4-Hydroxyamphetamine: Difference between revisions

{{Short description|Group of stereoisomers}}

{{Use mdy dates|date=April 2014}}

| INN=hydroxyamfetamine

| USAN=hydroxyamphetamine

| verifiedrevid = 606168923

| drug_name = Hydroxyamfetamine

| tradename = Hydroxyamfetamine, Paredrine

| routes_of_administration = Eye drops

| CAS_number_Ref = {{cascite|correct|CAS}}

| CAS_number = 103-86-6

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

| UNII = FQR280JW2N

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

| ChEMBL_Ref = {{ebicite|correct|EBI}}

| smiles = NC(C)Cc1ccc(O)cc1

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

| StdInChI = 1S/C9H13NO/c1-7(10)6-8-2-4-9(11)5-3-8/h2-5,7,11H,6,10H2,1H3

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

| StdInChIKey = GIKNHHRFLCDOEU-UHFFFAOYSA-N

'''4-Hydroxyamphetamine''' ('''4HA'''), also known as '''hydroxyamfetamine''', '''hydroxyamphetamine''', '''oxamphetamine''', '''norpholedrine''', '''''para''-hydroxyamphetamine''', and '''α-methyltyramine''', is a [[sympathomimetic drug|drug that stimulates the sympathetic nervous system]].

It is used medically in [[eye drops]] to dilate the [[pupil]] (a process called [[mydriasis]]), so that the back of the eye can be examined. It is also a major [[metabolite]] of [[amphetamine]] and certain [[substituted amphetamines]].

==Medical use==

4-Hydroxyamphetamine is used in [[eye drops]] to dilate the [[pupil]] (a process called [[mydriasis]]) so that the back of the eye can be examined. This is a [[diagnostic test]] for [[Horner's syndrome]]. Patients with Horner's syndrome exhibit [[anisocoria]] brought about by lesions on the nerves that connect to the [[nasociliary nerve|nasociliary]] branch of the [[ophthalmic nerve]].<ref name=Walton>{{cite journal | vauthors = Walton KA, Buono LM | title = Horner syndrome | journal = Current Opinion in Ophthalmology | volume = 14 | issue = 6 | pages = 357–63 | date = December 2003 | pmid = 14615640 | doi = 10.1097/00055735-200312000-00007 | s2cid = 11262166 }}</ref> Application of 4-hydroxyamphetamine to the eye can indicate whether the lesion is [[preganglionic nerve fibers|preganglionic]] or [[postganglionic nerve fibers|postganglionic]] based on the pupil's response. If the pupil dilates, the lesion is preganglionic. If the pupil does not dilate, the lesion is postganglionic.<ref name=Walton/>

4-hydroxyamphetamine has some limitations to its use as a diagnostic tool. If it is intended as an immediate follow up to another mydriatic drug ([[cocaine]] or [[apraclonidine]]), then the patient must wait anywhere from a day to a week before 4-hydroxyamphetamine can be administered.<ref name=Davagnanam>{{cite journal | vauthors = Davagnanam I, Fraser CL, Miszkiel K, Daniel CS, Plant GT | title = Adult Horner's syndrome: a combined clinical, pharmacological, and imaging algorithm | journal = Eye | volume = 27 | issue = 3 | pages = 291–8 | date = March 2013 | pmid = 23370415 | pmc = 3597883 | doi = 10.1038/eye.2012.281 }}</ref><ref name=Lepore>{{cite journal | vauthors = Lepore FE | title = Diagnostic pharmacology of the pupil | journal = Clinical Neuropharmacology | volume = 8 | issue = 1 | pages = 27–37 | pmid = 3884149 | doi = 10.1097/00002826-198503000-00003 | year = 1985 }}</ref> It also has the tendency to falsely localize lesions. False localization can arise in cases of acute onset; in cases where a postganglionic lesion is present, but the nerve still responds to residual norepinephrine; or in cases in which unrelated nerve damage masks the presence of a preganglionic lesion.<ref name=Walton/><ref name=Davagnanam/>

==Pharmacology==

Like amphetamine, 4-hydroxyamphetamine is an agonist of human [[TAAR1]].<ref>{{cite journal | vauthors = Lewin AH, Miller GM, Gilmour B | title = Trace amine-associated receptor 1 is a stereoselective binding site for compounds in the amphetamine class | journal = Bioorganic & Medicinal Chemistry | volume = 19 | issue = 23 | pages = 7044–7048 | date = December 2011 | pmid = 22037049 | pmc = 3236098 | doi = 10.1016/j.bmc.2011.10.007 }}</ref> 4-Hydroxyamphetamine acts as an [[sympathomimetic|indirect sympathomimetic]] and causes the release of [[norepinephrine]] from nerve synapses which leads to [[mydriasis]] (pupil dilation).<ref name=Lepore/><ref name=Cho/>

It decreases metabolism of [[serotonin]] (5-hydroxytryptamine) and certain other monoamines by inhibiting the activity of a family of enzymes called [[monoamine oxidase]]s (MAOs), particularly type A ([[MAO-A]]).{{Citation needed|date=February 2017}} The inhibition of MAO-A prevents metabolism of serotonin and [[catecholamines]] in the [[chemical synapse|presynaptic terminal]], and thus increases the amount of neurotransmitters available for release into the [[synaptic cleft]].<ref>{{cite journal | vauthors = Nakagawasai O, Arai Y, Satoh SE, Satoh N, Neda M, Hozumi M, Oka R, Hiraga H, Tadano T | display-authors = 6 | title = Monoamine oxidase and head-twitch response in mice. Mechanisms of alpha-methylated substrate derivatives | journal = Neurotoxicology | volume = 25 | issue = 1–2 | pages = 223–32 | date = January 2004 | pmid = 14697897 | doi = 10.1016/S0161-813X(03)00101-3 }}</ref> 4-Hydroxyamphetamine is a major [[metabolite]] of [[amphetamine]] and a minor metabolite of [[methamphetamine]]. In humans, amphetamine is metabolized to 4-hydroxyamphetamine by [[CYP2D6]], which is a member of the [[cytochrome P450]] superfamily and is found in the liver.<ref>{{cite journal | vauthors = Markowitz JS, Patrick KS | title = Pharmacokinetic and pharmacodynamic drug interactions in the treatment of attention-deficit hyperactivity disorder | journal = Clinical Pharmacokinetics | volume = 40 | issue = 10 | pages = 753–72 | pmid = 11707061 | doi = 10.2165/00003088-200140100-00004 | year = 2001 | s2cid = 20884365 }}</ref><ref>{{cite journal | vauthors = Haefely W, Bartholini G, Pletscher A | title = Monoaminergic drugs: general pharmacology | journal = Pharmacology & Therapeutics B | volume = 2 | issue = 1 | pages = 185–218 | pmid = 817330 | year = 1976 | doi = 10.1016/0306-039x(76)90030-1 }}</ref> 4-Hydroxyamphetamine is then metabolized by [[dopamine beta-hydroxylase]] into [[4-hydroxynorephedrine]] or eliminated in the urine.<ref name=Cho>{{cite journal | vauthors = Cho AK, Wright J | title = Pathways of metabolism of amphetamine and related compounds | journal = Life Sciences | volume = 22 | issue = 5 | pages = 363–72 | date = February 1978 | pmid = 347211 | doi = 10.1016/0024-3205(78)90282-5 }}</ref>

{{Amphetamine pharmacokinetics|caption=In humans, 4-hydroxyamphetamine is formed from [[CYP2D6]] metabolism of amphetamine; 4-hydroxyamphetamine may subsequently be metabolized by [[dopamine β-hydroxylase]] into [[4-hydroxynorephedrine]].}}

==Commercialization==

Hydroxyamphetamine is a component of two controlled (prescription only), name-brand ophthalmic mydriatics: '''Paredrine''' and '''Paremyd'''. Paredrine consists of a 1% solution of hydroxyamphetamine hydrobromide<ref>{{cite book | vauthors = Slamovits TL, Glaser JS | chapter = The Pupils and Accommodation. | title = Neuro-ophthalmology | veditors = Glaser JS | publisher = Lippincott, Williams, & Wilkins | location = Philadelphia, PA | date = 1999 | isbn = 978-0781717298}}</ref>{{rp|543}} while Paremyd consists of a combination of 1% hydroxyamphetamine hydrobromide and 0.25% [[tropicamide]].<ref name=OrangeBook/> In the 1990s, the trade name rights, patents, and [[new drug application]]s (NDAs) for the two formulations were exchanged among a few different manufacturers after a shortage of the raw material required for their production, which caused both drugs to be indefinitely removed from the market.<ref>{{cite web | work = Akorn press release | date = March 24, 1999 | url = http://www.thefreelibrary.com/Akorn+Acquires+Paredrine+-+Specialty+Ophthalmic+Diagnostic+Product...-a054197191 | title = Akorn Acquires Paredrine - Specialty Ophthalmic Diagnostic Product From Pharmics, Inc. | access-date = December 9, 2014 | archive-date = September 16, 2018 | archive-url = https://web.archive.org/web/20180916144249/https://www.thefreelibrary.com/Akorn+Acquires+Paredrine+-+Specialty+Ophthalmic+Diagnostic+Product...-a054197191 | url-status = dead }}</ref> Around 1997, [[Akorn|Akorn, Inc.]], obtained the rights to both Paredrine and Paremyd,<ref>{{cite web | url = http://investors.akorn.com/phoenix.zhtml?c=78132&p=irol-newsArticle&ID=247062 | title = Akorn press release }}{{Dead link|date=July 2023 |bot=InternetArchiveBot |fix-attempted=yes }}</ref> and in 2002, the company reintroduced Paremyd to the market as a fast acting ophthalmic mydriatic agent.<ref name=OrangeBook>{{cite web | url = http://www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?Appl_No=019261&TABLE1=OB_Rx | title = Hydroxyamphetamine Hydrobromide; Tropicamide | work = Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations | archive-url = https://web.archive.org/web/20160304052043/http://www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?Appl_No=019261&TABLE1=OB_Rx | archive-date = 4 March 2016 }}</ref><ref>{{cite web | url = http://www.akorn.com/about_timeline.php | title = Akorn timeline | archive-url = https://web.archive.org/web/20190626065749/http://www.akorn.com/about_timeline.php | archive-date=June 26, 2019 | access-date = December 9, 2014 }}</ref><ref>{{cite web | vauthors = Lurcott R | work = Ophthalmology Management | date = December 1, 2002 | url = http://www.ophthalmologymanagement.com/articleviewer.aspx?articleID=85623 | title = Unique Mydriatic Returns: The combination formula fosters patient flow efficiencies }}</ref>

==Notes==

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==Reference notes==

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{{reflist}}

{{Monoamine releasing agents}}

{{TAAR ligands}}

{{DEFAULTSORT:Hydroxyamphetamine, 4-}}

[[Category:Substituted amphetamines]]

[[Category:TAAR1 agonists]]

[[Category:Norepinephrine-dopamine releasing agents]]

[[Category:Human drug metabolites]]

[[Category:Recreational drug metabolites]]