Serum Quinidine Concentrations Research Articles

Investigation of potential mechanisms of sex differences in quinidine-induced torsade de pointes risk

IntroductionThe electrocardiographic index Tpeak-Tend has been proposed as a marker of dispersion of repolarization and may be a stronger predictor of torsade de pointes risk than QTc prolongation. Methods and resultsWe assessed whether quinidine-induced Tpeak-Tend prolongation is greater in women than men. The relationship between QTc prolongation and quinidine concentration was greater in women than men (38±10 vs. 28±9ms/μg/ml, p=0.02), but there was no difference for Tpeak-Tend prolongation (39±13 vs. 32±13ms/μg/ml, p=0.21). There was a delay (hysteresis) between peak concentration and both maximum QTc and Tpeak-Tend prolongation and a trend toward higher serum quinidine concentration in men than women. Analysis controlling for hysteresis showed no sex difference for QTc (55±18 vs. 43±19ms/μg/ml, p=0.14), without changing the lack of sex difference with Tpeak-Tend (61±22 vs. 55±21ms/μg/ml, p=0.49). ConclusionsWomen do not have a greater quinidine-induced Tpeak-Tend prolongation than men. Sex differences in hysteresis and serum quinidine concentration in this study may have contributed to sex differences in quinidine-induced QTc prolongation.

Effects of Low-Dose Quinidine on Ventricular Tachyarrhythmias in Patients With Brugada Syndrome

Quinidine is suggested as an effective agent to suppress ventricular fibrillation (VF) in the Brugada syndrome by inhibiting transient outward K(+) current (Ito) leading to the reduction and abbreviation of the disparity of repolarization in the right ventricular outflow region and ST segment elevation in the right precordial leads of electrocardiogram. We sought to assess the efficacy of low-dose (300-600 mg) quinidine sulfate on the prevention of ventricular fibrillation induction by programmed electrical stimulation (PES) and spontaneous ventricular fibrillation episodes during the subsequent follow-up period. Electrophysiologic study was performed in 14 patients with the Brugada syndrome (14 men, mean age 50 +/- 11 years, range 32-75) before and during the treatment with low-dose quinidine and evaluated the efficacy of the drug therapy. Ventricular fibrillation was induced in all the patients by programmed electrical stimulation at baseline. After oral quinidine administration (300 mg or 600 mg/d), programmed electrical stimulation was repeated. Ventricular fibrillation induction was prevented in 6 of 14 patients (44%). Serum quinidine concentration was higher in the patients with suppressed VF induction than those without (1.88 +/- 0.44 versus 1.31 +/- 0.43 microg/ml, respectively). After programmed electrical stimulation, 9 of 14 patients (64%), in whom four had implantable cardioverter defibrillator implantation, continued to receive quinidine. During a mean follow-up period of 31 months on quinidine, no side effects except one with diarrhea were observed (12.5%). There were no ventricular fibrillation recurrences in 3 of the 9 patients, who had frequent implantable cardioverter defibrillator discharges due to ventricular fibrillation attacks before treatment with quinidine. Low-dose quinidine has a potential as an adjunctive therapy for patients of the Brugada syndrome with frequent implantable cardioverter defibrillator discharges.

Serum quinidine concentrations and effect on QT dispersion and interval.

To establish a relationship between serum quinidine concentrations (SQCs) and QT interval dispersion, compared with corresponding QT intervals, in order to identify a reason why many reports describe torsade de pointes as occurring at subtherapeutic concentrations. Retrospective study. University teaching hospital. Eleven patients with atrial arrhythmias managed with quinidine therapy. Patients with subtherapeutic (<2 microg/mL) and therapeutic (2-5 microg/mL) SQCs with corresponding 12-lead electrocardiograms (ECGs) (25 mm/sec) and baseline ECG were evaluated for QT interval dispersion, calculated as the maximum minus the minimum QT interval on the 12-lead ECG. Mean +/- SD subtherapeutic and therapeutic SQCs were 1.48 +/- 0.39 microg/mL and 3.78 +/- 0.88 microg/mL (p < 0.001). Baseline values for QT/QTc intervals were 376.4 +/- 59.2/429.5 +/- 57.3 msec. At subtherapeutic and therapeutic SQCs, mean QT/QTc intervals were 403.6 +/- 59.9/450.5 +/- 38.5 msec and 439.1 +/- 48.9/472.4 +/- 44.6 msec, respectively. Mean QT dispersion was 47 +/- 16.2 msec at baseline, 98.2 +/- 27.5 msec at subtherapeutic SQC, and 70.9 +/- 33.9 msec at therapeutic SQCs (p = 0.001 for overall analysis; p < 0.001 for baseline vs. subtherapeutic concentrations; p = NS for therapeutic vs. subtherapeutic in post hoc comparison). Despite QT interval lengthening with increasing SQCs, QT dispersion was numerically greatest at subtherapeutic SQCs. Further study is required to determine the value of QT dispersion as a tool for identifying proarrhythmic risk with drugs that prolong the QT interval.

Serum Quinidine Concentrations and Effect on QT Dispersion and Interval

AbstractOBJECTIVE:To establish a relationship between serum quinidine concentrations (SQCs) and QT interval dispersion, compared with corresponding QT intervals, in order to identify a reason why many reports describe torsade de pointes as occurring at subtherapeutic concentrations.DESIGN:Retrospective study.SETTING:University teaching hospital.PARTICIPANTS:Eleven patients with atrial arrhythmias managed with quinidine therapy.MAIN OUTCOME MEASURES:Patients with subtherapeutic (<2 μg/mL) and therapeutic (2–5 μg/mL) SQCs with corresponding 12-lead electrocardiograms (ECGs) (25 mm/sec) and baseline ECG were evaluated for QT interval dispersion, calculated as the maximum minus the minimum QT interval on the 12-lead ECG.RESULTS:Mean ± SD subtherapeutic and therapeutic SQCs were 1.48 ± 0.39 μg/mL and 3.78 ± 0.88 μg/mL (p < 0.001). Baseline values for QT/QTc intervals were 376.4 ± 59.2/429.5 ± 57.3 msec. At subtherapeutic and therapeutic SQCs, mean QT/QTc intervals were 403.6 ± 59.9/450.5 ± 38.5 msec and 439.1 ± 48.9/472.4 ± 44.6 msec, respectively. Mean QT dispersion was 47 ± 16.2 msec at baseline, 98.2 ± 27.5 msec at subtherapeutic SQC, and 70.9 ± 33.9 msec at therapeutic SQCs (p = 0.001 for overall analysis; p < 0.001 for baseline vs. subtherapeutic concentrations; p = NS for therapeutic vs. subtherapeutic in post hoc comparison).CONCLUSIONS:Despite QT interval lengthening with increasing SQCs, QT dispersion was numerically greatest at subtherapeutic SQCs. Further study is required to determine the value of QT dispersion as a tool for identifying proarrhythmic risk with drugs that prolong the QT interval. ResumenOBJETIVO:Establecer una relación entre las concentraciones séricas de quinidina y la dispersión del intérvalo QT, en comparación con los intérvalos QT correspondientes, con el fin de identificar la razón por la cual ocurren informes de torsade de pointes a concentraciones subterapéuticas.DISEÑO:Estudio retrospectivoESCENARIO:Hospital de enseñanza universitariaPARTICIPANTES:Once pacientes con fibrilación auricular manejados con quinidina.MEDIDAS:Se evaluaron pacientes con concentraciones séricas de quinidina (SQCs, por sus siglas en inglés) subterapéuticas (<2 μg/mL) y terapéuticas (2–5 μg/mL) con sus correspondientes electrocardiogramas (ECG) de doce electrodos (25 mm/sec) y ECG base para dispersión de intérvalo QT, calculado como intérvalo QT máximo menos mínimo en el ECG de doce electrodos.RESULTADOS:La SQCs subterapéutica y terapéutica media ± SD fueron 1.48 ± 0.39 y 3.78 ± 0.88 μg/mL (p < 0.001). Los valores base de los intérvalos QT/QTc fueron 376 ± 59/430 ± 57 msec. A concentraciones subterapéuticas y terapéuticas la media de los intérvalos QT/QTc fueron 404 ± 60/450 ± 39 msec y 439 ± 60/472 ± 45 msec, respectivamente. La dispersión QT media fue 47 ± 16 msec en la base, 98 ± 28 msec a SQC subterapéuticas y 71 ± 34 msec a SQCs terapéuticas (p = 0.001 para todo el análisis, p < 0.001 para base vs.subterapéuticas, pero fue no significativo para terapéuticas vs. subterapéuticas).CONCLUSION:A pesar de que se alarga el intérvalo QT con un aumento en SQCs, la dispersión QT fue numéricamente mayor a SQCs subterapéuticas. Se necesitan estudios adicionales para determinar el valor de la dispersión de QT como herramienta para identificar el riesgo pro-arrítmico con fármacos que prolongan el intérvalo QT. RésuméOBJECTIF:Établir une relation entre les concentrations sériques de quinidine et la dispersion de l'intervalle QT, comparativement aux intervalles QT correspondants, dans le but de déterminer pourquoi plusieurs cas de torsades de pointes sont rapportés à des concentrations sous-thérapeutiques.DEVIS EXPÉRIMENTAL:Étude rétrospective.LIEU DE L'ÉTUDE:Hôpital universitaire.PARTICIPANTS:Onze patients avec des arythmies auriculaires sous traitement avec de la quinidine.MESURES DE L'EFFET:Des patients avec des concentrations sous-thérapeutiques (< 2 μg/mL) et thérapeutiques (2–5 μg/mL) de quinidine avec un ECG correspondant (25 mm/sec) et un ECG de base ont été évalués afin de déterminer la dispersion de leur intervalle QT, calculé comme étant l'intervalle QT maximum moins l'intervalle QT minimum à l'ECG.RÉSULTATS:Les concentrations sous-thérapeutiques et thérapeutiques de quinidine étaient en moyenne (écart type) de 1.48 ± 0.39 μg/mL et 3.78 ± 0.88 μg/mL (p < 0.001). Les valeurs de base pour les intervalles QT/QTc étaient 376 ± 59/430 ± 57 msec. Aux concentrations sous-thérapeutiques et thérapeutiques de quinidine, les intervalles QT/QTc étaient en moyenne de 404 ± 60/450 ± 39 msec et 439 ± 60/472 ± 45 msec, respectivement. La dispersion de l'intervalle QT était en moyenne de 47 ± 16 msec au niveau de base, 98 ± 28 msec aux concentrations sous-thérapeutiques de quinidine et 71 ± 34 msec aux concentrations thérapeutiques de quinidine (p = 0.001 pour l'analyse globale, p < 0.001 pour le niveau de base vs sous-thérapeutique, mais p = NS pour thérapeutique vs sous-thérapeutique).CONCLUSION:Malgré l'allongement de l'intervalle QT avec l'augmentation des concentrations sériques de quinidine, la dispersion de l'intervalle QT était numériquement plus élevée à des concentrations sous-thérapeutiques de quinidine. D'autres études seront nécessaires afin de déterminer si la dispersion de l'intervalle QT est un outil efficace pour évaluer le potentiel proarythmique des médicaments prolongeant l'intervalle QT.

Possible Pharmacokinetic Interaction with Quinidine: Ciprofloxacin or Metronidazole?

To discuss a potential pharmacokinetic interaction between quinidine, ciprofloxacin, and metronidazole. A 51-year-old black woman was admitted for shortness of breath, abdominal pain, and atrial fibrillation. Procainamide and diltiazem were begun for the atrial fibrillation and ciprofloxacin and metronidazole for suspected diverticulitis. The therapy was switched to quinidine on day 5 because of adverse events associated with procainamide. A trough serum quinidine concentration (SQC) on day 7 was 6.3 micrograms/mL (normal 2-5) with normal QT and QTc intervals. On day 8, the patient was discharged in normal sinus rhythm. She took her last doses of antibiotics on day 15 and a follow-up SQC on day 18 was 2.3 micrograms/mL. The possible explanations for the changes in SQCs include: (1) laboratory error, (2) compliance with medication regimen, and (3) altered hepatic metabolism. The first two are not likely in this case. The laboratory verified the elevated SQC and the patient had her prescriptions refilled within appropriate time limits. The third explanation seems more plausible. Quinidine is metabolized by the hepatic mixed-function oxidase system, specifically cytochrome P450 (CYP) 3A4. We found that metronidazole has been shown to inhibit CYP3A activity and ciprofloxacin has been shown to inhibit certain isozymes in the cytochrome P450 system as well. When metronidazole and ciprofloxacin are administered concomitantly with quinidine, clinicians should be aware of this potential interaction. Quinidine concentrations should be monitored and patients should be assessed for signs and symptoms of quinidine toxicity.

Quinidine administration increases steady state serum digoxin concentration in horses.

The aim of this study was to determine if quinidine administration increases steady state serum digoxin concentration in horses. Digoxin (0.01 mg/kg q. 12 h per os) was administered to 6 horses for 7 days. Steady state was confirmed by identifying statistically indistinguishable peak and trough serum digoxin concentrations on Days 4, 5, and 6. On Day 6, serum digoxin concentration was measured at baseline and 0.25, 0.5, 1, 2, 4, 6, 8 and 12 h after digoxin administration. On Day 7, quinidine (20 g at baseline and 10 g at 2, 4 and 6 h) was administered per os and serum digoxin concentration was measured at the same time intervals. Creatinine and renal digoxin clearances were measured on Days 6 and 7. Results indicated that there was approximately a doubling of serum digoxin concentration (from mean +/- s.d. 2.57 +/- 0.96 ng/ml at baseline to 4.28 +/- 1.31 at 15 min and 5.98 +/- 1.21 ng/ml at 30 min) after starting the administration of quinidine. This elevation persisted for the 12 h after starting quinidine administration. Renal digoxin and endogenous creatinine clearances decreased but the decrease in digoxin clearance was greater. Serum quinidine concentration achieved the therapeutic range (2-6 micrograms/ml) in 5 of the 6 horses. In summary, similar to findings in other species, quinidine administration increases steady state serum digoxin concentration in horses and this occurs, at least in part, due to a decrease in renal digoxin clearance. Some of the decrease in renal clearance is due to decreased glomerular filtration which is dissimilar to findings in other species.

Possible inhibition of hepatic metabolism of quinidine by erythromycin

To present and analyze a patient case illustrating a possible drug interaction between quinidine and erythromycin. This is a case report of one hospitalized patient. The setting for this analysis was a university hospital. Through a MEDLINE search of all English medical literature (1966 to 1994) documenting possible interactions between quinidine and erythromycin, retrospective patient chart review, and analysis of the relationship between serum quinidine concentrations and significant clinical events, deduce the possibility of a quinidine and erythromycin pharmacokinetic and pharmacodynamic interaction in this particular patient case. This case demonstrated a probable erythromycin-quinidine pharmacokinetic interaction that led to a decrease in quinidine apparent clearance, an increase in quinidine serum concentrations, and a possible quinidine toxicity. Serum quinidine concentrations, electrocardiograms, and other factors that may predispose patients to torsades de pointes, such as hypokalemia and hypomagnesemia, should be monitored closely if quinidine is coadministered with erythromycin.

Pharmacokinetics of quinidine in male patients. A population analysis.

Quinidine pharmacokinetic behaviour was evaluated in 139 adult hospitalised men receiving oral quinidine therapy. A total of 391 serum quinidine concentrations were measured by enzyme immunoassay for routine clinical purposes. The NONMEM programme was used to examine the relationship between quinidine pharmacokinetics and several potential covariates. A 1-compartment open model with first-order absorption and elimination was assumed. The mean apparent volume of distribution (Vd) was about 230L. When measured, alpha 1-acid glycoprotein (AAG) levels were not included in the analysis. Oral quinidine clearance (CL) decreased with age, severe congestive heart failure and renal disease, and increased in patients with a history of alcohol abuse. The interpatient variability in CL and the intrapatient residual variability expressed as coefficients of variation (CV) were 28 and 31%, respectively. When AAG values were incorporated into the analysis, the only important covariates of CL were the AAG measurements and the presence of renal dysfunction as indicated by a calculated creatinine clearance of less than 50 ml/min (3 L/h). The interpatient variability in CL and the residual intrapatient CVs decreased to approximately 24 and 26%, respectively. Improvement of the CL model by inclusion of measured AAG strongly suggests that quinidine elimination is dependent on the free concentration of drug in plasma and supports the use of free serum quinidine concentrations when evaluating and monitoring quinidine therapy.

Relationship between serum quinidine concentration and quinidine dosage.

This retrospective study was designed to identify and assess which patient-specific factors affect the relationship between the steady-state trough serum quinidine concentration (SQC) measured by fluorescence polarization immunoassay and quinidine dosage. Data were obtained from 100 hospitalized patients (72 males, 28 females) receiving quinidine for atrial or ventricular arrhythmias, or both, between ages 24 and 85 years (mean age 63 yrs). Age, lean body weight, creatinine clearance (ClCr), and sex were statistically significant factors affecting this relationship; ejection fraction, total body weight, smoking history, alcohol history, recent myocardial infarction, recent surgery, elevated liver function tests, and sampling time were not statistically significant. The ClCr alone provided the most additional information in predicting SQC, and ClCr and weight provided the most additional information in predicting dosage. Currently in clinical practice, quinidine dosage adjustments are not routinely recommended for patients with renal insufficiency. These data suggest that the calculated ClCr is important in predicting both SQC and dosage when a nonspecific quinidine assay is used. This dosing model must be evaluated prospectively.

Hemodynamic and neurohormonal effects of quinidine in patients with severe left ventricular dysfunction secondary to coronary artery disease or idiopathic dilated cardiomyopathy

Quinidine causes vasodilation directly and by inhibition of adrenergic vasoconstriction, but it also exerts negative inotropic activity. Although this drug is often administered to patients with severe congestive heart failure, the net consequences of these opposing actions have not been evaluated in such patients. The hemodynamic and neurohormonal response to oral quinidine (600 mg) in 19 patients with severe chronic heart failure was therefore determined. Vasodilation was the predominant effect of quinidine, with reductions in mean arterial, left ventricular filling and right atrial pressures of −9% (confidence interval [CI] −5 to −13), −8% (CI −19 to 3), −15% (CI −26 to −4), respectively. The quinidine-induced vasodilation increased plasma norepinephrine and epinehrine concentrations by 44% (CI +17 to +72) and 47% (CI +2 to +91), respectively. No change in cardiac performance was noted, with the cardiac index slightly increased (+10%, CI +2 to +17) and stroke work index unchanged (0%, CI −11 to +11) after quinidine. Although the mean serum quinidine concentration was within the therapeutic range or lower in all patients, the serum quinidine concentration and the change in mean arterial pressure did correlate (r 2 = 0.64). In conclusion, vasodilation is the predominant hemodynamic effect of oral quinidine in patients with congestive heart failure. However, potential adverse effects may be caused by consequent neurohormonal activation.

A randomized controlled trial of quinidine in the treatment of cirrhotic patients with muscle cramps

In an attempt to evaluate the effect of quinidine in the treatment of patients with cirrhosis and muscle cramps, 31 cirrhotic patients with muscle cramps were randomly divided into two groups and given orally 400 mg of quinidine sulfate per day or placebo, respectively. Baseline clinical and laboratory data for these two groups were similar. Four weeks after oral administration of quinidine, the number of cramps significantly decreased from 14.4 ± 1.7 (mean ± S.E.) to 1.4 ± 1.1 episodes ( p < 0.0001), but it remained unchanged in the placebo group (from 11.8 ± 1.0 to 11.5 ± 1.5 episodes, p > 0.05). In addition, 88% of the 16 patients on quinidine and 13% of the 15 patients on a placebo showed a greater than 50% reduction in the number of cramps during a 4-week treatment period ( p < 0.0001). The peak and trough serum levels of quinidine in patients having received quinidine for 2 weeks were 1.3 ± 0.1 and 0.7 ± 0.1 mg/l, respectively. There was a significant relationship between serum quinidine concentrations and attenuation of cramps. No significant adverse effect was observed during the study, except for five (31%) patients who developed mild diarrhea after quinidine therapy. Diarrhea subsided spontaneously or was controlled by medications without the interruption of quinidine therapy. It was concluded that quinidine is a safe and effective drug for the treatment of cirrhotic patients with muscle cramps.

Comparison of Assay Procedures Used to Measure Total and Unbound Concentrations of Quinidine

Individualized quinidine dosing through the assessment of serum concentrations is warranted because of the wide variability observed in its pharmacokinetic behavior and its reported narrow therapeutic index. The free fraction of quinidine also varies widely. Thus the development of procedures that could be widely used to determine quinidine free concentrations would be highly desirable. It was the purpose of this study to evaluate several procedures available to determine total serum quinidine concentrations (rate nephelometry [ICS], homogenous enzyme immunoassay [EMIT], and high-performance liquid chromatography [HPLC]). Furthermore, in samples from 46 patients, equilibrium dialysis and ultrafiltration procedures were compared for their ability to estimate quinidine free fraction. Finally, unbound concentrations of quinidine were compared using a modified EMIT procedure and a standard HPLC method to quantitate quinidine in ultrafiltrates from patient samples. For the measurement of total quinidine concentrations, reasonable agreement was seen when EMIT and ICS systems were compared with HPLC (ICS = 1.03.HPLC + 0.96, r = 0.93; EMIT = 1.08.HPLC + 0.38, r = 0.93) The mean errors, however, for these procedures were high (ICS +70 percent, range +7 to +233 percent; EMIT +35 percent, range 0 to 110 percent). Quinidine free fractions (QFF) determined by equilibrium dialysis (E) and ultrafiltration (U) showed good agreement (QFF(U) = 1.11.QFF(E) +0.0; r = 0.96). Unbound quinidine concentration determined by EMIT analysis of ultrafiltrate substantially overestimated the values obtained by HPLC analysis (mean error by EMIT 104 +/- 59 percent). It is concluded that HPLC is the method of choice for determining both total and unbound serum quinidine concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Treatment of severe malaria in the United States with a continuous infusion of quinidine gluconate and exchange transfusion.

During the past decade the incidence of Plasmodium falciparum malaria in the United States has increased 10-fold. Treatment may be delayed because the therapy recommended for severe or complicated disease, intravenous quinine dihydrochloride, is available only from the Centers for Disease Control. We studied 17 patients who were treated for severe or complicated P. falciparum malaria in the United States between 1985 and 1987. Five patients were treated with a continuous infusion of quinidine gluconate, 10 with an exchange transfusion in addition to the continuous infusion of quinidine gluconate, and 2 with intermittently administered intravenous quinine dihydrochloride and an exchange transfusion. All 16 patients with P. falciparum malaria (1 patient had P. vivax malaria) had hyperparasitemia at the time of diagnosis (6 to 54 percent of the erythrocytes infected; median, 13 percent). Three patients with marked hyperparasitemia (54, 38, and 30 percent) and multiple other indicators of a poor prognosis, including advanced age, died. The 13 patients who completed their courses of quinidine with or without exchange transfusion had a parasitemia level of 1.1 percent or less 28 to 72 hours (mean, 44.4 hours) after the start of therapy. Side effects of quinidine treatment were observed in only two patients, one of whom had a serum quinidine concentration above the toxic level. We conclude that the continuous infusion of quinidine gluconate is well tolerated alone and with exchange transfusion and is effective in the treatment of severe and complicated malaria.

Elucidation of the nifedipine-quinidine interaction.

Four case reports have been published that document a clinically significant drug interaction between nifedipine and quinidine in patients with left ventricular dysfunction. To define the population at risk and the mechanisms involved in manifestations of this interaction, 12 patients currently treated with quinidine for either ventricular or supraventricular arrhythmias were stratified into two groups based on left ventricular ejection fraction (EF) measurements (group A greater than 35%; group B less than 35%). The interaction was conducted through two phases: oral quinidine (Q) and oral quinidine plus nifedipine (N + Q). Pharmacokinetic modeling of total body clearance (CL) and AUC were assessed for each phase. One patient (group A, 70% EF) exhibited the interaction with a 41% decrease in steady-state serum quinidine concentrations. The patient's AUC and CL were 48.2 micrograms/ml.hr (Q) versus 28.6 micrograms/ml.hr (N + Q) and 94.4 ml/min (Q) versus 159.1 ml/min (N + Q), respectively. There was no difference in AUC or CL between the Q and N + Q phases or between groups A and B for the entire population. The N + Q interaction is not hemodynamically mediated. Clinical consideration of the possibility of this low-frequency interaction should be noted.

Quinidine: An update on therapeutics, pharmacokinetics and serum concentration monitoring

After 70 years of regular use, quinidine remains one of the most useful drugs in the management of both supraventricular and ventricular arrhythmias. Quinidine sulfate, from conventional dosage forms, is absorbed rapidly and reaches peak levels in 1 hour. Sustained-release quinidine sulfate and gluconate are absorbed more slowly and, thus, may provide a more satisfactory response with less fluctuation in the peak and trough at quinidine concentrations. The half-life and absorption characteristics of sustained-release quinidine suggest that an 8-to 12-hour dosage regimen will produce smooth, sustained quinidine levels. Whereas quinidine and digitalis have been used concomitantly for years, dramatic elevations in blood digoxin levels have been observed. When quinidine is added to the regimen of a patient taking digitalis, these increased digoxin levels may be responsible for some of the adverse effects previously attributed to quinidine administration and can be reduced by adjustment of the digoxin dosage. Drug monitoring of serum quinidine concentrations as well as peak levels is essential to assess patient compliance and to determine that therapeutic levels are maintained. This is especially important because of the drug's relatively narrow therapeutic index and the changes in clearance that can result from drug interactions and renal and hepatic disturbances. A personal computer program is available to carry out pharmacokinetic calculations and assist in determining appropriate doses for individual patients.

Comparative efficacy and safety of oral cibenzoline and quinidine in ventricular arrhythmias: A randomized crossover study

We compared the clinical efficacy and safety of oral cibenzoline and quinidine in 13 patients with complex ventricular arrhythmias using a randomized, open-label, crossover study. Employing an quinidine (300 mg every 6 hours and 400 mg every 6 hours) were administered for 7 days at each dose level, with preceding washout periods. ECG intervals, total number of ventricular premature depolarizations (VPDs), ventricularpairs (VP), and ventricular tachycardia (VT) events were analyzed at control on cibenzoline and on quinidine. Suppression of VPDs was comparable on both drugs (cibenzoline—six patients; quinidine—five patients). Mean serum quinidine concentration was 2.6 ± 1.2 μg/ml, and plasma cibenzoline concentration was 0.48 ± 0.27 μg/ml. Significant clinical and laboratory toxicity was more frequent with quinidine than with cibenzoline (p < 0.05). Chronic cibenzoline therapy maintained long-term arrhythmia suppression in five of six responders (mean follow-up, 23 ± 12 weeks). We conclude that cibenzoline and quinidine are equally effective for control of ventricular arrhythmias. Cibenzoline has a more desirable dosing regimen, superior safety profile, and better patient tolerance than quinidine.

Use of serum drug concentrations in outpatient clinics

A four-month retrospective study was conducted to analyze the use of serum drug concentrations (SDCs) in the outpatient clinics of a teaching hospital. The general internal medicine, asthma and allergy, cardiology, and neurology clinics were selected as frequent users of SDCs. Serum theophylline, digoxin, quinidine, procainamide, carbamazepine, phenytoin, and phenobarbital concentrations obtained during patient clinic visits were audited by trained pharmacy students using medical records and computer-generated laboratory data. The SDCs were evaluated for (1) the appropriateness of how they were obtained, (2) the appropriateness of the actions taken on the results, (3) the reasons they were ordered, and (4) the patient charges secondary to obtaining SDCs incorrectly or taking inappropriate actions on the results. Overall, the SDCs from all the clinics combined were obtained appropriately 251 (61.4%) of 409 times. Appropriate actions were taken on the SDC results 82.4% of the time. A change in therapy was made after an SDC was ordered 24.4% of the time. A total of $4975 of patient charges was associated with incorrectly obtained SDCs or inappropriate actions taken on SDC results. The asthma and allergy clinic, which was staffed by a clinical pharmacist, used SDCs more appropriately than the other clinics. Pharmacists or other professionals should be used to obtain accurate SDC information and to follow-up on SDC results to maximize drug therapy and reduce costs.

Nifedipine-induced aiterations in serum quinidine concentrations

Nifedipine-induced aiterations in serum quinidine concentrations

Relationship between saliva and serum quinidine concentrations and suppression of ventricular premature beats.

Saliva and serum quinidine concentrations were determined in six cardiac patients after twice-daily dosing with 324 or 648 mg quinidine gluconate and the relationship of these concentrations to the degree of suppression of ventricular premature beats (VPB) was evaluated. Mixed saliva and corresponding serum samples were obtained at various times after the 1st, 9th, and 19th doses. With serum quinidine concentrations ranging from 0.05 to 0.83 micrograms/ml after the first dose, the average saliva/serum ratios for quinidine varied between 0.25 and 1.35 (0.54 +/- 0.43). At steady state with the serum quinidine concentrations ranging between 0.36 and 3.35 micrograms/ml, the average saliva/serum ratios ranged from 0.27 to 1.79 (0.81 +/- 0.72) and from 0.19 to 1.84 (0.90 +/- 0.85) for the 9th and 19th doses, respectively. The interpatient variations in the saliva/serum ratio were large for the three doses (approximately 90%). On the other hand, the intrapatient variations were smaller and diminished with each succeeding sampled dose (from 31 to 18 to 12% for the 1st, 9th, and 19th doses, respectively). Moreover, the value for the quinidine saliva/serum ratio for a given patient was similar for all three doses. No significant correlation between the extent of VPB suppression and the concentrations of quinidine in the saliva or serum was observed. The data suggest that salivary quinidine concentrations may be clinically useful to monitor serum drug concentrations in a given patient. However, the relationship between saliva and serum quinidine concentrations and suppression of VPB measured by Holter monitoring is not clear-cut.

Update on the influence of quinidine and other agents on digitalis glycosides

Since this topic was last reviewed,’ additional data on previously described interactions have been published and certain new interactions have been described. This update follows the format of the earlier review by first discussing new data on the quinidine-digoxin interaction and then discussing related interactions by drug class or mechanism of interaction. QUINIDINE-DIGITALIS INTERACTIONS Ouinidine-digoxin interaction. As previously reviewed,’ quinidine therapy can be expected to double or triple the serum digoxin concentration (SDC) in most, if not all, patients who achieve a serum quinidine concentration (SQC) of 2 pg/ml or greater. This interaction occurs within a few hours after starting quinidine therapy but may require several days or even weeks before the new steady-state SDC is achieved. It appears that quinidine alters digoxin kinetics by reducing the apparent volume of distribution (Vd), renal clearance (Clr), and nonrenal clearance (Clnr). Although the degree of reduction of Clnr is probably not dependent on the SQC, the reduction in Vd and Clr is greater at higher SQC. Even though the data on the mechanisms of the interaction suggest that the interaction should occur in patients with renal failure, conflicting views exist. Doering erroneously suggested that the interaction should not occur in anuric patients, while others3’4 have demonstrated the interaction in such patients. Hirschberg et a1.3 found that 4 days of quinidine therapy produced a mean increase of 57% in the SDC. However, the graphic presentation of their data appears to suggest that the greatest increases in