Department of Clinical Toxicology

Loghman Poison Center

Mitra Rahimi MD

Digitalis Glycosides

Digitalis preparations, such as digoxin, are still used for the

treatment of AF & symptomatic CHF.

In addition to availability as pharmaceuticals, cardiac

glycosides are also found in plants such as foxglove, oleander,

red squill, and lily of the valley.

Similar steroids are also found in the skin of toads in the

Bufonidae family and in some herbal medications.

PATHOPHYSIOLOGY

Digoxin, like other cardiac glycosides, inhibits sodium-potassium ATPase.

This inhibition results in increased intracellular sodium and increased extracellular potassium.

As a result of the increased intracellular sodium, the sodium-calcium antiporter is not able to effectively remove calcium from the myocyte.

Consequently, there is an increase in intracellular calcium, which augments inotropy.

Cardiac glycosides also increase vagal tone via action at the

carotid body, thereby reducing conduction through the SA

and AV nodes.

In toxic concentrations, cardiac glycosides can increase

sympathetic tone.

CLINICAL FEATURES

Digoxin has a narrow therapeutic index, and toxicity results

from an exaggeration of its pharmacologic activity.

The timing and clinical presentation

of acute versus chronic digoxin toxicity differ significantly.

In addition to cardiac manifestations such as syncope and

dysrhythmia, digoxin toxicity may present with GI distress,

dizziness, headache, weakness, malaise, delirium, or

confusion.

Thus, an elderly patient taking digoxin who presents with

mental status changes should be evaluated for toxicity

ACUTE TOXICITY

GI symptoms, such as nausea, vomiting, anorexia, and vague

abdominal pain, are often the earliest manifestations of acute

toxicity.

ACUTE TOXICITY

Increased central vagal tone typically produces cardiac

manifestations such as bradydysrhythmias or atrioventricular

block.

Neurologic manifestations such as weakness or confusion can

occur independently of the blood pressure.

ACUTE TOXICITY

The classic description of digoxin toxicity includes viewing

yellow-green halos around objects, termed xanthopsia.

However, patients more frequently describe nonspecific changes in

their color vision.

ACUTE TOXICITY

Overall, the severity of acute toxicity

correlates most closely with the degree of hyperkalemia and

correlates

poorly with the early serum digoxin levels.

CHRONIC TOXICITY

Chronic toxicity occurs most typically in the elderly and is

often the result of drug–drug interactions or declining renal

function.

CHRONIC TOXICITY

Some of the more common drug interactions that predispose

to chronic digoxin toxicity include CCB, amiodarone, BB,

diuretics, indomethacin, clarithromycin, quinidine,

procainamide, & erythromycin.

CHRONIC TOXICITY

Neurologic manifestations, such as weakness, fatigue,

confusion, or delirium, are more prominent features in

chronic toxicity

DIAGNOSIS

The diagnosis of digoxin toxicity is a composite picture, using

history,P/E, and lab; no single element excludes or confirms

the diagnosis.

Digoxin toxicity can occur with a single ingestion of 1 to 2

milligrams in an adult, and fatalities have been reported

following an acute ingestion of 10 milligrams in an adult and

4 milligrams in a child.

Differential diagnosis

Other toxins that may induce bradydysrhythmias

such as calcium channel antagonists, β-receptor antagonists,

class IA antidysrhythmics (procainamide and quinidine), class

IC antidysrhythmics (flecainide and encainide), clonidine and

other imidazolines,

& organophosphate or carbamate insecticide poisoning.

EKG

Almost any cardiac dysrhythmia may be observed in digoxin

toxicity, with the exception of rapidly conducted atrial

dysrhythmias.

The most common dysrhythmia in digoxin toxicity is PVC.

Ventricular dysrhythmias occur more frequently

in chronic than in acute poisonings. Although rare and not

pathognomonic for digoxin toxicity,

Bidirectional ventricular tachycardia should be investigated

for possible toxicity because only a few xenobiotics are

known to produce this unique dysrhythmia digoxin included.

LAB

Generally accepted therapeutic digoxin levels are 0.5 to 2.0

nanograms/mL with corresponding toxic levels above 2.5

nanograms/mL.

Serum levels are most reliable when obtained 6 hours after

ingestion, when distribution is complete.

Importantly, the serum digoxin level should not be the sole

factor in establishing the diagnosis of digoxin toxicity, so do

not wait for a digoxin level before implementing therapy in

an unstable patient.

TREATMENT

Management of a digoxin-poisoned patient includes general

supportive care, treatment of specific complications of

toxicity, prevention of further drug absorption, enhancement

of drug elimination, antidote administration when indicated,

and safe disposition

Hyperkalemia is not typically the cause of the death; it is a

predictor of severe poisoning and increased mortality. Treatment

of digoxin-induced hyperkalemia with insulin, dextrose, sodium

bicarbonate, or exchange resins does not reduce mortality.

GI DECONTAMINATION AND ENHANCED ELIMINATION

Activated charcoal may be of benefit following the acute

ingestion of yellow oleander, although results of large,

randomized trials have been mixed.

Gastric lavage is not recommended; asystole has been

reported in a digoxin-toxic patient, presumably from vagal

stimulation during lavage, and no clinical benefit has been

demonstrated.

Digoxin-Fab

Choice in acute poisoning with hyperkalemia

(potassium>6.0 mEq/L) and in acute or chronic toxicity

with any life-threatening dysrhythmia.

Number of vials

serum concentration (nanograms/mL) ×patient weight

(kg)/100

Digoxin body load (milligrams) = 0.8 × suspected ingested

amount (milligrams)*

Digoxin body load (milligrams) = serum digoxin

concentration(nanograms/mL) × 5.6 L/kg × weight

(kg)/1000

An alternative approach

in Acute poisoning with a hemodynamically stable patient is

to give an 80-milligram (two vials) bolus of digoxin-Fab,

evaluate the effect, and repeat the dose every 30 to 60

minutes as necessary until dysrhythmias have resolved and

potassium has normalized.

An alternative approach

In chronic toxicity, in the hemodynamically

stable patient is to give a 40-milligram (one vial) bolus of

digoxin-Fab and repeat after 1 hour if the patient is still

symptomatic.

One to three vials (40 to 120 milligrams) of digoxin-Fab are

often adequate in reversing chronic toxicity.

DISPOSITION AND FOLLOW-UP

Extended observation with serial digoxin and potassium

levels is recommended for anyone with a confirmed acute

ingestion.

Asymptomatic patients should be observed until the serum

digoxin level is decreasing on serial measurements and the

potassium level has remained normal.

Patients with signs of toxicity or a history of a large (>6

milligrams in an adult) ingested dose should be admitted to a

monitored unit.

Patients receiving digoxin-Fab require intensive care unit

observation for 6 to 12 hours.

Patients in renal failure who receive digoxin-Fab

may be at risk of delayed toxicity, as the Fab-digoxin complex

can dissociate several days later.