To Kill or to Cure?

How plant poisons can surprisingly save life

by Jude Richardson

One of my earliest memories is helping my mother water the plants in the garden. I had my own mini watering can and would stand beneath a bank of beautiful, tall, white, pink and purple foxgloves in awe and fascination as I knew they were the one plant I was on no condition allowed to touch.

the sodium potassium ion pump causes the cells to depolarize and the negative internal charge of the nerve cell becomes temporarily positive due to increased intercellular sodium and calcium ion concentrations. This stimulates the nerve cell causing the heart to contract. The sodiumpotassium ion pump then readjusts the balance of ions and the cells repolarize as the positive potassium ions leave the cell. As they repolarize the heart relaxes (Fig 3).

By inhibiting the pump, the cells become more depolarized and the intercellular sodium levels increase, causing the strength with which the heart contracts to increase but also decreasing the pressure that the blood flows into the heart. In addition, the cells no longer have the ability to repolarize and the heart cannot relax as quickly. If it cannot relax as quickly, it cannot contract again so the rate at which it beats also slows down.

Foxglove or Digitalis (relating to the fingers) from the family Plantaginaceae is a plant that can grow up to six-feet-tall, with spires of tubular shaped flowers generally in shades from purple through to white. The bottom petal of the 5 fused petals has a delicate mottled effect, that folklore says are fairy handprints. Folklore also claims that foxes wear the flowers on their paws to keep dew off their fingers. Widespread throughout Europe, Asia and North America it was brought to the UK in 1694. Although beautiful, it is also highly toxic.

Foxglove poisoning

Foxgloves contain toxic cardiac glycosides, an organic compound that inhibits the cellular sodium-potassium ion pump in our bodies. This pump creates and maintains the electrochemical gradient of the neurones (or nerve cells) in the membrane around your heart.

The maintenance of this electrochemical balance (Fig 2) makes your heart beat (Klabunde, 2022). A nerve signal does not fire when the inside of the cell has a negative charge relative to the outside of the cell. This is called polarization, and consequently in this state the heart is at rest. However,

Ingesting just 140mg of any part of the foxglove plant is enough to stop a healthy person of average weight’s heart beating altogether. Foxglove will also kill the cells and poison the tissues of a foetus and is used by doctors in medicine used for abortion before the second trimester (John, 2022).

It is advisable not to grow foxgloves in allotments or the same soil as edible plants because even the roots are poisonous. Whilst simply touching it should not cause a problem, absorbing the digitoxin, digoxin and digitonin compounds contained within the plant via cuts or by transferring them to your eyes or mouth could be enough to slow your heart or cause arrythmia. Fortunately, perhaps, severe nausea, vomiting and diarrhoea are the more usual symptoms of poisoning.

For foxglove poisoning it is vital to seek urgent medical help. Activated charcoal is likely to be given in order to help absorb the poisons in the stomach. The porous nature of this type of charcoal trap the toxins enabling them to pass safely through the gut without being absorbed into the bloodstream. In addition, anti-digoxin immunoglobin will be administered which binds to the digoxin preventing it binding to the active site of the target cells within the body. It then accumulates in the blood and is filtered out as waste by the kidneys (Purohit, 2018).

Even deer and rabbit will avoid munching on its broad green leaves and columns of flowers as it is just as fatal eaten by wild animals or domestic ones like dogs and horses. However, this successful defence mechanism deterring herbivory and ensuring continuation of the species does not mean that humans have left it alone, instead we harvest it for its medicinal properties.

Foxglove in medicine

But foxglove also has an established history as a life saver and has been used in herbal medicine through the ages precisely for the characteristics that make it so deadly. Foxglove was first used by William Withering to treat 163 individuals suffering with Dropsy (a swelling under the skin often caused by heart failure) in 1775. Dramatically slowing a healthy heartbeat rate, or decreasing blood pressure significantly is not usually a great idea. However, if your heart is beating too fast or irregularly (tachycardia or arrythmia) or is not pumping effectively causing a high risk of a heart attack, then a very small dose of Digitalis to slow down and regulate the rhythm as well increasing the efficacy of its pumping action, might just save your life.

Unfortunately, it’s not as simple as just chewing on a leaf, the range within which digoxin is useful and within which it is toxic is miniscule, a difference of around 0.2 nanograms per litre of blood (Stoye, 2016). Consequently, in order for it to be measured so precisely, it has to be chemically extracted from the foxglove. Of the many glycosides within the foxglove, digoxin accounts for 90% of the world market. There are a number of ways digoxin is extracted from the plant, but essentially the foxglove leaves are first fermented, then the digoxin is percolated and further isolated and purified. It is generally sold under the name, Lanoxin and administered as either tablets, in liquid form or by injection in hospital (Novković et al, 2013).

Other plants containing cardiac glycosides

Foxglove is not the only plant in your garden that contains cardiac glycosides. Lily of the Valley, Convallaria majalis, (Fig 4) our late Queen’s favourite flower, is also capable of the same heart stopping effects as the foxglove. Fortunately, it is much less cumulative in effect as it is more commonly the cause of poisonings because it is often mistaken for wild garlic (Fig 5) and foraged. Thankfully you are more likely to suffer with dizziness, nausea and vomiting before a cardiac arrest (Lofton and Dasgupta, 2005).

Oleander, (Fig 6) from the Nerium family, is a beautiful evergreen flowering shrub, with slim grey green leaves and pink, white or red flowers. Although not native to the UK many gardeners, like my mother, have pots or boarders into which Oleander is nestled to protect it from the cold. Like the Foxglove and Lily of the Valley, Oleander is another source of cardiac glycosides and is a common suicide agent in Sri Lanka where poisonings exceed 150 per 100,000 each year.

Like the foxglove it has been used for centuries in herbal medicine to treat various cardiovascular problems, but it has also been used for the treatment of a much larger array of other conditions such as eczema, epilepsy, herpes, malaria, ringworm, abscesses and asthma to name a few, with varying degrees of success or poisoning.

Oleandrin, the most significant of five cardiac glycosides Oleander contains, unlike digoxin, has not been used by pharmaceutical companies in the development of potentially lifesaving heart medication. In fact, it has largely been ignored until very recently. This is partly due to a much more complex pharmacokinetics profile which makes it even more toxic. Ingesting even 20ng/ml is likely to be fatal. Touching the leaves or inhaling smoke from burning twigs is likely to cause any number of severe reactions from ulcerating of the skin and mouth, dizziness, headaches, nausea and vomiting to serious cardiovascular problems including heart failure (Zhai et al, 2022).

Oleander in medicine

Oleandrin obtained recent notoriety when Donald Trump’s Secretary of Housing and Urban Development, Ben Carson and Mike Lindell, an investor of a company that develops Oleandrin, suggested its use to treat COVID 19 in 2020.

Oleandrin tablets are available through various outlets as an herbal remedy, which considering the potential range of serious side effects is actually quite amazing. Consequently, the medical profession has been very quick to discredit these claims over fears of increased numbers of poisonings as people try to avoid COVID 19. However, a flurry of research was subsequently reviewed and compiled and studies later published in 2021 have shown Oleander is an excellent antioxidant (Plante et al, 2021).

Reactive species are by-products of crucial cellular processes, however they sometimes cause damage or mutations to proteins, lipids and DNA which in turn can lead to cancer. Fortunately, these reactive species and free radicals can be neutralised by natural antioxidants found not only in Oleander, but many types of plant thereby reducing their damaging effects.

References

Aronson, J.K. “Positive Inotropic Drugs and Drugs Used in Dysrhythmias.” Side Effects of Drugs Annual, 2008, pp. 209–222, www.sciencedirect.com/topics/ biochemistry-genetics-and-molecular-biology/cardiac-glycoside, https://doi. org/10.1016/s0378-6080(08)00017-2. Accessed 26 Feb. 2023.

Bueno-Orovio, Alfonso, et al. “Na/K Pump Regulation of Cardiac Repolarization: Insights from a Systems Biology Approach.” Pflügers Archiv - European Journal of Physiology, vol. 466, no. 2, 15 May 2013, pp. 183–193, https://doi.org/10.1007/s00424-013-1293-1.

In addition, Oleandrin and Anvirzel, both cardiac glycosides contained in Oleander have also been shown to induce immunogenic cell death in human cancer cells and the subsequent destruction of tumours. Even better, it seems they do this without the detrimental effects on normal somatic cells associated with traditional chemotherapy whereby healthy cells are also destroyed (Li et al, 2021).

With cancer now the leading cause of death in the UK (Whipple, 2016) it is no surprise that consequently Oleander is currently the primary focus of the pharmaceutical industry with treatments currently in phase I and II clinical trials of malignant diseases.

Back to the foxglove

Childhood memories and the magic of folklore have biased me in favour of the tough towering beauty of the foxglove over the more recent pampered purchase of my mother’s potted Oleander, so I must just point out that Digitalis was shown by Stenkvist to do very much the same to breast cancer cells 20 years earlier.

So, killing by foxglove is clearly easy, curing a lot more difficult. But understanding has moved on so much from herbal witchcraft where it was clearly often a gamble as to which the result might be. If we are careful the risks are small, if we are educated the benefits are enormous…

Discussion questions

1. According to the World Health Organisation 40% of pharmaceutical formulations in the Western world are based on ordinary plants, 11% from flowering ones, but is medicine looking hard enough at old traditional remedies for simpler solutions to our healthcare needs?

2. Paracetamol has been proven to be little more effective than a placebo, would doctors be better prescribing herbal alternatives for our aches and pains?

3. With the current trend for foraging, growing our own produce and eating less intensively farmed food, should people be educated and encouraged to use a range of plants as remedies for daily ailments rather than turning to highly processed pharmaceutical drugs?

Interested in learning more?

Here’s an article you might enjoy from the Natural History Museum:

Cheung “Cardiac Glycosides: What Are They, What Are They Used For, How Do They Work, Side Effects, and More | Osmosis.” Osmosis, 2017, www. osmosis.org/answers/cardiac-glycosides. Accessed 26 Feb. 2023.

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John, “How Much Foxglove Is Fatal – Superfoodly.” Superfoodly |, 16 May 2022, superfoodly.com/how-much-foxglove-is-fatal/. Accessed 26 Feb. 2023.

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Khan, Ibraheem, et al. “Acute Cardiac Toxicity of Nerium Oleander/Indicum Poisoning (Kaner) Poisoning.” Heart Views, vol. 11, no. 3, 2010, p. 115, www. ncbi.nlm.nih.gov/pmc/articles/PMC3089829/, https://doi.org/10.4103/1995705x.76803. Accessed 26 Feb. 2023.

Klabunde, R. E. “CV Pharmacology | Cardiac Glycosides (Digoxin).” Cvpharmacology.com, 2021, www.cvpharmacology.com/ cardiostimulatory/digitalis. Accessed 26 Feb. 2023.

Klabunde, R. E. “CV Physiology | Action Potentials.” Cvphysiology.com, 2021, www.cvphysiology.com/Arrhythmias/A010. Accessed 26 Feb. 2023.

Klabunde, R. E. “CV Physiology | Sodium-Potassium ATPase Pump.” Cvphysiology.com, 2021,www.cvphysiology.com/Arrhythmias/A007b. Accessed 26 Feb. 2023.

Li, X et al. “Oleandrin, a Cardiac Glycoside, Induces Immunogenic Cell Death via the PERK/ElF2α/ATF4/CHOP Pathway in Breast Cancer.” Cell Death & Disease, vol. 12, no. 4, 24 Mar. 2021, www.nature.com/articles/s41419-02103605-y, https://doi.org/10.1038/s41419-021-03605-y. Accessed 26 Feb. 2023.

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Novković, V.M “Extraction of Digoxin from Fermented Woolly Foxglove Foliage by Percolation.” Separation Science and Technology, 2014, www. tandfonline.com/doi/abs/10.1080/01496395.2013.864679. Accessed 26 Feb. 2023.

Pathak, Sen, Multani, Asha, Newman, Robert, Narayan, Satya, Kumar, Virendra. “Oleander Extract Induces Cell Death in Human but Not Murine ... : Anti-Cancer Drugs.” LWW, 2023, Plante, K.S., Dwivedi, V., Plante, J.A., Fernandez, D., Mirchandani, D., Bopp, N., Aguilar, P.V., Park, J.-G., Tamayo, P.P., Delgado, J., Shivanna, V., Torrelles, J.B., Martinez-Sobrido, L., Matos, R., Weaver, S.C., Sastry, K.J. and Newman, R.A. (2021). Antiviral activity of oleandrin and a defined extract of Nerium oleander against SARS-CoV-2. Biomedicine & Pharmacotherapy, [online] 138, p.111457. doi:https://doi.org/10.1016/j.biopha.2021.111457.

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Wei, Xingyu, et al. “Physiology, Cardiac Repolarization Dispersion and Reserve.” Nih.gov, StatPearls Publishing, 21 Apr. 2022, www.ncbi.nlm.nih.gov/ books/NBK537194/. Accessed 26 Feb. 2023.

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Zhai, Jinxiao, et al. “Oleandrin: A Systematic Review of Its Natural Sources, Structural Properties, Detection Methods, Pharmacokinetics and Toxicology.” Frontiers in Pharmacology, vol. 13, 21 Feb. 2022, www. ncbi.nlm.nih.gov/pmc/articles/PMC8902680/, https://doi.org/10.3389/ fphar.2022.822726. Accessed 26 Feb. 2023.

Images

Figure 1

Burnett, J. (2018). Growing Foxglove Flowers. [online] Flower Magazine. Available at: https://flowermag.com/growing-foxglove-plant-and-foxgloveflowers/ [Accessed 30 Apr. 2023].

Figure 2

Gsu.edu. (2023). The Sodium-Potassium Pump. [online] Available at: http:// hyperphysics.phy-astr.gsu.edu/hbase/Biology/nakpump.html [Accessed 30 Apr. 2023].

Figure 3

Twinkl. (2023). Twinkl Bahrain - Educational Resources across all School levels [online] Available at: https://www.twinkl.com.bh/ [Accessed 30 Apr. 2023].

Figure 4

Hartsnursery.co.uk. (2022). Product reviews: Convallaria Majalis ‘Lily of the valley ’ (Pack of 10). [online] Available at: https://www.hartsnursery.co.uk/reviews. php?productid=18066 [Accessed 30 Apr. 2023].

Figure 5 james (2018). Wild Garlic (Allium Ursinum) Identification -. [online] Totallywilduk.co.uk. Available at: https://totallywilduk.co.uk/2018/11/10/wildgarlic-identification-allium-ursinum/ [Accessed 30 Apr. 2023].

Figure 6

Living Color Garden Center. (2022). How To Safely Grow Oleander In Your Garden. [online] Available at: https://livingcolorgardencenter.net/gardening/ how-to-safely-grow-oleander-in-your-garden/ [Accessed 30 Apr. 2023].