Prolongación del tiempo QT
Eventos adversos de medicamentos
Variantes ✨Para la evaluación computacionalmente intensiva de las variantes, elija la suscripción estándar paga.
Explicaciones de las sustancias para pacientes.
No existen advertencias adicionales para la combinación de abarelix y doxepina. Consulte también la información especializada pertinente.
|Doxepina||1 [0.43,6.31] 1,2||1|
Los cambios informados en la exposición corresponden a los cambios en la curva de concentración plasmática-tiempo [ AUC ]. No esperamos ningún cambio en la exposición a abarelix, cuando se combina con doxepina (100%). No esperamos ningún cambio en la exposición a doxepina, cuando se combina con abarelix (100%). El AUC se encuentra entre 0 % y 100 % dependiendo del
Los parámetros farmacocinéticos de la población media se utilizan como punto de partida para calcular los cambios individuales en la exposición debidos a las interacciones.
Se desconoce la biodisponibilidad de la abarelix. La vida media terminal [ t12 ] es relativamente extensa a las 316.8 horas y los niveles plasmáticos constantes [ Css ] sólo se alcanzan después de más de 1267.2 horas. La unión a proteínas [ Pb ] es 100 % fuerte. Actualmente, se sigue trabajando en el metabolismo por citocromos.
La doxepina tiene una baja biodisponibilidad oral [ F ] del 100 %, por lo que el nivel plasmático máximo [Cmax] tiende a cambiar fuertemente con una interacción. La unión a proteínas [ Pb ] es moderadamente fuerte al 100 %. por eso, con una tasa de extracción hepática media de 0,9, tanto el flujo sanguíneo hepático [Q] como un cambio en la unión a proteínas [Pb] son relevantes. El metabolismo tiene lugar a través de CYP1A2, CYP2C19, CYP2C9 y CYP2D6, entre otros y el transporte activo tiene lugar especialmente a través de PGP.
|Efectos serotoninérgicos a||2||Ø||++|
Recomendación: Como medida de precaución, se deben tener en cuenta los síntomas de sobreestimulación serotoninérgica, especialmente después de aumentar la dosis y en dosis en el rango terapéutico superior.
Clasificación: La doxepina modula el sistema serotoninérgico en un grado moderado. El riesgo de síndrome serotoninérgico se puede clasificar como bajo con este medicamento si la dosis se encuentra en el rango habitual. Según nuestro conocimiento, la abarelix no aumenta la actividad serotoninérgica.
|Kiesel & Durán b||3||Ø||+++|
Recomendación: Como precaución, se debe prestar atención a los síntomas anticolinérgicos, especialmente después de aumentar la dosis y en dosis en el rango terapéutico superior.
Clasificación: La doxepina aumenta en gran medida la actividad anticolinérgica. Según nuestro conocimiento, la abarelix no aumenta la actividad anticolinérgica.
Prolongación del tiempo QT
Clasificación: En combinación, la abarelix y la doxepina pueden desencadenar potencialmente arritmias ventriculares del tipo torsades de pointes.
Efectos adversos generales
|Efectos secundarios||∑ frecuencia||aba||dox|
|Retención urinaria||1.0 %||n.a.||+|
|Infeccion de las vias respiratorias altas||1.0 %||n.a.||+|
|Muerte cardíaca súbita||0.0 %||n.a.||0.01|
|Arritmia ventricular||0.0 %||n.a.||0.01|
Con base en sus respuestas e información científica, evaluamos el riesgo individual de efectos secundarios adversos. Estas recomendaciones están destinadas a asesorar a los profesionales y no sustituyen la consulta con un médico. En la versión de prueba restringida (alfa), el riesgo de todas las sustancias aún no se ha evaluado de manera concluyente.
Abstract: The QT interval measuring depolarisation and repolarisation has, when lengthened, been implicated as a risk factor for the development of torsades de pointes and sudden death, particularly in patients predisposed to these complications due to cardiovascular impairment. Since some of the medications used in psychiatry have been implicated, an extensive review of available literature was made of the major classes, including antipsychotics, antidepressants, lithium, anticonvulsants and benzodiazepines. Further, where no publications were found on a particular medication, the pharmaceutical firms responsible for these items were contacted concerning possibly unpublished data. Results of the survey indicate that there may be difficulty in one of three situations: immediate (in the first minutes to hours after oral or parenteral administration), short-term use of 4 - 12 weeks or long-term use of 6 months. Based on this approach, the greatest concern is directed at the immediate application of haloperidol, droperidol, pimozide and trazodone, the short-term use of thioridazine, pimozide, sertindole, nortriptyline, clomipramine, doxepin and the long-term use of clozapine, olanzapine and carbamazepine. It is of interest that a reduction in QTc is reported with aripiprazole. Among the antidepressants, the tertiary tricyclic antidepressants (imipramine, amitriptyline and doxepin) appear to have a more general impact, while the secondary tricyclic antidepressants (nortriptyline, desipramine) may impact more on children and the elderly. Among other antidepressants, the only reports of torsades de pointes appeared to occur with mirtazapine. It was also of interest to find data showing no effect or reductions in QTc produced by sertraline, citalopram, paroxetine and bupropion in multiple studies. Effects of medications on other heart parameters are also briefly reviewed. In particular, the safety of sertraline in post-MI patients and of bupropion in heart disease patients is highlighted. Little information was available on other classes of medications used in psychiatric disorders. What is available concerning lithium, the anticonvulsants and the benzodiazepines indicates little effect on the QTc, although there may be effects on other cardiovascular parameters.
Abstract: 1. Commercial doxepin contains geometric isomers in the proportions Z:E = 15:85. Z-doxepin and its metabolite Z-N-desmethyldoxepin are both active antidepressants, whereas the corresponding E-isomers are less active therapeutically. 2. The present pharmacokinetic study was a balanced, randomized, two-treatment, two-period, two-sequence crossover design in which 12 healthy male volunteers were given single doses of commercial doxepin intravenously and orally on two occasions separated by a washout period. 3. A two-compartment model with no lag time and first-order elimination fitted the plasma concentration-time curves after intravenous dosing. Pharmacokinetic parameters estimated from the model were comparable with those estimated by non-compartmental methods. 4. All pharmacokinetic parameters displayed a wide between-subject variability. Both isomers of doxepin showed large volumes of distribution and relatively short half-lives in plasma, suggestive of extensive distribution and/or tissue binding. The mean fraction absorbed after oral administration was 0.29 for each isomer. Renal clearances of each isomer were very low after either oral or intravenous dosing, although all four analytes were quantifiable in the urine for prolonged periods. 5. After oral dosing, plasma concentrations of the doxepin isomers remained roughly in the ratio Z:E = 15:85, whereas those of N-desmethyldoxepin were closer to 1:1 in all but two outliers, who had high levels E-N-desmethyldoxepin.
Abstract: Anticholinergic Drug Scale (ADS) scores were previously associated with serum anticholinergic activity (SAA) in a pilot study. To replicate these results, the association between ADS scores and SAA was determined using simple linear regression in subjects from a study of delirium in 201 long-term care facility residents who were not included in the pilot study. Simple and multiple linear regression models were then used to determine whether the ADS could be modified to more effectively predict SAA in all 297 subjects. In the replication analysis, ADS scores were significantly associated with SAA (R2 = .0947, P < .0001). In the modification analysis, each model significantly predicted SAA, including ADS scores (R2 = .0741, P < .0001). The modifications examined did not appear useful in optimizing the ADS. This study replicated findings on the association of the ADS with SAA. Future work will determine whether the ADS is clinically useful for preventing anticholinergic adverse effects.
Abstract: The objective of this study was to measure the anticholinergic activity (AA) of medications commonly used by older adults. A radioreceptor assay was used to investigate the AA of 107 medications. Six clinically relevant concentrations were assessed for each medication. Rodent forebrain and striatum homogenate was used with tritiated quinuclidinyl benzilate. Drug-free serum was added to medication and atropine standard-curve samples. For medications that showed detectable AA, average steady-state peak plasma and serum concentrations (C(max)) in older adults were used to estimate relationships between in vitro dose and AA. All results are reported in pmol/mL of atropine equivalents. At typical doses administered to older adults, amitriptyline, atropine, clozapine, dicyclomine, doxepin, L-hyoscyamine, thioridazine, and tolterodine demonstrated AA exceeding 15 pmol/mL. Chlorpromazine, diphenhydramine, nortriptyline, olanzapine, oxybutynin, and paroxetine had AA values of 5 to 15 pmol/mL. Citalopram, escitalopram, fluoxetine, lithium, mirtazapine, quetiapine, ranitidine, and temazepam had values less than 5 pmol/mL. Amoxicillin, celecoxib, cephalexin, diazepam, digoxin, diphenoxylate, donepezil, duloxetine, fentanyl, furosemide, hydrocodone, lansoprazole, levofloxacin, metformin, phenytoin, propoxyphene, and topiramate demonstrated AA only at the highest concentrations tested (patients with above-average C(max) values, who receive higher doses, or are frail may show AA). The remainder of the medications investigated did not demonstrate any AA at the concentrations examined. Psychotropic medications were particularly likely to demonstrate AA. Each of the drug classifications investigated (e.g., antipsychotic, cardiovascular) had at least one medication that demonstrated AA at therapeutic doses. Clinicians can use this information when choosing between equally efficacious medications, as well as in assessing overall anticholinergic burden.
Abstract: OBJECTIVES: To examine the longitudinal relationship between cumulative exposure to anticholinergic medications and memory and executive function in older men. DESIGN: Prospective cohort study. SETTING: A Department of Veterans Affairs primary care clinic. PARTICIPANTS: Five hundred forty-four community-dwelling men aged 65 and older with diagnosed hypertension. MEASUREMENTS: The outcomes were measured using the Hopkins Verbal Recall Test (HVRT) for short-term memory and the instrumental activity of daily living (IADL) scale for executive function at baseline and during follow-up. Anticholinergic medication use was ascertained using participants' primary care visit records and quantified as total anticholinergic burden using a clinician-rated anticholinergic score. RESULTS: Cumulative exposure to anticholinergic medications over the preceding 12 months was associated with poorer performance on the HVRT and IADLs. On average, a 1-unit increase in the total anticholinergic burden per 3 months was associated with a 0.32-point (95% confidence interval (CI)= 0.05-0.58) and 0.10-point (95% CI=0.04-0.17) decrease in the HVRT and IADLs, respectively, independent of other potential risk factors for cognitive impairment, including age, education, cognitive and physical function, comorbidities, and severity of hypertension. The association was attenuated but remained statistically significant with memory (0.29, 95% CI=0.01-0.56) and executive function (0.08, 95% CI=0.02-0.15) after further adjustment for concomitant non-anticholinergic medications. CONCLUSION: Cumulative anticholinergic exposure across multiple medications over 1 year may negatively affect verbal memory and executive function in older men. Prescription of drugs with anticholinergic effects in older persons deserves continued attention to avoid deleterious adverse effects.
Abstract: BACKGROUND: Cognitive decline is common in Parkinson's disease (PD). Although some of the aetiological factors are known, it is not yet known whether drugs with anticholinergic activity (AA) contribute to this cognitive decline. Such knowledge would provide opportunities to prevent acceleration of cognitive decline in PD. OBJECTIVE: To study whether the use of agents with anticholinergic properties is an independent risk factor for cognitive decline in patients with PD. METHODS: A community-based cohort of patients with PD (n=235) were included and assessed at baseline. They were reassessed 4 and 8 years later. Cognition was assessed using the Mini-Mental State Examination (MMSE). A detailed assessment of the AA of all drugs prescribed was made, and AA was classified according to a standardised scale. Relationships between cognitive decline and AA load and duration of treatment were assessed using bivariate and multivariate statistical analyses. RESULTS: More than 40% used drugs with AA at baseline. During the 8-year follow-up, the cognitive decline was higher in those who had been taking AA drugs (median decline on MMSE 6.5 points) compared with those who had not taken such drugs (median decline 1 point; p=0.025). In linear regression analyses adjusting for age, baseline cognition and depression, significant associations with decline on MMSE were found for total AA load (standardised beta=0.229, p=0.04) as well as the duration of using AA drugs (standardised beta 0.231, p=0.032). CONCLUSION: Our findings suggest that there is an association between anticholinergic drug use and cognitive decline in PD. This may provide an important opportunity for clinicians to avoid increasing progression of cognitive decline by avoiding drugs with AA. Increased awareness by clinicians is required about the classes of drugs that have anticholinergic properties.
Abstract: Doxepin binds with high specificity and affinity to the histamine H(1) receptor compared with other receptors. Therefore, at low doses, doxepin selectively antagonises H(1) receptors, which is believed to promote the initiation and maintenance of sleep. In three large, well designed, phase III trials in adult or elderly patients with chronic primary insomnia, oral, low-dose doxepin 3 or 6 mg once daily improved wake time after sleep onset, total sleep time and sleep efficiency to a significantly greater extent than placebo. Significant between-group differences in polysomnographic sleep recordings that favoured low-dose doxepin were evident after a single administration of the drug. Other efficacy measures, including patient-reported sleep quality, also favoured low-dose doxepin over placebo. Symptom control was maintained for up to 12 weeks of low-dose doxepin administration and there was no evidence of physical dependence or worsening insomnia after doxepin withdrawal. Oral, low-dose doxepin 6 mg was also significantly more effective than placebo in a large, well designed trial modelling transient insomnia in healthy adults, according to polysomnographic recordings (e.g. in latency to persistent sleep). Oral, low-dose doxepin was generally well tolerated in clinical trials.
Abstract: Transporters in proximal renal tubules contribute to the disposition of numerous drugs. Furthermore, the molecular mechanisms of tubular secretion have been progressively elucidated during the past decades. Organic anions tend to be secreted by the transport proteins OAT1, OAT3 and OATP4C1 on the basolateral side of tubular cells, and multidrug resistance protein (MRP) 2, MRP4, OATP1A2 and breast cancer resistance protein (BCRP) on the apical side. Organic cations are secreted by organic cation transporter (OCT) 2 on the basolateral side, and multidrug and toxic compound extrusion (MATE) proteins MATE1, MATE2/2-K, P-glycoprotein, organic cation and carnitine transporter (OCTN) 1 and OCTN2 on the apical side. Significant drug-drug interactions (DDIs) may affect any of these transporters, altering the clearance and, consequently, the efficacy and/or toxicity of substrate drugs. Interactions at the level of basolateral transporters typically decrease the clearance of the victim drug, causing higher systemic exposure. Interactions at the apical level can also lower drug clearance, but may be associated with higher renal toxicity, due to intracellular accumulation. Whereas the importance of glomerular filtration in drug disposition is largely appreciated among clinicians, DDIs involving renal transporters are less well recognized. This review summarizes current knowledge on the roles, quantitative importance and clinical relevance of these transporters in drug therapy. It proposes an approach based on substrate-inhibitor associations for predicting potential tubular-based DDIs and preventing their adverse consequences. We provide a comprehensive list of known drug interactions with renally-expressed transporters. While many of these interactions have limited clinical consequences, some involving high-risk drugs (e.g. methotrexate) definitely deserve the attention of prescribers.
Abstract: BACKGROUND: Anticholinergic drugs put elderly patients at a higher risk for falls, cognitive decline, and delirium as well as peripheral adverse reactions like dry mouth or constipation. Prescribers are often unaware of the drug-based anticholinergic burden (ACB) of their patients. This study aimed to develop an anticholinergic burden score for drugs licensed in Germany to be used by clinicians at prescribing level. METHODS: A systematic literature search in pubmed assessed previously published ACB tools. Quantitative grading scores were extracted, reduced to drugs available in Germany, and reevaluated by expert discussion. Drugs were scored as having no, weak, moderate, or strong anticholinergic effects. Further drugs were identified in clinical routine and included as well. RESULTS: The literature search identified 692 different drugs, with 548 drugs available in Germany. After exclusion of drugs due to no systemic effect or scoring of drug combinations (n = 67) and evaluation of 26 additional identified drugs in clinical routine, 504 drugs were scored. Of those, 356 drugs were categorised as having no, 104 drugs were scored as weak, 18 as moderate and 29 as having strong anticholinergic effects. CONCLUSIONS: The newly created ACB score for drugs authorized in Germany can be used in daily clinical practice to reduce potentially inappropriate medications for elderly patients. Further clinical studies investigating its effect on reducing anticholinergic side effects are necessary for validation.