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PubMed1999

Intracoronary flecainide induces ST alternans and reentrant arrhythmia on intact canine heart: A role of 4-aminopyridine-sensitive current.

BACKGROUND: The electrical alternans shown on an ST segment, ST alternans, is known as one of the most important predictors of ventricular fibrillation (VF). It has also been reported that sodium channel inhibition changes action potential configuration, especially on the repolarization phase. Thus, the sodium channel blocker may produce ST alternans and trigger reentrant arrhythmia. METHODS AND RESULTS: A sodium channel blocker (disopyramide, lidocaine, or flecainide) was infused selectively into the left anterior descending coronary artery in anesthetized, open-chest dogs. Sixty unipolar electrograms were simultaneously recorded from the entire cardiac surface of the heart. The amplitude of ST alternans (STa) was determined as the difference in the ST-segment magnitude between 2 consecutive electrograms. We accepted the greatest STa among 60 leads for evaluation. High-dose flecainide (100 microg. kg-1. min-1) increased STa and evoked a spontaneous VF. The STa in high-dose flecainide loading (8.7+/-3.4 mV; mean+/-SEM) was significantly greater than that in disopyramide or lidocaine (0. 9+/-0.4 and 0.8+/-0.2 mV, P<0.05). Treatment of 4-aminopyridine (4-AP) suppressed the increase in STa and the occurrence of VF evoked by flecainide, while E4031 or verapamil did not inhibit those. CONCLUSIONS: Flecainide caused the ST alternans that was closely correlated to the occurrence of VF. Because the ST alternans was suppressed by 4-AP treatment, a 4-AP-sensitive current such as Ito or Isus may play an important role on this phenomenon.

4-Aminopyridine↗
PubMed1991

Metabolic, hemodynamic, and electrocardiographic responses to increased circulating adrenaline: effects of pretreatment with class 1 antiarrhythmics.

In order to study the effects of treatment with class 1 antiarrhythmics on the metabolic, hemodynamic, and electrocardiographic responses to adrenaline, 12 healthy volunteers were infused on four occasions, after pretreatment with placebo, disopyramide, mexiletine, and flecainide, respectively, with adrenaline at a rate producing serum adrenaline concentrations comparable with those seen in acute myocardial infarction. After pretreatment with placebo adrenaline caused significant falls in serum potassium, serum magnesium, serum calcium, and serum phosphate and a significant increase in blood glucose. Adrenaline also caused a significant increase in heart rate and systolic blood pressure and a significant fall in diastolic blood pressure. On the electrocardiogram a significant prolongation of QTc duration and a flattening of the T-wave amplitude were seen. Pretreatment with disopyramide had no effect on the hemodynamic response to adrenaline but caused a significant prolongation of Qtc duration before the adrenaline infusion. Pretreatment with mexiletine was associated with a significantly greater fall in serum potassium during adrenaline infusion, and pretreatment with flecainide with a greater fall in serum magnesium, as compared with placebo pretreatment Flecainide also caused a significant prolongation of the QRS duration before adrenalin infusion, and after all the active pretreatments a prolongation of QRS duration was seen during adrenaline infusion. The metabolic and hemodynamic changes during adrenaline infusion may not only reduce the antiarrhythmic efficacy of antiarrhythmics but may also increase the risk of proarrhythmic effects in a clinical setting. These results may help to explain why treatment with antiarrhythmics seems to be without beneficial effect on mortality in post-myocardial infarction patients.

Adult↗
PubMed1983

Availability of electrophysiological approach to the selection and assessment of antiarrhythmic drugs for recurrent ventricular tachycardia.

We performed serial electrophysiological-pharmacological studies on 21 patients with recurrent sustained or non-sustained ventricular tachycardia (VT). In 8 of 11 patients with recurrent sustained VT, VT could be induced repeatedly by programmed electrical stimulation and terminated by ventricular burst pacing. In 13 of the 21 patients, repetitive ventricular response (RVR) was successfully induced. In the 8 patients with induced VT, the efficacy of several antiarrhythmic drugs intravenously administered was assessed. Procainamide prevented the initiation of VT in 57%, disopyramide in 50% and mexiletine in 40%. However, lidocaine, propranolol and verapamil could not prevent VT in any of 5, 3 and 6 patients, respectively. Verapamil in combination with quinidine prevented the initiation of VT in one case. Each of disopyramide, propranolol and verapamil increased the VT zone in 2 patients. The drugs belonging to the same group classified by their electrophysiological properties were not interchangeable in 2 patients. Their ability to terminate induced VT did not always correlate with that to prevent its initiation in 2 patients. The effects of specific drugs were rather variable and unpredictable in each patients, and especially those of combination regimens using more than 2 antiarrhythmic drugs were more unpredictable. In all patients, the induced VT was morphologically identical to the spontaneously occurring VT and its rate was ranged within 13% of that of the spontaneously VT. In 10 of 13 patients with RVR, QRS configuration of RVR was not similar to the spontaneously occurring arrhythmia. The pharmacological suppression of RVR as an index for prevention against spontaneous VT remains controversial. This study concludes that the serial electrophysiological-pharmacological study provides a rapid prediction of effectiveness of a particular regimen and combination and a rapid identification of the deleterious effects of certain drugs in patients with recurrent sustained VT.

Adolescent↗
PubMed1985

Evaluation of antiarrhythmic drug efficacy using holter electrocardiographic technique.

This study was performed to investigate spontaneous variability in VPC frequency, to determine standards for distinguishing antiarrhythmic efficacy from the spontaneous variability, and to compare the effectiveness of disopyramide, mexiletine, aprindine, propranolol, and diltiazem. Holter ECG techniques were used for this study and the population studied consisted of 182 patients having more than 1000 VPCs/day. Forty patients had ischemic heart disease, 52 had miscellaneous heart disease and 90 were free of heart disease (idiopathic VPCs). Circadian variability of VPCs can be divided into 4 types; Type D (VPCs increasing during waking hours), Type DN (small VPC changes between waking and sleeping hours), Type N (VPCs increasing during sleeping hours) and Type Ir (irregularly occurring VPCs). The incidence of Type D, DN, N and Ir was 45%, 29%, 12% and 14%, respectively. VPC frequency in the first and second recordings at a 7 up to 21 day interval was highly reproducible (r = 0.951). The percent reduction in VPC frequency necessary to distinguish true drug response from spontaneous VPC variability, corresponded to 57% with 95% confidence level, and 67% with 99% confidence level. VPCs were reduced by at least 57% in 19 out of 33 patients (58%) with disopyramide, 9 of 15 (60%) with mexiletine, 11 of 18 (61%) with aprindine, 9 of 24 (38%) with propranolol and 8 of 22 (36%) with diltiazem. Concerning Prop., it is exclusively effective to the Type D VPCs (70%).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1993

Suppression of ventricular premature contractions continues after the washout of antiarrhythmic drugs.

The effects of the washout of antiarrhythmic drugs on the frequency of ventricular premature contraction (VPC) were investigated in 64 patients (VPCs > 2000/day). Included were patients on mexiletine (300-600 mg/day; 23 patients), disopyramide (300-600 mg/day; 19 patients) and atenolol (50 mg/day; 22 patients). Holter monitoring was repeated before, during and after the treatment with the above 3 drugs and the efficacies of the drugs were evaluated based on the spontaneous variability before the treatment. VPC reduction exceeding the calculated spontaneous variability during drugs therapy (drug-responders) and after the washout of the drugs (wash-responders) was noted in 17 (63%) and 3 (13%) of the mexiletine group; 11 (58%) and 5 (26%) of the disopyramide group; and 13 (59%) and 8 (36%) of the atenolol group, respectively. For the entire group of 64 patients, wash-responders were noted significantly (p < 0.05) more among drug-responders (14 of 41 patients; 34%) than drug-nonresponders (2 of 23 patients; 9%). Therefore, the antiarrhythmic effects of drugs observed during drugs therapy seem to continue even after the discontinuation of antiarrhythmic drugs in 34% of patients those whose VPC reduction exceeded the spontaneous variability (drug-responders).

Adult↗
PubMed1997

The rise time of the monophasic action potential--a new index of local use-dependent conductivity by sodium channel blockers in human myocardium.

The kinetics of global use-dependent conduction slowing produced by sodium channel blockers in the human heart, estimated as a change in the QRS width, are known to be similar to those of use-dependent block of the maximum rate of depolarization in in vitro studies. However, the kinetics of the regional use-dependent decrease in conductivity have not been investigated. We examined whether the rise time of the monophasic action potential would be clinically useful as a marker of the local use-dependent decrease in conductivity by sodium channel blockers. In 12 patients without organic heart disease, monophasic action potentials (MAPs) were recorded at the right ventricular endocardium using a contact electrode before and after the administration of disopyramide (n = 6, 2 mg/kg, i.v.) or pilsicainide (class Ic agents, n = 4, 1 mg/kg, i.v., and n = 2, 150 mg, po) while the stimulus frequency was abruptly increased from 100/min to 150/min. The rise time, defined as the interval from the pacing pulse to the first peak deflection of the monophasic action potential, and the ORS width were measured simultaneously. In the absence of the sodium channel blockers, the abrupt increase in heart rate did not alter the QRS width or the rise time. In the presence of the agents, both variables were lengthened exponentially. The rate constants of onset changes in the QRS width and the rise time were 2.1 +/- 0.5 beats and 2.1 +/- 0.4 beats after the administration of disopyramide, and 7.5 +/- 3.0 beats and 8.2 +/- 4.0 beats after pilsicainide, respectively. The rate constant of the rise time was closely correlated with that of the QRS width. The present results are very closely comparable with the onset rate constants of use-dependent block of the maximum rate of depolarization in in vitro studies. These results suggest that (1) the rise time is a good indicator of local use-dependent decrease in conductivity by sodium channel blockers in human hearts and (2) the local use-dependent decrease in conductivity has kinetics similar to those of use-dependent sodium channel blocks.

Action Potentials↗
PubMed1989

Effects of S-1389 (711389-S), a new antiarrhythmic agent, on the conduction in perfused guinea pig hearts.

In the His bundle and ventricular electrograms of Langendorff-perfused guinea pig hearts driven at a cycle length of 450 or 700 msec, S-1389 (711389-S), a new antiarrhythmic agent, above 3 x 10(-7) or 10(-6) M increased the basal conduction times in the following order: His-Purkinje system greater than ventricular and atrial muscles greater than atrioventricular (AV) node. Slowing of the ventricular and AV nodal conduction of extrasystoles with variable coupling intervals was also caused by S-1389. S-1389 above 10(-6) or 3 x 10(-6) M significantly prolonged the functional and/or effective refractory periods of the AV node and ventricle. Disopyramide (3 x 10(-6)-3 x 10(-5) M) also produced similar effects, but they were much less potent than those of S-1389. Although disopyramide did not produce the rate-dependent increases in the atrial and AV nodal conduction times and in the AV nodal refractory period, S-1389 increased these parameters rate-dependently.

Animals↗
PubMed1983

Intropic effects of several antiarrhythmic drugs.

The effects of intravenous administration of several quinidine-like antiarrhythmic drugs (bunaftine, monochloroacetyl ajmaline, lidocaine, mexiletine, disopyramide, aprindine, diphenylhydantoin, procainamide) on left ventricular performance, evaluated by systolic time intervals (STI), were studied in 100 patients with atherosclerotic heart disease. The STI were measured: the pre-ejection period (PEP), the isometric contraction time (ICT), the left ventricular ejection time (LVET), corrected LVET (LVETc), and the PEP/LVET ratio. The degree of impairment of left ventricular performance was maximal after aprindine and disopyramide administration. This was demonstrated by significant increases in the PEP, ICT, and PEP/LVET and by significant decreases in LVET and LVETc, in patients in both III-IV and I-II NYHA classes. Bunaftine, monochloroacetyl ajmaline, and lidocaine induced a less marked impairment of myocardial performance, since the PEP, ICT, and PEP/LVET increases were not significant compared to controls in patients in NYHA class I-II, and since no variation of LVET and LVETc were observed. Mexiletine effects on myocardial performance appear to be intermediate between these groups of drugs. Diphenylhydantoin and procainamide, considered separately because of their effects on heart rate and blood pressure which are not possessed by the other drugs, induced significant increases of PEP in NYHA class III-IV patients. However, the effects of these 2 drugs on myocardial performance may have been underestimated, due to the concomitant hemodynamic effect of these drugs.

Ajmaline↗
PubMed1985

Cardiovascular and respiratory effects of antiarrhythmic drugs on conscious beagles.

Cardiovascular effects of antiarrhythmic drugs and their effects on the respiratory rate were examined in conscious beagles. Disopyramide, 1.5 mg/kg i.v., increased the blood pressure and decreased the heart rate, but higher dose of 5 mg/kg i.v. increased both. Disopyramide showed no central nervous side effects. Procainamide, 20 and 60 mg/kg i.v., increased the blood pressure and heart rate without changing the respiratory rate. A higher dose (60 mg/kg i.v.) of procainamide induced vomiting. Lidocaine, 2 and 6 mg/kg i.v., and phenytoin, 3 and 10 mg/kg i.v., simultaneously increased the blood pressure, heart rate and respiratory rate accompanied by excitement, and with a higher dose (6 mg/kg i.v.) of lidocaine, by convulsions. Verapamil, 0.1 and 0.3 mg/kg i.v., induced tachycardia without serious neurological effects. In conscious healthy dogs cardiovascular depressant actions of antiarrhythmic drugs could only rarely be observed.

Animals↗
PubMed1992

[Prospective course of therapy arresting attacks of atrial fibrillation in patients with preexcitation syndromes].

A comparative study of antiarrhythmic drugs was performed in 81 patients with atrial fibrillation attacks in the presence of preexcitation syndrome. The first intravenous administration of cordarone was effective in 84.06%, disopyramide--in 69%, ajmaline in 44.8, verapamil in 42.1, novocaine amide in 39.4 and ethacizin in 38.5% of the patients. The first oral administration of quinidine and kinilentin arrested 80.4% of arrhythmia attacks, disopyramide 66.7% propranolol and mexitil 37.5 and 33.3%, respectively. Prospective evolution of antiarrhythmic therapy manifested with decreased therapeutic efficacy of the drugs from 55.7 to 26.2% in the whole group during the period of 1-5 years.

Adult↗
PubMedDate not supplied

Possible role of drug interactions in bupivacaine-induced problems related to intraventricular conduction disorders.

Clinically, bupivacaine has depressant effects on intraventricular conduction that may lead to serious atrioventricular blocks or reentrant arrhythmias at plasma levels below those required to produce these effects experimentally (2-3 micrograms/ml instead of 8-10 micrograms/ml). The difference could be due to drugs present in the blood at the time of regional anesthesia that similarly inhibit conduction. This hypothesis was examined in 30 anesthesized, closed-chest dogs by measuring conduction time in the ventricular contractile fibers as well as effective refractory period under pacing at a constant, relatively high (180 beats/minute) rate. Changes in sinus rate were limited, as well as changes in ventricular effective refractory period and blood pressure regardless of the drug tested. In contrast, cibenzoline, disopyramide, and propranolol increased conduction time and lengthened QRS duration. Clomipramine appeared to prolong conduction time and widen QRS only moderately in therapeutic doses, whereas verapamil did not manifest noticeable effects on conduction. Caution is therefore recommended in regional anesthesia with bupivacaine in subjects being treated with cardiovascular drugs, such as cibenzoline, disopyramide, and propranolol and their congeners, or even by tricyclic antidepressants.

Animals↗
PubMed1986

Simultaneous liquid-chromatographic determination of five antiarrhythmic drugs and their major active metabolites in serum.

We report an isocratic "high-performance" liquid chromatographic method for the simultaneous measurement of tocainide, lidocaine, procainamide, quinidine, disopyramide, and their major active metabolites in serum. The drugs are extracted from 200 microL of serum at pH 9.5 with 1.5 mL of 1,2-dichloromethane, concentrated by evaporation, and separated on a CN-bonded-phase column at 40 degrees C (flow rate 2 mL/min) with a pH 7.1 mobile phase of acetonitrile/methanol/phosphate buffer (60/7/33, by vol); the phosphate buffer contains 10 mmol of KH2PO4 and 0.5 mmol of triethylamine per liter. The antiarrhythmic drugs elute in the K' (capacity factor) range of 1.43 (lidocaine) to 5.7 (disopyramide). Results vary linearly with drug concentration to at least 30 mg/L; the detection limit is 0.1-0.2 mg/L. Within-run precision (CV) ranges from 0.9% to 5.0% and day-to-day precision from 2.1% to 6.2%, depending on the specific drug and its concentration in serum. Extraction efficiencies vary from 76% to 85% and analytical recoveries from 98.5% to 103%. At toxic serum concentrations, several basic drugs may interfere with the assay of some antiarrhythmics, but only hydroxyzine, verapamil, and certain local anesthetics interfere at therapeutic concentrations.

Anti-Arrhythmia Agents↗
PubMed1988

Recovery from use-dependent block of Vmax and restitution of action potential duration in canine cardiac Purkinje fibers.

The recovery kinetics during diastole of various plateau currents are thought to control the restitution of action potential duration (APD). Based on the assumption that the recovery of the residual plateau Na current parallels that of Vmax, the hypothesis that Na current recovery kinetics influence the restitution of APD was tested. Drugs that reduced Vmax in a use-dependent manner (tetrodotoxin 3 microM, lidocaine 15 microM, mexiletine 20 microM) were compared with interventions that reduced Vmax in a simply tonic fashion [( Na]o 75 mM, [K]o 6.5 mM, disopyramide 30 microM). Microelectrode techniques and programmed stimulation were used to determine in vitro the kinetics of restitution of APD and of time-dependent recovery of Vmax during rest. Tetrodotoxin, lidocaine and mexiletine induced a blockade of Vmax that showed partial or full time-dependent unblocking in accordance with the known use dependence of their blocking action. Dissipation of the time-dependent component of the block in each case followed a single exponential time course, time constants being 163 +/- 12, 115 +/- 12 and 121 +/- 20 ms, respectively. Analysis of the kinetics of the APD restitution curves showed that the time constant of the fast decaying exponential component of restitution (T1) was prolonged by these drugs from 129 +/- 5 in control fibers to 295 +/- 17, 235 +/- 11 and 242 +/- 26 ms for tetrodotoxin, lidocaine and mexiletine, respectively (P less than .05). Low [Na]o and disopyramide reduced Vmax in a simply tonic fashion and did not significantly prolong the T1 component of APD restitution.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗
PubMed1981

Factors influencing serum protein binding of lidocaine in humans.

Several factors that may affect protein binding of lidocaine in human serum were studied in normal volunteers. Evidence was obtained for the presence of two classes of lidocaine binding sites with strikingly different affinity constants (k) and capacities (nP); k1 equals 1.3 x 10(5)M(-1), n1P1 equals 1.7 x 10(-5)M, and k2 equals 6.4 x 10(1)M(-1), n2P2 equals 6.9 x 10(-3)M. The low affinity binding sites are probably on serum albumin, whereas the high affinity site may be located on alpha 1 acid glycoprotein. At a lidocaine serum concentration of approximately 1.4 microgram/ml, it was observed that acidosis (pH 7.4 leads to 7.2) caused lidocaine-free fraction to increase from 0.29 to 0.36 (p less than 0.01) and that the addition of the lidocaine metabolites 3-hydroxylidocaine, 4-hydroxylidocaine, monoethylglycinexylidide, and glycinexylidide had no effect on the binding of lidocaine. Bupivacaine, disopyramide, and quinidine (in concentrations that are observed clinically) caused a significant increase (p less than 0.01) in the free fraction of lidocaine in serum (23%, 21%, and 34%, respectively. Interestingly, N-depropyl disopyramide, dihydroquinidine, procainamide, N-acetyl procainamide, and propranolol had no effect on lidocaine binding.

Acecainide↗
PubMed1982

[Restless legs and nocturnal leg spasms--forgotten facts in diagnosis--new facts for therapy].

An angiologist's experience with the symptom of restless legs is reported. The condition was diagnosed in 103 patients presenting with pain in their legs occurring predominantly at rest and vanishing with walking. Organic lesions could not be identified (in 76%) or were not responsible for the discomfort (in 24%). A depressive state, most often masked, was recognized in 67%. In 42% anxiety was present alone, and in 49% frank depression was diagnosed. In 9% psychiatric treatment was mandatory. Patients with no depression were either not treated (33%) or were given type I-antiarrhythmic drugs (mostly disopyramide) with good results. These drugs were only transiently effective in depressed patients since anxiety was often intensified when the symptom of restless legs disappeared. Antidepressant agents, though ineffective when given alone, were most helpful when administered together with disopyramide.

Adult↗
PubMed1982

Canine-effective plasma concentrations of antiarrhythmic drugs on the two-stage coronary ligation arrhythmia.

Seven drugs were tested for their antiarrhythmic effects on ventricular arrhythmias 24 and 48 hr after two-stage coronary ligation in conscious beagles. Venous blood samples were drawn for plasma drug assays. Minimum effective plasma concentrations of drugs were calculated from derived concentration-time curves. Effective drugs and their minimum effective concentrations for the suppression of arrhythmias 24 and 48 hr after coronary ligation were: disopyramide, 4.2 and 2.3 micrograms/ml; procainamide, 26.4 and 27.0 micrograms/ml; phenytoin, 8.4 and 6.4 micrograms/ml; and a new beta-blocker, N-696, 7.6 and 8.7 micrograms/ml. The concentrations of disopyramide and phenytoin were almost the same as those reported for human antiarrhythmic concentrations, but those of procainamide were higher than those reported for man. Lidocaine, verapamil and a new beta-blocker, OPC-1427, were ineffective. Membrane-stabilizing effects seem to be important in suppressing the canine two-stage coronary ligation arrhythmia.

Animals↗
PubMed1996

The role of inactivation in open-channel block of the sodium channel: studies with inactivation-deficient mutant channels.

Inactivation has been implicated as an important determinant of the block of Na+ channel by local anesthetic-class drugs. This proposition has been difficult to examine because agents used to modify inactivation change other channel properties and both inactivated and blocked channels do not conduct. We used site-directed mutagenesis of Phe1304 to glutamine in the linker between the third and fourth domains of the mu-1 Na+ channel to slow inactivation. Wild-type and mutant channels were expressed in frog oocytes. Macropatch and single-channel currents were recorded in cell-attached membrane patches. The F1304Q mutation increased mean open time (1.7 fold at -20 mV) and reduced the probability that the channel would fail to open. Closed times were best fit by a double-exponential function, suggesting that the inactivated state transitions were no longer absorbing. In wild-type channels, 100 microM disopyramide decreased mean open time from 1.64 +/- 0.08 to 0.34 +/- 0.04 msec. Total open time per trial was decreased 2-fold. There also was a marked increase in the fraction of null sweeps. In the inactivation-deficient mutant channel, mean and total open times were also reduced. These data indicate that even when inactivation is slowed by a localized specific mutation, open-channel block by disopyramide persists. Inactivation may not be a necessary requirement for open-channel block.

Cloning, Molecular↗
PubMed1990

Binding of diltiazem to albumin, alpha 1-acid glycoprotein and to serum in man.

Binding of drugs can vary considerably. Therefore, binding of the calcium antagonist diltiazem was studied in protein solutions and in serum of healthy persons, patients with renal failure, patients with cirrhosis, patients with rheumatoid arthritis, patients with myocardial infarction, and intensive care patients. The effect of in vitro addition of some cardiovascular drugs (lidocaine, disopyramide, quinidine, and bupivacaine) on the binding of diltiazem in serum of healthy volunteers was also investigated. Diltiazem is bound as well to alpha 1-acid glycoprotein (AAG) as to albumin. In patients with renal failure, myocardial infarction, and rheumatoid arthritis and in intensive care patients, AAG concentrations are increased, and in the patients with myocardial infarction an increased binding of diltiazem is found. In patients with cirrhosis, AAG concentrations and diltiazem binding are decreased. In vitro addition of lidocaine, disopyramide, bupivacaine, or quinidine in concentrations between 5 and 100 micrograms/mL, before dialysis, decreases the binding of diltiazem; the displacing effect is most pronounced with bupivacaine.

Adult↗