Scopolamine

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Scopolamine
L-Scopolamin.svg
Scopolamine3DanBS.gif
Systematic (IUPAC) name
(–)-(S)-3-Hydroxy-2-phenylpropionic acid (1R,2R,4S,7S,9S)-9-methyl-3-oxa-9-azatricyclo[3.3.1.02,4]non-7-yl ester
Clinical data
Trade namesTransdermscop
AHFS/Drugs.commonograph
Pregnancy cat.B2 (AU) C (US)
Legal statusPrescription Only (S4) (AU) -only (CA) POM (UK) -only (US)
Routestransdermal, ocular, oral, subcutaneous, intravenous, sublingual, rectal, buccal transmucousal, intramuscular
Pharmacokinetic data
Bioavailability0.13-8% (Oral),[1][2] 3% (Rectal)[1]
MetabolismHepatic (liver)[2]
Half-life4.5 hours[3]
ExcretionRenal[2]
Identifiers
CAS number51-34-3 YesY
ATC codeA04AD01 N05CM05, S01FA02
PubChemCID 5184
IUPHAR ligand330
DrugBankDB00747
ChemSpider10194106 YesY
UNIIDL48G20X8X YesY
KEGGD00138 YesY
ChEBICHEBI:16794 YesY
ChEMBLCHEMBL1201024 N
Chemical data
FormulaC17H21NO4 
Mol. mass303.353 g/mol
 N (what is this?)  (verify)
 
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Scopolamine
L-Scopolamin.svg
Scopolamine3DanBS.gif
Systematic (IUPAC) name
(–)-(S)-3-Hydroxy-2-phenylpropionic acid (1R,2R,4S,7S,9S)-9-methyl-3-oxa-9-azatricyclo[3.3.1.02,4]non-7-yl ester
Clinical data
Trade namesTransdermscop
AHFS/Drugs.commonograph
Pregnancy cat.B2 (AU) C (US)
Legal statusPrescription Only (S4) (AU) -only (CA) POM (UK) -only (US)
Routestransdermal, ocular, oral, subcutaneous, intravenous, sublingual, rectal, buccal transmucousal, intramuscular
Pharmacokinetic data
Bioavailability0.13-8% (Oral),[1][2] 3% (Rectal)[1]
MetabolismHepatic (liver)[2]
Half-life4.5 hours[3]
ExcretionRenal[2]
Identifiers
CAS number51-34-3 YesY
ATC codeA04AD01 N05CM05, S01FA02
PubChemCID 5184
IUPHAR ligand330
DrugBankDB00747
ChemSpider10194106 YesY
UNIIDL48G20X8X YesY
KEGGD00138 YesY
ChEBICHEBI:16794 YesY
ChEMBLCHEMBL1201024 N
Chemical data
FormulaC17H21NO4 
Mol. mass303.353 g/mol
 N (what is this?)  (verify)

Scopolamine (USAN), hyoscine (BAN) also known as levo-duboisine or burundanga,[4] sold as Scopoderm, is a tropane alkaloid drug with muscarinic antagonist effects. It is among the secondary metabolites of plants from Solanaceae (nightshade) family of plants, such as henbane, jimson weed (Datura), angel's trumpets (Brugmansia), and corkwood (Duboisia).[5][6] Scopolamine exerts its effects by acting as a competitive antagonist at muscarinic acetylcholine receptors, specifically M1 receptors; it is thus classified as an anticholinergic, antimuscarinic drug. (See the article on the parasympathetic nervous system for details of this physiology.)

Its use in medicine is relatively limited, with its chief uses being in the treatment of motion sickness and postoperative nausea and vomiting.[2][7][8]

Scopolamine is named after the plant genus Scopolia.[6] The name "hyoscine" is from the scientific name for henbane, Hyoscyamus niger.[9]

Medical use[edit]

Scopolamine has a number of uses in medicine where it is used to treat:[10][11]

and is sometimes used as a premedication (especially to reduce respiratory tract secretions) to surgery, mostly commonly via injection.[10][11]

Adverse effects[edit]

Adverse effect incidence:[1][2][7][8][14]

Uncommon (0.1%-1% incidence) adverse effects include
Rare (<0.1% incidence) adverse effects include
Unknown frequency adverse effects include

Overdose[edit]

Physostigmine is an acetylcholinesterase inhibitor that readily crosses the blood-brain barrier, and has been used to treat the CNS depression symptoms of scopolamine overdose.[15] Other than this supportive treatment, gastric lavage and induced emesis (vomiting) are usually recommended as treatments for overdoses.[14] The symptoms of overdose include:[1][14]

Biosynthesis in plants[edit]

The biosynthesis of scopolamine 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).[16]

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-methyl-pyrrolium cation. In the next step, the pyrrolium cation condenses with acetoacetic acid yielding hygrine. No enzymatic activity could be demonstrated to catalyze this reaction. Hygrine further rearranges to tropinone.[16]

Subsequently, tropinone reductase I (EC 1.1.1.206) converts tropinone to tropine which condenses with phenylalanine-derived phenyllactate to littorine. A cytochrome P450 classified as Cyp80F1[17] oxidizes and rearranges littorine to hyoscyamine aldehyde. In the final step, hyoscyamine undergoes epoxidation catalyzed by 6beta-hydroxyhyoscyamine epoxidase (EC 1.14.11.14) yielding scopolamine.[16]

History[edit]

One of the earlier alkaloids isolated from plant sources, scopolamine has been in use in its purified forms (such as various salts, including hydrochloride, hydrobromide, hydroiodide and sulfate), since its isolation by the German scientist Albert Ladenburg in 1880, and as various preparations from its plant-based form since antiquity and perhaps prehistoric times. Following the description of the structure and activity of scopolamine by Ladenburg, the search for synthetic analogues of and methods for total synthesis of scopolamine and/or atropine in the 1930s and 1940s resulted in the discovery of diphenhydramine, an early antihistamine and the prototype of its chemical subclass of these drugs, and pethidine, the first fully synthetic opioid analgesic, known as Dolatin and Demerol amongst many other trade names.

Scopolamine was used in conjunction with morphine, oxycodone, or other opioids from before 1900 into the 1960s to put mothers in labor into a kind of "twilight sleep". The analgesia from scopolamine plus a strong opioid is deep enough to allow higher doses to be used as a form of anaesthesia.

Scopolamine mixed with oxycodone (Eukodal) and ephedrine was marketed by Merck as SEE (from the German initials of the ingredients) and Scophedal starting in 1928, and the mixture is sometimes mixed on site on rare occasions in the area of its greatest historical usage, namely Germany and Central Europe.

Scopolamine was also one of the active ingredients in Asthmador, an over-the-counter (OTC) smoking preparation marketed in the 1950s and '60s claiming to combat asthma and bronchitis. In November 1990, the US Food and Drug Administration forced OTC products with scopolamine and several hundred other ingredients that had allegedly not been proved effective off the market. Scopolamine shared a small segment of the OTC sleeping pill market with diphenhydramine, phenyltoloxamine, pyrilamine, doxylamine, and other first-generation antihistamines, many of which are still used for this purpose in drugs such as Sominex, Tylenol PM, NyQuil, etc.

Methods of administration[edit]

Scopolamine can be administered orally, subcutaneously, ophthalmically and intravenously, as well as via a transdermal patch.[18] The transdermal patch (e.g., Transderm Scōp) for prevention of nausea and motion sickness employs scopolamine base, and is effective for up to three days.[19] The oral, ophthalmic, and intravenous forms have shorter half-lives and are usually found in the form scopolamine hydrobromide (for example in Scopace, soluble 0.4 mg tablets or Donnatal).

NASA is currently developing a nasal administration method. With a precise dosage, the NASA spray formulation has been shown to work faster and more reliably than the oral form.[20]

Recreational use[edit]

While it is occasionally used recreationally for its hallucinogenic properties, the experiences are often mentally and physically extremely unpleasant, and frequently physically dangerous, so repeated use is rare.[21]

Scopolamine related hospitalizations[edit]

About one in five emergency room admissions for poisoning in Bogotá, Colombia, have been attributed to scopolamine.[4] In June 2008, more than 20 people were hospitalized with psychosis in Norway after ingesting counterfeit Rohypnol tablets containing scopolamine.[22]

Use in interrogation[edit]

The effects of scopolamine were studied by criminologists in the early 20th century.[23] In 2009, it was proved that Czechoslovak communist State Security secret police used scopolamine at least three times to obtain confessions from alleged anti-state conspirators.[24] Because of a number of undesirable side effects, scopolamine was shortly disqualified as a truth serum.[25]

Criminal use[edit]

In 1910, scopolamine was detected in the remains believed to be those of Cora Crippen, wife of Dr. Hawley Harvey Crippen, and was accepted at the time as the cause of her death, since her husband was known to have bought some at the start of the year.[26]

In 2008, Vice News aired an episode called Colombian Devil's Breath recounting the use of scopolamine by Colombian criminals as a suggestion drug. The two-part investigation contains multiple first-hand accounts of its use.[27]

Scopolamine is used criminally as a date rape drug in Drug facilitated sexual assaults and as an aid to robbery,[28][dead link] the most common act being the clandestine drugging of a victim's drink.[28]

Per the United States State Department (March 4, 2012): "One common and particularly dangerous method that criminals use in order to rob a victim is through the use of drugs. The most common has been scopolamine. Unofficial estimates put the number of annual scopolamine incidents in Colombia at approximately 50,000. Scopolamine can render a victim unconscious for 24 hours or more. In large doses, it can cause respiratory failure and death. It is most often administered in liquid or powder form in foods and beverages. The majority of these incidents occur in night clubs and bars, and usually men, perceived to be wealthy, are targeted by young, attractive women. To avoid becoming a victim of scopolamine, one should never accept food or beverages offered by strangers or new acquaintances or leave food or beverages unattended. Victims of scopolamine or other drugs should seek immediate medical attention."[29]

Research[edit]

Hyoscine has been found to produce rapid and robust antidepressant effects in patients with major depressive disorder[30][31] and bipolar depression[32] when intravenously infused. There seems to be a gender discrepancy favouring women for antidepressant and anxiolytic response over men.[33]

References[edit]

  1. ^ a b c d "Buscopan Tablets - Summary of Product Characteristics (SPC)". electronic Medicines Compendium. Boehringer Ingelheim Limited. 11 September 2013. Retrieved 22 October 2013. 
  2. ^ a b c d e "BUSCOPAN Tablets and Ampoules BUSCOPAN FORTE Tablets". TGA eBusiness Services (BOEHRINGER INGELHEIM PTY LIMITED). 8 November 2010. Retrieved 22 October 2013. 
  3. ^ Putcha, L.; Cintrón, N. M.; Tsui, J.; Vanderploeg, J. M.; Kramer, W. G. (1989). "Pharmacokinetics and Oral Bioavailability of Scopolamine in Normal Subjects". Pharmacology Research 6 (6): 481–485. doi:10.1023/A:1015916423156. PMID 2762223. 
  4. ^ a b Uribe-Granja, Manuel; Moreno-López, Claudia L.; Zamora S., Adriana; Acosta, Pilar J. (September 2005). "Perfil epidemiológico de la intoxicación con burundanga en la clínica Uribe Cualla S. A. de Bogotá, D. C" (pdf). Acta Neurológica Colombiana (in Spanish) 21 (3): 197–201. 
  5. ^ Muranaka, T.; Ohkawa, H.; Yamada, Y. (1993). "Continuous Production of Scopolamine by a Culture of Duboisia leichhardtii Hairy Root Clone in a Bioreactor System". Applied Microbiology and Biotechnology 40 (2–3): 219–223. doi:10.1007/BF00170370. 
  6. ^ a b The Chambers Dictionary. Allied Publishers. 1998. pp. 788, 1480. ISBN 978-81-86062-25-8. 
  7. ^ a b "TRANSDERM SCOP (scopalamine) patch, extended release [Baxter Healthcare Corporation]". DailyMed. Baxter Healthcare Corporation. April 2013. Retrieved 22 October 2013. 
  8. ^ a b "DBL™ HYOSCINE INJECTION BP". TGA eBusiness Services. Hospira Australia Pty Ltd. 30 January 2012. Retrieved 22 October 2013. 
  9. ^ Cattell, Henry Ware (1910). Lippincott's new medical dictionary: a vocabulary of the terms used in medicine, and the allied sciences, with their pronunciation, etymology, and signification, including much collateral information of a descriptive and encyclopedic character. Lippincott. p. 435. Retrieved 25 February 2012. 
  10. ^ a b Joint Formulary Committee (2013). British National Formulary (BNF) (65 ed.). London, UK: Pharmaceutical Press. pp. 49, 266, 822, 823. ISBN 978-0-85711-084-8.  edit
  11. ^ a b Rossi, S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN 978-0-9805790-9-3.  edit
  12. ^ Bitterman, N.; Eilender, E.; Melamed, Y. (1991). "Hyperbaric Oxygen and Scopolamine". Undersea Biomedical Research 18 (3): 167–174. PMID 1853467. Retrieved 2008-08-13. 
  13. ^ Williams, T. H.; Wilkinson, A. R.; Davis, F. M.; Frampton, C. M. (1988). "Effects of Transcutaneous Scopolamine and Depth on Diver Performance". Undersea Biomedical Research 15 (2): 89–98. PMID 3363755. 
  14. ^ a b c "Kwells 300 microgram tablets - Summary of Product Characteristics". electronic Medicines Compendium. Bayer plc. 7 January 2008. Retrieved 22 October 2013. 
  15. ^ Clinical anesthesia (6th ed. ed.). Philadelphia: Wolters Kluwer/Lippincott Williams & Wilkins. 2009. p. 346. ISBN 978-0-7817-8763-5. 
  16. ^ a b c Ziegler, J.; Facchini, P. J. (2008). "Alkaloid Biosynthesis: Metabolism and Trafficking". Annual Review of Plant Biology 59 (1): 735–769. doi:10.1146/annurev.arplant.59.032607.092730. PMID 18251710. 
  17. ^ Li, R.; Reed, D. W.; Liu, E.; Nowak, J.; Pelcher, L. E.; Page, J. E.; Covello, P. S. (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. 
  18. ^ White, P. F.; Tang, J.; Song, D. et al. (2007). "Transdermal Scopolamine: An Alternative to Ondansetron and Droperidol for the Prevention of Postoperative and Postdischarge Emetic Symptoms". Anesthesia and Analgesia 104 (1): 92–96. doi:10.1213/01.ane.0000250364.91567.72. PMID 17179250. 
  19. ^ "Transderm Scop patch prescribing information". 
  20. ^ "NASA Signs Agreement to Develop Nasal Spray for Motion Sickness". 
  21. ^ Freye, E. (2010). "Toxicity of Datura Stramonium". Pharmacology and Abuse of Cocaine, Amphetamines, Ecstasy and Related Designer Drugs. Netherlands: Springer. pp. 217–218. doi:10.1007/978-90-481-2448-0_34. ISBN 978-90-481-2447-3. 
  22. ^ "Bilsykemedisin i falske rohypnol-tabletter". Aftenposten.no. 
  23. ^ House, R. E. (September 1922). "The Use of Scopolamine in Criminology". Texas State Journal of Medicine 18: 256–263. 
    reprinted House, R. E. (1931). "The Use of Scopolamine in Criminology". American Journal of Police Science (Northwestern University) 2 (4): 328–336. doi:10.2307/1147361. JSTOR 1147361. 
  24. ^ Gazdík, J.; Navara, L. (2009-08-08). "Svědek: Grebeníček vězně nejen mlátil, ale dával jim i drogy" [A witness: Grebeníček not only beat prisoners, he also administered drugs to them] (in Czech). iDnes. Retrieved 2009-08-10. 
  25. ^ ""Truth" Drugs in Interrogation". Central Intelligence Agency. Retrieved 14 June 2012. 
  26. ^ "The Trial of H.H. Crippen" ed. by Filson Young (Notable British Trials series, Hodge, 1920), p. xxvii; see also evidence, pp. 68-77.
  27. ^ Andrews, Dale (2013-02-28). "Daturas". Crime Poisons. SleuthSayers. Retrieved 4 March 2013 location=Washington. 
  28. ^ a b http://www.sobercircle.com/index.asp?node=resources&section=articles&fileid=8%7C Retrieved 20/11/07
  29. ^ https://www.osac.gov/Pages/ContentReportDetails.aspx?cid=12118 Colombia 2012 Crime and Safety Report: Cartagena
  30. ^ Han, C; Pae, CU (January 2013). "Oral scopolamine augmentation for major depression". Expert Review of Neurotherapeutics 13 (1): 19–21. doi:10.1586/ern.12.150. PMID 23253388. 
  31. ^ Martinowich, K; Jimenez, DV; Zarate, CA; Jr, Manji, HK (August 2013). "Rapid antidepressant effects: moving right along". Molecular Psychiatry 18 (8): 856–863. doi:10.1038/mp.2013.55. PMID 23689537. 
  32. ^ Frankel, E; Drevets, W; Luckenbaugh, D; Speer, A; Nugent, A; Zarate, C; Furey, M (June 2011). "Scopolamine as a fast-acting antidepressant agent in bipolar depression: A randomized placebo-controlled clinical trial". Bipolar disorders (Wiley-Blackwell) 13 (s1): 45. ISSN 1398-5647. 
  33. ^ Furey, ML; Khanna, A; Hoffman, EM; Drevets, WC (November 2010). "Scopolamine produces larger antidepressant and antianxiety effects in women than in men". Neuropsychopharmacology 35 (12): 2479–2488. doi:10.1038/npp.2010.131. PMID 20736989.