Poisons, Drugs and Medicine: on the Use of Atropine and Scopolamine in Medicine and Ophthalmology: an Historical Review of Their Applications

Journal of Eye Study and Treatment ISSN: 2652-5046 10.33513/JEST/1901-13 OCIMUM Scholtz S et al. J Eye Stud Treat 2019(01): 51-58.

Historical Review 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 Abstract Krogmann1,2 and Gerd U Auffarth1 Purpose: For thousands of years all kinds of ingredients of plants were 1International Vision Correction Research Centre used to treat diseases. Among other highly active ingredients, plants like (IVCRC), Department of Ophthalmology, University belladonna, datura, henbane and mandrake contain alkaloids and even highly of Heidelberg, Heidelberg, Germany toxic alkaloids like atropine and scopolamine. Our article will show major 2General Manager and Member of Board of historical facts about the mentioned two drugs and the origin of their names. Directors, Julius-Hirschberg-Society, Vienna, The history of the discovery of atropine and scopolamine, Austria Methods: two highly poisonous alkaloids, was analysed and interpreted based on a selective literature research of books and journal articles via PubMed, Received: 13 June 2019 Google Scholar and Google. Accepted: 26 July 2019 Version of Record Online: 31 July 2019 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 Citation medicine and in ophthalmology. The name has its source in the legends of Scholtz S, MacMorris L, Krogmann F, Auffarth Greek mythology and refers to the Greek goddess, Atropos. Scopolamine is GU (2019) Poisons, Drugs and Medicine: On the named after its discoverer, Giovanni Antonio Scopoli, a Tyrolean physician Use of Atropine and Scopolamine in Medicine and and naturalist of the 18th century, who was the first to describe the plant Ophthalmology: An Historical Review of their from which the alkaloid “Scopolamine” was isolated: Scopolia carniolica. Applications. J Eye Stud Treat 2019(1): 51-58. The substance Scopolamine is used in ophthalmology and general medicine.

Correspondence should be addressed to Discussion: Plants of the nightshade family, Solanaceae are true masters Sibylle Scholtz, Germany of chemical warfare. Even today alkaloids in medicine are indispensable E-mail: [email protected] 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 Copyright located in the region of today’s Azerbaijan. Giovanni Antonio Scopoli, Copyright © 2019 Sibylle Scholtz et al. This is an as name giver for scopolamine was one of the most respected scholars of open-access article distributed under the Creative the 18th century. His interdisciplinary research has profited the fields of Commons Attribution License which permits ophthalmology, general medicine as well as botany. unrestricted use, distribution, and reproduction in any medium, provided the original author and Keywords work is properly cited. Alkaloids; Atropine; History of Ophthalmology; Ophthalmology; Scopolamine

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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): 51-58. DOI: 10.33513/JEST/1901-13 Introduction The dark side of “belladonna” - Antique Greek Mythology meets biology, chemistry - and Using the ingredients of plants to treat diseases has been known for thousands of years. Time and again, young people especially, medicine who are in search of legal drugs, tend to use plants containing In Greek mythology she was the oldest of the three Moirai, the psychoactive ingredients, including angel’s trumpets, datura, personification of the “inevitable”. She chose the mechanism of belladonna and other representatives of the nightshade family the death of each mortal, by cutting the thread of life, which Solanaceae. The alkaloids of these plants, like atropine and her sister Clotho has spun and Lachesis had measured (Figure scopolamine, lead to drowsiness, intoxication and hallucinations 1) [1-9]. She lent her name to an ancient kingdom, a poisonous of flying. They can be obtained quite easily. While these plants plant and a hawk moth. Atropos, the daughter of Zeus, one of grow wild by the roadside, they are popular as ornamental the three Moirai, the goddesses of fate and destiny, from whom plants. What nature offers, however, is by no means, harmless. the legendary poison has its name: Atropine, an alkaloid of Solanaceae are considered as highly toxic - as well as they can the deadly nightshade, Atropa belladonna (Figures 2,3) [1-3]. be essential drugs in medicine. Scopolamine also acts as a Atropine is an extremely potent poison and still an essential parasympatholytic, but in comparison to atropine, rather drug in today’s medicine [10-13]. The name has its source in calming and muffling. It provides a state of lack of will and the legends of Greek mythology [1-3,14,15]. apathy, similar to hypnosis. It was once used as a truth drug [1-5].

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

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.02. 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): 51-58. DOI: 10.33513/JEST/1901-13

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

Figure 3: Atropa belladonna, fruits [17].

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With the pattern of a skull on its back, the Latin name of The physiological effect of atropine was scientifically proved the death’s head hawk moth (Acherontia atropos) reminds in 1819 when the German chemist F. Runge described the one of the deadly effects of Atropos [18]. The Latin name of pupil-dilating effect of extracts of the deadly nightshade in deadly nightshade, Atropa belladonna and its poison atropine his dissertation. In 1831, the pharmacist Mein succeeded remind one of Zeus’ daughter. The byname “belladonna” in preparing atropine in pure crystalline form. Geiger and means “beautiful lady”, since in the Middle Ages the juice Hesse isolated in 1833 hyoscyamine from the plants and in of the berries was used cosmetically to enlarge women’s the same year Merck (Darmstadt) started the production of pupils to make them more beautiful [1-5]. The chemistry is atropine by processing the roots of deadly nightshade [11- confusing: atropine is a mixture of two isomeric varieties of 13,19-25,29,31-34]. the hyoscyamine molecule (right- and left-turning) (Figure 2). In nature, only l-hyoscyamine occurs in Solanaceae, which In 1863, the chemical structure of the alkaloid was defined is the pharmacologically active substance. After isolation it and 1866 Bernstein described its mydriatic effect. Since becomes a racemic mixture of d- and l-hyoscyamine, which 1867, extracts of deadly nightshade have been administered is called atropine. Birds can consume the berries of the deadly with Parkinson (“Bulgarische Kur” [35] [“Bulgarian Cure”, nightshade without being harmed, humans cannot do so. translation by authors]). 1872 it was found that atropine Generally, 3 to 4 berries with children, 10 to 12 berries with could inhibit salivation and 1878 its effect on the intestines adults are considered to be lethal [12,13,19-23]. was discovered. In 1901, Richard Willstätter first synthesized atropine. The production of atropine-sulfate made clinical In ancient times, atropine was widely used in medicine, e.g. as application possible [11-13,19-23,25,31-34]. analgesic for hepatitis, edema, scarlet fever and mental diseases as well as a poison. The poisonous effect on the parasympathetic Today ingredients of deadly nightshades are no longer used nervous system has been known for a long time. Attalos III. in popular medicine. As atropine binds to muscarine type of (171-133 B. C.) grew Solanaceae and proved its effect with receptors in the iris it is used in uveitis or iritis treatment to animals and with persons condemned to death. dilate the pupil which relieves the pain. The sympatholytic function can cause, especially in small children in hot countries Atropine is part of the “belladonna” extract that young overheating leading to death. Nevertheless, there is an increase women in ancient Venice applied to their eyes in order to of intoxication incidents caused by abuse of hallucinogenic have “beautiful” dilated pupils. In antiquity the berry of the drugs [36]. For certain clinical pictures atropine is still a deadly nightshade traditionally was used as analgetic and in the widely used, indispensable drug, especially in emergency Eastern world it was added to beer and wine. Theophrastus of medicine. It can serve as treatment of insecticide poisoning Eresos knew “Atropa” as poison and mydriatic. Atropine was and as an antidote for nerve gases. In the preparation for an also responsible for the outcome of a war. The Scottish king operation, atropine lowers the activity of glands, reduces Duncan I. used “Atropa” as toxic agent against the Norwegian the seizures of the smooth muscles and, is generally used in enemies by poisoning their food and thus winning the battle. ophthalmology to dilate the pupil and inhibit accommodation Both in the works of Hildegard von Bingen in the 12th century [11-13,37]. Homoeopathy frequently uses the effects of this as well as with Leonhardt Fuchs 1542 an illustration of the highly poisonous agent in a dilution of D6 up to D12 to treat deadly nightshade can be found [1-5,22,24-30]. cramps in all hollow organs, asthma, stomach ulcer, gout and menstruation pains [10,15,38]. The information about the application of deadly nightshade, mainly to relieve pain became more explicit during the A doctor and his love for flowers… Middle Ages. Later, the increase of the dose rate led to “witch ointments”. The expression “Belladonna” originated in Venice Among other highly active ingredients, plants like belladonna, in the 16th century and refers to the application of the juice of datura, henbane and mandrake contain the substance Atropa berries in order to enlarge the pupils. In a book about scopolamine. There is speculation that Joan of Arc owed her herbs from 1731 it is said that an external application of the victories over the English to mandragora (a highly biologically cut green parts can help to reduce ulcers and swellings, heal active alkaloid). Other plants, including deadly nightshade, an inflammation of the stomach and the liver by reducing the angel’s trumpet and henbane also contain scopolamine, named fever. Even in the 19th century extracts from the plant and its after its discoverer, Giovanni Antonio Scopoli (Figure 4) roots were used in the treatment of pains, jaundice, dropsy, [39-44]. pertussis, nervous diseases, scarlet fever, epilepsy, neuroses, To cure illnesses, relieve pain or to “escape” the everyday life, skin diseases and many others. were desires of all cultures at all times. As old is the knowledge

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.04. 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): 51-58. DOI: 10.33513/JEST/1901-13 of plants that make this possible (or at least the belief in them). increase potency, as an abortive and anticonvulsant agents as The list goes next to many others from the fly agaric to the well as used for narcosis and also just for getting high. They deadly nightshade, datura, henbane and mandragora. They - all contain the substance scopolamine (Figure 5), which has regarded as classical witches’ drugs used for love potions, magic been used as medicine and as a narcotic for thousands of years salve or “flying ointment” - were also used as painkillers, to because of its psychotropic effect [40-42,45-47].

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

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

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More than 3000 years ago, mandragora berries were placed in For 15 years Scopoli remained in Idria as a doctor. He stayed the coffin of Egyptian Pharaoh Tut Ench Amon. The physicians true to his job and his hobby. In 1760, he published “Flora of the School of Alexandria knew of the narcotic effect of Carniolica”, a description of the flora of Carniola, undertaken mandragora two thousand years ago [40-42,45-47]. when Scopoli lived in Idrija [39,42-44,49,51,52]. Giovanni Antonio Scopoli, Tyrolean physician and naturalist of In 1761, he described the causes, symptoms and treatment the 18th century, was the first to describe the plant from which of the diseases of the miners; in 1763 his work on the insect the alkaloid “Scopolamine” was isolated: Scopolia carniolica “Entomologica carniolica” set standards which are still used. (Figure 6). Giovanni Antonio Scopoli was born June, 13th Scopoli went to Schemnitz (today Banská Štiavnica, Slovakia). 1723 in Cavalese/Val di Fiemme, formerly Austria. His father Although private endeavors were not permitted there, he was lieutenant in the service of the prince-bishop of Trento. He continued to publish books. In 1777, he was appointed went to school in Trento and studied medicine at the University Professor of Botany and Chemistry at the University of Pavia. of Innsbruck, where he received his doctor degree at the age Here, at last, he was able to pursue his scientific interests: he set of 20 years. After that he worked as a doctor in Trento and up a botanical garden and founded both a chemical laboratory Venice. Scopoli was highly interested in nature; he collected and a naturalist cabinet [39,42-44,49,51,53]. plants in Tyrol and Bavaria and started to characterize them. Here he followed the system of world-famous botanist Carl A disease of the eyes cut short his scientific activities. von Linné. Two years later Scopoli switched to the University Unfortunately, there is little information available about his of Vienna [39,42-49]. illness; it is assumed that Scopoli suffered from glaucoma or

Figure 6: Scopolia carniolica [50].

In 1754, Scopoli took a position as a doctor in a mercury macular degeneration. On May, 8th 1788 at the age of 64 in mine in Idria (Idrija) in the Slovenian province of Krain (today Pavia, Johann Anton Scopoli died [39,42-44,49,51]. Krajinska). Here he taught metal chemistry to the mining students. Continuing his interest in and love of nature, he Even if scopolamine can also be produced synthetically today, published his “Flora carniolica,” (1760) describing the plants the natural form is still used for privately prepared intoxicating of the region of Krain. In this region the “Scopolia carniolica,” beverages. Recent medical benefit of this substance in also known as the “henbane bell,” flourishes and blooms in ophthalmology is as a mydriatic agent in diagnosis and therapy. April [39,42-44,49,51]. In general medicine, the substance was used as scopolamine-

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.06. 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): 51-58. DOI: 10.33513/JEST/1901-13 containing cigarettes available for asthma treatment in 5. Karger-Decker B (2000) Die Geschichte der Medizin. pharmacies until the 1970s. Today it is used for therapy and Bibliographisches Institut, Mannheim , Germany. prophylaxis of motion sickness, postoperative nausea and as 6. Schultes RE, Hofmann A (1980) Pflanzen der Götter. Hallmann spasmolytic agent treating mild to moderate cramps of the Verlag, Bern und Stuttgart, Germany. gastrointestinal tract. The World Health Organization includes 7. Beltz W (1975) Gott und die Götter. Aufbau-Verlag, Berlin und it in the List of Essential Medicines as one of the most effective Weimar , Germany. and safe medicines needed in a health system [39-48,51]. 8. http://de.wikipedia.org/wiki/Atropos, Accessed January 26, Conclusion 2019. 9. http://en.wikipedia.org/wiki/Atropos, Accessed January 26, Alkaloids, such as atropine and scopolamine are essential drugs 2019. in medicine. Today’s use of atropine is small but important, e.g. in emergency medicine and as mydriatic agent in ophthalmology 10. Schilsky B (1969) Homöopathiefibel für Ärzte. Haug, Germany. [11]. The name “atropine” has a long mythological history [1- 11. Rote Liste 2012, Rote Liste Service 2012. 9]. Apart from its immense importance as a poison and a drug, 12. Mutschler E (2008) Arzneimittelwirkung: Lehrbuch der even a kingdom was named after Atropos: Atropatene, which Pharmakologie und Toxikologie. Wissenschaftliche has been located in the region of today’s Azerbaijan [30]. The Verlagsgesellschaft, Germany. kingdom of Atropatene has been long lost in history [30]. Atropine, however, still exists and is used in modern medicine 13. Kuschinsky G, Lüllmann H (1989) Kurzes Lehrbuch der Pharmakologie und Toxikologie. Thieme, Stuttgart and New certainly also in today’s Azerbaijan. It would be interesting York. to learn whether the album of the Norwegian rock-band “Gazpacho” called “Missa Atropos”, which seems to be a late 14. http://de.wikipedia.org/wiki/Moiren, Accessed January 26, 2019. hymn to the lost battle in ca. 1035 is known there too. 15. www.dr-oberhofer.at/profil/philosophie/die-moiren/index.html, Not only medicine benefits from Scopoli’s interdisciplinary Accessed January 26, 2019. research, the species described by him added “Scop.” to its botanical name. Johann Anton Scopoli was one of the most 16. http://commons.wikimedia.org/wiki/File:The_Triumph_of_ Death,_or_The_Three_Fates.jpg?uselang=de, Accessed distinguished scholars of the 18th century. His discovery January 26, 2019. is still with us: the alkaloid “Scopolamine” bears his name. Scopoli’s interdisciplinary research has profited the fields of 17. https://de.wikipedia.org/wiki/Atropin, Accessed January 26, 2019. ophthalmology, general medicine as well as botany. In his honor many commemorative items bear his name, especially 18. https://en.wikipedia.org/wiki/Acherontia_atropos, Accessed in Tyrol and northern Italy [39-44]. January 26, 2019. Alkaloid-containing plants have been used by humans since 19. Auterhoff H, Knabe J, Höltje H-D (1999) Lehrbuch der Pharmazeutischen Chemie, 14.Aufl., Wissenschaftliche ancient times for therapeutic and recreational purposes as Verlagsgesellschaft, Stuttgart, Germany. well as for poisoning. The development of the chemistry of alkaloids was accelerated by the emergence of spectroscopic 20. Schneider G, Hiller K (1999) Arzneidrogen, 4.Aufl., Spektrum Akademischer Verlag, Heidelberg, Germany. and chromatographic methods in the 20th century, so that more than 12.000 alkaloids had been identified by 2008. 21. Frohne D, Pfänder HJ (1997) Giftpflanzen, 4.Aufl., Wissenschaftlich Verlagsgesellschaft, Stuttgart, Germany. References 22. Rätsch Chr (1998) Enzyklopädie der psychoaktiven Pflanzen, Botanik, Ethnopharmakologie und Anwendung, ATVerlag, 1. Giebelmann R, Logemann E (2004) Kulturgeschichtliches Aarau, Switzerland. zum Atropin. T+ K 71: 32-37. 23. Riebe F (2009) Isolierung und Strukturaufklärung bioaktiver 2. Giebelmann R, Karlovsek Zorec M, von Meyer L (2002) Naturstoffe aus schwammassoziierten Pilzen, Dissertation, Kulturgeschichtliches zur Alraune. T + K 69: 73-77. Düsseldorf, Germany.

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.08.