Cardiac Glycoside Plant Poisoning

Cardiac glycosides are found in a diverse group of plants including the following ^[] :

• Digitalis purpurea and Digitalis lanata (foxgloves; see the image below)
• 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)
• Cheiranthus cheiri (wallflower)
• Cerbera odollam and Cerbera manghas (bintaro--"Indian suicide tree")

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 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. ^[]

Therapeutic use of herbal cardiac glycosides continues to be a source of toxicity today. For example, human toxicity resulted when D lanata was mistakenly substituted for plantain in herbal products marketed to cleanse the bowel. ^[] 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 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. This increases intracellular sodium and decreases intracellular potassium.

In myocytes, elevated intracellular sodium concentrations produce increased intracellular calcium concentrations via an 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 block. 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 digoxin toxicity. Other dysrhythmias often associated with cardiac glycoside toxicity include the following:

• Bradydysrhythmia
• Sinus bradycardia with all types of AV nodal block
• Junctional rhythms
• Sinus arrest

Dysrhythmias characterized by increased automaticity and conduction blockade, when combined, are highly suggestive of cardiac toxicity. These dysrhythmias include the following:

• Tachydysrhythmia, 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. Progression into a rapidly life-threatening rhythm, such as ventricular tachycardia, may occur abruptly.

Exposure to plants containing glycosides can occur through ingestion of sap, berries, leaves, blossoms, seeds, or of teas brewed from plant parts. Plant extracts also have been intentionally injected. Other implicated routes of exposures, perhaps more folkloric than well documented, include drinking water from a vase that has held lily-of-the-valley, eating food prepared with or stirred by poisonous plant parts, and inhaling smoke from burning plants.

While there are many plant sources of cardiac glycosides, common ones include the following:

• Digitalis purpurea and Digitalis lanata (foxgloves; see the image below)
• 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)
• Cheiranthus cheiri (wallflower)
• Cerbera odollam and Cerbera manghas (bintaro--"Indian suicide tree")

United States statistics

Toxic exposure to plants containing cardiac glycosides is rare. Of 47,956 single exposures to plants reported by the American Association of Poison Control Centers (AAPCC) in 2022, 2007 were due to exposure to plants containing cardiac glycosides. Cardiac glycoside exposure from plants accounts for approximately 4% of plant exposures in the 2022 report. ^[]

International statistics

Deliberate ingestion of yellow oleander seeds (Thevetia peruviana), known as "lucky nuts," is a popular method of self-harm in northern Sri Lanka. Thousands of cases are reported yearly, with a case-fatality rate in untreated patients ranging from 5% to 10%. ^[] Exposure rates may be higher in countries or communities that rely heavily on folk or herbal medicines including plants containing cardiac glycosides.

Ingestion of a single seed of bintaro (Cerbera odollam and Cerbera manghas) can cause sudden death due to heart failure. In the South Indian state of Kerala, half of all cases of plant poisoning are attributed to bintaro. ^[]

Age-related differences in incidence

AAPCC data from 2022 show the following age breakdowns for plant cardiac glycoside exposure ^[] :

• Infants and children younger than 6 years - 52%
• Children aged 6-19 years - 17%
• Adults older than 19 years - 31%

Unintentional ingestion of plants containing cardiac glycosides rarely results in death. However, other plants capable of inducing a similar syndrome of cardiac toxicity (eg, aconite) have been responsible for deaths after ingestion. When death occurs, it generally is due to lethal dysrhythmias and refractory hyperkalemia. The magnitude of hyperkalemia is predictive of outcome.

Complications

Complications of herbal cardiac glycoside toxicity are secondary to inadequate tissue perfusion caused by dysrhythmia-induced hypotension and include the following:

• Hypoxic seizures
• Encephalopathy or ischemic stroke
• Myocardial ischemia
• Acute tubular necrosis

Mortality/morbidity

Factors increasing morbidity and mortality are 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 2022, the AAPCC reported one death from exposure to cardiac glycoside–containing plants, during the same period, 29 fatalities were reported from 1051 exposures to pharmaceutical cardiac glycosides. ^[]

The AAPCC noted moderate-to-major morbidity in 2% of cardiac glycoside–containing plant exposures. In contrast, moderate-to-major morbidity occurred in 55% of pharmaceutical cardiac glycoside exposures. ^[] In part, this may reflect lower concentrations of bioactive cardiac glycosides in plants.

In addition, pharmaceutical exposures generally occur in an older population (>60 y) and more often are due to intentional 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.