Oleander toxicity: a focus on oleandrin

Author: alice parisi
Date: 22/08/2014


Alice Parisi
Federica Ventrella


Actually cardiac glycosides are used for the treatment of congestive heart failure (CHF) and cardiac arrhythmia as atrial fibrillation. These glycosides are found as secondary metabolites in several species of plants from at least 12 different families (for example Digitalis purpurea, Digitalis lanata, Strophanthus gratus and Strophanthus kombe) and in some animals, such as the milkweed butterflies. The most famous molecules of this family are Digoxin (that is derived from the foxglove plant and is used clinically) and Ouabain (that is used only experimentally due to its extremely high potency).

Figure: Foxglove plant ( Digitalis purpurea )

Figure: Milkweed butterfly

Oleandrin: A cardiac glycosides with potent cytotoxicity, 2013

Plants sources of cardiotonic steroids

The family Apocyanaceae (for example Carissa acokanthera and Strophantus hispidus) are sources of African arrow poisons and also contain many of the most beautiful but deadly tropical flowering shrubs such as Plumeria rubra (‘frangipani’), Nerium Oleander (‘common, pink or white oleander’) and Thevetia peruviana (‘yellow oleander’, that contains at least eight different cardiac glycosides, including Thevetin A, Thevetin B (cerberoside) Thevetoxin, Neriifolin, Peruvoside and Ruvoside, expecially in the seeds).

Acute cardiac toxicity of Nerium oleander/indicum poisoning (Kaner) poisoning, 2010

Management of acute yellow oleander poisoning, 1999

Plant description

Nerium Oleander is an evergreen shrub or small tree (family Apocyanaceae, genus Nerium), commonly known as oleander, from its superficial resemblance to the unrelated olive Olea (“oleander” is an idiom for plants of the N. oleander L, N. indicum, and Nerium odorum species and other common names are soland, lorier bol, rosebay, and rose laurel and kaner). It is so widely cultivated that no precise region of origin has been identified, but probably it is from Southwest Asia. This plant is one of the most poisonous of commonly grown garden plants (it is used as an ornamental plant in landscapes, in parks, along the roads, in private gardens) and toxicity is reported in all its parts.

Management of acute yellow oleander poisoning, 1999

Oleandrin: A cardiac glycosides with potent cytotoxicity, 2013

Active molecules description

Cardiac glycosides are of two types (defined by the R group at the 17-position):

  • cardenolides (C-23 steroids with methyl groups at C-10 and C-13 and a five member unsaturated lactone ring at C-17 as R group)
  • bufadienolide (molecules who show a C-17 a-pyrone ring with two double bounds inside it)

All agents are composed by two structural features:

  • the carbohydrate or sugar portion (glycoside, attached through an oxygen bridge to carbon 3 of the ‘A’ ring of the steroid)
  • the non-sugar portion (aglycone-steroid, the most important moiety for the cardiac action)

Oleandrin has a structure similar to other glycosides, and it contains a central steroid nucleus with an unsaturated lactone structure on C-17 and an arabinose group on C-3. In addition, the steroid ring has a substitute of an acetyloxy group on C-16.

Oleandrigenin is a de-glycosylated metabolite of oleandrin and is a more powerful than ouabain.

Figure: Oleandrin

Figure: Oleandrigenin

Management of acute yellow oleander poisoning, 1999

Oleandrin: A cardiac glycosides with potent cytotoxicity, 2013


Apart from Oleandrin, the most known toxic molecule, other constituents are folinerin and digitoxigenin which absolute and relative concentrations vary with the part of the plant and the season in which it’s examinate. There are also several chemical constituents in its seeds, in the bark and also in the roots, lymph, leaves as other steroids, minerals, alpha-tocopherol, tannins, glucose, paraffin and vitamin C.

Oleandrin: A cardiac glycosides with potent cytotoxicity, 2013


Oleandrin has lipophilic property and it can be easily absorbed in the gastrointestinal tract after oral dosing.

Pharmacokinetic studies of oleandrin were conducted in mice after either an intravenous (i.v.) dose or a p.o. dose. It was rapidly absorbed after oral dosing (C max at 20 min) with a bioavailability of approximately 30% and the elimination half-life was longer (2.3 ± 0.5 h) than that after i.v. dosing (0.4 ± 0.1 h). The AUC 0-∞ values obtained after i.v. and p.o. dosing were 24.6 ± 11.1 and 14.4 ± 4.3 (ng h/ml) respectively.

It is excreted mostly through biliary tract in feces, but also in urine. As excretion in urine is only a smaller route, the kidneys are less exposed than the liver. There is also accumulation in the cardiac tissue, which explains its potential for cardiac toxicity.

In mouse studies, it shows a rapid accumulation in brain tissue as it can pass through the blood-brain barrier. The data suggest that other components within oleander extract may enhance transport of oleandrin across the blood-brain barrier.

Oleandrin: A cardiac glycosides with potent cytotoxicity, 2013

Molecular mechanism

Physiologically, Na+ - K+ ATPase in the myocytes pumps the potassium ions inside and sodium ions out of the cell. Another membrane ion exchanger, Na+ - Ca++ exchanger, pumps three calcium ions out of the cell and two sodium ions inside it.

Cardiac glycosides inhibit the Na+ - K+ ATPase by stabilizing it in the E 2 – P transition state: it causes intracellular sodium levels increase so that it can inhibit the Na+ - Ca++ exchanger. This is responsible of the increase of intracellular calcium levels that causes increased calcium uptake into the sarcoplasmic reticulum (SR) through the sarcoplasmic/endoplasmic reticulum Ca++ - ATPase transporter.

Raised calcium stores in the SR allow for greater calcium release on stimulation so that

  • myocytes could achieve faster and more powerful contraction by cross-bridge cycling ( positive inotropic effect )
  • the refractory period of the AV node is increased. Apart from this direct action, they have also an indirect effect on parasympatic tone (both these effects leads to negative chronotropism)

Binding of glycosides to Na+ - K+ ATPase is slow, but, after binding, intracellular calcium levels increase gradually, thus the action of these molecules is delayed. Raised extracellular K+ decreases binding of cardiac glycoside to the pump. Consequently, a mayor toxicity of these drugs is observed in the presence of hypokalemia.

Oleandrin: A cardiac glycosides with potent cytotoxicity, 2013


Oleandrin poisoning by eating oleander leaves can be lethal at low dosages (cases of sheep lethality has been reported to only one leaf of the plant and the lethal dosage for animals is estimated to be about 0.5 mg/kg). The symptoms that poisoned animals show include bloody diarrhea and colic (for example in horses). Because the leaf is quite bitter, only starving animals will be likely to eat the plant.

Intossication modalities reported in humans are accidental poisoning by ingestion (even one leaf could be lethal in children! It is calculated that the lethal oleander leaf dose is approximately 4 mg) and by inalation of smoke of burning oleanders (heat does not inactivate the toxic glycosides); cases have been reported from Hawaii, the Solomon Islands, Southern Africa, Australia, Europe, the Far East and the United State. Deliberate poisonings have been recorded in suicide attempts, abortion, herbal remedies (for example in India, Thailand, Brazil and elsewhere) and in criminal cases of homicide. In particular, in Sri Lanka, this suicide method (by eating oleander seeds) is very popular, due to the death of two girls who intentionally ate yellow oleander seeds in 1980. This fact was widely reported in local newspapers so that the number of cases admitted to Jaffna hospital increased from zero in 1979 to 103 in 1983 and is still high nowadays: currently several thousand cases occur each year and at least 10% of the patients die, mostly young women and children.

Oleander poisoning, 2001

Management of acute yellow oleander poisoning, 1999

Oleandrin: A cardiac glycosides with potent cytotoxicity, 2013


Cardiac symptoms : In humans, if SR stores of calcium become too high, some ions are released spontaneously through SR receptors. After depolarization, this effect leads initially to bigeminy (regular ectopic beats following each ventricular contraction). If higher glycoside doses are given, rhythm is lost and it is possible to see ventricular arrhythmias, eventually followed by fibrillation. It can also cause bradycardia and heart arrest.

Gastrointestinal symptoms : The symptoms range from nausea and vomiting to cramping and bloody diarrhea. It causes also irritation of the mucosal membranes resulting in burning around the mouth and increased salivation.

Neurological symptoms : Oleander causes confusion, dizziness, sleepiness, weakness, visual disturbances and mydriasis.

Acute yellow oleander ( Thevetia peruviana ) poisoning: cardiac arrhythmias, electrolyte disturbances, and serum cardiac glycoside concentrations on presentation to hospital, 2000

Management of acute yellow oleander poisoning, 1999


Electrocardiography often reveals an increased PR interval, a decreased QRS-T interval, and T wave flattening or inversion.

Most cases of cardiac glycoside poisoning have been in patients overdosed during long-term digoxin therapy for cardiovascular diseases: they usually are aged or anyway they are older than oleander poisoned one. This kind of patients showed arrhythmias as ventricular extrasystolies and tachycardias. Most patients have pre-existing hypokalemia due to the many other drugs that they are taking as diuretics (and it causes a mayor binding of steroids to the Na + - K + ATPase). It is reported that hypomagnesaemia predisposes to digoxin toxicity.

Oleander-poisoned patients are usually healthier and younger than digoxin-poisoned ones. They often show AV node conduction block (Mobitz type II), sinus node block or even a block affecting both nodes. These patients are normokalemic before the poisoning, than they present elevate serum potassium levels after severe intossication.

Management of acute yellow oleander poisoning, 1999


The treatment of oleander poisoning is empirically based on the treatment of digitalis-glycoside toxicity and consists of supporting the patient hemodynamically. This may include the rapid correction of electrolyte disturbances, the use of atropine for severe bradycardia, phenytoin or lidocaine hydrochloride to control dysrhythmias, placing a temporary pacemaker or electrical counter shock and administering digoxin-specific neutralizing Fab antibody fragments ( Digibind ).

Polyclonal anti-digoxin Fab fragments are, indeed, effective in digitalis poisoning and their use is recommended in the USA for life-threatening intoxications with other cardiotonic steroids even if it is not based on clinical trials but only on some case - reports. It was reported that Fab could rapidly recover yellow - oleander - induced arrhythmias, bradycardias and hyperkalemia.

Other treatment methods have the aim to remove the toxic substance from the stomach by emesis. It is necessary to pay special attention to patients with bradycardia: emesis, in these cases, can worsening the cardiac rhythm due to the vagal reaction. Another way to reach this goal is to give various binding agents that bind the toxic molecules in the gut (this therapy should not be used in patients with advanced toxicity). Activated charcoal has been shown to be useful in preventing further absorption of the cardiac glycosides (it could improve the outcome in oleander-poisoned patients and reduce the need for expensive antibodies).

Management of acute yellow oleander poisoning, 1999

Acute cardiac toxicity of Nerium oleander/indicum poisoning (Kaner) poisoning, 2010

Oleander poisoning, 2001

Case reports of intossication

A case of intentional oleander ingestion

A 21-year-old woman showed vomiting and dizziness 15 hours after ingestion of common oleander aqueous leaf extract (10-20 leaves) because she was adviced to take it in order to conceive a baby. She clinically presented normal blood pressure but an irregular bradycardic pulse. The general physical examination was normal but cardiovascular auscultation revealed an irregular rhythm with soft S1 and normal S2 over the apex. The ECG showed inverted P wave in inferior lead, prolonged PR interval (intermittent I degree AV block) and normal QRS duration. She was treated with intravenous atropine sulfate and orciprenaline (a non selective beta - agonist, LABA).

Acute cardiac toxicity of Nerium oleander/indicum poisoning (Kaner) poisoning, 2010

A case of indirect cardiac glycosides intoxication with poisoned food

A women aged 43 and a male aged 66 presented nausea, vomiting, diarrhea and cardiovascular symptoms 8 – 10 hours after a meal with an undefined amount of escargot (snail of the species Helix pomatia) stew. The ECG showed ectopic beats, bradycardia (36 bpm), similar to cases of Nerium oleander poisoning. The initial hypothesis was oleander intoxication because patients found the snails in their garden near the tree, but an expert opinion declared that oleander leaves are too hard to be eaten by snails. It was supposed that the snails could have eaten foxglove leaves, also present in the patients’ garden: peasant wisdom suggest that snails generally cling to the shrub twigs, but eat the surrounding grass and they could be contaminated by the plant juice adsorbed via their own slime. Fortunately, by the third day the patients recovered fully with reversion to a normal sinus rhythm.

Unexpectedely Dangerous Escargot Stew: Oleandrin Poisoning through the Alimentary Chain, 2006

Oleandrin action mechanism as anti-cancer therapy

Oleandrin has potent anticancer activity and it is studied for treatment of variety of cancers such as colon cancer, non-small cell lung cancer, leukemia, pancreas, melanoma and prostate (the trial of the drug Anvirzel™ is currently in process).

It is chemosensitizer and this may be due to his inhibition of P-glycoprotein, a transporter responsible for resistance to chemotherapeutic agents.

Furthermore, oleandrin has shown to be a potent radiosensitizer: it increases caspase activity in radiodamaged tumor cells and therefore, increases radiation-induced apoptosis.

Other action mechanism include the membrane fluidity alteration, the reduction of the activation of NF-κB, JNK and AP-1, the increased intracellular calcium, expression of FasL, ROS production, oxidative injury and mitochondrial injury, decreased phosphorylation of Akt. It inhibits the cellular transport of tumor growth factors (FGF-2), it decreases the regulation of IL-8Rs, it stimulates the apoptotic and the non-apoptotic cell death (by autophagy and cell cycle arrest).

Oleandrin: A cardiac glycosides with potent cytotoxicity, 2013

Nerium Biotechnology, INC.® - Cancer Research

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