Propylhexedrine

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Propylhexedrine
Propylhexedrine.svg
Propylhexedrine.gif
Systematic (IUPAC) name
(RS)-N,α-dimethyl-cyclohexylethylamine
Clinical data
AHFS/Drugs.commonograph
Pregnancy cat.
  • C
Legal status
RoutesMedical: Intranasal (inhaler) and oral.
Recreational: Oral and parenteral routes.
Pharmacokinetic data
Bioavailability?
Metabolism?
Half-life4 ± 1.5 hrs.
Excretion?
Identifiers
CAS number3595-11-7 N
ATC code?? ?
PubChemCID 7558
DrugBankDB06714
ChemSpider7277 YesY
UNIILQU92IU8LL YesY
KEGGD05637 YesY
SynonymsHexahydrodesoxyephedrine; Hexahydromethamphetamine; Dimethylcyclohexaneethanamine; Cycohexylisopropylmethylamine
Chemical data
FormulaC10H21N 
Mol. mass155.29 g/mol
 N (what is this?)  (verify)
 
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Propylhexedrine
Propylhexedrine.svg
Propylhexedrine.gif
Systematic (IUPAC) name
(RS)-N,α-dimethyl-cyclohexylethylamine
Clinical data
AHFS/Drugs.commonograph
Pregnancy cat.
  • C
Legal status
RoutesMedical: Intranasal (inhaler) and oral.
Recreational: Oral and parenteral routes.
Pharmacokinetic data
Bioavailability?
Metabolism?
Half-life4 ± 1.5 hrs.
Excretion?
Identifiers
CAS number3595-11-7 N
ATC code?? ?
PubChemCID 7558
DrugBankDB06714
ChemSpider7277 YesY
UNIILQU92IU8LL YesY
KEGGD05637 YesY
SynonymsHexahydrodesoxyephedrine; Hexahydromethamphetamine; Dimethylcyclohexaneethanamine; Cycohexylisopropylmethylamine
Chemical data
FormulaC10H21N 
Mol. mass155.29 g/mol
 N (what is this?)  (verify)

Propylhexedrine (Benzedrex, Obesin) is a stimulant drug used mainly to provide temporary symptomatic relief of nasal congestion due to colds, allergies and allergic rhinitis. Being a vasoconstrictor used to decongest nasal mucosa, it is administered by inhalation.

Propylhexedrine is most commonly found in over-the-counter Benzedrex inhaler. Benzedrex was first manufactured by Smith, Kline and French after the Benzedrine inhaler, which contained racemic amphetamine, became unavailable following the placement of amphetamines on the US Schedule II status (second highest abuse potential with limited medicinal use). Benzedrex is currently manufactured by B.F. Ascher & Co. Inc. Pharmaceuticals.[2] Propylhexedrine has also seen use in Europe as an appetite suppressant under the trade name Obesin[3] and 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.[3] Levopropylhexedrine is also used as an anorectic under the brand name Eventin.[4]

Chemistry[edit]

Free base propylhexedrine is a volatile, oily liquid at room temperature. The slow vaporization of free base propylhexedrine allows it to be administered via inhalation.[5] Acid salts of propylhexedrine (such as propylhexedrine HCl) often present as a stable, clear to off-white crystalline powder that readily dissolves in water.[6]

Propylhexedrine is structurally similar to methamphetamine and other phenylethylamines, with the only structural difference being the substitution of an alicyclic cyclohexyl group for the aromatic phenyl group of phenethylamine. Propylhexedrine is not an amphetamine, nor even a phenethylamine, but instead can be referred to as a cycloalkylamine. Because propylhexedrine is not an amphetamine, it is somewhat less potent than structurally similar amphetamines such as methamphetamine.

Propylhexedrine is a chiral compound (the α-carbon is chiral), and active ingredient contained in Benzedrex inhalers is racemic (RS)-propylhexedrine as the free base. (S)-Propylhexedrine, also known as levopropylhexedrine, is believed to be the more biologically active isomer of the two.[7] (S)-Propylhexedrine can be synthesized from dextromethamphetamine.[8]

Synthesis[edit]

Propylhexedrine can be synthesized starting with cyclohexylacetone in a similar fashion to the phenylacetone synthesis of methamphetamine.[9] However, more commonly propylhexedrine is prepared by reacting methamphetamine with Adams' catalyst, reducing methamphetamine's aromatic ring to a cyclohexyl moiety.

Preparation of Propylhexedrine.[10]


Pharmacology[edit]

Propylhexedrine is a TAAR1 agonist like amphetamine.[11] Consequently, it reverses the transporters for dopamine, norepinephrine and serotonin, leading to a release of monoamines from presynaptic vesicles into the synaptic cleft.[11] The increased level of monoamines within the synapse results in increased activity at these receptors. Additionally, propylhexedrine appears to antagonize the VMAT2 transporter, leading to a further increase in the aforementioned monoamines.[11] The pharmacological actions of propylhexedrine are similar to that of structurally similar stimulant phenethylamines, such as amphetamine.[11]

Metabolism[edit]

Propylhexedrine undergoes metabolism to form various metabolites including norpropylhexedrine, cyclohexylacetoxime, cis- and trans-4-hydroxypropylhexedrine.[12]

Contraindications[edit]

Propylhexedrine should not be used if an MAOI has been used in the past 14 days, or is being currently used, as this can lead to a hypertensive crisis. People with cardiac disease should not use propylhexedrine.[13]

Additionally, drugs such as stimulants and sympathomimetics should not be taken along with propylhexedrine, as this can lead to potentially dangerous spikes in blood pressure and irregular heart rhythms.[14]

There is one case of death resulting from the combination of propylhexedrine and kratom.[15]

Medical use[edit]

Propylhexedrine is used to treat acute nasal congestion related to common cold,[2] allergies and hay fever. For nasal congestion, the dosage is listed as two inhalations (one inhalation per nostril) every two hours for adults and children 6–12 years of age. Each inhalation delivers 0.4 to 0.5 milligrams (400 to 500 μg) in 800 millilitres of air.[2][16] Historically, it has also been used for weight loss.[17]

Recreational use[edit]

Propylhexedrine has been reported to be used recreationally, obtained as free base from the cotton rods that Benzedrex inhalers contain.

Effects[edit]

Propylhexedrine has sympathomimetic, adrenergic, vasocontricive and psychostimulant effects when taken above the medical dosage. Effects include increased sweating, talkativeness, euphoria, mydriasis, emotional lability, anorexia, tachycardia, palpitations, dry mouth, bruxism, anxiety, dysphoria, increased aggressiveness, paranoia, headache, dizziness, psychosis, slurred or impaired speech, rarely convulsions and serious heart problems.[18] Propylhexedrine can also cause swelling, dryness and irritation of mucous membranes.[19]

Withdrawal effects can occur and include fatigue, depression, suicidal tendencies, hunger and extreme desire for sleep.

Recreational use potential[edit]

Propylhexedrine has a lower potential for abuse than other stimulants, partially because methods of its use are limited, unlike more commonly abused amphetamine, methamphetamine and methylphenidate. It has gained popularity as an over the counter high, but it is not as popular as other OTC drugs with abuse potential, such as dextromethorphan and diphenhydramine. Oral ingestion being the most practical method of consumption, the inactive ingredients in a Benzedrex inhaler (menthol and lavender oil) are also ingested - most users report the taste and smell to be very unpleasant, resulting in "menthol burps" (frequent belching releasing the smell of the two) that often cause the user discomfort and sometimes nausea. Many drug users find propylhexedrine has a very heavy comedown compared to the "high" it causes. The abuse potential is considered to be low enough that neither the DEA nor the WHO consider it a drug of concern at the present, unlike ephedrine and its salts, which are known to be used as precursor chemicals in illicit manufacture of methamphetamine (and occasionally amphetamine). Propylhexedrine is controlled in some jurisdictions - for example, placed behind the counter like ephedrine to combat theft.

Injection risks[edit]

While propylhexedrine is limited in a number of administration routes, attempts to extract the drug from the nasal inhaler and then inject it have been reported. Recreational use by intravenous injection (IV) is dangerous and could result in serious bodily harm or death. IV use of propylhexedrine is known to cause transient diplopia and brainstem dysfunction, and deaths have been recorded in the medical literature. Typically, recorded cases of IV use are prepared by forming propylhexedrine HCl in a solution with hydrochloric acid, the solution is then heated to evaporate and the resulting crystals are dissolved in water for injection.[20][21][22]

Drug risks[edit]

As with similar drugs, using propylhexedrine to keep oneself awake for extended times can lead to a temporary state of sleep deprivation, during which an individual may experience hallucinations, including auditory, visual and tactile sensations (formication), paranoia, irritability and impaired memory. Ingestion of the cotton rod can cause bowel obstruction and various conditions involving the lower intestine.

Propylhexedrine, being a vasoconstrictor and a stimulant, may carry a further risk as blood pressure and heart rate are raised, sometimes severely. Hypertension experienced by users of propylhexedrine can be dangerous, especially in those who have pre-existing blood pressure problems. The increase in heart rate can lead to lower levels of oxygen, discomfort, panic, and in severe cases, heart attack or serious arrhythmias. Again, this risk is higher if the user has existing heart problems.

The use of all inhaled vasoconstrictors in the nose risks desensitizing the nose both to natural and therapeutic levels of decongestants. Desensitization is accompanied by "rebound" increase in congestion. Short acting decongestants, requiring frequent dosing, carry a high risk of dependency.

See also[edit]

References[edit]

  1. ^ "Controlled Drugs and Substances Act". Retrieved 20 August 2009. 
  2. ^ a b c "Benzedrex Inhaler Nasal Decongestant Inhaler". Benzedrex Inhaler Nasal Decongestant Inhaler. B.F. Ascher & Company, inc. Retrieved 27 March 2013. 
  3. ^ a b Wesson DR (June 1986). "Propylhexdrine". Drug and Alcohol Dependence 17 (2–3): 273–8. doi:10.1016/0376-8716(86)90013-X. PMID 2874970. 
  4. ^ "Eventin". Drugs.com. Retrieved 27 March 2013. 
  5. ^ Nasal Inhaler, US 4095596 
  6. ^ Mancusi-Ungaro, H. R. Jr. M.D.; Decker, W. J. Ph.D.; Forshan, V. R. D. O.; Blackwell, S. J. M.D.; Lewis, S. R. M.D. (1983). "Tissue Injuries Associated With Parenteral Propylhexedrine Abuse". Journal of Trauma-Injury Infection & Critical Care 23 (7): 650. doi:10.1097/00005373-198307000-00114. 
  7. ^ A. M. Lands, V. L. Nash, H. R. Granger and B. L. Dertinger (1947). "The Pharmacologic Activity of N-Methyl-β-cyclohexylisopropylamine Hydrochloride". JPET 89 (3): 382–385. 
  8. ^ Textbook of organic medicinal and pharmaceutical chemistry, Charles Owens Wilson, Ole Gisvold, Robert F. Doerge, page 491
  9. ^ Merck Index 7761 - Kleeman & Engel p.774 OCDS Vol.1 p.37 (1977) I.N. p.817
  10. ^ Zenitz, B. L.; Macks, E. B.; Moore, M. L. (1947). "Preparation of Some Primary and Secondary β-Cyclohexylalkylamines1". Journal of the American Chemical Society 69 (5): 1117. doi:10.1021/ja01197a039. PMID 20240502.  edit
  11. ^ a b c d http://www.drugbank.ca/drugs/DB06714 Propylhexedrine's DrugBank Entry
  12. ^ Midha, KK; Beckett, AH; Saunders, A (1974). "Identification of the major metabolites of propylhexedrine in vivo (in man) and in vitro (in guinea pig and rabbit).". Xenobiotica 4 (10): 627–635. PMID 4428789. 
  13. ^ http://reference.medscape.com/drug/benzedrex-propylhexedrine-343411#5 Propylhexedrine Contraindications - Medscape
  14. ^ http://www.nida.nih.gov/researchreports/prescription/prescription4.html#Safe Safety of mixing stimulants with medications - NIDA
  15. ^ "A drug toxicity death involving propylhexedrine and mitragynine". Journal of analytical toxicology. january/february 2011. Retrieved August 28, 2014.  Check date values in: |date= (help)
  16. ^ Benzedrex Inhaler Nasal Decongestant Inhaler | Walgreens - Product/dosage informations
  17. ^ Docherty, J.R. "Pharmacology of Stimulants prohibited by the World Anti-Doping Agency". US National Institutes of Health. British Journal Of Pharmacology. Retrieved August 17, 2014. 
  18. ^ Fornazzari, L; Carlen, PL; Kapur, BM (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): 337–9. PMID 2877725. 
  19. ^ https://www.caymanchem.com/msdss/12058m.pdf
  20. ^ "Proposed Rules". Federal Register 50 (10): 2226–2227. 
  21. ^ Prince v. Ascher, 90 P.3d 1020 (2004).
  22. ^ Fornazzari L, Carlen PL, Kapur BM. "Intravenous abuse of propylhexedrine (Benzedrex) and the risk of brainstem dysfunction in young adults." Canadian Journal of Neurological Science. 1986 Nov;13(4):337-9. PMID 2877725