Intervallo QT lungo
Reazione avversa da farmaco (ADR)
Varianti ✨Per l'analisi computazionale dettagliata delle varianti, si prega di selezionare l'abbonamento standard a pagamento.
Informazioni dei farmaci per i pazienti
Non abbiamo ulteriori avvertenze per la co-somministrazione di dibenzepina e diltiazem. Si prega di consultare le informazioni specialistiche pertinenti.
I cambiamenti riportati in seguito all'esposizione corrispondono ai cambiamenti nell'area sottesa alla curva concentrazione plasmatica-tempo [ AUC ]. Non ci aspettiamo nessun cambiamento nell'esposizione alla dibenzepina, quando è co-somministrata con la diltiazem (100%). Non ci aspettiamo nessun cambiamento nell'esposizione alla diltiazem, quando è co-somministrata con la dibenzepina (100%).
I parametri farmacocinetici della popolazione media sono utilizzati come punto di partenza per calcolare i cambiamenti del singolo individuo esposto alle interazioni farmacologiche
La dibenzepina ha una bassa biodisponibilità [ F ] orale, perciò nel corso di un interazione farmacologica la concentrazione plasmatica massima (Cmax) tende fortemente a cambiare. L'emivita [ t12 ] del farmaco è piuttosto breve in 5 ore e lo stato stazionario [Css] si raggiunge molto velocemente. Il legame proteico [ Pb ] è moderatamente forte al 80%. Il metabolismo non avviene attraverso i tipici citocromi. .
La diltiazem ha una bassa biodisponibilità [ F ] orale, perciò nel corso di un interazione farmacologica la concentrazione plasmatica massima (Cmax) tende fortemente a cambiare. L'emivita [ t12 ] del farmaco è piuttosto breve in 6 ore e lo stato stazionario [Css] si raggiunge molto velocemente. Il legame proteico [ Pb ] è moderatamente forte al 77.5% e il volume di distribuzione [ Vd ] è molto grande in 350 litri. per cui, con un significativo tasso di estrazione epatico dello 0.53, hanno importanza sia il flusso ematico a livello del fegato [Q] sia le variazioni di legame alle proteine plasmatiche [Pb]. Tra l'altro, il metabolismo avviene rispettivamente attraverso gli enzimi CYP2D6 e CYP3A4. e il trasporto attivo avviene in particolare attraverso i trasportatori PGP e TRA8X8.
|Effetti serotoninergici a||0||Ø||Ø|
Valutazione: Sulla base dei dati a nostra disposizione, né la dibenzepina né la diltiazem potenziano l'attività serotoninergica.
|Kiesel & Durán b||1||+||Ø|
Avvertenze e precauzioni: Per precauzione, si dovrebbe porre attenzione ai sintomi di tipo anticolinergico, soprattutto se il dosaggio è stato aumentato oppure se è al di sopra dell'intervallo terapeutico.
Valutazione: Somministrata unicamente, la Dibenzepina possiede lievi effetti anticolinergici. Il rischio di sindrome anticolinergica è molto basso se si rispettano i dosaggi abituali. L'effetto anticolingerico della diltiazem non è rilevante.
Intervallo QT lungo
Non è noto se la dibenzepina e la diltiazem siano in grado di prolungare l'intervallo QT
Effetti collaterali generali
|Effetti collaterali||∑ frequenza||dib||dil|
|Edema periferico||6.3 %||n.a.||6.3|
|Mal di testa||4.6 %||n.a.||4.6|
|Insufficienza cardiaca||1.9 %||n.a.||1.9|
|Blocco atrioventricolare||1.0 %||n.a.||+|
|Reazioni allergiche della pelle||1.0 %||n.a.||+|
|Infarto miocardico||0.0 %||n.a.||0.01|
Abbiamo valutato il rischio individuale di effetti indesiderati in base alle risposte fornite ed alle informazioni scientifiche disponibili. Le informazioni contenute nel sito hanno esclusivamente scopo informativo e non sostituiscono il parere del medico. Si accomanda pertanto di chiedere sempre il parere del proprio medico curante e/o di specialisti riguardo qualsiasi indicazione riportata. Nella versione alpha test, il rischio di tutti i farmaci non è stato ancora completamente valutato.
Abstract: The antimuscarinic potency of dibenzepin (Noveril) was estimated by measuring (a) central in vivo effects in mice (antihypothermia and antitremor, both induced by oxotremorine), (b) peripheral in vivo activity (mydriasis caused by systemic administration of the drug), (c) the effects of dibenzepin on isolated smooth muscle from guinea pig ileum, and (d) in vitro determination of the affinity constant of dibezepine toward the muscarinic binding sites in whole mouse-brain homogenate. The data allowed the construction of a normalized antimuscarinic potency scale for some of the common tricyclic antidepressants. With a value of 1 for scopolamine, the following relative anticholinergic potencies were calculated: dibenzepin--1/600, nortriptylne--1/300, imipramine - 1/200, and amitriptyline - 1/75. These values suggest an explanation for the absence of clinically detectable anticholinergic side effects during treatment of depression with high doses of dibenzepin. Structural and spatial interrelations among various tricyclic antidepressants and scopolamine are discussed.
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: 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.