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 alfuzosina y diltiazem. Consulte también la información especializada pertinente.
Los cambios en la exposición mencionados se refieren a cambios en la curva de concentración plasmática-tiempo [AUC]. La exposición a alfuzosina aumenta al 157%, cuando se combina con diltiazem (157%). Esto puede provocar un aumento de los efectos secundarios. No esperamos ningún cambio en la exposición a diltiazem, cuando se combina con alfuzosina (100%).
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 alfuzosina tiene una biodisponibilidad oral media [ F ] del 49%, por lo que los niveles plasmáticos máximos [Cmax] tienden a cambiar con una interacción. La vida media terminal [ t12 ] es de 9.55 horas y se alcanzan niveles plasmáticos constantes [ Css ] después de aproximadamente 38.2 horas. La unión a proteínas [ Pb ] es moderadamente fuerte al 86% y el volumen de distribución [ Vd ] es muy grande a 224 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 principalmente a través de CYP3A4..
La diltiazem tiene una baja biodisponibilidad oral [ F ] del 39%, por lo que el nivel plasmático máximo [Cmax] tiende a cambiar fuertemente con 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 moderadamente fuerte al 77.5% y el volumen de distribución [ Vd ] es muy grande a 350 litros. 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 CYP2D6 y CYP3A4, entre otros. y el transporte activo tiene lugar en particular a través de PGP.
|Efectos serotoninérgicos a||0||Ø||Ø|
Clasificación: Según nuestro conocimiento, ni la alfuzosina ni la diltiazem aumentan la actividad serotoninérgica.
|Kiesel & Durán b||0||Ø||Ø|
Clasificación: Según nuestros hallazgos, la alfuzosina no aumenta la actividad anticolinérgica. El efecto anticolinérgico de diltiazem no es relevante.
Extensión de tiempo QT
La alfuzosina puede aumentar potencialmente el tiempo de QT, pero no sabemos acerca de las arritmias torsades de pointes. No conocemos ningún potencial de prolongación del intervalo QT para la diltiazem.
Efectos secundarios generales
|Efectos secundarios||∑ frecuencia||alf||dil|
|Dolor de cabeza||7.5 %||3.0||4.6|
|Edema periférico||6.3 %||n.a.||6.3|
|Infeccion de las vias respiratorias altas||3.0 %||3.0||n.a.|
|Insuficiencia cardiaca||1.9 %||n.a.||1.9|
|Dolor abdominal||1.0 %||+||n.a.|
Bloqueo auriculoventricular: diltiazem
Hipotensión ortostática: alfuzosina
Infarto de miocardio: diltiazem
Reacciones alérgicas de la piel: diltiazem
Síndrome de iris flácido intraoperatorio: alfuzosina
Con base en sus
Referencias de literatura
Abstract: The aim of this study was to assess the linearity of pharmacokinetic of alfuzosin, administered by oral route, at the doses of 1, 2.5, and 5 mg to 12 young healthy volunteers. The pharmacokinetic parameters (tmax, Cmax, AUC, t1/2 beta) obtained from plasma alfuzosin concentrations after administration of the three doses show that pharmacokinetics of alfuzosin is linear in the range of doses 1-5 mg. Mean pharmacokinetic parameters of alfuzosin observed after 1, 2.5, and 5 mg were, respectively: tmax (h) 1.5 +/- 0.3, 1.1 +/- 0.2, 1.3 +/- 0.1; Cmax (ng ml-1) 2.6 +/- 0.3, 9.4 +/- 1.2, 13.5 +/- 1.0; AUC (ng ml-1 h) 17.7 +/- 2.9, 51.7 +/- 7.1, 99.0 +/- 14.1; t1/2 (h) 3.7 +/- 0.4, 3.9 +/- 0.2, 3.8 +/- 0.3. Cmax (corrected by the dose) obtained after 2.5 mg was significantly higher than those obtained after 1 and 5 mg. This difference seems to be due principally to the intraindividual variability. The absence of statistically significant difference on individual values of AUC corrected by the administered dose, supports the linearity of the pharmacokinetics of alfuzosin in the range of doses between 1 and 5 mg. Some postural hypotension, clinical criterion, was observed with a frequency increasing with the dose in these healthy subjects: 0 volunteers of 12 after 1 mg, 3 volunteers of 12 after 2.5 mg and 4 volunteers of 12 after 5 mg.
Abstract: The calcium antagonists are valuable and widely used agents in the management of essential hypertension and angina. There is an increasing number of new agents to add to the 3 prototype substances nifedipine, diltiazem and verapamil. These new agents are dihydropyridines structurally related to nifedipine. However, they tend to have longer elimination half-lives (t 1/2 beta) and may be suitable for twice-daily administration. Amlodipine is an exception with a t 1/2 beta in excess of 30h. Apart from elimination rates, however, the pharmacokinetic characteristics of the newer agents have a notable tendency to resemble those of the established agents. They are highly cleared drugs, are relatively highly protein bound. As they are subject to significant first-pass metabolism, old age and hepatic impairment will increase their plasma concentrations due to a reduced first-pass effect. Renal impairment does little to their pharmacokinetics since the fraction eliminated unchanged by the kidney is small. For most agents, plasma concentration-response relationships have been described. Interesting areas for further research include chronopharmacokinetics, stereoselective pharmacokinetics and lipid solubility. Drugs affecting hepatic blood flow and drug metabolising capacity have predictable interaction potential. Some of the newer calcium antagonists will, like verapamil, increase plasma digoxin concentrations. Verapamil and diltiazem decrease phenazone (antipyrine) metabolism and therefore tend to decrease the metabolism of other drugs.
Abstract: We have investigated the pharmacokinetics of 14C-labeled diltiazem, 20 mg, given as an i.v. infusion over 20 min in 10 healthy volunteers. This disposition of the drug could be described using a two-compartment model with half-lives of 0.40 +/- 0.48 h (mean +/- SD) in the alpha phase and 2.77 +/- 0.82 h in the beta phase. Systemic clearance was 992 +/- 159 ml/min; the volume of the central compartment was 119 +/- 77 L, and the volume of distribution at steady state was 209 +/- 56 L. The concentrations of metabolites (deacetyldiltiazem, N-demethyldiltiazem, and N-demethyl-deacetyldiltiazem) were low, and no pharmacokinetic parameters for these could be calculated. The median cumulative excretion of radioactivity during 120 h was 87.3%. The drug was mainly excreted in urine (71.1 +/- 7.8%), and the remaining amounts was excreted in feces. There were slight but significant decreases in supine systolic and diastolic blood pressures and heart rate. The PQ interval was significantly prolonged for 5 h, and in multiple regression analyses there were good correlations (p less than 0.01) between PQ intervals and logarithms of plasma concentrations of diltiazem.
Abstract: Six healthy male volunteers received single doses of diltiazem hydrochloride on three occasions separated by at least 10 days. Modes of administration were: 10-minute intravenous infusion of a 20-mg dose; oral administration of 120 mg in solution form; and oral administration of 120 mg as two 60-mg sustained-release tablets. Diltiazem concentrations were measured by electron-capture gas chromatography in multiple plasma samples drawn during the 36 hours after dosage. Following intravenous administration, mean (+/- S.E.) pharmacokinetic variables were: elimination half-life, 11.2 (+/- 2.1) hours; volume of distribution, 11.1 (+/- 3.0) liters/kg; and total clearance, 11.5 (+/- 0.7) ml/min/kg. Oral diltiazem in solution form was rapidly absorbed, with peak plasma levels attained at 38 (+/- 6) minutes after the dose. Absolute systemic availability averaged 44% (+/- 4%). Oral administration of sustained-release tablets yielded, as predicted, slower absorption, with peak plasma concentrations attained at an average of 165 (+/- 22) minutes after dosage. Thus, oral diltiazem is incompletely bioavailable after oral administration, mainly because of first-pass hepatic extraction.
Abstract: OBJECTIVE: In a previous study of diltiazem (DTZ) pharmacokinetics in renal transplant patients, we speculated that a polymorphic enzyme could be involved in O-demethylation of diltiazem. The aim of this in vitro study was to investigate whether O-demethylation of DTZ is mediated by cytochrome P450-2D6 (CYP2D6). METHODS: DTZ was incubated with transfected human liver epithelial (THLE) cells expressing CYP2D6 (T5-2D6 clone). Metabolism of DTZ was studied over a concentration range of 12.5-400 microM and in the presence of quinidine (a CYP2D6 inhibitor) or erythromycin (a CYP3A4 inhibitor). THLE cells lacking CYP2D6 activity (T5-neo clone) were used as control. The culture medium of the cells, in which DTZ was dissolved, was analysed for DTZ and metabolites prior to and after 8 h of incubation using high-performance liquid chromatography (HPLC, UV detection). Authentic O-demethyl-DTZ (Mx) was not available, and this metabolite was therefore not identifiable. RESULTS: Desacetyl-O-demethyl-DTZ (M4) was exclusively produced during incubations of DTZ with THLE cells expressing CYP2D6. The rate of M4 formation was described using Michaelis Menten kinetics in the concentration range of DTZ used. Production of M4 was inhibited by quinidine, but not erythromycin. An unidentified chromatographic peak, which was interpreted to be Mx, showed the same pattern of formation as M4 both in absence and presence of inhibitors. N-demethylated metabolites, formed by CYP3A4, were not observed in any of the cell lines. CONCLUSION: Evidence was provided in vitro that O-demethylation of DTZ is mediated by the polymorphic isoenzyme CYP2D6. Involvement of CYP2D6 in the metabolism of DTZ may have clinical implications regarding pharmacokinetic variability and interactions.
Abstract: It has earlier been shown that the isoenzymes CYP2D6 and CYP3A4 are involved in O- and N-demethylation of diltiazem (DTZ), respectively. Apparently, CYP3A4 plays a more prominent role than CYP2D6 in the overall metabolism of DTZ. However, previous observations indicate that the opposite might be true for the pharmacologically active metabolite desacetyl-DTZ (M1). Thus, the aim of the present in vitro investigation was to study the relative affinity of M1 to CYP2D6 and CYP3A4. Immortalized human liver epithelial cells transfected with either CYP2D6 or CYP3A4 were used as a model system, and the presence of M1 and its metabolites in the cell culture medium was analyzed by high-performance liquid chromatography/UV detection both before and following 90 min of incubation. The estimated K(m) value for the CYP2D6-mediated O-demethylation of M1 was approximately 5 microM. In comparison, the affinity of M1 to CYP3A4 (N-demethylation) was about 100 times lower (K(m), approximately 540 microM) than to CYP2D6. These in vitro data suggest that M1 metabolism via CYP2D6, in contrast to the parent drug, probably is the preferred pathway in vivo. Metabolism mediated through CYP2D6 is associated with a substantial interindividual variability, and since M1 expresses pharmacological activity, individual CYP2D6 metabolic capacity might be an aspect to consider when using DTZ.
Abstract: OBJECTIVES: Recently, it was shown in vitro that the polymorphic enzyme cytochrome P450 (CYP) 2D6 mediates O-demethylation of diltiazem. The aim of this study was to compare the pharmacokinetics of diltiazem and its major metabolites in healthy human volunteers representing different CYP2D6 genotypes. METHODS: Norwegians of Caucasian origin were screened for their CYP2D6 genotype on the LightCycler (Roche Diagnostics, Mannheim, Germany) by melting-curve analysis of allele-specific fluorescence resonance energy transfer probes hybridized to polymerase chain reaction-amplified deoxyribonucleic acid. The first 5 individuals identified with genotypes corresponding to a homozygous extensive, heterozygous extensive, or homozygous poor CYP2D6-metabolizing phenotype, respectively, were voluntarily enrolled in the pharmacokinetic study. The participants received diltiazem, 120 mg, as a single oral dose, and plasma samples were collected up to 24 hours after administration. Plasma samples were purified by solid phase extraction. Diltiazem and 7 phase I metabolites were analyzed by liquid chromatography-mass spectrometry. RESULTS: The pharmacokinetics of diltiazem was not significantly different between the subgroups. However, the systemic exposure of the pharmacologically active metabolites desacetyl diltiazem and N-demethyldesacetyl diltiazem was > or = 5 times higher in poor CYP2D6 metabolizers than in extensive CYP2D6 metabolizers (P <.01). CONCLUSIONS: CYP2D6 activity does not have a major impact on the disposition of diltiazem. In contrast, desacetyl diltiazem and N-demethyldesacetyl diltiazem are markedly accumulated in individuals expressing a deficient CYP2D6 phenotype. Because these metabolites exhibit pharmacologic properties of possible importance, individual CYP2D6 activity might be an aspect to consider in the clinical use of diltiazem.
Abstract: The effect of renal impairment on the safety and pharmacokinetics of a once-daily formulation of alfuzosin, 10 mg, was evaluated. In an open, single-dose study, 26 volunteers, ages 18 to 65 years, were classified as having normal renal function (n = 8) or mild (n = 6), moderate (n = 6), or severe (n = 6) renal impairment. Mean Cmax values increased by a factor of 1.20, 1.52, and 1.20 in subjects with mild, moderate, or severe renal impairment, respectively, compared with controls. Values for AUC(0-infinity) were 1.46, 1.47, and 1.44, respectively. The t(1/2z) was increased only in the group with severe renal impairment. Emergent vasodilatory adverse events were reported by 4 of 26 subjects. No discontinuations due to adverse events occurred. Laboratory parameters were satisfactory in all groups. In conclusion, once-daily alfuzosin, 10 mg, could be safely administered to patients with impaired renal function, and dosage adjustment does not seem necessary.
Abstract: BACKGROUND: The formulas for heart rate (HR) correction of QT interval have been shown to overcorrect or undercorrect this interval with changes in HR. A Holter-monitoring method avoiding the need for any correction formulas is proposed as a means to assess drug-induced QT interval changes. METHODS: A thorough QT study included 2 single doses of the alpha1-adrenergic receptor blocker alfuzosin, placebo, and a QT-positive control arm (moxifloxacin) in 48 healthy subjects. Bazett, Fridericia, population-specific (QTcN), and subject-specific (QTcNi) correction formulas were applied to 12-lead electrocardio-graphic recording data. QT1000 (QT at RR = 1000 ms), QT largest bin (at the largest sample size bin), and QT average (average QT of all RR bins) were obtained from Holter recordings by use of custom software to perform rate-independent QT analysis. RESULTS: The 3 Holter end points provided similar results, as follows: Moxifloxacin-induced QT prolongation was 7.0 ms (95% confidence interval [CI], 4.4-9.6 ms) for QT1000, 6.9 ms (95% CI, 4.8-9.1 ms) for QT largest bin, and 6.6 ms (95% CI, 4.6-8.6 ms) for QT average. At the therapeutic dose (10 mg), alfuzosin did not induce significant change in the QT. The 40-mg dose of alfuzosin increased HR by 3.7 beats/min and induced a small QT1000 increase of 2.9 ms (95% CI, 0.3-5.5 ms) (QTcN, +4.6 ms [95% CI, 2.1-7.0 ms]; QTcNi, +4.7 ms [95% CI, 2.2-7.1 ms]). Data corrected by "universal" correction formulas still showed rate dependency and yielded larger QTc change estimations. The Holter method was able to show the drug-induced changes in QT rate dependence. CONCLUSIONS: The direct Holter-based QT interval measurement method provides an alternative approach to measure rate-independent estimates of QT interval changes during treatment.
Abstract: BACKGROUND: Anticholinergic drugs are often involved in explicit criteria for inappropriate prescribing in older adults. Several scales were developed for screening of anticholinergic drugs and estimation of the anticholinergic burden. However, variation exists in scale development, in the selection of anticholinergic drugs, and the evaluation of their anticholinergic load. This study aims to systematically review existing anticholinergic risk scales, and to develop a uniform list of anticholinergic drugs differentiating for anticholinergic potency. METHODS: We performed a systematic search in MEDLINE. Studies were included if provided (1) a finite list of anticholinergic drugs; (2) a grading score of anticholinergic potency and, (3) a validation in a clinical or experimental setting. We listed anticholinergic drugs for which there was agreement in the different scales. In case of discrepancies between scores we used a reputed reference source (Martindale: The Complete Drug Reference®) to take a final decision about the anticholinergic activity of the drug. RESULTS: We included seven risk scales, and evaluated 225 different drugs. Hundred drugs were listed as having clinically relevant anticholinergic properties (47 high potency and 53 low potency), to be included in screening software for anticholinergic burden. CONCLUSION: Considerable variation exists among anticholinergic risk scales, in terms of selection of specific drugs, as well as of grading of anticholinergic potency. Our selection of 100 drugs with clinically relevant anticholinergic properties needs to be supplemented with validated information on dosing and route of administration for a full estimation of the anticholinergic burden in poly-medicated older adults.
Abstract: PURPOSE: To assess the possibility of using CYP2D6 10 +/- CYP3A5*3 as biomarkers to predict the pharmacokinetics of diltiazem and its two metabolites among healthy Chinese subjects. METHODS 41 healthy Chinese were genotyped for CYP3A5 3 and CYP2D6 10, and then received a single oral dose of diltiazem hydrochloride capsules (300 mg). Multiple blood samples were collected over 48 h, and the plasma concentrations of diltiazem, N-desmethyl diltiazem and desacetyl diltiazem were determined by HPLC-MS/MS. The relationships between the genotypes and pharmacokinetics were investigated. RESULTS: The pharmacokinetics of diltiazem, N-desmethyl diltiazem were not significantly affected by both CYP3A5 3 and CYP2D6*10 alleles. However, the systemic exposure of the pharmacologyically active metabolites, desacetyl diltiazem, was 2-fold higher in CYP2D6 10/10 genotype carriers than in 1/10 or 1/1 ones (AUC(o-inf) of CYP2D6 1/1, 1/10 and 10/10 are 398.2 +/- 162.9, 371,0 69.2 and 726.2 +/- 468.1 respectively, p <0.05). CONCLUSIONS: Two of the most frequent alleles, CYP3A5 3 and CYP2D6 10, among Chinese do not have major impacts on the disposition of diltiazem and N-desmethyl diltiazem. However, the desacetyl diltiazem showed 2-fold accumulation in individuals with CYP2D6 10/10 genotype. Despite this, the effect of genotype of CYP2D6 on clinical outcome of diltiazem treatment is expected to be limited.
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.