Extensión de tiempo QT
Efectos adversos de las drogas
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 ranitidina, voriconazol y cimetidina. Consulte también la información especializada pertinente.
|Voriconazol||1.66 [1.03,3.68] 1||1.05||1.55|
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 ranitidina. Actualmente no podemos estimar la influencia de voriconazol y cimetidina. La exposición a voriconazol aumenta al 166%, cuando se combina con ranitidina (105%) y cimetidina (155%). El AUC está entre 103% y 368% 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.
La ranitidina tiene una biodisponibilidad oral media [ F ] del 50%, por lo que los niveles plasmáticos máximos [Cmax] tienden a cambiar con una interacción. La vida media terminal [ t12 ] es bastante corta a las 2.5 horas y se alcanzan rápidamente niveles plasmáticos constantes [ Css ]. La unión a proteínas [ Pb ] es muy débil al 15%. El metabolismo tiene lugar a través de CYP1A2, CYP2C19 y CYP2D6, entre otros. y el transporte activo tiene lugar en particular a través de PGP.
La voriconazol tiene una alta biodisponibilidad oral [ F ] del 88%, por lo que los niveles plasmáticos máximos [Cmax] tienden a cambiar poco durante una interacción. La vida media terminal [ t12 ] es bastante corta a las 6 horas y se alcanzan rápidamente niveles plasmáticos constantes [ Css ]. La unión a proteínas [ Pb ] es bastante débil al 58% y el volumen de distribución [ Vd ] es muy grande a 90 litros, Dado que la sustancia tiene una tasa de extracción hepática baja de 0,9, el desplazamiento de la unión a proteínas [Pb] en el contexto de una interacción puede aumentar la exposición. El metabolismo tiene lugar a través de CYP2C19, CYP2C9 y CYP3A4, entre otros..
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||0||Ø||Ø||Ø|
Clasificación: Según nuestro conocimiento, ni la ranitidina, voriconazol ni la cimetidina aumentan la actividad serotoninérgica.
|Kiesel & Durán b||2||+||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: Ranitidina 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. Según nuestros hallazgos, la voriconazol no aumenta la actividad anticolinérgica.
Extensión de tiempo QT
Clasificación: En combinación, la voriconazol y la cimetidina pueden desencadenar potencialmente arritmias ventriculares del tipo torsades de pointes. No conocemos ningún potencial de prolongación del intervalo QT para la ranitidina.
Efectos secundarios generales
|Efectos secundarios||∑ frecuencia||ran||vor||cim|
|Visión borrosa||26.0 %||n.a.||26.0||n.a.|
|Dolor abdominal||12.0 %||n.a.||12.0||n.a.|
Hepatitis colestásica (4.9%): voriconazol, ranitidina
Hepatotoxicidad (1.9%): voriconazol
Ictericia (1.9%): voriconazol
Insuficiencia hepática (1.9%): voriconazol
Vómitos (4.4%): voriconazol
Diarrea (1.9%): voriconazol
Pancreatitis: voriconazol, cimetidina, ranitidina
Ginecomastia (4%): cimetidina
Dolor de cabeza (3%): voriconazol
Edema periférico (1.9%): voriconazol
Bloqueo auriculoventricular: ranitidina
Eritema multiforme (1.9%): voriconazol, ranitidina
Melanoma maligno (1.9%): voriconazol
Carcinoma de células escamosas (1.9%): voriconazol
Síndrome de Stevens-Johnson (1.9%): voriconazol
Necrolisis epidérmica toxica (1.9%): voriconazol
Neuritis óptica: voriconazol
Insuficiencia renal: voriconazol
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: 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: BACKGROUND: No standard methods exist for determining the onset of action of gastric antisecretory agents in human subjects. METHODS: Intragastric pH was measured when placebo, ranitidine 150 mg, ranitidine 75 mg or famotidine 10 mg were administered 30 min after the end of a meal. RESULTS: When the onset of action was defined as the earliest time that mean gastric pH with active treatment was statistically significantly higher (P < 0.05) than the corresponding placebo value, the onsets of action of ranitidine 75 mg and 150 mg were 55 min, and of famotidine 10 mg, 90 min. When onset was defined in terms of a particular decrease in gastric acid concentration for the group as a whole or for individual subjects, there was an important variation in the relative times of onset of ranitidine 75 mg and famotidine 10 mg. CONCLUSIONS: When administered after a meal, the onset of action of ranitidine and famotidine on gastric pH can be determined for individual subjects as well as for the group as a whole. When onset was determined for the group using statistical significance, which does not depend on arbitrary cut-off points, ranitidine 75 mg had an earlier onset of action than did famotidine 10 mg.
Abstract: No Abstract available
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: This review presents the published clinical pharmacokinetic data for the antifungal agent voriconazole. Aspects regarding absorption, tissue distribution, elimination and kinetic interactions are also discussed.
Abstract: Voriconazole is the first available second-generation triazole with potent activity against a broad spectrum of clinically significant fungal pathogens, including Aspergillus,Candida, Cryptococcus neoformans, and some less common moulds. Voriconazole is rapidly absorbed within 2 hours after oral administration and the oral bioavailability is over 90%, thus allowing switching between oral and intravenous formulations when clinically appropriate. Voriconazole shows nonlinear pharmacokinetics due to its capacity-limited elimination, and its pharmacokinetics are therefore dependent upon the administered dose. With increasing dose, voriconazole shows a superproportional increase in area under the plasma concentration-time curve (AUC). In doses used in children (age < 12 years) voriconazole pharmacokinetics appear to be linear. Steady-state plasma concentrations are reached approximately 5 days after both intravenous and oral administration; however, steady state is reached within 24 hours with voriconazole administered as an intravenous loading dose. The volume of distribution of voriconazole is 2-4.6 L/kg, suggesting extensive distribution into extracellular and intracellular compartments. Voriconazole was measured in tissue samples of brain, liver, kidney, heart, lung as well as cerebrospinal fluid. The plasma protein binding is about 60% and independent of dose or plasma concentrations. Clearance is hepatic via N-oxidation by the hepatic cytochrome P450 (CYP) isoenzymes, CYP2C19, CYP2C9 and CYP3A4. The elimination half-life of voriconazole is approximately 6 hours, and approximately 80% of the total dose is recovered in the urine, almost completely as metabolites. As with other azole drugs, the potential for drug interactions is considerable. Voriconazole shows time-dependent fungistatic activity against Candida species and time-dependent slow fungicidal activity against Aspergillus species. A short post-antifungal effect of voriconazole is evident only for Aspergillus species. The predictive pharmacokinetic/pharmacodynamic parameter for voriconazole treatment efficacy in Candida infections is the free drug AUC from 0 to 24 hour : minimum inhibitory concentration ratio.
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: We describe 2 patients who developed prolonged QTc interval on electrocardiogram while being treated with voriconazole. The first patient had undergone induction chemotherapy for acute myelogenous leukemia, and her course had been complicated by invasive aspergillosis and an acute cardiomyopathy. She developed torsades de pointes 3 weeks after starting voriconazole therapy. She was re-challenged with voriconazole without recurrent QTc prolongation or cardiac dysfunction. The second patient had a significantly prolonged QTc interval while on voriconazole therapy. We recommend careful monitoring for QTc prolongation and arrhythmia in patients who are receiving voriconazole, particularly those who have significant electrolyte disturbances, are on concomitant QT prolonging medications, have heart failure such as from a dilated cardiomyopathy, or have recently received anthracycline-based chemotherapy. The potential for synergistic cardiotoxicity must be carefully considered.
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: The objective of this study was to evaluate the pharmacokinetics of voriconazole and the potential correlations between pharmacokinetic parameters and patient variables in liver transplant patients on a fixed-dose prophylactic regimen. Multiple blood samples were collected within one dosing interval from 15 patients who were initiated on a prophylactic regimen of voriconazole at 200 mg enterally (tablets) twice daily starting immediately posttransplant. Voriconazole plasma concentrations were measured using high-pressure liquid chromatography (HPLC). Noncompartmental pharmacokinetic analysis was performed to estimate pharmacokinetic parameters. The mean apparent systemic clearance over bioavailability (CL/F), apparent steady-state volume of distribution over bioavailability (Vss/F), and half-life (t1/2) were 5.8+/-5.5 liters/h, 94.5+/-54.9 liters, and 15.7+/-7.0 h, respectively. There was a good correlation between the area under the concentration-time curve from 0 h to infinity (AUC0-infinity) and trough voriconazole plasma concentrations. t1/2, maximum drug concentration in plasma (Cmax), trough level, AUC0-infinity, area under the first moment of the concentration-time curve from 0 h to infinity (AUMC0-infinity), and mean residence time from 0 h to infinity (MRT0-infinity) were significantly correlated with postoperative time. t1/2, lambda, AUC0-infinity, and CL/F were significantly correlated with indices of liver function (aspartate transaminase [AST], total bilirubin, and international normalized ratio [INR]). The Cmax, last concentration in plasma at 12 h (Clast), AUMC0-infinity, and MRT0-infinity were significantly lower in the presence of deficient CYP2C19*2 alleles. Donor characteristics had no significant correlation with any of the pharmacokinetic parameters estimated. A fixed dosing regimen of voriconazole results in a highly variable exposure of voriconazole in liver transplant patients. Given that trough voriconazole concentration is a good measure of drug exposure (AUC), the voriconazole dose can be individualized based on trough concentration measurements in liver transplant patients.
Abstract: No Abstract available
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: The accurate estimation of "in vivo" inhibition constants () of inhibitors and fraction metabolized () of substrates is highly important for drug-drug interaction (DDI) prediction based on physiologically based pharmacokinetic (PBPK) models. We hypothesized that analysis of the pharmacokinetic alterations of substrate metabolites in addition to the parent drug would enable accurate estimation of in vivoandTwenty-four pharmacokinetic DDIs caused by P450 inhibition were analyzed with PBPK models using an emerging parameter estimation method, the cluster Newton method, which enables efficient estimation of a large number of parameters to describe the pharmacokinetics of parent and metabolized drugs. For each DDI, two analyses were conducted (with or without substrate metabolite data), and the parameter estimates were compared with each other. In 17 out of 24 cases, inclusion of substrate metabolite information in PBPK analysis improved the reliability of bothandImportantly, the estimatedfor the same inhibitor from different DDI studies was generally consistent, suggesting that the estimatedfrom one study can be reliably used for the prediction of untested DDI cases with different victim drugs. Furthermore, a large discrepancy was observed between the reported in vitroand the in vitro estimates for some inhibitors, and the current in vivoestimates might be used as reference values when optimizing in vitro-in vivo extrapolation strategies. These results demonstrated that better use of substrate metabolite information in PBPK analysis of clinical DDI data can improve reliability of top-down parameter estimation and prediction of untested DDIs.