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Trade names | Xenazine, Xentra, Nitoman, others |
Other names | Ro-1-9569 |
AHFS/Drugs.com | Consumer Drug Information |
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Routes of administration | By mouth |
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Pharmacokinetic data | |
Bioavailability | Low, extensive first pass effect |
Protein binding | 82–85% |
Metabolism | Liver (CYP2D6-mediated) |
Elimination half-life | 10 hours parent compound (2 to 8 hours active metabolites) [3] |
Excretion | Kidney (~75%) and fecal (7–16%) [4] |
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ECHA InfoCard | 100.000.348 |
Chemical and physical data | |
Formula | C19H27NO3 |
Molar mass | 317.429 g·mol−1 |
3D model (JSmol) | |
Chirality | Racemic mixture |
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Tetrabenazine is a drug for the symptomatic treatment of hyperkinetic movement disorders. It is sold under the brand names Nitoman and Xenazine among others. On August 15, 2008, the U.S. Food and Drug Administration approved the use of tetrabenazine to treat chorea associated with Huntington's disease. Although other drugs had been used "off label," tetrabenazine was the first approved treatment for Huntington's disease in the U.S. [5] The compound has been known since the 1950s.
Tetrabenazine is used as a treatment, but not as a cure, for hyperkinetic disorders such as: [6] [7]
Tetrabenazine has been used as an antipsychotic in the treatment of schizophrenia, both in the past [9] [10] [11] [12] [13] [14] [15] [16] and in modern times. [17] [18] [19]
The most common adverse reactions, which have occurred in at least 10% of subjects in studies and at least 5% greater than in subjects who received placebo, have been: sedation or somnolence, fatigue, insomnia, depression, suicidal thoughts, akathisia, anxiety, and nausea. [4] It has also been reported to produce apathy. [20]
There is a boxed warning associated with the use of tetrabenazine: [4]
The precise mechanism of action of tetrabenazine is unknown. Its anti-chorea effect is believed to be due to a reversible depletion of monoamines such as dopamine, serotonin, norepinephrine, and histamine from nerve terminals. Tetrabenazine reversibly inhibits vesicular monoamine transporter 2, resulting in decreased uptake of monoamines into synaptic vesicles, as well as depletion of monoamine storage. [4]
Tetrabenazine is used in the only animal model of motivational dysfunction. [21] [22] The drug results in selective depletion of dopamine at low doses of 0.25 to 1.0 mg/kg and induces a low-effort bias in effort-based decision-making tasks at these doses. [20] [21] [22] It has been found to reduce striatal or nucleus accumbens dopamine levels by 57 to 75% at a dose of 0.75–1.0 mg/kg in rats. [20] In contrast, levels of serotonin and norepinephrine are only reduced by up to 15 to 30% at this dosage. [20] A 10-fold higher dosage of 10 mg/kg is needed to decrease serotonin levels as much as the reduction in dopamine levels at 1 mg/kg. [20] The low-effort bias of systemic administration of tetrabenazine also occurs when it is injected directly into the nucleus accumbens but not the overlying medial neostriatum (i.e., dorsal striatum). [20] Dopamine D1 receptor antagonists like ecopipam and dopamine D2 receptor antagonists like haloperidol have similar amotivational effects as tetrabenazine in animals. [20] [22]
A number of drugs have been found to reverse the amotivational effects of tetrabenazine. [20] [21] [22] These include the dopamine releasing agent lisdexamfetamine, the dopamine reuptake inhibitors methylphenidate, bupropion, modafinil, vanoxerine, PRX-14040, and MRZ-9547, and the MAO-B inhibitor and catecholaminergic activity enhancer selegiline. [20] [21] [22] [23] [24] Selegiline shows a complicated U-shaped dose–response curve in its efficacy in the model. [21] [24] In contrast to the preceding agents, many antidepressants, including selective serotonin reuptake inhibitors (SSRIs) like fluoxetine and citalopram, the norepinephrine reuptake inhibitors (NRIs) desipramine and atomoxetine, the selective MAO-A inhibitor moclobemide, and the non-selective monoamine oxidase inhibitor pargyline, are ineffective in reversing tetrabenazine-induced amotivational symptoms. [20] [21] [22] [23] [24] SSRIs and NRIs actually induced further motivational impairments at high doses. [21] [23]
Monoamine oxidase inhibitors (MAOIs) are a class of drugs that inhibit the activity of one or both monoamine oxidase enzymes: monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B). They are best known as effective antidepressants, especially for treatment-resistant depression and atypical depression. They are also used to treat panic disorder, social anxiety disorder, Parkinson's disease, and several other disorders.
Monoamine neurotransmitters are neurotransmitters and neuromodulators that contain one amino group connected to an aromatic ring by a two-carbon chain (such as -CH2-CH2-). Examples are dopamine, norepinephrine and serotonin.
Tranylcypromine, sold under the brand name Parnate among others, is a monoamine oxidase inhibitor (MAOI). More specifically, tranylcypromine acts as nonselective and irreversible inhibitor of the enzyme monoamine oxidase (MAO). It is used as an antidepressant and anxiolytic agent in the clinical treatment of mood and anxiety disorders, respectively. It is also effective in the treatment of ADHD.
Monoamine transporters (MATs) are proteins that function as integral plasma-membrane transporters to regulate concentrations of extracellular monoamine neurotransmitters. The three major classes are serotonin transporters (SERTs), dopamine transporters (DATs), and norepinephrine transporters (NETs) and are responsible for the reuptake of their associated amine neurotransmitters. MATs are located just outside the synaptic cleft (peri-synaptically), transporting monoamine transmitter overflow from the synaptic cleft back to the cytoplasm of the pre-synaptic neuron. MAT regulation generally occurs through protein phosphorylation and post-translational modification. Due to their significance in neuronal signaling, MATs are commonly associated with drugs used to treat mental disorders as well as recreational drugs. Compounds targeting MATs range from medications such as the wide variety of tricyclic antidepressants, selective serotonin reuptake inhibitors such as fluoxetine (Prozac) to stimulant medications such as methylphenidate (Ritalin) and amphetamine in its many forms and derivatives methamphetamine (Desoxyn) and lisdexamfetamine (Vyvanse). Furthermore, drugs such as MDMA and natural alkaloids such as cocaine exert their effects in part by their interaction with MATs, by blocking the transporters from mopping up dopamine, serotonin, and other neurotransmitters from the synapse.
Serotonin–norepinephrine reuptake inhibitors (SNRIs) are a class of antidepressant medications used to treat major depressive disorder (MDD), anxiety disorders, social phobia, chronic neuropathic pain, fibromyalgia syndrome (FMS), and menopausal symptoms. Off-label uses include treatments for attention-deficit hyperactivity disorder (ADHD), obsessive–compulsive disorder (OCD), and migraine prevention. SNRIs are monoamine reuptake inhibitors; specifically, they inhibit the reuptake of serotonin and norepinephrine. These neurotransmitters are thought to play an important role in mood regulation. SNRIs can be contrasted with the selective serotonin reuptake inhibitors (SSRIs) and norepinephrine reuptake inhibitors (NRIs), which act upon single neurotransmitters.
Selegiline, also known as L-deprenyl and sold under the brand names Eldepryl, Zelapar, and Emsam among others, is a medication which is used in the treatment of Parkinson's disease and major depressive disorder. It has also been studied for a variety of other indications, but has not been formally approved for any other use. The medication in the form licensed for depression has modest effectiveness for this condition that is similar to that of other antidepressants. Selegiline is provided as a swallowed tablet or capsule or an orally disintegrating tablet (ODT) for Parkinson's disease and as a patch applied to skin for depression.
Reserpine is a drug that is used for the treatment of high blood pressure, usually in combination with a thiazide diuretic or vasodilator. Large clinical trials have shown that combined treatment with reserpine plus a thiazide diuretic reduces mortality of people with hypertension. Although the use of reserpine as a solo drug has declined since it was first approved by the FDA in 1955, the combined use of reserpine and a thiazide diuretic or vasodilator is still recommended in patients who do not achieve adequate lowering of blood pressure with first-line drug treatment alone. The reserpine-hydrochlorothiazide combo pill was the 17th most commonly prescribed of the 43 combination antihypertensive pills available in 2012.
Isocarboxazid is a non-selective, irreversible monoamine oxidase inhibitor (MAOI) of the hydrazine class used as an antidepressant. Along with phenelzine and tranylcypromine, it is one of only three classical MAOIs still available for clinical use in the treatment of psychiatric disorders in the United States, though it is not as commonly employed in comparison to the others.
Dopaminergic means "related to dopamine" (literally, "working on dopamine"), dopamine being a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain. Dopaminergic brain pathways facilitate dopamine-related activity. For example, certain proteins such as the dopamine transporter (DAT), vesicular monoamine transporter 2 (VMAT2), and dopamine receptors can be classified as dopaminergic, and neurons that synthesize or contain dopamine and synapses with dopamine receptors in them may also be labeled as dopaminergic. Enzymes that regulate the biosynthesis or metabolism of dopamine such as aromatic L-amino acid decarboxylase or DOPA decarboxylase, monoamine oxidase (MAO), and catechol O-methyl transferase (COMT) may be referred to as dopaminergic as well. Also, any endogenous or exogenous chemical substance that acts to affect dopamine receptors or dopamine release through indirect actions (for example, on neurons that synapse onto neurons that release dopamine or express dopamine receptors) can also be said to have dopaminergic effects, two prominent examples being opioids, which enhance dopamine release indirectly in the reward pathways, and some substituted amphetamines, which enhance dopamine release directly by binding to and inhibiting VMAT2.
The norepinephrine transporter (NET), also known as noradrenaline transporter (NAT), is a protein that in humans is encoded by the solute carrier family 6 member 2 (SLC6A2) gene.
Milnacipran is a serotonin–norepinephrine reuptake inhibitor (SNRI) used in the clinical treatment of fibromyalgia. It is not approved for the clinical treatment of major depressive disorder in the US, but it is in other countries.
Moclobemide, sold under the brand names Amira, Aurorix, Clobemix, Depnil and Manerix among others, is a reversible inhibitor of monoamine oxidase A (RIMA) drug primarily used to treat depression and social anxiety. It is not approved for use in the United States, but is approved in other Western countries such as Canada, the UK and Australia. It is produced by affiliates of the Hoffmann–La Roche pharmaceutical company. Initially, Aurorix was also marketed by Roche in South Africa, but was withdrawn after its patent rights expired and Cipla Medpro's Depnil and Pharma Dynamic's Clorix became available at half the cost.
Rasagiline, sold under the brand name Azilect among others, is a medication which is used in the treatment of Parkinson's disease. It is used as a monotherapy to treat symptoms in early Parkinson's disease or as an adjunct therapy in more advanced cases. The drug is taken by mouth.
Benzofuranylpropylaminopentane (BPAP) is an experimental drug related to selegiline which acts as a monoaminergic activity enhancer (MAE). It is orally active.
Levoamphetamine is a stimulant medication which is used in the treatment of certain medical conditions. It was previously marketed by itself under the brand name Cydril, but is now available only in combination with dextroamphetamine in varying ratios under brand names like Adderall and Evekeo. The drug is known to increase wakefulness and concentration in association with decreased appetite and fatigue. Pharmaceuticals that contain levoamphetamine are currently indicated and prescribed for the treatment of attention deficit hyperactivity disorder (ADHD), obesity, and narcolepsy in some countries. Levoamphetamine is taken by mouth.
A norepinephrine–dopamine reuptake inhibitor (NDRI) is a drug used for the treatment of clinical depression, attention deficit hyperactivity disorder (ADHD), narcolepsy, and the management of Parkinson's disease. The drug acts as a reuptake inhibitor for the neurotransmitters norepinephrine and dopamine by blocking the action of the norepinephrine transporter (NET) and the dopamine transporter (DAT), respectively. This in turn leads to increased extracellular concentrations of both norepinephrine and dopamine and, therefore, an increase in adrenergic and dopaminergic neurotransmission.
Monoaminergic activity enhancers (MAE), also known as catecholaminergic/serotonergic activity enhancers (CAE/SAE), are a class of compounds that enhance the action potential-evoked release of monoamine neurotransmitters in the nervous system. MAEs are distinct from monoamine releasing agents (MRAs) like amphetamine and fenfluramine in that they do not induce the release of monoamines from synaptic vesicles but rather potentiate only nerve impulse propagation-mediated monoamine release. That is, MAEs increase the amounts of monoamine neurotransmitters released by neurons per electrical impulse.
MRZ-9547, also known as (R)-phenylpiracetam, (R)-phenotropil, or (R)-fonturacetam, is a selective dopamine reuptake inhibitor (IC50Tooltip half-maximal inhibitory concentration = 14.5 μM) that was developed by Merz Pharma. It is the (R)-enantiomer of the racetam and nootropic phenylpiracetam (phenotropil; fonturacetam).