Journal of Eye Study and Treatment

Historical Article

Poisons, Drugs and Medicine: On the Use of Atropine and Scopolamine in Medicine and Ophthalmology: An Historical Review of their Applications

Sibylle Scholtz1*, Lee MacMorris1, Frank Krogmann1,2 and Gerd U Auffarth1

1International Vision Correction Research Centre (IVCRC), Department of Ophthalmology, University of Heidelberg, Heidelberg, Germany

2General Manager and Member of Board of Directors, Julius-Hirschberg-Society, Vienna, Austria

Received: 13 June 2019

Accepted: 26 July 2019

Version of Record Online: 31 July 2019

Citation

Scholtz S, MacMorris L, Krogmann F, Auffarth GU (2019) Poisons, Drugs and Medicine: On the Use of Atropine and Scopolamine in Medicine and Ophthalmology: An Historical Review of their Applications. J Eye Stud Treat 2019(1): 01-07.

Correspondence should be addressed to
Sibylle Scholtz, Germany

E-mail: sibylle.scholtz@gmx.de
DOI:
10.33513/JEST/1901-13

Copyright

Copyright © 2019 Sibylle Scholtz et al. This is an open-access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and work is properly cited.

Abstract

Purpose: For thousands of years all kinds of ingredients of plants were used to treat diseases. Among other highly active ingredients, plants like belladonna, datura, henbane and mandrake contain alkaloids and even highly toxic alkaloids like atropine and scopolamine. Our article will show major historical facts about the mentioned two drugs and the origin of their names.

Methods: The history of the discovery of atropine and scopolamine, two highly poisonous alkaloids, was analysed and interpreted based on a selective literature research of books and journal articles via PubMed, Google Scholar and Google.

Results: Both alkaloids, used in antiquity, are essential drugs in modern medicine. Atropine is an extremely potent poison and, as a medicine, was widely used in ancient times. Today it is still an essential drug in today’s medicine and in ophthalmology. The name has its source in the legends of Greek mythology and refers to the Greek goddess, Atropos. Scopolamine is named after its discoverer, Giovanni Antonio Scopoli, a Tyrolean physician and naturalist of the 18th century, who was the first to describe the plant from which the alkaloid “Scopolamine” was isolated: Scopolia carniolica. The substance Scopolamine is used in ophthalmology and general medicine.

Discussion: Plants of the nightshade family, Solanaceae are true masters of chemical warfare. Even today alkaloids in medicine are indispensable drugs in medicine, also in ophthalmology. The name “atropine” has a long mythological history. Apart from its immense importance as a poison and a drug, even a kingdom was named after Atropos: Atropatene, which was located in the region of today’s Azerbaijan. Giovanni Antonio Scopoli, as name giver for scopolamine was one of the most respected scholars of the 18th century. His interdisciplinary research has profited the fields of ophthalmology, general medicine as well as botany.

Keywords 

Alkaloids; Atropine; History of Ophthalmology; Ophthalmology; Scopolamine

Introduction

Using the ingredients of plants to treat diseases has been known for thousands of years. Time and again, young people especially, who are in search of legal drugs, tend to use plants containing psychoactive ingredients, including angel’s trumpets, datura, belladonna and other representatives of the nightshade family Solanaceae. The alkaloids of these plants, like atropine and scopolamine, lead to drowsiness, intoxication and hallucinations of flying. They can be obtained quite easily. While these plants grow wild by the roadside, they are popular as ornamental plants. What nature offers, however, is by no means, harmless. Solanaceae are considered as highly toxic - as well as they can be essential drugs in medicine. Scopolamine also acts as a parasympatholytic, but in comparison to atropine, rather calming and muffling. It provides a state of lack of will and apathy, similar to hypnosis. It was once used as a truth drug [1-5].

The dark side of “belladonna” - Antique Greek Mythology meets biology, chemistry - and medicine

In Greek mythology she was the oldest of the three Moirai, the personification of the “inevitable”. She chose the mechanism of the death of each mortal, by cutting the thread of life, which her sister Clotho has spun and Lachesis had measured (Figure 1) [1-9]. She lent her name to an ancient kingdom, a poisonous plant and a hawk moth. Atropos, the daughter of Zeus, one of the three Moirai, the goddesses of fate and destiny, from whom the legendary poison has its name: Atropine, an alkaloid of the deadly nightshade, Atropa belladonna (Figures 2,3) [1-3]. Atropine is an extremely potent poison and still an essential drug in today’s medicine [10-13]. The name has its source in the legends of Greek mythology [1-3,14,15].

Poisons, Drugs and Medicine: On the Use of Atropine and Scopolamine in Medicine and Ophthalmology: An Historical Review of their Applications

Figure 1: The Triumph of Death, or The Three Fates [16].

Poisons, Drugs and Medicine: On the Use of Atropine and Scopolamine in Medicine and Ophthalmology: An Historical Review of their Applications

Figure 2: Chemical structure of (S)- and (L)-Hyoscyamine [17].

Poisons, Drugs and Medicine: On the Use of Atropine and Scopolamine in Medicine and Ophthalmology: An Historical Review of their Applications

Figure 3: Atropa belladonna, fruits [17].

With the pattern of a skull on its back, the Latin name of the death’s head hawk moth (Acherontia atropos) reminds one of the deadly effects of Atropos [18]. The Latin name of deadly nightshade, Atropa belladonna and its poison atropine remind one of Zeus’ daughter. The byname “belladonna” means “beautiful lady”, since in the Middle Ages the juice of the berries was used cosmetically to enlarge women’s pupils to make them more beautiful [1-5]. The chemistry is confusing: atropine is a mixture of two isomeric varieties of the hyoscyamine molecule (right- and left-turning) (Figure 2). In nature, only l-hyoscyamine occurs in Solanaceae, which is the pharmacologically active substance. After isolation it becomes a racemic mixture of d- and l-hyoscyamine, which is called atropine. Birds can consume the berries of the deadly nightshade without being harmed, humans cannot do so. Generally, 3 to 4 berries with children, 10 to 12 berries with adults are considered to be lethal [12,13,19-23].

In ancient times, atropine was widely used in medicine, e.g. as analgesic for hepatitis, edema, scarlet fever and mental diseases as well as a poison. The poisonous effect on the parasympathetic nervous system has been known for a long time. Attalos III. (171-133 B. C.) grew Solanaceae and proved its effect with animals and with persons condemned to death.

Atropine is part of the “belladonna” extract that young women in ancient Venice applied to their eyes in order to have “beautiful” dilated pupils. In antiquity the berry of the deadly nightshade traditionally was used as analgetic and in the Eastern world it was added to beer and wine. Theophrastus of Eresos knew “Atropa” as poison and mydriatic. Atropine was also responsible for the outcome of a war. The Scottish king Duncan I. used “Atropa” as toxic agent against the Norwegian enemies by poisoning their food and thus winning the battle. Both in the works of Hildegard von Bingen in the 12th century as well as with Leonhardt Fuchs 1542 an illustration of the deadly nightshade can be found [1-5,22,24-30].

The information about the application of deadly nightshade, mainly to relieve pain became more explicit during the Middle Ages. Later, the increase of the dose rate led to “witch ointments”. The expression “Belladonna” originated in Venice in the 16th century and refers to the application of the juice of Atropa berries in order to enlarge the pupils. In a book about herbs from 1731 it is said that an external application of the cut green parts can help to reduce ulcers and swellings, heal an inflammation of the stomach and the liver by reducing the fever. Even in the 19th century extracts from the plant and its roots were used in the treatment of pains, jaundice, dropsy, pertussis, nervous diseases, scarlet fever, epilepsy, neuroses, skin diseases and many others.

The physiological effect of atropine was scientifically proved in 1819 when the German chemist F. Runge described the pupil-dilating effect of extracts of the deadly nightshade in his dissertation. In 1831, the pharmacist Mein succeeded in preparing atropine in pure crystalline form. Geiger and Hesse isolated in 1833 hyoscyamine from the plants and in the same year Merck (Darmstadt) started the production of atropine by processing the roots of deadly nightshade [11-13,19-25,29,31-34].

In 1863, the chemical structure of the alkaloid was defined and 1866 Bernstein described its mydriatic effect. Since 1867, extracts of deadly nightshade have been administered with Parkinson (“Bulgarische Kur” [35] [“Bulgarian Cure”, translation by authors]). 1872 it was found that atropine could inhibit salivation and 1878 its effect on the intestines was discovered. In 1901, Richard Willstätter first synthesized atropine. The production of atropine-sulfate made clinical application possible [11-13,19-23,25,31-34].

Today ingredients of deadly nightshades are no longer used in popular medicine. As atropine binds to muscarine type of receptors in the iris it is used in uveitis or iritis treatment to dilate the pupil which relieves the pain. The sympatholytic function can cause, especially in small children in hot countries overheating leading to death. Nevertheless, there is an increase of intoxication incidents caused by abuse of hallucinogenic drugs [36]. For certain clinical pictures atropine is still a widely used, indispensable drug, especially in emergency medicine. It can serve as treatment of insecticide poisoning and as an antidote for nerve gases. In the preparation for an operation, atropine lowers the activity of glands, reduces the seizures of the smooth muscles and, is generally used in ophthalmology to dilate the pupil and inhibit accommodation [11-13,37]. Homoeopathy frequently uses the effects of this highly poisonous agent in a dilution of D6 up to D12 to treat cramps in all hollow organs, asthma, stomach ulcer, gout and menstruation pains [10,15,38].

A doctor and his love for flowers…

Among other highly active ingredients, plants like belladonna, datura, henbane and mandrake contain the substance scopolamine. There is speculation that Joan of Arc owed her victories over the English to mandragora (a highly biologically active alkaloid). Other plants, including deadly nightshade, angel’s trumpet and henbane also contain scopolamine, named after its discoverer, Giovanni Antonio Scopoli (Figure 4) [39-44].

Poisons, Drugs and Medicine: On the Use of Atropine and Scopolamine in Medicine and Ophthalmology: An Historical Review of their Applications

Figure 4: Giovanni Antonio Scopoli (1723-1788) [44].

To cure illnesses, relieve pain or to “escape” the everyday life, were desires of all cultures at all times. As old is the knowledge of plants that make this possible (or at least the belief in them). The list goes next to many others from the fly agaric to the deadly nightshade, datura, henbane and mandragora. They - regarded as classical witches’ drugs used for love potions, magic salve or “flying ointment” - were also used as painkillers, to increase potency, as an abortive and anticonvulsant agents as well as used for narcosis and also just for getting high. They all contain the substance scopolamine (Figure 5), which has been used as medicine and as a narcotic for thousands of years because of its psychotropic effect [40-42,45-47].

Poisons, Drugs and Medicine: On the Use of Atropine and Scopolamine in Medicine and Ophthalmology: An Historical Review of their Applications

Figure 5: Structural formula of Scopolamine C17H21NO4 [46].

More than 3000 years ago, mandragora berries were placed in the coffin of Egyptian Pharaoh Tut Ench Amon. The physicians of the School of Alexandria knew of the narcotic effect of mandragora two thousand years ago [40-42,45-47].

Giovanni Antonio Scopoli, Tyrolean physician and naturalist of the 18th century, was the first to describe the plant from which the alkaloid “Scopolamine” was isolated: Scopolia carniolica (Figure 6). Giovanni Antonio Scopoli was born June, 13th 1723 in Cavalese/Val di Fiemme, formerly Austria. His father was lieutenant in the service of the prince-bishop of Trento. He went to school in Trento and studied medicine at the University of Innsbruck, where he received his doctor degree at the age of 20 years. After that he worked as a doctor in Trento and Venice. Scopoli was highly interested in nature; he collected plants in Tyrol and Bavaria and started to characterize them. Here he followed the system of world-famous botanist Carl von Linné. Two years later Scopoli switched to the University of Vienna [39,42-49].

Poisons, Drugs and Medicine: On the Use of Atropine and Scopolamine in Medicine and Ophthalmology: An Historical Review of their Applications

Figure 6: Scopolia carniolica [50].

In 1754, Scopoli took a position as a doctor in a mercury mine in Idria (Idrija) in the Slovenian province of Krain (today Krajinska). Here he taught metal chemistry to the mining students. Continuing his interest in and love of nature, he published his “Flora carniolica,” (1760) describing the plants of the region of Krain. In this region the “Scopolia carniolica,” also known as the “henbane bell,” flourishes and blooms in April [39,42-44,49,51].

For 15 years Scopoli remained in Idria as a doctor. He stayed true to his job and his hobby. In 1760, he published “Flora Carniolica”, a description of the flora of Carniola, undertaken when Scopoli lived in Idrija [39,42-44,49,51,52].

In 1761, he described the causes, symptoms and treatment of the diseases of the miners; in 1763 his work on the insect “Entomologica carniolica” set standards which are still used. Scopoli went to Schemnitz (today Banská Štiavnica, Slovakia). Although private endeavors were not permitted there, he continued to publish books. In 1777, he was appointed Professor of Botany and Chemistry at the University of Pavia. Here, at last, he was able to pursue his scientific interests: he set up a botanical garden and founded both a chemical laboratory and a naturalist cabinet [39,42-44,49,51,53].

A disease of the eyes cut short his scientific activities. Unfortunately, there is little information available about his illness; it is assumed that Scopoli suffered from glaucoma or macular degeneration. On May, 8th 1788 at the age of 64 in Pavia, Johann Anton Scopoli died [39,42-44,49,51].

Even if scopolamine can also be produced synthetically today, the natural form is still used for privately prepared intoxicating beverages. Recent medical benefit of this substance in ophthalmology is as a mydriatic agent in diagnosis and therapy. In general medicine, the substance was used as scopolamine-containing cigarettes available for asthma treatment in pharmacies until the 1970s. Today it is used for therapy and prophylaxis of motion sickness, postoperative nausea and as spasmolytic agent treating mild to moderate cramps of the gastrointestinal tract. The World Health Organization includes it in the List of Essential Medicines as one of the most effective and safe medicines needed in a health system [39-48,51].

Conclusion

Alkaloids, such as atropine and scopolamine are essential drugs in medicine. Today’s use of atropine is small but important, e.g. in emergency medicine and as mydriatic agent in ophthalmology [11]. The name “atropine” has a long mythological history [1-9]. Apart from its immense importance as a poison and a drug, even a kingdom was named after Atropos: Atropatene, which has been located in the region of today’s Azerbaijan [30]. The kingdom of Atropatene has been long lost in history [30]. Atropine, however, still exists and is used in modern medicine certainly also in today’s Azerbaijan. It would be interesting to learn whether the album of the Norwegian rock-band “Gazpacho” called “Missa Atropos”, which seems to be a late hymn to the lost battle in ca. 1035 is known there too.

Not only medicine benefits from Scopoli’s interdisciplinary research, the species described by him added “Scop.” to its botanical name. Johann Anton Scopoli was one of the most distinguished scholars of the 18th century. His discovery is still with us: the alkaloid “Scopolamine” bears his name. Scopoli’s interdisciplinary research has profited the fields of ophthalmology, general medicine as well as botany. In his honor many commemorative items bear his name, especially in Tyrol and northern Italy [39-44].

Alkaloid-containing plants have been used by humans since ancient times for therapeutic and recreational purposes as well as for poisoning. The development of the chemistry of alkaloids was accelerated by the emergence of spectroscopic and chromatographic methods in the 20th century, so that more than 12.000 alkaloids had been identified by 2008.

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