Atropine

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Atropine
Atropine.svg
Atropine-D-and-L-isomers-from-DL-xtal-2004-3D-balls.png
Clinical data
Trade names Atropen, others
Other namesDaturin [1]
AHFS/Drugs.com Monograph
MedlinePlus a682487
License data
Pregnancy
category
  • AU:A
Routes of
administration 		By mouth, intravenous, intramuscular, rectal, ophthalmic
Drug class antimuscarinic (anticholinergic)
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 25%
Metabolism ≥50% hydrolysed to tropine and tropic acid
Onset of action c. 1 minute [5]
Elimination half-life 2 hours
Duration of action 30 to 60 min [5]
Excretion 15–50% excreted unchanged in urine
Identifiers
  • (RS)-(8-Methyl-8-azabicyclo[3.2.1]oct-3-yl) 3-hydroxy-2-phenylpropanoate
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
ECHA InfoCard 100.000.096 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C17H23NO3
Molar mass 289.375 g·mol−1
3D model (JSmol)
  • CN3[C@H]1CC[C@@H]3C[C@@H](C1)OC(=O)C(CO)c2ccccc2
  • InChI=1S/C17H23NO3/c1-18-13-7-8-14(18)10-15(9-13)21-17(20)16(11-19)12-5-3-2-4-6-12/h2-6,13-16,19H,7-11H2,1H3/t13-,14+,15+,16? Yes check.svgY
  • Key:RKUNBYITZUJHSG-SPUOUPEWSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Atropine is a tropane alkaloid and anticholinergic medication used to treat certain types of nerve agent and pesticide poisonings as well as some types of slow heart rate, and to decrease saliva production during surgery. [6] It is typically given intravenously or by injection into a muscle. [6] Eye drops are also available which are used to treat uveitis and early amblyopia. [7] [8] The intravenous solution usually begins working within a minute and lasts half an hour to an hour. [5] Large doses may be required to treat some poisonings. [6]

Contents

Common side effects include dry mouth, abnormally large pupils, urinary retention, constipation, and a fast heart rate. [6] It should generally not be used in people with closed-angle glaucoma. [6] While there is no evidence that its use during pregnancy causes birth defects, this has not been well studied so sound clinical judgment should be used. [9] It is likely safe during breastfeeding. [9] It is an antimuscarinic (a type of anticholinergic) that works by inhibiting the parasympathetic nervous system. [6]

Atropine occurs naturally in a number of plants of the nightshade family, including deadly nightshade (belladonna), Jimson weed, and mandrake. [10] It was first isolated in 1833, [11] It is on the World Health Organization's List of Essential Medicines. [12] It is available as a generic medication. [6] [13] [14]

Medical uses

An ampoule containing atropine injection 0.5mg/1mL Atropine injection ampoule.JPG
An ampoule containing atropine injection 0.5mg/1mL

Eyes

Topical atropine is used as a cycloplegic, to temporarily paralyze the accommodation reflex, and as a mydriatic, to dilate the pupils. [15] Atropine degrades slowly, typically wearing off in 7 to 14 days, so it is generally used as a therapeutic mydriatic, whereas tropicamide (a shorter-acting cholinergic antagonist) or phenylephrine (an α-adrenergic agonist) is preferred as an aid to ophthalmic examination. [15]

In refractive and accommodative amblyopia, when occlusion is not appropriate sometimes atropine is given to induce blur in the good eye. [16] Evidence suggests that atropine penalization is just as effective as occlusion in improving visual acuity. [17] [18]

Antimuscarinic topical medication is effective in slowing myopia progression in children; accommodation difficulties and papillae and follicles are possible side effects. [19] All doses of atropine appear similarly effective, while higher doses have greater side effects. [20] The lower dose of 0.01% is thus generally recommended due to fewer side effects and potential less rebound worsening when the atropine is stopped. [20] [21]

Heart

Injections of atropine are used in the treatment of symptomatic or unstable bradycardia.

Atropine was previously included in international resuscitation guidelines for use in cardiac arrest associated with asystole and PEA but was removed from these guidelines in 2010 due to a lack of evidence for its effectiveness. [22] For symptomatic bradycardia, the usual dosage is 0.5 to 1 mg IV push; this may be repeated every 3 to 5 minutes, up to a total dose of 3 mg (maximum 0.04 mg/kg). [23]

Atropine is also useful in treating second-degree heart block Mobitz type 1 (Wenckebach block), and also third-degree heart block with a high Purkinje or AV-nodal escape rhythm. It is usually not effective in second-degree heart block Mobitz type 2, and in third-degree heart block with a low Purkinje or ventricular escape rhythm.[ citation needed ]

Atropine has also been used to prevent a low heart rate during intubation of children; however, the evidence does not support this use. [24]

Secretions

Atropine's actions on the parasympathetic nervous system inhibit salivary and mucous glands. The drug may also inhibit sweating via the sympathetic nervous system. This can be useful in treating hyperhidrosis, and can prevent the death rattle of dying patients. Even though atropine has not been officially indicated for either of these purposes by the FDA, it has been used by physicians for these purposes. [25]

Poisonings

Atropine is not an actual antidote for organophosphate poisoning. However, by blocking the action of acetylcholine at muscarinic receptors, atropine also serves as a treatment for poisoning by organophosphate insecticides and nerve agents, such as tabun (GA), sarin (GB), soman (GD), and VX. Troops who are likely to be attacked with chemical weapons often carry autoinjectors with atropine and oxime, for rapid injection into the muscles of the thigh. In a developed case of nerve gas poisoning, maximum atropinization is desirable. Atropine is often used in conjunction with the oxime pralidoxime chloride.

Some of the nerve agents attack and destroy acetylcholinesterase by phosphorylation, so the action of acetylcholine becomes excessive and prolonged. Pralidoxime (2-PAM) can be effective against organophosphate poisoning because it can re-cleave this phosphorylation. Atropine can be used to reduce the effect of the poisoning by blocking muscarinic acetylcholine receptors, which would otherwise be overstimulated, by excessive acetylcholine accumulation.

Atropine or diphenhydramine can be used to treat muscarine intoxication.[ medical citation needed ]

Atropine was added to cafeteria salt shakers in an attempt to poison the staff of Radio Free Europe during the Cold War. [26] [27]

Irinotecan-induced diarrhea

Atropine has been observed to prevent or treat irinotecan induced acute diarrhea. [28]

Side effects

Adverse reactions to atropine include ventricular fibrillation, supraventricular or ventricular tachycardia, dizziness, nausea, blurred vision, loss of balance, dilated pupils, photophobia, dry mouth and potentially extreme confusion, deliriant hallucinations, and excitation especially among the elderly. These latter effects are because atropine can cross the blood–brain barrier. Because of the hallucinogenic properties, some have used the drug recreationally, though this is potentially dangerous and often unpleasant.[ medical citation needed ]

In overdoses, atropine is poisonous.[ medical citation needed ] Atropine is sometimes added to potentially addictive drugs, particularly antidiarrhea opioid drugs such as diphenoxylate or difenoxin, wherein the secretion-reducing effects of the atropine can also aid the antidiarrhea effects.[ medical citation needed ]

Although atropine treats bradycardia (slow heart rate) in emergency settings, it can cause paradoxical heart rate slowing when given at very low doses (i.e. <0.5 mg), [29] presumably as a result of central action in the CNS. [30] One proposed mechanism for atropine's paradoxical bradycardia effect at low doses involves blockade of inhibitory presynaptic muscarinic autoreceptors, thereby blocking a system that inhibits the parasympathetic response. [31]

Atropine is incapacitating at doses of 10 to 20 mg per person. Its LD50 is estimated to be 453 mg per person (by mouth) with a probit slope of 1.8. [32] The antidote to atropine is physostigmine or pilocarpine.[ medical citation needed ]

A common mnemonic used to describe the physiologic manifestations of atropine overdose is: "hot as a hare, blind as a bat, dry as a bone, red as a beet, and mad as a hatter". [33] These associations reflect the specific changes of warm, dry skin from decreased sweating, blurry vision, decreased lacrimation, vasodilation, and central nervous system effects on muscarinic receptors, type 4 and 5. This set of symptoms is known as anticholinergic toxidrome, and may also be caused by other drugs with anticholinergic effects, such as hyoscine hydrobromide (scopolamine), diphenhydramine, phenothiazine antipsychotics and benztropine. [34]

Contraindications

It is generally contraindicated in people with glaucoma, pyloric stenosis, or prostatic hypertrophy, except in doses ordinarily used for preanesthesia. [3]

Chemistry

Atropine, a tropane alkaloid, is an enantiomeric mixture of d -hyoscyamine and l-hyoscyamine, with most of its physiological effects due to l-hyoscyamine. Its pharmacological effects are due to binding to muscarinic acetylcholine receptors. It is an antimuscarinic agent. Significant levels are achieved in the CNS within 30 minutes to 1 hour and disappear rapidly from the blood with a half-life of 2 hours. About 60% is excreted unchanged in the urine, and most of the rest appears in the urine as hydrolysis and conjugation products. Noratropine (24%), atropine-N-oxide (15%), tropine (2%), and tropic acid (3%) appear to be the major metabolites, while 50% of the administered dose is excreted as apparently unchanged atropine. No conjugates were detectable. Evidence that atropine is present as (+)-hyoscyamine was found, suggesting that stereoselective metabolism of atropine probably occurs. [35] Effects on the iris and ciliary muscle may persist for longer than 72 hours.

The most common atropine compound used in medicine is atropine sulfate (monohydrate) ( C
17 H
23 N O
3)2·H2SO4·H2O, the full chemical name is 1α H, 5α H-Tropan-3-α ol (±)-tropate(ester), sulfate monohydrate.

Pharmacology

In general, atropine counters the "rest and digest" activity of glands regulated by the parasympathetic nervous system. This occurs because atropine is a competitive, reversible antagonist of the muscarinic acetylcholine receptors (acetylcholine being the main neurotransmitter used by the parasympathetic nervous system).

Atropine is a competitive antagonist of the muscarinic acetylcholine receptor types M1, M2, M3, M4 and M5. [36] It is classified as an anticholinergic drug (parasympatholytic).

In cardiac uses, it works as a nonselective muscarinic acetylcholinergic antagonist, increasing firing of the sinoatrial node (SA) and conduction through the atrioventricular node (AV) of the heart, opposes the actions of the vagus nerve, blocks acetylcholine receptor sites, and decreases bronchial secretions.

In the eye, atropine induces mydriasis by blocking the contraction of the circular pupillary sphincter muscle, which is normally stimulated by acetylcholine release, thereby allowing the radial iris dilator muscle to contract and dilate the pupil. Atropine induces cycloplegia by paralyzing the ciliary muscles, whose action inhibits accommodation to allow accurate refraction in children, helps to relieve pain associated with iridocyclitis, and treats ciliary block (malignant) glaucoma.

The vagus (parasympathetic) nerves that innervate the heart release acetylcholine (ACh) as their primary neurotransmitter. ACh binds to muscarinic receptors (M2) that are found principally on cells comprising the sinoatrial (SA) and atrioventricular (AV) nodes. Muscarinic receptors are coupled to the Gi subunit; therefore, vagal activation decreases cAMP. Gi-protein activation also leads to the activation of KACh channels that increase potassium efflux and hyperpolarizes the cells.

Increases in vagal activities to the SA node decrease the firing rate of the pacemaker cells by decreasing the slope of the pacemaker potential (phase 4 of the action potential); this decreases heart rate (negative chronotropy). The change in phase 4 slope results from alterations in potassium and calcium currents, as well as the slow-inward sodium current that is thought to be responsible for the pacemaker current (If). By hyperpolarizing the cells, vagal activation increases the cell's threshold for firing, which contributes to the reduction in the firing rate. Similar electrophysiological effects also occur at the AV node; however, in this tissue, these changes are manifested as a reduction in impulse conduction velocity through the AV node (negative dromotropy). In the resting state, there is a large degree of vagal tone in the heart, which is responsible for low resting heart rates.

There is also some vagal innervation of the atrial muscle, and to a much lesser extent, the ventricular muscle. Vagus activation, therefore, results in modest reductions in atrial contractility (inotropy) and even smaller decreases in ventricular contractility.

Muscarinic receptor antagonists bind to muscarinic receptors thereby preventing ACh from binding to and activating the receptor. By blocking the actions of ACh, muscarinic receptor antagonists very effectively block the effects of vagal nerve activity on the heart. By doing so, they increase heart rate and conduction velocity.

History

Atropa belladonna Atropa bella-donna0.jpg
Atropa belladonna

The name atropine was coined in the 19th century, when pure extracts from the belladonna plant Atropa belladonna were first made. [37] The medicinal use of preparations from plants in the nightshade family is much older however. Mandragora (mandrake) was described by Theophrastus in the fourth century B.C. for the treatment of wounds, gout, and sleeplessness, and as a love potion. By the first century A.D. Dioscorides recognized wine of mandrake as an anaesthetic for treatment of pain or sleeplessness, to be given before surgery or cautery. [33] The use of nightshade preparations for anesthesia, often in combination with opium, persisted throughout the Roman and Islamic Empires and continued in Europe until superseded in the 19th century by modern anesthetics.[ citation needed ]

Atropine-rich extracts from the Egyptian henbane plant (another nightshade) were used by Cleopatra in the last century B.C. to dilate the pupils of her eyes, in the hope that she would appear more alluring. Likewise in the Renaissance, women used the juice of the berries of the nightshade Atropa belladonna to enlarge their pupils for cosmetic reasons. This practice resumed briefly in the late nineteenth and early twentieth century in Paris.[ citation needed ]

The pharmacological study of belladonna extracts was begun by the German chemist Friedlieb Ferdinand Runge (1795–1867). In 1831, the German pharmacist Heinrich F. G. Mein (1799-1864) [38] succeeded in preparing a pure crystalline form of the active substance, which was named atropine. [39] [40] The substance was first synthesized by German chemist Richard Willstätter in 1901. [41]

Natural sources

Atropine is found in many members of the family Solanaceae. The most commonly found sources are Atropa belladonna (the deadly nightshade), Datura innoxia , D. wrightii , D. metel , and D. stramonium . Other sources include members of the genera Brugmansia (angel's trumpets) and Hyoscyamus .[ citation needed ]

Synthesis

Atropine can be synthesized by the reaction of tropine with tropic acid in the presence of hydrochloric acid.

Biosynthesis

The biosynthesis of atropine starting from l-phenylalanine first undergoes a transamination forming phenylpyruvic acid which is then reduced to phenyl-lactic acid. [42] Coenzyme A then couples phenyl-lactic acid with tropine forming littorine, which then undergoes a radical rearrangement initiated with a P450 enzyme forming hyoscyamine aldehyde. [42] A dehydrogenase then reduces the aldehyde to a primary alcohol making (−)-hyoscyamine, which upon racemization forms atropine. [42]

Name

The species name "belladonna" ('beautiful woman' in Italian) comes from the original use of deadly nightshade to dilate the pupils of the eyes for cosmetic effect. Both atropine and the genus name for deadly nightshade derive from Atropos, one of the three Fates who, according to Greek mythology, chose how a person was to die. [33]

See also

Related Research Articles

<span class="mw-page-title-main">Scopolamine</span> Tropane alkaloid & anticholinergic drug

Scopolamine, also known as hyoscine, or Devil's Breath, is a natural or synthetically produced tropane alkaloid and anticholinergic drug that is used as a medication to treat motion sickness and postoperative nausea and vomiting. It is also sometimes used before surgery to decrease saliva. When used by injection, effects begin after about 20 minutes and last for up to 8 hours. It may also be used orally and as a transdermal patch since it has been long known to have transdermal bioavailability.

<span class="mw-page-title-main">Acetylcholine</span> Organic chemical and neurotransmitter

Acetylcholine (ACh) is an organic compound that functions in the brain and body of many types of animals as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Parts in the body that use or are affected by acetylcholine are referred to as cholinergic.

<span class="mw-page-title-main">Atropa belladonna</span> Species of toxic flowering plant in the nightshade family

Atropa bella-donna, commonly known as deadly nightshade or belladonna, is a toxic perennial herbaceous plant in the nightshade family Solanaceae, which also includes tomatoes, potatoes and aubergine (eggplant). It is native to Europe and Western Asia, including Turkey, its distribution extending from England in the west to western Ukraine and the Iranian province of Gilan in the east. It is also naturalised or introduced in some parts of Canada, North Africa and the United States.

<span class="mw-page-title-main">Mydriasis</span> Excessive dilation of the pupil

Mydriasis is the dilation of the pupil, usually having a non-physiological cause, or sometimes a physiological pupillary response. Non-physiological causes of mydriasis include disease, trauma, or the use of certain types of drug. It may also be of unknown cause.

<span class="mw-page-title-main">Hyoscyamine</span> Tropane alkaloid

Hyoscyamine is a naturally occurring tropane alkaloid and plant toxin. It is a secondary metabolite found in certain plants of the family Solanaceae, including henbane, mandrake, angel's trumpets, jimsonweed, the sorcerers' tree, and Atropa belladonna. It is the levorotary isomer of atropine and thus sometimes known as levo-atropine.

<span class="mw-page-title-main">Muscarine</span> Chemical compound

Muscarine, L-(+)-muscarine, or muscarin is a natural product found in certain mushrooms, particularly in Inocybe and Clitocybe species, such as the deadly C. dealbata. Mushrooms in the genera Entoloma and Mycena have also been found to contain levels of muscarine which can be dangerous if ingested. Muscarine has been found in harmless trace amounts in Boletus, Hygrocybe, Lactarius and Russula. Trace concentrations of muscarine are also found in Amanita muscaria, though the pharmacologically more relevant compound from this mushroom is the Z-drug-like alkaloid muscimol. A. muscaria fruitbodies contain a variable dose of muscarine, usually around 0.0003% fresh weight. This is very low and toxicity symptoms occur very rarely. Inocybe and Clitocybe contain muscarine concentrations up to 1.6%.

<span class="mw-page-title-main">Cyclopentolate</span> Pair of enantiomers

Cyclopentolate is a muscarinic antagonist. It is commonly used as an eye drop during pediatric eye examinations to dilate the eye (mydriatic) and prevent the eye from focusing/accommodating (cycloplegic). Cyclopentolate or atropine can also be administered to reverse muscarinic and central nervous system effects of indirect cholinomimetic (anti-AChase) administration.

Anticholinergics are substances that block the action of the acetylcholine (ACh) neurotransmitter at synapses in the central and peripheral nervous system.

<span class="mw-page-title-main">Physostigmine</span> Chemical compound

Physostigmine is a highly toxic parasympathomimetic alkaloid, specifically, a reversible cholinesterase inhibitor. It occurs naturally in the Calabar bean and the fruit of the Manchineel tree.

<span class="mw-page-title-main">Muscarinic acetylcholine receptor</span> Acetylcholine receptors named for their selective binding of muscarine

Muscarinic acetylcholine receptors (mAChRs) are acetylcholine receptors that form G protein-coupled receptor complexes in the cell membranes of certain neurons and other cells. They play several roles, including acting as the main end-receptor stimulated by acetylcholine released from postganglionic fibers. They are mainly found in the parasympathetic nervous system, but also have a role in the sympathetic nervous system in the control of sweat glands.

<span class="mw-page-title-main">Ipratropium bromide</span> Type of anticholinergic

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<span class="mw-page-title-main">Deliriant</span> Class of psychoactive drugs

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A cholinergic crisis is an over-stimulation at a neuromuscular junction due to an excess of acetylcholine (ACh), as a result of the inactivity of the AChE enzyme, which normally breaks down acetylcholine.

<span class="mw-page-title-main">Biperiden</span> Group of stereoisomers

Biperiden, sold under the brand name Akineton among others, is a medication used to treat Parkinson disease, certain drug-induced movement disorders and Tourette Syndrome. It is not recommended for tardive dyskinesias. It is taken by mouth, injection into a vein, or muscle.

<span class="mw-page-title-main">Tropicamide</span> Chemical compound

Tropicamide, sold under the brand name Mydriacyl among others, is a medication used to dilate the pupil and help with examination of the eye. Specifically it is used to help examine the back of the eye. It is applied as eye drops. Effects occur within 40 minutes and last for up to a day.

<span class="mw-page-title-main">Homatropine</span> Medication

Homatropine is an anticholinergic medication that is an antagonist at muscarinic acetylcholine receptors and thus the parasympathetic nervous system. It is used in eye drops as a cycloplegic, and as a mydriatic.

<span class="mw-page-title-main">Muscarinic antagonist</span> Drug that binds to but does not activate muscarinic cholinergic receptors

A muscarinic acetylcholine receptor antagonist, also simply known as a muscarinic antagonist or as an antimuscarinic agent, is a type of anticholinergic drug that blocks the activity of the muscarinic acetylcholine receptors (mAChRs). The muscarinic receptors are proteins involved in the transmission of signals through certain parts of the nervous system, and muscarinic receptor antagonists work to prevent this transmission from occurring. Notably, muscarinic antagonists reduce the activation of the parasympathetic nervous system. The normal function of the parasympathetic system is often summarised as "rest-and-digest", and includes slowing of the heart, an increased rate of digestion, narrowing of the airways, promotion of urination, and sexual arousal. Muscarinic antagonists counter this parasympathetic "rest-and-digest" response, and also work elsewhere in both the central and peripheral nervous systems.

<span class="mw-page-title-main">Methoctramine</span> Chemical compound

Methoctramine is a polymethylene tetraamine that acts as a muscarinic antagonist. It preferentially binds to the pre-synaptic receptor M2, a muscarinic acetylcholine ganglionic protein complex present basically in heart cells. In normal conditions -absence of methoctramine-, the activation of M2 receptors diminishes the speed of conduction of the sinoatrial and atrioventricular nodes thus reducing the heart rate. Thanks to its apparently high cardioselectivity, it has been studied as a potential parasymphatolitic drug, particularly against bradycardia. However, currently it is only addressed for research purposes, since the administration to humans is still unavailable.

Autonomic drugs are substances that can either inhibit or enhance the functions of the parasympathetic and sympathetic nervous systems. This type of drug can be used to treat a wide range of diseases an disorders, including glaucoma, asthma, and disorders of the urinary, gastrointestinal and circulatory systems.

<span class="mw-page-title-main">Cholinergic blocking drug</span> Drug that block acetylcholine in synapses of cholinergic nervous system

Cholinergic blocking drugs are a group of drugs that block the action of acetylcholine (ACh), a neurotransmitter, in synapses of the cholinergic nervous system. They block acetylcholine from binding to cholinergic receptors, namely the nicotinic and muscarinic receptors.

References

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  17. ↑ "A patch or eye drops are similarly effective for the treatment of "lazy eye" in children". NIHR Evidence (Plain English summary). National Institute for Health and Care Research. 2019-12-05. doi:10.3310/signal-000849. S2CID   243130859. Archived from the original on 2024-05-26. Retrieved 2022-09-16.
  18. ↑ Li T, Qureshi R, Taylor K (August 2019). "Conventional occlusion versus pharmacologic penalization for amblyopia". The Cochrane Database of Systematic Reviews. 8 (8): CD006460. doi:10.1002/14651858.CD006460.pub3. PMC   6713317 . PMID   31461545.
  19. ↑ Walline JJ, Lindsley KB, Vedula SS, Cotter SA, Mutti DO, Ng SM, Twelker JD (13 Jan 2020). "Interventions to slow progression of myopia in children". Cochrane Database Syst Rev. 1 (9): CD004916. doi:10.1002/14651858.CD004916.pub4. PMC   6984636 . PMID   31930781.
  20. 1 2 Gong Q, Janowski M, Luo M, Wei H, Chen B, Yang G, Liu L (June 2017). "Efficacy and Adverse Effects of Atropine in Childhood Myopia: A Meta-analysis". JAMA Ophthalmology. 135 (6): 624–630. doi:10.1001/jamaophthalmol.2017.1091. PMC   5710262 . PMID   28494063.
  21. ↑ Fricke T, Hurairah H, Huang Y, Ho SM (2019). "Pharmacological interventions in myopia management". Community Eye Health. 32 (105): 21–22. PMC   6688412 . PMID   31409953.
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  23. ↑
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  25. ↑ "Death Rattle and Oral Secretions, 2nd ed". eperc.mcw.edu. Archived from the original on 2014-04-14. Retrieved 2019-10-20.
  26. ↑ The Battle Over Hearts and Minds A Cold War of Spies: Episode 4 |https://www.imdb.com/title/tt27484449/?ref_=ttep_ep4 Archived 2024-05-26 at the Wayback Machine
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  33. 1 2 3 Holzman RS (July 1998). "The legacy of Atropos, the fate who cut the thread of life". Anesthesiology. 89 (1): 241–9. doi: 10.1097/00000542-199807000-00030 . PMID   9667313. S2CID   28327277 . Retrieved 2007-05-21. citing J. Arena, Poisoning: Toxicology-Symptoms-Treatments, 3rd edition. Springfield, Charles C. Thomas, 1974, p 345
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  35. ↑ Van der Meer MJ, Hundt HK, Müller FO (October 1986). "The metabolism of atropine in man". The Journal of Pharmacy and Pharmacology. 38 (10): 781–4. doi:10.1111/j.2042-7158.1986.tb04494.x. PMID   2879005. S2CID   27306334.
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  37. ↑ Goodman and Gilman's Pharmacological Basis of Therapeutics, q.v. "Muscarinic receptor antagonists - History", p. 163 of the 2001 edition.
  38. ↑ "Heinrich Friedrich Georg Mein". ostfriesischelandschaft.de (in German). Archived from the original on 2013-05-11. Retrieved 2019-10-20.{{cite web}}: CS1 maint: unfit URL (link)
  39. ↑ Heinrich Friedrich Georg Mein (1833). "Ueber die Darstellung des Atropins in weissen Kristallen" [On the preparation of atropine as white crystals]. Annalen der Pharmacie (in German). Vol. 6 (1 ed.). pp. 67–72. Archived from the original on 2016-05-15. Retrieved 2016-01-05.
  40. ↑ Atropine was also independently isolated in 1833 by Geiger and Hesse:
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    • Geiger, Hesse (1833). "Fortgesetzte Versuche über Atropin" [Continued experiments on atropine]. Annalen der Pharmacie (in German). Vol. 6. pp. 44–65. Archived from the original on 2016-06-10. Retrieved 2016-01-05.
  41. ↑ See:
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