Extensión de tiempo QT
Efectos adversos de las drogas
|Dolor de cabeza|
Variantes ✨Para la evaluación computacionalmente intensiva de las variantes, elija la suscripción estándar paga.
Áreas de aplicación
Explicaciones para pacientes
No tenemos advertencias adicionales para la combinación de nefazodon y cimetidina. Consulte también la información especializada pertinente.
Los cambios en la exposición mencionados se refieren a cambios en la curva de concentración plasmática-tiempo [AUC]. No detectamos ningún cambio en la exposición a nefazodon. Actualmente no podemos estimar la influencia de la cimetidina. No detectamos ningún cambio en la exposición a cimetidina. Actualmente no podemos estimar la influencia de la nefazodon.
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.
La nefazodon tiene una baja biodisponibilidad oral [ F ] del 20%, por lo que el nivel plasmático máximo [Cmax] tiende a cambiar fuertemente con una interacción. La unión a proteínas [ Pb ] es muy fuerte al 99%. El metabolismo tiene lugar principalmente a través de CYP3A4..
La cimetidina tiene una biodisponibilidad oral media [ F ] del 65%, por lo que los niveles plasmáticos máximos [Cmax] tienden a cambiar con una interacción. La vida media terminal [ t12 ] es bastante corta a las 1.6333333 horas y se alcanzan rápidamente niveles plasmáticos constantes [ Css ]. La unión a proteínas [ Pb ] es muy débil al 19% y el volumen de distribución [ Vd ] es muy grande a 91 litros. El metabolismo no tiene lugar a través de los citocromos comunes. y el transporte activo se realiza en parte a través de BCRP y PGP.
|Efectos serotoninérgicos a||2||++||Ø|
Recomendación: Como medida de precaución, se deben tener en cuenta los síntomas de la sobreestimulación serotoninérgica, especialmente después de un aumento de la dosis y a dosis en el rango terapéutico superior.
Clasificación: La nefazodon modula el sistema serotoninérgico en un grado moderado. El riesgo de un síndrome serotoninérgico se puede clasificar como bajo con este medicamento si la dosis está en el rango habitual. Según nuestro conocimiento, la cimetidina no aumenta la actividad serotoninérgica.
|Kiesel & Durán b||2||+||+|
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: Nefazodon y cimetidina solo tienen un efecto leve sobre el sistema anticolinérgico. El riesgo de síndrome anticolinérgico con este medicamento es bastante bajo si la dosis se encuentra en el rango habitual.
Extensión de tiempo QT
Recomendación: Asegúrese de minimizar los factores de riesgo influibles. Las alteraciones electrolíticas, como los bajos niveles de calcio, potasio y magnesio, deben compensarse. Se debe usar la dosis efectiva más baja de cimetidina.
Clasificación: La cimetidina puede prolongar potencialmente el tiempo QT y, si hay factores de riesgo, se pueden favorecer las arritmias del tipo torsades de pointes. No conocemos ningún potencial de prolongación del intervalo QT para la nefazodon.
Efectos secundarios generales
|Efectos secundarios||∑ frecuencia||nef||cim|
|Dolor de cabeza||39.0 %||39.0||n.a.|
|Visión borrosa||6.0 %||6.0||n.a.|
Hipotensión ortostática (3.4%): nefazodon
Síndrome de Stevens-Johnson: nefazodon
Insuficiencia hepática: nefazodon
Reacción de hipersensibilidad: nefazodon
Con base en sus
Referencias de literatura
Abstract: Recently, the use of astemizole and terfenadine, both non-sedating H1-antihistamines, caused considerable concern. Several case reports suggested an association of both drugs with an increased risk of torsades de pointes, a special form of ventricular tachycardia. The increased risk of both H1-antihistamines was associated with exposure to supratherapeutic doses; for terfenadine the risk was also associated with concomitant exposure to the cytochrome P-450 inhibitors ketoconazole, erythromycin and cimetidine. To predict the size of the population that runs the risk of developing this potentially fatal adverse reaction in the Netherlands, the prevalence of prescribing supratherapeutic doses and the concomitant exposure to terfenadine and cytochrome P-450 inhibitors was studied. Data were obtained from the PHARMO data base in 1990, a pharmacy-based record linkage system encompassing a catchment population of 300,000 individuals. The results of the study showed that the prescribing of supratherapeutic doses and the concomitant exposure to terfenadine and cytochrome P-450 inhibitors was low. Furthermore, the results of a sensitivity analysis showed that the risk of fatal torsades de pointes has to be as high as 1 in 10,000 to cause one death in the Netherlands in one year.
Abstract: Nefazodone is a new antidepressant drug, chemically unrelated to the tricyclic, tetracyclic or selective serotonin uptake inhibitors. Nefazodone blocks the serotonin 5-HT2 receptors and reversibly inhibits serotonin reuptake in vivo. Nefazodone is completely and rapidly absorbed after oral administration with a peak plasma concentration observed within 2 hours of administration. Nefazodone undergoes significant first-pass metabolism resulting in an oral bioavailability of approximately 20%. Although there is an 18% increase in nefazodone bioavailability with food, this increase is not clinically significant and nefazodone can be administered without regard to meals. Three pharmacologically active nefazodone metabolites have been identified: hydroxy-nefazodone, triazoledione and m-chlorophenylpiperazine (mCPP). The pharmacokinetics of nefazodone are nonlinear. The increase in plasma concentrations of nefazodone are greater than would be expected if they were proportional to increases in dose. Steady-state plasma concentrations of nefazodone are attained within 4 days of the commencement of administration. The pharmacokinetics of nefazodone are not appreciably altered in patients with renal or mild-to-moderate hepatic impairment. However, nefazodone plasma concentrations are increased in severe hepatic impairment and in the elderly, especially in elderly females. Lower doses of nefazodone may be necessary in these groups. Nefazodone is a weak inhibitor of cytochrome P450 (CYP) 2D6 and does not inhibit CYP1A2. It is not anticipated that nefazodone will interact with drugs cleared by these isozymes. Indeed, nefazodone did not affect the pharmacokinetics of theophylline, a compound cleared by CYP1A2. Nefazodone is metabolised by and inhibits CYP3A4. Clinically significant interactions have been observed between nefazodone and the benzodiazepines triazolam and alprazolam, cyclosporin and carbamazepine. The potential for a clinically significant interaction between nefazodone and other drugs cleared by CYP3A4 (e.g. terfenadine) should be considered before the coadministration of these compounds. There was an increase in haloperidol plasma concentrations when coadministered with nefazodone; nefazodone pharmacokinetics were not affected after coadministration. No clinically significant interaction was observed when nefazodone was administered with lorazepam, lithium, alcohol, cimetidine, warfarin, theophylline or propranolol.
Abstract: Astemizole (Hismanal), an antihistamine agent, has been reported to be associated with ventricular arrhythmias. In this paper we present a case of QT prolongation and torsades de pointes (TdP) in a 77-year-old woman who had been taking astemizole (10 mg/day) for 6 months because of allergic skin disease. At the time of admission, the serum concentration of astemizole and its metabolites was markedly elevated at 15.85 ng/ml, approximately 3 times the normal level. The patient was also taking cimetidine, a known inhibitor of cytochrome P-450 enzymatic activity, and during her admission was diagnosed as having vasospastic angina. To the best of our knowledge, this is the first report of astemizole-induced QT prolongation and TdP in Japan.
Abstract: Nefazodone is an antidepressant with a relatively unique structure and mechanism of action. The current study was conducted to assess the potential for nefazodone to have metabolic drug interactions associated with cytochrome P450 (CYP) enzymes. Nefazodone is metabolised to hydroxynefazodone (OH-NEF), triazoledione (TD), and m-chlorophenylpiperazine (m-CPP), and OH-NEF is metabolised to TD and m-CPP. Correlations with enzyme activities in a panel of microsomes prepared from human livers, incubations with heterologously expressed human CYP enzymes, and incubations with enzyme inhibitors were used to study these metabolic pathways. The results suggest that the metabolism of NEF and OH-NEF to each of their active metabolites is catalysed mainly by CYP3A4, which is in agreement with clinical reports of drug--drug interactions of nefazodone with substrates and inhibitors of CYP3A4.
Abstract: Renal drug interactions can result from competitive inhibition between drugs that undergo extensive renal tubular secretion by transporters such as P-glycoprotein (P-gp). The purpose of this study was to evaluate the effect of itraconazole, a known P-gp inhibitor, on the renal tubular secretion of cimetidine in healthy volunteers who received intravenous cimetidine alone and following 3 days of oral itraconazole (400 mg/day) administration. Glomerular filtration rate (GFR) was measured continuously during each study visit using iothalamate clearance. Iothalamate, cimetidine, and itraconazole concentrations in plasma and urine were determined using high-performance liquid chromatography/ultraviolet (HPLC/UV) methods. Renal tubular secretion (CL(sec)) of cimetidine was calculated as the difference between renal clearance (CL(r)) and GFR (CL(ioth)) on days 1 and 5. Cimetidine pharmacokinetic estimates were obtained for total clearance (CL(T)), volume of distribution (Vd), elimination rate constant (K(el)), area under the plasma concentration-time curve (AUC(0-240 min)), and average plasma concentration (Cp(ave)) before and after itraconazole administration. Plasma itraconazole concentrations following oral dosing ranged from 0.41 to 0.92 microg/mL. The cimetidine AUC(0-240 min) increased by 25% (p < 0.01) following itraconazole administration. The GFR and Vd remained unchanged, but significant reductions in CL(T) (655 vs. 486 mL/min, p < 0.001) and CL(sec) (410 vs. 311 mL/min, p = 0.001) were observed. The increased systemic exposure of cimetidine during coadministration with itraconazole was likely due to inhibition of P-gp-mediated renal tubular secretion. Further evaluation of renal P-gp-modulating drugs such as itraconazole that may alter the renal excretion of coadministered drugs is warranted.
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: BACKGROUND: Adverse effects of anticholinergic medications may contribute to events such as falls, delirium, and cognitive impairment in older patients. To further assess this risk, we developed the Anticholinergic Risk Scale (ARS), a ranked categorical list of commonly prescribed medications with anticholinergic potential. The objective of this study was to determine if the ARS score could be used to predict the risk of anticholinergic adverse effects in a geriatric evaluation and management (GEM) cohort and in a primary care cohort. METHODS: Medical records of 132 GEM patients were reviewed retrospectively for medications included on the ARS and their resultant possible anticholinergic adverse effects. Prospectively, we enrolled 117 patients, 65 years or older, in primary care clinics; performed medication reconciliation; and asked about anticholinergic adverse effects. The relationship between the ARS score and the risk of anticholinergic adverse effects was assessed using Poisson regression analysis. RESULTS: Higher ARS scores were associated with increased risk of anticholinergic adverse effects in the GEM cohort (crude relative risk [RR], 1.5; 95% confidence interval [CI], 1.3-1.8) and in the primary care cohort (crude RR, 1.9; 95% CI, 1.5-2.4). After adjustment for age and the number of medications, higher ARS scores increased the risk of anticholinergic adverse effects in the GEM cohort (adjusted RR, 1.3; 95% CI, 1.1-1.6; c statistic, 0.74) and in the primary care cohort (adjusted RR, 1.9; 95% CI, 1.5-2.5; c statistic, 0.77). CONCLUSION: Higher ARS scores are associated with statistically significantly increased risk of anticholinergic adverse effects in older patients.
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: 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.