4-Hydroxyamphetamine

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"Hydroxyamfetamine" redirects here. For other uses, see Hydroxyamphetamine.
4-Hydroxyamphetamine
P-Hydroxyamphetamine.svg
Systematic (IUPAC) name
4-(2-aminopropyl)phenol
Clinical data
Trade names Hydroxyamfetamine, Paredrine
Legal status
  • Prescription only
Routes Topical (ocular)
Identifiers
CAS number 1518-86-1 YesY
ATC code None
PubChem CID 3651
ChemSpider 3525 YesY
ChEMBL CHEMBL1546 YesY
Chemical data
Formula C9H13NO 
Mol. mass 151.206 g/mol
 YesY (what is this?)  (verify)

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

When used in eye drops, it dilates the pupil. 4-Hydroxyamphetamine is sold in combination with tropicamide under the brand name Paremyd.

Pharmacology[edit]

Pharmacokinetics[edit]

4-Hydroxyamphetamine is a major metabolite of amphetamine. 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.[1][2] 4-Hydroxyamphetamine is then eliminated in the urine.[3]

Metabolic pathways of amphetamine

Graphic of several routes of amphetamine metabolism
4-Hydroxyamphetamine
Para-
Hydroxylation
Para-
Hydroxylation
Para-
Hydroxylation
Beta-
Hydroxylation
Beta-
Hydroxylation
Oxidative
Deamination
Oxidation
Glycine
Conjugation
In humans, 4-hydroxyamphetamine is a metabolite of amphetamine. The hydroxylation of substituted amphetamines is typically mediated by CYP2D6 and dopamine β-hydroxylase.


Pharmacodynamics[edit]

4-Hydroxyamphetamine acts as an indirect sympathomimetic.[4] When injected into the bloodstream or into the brain, it disrupts the regulation of serotonin (5-hydroxytryptamine or 5-HT) by inhibiting the activity of a family of enzymes called monoamine oxidases (MAOs), particularly type A (MAO-A). The inhibition of MAO-A prevents metabolism of serotonin in the presynaptic terminal, and thus causes a build up of serotonin. Excessive amounts of serotonin are then released into the synaptic cleft. The released serotonin binds to serotonin receptors on the postsynaptic terminal, causing excessive nerve response. Reuptake of unbound serotonin perpetuates the response by replenishing the any deficit of serotonin in the presynaptic terminal that might have been caused by the release of serotonin into the synaptic cleft.[5]

4-Hydroxyamphetamine is also an agonist of human TAAR1.[6]

Diagnostic Use[edit]

If instilled in the eye using an appropriate eye drop dosage and formulation, 4-hydroxyamphetamine causes the release of norepinephrine from the nerve synapses leading to mydriasis.[7] 4-Hydroxyamphetamine hydrobromide is a known formulation that can be used as a diagnostic tool for Horner's syndrome. Patients with Horner’s syndrome exhibit anisocoria brought about by lesions on the nerves that connect to the nasociliary branch of the ophthalmic nerve.[8] Application of 4-hydroxyamphetamine to the eye can indicate whether the lesion is preganglionic or 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.[9]

Unfortunately, 4-hydroxyamphetamine has a few 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.[10][11] 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.[12][13][14]

Commercialization[edit]

Hydroxyamphetamine is a known component of two controlled (prescription only), name-brand ophthalmic mydriatics: Paredrine and Paremyd. Paredrine consists of a 1% solution of hydroxyamphetamine hydrobromide[15] while Paremyd consists of a combination of 1% hydroxyamphetamine hydrobromide and 0.25% tropicamide.[16] In the 1990s, the trade name rights, patents, and new drug applications (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.[1] Around 1997, Akorn, Inc., obtained the rights to both Paredrine and Paremyd[2], and in 2002, the company reintroduced Paremyd to the market as a fast acting ophthalmic mydriatic and cycloplegic.[3][4][5]

See also[edit]

External links[edit]


References[edit]

  1. ^ Markowitz JS & Patrick KS (2001). "Pharmacokinetic and pharmacodynamic drug interactions in the treatment of attention-deficit hyperactivity disorder." Clinical pharmacokinetics. 40(10):757-758 PMID 11707061
  2. ^ Haefely W, Bartholini G, & Pletscher A (1976). "Monoaminergic drugs: general pharmacology." Pharmacology & therapeutics. Part B: General & systematic pharmacology. 2(1):197 PMID 817330
  3. ^ Cho AK & Wright J (1978). "Pathways of metabolism of amphetamine and related compounds." Life sciences. 22(5):368 PMID 347211
  4. ^ Cho AK & Wright J (1978). "Pathways of metabolism of amphetamine and related compounds." Life sciences. 22(5):368 PMID 347211
  5. ^ Nakagawasai O, et al. (2004). "Monoamine oxidase and head-twitch response in mice. Mechanisms of alpha-methylated substrate derivatives." Neurotoxicology. 25(1-2):223-232 PMID 14697897
  6. ^ "Articleid 50034244". Binding Database. Retrieved 29 April 2014. 
  7. ^ Lepore FE (1985). "Diagnostic pharmacology of the pupil." Clinical neuropharmacology. 8(1):31 PMID 3884149
  8. ^ Walton KA & Buono LM (2003). "Horner syndrome." Current opinion in ophthalmology. 14(6):357 PMID 14615640
  9. ^ Walton KA & Buono LM (2003). "Horner syndrome." Current opinion in ophthalmology. 14(6):359 PMID 14615640
  10. ^ Davagnanam I, Fraser CL, Miszkiel K, Daniel CS, & Plant GT (2013). "Adult Horner's syndrome: a combined clinical, pharmacological, and imaging algorithm." Eye (London, England). 27(3):291,294 PMID 23370415
  11. ^ Lepore FE (1985). "Diagnostic pharmacology of the pupil." Clinical neuropharmacology. 8(1):29 PMID 3884149
  12. ^ Davagnanam I, Fraser CL, Miszkiel K, Daniel CS, & Plant GT (2013). "Adult Horner's syndrome: a combined clinical, pharmacological, and imaging algorithm." Eye (London, England). 27(3):294 PMID 23370415
  13. ^ Walton KA & Buono LM (2003). "Horner syndrome." Current opinion in ophthalmology. 14(6):359 PMID 14615640
  14. ^ Lepore FE (1985). "Diagnostic pharmacology of the pupil." Clinical neuropharmacology. 8(1):31-32 PMID 3884149
  15. ^ Slamovits TL and JS Glase (1999). 'The Pupils and Accommodation." in Neuro-ophthamology, ed Glaser JS (Lippincott, Williams, & Wilkins; Philadelphia, PA), p 543 Google Books Accessed 10 Dec 2014
  16. ^ FDA Orange Book. Search Proprietary Name: Paremyd. Accessed 03 Dec 2014