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Questions And Answer

• Overview

  Tetrabenazine(TBZ) is a drug formerly used as an antipsychotic but now used primarily in the symptomatic treatment of various hyperkinetic disorders. It is a monoamine depletor and used as symptomatic treatment of chorea associated with Huntington's disease. FDA approved on August 15, 2008. Tetrabenazine, a dopamine-depleting agent first synthesized half a century ago, was initially developed for the treatment of schizophrenia. Although psychotic disorders have since been treated more successfully with other neuroleptic medications, many studies have shown this drug to be effective in the treatment of hyperkinetic movement disorders (hyperkinesias). Hyperkinesias are neurologic disorders characterized by abnormal involuntary movements such as chorea associated with Huntington's disease, tics in Tourette's syndrome and stereotypies in tardive dyskinesia.
  In the United States, only tetrabenazine(TBZ) is indicated by the US Food and Drug Administration(FDA) for chorea of HD, haloperidol and pimozide for TS, and botulinum toxin injectable for idiopathic focal dystonias^[1-4]. TBZ is a benzoquinolizine pharmacophore that selectively depletes monoamines and improves hyperkinetic movement symptoms^[5]. Although initially tested as a potential antiparasitic agent as well as a potential antihypertensive, TBZ was first marketed in Switzerland in 1959 as a tranquilizer. Clinicians soon observed that TBZ improved hyperkinetic movements and, in 1971, the United Kingdom and Ireland were the first countries to market TBZ for hyperkinetic movement disorders. Subsequently, TBZ become available in several countries for official use in various hyperkinetic movement disorders. In 2008, the United States approved TBZ for the management of chorea associated with HD. A literature search revealed that recent TBZ review articles primarily highlight its role in the management of HD chorea^[6-10] and one review focused on the off-label use of TBZ for TDk^[11]. Two recent reviews of TBZ summarized efficacy and tolerability for a broader range of hyperkinetic movement disorders^{[5, 12]}.
  TBZ, also named Ro 1-9569 by Hoffmann-LaRoche, Inc., is a benzoquinolizine derivative with the chemical name, 2-oxo-3isobutyl-9, 10-dimethoxy-1, 2, 3, 4, 6, 7-hexahydrobenzo(a) quinolizine FIGURE 1. In contrast to an analogous drug, reserpine, TBZ lacks an indole group^[13]. Based on the acid–basic transition, TBZ is characterized by a negative logarithm of the acid ionization constant (pKa) of 6.0^[14]. Chromatographic analysis of TBZ reveals peak fluorescence at 282 nm^[15].
  
  Figure 1 the chemical structure of tetrabenazine;

• Indications

  Tetrabenazine is used for the treatment of hyperkinetic movement disorders like chorea in Huntington's disease, hemiballismus, senile chorea, Tourette syndrome and other tic disorders, and tardive dyskinesia (TD). ;

• Pharmacokinetics

  A thorough review of the medical literature reveals a paucity of information regarding the pharmacodynamics of TBZ. After intravenous administration of radiolabeled 3H-TBZ, 54% was excreted in urine after 48h^[16]. A 1987 study found no evidence of unchanged TBZ in the urine of four patients indicating extensive metabolism^[17]. TBZ is excreted in human breast milk, thus breastfeeding while taking TBZ should be avoided. Although no case of teratogenicity has been reported, TBZ does cross the placenta^[18].
  After oral administration, TBZ is rapidly absorbed within 1 hour; however, the systemic bioavailability of the parent drug is low(5%) due to a high first-pass metabolism^[19]. TBZ undergoes first-pass metabolism, by hepatic carbonyl reductase, to at least two isomers of dihydrotetrabenazine (DHTBZ): alpha-DHTBZ and beta-DHTBZ^[20]. Both metabolites are pharmacologically active, with alpha-DHTBZ demonstrating activity similar to the parent drug^[6]. Both metabolites reach Cmax within 1 to 2 hours and are primarily metabolized by cytochrome P450(CYP) 2D6(CYP2D6). The t1⁄2 of alphaand beta-DHTBZ ranges from 2 to 8 hours and 2 to 5 hours, respectively^{[6, 7]}.
  In humans, the steady-state AUC values of the DHTBZ metabolites are 82.6 to 199 fold higher than that of TBZ^[21]. In rats; the mean (SD) Vd of DHTBZ is 7.8 (4.08) L/kg. Protein binding of TBZ, alpha-DHTZ, and beta-DHTBZ ranges from 82% to 85%, 60% to 68%, and 59% to 63%, respectively^[6].
  Neither TBZ nor its metabolites induce or inhibit major CYP450 isozymes. Therefore, TBZ will not interfere with metabolism of other drugs that are CYP450 substrates. However, because some of the DHTBZ metabolites are substrates for CYP2D6, other drugs that induce or inhibit this isozyme may alter DHTBZ concentrations^{[6, 7]}. ;

• Mode of action

  In the CNS, neurons communicate with one another through the release of neurotransmitters. Neurotransmitters are synthesized in the neuronal cytoplasm and then packaged into vesicles; otherwise, they undergo rapid degradation by ubiquitous monoamine oxidases. TBZ acts as a reversible inhibitor of monoamine uptake into granular vesicles of presynaptic neurons^[22,23] through its ability to bind to vesicular monoamine transporter (VMAT)-2^[24] thereby potentiating monoamine degradation in the cytoplasm. Monoamine neurotransmitters that are depleted via VMAT2 inhibition by TBZ include serotonin, dopamine, and norepinephine^{[23, 25]}. In one in vivo study of rats, TBZ decreased dopamine levels by 40%, serotonin by 44% and norepinephrine by 41% in the brain^[26]. Levels of acetylcholine, aspartate and glutamate were decreased to a lesser degree. In an autopsy study of 18 patients with Huntington’s disease(HD), those who had received TBZ displayed an overall depletion of monoamines in the caudate, amygdala, hip-pocampus and temporal lobe when compared with patients not exposed to TBZ^[27,28]. The most pronounced depletion involved dopamine in the caudate nucleus.
  VMAT2, a large protein with 12 transmembrane helices encoded by the VMAT2 gene and localized to chromosome 10q25, is expressed mostly in the brain. In contrast, VMAT1, encoded by a gene on chromosome 8p21.3, is expressed in the periphery^[29]. TBZ binds with high affinity to VMAT2, but not to VMAT1^[30].
  Although in vitro studies have shown that TBZ blocks dopamine D2 receptors, as suggested by its ability to inhibit(3H) spiperone binding to striatal membranes with a Ki of approximately 2.1 × 10-6M, this affinity is 1000-fold lower than its affinity for VMAT2^[31,32]. Therefore, it is unlikely that the weak D2 receptor antagonism is responsible for TBZ clinical effects, although it may be possibly involved in acute dystonic reactions rarely reported with TBZ^[33]. Although TBZ has also been found to block the pharmacologic action of apomorphine, a dopamine agonist^[23], providing further evidence of dopamine receptor-blocking activity, this action of TBZ is relatively weak and most likely explains the low risk of TBZ-induced TD. The presynaptic depletion and weak postsynaptic dopamine receptor inhibition may be responsible for increased dopamine turnover as suggested by the increased levels of the major dopamine metabolite, homovanillic acid, in the cerebrospinal fluid of patients with HD taking TBZ^[7]. ;

• Safety & Tolerability

  TBZ has been used most commonly in the range of 25 200mg/day, although a typical therapeutic dose is 50 75 mg/day. In studies and in daily practice, TBZ is slowly titrated from approximately 25 mg/day in two or three divided doses up to 150mg/day in increments of 25 mg/week. Given the short half-life, dosing three-times per day is sometimes necessary. The dose escalation is stopped when the patient experiences intolerable side effects or a satisfactory effect. Nearly all drug-related side effects can be eradicated by lowering the dose. Therefore, most studies with TBZ are designed to increase the dose until intolerable side effects are noted and then the dose is slightly decreased to alleviate the side effects. Using this technique of dose escalation, it is not surprising that many patients develop side effects. The dose-dependent nature of side effects is an important point to consider when discussing the adverse event profile of TBZ^[18,34,35]. Common side effects include sedation, parkinsonism, depression, insomnia, and akathisia, all of which are reversible^[16]. Several investigators have observed that younger patients tolerate TBZ better than the elderly. These findings have been confirmed and reported that younger patients (<50 years) experienced more insomnia and depression, while older patients were more likely to develop parkinsonism^[37]. Serious side effects of TBZ described in the literature include severe hyperthermia, neuroleptic malignant syndrome (NMS), acute dystonic reaction^[33], pneumonia, severe dysphagia^[1,10] and suicide^[6]. NMS usually occurs within the first 4 weeks of treatment, but may be delayed several years^[38,39]. Prescribing physicians should be aware that a number of publications mention fatalities occurring in those taking TBZ without an obvious etiology. It should be considered that the frequency of dysphagia, suicide and death would be expected to be increased in a study population of patients with HD. Most authors state that the deaths were not directly related to TBZ, but the frequency of unexplained death in certain clinical studies warrants caution and close monitoring of patients' physical and mental well-being throughout the course of treatment. ;

• Precautions

  When you take tetrabenazine, you should follow the following tips^[40]:
  Tell all of your health care providers that you take tetrabenazine including your doctors, nurses, pharmacists, and dentists.
  You should avoid driving and doing other tasks or actions that call for you to be alert until you see how tetrabenazine affects you.
  To lower the chance of feeling dizzy or passing out, you should rise slowly if you have been sitting or lying down. Be careful when you go up and down stairs.
  You should often have your blood pressure checked and keep in touch with your doctor. Talk with your doctor before you drink alcohol or use other drugs and natural products that slow your actions. If you have Huntington's disease, your signs can still get worse while you use drugs like this one. Call your doctor right away if you have any signs that are new or worse. Tell your doctor if you are pregnant or plan on getting pregnant. You will need to talk about the benefits and risks of using tetrabenazine while you are pregnant. Tell your doctor if you are breast-feeding. You will need to talk about any risks to your baby. ;

• Reference

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  13. Quinn GP, Shore PA, Brodie BB. Biochemical and pharmacological studies of RO 19569 (tetrabenazine), a nonindole tranquilizing agent with reserpine-like effects. J. Pharmacol. Exp. Ther. 127, 103–109 (1959).
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  40. https://www.drugs.com/cdi/tetrabenazine.html
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