Background Quinine is the diastereomer of quinidine. In dogs, it has similar effects on conduction time but does not prolong epicardial repolarization time or ventricular refractoriness. It has antiarrhythmic effects in both cats and dogs. We assessed the antiarrhythmic potential of quinine in suppressing ventricular arrhythmias in humans.
Methods and Results Patients underwent open-label, dose-ranging trials of quinine with daily doses of 600, 1200, and 1800 mg in a twice-daily dosing regimen. In 17 patients with frequent spontaneous ventricular ectopy, oral quinine suppressed arrhythmia in 11 of 12 patients who finished the study and was not tolerated by 4 patients, and 1 patient withdrew from the study. The mean effective daily dosage was 927 mg, the mean effect trough serum level was 11 μmol/L (range, 4 to 17 μmol/L), and the half-life was 20±7 hours. In a second open-label, dose-ranging trial in 10 patients with inducible ventricular tachycardia and reduced left ventricular systolic function (left ventricular ejection fraction, 35±16%), quinine suppressed inducibility of ventricular tachycardia in 3 of 10 patients. At a basic pacing cycle length of 500 milliseconds, ventricular effective refractory period was prolonged (279±21 versus 247±10 milliseconds, quinine versus drug free, P=.003). In the remaining patients, ventricular tachycardia cycle length was prolonged (373±48 versus 253±30 milliseconds, quinine versus drug free, P<.001). The corrected QT interval was not prolonged.
Conclusions Quinine is an effective and convenient antiarrhythmic drug for the suppression of ventricular arrhythmias in humans.
Quinine is the diastereomer of quinidine. Both stereoisomers block the cardiac sodium channel, but only quinidine prolongs action potential duration in vitro and repolarization time in vivo in dogs.1 2 3 4 These results suggested that quinine might be an effective antiarrhythmic drug without the potential for excessive prolongation of repolarization, resulting in torsades de pointes.5
Several studies have addressed the antiarrhythmic potential of quinine in animal models. Klevans et al6 showed that both quinidine and quinine raised ventricular fibrillation thresholds in cats and decreased ouabain-induced premature ventricular complexes in dogs. Jurkiewicz et al2 reported that both isomers were equally effective in preventing ventricular tachycardia and ventricular fibrillation in a canine model of acute ischemia. We used a canine model of inducible ventricular tachycardia late after occlusion-reperfusion injury in dogs7 to compare the electrophysiological and antiarrhythmic properties of quinine and quinidine.8 Both drugs prolonged conduction times to a similar extent, but quinidine prolonged local epicardial repolarization time8 and refractoriness significantly more than did quinine. Limited antiarrhythmic efficacy was seen only with quinidine, and only quinidine prolonged ventricular tachycardia cycle length. Therefore, the data about the antiarrhythmic effects of quinine in animals were inconclusive.
The purpose of the present study was to evaluate the antiarrhythmic potential of quinine in suppressing spontaneous and inducible ventricular arrhythmias in humans. Our primary goal was to determine the ability of oral quinine in open-label, dose-ranging protocols to suppress spontaneous and inducible ventricular arrhythmias. Also, we wanted to determine its ECG and electrophysiological characteristics. In addition, we wanted to establish dose-concentration, dose-response, and concentration-response relations.
There were two studies. Study 1 was an open-label, dose-ranging protocol, with each step lasting 3 to 5 days. This interval was selected based on two pharmacokinetic studies in malarial patients9 and patients with quinine overdoses10 that estimated quinine mean half-lives of 11 to 27 hours. Patients initially received 600 mg quinine daily in a twice-daily dosing regimen. Efficacy by ambulatory ECG and side effects were assessed after 3 to 5 days, and individuals with neither efficacy nor side affects then received 1200 mg quinine daily in a second step. If necessary, patients also received quinine 1800 mg daily in a third step. The doses of quinine were selected based on earlier animal data suggesting that serum levels of 10 to 30 μmol/L might be necessary to demonstrate efficacy.8 The oral doses necessary to establish these levels were estimated from a compilation of dose-response data of quinine in malaria.9 11 12 13 The maximum dose was selected to keep quinine levels at <30 μmol/L to avoid ocular and aural toxicity.9 10 13
Patients were allowed to withdraw at any time, and all patients who entered the study are reported. Study 1 was conceived and completed before publication of the results of the Cardiac Arrhythmia Suppression Trial.14 15
Study 2 was similar in design to study 1, but patients received the maximum tolerated dose of quinine before undergoing evaluation of drug effectiveness by programmed electrical stimulation. Assessments of drug efficacy using either ECG, ambulatory ECG, or programmed electrical stimulation were performed after a minimum period of 72 hours on the relevant quinine dose. This interval was selected based on an estimated mean half-life of 19 hours9 10 and was intended to correspond to ≈4 half-lives. At this interval, the serum concentration should be within 6% of a theoretical steady state level. The ambulatory ECG studies spanned two drug doses, and the invasive studies were performed 3 to 9 hours after a quinine dose.
All patients who entered the protocol are reported. All patients gave informed consent, and both studies were approved by the University of Calgary Conjoint Medical Ethics Committee.
In study 1, adult patients were eligible for inclusion if they had 30 or more premature ventricular complexes per hour during 24-hour ambulatory ECG. In study 2, adult patients were eligible for inclusion if they had reproducibly inducible sustained monomorphic ventricular tachycardia in the setting of structural heart disease and had either not tolerated or failed to respond to at least one other antiarrhythmic drug during programmed electrical stimulation. Sustained ventricular tachycardia was defined as consecutive ventricular depolarizations ≥120 beats per minute lasting >30 seconds or requiring cardioversion because of hemodynamic deterioration. Patients were excluded from both studies if they had developed side effects from quinidine, might become pregnant, had New York Heart Association Class III or IV congestive heart failure, had received amiodarone, or were receiving other antiarrhythmic drugs that could not be discontinued.
Recordings were made at a speed of 25 mm/s. Rate-corrected repolarization times (QTc) were calculated using Bazett’s formula (QTc=QT/√RR). Rate-corrected JT intervals (JTc) were calculated using the formula JTc=(QT—QRS)/√RR. ECGs with bundle-branch block or ventricular pacing were excluded from QTc and JTc measurements.
Two-channel ambulatory ECG recordings were analyzed with computer assistance using the Marquette 8000 Scanner with version 5.7 of the Marquette Arrhythmia Analysis program to identify and label each QRS. Tapes unsuitable for automated analysis were fully disclosed, and arrhythmias were counted manually. Records with less than 18 hours of analyzable ECG tracings were excluded.
A conventional protocol was used.16 Single, double, and triple extrastimuli were introduced during diastole after eight-beat trains of ventricular pacing cycle lengths of 600, 500, and 400 milliseconds (ms) at the right ventricular apex, followed if necessary by alternating trains of 4 and 15 beats in duration of rapid ventricular pacing at cycle lengths of 300 to 240 ms in 10-ms decrements. The minimum extrastimulus coupling interval was 180 ms. If ventricular tachycardia was not reproducibly induced, the stimulation protocol was repeated from the right ventricular outflow tract and, if necessary, during an infusion of isoproterenol. At baseline, the end point was considered to be completion of the protocol or reproducible induction of sustained ventricular tachycardia lasting >30 seconds or requiring early termination because of hemodynamic deterioration.
Serum from study 1 patients was obtained for quinine levels either 30 minutes preceding a dose to determine trough levels or periodically after discontinuation of quinine to determine the pharmacokinetic half-life. Quinine levels were assayed using high-pressure liquid chromatography.8
Left ventricular ejection fraction was determined by quantitative radionuclide ventriculography using the multiple-gated blood pool equilibrium method.17 Ejection fractions were measured in study 2 patients in the absence of antiarrhythmic agents and negative inotropic agents and subsequently while receiving quinine.
Criteria for Drug Efficacy
In study 1, a drug dose was deemed to be effective if it suppressed at least 80% of single premature ventricular complexes, 90% of couplets, and 100% of runs of ventricular tachycardia (three or more consecutive premature ventricular complexes at a rate ≥120 min−1).16 In study 2, a drug dose was deemed to be effective if fewer than 16 beats of ventricular tachycardia could be induced despite the application of up to three extrastimuli at basic pacing cycle lengths of 600, 500, and 400 ms and burst pacing at the same pacing site at which ventricular tachycardia was originally induced.16
Results are expressed as mean±SD. One-way ANOVA was used to compare the differences between multiple groups. The differences between subgroups were tested with the Newman-Keuls test. Student’s t tests (paired or unpaired) were used to compare differences between pairs of groups. The correlation of continuous variables between groups was determined by linear regression analysis. The null hypothesis was rejected at a level of P<.05.
Twenty-four subjects participated in these studies. Of these, 17 participated in study 1, 10 participated in study 2, and 3 participated in both studies. Data common to both studies are presented first.
ECG data were obtained from all 24 subjects in studies 1 and 2 who were in the drug-free state, 23 subjects receiving 600 mg quinine daily, 15 subjects receiving 1200 mg quinine daily, and 6 subjects receiving 1800 mg daily. The data in the Table⇓ document mean resting heart rate, QRS duration, QT interval, and QTc interval in the total study population (top), study 1 (middle), and study 2 (bottom). Mean QRS duration was significantly longer in subjects receiving 1200 mg quinine daily than in drug-free patients (120±41 versus 91±23 ms, P<.05, Newman-Keuls test). In study 1 patients, the QRS durations in drug-free patients and patients receiving quinine 1200 mg daily were 81±11 and 93±16 ms, respectively, whereas the QRS durations in comparable study 2 patients were 106±27 versus 143±37 ms. The small number of patients who received quinine 1800 mg daily precluded the use of ANOVA in study 1 and study 2.
To explore further the effects of quinine on ECG characteristics, we analyzed the differences in 15 drug-free patients and the same patients receiving quinine 1200 mg daily. The use of quinine increased QTc by 22±59 ms, increased QRS duration by 22±27 ms, and increased JTc by 2±53 ms. Multiple linear regression analysis revealed the relation (ΔQTc), ms=(2 ms+1.0 (Δ[QRS]), ms+1.0 (Δ[JTc]), ms (r2=.95, P<.001). Although the effects of quinine on QTc and JTc were closely correlated (r=.85), the direction of these effects were variable, as manifest by the change in JTc of 2±53 ms. In contrast, quinine increased QRS duration, and this also correlated with an increase in QTc interval (r=.46).
Suppression of Spontaneous Ventricular Arrhythmias (Study 1)
The mean age of the subjects in study 1 was 61±8 years, and 14 of 17 were men. Fourteen had structurally normal hearts and were either asymptomatic or had palpitations, whereas 3 had old myocardial infarctions and presented with sustained ventricular tachyarrhythmias. The mean baseline frequency of ventricular arrhythmias in all 17 enrolled patients was 468±580 premature ventricular complexes per hour, 14±23 couplets per hour, and 4±8 runs of nonsustained ventricular tachycardia per hour.
During quinine daily doses of 600, 1200, and 1800 mg in study 1 patients, the quinine trough serum levels were 9.0±3.7, 11.7±3.4, and 19.0±2.7 μmol/L, respectively. Data for the rate of disappearance of quinine from serum after drug discontinuation were obtained from 7 subjects. Fig 1⇓ shows that quinine was cleared monoexponentially with a mean half-life of 20±7 hours (range, 11.2 to 27.5 hours). These data support the appropriateness of twice-daily dosing and suggest that dose-ranging steps of 3 to 5 days allow serum levels to approach steady state.
Of the 17 patients in study 1, 12 completed the protocol. Of the 5 patients who withdrew, 2 had gastrointestinal side effects, 1 had tinnitus, 1 was noncompliant, and 1 had flulike symptoms. An effective and tolerated dose of quinine was found for 11 of 12 patients (92%), and 1 patient did not respond to 1800 mg quinine daily. In the 11 responding patients, the mean baseline frequency of ventricular arrhythmias was 334±335 premature ventricular complexes per hour, 16±27 couplets per hour, and 4±8 runs of ventricular tachycardia per hour. The mean frequency of ventricular arrhythmias at the well-tolerated and effective quinine dose was 16±27 premature ventricular complexes per hour, 0.25±0.42 couplet per hour, and no ventricular tachycardia. The individual data for the 11 suppressed patients and 1 incompletely suppressed patient are shown in Fig 2⇓. No patients had proarrhythmia or new heart block on quinine.
The dose-response relation is as follows. Of the 17 patients who received quinine 600 mg daily and underwent ambulatory ECG, 6 had suppression of ventricular arrhythmias. Of the 11 patients who received quinine 1200 mg daily, 5 withdrew and 4 of 6 had effective suppression of ventricular arrhythmias. Of the 2 patients who received quinine 1800 mg daily, 1 had suppression of ventricular arrhythmias. On an intent-to-treat basis, the three doses of quinine were cumulatively effective in 35%, 59%, and 65% of 17 patients. On a therapy-delivered basis, the three doses of quinine cumulatively were effective in 33%, 83%, and 92% of 12 patients (Fig 3⇓). The numbers of patients responding to each dose were 6 patients receiving 600 mg daily, 4 receiving 1200 mg daily, and 1 receiving 1800 mg daily. The mean daily effective dose was 927 mg.
The relation between quinine trough levels and the probability of antiarrhythmic response is shown in Fig 4⇓. There is an apparently linear relation between the cumulative response rate and serum quinine level. The quinine trough level that was associated with an antiarrhythmic response in 50% of subjects was 11±5 μmol/L, and the range of effective concentrations was 4 to 17 μmol/L.
In summary, oral quinine was well tolerated in 12 of 17 subjects (71%) and effectively suppressed spontaneous ventricular arrhythmias in 11 of 12 completely evaluable subjects (92%). The mean effective daily dose was 927 mg, and the mean effective trough serum level was 11±5 μmol/L.
Suppression of Inducible Ventricular Tachycardia (Study 2)
The ability of oral quinine to prevent the induction of sustained monomorphic ventricular tachycardia was tested in 10 male subjects with structural heart disease and inducible ventricular tachycardia. Their mean age was 67±6 years, 9 had had an old myocardial infarction, and 1 had a dilated cardiomyopathy. The mean left ventricular ejection fraction was 35±16%. One presented with a cardiac arrest, 7 with sustained ventricular tachycardia and syncope or presyncope, and 2 with sustained ventricular tachycardia and angina and dyspnea. Each of the 10 subjects had failed to respond to at least one antiarrhythmic drug (quinidine or procainamide, 7; mexiletine and either quinidine or procainamide, 2; propafenone, 2; sotalol, 2).
Six patients had received quinidine before receiving quinine. While on quinidine, 2 had torsades de pointes and a third had a cardiac arrest due to ventricular fibrillation. An additional 2 patients developed markedly long QT intervals without torsades de pointes, and the sixth patient had inducible ventricular tachycardia while taking quinidine. None had evidence of these events while taking quinine.
The highest tolerated daily quinine doses during which patients underwent electrophysiological studies were 600 mg (n=1), 1200 mg (n=7), and 1800 mg (n=2). The mean daily dose of quinine was 1260±340 mg. There were no significant differences in His-to-ventricle times between patients who were drug free and those who were receiving quinine (55±18 versus 60±17 ms, respectively). However, ventricular effective refractory periods increased significantly during treatment with quinine. At a basic pacing cycle length of 500 ms, the effective refractory period increased from 247±10 to 279±21 ms (n=10, P=.003, paired t test). The individual data obtained a pacing cycle length of 500 ms are shown in Fig 5⇓. Similarly, at a pacing cycle length of 600 ms, the effective refractory period increased from 255±9 to 291±23 ms (n=8, P=.002), and at a pacing cycle length of 400 ms, the refractory period increased from 254±10 to 284±21 ms (n=7, P=.012). In 6 patients who received quinidine before quinine, the QTc intervals were 513±69 and 434±53 ms for quinidine and quinine, respectively (P=.013).
Quinine prevented ventricular tachycardia induction in 3 of 10 patients. Two of these 3 patients had developed torsades de pointes while taking quinidine. In the remaining 7 of 10 patients, quinine prolonged ventricular tachycardia cycle length from 253±30 to 373±48 ms (P<.001). The change in cycle length did not correlate with changes in QRS duration or QTc interval. The individual cycle length data are shown in Fig 6⇓. Quinine also improved the symptomatic outcome of the electrophysiological study: in the absence and presence of quinine, 7 and 1 of 10 patients, respectively, became syncopal and required cardioversion. No patients had proarrhythmia or new heart block on quinine.
The effect of quinine on systolic left ventricular function was assessed by measuring left ventricular ejection fraction in study 2 in drug-free patients and in patients receiving quinine. There was no significant difference between drug-free patients (left ventricular ejection fraction, 35±16%) and patients receiving quinine (left ventricular ejection fraction, 31±13%).
Eight patients left hospital on quinine. None of 3 patients rendered noninducible by quinine have had recurrences after 24, 41, and 49 months. Of 5 patients receiving quinine as a “second-best” treatment, 3 had well-tolerated recurrences after 1 day, 3 months, and 7 months, and 1 developed side effects after 4 months and required readmission for medication change.
In summary, oral quinine suppressed ventricular tachycardia induction in 3 of 10 patients and markedly prolonged ventricular refractoriness and ventricular tachycardia cycle length.
The data in this report demonstrate the antiarrhythmic potential of quinine, the diastereomer of quinidine. Quinine was selected for study because it has similar sodium channel–blocking properties as quinidine, has a known side effect profile, and has a conveniently long half-life in malarial patients. Unlike quinidine, quinine has relatively little effect on epicardial repolarization time in vitro or in vivo or QT interval in vivo and thus offers the potential of antiarrhythmic efficacy without the proarrhythmic potential of causing torsades de pointes.5
Antiarrhythmic Efficacy and Tolerance
On an intent-to-treat basis, quinine suppressed spontaneous ventricular arrhythmias using conventional suppression criteria in 11 of 17 patients (65%). On a treatment-delivered basis, quinine suppressed spontaneous ventricular arrhythmias in 11 of 12 patients (92%). These response rates compare well with those of the Cardiac Arrhythmia Pilot Study,18 in which 52% to 83% of patients responded to the class I antiarrhythmic drug to which they were first randomized. The drugs in this study were encainide, flecainide, morizicine, and imipramine.
Similarly, quinine suppressed inducible ventricular tachycardia in 3 of 10 patients, each of whom had failed to tolerate or respond to at least one previous antiarrhythmic drug. This antiarrhythmic efficacy is comparable to other antiarrhythmic drugs. Quinine also caused significant prolongation of ventricular tachycardia cycle length in the remaining patients.
Although quinine was generally well tolerated, 4 of 17 subjects (24%) dropped out of study 1 due to intolerance. Quinine had no significant effect on left ventricular ejection fraction in patients with structural heart disease and sustained ventricular tachycardia. None of the 24 subjects developed proarrhythmia or heart block, and neither of the patients who developed torsades de pointes on quinidine had this arrhythmia on quinine. Thus, quinine effectively suppresses both spontaneous and inducible ventricular arrhythmias but has an appreciable side effect profile, even in a healthy, ambulatory population.
The desirable characteristics of a clinically useful drug include not only a reasonable benefit/toxicity profile but also a convenient dosing interval and predictable dose-response and concentration-response relations. Two previous pharmacokinetic studies of quinine have been reported. White et al9 showed that the mean half-life of quinine in malarial patients was ≈17 hours and that this dropped to 11 hours when patients were studied after recovery. Bateman et al10 reported the mean half-life of quinine in patients with clinical toxicity due to quinine overdosage to be ≈26 hours. Given this range of estimates, we believed that it was warranted to determine the elimination half-life of quinine in aging patients with ventricular arrhythmias. We report that quinine is cleared monoexponentially with a half-life of 20±7 hours, which is consistent with the previous findings. Most patients who responded to quinine did so at doses of 600 to 1200 mg daily with an effective mean daily dose of quinine for suppressing spontaneous ventricular ectopy of 927 mg. These doses are below typical antimalarial daily doses of 30 mg/kg, or ≈2.1 g/day for a 70-kg person,9 and produced a mean effective trough serum concentration of 11 μmol/L. The antiarrhythmic response to quinine was linearly related to serum quinine levels. Thus, the therapeutic response to quinine has predictable dose-response and concentration-response relations and demonstrated no proarrhythmia or heart block, and the serum half-life is sufficiently long that once- or twice-daily drug administration is feasible.
Electrophysiological Effects of Quinine
This is the first report to document the electrophysiological effects of quinine in humans. Like quinidine, quinine is a sodium channel–blocking agent. It binds to the class I antiarrhythmic drug receptor on freshly isolated cardiac myocytes3 and prolongs conduction time in dogs,1 2 8 both in vitro and in vivo. Consistent with this, we have shown that it prolongs surface QRS duration (P<.05) in patients receiving 1200 mg of quinine daily. In contrast to quinidine, quinine has very little effect on QT intervals, even in patients with inducible ventricular tachycardia. The increase in QTc in patients who received quinine 1200 mg daily was 22±59 ms, but of this relatively little (2±53 ms) was due to an increase in JTc. QTc was also significantly shorter in patients receiving quinine than in the same patients who received quinidine. These data are consistent with the negligible effects of quinine in dogs on action potential duration in vitro1 2 and epicardial repolarization time in vivo8 and suggest that quinine may have at most a minor effect on the potassium currents blocked by quinidine.
In light of this, the marked prolongation of refractoriness by quinine is a striking finding. This may be due to an interaction of quinine with the sodium channel, given the correlation between the prolongation of QRS duration and repolarization time. Quinine is known to bind to the class I drug receptor associated with the cardiac sodium channel3 and decreases the maximum velocity of the upstroke of the action potential in canine Purkinje fibers.4 Quinine appears to differ from propafenone,17 18 which prolongs conduction time, prevents induction of ventricular tachycardia, prolongs ventricular tachycardia cycle length, but does not prolong refractoriness.
Potential Study Limitations
Quinine is a sodium channel–blocking drug, and the routine use of these drugs for the suppression of asymptomatic ventricular arrhythmias using spontaneous suppression is no longer advocated.14 15 Also, the usefulness of the selection of effective class I drugs with programmed electrical stimulation has been called into question by the results of the ESVEM study,21 although debate continues regarding the structure and implications of this study (16). Two potential limitations arise due to the patient population and the mode of testing of drug efficacy. Only 3 of 17 study 1 patients had coronary artery disease, and therefore the study 1 population might be expected to be more responsive to antiarrhythmic therapy and less prone to proarrhythmic effects. Thus, the study might overestimate the response to quinine of patients with structural heart disease. Second, quinine was judged to be effective if no more than 16 beats of ventricular tachycardia could be induced throughout a complete study and at the same site at which it was originally induced. Possibly more stringent criteria, such as suppressing inducibility to no more than four beats or performing a complete drug study at two sites, might have resulted in a lower estimate of the efficacy of quinine. However, optimal protocol and criteria have not been defined or adopted universally, and our criteria are broadly representative of other centers.16 Finally, changing criteria would not have altered the other electrophysiological effects reported here or changed the noted effect on ventricular tachycardia cycle length.
Second, the effect of quinine on atrial myocardium and atrioventricular nodal tissue has not been determined.
A third potential limitation is the small size of this study, which prevented meaningful conclusions on the long-term outcome of patients taking quinine. The small size of the study might account for our inability to demonstrate that quinine prolongs the HV interval, as would be expected of a sodium channel–blocking drug. However, the purpose of this study was to determine the antiarrhythmic potential of quinine, and as such was ethically limited to a small number of patients.
Quinine has several interesting features that suggest further investigation and use. It is reasonably well tolerated, has a long half-life that should allow once- or twice-daily use, does not significantly depress left ventricular ejection fraction, and should not cause torsades de pointes. In patients with sustained ventricular tachycardia, quinine may be useful in slowing ventricular tachycardia, thereby being an effective “second-best” medication.22 The latter effect may be useful in patients receiving frequent shocks from implantable defibrillators for rapid ventricular tachycardia. Quinine may slow ventricular tachycardia to a rate not associated with hemodynamic compromise and therefore more amenable to antitachycardia pacing therapies.23
This work was supported by grants from the Medical Research Council of Canada, Ottawa, Ontario (PG11188), and the Calgary General Hospital and Foothills Hospital Research and Development Committees, Calgary, Alberta, Canada. Dr Sheldon was a Scholar of the Heart and Stroke Foundation of Canada, and Dr Duff is a Scientist of the Alberta Heritage Foundation for Medical Research.
- Received March 20, 1995.
- Revision received June 12, 1995.
- Accepted June 25, 1995.
- Copyright © 1995 by American Heart Association
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