A is for Arsenic (13 page)

The digitalis story

‘Digitalis' refers to a group of related compounds extracted from plants of the genus
Digitalis
, commonly known as
foxgloves. There are more than twenty species, all containing digitalis compounds in varying amounts and proportions. In the plant, digitalis compounds act as a deterrent against animals that try to eat it. In mammals these compounds have a specific and dramatic effect on the heart. The chemical structure of these compounds includes a component known as a glycoside, hence digitalis compounds are known as ‘cardiac glycosides'. Toxic digitalis compounds are found in all parts of the plant; they can irritate the skin, and cause delirium, tremors, convulsions, headaches and fatal heart problems if ingested.

Digitalis plants are native to western Europe, western and central Asia, north-western Africa and Australasia. Though the plants grow wild, they are often cultivated because of their spectacular spikes of flowers in a range of colours. In their first year foxglove plants produce just a stem and soft, hairy, lance-shaped leaves. In two Agatha Christie stories, the short story
The Herb of Death
and the novel
Postern of Fate
, foxglove leaves are used to poison a meal by mixing them with sage and spinach leaves. One murderer deliberately planted foxgloves in a kitchen garden amongst the sage so the leaves would be picked by accident (this seems an unlikely mistake for an experienced cook to make). The distinctive flowers appear in the second year of growth, and look like caps or bells.

The name ‘foxglove' has been in use for hundreds of years, since at least the fourteenth century, but the origins of the name are obscure and many theories have been put forward to explain it. An attempt was made to throw some light on the subject by Dr Prior, an authority on the origin of popular names, in the 1866 book
English Botany
:

Its Norwegian name,
Revbielde
, foxbell, is the only foreign one that alludes to that animal … In France it is called
Gants de Notre Dame
; in Germany
Fingerhut
. It seems most probable that the name was, in the first place, foxes' glew, or music, in reference to that favourite instrument of an earlier time, a ring of bells hung on an arched support …

Prior proposed an alternative theory in the same book. ‘The “folks” of our ancestors were the “fairies”, and nothing was more likely than that the pretty coloured bells of the plants would be designated “Folksgloves”, afterwards “Foxglove”.' The foxglove plant has been part of folklore for centuries and traditional medicine for just as long, where it has been used to treat heart conditions and dropsy. The first systematic and scientific study of extracts of the plant was not made until the late eighteenth century by William Withering (1741–1799), a doctor from Shropshire. Withering noticed that one of his patients suffering from dropsy recovered after using a herbal remedy given to him by ‘the old woman of Shropshire'.

Dropsy, now known as oedema, is swelling caused by an accumulation of fluid in the body. Oedema has several causes, but is often due to either weak action of the heart or cirrhosis of the liver. Fluid filters out of the blood and is reabsorbed at the capillaries. The balance between filtering and reabsorption depends on the resistance of the blood and blood pressure. Under normal conditions the rate of filtration is higher than that of absorption, and the excess fluid is removed from the tissues by the lymphatic system. Fluid is returned to the blood from the lymphatic system at the superior vena cava, one of the large veins that take deoxygenated blood back to the heart. Fluid is permanently removed from the blood by filtration through the kidneys. All the blood in a human is filtered by the kidneys roughly every half-hour, and excess water is excreted via the bladder.

A person with a weak pulse due to heart failure is unable to expel blood from the ventricles of the heart efficiently. This results in an increase in blood pressure, and therefore an increase in the filtering of fluid into the tissues. The kidneys respond by retaining more fluid, so there is very little urine output. This leads to swelling in the legs and arms, and difficulty breathing as fluid builds up around the lungs.

After observing the successful treatment of his patient, William Withering sought out ‘the old woman of Shropshire' and asked her what went into her herbal treatment.
She wouldn't disclose the recipe, but Withering persuaded her to give him some of the preparations. By examining them under a microscope he identified fragments of foxglove.

Withering began what were effectively clinical trials of digitalis, which ultimately involved 163 patients. He gave his dropsy patients small amounts of various foxglove preparations, and observed their effects. He found dried and powdered foxglove leaves given by mouth to be the most effective treatment. Carefully increasing the dose, he monitored his patients' progress, recording results, both successful and unsuccessful, in his notebook.

The principles behind clinical trials have ancient origins stretching back to the time of the Old Testament, but they were not routinely used to assess the positive and negative effects of diet or drugs until the twentieth century. Withering's detailed study stands out because of his systematic approach to the use of foxglove preparations, and his careful notation of the adverse as well as the beneficial effects of these preparations. In his investigation, Withering noted that foxglove was extremely effective for some of his patients but not others. We now know that herbal preparations would be effective for dropsy caused by heart conditions, but they offered no help to those who were suffering from dropsy caused by cirrhosis of the liver. Withering also noted that at higher doses toxic effects developed, and he described the symptoms in detail.

Withering wrote up his observations in a treatise entitled
An Account of the Foxglove and some of its Medical Uses
(1785), still considered a classic of its kind. The book was widely read, and treatments were given to an increasing number of patients. However, some doctors grew impatient with the cautious and slow approach to foxglove treatments. Withering recommended that very small doses should be given initially and slowly increased until the desired effect was observed, in order to prevent toxic side effects. The extreme potency of the compounds within foxglove meant that it was exceptionally dangerous, and it was very easy to give an overdose. Even a ‘raw' dose (without purification of the active ingredients) will kill in
quantities as low as 2g. Toxicity can also build up over time, as some digitalis compounds have a long half-life within the body.

Despite the known toxicity of foxglove preparations, physicians continued to experiment with them until after Withering's death, when digitalis fell out of favour. When Withering himself became ill his friends commented that ‘The flower of physic is indeed Withering'.
⁴²
He died in 1799 of consumption (i.e. tuberculosis), and a foxglove was carved on his tombstone. Interest in digitalis was only revived in the early 1900s.

Withering used raw foxglove leaf in his treatments, but with developments in chemistry it became possible to refine the drug into a blend of several cardiac glycosides extracted from the plant. Even so, many of these compounds were inactive at best, and possibly harmful. In
Appointment with Death
, Agatha Christie lists four active principles of the foxglove – digitalin, digitonin, digitalein and digitoxin – a bit of a mouthful, admittedly. In her time these compounds were not easy to isolate as they are relatively fragile and could decompose during the extraction processes that were used in the late nineteenth and early twentieth centuries. They are also quite large molecules and their precise structures were not elucidated until years after their isolation (for example, digitoxin was identified in 1875 but its structure wasn't determined until 1962).

Of the compounds listed by Christie, digitonin is now known not to be a cardiac glycoside, because it has no effect on the heart (it does cause the breakdown of red blood cells, though). Digitonin is a saponin, meaning it forms a soap-like foam when shaken with water. Digitalein is something of an unknown; the word fell out of use in the scientific literature around 1921. It was probably not a single pure compound; as
scientists painstakingly isolated and identified more compounds from foxgloves, the name digitalein became irrelevant. The other two, digitoxin and digitalin, are still prescribed today. Digitalin is now known as digoxin, and is the more potent of the two (being between ten and twenty times more effective).

Digitalis compounds are complex and difficult to synthesise in the laboratory, so the drug is still obtained from the natural source by extraction from the plant
Digitalis purpurea
, the purple foxglove that grows wild in Britain, which contains both digoxin and digitoxin.
⁴³
Digitoxin is now rarely prescribed as it has a considerably longer half-life in the body, six days as opposed to 24–48 hours for digoxin, and it delivers an increased risk of side effects. Digoxin has one of the narrowest therapeutic ranges of any drug on the market – just 20–50 times a normal dose can prove fatal. Such a small gap between a healthy and a dangerous dose would not normally be tolerated in a new drug coming to market, but digoxin is considered an essential medicine because, with careful monitoring of the patient, the benefits greatly outweigh the risks.

How digitalis kills

Digoxin and digitoxin are completely absorbed through the gastrointestinal tract, so they can be administered in tablet form or as drops as well as by injection. The drugs primarily affect the action of the heart, with injections acting within seconds, but doses administered by mouth may take an hour or so to be absorbed and take effect.

The heart is effectively two pumps working to move blood around the body. The right side of the heart pumps venous, de-oxygenated blood to the lungs, where the red blood cells collect oxygen. This oxygenated blood then moves to the left side of the heart, where it is pumped out to the rest of the
body, to deliver the oxygen necessary for our cells to produce energy. Each side of the heart has two chambers, the atrium and the ventricle. Blood enters the atrium, then moves into its corresponding ventricle. The contraction of the ventricles pumps the blood on to its destination, either the rest of the body (from the left side) or the lungs (from the right).

Digitalis compounds affect the heart in two ways: they intensify its contractions, and they reduce the transmission of electrical signals from the atria to the ventricles that coordinate these movements. Many of the toxic effects of digitalis compounds represent exaggerations of the normal activity of the heart.

The human heart.

In some cases, the electrical impulses that coordinate the heartbeat across the atria can become disorganised, and irregular pulses are subsequently transmitted to the ventricles. Cardiac glycosides slow the transmission of these electrical signals across the heart; these compounds are therefore of benefit to patients suffering from atrial fibrillation, the rapid and irregular contraction of the atria. This condition is quite common, and can be effectively treated with drugs. In susceptible patients atrial fibrillation can result in the ventricles beating independently of the atria. This ‘heart block' is not normally a serious problem in younger subjects, but it can be a significant complication in older patients with other cardiac disorders. High doses of digoxin completely bar transmission of electrical signals between the atria and the ventricles, which can lead to death in minutes. The heart is effectively paralysed.

The structures within the heart that contract to pump the blood are the cardiac muscle cells, or cardiac myocytes. These are the largest cells in the heart, and they make up the bulk of the mass of the organ. Around 50 per cent of each cardiac myocyte is made of microfibrils, an arrangement of thick and thin filaments that slide over each other to cause the physical contraction of the cell. The coordinated contraction of these cells results in the overall movement of the heart, squeezing the atria and ventricles to pump the blood. The sliding action of the microfibrils is as a result of the movement of sodium (Na
+
), potassium (K
+
) and calcium (Ca
2+
) ions.
⁴⁴
The movement of sodium into a cell triggers a cascade of events that induces calcium ions also to move into the cell. It is the movement of calcium ions that causes the microfibrils to alter their shape and contract the heart.