Interaction Of Antiarrhythmic Drugs Research Articles

Вопросы безопасности антиаритмической терапии при фибрилляции предсердий

The article discusses the safety of antiarrhythmic therapy for atrial fibrillation in the light of the development of cardiac and non-cardiac side effects, the presence of drug-drug interactions of antiarrhythmic drugs in the near (with anticoagulants) and far circle. The features of the choice of antiarrhythmic therapy for the prevention of relapses of atrial fibrillation, restoration of sinus rhythm, as well as heart rate control are presented, and aspects of the tactics of managing these patients are highlighted.

EFFECT OF BASELINE ANTIARRHYTHMIC DRUG ON OUTCOMES WITH ABLATION IN ISCHEMIC VENTRICULAR TACHYCARDIA: A VANISH SUBSTUDY

The interaction of antiarrhythmic drugs with catheter ablation for ventricular tachycardia has not been previously described. Using data from the VANISH study, we sought to examine the effect of these treatments by antiarrhythmic drug prescribed at baseline. All patients enrolled in the VANISH study were included (n=259). Analysis was conducted based on whether patients had recurrent VT refractory to Amio as compared to sotalol. Baseline characteristics and outcomes were compared between the two groups. Outcomes were death, VT storm or appropriate ICD shock. At baseline, 169 (65.2%) were on Amio, 90 (34.7%) on sotalol (1 was on procainamide). Patients on Amio had more renal insufficiency (23.7% vs 10%, p=0.0008), worse NYHA class (82.3% II/III vs 65.5%, p=0.0003), lower ejection fraction (29 ± 9.7% vs 35.2 ± 11, p < 0.0001). After adjusting for these baseline differences, there was no difference in the primary outcome or its components. When examined within the escalated drug therapy arm, patients on Amio had a higher primary outcome (HR 1.94 95%CI 1.14,3.29, p=0.0144), and trend to higher mortality (HR 2.4 95%CI 0.93, 6.22, p=0.07). Within the Amio group, ablation was significantly better than escalated drug therapy in reduction of any ventricular arrhythmia (HR 0.53 95%CI 0.31,0.9, p=0.0195). Patients on sotalol had a trend towards higher mortality and VT storm with ablation, as compared to escalated drug therapy, with no effect on ICD shocks. The benefit of catheter ablation is greater for patients with VT despite amiodarone than for patients with VT despite sotalol who are then switched to amiodarone.

Safety and Interactions of Direct Oral Anticoagulants with Antiarrhythmic Drugs.

Direct oral anticoagulants (DOACs) are novel direct-acting medications that are selective for either thrombin or activated factor X. Due to their obvious benefits for patients (fewer interactions, broader therapeutic window, etc.), they are increasingly used as an alternative to warfarin, phenprocoumon, or acenocoumarol. One of the major indications for use of DOACs is stroke prevention in patients with atrial fibrillation (AF). However, interactions still exist, especially in combination with antiarrhythmic drugs (AADs), which are frequently given to AF patients for rhythm or rate control. These interactions are due to the cytochrome P450 system and the P-glycoprotein (permeability glycoprotein or multidrug resistance protein) transport system. For some combinations, dose reduction of the DOAC is recommended and in some cases contraindications exist. In addition, impairment in renal and hepatic function plays an important role in this context. However, compared with pure interactions where data are quite convincing, the latter topic has been studied only rudimentarily. This review summarizes the literature on the safety and interactions of AADs when used with DOACs [dabigatran (a direct inhibitor of factor IIa) and rivaroxaban, apixaban and edoxaban (direct inhibitors of factor Xa)] and the impact of renal and hepatic impairment.

Interactions of antiarrhythmic drugs and implantable devices in controlling ventricular tachycardia and fibrillation.

Implantable cardioverter defibrillators (ICDs) have proven highly successful in the treatment of life-threatening ventricular arrhythmias. Despite the efficacy of the ICD in terminating ventricular arrhythmias, antiarrhythmic drugs remain an important adjunct to ICD therapy. The use of antiarrhythmic drug therapy in combination with the ICD is synergistic in terms of beneficial effects, but also has the potential for some adverse interactions. Knowledge and recognition of these potential interactions is important for any physician managing patients with an ICD. This review summarizes the benefits and adverse effects of ICD in combination with antiarrhythmic drug therapy, and provides guidelines to ensure safe application of this hybrid therapy.

Interactions of antiarrhythmic drugs with implantable defibrillator therapy for atrial and ventricular tachyarrhythmias.

Implantable cardioverter defibrillators (ICDs) have proven highly successful in the treatment of recurrent ventricular and atrial arrhythmias. Despite their high efficacy in terminating arrhythmias, concomitant therapy with antiarrhythmic drugs in ICD recipients remains common. Antiarrhythmic drugs are employed in an attempt to to limit patient exposure to high-energy shocks, primarily by reducing the number of arrhythmia reccurrences, suppressing coexisting arrhythmias, affecting rate and organization of tachycardias, and increasing efficacy of painless pacing therapies. Data regarding interaction of antiarrhythmic drugs with ICDs are incomplete and mostly based on animal models; however, it is clear that antiarrhythmic drugs affect all aspects of function of devices such as defibrillation threshold, pacing threshold, and sensing of both atrial and and ventricular arrhythmias. Because significant change in any of these functions may result in a nonfunctional device, and magnitude of drug effect in an individual patient is unpredictable, careful assessment of ICD function after an institution of therapy with antiarrhythmic drugs is mandatory.

Interaction of antiarrhythmic drugs with model membranes

Several hypotheses link the molecular mechanism of action of the antiarrhythmic drugs (AAD) that belong to class I to nonspecific interactions with phospholipids sited in the neighborhood of the sodium channels in the membrane of the myocard. The interactions of asocainol (ASOC), procainamide (PROC) and quinidine (QUIN) with: (a) multibilayers of dimyristoylphosphatidylcholine (DMPC) and of dimyristoylphosphatidylethanolamine (DMPE), in both a hydrophobic and a hydrophilic medium, and (b) DMPC vesicles, were studied, respectively, by X-ray diffraction and fluorescence spectroscopy. It was found that the three AAD interacted with the lipid bilayers. However, the extension of these interactions depended on the nature and concentration of the lipids and AAD as well as on the medium where the interactions were performed. The different capacity of ASOC and PROC to perturb the bilayer structures, mainly that of DMPC, indicated that the interactions were strongly dependent on the lipophilicity of these drugs. The fact that QUIN did not completely interact in accordance to its lipophilicity suggested that other factors also play a role in these interactions. It is concluded that it may be valid the suggested molecular mechanisms of action of class I AAD involving their interaction with the membrane phospholipids.

Kinetic effects of quaternary lidocaine block of cardiac sodium channels: a gating current study.

The interaction of antiarrhythmic drugs with ion channels is often described within the context of the modulated receptor hypothesis, which explains the action of drugs by proposing that the binding site has a variable affinity for drugs, depending upon whether the channel is closed, open, or inactivated. Lack of direct evidence for altered gating of cardiac Na channels allowed for the suggestion of an alternative model for drug interaction with cardiac channels, which postulated a fixed affinity receptor with access limited by the conformation of the channel (guarded receptor hypothesis). We report measurement of the gating currents of Na channels in canine cardiac Purkinje cells in the absence and presence of QX-222, a quaternary derivative of lidocaine, applied intracellularly, and benzocaine, a neutral local anesthetic. These data demonstrate that the cardiac Na channel behaves as a modulated rather than a guarded receptor in that drug-bound channels gate with altered kinetics. In addition, the results suggest a new interpretation of the modulated receptor hypothesis whereby drug occupancy reduces the overall voltage-dependence of gating, preventing full movement of the voltage sensor.

The Interaction of Antiarrhythmic Drugs and the Energy for Cardioversion of Chronic Atrial Fibrillation

Antiarrhythmic drugs may alter the energy for cardioversion of ventricular arrhythmias. This study compares the energy necessary for cardioverting chronic atrial fibrillation in 57 patients taking type Ia, Ic, or type III antiarrhythmic drugs. Patients taking Ia (n = 22) or III (n = 14) drugs had a median energy for cardioversion of 100 joules, while the patients taking Ic (n = 17) drugs had a median energy of 200 joules (P = 0.03). There were no differences in the frequency of unsuccessful cardioversion. There were no serious adverse events in any of the three groups, although three patients in the Ic group had greater than 3 second pauses after the shock. The data suggest that the use of Ic antiarrhythmic drugs results in a higher energy for cardioversion of atrial fibrillation. However with higher energies, conversion is as successful as for type Ia and type III.

Modulated Receptor Hypothesis: Selectivity and Interactions of Antiarrhythmic Drugs

The modulated receptor hypothesis is useful in understanding the kinetics of Na+ channels and the changes produced by various antiarrhythmic drugs.

Antiarrhythmic drug interactions: are they important?

Most cardiac patients who have cardiac arrhythmias and are treated by antiarrhythmic agents will receive other cardiovascular drugs to treat coexistent problems, for example heart failure, angina or hypertension. Also, two antiarrhythmic drugs may be simultaneously prescribed to these patients in the search for better efficacy and fewer side effects. Finally these patients may well take noncardiovascular drugs such as cimetidine for the treatment of peptic ulcer disease or other hypersecretory disorders. In all cases, complex pharmacodynamic and pharmacokinetic drug interactions are likely to occur. These interactions have been extensively reviewed by Bigger and Giardina. The purpose of this work is to focus on the potentially important interactions with antiarrhythmic drugs. It is of interest for the cardiologist to be aware of the most common and meaningful drug interactions in order to prevent lack of efficacy or a risk of drug toxicity that could result from the simultaneous administration of different drugs to a patient. In this regard the interactions of antiarrhythmic drugs with digitalis, cimetidine, beta-blocking agents and other antiarrhythmic drugs will be briefly reviewed.

Anticholinergic effects of disopyramide and quinidine on guinea pig myocardium. Mediation by direct muscarinic receptor blockade.

We studied the interaction of disopyramide, quinidine, and procainamide with cardiac muscarinic receptors. In electrophysiological experiments, the effects of disopyramide, quinidine, procainamide, and atropine were determined on spontaneously depolarizing guinea pig right atria (GPRA) both in the presence and absence of pharmacologically induced (physostigmine) cholinergic stimulation. All four agents demonstrated a concentration-dependent antagonism of the negative chronotropic effects of physostigmine. The order of anticholinergic potency was atropine greater than disopyramide greater than quinidine greater than procainamide. The ability of disopyramide to antagonize the physostigmine induced slowing was stereoselective, (+)disopyramide greater than (-)disopyramide. In contrast, the ability of quinidine to antagonize the negative chronotropic effects of physostigmine was non-stereoselective, quinidine = quinine. In parallel experiments, we studied the ability of disopyramide, quinidine, procainamide, and atropine to compete with the radiolabeled muscarinic receptor antagonist [3H] quinuclidinyl benzilate ([3H]QNB) for binding to muscarinic receptors in crude homogenates of GPRA and membrane vesicles from canine ventricular myocardium. All four agents inhibited [3H]QNB binding to muscarinic receptors. The order of anticholinergic potency determined by the receptor binding studies was identical to that determined by the physiological studies. The interaction of disopyramide with muscarinic receptors was stereoselective, (+)disopyramide > (-)disopyramide. Quinidine was only slightly more potent than quinine in inhibiting [3H]QNB binding to muscarinic receptors. Interaction of antiarrhythmic drugs with muscarinic receptors satisfied criteria for a competitive interaction. The data from this study localize the anticholinergic effects of disopyramide and quinidine to the muscarinic receptor.

Correlation between antiarrhythmic activity of acyl derivatives of phenothiazine and their affinity for phospholipid membranes

The interaction of thirteen antiarrhythmic active phenothiazine 10-acylaminopropionil derivatives with artificial phospholipid membranes was studied. Blinding constant (K) of this interaction was determined by means of a fluorescent probe. There was found a valid correlation between K and antiarrhythmic activity (A) for 10 substances; the greater the K--the greater the A. Three substances characterized by the greatest K had, however, a low A. It can be assumed that the interaction of antiarrhythmic drugs with phospholipids of target membranes in vivo is an important element of the molecular mechanism of action. At the same time a very high affinity to lipids can possibly cause a delocalization of the drug in the organism and a decrease of its antiarrhythmic activity.

Applications of Hodgkin-Huxley equations to excitable tissues.

Denis Noble, “Applications of Hodgkin-Huxley Equations to Excitable Tissue,” p. 4, eq. 6a, should read: See PDF for Equation