Hyoscyamine

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Hyoscyamine
Hyoscyamine.svg
Hyoscyamine-from-xtal-3D-balls.png
Clinical data
Trade names Anaspaz, Levbid, Levsin
AHFS/Drugs.com Monograph
MedlinePlus a684010
Routes of
administration 		By mouth, Injection
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 50% protein binding
Metabolism Liver
Elimination half-life 3–5 hrs.
Excretion Kidney
Identifiers
  • (S)-(1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 3-hydroxy-2-phenylpropanoate
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.002.667 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@H](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-/m1/s1 Yes check.svgY
  • Key:RKUNBYITZUJHSG-FXUDXRNXSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Hyoscyamine (also known as daturine or duboisine) 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 (deadly nightshade). It is the levorotary isomer of atropine (third of the three major nightshade alkaloids) and thus sometimes known as levo-atropine. [1] [ better source needed ]

Contents

In 2021, it was the 272nd most commonly prescribed medication in the United States, with more than 900,000 prescriptions. [2] [3]

Medical uses

Brand names for hyoscyamine include Symax, HyoMax, Anaspaz, Egazil, Buwecon, Cystospaz, Levsin, Levbid, Levsinex, Donnamar, NuLev, Spacol T/S, and Neoquess. [4]

Hyoscyamine is used to provide symptomatic relief of spasms caused by various lower abdominal and bladder disorders including peptic ulcers, irritable bowel syndrome, diverticulitis, pancreatitis, colic, and interstitial cystitis. [5] [6] [7] It has also been used to relieve some heart problems, control some of the symptoms of Parkinson's disease, as well as for control of abnormal respiratory symptoms and "hyper-mucus secretions" in patients with lung disease. [8]

It is also useful in pain control for neuropathic pain, chronic pain and palliative care — "comfort care" — for those with intractable pain from treatment resistant, untreatable, and incurable diseases. When combined with opioids it increases the level of analgesia (pain relief) obtained. [9] Several mechanisms are thought to contribute to this effect. The closely related drugs atropine and hyoscine and other members of the anticholinergic drug group like cyclobenzaprine, trihexyphenidyl, and orphenadrine are also used for this purpose. [10] When hyoscyamine is used along with opioids or other anti-peristaltic agents, measures to prevent constipation are especially important given the risk of paralytic ileus. [11]

Adverse effects

Side effects include dry mouth and throat, increased appetite leading to weight gain, eye pain, blurred vision, restlessness, dizziness, arrhythmia, flushing, and faintness. [6] An overdose will cause headache, nausea, vomiting, and central nervous system symptoms including disorientation, hallucinations, euphoria, sexual arousal, short-term memory loss, and possible coma in extreme cases. The euphoric and sexual effects are stronger than those of atropine but weaker than those of hyoscine, as well as dicycloverine, orphenadrine, cyclobenzaprine, trihexyphenidyl, and ethanolamine antihistamines like phenyltoloxamine. [12] [13]

Pharmacology

Pharmacodynamics

Hyoscyamine is an antimuscarinic; i.e., an antagonist of muscarinic acetylcholine receptors. It blocks the action of acetylcholine at sweat glands (sympathetic) and at parasympathetic sites in salivary glands, stomach secretions, heart muscle, sinoatrial node, smooth muscle in the gastrointestinal tract, and the central nervous system. It increases cardiac output and heart rate, lowers blood pressure and dries secretions. [14] It may antagonize serotonin. [15] [ better source needed ] At comparable doses, hyoscyamine has 98 percent of the anticholinergic power of atropine; the other major Atropa belladonna-derived drug hyoscine (known in the United States as scopolamine) has 92 per cent of the antimuscarinic potency of atropine. [15] [ better source needed ]

Hyoscyamine has been described as a selective muscarinic acetylcholine M2 receptor antagonist without significant effects at the other muscarinic acetylcholine receptors. [16] [17] This is in contrast to related antimuscarinics like atropine and scopolamine, which are non-selective antagonists of all five muscarinic acetylcholine receptors. [16] [17] Antagonism of both the muscarinic acetylcholine M1 receptor and M2 receptor has been implicated as having negative effects on memory and cognition. [17] Hyoscyamine has been described as having deliriant effects similarly to scopolamine, atropine, and other antimuscarinics. [16] However, other sources have reported that hyoscyamine potently antagonizes all five muscarinic acetylcholine receptor subtypes. [18]

Biosynthesis in plants

Biochemistry of tropane class compounds. Hyoscyamine and scopolamine are present and labeled in the diagram. Tropane alkaloids biochemistry.png
Biochemistry of tropane class compounds. Hyoscyamine and scopolamine are present and labeled in the diagram.

Hyoscyamine can be extracted from plants of the family Solanaceae, notably Datura stramonium . As hyoscyamine is a direct precursor in the plant biosynthesis of hyoscine, it is produced via the same metabolic pathway. [19]

A generic presentation of the steps in the biosynthesis of hyoscine, adapted from the review of Ziegler and Facchini, is illustrated below. [19] It begins with the decarboxylation of L-ornithine to putrescine by ornithine decarboxylase (EC 4.1.1.17). Putrescine is methylated to N-methylputrescine by putrescine N-methyltransferase (EC 2.1.1.53). [19]

A putrescine oxidase (EC 1.4.3.10) that specifically recognizes methylated putrescine catalyzes the deamination of this compound to 4-methylaminobutanal which then undergoes a spontaneous ring formation to N-methylpyrrolium cation. In the next step, the pyrrolium cation condenses with acetoacetic acid yielding hygrine. No enzymatic activity could be demonstrated that catalyzes this reaction. Hygrine further rearranges to tropinone. [19]

Scopolamine biosynthesis.svg

Subsequently, tropinone reductase I (EC 1.1.1.206) converts tropinone to tropine which condenses with phenylalanine-derived phenyllactate to littorine.[ citation needed ] A cytochrome P450 classified as Cyp80F1 oxidizes and rearranges littorine to hyoscyamine aldehyde. [20]

Ethnopharmacology

A plant extract used "for catching fish, in ceremony to connect with the spiritual realm", and as a bush medicine, "in a sleeping potion and for a variety of other uses", was developed by Aboriginal peoples from the soft corkwood tree, Duboisia myoporoides , found "in South Eastern NSW [ New South Wales ] across to Northern Queensland, Australia"; modern studies have shown the Aboriginal medicine to contain the alkaloids hyoscyamine and scopolamine. [21]

Ingredients of a "Clap Mixture" (medical formulation), putatively hyoscyamine-containing, "Clap" being a colloquial synonym for "the sexually transmitted infection, gonorrhea". Interpretation of the label by Wikipedia editors deduce the "Extr. H..." (label obscured, at end of the first text line under the title) to refer to the article title subject, hysoscyamine, here putatively as a natural product extracted from an unspecified plant. Other indicated ingredients are interpreted to be: "Sod. Cit.", sodium citrate; "Sod. Bic., sodium bicarbonate; "Chlorof.", chloroform; "Aq.", aqueous, hence, the deduction is that this is an extract of hyoscyamine formulated for treatment of "the clap," also containing sodium citrate and sodium bicarbonate, in a solution/mixture of chloroform and water. Early "Clap" Medicinal Formulation, Possibly Containing Hysoscyamine, Possibly From the New Orleans Pharmacy Museum.jpg
Ingredients of a "Clap Mixture" (medical formulation), putatively hyoscyamine-containing, "Clap" being a colloquial synonym for "the sexually transmitted infection, gonorrhea". Interpretation of the label by Wikipedia editors deduce the "Extr. H..." (label obscured, at end of the first text line under the title) to refer to the article title subject, hysoscyamine, here putatively as a natural product extracted from an unspecified plant. Other indicated ingredients are interpreted to be: "Sod. Cit.", sodium citrate; "Sod. Bic., sodium bicarbonate; "Chlorof.", chloroform; "Aq.", aqueous, hence, the deduction is that this is an extract of hyoscyamine formulated for treatment of "the clap," also containing sodium citrate and sodium bicarbonate, in a solution/mixture of chloroform and water.

Society and culture

German-Australian botanist Baron Sir Ferdinand Jacob Heinrich von Mueller, on finding that Aboriginal communities had used a soft corkwood tree ( Duboisia myoporoides ) extract as a medicine, including for seasickness, led an effort to export the natural product isolate from Australia, and to create a "mystery pill" that was used by the Allies in World War II, specifically, to prevent seasickness among soldiers ferried across the English Channel during the Invasion of Normandy. [21] Later, it was found that components of the same natural product isolate, hyoscyamine and scopolamine, could be used in pharmaceutical production—which, by virtue of use in eye surgery, led to the growth of a multi-million dollar industry in Queensland. [21]

A separate historic, apparent, but unsubstantiated off-label use of hysoscyamine was in the treatment of sexually transmitted infections.[ citation needed ][ dubious – discuss ]

Further reading

References

  1. ↑ Ushimaru R, Ruszczycky MW, Liu HW (January 2019). "Changes in Regioselectivity of H Atom Abstraction during the Hydroxylation and Cyclization Reactions Catalyzed by Hyoscyamine 6β-Hydroxylase". Journal of the American Chemical Society. 141 (2): 1062–1066. Bibcode:2019JAChS.141.1062U. doi:10.1021/jacs.8b11585. PMC   6488026 . PMID   30545219.[ non-primary source needed ]
  2. ↑ "The Top 300 of 2021". ClinCalc. Archived from the original on 15 January 2024. Retrieved 14 January 2024.
  3. ↑ "Hyoscyamine - Drug Usage Statistics". ClinCalc. Retrieved 14 January 2024.
  4. ↑ "Hyoscyamine - brand name list from Drugs.com". Drugs.com . Archived from the original on 20 August 2022. Retrieved 20 August 2022.
  5. ↑ National Clinical Guideline Centre (UK) (2012). Treatment to improve bladder storage. NBK132836 (8th ed.). United Kingdom: Royal College of Physicians. p. 83 – via National Library of Medicine.
  6. 1 2 "Hyoscyamine Uses, Side Effects & Warnings". Drugs.com . Archived from the original on 20 August 2022. Retrieved 20 August 2022.
  7. ↑ "Bladder Control Medicines | NIDDK". National Institute of Diabetes and Digestive and Kidney Diseases . Archived from the original on 20 August 2022. Retrieved 20 August 2022.
  8. ↑ "Hyoscyamine: MedlinePlus Drug Information". medlineplus.gov . Archived from the original on 20 August 2022. Retrieved 20 August 2022.
  9. ↑ Harden RN (March 2005). "Chronic neuropathic pain. Mechanisms, diagnosis, and treatment". The Neurologist. 11 (2): 111–122. doi:10.1097/01.nrl.0000155180.60057.8e. PMID   15733333. S2CID   12602416.
  10. ↑ Ali-Melkkilä T, Kanto J, Iisalo E (October 1993). "Pharmacokinetics and related pharmacodynamics of anticholinergic drugs". Acta Anaesthesiologica Scandinavica. 37 (7): 633–642. doi:10.1111/j.1399-6576.1993.tb03780.x. PMID   8249551. S2CID   22808654.
  11. ↑ Kamimura A, Howard S, Weaver S, Panahi S, Ashby J (December 2020). "The Use of Complementary and Alternative Medicine Strategies, Opioids, and Nonsteroidal Anti-Inflammatory Drugs (NSAIDS) Among Patients Attending a Free Clinic". Journal of Patient Experience. 7 (6): 1701–1707. doi:10.1177/2374373520937514. PMC   7786764 . PMID   33457633.
  12. ↑ Kang M, Galuska MA, Ghassemzadeh S (2022). "Benzodiazepine Toxicity". StatPearls. Treasure Island (FL): StatPearls Publishing. PMID   29489152. Archived from the original on 20 August 2022.
  13. ↑ "Hyoscyamine Sulfate Sublingual Tablets, 0.125 mgRx Only". www.dailymed.nlm.nih.gov. Archived from the original on 20 August 2022. Retrieved 20 August 2022.
  14. ↑ Edwards Pharmaceuticals, Inc., Belcher Pharmaceuticals, Inc. (May 2010). "DailyMed". U.S. National Library of Medicine. Retrieved 13 January 2013.
  15. 1 2 Kapoor AK, Raju SM (2013). "2.3 Cholinergic Drugs—Antagonists (Inhibition) of Cholinergic Receptors". Illustrated Medical Pharmacology. New Delhi, India: Jaypee Brothers Medical Publishers. pp. 127, 129–131, esp. 131. ISBN   9789350906552 . Retrieved 11 January 2014.[ better source needed ] Note, no actual content is available via the current web link.
  16. 1 2 3 Lakstygal AM, Kolesnikova TO, Khatsko SL, Zabegalov KN, Volgin AD, Demin KA, et al. (May 2019). "DARK Classics in Chemical Neuroscience: Atropine, Scopolamine, and Other Anticholinergic Deliriant Hallucinogens". ACS Chem Neurosci. 10 (5): 2144–2159. doi:10.1021/acschemneuro.8b00615. PMID   30566832.
  17. 1 2 3 Shim KH, Kang MJ, Sharma N, An SS (September 2022). "Beauty of the Beast: Anticholinergic Tropane Alkaloids in Therapeutics". Nat Prod Bioprospect. 12 (1) 33. doi:10.1007/s13659-022-00357-w. PMC   9478010 . PMID   36109439. Antagonism at M1 and M2 receptors have negative impact on memory and cognition [60]. [...] Atropine and scopolamine are non-selective competitive antagonist of muscarinic receptors. Atropine has the highest affinity for subtype M1, followed by M2 and M3 and weak affinity for M4 and M5 [71]. On the other hand, scopolamine has strong affinity for M1-M4 compared to M5 [72] while hyoscyamine binds to M2 only [73].
  18. ↑ Lavrador M, Cabral AC, Veríssimo MT, Fernandez-Llimos F, Figueiredo IV, Castel-Branco MM (January 2023). "A Universal Pharmacological-Based List of Drugs with Anticholinergic Activity". Pharmaceutics. 15 (1): 230. doi: 10.3390/pharmaceutics15010230 . PMC   9863833 . PMID   36678858.
  19. 1 2 3 4 Ziegler J, Facchini PJ (2008). "Alkaloid biosynthesis: metabolism and trafficking" . Annual Review of Plant Biology. 59 (1): 735–769. Bibcode:2008AnRPB..59..735Z. doi:10.1146/annurev.arplant.59.032607.092730. PMID   18251710.
  20. ↑ Li R, Reed DW, Liu E, Nowak J, Pelcher LE, Page JE, et al. (May 2006). "Functional genomic analysis of alkaloid biosynthesis in Hyoscyamus niger reveals a cytochrome P450 involved in littorine rearrangement". Chemistry & Biology. 13 (5): 513–520. doi: 10.1016/j.chembiol.2006.03.005 . PMID   16720272.
  21. 1 2 3 KCL Staff & Healy, Jacky (7 June 2019). "Visitors to Art of Healing Exhibition Told How Australian Indigenous Bush Medicine Was Given to Every Allied Soldier Landing at Normandy on D-Day". KCL.ac.uk. London, England: Bush House, King's College London (KCL). Retrieved 12 August 2025.
  22. ↑ Merriam-Webster. (n.d.). "The Clap. In Merriam-Webster.com dictionary" . Retrieved 12 August 2025. From https://www.merriam-webster.com/dictionary/the%20clap.
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