Atropine

Structural formula
( R ) shape (top) and ( S ) shape (bottom)
General
Surname	Atropine; (±) -hyoscyamine
other names	(±) -Tropintropat ( RS ) -Tropintropat rac -Tropintropat (±) -β-Phenyl-γ-hydroxypropionic acid tropyl ester ( RS ) -β-Phenyl-γ-hydroxypropionic acid tropyl ester
Molecular formula	C 17 H 23 NO 3
Brief description	colorless prisms
External identifiers / databases
CAS number 51-55-8 5908-99-6 (atropine sulfate monohydrate) EC number 200-104-8 ECHA InfoCard 100,000.096 PubChem 174174 ChemSpider 10194105 DrugBank DB00572 Wikidata Q26272
Drug information
ATC code	A03 BA01 S01 FA01
Drug class	Parasympatholytic agent
properties
Molar mass	289.38 g mol −1
Physical state	firmly
Melting point	118 ° C
pK s value	9.43
solubility	slightly soluble in water (2.2 g l −1 at 25 ° C)
safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed GHS hazard labeling from  Regulation (EC) No. 1272/2008 (CLP) , expanded if necessary danger H and P phrases H: 300 + 330 P: 260-264-284-301 + 310-310
Toxicological data	75 mg kg −1 ( LD 50 ,  mouse ,  oral ) 1100 mg · kg -1 ( LD 50 ,  guinea pigs ,  oral ) 33 μg kg −1 ( TD Lo ,  human ,  oral ) 143 μg kg −1 ( LD Lo ,  human , unknown )
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Atropine (derived from Atropos , Greek goddess of fate) is a very poisonous tropane alkaloid ; it is a racemate (1: 1 mixture) of the isomers ( R ) - and ( S ) - hyoscyamine , which is formed during isolation by racemization from the natural product ( S ) -hyoscyamine.

History and occurrence

The poisonous berries of the deadly nightshade ( Atropa belladonna )

( S ) -Hyoscyamine occurs in nightshade plants such as mandrake ( Mandragora ), angel's trumpet ( Brugmansia ), thorn apple ( Datura stramonium ) and deadly nightshade ( Atropa ). The alkaloid owes its name to the black belladonna ( Atropa belladonna ).

The Heidelberg pharmacist Philipp Lorenz Geiger (1785–1836) is considered to be the discoverer of atropine . The effect of atropine was studied by Friedlieb Ferdinand Runge (1795–1867) , among others . In 1831 the German pharmacist Heinrich FG Mein (1799–1864) produced atropine in crystalline form. From 1833 on, the Darmstadt company Merck produced atropine from the roots of the deadly nightshade. The chemist Richard Willstätter achieved the first synthesis in 1901.

Chemical structure

Atropine is the racemized form of the naturally occurring ( S ) - hyoscyamine . The racemization already takes place during the isolation when alkalis are used; an enolate is formed as an intermediate . The racemization of ( S ) -hyoscyamine can be suppressed by working up under neutral conditions (pH 7) . The importance of the enantiomeric purity of drugs is increasingly being paid attention to, because the two enantiomers of a chiral drug almost always show different pharmacodynamics and pharmacokinetics . In the past, this was often ignored due to a lack of knowledge of stereochemical relationships. Medicinal products contain the drug atropine as a racemate (1: 1 mixture of the enantiomers), whereby the use of the enantiomer which is more effective or has fewer side effects would be preferable for fundamental reasons.

The ( S ) -hyoscyamine is an ester of tropic acid with α- tropine and is thus one of the tropane alkaloids . Only the 1: 1 mixture of ( R ) - and ( S ) -hyoscyamine is called atropine (see Cahn-Ingold-Prelog convention for naming). An alkaloid structurally closely related to hyoscyamine is scopolamine ( hyoscine ).

Effects

Atropine is one of the parasympatholytics (also called anticholinergics ). Atropine has an antagonistic effect and thus competes on the muscarinic receptors of the parasympathetic nervous system with the neurotransmitter acetylcholine . Atropine partially blocks the receptors and thus inhibits the parasympathetic nervous system . The effect of acetylcholine decreases. The influence of the parasympathetic system decreases, whereby the influence of the sympathetic system predominates.

Atropine has the following physical effects:

• Acceleration of the heart rate (positive chronotropy )
• Acceleration of the transmission of excitation to the heart (positive dromotropia )
• Widening of the bronchi (bronchodilation)
• Widening of the pupils (= mydriasis , see Atropa belladonna , black deadly nightshade )
• greatly reduced perspiration
• decreased salivation
• Inhibition of gastrointestinal activity (decreased secretion and peristalsis)
• Relaxation of the smooth muscles (spasmolysis)
• decreased vision, especially in the vicinity (inhibition of accommodation )
• strong sensitivity to light ( photophobia )
• blocks receptors of nerve cells (transmitters cannot reach the receptors; receptors remain inactive)

Medical use

Cardiac arrest

Atropine was used in cardiopulmonary resuscitation in asystole and pulseless electrical activity (PEA) , doses of 0.5 to a maximum of 3 mg were administered intravenously. Due to a lack of evidence, the administration of atropine during resuscitation is no longer recommended according to the guidelines of the European Resuscitation Council . Paradoxically, too low a dose can lead to severe bradycardia and should be avoided accordingly (at least 0.02 mg / kg body weight).

Use in bradycardia

Atropine is used in anesthesia , intensive care and emergency medicine for the symptomatic treatment of a heart rate that is too low ( bradycardia ). If it is not effective, for example in the case of higher-grade AV blocks , the use of catecholamines ( adrenaline ) and pacemaker therapy is necessary.

Ophthalmology

Atropine is used in ophthalmology for diagnostic and therapeutic accommodation paralysis . As a mydriatic , atropine is used for therapeutic, but not for short-term diagnostic dilation of the pupils due to its long duration of action.

Large pupils were considered beautiful in women , especially during the Renaissance ( Italian: bella donna "beautiful woman"). The instillation of ( S ) -hyoscyamine containing belladonna extracts in the eye caused an up to several days lasting dilation of the pupils ( "fiery glance").

In addition, studies have shown the effectiveness of atropine to slow down progressive myopia in childhood.

Use as an antidote

Atropine inhibits the muscarinic effects of acetylcholine through competitive inhibition of the acetylcholine receptors on the postsynaptic membrane and interrupts signal transmission in the nerve conduction. In very high doses, atropine probably also inhibits some subtypes of the nicotinic acetylcholine receptor .

Due to this mechanism of action, atropine is used as an antidote for poisoning with certain pesticides ( insecticides ) and nerve agents, the toxic effect of which is based on an irreversible inhibition of acetylcholinesterase (e.g. organic phosphoric acid esters and phosphonic acid esters such as parathion , tabun or paraoxon ). Patients (e.g. soldiers contaminated with sarin ) are given 2 mg atropine sulfate or 2 mg atropine sulfate plus 220 mg obidoxime chloride by autoinjector .

Premedication

Atropine mainly inhibits the M ₁ , M ₂ and M ₃ receptors and thus causes an increase in heart rate (M ₂ ), a reduction in gastric acid production (M ₁ ) and a reduction in saliva (M ₃ ). Together with a subtle bronchodilation (M ₃ ), these effects are also beneficial for induction of anesthesia . A general use in the premedication (drug preparation) of anesthetized patients is no longer recommended today, because the benefit-side effect ratio of atropine sulfate is poor.

Atropine reduces the secretion of saliva and mucus, which can be used for operations in the mouth and throat area as well as for fiberoptic intubations and bronchoscopies .

Rare areas of application

Atropine is less commonly used in smooth muscles in the gastrointestinal tract . Atropine can also be given for urinary incontinence and to treat irritable bladder. Atropine has rarely been used in gynecology for dysmenorrhea (painful menstrual bleeding). The same effect can be achieved today with butylscopolamine , a chemically further developed derivative of scopolamine, which has a relaxing effect on cramped smooth muscles and is available without a prescription due to the fewer side effects. Atropine is no longer used as an asthma drug; better-tolerated drugs are used instead. The atropine test can be used for cardiological diagnosis and as an aid in determining brain death .

Atropine is also used against excessive sweating ( hyperhidrosis ) ( off-label use ).

Abuse, overdose, poisoning

The effects on the heart and circulation are in the foreground even with low doses (e.g. for induction of anesthesia). Psychological (“intoxicating”) effects are only to be expected at high doses, at which unpleasant and dangerous physical side effects occur.

Symptoms of poisoning reported at high doses (see anticholinergic syndrome ) include reddening of the skin, mydriasis , rapid heartbeat and confusion such as hallucinations . At even higher doses, unconsciousness occurs , which may be followed by respiratory paralysis; in the case of respiratory paralysis, the poisoning is usually fatal. The LD50 (oral) for humans is 453 mg. From 10 mg deliria and hallucinations occur. From 100 mg, fatal respiratory paralysis can set in. Children in particular are at risk even with smaller doses of 10 mg or more.

In addition to poisoning through voluntary or involuntary consumption of parts of plants (for example deadly nightshade ), medical poisoning occurs as a result of overdosing, mix-ups or incorrect use. For example, in 2016 the Food and Drug Administration (FDA) investigated globules in connection with ten deaths in the United States of young children who died after being given this agent, which contained atropine. The atropine was obviously too high in concentration in the globules. The agency ordered the manufacturers to recall the tablets.

The first aid in case of atropine, there is in immediate emptying of the gastrointestinal tract ( vomiting , gastric lavage ) and, if necessary, artificial respiration or artificial respiration . The extended measures aim to inhibit acetylcholinesterase with drugs, using physostigmine as an antidote , which delays the breakdown of acetylcholine. As a result, the concentration in the synaptic cleft increases. A parasympathetic effect is thus achieved indirectly at the receptor itself. The atropine is displaced from the area of ​​the receptors and the conduction of stimuli is restored.

Trade names

Monopreparations

Bellafit (CH), Dysurgal (D), Generics (D, A, CH)

in former combination preparations

Eucard (D)

literature

• Wolf-Dieter Müller-Jahncke : Atropine. In: Werner E. Gerabek , Bernhard D. Haage, Gundolf Keil , Wolfgang Wegner (eds.): Enzyklopädie Medizingeschichte. De Gruyter, Berlin / New York 2005, ISBN 3-11-015714-4 , p. 115 f.

Web links

Wiktionary: Atropine  - explanations of meanings, word origins, synonyms, translations

Commons : Atropine  - Collection of pictures, videos and audio files

• Explanation of the difference between atropine and hyoscyamine
• PTA forum: Atropine: The women with beautiful eyes . (2015).

Individual evidence

1. ↑ ^{a b} entry on atropine. In: Römpp Online . Georg Thieme Verlag, accessed on November 10, 2014.
2. ↑ ^{a b c d e f g} Entry on atropine in the ChemIDplus database of the United States National Library of Medicine (NLM) .
3. ↑ ^{a b} Entry on atropine in the GESTIS substance database of the IFA , accessed on February 1, 2016(JavaScript required) .
4. ↑ Entry on Atropine in the Classification and Labeling Inventory of the European Chemicals Agency (ECHA), accessed on August 1, 2016. Manufacturers or distributors can expand the harmonized classification and labeling .
5. ^ Raymond L. Cahen, Kristen Tvede: Homatropine Methylbromide: A Pharmacological Reevaluation. In: Journal of Pharmacology and Experimental Therapeutics . Vol. 105, No. 2, June 1952, pp. 166-177.
6. ^ Daniel Bovet , Filomena Bovet-Nitti: Structure et Activité Pharmacodynamique des Médicaments du Système Nerveux Végétatif. S. Karger, Basel 1948, p. 482.
7. ^ Geiger, Philipp Lorenz. In: Edward Kremers, George Urdang: Kremers and Urdang's History of Pharmacy. Reprint of the 4th Edition. American Institute of the History of Pharmacy, Madison WI 1986, ISBN 0-931292-17-4 , p. 459.
8. ↑ Biography of Heinrich Friedrich Georg Mein (1799–1864)
9. ↑ Heinrich Friedrich Georg Mein (1831): About the representation of atropine in white crystals , In: Annalen der Pharmacie , 6 (1): P. 67-72 ( limited preview in the Google book search).
   Independently of this, atropine was isolated by Geiger and Hesse in 1833:
   1. Geiger and Hesse (1833): Representation of atropine , In: Annalen der Pharmacie , 5 : pp. 43–81 ( limited preview in the Google book search).
   2. Geiger and Hesse (1833): Continued attempts over atropine , In: Annalen der Pharmacie , 6 : S. 44-65 ( limited preview in the Google book search).
10. ^ Richard Willstätter (1901) Synthesis of Tropidine , Reports of the German Chemical Society in Berlin , 34 : pp. 129–144.
11. ^ Richard Willstätter (1901) Conversion of tropidine into tropine , reports of the German chemical society in Berlin , 34 : pp. 3163-3165.
12. ↑ Woldemar Schneider: On the knowledge of 1-hyoscyamine and atropine. In: Archives of Pharmacy . Vol. 284, No. 5/6, 1951, pp. 306-318; doi: 10.1002 / ardp.19512840514 .
13. ^ EJ Ariëns: Stereochemistry, a Basis for Sophisticated Nonsense in Pharmacokinetics and Clinical Pharmacology. In: European Journal of Clinical Pharmacology . Vol. 26, No. 6, 1984, pp. 663-668; doi: 10.1007 / BF00541922 .
14. ^ ^{A b} Charles D. Deakin, Jerry P. Nolan, Jasmeet Soar, Kjetil Sunde, Rudolph W. Koster, Gary B. Smith, Gavin D. Perkins: European Resuscitation Council Guidelines for Resuscitation 2010 Section 4. Adult advanced life support. In: Resuscitation. Vol. 81, No. 10, October 2010, pp. 1305-1352, PMID 20956049 , doi: 10.1016 / j.resuscitation.2010.08.017 .
15. ↑ Deutscher Ärzteverlag GmbH, editorial office of the Deutsches Ärzteblatt: Prevention of the progression of myopia: low-dose atropine is obviously a good compromise. May 13, 2016, accessed November 10, 2019 . 
16. ↑ Ruud Zwart, Henk PM Vijverberg: Potentiation and inhibition of neuronal nicotinic receptors by atropine: competitive and noncompetitive effects. In: Molecular Pharmacology . Vol. 52, No. 5, November 1997, pp. 886-895, PMID 9351980 , (experiment on frog egg cells).
17. ^ E. Goodman, J. Ketchum, R. Kirby: Historical Contributions to the Human Toxicology of Atropine. In: Eximdyne , 2010, ISBN 978-0-9677264-3-4 , p. 120.
18. ↑ Homeopathy: Ten children died after taking globules . Zeit Online , February 23, 2017; accessed on May 10, 2017.
19. ↑ Eucard. (Advertisement by Südmedica GmbH, Munich) In: Munich Medical Weekly. Born 1953, No. 1 (January) 1953, p. CXXXV.

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