Cardiac Glycoside Plant Poisoning 

Cardiac glycosides are found in a diverse group of plants including Digitalis purpurea and Digitalis lanata (foxgloves), Nerium oleander (common oleander), Thevetia peruviana (yellow oleander), Convallaria majalis (lily of the valley), Urginea maritima and Urginea indica (squill), Strophanthus gratus (ouabain), Apocynum cannabinum (dogbane), and Cheiranthus cheiri (wallflower). In addition, the venom gland of cane toad (Bufo marinus) contains large quantities of a purported aphrodisiac substance that has resulted in cardiac glycoside poisoning.

Ancient Egyptians and Romans first used plants containing cardiac glycosides medicinally as emetics and for heart ailments. Toxicity from herbal cardiac glycosides was well recognized by 1785, when William Withering published his classic work describing therapeutic uses and toxicity of foxglove, D purpurea.^[1]

Therapeutic use of herbal cardiac glycosides continues to be a source of toxicity today. Recently, D lanata was mistakenly substituted for plantain in herbal products marketed to cleanse the bowel; human toxicity resulted. Cardiac glycosides have been also found in Asian herbal products and have been a source of human toxicity.

Toxicity may occur after consuming teas brewed from plant parts or after consuming leaves, flowers, or seeds from plants containing cardiac glycosides. Significant toxicity usually is a result of suicide attempt or inappropriate self-administration for the therapeutic purposes.

More than 200 naturally occurring cardiac glycosides have been identified. These bind to a site on the cell membrane, producing reversible inhibition of the sodium (Na⁺)-potassium (K⁺)-adenosine triphosphatase (ATPase) pump, which causes increased intracellular sodium and decreased intracellular potassium. In myocytes, elevated intracellular sodium concentrations produce increased intracellular calcium concentrations via a Na⁺ -calcium (Ca⁺⁺)-exchanger. In response to the increased intracellular calcium, the sarcoplasmic reticulum releases additional calcium intracellularly resulting in depolarization of the cell.

As a result of this excessive intracellular calcium, enhanced cardiac contractions, which are delayed after depolarizations, occur. These clinically manifest as aftercontractions, such as premature ventricular contractions (PVCs). Cardiac glycosides also have vagotonic effects, resulting in bradycardia and heart blocks. Inhibition of Na⁺ -K⁺ -ATPase in skeletal muscle results in increased extracellular potassium and contributes to hyperkalemia.

Cardiac glycosides primarily affect cardiovascular, neurologic, and gastrointestinal systems. Of these, effects on the cardiac system are most significant. The pathophysiology that produces cardiotoxicity involves prolonging refractory period in atrioventricular (AV) node, shortening refractory periods in atria and ventricles, and decreasing resting membrane potential (increased excitability). At therapeutic doses, cardiac glycosides also may increase inotropy. Any dysrhythmia characterized by both increased automaticity and depressed conduction is suggestive of cardiac glycoside toxicity.

Sinus rhythm with PVCs is the most common rhythm associated with digitalis toxicity. Other dysrhythmias often associated with cardiac glycoside toxicity include bradydysrhythmias, sinus bradycardia with all types of AV nodal block, junctional rhythms, and sinus arrest. Dysrhythmias characterized by increased automaticity and conduction blockade, when combined, are highly suggestive of cardiac toxicity. These dysrhythmias include the following:

• Tachydysrhythmias, such as atrial tachycardia with block
• Junctional tachycardia
• Ventricular tachycardia
• Ventricular fibrillation
• Paroxysmal atrial tachycardia with block
• Bidirectional ventricular tachycardia

More than a single dysrhythmia may be present and progression into a rapidly life-threatening rhythm, such as ventricular tachycardia, may abruptly occur.

Frequency

United States

Toxic exposure to plants containing cardiac glycosides is rare. Of 1.33 million exposures to toxic, nonpharmaceutical substances reported by the American Association of Poison Control Centers (AAPCC) in 2006, only 1,405 were due to exposure to plants containing cardiac glycosides. Cardiac glycoside exposure from plants accounts for only 1.0% of plant exposures and 0.1% of exposures in the 2006 report.^[2]

International

Deliberate ingestion of yellow oleander seeds (Thevetia peruviana), known as "lucky nuts," has recently become a popular method of self-harm in northern Sri Lanka. Thousands of cases are reported yearly, with a case-fatality rate of untreated patients ranging between 5 and 10%.^[3]

Exposure rates may be higher in countries or communities that rely heavily on folk or herbal medicines including plants containing cardiac glycosides.

Mortality/Morbidity

Factors increasing morbidity and mortality and similar to those affecting digoxin-poisoned patients and may be divided into host-specific and plant-specific categories. Host-specific factors include advanced age, renal impairment, myocardial ischemia, hypothyroidism, hypoxia, and electrolyte abnormalities (eg, hypokalemia, hyperkalemia, hypomagnesemia, hypercalcemia). Plant-specific factors include species, part ingested, specific type of cardiac glycosides contained in the plant, and concentration of cardiac glycosides.

Mortality is rare, but case reports documenting fatalities from oleander, foxglove, squill, and other related plants do exist. In 2006, although the AAPCC reported no deaths in 1,405 exposures to cardiac glycoside-containing plants, during the same period, 22 fatalities were reported from 2,610 exposures to pharmaceutical cardiac glycosides. The AAPCC noted moderate-to-major morbidity in only 2% of cardiac glycoside-containing plant exposures. In contrast, moderate-to-major morbidity occurred in 20% of pharmaceutical cardiac glycoside exposures.^[2]

Morbidity associated with exposure to cardiac glycoside-containing plants tends to be less severe than that associated with pharmaceutical cardiac glycosides. This may reflect age differences, lower concentrations of bioactive cardiac glycosides, and intentional versus unintentional exposure ratios. Pharmaceutical exposures generally occur in an older population (>60 y) and more often are due to intentional acute or chronic ingestion. Most plant exposures occur in children younger than 6 years and are usually unintentional and without associated significant toxicity. More serious toxicity occurs with intentional ingestions by adolescents and adults.

Age

AAPCC data from 2006 show the following age breakdowns for plant cardiac glycoside exposure^[2] :

• Infants and children younger than 6 years - 56%
• Children aged 6-19 years - 17%
• Adults older than 19 years - 20%