, or severe renal impairment. Digoxin serum concentrations relative to the
administered loading dose may be proportionally increased among persons with low muscle
mass and/or renal impairment, and a reduced loading dose should be considered.
Renal impairment The digoxin loading dose should be reduced by approximately one-third to one-half
in the setting of severe chronic renal insufficiency, including hemodialysis [1-3]. The reduced loading dose
may be supplemented after six hours if clinical response is inadequate, in absence of toxicity.
Lean body weight In general, it is reasonable to select an initial loading dose in the lower range (ie,
0.75 to 1 mg) for patients of low to average lean body weight (eg, 45 to 70 kg) and in the upper part of the
dose range (ie, 1 to 1.5 mg) for patients of average to above average lean body weight (eg, 71 to 90 kg)
(calculator 1 and calculator 2).
Patients with low body weight Patients with body weight of less than 45 kg should receive 50
percent of the normal loading dose.
Patients who are obese Compared with normal weight subjects, neither volume of distribution nor
clearance of digoxin are consistently altered by changes in body composition associated with obesity [4-
6]. Therefore, normal (non-weight based) loading doses should be used. However, if a weight based dose
is used, it should be based upon estimated lean body weight (calculator 1 and calculator 2).
Maintenance digoxin dosing For most patients, the maintenance dose of digoxin will be between
0.125 mg and 0.25 mg daily. The daily maintenance dose will vary depending on the indication for digoxin
therapy, with patients receiving digoxin for heart failure typically requiring lower doses (and targeting
lower serum levels) than those who are taking digoxin for ventricular rate control. Additionally, the
maintenance dose is affected by renal function, body weight, and the presence or absence of other
medications which are known to alter the metabolism of digoxin. (See 'Dose adjustments' below.)
Heart failure For patients taking digoxin for heart failure, in whom the target serum digoxin level
is between 0.5 and 0.8 ng/mL (0.65 to 1 nmol/L), the typical daily dose will range from 0.0625 mg
(given as 0.125 mg every other day) to 0.25 mg. A nomogram for determining an initial
maintenance dose for patients with congestive heart failure based upon ideal body weight and
renal function and targeting a serum concentration of 0.7 ng/mL is provided in the table (table 1)
[7]. Slow oral digitalization (ie, without a loading dose) requires 7 to 10 days in most subjects and
up to 3 weeks in the setting of severe renal impairment to reach a steady state serum
concentration. The evaluation of serum digoxin levels and consideration of dose adjustment
should be deferred until after a steady state concentration is achieved. (See 'Monitoring serum
digoxin' below.)
Ventricular rate control For patients taking digoxin for ventricular rate control in the setting of
atrial arrhythmias, the typical maintenance dose is between 0.125 and 0.25 mg daily. In contrast
to digoxin use for heart failure, there is no particular serum digoxin level which is targeted, as the
medication should be adjusted to maintain optimal ventricular rate control. However, serum
digoxin levels higher than 2 ng/mL (2.6 nmol/L) should be avoided to reduce the risk of digoxin
toxicity.
Dose adjustments Bioavailability is between 70 and 80 percent for conventional digoxin tablets and
between 75 and 85 percent for digoxin elixir, and the T1/2 of digoxin ranges from 33 to 50 hours when
renal function is normal (table 2). Unlike certain other drugs (eg, furosemide), the bioavailability of the oral
dose forms of digoxin does not appear to be affected by heart failure. Dose adjustments of digoxin are
necessary in patients with renal dysfunction, patients with low body weight, and with the concomitant use
of certain medications. The effect of digoxin in patients with heart failure and the need for dose
adjustments in such patients are discussed separately. (See "Use of digoxin in heart failure due to
systolic dysfunction".)
Dose adjustment in renal disease Approximately 70 to 80 percent of digoxin is eliminated
unchanged in the urine, leading to prolongation of the half-life in patients with renal insufficiency. Renal
insufficiency also decreases the extravascular volume of distribution of digoxin, another effect that can
elevate plasma drug levels. As a result,both the initial loading dose and the maintenance dose must
be reduced in patients with underlying renal disease. In end-stage renal disease, for example, the
loading dose should be one-half to two-thirds normal.
Adjustment of loading dose The adjustment of the digoxin loading dose is discussed above.
(See 'Renal impairment' above.)
Adjustment of maintenance dose The initial maintenance dose for congestive heart failure adjusted
for ideal body weight and renal function is presented in the table (table 1).
Dose adjustment with hepatic disease Hepatic disease has little influence on digoxin metabolism or
clearance; therefore, no dose adjustment is necessary.
Dose adjustment with concomitant medications There are a number of important drug interactions:
Quinidine, propafenone, verapamil, and amiodarone can increase serum digoxin levels. With
concurrent quinidine administration, for example, the digoxin dose should be reduced by one-half
[8-11].
Cholestyramine and antacids, on the other hand, can decrease the intestinal absorption
of digoxin by 20 to 35 percent, necessitating an increase in the daily dose. To avoid these
interactions, digoxin should be dosed one hour before or two to three hours after the
administration of the antacids or cholestyramine.
Diuretics may increase digitalis toxicity as a result of a decrease in the glomerular filtration rate
and the development of electrolyte abnormalities, especially hypokalemia.
Tetracycline and erythromycin can interfere with the sequential hydrolysis pathway
of digoxin metabolism (which begins in the stomach and is responsible for less than 15 percent of
the metabolism in most patients but which can be significantly more active in a minority of
patients). As such, these drugs increase digoxin levels in approximately 10 percent of patients in
whom this pathway is a significant component of the drug's metabolism.
Digoxin in pregnancy Digoxin crosses the placenta and has been used for both fetal and maternal
cardiac indications without report of fetal harm or teratogenicity [12]. As such, there is no contraindication
for using digoxin during pregnancy or during lactation.
Digoxin in patients with amyloidosis The inotropic effects of digoxin are not generally beneficial in
patients with amyloidosis. Moreover, because digoxin binds avidly to amyloid fibrils, patients with
amyloidosis who take digoxin may be at an increased risk of digoxin toxicity [13]. Additionally, as a result
of the binding of digoxin to myocardial amyloid fibrils, cardiac digoxin concentration may be higher than
serum digoxin concentration, leading to toxicity in the setting of "therapeutic" serum digoxin levels.
However, in a patient with atrial fibrillation with a rapid ventricular response, careful digoxin administration
is usually safe and effective for reducing the ventricular rate [14].
MONITORING SERUM DIGOXIN
Monitoring Given the relatively narrow therapeutic window of digoxin, with substantial overlap
between so-called therapeutic and toxic levels, patients taking digoxin require monitoring of the serum
digoxin concentration, with the "optimal" level varying with the clinical setting. Monitoring the serum
digoxin level is particularly important in persons with chronic renal dysfunction or rapidly changing renal
function, as significantly decreased renal function can lead to accumulation of digoxin and its metabolites
and predispose to digoxin toxicity. Additionally, patients with electrolyte disturbances, particularly
hypokalemia and hypomagnesemia, which may be related to diuretic therapy or other medications, are at
increased risk for digoxin-associated arrhythmias and should undergo monitoring of the serum digoxin
level until serum potassium level and magnesium concentration return to the normal range [15].
(See 'Dose adjustments' above and "Cardiac arrhythmias due to digoxin toxicity", section on 'Plasma
digoxin levels associated with toxicity'.)
Monitoring the serum digoxin concentration is most important when digoxin is used in the treatment of
heart failure with systolic dysfunction, whereas levels are only checked when used in patients with atrial
fibrillation if toxicity is suspected. Blood samples should be obtained at least 6 hours, but optimally 12
hours, after administration of digoxin to ensure completion of distribution from the blood to the tissues. In
patients with advanced kidney disease or who are on hemodialysis, the digoxin level should be checked
at least 12 to 24 hours after the prior dose. Serum digoxin concentrations measured prior to these times
may be falsely elevated.
Adjusting the digoxin dose Assuming that the digoxin level was drawn at the correct time, at steady
state, and under conditions of stable renal function, there is a linear relationship between digoxin dose
and serum concentration. As an example, a steady state concentration is measured and returns at
1.6 ng/mL (2.05 nmol/L) in a patient taking a daily maintenance dose (for this example, 0.25 mg daily).
Assuming the desired serum concentration is 0.8 ng/mL (1.0 nmol/L), the dose should be reduced by 50
percent (to 0.125 mg daily in this example). The same linear relationship is true for patients whose serum
concentration is lower than desired in whom a dose increase is needed.
Heart failure When digoxin is used in the treatment of heart failure, the serum digoxin level should be
measured 7 to 10 days after starting digoxin or changing the dose of digoxin, at which point a steady
state should have been achieved. For patients with heart failure, the target serum digoxin level for
maximal efficacy and minimal risk of toxicity is between 0.5 and 0.8 ng/mL (0.65 to 1 nmol/L) for maximal
efficacy with minimal risk of toxicity (figure 1) [16,17]. Higher serum levels should be avoided since they
are associated with an increased risk of toxicity without clear evidence of enhanced efficacy. If the patient
is subsequently stable, monitoring is repeated every 3 to 6 months or when there is a change in clinical
status or toxicity is suspected.
Clinical trials in patients with normal sinus rhythm that demonstrated benefit from digoxin therapy have
targeted mean serum digoxin concentrations ranging from 0.5 to 1.75ng/mL (0.65 to 2.25 nmol/L) [18-20].
The doses used to achieve these values ranged from 0.125 to 0.5 mg per day [18]. Post hoc analyses
from the DIG trial demonstrated improved outcomes in patients with serum digoxin levels of 0.5 to
0.8 ng/mL (0.65 to 1 nmol/L) [16,21,22]. In contrast, higher serum levels were associated with increased
mortality. (See "Use of digoxin in heart failure due to systolic dysfunction", section on 'Optimal digoxin
level'.)
Atrial fibrillation Digoxin is generally less effective for rate control of atrial fibrillation (AF) than beta
blockers or calcium channel blockers, is less likely to control the ventricular rate during exercise (when
vagal tone is low and sympathetic tone is high), has little or no ability to terminate the arrhythmia, and
often does not slow the heart rate with recurrent AF. Thus, large doses of digoxin are often required for
monotherapy, and patients frequently require the addition of a beta blocker or calcium channel blocker for
optimal rate control. (See "Control of ventricular rate in atrial fibrillation: Pharmacologic therapy".)
When digoxin is used strictly for ventricular rate control in AF, serum digoxin levels should be monitored
periodically, although the drug concentration often does not correlate with ventricular rate control and is
used more as a guide to toxicity than to therapy. Junctional escape beats (as detected by the equality of
all the longest observed R-R intervals on the electrocardiogram) are common when digitalis has
successfully slowed the ventricular rate. Giving more digoxin in this setting will increase the degree of AV
nodal block and produce periods of regular junctional rhythm. The change from single junctional escapes
to periodic junctional rhythm usually signifies the development of digoxin toxicity. (See "The
electrocardiogram in atrial fibrillation", section on 'Effect of high degrees of AV nodal block and exit block
on ventricular response' and "Cardiac arrhythmias due to digoxin toxicity", section on 'Junctional rhythm,
tachycardia, and bradycardia'.)
Relation to digoxin toxicity The sympatholytic effects of digoxin may occur at serum drug
concentrations less than those used to produce an inotropic effect. As an example, one study found that
increasing the digoxin dose from a mean of 0.2 to 0.39 mg/day (corresponding to an increase in serum
concentrations from 0.67 to 1.22ng/mL [0.85 to 1.55 nmol/L]) increased ejection fraction; however, there
was no increase in exercise tolerance or decrease in venous norepinephrine levels [23].
Digoxin-related cardiac arrhythmias and extracardiac symptoms can occur when the serum digoxin
concentration is in the therapeutic or even subtherapeutic range; as a result, the presence of digoxin
toxicity or excess is often a clinical diagnosis irrespective of circulating levels (unless of course the
value is zero). (See "Cardiac arrhythmias due to digoxin toxicity".)
SUMMARY AND RECOMMENDATIONS
Cardiac glycosides such as digoxin have important positive inotropic, neurohormonal, and
electrophysiologic actions which are the basis for its use in two clinical situations: heart failure
due to systolic dysfunction, and in certain supraventricular tachyarrhythmias, primarily atrial
fibrillation (AF) and atrial flutter. (See 'Introduction'above.)
Rapid intravenous and oral digitalization is used to control the ventricular response in AF and
atrial flutter (see 'Rapid digoxin loading' above):
Initial intravenous doses of 0.25 to 0.5 mg of digoxin are given over several minutes, followed
by 0.25 mg every six hours for a total dose of 0.75 to 1.5 mg with appropriate dosing
adjustments for renal failure and the concomitant use of certain medications. (See 'Dose
adjustment in renal disease' above and 'Dose adjustment with concomitant
medications' above.)
Rapid oral digitalization can be accomplished by giving 0.5 mg initially followed by 0.25 mg
every six hours for a total loading dose of 0.75 to 1.5 mg.
Slow oral loading of digoxin can be achieved by starting a maintenance dose of 0.125 to 0.25 mg
daily, which results in a steady state serum level of drug in approximately 7 to 10 days in the
average subject. (See 'Slow digoxin loading' above.)
Given the relatively narrow therapeutic window of digoxin, with substantial overlap between so-
called therapeutic and toxic levels, patients taking digoxin require monitoring of the serum digoxin
concentration, with the "optimal" level varying with the clinical setting. Monitoring the serum
digoxin level is particularly important in persons with chronic renal dysfunction, rapidly changing
renal function, or electrolyte disturbances (eg, hypokalemia, hypomagnesemia). (See 'Monitoring
serum digoxin' above.)
Assuming that the digoxin level was drawn at the correct time, at steady state, and under
conditions of stable renal function, there is a linear relationship between digoxin dose and serum
concentration which should be followed for any necessary dose adjustments. (See 'Adjusting the
digoxin dose' above.)
When digoxin is used in the treatment of heart failure, a loading dose is not usually required, and
the initial maintenance dose varies depending on ideal body weight and renal function (table 1).
The serum digoxin level should be measured 7 to 10 days after starting digoxin or changing the
dose of digoxin, at which point a steady state should have been achieved. For patients with heart
failure, we suggest maintaining digoxin levels between 0.5 and 0.8 ng/mL (0.65 to 1 nmol/L) for
maximal efficacy with minimal risk of toxicity. (See 'Heart failure' above.)
When digoxin is used strictly for ventricular rate control in AF, serum digoxin levels should be
monitored periodically, although the drug concentration often does not correlate with ventricular
rate control and is used more as a guide to toxicity than to therapy. (See 'Atrial fibrillation' above.)
Approximately 70 to 80 percent of digoxin is eliminated unchanged in the urine, leading to
prolongation of the half-life in patients with renal insufficiency. Renal insufficiency also decreases
the extravascular volume of distribution of digoxin, another effect that can elevate plasma drug
levels. As a result, both the initial loading dose and the maintenance dose must be reduced in
patients with underlying renal disease. (See 'Dose adjustment in renal disease' above.)
Quinidine, verapamil, and amiodarone can increase serum digoxin levels, thereby requiring a
reduction in the daily digoxin dose. Cholestyramine and antacids, on the other hand, can
decrease the intestinal absorption of digoxin, necessitating spacing of the doses or an increase in
the daily digoxin dose. In some patients, use of antibiotics such
as tetracycline and erythromycin may impair gastrointestinal metabolism of digoxin, leading to
higher serum digoxin concentrations. (See 'Dose adjustment with concomitant
medications' above.)