Enfermedad de Huntington: Epidemiología, Fisiopatología y Síntomas
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Enfermedad de Huntington: Epidemiología, Fisiopatología y Síntomas
- 1. ENFERMEDAD DE HUNTINGTON (EH/HD) Dra. Esther Suárez San Martín Sesiones Clínicas de Neurología HUCA Oviedo, 26 de junio de 2009
- 9. FISIOPATOLOGÍA (VI) DOPAMINA DOPAMINA DOPAMINA ACETILCOLINA ACETILCOLINA ACETILCOLINA NORMAL SÍNDROME DE PARKINSON Acinético Hipertónico SÍNDROME DE COREA Hipercinético Hipotónico
- 22. TRATAMIENTO DE LA ENFERMEDAD DE HUNTINGTON
- 24. Nitoman 25 mg ® (Tetrabenazina)
- 26. Fórmula estructural de Tetrabenazina Fórmula Molecular = C 19 H 27 NO 3 Peso Molecular = 317.43 O N CH 2 CH(CH 3 ) 2 CH 3 O CH 3 O
- 28. Bloqueo de receptores dopaminérgicos postsinápticos T T T T DOPA POST-SINAPSIS El antagonismo dopaminérgico postsináptico de tetrabenazina es similar al del resto de neurolépticos Ficha técnica de producto T
- 32. Hidroxitetrabenazina vs Tetrabenazina No se produce acumulación en la administración diaria Farmacocinética Ficha técnica de producto Biodisponibilidad Oral Tetrabenazina 5±3% Biodisponibilidad Oral H i drox i tetrabenazin a 80% Vida Media Tetrabenazina 3-9 h. Vida Media H i drox i tetrabenazin a >12 h.
- 33. Efectos Adversos del tratamiento con Tetrabenazina Efecto Porcentaje de aparición Jankovic y Orman, 1988 (n=217) Jankovic y Beach, 1997 (n=400) Parkinsonism o (sign o s y síntomas ) 24.4 28.5 Fatiga, adormecimiento 12.9 36.5 Depresi ó n 10.6 15.0 Ansiedad, nerviosismo 7.4 10.3 Insomni o 5.1 11.0 Acatisia 4.6 9.5 Sialorrea – – Irritabilidad, agitación 2.3 – Nauseas, vómitos 2.3 4.8 Confusión, desorientación – 2.3 Hipotensión 1.8 1.5 Mareo 1.8 1.0
- 34. Tetrabenazine ™ 25 comprimidos y presentación 112 comprimidos por frasco Ficha técnica de producto
- 35. 12,5 mg 12,5 mg Dosis y administración (II) Ejemplo de titulación Ficha técnica: “Las dosis y forma de administración pueden ser variables por lo que se facilitan pautas orientativas”
- 42. ESTUDIOS SOBRE LA EFICACIA DE LA TETRABENAZINA EN PACIENTES CON COREA DE HUNTINGTON
- 43. GRACIAS
Notas do Editor
- Xenazine ™ 25 has therapeutic indications for movement disorders associated with central nervous system conditions e.g., Huntington ’ s chorea, hemiballismus and senile chorea. This effectively covers a wide range of hyperkinetic movement disorders. In addition to the indications for organic conditions, Xenazine ™ 25 is also indicated for the treatment of moderate to severe tardive dyskinesia – a drug-induced movement disorder. The use of Xenazine ™ 25 is specified for cases of tardive dyskinesia that are disabling and/or socially embarrassing, and persist despite dose reduction or withdrawal of antipsychotic medication. Xenazine ™ 25 may also be used in tardive dyskinesia that persists when the therapy is switched to atypical antipsychotic medication, or where removing the antipsychotic medication is not a feasible option.
- The structural formula of tetrabenazine is shown here, alongside its molecular formula and molecular weight.
- Tetrabenazine interferes with the normal action of dopamine. It achieves this by two modes of action – blocking postsynaptic dopamine receptors, and depleting stores of dopamine in presynaptic vesicles. These two actions result in reduced transmission along the dopamine pathways, and it is in this way that tetrabenazine is believed to have its clinical effects in man. The postsynaptic dopamine antagonism of tetrabenazine is similar to that of the antipsychotics, but it was not developed for this indication. It was in the 1960s that the compound was developed as a treatment for hyperkinetic movement disorders. Laboratory trials on animals have shown that tetrabenazine depletes the storage of biogenic amines – including dopamine, serotonin and noradrenaline – by affecting their uptake into a subset of presynaptic vesicles. There are several distinct sets of vesicular transporters in the membranes of presynaptic vesicles, but the latter effect occurs due to tetrabenazine reversibly binding to vesicular monoamine transporter 2 (VMAT2) – found primarily in the presynaptic vesicles of the CNS.
- VMAT2 uses a proton (H + ) pump to set up an H + gradient across the vesicular membrane. The proton gradient drives the uptake of biogenic amines, such as dopamine and serotonin, into the vesicle. Tetrabenazine reversibly binds to VMAT2, thereby blocking the uptake of neurotransmitter, as well as allowing the stored contents of the vesicles to leak back out into the cell cytoplasm.
- Tetrabenazine is extensively metabolised during first pass metabolism, resulting in low plasma concentrations and little or no unchanged tetrabenazine detected in the urine. The duration of tetrabenazine action ranges from 16 – 24 hours. The major tetrabenazine metabolite is hydroxytetrabenazine, and this is formed by reduction. Although tetrabenazine itself has a very low systemic oral availability, studies have demonstrated that hydroxytetrabenazine, has much higher plasma levels. For example, Roberts et al (1986) have demonstrated that during intravenous administration, tetrabenazine has a moderate half-life of 6.5 hours, whereas the half-life of hydroxytetrabenazine is almost double that value (10 hours). In addition, hydroxytetrabenazine is reported to be as active as tetrabenazine in blocking the storage of biogenic amines, and may therefore be the major therapeutic agent.
- The most common adverse reactions to treatment with Xenazine ™ 25 are listed here alongside their occurrence in two follow-up studies of patients treated with tetrabenazine – Jankovic and Orman (1988) and Jankovic and Beach (1997). When considering the apparently high levels of some of the side effects observed, it is worth reviewing the dosing strategies employed in these two studies. In both studies there was a tendency to increase doses too quickly, to administer too high a dose or, most significantly, to increase the dose until side effects were seen. For example, in Jankovic and Orman the dose was increased to either 100mg or a level where side effects were seen (whichever occurred first). In the study by Jankovic and Beach, patients treated prior to 1991 were given a starting dose of 25mg/day followed by a daily dose increase of 25mg, up to a maximum daily dose of 150-200mg or until side effects were observed. Some patients had resultant doses as high as 400mg/day i.e., twice the maximum licensed dose.
- Xenazine™ 25 is available in tablet form for oral administration only. Each tablet is round, yellow/buff coloured and contains 25 mg tetrabenazine. The other tablet components are cornstarch, iron oxide, lactose, magnesium stearate and talc. ‘CL25’ is imprinted on one side of each tablet, and a single break bar on the other side. The tablets are supplied in bottles of 112.