Blockade Of Cardiac Sodium Channels Research Articles

This Month in Anesthesiology

This Month in Anesthesiology

Local Anesthetic Cardiac Toxicity Is Mediated by Cardiomyocyte Calcium Dynamics.

Long-lasting local anesthetic use for perioperative pain control is limited by possible cardiotoxicity (e.g., arrhythmias and contractile depression), potentially leading to cardiac arrest. Off-target cardiac sodium channel blockade is considered the canonical mechanism behind cardiotoxicity; however, it does not fully explain the observed toxicity variability between anesthetics. The authors hypothesize that more cardiotoxic anesthetics (e.g., bupivacaine) differentially perturb other important cardiomyocyte functions (e.g., calcium dynamics), which may be exploited to mitigate drug toxicity. The authors investigated the effects of clinically relevant concentrations of racemic bupivacaine, levobupivacaine, or ropivacaine on human stem cell-derived cardiomyocyte tissue function. Contractility, rhythm, electromechanical coupling, field potential profile, and intracellular calcium dynamics were quantified using multielectrode arrays and optical imaging. Calcium flux differences between bupivacaine and ropivacaine were probed with pharmacologic calcium supplementation or blockade. In vitro findings were correlated in vivo using an anesthetic cardiotoxicity rat model (females; n = 5 per group). Bupivacaine more severely dysregulated calcium dynamics than ropivacaine in vitro (e.g., contraction calcium amplitude to 52 ± 11% and calcium-mediated repolarization duration to 122 ± 7% of ropivacaine effects, model estimate ± standard error). Calcium supplementation improved tissue contractility and restored normal beating rhythm (to 101 ± 6%, and 101 ± 26% of control, respectively) for bupivacaine-treated tissues, but not ropivacaine (e.g., contractility at 80 ± 6% of control). Similarly, calcium pretreatment mitigated anesthetic-induced arrhythmias and cardiac depression in rats, improving animal survival for bupivacaine by 8.3 ± 2.4 min, but exacerbating ropivacaine adverse effects (reduced survival by 13.8 ± 3.4 min and time to first arrhythmia by 12.0 ± 2.9 min). Calcium channel blocker nifedipine coadministration with bupivacaine, but not ropivacaine, exacerbated cardiotoxicity, supporting the role of calcium flux in differentiating toxicity. Our data illustrate differences in calcium dynamics between anesthetics and how calcium may mitigate bupivacaine cardiotoxicity. Moreover, our findings suggest that bupivacaine cardiotoxicity risk may be higher than for ropivacaine in a calcium deficiency context.

Lipid Emulsion for Treating Local Anesthetic Systemic Toxicity.

Lipid emulsion has been shown to be an effective treatment for systemic toxicity induced by local anesthetics, which is reflected in case reports. A systemic review and meta-analysis confirm the efficacy of this treatment. Investigators have suggested mechanisms associated with the lipid emulsion-mediated recovery of cardiovascular collapse caused by local anesthetic systemic toxicity; these mechanisms include lipid sink, a widely accepted theory in which highly soluble local anesthetics (particularly bupivacaine) are absorbed into the lipid phase of plasma from tissues (e.g., the heart) affected by local-anesthetic-induced toxicity; enhanced redistribution (lipid shuttle); fatty acid supply; reversal of mitochondrial dysfunction; inotropic effects; glycogen synthase kinase-3β phosphorylation associated with inhibition of the mitochondrial permeability transition pore opening; inhibition of nitric oxide release; and reversal of cardiac sodium channel blockade. The current review includes the following: 1) an introduction, 2) a list of the proposed mechanisms, 3) a discussion of the best lipid emulsion treatment for reversal of local anesthetic toxicity, 4) a description of the effect of epinephrine on lipid emulsion-mediated resuscitation, 5) a description of the recommended lipid emulsion treatment, and 6) a conclusion.

A Literature Review of the Use of Sodium Bicarbonate for the Treatment of QRS Widening.

Sodium bicarbonate is a well-known antidote for tricyclic antidepressant (TCA) poisoning. It has been used for over half a century to treat toxin-induced sodium channel blockade as evidenced by QRS widening on the electrocardiogram (ECG). The purpose of this review is to describe the literature regarding electrophysiological mechanisms and clinical use of this antidote after poisoning by tricyclic antidepressants and other agents. This article will also address the literature supporting an increased serum sodium concentration, alkalemia, or the combination of both as the responsible mechanism(s) for sodium bicarbonate's antidotal properties. While sodium bicarbonate has been used as a treatment for cardiac sodium channel blockade for multiple other agents including citalopram, cocaine, flecainide, diphenhydramine, propoxyphene, and lamotrigine, it has uncertain efficacy with bupropion, propranolol, and taxine-containing plants.

Cardiac sodium channel blockade after an intentional ingestion of lacosamide, cyclobenzaprine, and levetiracetam: Case report

Context. Lacosamide treats partial seizures by enhancing slow inactivation of voltage-gated sodium channels. The described cardiac toxicity of lacosamide in the literature to date includes atrioventricular blockade (PR prolongation), atrial flutter, atrial fibrillation, sinus pauses, ventricular tachycardia and a single cardiac arrest. We report a second case of cardiac arrest following an intentional lacosamide overdose. Case details. A 16 year-old female with a seizure disorder was found unresponsive in pulseless ventricular tachycardia after intentionally ingesting 4.5 g (76 mg/kg) lacosamide, 120 mg (2 mg/kg) cyclobenzaprine and an unknown amount of levetiracetam. Exact time of ingestion was unknown. Her initial electrocardiogram (ECG) demonstrated sinus tachycardia at 139 beats per minute, QRS duration 112 ms, and terminal R-wave in lead aVR > 3 mm. Despite treatment with 150 mEq of sodium bicarbonate, she had persistent EKG findings eight hours after presentation. Her serum lacosamide concentration nine hours after presentation was elevated at 22.8 μg/mL, while serum cyclobenzaprine concentration was 16 ng/mL (therapeutic: 10–30 ng/mL), and serum levetiracetam concentration was 22.7 μg/mL (therapeutic: 12–46 μg/mL). On hospital day three, ECG demonstrated resolution of the terminal R-wave with QRS of 78 ms. The patient recovered without physical or neurologic sequelae. Discussion. The patient's lacosamide, cyclobenzaprine and levetiracetam overdose was associated with QRS prolongation and terminal right axis deviation – suggesting sodium channel blockade as a likely etiology for her cardiac arrest. Cyclobenzaprine has potential for sodium channel blockade and ventricular dysrhthmias although cardiac toxicity due to cyclobenzaprine alone is rare. The combination of cyclobenzaprine with lacosamide may have resulted in cardiovascular collapse. In conclusion, overdose of lacosamide combined with therapeutic concentrations of sodium channel blocking xenobiotics may cause cardiac conduction delays and cardiac arrest.

Cardiotoxicity in a Citalopram and Olanzapine Overdose

BackgroundThis is a case of a citalopram and olanzapine overdose causing seizures and severe cardiotoxicity. Case ReportA 21-year-old man presented unresponsive, with seizures, to an Emergency Department. The patient’s initial electrocardiogram demonstrated a widened QRS of 160 ms and a normal QT/QTc interval of 400/487 ms consistent with cardiac sodium channel blockade. Within 30 min of arrival, peak citalopram and olanzapine levels were measured to be 522 ng/mL and 505 ng/mL, respectively. Measured levels remained supratherapeutic until 13.6 h and 42.6 h after arrival for citalopram and olanzapine, respectively. The patient developed bradycardia and hypotension that required multimodal therapies including sodium bicarbonate boluses, vasopressors, and transvenous pacing. Seizures and cardiotoxicity continued while citalopram, but not olanzapine, was supratherapeutic. ConclusionsThis case describes cardiotoxicity directly correlated with supratherapeutic citalopram levels in overdose.

Brugada Electrocardiographic Pattern Induced by Amitriptyline Overdose

Tricyclic antidepressants (TCAs) remain a common cause of fatal drug poisoning as a result of their cardiovascular toxicity manifested by electrocardiographic abnormalities, arrhythmias, and hypotension. The principal mechanism of toxicity is cardiac sodium channel blockade. Brugada electrocardiographic pattern (BEP) has also been described in TCA overdose. Currently, very little is known about the relationship between the Brugada syndrome and TCAs. We report the case of a patient who presented with BEP after intake of a high dose of amitriptyline. The patient was treated with continuous sodium bicarbonate infusion leading to resolution of BEP.

Tricyclic Antidepressant Poisoning

Tricyclic antidepressants remain a common cause of fatal drug poisoning as a result of their cardiovascular toxicity manifested by ECG abnormalities, arrhythmias and hypotension. Dosulepin and amitriptyline appear to be particularly toxic in overdose. The principal mechanism of toxicity is cardiac sodium channel blockade, which increases the duration of the cardiac action potential and refractory period and delays atrioventricular conduction. Electrocardiographic changes include prolongation of the PR, QRS and QT intervals, nonspecific ST segment and T wave changes, atrioventricular block, right axis deviation of the terminal 40 ms vector of the QRS complex in the frontal plane (T 40 ms axis) and the Brugada pattern (downsloping ST segment elevation in leads V1-V3 in association with right bundle branch block). Maximal changes in the QRS duration and the T 40 ms axis are usually present within 12 hours of ingestion but may take up to a week to resolve. Sinus tachycardia is the most common arrhythmia due to anticholinergic activity and inhibition of norepinephrine uptake by tricyclic antidepressants but bradyarrhythmias (due to atrioventricular block) and tachyarrhythmias (supraventricular and ventricular) may occur. Torsade de pointes occurs uncommonly. Hypotension results from a combination of reduced myocardial contractility and reduced systemic vascular resistance due to alpha-adrenergic blockade. Life-threatening arrhythmias and death due to tricyclic antidepressant poisoning usually occurs within 24 hours of ingestion. Rapid deterioration is common. Level of consciousness at presentation is the most sensitive clinical predictor of serious complications. Although a QRS duration >100 ms and a rightward T 40 ms axis appear to be better predictors of cardiovascular toxicity than the plasma tricyclic drug concentration, they have at best moderate sensitivity and specificity for predicting complications.

Characterisation of recombinant HERG K + channel blockade by the Class Ia antiarrhythmic drug procainamide

Class Ia antiarrhythmic drugs, including procainamide (PROC), are associated with cardiac sodium channel blockade, delayed ventricular repolarisation and with a risk of ventricular pro-arrhythmia. The HERG K + channel is frequently linked to drug-induced pro-arrhythmia. Therefore, in this study, interactions between PROC and HERG K + channels were investigated, with particular reference to potency and mechanism of drug action. Whole-cell patch-clamp recordings of HERG current ( I HERG) were made at 37 °C from human embryonic kidney (HEK 293) cells stably expressing the HERG channel. Following activating pulses to +20 mV, I HERG tails were inhibited by PROC with an IC 50 value of ∼139 μM. I HERG blockade was found to be both time- and voltage-dependent, demonstrating contingency upon HERG channel gating. However, I HERG inhibition by PROC was relieved by depolarisation to a highly positive membrane potential (+80 mV) that favoured HERG channel inactivation. These data suggest that PROC inhibits the HERG K + channel by a primarily ‘open’ or ‘activated’ channel state blocking mechanism and that avidity of drug-binding is decreased by extensive I HERG inactivation. The potency of I HERG blockade by PROC is much lower than for other Class Ia agents that have been studied previously under analogous conditions (quinidine and disopyramide), although the blocking mechanism appears similar. Thus, differences between the chemical structure of PROC and other Class Ia antiarrhythmic drugs may help provide insight into chemical determinants of blocking potency for agents that bind to open/activated HERG channels.

Does lidocaine protect the heart during coronary revascularisation?

Lidocaine has been used as the primary antiarrhythmic agent for ventricular arrhythmias during acute myocardial infarction (MI) and open heart surgery. Its cardioprotective effects have been studied in experimental settings and also during angioplastic reperfusion and coronary revascularisation. The basic mechanism of action, probably also involved with cardioprotection, has been demonstrated to be blockade of cardiac sodium channels. In this open study we investigated the contribution of continuous lidocaine infusion to cardioprotection during coronary revascularisation with blood cardioplegia. During coronary revascularisation with cold blood cardioplegia, a study group of 50 patients received a prophylactic lidocaine infusion for 20 h started with a bolus dose before aortic clamping; another group of 50 patients without the infusion served as a control group. Serum troponin T concentration, serum creatine kinase MB activity and electrocardiography were the main parameters recorded. Serial measurement of Troponin T (P = 0.06) and CK-MB values: (P = 0.09) were slightly lower in the lidocaine group, but the differences were not statistically significant. Lacking statistically significant evidence of improved cardioprotection, lidocaine infusion cannot be recommended as a routine treatment during coronary revascularisation.

AN-132 block of cardiac sodium channels: a gate-related receptor analysis.

Based on the gate-related receptor hypothesis, an analysis of kinetics of AN-132, a new antiarrhythmic agent, blockade of cardiac sodium channels and the gate-related receptor which is bound by the drug was performed by computer simulation. Model-predicted apparent rates of onset of AN-132 (30 mumol/L) blocking were 0.051, 0.038, and 0.034 AP-1 at stimulation frequencies of 1.0, 2.0 and 3.0 Hz, respectively. The time constant of recovery from block by AN-132 at resting potential -90 mV was 39.5 s. These findings are in agreement with those experimental data documented. The analysis of gate-related receptor shows that AN-132 binds the inactivation gate-related receptor, and the binding and unbinding are modulated by the inactivation process.

Mechanisms of action of sodium channel blocker: gate-related receptor hypothesis.

A new hypothesis on mechanisms of action of the sodium channel blocker, the gate-related receptor hypothesis, has been proposed in this paper. Furthermore, a mathematic model and parameter estimation procedure for the kinetics analysis have also been given. Using the model and procedure, modeling and analyzing of cardiac sodium channel blockade by lidocaine and dauricine have been performed. The model-estimated results were not only coincident with those documented, but also provided some new information which may be helpful for understanding mechanism of blocking action of both drugs on sodium channels. The studies suggested that the gate-related receptor hypothesis is good for the elucidation of mechanisms of action of the sodium channel blocker.

Blockade of cardiac sodium channels. Competition between the permeant ion and antiarrhythmic drugs.

A number of basic and clinical studies suggest that elevation of external sodium concentrations, [Na]o, may reverse the cardiotoxic effect of local anesthetic-class drugs. The mechanisms of reversal are uncertain. The blocking action of lidocaine and disopyramide were studied over a range of [Na]o. Both whole-cell voltage clamp and single-channel recordings were performed on isolated rabbit myocytes at 17 and 22 degrees C, respectively. In the presence of lidocaine, an inactivated channel blocker, the level of steady-state block in response to pulse train stimulation was not affected by variations in [Na]o from 20 to 150 mM. Estimates of the rate of dissociation of drug from the channel also were unaffected. In contrast, steady-state block by disopyramide, a drug that blocks open channels, was decreased as [Na]o was increased. Single-channel measurements suggest that the influence of [Na]o on channel current amplitude was small, 12% for a 25 mM increase in [Na]o. This increase in single-channel current amplitude would affect drug-free channels only, in that our studies suggest that drug-associated channels do not conduct. The association rate constant of disopyramide with open single sodium channels was decreased from 10 x 10(6) to 5 x 10(6)/M per s by an increase in [Na]o from 120 to 180 mM. Elevation of [Na]o may reverse the blocking action of local anesthetic-class drugs by an increase in single-channel current amplitude or by a decrease in drug association rate with the sodium channel. The occurrence of the latter action depends on the mode of block of the specific agent.

Computer simulation of metoclopramide block of cardiac sodium channels.

Based on the gate-related receptor hypothesis, a quantitative study on kinetics and state-dependency of metoclopramide (Met) blockade of cardiac sodium channels was performed by computer simulation. The characteristics of Met, a sodium channel blocker modulated simultaneously by both activation and inactivation gates were described and analyzed for the first time. The time constant of recovery from blocking for Met at resting potential -85 mV was 2.82 s, which was increased during depolarization or hyperpolarization. Its apparent rate of onset of blocking was 0.49 AP-1 at a stimulation frequency of 2.0 Hz. A concentration-dependent shift of h infinity curve was found at doses higher than 100 mumol/L Met. This study provides a new test and verification for our gate-related receptor hypothesis.

Blockade of cardiac sodium channels by lidocaine. Single-channel analysis.

The mechanism of interaction of lidocaine with cardiac sodium channels during use-dependent block is not well defined. We examined the blockade of single cardiac sodium channels by lidocaine and its hydrophobic derivative RAD-242 in rabbit ventricular myocytes. Experiments were performed in cell-attached and inside-out patches. Use-dependent block was assessed with trains of ten 200-msec pulses with interpulse intervals of 500 msec and test potentials of -60 to -40 mV. Single-channel kinetics sometimes showed time-dependent change in the absence of drug. During exposure to 80 microM lidocaine, use-dependent block during the trains was associated with a decrease in the average number of openings per step. At -60 mV, mean open time was not significantly changed (control, 1.4 +/- 0.6 msec; lidocaine, 1.2 +/- 0.3 msec, p greater than 0.05). Greater block developed during trains of 200-msec pulses compared with trains of 20-msec pulses at the same interpulse interval at test potentials during which openings were uncommon later than 20 msec (-50 and -40 mV). Prolonged bursts of channels showing slow-gating kinetics were observed both in control and the presence of 80 microM lidocaine. However, lidocaine may decrease the late sodium current by altering the kinetics of slow gating. The hydrophobic lidocaine derivative RAD-242, which has a 10-fold greater lipid solubility than lidocaine, decreased the peak averaged current during pulse train stimulation by 60% without a change in the mean open time. Our results suggest that the major effect of lidocaine during use-dependent block involves the interaction with a nonconducting state of the sodium channel followed by a failure to open during subsequent depolarization.

Interaction of lidocaine and benzocaine in depressing V̇max of ventricular action potentials

This paper reports the interactions between lidocaine and benzocaine with cardiac sodium channels. The magnitude of the maximum upstroke velocity (Vmax) of the guinea-pig papillary muscle action potential was taken as an indirect measurement of the sodium current. The hypothesis that both the charged and neutral forms of local anaesthetics share a common receptor was tested. In preparations stimulated at a frequency of 0.1 Hz, a mixture of equieffective concentrations of benzocaine and lidocaine produced a decrease in Vmax similar to that obtained with each of the drugs alone. Therefore, the tonic blockade produced with this mixture of anaesthetics was comparable with the theoretical values predicted by equilibrium binding equations, which is indicative of a common receptor for both drugs. Although benzocaine did not produce frequency-dependent effects, it did attenuate those produced by lidocaine when both anaesthetics were applied. During repeated action potentials, using short diastolic intervals, the frequency-dependent effects of lidocaine were due to the accumulation of blocked sodium channels. The binding of lidocaine to both open and inactivated channels during a conditioning action potential was determined by the zero-time intercept of the slow component of the recovery of Vmax induced by the drug. Under these conditions, benzocaine decreased the fraction of channels blocked by lidocaine. Hence, the parallel shift produced by benzocaine on the dose-response (fraction of blocked Vmax) curves of lidocaine, strongly suggests that both drugs competed for the same receptor site. Furthermore, this receptor, mediating the blockade of cardiac sodium channels, seems to be responsible for both the tonic and frequency-dependent effect of lidocaine on the heart.