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Homeostasis of Dopamine
Published in Nira Ben-Jonathan, Dopamine, 2020
Tetrabenazine has been approved for use in the United States for the treatment of choreiform movements in Huntington disease. Tetrabenazine is structurally related to several antipsychotics and has similar side effects, including akathisia, Parkinsonism, dizziness, and depression. Tetrabenazine interacts with VMAT at a different site than does reserpine and differentially inhibits VMAT1 and VMAT2. Despite differences in their binding sites, tetrabenazine inhibits reserpine binding, presumably via allosteric interactions. Two DAT inhibitors, GBR 12909 and 12935, also inhibit VMAT2 at low nanomolar concentrations [38]. Additional VMAT inhibitors include ketanserin, amiodarone, and some derivatives of 3-amino-2-phenylpropene (APP).
Drugs Affecting Storage and Release from Sympathetic Neurones
Published in Kenneth J. Broadley, Autonomic Pharmacology, 2017
Tetrabenazine, in contrast, causes short-lasting depletion of noradrenaline and dopamine selectively from central sites (Table 6.2). It interacts with the same binding sites on catecholamine storage vesicles as does reserpine, which it may displace in competition binding experiments. Reserpine does not cause further depletion of brain catecholamines when administered after tetrabenazine, indicating the same sites of action. Tetrabenazine produces similar effects of sedation and depression, and extrapyramidal signs of Parkinson’s-like hypokinesia. It may therefore be used in the treatment of Huntington’s chorea, a genetic disorder of hyperkinesia or jerking movement associated with elevated dopamine levels of the corpus striatum.
Neurotransmitters and pharmacology
Published in Mark J. Ashley, David A. Hovda, Traumatic Brain Injury, 2017
Ronald A. Browning, Richard W. Clough
Reserpine is the classical drug for inhibiting the storage of catecholamines (NE, Epi, and DA) and serotonin (see the following text). Reserpine binds irreversibly to the vesicle membrane and interferes with the VMAT-mediated uptake of monoamines into the vesicle,1 rendering the vesicle nonfunctional. When NE cannot be stored in the vesicle, it is not protected and is degraded by MAO. Thus, reserpine leads to a depletion of the NE from the nerve terminals. It is primarily used in combination with other drugs as an antihypertensive agent.72Tetrabenazine (Xenazine®) is similar to reserpine but binds reversibly to VMAT and therefore has a shorter duration of action. Tetrabenazine is approved for the use in Huntington disease to deplete striatal DA and reduce hyperkinesia.73
State-of-the-art pharmacological approaches to reduce chorea in Huntington’s disease
Published in Expert Opinion on Pharmacotherapy, 2021
Jessie S. Gibson, Daniel O. Claassen
VMAT-2 inhibitors deplete vesicular monoamines (e.g., dopamine), preventing their release from presynaptic vesicles [88]. This is thought to prevent dopamine from reaching upregulated D2 receptors, thereby reducing chorea. Tetrabenazine was the first VMAT-2 inhibitor to be approved, and it has been indicated for the treatment of HD chorea in the US since 2008 [88]. It is worth noting that reserpine was another early VMAT inhibitor which bound irreversibly to VMAT-1 and VMAT-2 receptors, causing long-lasting off-target effects such as hypotension and depression, and limiting its further use [18,89]. For years, tetrabenazine was the only medication approved by the FDA to treat HD chorea, and this is reflected in its continued frequent use by HD physicians [39]. Tetrabenazine is shown to be effective for reducing chorea severity in HD, though it is also associated with significant adverse effects including somnolence, akathisia, depression, and elevated risk for suicidality [18]. Tetrabenazine carries a black box warning for increased risk of suicidality in patients with HD, possibly due to off-target depletion of 5-HT and NE, and it is contraindicated in patients with uncontrolled depression [88]. However, some have argued that this in an over-cautious statement based on a small effect in a single trial, as follow-up analyses with larger samples have not found evidence of this risk [90,91]. Major metabolites of tetrabenazine have half-lives between 7 and 12 h, and it is recommended to be taken in divided doses up to three times per day [92].
Deutetrabenazine for treatment of involuntary movements in patients with tardive dyskinesia
Published in Expert Review of Neurotherapeutics, 2021
Benjamin J. Dorfman, Joohi Jimenez-Shahed
Deutetrabenazine carries a black box warning with regards to risk of depression and suicidality in patients with HD [48] based on a completed suicide that occurred in the pivotal TETRA-HD trial [30]. No such event occurred in clinical trials of deutetrabenazine for TD or other indications, and the warning is not directed toward patients treated for TD. Use of deutetrabenazine along with DRBAs may increase patients’ risk of parkinsonism and neuroleptic malignant syndrome, while taking it along with MAO inhibitors may lead to hypertensive emergency due to decreased degradation of catecholamine precursors. Taking deutetrabenazine can cause excess sedation if taken with alcohol or sedatives. Although it has not been studied in hepatic or renal disease, based on results of studies with tetrabenazine, hepatic dysfunction is considered a contraindication for the use of deutetrabenazine due to decreased activity of carbonyl reductase resulting in markedly increased drug exposure.
Pharmacogenomics of drugs used to treat brain disorders
Published in Expert Review of Precision Medicine and Drug Development, 2020
Huntington’s disease (HD) is an autosomal dominant progressive NDD linked to a heterozygous expanded trinucleotide repeat (CAG)n (normal range: 9–36; HD>39), encoding glutamine, in the huntingtin (HTT) gene on chromosome 4p16. HD phenotype is characterized by selective neuronal loss and atrophy in the caudate and putamen, together with progressive chorea, rigidity, and dementia. Symptomatic treatments to ameliorate Huntington’s chorea include tetrabenazine, neuroleptics and major tranquilizers. Tetrabenazine interferes with and depletes monoamine neurotransmitters (including dopamine, serotonin, and norepinephrine) in presynaptic vesicles of the basal ganglia (probably through actions on vesicle monoamine transporter). Tetrabenazine inhibits presynaptic dopamine release and also blocks CNS dopamine receptors, resembling reserpine effects but with less peripheral activity and shorter duration of action. Tetrabenazine improves hyperkinetic movement disorders, including Huntington’s chorea, hemiballismus, senile chorea, tics, Gilles de la Tourette’s syndrome, and tardive dyskinesia. Tetrabenazine is a major substrate of CYP2D6 and is transported by ABCB1, SLC18A1, SLC18A2, SLC6A3 and SLC6A4. Caution and personalized dose adjustment are required in patients with the following genotypes: CYP2D6*2, CYP2D6*3, CYP2D6*4, CYP2D6*5, CYP2D6*6, CYP2D6*7, CYP2D6*8, CYP2D6*10, CYP2D6*17, CYP2D6*1xN [8, 9, 156].