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Propylhexedrine

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Propylhexedrine
Clinical data
Trade namesBenzedrex, Obesin, and others
Other namesHexahydrodesoxyephedrine Cyclohexylisopropylmethylamine
AHFS/Drugs.comMonograph
Pregnancy
category
  • C
Routes of
administration		Medical: Intranasal (inhaler) and oral
Recreational: Oral and parenteral routes
ATC code
Legal status
Legal status
Pharmacokinetic data
Elimination half-life4 ± 1.5 hours
Identifiers
  • (±)-1-cyclohexyl-N-methylpropan-2-amine
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
CompTox Dashboard (EPA)
ECHA InfoCard100.002.673 Edit this at Wikidata
Chemical and physical data
FormulaC10H21N
Molar mass155.285 g·mol−1
3D model (JSmol)
ChiralityRacemic mixture
  • N(C(CC1CCCCC1)C)C
  • InChI=1S/C10H21N/c1-9(11-2)8-10-6-4-3-5-7-10/h9-11H,3-8H2,1-2H3 checkY
  • Key:JCRIVQIOJSSCQD-UHFFFAOYSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Propylhexedrine, commonly sold under the brand name Benzedrex, is an adrenergic alkylamine primarily utilized as a topical nasal decongestant.[1] Its main uses are relief of congestion due to colds, allergies, and allergic rhinitis.[2]

Propylhexedrine is found in over-the-counter inhalers such as Benzedrex. Benzedrex was first manufactured by Smith, Kline and French as an eventual replacement to their earlier inhaler products.[3] Benzedrex is currently manufactured by B.F. Ascher & Co. Inc. Pharmaceuticals.[4]

Medical use

Propylhexedrine is used to treat acute nasal congestion related to common cold, allergies and hay fever. For nasal congestion, the dosage is listed as four inhalations (two inhalations per nostril) every two hours for adults and children 6–12 years of age. Each inhalation delivers 0.4 to 0.5 milligram (400 to 500 μg) in 800 millilitres of air.[2][5] Use is not to exceed three days.[2]

Historically, it has also been used for weight loss in oral tablet preparations at doses ranging from 5 to 30 milligrams.[6][7] No medications containing propylhexedrine are currently approved for weight loss in the United States.[8] Such products have been used in European countries, however.

Contraindications

Propylhexedrine should not be used if a MAOI has been used in the past 14 days or is currently in use, for this can result in hypertensive crisis. People with cardiovascular disease should not use propylhexedrine.[9]

Additionally, stimulant drugs and sympathomimetics should not be taken with propylhexedrine. This can lead to a potentially dangerous spike in blood pressure and irregular heart rhythms.[10]

Propylhexedrine is contraindicated in individuals under six years old.[11] There is at least one case of reported accidental poisoning resulting from a child’s access to a propylhexedrine product.[12]

Adverse effects

The most common adverse effects warned about for propylhexedrine inhalers are temporary discomfort (e.g., stinging or burning sensations), worsened nasal congestion, and ill effects if taken internally.[2] The sharing of propylhexedrine inhalers may spread infection.[2] The occurrence of these adverse effects is uncommon as propylhexedrine is generally recognized as safe and effective.[13]

Overdose

Reports of overdoses from propylhexedrine have been documented, but they are uncommon.[14] Most instances of overdoses attributed to propylhexedrine have been the result of intentional misuse or abuse.[15] As noted by the FDA, the most common symptoms of propylhexedrine overdose are the following; “…[R]apid heart rate, agitation, high blood pressure, chest pain, tremor, hallucinations, delusions, confusion, nausea, and vomiting.”[15]  The use of propylhexedrine products in manners inconsistent with their labeling has proven fatal in some cases.[16] Propylhexedrine products are considered safe and effective if used as intended.[15] Regardless, medical attention should be sought in the case of suspected overdose.[17]

Interactions

As referred to earlier, most of propylhexedrine’s interactions with other medications have to do with its adrenergic properties. This means that propylhexedrine may interact adversely with certain stimulants, bronchodilators, sympathomimetics, nasal decongestants, and antidepressants. Caution should be exercised when administering propylhexedrine concurrently with other medicines.[18]

Pharmacology

Mechanism of action

Propylhexedrine is a TAAR1 agonist.[18] Consequently, it reverses the transporters for dopamine, norepinephrine, and serotonin. This leads to a release of monoamines from presynaptic vesicles into the synaptic cleft.[18] The increased level of monoamines within the synapse results in increased activity at their respective receptors. Additionally, propylhexedrine appears to inhibit VMAT2; resultantly, leading to a further increase in the aforementioned monoamines.[18] Propylhexedrine is also an adrenergic agonist.[18] The pharmacological actions of propylhexedrine are akin to that of structurally similar compounds.[18]

Pharmacokinetics

Propylhexedrine undergoes metabolism to form various metabolites including norpropylhexedrine, cyclohexylacetoxime, cis- and trans-4-hydroxypropylhexedrine.[19]

Chemistry

Freebase propylhexedrine is a volatile, oily liquid at room temperature. The slow evaporation of freebase propylhexedrine allows it to be administered via inhalation.[20] As an amine, it can easily be protonated to form various salts. These salts include propylhexedrine hydrochloride, propylhexedrine citrate, or propylhexedrine acetate. The salt formed is dependent on the acid used. These salts are stable, clear to off-white crystalline substances that readily dissolve in water.[21]

Propylhexedrine is structurally similar to phenylethylamines. The only structural difference is the substitution of an alicyclic cyclohexyl group for the aromatic phenyl group of phenethylamine. Propylhexedrine is not an amphetamine, nor even a phenethylamine. It is instead an alkylamine.[22]

Propylhexedrine is a chiral compound (the α-carbon is chiral), and the active ingredient contained in Benzedrex inhalers is racemic (RS)-propylhexedrine as the free base.[4] (S)-Propylhexedrine, also known as levopropylhexedrine, is believed to be the more biologically active isomer of the two.[23] The dextrorotatory counterpart, which is mainly unused, is dextropropylhexedrine. (S)-Propylhexedrine can be synthesized from methamphetamine.[24]

Synthesis

Propylhexedrine can be synthesized starting with cyclohexylacetone in a similar fashion to the phenylacetone synthesis of methamphetamine.[25]

However, more commonly propylhexedrine is prepared by reacting methamphetamine with Adams' catalyst. This reduces methamphetamine's aromatic ring to a cyclohexyl moiety.

Preparation of racemic propylhexedrine via catalytic hydrogenation of methamphetamine.[26]

Detection in bodily fluids

Due to its structure, administration of propylhexedrine can lead to false-positives for phenethylamine-derivatives on urinalysis panels.[27]

History

Propylhexedrine’s medical use as a decongestant evolved from desires to find safer alternatives to previous agents.[3] After searching for such an agent, Dr. Glenn E. Ullyot patented propylhexedrine as a decongestant in 1948. This patent was issued for benefit of Smith, Kline & French.[28] Subsequently, propylhexedrine underwent market trials in California before being sold nationally in the United States. Propylhexedrine (under the brandname Benzedrex) was first introduced into interstate commerce on August 4, 1949.[29] Approval for use in Canada was granted in 1998.[30]

Barbexaclone, an anticonvulsant containing propylhexedrine, was used in Turkey until its withdrawal from the market in 2009. Barbexaclone’s former niche in Turkish medicine is now largely-occupied by Levetiracetam.[31]

Manufacturing

The manufacture of propylhexedrine products is typically performed based on guidelines established in government regulations and pharmacopeial monographs.[32][5]

Society and culture

International control

Propylhexedrine was placed under international control by the Convention on Psychotropic Substances in 1985. This action was reversed in 1991.[33]

Australia

Propylhexedrine is an S4 drug in Australia.[34]

Canada

Propylhexedrine is reported to be a Schedule V drug in Canada.[35]

Germany

Propylhexedrine is regulated as a prescription drug in Germany.[36]

United Kingdom

The drug was formerly a Class C controlled drug in the United Kingdom, but was deregulated in 1995.[37]

United States

On the 4th of April 1988, propylhexedrine was designated a controlled substance (Schedule V) in the United States.[38] This was done to satisfy U.S. compliance with an international treaty. However, in 1991 this action was reversed and propylhexedrine was removed from control under the Controlled Substances Act. This was based on the opinion of the Drug Enforcement Administration that propylhexedrine did not warrant control.[39] The substance has remained unregulated under the Controlled Substances Act in the United States ever since. Furthermore, pursuant to 21 C.F.R 1308.22, Benzedrex is specifically exempt from the Controlled Substances Act.[40][41]

Recreational use

First reported in the literature as early as 1959, propylhexedrine products have been misused for their monoamine-releasing effects.[42] Recreational misuse can be fatal, its risks are magnified when administering the substance through injection means, and the adverse effects of misuse are similar to that of related substances.[15][43][44][45] The undesirable side effects of propylhexedrine at recreational doses are less tolerable compared to other commonly abused monoaminergic substances; consequently, making it less desirable for recreational use.[17][46][16] Propylhexedrine is also less potent than comparable recreational substances.[47] Even in areas with prevalent substance use, the use of propylhexedrine was reported as not of significant interest.[14] The misuse of nasal decongestant,[46] anoretic,[42] and anticonvulsant preparations[48] have all been reported.

Economics

Propylhexedrine, under the brand name Benzedrex, is sold online by retailers such as Amazon, Ebay, and Walmart.[4] Propylhexedrine has been sold in some countries as an anoretic or as part of an anticonvulsant preparation; however, such products are not sold freely to consumers and require a physician’s prescription.

Brand names

Propylhexedrine, as a nasal decongestant, is marketed under the trade name Benzedrex. The name Benzedrex was initially trademarked by Smith, Kline & French in 1944.[49] Later, this trademark became owned by B. F. Ascher & Co. in 1998.[50]

It has also seen use in Europe as an appetite suppressant, under the trade name Obesin.[51] Obesin has been referenced in literature dating back to the 1950s.[12][42]

Propylhexedrine is a component in the anticonvulsant preparation barbexaclone. Its S-isomer (levopropylhexedrine or L-propylhexedrine) is bonded with phenobarbital for the purpose of offsetting the barbiturate-induced sedation.[51] Barbexaclone has been known under the brand name of Maliasin, manufactured by Abbott Laboratories, as early as 1965.[52][53] In 2010, Abbott discontinued sale of its barbexaclone preparation in many countries.[54]

Levopropylhexedrine has been used as an anorectic, under the brand name Eventin.[55] Eventin’s use has been documented as early as 1958.[56]

References

  1. ^ "COLD, COUGH, ALLERGY, BRONCHODILATOR, AND ANTIASTHMATIC DRUG PRODUCTS FOR OVER-THE-COUNTER HUMAN USE". FDA. 7 June 2023. Archived from the original on 6 July 2023. Retrieved 5 July 2023.{{cite web}}: CS1 maint: bot: original URL status unknown (link)
  2. ^ a b c d e "Benzedrex". dailymed.nlm.nih.gov. Archived from the original on 15 July 2023. Retrieved 15 July 2023.
  3. ^ a b Schwarez J. "Sniffing Benzedrine Inhalers". Office for Science and Society. McGill University. Archived from the original on 16 July 2023. Retrieved 15 July 2023.
  4. ^ a b c "Benzedrex Inhaler". B. F. Ascher and Company. Archived from the original on 8 July 2023. Retrieved 8 July 2023.
  5. ^ a b "USP Monographs: Propylhexedrine Inhalant". www.pharmacopeia.cn. Archived from the original on 16 July 2023. Retrieved 16 July 2023.
  6. ^ Docherty JR (June 2008). "Pharmacology of stimulants prohibited by the World Anti-Doping Agency (WADA)". British Journal of Pharmacology. 154 (3): 606–622. doi:10.1038/bjp.2008.124. PMC 2439527. PMID 18500382.
  7. ^ "Obesin Dosage, Interactions". Archived from the original on 8 July 2023. Retrieved 23 October 2017.
  8. ^ "NCATS Inxight Drugs — PROPYLHEXEDRINE HYDROCHLORIDE". drugs.ncats.io. Archived from the original on 16 July 2023. Retrieved 15 July 2023.
  9. ^ "Propylhexedrine Contraindications". Medscape. Archived from the original on 28 February 2013. Retrieved 8 July 2023.
  10. ^ "Safety of mixing stimulants with medications". NIDA. Archived from the original on 14 July 2016. Retrieved 8 July 2023.
  11. ^ "Propylhexedrine". www.mskcc.org. Memorial Sloan Kettering Cancer Center. Retrieved 16 July 2023.
  12. ^ a b Polster H (February 1965). "[On Poisoning With the Appetite Depressant Propylhexedrine, "Obesin" in a 3-Year-Old Child]". Archiv für Toxikologie. 20: 271–273. doi:10.1007/BF00577551. PMID 14272412. S2CID 19812917.
  13. ^ "Benzedrex (propylhexedrine): Drug Safety Communication". FDA. 25 March 2021. Retrieved 16 July 2023.
  14. ^ a b Smith DE, Wesson DR, Sees KL, Morgan JP (1 October 1988). "An epidemiological and clinical analysis of propylhexedrine abuse in the United States". Journal of Psychoactive Drugs. 20 (4): 441–442. doi:10.1080/02791072.1988.10472514. PMID 2907528.
  15. ^ a b c d Center for Drug Evaluation and Research (15 April 2021). "FDA warns that abuse and misuse of the nasal decongestant propylhexedrine causes serious harm". FDA. U.S. Food and Drug Administration. Archived from the original on 23 February 2023. Retrieved 8 July 2023.
  16. ^ a b Sturner WQ, Spruill FG, Garriott JC (July 1974). "Two propylhexedrine-associated fatalities: Benzedrine revisited". Journal of Forensic Sciences. 19 (3): 572–574. doi:10.1520/JFS10213J. PMID 4137337.
  17. ^ a b "Propylhexedrine (Benzedrex)". National Capital Poison Control. Archived from the original on 16 July 2023. Retrieved 16 July 2023.
  18. ^ a b c d e f "Propylhexedrine". DrugBank. Archived from the original on 15 March 2012. Retrieved 8 July 2023.
  19. ^ Midha KK, Beckett AH, Saunders A (October 1974). "Identification of the major metabolites of propylhexedrine in vivo (in man) and in vitro (in guinea pig and rabbit)". Xenobiotica; the Fate of Foreign Compounds in Biological Systems. 4 (10): 627–635. doi:10.1080/00498257409169765. PMID 4428789.
  20. ^ US granted 4095596, Grayson M, "Nasal Inhaler", issued 20 June 1978, assigned to Smithkline Corp. 
  21. ^ Mancusi-Ungaro HR, Decker WJ, Forshan VR, Blackwell SJ, Lewis SR (1983). "Tissue injuries associated with parenteral propylhexedrine abuse". Journal of Toxicology. Clinical Toxicology. 21 (3): 359–372. doi:10.1097/00005373-198307000-00114. PMID 6144800.
  22. ^ "Medical Definition of ALKYLAMINE". www.merriam-webster.com. Archived from the original on 16 July 2023. Retrieved 15 July 2023.
  23. ^ Lands AM, Nash VL (April 1947). "The pharmacologic activity of N-methyl-beta-cyclohexyl-isopropylamine hydrochloride". The Journal of Pharmacology and Experimental Therapeutics. 89 (4): 382–385. PMID 20295519.
  24. ^ Wilson CO, Gisvold O, Doerge RF (1971). Textbook of organic medicinal and pharmaceutical chemistry. Lippincott. p. 491. ISBN 9780397520558.
  25. ^ Lednicer D, Mitscher LA (1977). Organic Chemistry of Drug Synthesis. Vol. 1. New York, NY: Wiley. p. 37. ISBN 978-0-471-52141-9.
  26. ^ Zenitz BL, Macks EB, Moore ML (May 1947). "Preparation of some primary and secondary beta-cyclohexylalkylamines". Journal of the American Chemical Society. 69 (5): 1117–1121. doi:10.1021/ja01197a039. PMID 20240502.
  27. ^ Thurman EM, Pedersen MJ, Stout RL, Martin T (1992). "Distinguishing sympathomimetic amines from amphetamine and methamphetamine in urine by gas chromatography/mass spectrometry". Journal of Analytical Toxicology. 16 (1): 19–27. doi:10.1093/jat/16.1.19. PMID 1640694.
  28. ^ US2454746A, Ullyot, Glenn E., "Cyclohexylalkylamines", issued 1948-11-23 
  29. ^ Grant G (4 August 1949). "H.R. 2969 - Bezedrine Inhalers". Congressional Record: Proceedings and Debates of the ... Congress (PDF). Vol. 95. Government Publishing Office. pp. A5052. Retrieved 15 July 2023. {{cite book}}: |work= ignored (help)
  30. ^ "Propylhexedrine - NAPRA". www.napra.ca. Archived from the original on 15 July 2023. Retrieved 15 July 2023.
  31. ^ Bolukbasi F, Delil S, Bulus E, Senturk A, Yeni N, Karaagac N (September 2013). "End of the barbexaclone era: an experience of treatment withdrawal". Epileptic Disorders. 15 (3): 311–313. doi:10.1684/epd.2013.0605. PMID 23981808. S2CID 39112148.
  32. ^ "Federal Register Vol. 41, No. 176" (PDF). Government Publishing Office. 9 September 1976. p. 38402.
  33. ^ "Expert Committee on Drug Dependence's Twenty-Seventh Report" (PDF). World Health Organization. Expert Committee on Drug Dependence. 28 September 1990. Retrieved 3 July 2023.
  34. ^ "Schedule 4 Appendix D drugs - Prescribed restricted substances - Pharmaceutical services". www.health.nsw.gov.au. Archived from the original on 15 July 2023. Retrieved 15 July 2023.
  35. ^ "Erowid Propylhexedrine (Benzedrex) Vault : Law". Erowid. Archived from the original on 16 July 2023. Retrieved 15 July 2023.
  36. ^ "Anlage 1 AMVV - Einzelnorm". www.gesetze-im-internet.de. Archived from the original on 30 November 2015. Retrieved 16 July 2023.
  37. ^ "The Misuse of Drugs Act 1971 (Modification) Order 1995". Office of Public Sector Information. Retrieved 15 June 2009.
  38. ^ "Federal Register Vol. 53 No. 64" (PDF). National Archives. Archived (PDF) from the original on 28 December 2022. Retrieved 9 July 2022.
  39. ^ "Federal Register Vol. 56 No. 232" (PDF). National Archives. Archived (PDF) from the original on 28 December 2022. Retrieved 9 July 2022.
  40. ^ "Sec. 1308.22 Excluded substances". Code of Federal Regulations. Drug Enforcement Administration. Archived from the original on 30 May 2023. Retrieved 30 May 2023.
  41. ^ Haislip G (11 January 1989). "Excluded Nonnarcotic Over-the- Counter Substances" (PDF). National Archives and Records Administration. DEA. Archived from the original (PDF) on 16 June 2023. Retrieved 26 June 2023. {{cite web}}: |archive-date= / |archive-url= timestamp mismatch; 27 June 2023 suggested (help)
  42. ^ a b c Rose W (September 1959). "Arzneimittelsucht durch Mißbrauch von sogenannten Appetitzüglern (Obesin)". Archiv für Toxikologie (in German). 17 (5): 331–335. doi:10.1007/BF00577633. ISSN 1432-0738. S2CID 31539217.
  43. ^ Fornazzari L, Carlen PL, Kapur BM (November 1986). "Intravenous abuse of propylhexedrine (Benzedrex) and the risk of brainstem dysfunction in young adults". The Canadian Journal of Neurological Sciences. Le Journal Canadien des Sciences Neurologiques. 13 (4): 337–339. doi:10.1017/S0317167100036696. PMID 2877725.
  44. ^ "Propylhexedrine (hydrochloride)" (PDF). Safety Data Sheet. Cayman Chemical. Archived from the original (PDF) on 16 April 2014. Retrieved 8 July 2023.
  45. ^ Holler JM, Vorce SP, McDonough-Bender PC, Magluilo J, Solomon CJ, Levine B (January 2011). "A drug toxicity death involving propylhexedrine and mitragynine". Journal of Analytical Toxicology. 35 (1): 54–59. doi:10.1093/anatox/35.1.54. PMID 21219704.
  46. ^ a b Anderson ED (May 1970). "Propylhexedrine (Benzedrex) psychosis". The New Zealand Medical Journal. 71 (456): 302. PMID 5270979. S2CID 30786926.
  47. ^ Garriott JC (1975). "Editorial: Propylhexadrine - a new dangerous drug?". Clinical Toxicology. 8 (6): 665–666. doi:10.3109/15563657508990092. PMID 6189.
  48. ^ Darcın AE, Dilbaz N, Okay IT (October 2010). "Barbexaclone abuse in a cannabis ex-user". Substance Abuse. 31 (4): 270–272. doi:10.1080/08897077.2010.514246. PMID 21038181. S2CID 7076881.
  49. ^ "BENZEDREX Trademark of B.F. ASCHER & COMPANY INC - Registration Number 0896775 - Serial Number 72340742". Justia. Archived from the original on 16 July 2023. Retrieved 16 July 2023.
  50. ^ Robertson V (17 February 2004). "Prince v. B.F. Ascher Company, Inc., 90 P.3d 1020 (Okla. Civ. App. 2004)". CaseText. Archived from the original on 16 July 2023. Retrieved 16 July 2023.
  51. ^ a b Wesson DR (June 1986). "Propylhexdrine". Drug and Alcohol Dependence. 17 (2–3): 273–278. doi:10.1016/0376-8716(86)90013-X. PMID 2874970.
  52. ^ Krueger HJ, Schwarz H (April 1965). "[Clinical Communication on the Therapy of Epilepsy With Maliasin]". Die Medizinische Welt. 14: 690–692. PMID 14276849.
  53. ^ "MALIASIN Trademark - Registration Number 0797076 - Serial Number 72213021". Justia. Archived from the original on 16 July 2023. Retrieved 16 July 2023.
  54. ^ Serracchiani D (31 January 2011). "Parliamentary question | Maliasin | P-001035/2011 | European Parliament". European Parliament. Archived from the original on 16 July 2023. Retrieved 16 July 2023.
  55. ^ "Eventin". Drugs.com. Retrieved 27 March 2013.
  56. ^ Hofer R, Locker A (April 1958). "[Therapeutic experiences with the appetite depressant eventin]". Wiener Medizinische Wochenschrift. 108 (14): 304–306. PMID 13558159.
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