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| Trade names | Paredrine, Paremyd, Pedrolon, Mycadrine, Paredrinex, others |
| Other names | 4-Hydroxyamphetamine; 4-HA; Hydroxyamfetamine; Oxamphetamine; Norpholedrine;para-Hydroxyamphetamine; PHA; α-Methyltyramine; Methyltyramine, Hydroxyamphetamine (USANUS) |
| Routes of administration | Eye drops |
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| ECHA InfoCard | 100.002.866 |
| Chemical and physical data | |
| Formula | C9H13NO |
| Molar mass | 151.209 g·mol−1 |
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Hydroxyamphetamine, also known as4-hydroxyamphetamine ornorpholedrine and sold under the brand namesParedrine andParemyd among others, is asympathomimeticmedication used ineye drops todilate the pupil foreye examinations.[1][2][3][4]
Hydroxyamfetamine acts as anorepinephrine releasing agent and hence is an indirectly acting sympathomimetic.[5][6] It is asubstituted phenethylamine andamphetamine.[4]
Hydroxyamphetamine appeared to remain marketed only in theCzech Republic as of 2004.[3]
Hydroxyamphetamine is used ineye drops to dilate thepupil (a process calledmydriasis) so that the back of the eye can be examined. This is adiagnostic test forHorner's syndrome. Patients with Horner's syndrome exhibitanisocoria brought about by lesions on the nerves that connect to thenasociliary branch of theophthalmic nerve.[7] Application of hydroxyamphetamine to the eye can indicate whether the lesion ispreganglionic orpostganglionic 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 orapraclonidine), 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]
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]
Hydroxyamphetamine acts as anindirect sympathomimetic andinduces the release of norepinephrine which leads tomydriasis (pupil dilation).[5][6]
It has also been found to act as aserotonin releasing agent.[11] The drug produces thehead-twitch response, a behavioral proxy ofpsychedelic effects, when it is given byintracerebroventricular injection in animals.[11] This effect is blocked by theserotonin receptor antagonistscyproheptadine anddimethothiazine, by theserotonin reuptake inhibitorfluoxetine, and by theserotonin synthesis inhibitorpara-chlorophenylalanine (PCPA).[11] These findings suggest that hydroxyamphetamine-induced head twitches are due to activation of theserotonin5-HT2A receptor and that they are mediated by induction of serotonin release as opposed to directagonism of the serotonin 5-HT2A receptor.[11] Although hydroxyamphetamine produces the head-twitch response in animals, serotonin releasing agents are not necessarilyhallucinogenic in humans, and hence their induction of head twitches in animals has been considered a false positive for psychedelic effects.[12][13][14]
It additionally decreases metabolism ofserotonin and certain othermonoamines by inhibiting the activity ofmonoamine oxidases (MAOs), particularly type A (MAO-A).[citation needed] The inhibition of MAO-A prevents metabolism of serotonin andcatecholamines in thepresynaptic terminal, and thus increases the amount of neurotransmitters available for release into thesynaptic cleft.[11]
Like amphetamine, hydroxyamphetamine is an agonist of humanTAAR1.[15]
Hydroxyamphetamine is a majormetabolite ofamphetamine and a minor metabolite ofmethamphetamine. In humans, amphetamine is metabolized to hydroxyamphetamine byCYP2D6, which is a member of thecytochrome P450 superfamily and is found in theliver.[16][17] 4-Hydroxyamphetamine is then metabolized bydopamine β-hydroxylase into4-hydroxynorephedrine oreliminated in theurine.[6]
Metabolic pathways of amphetamine in humans[sources 1]  Para- Hydroxylation Para- Hydroxylation Para- Hydroxylation unidentified Beta- Hydroxylation Beta- Hydroxylation Oxidative Deamination Oxidation unidentified Glycine Conjugation  |
Hydroxyamphetamine, also known as 4-hydroxy-α-methylphenethylamine, 4-hydroxyamphetamine, or α-methyltyramine, is asubstituted phenethylamine andamphetaminederivative. It is the 4-hydroxylatedanalogue ofamphetamine, theN-demethylated analogue 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 P of 0.58 to 1.4.[29][4][30]
Hydroxyamphetamine is usedpharmaceutically as thehydrobromidesalt.[1]
Hydroxyamphetamine was firstsynthesized by 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.[31] Around 1997,Akorn, Inc., obtained the rights to both Paredrine and Paremyd,[32] and in 2002, the company reintroduced Paremyd to the market as a fast acting ophthalmic mydriatic agent.[10][33][34]
In 2004, hydroxyamphetamine appeared to remain marketed only in theCzech Republic.[3]
Hydroxyamphetamine is thegeneric name of the drug and itsBANTooltip British Approved Name andDCFTooltip Dénomination Commune Française, whilehydroxyamfetamine is itsINNTooltip International Nonproprietary Name.[1][2][3] In the case of thehydrobromidesalt, its generic name ishydroxyamphetamine hydrobromide and this is itsUSANTooltip United States Adopted Name.[1][2][3] It is also known by synonyms includingmethyltyramine,norpholedrine, andoxamphetamine.[1][2][3][29] The drug is sold under brand names includingParedrine,Paredrinex,Paremyd,Pedrolon, andMycadrine.[1][3]
4-Hydroxyamphetamine is also ametabolite ofamphetamine and certain other amphetamines.[2]
Amphetamine and methamphetamine, which act primarily by increasing carrier-mediated release of dopamine and norepinephrine, do not provoke head twitches (Corne and Pickering 1967; Silva and Calil 1975; Yamamoto and Ueki 1975; Jacobs et al. 1976; Bedard and Pycock 1977; Halberstadt and Geyer 2013). By contrast, the 5-HT releasing drugs fenfluramine and p-chloroamphetamine (PCA) do produce a robust HTR (Singleton and Marsden 1981; Darmani 1998a). Fenfluramine and PCA are thought to act indirectly, by increasing carrier-mediated release of 5-HT, because the response can be blocked by inhibition of the 5-HT transporter (Balsara et al. 1986; Darmani 1998a) or by depletion of 5-HT (Singleton and Marsden 1981; Balsara et al. 1986). [...] Because indirect 5-HT agonists such as fenfluramine, PCA, and 5-HTP are not hallucinogenic (Van Praag et al. 1971; Brauer et al. 1996; Turner et al. 2006), their effects on HTR can potentially be classified as false-positive responses.
Indirect 5-HT2A agonists such as fenfluramine, p-chloroamphetamine (PCA), and 5-hydroxytryptophan (5-HTP) induce head twitches in rodents (Corne et al. 1963; Singleton and Marsden 1981; Darmani 1998) but do not act as hallucinogens in humans (van Praag et al. 1971; Brauer et al. 1996; Turner et al. 2006), However, overdoses of compounds that increase serotonin (5-HT) release can result in 5-HT syndrome, which sometimes includes hallucinations (Birmes et al. 2003; Evans and Sebastian 2007).
While some false positives have been identified, such as fenfluramine, p-chloroamphetamine, and 5-hydroxytryptophan, the test predominantly exhibits specificity for 5-HT2A receptor agonists [15].
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.
Dopamine-β-hydroxylase catalyzed the removal of the pro-R hydrogen atom and the production of 1-norephedrine, (2S,1R)-2-amino-1-hydroxyl-1-phenylpropane, fromd-amphetamine.
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.
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.
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).
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.
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.
