Class Ib Antiarrhythmic Drug Research Articles

Mexiletine: Antiarrhythmic mechanisms, emerging clinical applications and mortality.

Mexiletine, a class Ib antiarrhythmic drug, exhibits its major antiarrhythmic effect via inhibition of the fast and late Na+ currents in myocardial tissues that are dependent on the opening of Na+ channels for their excitation. Through a comprehensive examination of mexiletine's therapeutic benefits and potential risks, we aim to provide valuable insights that reinforce its role as a vital therapeutic option for patients with ventricular arrhythmias, long QT syndrome, and other heart rhythm disorders. This review will highlight the current understandings of the antiarrhythmic effects and rationales for recent off-label use and address the mortality and proarrhythmic effects of mexiletine utilizing published basic and clinical studies over the past five decades.

Assessment of impact of a new derivative 2-(diethylamino)-N-(o-toluyl) acetamide, manifesting antiarrhythmic effect in heart rhythm disorders of peripheral origin, on cardiovascular system

Objective. To study the effect of a new derivative of arylamides of aminocarboxylic acids, which has a high antiarrhythmic activity on the state of the cardiovascular system.
 Materials and methods. To study the antiarrhythmic activity of the compound, the experiment was carried out on a model of arrhythmia caused by intravenous administration of aconitine. The effect was evaluated by its ability to prevent the occurrence of arrhythmia or to prolong the survival time of animals. In addition, an analysis of the electrocardiogram of awake rats and rabbits was carried out. The test compound and the comparison drug, lidocaine, were intravenously administered to animals in effective antiarrhythmic doses.
 Results. Diethylaminoacetic acid ortho-toluidide nitrate under conditions of aconitine arrhythmia shows a pronounced antiarrhythmic effect; under its influence, there is a statistically significant reduction in the duration of arrhythmia attacks in animals by 2.4 times compared with the control as well as protection from death. The compound does not change the parameters of electrocardiogram of animals, no statistically significant differences from the control results were found.
 Conclusions. 1. A new compound, diethylaminoacetic acid ortho-toluidide nitrate, exhibits a pronounced antiarrhythmic effect. Probably, it can be attributed to class IB antiarrhythmic drugs, since it exhibits high activity on calcium chloride and aconitine models of arrhythmia.
 2. Given that the studied compound combines high antiarrhythmic activity with no negative effect on ECG parameters, a drug based on it can be used as an effective antiarrhythmic drug.

Mexiletine Block of Voltage-Gated Sodium Channels: Isoform- and State-Dependent Drug–Pore Interactions

Mexiletine is a class Ib antiarrhythmic drug and is also used clinically to reduce or prevent myotonia. In addition, mexiletine has neuroprotective effects in models of brain ischemia. We compared state-dependent affinities of mexiletine for Nav1.2, Nav1.4, and Nav1.5 and examined the effects of mutations of transmembrane segment S6 residues on mexiletine block of Nav1.5. Three channel isoforms had similar affinities of mexiletine for the rested state, and Nav1.4 and Nav1.5 had similar affinities for the open and inactivated states, while Nav1.2 had lower affinity for these states than Nav1.4 and Nav1.5. Mutational studies revealed that the largest affinity change was observed for an Ala substitution of Phe in domain IV S6. In our homology modeling based on the bacterial Na+ channel, mexiletine changed its location and orientation in the pore depending on the state of the channel, irrespective of the channel isoform. Mexiletine occurred in the upper part in the pore in the open state and lower in the closed state. High-affinity binding of mexiletine in the open states of Nav1.4 and Nav1.5 was caused by a π-π interaction with Phe, whereas mexiletine was located away from Phe in the open state of Nav1.2. These results provide crucial information on the mechanism of isoform differences in state-dependent block by local anesthetics and related drugs. Mexiletine at upper locations in the open state may effectively cause an electrostatic mechanism of block.

Mexiletine and its Interactions with Classical Antiepileptic Drugs: An Isobolographic Analysis.

Using the mouse maximal electroshock test, the reference model of tonic-clonic seizures, the aim of the present study was to determine the type of interaction between mexiletine (a class IB antiarrhythmic drug) and classical antiepileptics: valproate, carbamazepine, phenytoin, and phenobarbital. Isobolographic analysis of obtained data indicated antagonistic interactions between mexiletine and valproate (for fixed ratio combinations of 1:1 and 3:1). Additivity was observed between mexiletine and valproate applied in proportion of 1:3 as well as between mexiletine and remaining antiepileptics for the fixed ratios of 1:3, 1:1, and 3:1. Neither motor performance nor long-term memory were impaired by mexiletine or antiepileptic drugs regardless of whether they were administered singly or in combination. Mexiletine did not significantly affected brain concentrations of carbamazepine, phenobarbital or phenytoin. In contrast, the antiarrhythmic drug decreased by 23% the brain level of valproate. This could be, at least partially, the reason of antagonistic interaction between the two drugs. In conclusion, the observed additivity suggests that mexiletine can be safely applied in epileptic patients treated with carbamazepine, phenytoin or phenobarbital. Because of undesirable pharmacodynamics and pharmacokinetic interactions with valproate, mexiletine should not be used in such combinations.

Mexiletine Metabolites: A Review

Mexiletine belongs to class IB antiarrhythmic drugs and it is still considered a drug of choice for treating myotonias. However some patients do not respond to mexiletine or have significant side effects limiting its use; thus, alternatives to this drug should be envisaged. Mexiletine is extensive metabolized in humans via phase I and phase II reactions. Only a small fraction (about 10%) of the dose of mexiletine administered is recovered without modifications in urine. Although in the past decades Mex metabolites were reported to be devoid of biological activity, recent studies seem to deny this assertion. Actually, several hydroxylated metabolites showed pharmacological activity similar to that of Mex, thus contributing to its clinical profile. Purpose of this review is to summarize all the studies proposed till now about mexiletine metabolites, regarding structureactivity relationship studies as well as synthetic strategies. Biological and analytical studies will be also reported.

Searching for new antiarrhythmic agents: Evaluation of meta-hydroxymexiletine enantiomers

Mexiletine is a very well-known class IB antiarrhythmic drug, whose enantiomers differ in both pharmacodynamic and pharmacokinetic properties, the (R)-isomer being the eutomer on experimental arrhythmias and in binding studies on cardiac voltage-gated sodium channels. meta-Hydroxymexiletine (MHM) is a minor metabolite of mexiletine, which has demonstrated to be more potent than the parent compound. Herein we report the synthesis and biological evaluation of MHM enantiomers for their potential antiarrhythmic activity. The same stereoselectivity pattern observed for mexiletine was found for MHM: the (R)-enantiomer of MHM was the eutomer on ac-arrhythmia also showing a negative inotropism higher than the one displayed by mexiletine and, at the same time, a decreased vasorelaxant activity on guinea-pig left atrium and guinea-pig ileum longitudinal smooth muscle.

Stereospecific Synthesis of m-Hydroxymexiletine Enantiomers

m-Hydroxymexiletine (MHM) is a metabolite of mexiletine, a well known class IB anti-arrhythmic drug, which presents almost twice the activity of the parent compound on cardiac voltage-gated sodium channels. Given the different activity of mexiletine enantiomers on sodium currents (being the R-isomer the eutomer), it is conceivable that (R)- and(S)-MHM could differ in pharmacodynamic and pharmacokinetic properties, too. Herein we report the efficient synthesis of MHM enantiomers that could represent useful tools for further investigations on stereospecific requirements of the voltage-gated sodium channel binding site. MHM enantiomers and all the homochiral intermediates were fully characterized. The ee values for (R)- and (S)-MHM were >99%, as assessed by capillary electrophoresis using β-cyclodextrin sulfated sodium salt as a chiral selector.

An Improved Synthesis of m-Hydroxymexiletine, a Potent Mexiletine Metabolite

m-Hydroxymexiletine (MHM), a minor metabolite of the class IB anti-arrhythmic drug mexiletine, is about two fold more potent than the parent compound on human cardiac voltage-gated sodium channels (hNav1.5), and equipotent to mexiletine on human skeletal-muscle voltage-gated sodium channels (hNav1.4). Herein, an alternative and simplified synthesis of this promising compound has been accomplished. This route, as well as being more efficient, has the advantage, over the first, to avoid the use of oxidizing agents, such as the meta-chloroperoxybenzoic acid.

COMPARISON OF AMIODARONE AND LIDOCAINE IN A PROLONGED VENTRICULAR FIBRILLATION CANINE MODEL

COMPARISON OF AMIODARONE AND LIDOCAINE IN A PROLONGED VENTRICULAR FIBRILLATION CANINE MODEL

An Improved Synthesis of m-Hydroxymexiletine, a Potent Mexiletine Metabolite

m-Hydroxymexiletine (MHM), a minor metabolite of the class IB anti-arrhythmic drug mexiletine, is about two fold more potent than the parent compound on human cardiac voltage-gated sodium channels (hNav1.5), and equipotent to mexiletine on human skeletal-muscle voltage-gated sodium channels (hNav1.4). Herein, an alternative and simplified synthesis of this promising compound has been accomplished. This route, as well as being more efficient, has the advantage, over the first, to avoid the use of oxidizing agents, such as the meta-chloroperoxybenzoic acid.

A patient with mexiletine-related psychosis

Mexiletine is a commonly used Class IB (Vaughan William classification) antiarrhythmic drug. We report a case of mexiletine-induced psychosis that was successfully managed by decreasing the dose and using alternative medications for management of ventricular tachycardia.

A rare association of long QT syndrome and syndactyly: Timothy Syndrome (LQT 8)

A rare association of long QT syndrome and syndactyly: Timothy Syndrome (LQT 8)

Hydroxylated Analogs of Mexiletine as Tools for Structural‐Requirements Investigation of the Sodium Channel Blocking Activity

[2-(2-Aminopropoxy)-1,3-phenylene]dimethanol 1 and 4-(2-aminopropoxy)-3-(hydroxymethyl)-5-methylphenol 2, two dihydroxylated analogs of mexiletine - a well known class IB anti-arrhythmic drug - were synthesized and used as pharmacological tools to investigate the blocking-activity requirements of human skeletal muscle, voltage-gated sodium channel. The very low blocking activity shown by newly synthesized compounds corroborates the hypothesis that the presence of a phenolic group in the para-position to the aromatic moiety and/or benzylic hydroxyl groups on the aromatic moiety of local anesthetic-like drugs impairs either the transport to or the interaction with the binding site in the pore of Na(+) channels.

Inhibitory Effects of Lidocaine and Mexiletine on Vasorelaxation Mediated by Adenosine Triphosphate–sensitive K+Channels and the Role of Kinases in the Porcine Coronary Artery

Effects of antiarrhythmic drugs on coronary vasodilation mediated by K channels have not been studied. Modulator roles of protein kinase C and tyrosine kinase in the activity of K channels have also been unclear in the coronary artery. The current study examined whether lidocaine and mexiletine in the porcine coronary artery modify the vasorelaxation mediated by adenosine triphosphate-sensitive K channels via activation of protein kinase C and tyrosine kinase. Porcine coronary arteries without endothelium were suspended for isometric force recording, and vasorelaxation to levcromakalim (10 to 10 m) was obtained. Changes in membrane potentials produced by levcromakalim (10 m) were also recorded. Glibenclamide completely abolished vasorelaxation as well as hyperpolarization in response to levcromakalim. Lidocaine and mexiletine significantly reduced these responses. Calphostin C, Go 6976, genistein, and erbstatin A partly restored vasorelaxation or hyperpolarization in response to levcromakalim in arteries treated with mexiletine but not in those with lidocaine, whereas these inhibitors did not alter the vasorelaxation to levcromakalim. Phorbol 12-myristate 13-acetate produced reduction of vasorelaxation in response to levcromakalim, which is recovered by calphostin C or Go 6976. Therefore, lidocaine and mexiletine inhibit vasorelaxation mediated by the activation of adenosine triphosphate-sensitive K channels in the coronary artery. Protein kinase C and tyrosine kinase seem to have roles in the inhibitory effect of mexiletine but not in that of lidocaine. Class Ib antiarrhythmic drugs may reduce coronary vasodilation mediated by adenosine triphosphate-sensitive K channels via the differential modulator effects on these kinases.

Rescue ablation of electrical storm in patients with ischemic cardiomyopathy: A potential-guided ablation approach by modifying substrate of intractable, unmappable ventricular tachycardias

The purpose of this study was to evaluate a substrate-modifying, primarily potential-guided catheter ablation approach as a bailout therapy in patients with complex myocardial infarction and electrical storms due to ventricular tachycardias (VTs). Management of electrical storm is a domain of medical treatment. A definite trigger or delineated scar has been characterized as a requirement for substrate-orientated ablation of intractable unmappable ventricular tachyarrhythmias but can be absent, as shown in the presented cases. Five patients who presented with ischemic cardiomyopathy and severe reduced left ventricular ejection fraction also suffered from multiple types of unstable VTs that deteriorated into drug-refractory electrical storm. Patients had 96 to 580 VT episodes requiring therapy with an implantable cardioverter-defibrillator (ICD) and received 3 to 310 shock deliveries prior to ablation. Treatment with beta-blockers, amiodarone, class IB antiarrhythmic drugs, deep sedation, and overdrive pacing and/or cardioversion of incessant VTs failed to stabilize the electrical storm but enabled left ventricular electroanatomic voltage mapping. A simplified substrate modification was performed by ablation of delayed fractionated potentials in areas identified by pace mapping, matching three to eight documented types of VTs per patient in complex scar areas. All patients could be stabilized after ablation. During 12 to 30 months of follow-up, three patients remained free of any VT episode requiring ICD treatment, and two patients had <1 VT episode per month. The cases presented demonstrate that rescue VT ablation of drug-refractory electrical storm is possible by a substrate-orientated ablation approach even in patients with complex chronic infarction and various VTs.

Characterization of mexiletine as an antagonist of β-adrenoceptor in Chinese hamster ovary cells expressing cloned human β-adrenoceptors

We characterized the β-adrenoceptor-blocking property of mexiletine, a class Ib antiarrhythmic drug, on Chinese hamster ovary (CHO) cells stably expressing cloned human β 1-, β 2-, and β 3-adrenoceptors. In radioligand binding experiments, mexiletine (10 μM–1 mM) concentration-dependently displaced the specific binding of [ 125 I ]cyanopindolol to human β 1- and β 2-adrenoceptors in the membrane fraction of the cells. High concentration (100 μM–1 mM) of mexiletine partially displaced the specific binding of [ 125 I ]cyanopindolol to human β 3-adrenoceptor. On the other hand, high concentration (300 μM and 1 mM) of lidocaine, another class Ib antiarrhythmic drug, partially displaced the specific binding of [ 125 I ]cyanopindolol to human β 1-adrenoceptor, whereas it did not affect the specific binding of [ 125 I ]cyanopindolol to human β 2- and β 3-adrenoceptors. Mexiletine (5, 50, and 500 μM) reduces basal adenosine 3′,5′-cyclic monophosphate (cAMP) level and isoprenaline-induced cAMP accumulation on CHO cells stably expressing cloned human β 1- and β 2-adrenoceptors. Lidocaine (10 and 100 μM and 1 mM) tend to reduce basal cAMP level on CHO cells stably expressing cloned human β 1-adrenoceptors, whereas the drug did not reduce the isoprenaline-induced cAMP accumulation on CHO cells stably expressing cloned human β 1-, β 2-, and β 3-adrenoceptors. Mexiletine and lidocaine have no effect on forskolin (0.1, 1, and 3 μM)-induced cAMP accumulation. These results demonstrate that mexiletine blocks the binding of agonists to β 1- and β 2-adrenoceptors, and thereby attenuates the agonist-induced cAMP accumulation, and that the action of mexiletine as an antagonist of β 1- and β 2-adrenoceptors is independent of its antiarrhythmic property.

Mexiletine inhibits nonadrenergic noncholinergic lower oesophageal sphincter relaxation in rabbits

Nonadrenergic noncholinergic (NANC) nerves are known to be nitrergic and to have an important role in the regulation of gastrointestinal motility and function. Cardiac antiarrhythmic therapy in humans is accompanied by a high incidence of gastrointestinal side–effects. We investigated the effect of mexiletine, a class Ib antiarrhythmic drug, on NANC lower oesophageal sphincter relaxation. Mexiletine concentration dependently inhibited the NANC relaxation induced by 30 mM KCl (EC 50=4.4×10 −6 M); the production of 3′,5′-cyclic guanosine monophosphate (cGMP) after KCl stimulation was concentration dependently decreased. The relaxation induced by the exogenous nitric oxide (NO) donor, diethylamine NONOate (10 −5 M), was not inhibited by mexiletine, and the cGMP production after diethylamine NONOate application was not altered. Mexiletine did not alter the activity of NO synthase. These findings suggest that mexiletine inhibits NANC relaxation via NO-cGMP pathway modulation, possibly by inhibiting myenteric nitrergic neurotransmission in the lower oesophageal sphincter in rabbits.

Cardioprotective effect of mexiletine in acute myocardial ischemia tudies in the rabbit closed chest ischemia mode.

ATP-sensitive K+ (KATP) channel openers have a cardioprotective effect and so mexiletine (Mex), a class Ib anti-arrhythmic drug, may also be cardioprotective because of its KATP channel-opening effect. The present study examined the effect of Mex on acute myocardial ischemia in a closed-chest acute ischemia and reperfusion model in rabbits. The rabbits were divided into 3 groups: (1) control (n=8); (2) Mex (n=8), continuous infusion of mexiletine (24 mg x kg(-1) h(-1)); and (3) Mex+Gli (n=8), pre-administration of glibenclamide (Gli; 0.5mg/kg) followed by mexiletine infusion. The incidence of arrhythmia, the hemodynamics and left ventricular ejection fraction (LVEF), and the infarct size were evaluated and compared among the 3 groups. The incidence of fatal ventricular fibrillation (VF) was least in the Mex group. The LVEF at 30 min after reperfusion was least in the Mex group, but at 360 min after reperfusion, it was least in the Mex+Gli group. The area of myocardial infarction determined by 2,3-triphenyltetrazolium chloride (TTC) staining was smallest in the Mex group. In this model, Mex reduced infarct size and improved left ventricular function during the late phase after reperfusion, although the effect was totally negated by the addition of glibenclamide.

A review of HNS-32: a novel azulene-1-carboxamidine derivative with multiple cardiovascular protective actions.

HNS-32 [N(1),N(1)-dimethyl-N(2)-(2-pyridylmethyl)-5-isopropyl-3,8-dimethylazulene-1- carboxamidine] (CAS Registry Number: 186086-10-2) is a newly synthesized azulene derivative. Computer simulation showed that its three dimensional structure is similar to that of the class Ib antiarrhythmic drugs, e.g., lidocaine or mexiletine. HNS-32 potently suppressed ventricular arrhythmias induced by ischemia due to coronary ligation and/or ischemia-reperfusion in dogs and rats. In the isolated dog and guinea pig cardiac tissues, HNS-32 had negative inotropic and chronotropic actions, prolonged atrial-His and His-ventricular conduction time and increased coronary blood flow. In the isolated guinea pig ventricular papillary muscle, HNS-32 decreased maximal rate of action potential upstroke (Vmax) and shortened action potential duration (APD). These findings suggest that HNS-32 inhibits inward Na+ and Ca2+ channel currents. In the isolated pig coronary and rabbit conduit arteries, HNS-32 inhibited both Ca2+ channel-dependent and -independent contractions induced by a wide variety of chemical stimuli. HNS-32 is a potent inhibitor of protein kinase C (PKC)-mediated constriction of cerebral arteries. It is likely to block both, Na+ and Ca2+ channels expressed in cardiac and vascular smooth muscles. These multiple ion channel blocking effects are largely responsible for the antiarrhythmic and vasorelaxant actions of HNS-32. This drug may represent a novel approach to the treatment of arrhythmias.

Mexiletine inhibits pharmacological actions of salbutamol through blockade of beta2-adrenoceptors in bovine tracheal smooth muscle.

We examined the effects of mexiletine, a class Ib antiarrhythmic drug, on the changes in tension and adenosine 3',5'-cyclic monophosphate (cAMP) content induced by salbutamol and forskolin in bovine tracheal smooth muscle. Salbutamol (0.0001-1 microM) produced concentration-dependent relaxation in bovine tracheal smooth muscle contracted with methacholine (0.3 microM). Mexiletine (5-500 microM) caused the rightward shifts of concentration-response curves for the relaxant responses to salbutamol in a concentration-dependent manner. Mexiletine (5, 50 or 500 microM) did not change basal cAMP levels, whereas it concentration-dependently attenuated the salbutamol (0.1 microM)-induced cAMP accumulation. On the other hand, mexiletine (500 microM) did not change the concentration-response curves for the relaxant responses to forskolin (0.001-10 microM). Mexiletine slightly but significantly (P<0.05) increased forskolin (1 microM)-induced cAMP accumulation. In radioligand binding experiments, mexiletine concentration-dependently displaced the specific binding of [125I]cyanopindolol to beta-adrenoceptors on bovine tracheal smooth muscle membranes. By contrast, lidocaine, another class Ib antiarrhythmic drug, did not change the binding of [125I]cyanopindolol. These results demonstrate that mexiletine prevents the binding of beta2-adrenoceptor agonists to their receptors and thereby suppresses manifestation of subsequent pharmacological responses.