Cytochrome P450-mediated drug interactions affecting lidocaine

Lidocaine is a widely used local anaesthetic agent that also has anti-arrhythmic effects. It is classified as a type Ib anti-arrhythmic agent and is used to treat ventricular tachycardia or ventricular fibrillation. Lidocaine is eliminated mainly by metabolism, and less than 5% is excreted unchanged in urine. Lidocaine is a drug with a medium to high extraction ratio, and its bioavailability is about 30%. Based on in vitro studies, the earlier understanding was that CYP3A4 is the major cytochrome P450 (CYP) enzyme involved in the metabolism of lidocaine. When this work was initiated, there was little human data on the effect of inhibitors of CYP enzymes on the pharmacokinetics of lidocaine. Because lidocaine has a low therapeutic index, medications that significantly inhibit lidocaine clearance (CL) could increase the risk of toxicity. These studies investigated the effects of some clinically important CYP1A2 and CYP3A4 inhibitors on the pharmacokinetics of lidocaine administered by different routes. All of the studies were randomized, double-blind, placebo-controlled cross-over studies in two or three phases in healthy volunteers. Pretreatment with clinically relevant doses of CYP3A4 inhibitors erythromycin and itraconazole or CYP1A2 inhibitors fluvoxamine and ciprofloxacin was followed by a single dose of lidocaine. Blood samples were collected to determine the pharmacokinetic parameters of lidocaine and its main metabolites monoethylglycinexylidide (MEGX) and 3-hydroxylidocaine (3-OH-lidocaine). Itraconazole and erythromycin had virtually no effect on the pharmacokinetics of intravenous lidocaine, but erythromycin slightly prolonged the elimination half-life (t½) of lidocaine (Study I). When lidocaine was taken orally, both erythromycin and itraconazole increased the peak concentration (Cmax) and the area under the concentration-time curve (AUC) of lidocaine by 40-70% (Study II). Compared with placebo and itraconazole, erythromycin increased the Cmax and the AUC of MEGX by 40-70% when lidocaine was given intravenously or orally (Studies I and II). The pharmacokinetics of inhaled lidocaine was unaffected by concomitant administration of itraconazole (Study III). Fluvoxamine reduced the CL of intravenous lidocaine by 41% and prolonged the t½ of lidocaine by 35%. The mean AUC of lidocaine increased 1.7-fold (Study IV). After oral administration of lidocaine, the mean AUC of lidocaine in-creased 3-fold and the Cmax 2.2-fold by fluvoxamine (Study V). During the pretreatment with fluvoxamine combined with erythromycin, the CL of intravenous lidocaine was 53% smaller than during placebo and 21% smaller than during fluvoxamine alone. The t½ of lidocaine was significantly longer during the combination phase than during the placebo or fluvoxamine phase. The mean AUC of intravenous lidocaine increased 2.3-fold and the Cmax 1.4-fold (Study IV). After oral administration of lidocaine, the mean AUC of lidocaine increased 3.6-fold and the Cmax 2.5-fold by concomitant fluvoxamine and erythromycin. The t½ of oral lidocaine was significantly longer during the combination phase than during the placebo (Study V). When lidocaine was given intravenously, the combination of fluvoxamine and erythromycin prolonged the t½ of MEGX by 59% (Study IV). Compared with placebo, ciprofloxacin increased the mean Cmax and AUC of intravenous lidocaine by 12% and 26%, respectively. The mean plasma CL of lidocaine was reduced by 22% and its t½ prolonged by 7% (Study VI). These studies clarify the principal role of CYP1A2 and suggest only a modest role of CYP3A4 in the elimination of lidocaine in vivo. The inhibition of CYP1A2 by fluvoxamine considerably reduces the elimination of lidocaine. Concomitant use of fluvoxamine and the CYP3A4 inhibitor erythromycin further increases lidocaine concentrations. The clinical implication of this work is that clinicians should be aware of the potentially increased toxicity of lidocaine when used together with inhibitors of CYP1A2 and particularly with the combination of drugs inhibiting both CYP1A2 and CYP3A4 enzymes.

Spiral-Wave Turbulence and Its Control in the Presence of Inhomogeneities in Four Mathematical Models of Cardiac Tissue

Regular electrical activation waves in cardiac tissue lead to the rhythmic contraction and expansion of the heart that ensures blood supply to the whole body. Irregularities in the propagation of these activation waves can result in cardiac arrhythmias, like ventricular tachycardia (VT) and ventricular fibrillation (VF), which are major causes of death in the industrialised world. Indeed there is growing consensus that spiral or scroll waves of electrical activation in cardiac tissue are associated with VT, whereas, when these waves break to yield spiral- or scroll-wave turbulence, VT develops into life-threatening VF: in the absence of medical intervention, this makes the heart incapable of pumping blood and a patient dies in roughly two-and-a-half minutes after the initiation of VF. Thus studies of spiral- and scroll-wave dynamics in cardiac tissue pose important challenges for in vivo and in vitro experimental studies and for in silico numerical studies of mathematical models for cardiac tissue. A major goal here is to develop low-amplitude defibrillation schemes for the elimination of VT and VF, especially in the presence of inhomogeneities that occur commonly in cardiac tissue. We present a detailed and systematic study of spiral- and scroll-wave turbulence and spatiotemporal chaos in four mathematical models for cardiac tissue, namely, the Panfilov, Luo-Rudy phase 1 (LRI), reduced Priebe-Beuckelmann (RPB) models, and the model of ten Tusscher, Noble, Noble, and Panfilov (TNNP). In particular, we use extensive numerical simulations to elucidate the interaction of spiral and scroll waves in these models with conduction and ionic inhomogeneities; we also examine the suppression of spiral- and scroll-wave turbulence by low-amplitude control pulses. Our central qualitative result is that, in all these models, the dynamics of such spiral waves depends very sensitively on such inhomogeneities. We also study two types of control chemes that have been suggested for the control of spiral turbulence, via low amplitude current pulses, in such mathematical models for cardiac tissue; our investigations here are designed to examine the efficacy of such control schemes in the presence of inhomogeneities. We find that a local pulsing scheme does not suppress spiral turbulence in the presence of inhomogeneities; but a scheme that uses control pulses on a spatially extended mesh is more successful in the elimination of spiral turbulence. We discuss the theoretical and experimental implications of our study that have a direct bearing on defibrillation, the control of life-threatening cardiac arrhythmias such as ventricular fibrillation.

Scroll-Wave Dynamics in Human Cardiac Tissue: Lessons from a Mathematical Model with Inhomogeneities and Fiber Architecture

Cardiac arrhythmias, such as ventricular tachycardia (VT) and ventricular fibrillation (VF), are among the leading causes of death in the industrialized world. These are associated with the formation of spiral and scroll waves of electrical activation in cardiac tissue; single spiral and scroll waves are believed to be associated with VT whereas their turbulent analogs are associated with VF. Thus, the study of these waves is an important biophysical problem. We present a systematic study of the combined effects of muscle-fiber rotation and inhomogeneities on scroll-wave dynamics in the TNNP (ten Tusscher Noble Noble Panfilov) model for human cardiac tissue. In particular, we use the three-dimensional TNNP model with fiber rotation and consider both conduction and ionic inhomogeneities. We find that, in addition to displaying a sensitive dependence on the positions, sizes, and types of inhomogeneities, scroll-wave dynamics also depends delicately upon the degree of fiber rotation. We find that the tendency of scroll waves to anchor to cylindrical conduction inhomogeneities increases with the radius of the inhomogeneity. Furthermore, the filament of the scroll wave can exhibit drift or meandering, transmural bending, twisting, and break-up. If the scroll-wave filament exhibits weak meandering, then there is a fine balance between the anchoring of this wave at the inhomogeneity and a disruption of wave-pinning by fiber rotation. If this filament displays strong meandering, then again the anchoring is suppressed by fiber rotation; also, the scroll wave can be eliminated from most of the layers only to be regenerated by a seed wave. Ionic inhomogeneities can also lead to an anchoring of the scroll wave; scroll waves can now enter the region inside an ionic inhomogeneity and can display a coexistence of spatiotemporal chaos and quasi-periodic behavior in different parts of the simulation domain. We discuss the experimental implications of our study.

Heart Rhythm UK position statement on clinical indications for implantable cardioverter defibrillators in adult patients with familial sudden cardiac death syndromes

Whilst the decision regarding defibrillator implantation in a patient with a familial sudden cardiac death syndrome is likely to be most significant for any particular individual, the clinical decision-making process itself is complex and requires interpretation and extrapolation of information from a number of different sources. This document provides recommendations for adult patients with the congenital Long QT syndromes, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, hypertrophic cardiomyopathy, and arrhythmogenic right ventricular cardiomyopathy. Although these specific conditions differ in terms of clinical features and prognosis, it is possible and logical to take an approach to determining a threshold for implantable cardioveter-defibrillator implantation that is common to all of the familial sudden cardiac death syndromes based on estimates of absolute risk of sudden death. Published on behalf of the European Society of Cardiology. © The Author 2010.

Troubles du rythme cardiaque dans les modèles murins transgéniques

Thèse en cotutelle avec Université de Nantes - Pays de La Loire - France (2005-2010)

Dynamique spatio-temporelle de circuits de réentrée chez le sujet humain et dans un modèle d'infarctus du myocarde chez le chien

Thèse numérisée par la Division de la gestion de documents et des archives de l'Université de Montréal

Incidencia de fibrilación auricular en pacientes con dispositivos de estimulación cardiaca con cardiopatía chagásica y no chagásica

La posible asociación entre el desarrollo de fibrilación auricular (FA) con la presencia de cardiopatía chagásica en una población portadora de dispositivos cardiacos de estimulación no está descrita. Se presenta un estudio de tipo cohorte retrospectivo realizado en la FCI que recopila las principales características clínicas de una población de pacientes con cardiopatía de variada etiología y portadores de dispositivos cardiacos buscando evaluar la incidencia de FA en presencia de cardiomiopatía de origen chagásico y no chagásico. A la fecha no se cuenta con una base de datos institucional ni regional que contenga las variables analizadas. Durante los 5 meses que duró la construcción de la base de datos se incluyeron 99 sujetos de investigación. Se implantaron 42 marcapasos bicamerales, 39 cardiodesfibriladores bicamerales, 6 dispositivos correspondientes cardiodesfibrilador con función de resincronización cardiaca, 2 resincronizadores cardiacos sin función de cardiodesfibrilador y 7 cardiodesfibriladores unicamerales. De los 99 sujetos recolectados se presentaron 8 desenlaces (FA de novo) y de esos solamente 1 pertenece al grupo de pacientes con cardiomiopatía chagásica. Este número reducido de desenlaces no permitió desarrollar un modelo de regresión de Cox y ni otros tipos de análisis estadísticos planteados en el protocolo inicial debido al bajo número de casos y pobre poder estadístico. Esta dificultad es inherente a la naturaleza del problema a estudiar y al corto tiempo de seguimiento. Por lo anterior no se puede establecer si existe una relación entre la presencia de serología positiva para infección por T. Cruzi y la presencia de FA de novo.

Prevalencia de anormalidades estructurales cardiacas en pacientes con enfermedad isquémica. Bogotá 2007 – 2009

Introducción: Las enfermedades cardiovasculares son la causa de muerte más frecuente en el mundo desarrollado, la mayoría de éstas se relacionan con alteraciones de las arterias coronarias, sin embargo un subgrupo de pacientes presentan como causa de isquemia cardiaca alteraciones estructurales. Material y métodos: Estudio Descriptivo. Se utilizó la base de datos recolectada en un servicio de hemodinamia de Bogotá durante dos años. Se aplicaron criterios de inclusión y exclusión y se determinaron cuatro grupos etáreos, a todos los pacientes se les practicó cateterismo cardiaco diagnóstico. Las variables analizadas fueron: diagnóstico de referencia, antecedentes y resultados del cateterismo incluyendo presencia de anomalías estructurales como las valvulopatias, el origen anómalo de las coronarias y los puentes miocárdicos. Para el análisis descriptivo se utilizó reporte de prevalencias y para el análisis de asociaciones se utilizaron tablas de contingencia y el estadístico de prueba Chi cuadrado, no se realizó análisis multivariado debido a que no se encontraron asociaciones estadísticamente significativas. Resultados: La edad promedio de los pacientes fue de 62 años (DS= 10,5), la representación del género masculino fue del 61,7%, la prevalencia de angina estable fue del 61,6%, los 3 antecedentes más prevalentes fueron: hipertensión arterial (41,4%), la hiperlipidemia (19,1%) y la Diabetes Mellitus (17,7%). La prevalencia de las alteraciones estructurales en la población de estudio de manera general fue del 12,9%, y su distribución por tipo fue: 1,4% para puentes miocárdicos, 0,7% para origen anómalo de las arterias coronarias y 10,8% de enfermedad valvular. Conclusiones: Se encontró una asociación entre los antecedentes médicos y la presencia de valvulopatias cardiacas. Se evidenció que el género no tiene relación con la presencia de alteraciones cardíacas a pesar de la mayor participación de hombres en la población de estudio. Las limitantes de este estudio se relacionaron con el tamaño de muestra, debido a la baja prevalencia de las anomalías estructurales medidas.

Incidencia de fibrilación auricular en las primeras 72 horas del post operatorio de revascularización miocárdica

Determinar la incidencia de fibrilación auricular en las primeras 72 horas del post operatorio en pacientes llevados a revascularización miocárdica utilizando dos técnicas de anestésia una convencional (AC) con anestésicos inhalados y opioides y otra con dexmedetomidina (AD.). cohorte retrospectivo, en donde se seleccionarán dos grupos de estudio, un grupo de expuestos, pacientes llevados a revascularización miocárdica con utilización técnica anestésica convencional y un grupo de no expuestos pacientes llevados a revascularización miocárdica con uso de dexmedetomidina como técnica de anestesia; A estos grupos se les hizo seguimiento por 72 horas para determinar la presencia de fibrilación auricular y la terapéutica instaurada.

Isquemia silenciosa e arritmias ventriculares são preditores independentes de evenos no pós-infarto do miocárdio de baixo risco

pós-infarto agudo do miocárdio (IAM) têm mostrado baixo valor preditivo positivo quando estudados isoladamente. A possibilidade da Eletrocardiografia Dinâmica de 24 horas (ECGD) fornecer dados referentes a isquemia silenciosa (IS), arritmias ventriculares e modulação autonômica do coração pelo estudo da variabilidade da freqüência cardíaca (VFC), levou o autor a empregar este método em pacientes acometidos de IAM com o objetivo de avaliar se estas três variáveis estariam relacionadas a presença de eventos desfavoráveis em evolução a médio prazo. Material e Métodos – Foram selecionados 91 pacientes acometidos de um primeiro IAM não-complicado e realizados exames de ECGD de 24 h por dois dias consecutivos, antes da alta hospitalar. Os parâmetros pesquisados nos exames foram: isquemia silenciosa, identificação e quantificação de arritmias ventriculares e determinação dos índices de VFC pelos métodos do domínio do tempo e do mapa de retorno tridimensional. Foram considerados como desfechos: re-infarto, angina instável, taquicardia ventricular sustentada e morte. Resultados – No seguimento médio de 27,7 meses (DP=15,45), 23 (25%) dos pacientes apresentaram eventos, sendo nove fatais. Os eventos foram mais freqüentes entre os pacientes que apresentaram extra-sístoles ventriculares ≥10/hora (p=0,01) e também naqueles com IS (p=0,02). Em modelo de análise multifatorial, a presença de dislipidemia elevou o valor preditivo positivo dessas variáveis. Nenhum dos índices de VFC esteve significativamente relacionado ao surgimento de eventos. Conclusões – Em pacientes pós-IAM de baixo risco, a presença de arritmias ventriculares freqüentes ou de isquemia silenciosa está relacionada a um prognóstico desfavorável. O estudo da VFC não mostrou utilidade na estratificação de risco destes pacientes.

Clinical and electrocardiographic evaluation during experimental toad poisoning in dogs

Accidents involving toad poisoning are frequent and dogs are the most common victims; they become poisoned by biting or ingesting a toad. When released in the organism, the venom is absorbed by both the oral mucosa and the digestive tract, initiating its toxic action. The aim of this work was to evaluate the clinical and electrocardiographic aspects of dogs subjected to experimental toad poisoning, as well as their response to treatment with propranolol. Twenty dogs were divided into two groups, a control group (n = 5) and a poisoned group (n = 15). After general anesthesia, the control group received a placebo, while the poisoned group received a venom aliquot through an orogastric tube. Results were tested through multivariate analysis (p < 0.05). The animals in the poisoned group had gastrointestinal symptoms including emesis, intense salivation, hyperemic or congested oral mucosa and pasty diarrhea. Non-responsive mydriasis, nystagmus, depression, stupor, tachypnea, opisthotonus and ataxia were also manifested by 100% of the poisoned animals. Affected dogs had an increase in blood pressure, statistically significant throughout study. Five poisoned animals developed ventricular tachycardia and were treated with propranolol (0.5 mg/kg IV). All propranolol-treated animals returned to normal sinus rhythm, which evidences the efficacy of this drug to treat ventricular arrhythmias caused by toad venom.

Ação antiarrítmica do isofluorano em cães submetidos à arritmias ventriculares induzidas por cloreto de bário

Avaliou-se a ação antiarrítmica do isofluorano em cães submetidos a arritmias ventriculares pelo uso de cloreto de bário, utilizando-se de seis cães, machos e fêmeas, que receberam uma dose de 3mg/kg de peso IV de cloreto de bário a 2,5% (G1). O mesmo protocolo foi repetido, nos mesmos animais, sob anestesia geral com isofluorano (G2). Usou-se a eletrocardiografia computadorizada para avaliar o ritmo cardíaco, a duração e/ou amplitude das ondas e os intervalos eletrocardiográficos. Não se verificou alteração no ritmo cardíaco em G2, diferente de G1, que apresentou freqüentes arritmias ventriculares na forma de bigeminismo e taquicardia ventricular multifocal. Houve diferença significativa entre os grupos em relação à freqüência cardíaca nos minutos iniciais de observação, quando ocorreu aumento na freqüência cardíaca em G1. A utilização do isofluorano conferiu ação antiarrítmica em cães com arritmias induzidas pelo cloreto de bário, reforçando suas indicações a pacientes com risco considerável de desenvolvimento de arritmias ventriculares.

Assessment of electrocardiographic parameters in healthy dogs undergoing dobutamine stress testing

The electrocardiographic effects of dobutamine stress testing (10 to 40 mu g/kg/minute) were investigated in five conscious healthy dogs. We studied the changes in the duration and amplitude of P wave, PR interval, duration of QRS complex, R wave amplitude, QT interval, and heart rate. Development of arrhythmias and ST segment abnormalities were also recorded. It was observed that dobutamine significantly affects atrioventricular-nodal conduction and total electrical systole time at higher infusion rates. Only a single episode of sustained ventricular tachycardia was observed, which was promptly restored to sinus rhythm shortly after dobutamine infusion was discontinued. No ST segment abnormalities were detected. Dobutamine stress testing was concluded to play a role in some ECG parameters at higher infusion rates.