Viloxazine is a bicyclic

Heterocyclic compound

A heterocyclic compound is a cyclic compound which has atoms of at least two different elements as members of its ring. The counterparts of heterocyclic compounds are homocyclic compounds, the rings of which are made of a single element....

 antidepressant

Antidepressant

An antidepressant is a psychiatric medication used to alleviate mood disorders, such as major depression and dysthymia and anxiety disorders such as social anxiety disorder. According to Gelder, Mayou &*Geddes people with a depressive illness will experience a therapeutic effect to their mood;...

morpholine

Morpholine

Morpholine is an organic chemical compound having the chemical formula O2NH. This heterocycle, pictured at right, features both amine and ether functional groups. Because of the amine, morpholine is a base; its conjugate acid is called morpholinium...

 derivative that acts as a selective norepinephrine reuptake inhibitor

Norepinephrine reuptake inhibitor

A norepinephrine reuptake inhibitor or adrenergic reuptake inhibitor , is a type of drug which acts as a reuptake inhibitor for the neurotransmitters norepinephrine and epinephrine by blocking the action of the norepinephrine transporter...

 (NRI). It is a racemic

Racemic

In chemistry, a racemic mixture, or racemate , is one that has equal amounts of left- and right-handed enantiomers of a chiral molecule. The first known racemic mixture was "racemic acid", which Louis Pasteur found to be a mixture of the two enantiomeric isomers of tartaric acid.- Nomenclature :A...

 compound

Chemical compound

A chemical compound is a pure chemical substance consisting of two or more different chemical elements that can be separated into simpler substances by chemical reactions. Chemical compounds have a unique and defined chemical structure; they consist of a fixed ratio of atoms that are held together...

 with two stereoisomers, the (S)-(–)-isomer being five times as pharmacologically active as the (R)-(+)-isomer.

Approved

Viloxazine hydrochloride was approved in Italy, Belgium, the United States, England, Ireland, Germany, Portugal, Spain, the former Yugoslavia

Yugoslavia

Yugoslavia refers to three political entities that existed successively on the western part of the Balkans during most of the 20th century....

, France, Slovakia, for the treatment of clinical depression

Clinical depression

Major depressive disorder is a mental disorder characterized by an all-encompassing low mood accompanied by low self-esteem, and by loss of interest or pleasure in normally enjoyable activities...

.

Unapproved/off-Label/investigational

Viloxazine has undergone two randomized controlled trials for nocturnal enuresis (bedwetting) in children, both of those times versus imipramine.^, By 1990, it was seen as a less cardiotoxic alternative to imipramine, and to be especially effective in heavy sleepers.

In narcolepsy

Narcolepsy

Narcolepsy is a chronic sleep disorder, or dyssomnia, characterized by excessive sleepiness and sleep attacks at inappropriate times, such as while at work. People with narcolepsy often experience disturbed nocturnal sleep and an abnormal daytime sleep pattern, which often is confused with insomnia...

, viloxazine has been shown to suppress auxiliary symptoms such as cataplexy

Cataplexy

Cataplexy is a sudden and transient episode of loss of muscle tone, often triggered by emotions. It is a rare disease , but affects roughly 70% of people who have narcolepsy...

 and also abnormal sleep-onset REM without really improving daytime somnolence

Somnolence

Somnolence is a state of near-sleep, a strong desire for sleep, or sleeping for unusually long periods . It has two distinct meanings, referring both to the usual state preceding falling asleep, and the chronic condition referring to being in that state independent of a circadian rhythm...

.

In a cross-over trial (56 participants) viloxazine significantly reduced EDS and cataplexy. {ref Vignatelli L, D'Alessandro R, Candelise L. Antidepressant drugs for narcolepsy. Cochrane Database of Systematic Reviews 2007, Issue 4. Art. No.: CD003724. DOI: 10.1002/14651858.CD003724.pub3}

Viloxazine has also been studied for the treatment of alcoholism

Alcoholism

Alcoholism is a broad term for problems with alcohol, and is generally used to mean compulsive and uncontrolled consumption of alcoholic beverages, usually to the detriment of the drinker's health, personal relationships, and social standing...

, with some success.

While viloxazine may be effective in clinical depression, it did relatively poorly in a double-blind randomized controlled trial versus amisulpride

Amisulpride

Amisulpride , is an atypical antipsychotic used to treat psychosis in schizophrenia and episodes of mania in bipolar disorder. In small doses it is also used to treat depression. It was introduced by Sanofi-Aventis in the 1990s.-Pharmacology:Amisulpride functions primarily as a D2 and D3 receptor...

 in the treatment of dysthymia, according to Leon and colleagues at the University of Valle in Colombia.

Mechanism of action

In 1976, Lippman and Pugsley reported that viloxazine, like imipramine

Imipramine

Imipramine , also known as melipramine, is an antidepressant medication, a tricyclic antidepressant of the dibenzazepine group...

, inhibited norepinephrine reuptake in the hearts of rats and mice; unlike imipramine, (or desipramine

Desipramine

Desipramine is a tricyclic antidepressant . It inhibits the reuptake of norepinephrine and to a lesser extent serotonin. It is used to treat depression, but not considered a first line treatment since the introduction of SSRI antidepressants...

 or amitriptyline

Amitriptyline

Amitriptyline is a tricyclic antidepressant . It is the most widely used TCA and has at least equal efficacy against depression as the newer class of SSRIs...

, for that matter) it did not block reuptake of norepinephrine in either the medulla

Medulla oblongata

The medulla oblongata is the lower half of the brainstem. In discussions of neurology and similar contexts where no ambiguity will result, it is often referred to as simply the medulla...

e or the hypothalami

Hypothalamus

The Hypothalamus is a portion of the brain that contains a number of small nuclei with a variety of functions...

 of rats. As for serotonin

Serotonin

Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...

, while its reuptake inhibition was comparable to that of desipramine (i.e., very weak), viloxazine did potentiate serotonin-mediated brain functions in a manner similar to amitriptyline and imipramine, which are relatively potent inhibitors of serotonin reuptake. Unlike any of the other drugs tested, it did not exhibit any anticholinergic effects.

It is also known to up-regulate GABA_B receptor

GABA B receptor

GABAB receptors are metabotropic transmembrane receptors for gamma-aminobutyric acid that are linked via G-proteins to potassium channels...

s in the frontal cortex

Frontal lobe

The frontal lobe is an area in the brain of humans and other mammals, located at the front of each cerebral hemisphere and positioned anterior to the parietal lobe and superior and anterior to the temporal lobes...

.

Side effects

Side effects include nausea

Nausea

Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...

, vomiting, insomnia

Insomnia

Insomnia is most often defined by an individual's report of sleeping difficulties. While the term is sometimes used in sleep literature to describe a disorder demonstrated by polysomnographic evidence of disturbed sleep, insomnia is often defined as a positive response to either of two questions:...

, loss of appetite, increased erythrocyte sedimentation, EKG

Electrocardiogram

Electrocardiography is a transthoracic interpretation of the electrical activity of the heart over a period of time, as detected by electrodes attached to the outer surface of the skin and recorded by a device external to the body...

 and EEG anomalies, epigastric pain, diarrhea, constipation

Constipation

Constipation refers to bowel movements that are infrequent or hard to pass. Constipation is a common cause of painful defecation...

, vertigo

Vertigo (medical)

Vertigo is a type of dizziness, where there is a feeling of motion when one is stationary. The symptoms are due to a dysfunction of the vestibular system in the inner ear...

, orthostatic hypotension

Hypotension

In physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the...

, edema

Edema

Edema or oedema ; both words from the Greek , oídēma "swelling"), formerly known as dropsy or hydropsy, is an abnormal accumulation of fluid beneath the skin or in one or more cavities of the body that produces swelling...

 of the lower extremities, dysarthria

Dysarthria

Dysarthria is a motor speech disorder resulting from neurological injury of the motor component of the motor-speech system and is characterized by poor articulation of phonemes...

, tremor

Tremor

A tremor is an involuntary, somewhat rhythmic, muscle contraction and relaxation involving to-and-fro movements of one or more body parts. It is the most common of all involuntary movements and can affect the hands, arms, eyes, face, head, vocal folds, trunk, and legs. Most tremors occur in the...

, psychomotor agitation, mental confusion, inappropriate secretion of antidiuretic hormone, increased transaminase

Transaminase

In biochemistry, a transaminase or an aminotransferase is an enzyme that catalyzes a type of reaction between an amino acid and an α-keto acid. To be specific, this reaction involves removing the amino group from the amino acid, leaving behind an α-keto acid, and transferring it to the...

s, seizure

Seizure

An epileptic seizure, occasionally referred to as a fit, is defined as a transient symptom of "abnormal excessive or synchronous neuronal activity in the brain". The outward effect can be as dramatic as a wild thrashing movement or as mild as a brief loss of awareness...

, (there were three cases worldwide, and most animal studies (and clinical trials that included epilepsy

Epilepsy

Epilepsy is a common chronic neurological disorder characterized by seizures. These seizures are transient signs and/or symptoms of abnormal, excessive or hypersynchronous neuronal activity in the brain.About 50 million people worldwide have epilepsy, and nearly two out of every three new cases...

 patients) indicated the presence of anticonvulsant properties, so is not completely contraindicated in epilepsy,) and increased libido.

Drug interactions

Viloxazine is known to increase plasma

Blood plasma

Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...

 levels of phenytoin

Phenytoin

Phenytoin sodium is a commonly used antiepileptic. Phenytoin acts to suppress the abnormal brain activity seen in seizure by reducing electrical conductance among brain cells by stabilizing the inactive state of voltage-gated sodium channels...

 by an average of 37%. It is also known to significantly increase plasma levels of theophylline

Theophylline

Theophylline, also known as dimethylxanthine, is a methylxanthine drug used in therapy for respiratory diseases such as COPD and asthma under a variety of brand names. Because of its numerous side-effects, the drug is now rarely administered for clinical use. As a member of the xanthine family, it...

and decrease its clearance from the body, sometimes resulting in accidental overdose of theophylline.