Effect of total parenteral nutrition on the pharmacokinetics of digoxin and phenytoin in male rabbits

Total parenteral nutrition [TPN] is a therapeutic intervention designed to provide sufficient calories and nitrogen to sustain patients who are unable to consume adequate nourishment by mouth and are therefore at risk of developing malnutrition. Unfortunately, alterations in both hepatic and intestinal function accompany therapy with TPN. TPN depresses both hepatic oxidative and conjugative biotransformation, consequently, the metabolism and elimination rate of drugs may be affected. To give insight about this situation, the present study was designed to investigate the effect of total parenteral nutrition on single dose pharmacokinetics of digoxin and phenytoin in male rabbits. Thirty six rabbits were divided into six groups as follow: the first three groups[I,II and III] were fed dry food and water, and the other three groups [IV, V and VI] received a total parenteral nutrition for ten days. Each group received a single IV dose of one drug as follow: group I and IV received digoxin [0.02 mg/kg,iv], group II and V received phenytoin [10 mg/ kg, iv],and group III and VI received midazolam [1 mg/kg, iv]. Serum alanine aminotrasnferase [ALT], aspartate aminotransferase [AST] and total bilirubin were determined. Plasma nitric oxide was estimated by Griess reaction. Sleeping time induced by midazolam was recorded. To study the pharrnacokinetic behaviour of digoxin or phenytoin, blood was collected 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12.0 and /or 24.0 hours after digoxin or phenytoin administration for determination of their blood levels. Total parenteral nutrition induced a significant increase in liver functions, plasma nitric oxide levels, and sleeping time of midazolam. In addition, Total parenteral nutrition induced a significant increase in the area under plasma digoxin or phenytoin concentration-time curves [AUC]and half life [t 1/2] of both drugs. Moreover, TPN induced a significant decrease in the clearance rate [Cl] for both drugs. The present study revealed that, in case of TPN,it is necessary to take in consideration the possibility of significant pharmacokinetic changes of some drugs, especially those having a narrow therapeutic index as digoxin and phenytoin. Therefore. digoxin and phenytoin blood levels must be monitored carefully in patients under TPN, and the doses of digoxin and phenytoin may need readjustment in those patients

Pharmacokinetics of digoxin in children with congestive heart failure aggravated by other diseases / Farmacocinética de la digoxina en niños con insuficiencia cardiaca congestiva agravada por otras enfermedades

Objective. To determine individual digoxin level variations and the effect of some common diseases those aggravate congestive heart failure (CHF) on digoxin pharmacokinetics in children. Design. Digoxin pharmacokinetics was evaluated in 11 children with CHF and an additional disease, such as rheumatic fever, anemia or infections. Digoxin plasma levels were monitored in patients on multiple-dose regime. Setting. Third level pediatric hospital. Results. Pharmacokinetic parameters showed extensive variation; median values were: elimination half-life 42.0 hrs (8.3-77.0), volume of distribution 1.01 L/kg (0.654-6.25), and clearance 15.0 mL/kg/h (6.0-331.8), which differed from results in patients with only CHF, reported previously. Dosage schemes in use at the Cardiology Service produced the following results: 40.5% of patients reached therapeutic levels, 10.8% toxic levels and 48.6% sub-therapeutic levels. Conclusion. The range of dosage required in order to adjust individual treatments was very wide, leading us to the conclusion that therapeutic schemes for this population should be individualized based on their pharmacokinetic parameters, and therapeutic monitoring of drugs should be performed.

El objetivo del presente estudio es determinar el efecto de algunas enfermedades que agravan la insuficiencia cardiaca congestiva (ICC) sobre la farmacocinètica de digoxina en niños. Diseño. Se estudió la farmacocinètica de digoxina en 11 niños con ICC, agravada por otras enfermedades como fiebre reumática, anemia o infecciones. Posteriormente se llevó a cabo monitoreo de los niveles de digoxina mientras seguían un règimen de dosis múltiple. Lugar. Centro de atención de tercer nivel. Resultados. Los parámetros farmacocinèticos mostraron amplia variabilidad: los valores de las medianas fueron: vida media de eliminación 42.0 horas (8.3-77.0), volumen de distribución 1.01 L/kg (0.654-6.25), y depuración 15.0 mL/kg/h (6.0-331.8) los cuales son diferentes a los de los pacientes que únicamente padecen ICC previamente reportados. Con el esquema de dosis usado en el Servicio de Cardiología se encontraron los siguientes resultados: 40.5% de las muestras de pacientes alcanzaron niveles terapèuticos, 10.8% niveles tóxicos y 48.6% subterapèuticos. Conclusión. Debido a la variación en los parámetros farmacocinèticos individuales, ocasionados por las patologías que agravan la ICC, se recomienda individualizar los esquemas de dosificación a partir de criterios farmacocinèticos, sin prescindir del monitoreo terapèutico del fármaco.

Evaluation of the relationship between steady state serum digoxin concentration and toxicity

This study was conducted to determine the serum digoxin concentration [SDC] at which there is an increase in the signs and symptoms of digoxin toxicity. Demographic characteristics, disease[s], clinical and para-clinical signs and symptoms of 79 patients who were using digoxin for at least one month were recorded. Prolonged PR, bradycardia, shortened QT, PVC [especially with bigeminy], sinus arrest, junctional extrasystole and symptoms like nausea/vomiting, diarrhoea, anorexia, fatigue, headache and visual disturbances were defined as symptoms of toxicity. From 1.2 ng/ml an increase in electrophysiological signs of toxicity was observed and it rose steeply at SDCs above 1.6 ng/ml. No relationship was found between SDC and symptoms of toxicity. Signs of digoxin toxicity appear even at levels below 2.0 ng/ml. Thus, target SDC should not exceed 1.6 ng/ml

Effects of monensin sodium on digoxin kinetics in conscious male rabbits

The investigation was performed on male rabbits equally divided into two groups: digoxin treated group and monensin plus digoxin treated group. Digoxin [0.2 mg/kg] was administered orally as a single dose to normal and monensin [6mg/kg for three successive days] pretreated rabbits. Blood samples were obtained at 0.5, 1.0, 1.5, 2.0, 4.0, 6.0, 8.0 and 12.0 hr. after digoxin administration. Pharmacokinetic parameters of digoxin were indicated by determination of area under the curve from time 0 to time t [AUC[t]], the area under the curve from time zero to infinity[AUC[alpha]], the half-life of the drug [t[1/2]], time required to reach maximum drug concentration[t[max]], maximum drug concentration in the blood [C[max]], drug clearance [C1] and the area under first moment curve [AUMC]. A significant increase in area under the serum concentration -time curve [AUC], increase in maximum concentration [C[max]], and area under moment curve [AUMC] were observed. In addition, Digoxin clearance [C1] was significantly reduced in rabbits pretreated with monensin. While, half-life [t[1/2]] and time required to reach maximum concentration [t[max]] was non significantly changed. The current results suggest that monensin enhance the adverse effects of digoxin in male rabbits. This interaction is played at least in part through an increase of digoxin plasma levels

Manejo de la intoxicación por digitálicos / Management of digitalic intoxication

La intoxicación por digitálicos en pediatría es poco frecuente, pero sus manifestaciones y complicaciones ponen en riesgo la vida del paciente, por lo que es fundamental un diagnóstico precoz y un manejo adecuado. Es importante destacar que el espectro de pacientes en que se presenta es muy variado, desde niños que accidentalmente ingieren este medicamento, hasta pacientes cardiópatas con ingesta crónica de estos medicamentos. En estos últimos, dado el estrecho margen terapéutico y condiciones propias del paciente, pueden tener manifestaciones de toxicidad aun en las dosis recomendadas

Comparación de digoxina y enalapril en insuficiencia cardíaca secundaria a insuficiencia mitral / Comparison of the effects of digoxin or enalapril in the treatment of heart failure due to mitral insufficiency

Background: There is not much evidence about the usefulness of digoxin or enalapril in the treatment of heart failure due to mitral insufficiency. Aim: to compare digoxin and enalapril in the treatmen of heart failure due to mitral insufficiency. Patients and methods: Patients with mitral insufficiency, in sinus rhythm, with a heart failure grade II or III and with echocardiographic left ventricular dilatation were eligible for the study. They received sequentially, during 12 weeks each, digoxin 0.25 mg/day or enalapril in doses up to 20 mg/day, with a washout in-between period of 2 weeks. The order of the sequence was determined randomly. At the start and end of treatment, functional class according to NYHA and maximal exercise tolerance in the treadmil were assessed and a color Doppler echocardiogram was done to measure ventricular dimensions, function and degree of mitral insufficiency. Results: Nine patients on enalapril and 12 on digoxin improved their functional capacity. Digoxin improved exercise time in 76ñ168 sec (p= 0.022), whereas this change was not significant with enalapril (38ñ158 sec; p= 0.2). With enalapril treatmen, ventricular diastolic dimensiondecreased from 59.3ñ8.1 to 58ñ9.3 mm and the area of mitral insufficiency decreased from 8.1ñ3.5 to 6.6ñ3.1 cm2. Digoxin did not induce any significant echocardiographic change. Conclusions: In these patients, digoxin and enalapril improved functional class. Digoxin improved exercise time and enalapril reduced ventricular dimensions and mitral insufficiency

Digoxina: ¿tratamiento continuo o discontinuo? / Digoxin: continuous or discontinuous treatment?

En nuestro país los pacientes con insuficiencia cardíaca (IC) que reciben tratamiento crónico con digoxina, habitualmente lo suspenden dos días consecutivos a la semana por indicación médica. Probablemente el objetivo sea disminuir la toxicidad digitálica. Conociendo la farmacocinética de la droga, esta suspensión reduciría su concentración plasmáatica alrededor del 40 al 50 por ciento, quedando debajo de los niveles considerados terapéuticos (0.8 mug/l a 2 mug/l). Los objetivos del trabajo fueron: 1) analizar la disminución de los nivels plasmáticos de digoxina luego de interrumpir la droga durante dos días consecutivos 2) comparar las concentraciones plasmáticas de digoxina entre pacientes que reciben la droga en forma continua y aquellos que realizan tratamiento discontinuo. Se efectuó un ensayo clínico randomizado, con ciego simple. Se incluyeron 36 pacientes con insuficiencia cardíaca por disfunción sistólica con ritmo sinusal o fibrilación auricular. El grupo 1 (19 pacientes) recibió tratamiento continuo y el grupo 2 (17 pacientes) tratamiento discontinuo de lunes a viernes. En el grupo continuo los valores del lunes (1.06 + 0.55 mug/l) no mostraron diferencias estadísticamente significativas con los del viernes (1.1 + 0.57 mug/l). En el grupo discontinuo los niveles del lunes (0.611 + 0.396 mug/l) disminuyeron significativamente con la suspensión de la droga con respecto a los del viernes (1.04 + 0.58 mug/l) siendo la p =0.000002. Se concluye que el régimen con suspensión semanal durante dos días consecutivos disminuye significativamente los niveles séricos de digoxina a concentraciones consideradas subterapéuticas. El régimen de tratamiento continuo demostró que mantiene la digoxinemia constante y en rango útil. Ajustando la dosis de digoxina según el clearance de creatinina los nivels séricos promedio de la droga son adecuados (alrededor de 1 mug/l). Estos resultados sugieren que la intoxicación digitálica se podría prevenir ajustando la dosis diaria de la droga de acuerdo a la función renal del paciente, más que interrumpiendo el tratameiento como es habitual en nuestro país.

Effect of propafenone on digoxin kinetics in dogs

The effect of short-term treatment with propafenone on IV bolus digoxin kinetics has been investigated in six normal dogs. A dose of 0.05 mg/kg IV digoxin was given to each dog and blood samples were collected for digoxin assay. The dogs were then given propafenone orally in a dose of 40 mg/kg daily for ten days followed by the same IV bolus dose of digoxin, and blood samples were recollected for digoxin assay. The results showed that the distribution pharmacokinetic parameters of digoxin; namely, the central [Vc] and apparent [Vd] volumes of distribution and the distribution half life [T1/2 alpha] did not significantly change by propafenone treatment. However, the elimination half life [T1/2 beta] was significantly increased by 36.7% [p <0.05] as a result of the significant reduction in digoxin total body clearance by 28.4% [p <0.01]. This led to 37.1% increase [p <0.05] in the area under digoxin concentration time curve [AUC]

Control de concentraciones terapéuticas de digoxina en el neonato: estudio de tres casos / Control of therapeutic digoxin concentration in the neonate: report of threee cases

El control de las concentraciones de fármacos como la digoxina es de gran importancia en las decisiones clínicas para obtener una terapéutica eficaz y segura, principalmente cuando la presencia de factores genéticos, cambios fisiológicos, padecimientos e interacciones farmacológicas alteran la farmacocinética. Esto es especialmente importante en el neonato y durante los primeros meses de vida, cuando los procesos de maduración del organismo afectan la disposición de los fármacos. En estas condiciones, las dosis pediátricas recomendadas pueden presentar una gran variabilidad en la respuesta a un fármaco, en donde la evaluación de las concentraciones y el estado clínico, permite ajustar las dosis. Se informan tres casos de niños pretérmino con cardiopatía congénita, quienes recibieron la misma dosis de mantenimiento de digoxina de 7 mcg/kg cada 24 horas. Las determinaciones de las concentraciones sanguíneas del fármaco se realizaron en diferentes días después de haber iniciado el tratamiento. Por medio de su evaluación clínica y farmacocinética, en el primer niño se continuó con el esquema inicial; el segundo niño con problemas de función renal, requirió una disminución de 71.5 por ciento de la dosis para evitar toxicidad, debido a una eliminación muy lenta del fármaco; y en el tercer niño por eliminación rápida, y concentración ocho horas posdosis de digoxina mayor a la gama terapéutica, se ajustó el intervalo de dosis a 3.5 mcg/kg cada 12 horas. Las concentraciones posteriores se encontraron en niveles terapéuticos

Concentraciones de fármacos en sangre. Utilidad clínica en el embarazo y recién nacido / Drug concentration in blood: clinical utiliry during pregnancy and in the new born

En elpresente trabajo se analizan los resultados de 2,168 exámenes de laboratorio que se realizaron en 50 pacientes (78 en mujeres embarazadas y 26 en recién nacidos) para determinar los niveles de teofilina, fenobarbital, difenilhidantoína o digoxina. El 62.7%(1,359) de las concentraciones estuvieron entre los niveles terapéuticos recomendados para cada fármaco; el 21.8%(472) presentaron concentraciones subterapéuticas; y el 15.5%(337) fueron altas. En algunos pacientes se determinó la vida media de eliminación del medicamento. Estas actividades tienen como objetivo evaluar los resultados de las concentraciones con la información clínica para recomendar ajuste de dosis cuando es necesario, lo que permite controlar con mayor eficacia los esquemas de dosificación y aumentar el beneficio clínico de fármacos con índice terapéutico reducido y/o de aquellos en que la respuesta terapéutica es muy variable por factores diversos que afectan su cinética.