4-Hydroxyamphetamine (4HA), also known as hydroxyamfetamine, hydroxyamphetamine, oxamphetamine, norpholedrine, para-hydroxyamphetamine, and α-methyltyramine, is a drug that stimulates the sympathetic nervous system.
|Trade names||Hydroxyamfetamine, Paredrine|
|Other names||hydroxyamphetamine (USAN US)|
|CompTox Dashboard (EPA)|
|ECHA InfoCard||100.002.866 |
|Chemical and physical data|
|Molar mass||151.206 g/mol g·mol−1|
|3D model (JSmol)|
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.
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 branch of the ophthalmic nerve. 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.
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. 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.
Like amphetamine, 4-hydroxyamphetamine is an agonist of human TAAR1. 4-Hydroxyamphetamine acts as an indirect sympathomimetic and causes the release of norepinephrine from nerve synapses which leads to mydriasis (pupil dilation).
It decreases metabolism of serotonin (5-hydroxytryptamine) and certain other monoamines 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 and catecholamines in the presynaptic terminal, and thus increases the amount of neurotransmitters available for release into the synaptic cleft. 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. 4-Hydroxyamphetamine is then metabolized by dopamine beta-hydroxylase into 4-hydroxynorephedrine or eliminated in the urine.
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:543 while Paremyd consists of a combination of 1% hydroxyamphetamine hydrobromide and 0.25% tropicamide. 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. Around 1997, Akorn, Inc., obtained the rights to both Paredrine and Paremyd, and in 2002, the company reintroduced Paremyd to the market as a fast acting ophthalmic mydriatic agent.
- 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. 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; however, other evidence from animal studies suggests that this reaction is catalyzed by DBH in synaptic vesicles within noradrenergic neurons in the brain.
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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 to p-hydroxyamphetamine. ... Subsequent oxidation at the benzylic position by DA β-hydroxylase affords p-hydroxynorephedrine. Alternatively, direct oxidation of amphetamine by DA β-hydroxylase can afford norephedrine.
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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, from d-amphetamine.
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Table 5: N-containing drugs and xenobiotics oxygenated by FMO
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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.
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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.
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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).
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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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The metabolism of p-OHA to p-OHNor is well documented and dopamine-β hydroxylase present in noradrenergic neurons could easily convert p-OHA to p-OHNor after intraventricular administration.
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