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PubMedDate not supplied

Relative electrophysiological potencies of quinidine, 3-OH quinidine and quinidine-N-oxide in guinea-pig heart.

The relative potencies of the quinidine metabolites, 3-OH quinidine (3OHQ) and quinidine-N-oxide (QNO), to their parent drug, quinidine, were obtained electrophysiologically using guinea-pig hearts. The items examined were QT interval of local extracellular electrogram in a Langendorff's perfused heart, effective refractory period (ERP) and action potential duration at 90% repolarization (APD90) in the right papillary muscle. Quinidine (0.125-1 mg/l) and 3OHQ (0.5-4 mg/l) prolonged QT interval in a concentration-dependent manner and the relative potency of 3OHQ to quinidine was 0.25. The effect of QNO on QT interval within the range of concentration used (up to 8 mg/l) was small and the relative potency was 0.04 at the most. An apparent additive effect of 3OHQ to that of quinidine was revealed, but QNO of 4 mg/l has no effect on the concentration-effect relationship of quinidine for prolonging QT interval. These results were quite similar to those in humans reported previously. Quinidine (0.5-4 mg/l), 3OHQ (1-8 mg/l) and QNO (2-8 mg/l) prolonged APD90 in a concentration-dependent manner. These effects were accompanied by the prolongation of ERP in similar degrees. The relative potencies of 3OHQ to Q were 0.22 for APD90 and 0.27 for ERP and those of QNO were 0.087 for APD90 and 0.084 for ERP. Quinidine (10(-5) M) depressed the maximum upstroke of action potential (Vmax) in a frequency-dependent manner. 3OHQ of the same concentration also depressed it in the same manner to a much lesser extent and QNO had no effect. In conclusion, relative potencies of quinidine metabolites to quinidine for prolonging QT interval of local extracellular electrogram represent those to prolong APD90 and ERP, suggesting the relative potencies for antiarrhythmic activity in the same order. In the physiological range of concentrations of metabolites, 3OHQ may contribute to the antiarrhythmic effect of quinidine in an additive way, but QNO may have little effect when we take into account the fact that the free fraction of 3OHQ is 2.5 times that of quinidine.

Action Potentials↗
PubMed1990

Low dose quinidine-mexiletine combination therapy versus quinidine monotherapy for treatment of ventricular arrhythmias.

Low dose quinidine-mexiletine combination therapy was compared with quinidine monotherapy in 15 patients with frequent ventricular premature complexes and nonsustained ventricular tachycardia in a dose escalation cross-over study. Oral combination therapy was initiated with quinidine gluconate (165 mg) plus mexiletine (150 mg) every 8 h. If ventricular premature complexes were not suppressed greater than or equal to 80% and nonsustained ventricular tachycardia greater than or equal to 90%, the dose was increased to a maximum of 330 mg of quinidine plus 200 mg of mexiletine. Quinidine monotherapy was initiated with 330 mg and escalated to a maximum of 660 mg every 8 h if criteria for effectiveness were not met. Combination quinidine-mexiletine therapy suppressed 80% of ventricular premature complexes in 13 of 14 patients and suppressed 100% of episodes of ventricular tachycardia in 6 of 8 patients (mean quinidine dose 200 +/- 70 mg; mean mexiletine dose 146 +/- 24 mg every 8 h). The mean effective trough quinidine and mexiletine concentration was 1.0 +/- 0.7 and 0.9 +/- 0.4 microgram/ml, respectively. Monotherapy was less effective; that is, greater than or equal to 80% suppression of ventricular premature complexes was observed in 5 of 15 patients and 100% suppression of ventricular tachycardia in 2 of 9 patients. The mean quinidine monotherapy dose was 462 +/- 155 mg every 8 h; the mean quinidine concentration was 1.8 +/- 0.8 microgram/ml. Adverse systemic effects occurred in 3 patients on quinidine-mexiletine therapy and in 11 on quinidine monotherapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Arrhythmias, Cardiac↗
PubMed1990

Role of quinidine in the mexiletine-quinidine interaction: electrophysiologic correlates of enhanced antiarrhythmic efficacy.

Quinidine has multiple electrophysiologic effects, including prolongation of ventricular conduction time, repolarization, and refractoriness. The purpose of this study was to address the relative contributions of these electrophysiologic effects to the enhanced anti-arrhythmic activity observed when quinidine is combined with mexiletine. We compared antiarrhythmic and electrophysiologic effects observed when quinidine or its stereoisomer quinine were combined with mexiletine. Quinine and quinidine both prolong conduction time; however, these agents have divergent effects on ventricular repolarization time and refractoriness. The modest prolongation of conduction time observed with quinine and mexiletine-quinine in the absence of change of ventricular refractoriness was not associated with antiarrhythmic efficacy. The antiarrhythmic efficacy of mexiletine-quinidine exceeds that of mexiletine-quinine, suggesting that the ability of quinidine to prolong refractoriness and repolarization contributes to the antiarrhythmic efficacy of mexiletine-quinidine. Although, both the mexiletine-quinidine combination and quinidine monotherapy prolonged refractoriness to a similar extent, the mexiletine-quinidine combination produced greater antiarrhythmic efficacy and prolonged interventricular conduction within the periinfarct zone to an extent greater than did quinidine alone. We concluded that the role of quinidine in producing enhanced antiarrhythmic activity when combined with mexiletine includes both prolongation of refractoriness and conduction time in the periinfarct zone.

Action Potentials↗
PubMedDate not supplied

Relative bioavailability of quinidine gluconate and quinidine sulfate in healthy volunteers.

A comparison of the bioavailability of quinidine sulfate to quinidine gluconate tablets in a single-dose randomized cross-over design with 20 healthy volunteers shows that the sulfate salt is more rapidly absorbed and provides significantly greater peak concentrations 1 hour after administration as compared to the peak levels achieved with the gluconate salt at approximately 5 hours after administration. When adjusted for the actual amount of quinidine contained in each tablet, there was no significant difference in the amount of quinidine bioavailable. Since quinidine gluconate absorption is significantly slower than quinidine sulfate, a combination of the two dosage forms may be utilized in providing the loading dose. Based on the computer modeling and the clinical data accumulated by this laboratory (unpublished) over the past four years, quinidine gluconate, in the dosage form utilized in this study, provides more constant blood levels with smaller differences between the Cpmax and Cpmin than the sulfate when administered every 6 or 8 hours. Further controlled clinical studies are needed to confirm these observations in patients.

Adult↗
PubMed1991

High-performance liquid chromatographic method for the quantitation of quinidine and selected quinidine metabolites.

A specific and sensitive assay for the separation and quantitation of quinidine, 3-hydroxyquinidine, quinidine-N-oxide, O-desmethylquinidine and dihydroquinidine is presented. The assay is shown to be sensitive to concentrations of 0.1 microgram/ml for all the above compounds when using a serum sample of 0.1 ml. The standard curve demonstrates linearity at concentrations from 0.1 to 5 micrograms/ml. The extraction procedure consists of adjusting the serum to an alkaline pH and extracting once with a mixture of methanol-dichloromethane (15:85). The organic extract is dried and the residue is solubilized in mobile phase. The chromatographic conditions are an isocratic delivery of the mobile phase 0.01 M K2HPO4-acetonitrile (96:4) through a C18 column at ambient temperature. Detection of the compounds of interest is by ultraviolet absorption at a wavelength of 210 nm. For each compound the inter-assay variation is less than 10% and the intra-assay variation is less than 15%. No interfering compounds were detected when a commercially prepared serum spiked with 28 commonly used therapeutic compounds was assayed by this method. The analytical method presented here for the isolation and quantitation of quinidine, several active metabolites, and dihydroquinidine has adequate sensitivity and specificity for monitoring the concentration of quinidine and quinidine metabolites in patient samples.

Chromatography, High Pressure Liquid↗
PubMed1976

Serum quinidine levels after chronic administration of four different quinidine formulations.

The serum levels produced by four different quinidine formulations have been studied. The relative bioavailability of the formulations was demonstrated as were the mean peak serum levels and their timing in relation to dosage. From the data obtained, the biological half-lives were measured and the apparent volume of distribution and total body clearance were calculated for each formulation. The generic tablets of quinidine monosulphate from five different manufacturers were not significantly different from each other in any respect and produced the expected peak and trough serum level curves. The serum level curves resulting from administration of quinidine polygalacturonate (Cardioquin) were not significantly different from those resulting from the generic tablets, and this formulation may be regarded as therapeutically equivalent to the generic formulations. Both sustained-release formulations of quinidine bisulphate, Durettes and Kiditard (given at the same dosage) were shown to offer a means whereby, with simple twice-daily dosage, quinidine maintenance treatment may be continued with the confidence that the serum levels may be maintained throughout each 24-hour period without peaks into the toxic levels and troughs into the levels of no effect.

Adult↗
PubMed1992

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.

Adult↗
PubMedDate not supplied

Synthesis of 10,11-dihydroxydihydroquinidine N-oxide, a new metabolite of quinidine. Preparation and 1H-nmr spectroscopy of the metabolites of quinine and quinidine and conformational analysis via 2D COSY nmr spectroscopy.

The first synthesis of 10,11-dihydroxydihydroquinidine N-oxide [7b], a recently isolated metabolite of quinidine, was accomplished in three steps from 1b. The related congener 7a in the quinine series was also prepared, as well as two other analogues 3a and 4a. In addition, the previously reported human metabolites 2a, 5a, and 6a of quinine [1a] and those 2b, 3b, 4b, 5b, and 6b of quinidine [1b] were synthesized. The chemical shift and coupling constants for all of the metabolites of quinine and quinidine were assigned via 2D COSY 1H-nmr spectroscopy. Moreover, the conformations of these metabolites in solution were found to parallel those of the parent alkaloids, quinine [1a] and quinidine [1b], respectively.

Molecular Conformation↗
PubMed1978

[Ventricular fibrillation under quinidine medication--quinidine syncope (author's transl)].

Ventricular fibrillation which may occur unexpected under quinidine medication--called quinidine syncope--is one of the most dangerous complications of quinidine application. These life threatening accidents occur in 0,5-4,4% treated cases. The quinidine syncope occurs mostly at the attempt to eliminate atrial fibrillation or flutter. This dangerous side effect is dose independent. The ECG shows an increased QT duration and large U-waves. It seems to be a reentry-tachycardia caused by unequal recovery times in different parts of the ventricular myocardium.

Digitoxin↗
PubMed1990

Quinidine oxidative metabolism. Identification and biosynthesis of quinidine 10,11-dihydrodiol stereoisomers.

The isocratic reversed phase high performance liquid chromatographic method proposed for quinidine metabolic studies facilitates particularly the separation of 10(R) and (S) isomers of quinidine 10,11-dihydrodiols. The finding of each of these forms following a new synthetic pathway allows us to identify and quantify them in biological fluids. These two isomers have especially been observed in rat bile and hepatocyte secretions. The metabolic inducing effect of phenobarbital on the oxidative metabolism of quinidine is verified in rat isolated hepatocytes. Simultaneous secretion of the two dihydrodiols is also verified in human urine by a gas chromatography/mass spectrometry procedure.

Animals↗
PubMed1977

Bioavailability of quinidine in slow-release form. A comparison between two preparations containing quinidine bisulphate as the active constituent.

Two different slow-release preparations of quinidine bisulphate (A and B) have been tested. The in vitro dissolution rate of preparation B was substantially lower in intestinal than in gastric juice, whereas the release rate of quinidine from preparation A was virtually unaffected by the pH of the dissolution medium. After a single dose of two tablets of each of the preparations to 6 healthy volunteers, corresponding to 386 mg (B) and 320 mg of quinidine base (A), the maximum plasma concentration was attained after about 4.5 h. The peak concentration was 5.2 +/- 0.5 mumol/l for preparation A and 4.1 +/- 0.4 mumol/l for B. A similar difference was found in the area under the plasma concentration curve (AUC), which was 68 +/- 10 mumol-h/l and 54 +/- 5 mumol-h/l, respectively. Taking into consideration that preparation B contained 20.6% more active drug per tablet these values indicate that the extent of bioavailability is about 50% higher for tablet A than for tablet B.

Administration, Oral↗
PubMed1976

Quinidine syncope: torsade de pointes with low quinidine plasma concentrations.

In 2 patients without clinically significant ischemic heart diseases, oral quinidine was used to control supraventricular arrhythmias. In both patients, syncopal attacks occurred, caused by a particular type of ventricular tachyarrhythmia called torsades de pointes. Quinidine plasma concentrations were low (2.6 and 1.2 mg/1, respectively); QRS duration was normal, but the Q-T interval was markedly prolonged.

Aged↗
PubMed1992

Concentration-dependent exsorption of quinidine in the rat intestine.

During intravenous infusion, the luminal concentration of quinidine was higher than the plasma concentration. The intestinal clearance (CLi) of the drug was measured by dividing the rate of appearance of the drug in the intestinal luminal perfusate by the plasma concentration. The CLi of quinidine was therefore much higher than the rate of luminal perfusion. Over the infusion dose range of 0.1-2 mg h-1, the CLi of quinidine decreased with increasing plasma concentration of quinidine. Adding quinidine into the luminal perfusate had little effect on the CLi of quinidine. Co-administration of quinidine with other agents intravenously did not alter the CLi of salicylic acid and urea, while the same treatment decreased the CLi of theophylline and S-disopyramide. In-vitro experiments on brush-border membrane vesicles showed that quinidine decreased the rate of Na+ uptake and H+ efflux. The inhibition was significant at quinidine concentrations above 20 microM. Quinidine was a more potent inhibitor than amiloride. At quinidine infusion rates less than 2 mg h-1, quinidine concentration in plasma or in the luminal perfusate was at the lower limit of the inhibitory concentration. Microclimate pH at the intestinal surface was also measured. At mid-jejunum, the microclimate pH increased 0.3 pH units by infusing 2 mg h-1 of quinidine, while the microclimate pH at most other measuring sites was not significantly altered by quinidine infusion. It was concluded that quinidine is exsorbed from blood into the intestinal lumen by a carrier-mediated pathway in addition to the passive diffusion. At high plasma concentration, quinidine exsorption becomes saturated.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1978

Quinidine pharmacokinetics in patients with cirrhosis or receiving propranolol.

Quinidine pharmacokinetics (half-life, volume of distribution, and clearance) as well as protein binding were evaluated following a single 200 mg. oral dose of quinidine sulfate in eight control patients, in eight patients with moderate to severe cirrhosis, and in seven patients receiving 40 to 400 mg./day of propranolol. Patients with cirrhosis had a significantly longer quinidine half-life (9 +/- 1 hr; p less than .01) when compared to control patients (6 +/- 0.5h). This was not related to a reduced quinidine clearance rate but rather to an increase in quinidine volume of distribution (4.1 +/- .4 L./Kg. in cirrhotic patients vs 2.6 +/- 1 L./Kg. in control patients; p less than .01). Abnormal quinidine binding (greater than 25 per cent unbound fraction) was noted in seven of the eight cirrhotic patients. In contrast, patients receiving propranolol had a normal quinidine half-life of 6 +/- 0.5 hr. However, these patients had a significantly reduced quinidine clearance (3.3 +/- .7 ml./min./Kg. vs. 5.3 +/- .5 ml./min./Kg. in controls; p less than .05) and higher peak concentrations (1.25 +/- .20 micrograms/ml. vs. .80 +/- .5 micrograms/ml. in controls; p less than .05). Therefore in patients receiving propranolol, quinidine levels may be higher than expected shortly after dosage, and therefore a potential for transient toxicity exists in these patients. Maintenance quinidine dosage may have to be reduced in patients with moderate to severe hepatic cirrhosis, but not in patients receiving propranolol. Total quinidine concentration measurement underestimate free quinidine concentrations in most cirrhotic patients.

Adult↗