A is for Arsenic (19 page)

The name
Conium
comes from the Greek
konas
, meaning ‘to spin like a top', one of the symptoms experienced after ingesting the plant;
maculatum
is from the Latin meaning ‘spotted' because of the brownish-reddish spots found on the stem of the plant. As well as the name ‘spotted hemlock',
Conium maculatum
is known as poison hemlock, the Devil's bread and the Devil's porridge. The plant is native to Europe, where it grows wild beside rivers, in wasteland and on road verges, but it can be found in many other parts of the globe. The species was introduced to the United States as a garden plant, and has been accidentally transported to other countries when its seeds have contaminated grain.

The seeds germinate very easily, and the plant is a noted ‘pioneer' species, being one of the first to grow in disturbed soil, and leading the way for colonisation by other plants. Due to its to ease of germination, hemlock is often one of the first plants to appear in spring, so it is of particular significance to farmers. Animals grazing on land where there is little else to eat can become ill from eating hemlock; it is more poisonous to cows than to any other species. Hemlock causes a staggering gait, increased salivation and tears, and respiratory distress, all of which can lead to death. Cows are hardy and can recover from many of these toxic effects, but some of the compounds within spotted hemlock can produce lasting problems because they are known to be teratogenic. Teratogenic compounds cause abnormalities in the unborn foetus. Skeletal malformations can be present in the calves born to cows that have ingested this plant (and similar effects have been seen in sheep, goats and pigs).

Some other animal species appear to be unaffected by hemlock. Quail, for example, are said to eat hemlock seeds with impunity, but it makes their flesh poisonous. There have been several reported cases of indirect hemlock poisoning in humans through eating songbirds that had fed on hemlock seeds. Seventeen such cases occurred in Italy between 1972
and 1990. There were four deaths, three from renal failure and one from prolonged paralysis.

Symptoms of gastritis and loss of coordination begin to appear around 30 minutes after ingestion of hemlock or its toxic alkaloids. The pulse becomes rapid and weak, vision dims and there is a gradual loss of movement, towards paralysis. Consciousness is maintained throughout, until the victim suffocates from respiratory paralysis.

Conium maculatum
contains several toxic alkaloids, but coniine is the most studied, and this compound is used as the means of murder in Agatha Christie's
Five Little Pigs
. All of the hemlock alkaloids are classed as piperidines (because they are all based on the structure of a chemical called piperidine – see Appendix 2). Seven spotted hemlock alkaloids have been identified and isolated so far;
⁵⁶
the toxicity of hemlock is due to the sum of all the toxic compounds present and their relative abundance can vary hugely. To produce these alkaloids, the plant carries out a series of reactions that subtly modify the structure from one to the next, resulting in a cascade of chemicals. γ-coniceine is the first to be produced, and it is this from which all the other alkaloids are manufactured. Experiments with mice have shown γ-coniceine to be the most toxic of these compounds, and this explains hemlock's particularly staggering toxicity in early spring, when γ-coniceine levels are at their highest. However, the concentrations and relative proportions of the different
Conium
alkaloids appear to depend on factors such as temperature, moisture, time and age of the plant. According to research γ-coniceine is predominant in the rainy season and coniine in the dry, but huge changes in concentrations occur during the
life of the plant, especially during flowering and fruit-forming stages.

Coniine was the first of the alkaloids to be isolated from hemlock, and it is highly toxic. A dose of 100–130mg of coniine would be fatal for an adult human. Pure coniine is a colourless, oily substance, with a pungent odour sometimes described as being like mouse urine. The oil is quite volatile, and is partly responsible for the characteristic (and unpleasant) smell produced when the leaves of
Conium maculatum
are crushed.

The credit for the discovery of coniine goes to a chemist,
L. Gi
eseke, in 1827, but he did not offer any suggestions as to what the chemical formula of coniine might be. The structure was not confirmed until 1881 by August Wilhelm von Hofmann (1818–1892). Today, there is an array of techniques that can be applied to compounds to identify and determine their exact composition, and the arrangement of atoms within the molecule. In Hofmann's time he would have had to use a series of painstaking chemical reactions, and analysis of the products of those reactions, to identify fragments of the original. Those fragments would then be slowly pieced together, as a detective might string together clues to identify a culprit. This was not easy, even for a relatively simple molecule such as coniine. Five years after Hofmann determined the structure, fellow scientist Albert Ladenburg (1842–1911) devised a method for coniine's chemical synthesis. It was the first plant alkaloid to be fully characterised and synthesised, more than 50 years after it was first isolated.

How hemlock kills

Coniine and the other alkaloids that occur in spotted hemlock are neurotoxins. The toxic effects of coniine are due to the molecule's similarity to nicotine, and it acts in a similar way.

Coniine interacts with receptors in the synapse (the junctions between neurons), those that normally bind acetylcholine (see page
here
); specifically, nicotinic-type receptors. The interaction
blocks acetylcholine from binding to the receptors and stops signals from being received from the connecting nerve.

The peripheral nervous system (PNS) connects the body to the central nervous system (the brain and spinal cord – the CNS), and acts as a relay for messages to and from the brain and body. One branch of the PNS, the autonomic nervous system, controls automatic functions – heart rate and the production of tears, for example; the other branch, the somatic nervous system, relays messages from the brain and spine to the muscles that control our movement, and is largely under our conscious control. Coniine interactions with receptors in the autonomic nervous system lead to symptoms such as increased salivation, pupil dilation, and an increased heart rate (tachycardia) followed by a very slow heart rate (brachycardia). Coniine also
blocks
receptors in the central nervous system (the spinal cord), resulting in a creeping paralysis that starts with the feet and legs and spreads throughout the body. Initially there will be numbness in the legs and difficulty walking. Death, which may occur several hours later, is as a result of paralysis of the muscles responsible for breathing.

The specific toxicity of all of the
Conium
alkaloids has not been studied, but it seems that the shape of the molecule is particularly important. A propyl group (a chain of three carbon atoms) attached to a nitrogen-containing ring structure is needed to confer toxicity. Coniine is also a chiral compound (see page
here
), meaning it can exist in two forms (or hands) with identical chemical composition but that are mirror images of each other. In the case of coniine, one form (the left-handed or
l
-form) is nearly twice as toxic as the other and is the form that dominates in hemlock plants. The synthetic coniine produced in 1886 would have been an equal mixture of both forms of coniine.

The consequences of not fully investigating biological interactions of the pure forms of a chiral compound were only realised with the thalidomide disaster of the 1950s. Thalidomide, a chiral compound, was prescribed as a mixture of both left- and right-handed forms, to treat morning sickness. Though it
was effective in treating this, one hand of thalidomide (the left one) is a teratogen; it caused serious malformations in the babies that were born to mothers taking the drug, and thalidomide was withdrawn from the market in 1961.

The paralysing and numbing effects of coniine suggest that it could be used in medicine, and in the past it has been used to treat asthma. Coniine salts are described in the 1912 book
The Art of Dispensing
as being ‘rarely prescribed' for the treatment of asthma. This was one of the books Agatha Christie would have studied for her dispensing exams in 1917. Coniine was also listed in the
British Pharmacopeia
as a sedative and antispasmodic, which led to its recommendation as an antidote to strychnine poisoning; it would have been administered in capsules or tonics. Pure coniine is an oil, which is reasonably soluble in water, but solids are preferable to work with when weighing and mixing drugs for prescriptions, especially when the oils are volatile and the vapour produces smells like mouse urine. Oils such as coniine might be converted to a salt for ease of use and storage in medical prescriptions. Coniine was usually prescribed as its hydrobromide salt, in doses of 1/100 or 1/60 of a grain (approximately 1mg). The drug's use was already waning by 1912, and coniine had completely disappeared from the
Pharmacopeia
by 1934; the therapeutic dose was found to be too close to the toxic one to be practical.

The way coniine relaxes muscles may still be of interest in medical research, so the physiological interactions of both its chiral forms are important to understand. Coniine would not currently be suitable for use in medicine without some modifications, as the compound does not bind selectively to receptors in the central nervous system, resulting in side effects. Modifications to coniine may be able to remove its teratogenic effects, too. This modified drug, whatever it might be, has potential applications in surgery.

Is there an antidote?

Treatment for hemlock poisoning is the same today as it would have been in the 1920s, when Amyas Crale is poisoned in Christie's
Five Little Pigs
, owing to the fact that there is no antidote. A stomach pump and treatment with activated charcoal are required to prevent more of the poison being absorbed from the stomach into the bloodstream; artificial respiration can then be used to support the patient while the body's metabolic processes eliminate the poison. This may take two or three days, but a patient receiving this treatment can expect to make a full recovery.

Agatha and hemlock

Coniine and its toxic properties are discussed in some detail in Agatha Christie's
Five Little Pigs
. Christie used the character of Meredith Blake, an amateur chemist who dabbles in herbs, to give the five suspects all the information and opportunity necessary to poison Amyas Crale. Five suspects were at the home of Amyas and his wife Caroline at the time of the murder. They were Philip Blake, a friend of Amyas; Meredith Blake, Philip's brother who lived nearby; Elsa Greer, a spoilt society beauty whose portrait Amyas was painting, and with whom he was having an affair; Angela Warren, Caroline's younger sister; and Cecilia Williams, Angela's governess.

Amyas and the rest of the Crale household visited Meredith the morning before Amyas's death. Meredith gave a tour of his laboratory, and pointed out various preparations he had made from plants. He took particular time discussing his preparation of coniine, which, he told the assembled audience, he had extracted from spotted hemlock. Meredith went on to describe the properties of coniine, and lamented the fact that it had disappeared from the
Pharmacopoeia
– Agatha Christie clearly kept up to date with changes in pharmaceutical practice. Meredith had found coniine to be effective in the treatment of asthma and whooping cough; coniine may relieve the symptoms of these, by numbing the pain and relaxing the muscles, but it would not treat the underlying conditions.
Meredith also read out a passage from
Phaedo,
where Plato describes the death of Socrates.