by Natalia Blicharska
Over 200 years have passed since Digitalis purpurea L. (the common foxglove) gained a place in the armamentarium of cardiologists thanks to the work of Dr. William Withering. An attractive biennial plant distributed widely across Europe including the UK, it was considered at the time to be one of the most important medicinal plants in Britain, especially in light of lacking viable and efficacious treatment options for “dropsy” (now known as oedema, likely the result of congestive heart failure). It was not until later that cardioactive glycosides present in Digitalis sp. were identified as the main pharmacologically active ingredients responsible for the treatment of heart failure and atrial fibrillation. Their use in treating heart failure and atrial fibrillation have proven to be invaluable, and despite their potential toxic effects, these drugs continue to play an important role in modern day therapy.
Digitalis purpurea L., also known as the common foxglove, purple foxglove or by its affectionate name “fairy fingers” (Board of Trustees of the Royal Botanic Gardens, Kew, 2017), is an herbaceous, biennial plant, characterized by a dense rosette of leaves and a hollow stalk with a cluster of purple tube-like flowers that grow in its second year (Bruneton, 1999). Once native to the British Isles and Western Europe, D. purpurea is now commonly found growing across Europe in disturbed areas, woodland areas, embankments, heaths, hedgerows and gardens (Bruneton, 1999; Cooper et al, 2003; Board of Trustees of the Royal Botanic Gardens, Kew, 2017) such as the Mecklenburgh Square Garden in central London.
Digitalis purpurea. Photo: Jcart1534.
Distributed under Creative Commons CC BY-SA 3.0 License
D. purpurea is a member of the Plantaginaceae (Board of Trustees of the Royal Botanic Gardens, Kew, 2017) and was previously placed in the Scrophulariaceae. Members of this genus and related ones produce cardioactive glycosides such as digoxin, digitoxin and digitoxigenin. These cardioactive glycosides are found throughout the entire plant and are of therapeutic importance, especially when it comes to treating heart disorders such as heart failure and atrial fibrillation. However, these cardioactive glycosides are capable of inducing digitalis intoxication and poisoning (Bessen, 1986; Bruneton, 1999; Cooper et al, 2003).
Digitalis Therapy: From Traditional Uses and Folk History to the Discovery of Cardioactive Glycosides
The historical origins of Digitalis use in medicinal practices is not well known and there is much debate as to when Digitalis was first introduced in medicine. Some sources claim that Digitalis was used medicinally by the ancient Egyptians, Greeks and Romans (Felicilda-Reynaldo, 2013), while others argue that it was not in use until the Middle Ages (Groves and Bisset, 1991), claiming that the first uses of Digitalis were by Welsh physicians practicing in the 13th century. Yet even other sources suggest that Digitalis was not in use until the early 16th century. However, what is certain is that Digitalis had been historically considered a cure-all plant, indiscriminately used to treat various ailments (Somberg, Greenfield, and Tepper, 1986; Groves and Bisset, 1991; Weisse, 2010), which eventually led to its removal from the London pharmacopeia in 1745 due to indiscriminate use, severe toxicity and rampant therapeutic failure (Somberg, Greenfield, and Tepper, 1986; Bessen, 1986).
It was not until the late 18th century that D. purpurea was reintroduced into mainstream medical practices, thanks to the pioneering work of the English physician Dr. William Withering. In fact, unbeknownst to him at the time, Withering was the first physician to use digitalis for the treatment of heart failure and atrial fibrillations (Felicilda-Reynaldo, 2013; Ziff et al, 2015). However, how did a physician from Birmingham discover the therapeutic benefits of Digitalis considering its history of indiscriminate use to treat all ailments and what led him to develop the first effective therapies for the treatment of heart failure and atrial fibrillations?
The story goes that Withering once met an old woman in Shropshire, who through the preparation of an herbal remedy was able to provide cures for dropsy where others have failed (Somberg, Greenfield, and Tepper, 1986; Marullaz, 1991). This herbal remedy contained D. purpurea, a plant that Withering instinctively knew was responsible for the observed therapeutic effects. Following this encounter, Withering began to administer D. purpurea preparations in his clinic in an attempt to provide a remedy for “dropsy”. He produced and administered standard Digitalis preparations to 163 patients (Somberg, Greenfield, and Tepper, 1986), carefully noting his clinical observations. In doing so, Withering successfully treated patients with “dropsy” (Somberg, Greenfield, and Tepper, 1986), and gathered evidence to suggest that Digitalis worked both on the heart and as a diuretic, which contrary to his belief at the time, is now known not to be the primary effect of Digitalis (Somberg, Greenfield, and Tepper, 1986; Bessen, 1986).
Withering’s careful, thorough and well-documented work (Bessen, 1986), summarized in his book “An account of the foxglove, and some of its medical uses: with practical remarks on dropsy and other diseases,” led to the ‘discovery’ of Digitalis’ therapeutic benefits as a cardiac stimulant and in the treatment of “dropsy”, now known as oedema, likely caused by congestive heart failure, (Groves and Bisset, 1991; Stucky and Goldberger, 2015). His work also reported on the signs and symptoms associated with Digitalis toxicity (Bessen, 1986; Somberg, Greenfield, and Tepper, 1986; Groves and Bisset, 1991 Ganpisetti et al, 2016) and provided recommendations and guidelines as to the conditions that Digitalis may be used to treat (Somberg, Greenfield, and Tepper, 1986; Groves and Bisset, 1991; Marullaz, 1991). Were it not for his clinical trials, careful documentation and standardized methodology and preparations, the use of D. purpurea may very well have continued to be indiscriminately used, and perhaps eventually removed from herbal therapies due to adverse effects and lack of therapeutic efficacy.
However, despite Withering’s progress in developing the mainstream understanding of the therapeutic potential of D. purpurea, it was not until later that the primary site of action and the mechanism of action was discovered. In 1799, it was discovered by John Ferrier that the heart is the primary site of action of Digitalis (Somberg, Greenfield, and Tepper, 1986), and later that same year, Thomas Beddos reported that Digitalis increased the action of cardiac fibres (Somberg, Greenfield, and Tepper, 1986), thus bringing us closer to the modern day understanding of cardioactive glycoside mechanisms of action.
This knowledge, however, was not sufficient for the scientific community at the time, and every effort was made to determine the active constituents of D. purpurea. In fact, a contest sponsored by the Société de Pharmacie de Paris was announced in 1835, whose main goal was to stimulate D. purpurea research and determine the active principles responsible for its observed medical properties (Somberg, Greenfield, and Tepper, 1986; Marullaz, 1991). It is thanks to this contest that a partly crystalline material digitaline (believed to contain mainly digitoxin) was prepared by Eugène Homalle (1808-1883) from the leaves of D. purpurea in 1841 (Marullaz, 1991). It was not until 1872 that the active constituents of Digitalis were isolated by Claude Adolphe Nativelle (Somberg, Greenfield, and Tepper, 1986).
Cardiac Glycosides: The Active Constituents of Digitalis species
Cardiac glycosides found in Digitalis sp. are composed of a cardenolide (a type of steroid) and oligosaccharide (sugar) chain (Bruneton, 1999). Each cardiac glycoside is differentiated from another based on the number of sugar groups in the oligosaccharide chain as well as the position on the cardenolide to which this chain attaches (Bruneton, 1999). These differences, albeit subtle, have very important consequences on the biological activity and toxicity of the resulting glycoside (Bruneton, 1999).
For instance, two common glycosides found in Digitalis species include digoxin and digitoxin. These two compounds, illustrated here, possess minor structural differences (illustrated in green bubbles). However these differences have been shown to have tremendous effects on the safety profile of the compounds. In fact, digitoxin, initially isolated from D. purpurea, has been shown to have a less favorable safety profile and less favorable medicinal characteristics compared to digoxin, obtained from Digitalis lanata (Bessen, 1986; Weisse, 2010), thus limiting its use in therapy (Marullaz, 1991).
Digoxin (Left) and Digitoxin (Right) with major difference outlined. Photo: Edgar181. Distributed to Public Domain
At the molecular level, cardiac glycosides such as digoxin, bind to Sodium/Potassium (Na+/K+) ATPase, an enzyme bound in the membrane of cardiac cells that is responsible for regulating the balance between sodium and potassium levels inside cardiac cells (Klabunde, 2012; Felicilda-Reynaldo, 2013; Stucky and
Goldberger, 2015; Ganpisetti et al, 2016). Binding to this enzyme with high affinity and selectivity (Stucky and Goldberger, 2015) prevents the transport of sodium and potassium ions through the channel. This disrupts the ion balance normally present in the cells and sets off a series of events that subsequently alter the concentrations of sodium and calcium (Ca2+) ions within the cell (Stucky and Goldberger, 2015). This is because blocking the Na+/K+ ATPase enzyme, causes a buildup of sodium inside the cardiac cell which subsequently prevents the elimination of calcium ions from the cell via the Sodium/Calcium (Na+/Ca2+) exchanger normally responsible for maintaining the balance between sodium and calcium ions (Ganpisetti et al, 2016). Since less calcium is eliminated from the cell, calcium accumulates inside the cell (Klabunde, 2012; Stucky and Goldberger, 2015; Ganpisetti et al, 2016), and is then pumped into the sarcoplasmic reticulum, increasing calcium stores (Stucky and Goldberger, 2015). These increased calcium stores are responsible for increasing the contractility of cardiac muscles (Stucky and Goldberger, 2015; Ganpisetti et al, 2016) which is necessary in treating heart failure.
Digitalis in Modern-day Therapy: The Clinical Evidence
Cardioactive glycosides, isolated from various Digitalis sp., are currently used in the treatment of congestive heart failure and atrial fibrillation (Felicilda-Reynaldo, 2013; Chan and Buckley, 2014; Stucky and Goldberger, 2015; Ziff et al, 2015; Ganpisetti et al, 2016). They are useful in the treatment of these conditions due to their direct action on cardiac muscle as positive ionotropic agents (Bessen, 1986; Ganpisetti et al, 2016), increasing the force and velocity of contraction as well as slowing the heart rate and the conduction velocity of signals through the heart’s atrioventricular (AV) node (Ganpisetti et al, 2016).
Heart failure is a condition that results when the weakened heart muscle is incapable of effective contraction required to circulate blood throughout the body, thus increasing the work-load of the heart (Felicilda-Reynaldo, 2013). When the heart can no longer compensate for this increased workload, congestion results and is manifested as oedema (dropsy) and dyspnea (difficulty in breathing) (Felicilda-Reynaldo, 2013). The use of cardioactive glycosides in the treatment of heart failure is based on their positive ionotropic effects enhancing the contractility of cardiac muscles (Bessen, 1986; Ganpisetti et al, 2016), while the ability to block/slow the conduction of signals through the AV node helps to slow the response rate of ventricles in patients with atrial fibrillation (Bessen, 1986; Ganpisetti et al, 2016).
The effectiveness of cardioactive glycosides in treating heart failure in particular, has been demonstrated in multiple clinical trials, one of which was performed by the Digitalis Investigation Group in 1997. At the time of their trial, the use of cardioactive glycosides in the treatment of chronic heart failure was controversial (Digitalis Investigation Group, 1997). According to their randomized, double-blind, placebo-controlled clinical trial, the Digitalis Investigation Group randomly administered digoxin or placebo to patients experiencing heart failure and monitored their health over a 3-5 year period (Digitalis Investigation Group, 1997). In doing so, the Digitalis Investigation Group found that digoxin had no effect on overall mortality of patients, although there were fewer deaths from the worsening of heart failure in patients treated with digoxin (Digitalis Investigation Group, 1997). In fact, the results of this study demonstrated that digoxin did not significantly reduce mortality in treated patients compared to control. However, it was capable of reducing the overall risk of hospitalization, as well as specifically due to worsening heart failure (Digitalis Investigation Group, 1997). The safety and effectiveness of digoxin treatment was further confirmed by Ziff et al. (2015) in a meta-analysis (which covered over 600 000 patients), and which concluded that digoxin treatment had a neutral effect on mortality in randomized trials and that a reduction in hospital admissions was consistently observed in all studies reviewed (Ziff et al, 2015).
However, despite their 200-year use and demonstrated efficacy in treating heart failure and atrial fibrillations, concerns over toxicity have caused cardiac glycosides to fall out of use in favour of other safer and more effective drugs such as, diuretics, ACE-inhibitors, β-blockers, angiotensin and mineralocorticoid receptor blockers (Weisse, 2010; Felicilda-Reynaldo, 2013; Stucky and Goldberger, 2015). In addition, several features of Digitalis treatment have proven to be problematic, limiting their favourability in treatment.
Cardiac Glycosides: Problems and Limitations
Digitalis cardiac glycosides exert direct action on cardiac muscle. They are capable of concentrating inside the heart muscle tissue (Ganpisetti et al, 2016). This, is in many ways a positive feature of therapy because it ensures that the glycosides reach the heart where they are intended to carry out their effects. However, this can also be problematic because when a significant portion of the drug is bound to heart tissue, a small amount of drug is found freely floating (unbound) in the blood. This is concerning, especially in patients with cardiac glycoside toxicity, because only the drugs that are found freely floating in the blood can be eliminated from the body.
It has also been shown that digoxin, the cardioactive glycoside most commonly used in therapy, is very poorly metabolized by the body (Felicilda-Reynaldo, 2013; Ganpisetti et al, 2016). In fact, most of the drug is eliminated in the urine in its unchanged form. Since digoxin has a half-life (the time it takes for a drug to reach half of its original concentration) of 1.5-2 days and longer in patients with kidney diseases (Ganpisetti et al, 2016), the risk of accumulating higher concentrations of digoxin to potentially toxic levels is of concern, especially in patients suffering with renal insufficiency or kidney damage (Felicilda-Reynaldo, 2013).
Further issues that limit the wide-spread use of cardiac glycosides such as digoxin are linked to concerns relating to pregnant and breastfeeding women. The glycosides are capable of reaching a baby through the placenta and breast milk and are capable of crossing the blood-brain barrier, causing an array of neurological disturbances associated with toxicity (Felicilda-Reynaldo, 2013; Ganpisetti et al, 2016).
Dangers of Digitalis: Safety, Toxicity and Treatment
Paracelsus, a Swiss-German scholar of the 16th century has been quoted with saying, “Everything is a poison. There is not one thing that is not a poison. It is the dose that distinguishes a poison from a remedy.” This quote perfectly applies to the case of Digitalis toxicity. The toxicity associated with D. purpurea among other Digitalis species is due to accumulation of the cardioactive glycosides (Felicilda-Reynaldo, 2013). Adverse reactions to cardioactive glycoside therapy has been shown to be dose dependant and generally occur at doses greater than those required therapeutically (Ganpisetti et al, 2016). In fact, lethal doses of digitalis are about 5-10 times greater than the minimum therapeutic levels (Ganpisetti et al, 2016). Though there are no standard accepted therapeutic levels for digoxin administration, the general consensus is that therapeutic levels of digoxin range from 0.5 – 2.0 ng/dL (Felicilda-Reynaldo, 2013). Therefore, with careful monitoring of digoxin to ensure levels fall within these therapeutic levels, adverse reactions are much less likely to occur (Ganpisetti et al, 2016), especially when lower therapeutic levels (ranging from 0.5 and 1.0 ng/mL) are used as they have been associated with decreased mortality and hospitalizations (Stucky and Goldberger, 2015).
However, despite of the careful monitoring of cardiac glycoside levels minimizing their over-administration, toxicity and adverse reactions may still occur when the drug is accumulated in the body due to impaired liver and kidney function (Felicilda-Reynaldo, 2013), interactions with other drugs (Felicilda-Reynaldo, 2013) or from the accidental exposure to cardiac glycosides or Digitalis plants (Felicilda-Reynaldo, 2013; Stucky and Goldberger, 2015).
Accidental exposure to cardiac glycosides from Digitalis species is not as far-fetched as it may seem. Cardioactive glycosides are found throughout the plant (Bruneton, 1999) and it is estimated that 1 fresh leaf of D. purpurea contains 1.6 – 4.8 mg of glycosides, significantly greater than the recommended therapeutic levels. Processing of raw plant material (such as through drying and boiling to prepare teas) does not reduce their toxicity (Cooper et al, 2003). This has resulted in several cases of accidental poisoning, which have often resulted from the ingestion of Digitalis by mistaking them for comfrey (Symphytum officinale L.) (Bruneton, 1999; Cooper et al, 2003). It is a classic case of a misidentification, which can happen because without flowers / fruits, the leaves looks somewhat similar. However, see the monograph on comfrey for concerns about using this species, since it is rich in highly toxic pyrrolizidine alkaloids.
Symphytum officinale. Photo: H. Zell.
Distributed under GNU Free Documentation License, version 1.2
Regardless of the method through which an individual is exposed to toxic levels of cardioactive glycosides, there are several adverse reactions characteristic of Digitalis poisoning:
– Gastrointestinal Disturbances:
Abdominal pain, nausea, vomiting, occasionally diarrhea, anorexia (Wenger et al, 1985; Bessen, 1986; Bruneton, 1999; Cooper et al, 2003; Stucky and Goldberger, 2015; Ganpisetti et al, 2016)
– Cardiac Disturbances:
Any number of cardiac dysrhythmias, palpitations, bradycardia (Bruneton, 1999; Cooper et al, 2003; Felicilda-Reynaldo, 2013; Ganpisetti et al, 2016)
– Visual Disturbances:
floating yellow halos (Cooper et al, 2003; Stucky and Goldberger, 2015)
– Neurological Disturbances:
Headache, fatigue, confusion, hallucinations and delirium
(Bessen, 1986, Bruneton, 1999; Cooper et al, 2003; Stucky and Goldberger, 2015; Ganpisetti et al, 2016),
– Other Manifestations of Toxicity:
Hyperkalemia, dyspnea (labored breathing), hypotension, malaise
(Wenger et al, 1985; Bessen, 1986; Ganpisetti et al, 2016; Stucky and Goldberger, 2015).
Since cardioactive glycosides are mostly bound to cardiac tissue in the body, these compounds are not effectively removed from the body with dialysis or exchange transfusion because these methods can only remove free flowing and unbound drugs from the blood (Ganpisetti et al, 2016). Treatment of Digitalis cardioactive glycoside toxicity consists of the symptomatic treatment of poisoning and the use of digoxin-specific antibody fragments (Digoxin-Fab) in severe cases and when other treatment options have failed (Wenger et al, 1985; Bruneton, 1999; Felicilda-Reynaldo, 2013; Chan and Buckley, 2014; Stucky and Goldberger, 2015; Ganpisetti et al, 2016).
Digoxin-Fab antibody fragments, prepared from sheep antiserum (Wenger et al, 1985; Chan and Buckley, 2014), work by binding to digoxin that is found freely floating in the blood. In doing so, they form a large molecule that cannot be absorbed by the body’s tissues and will consequently be eliminated in the urine (Wenger et al, 1985; Felicilda-Reynaldo, 2013). Their use has been highly recommended, and a recent review of Digoxin-Fab antibody treatment has revealed Digoxin-Fab to be a safe treatment and highly recommended in patients with life-threatening digoxin toxicity (Chan and Buckley, 2014). In fact, one study by Wenger et al, (1985) found that patients who had been administered an appropriate dose of Digoxin-Fab responded to the antibody treatment within 30 minutes of administration (Wenger et al, 1985) and that levels of unbound digoxin in the blood significantly dropped, even to undetectable levels, within minutes of treatment (Wenger et al, 1985). Moreover, the study found that Digitalis toxicity was completely reversed in most cases (Wenger et al, 1985), illustrating its tremendous value in treating digoxin poisoning. However, despite its usefulness in treating digoxin poisoning, it is an expensive treatment that limits its use in patients with life-threatening toxicity (Chan and Buckley, 2014).
The Future of Foxgloves: Treading Murky Waters?
Our increased knowledge on the toxicity of Digitalis and its glycosides, better understanding of the therapeutic levels of glycosides and improved antidotes to toxicity have resulted in a tremendous decrease in toxicity over the past two centuries and improved the lives of countless patients suffering from heart failure and atrial fibrillation. However, due to serious issues concerning the safety and toxicity of Digitalis and its cardioactive glycosides, the use of Digitalis and its glycosides have dropped over the past few decades (Weisse, 2010). Scientists and physicians alike have seriously questioned the value of these compounds in the treatment of heart failure and atrial fibrillation, especially in light of the development of safer and more effective therapies such as new ionotropic agents (Bessen, 1986). However, despite the toxicities that may be brought on by high doses of cardiac glycosides, a search of the available literature has shown that digoxin remains for many, an indispensable drug in the cardiology armamentarium (Stucky and Goldberger, 2015; Ganpisetti et al, 2016) and will continue to play an important role in treating cardiac problems, particularly when administered to patients for which other therapeutic options have failed.
The information provided in this essay is intended for educational purposes only, and should in no way be considered sufficient guidance for the use of Digitalis purpurea or its active glycosides. This essay in no way serves as a recommendation or endorsement for any particular products or medical treatments. Due to the highly toxic nature of Digitalis purpurea and the potential adverse effects that may result from the consumption of digitalis glycosides, the use of these products must be based solely on the appropriate advice and prescription of suitably qualified healthcare professionals.
© 2017 Natalia Blicharska
About the Author:
Natalia Blicharska, MSc Student (2016-2017) in Medicinal Natural Products and Phytochemistry at the UCL School of Pharmacy, University of London
Research Cluster Biodiversity and Medicines/Centre for Pharmacognosy and Phytotherapy, 29-39 Brunswick Sq. London. WC1N 1AX
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