Quinidine Concentrations Research Articles

Effect of Quinidine Instilled into Canine Pericardial Sac on Cardiac Effective Refractory Period

Background:Atrial fibrillation (Af) after open heart surgery may result in hypotension, heart failure, embolic complication and prolongation in length of hospital stay. Several studies have investigated the efficacy of pharmacological prophylaxis in reducing the incidence of Af after cardiac surgery. The pericardial sac represents a natural physical barrier and provides a drug receptacle to restrict drug delivery to the heart. The overall objective of this study was to determine whether the pericardial sac could function as a delivery chamber for antiarrhythmic drugs. We investigated whether quinidine delivered into the pericardial sac exerted an effect on atrial and ventricular refractoriness, impulse generation, and conduction. Methods:All animals were anesthetized with α-chloralose. After a sternotomy, the pericardium was opened and cradled to produce a “container” of approximately 30 ml. Experimental animals received quinidine, 3.33 mg/ml, dissolved in Krebs-Henseleit solution instilled into their pericardial sacs for 30 minutes. Baseline and 5, 10 and 30 minutes postinstillation electrophysiologic studies were performed. Plasma quinidine levels were measured at each of the time intervals in three different sites i.e., right ventricle (RV), aortic root and femoral vein (FV). Results:Baseline systolic (SAP) and diastolic aortic pressure (DAP) were 148±16.8 mmHg, and 111±23.9 mmHg, respectively. Both SAP and DAP were significantly decreased at 5, 10 and 30 minutes after instillation of quinidine solution into pericardial sac. In electrocardiographic parameters, the increase in sinus cycle length and corrected QT interval were significantly greater compared with baseline at each of the time intervals after instillation of quinidine solution into pericardial sac. All electrophysiologic parameters including 1:1 AV conduction, effective refractory period (ERP) of RA and RV were significantly increased compared with baseline at three time points. Quinidine concentrations in RV and aorta were significantly higher than in FV at three time points. In RV and aorta, quinidine concentrations at 30 min were significantly lower than those at 5 and 10 min postinstillation periods. There were significant correlations between plasma quinidine levels and corrected QT interval or RAERP. Conclusion:Above results showed that quinidine instilled into the pericardial sac migrates transmurally and produces significant prolongation of effective 논문접수일:1999년 9월 27일 심사완료일:2000년 2월 17일 교신저자:김재형, 130-709 서울 동대문구 전농동 620-56 가톨릭대학교 의과대학 내과학교실 전화:(02) 958-2388·전송:(02) 968-7250 E-mail:jhkim@sph.cuk.ac.kr

Identitication of Cytochrome P450 Involved in the Metabolism of Donepezil and In Vitro Drug Interaction Study in Human Liver Microsomes.

Donepezil hydrochloride is a reversible cholinesterase inhibitor with high specificity for centrally active cholinesterases, and is currently used for the treatment of Alzheimer's disease as Aricept® in many countries. In human liver microsomes donepezil is metabolized mainly to M4 by N-dealkylation, and to a lesser extent to M1 and M2 by O-dealkylation. In this study, cytochrome P450 involved in the metabolism of donepezil was identified and may serve to predict the potential for interaction with other drugs. The results showed that M4 was formed mainly by CYP3A4 and to a lesser extent by CYP2C9. The formations of M1 and M2 were both mediated mainly by CYP2D6. To predict possible drug interactions with donepezil in vivo, the effects of known inhibitors of drug metabolism, cimetidine, theophylline, erythromycin, quinidine and ketoconazole, on the formation of M1, M2 and M4 were studied by using human liver microsomes. The results suggested that cimetidine, theophylline and erythromycin have little or no effect on the metabolism of donepezil in vivo. On the other hand, quinidine and ketoconazole are predicted to inhibit donepezil metabolism. Quinidine significantly inhibited the formation of M1 and M2 mediated principally by CYP2D6. The Ki values of quinidine for M1 and M2 formation were 0.526 and 1.372 μM, respectively. In the presence of 0.7, μM of quinidine (the effective unbound plasma concentration of quinidine in clinical use) the hepatic intrinsic clearance of donepezil (a total of Vmax/Km for M1, M2 and M4 formation) was assessed to be reduced to 82.0%, and the elevation of the plasma concentration of donepezil by the co-administration of quinidine will be at most 1.2 times. Ketoconazole was a high affinity inhibitor of M1, M2 and M4 formation and the Ki values were 0.117, 0.563, and 0.102, μM, respectively. The hepatic intrinsic clearance of donepezil will be reduced to 57.9% in the presence of 0.08 μM (the effective unbound plasma concentration of ketoconazole in clinical use) of ketoconazole, and the plasma concentration of donepezil was predicted to increase at most 1.7 times. By the present study, the inhibitory profiles of quinidine and ketoconazol on metabolism of donepezil were confirmed. A drug interaction may occur by co-administration of substrate or inhibitor for CYP2D6 as well as CYP3A4 with donepezil, although the contribution of CYP2D6 to hepatic intrinsic clearance for donepezil is lower than that of CYP3A4.

Unmasking of a Novel Potassium Current in Drosophilaby a Mutation and Drugs

The delayed rectifier potassium current plays a critical role in cellular physiology. This current (I(K)) in Drosophila larvae is believed to be a single current. However, a likely null mutation in the Shab K(+) channel gene (Shab(3)) reduces I(K) but does not eliminate it. This raises a question as to whether or not the entire I(K) passes through channels encoded by one gene. Similarly, an incomplete blockade of I(K) by high concentrations of quinidine, a selective I(K) blocker, raises a question as to whether I(K) consists of two components that are differentially sensitive to quinidine. We have addressed these questions by a combined use of genetics, pharmacology, and physiology. The current component removed by the Shab(3) mutation differed from the remaining component in activation kinetics, inactivation kinetics, threshold of activation, and voltage dependence. The two components showed strong differences in sensitivity to quinidine. Physiological properties of the current component removed by the Shab(3) mutation were similar to those of the quinidine-sensitive fraction of I(K). Complementary to this, properties of the current component remaining in the Shab(3) mutant muscles were similar to those of the quinidine-resistant fraction of I(K). These observations strongly suggest that, in contrast to the current belief, I(K) consists of two components in Drosophila, which are genetically, pharmacologically, and physiologically distinct. These components are being called I(KS) and I(KF). I(KS) is carried via Shab-encoded channels. I(KF) defines a new voltage-activated K(+) current in Drosophila.

Role of P-glycoprotein in distribution of rhodamine 123 into aqueous humor in rabbits

Purpose. Examination of the contribution of functional P-glycoprotein (P-gp), an ATP-dependent efflux pump, in blood-aqueous barrier in rabbits. Methods. Rhodamine-123 (Rho-123), a P-gp substrate, was administered intravenously via the marginal ear vein of rabbits. Rhodamine B (Rho-B), an analogue of Rho-123, was also injected with the same dose, as a reference compound. Quinidine at different concentrations was applied topically to the corneal surface by eye drops prior to the intravenous administration of a Rho compound. The aqueous distribution (a ratio of concentration in aqueous humor to that in plasma) of these Rho compounds was analyzed in relation to the aqueous concentration of quinidine. Transport study across Caco-2 cell monolayers was carried out to examine the involvement of P-gp in Rho-B transport. Results. It was proved that Rho-B is not a P-gp substrate by a transport study across Caco-2 cell monolayers, in contrast to Rho-123 (a P-gp substrate). The aqueous distribution of Rho-123 given intravenously was significantly lower than that of Rho-B. Topical quinidine (a P-gp inhibitor) markedly increased the aqueous distribution of Rho-123, depending on the aqueous concentrations of quinidine, though it did not affect the aqueous distribution of Rho-B. Conclusions. The contribution of functional P-gp in blood-aqueous barrier was clearly demonstrated by analyzing the aqueous distribution of Rho-123 in the presence or absence of quinidine. These experiments only allow us to address one part of the blood-aqueous barrier, the capillary endothelium, and, to do so by using different substrates for P-gp, a sort of chemical analogy with the presumed blood-aqueous barrier across capillary endothelia. The alteration of P-gp function by pharmacotherapy or in pathological state should be considered in the ophthalmic medical treatment.

Quinidine normalizes the open duration of slow-channel mutants of the acetylcholine receptor.

Quinidine is a long-lived open-channel blocker of the wild-type endplate acetylcholine receptor (AChR). To test the hypothesis that quinidine can normalize the prolonged channel opening events of slow-channel mutants of human AChR, we expressed wild-type AChR and five well characterized slow-channel mutants of AChR in HEK 293 cells and monitored the effects of quinidine on acetylcholine-induced channel currents. Quinidine shortens the longest component of channel opening burst (tau3b) of both wild-type and mutant AChRs in a concentration-dependent manner, and 5 microM quinidine reduces tau3b of the mutant AChRs to that of wild-type AChRs in the absence of quinidine. Because this concentration of quinidine is attainable in clinical practice, the findings predict a therapeutic effect for quinidine in the slow-channel congenital myasthenic syndrome.

Effects of hypokalaemia on arrhythmogenic risk of quinidine in rats

Plasma potassium concentration plays an important role in the induction of arrhythmia and is closely related to the arrhythmogenicity of various drugs. We quantitatively analyzed the influence of plasma potassium concentration on QT intervals before drug administration and on drug-induced QT prolongation, to estimate the risk of drug-induced arrhythmia under hypokalaemic conditions. The hypokalaemic models were produced by intraperitoneal administration of furosemide and hydrochlorothiazide in male Sprague-Dawley rats. The relationship between the changes in QT intervals and time profiles of plasma quinidine (QND) concentration were analyzed during constant intravenous infusion of QND (10 or 30 mg/kg/h) and post infusion in normal and hypokalaemic rats. The plasma QND concentration reached the therapeutic range (3–7 μg ml ) at the high infusion rate (30 mg/kg/h). No pharmacokinetic differences between normal and hypokalaemic rats were observed. QND induced QT prolongation in parallel with the plasma concentration without hysteresis. Although the potency of QND for QT prolongation was not affected by hypokalaemia, the QT intervals before drug administration were significantly prolonged in hypokalaemic rats (65.90 ± 1.40 vs 56.60 ± 0.748 msec, mean ± SEM, p < 0.0001). Thus, the prolongation of QT intervals before drug administration may act as a risk factor of arrhythmia under hypokalaemic conditions.

Stereoselective Inhibition by the Diastereomers Quinidine and Quinine of Uptake of Cardiac Glycosides into Isolated Rat Hepatocytes

□ The pharmacokinetic interaction between quinidine and digoxin in patients is well-known, in general requiring a dose reduction of digoxin in patients concomitantly treated with quinidine. Quinine, the diastereomer of quinidine, has not been as extensively studied in this respect. in addition to an interaction with the renal clearance of digoxin by quinidine, both diastereomers have been reported to inhibit the biliary clearance of digoxin in man. To further investigate the mechanisms of these hepatobiliary transport interactions at the cellular level, we compared the effects of quinidine and quinine, as well as of the calcium antagonist verapamil, on the uptake of digoxin and ouabain in isolated rat hepatocytes. initial uptake rates of digoxin and ouabain were determined in the presence of various concentrations of quinine and quinidine. A concentration dependent inhibition of the cellular uptake of both cardiac glycosides by quinine and quinidine was found, quinine being a more potent inhibitor than quinidine. Our results indicate a stereoselective inhibition of the hepatocellular uptake by the two diastereomers quinidine and quinine, the latter being about equipotent to verapamil. This unequal inhibitory potency of the two basic drugs was detected earlier in oocyte studies with the cloned organic cation transporter OCT1.

Effects of quinidine on repolarization in canine epicardium, midmyocardium, and endocardium: II. In vivo study.

In the companion article, we report a significant difference in quinidine effects on the action potential duration between surface (epicardial and endocardial) cells and midmyocardial cells (M cells) of canine left ventricle in vitro. This article considers two questions raised by the previous study: (1) Are the complex quinidine effects in vitro reflected in its actions on the heart in situ? (2) What are the cellular determinants of quinidine effects on QT interval in ECG? We used plunge and surface electrodes to measure activation-recovery intervals (ARIs) of bipolar electrograms obtained from epicardium, endocardium, and midmyocardium (3, 5, and 9 mm from epicardium) of canine left ventricle in conditions of AV block and right ventricular pacing. Quinidine was infused continuously; its plasma level increased from 1.6+/-0.1 microg/mL at 30 minutes to 7.6+/-0.7 microg/mL at 180 minutes. At cycle lengths (CLs) from 300 to 1500 ms, there was no ARI gradient across the ventricular wall before and during quinidine infusion. At a CL of 300 ms, therapeutic concentrations of quinidine prolonged ARIs and QT intervals. At a CL of 1500 ms, ARIs were significantly prolonged at low quinidine concentrations. With an increase of quinidine concentration, this effect subsided and disappeared. In situ, quinidine-induced prolongation of repolarization is uniform in all myocardial layers and follows the pattern observed in M cells in vitro. The ability of quinidine in therapeutic concentrations to prolong repolarization at rapid heart rates can contribute to its antiarrhythmic efficacy.

Differential effects of D-sotalol, quinidine, and amiodarone on dispersion of ventricular repolarization in the isolated rabbit heart.

Increased dispersion of ventricular repolarization has been suggested as a cause of proarrhythmic effects of Class IA or III antiarrhythmic drugs, such as d-sotalol, quinidine, and amiodarone. The influence of d-sotalol, quinidine, and amiodarone on the dispersion of monophasic action potential (MAP) durations was studied in 55 isolated Langendorff-perfused rabbit hearts at different pacing cycle lengths (CLs). MAP duration measured at 90% repolarization (APD90) was determined from 6 to 8 endocardial and epicardial MAP recordings with dispersion of ventricular repolarization defined as the range of APD90. The protocol was repeated 60 minutes after initiation of a perfusate containing increasing concentrations of d-sotalol (n = 12, 10[-6] M, 10[-5] M, and 5 x 10[-5] M) and quinidine (n = 8, 10[-6] M and 10[-5] M). Seventeen rabbits were fed with an aqueous solution of amiodarone (50 mg/kg per day over 4 weeks). The data of these experiments (n = 17) were compared with a series of 18 untreated control rabbits. Dispersion of ventricular repolarization was unchanged with the low concentration of d-sotalol (10[-6] M) but was increased-particularly at long CLs-with higher d-sotalol concentrations. With both concentrations of quinidine, dispersion of ventricular repolarization was increased in a rate-independent manner. Amiodarone did not affect dispersion of ventricular repolarization. Rate-dependent and concentration-dependent increases in dispersion of ventricular repolarization by d-sotalol and quinidine in this isolated rabbit heart model may help explain their proarrhythmic effects while the absence of an increase in dispersion of ventricular repolarization with amiodarone correlates with its clinically observed lower incidence of proarrhythmia.

Cardiac effects of quinidine on guinea-pig isolated perfused hearts after in vivo quinidine pretreatment.

1 Experimental and clinical studies suggest that class I and class III antiarrhythmic drugs may be subject to pharmacological tolerance during long term treatment, leading to loss of therapeutic effectiveness. 2 The aim of this study was to ascertain whether prolonged in vivo treatment with the Class Ia agent quinidine can modify cardiac (electrical and mechanical) responses to the drug. 3 A group of guinea-pigs (n = 7) was treated intraperitoneally (q.d.) for 6 days with 75 mg kg-1 quinidine sulphate. Preliminary pharmacokinetic experiments indicated that this dose could attain Plasma concentrations similar to those that are therapeutic in man (2-5 mg l-1). A control group (n = 7) received a saline solution for the same period. 4 Twenty-four hours after the last administration hearts were removed and retrogradely perfused at constant flow (stimulation frequency: 2.5 Hz). The following parameters were measured: maximal derivative of intraventricular pressure (dP/dtmax); coronary perfusion pressure (Cp); PR, QRS and JT intervals, on surface ECG. The effects of quinidine on these parameters were measured at different concentrations (2, 4, 8, 12, 16, 20 microns) and compared in the two experimental groups. 5 In the group quinidine decreased in a dose-dependent manner dP/dt and increased PR and QRS intervals. JT interval was increased at the lowest concentrations and decreased at the highest (biphasic effect). Cp did not change significantly. 6 In the pretreated group quinidine qualitatively produced the same effects on dP/dt and ECG intervals as in control group. Also the magnitude of these effects was not significantly different between the two groups. In contrast with findings in control experiments. Cp was significantly decreased by increasing quinidine concentration. Mean baseline Cp was higher in pretreated than in the control group (though not significantly, P = 0.072) and quinidine addition abolished this difference. Thus, it is suggested that quinidine withdrawal induced a rebound increase in coronary tone, due to the unmasking of vasoconstrictor homeostatic mechanisms elicited by the in vivo vasodilating effect of the drug. 7 In conclusion, our data do not support the possibility that tolerance ensues during long term quinidine treatment, at least as far as electrophysiological and contractility effects are concerned. Further experimental work is needed to explain the appearance of a coronary vasodilating effect in pretreated hearts.

Gating charge and ionic currents associated with quinidine block of human Kv1.5 delayed rectifier channels.

1. The mechanism of quinidine-induced ionic and gating current inhibition was studied in human Kv1.5 (hKv1.5) delayed rectifier channels expressed in human embryonic kidney cells. In the steady state, quinidine produced a voltage-dependent block between +30 and +120 mV (Kd at +60 mV = 7.2 microM) with an equivalent electrical distance, delta, of 0.29 +/- 0.06 and 0.26 +/- 0.05 at 10 and 50 microM quinidine, respectively. The apparent affinity at 0 mV (Kd) was 25 microM at 10 microM quinidine and 38 microM at 50 microM quinidine. The data suggested a quinidine binding site that sensed 20-30% of the transmembrane electrical field, from the inside. Non-steady-state measurements indicated rapid open channel block with mean time constants of 2.1 +/- 0.9 and 1.2 +/- 0.2 ms at 10 and 50 microM quinidine, respectively. 2. 'On' gating current (on-Ig) was unaffected over a wide range of potentials and between 10 and 100 microM quinidine. On-gating charge (Qon) was similarly conserved in the steady state between -100 and +50 mV. On return to -100 mV, quinidine slowed the off-gating current (off-Ig) after depolarizations more positive than -25 mV. After depolarizations to +50 mV, only 59 +/- 3.4% (10 microM quinidine) and 6.6 +/- 9.5% (100 microM quinidine) of the charge returned within 25 ms, compared with 100% in control. Due to the conservation of Qon in subsequent pulses, the remaining charge must have returned during the subsequent 10 s interpulse interval. 3. A threshold for quinidine action on off-Ig was established positive to -25 mV. The voltage dependence of Qoff immobilization at more positive potentials than +20 mV had an equivalent electrical distance of 0.32 +/- 0.04 (10 microM quinidine) and 0.20 +/- 0.32 (100 microM quinidine) with calculated Kd values of 21.6 +/- 4.6 and 16.2 +/- 8.4 microM at 10 and 100 microM quinidine, respectively. These characteristics of block are in good agreement with values obtained from ionic data. 4. Simultaneous measurements of ionic and gating currents confirmed, after subtraction, an ionic current threshold at -21.8 +/- 1.8 mV. The gating current data confirm directly that ionic current block by quinidine occurs by binding at a site on the hKv1.5 channel that becomes accessible when the channel opens. There was no evidence for action of quinidine on kinetic states prior to the open state at concentrations of quinidine up to 100 microM.

Evidence that adenosine triphosphate or a related nucleotide is the transmitter substance released by non-adrenergic inhibitory nerves in the gut. 1970.

Summary . Stimulation of the vagal non‐adrenergic inhibitory innervation caused the release of adenosine and inosine into vascular perfusates from the stomachs of guinea‐pigs and toads. . Stimulation of portions of Auerbach's plexus isolated from turkey gizzard caused the release of adenosine triphosphate (ATP), adenosine diphosphate (ADP) and adenosine monophosphate (AMP). . ATP, added to solutions perfused through the toad stomach vasculature, was broken down to adenosine, inosine and adenine. . Of a series of purine and pyrimidine derivatives tested for inhibitory activity on the guinea‐pig isolated taenia coli, ATP and ADP were the most potent. . ATP caused inhibition of twelve other gut preparations previously shown to contain non‐adrenergic inhibitory nerves. The inhibitory action of ATP was not prevented by tetrodotoxin. . Quinidine antagonized relaxations of the guinea‐pig taenia coli caused by catecholamines or adrenergic nerve stimulation. Higher concentrations of quinidine antagonized relaxations caused by ATP or non‐adrenergic inhibitory nerve stimulation. . When tachyphylaxis to ATP had been produced in the rabbit ileum, there was a consistent depression of the responses to non‐adrenergic inhibitory nerve stimulation but not of responses to adrenergic nerve stimulation. . It is suggested that ATP or a related nucleotide is the transmitter substance released by the non‐adrenergic inhibitory innervation of the gut.

Possible Pharmacokinetic Interaction with Quinidine: Ciprofloxacin or Metronidazole?

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

Stereoselective effects of the enantiomers, quinidine and quinine, on depolarization- and agonist-mediated responses in rat isolated aorta.

1. The effects of the two enantiomers, quinidine and quinine, were studied on depolarization- and agonist-induced isometric contractions in rat isolated thoracic aortic rings. 2. Quinidine or quinine (10(-6)M-3 x 10(-4)M) produced a concentration-dependent relaxation of 80 mM KCl-contracted rings, the pD2 values being 4.89 and 4.23, respectively. Thus, quinidine was about 4-5 times more potent than quinine. 3. The voltage-dependence of quinidine- and quinine-induced inhibition was studied in rings that had been incubated in 5 or 40 mM KCl Ca(2+)-free solution and then contracted by changing the bath solution to 100 mM KCl and 2 mM Ca2+. The inhibitory effects of quinidine were significantly enhanced when the rings were preincubated in 40 mM KCl (depolarizing conditions), when compared to normally polarized rings. In contrast, the effects of quinine were similar in 5 or 40 mM KCl solution. 4. The antagonism of noradrenaline (NA)-induced contractions by low concentrations of quinidine (< 10(-4)M) and quinine (< 3 x 10(-4)M) was competitive, as demonstrated by the concentration-dependent parallel rightward shift of the NA concentration-response curves (pA2 values 6.20 and 5.68, respectively, P < 0.05). 5. At low concentrations (< or = 3 x 10(-5)M), quinidine and quinine did not shift the concentration-response curve to 5-hydroxytryptamine (5-HT) or endothelin-1, whereas at higher concentrations they produced a downward shift of these curves. Quinidine and quinine (> 10(-4)M) inhibited to a similar extent both the phasic (induced in Ca(2+)-free media) and tonic responses (after restoring extracellular Ca2+) induced by 5-HT. 6. In conclusion, quinidine and quinine produced a stereoselective inhibition of depolarization and NA-induced contractions, quinidine being more potent than quinine. The inhibition of KCl-induced contractions could be attributed to inhibition of Ca2+ entry. Both drugs also behaved as competitive antagonists of alpha 1D-adrenoceptors. At high concentrations, quinidine and quinine also decreased the contractions induced by endothelin-1 and 5-HT in a non-stereoselective manner.

Quinidine administration increases steady state serum digoxin concentration in horses.

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

Electrocardiological profile and proarrhythmic effects of quinidine, verapamil and their combination: a mapping study.

Quinidine and verapamil are widely used as antiarrhythmic agents and their combination is often used in the treatment of supraventricular tachycardia. This study was undertaken to clarify, whether these drugs exert proarrhythmic effects on the ventricles in therapeutic concentrations and whether possible arrhythmogenic effects might be enhanced by combination. Isolated rabbit hearts perfused according to the Langendorff technique were treated with increasing concentrations of quinidine (0.05 to 3.5 microM) or verapamil (5 to 50 nM) or of their combination (70:1 or 10:1, quinidine:verapamil) corresponding to common low, medium and high free therapeutic concentrations. The epicardial activation process was measured using a computer assisted mapping system for unipolar multichannel recording (256 channels simultaneously). Both substances prolonged the atrioventricular conduction time PQ. This effect was even more pronounced if the 70:1 combination was administered. The activation pattern was altered by both drugs and their combination to the same extent as became obvious from analysis of local activation vectors and of localisation of breakthroughpoints of epicardial activation for heart beats under control conditions and under drug treatment. The epicardial potential durations were prolonged by quinidine and to the same degree by the combinations, but not by verapamil alone. The total activation time was prolonged under the influence of quinidine and if the 70:1 combination was given. Both substances exerted a negative inotropic effect which was enhanced in an additive manner if both drugs were combined. In parallel the coronary flow was diminished.(ABSTRACT TRUNCATED AT 250 WORDS)

Treatment of atrial fibrillation in horses: new perspectives.

Forty-one horses were treated for atrial fibrillation (AF) with 22 mg/kg quinidine sulfate via nasogastric tube every 2 hours until conversion to sinus rhythm, a cumulative dose of 88 to 132 mg/kg had been administered in 2-hour increments, or the horse had adverse or toxic effects from the drug. Treatment intervals were prolonged to every 6 hours if conversion had not occurred. Digoxin was administered before treatment if the horse had a fractional shortening < or = 27% (3 horses), was prone to tachycardia (resting heart rate > or = 60 beats/min) (1 horse), or had a previous history of sustained tachycardia of over 100 beats/min during prior conversion (3 horses). Digoxin was administered during day 1 of quinidine sulfate treatment if the horse developed a sustained tachycardia of over 100 beats/min during treatment (11 horses) or on day 2 if conversion had not occurred (7 horses). Plasma quinidine concentrations within 1 hour of conversion of AF to sinus rhythm ranged from 1.7 to 7.5 micrograms/mL (mean, 4.05 +/- 1.6) and ranged from 1.7 to 4.7 micrograms/mL in 97% of horses. Most horses (92%) with plasma quinidine concentrations > 5 micrograms/mL exhibited an adverse or toxic effect of quinidine sulfate (clinical or electrocardiographic). There was no statistical association between plasma quinidine concentrations and sustained tachycardia (> 100 beats/min), diarrhea, or colic. Ataxia and upper respiratory tract stridor were significantly associated with plasma quinidine concentrations. In most instances (98%) conversion did not occur while toxic or adverse effects of quinidine sulfate were present or when plasma quinidine concentrations were > 5 micrograms/mL.

Possible inhibition of hepatic metabolism of quinidine by erythromycin

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

Quinine and quinidine inhibit and reveal heterogeneity of K-Cl cotransport in low K sheep erythrocytes

Low K (LK) sheep red blood cells (SRBCs) serve as a model to study K-Cl cotransport which plays an important role in cellular dehydration in human erythrocytes homozygous for hemoglobin S. Cinchona bark derivatives, such as quinine (Q) and quinidine (QD), are effectively used in the treatment of malaria. In the present study, we investigated in LK SRBCs, the effect of various concentrations of Q and QD on Cl-dependent K efflux and Rb influx (K(Rb)-Cl flux), activated by either swelling in hyposmotic media, thiol alkylation with N-ethylmaleimide (NEM), or by cellular Mg (Mgi) removal through A23187 in the presence of external chelators. K efflux or Rb influx were determined in Cl and NO3 medium and K(Rb)-Cl flux was defined as the Cl-dependent (Cl minus NO3) component. K(Rb)-Cl flux stimulated by all three interventions was inhibited by both Q and QD in a dose-dependent manner. Maximum inhibition of K(Rb)-Cl flux occurred at Q and QD concentrations > or = 1 mM. The inhibitory effect of Q was manifested in Cl, but not in NO3, whereas QD reduced K and Rb fluxes both in Cl and NO3 media. The mean 50% inhibitory concentration (IC50) of Q and QD to inhibit K(Rb)-Cl flux varied between 0.23 and 2.24 mM. From determinations of the percentages of inhibition of the different components of K and Rb fluxes, we found that SRBCs possess a Cl-dependent QD-sensitive and a Cl-dependent QD-insensitive K efflux and Rb influx. These two components vary in magnitude depending on the manipulation and directional flux, but in average they are about 50% of the total Cl-dependent flux. This study raises the possibility that, in SRBCs, the Cl-dependent K(Rb) fluxes are heterogeneous.

Age-related Quinidine Effects on Ionic Currents of Rabbit Cardiac Myocytes

Age-related cardiac actions of quinidine have been shown in prolongation of action potential duration, but not in the tonic and use-dependent block of the maximal velocity of action potential upstroke. To elucidate the underlying ionic mechanisms, currents through the Na, Ca and K channels were examined by using a whole-cell voltage clamp technique on isolated neonatal (<5 day) and adult (>3 months) rabbit cardiac myocytes under various concentrations (0.5, 1.5 and 4.5 μM) of quinidine. In neonatal and adult myocytes, quinidine caused a comparable degree of dose-dependent effects on Na currents including decrease in peak Na currents, left-shift of steady-state availability curve and slowing of the recovery from inactivation. However, the inwardly rectifier K current and the transient outward current were suppressed to a greater extent in the neonatal myocytes than in the adult ( P=0.0002 and 0.02, respectively). On the contrary, the magnitude of decrease in peak Ca currents after quinidine treatment was much smaller in the neonatal myocytes than in the adult ( P=0.01). These findings indicate that age-related ionic channel-block by quinidine is complex; and shows major differences in the Ca and K currents of cardiac myocytes. Accordingly, a differential therapeutic potential of quinidine may exist in hearts of different ages.