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Different methods for the spectrofluorometric determination of quinidine in plasma and urine were studied. The alkaline washings of plasma and urine extracts remove fluorescent metabolites, as shown by TLC analysis of urine extracts, and do not lead to a significant loss of alkaloids. The spectrofluormetric assays without alkaline washings of the benzene extract averaged 18% higher than the assays with alkaline washings. Since unchanged quinidine and hydroquinidine are responsible for antiarrhythmic activity, the method with alkaline washing is more appropriate for the control of quinidinemia than are other methods. The therapeutic plasma concentration range becomes 0.8-2.5 microng/ml with this methods.

A comparison of two analytical methods of quinidine plasma determination--the modified extraction fluorometric method and the mass spectrometric method--was made. Plasma supplies collected at steady state from normal human volunteers participating in a bioavailability study were analyzed, using both methods. A total of 359 samples were analyzed. Comparison of both sets of values, by linear regression, yielded an r2 value of 0.84. The results of this comparison were consistent with the results reported by others, confirming that the commonly used extraction fluorometric method of quinidine determination is sufficiently accurate for monitoring quinidine plasma concentrations in the patient care setting, as well as for bioavailability comparisons between products.

Although most assays for measuring drug levels in serum determine the total concentration, effects from a drug are determined better by measuring the concentration of unbound (free) drug in serum. When the free fraction of a drug is constant, the total drug concentration may act as a good guide in predicting drug activity. However, if the free fraction is altered from normal, the serum concentration of the total drug may be misinterpreted. Quinidine has a high binding affinity for alpha-1-acid glycoprotein. We present the case of a woman who had a myocardial infarction; after cardiac surgery, she was found to have high concentrations of alpha-1-acid glycoprotein (228 mg/dL) and a low free fraction of quinidine (0.032). At that time the patient had a total concentration of quinidine of 33.9 mumol/L (11 micrograms/mL) but showed no signs or symptoms of toxicity because the concentration of free quinidine was not high. Physicians should be aware of the limitations of assays in determining the unbound concentration of drugs in serum. This awareness is particularly crucial with drugs that bind well to serum proteins, especially when pathologic conditions change the extent of binding.

Quinidine pharmacokinetics are known to be altered by a number of drugs. We present a case where dose-related increases in quinidine serum concentrations were significantly suppressed by concurrent nifedipine therapy. Clinicians should be alert to the possibility of an alteration in quinidine serum concentrations when instituting or discontinuing nifedipine in patients receiving quinidine.

Quinidine therapy is one of the most common causes of the acquired long QT syndrome and torsade de pointes. In reviewing clinical data in 24 patients with the quinidine-associated long QT syndrome, 20 of whom had torsade de pointes, we have delineated several heretofore unreported or underemphasized features. (1) This adverse drug reaction occurred either in patients who were being treated for frequent nonsustained ventricular arrhythmias or for atrial fibrillation or flutter. (2) In patients being treated for atrial fibrillation, torsade de pointes occurred only after conversion to sinus rhythm. (3) Although most patients developed the syndrome within days of starting quinidine, four had torsade de pointes during long-term quinidine therapy, usually in association with hypokalemia. (4) Because of the large experience with this entity at our institution, we have been able to estimate the risk as at least 1.5% per year. (5) Twenty of the 24 patients had at least one major, easily identifiable, associated risk factor including serum potassium below 3.5 mEq/L (four); serum potassium between 3.5 and 3.9 mEq/L (nine); high-grade atrioventricular block (four); and marked underlying, (unrecognized) QT prolongation (two). Plasma quinidine concentrations were low, being at or below the lower limit of the therapeutic range in half of patients. The ECG features typically included absence of marked QRS widening, marked QT prolongation (by definition), and a stereotypic series of cycle length changes just prior to the onset of torsade de pointes. Torsade de pointes started after the T wave of a markedly prolonged QT interval that followed a cycle that had been markedly prolonged (usually by a post ectopic pause).(ABSTRACT TRUNCATED AT 250 WORDS)

We evaluated the effect of quinidine on digoxin pharmacokinetic in six patients with severe renal failure. Quinidine reduced the total body clearance of digoxin from 1.87 to 1.06 l/hour (p less than 0.001), and prolonged the digoxin half-life of elimination from 5.20 to 9.61 days (p less than 0.01). The digoxin volume of distribution was unchanged. Renal clearance of digoxin was negligible; thus, the decrease in total body clearance was due to a decrease in the nonrenal clearance of digoxin. The mean trough serum concentrations of quinidine ranged from 1.0 to 3.0 micrograms/ml. We conclude that in patients with chronic renal failure, the dose of digoxin should be decreased by 50% if quinidine therapy is initiated.

The free level ultrafiltration (UF) assay by the enzyme multiplied immunoassay technique (EMIT) for determination of unbound quinidine concentration in serum (Qf) was evaluated in 50 samples obtained from cardiac patients treated with quinidine for ventricular arrhythmias. Equilibrium dialysis (ED) at 37 degrees C and high performance liquid chromatography (HPLC) served as standard methods for comparison. A good agreement was found between EMIT and HPLC at the low range of free quinidine concentration (0.1-0.7 mg/L) observed in our patients (r = 0.959). Although the correlation between UF and ED was high (r = 0.972), Qf was systematically underestimated by UF. This bias was due to the fact that UF was performed according to the recommendations of the manufacturer at 25 degrees C. No systematic differences were found when 20 additional samples were assayed by the two methods at the same temperature (25 degrees C; r = 0.992). The quinidine binding ratio showed a correlation with the serum concentration of alpha 1-acid-glycoprotein (r = 0.61). The metabolites 3(S)-hydroxyquinidine and quinidine-N-oxide did not influence the protein binding of the parent drug. The importance of adjusting the serum pH to physiological values before measurement of Qf was confirmed in this study. Our results show that, if performed under the same conditions, ED and UF yield practically identical values. Because of easy handling, the EMIT Free Level System II should be applicable under clinical conditions.

The blood cell/plasma concentration ratio of quinidine, as influenced by the plasma protein binding, was studied in normal and anuric rats by applying incubation and equilibrium dialysis techniques on blood and plasma, respectively, from normal and anuric rats. The plasma protein binding of quinidine in anuria was increased at concentrations of unbound drug of less than 1.75 X 10(-4) M and decreased above this concentration. At an assumed "therapeutic" quinidine concentration (1 X 10(-5) M), the mean concentration ratio (total quinidine in blood cells)/(total quinidine in plasma) was 1.84 in normals and 0.46 in anuria, and the mean ratio (total quinidine in blood cells)/(unbound in plasma) was 4.45 and 1.81, respectively. As the latter ratios were concentration dependent and greater than could be accounted for by pH-dependent distribution, quinidine is presumably bound in/on the blood cells. Reduced distribution ratio in anuria, even when related to unbound quinidine in plasma, also indicates changed binding in blood cells, a finding confirmed by applying the data to modified Scatchard plot. this may have implication for the use of blood cell/plasma concentration ratio as screening procedure for the altered plasma binding of quinidine in patients.

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)

Quinidine is a commonly used drug for the treatment of cardiac arrhythmias. Avoidance of toxicity and monitoring of therapy can be readily accomplished by determining serum concentrations of quinidine by enzyme immunoassay (Emit) using a centrifugal analyzer and reducing the data with a desk-top microcomputer. For therapeutic and toxic drug ranges maximum within-run CV was under 6.0%, while between-run CV was under 10.0% in the therapeutic range and under 15.0% in the toxic range.

Quinidine and dihydroquinidine were administered as the sulphates in an oral solution to seven healthy volunteers. In all subjects, dihydroquinidine was absorbed to a lesser extent than quinidine. On the basis of comparative AUC pu to 6 h after administration, dihydroquinidine was 73% as available as quinidine. Rates of elimination of the compounds were similar. No correlation could be found between saliva and plasma levels for either compound. Limits for content of dihydroquinidine in commercial quinidine preparations seem essential to ensure adequate bioavailability.

Accelerated quinidine metabolism was observed in a 94-year-old woman also receiving daily doses of digoxin and pentobarbital sodium. Discontinuation of pentobarbital produced a sharp increase in serum digoxin concentrations coupled with symptoms highly suggestive of digoxin toxicity. Associated with these findings was 3.8-fold increase in quinidine half-life. These data seemed consistent with an interaction between quinidine and digoxin that was precipitated by pentobarbital withdrawal.

1. Little is known about the comparative plasma protein binding of the antimalarial agents quinine (QN) and its isomer quinidine (QD). We have examined the in vitro binding of QN and QD to albumin, alpha 1-acid glycoprotein, normal human plasma, and maternal and foetal umbilical cord plasma. 2. QN was more avidly bound than QD, and binding of both drugs was substantially higher to alpha 1-acid glycoprotein than to albumin, indicating that alpha 1-acid glycoprotein is the more important binding protein. 3. Protein and drug concentration dependent binding was evident for both QN and QD. The unbound fraction of both drugs fell with increasing albumin (10 to 60 g l-1) and alpha 1-acid glycoprotein (0.5 to 2.0 g l-1) concentration, and there was a marked increase in unbound fraction of QN (6 to 19%) and QD (13 to 36%) in human plasma when drug concentrations were increased over the antimalarial therapeutic range (0.5 to 10 mg l-1). 4. In human volunteer plasma, the unbound fractions of QN and QD were 7.5 +/- 2.2% and 12.3 +/- 2.3% respectively, whilst the unbound fractions for both drugs were significantly higher in maternal plasma (QN = 13.0 +/- 5.4%, QD = 18.3 +/- 2.5%) and significantly higher still in foetal umbilical cord plasma (QN = 25.7 +/- 10%, QD = 35 +/- 5.3%).

Quinidine binding to serum proteins was quantitated in 10 regularly dialyzed patients with end-stage renal disease, both under baseline conditions and after heparin during a single hemodialysis. Quinidine binding was determined in vitro, after the addition of 2 micrograms/ml quinidine sulfate, by ultrafiltration combined with spectrophotofluorometry. The baseline percent unbound quinidine concentration in our patients was 6.5 +/- 2.3% (mean +/- SD), a value lower than in normal subjects (9.9 +/- 3.0%, n = 18, p less than 0.005). Binding correlated with both serum albumin (r = 0.72, p less than 0.02) and free fatty acid (r = 0.65, p less than 0.05) concentrations. After heparin there was a rise in percent unbound quinidine (12.2 +/- 5.6%, p less than 0.025) and in free fatty acid concentration (1111 +/- 1202 microEq/l, p = 0.004) in each subject. After heparin the relationship between quinidine binding and free fatty acid concentration was again evident (r = 0.97, p less than 0.001). Dynamic changes in the levels of free quinidine, as well as other drugs during hemodialysis, may require adjustments to avoid toxicity and adverse interactions.

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.

We used positron emission tomography to monitor the distribution of radioactivity in dog brain and muscle following i.v. administration of 11C-labelled antipyrine, imipramine, and quinidine. Twenty-five sequential scans of a transaxial slice of the head were performed within 90 min; radioactivity in plasma was measured in a gamma-counter. Following i.v. injection of [11C]antipyrine (50 mg kg-1; 9-68 mCi; n = 10), the decay of plasma activity was accompanied by rapid uptake in brain and variable uptake in muscle, immediately followed by a redistribution leading to equalization of the radioactivity in the tissues. Administration of [11C]imipramine (4 mg kg-1; 30-110 mCi; n = 8) was followed by a rapid build-up of a sustained gradient between high brain, and low plasma and muscle radioactivity. After i.v. injection of [11C]quinidine (1 mg kg-1; 11-87 mCi; n = 10), radioactivity in brain was low, with higher activity in plasma and muscle throughout the experiment. Positron emission tomography thus revealed for each drug a distinct pattern of distribution consistent with established properties of the compounds. This technique seems promising for the study of early drug distribution, notwithstanding certain limitations.

Performance characteristics of substrate-labeled fluorescent immunoassays for the drugs phenytoin, phenobarbital, primidone, carbamazepine, theophylline, gentamicin, tobramycin, amikacin, and quinidine run on an Optimate automated fluorometric analyzer were compared with those of automated enzyme multiplied immunoassays (EMIT) for the same drugs performed on a Cobas centrifugal analyzer for patient samples and controls. For 100 patient samples assayed by both systems for each drug, excellent correlations were obtained, with correlation coefficients ranging from 0.96 to 0.99. Likewise, very good within-run (n = 10) and between-run (n = 30) precision was obtained by both methods. Values for controls and clinical specimens by the Optimate methods calculated using the same-day calibration curves were not significantly different from those calculated from calibration curves stored 14 days, indicating at least 14-day curve stability for all assays.

The kinetics of quinidine and propranolol, administered singly and in combination, were evaluated in 5 healthy subjects. The orally administered doses resulted in plasma concentrations within the therapeutic range. For each drug the average steady-state plasma concentration, maximal plasma concentration, and time of maximum plasma concentration were not altered by the presence of the other drugs. This study shows no kinetic interaction between quinidine and propranolol in normal subjects.

Various factors influencing the apparent protein binding of quinidine were examined. Different binding values in rabbit plasma were obtained by equilibrium dialysis techniques employing three commonly used buffers. Binding values comparable to those found by ultrafiltration were achieved after dialysis against isotonic phosphate buffer for approximately 4 hr. Dialysis beyond 8 hr gave an increased free fraction with time. The reported effect of in vitro added heparin on plasma protein binding could be prevented by reducing the final concentration in blood from 20 to 5 U/ml, a concentration still sufficient to prevent clotting of the blood sample. Daily freezing and thawing of plasma samples over 1 week did not alter the binding of quinidine. The samples were stable for at least 2 months at -20 degrees.

Both quinidine and verapamil are known to increase the serum digoxin concentration (SDC), and other calcium channel blockers may have a similar effect. Since an increasing number of patients is likely to be treated concurrently with digoxin, quinidine and a calcium channel blocker, a study was done to show whether coadministered quinidine and verapamil would cooperate to elevate the SDC. Nine healthy volunteers on basic digoxin treatment (Leanoxin 0.125 mg t.i.d.) were treated with placebo, verapamil 80 mg t.i.d. and the combination (verapamil 80 mg plus quinidine base 160 mg t.i.d.), for 2 weeks in a randomized sequence. Drug concentration and various cardiovascular parameters were measured each week and/or at the end of each treatment period. Steady state concentrations were always obtained within 1 week and drug levels at the end of the first and second weeks of treatment were almost identical. The plasma verapamil concentration (PVC) was 25.8 +/- 9.9 ng/ml during coadministration of verapamil and digoxin, and 15.7 +/- 6.9 ng/ml during combined verapamil-quinidine coadministration, when the serum quinidine concentration (SQC) was 1.26 +/- 0.50 micrograms/ml. Compared to placebo SDC rose by 53% from 0.62 +/- 0.16 to 0.95 +/- 0.29 ng/ml (p less than 0.001) during verapamil treatment and further to 1.58 +/- 0.38 ng/ml (155% rise; p less than 0.001) during combined verapamil-quinidine coadministration. Thus each drug maintained its own effect on SDC in the presence of the other, and their actions became combined in increasing the SDC.(ABSTRACT TRUNCATED AT 250 WORDS)

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 incremental dose titration protocol, cibenzoline (130 mg twice daily and 160 mg twice daily) and 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), ventricular pairs (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 micrograms/ml, and plasma cibenzoline concentration was 0.48 +/- 0.27 micrograms/ml. Significant clinical and laboratory toxicity was more frequent with quinidine than with cibenzoline (p less than 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.

The disposition and plasma protein binding of quinidine after intravenous administration were studied in 13 healthy subjects. Plasma protein binding, expressed as the fraction of quinidine unbound ranged from 0.134--0.303 (mean 0.221). Elimination rate constant (beta) varied from 0.071 to 0.146 h-1 (mean 0.113), and apparent volume of distribution (Vbeta) varied from 1.39--3.20 1 . kg-1 beta (mean 2.27). Total body clearance was 2.32--6.49 ml min-1 . kg-1. There was a positive linear correlation between the plasma fraction of unbound quinidine and both V beta (r = 0.885, p less than 0.01) and total body clearance (r = 0.668, p less than 0.05). No significant correlation existed between the fraction of unbound quinidine in plasma and the elimination rate constant. The results show that both the apparent volume of distribution and total body clearance of quinidine are proportional to the unbound fraction in plasma. This implies that the total plasma concentration of quinidine at steady state will change with alterations in plasma binding, whilst the concentration of unbound compound and its elimination rate will remain unaffected.

Serum and saliva quinidine concentrations were measured in eight subjects with cardiac arrhythmias on various dosage regimens. There was good correlation between serum and saliva quinidine concentration after a single dose, but there was no such relationship after repeated dosing. Comparison of the area under a hysteresis loop, obtained by plotting the saliva/serum quinidine concentration ratio as a function of serum quinidine concentration over a dosing interval, indicated an exponential increase with increasing mean serum quinidine concentration. Salivary quinidine concentration predictions based on the Henderson-Hasselbalch equation did not correlate with the serum quinidine concentration under the steady-state conditions. These data suggest that quinidine concentration in saliva is not a direct reflection of its serum concentration in cardiac patients on maintenance (steady-state) therapy and hence not useful for therapeutic drug monitoring.

A reversed-phase high performance liquid chromatographic method for determination of quinidine in serum, blood, and urine has been developed. An alkylnitrile column is used with a mobile phase of acetonitrile in an acetate buffer. The method was rigorously tested and shown to be specific for quinidine using the following methods: comparison of capacity factors among methanolic reference standards of quinidine, known metabolites, and 36 other drugs; comparison of the quinidine capacity factor with the capacity factors from components in patient sera and urines, from which quinidine was selectively removed by thin-layer chromatography; and, correlation of quinidine concentrations in patient sera using ultraviolet absorbance versus fluorescence detection. Application of the method to a single-dose pharmacokinetic study, including serum protein binding and blood/serum concentration ratio measurements.

Quinidine is determined in serum by direct and extraction spectrofluorometry, by reflectance fluorescence scanning thin-layer chromatography (TLC), and by high-performance liquid chromatography (HPLC). Least-squares analyses of patients' sera (n = 62) analyzed first by direct fluorometry (x) and then HPLC (y) gave a slope of 0.52, an y-intercept of -0.40, a standard error of estimate of 0.65, and a correlation coefficient of 0.83. Comparison of patients' sera (n = 59) determined by extraction fluorometry (x) and then HPLC (y) gave a slope of 0.998, an y-intercept of -0.175, a standard error of estimate of 0.30, and a correlation coefficient of 0.96. Comparison of patients' sera (n = 36) by HPLC (x) and then reflectance fluorescence scanning TLC (y) gave a slope of 0.837, an y-intercept of 0.152, and a correlation coefficient of 0.94. Methaqualone and oxazepam interfere with HPLC. Within-run precision is 1.6, 1.0, 5.2 and 3.0% by direct fluorometry, extraction fluorometry, TLC and HPLC while between-run precision is 5, 3.5, 9 and 6.0%, respectively.

Recent developments of clinical pharmacology show that in particular circumstances the determination of the plasmatic levels of drugs seems to be the best way to insure the best dosage schedules for each patient. For this and other reasons, at the Hospital Pharmacological Service a clinical pharmacokinetic laboratory was set up about two years ago. It is involved both in pharmacokinetic research with the aim of pointing out the reasons of a quantitatively or qualitatively unusual response to the drug (generally lack of therapeutic effect or untoward effects) and in finding the best practical administration route for each patient of those drugs which show a high incidence of undesirable side effects. At the moment, salicylates, quinidine, phenobarbital, phenytoin, theophylline, digoxin and gentamicin are routinely monitored. Other drugs under examination are valporic acid, methotrexate, etc. In the present paper the first results obtained are reported.

The plasma binding of quinidine and phenytoin has been studied pre- and postoperatively in nine patients submitted to planned gastric surgery. The binding of phenytoin showed a slight and transient reduction, whilst quinidine binding was markedly increased, on average from 78.5% on the day of operation to a maximum of 87.5%, after 2-4 days. The time course of the increase was strikingly parallel to that of the concentration of certain acute phase proteins.

To convert atrial fibrillation 19 patients (8 male and 11 female) were administered (5-vinyl-2-quinuclidinyl)-(6-methoxy-4-quinolyl)-methanol, a new slow-release quinidine formulation (Chinidinorm), containing 250 mg quinidine bisulphate x 4 H2O per tablet, corresponding to 200 mg quinidine sulphate or 164 mg quinidine base respectively. After careful titration of the effective dosage sinus rhythm could be obtained in 17 patients and auriculo-ventricular rhythm in one patient. The drug failed only in one female patient for the occurrence of diarrhoea. Minimum as well as maximum quinidine levels measured in plasma correlated significantly to the quinidine dosages/kg b.w. administered. Part of the quinidine concentrations measured in plasma was at or under the minimum effective levels, respectively, in literature. According to our results it should therefore be discussed to slightly reduce the lower limit of efficacy for plasma quinidine levels. The new quinidine formulation proved to be effective and poor of side-effects with little variations in effective plasma level. Therefore it is to be considered equivalent to all quinidine retard-formulations on the market at present.

Digoxin kinetics are substantially altered by quinidine and by spironolactone. We evaluated the effect of the combination of quinidine and spironolactone on digoxin kinetics and compared it to the effect on digoxin of each drug alone. Six normal subjects each received a 1.0-mg intravenous dose of digoxin alone, digoxin with quinidine, digoxin with spironolactone, and digoxin with both quinidine and spironolactone. Spironolactone and quinidine, alone and in combination, reduced digoxin systemic, renal, and nonrenal clearances and prolonged digoxin elimination t 1/2. A greater alteration in digoxin kinetics was induced by quinidine than by spironolactone, and an even greater effect resulted from the combination. We did not assess clinical consequences of the interaction. We advise reduction in digoxin dose, careful clinical evaluation, and measurement of serum digoxin concentrations when digoxin is used in combination with quinidine and spironolactone.

Recent reports indicate that the metabolite of quinidine, 3-hydroxyquinidine, is pharmacologically active. It was the primary purpose of this study to determine total and unbound concentrations of quinidine and 3-hydroxyquinidine in 25 patients receiving quinidine for therapeutic purposes. At the peak, total quinidine and 3-hydroxyquinidine concentrations were 2.7 +/- 1.2 micrograms/ml and 0.57 +/- 0.33 micrograms/ml, respectively, and at the trough they averaged 2.0 +/- 0.91 micrograms/ml and 0.44 +/- 0.25 micrograms/ml. Interestingly, the unbound 3-hydroxyquinidine concentration frequently exceeded the unbound quinidine concentration, averaging 0.30 +/- 0.28 micrograms/ml at the peak and 0.22 +/- 0.14 micrograms/ml at the trough. Quinidine concentrations averaged 0.24 +/- 0.15 micrograms/ml and 0.18 +/- 0.12 micrograms/ml. The ratio of unbound 3-hydroxyquinidine: quinidine was significantly influenced by the unbound clearance of quinidine (r = 0.66). At low clearance values concentrations of both substances were elevated, with the quinidine concentration consistently exceeding that of 3-hydroxyquinidine. In contrast, at high clearance values 3-hydroxyquinidine concentrations were elevated and consistently exceeded the quinidine concentration. Thus, when quinidine concentrations are used to monitor the pharmacodynamic effect of quinidine, it is most appropriate to evaluate unbound concentrations of both quinidine and 3-hydroxyquinidine.

Combination treatment with mexiletine and quinidine has been shown to be more effective than either monotherapy in the treatment of ventricular tachycardia in humans. The purpose of this study was to assess the electrophysiologic changes which correlated with enhanced antiarrhythmic activity during treatment with the monotherapies and this combination. Twenty-seven dogs with inducible sustained ventricular tachyarrhythmias (VT) late after ischemic injury were treated with mexiletine and quinidine, alone and in combination. Conscious but sedated animals were assigned randomly to receive serial drug treatments. Sustained VT was consistently inducible during serial placebo studies. In 13 dogs who received all four drug treatments (mexiletine, quinidine, combination and placebo) significantly greater antiarrhythmic efficacy was seen with combination therapy (8 of 13) than was seen with mexiletine alone (1 of 13), quinidine alone (3 of 13) and saline (0 of 13) (P less than .005). This enhanced antiarrhythmic activity was paralleled by greater prolongation of intraventricular conduction to the border zone and increase in excitability threshold at the border zone and increase in ventricular effective refractory period in the infarct zone. Serum concentrations of quinidine were 19 +/- 5 microM when given alone and 15 +/- 5 microM when given in combination. Mexiletine concentrations were 3.6 microM when given alone and 4.2 microM when given in combination. In conclusion, mexiletine and quinidine in combination produced enhanced antiarrhythmic activity which was paralleled by electrophysiologic changes occurring in the perinfarct zone. These electrophysiologic changes appear to be correlates of enhanced antiarrhythmic activity.

The safety and efficacy of intravenous quinidine gluconate, using intermittent boluses of 80 mg/cc every 5 minutes to a total dose of 800 mg, was evaluated in 61 patients referred for electrophysiologic studies (EPS). Patients were referred because of out-of-hospital cardiac arrest (12), symptomatic ventricular tachycardia (VT) (24), asymptomatic VT (18), syncope of unknown origin (6), and supraventricular arrhythmias (1). Clinical heart failure was present in 74% of patients, with a mean ejection fraction of 45 +/- 3 for all patients. Quinidine prevented VT induction in 78% of patients at a mean dose of 9.6 mg/kg and facilitated VT induction in 7% of patients. Quinidine failed to decrease mean arterial pressure in 14 patients, and in the remaining 47 patients arterial pressure decreased by 16%. Six patients had hemodynamically significant hypotension. Two patients had hypotension severe enough to require saline administration, while four had hypotension not needing fluid replacement. Sixteen percent of patients experienced other side effects. Quinidine can be administered safely by intermittent infusion and is effective in preventing programmed stimulation induction of VT. Carefully monitored, intravenous intermittent bolus administration of quinidine should be utilized more frequently in EPS, since significant adverse side effects are infrequent.

A rapid, sensitive, accurate method for determination of quinidine in plasma has been developed using ion-pair extraction and high-performance liquid chromatography. The method, which is capable of distinguishing between quinidine and dihydroquinidine, involves acidification of plasma with perchloric acid, extraction with methyl isobutyl ketone and chromatography of the carbonate-washed extract on a silica gel column with a mobile phase of methylene chloride-hexane-methanol--perchloric acid (60:35:5.5:0.1) followed by fluorometric detection. The procedure is sensitive to below 50 ng/ml (coefficient of variation 6.6%) and compares favourably with a standard spectrofluorometric method when tested with plasma from volunteer subjects.

A contact electrode catheter, which permits clinical recording of cardiac monophasic action potentials (MAPs), was used as a means of quantifying the electrophysiologic effect of 2 antiarrhythmic drugs, procainamide and quinidine. MAP recordings were made in continuous fashion from the right ventricle in 16 patients, before and after the intravenous administration of procainamide (11 patients) or quinidine (5). Increases in the MAP duration at 90% repolarization (MAPD90) were used as indexes of drug effect and related to plasma drug level. Surface electrocardiographic (QRS duration, corrected QT interval [QTC]) and electrophysiologic (ventricular effective refractory period) measurements, in addition to MAPD90, were made at the same time as blood sampling for plasma drug level determination. Dose response curves, plotting change in MAPD90 versus plasma drug level, showed strong linear correlation for both procainamide (p less than 0.0001) and quinidine (p less than 0.0001). The variance (error of estimation) of the predictive relation, change in MAPD90 versus plasma drug level, was significantly lower than that of change in QTC (p less than 0.001), QRS duration (p less than 0.0001) or ventricular effective refractory period (p less than 0.0001) versus plasma drug level for both procainamide and quinidine. Changes in MAP duration closely correlate with plasma drug level, and as such, may serve as an immediate, quantitative indicator of myocardial drug effect during the administration of antiarrhythmic agents.

The current extensive use of digoxin in elderly patients with left ventricular failure and sinus rhythm may not be clinically justifiable; in a significant proportion of these patients the frequency of digitalis toxicity may outweight the therapeutic benefits of the drug. When digoxin is used in elderly patients, the specific geriatric pharmacology of the drug must be considered. Clinical benefit should be documented before proceeding to long-term maintenance therapy. In selected elderly patients, withdrawal of digoxin with careful follow-up may be a worthwhile procedure. Studies are needed comparing the relative benefits and toxicities of digoxin versus diuretics in the management of heart failure in the elderly.