In refractive and accommodativeamblyopia, 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]
Injections of atropine are used in the treatment of symptomatic or unstablebradycardia.
Atropine was previously included in international resuscitation guidelines for use in cardiac arrest associated withasystole andPEA 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'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 treatinghyperhidrosis, and can prevent thedeath 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]
Some of the nerve agents attack and destroyacetylcholinesterase byphosphorylation, 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.
In overdoses, atropine ispoisonous.[medical citation needed] Atropine is sometimes added to potentially addictive drugs, particularly antidiarrhea opioid drugs such asdiphenoxylate ordifenoxin, wherein the secretion-reducing effects of the atropine can also aid the antidiarrhea effects.[medical citation needed]
Although atropine treatsbradycardia (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 muscarinicautoreceptors, 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 isphysostigmine orpilocarpine.[medical citation needed]
A commonmnemonic 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 onmuscarinic receptors, type 4 and 5. This set of symptoms is known asanticholinergic toxidrome, and may also be caused by other drugs with anticholinergic effects, such ashyoscine hydrobromide (scopolamine),diphenhydramine,phenothiazineantipsychotics andbenztropine.[34]
Atropine, atropane alkaloid, is anenantiomeric mixture ofd-hyoscyamine andl-hyoscyamine,[35] with most of its physiological effects due tol-hyoscyamine, the 3(S)-endo isomer of atropine. Its pharmacological effects are due to binding tomuscarinic 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.[36] Effects on the iris and ciliary muscle may persist for longer than 72 hours.
The most common atropine compound used in medicine is atropinesulfate (monohydrate) (C 17H 23NO 3)2·H2SO4·H2O, the full chemical name is 1α H, 5α H-Tropan-3-α ol (±)-tropate(ester), sulfate monohydrate.
In general, atropine counters the "rest and digest" activity ofglands regulated by theparasympathetic nervous system, producing clinical effects such as increased heart rate and delayed gastric emptying. This occurs because atropine is a competitive, reversible antagonist of themuscarinic acetylcholine receptors (acetylcholine being the mainneurotransmitter used by the parasympathetic nervous system).
In the eye, atropine inducesmydriasis by blocking the contraction of the circularpupillary sphincter muscle, which is normally stimulated by acetylcholine release, thereby allowing the radialiris dilator muscle to contract and dilate thepupil. Atropine inducescycloplegia by paralyzing theciliary muscles, whose action inhibits accommodation to allow accurate refraction in children, helps to relieve pain associated withiridocyclitis, 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 theGi subunit; therefore, vagal activation decreases cAMP. Gi-protein activation also leads to the activation ofKACh 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.
The nameatropine was coined in the 19th century, when pure extracts from the belladonna plantAtropa belladonna were first made.[38] The medicinal use of preparations fromplants in the nightshade family is much older however.Mandragora (mandrake) was described byTheophrastus in the fourth century B.C. for the treatment of wounds, gout, and sleeplessness, and as a lovepotion. By the first century A.D.Dioscorides recognized wine of mandrake as ananaesthetic for treatment of pain or sleeplessness, to be given before surgery or cautery.[33] The use of nightshade preparations for anesthesia, often in combination withopium, 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 Egyptianhenbane plant (another nightshade) were used byCleopatra in the last century B.C. to dilate thepupils of her eyes, in the hope that she would appear more alluring. Likewise in theRenaissance, women used the juice of the berries of the nightshadeAtropa 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 ofbelladonna extracts was begun by theGermanchemistFriedlieb Ferdinand Runge (1795–1867). In 1831, the German pharmacist Heinrich F. G. Mein (1799-1864)[39] succeeded in preparing a pure crystalline form of the active substance, which was namedatropine.[40][41] The substance was first synthesized by German chemistRichard Willstätter in 1901.[42]
The biosynthesis of atropine starting froml-phenylalanine first undergoes atransamination formingphenylpyruvic acid which is then reduced to phenyl-lactic acid.[43] Coenzyme A then couples phenyl-lactic acid withtropine forminglittorine, which then undergoes a radical rearrangement initiated with aP450 enzyme forming hyoscyamine aldehyde.[43] Adehydrogenase then reduces the aldehyde to a primary alcohol making (−)-hyoscyamine, which upon racemization forms atropine.[43]
The species name "belladonna" ('beautiful woman' inItalian) 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 fromAtropos, one of the threeFates who, according to Greek mythology, chose how a person was to die.[33]
^"Amblyopia (Lazy Eye)".National Eye Institute. 2019-07-02.Archived from the original on 2020-01-31. Retrieved2020-01-31.Putting special eye drops in the stronger eye. A once-a-day drop of the drug atropine can temporarily blur near vision, which forces the brain to use the other eye. For some children, this treatment works as well as an eye patch, and some parents find it easier to use (for example, because young children may try to pull off eye patches).
^World Health Organization (2021).World Health Organization model list of essential medicines: 22nd list (2021). Geneva: World Health Organization.hdl:10665/345533. WHO/MHP/HPS/EML/2021.02.
^Georgievski Z, Koklanis K, Leone J (2008). "Fixation behavior in the treatment of amblyopia using atropine".Clinical and Experimental Ophthalmology.36 (Suppl 2):A764 –A765.
^Field JM, Hazinski MF, Sayre MR, Chameides L, Schexnayder SM, Hemphill R, et al. (November 2010). "Part 1: executive summary: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care".Circulation.122 (18 Suppl 3): S640-56.doi:10.1161/CIRCULATIONAHA.110.970889.PMID20956217.S2CID1031566.
^*Bledsoe BE, Porter RS, Cherry RA (2004). "Ch. 3".Intermediate Emergency Care. Upper Saddle River, NJ: Pearson Prentice Hill. p. 260.ISBN0-13-113607-0.
^Yumuk PF, Aydin SZ, Dane F, Gumus M, Ekenel M, Aliustaoglu M, et al. (November 2004). "The absence of early diarrhea with atropine premedication during irinotecan therapy in metastatic colorectal patients".International Journal of Colorectal Disease.19 (6):609–610.doi:10.1007/s00384-004-0613-5.PMID15293062.S2CID11784173.
^Rang HP, Dale MM, Ritter JM, Moore P (2003).Pharmacology. Elsevier. p. 139.ISBN978-0-443-07145-4.
^Goodman and Gilman's Pharmacological Basis of Therapeutics, q.v. "Muscarinic receptor antagonists - History", p. 163 of the 2001 edition.
^"Heinrich Friedrich Georg Mein".ostfriesischelandschaft.de (in German). Archived from the original on 2013-05-11. Retrieved2019-10-20.
^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. Retrieved2016-01-05.
^Atropine was also independently isolated in 1833 by Geiger and Hesse:
Geiger, Hesse (1833). "Darstellung des Atropins" [Preparation of atropine].Annalen der Pharmacie (in German). Vol. 5. pp. 43–81.Archived from the original on 2016-05-14. Retrieved2016-01-05.
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. Retrieved2016-01-05.
