Quinidine Preparations Research Articles

Quinidine, A Life-Saving Medication for Brugada Syndrome, Is Inaccessible in Many Countries

The aim of this study was to determine the availability of quinidine throughout the world. Quinidine is the only oral medication that is effective for preventing life-threatening ventricular arrhythmias due to Brugada syndrome and idiopathic ventricular fibrillation. However, because of its low price and restricted indication, this medication is not marketed in many countries. We conducted a survey of the availability of quinidine by contacting professional medical societies and arrhythmia specialists worldwide. Physicians were e-mailed questionnaires requesting information concerning the quinidine preparation available at their hospital. We also requested information concerning cases of adverse arrhythmic events resulting from unavailability of quinidine. A total of 273 physicians from 131 countries provided information regarding the availability of quinidine. Quinidine was readily available in 19 countries (14%), not accessible in 99 countries (76%), and available only through specific regulatory processes that require 4 to 90 days for completion in 13 countries (10%). We were able to gather information concerning 22 patients who had serious arrhythmias probably related (10 cases) or possibility related (12 cases) to the absence of quinidine, including 2 fatalities possibly attributable to the unavailability of quinidine. The lack of accessibility of quinidine is a serious medical hazard at the global level.

Is Quinidine the Ideal Drug for Brugada Syndrome?

Brugada syndrome (BrS) is a cardiac disease caused by an inherited ion channelopathy that is associated with a propensity to develop ventricular fibrillation (VF). Patients with BrS and a history of cardiac arrest are considered to be at the highest risk for recurrent arrhythmic events and should be treated with an implantable cardioverter-defibrillator (ICD). However, the beneficial effects of an ICD are solely the result of VF termination by the device, whereas the device does not affect VF occurrence. For the past 3 decades, our group at the Tel-Aviv Medical Center has developed an alternative therapeutic approach to ICD use in BrS patients based on the high efficacy (90%) of quinidine bisulfate at a mean dose of 1.5 g daily to prevent inducibility of VF. This approach has been associated with both excellent reproducibility of electrophysiologic (EP) results and clinical efficacy during the long term as attested by the fact that none of our drug-responder and drug-tolerant patients has yet exhibited a recurrent arrhythmic event. Hermida et al obtained similar results using another slowrelease quinidine preparation (quinidine hydrochloride 600– 900 mg daily). We have been using the latter medication for the past 5 years because of AstraZeneca’s decision to stop production of quinidine bisulfate. Electric storms of VF represent the more malignant form of ventricular arrhythmias in patients with BrS, accounting for up to 10% of the untreated patient population and up to 38% of arrhythmic events in ICD patients. The arrhythmic storms may reveal the disease or occur after ICD implantation, and they are frequently, but not always, triggered by fever. They may lead to multiple DC shocks or ICD discharges with multiple consequences, such as psychologic disorders, proarrhythmia, deleterious effect on cardiac function, electromechanical dissociation, and death. Heart transplantation has even been used as the last resort in a patient with intractable VF (see references in Belhassen et al). Isoproterenol infusion has been shown to be very effective for the acute management of arrhythmic storms in the setting of BrS. However, it can be administered only during a short period of time, and the arrhythmia frequently recurs

Induction of esophageal injuries by doxycycline and other pills. A frequent but preventable occurrence.

Many specialists and general physicians remain unaware of the potential for and pathogenesis of drug-induced esophageal ulcerations. To promote a greater awareness of the importance of this problem, we have reviewed the literature, particularly in regard to the mechanisms of action and the clinical and therapeutic implications of these chemical injuries to the esophagus. There can be no doubt that the frequency of occurrence of drug-induced esophageal ulceration far exceeds that reflected in the reported cases appearing in the medical literature. Nor can we deny that much of the responsibility for this situation lies in the failure of the prescribing physician to educate his patients (and himself!) in the art of taking potentially harmful pills and capsules, particularly tetracycline, doxycycline, potassium chloride, and quinidine preparations. Although most such drug injuries are self-limited events, there have been a number of fatalities reported and at the very least they involve acute discomfort.

Quinidine Assays

Plasma quinidine results determined by enzyme multiplied immunoassay (EMIT) (Syva) were compared with results from a quinidine-specific high performance liquid chromatographic (HPLC) assay. During a clinical study, 16 patients with stable ventricular arrhythmias were treated with three oral quinidine preparations given during three consecutive 3-day periods. Seventeen plasma samples were drawn from each patient at steady-state during each period. Each specimen was divided into two portions, one for assay by EMIT and the other for assay by HPLC. EMIT assays were done on a Syva Autolab 6000 System using Syva quinidine kits and bilevel Ortho Diagnostics controls. The overall mean (+/- SD) quinidine concentrations by EMIT and HPLC were 2.16 +/- 0.58 and 1.81 +/- 0.60, respectively, n = 816, with a mean overall EMIT/HPLC ratio of 1.23 +/- 0.18. Mean ratios in individual patients ranged from 1.01 to 1.56; the average of mean individual ratios was 1.23 +/- 0.13. The EMIT assay, which also reports dihydroquinidine and small amounts of quinidine metabolites as quinidine, reported quinidine values that averaged 1.2-fold greater than results from a quinidine-specific HPLC method.

Increased quinidine plasma concentrations during administration of verapamil: A new quinidine-verapamil interaction

A number of drug interactions that involve quinidine have been reported. 1 These include both pharmacokinetic interactions in which plasma concentrations of other drugs, most notably digoxin, are influenced by quinidine, and pharmacologic interactions. The latter is exemplified by a recent report of marked hypotension when intravenous verapamil was given to patients receiving oral quinidine preparations. 2 This hypotension was presumably due to α-adrenergic blockade and the peripheral vasodilatation was a result of both quinidine and verapamil. We report a patient with cyanotic congenital heart disease and atrial flutter with 1:1 atrioventricular conduction who had a previously unreported quinidine-verapamil pharmacokinetic interaction.

Comparative efficacy and safety of short-acting and sustained release quinidine in the treatment of patients with ventricular arrhythmias

A comparative, fixed-dose, parallel, randomized, blinded trial to define the efficacy and safety of a new once-a-day quinidine preparation, Quiniday, at 1200 mg per day, was compared to quinidine sulfate (as Quinora, 300 mg four times daily, and Quinidex Extentabs, 600 mg twice daily) and to quinidine gluconate (as Quinaglute Dura-Tabs, 648 mg twice daily). After placebo washout from all prior antiarrhythmic agents, 76 patients with at least 30 ventricular premature complexes (VPCs)/hr on 48-hour ambulatory monitoring were randomized to 3 weeks of treatment with one of the four study drugs. There was no difference in the etiologic, demographic, New York Heart Association therapeutic classification, or ventricular arrhythmia frequency at baseline between the patients randomized to the four groups. There was no statistically significant difference between the percent efficacy for VPC reduction on any drug compared to baseline or in the percent efficacy of reduction in beats of ventricular tachycardia. There was no difference between the four agents in terms of types of side effects noted nor in their overall prevalence or need for premature discontinuation of therapy. This study demonstrated that a variety of quinidine preparations exist that do not differ in terms of their efficacy or safety, but that a long-acting, once-a-day preparation (Quiniday) was as effective and safe as other forms of quinidine despite its once-a-day dosing schedule. More compliant dosing regimens with effective well-known antiarrhythmic agents are important in the treatment of patients with potentially lethal ventricular arrhythmias, in the hope that sudden cardiac death can be prevented.

Isolation, characterisation and synthesis of a new quinidine metabolite.

In addition to the well-known quinidine metabolites, 2'-quinidinone and 3-hydroxy-quinidine, a third metabolic product was detected in the plasma of cardiac patients receiving quinidine therapy. Mass spectroscopic, 13C- and 1H-NMR studies, together with information on UV and IR properties of the isolated and also synthetically accessible compound, suggested the presence of an aliphatic N-oxide group. The structure of quinidine-N-oxide for the hitherto unknown metabolite was finally confirmed by X-ray diffraction analysis. Evidence was found to indicate that a contaminant in quinidine preparations, dihydroquinidine, is metabolized with respect to N-oxidation in the same way as quinidine.

The specificity of the extraction fluorescence assay for serum or plasma quinidine.

A series of 26 randomly selected serum samples from patients receiving long-term antiarrhythmic therapy with oral quinidine preparation were assayed by both a modification of the extraction fluorescence technique and high-pressure liquid chromatography, with highly comparable results (r = 0.98). A review of the literature on comparing the extraction fluorescence technique's results with other methods indicates a high degree of agreement. However, because variations from study to study exist, investigators using the extraction fluorescence technique should assess the specificity of the method in their own laboratory.

Effects of dihydroquinidine on in vitro and in vivo quinidine disposition

The effects of dihydroquinidine on the metabolism of quinidine by 10,000 g supernatant fractions of rabbit and rat liver homogenates and on the disposition of quinidine in the rabbit were investigated. From Lineweaver-Burk plots, the following mean ± S.E.M. values for V max and K m for quinidine and K i for dihydroquinidine for the rabbit liver preparations were obtained: 240 ± 50 nmoles/min/g liver,0.55 ± 0.14 mM, and 0.56 ± 0.09 mM respectively. The corresponding values for the rat liver homogenates were 74 ± 6 nmoles/ min/ g liver, 0.12 ± 0.02 mM and 0.14 ± 0.06 mM. From Dixon plots, the following values for K i for dihydroquinidine were obtained:0.54 ± 0.09 mM for the rabbit liver preparations and 0.14 ± 0.04 mM for the rat liver homogenates. In rabbits pretreated with dihydroquinidine for an average of 26 days, no changes in the distribution and elimination half-life values for quinidine, total body clearance, or apparent volume of drug distribution were observed when compared to the control quinidine disposition constants obtained in the same animals. As their structures suggested, the data showed that the interactions of dihydroquinidine and quinidine during drug metabolism by rabbit and rat liver 10,000 g supernatant fractions were competitive. Additionally, the affinities of dihydroquinidine and quinidine for the drug-metabolizing enzymes in these preparations were the same. The data also suggested that the small amounts of dihydroquinidine normally found in quinidine preparations probably have no significant effect on the disposition of quinidine in the body when therapeutic doses of the drug are used.

Pharmacokinetics of dihydroquinidine in congestive heart failure patients after intravenous quinidine administration.

The pharmacokinetics of dihydroquinidine were studied in 8 patients with congestive heart failure following a 22 min intravenous infusion of a quinidine preparation that contained 5.9% dihydroquinidine as an impurity. Using a thin layer chromatography-fluorometric assay procedure for dihydroquinidine, the post-infusion plasma dihydroquinidine concentrations declined biexponentially. The half-life of the fast and slow dispositional processes was 4.42 +/- 1.81 min and 6.52 +/- 2.40 h, respectively. The central compartment volume for dihydroquinidine in these patients was 0.44 +/- 0.11 l/kg with an overall apparent volume of distribution of 1.14 +/- 0.38 l/kg. The computed values of total body plasma clearance of dihydroquinidine ranged from 1.29 to 2.69 ml/min/kg with a mean value of 1.94 +/- 0.60 ml/min/kg. In these patients, approximately 16% of the administered dihydroquinidine dose was excreted intact into the urine in 48 h. The estimated value of renal clearance was 0.314 +/- 0.129 ml/min/kg. When compared to control cardiac patients, the data showed that the apparent volume of distribution for dihydroquinidine is smaller in patients with congestive heart failure and as a result of this diminished volume, the clearance rate of dihydroquinidine was slower. The net effect of these differences was the production of higher plasma concentrations of dihydroquinidine in the heart failure group.

Evaluation of Quinidine Lipettes®— a Sustained Release Preparation

A new sustained release preparation (Lipettes) of quinidine has been evaluated with regard to dissolution, absorption, serum concentration and side-effects. The serum levels of quinidine after single oral doses and after long-term treatment have been compared with the serum levels after administration of some other quinidine preparations on the Swedish market. The side-effects of the sustained release preparations have also been studied. Results indicated that this new sustained release quinidine preparation yields more even serum concentrations of quinidine and seemed to cause less troublesome side-effects than the marketed preparations.

Oesophagitis and Oesophageal Obstruction from Quinidine Tablets in Association With Left Atrial Enlargement

Bohane, T. D., Perrault, J. and Fowler, R. S. (1978). Aust. Paediatr. J., 14, 191–192. Oesophagitis and oesophageal obstruction from quinidine tablets in association with left atrial enlargement: A case report. A 12‐year‐old girl with left atrial enlargement developed oesophagitis and oesophageal obstruction following administration of quinidine bisulphate tablets, a sustained‐release quinidine preparation. Substitution by powdered quinidine sulphate resulted in rapid disappearance of all oesophageal symptoms. Left atrial enlargement may result in delayed passage of potentially irritant tablets and lead to oesophagitis which further aggravates oesophageal obstruction.

Serum quinidine levels after administration of three different quinidine preparations

In a single-blind cross-over study, 6 healthy volunteers took three different formulations, each containing 0.33 g of quinidine base, every 12 h for 96 h. A mean steady state serum level of 1.8 mg/l of quinidine base was produced by bisulphate tablets that dissolved rapidly. Long-acting Quinidine Durules® (sustained-release quinidine bisulphate) produced a mean steady state serum level that was 23% lower (NS) and Longacor® (quinidine arabogalactone sulphate) led to one that was 46% lower (p<0.05). The time taken to reach a steady state was longer after Longacor® than Quinidine Durules®. The results are discussed in relation to the conventional clinical use of quinidine, methods of estimating its concentration in serum, and the relative value of different formulations of quinidine salts.

A cross-over trial of long and short acting quinidine preparations for the maintenance of sinus rhythm after defibrillation

A second part of a cross-over study was performed for fifteen months in 16 patients to compare the efficiency of long-acting and conventional quinidine in maintaining sinus rhythm after electrical conversion of atrial fibrillation. Both quinidine preparations in adequate dosage were capable of maintaining sinus rhythm. The long-acting form of quinidine produced more stable blood levels with less fluctuation in concentration. The long-acting preparation caused fewer side effects than the conventional form of quinidine sulphate.

Comparative study of a long-acting quinidine preparation and quinidine sulphate in chronic atrial fibrillation

Comparative studies were performed for about fifteen months in 26 patients with chronic atrial fibrillation to evaluate the efficiency of Quinidine Durules or quinidine sulphate in maintaining sinus rhythm. There was no difference in the two groups as to underlying disease, type of rhythmic disturbance and its duration, nor in the frequency of occurrence of congestive heart failure prior to DC shock applied for restoration of sinus rhythm. On the basis of our observations made during a period of about 15 months adequate doses of quinidine sulphate and Quinidine Durules — monitored by the plasma quinidine levels — proved equally suited for the maintenance of sinus rhythm. Quinidine sulphate elicited side effects (toxic symptoms) more frequently than did the long-acting Quinidine Durules. With two daily dosages of Quinidine Durules — more convenient for the patient than four daily administrations of quinidine sulphate — a more stable plasma quinidine level was maintained. That in turn might explain the less frequent occurrence of side effects.

The metabolic fate of orally administered quinidine gluconate in humans

Oral administration of quinidine (I) preparations to humans has been shown by mass spectroscopy(ms),gas-liquid chromatography/ms(GLC/ms)and other analytical techniques to give a wide range of urinary metabolites. These are found as the free, or to a minor extent, as the β-glucosiduronate conjugates. The major metabolites isolated and characterized represent two oxidative modifications of (I), and of 2'-quinolone and hydroxyquinuclidine derivatives. Also found were polyoxygenated quinidine derivatives. Current supplies of quinidine were found consistently to contain 10 to 30 per cent of an impurity.

A new quinidine preparation with sustained release.

Acta Medica ScandinavicaVolume 173, Issue 4 p. 511-519 A New Quinidine Preparation with Sustained Release Gun Cramér, Gun Cramér Medical Service I, Sahlgren's Hospital, Göteborg, SwedenSearch for more papers by this authorEdvardas Varnauskas, Edvardas Varnauskas Medical Service I, Sahlgren's Hospital, Göteborg, SwedenSearch for more papers by this authorLars Werkö, Lars Werkö Medical Service I, Sahlgren's Hospital, Göteborg, SwedenSearch for more papers by this author Gun Cramér, Gun Cramér Medical Service I, Sahlgren's Hospital, Göteborg, SwedenSearch for more papers by this authorEdvardas Varnauskas, Edvardas Varnauskas Medical Service I, Sahlgren's Hospital, Göteborg, SwedenSearch for more papers by this authorLars Werkö, Lars Werkö Medical Service I, Sahlgren's Hospital, Göteborg, SwedenSearch for more papers by this author First published: January/December 1963 https://doi.org/10.1111/j.0954-6820.1963.tb17435.xCitations: 15AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume173, Issue4January/December 1963Pages 511-519 RelatedInformation

Use of a long-acting quinidine preparation in the reversion of atrial fibrillation

A specially compounded quinidine gluconate preparation is now available which has been shown by quantitative measurement to attain significantly prolonged therapeutic serum quinidine levels. A clinical study to evaluate specifically the efficacy of this compound in the reversion of atrial fibrillation was performed in eighteen patients with electrocardiographically confirmed atrial fibrillation. In all but one of the patients the arrythmia was successfully reverted to normal sinus rhythm. In only one patient did evidence of quinidine toxicity develop which necessitated termination of therapy without successful reversion. It is believed that the results of this series are encouraging and the long-acting quinidine preparation utilized has definite value as an antifibrillatory agent.

Study of a long-acting quinidine preparation: experience in normal subjects and in patients with myocardial abnormality.

Since 1918 quinidine has been used successfully in the treatment and prevention of various cardiac arrhythmias, particularly extrasystoles, paroxysmal tachycardia, atrial fibrillation, and flutter. Since the oral ingestion of quinidine derivatives reach a blood plasma peak relatively quickly and the concentration following a single dose falls rather rapidly, 1-5 it is necessary to administer not only multiple daily doses but frequently night doses to maintain an effective plasma level. In order to avoid multiple doses, attempts have been made at various times to administer a slower- and longer-acting preparation. Sampson et al. (1952), 6 in an effort to find a more slowly absorbed and longer-acting preparation of quinidine, used a delayed-absorptive-coated tablet of quinidine sulfate. They gave 0.8 gm. as a single dose to five patients. The maximum quinidine level, which ranged from 2.3 to 3.3 mg. per liter (average, 2.72 mg. per liter) was reached in 5 to 12

Paroxysmal ventricular tachycardia treated intravenous injections of quinidine.

THE INTRAVENOUS administration of quinidine has not been accepted generally because of serious reactions following its use by this route.1Although intravenous quinidine preparations are known to be effective in terminating paroxysmal ventricular tachycardia,2their use has been delayed because serious sideeffects have occurred when they have been given for this purpose.3There are few reports describing its use in a significant number of attacks of ventricular tachycardia. Hepburn and Rykert2grecorded nine instances, and normal sinus rhythm was restored in eight. Recently Armbrust and Levine,2ain analyzing 107 cases of paroxysmal ventricular tachycardia, described 31 attacks treated with intravenous quinidine. In 20 of the attacks, conversion to normal sinus rhythm occurred at a time which indicated a response to quinidine therapy. Herrmann and Hejtmancik2ffound it effective in two of three cases, and Clagett2bsuccessfully treated three patients. Strong and Munroe2eand, more recently, Bell and his associates2chave