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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 Based on the computer modeling and the clinical data accumulated by this laboratory (unpublished) over the past four years, quinidine gluconate, in the dosage form utilized in this study, provides more constant blood levels with smaller differences between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↗
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↗
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↗
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↗
PubMed1976

Mechanism of action of quinidine on squid axon membranes.

The mechanism of action of quinidine on squid axons has been examined by means of voltage clamp and internal perfusion techniques. When applied either externally or internally, quinidine HCl suppresses both sodium and potassium conductance increases, the effect on the former accounting for the observed decrease in action potential. The potassium conductance in quinidine undergoes a marked inactivation in a manner dependent upon the membrane potential and time, accounting for the observed prolongation of the terminal falling phase of the action potential. Quinidine methiodide exhibits the effect similar to that of quinidine HCl only when applied internally. The dissociation constants of quinidine in suppressing the sodium conducting system are estimated to be 2.4 x 10(-4) and 4.0 x 10(-4) M for quinidine HCl and methiodide, respectively. The dissociation constant of quinidine in suppressing the potassium-conducting system decreases with increasing step depolarization. When applied externally to the intact axons, quinidine HCl is more effective at external pH 8.6 than at 7.3. When perfused internally, quinidine HCl is more effective at internal pH 7.0 than at 8.0, and the potency is related to the calculated internal concentration of the charged form rather than that of the uncharged form. These results lead to the conclusion that quinidine HCl penetrates the nerve membrane in the uncharged form, is ionized in the axon and blocks the sodium and potassium conductances primarily in the charged form. Thus, quinidine and local anesthetics share some features in the terms of the site of action and active form.

Action Potentials↗
PubMed1979

[Average steady-state plasma levels with slow release quinidine preparations].

Arabogalactane sulphate of quinidine (AGSQ) is a slow release preparation of quinidine. The aim of this study was to compare the plasma levels of quinidine obtained by different preparations of AGSQ (AGSQ I, II and III) and to determine which was best suited to therapeutics. The "in vitro" study showed different amounts of quinidine liberated in 6 hours, 34% with AGSQ I, 58% with AGSQ II and 100% with AGSQ III. The plasma quinidine levels were studied after administration of a dose corresponding to 330 mg quinidine base, morning and evening for 7 consecutive days to 27 hospitalised patients; 7 received AGSQ I, 11 received AGSQ II 5, received AGSQ III and 4 quinidine sulphate. The delay in reaching a steady state was 24 hours for the quinidine sulphate 36 hours for AGSQ I, 48 hours for AGSQ II and 60 hours for AGSQ III. The average plasma level on the 7th day (Cee) was 2.74 +/- 0.71 microgram/ml, 2.62 +/- 0.74 microgram/ml and 3.29 +/- 0.72 microgram/ml respectively. The plasma quinidine levels were maintained between toxic and therapeutic levels (3,5 and 1,7 microgram/ml) only with AGSQ II by suppressing the peak observed 1 hour administration of quinidine sulphate. An excellent correlation (r = 0,984) was observed between the plasma quinidine 6 hours after ingestion and the Cee. A blood test during the steady state, 6 hours after ingestion of the drug, is useful in adjusting the dosage. These results suggest that AGSQ II is the preparation best suited for therapeutic usage although it does not give the best relative bioavailability of the drug.

Delayed-Action Preparations↗
PubMed1979

A previously unrecognized drug interaction between quinidine and digoxin.

Following the development of digoxin radioimmunoassay, we noted that serum digoxin concentrations appeared to rise in patients given quinidine. To further evaluate this important possible interaction between digoxin and quinidine, charts from 863 cardiology patients were reviewed. Ninety two patients received both drugs after having been on digoxin alone; 38 were ineligible for the study because of insufficient data and 27 were excluded because of changing renal function and/or concomitant antiarrhythmic drug therapy, leaving 27. Serum digoxin increased in 25 of the 27 study patients (93%) during quinidine therapy; mean serum digoxin rose from 1.4 ng/ml before quinidine to 3.2 ng/ml during quinidine. Anorexia, nausea and/or vomiting developed in 16 patients (59%) during quinidine therapy, but disappeared in all 10 patients in whom digoxin alone was reduced in dose, suggesting that digoxin had a causative role in the appearance of these symptoms although they developed only after quinidine had begun. Three of thirteen patients with only atrial arrhythmias on digoxin prior to quinidine developed new ventricular premature depolarizations (VPD) after starting quinidine; two of these three as well as four patients with prior VPDs developed new ventricular tachycardia, ventricular fibrillation, asystole, or sudden death. When starting quinidine in patients who are taking digoxin, the clinical course, ECG and serum digoxin should be followed closely.

Adult↗
PubMedDate not supplied

Electrophysiological study of human ventricular heart muscle treated with quinidine: interaction with isoprenaline.

We have investigated the effects of quinidine on the force of contraction and the intracellularly recorded action potential in papillary muscles isolated from human hearts. All preparations were obtained from patients undergoing corrective open heart surgery. The following results were obtained: (1) quinidine had a depressant effect on myocardial contractile force; (2) quinidine reduced the maximal upstroke velocity of the action potential; (3) quinidine shortened the plateau phase and prolonged the terminal repolarization of the action potential; (4) at higher concentrations quinidine reduced the resting potential; and (5) the depression by quinidine of both the plateau and the force of contraction was antagonized by isoprenaline. It is concluded that quinidine reduces the membrane conductances for sodium, calcium, and potassium ions. All of these actions of quinidine may contribute to the antiarrhythmic effects of the drug. The negative inotropic effect of quinidine can be explained by a depression of the calcium conductance at the myocardial cell membrane. The results show that earlier findings in laboratory animals regarding the effects of quinidine on the upstroke velocity and repolarization phase of the action potential are applicable to the human heart.

Action Potentials↗
PubMed1977

Increased plasma binding and decreased blood cell binding of quinidine in blood from anuric rats.

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

Animals↗
PubMed1978

Steady-state serum levels of quinidine and active metabolites in cardiac patients with varying degrees of renal function.

The concentrations of quinidine, (3S)-3-hydroxyquinidine (3-OH), and 2'-oxoquinidinone (2'-OXO) in serum samples from 25 patients on long-term quinidine therapy were determined by a high-pressure liquid chromatography assay. Large individual variation in the levels of each of the compounds measured was observed. After correcting for differences in protein binding, the ratio of 3-OH/quinidine in serum water is 0.61 +/- 0.31 (SD) and the ratio of 2'-OXO/quinidine is 0.39 +/- 0.44. Seven of the 25 patients had serum water levels of one of these metabolites similar to or greater than that of quinidine. The quinidine levels, after normalizing for dose, are significantly higher in hemodialysis patients (about twice) than in nonazotemic patients; azotemic patients have mean values intermediate between them. Quinidine, 3-OH, and 2'-OXO are equally potent antiarrhythmic drugs (ED50 = 0.18, 0.17, and 0.21 mmoles/kg, respectively) when tested against chloroform- and hypoxia-induced ventricular fibrillation in mice. O-Desmethylquinidine, a new metabolite detected in urine of quinidine-treated patients, is less active. Quinidine and 2'-OXO are equally potent (ED50 = 0.010 mmoles/kg), while 3-OH seems less potent and more toxic when tested against BaCl2-induced ventricular arrhythmias in rabbits. Thus, these metabolites appear to contribute to the effects of quinidine and may make a significant contribution in some cases.

Adult↗
PubMed1979

Blood collection techniques, heparin and quinidine protein binding.

With the use of glass syringes without heparin and all glass equipment, the percent of unbound quinidine was measured by ultrafiltration and a double-extraction assay method after addition of 2 microgram/ml of quinidine sulfate. Compared to the all-glass method, collection of blood using Vacutainers resulted in an erroneous and variable decrease in quinidine binding related to blood to rubber-stopper contact. With glass, the unbound quinidine fraction was (mean +/- standard error) 10 +/- 1% in 10 normal volunteers, 8.5 +/- 1.5% in 10 patients with congestive heart failure, and 11 +/- 2% in 11 patients with chronic renal failure (although in 8 of the latter 11 patients the percent of unbound quinidine was 4 or more standard errors from the mean of the normal group). During cardiac catheterization, patients had markedly elevated unbound quinidine fractions: 24 +/- 2% (p less than 0.001). This abnormality coincided with the addition of heparin in vivo and was less apparent after the addition of up to 10 U/ml of heparin in vitro (120% and 29% increase in unbound quinidine fractions, respectively). Quinidine binding should be measured with all glass or equivalent equipment.

Blood Proteins↗
PubMed1979

Quinidine and dihydroquinidine interactions in human plasma.

The protein-binding characteristics of dihydroquinidine, a known impurity in drug grade quinidine, in human plasma and the effects of dihydroquinidine on quinidine interactions with these plasma constituents were studied by equilibrium dialysis. In the plasma concentration range of 1.75-23.0 mg/liter, dihydroquinidine binding was similar to the binding observed with quinidine. The data suggested the presence of a single class of binding sites for both compounds in the plasma drug concentration range and samples studied. The mean values for the association constant, K, and the total concentration of binding sites, nPt, for dihydroquinidine were 4.75 +/- 0.67 X 10(4) M-1 and 5.78 +/- 0.17 x 10(-5) M, respectively. The corresponding values for quinidine were 4.78 +/- 1.00 x 10(4) M-1 and 5.65 +/- 0.48 x 10(-5) M. In the presence of 5 and 10% (of total alkaloid content) dihydroquinidine, the plasma concentration of unbound quinidine did not change significantly. At a 20% level of dihydroquinidine, however, an increase in unbound quinidine was observed (p less than 0.05). The elevations in free quinidine concentrations were directly related to the level of dihydroquinidine present. The results of this study indicate that the interactions between dihydroquinidine and quinidine for binding sites on human plasma proteins are competitive.

Binding, Competitive↗
PubMed1979

Quinidine therapy in hospitalized patients with ventricular arrhythmias.

Quinidine serum levels and pharmacokinetic data were assessed during steady state therapy with oral quinidine sulfate in 19 hospitalized patients who were being treated for ventricular arrhythmias. A new high performance liquid chromatography assay was employed. Four patients were studied both after the first dose of quinidine and at steady state, and the initial dose pharmacokinetic values were found not to be predictive of steady state. The mean half-life of quinidine was 4.5 hours, but there was wide individual variation. The elimination rate constant for quinidine was significantly lower in patients with echocardiographic evidence of left ventricular dilatation than in patients with normal echocardiographic left ventricular size. The average urinary excretion of quinidine was only 11.3%. The pharmacokinetic data in seven chronic alcoholic patients without clinical or laboratory evidence of hepatic insufficiency did not differ from the data obtained in nonalcoholic patients. However, with severely impaired liver function, there may be marked prolongation of quinidine half-life predisposing to quinidine toxicity. The possible clinical implications of these findings are discussed.

Aged↗
PubMed1978

Reduced quinidine clearance in elderly persons.

The influence of age on quinidine pharmacokinetics was assessed in 22 healthy male and female volunteers; 14 of the subjects were young (aged 23 to 34 years) and 8 elderly (aged 60 to 69 years). All subjects received 180 to 300 mg of quinidine base by constant rate intravenous infusion over 10 to 15 minutes. The concentration of total and unbound quinidine in multiple serum samples and in urine collected within 48 hours after the administration of quinidine qas determined with spectrophotofluorometric assay. Mean kinetic values for total quinidine in the young subjects were: elimination half-life (t 1/2 beta), 7.3 hours; total volume of distribution (Vd), 2.39 liters/kg; total clearance, 4.04 ml/min per kg; renal clearance 1.43 ml/min per kg; and percent unbound, 24.6 In the elderly subjects, the values for Vd (2.18 liters/kg) and percent unbound (28.2) did not differ significantly from these values in the young subjects. However, in the elderly subjects t 1/2 beta was significantly longer (9.7 hours, P less than 0.05) and total quinidine clearance significantly less (2.64 ml/min per kg, P less than 0.005) than in the young subjects. Renal clearance of quinidine in the elderly was also significantly less (0.99 ml/min per kg, P less than 0.05) than in the young and was associated with lower rates of creatinine clearance in the elderly (r = 0.66). Reduced clearance of quinidine and prolongation of its elimination half-life could predispose to toxicity in the elderly unless the dose were appropriately adjusted.

Adult↗
PubMed1979

Effects of oral quinidine on left ventricular performance in normal subjects and patients with congestive cardiomyopathy.

To evaluate the effects of oral quinidine therapy on left ventricular performance, 10 normal subjects and 8 patients with cardiomyopathy were studied with echocardiography at rest, after intravenous injection of atropine and during infusion with phenylephrine. The echocardiographic studies were performed during oral quinidine therapy and during placebo administration. In the normal subjects heart rate was significantly faster with quinidine than with placebo (74 +/- 8 (standard deviation) versus 68 +/- 9 beats/min, P less than 0.01), but there was no significant change in blood pressure or left ventricular size and performance. After administration of atropine, heart rate was identical with and without quinidine but the mean normalized velocity of left ventricular dimension shortening was significantly less with quinidine than with placebo (1.28 +/- 0.19 versus 1.44 +/- 0.21, P less than 0.01). During acute pressure loading with phenylephrine there was no difference in left ventricular size or performance during quinidine therapy. In the patients with cardiomyopathy, no significant differences in left ventricular function were detected with this protocol during quinidine therapy. It is concluded that oral quinidine therapy appears to have little adverse effect on left ventricular performance at rest or during acute pressure loading.

Adult↗