piperidines and Atrioventricular-Block

Acetylcholinesterase inhibitors such as donepezil delay the progression of Alzheimer's dementia by increasing acetylcholine concentrations in the central nervous system. However, it is becoming apparent that cholinesterase inhibition by donepezil is not confined to the brain. This is supported by previous case reports of peripheral cholinergic side effects and adverse cardiac arrhythmias such as Torsades de Pointes which are reversible upon cessation of donepezil. The augmented acetylcholine concentrations and I

Topics: Alzheimer Disease; Animals; Arrhythmias, Cardiac; Atrioventricular Block; Cholinesterase Inhibitors; Dogs; Donepezil; Halothane; Indans; Piperidines

We analyzed torsadogenic and pharmacokinetic profile of E-4031 using chronic atrioventricular block dogs. E-4031 in intravenous doses of 0.03, 0.1 and 0.3 mg/kg over 10 min prolonged QT/QTc, and increased short-term variability of QT in a dose-related manner (n = 4), resulting in onset of torsade de pointes in 1 animal after the middle dose and 4 animals after the high dose, while it attained peak plasma concentrations of 16.5, 60.5 and 182.5 ng/mL at 10 min after their start of administration, respectively (n = 2). These results bridge the gap of information between in vitro proarrhythmia assay and clinical observation in human subjects.

Topics: Animals; Anti-Arrhythmia Agents; Atrioventricular Block; Chronic Disease; Dogs; Dose-Response Relationship, Drug; Electrocardiography; Humans; Infusions, Intravenous; Piperidines; Pyridines; Torsades de Pointes

We report a case of first-degree atrioventricular (A-V) block progressing to second-degree (Wenckebach-type) A-V block after administration of indigo carmine in a patient undergoing hysterectomy under general anesthesia. We believe that the onset of Wenckebach-type A-V block may have been induced by one or more of three factors: 1) preoperative first-degree A-V block, 2) the anesthetics used (propofol and remifentanil), and 3) administration of indigo carmine.

Topics: Adult; Anesthesia, General; Atrioventricular Block; Coloring Agents; Disease Progression; Electrocardiography; Female; Humans; Hysterectomy; Indigo Carmine; Intraoperative Complications; Leiomyoma; Piperidines; Propofol; Remifentanil; Ureter; Uterine Neoplasms; Vagus Nerve

Several drugs blocking the rapidly activating potassium (K(r)) channel cause malformations (including cardiac defects) and embryonic death in animal teratology studies. In humans, these drugs have an established risk for acquired long-QT syndrome and arrhythmia. Recently, associations between cardiac defects and spontaneous abortions have been reported for drugs widely used in pregnancy (e.g. antidepressants), with long-QT syndrome risk. To investigate whether a common embryonic adverse-effect mechanism exists in the human, rat, and rabbit embryos, we made a comparative study of embryonic cardiomyocytes from all three species.. Patch-clamp and quantitative-mRNA measurements of K(r) and slowly activating K (K(s)) channels were performed on human, rat, and rabbit primary cardiomyocytes and cardiac samples from different embryo-foetal stages. The K(r) channel was present when the heart started to beat in all species, but was, in contrast to human and rabbit, lost in rats in late organogenesis. The specific K(r)-channel blocker E-4031 prolonged the action potential in a species- and development-dependent fashion, consistent with the observed K(r)-channel expression pattern and reported sensitive periods of developmental toxicity. E-4031 also increased the QT interval and induced 2:1 atrio-ventricular block in multi-electrode array electrographic recordings of rat embryos. The K(s) channel was expressed in human and rat throughout the embryo-foetal period but not in rabbit.. This first comparison of mRNA expression, potassium currents, and action-potential characteristics, with and without a specific K(r)-channel blocker in human, rat, and rabbit embryos provides evidence of K(r)-channel inhibition as a common mechanism for embryonic malformations and death.

Topics: Action Potentials; Animals; Atrioventricular Block; Cells, Cultured; Electrocardiography; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels; Gene Expression Regulation, Developmental; Gestational Age; Heart Defects, Congenital; Humans; KCNQ1 Potassium Channel; Kinetics; Long QT Syndrome; Myocytes, Cardiac; Organogenesis; Patch-Clamp Techniques; Piperidines; Polymerase Chain Reaction; Potassium Channel Blockers; Potassium Channels, Voltage-Gated; Pyridines; Rabbits; Rats; Rats, Sprague-Dawley; Rats, Wistar; RNA, Messenger; Species Specificity; Teratogens

Donepezil is a commonly used drug in older people that due to its procholinergic effects can provoke bradycardia and neurocardiogenic syncope. Donepezil is metabolized by the cytochrome P450 isozyme 3A4 (CYP3A4). Clarithromycin is a potent inhibitor of CYP3A4, and patients taking both of these drugs may be at increased risk of cardiac adverse events.. The aim of this study was to evaluate the association between recent use of clarithromycin and adverse cardiovascular events in elderly patients receiving donepezil.. A population-based, nested case-control study using provincial healthcare databases was conducted. The base cohort was made up of persons 66 years of age or older who were prescribed donepezil and also were prescribed clarithromycin, erythromycin, azithromycin, cefuroxime, moxifloxacin or levofloxacin. Cases were those members of the base cohort hospitalized for bradycardia, syncope or complete atrioventricular block. For each case patient, five controls were matched according to age, sex and residence (community or long-term care).. Between July 2002 and March 2010, 17,712 patients continuously receiving donepezil were prescribed one of the antibacterials. In 1400 person-years of follow-up, 59 cases were identified. As compared with azithromycin, there was no statistically significant association between use of clarithromycin in donepezil users and subsequent adverse cardiovascular events (odds ratio 0.67; 95% CI 0.28, 1.63). There was no significant risk associated with exposure to either cefuroxime or respiratory quinolones.. The use of clarithromycin in elderly donepezil users did not significantly increase the risk of adverse cardiovascular outcomes. However, our study cannot rule out a possible small increase in risk. Although antibacterials can be beneficial, care should be taken in selecting antibacterials for use in older people receiving donepezil.

Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; Atrioventricular Block; Bradycardia; Cardiovascular Diseases; Case-Control Studies; Cholinesterase Inhibitors; Clarithromycin; Cohort Studies; Cytochrome P-450 CYP3A Inhibitors; Donepezil; Drug Interactions; Drug Prescriptions; Enzyme Inhibitors; Female; Humans; Indans; Macrolides; Male; Ontario; Piperidines; Syncope

Acetylcholinesterase inhibitors (AChIs) are widely used in the treatment of mild-to-moderate Alzheimer's disease (AD), but their cholinergic effects could generate adverse side effects in the cardiovascular system. This report presents the cases of 2 patients who experienced adverse side effects of cardiac rhythm with QT prolongation caused by Donepezil. Both of them improved to the original rhythm and shortened QT intervals after the discontinuation of Donepezil. The present cases suggest that the cholinergic effects of Donepezil could induce adverse side effects on cardiac rhythm and careful consideration is needed for the patients treated by Donepezil.

Topics: Aged, 80 and over; Atrioventricular Block; Cholinesterase Inhibitors; Donepezil; Female; Humans; Indans; Male; Piperidines; Torsades de Pointes