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4-Hydroxyamphetamine

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"Hydroxyamfetamine" redirects here. For other uses, seeHydroxyamphetamine.

Hydroxyamphetamine
INN:Hydroxyamfetamine
Clinical data
Trade namesParedrine, Paremyd, Pedrolon, Mycadrine, Paredrinex, others
Other names4-Hydroxyamphetamine; 4-HA; Hydroxyamfetamine; Oxamphetamine; Norpholedrine;para-Hydroxyamphetamine; α-Methyltyramine; Methyltyramine, Hydroxyamphetamine (USANUS)
Routes of
administration		Eye drops
ATC code
  • None
Legal status
Legal status
  • In general: ℞ (Prescription only)
Identifiers
  • 4-(2-aminopropyl)phenol
CAS Number
PubChemCID
ChemSpider
UNII
ChEMBL
CompTox Dashboard(EPA)
ECHA InfoCard100.002.866Edit this at Wikidata
Chemical and physical data
FormulaC9H13NO
Molar mass151.209g·mol−1
3D model (JSmol)
  • NC(C)Cc1ccc(O)cc1
  • InChI=1S/C9H13NO/c1-7(10)6-8-2-4-9(11)5-3-8/h2-5,7,11H,6,10H2,1H3checkY
  • Key:GIKNHHRFLCDOEU-UHFFFAOYSA-NcheckY
(verify)

Hydroxyamphetamine,also known as4-hydroxyamphetamineornorpholedrineand sold under the brand namesParedrineandParemydamong others, is asympathomimeticmedicationused ineye dropstodilate the pupilforeye examinations.[1][2][3][4]

Hydroxyamfetamine acts as anorepinephrine releasing agentand hence is an indirectly acting sympathomimetic.[5][6]It is asubstituted phenethylamineandamphetamine.[4]

Hydroxyamphetamine appeared to remain marketed only in theCzech Republicas of 2004.[3]

Medical uses

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Hydroxyamphetamine is used ineye dropsto dilate thepupil(a process calledmydriasis) so that the back of the eye can be examined. This is adiagnostic testforHorner's syndrome.Patients with Horner's syndrome exhibitanisocoriabrought about by lesions on the nerves that connect to thenasociliarybranch of theophthalmic nerve.[7]Application of hydroxyamphetamine to the eye can indicate whether the lesion ispreganglionicorpostganglionicbased on the pupil's response. If the pupil dilates, the lesion is preganglionic. If the pupil does not dilate, the lesion is postganglionic.[7]

Hydroxyamphetamine has some limitations to its use as a diagnostic tool. If it is intended as an immediate follow up to another mydriatic drug (cocaineorapraclonidine), then the patient must wait anywhere from a day to a week before hydroxyamphetamine can be administered.[8][5]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.[7][8]

Available forms

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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[9]: 543 while Paremyd consists of a combination of 1% hydroxyamphetamine hydrobromide and 0.25%tropicamide.[10]

Pharmacology

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Pharmacodynamics

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Like amphetamine, hydroxyamphetamine is an agonist of humanTAAR1.[11]Hydroxyamphetamine acts as anindirect sympathomimeticandinduces the release of norepinephrinewhich leads tomydriasis(pupil dilation).[5][6]

It additionally decreases metabolism ofserotoninand certain othermonoaminesby inhibiting the activity ofmonoamine oxidases(MAOs), particularly type A (MAO-A).[citation needed]The inhibition of MAO-A prevents metabolism of serotonin andcatecholaminesin thepresynaptic terminal,and thus increases the amount of neurotransmitters available for release into thesynaptic cleft.[12]

Pharmacokinetics

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Hydroxyamphetamine is a majormetaboliteofamphetamineand a minor metabolite ofmethamphetamine.In humans, amphetamine is metabolized to hydroxyamphetamine byCYP2D6,which is a member of thecytochrome P450superfamily and is found in theliver.[13][14]4-Hydroxyamphetamine is then metabolized bydopamine β-hydroxylaseinto4-hydroxynorephedrineoreliminatedin theurine.[6]

Metabolic pathways of amphetamine in humans[sources 1]
Graphic of several routes of amphetamine metabolism
Para-
Hydroxylation
Para-
Hydroxylation
Para-
Hydroxylation
unidentified
Beta-
Hydroxylation
Beta-
Hydroxylation
Oxidative
Deamination
Oxidation
unidentified
Glycine
Conjugation
The image above contains clickable links
In humans, 4-hydroxyamphetamine is formed fromCYP2D6metabolism of amphetamine; 4-hydroxyamphetamine may subsequently be metabolized bydopamine β-hydroxylaseinto4-hydroxynorephedrine.


Chemistry

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Hydroxyamphetamine, also known as 4-hydroxy-α-methylphenethylamine, 4-hydroxyamphetamine, or α-methyltyramine, is asubstituted phenethylamineandamphetaminederivative.It is the 4-hydroxylatedanalogueofamphetamine,theN-demethylatedanalogue ofpholedrine(4-hydroxy-N-methylamphetamine), and the α-methylated analogue oftyramine(4-hydroxyphenethylamine). Other analogues includeα-methyldopamine,corbadrine(levonordefrin; α-methylnorepinephrine), anddioxifedrine(α-methylepinephrine).

It has a predictedlog Pof 0.58 to 1.4.[26][4][27]

Hydroxyamphetamine is usedpharmaceuticallyas thehydrobromidesalt.[1]

History

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Hydroxyamphetamine was firstsynthesizedby 1910.[1]

In the 1990s, the trade name rights, patents, andnew drug applications(NDAs) for Paredrine and Paremyd 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.[28]Around 1997,Akorn, Inc.,obtained the rights to both Paredrine and Paremyd,[29]and in 2002, the company reintroduced Paremyd to the market as a fast acting ophthalmic mydriatic agent.[10][30][31]

In 2004, hydroxyamphetamine appeared to remain marketed only in theCzech Republic.[3]

Society and culture

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Names

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Hydroxyamphetamineis thegeneric nameof the drug and itsBANTooltip British Approved NameandDCFTooltip Dénomination Commune Française,whilehydroxyamfetamineis itsINNTooltip International Nonproprietary Name.[1][2][3]In the case of thehydrobromidesalt,its generic name ishydroxyamphetamine hydrobromideand this is itsUSANTooltip United States Adopted Name.[1][2][3]It is also known by synonyms includingmethyltyramine,norpholedrine,andoxamphetamine.[1][2][3][26]The drug is sold under brand names includingParedrine,Paredrinex,Paremyd,Pedrolon,andMycadrine.[1][3]

Other drugs

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4-Hydroxyamphetamine is also ametaboliteofamphetamineand certain other amphetamines.[2]

Notes

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  1. ^4-Hydroxyamphetaminehas been shown to be metabolized into4-hydroxynorephedrineby dopamine beta-hydroxylase (DBH)in vitroand it is presumed to be metabolized similarlyin vivo.[16][21]Evidence from studies that measured the effect of serum DBH concentrations on4-hydroxyamphetaminemetabolism in humans suggests that a different enzyme may mediate the conversion of4-hydroxyamphetamineto4-hydroxynorephedrine;[21][23]however, other evidence from animal studies suggests that this reaction is catalyzed by DBH insynaptic vesicleswithin noradrenergic neurons in the brain.[24][25]

Reference notes

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  1. ^[15][16][17][18][19][20][21][22]

References

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  1. ^abcdefgElks J (2014).The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies.Springer US. p. 74.ISBN978-1-4757-2085-3.RetrievedAugust 30,2024.
  2. ^abcdeMorton IK, Hall JM (2012).Concise Dictionary of Pharmacological Agents: Properties and Synonyms.Springer Netherlands. p. 90.ISBN978-94-011-4439-1.RetrievedAugust 30,2024.
  3. ^abcdefgSchweizerischer Apotheker-Verein (2004).Index Nominum: International Drug Directory.Index Nominum: International Drug Directory. Medpharm Scientific Publishers. p. 609.ISBN978-3-88763-101-7.RetrievedAugust 30,2024.
  4. ^abc"Hydroxyamphetamine: Uses, Interactions, Mechanism of Action".DrugBank Online.January 30, 1992.RetrievedAugust 30,2024.
  5. ^abcLepore FE (1985). "Diagnostic pharmacology of the pupil".Clinical Neuropharmacology.8(1): 27–37.doi:10.1097/00002826-198503000-00003.PMID3884149.
  6. ^abcCho AK, Wright J (February 1978). "Pathways of metabolism of amphetamine and related compounds".Life Sciences.22(5): 363–372.doi:10.1016/0024-3205(78)90282-5.PMID347211.
  7. ^abcWalton KA, Buono LM (December 2003). "Horner syndrome".Current Opinion in Ophthalmology.14(6): 357–363.doi:10.1097/00055735-200312000-00007.PMID14615640.S2CID11262166.
  8. ^abDavagnanam I, Fraser CL, Miszkiel K, Daniel CS, Plant GT (March 2013)."Adult Horner's syndrome: a combined clinical, pharmacological, and imaging algorithm".Eye.27(3): 291–298.doi:10.1038/eye.2012.281.PMC3597883.PMID23370415.
  9. ^Slamovits TL, Glaser JS (1999). "The Pupils and Accommodation.". In Glaser JS (ed.).Neuro-ophthalmology.Philadelphia, PA: Lippincott, Williams, & Wilkins.ISBN978-0781717298.
  10. ^ab"Hydroxyamphetamine Hydrobromide; Tropicamide".Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations.Archived fromthe originalon March 4, 2016.
  11. ^Lewin AH, Miller GM, Gilmour B (December 2011)."Trace amine-associated receptor 1 is a stereoselective binding site for compounds in the amphetamine class".Bioorganic & Medicinal Chemistry.19(23): 7044–7048.doi:10.1016/j.bmc.2011.10.007.PMC3236098.PMID22037049.
  12. ^Nakagawasai O, Arai Y, Satoh SE, Satoh N, Neda M, Hozumi M, et al. (January 2004). "Monoamine oxidase and head-twitch response in mice. Mechanisms of alpha-methylated substrate derivatives".Neurotoxicology.25(1–2): 223–232.doi:10.1016/S0161-813X(03)00101-3.PMID14697897.
  13. ^Markowitz JS, Patrick KS (2001). "Pharmacokinetic and pharmacodynamic drug interactions in the treatment of attention-deficit hyperactivity disorder".Clinical Pharmacokinetics.40(10): 753–772.doi:10.2165/00003088-200140100-00004.PMID11707061.S2CID20884365.
  14. ^Haefely W, Bartholini G, Pletscher A (1976). "Monoaminergic drugs: general pharmacology".Pharmacology & Therapeutics B.2(1): 185–218.doi:10.1016/0306-039x(76)90030-1.PMID817330.
  15. ^"Adderall XR Prescribing Information"(PDF).United States Food and Drug Administration.Shire US Inc. December 2013. pp. 12–13.RetrievedDecember 30,2013.
  16. ^abGlennon RA (2013)."Phenylisopropylamine stimulants: amphetamine-related agents".In Lemke TL, Williams DA, Roche VF, Zito W (eds.).Foye's principles of medicinal chemistry(7th ed.). Philadelphia, US: Wolters Kluwer Health/Lippincott Williams & Wilkins. pp. 646–648.ISBN9781609133450.The simplest unsubstituted phenylisopropylamine, 1-phenyl-2-aminopropane, or amphetamine, serves as a common structural template for hallucinogens and psychostimulants. Amphetamine produces central stimulant, anorectic, and sympathomimetic actions, and it is the prototype member of this class (39).... The phase 1 metabolism of amphetamine analogs is catalyzed by two systems: cytochrome P450 and flavin monooxygenase.... Amphetamine can also undergo aromatic hydroxylation top-hydroxyamphetamine.... Subsequent oxidation at the benzylic position by DA β-hydroxylase affordsp-hydroxynorephedrine. Alternatively, direct oxidation of amphetamine by DA β-hydroxylase can afford norephedrine.
  17. ^Taylor KB (January 1974)."Dopamine-beta-hydroxylase. Stereochemical course of the reaction"(PDF).Journal of Biological Chemistry.249(2): 454–458.doi:10.1016/S0021-9258(19)43051-2.PMID4809526.RetrievedNovember 6,2014.Dopamine-β-hydroxylase catalyzed the removal of the pro-Rhydrogen atom and the production of 1-norephedrine, (2S,1R)-2-amino-1-hydroxyl-1-phenylpropane, fromd-amphetamine.
  18. ^Krueger SK, Williams DE (June 2005)."Mammalian flavin-containing monooxygenases: structure/function, genetic polymorphisms and role in drug metabolism".Pharmacology & Therapeutics.106(3): 357–387.doi:10.1016/j.pharmthera.2005.01.001.PMC1828602.PMID15922018.
    Table 5: N-containing drugs and xenobiotics oxygenated by FMO
  19. ^Cashman JR, Xiong YN, Xu L, Janowsky A (March 1999). "N-oxygenation of amphetamine and methamphetamine by the human flavin-containing monooxygenase (form 3): role in bioactivation and detoxication".Journal of Pharmacology and Experimental Therapeutics.288(3): 1251–1260.PMID10027866.
  20. ^Santagati NA, Ferrara G, Marrazzo A, Ronsisvalle G (September 2002). "Simultaneous determination of amphetamine and one of its metabolites by HPLC with electrochemical detection".Journal of Pharmaceutical and Biomedical Analysis.30(2): 247–255.doi:10.1016/S0731-7085(02)00330-8.PMID12191709.
  21. ^abcSjoerdsma A, von Studnitz W (April 1963)."Dopamine-beta-oxidase activity in man, using hydroxyamphetamine as substrate".British Journal of Pharmacology and Chemotherapy.20(2): 278–284.doi:10.1111/j.1476-5381.1963.tb01467.x.PMC1703637.PMID13977820.Hydroxyamphetamine was administered orally to five human subjects... Since conversion of hydroxyamphetamine to hydroxynorephedrine occurs in vitro by the action of dopamine-β-oxidase, a simple method is suggested for measuring the activity of this enzyme and the effect of its inhibitors in man.... The lack of effect of administration of neomycin to one patient indicates that the hydroxylation occurs in body tissues.... a major portion of the β-hydroxylation of hydroxyamphetamine occurs in non-adrenal tissue. Unfortunately, at the present time one cannot be completely certain that the hydroxylation of hydroxyamphetamine in vivo is accomplished by the same enzyme which converts dopamine to noradrenaline.
  22. ^Badenhorst CP, van der Sluis R, Erasmus E, van Dijk AA (September 2013). "Glycine conjugation: importance in metabolism, the role of glycine N-acyltransferase, and factors that influence interindividual variation".Expert Opinion on Drug Metabolism & Toxicology.9(9): 1139–1153.doi:10.1517/17425255.2013.796929.PMID23650932.S2CID23738007.Figure 1. Glycine conjugation of benzoic acid. The glycine conjugation pathway consists of two steps. First benzoate is ligated to CoASH to form the high-energy benzoyl-CoA thioester. This reaction is catalyzed by the HXM-A and HXM-B medium-chain acid:CoA ligases and requires energy in the form of ATP.... The benzoyl-CoA is then conjugated to glycine by GLYAT to form hippuric acid, releasing CoASH. In addition to the factors listed in the boxes, the levels of ATP, CoASH, and glycine may influence the overall rate of the glycine conjugation pathway.
  23. ^Horwitz D, Alexander RW, Lovenberg W, Keiser HR (May 1973). "Human serum dopamine-β-hydroxylase. Relationship to hypertension and sympathetic activity".Circulation Research.32(5): 594–599.doi:10.1161/01.RES.32.5.594.PMID4713201.S2CID28641000.The biologic significance of the different levels of serum DβH activity was studied in two ways. First, in vivo ability to β-hydroxylate the synthetic substrate hydroxyamphetamine was compared in two subjects with low serum DβH activity and two subjects with average activity.... In one study, hydroxyamphetamine (Paredrine), a synthetic substrate for DβH, was administered to subjects with either low or average levels of serum DβH activity. The percent of the drug hydroxylated to hydroxynorephedrine was comparable in all subjects (6.5-9.62) (Table 3).
  24. ^Freeman JJ, Sulser F (December 1974). "Formation of p-hydroxynorephedrine in brain following intraventricular administration of p-hydroxyamphetamine".Neuropharmacology.13(12): 1187–1190.doi:10.1016/0028-3908(74)90069-0.PMID4457764.In species where aromatic hydroxylation of amphetamine is the major metabolic pathway,p-hydroxyamphetamine (POH) andp-hydroxynorephedrine (PHN) may contribute to the pharmacological profile of the parent drug.... The location of thep-hydroxylation and β-hydroxylation reactions is important in species where aromatic hydroxylation of amphetamine is the predominant pathway of metabolism. Following systemic administration of amphetamine to rats, POH has been found in urine and in plasma.
    The observed lack of a significant accumulation of PHN in brain following the intraventricular administration of (+)-amphetamine and the formation of appreciable amounts of PHN from (+)-POH in brain tissue in vivo supports the view that the aromatic hydroxylation of amphetamine following its systemic administration occurs predominantly in the periphery, and that POH is then transported through the blood-brain barrier, taken up by noradrenergic neurones in brain where (+)-POH is converted in the storage vesicles by dopamine β-hydroxylase to PHN.
  25. ^Matsuda LA, Hanson GR, Gibb JW (December 1989). "Neurochemical effects of amphetamine metabolites on central dopaminergic and serotonergic systems".Journal of Pharmacology and Experimental Therapeutics.251(3): 901–908.PMID2600821.The metabolism ofp-OHA top-OHNor is well documented and dopamine-β hydroxylase present in noradrenergic neurons could easily convertp-OHA top-OHNor after intraventricular administration.
  26. ^ab"4-(2-Aminopropyl)phenol".PubChem.RetrievedAugust 30,2024.
  27. ^"C9H13NO".Hydroxyamphetamine.August 30, 2024.RetrievedAugust 30,2024.
  28. ^"Akorn Acquires Paredrine - Specialty Ophthalmic Diagnostic Product From Pharmics, Inc".Akorn press release.March 24, 1999. Archived fromthe originalon September 16, 2018.RetrievedDecember 9,2014.
  29. ^"Akorn press release".[permanent dead link]
  30. ^"Akorn timeline".Archived fromthe originalon June 26, 2019.RetrievedDecember 9,2014.
  31. ^Lurcott R (December 1, 2002)."Unique Mydriatic Returns: The combination formula fosters patient flow efficiencies".Ophthalmology Management.
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