4-Hydroxyamphetamine

Last updated

Hydroxyamfetamine
INN: Hydroxyamfetamine
P-Hydroxyamphetamine.svg
Clinical data
Trade names Paredrine, Paremyd, Pedrolon, Mycadrine, Paredrinex, others
Other names4-Hydroxyamphetamine; 4-HA; Hydroxyamfetamine; Oxamphetamine; Norpholedrine; para-Hydroxyamphetamine; α-Methyltyramine; Methyltyramine, Hydroxyamphetamine (USAN US)
Routes of
administration 		Eye drops
ATC code
  • None
Legal status
Legal status
  • In general: ℞ (Prescription only)
Identifiers
  • 4-(2-aminopropyl)phenol
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.002.866 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C9H13NO
Molar mass 151.209 g·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,6,10H2,1H3 Yes check.svgY
  • Key:GIKNHHRFLCDOEU-UHFFFAOYSA-N Yes check.svgY
   (verify)

Hydroxyamphetamine, also known as 4-hydroxyamphetamine or norpholedrine and sold under the brand names Paredrine and Paremyd among others, is a sympathomimetic medication used in eye drops to dilate the pupil for eye examinations. [1] [2] [3] [4]

Contents

Hydroxyamfetamine acts as a norepinephrine releasing agent and hence is an indirectly acting sympathomimetic. [5] [6] It is a substituted phenethylamine and amphetamine. [4] The drug is also a metabolite of amphetamine and certain other amphetamines. [2]

Hydroxyamphetamine appeared to remain marketed only in the Czech Republic as of 2004. [3]

Medical uses

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 branch of the ophthalmic nerve. [7] Application of 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. [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 (cocaine or apraclonidine), 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

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

Pharmacodynamics

Like amphetamine, hydroxyamphetamine is an agonist of human TAAR1. [11] Hydroxyamphetamine acts as an indirect sympathomimetic and induces the release of norepinephrine which leads to mydriasis (pupil dilation). [5] [6]

It additionally decreases metabolism of serotonin and certain other monoamines by inhibiting the activity of monoamine oxidases (MAOs), particularly type A (MAO-A).[ citation needed ] The inhibition of MAO-A prevents metabolism of serotonin and catecholamines in the presynaptic terminal, and thus increases the amount of neurotransmitters available for release into the synaptic cleft. [12]

Pharmacokinetics

Hydroxyamphetamine is a major metabolite of amphetamine and a minor metabolite of methamphetamine. In humans, amphetamine is metabolized to hydroxyamphetamine by CYP2D6, which is a member of the cytochrome P450 superfamily and is found in the liver. [13] [14] 4-Hydroxyamphetamine is then metabolized by dopamine β-hydroxylase into 4-hydroxynorephedrine or eliminated in the urine. [6]

Chemistry

Hydroxyamphetamine, also known as 4-hydroxy-α-methylphenethylamine, 4-hydroxyamphetamine, or α-methyltyramine, is a substituted phenethylamine and amphetamine derivative. It is the 4-hydroxylated analogue of amphetamine, the N-demethylated analogue of pholedrine (4-hydroxy-N-methylamphetamine), and the α-methylated analogue of tyramine (4-hydroxyphenethylamine).

It has a predicted log P of 0.58 to 1.4. [26] [4] [27]

Hydroxyamphetamine is used pharmaceutically as the hydrobromide salt. [1]

History

Hydroxyamphetamine was first synthesized by 1910. [1]

In the 1990s, the trade name rights, patents, and new 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 the Czech Republic. [3]

Society and culture

Names

Hydroxyamphetamine is the generic name of the drug and its BAN Tooltip British Approved Name and DCF Tooltip Dénomination Commune Française, while hydroxyamfetamine is its INN Tooltip International Nonproprietary Name. [1] [2] [3] In the case of the hydrobromide salt, its generic name is hydroxyamphetamine hydrobromide and this is its USAN Tooltip United States Adopted Name. [1] [2] [3] It is also known by synonyms including methyltyramine, norpholedrine, and oxamphetamine. [1] [2] [3] [26] The drug is sold under brand names including Paredrine, Paredrinex, Paremyd, Pedrolon, and Mycadrine. [1] [3]

Notes

  1. ↑ 4-Hydroxyamphetamine has been shown to be metabolized into 4-hydroxynorephedrine by dopamine beta-hydroxylase (DBH) in vitro and it is presumed to be metabolized similarly in vivo . [16] [21] Evidence from studies that measured the effect of serum DBH concentrations on 4-hydroxyamphetamine metabolism in humans suggests that a different enzyme may mediate the conversion of 4-hydroxyamphetamine to 4-hydroxynorephedrine; [21] [23] however, other evidence from animal studies suggests that this reaction is catalyzed by DBH in synaptic vesicles within noradrenergic neurons in the brain. [24] [25]

Reference notes

Related Research Articles

<span class="mw-page-title-main">Amphetamine</span> Central nervous system stimulant

Amphetamine is a central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, and obesity. Amphetamine was discovered as a chemical in 1887 by Lazăr Edeleanu, and then as a drug in the late 1920s. It exists as two enantiomers: levoamphetamine and dextroamphetamine. Amphetamine properly refers to a specific chemical, the racemic free base, which is equal parts of the two enantiomers in their pure amine forms. The term is frequently used informally to refer to any combination of the enantiomers, or to either of them alone. Historically, it has been used to treat nasal congestion and depression. Amphetamine is also used as an athletic performance enhancer and cognitive enhancer, and recreationally as an aphrodisiac and euphoriant. It is a prescription drug in many countries, and unauthorized possession and distribution of amphetamine are often tightly controlled due to the significant health risks associated with recreational use.

<span class="mw-page-title-main">Catecholamine</span> Class of chemical compounds

A catecholamine is a monoamine neurotransmitter, an organic compound that has a catechol and a side-chain amine.

<span class="mw-page-title-main">Phenethylamine</span> Organic compound, a stimulant in humans

Phenethylamine (PEA) is an organic compound, natural monoamine alkaloid, and trace amine, which acts as a central nervous system stimulant in humans. In the brain, phenethylamine regulates monoamine neurotransmission by binding to trace amine-associated receptor 1 (TAAR1) and inhibiting vesicular monoamine transporter 2 (VMAT2) in monoamine neurons. To a lesser extent, it also acts as a neurotransmitter in the human central nervous system. In mammals, phenethylamine is produced from the amino acid L-phenylalanine by the enzyme aromatic L-amino acid decarboxylase via enzymatic decarboxylation. In addition to its presence in mammals, phenethylamine is found in many other organisms and foods, such as chocolate, especially after microbial fermentation.

<span class="mw-page-title-main">Dextroamphetamine</span> CNS stimulant and isomer of amphetamine

Dextroamphetamine (INN:dexamfetamine) is a potent central nervous system (CNS) stimulant and enantiomer of amphetamine that is prescribed for the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. It is also used as an athletic performance and cognitive enhancer, and recreationally as an aphrodisiac and euphoriant. Dextroamphetamine is generally regarded as the prototypical stimulant.

<span class="mw-page-title-main">Phenylpropanolamine</span> Sympathomimetic agent

Phenylpropanolamine (PPA), sold under many brand names, is a sympathomimetic agent which is used as a decongestant and appetite suppressant. It was previously commonly used in prescription and over-the-counter cough and cold preparations. The medication is taken by mouth.

<span class="mw-page-title-main">Adderall</span> Drug mixture used mainly to treat ADHD and narcolepsy

Adderall and Mydayis are trade names for a combination drug containing four salts of amphetamine. The mixture is composed of equal parts racemic amphetamine and dextroamphetamine, which produces a (3:1) ratio between dextroamphetamine and levoamphetamine, the two enantiomers of amphetamine. Both enantiomers are stimulants, but differ enough to give Adderall an effects profile distinct from those of racemic amphetamine or dextroamphetamine, which are marketed as Evekeo and Dexedrine/Zenzedi, respectively. Adderall is used in the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. It is also used illicitly as an athletic performance enhancer, cognitive enhancer, appetite suppressant, and recreationally as a euphoriant. It is a central nervous system (CNS) stimulant of the phenethylamine class.

<span class="mw-page-title-main">Phenylephrine</span> Decongestant medication

Phenylephrine, sold under the brand names Neosynephrine and Sudafed PE among numerous others, is a medication used as a decongestant for uncomplicated nasal congestion, used to dilate the pupil, used to increase blood pressure, and used to relieve hemorrhoids. It can be taken by mouth, as a nasal spray, given by injection into a vein or muscle, applied to the skin, or as a rectal suppository.

<span class="mw-page-title-main">Dopaminergic</span> Substance related to dopamine functions

Dopaminergic means "related to dopamine", a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain.

<span class="mw-page-title-main">Phenylacetone</span> Chemical compound

Phenylacetone, also known as phenyl-2-propanone, is an organic compound with the chemical formula C6H5CH2COCH3. It is a colorless oil that is soluble in organic solvents. It is a mono-substituted benzene derivative, consisting of an acetone attached to a phenyl group. As such, its systematic IUPAC name is 1-phenyl-2-propanone.

<span class="mw-page-title-main">Lisdexamfetamine</span> Central nervous system stimulant prodrug

Lisdexamfetamine, sold under the brand names Vyvanse and Elvanse among others, is a stimulant medication that is used to treat attention deficit hyperactivity disorder (ADHD) in children and adults and for moderate-to-severe binge eating disorder in adults. Lisdexamfetamine is taken by mouth. Its effects generally begin within two hours and last for up to 14 hours.

<span class="mw-page-title-main">Methamphetamine</span> Central nervous system stimulant

Methamphetamine is a potent central nervous system (CNS) stimulant that is mainly used as a recreational drug and less commonly as a second-line treatment for attention deficit hyperactivity disorder and obesity. Methamphetamine was discovered in 1893 and exists as two enantiomers: levo-methamphetamine and dextro-methamphetamine. Methamphetamine properly refers to a specific chemical substance, the racemic free base, which is an equal mixture of levomethamphetamine and dextromethamphetamine in their pure amine forms, but the hydrochloride salt, commonly called crystal meth, is widely used. Methamphetamine is rarely prescribed over concerns involving its potential for recreational use as an aphrodisiac and euphoriant, among other concerns, as well as the availability of safer substitute drugs with comparable treatment efficacy such as Adderall and Vyvanse. Dextromethamphetamine is a stronger CNS stimulant than levomethamphetamine.

<span class="mw-page-title-main">Gepefrine</span> Sympathomimetic drug in the amphetamine family

3-Hydroxyamphetamine, also known as meta-hydroxyamphetamine, and α-methyl-meta-tyramine, is an antihypotensive or sympathomimetic agent of the amphetamine family that is marketed in certain European countries.

<span class="mw-page-title-main">Dopamine beta-hydroxylase</span> Mammalian protein found in Homo sapiens

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<span class="mw-page-title-main">Oxyfedrine</span> Chemical compound

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<span class="mw-page-title-main">Levoamphetamine</span> CNS stimulant and isomer of amphetamine

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<i>para</i>-Chloroamphetamine Chemical compound

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<span class="mw-page-title-main">Pholedrine</span> Chemical compound

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<i>p</i>-Hydroxynorephedrine Chemical compound

p-Hydroxynorephedrine (PHN), or 4-hydroxynorephedrine, is the para-hydroxy analog of norephedrine and an active sympathomimetic metabolite of amphetamine in humans. When it occurs as a metabolite of amphetamine, it is produced from both p-hydroxyamphetamine and norephedrine.

<span class="mw-page-title-main">4-Hydroxyphenylacetone</span> Chemical compound

4-Hydroxyphenylacetone is the para-hydroxy analog of phenylacetone, an inactive metabolite of amphetamine in humans. When it occurs as a metabolite of amphetamine, it is produced directly from the inactive metabolite phenylacetone.

<span class="mw-page-title-main">Threohydrobupropion</span> Type of substituted amphetamine derivative

Threohydrobupropion is a substituted amphetamine derivative—specifically a β-hydroxyamphetamine—and a major active metabolite of the antidepressant drug bupropion (Wellbutrin). Bupropion is a norepinephrine–dopamine reuptake inhibitor and nicotinic acetylcholine receptor negative allosteric modulator, with its metabolites contributing substantially to its activities. Threohydrobupropion exists as two isomers, (1R,2R)-threohydrobupropion and (1S,2S)-threohydrobupropion. Other metabolites of bupropion include hydroxybupropion and erythrohydrobupropion.

References

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    Table 5: N-containing drugs and xenobiotics oxygenated by FMO
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  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. PMID   12191709.
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  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. PMID   23650932. S2CID   23738007. 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. PMID   4713201. S2CID   28641000. 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. PMID   4457764. In species where aromatic hydroxylation of amphetamine is the major metabolic pathway, p-hydroxyamphetamine (POH) and p-hydroxynorephedrine (PHN) may contribute to the pharmacological profile of the parent drug. ... The location of the p-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.
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  27. ↑ "C9H13NO". Hydroxyamphetamine. August 30, 2024. Retrieved August 30, 2024.
  28. ↑ "Akorn Acquires Paredrine - Specialty Ophthalmic Diagnostic Product From Pharmics, Inc". Akorn press release. March 24, 1999. Archived from the original on September 16, 2018. Retrieved December 9, 2014.
  29. ↑ "Akorn press release".[ permanent dead link ]
  30. ↑ "Akorn timeline". Archived from the original on June 26, 2019. Retrieved December 9, 2014.
  31. ↑ Lurcott R (December 1, 2002). "Unique Mydriatic Returns: The combination formula fosters patient flow efficiencies". Ophthalmology Management.
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