4-Hydroxyamphetamine (4HA), also known as hydroxyamfetamine, hydroxyamphetamine, oxamphetamine, norpholedrine, ''para''-hydroxyamphetamine, and α-methyltyramine, is a drug that stimulates the sympathetic nervous system. It is used medically in

eye drops Eye drops or eyedrops are liquid drops applied directly to the surface of the eye usually in small amounts such as a single drop or a few drops. Eye drops usually contain saline to match the salinity of the eye. Drops containing only saline ...

to dilate the

pupil The pupil is a black hole located in the center of the iris of the eye that allows light to strike the retina.Cassin, B. and Solomon, S. (1990) ''Dictionary of Eye Terminology''. Gainesville, Florida: Triad Publishing Company. It appears black ...

(a process called

mydriasis Mydriasis is the dilation of the pupil, usually having a non-physiological cause, or sometimes a physiological pupillary response. Non-physiological causes of mydriasis include disease, trauma, or the use of certain types of drugs. Normally, as ...

), so that the back of the eye can be examined. It is also a major

metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...

amphetamine Amphetamine (contracted from alpha- methylphenethylamine) is a strong central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, and obesity. It is also commonly used ...

and certain

substituted amphetamines Substituted amphetamines are a class of compounds based upon the amphetamine structure; it includes all derivative compounds which are formed by replacing, or substituting, one or more hydrogen atoms in the amphetamine core structure with sub ...

Medical use

4-Hydroxyamphetamine is used in

to dilate the

(a process called

) so that the back of the eye can be examined. This is a

diagnostic test A medical test is a medical procedure performed to detect, diagnose, or monitor diseases, disease processes, susceptibility, or to determine a course of treatment. Medical tests such as, physical and visual exams, diagnostic imaging, genetic ...

for

Horner's syndrome Horner's syndrome, also known as oculosympathetic paresis, is a combination of symptoms that arises when a group of nerves known as the sympathetic trunk is damaged. The signs and symptoms occur on the same side (ipsilateral) as it is a lesion o ...

. Patients with Horner's syndrome exhibit

anisocoria Anisocoria is a condition characterized by an unequal size of the eyes' pupils. Affecting up to 20% of the population, anisocoria is often entirely harmless, but can be a sign of more serious medical problems. Causes Anisocoria is a common condit ...

brought about by lesions on the nerves that connect to the nasociliary branch of the

ophthalmic nerve The ophthalmic nerve (V1) is a sensory nerve of the face. It is one of three divisions of the trigeminal nerve (CN V). It has three branches that provide sensory innervation to the eye, the skin of the upper face, and the skin of the anterior sca ...

. Application of 4-hydroxyamphetamine to the eye can indicate whether the lesion is

preganglionic In the autonomic nervous system, fibers from the CNS to the ganglion are known as preganglionic fibers. All preganglionic fibers, whether they are in the sympathetic division or in the parasympathetic division, are cholinergic (that is, these f ...

postganglionic In the autonomic nervous system, fibers from the ganglion to the wikt:effector, effector organ are called postganglionic fibers. Neurotransmitters The neurotransmitters of postganglionic fibers differ: * In the parasympathetic division, neuro ...

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 Cocaine (from , from , ultimately from Quechuan languages, Quechua: ''kúka'') is a central nervous system (CNS) stimulant mainly recreational drug use, used recreationally for its euphoria, euphoric effects. It is primarily obtained from t ...

apraclonidine Apraclonidine ( INN), also known under the brand name Iopidine, is a sympathomimetic used in glaucoma therapy. It is an α2 adrenergic receptor agonist and a weak α1 adrenergic receptor agonist. Topical apraclonidine is administered at a conc ...

), 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.

Pharmacology

Like amphetamine, 4-hydroxyamphetamine is an agonist of human

TAAR1 Trace amine-associated receptor 1 (TAAR1) is a trace amine-associated receptor (TAAR) protein that in humans is encoded by the ''TAAR1'' gene. TAAR1 is an intracellular amine-activated and G protein-coupled receptor (GPCR) that is primarily exp ...

. 4-Hydroxyamphetamine acts as an indirect sympathomimetic and causes the release of

norepinephrine Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as both a hormone and neurotransmitter. The name "noradrenaline" (from Latin '' ad'', ...

from nerve synapses which leads to

(pupil dilation). It decreases metabolism of

serotonin Serotonin () or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter. Its biological function is complex and multifaceted, modulating mood, cognition, reward, learning, memory, and numerous physiological processes such as vomiting and vas ...

(5-hydroxytryptamine) and certain other monoamines by inhibiting the activity of a family of enzymes called

monoamine oxidase Monoamine oxidases (MAO) () are a family of enzymes that catalyze the oxidation of monoamines, employing oxygen to clip off their amine group. They are found bound to the outer membrane of mitochondria in most cell types of the body. The first ...

s (MAOs), particularly type A (

MAO-A Monoamine oxidase A, also known as MAO-A, is an enzyme that in humans is encoded by the ''MAOA'' gene. This gene is one of two neighboring gene family members that encode mitochondrial enzymes which catalyze the oxidative deamination of amines, s ...

). The inhibition of MAO-A prevents metabolism of serotonin and

catecholamines A catecholamine (; abbreviated CA) is a monoamine neurotransmitter, an organic compound that has a catechol (benzene with two hydroxyl side groups next to each other) and a side-chain amine. Catechol can be either a free molecule or a substi ...

in the

presynaptic terminal Chemical synapses are biological junctions through which neurons' signals can be sent to each other and to non-neuronal cells such as those in muscles or glands. Chemical synapses allow neurons to form circuits within the central nervous syste ...

, and thus increases the amount of neurotransmitters available for release into the

synaptic cleft Chemical synapses are biological junctions through which neurons' signals can be sent to each other and to non-neuronal cells such as those in muscles or glands. Chemical synapses allow neurons to form circuits within the central nervous syste ...

. 4-Hydroxyamphetamine is a major

and a minor metabolite of

methamphetamine Methamphetamine (contracted from ) 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. Methamph ...

. In humans, amphetamine is metabolized to 4-hydroxyamphetamine by

CYP2D6 Cytochrome P450 2D6 (CYP2D6) is an enzyme that in humans is encoded by the ''CYP2D6'' gene. ''CYP2D6'' is primarily expressed in the liver. It is also highly expressed in areas of the central nervous system, including the substantia nigra. CYP2D ...

, which is a member of the

cytochrome P450 Cytochromes P450 (CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are ...

superfamily and is found in the liver. 4-Hydroxyamphetamine is then metabolized by

dopamine beta-hydroxylase Dopamine beta-hydroxylase (DBH), also known as dopamine beta-monooxygenase, is an enzyme () that in humans is encoded by the DBH gene. Dopamine beta-hydroxylase catalyzes the conversion of dopamine to norepinephrine. The three substrates of ...

into 4-hydroxynorephedrine or eliminated in the urine.

Commercialization

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 while Paremyd consists of a combination of 1% hydroxyamphetamine hydrobromide and 0.25%

tropicamide Tropicamide, sold under the brand name Mydriacyl among others, is a medication used to dilate the pupil and help with examination of the eye. Specifically it is used to help examine the back of the eye. It is applied as eye drops. Effects occ ...

. 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.Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations
/ref>Rebecca Lurcott for Ophthalmology Management. December 1, 200
Unique Mydriatic Returns: The combination formula fosters patient flow efficiencies
/ref>

Notes

Reference notes

References

External links

* {{DEFAULTSORT:Hydroxyamphetamine, 4- Phenols Sympathomimetics Amphetamine Substituted amphetamines TAAR1 agonists Norepinephrine-dopamine releasing agents