mephentermine

{{Short description|Adrenergic and dopaminergic cardiac stimulant}}

{{Drugbox

| Verifiedfields = changed

| verifiedrevid = 462248502

| IUPAC_name = N,2-dimethyl-1-phenylpropan-2-amine

| image = Mephentermine.svg

| width = 200px

| tradename = Wyamine, Fentermin, Mephentine

| pregnancy_AU =

| pregnancy_US =

| pregnancy_category =

| legal_AU =

| legal_CA =

| legal_UK =

| legal_US = Schedule I

| legal_status =

| routes_of_administration = Intravenous, intramuscular, oral, inhalation

| bioavailability =

| protein_bound =

| metabolism =

| elimination_half-life =

| excretion =

| IUPHAR_ligand = 7222

| CAS_number_Ref = {{cascite|correct|??}}

| CAS_number = 100-92-5

| ATC_prefix = C01

| ATC_suffix = CA11

| PubChem = 3677

| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

| DrugBank = DB01365

| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

| ChemSpiderID = 3549

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = TEZ91L71V4

| KEGG_Ref = {{keggcite|correct|kegg}}

| KEGG = D08180

| ChEMBL_Ref = {{ebicite|changed|EBI}}

| ChEMBL = 1201234

| ChEBI = 6755

| synonyms = Mephenterdrine; Mephetedrine; N-Methylphentermine; N,α,α-Trimethylphenethylamine; N,α,Dimethylampetamine; α-Methylmethamphetamine; Mephenteramine

| C=11 | H=17 | N=1

| SMILES = N(C(Cc1ccccc1)(C)C)C

| StdInChI_Ref = {{stdinchicite|correct|chemspider}}

| StdInChI = 1S/C11H17N/c1-11(2,12-3)9-10-7-5-4-6-8-10/h4-8,12H,9H2,1-3H3

| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}

| StdInChIKey = RXQCGGRTAILOIN-UHFFFAOYSA-N

}}

Mephentermine, sold under the brand name Wyamine among others, is a sympathomimetic medication which was previously used in the treatment of low blood pressure but is mostly no longer marketed.{{cite journal | vauthors = Docherty JR | title = Pharmacology of stimulants prohibited by the World Anti-Doping Agency (WADA) | journal = Br J Pharmacol | volume = 154 | issue = 3 | pages = 606–622 | date = June 2008 | pmid = 18500382 | pmc = 2439527 | doi = 10.1038/bjp.2008.124 | url = }} It is used by injection into a vein or muscle, by inhalation, and by mouth.

Side effects of mephentermine include dry mouth, sedation, reflex bradycardia, arrhythmias, and hypertension. Mephentermine induces the release of norepinephrine and dopamine and is described as an indirectly acting sympathomimetic and psychostimulant. Its sympathomimetic effects are mediated by indirect activation of α- and β-adrenergic receptors. Chemically, it is a substituted phenethylamine and amphetamine and is closely related to phentermine and methamphetamine.

Mephentermine was first described and introduced for medical use by 1952. It was discontinued in the United States between 2000 and 2004. The medication appears to remain available only in India. Misuse of mephentermine for recreational and performance-enhancing purposes has been increasingly encountered in modern times, especially in India.

Medical uses

For maintenance of blood pressure in hypotensive states, the dose for adults is 30 to 45{{nbsp}}mg as a single dose, repeated as necessary or followed by intravenous infusion of 0.1% mephentermine in 5% dextrose, with the rate and duration of administration depending on the patient's response.{{Citation needed|date=July 2024}}

For hypotension secondary to spinal anesthesia in obstetric patients, the dose for adults is 15{{nbsp}}mg as a single dose, repeated if needed. The maximum dose 30{{nbsp}}mg.{{Citation needed|date=July 2024}}

Mephentermine has also been used as a decongestant.

=Available forms=

Mephentermine is available in the form of 15 and 30{{nbsp}}mg/mL solutions for intravenous infusion or intramuscular injection and in the form of 10{{nbsp}}mg oral tablets. It has also been available in the form of inhalers.

Contraindications

Low blood pressure caused by phenothiazines, hypertension, and pheochromocytoma.{{Citation needed|date=July 2024}}

Patients receiving monoamine oxidase inhibitors.{{Citation needed|date=July 2024}}

For shock due to loss of blood or fluid, give fluid replacement therapy primarily, cardiovascular disease, hypertension, hyperthyroidism, chronic illnesses, lactation, pregnancy, skin dryness. headache.{{Citation needed|date=July 2024}}

Side effects

The most common side effects of mephentermine are drowsiness, incoherence, hallucinations, convulsions, slow heart rate (reflex bradycardia). Fear, anxiety, restlessness, tremor, insomnia, confusion, irritability, and psychosis. Nausea, vomiting, reduced appetite, urinary retention, dyspnea, weakness, and neck pain.{{Citation needed|date=July 2024}}

Potentially fatal reactions are due to atrioventricular block, central nervous system stimulation, cerebral hemorrhage, pulmonary edema, and ventricular arrhythmias.{{Citation needed|date=July 2024}}

Interactions

Mephentermine antagonizes effect of agents that lower blood pressure. Severe hypertension may occur with monoamine oxidase inhibitors and possibly tricyclic antidepressants. Additive vasoconstricting effects occur with ergot alkaloids, and oxytocin.{{Citation needed|date=July 2024}}

Potentially fatal drug interactions are the risk of abnormal heart rhythm in people undergoing anesthesia with cyclopropane and halothane.{{Citation needed|date=July 2024}}

Pharmacology

=Pharmacodynamics=

Mephentermine is thought to act as a releasing agent of norepinephrine and dopamine. It is described as an indirectly acting sympathomimetic, cardiac stimulant, adrenergic, vasoconstrictor, antihypotensive agent, and psychostimulant.{{cite web | title=Mephentermine | website=drugs.com | date=5 August 2020 | url=https://drugs.com/international/mephentermine.html | archive-url=https://web.archive.org/web/20200805172226/https://drugs.com/international/mephentermine.html | archive-date=5 August 2020 | url-status=dead | access-date=28 July 2024}} Its sympathomimetic effects are mediated by indirect activation of α- and β-adrenergic receptors.

Mephentermine appears to act by indirect stimulation of β-adrenergic receptors through causing the release of norepinephrine from its storage sites. It has a positive inotropic effect on the myocardium. AV conduction and refractory period of AV node is shortened with an increase in ventricular conduction velocity. It dilates arteries and arterioles in the skeletal muscle and mesenteric vascular beds, leading to an increase in venous return.{{Citation needed|date=July 2024}}

=Pharmacokinetics=

Its onset of action is 5 to 15{{nbsp}}minutes with intramuscular injection and is immediate with intravenous administration.{{Citation needed|date=July 2024}} Its duration of action is 4{{nbsp}}hours with intramuscular injection and 30{{nbsp}}minutes with intravenous administration.{{Citation needed|date=July 2024}}

Mephentermine, along with phentermine, is known to be produced as a metabolite of the orally administered local anesthetic oxetacaine (oxethazaine).{{cite journal | vauthors = Hsu MC, Lin SF, Kuan CP, Chu WL, Chan KH, Chang-Chien GP | title = Oxethazaine as the source of mephentermine and phentermine in athlete's urine | journal = Forensic Sci Int | volume = 185 | issue = 1–3 | pages = e1–5 | date = March 2009 | pmid = 19157735 | doi = 10.1016/j.forsciint.2008.12.009 | url = }}{{cite journal | vauthors = Huang WH, Liu CH, Liu RH, Tseng YL | title = Confirming urinary excretion of mephentermine and phentermine following the ingestion of oxethazaine by gas chromatography-mass spectrometry analysis | journal = J Anal Toxicol | volume = 34 | issue = 2 | pages = 73–77 | date = March 2010 | pmid = 20223098 | doi = 10.1093/jat/34.2.73 | url = }}

Chemistry

Mephentermine, also known as N,α,α-trimethylphenethylamine or N,α-dimethylampetamine, is a phenethylamine and amphetamine derivative. It is the N-methylated analogue of phentermine (α-methylamphetamine) and is also known as N-methylphentermine. In addition, mephentermine is the α-methylated analogue of methamphetamine or the α,α-dimethylated derivative of amphetamine. The cathinone (β-keto) derivative of mephentermine is α-methylmethcathinone (βk-mephentermine; RAD-081).{{cite journal | vauthors = Davies RA, Baird TR, Nguyen VT, Ruiz B, Sakloth F, Eltit JM, Negus SS, Glennon RA | title = Investigation of the Optical Isomers of Methcathinone, and Two Achiral Analogs, at Monoamine Transporters and in Intracranial Self-Stimulation Studies in Rats | journal = ACS Chem Neurosci | volume = 11 | issue = 12 | pages = 1762–1769 | date = June 2020 | pmid = 32356961 | pmc = 10019599 | doi = 10.1021/acschemneuro.9b00617 | url = }}{{cite journal | last=Nguyen | first=Vy | title=Analyzing Interactions Between Methcathinone Analogs and the Human Monoamine Transporters | journal=VCU Theses and Dissertations | date=2019 | doi=10.25772/T1DW-MG60 | page=}}{{cite thesis | last=Davies | first=Rachel A | title=Structure-Activity Relationship Studies of Synthetic Cathinones and Related Agents | website=VCU Scholars Compass | date=10 July 2019 | doi=10.25772/TZSA-0396 | url=https://scholarscompass.vcu.edu/etd/5953/ | access-date=24 November 2024}}

=Synthesis=

Mephentermine can by synthesized beginning with a Henry reaction between benzaldehyde (1) and 2-nitropropane (2) to give 2-methyl-2-nitro-1-phenylpropan-1-ol (3).William F Bruce, Szabo Joseph Lester, Tubis Samuel, {{US patent|2597445}} (1952 to Wyeth Corp) The nitro group is reduced with zinc in sulfuric acid giving 2-phenyl-1,1-dimethylethanolamine (4). Imine formation by dehydration with benzaldehyde gives (5). Alkylation with iodomethane leads to (6). Halogenation with thionyl chloride gives (7). Lastly, a Rosenmund reduction completes the synthesis of mephentermine (8).

File:Mephentermine synthesis.svg

Mephentermine can also be synthesized by condensation of phentermine with benzaldehyde to get a Schiff base which can be alkylated with methyl iodide to give mephentermine.{{cite journal | doi = 10.1021/ja01183a019 | title = Preparation of α,α-Dimethyl- and N,α,α-Trimethyl-β-cyclohexylethylamine | date = 1948 | journal = Journal of the American Chemical Society | volume = 70 | issue = 3 | pages = 955–957 | vauthors = Zenitz BL, Macks EB, Moore ML }}

History

Mephentermine was first described in the literature and was introduced for medical use under the brand name Wyamine by 1952.{{cite journal | vauthors = Brofman BL, Hellerstein HK, Caskey WH | title = Mephentermine: an effective pressor amine; clinical and laboratory observations | journal = Am Heart J | volume = 44 | issue = 3 | pages = 396–406 | date = September 1952 | pmid = 14952463 | doi = 10.1016/0002-8703(52)90261-5 | url = }} It was discontinued in the United States between 2000 and 2004.{{cite book | author=Schweizerischer Apotheker-Verein | title=Index Nominum: International Drug Directory | publisher=Medpharm Scientific Publishers | year=2004 | isbn=978-3-88763-101-7 | url=https://books.google.com/books?id=EgeuA47Ocm4C&pg=PA757 | access-date=28 July 2024 | page=757}}

Society and culture

=Names=

Mephentermine is the generic name of the drug and its {{Abbrlink|INN|International Nonproprietary Name}}, {{Abbrlink|BAN|British Approved Name}}, and {{Abbrlink|DCF|Dénomination Commune Française}}.{{cite book | vauthors = Elks J | title=The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies | publisher=Springer US | year=2014 | isbn=978-1-4757-2085-3 | url=https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA968 | access-date=28 July 2024 | page=968}}{{cite book | author=Schweizerischer Apotheker-Verein | title=Index Nominum 2000: International Drug Directory | publisher=Medpharm Scientific Publishers | year=2000 | isbn=978-3-88763-075-1 | url=https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA647 | access-date=28 July 2024 | page=647}}{{cite book | vauthors = Morton IK, Hall JM | title=Concise Dictionary of Pharmacological Agents: Properties and Synonyms | publisher=Springer Netherlands | year=2012 | isbn=978-94-011-4439-1 | url=https://books.google.com/books?id=tsjrCAAAQBAJ&pg=PA175 | access-date=28 July 2024 | page=175}} In the case of the sulfate salt, its {{Abbrlink|USAN|United States Adopted Name}} is mephentermine sulfate and its {{Abbrlink|BANM|British Approved Name}} is mephentermine sulphate. Synonyms of mephentermine include mephetedrine and mephenterdrine.{{cite web | title=Mephentermine | website=PubChem | url=https://pubchem.ncbi.nlm.nih.gov/compound/3677 | access-date=28 July 2024}} Brand names of mephentermine include Wyamine ({{Abbrlink|US|United States}}), Fentermin ({{Abbrlink|PT|Portugal}}), and Mephentine ({{Abbrlink|IN|India}}).

=Availability=

Mephentermine is no longer available in the United States and remains available in few or no other countries. However, it appears to remain available in India. It has also remained available in Brazil for use in veterinary medicine.

=Recreational use=

Misuse of mephentermine for recreational and/or performance-enhancing purposes has been reported along with addiction and dependence and serious health complications.{{cite journal | vauthors = Angrist BM, Schweitzer JW, Gershon S, Friedhoff AJ | title = Mephentermine psychosis: misuse of the Wyamine inhaler | journal = Am J Psychiatry | volume = 126 | issue = 9 | pages = 1315–1317 | date = March 1970 | pmid = 5413209 | doi = 10.1176/ajp.126.9.1315 | url = }}{{cite journal | vauthors = Uday GJ, Josh UG, Bhat SM | title = Mephentermine dependence with psychosis. A case report | journal = Br J Psychiatry | volume = 152 | issue = | pages = 129–131 | date = January 1988 | pmid = 3167321 | doi = 10.1192/bjp.152.1.129 | url = }}{{cite journal | vauthors = Mendhekar DN, Sharma H, Dali JS | title = Case report of substance dependence with buprenorphine and mephentermine | journal = Indian J Psychiatry | volume = 41 | issue = 2 | pages = 160–162 | date = April 1999 | pmid = 21455380 | pmc = 2962841 | doi = | url = }}{{cite journal | vauthors = de Sousa HF, de Oliveira MF, da Costa Lima MD, de Oliveira JR | title = Mephentermine dependence without psychosis: a Brazilian case report | journal = Addiction | volume = 105 | issue = 6 | pages = 1129–1130 | date = June 2010 | pmid = 20456293 | doi = 10.1111/j.1360-0443.2010.02935.x | url = }}{{cite journal | vauthors = Oliveira MF, Sousa HF, Lima MC, Oliveira JR | title = Mephentermine: rediscovering its biology and use, misuse and their implications | journal = Braz J Psychiatry | volume = 33 | issue = 1 | pages = 98–99 | date = March 2011 | pmid = 21537728 | doi = 10.1590/s1516-44462011000100019 | url = | doi-access = free }}{{cite journal | vauthors = Kumar Mattoo S, Parakh P | title = Mephentermine dependence: an emerging challenge | journal = CNS Neurosci Ther | volume = 18 | issue = 6 | pages = 509–510 | date = June 2012 | pmid = 22672305 | pmc = 6493632 | doi = 10.1111/j.1755-5949.2012.00328.x | url = }}{{cite journal | vauthors = Gehlawat P, Singh P, Gupta R, Arya S | title = Mephentermine dependence with psychosis | journal = Gen Hosp Psychiatry | volume = 35 | issue = 6 | pages = 681.e9–10 | date = 2013 | pmid = 23759255 | doi = 10.1016/j.genhosppsych.2013.04.019 | url = }}{{cite journal | vauthors = Gowda GS, Singh A, Ravi M, Math SB | title = Mephentermine dependence syndrome - A new emerging trend of substance use | journal = Asian J Psychiatr | volume = 17 | issue = | pages = 101–102 | date = October 2015 | pmid = 26236018 | doi = 10.1016/j.ajp.2015.07.006 | url = }}{{cite journal | vauthors = Singh S, Gupta A, Sarkar S | title = Mephentermine Dependence in a Young Athlete: Case Report With Review of Literature | journal = J Addict Med | volume = 11 | issue = 4 | pages = 328–330 | date = 2017 | pmid = 28574863 | doi = 10.1097/ADM.0000000000000313 | url = }}{{cite journal | vauthors = Somani A | title = Mephentermine dependence in a young Indian adult without psychosis | journal = BMJ Case Rep | volume = 13 | issue = 11 | pages = e236924| date = November 2020 | pmid = 33139366 | pmc = 7607562 | doi = 10.1136/bcr-2020-236924 | url = }}{{cite journal | vauthors = Roy P, Shah B, Karia S, Desousa A, Shah N | title = Mephentermine abuse - A case report | journal = Indian J Psychiatry | volume = 63 | issue = 4 | pages = 400–401 | date = 2021 | pmid = 34456355 | pmc = 8363899 | doi = 10.4103/psychiatry.IndianJPsychiatry_934_20 | doi-access = free | url = }}{{cite journal | vauthors = Singal AK, Deepti S, Sharma G, Kothari SS | title = Herculean mistake: mephentermine associated cardiomyopathy | journal = Phys Sportsmed | volume = 49 | issue = 1 | pages = 116–122 | date = February 2021 | pmid = 32404042 | doi = 10.1080/00913847.2020.1763146 | url = }}{{cite journal | vauthors = Bhardwaj A, Yadav J, Arya S, Gupta R | title = Mephentermine Misuse: An Impending Crisis among Sportspersons | journal = J Psychoactive Drugs | volume = 54 | issue = 2 | pages = 196–198 | date = 2022 | pmid = 34126873 | doi = 10.1080/02791072.2021.1936701 | url = }}{{cite journal | vauthors = Malik YK, Bhardwaj A, Ray A, Malik B, Gupta R | title="Mephentermine Abuse" an Age-old Concern with New Challenges: Review of Literature with Case Series | journal=Annals of Indian Psychiatry | volume=7 | issue=3 | date=2023 | issn=2588-8366 | doi=10.4103/aip.aip_59_23 | doi-access=free | pages=262–266}} It has been especially encountered in India, the only country in which mephentermine appears to remain available for medical use.

=Exercise and sports=

Mephentermine has been used as a performance-enhancing drug in exercise and sports. It is on the World Anti-Doping Agency (WADA) list of prohibited substances.{{cite web | title=The Prohibited List | website=World Anti Doping Agency | date=1 January 2024 | url=https://www.wada-ama.org/en/prohibited-list | access-date=28 July 2024}}

Research

Mephentermine was evaluated in the treatment of congestive heart failure in one small clinical study but was found to be ineffective.{{cite journal | vauthors = Goldberg LI | title = Use of sympathomimetic amines in heart failure | journal = Am J Cardiol | volume = 22 | issue = 2 | pages = 177–182 | date = August 1968 | pmid = 4874959 | doi = 10.1016/0002-9149(68)90223-3 | url = }}{{cite journal | vauthors = Frye RL, Kahler RL, Braunwald E | title = The ineffectiveness of an inotropic agent, mephentermine (Wyamine), in the treatment of congestive heart failure | journal = Am Heart J | volume = 62 | issue = 3| pages = 301–303 | date = September 1961 | pmid = 13702337 | doi = 10.1016/0002-8703(61)90395-7 | url = }}