Rate Dependence of Antiarrhythmic and Proarrhythmic Properties of Class I and Class III Antiarrhythmic Drugs

Weirich, J.

doi:10.1007/978-3-642-60851-3_5

Cited by 13 publications

(18 citation statements)

References 26 publications

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“…Under normal physiological conditions, the binding sites of lidocaine on the cardiomyocytes are not continuously available 7. Inhibition of sodium channels by lidocaine increases during systole when the drug-binding sites are available, and decreases during diastole 21.…”

Section: Discussionmentioning

confidence: 99%

Anticonvulsant treatment of asphyxiated newborns under hypothermia with lidocaine: efficacy, safety and dosing

Broek

Rademaker

Straaten

et al. 2013

Arch Dis Child Fetal Neonatal Ed

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Section: Discussionmentioning

confidence: 99%

Anticonvulsant treatment of asphyxiated newborns under hypothermia with lidocaine: efficacy, safety and dosing

Broek

Rademaker

Straaten

et al. 2013

Arch Dis Child Fetal Neonatal Ed

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“…Channels mediating I Kr are formed by proteins encoded by hERG ( human Ether-à-go-go Related Gene; alternative nomenclature KCNH2 [3], [4]). Native I Kr and hERG channels exhibit sensitivity to pharmacological blockade by diverse drugs, including both Class Ia and Class III antiarrhythmic agents; excessive pharmacological inhibition of I Kr /hERG leads to acquired long QT syndrome (LQTS [5]–[8]). Loss-of-function KCNH2 mutations are responsible for the LQT2 form of heritable long QT syndrome [9], [10], whilst gain-of-function mutations are responsible for the SQT1 form of heritable Short QT syndrome (SQTS [11], [12]).…”

Section: Introductionmentioning

confidence: 99%

Action Potential Clamp and Pharmacology of the Variant 1 Short QT Syndrome T618I hERG K+ Channel

et al. 2012

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BackgroundThe familial Short QT Syndrome (SQTS) is associated with an increased risk of cardiac arrhythmia and sudden death. Gain-of-function mutations in the hERG K+ channel protein have been linked to variant 1 of the SQTS. A hERG channel pore (T618I) mutation has recently been identified in families with heritable SQTS. This study aimed to determine effects of the T618I-hERG mutation on (i) hERG current (IhERG) elicited by ventricular action potentials; (ii) the sensitivity of IhERG to inhibition by four clinically used antiarrhythmic drugs.MethodsElectrophysiological recordings of IhERG were made at 37°C from HEK 293 cells expressing wild-type (WT) or T618I hERG. Whole-cell patch clamp recording was performed using both conventional voltage clamp and ventricular action potential (AP) clamp methods.ResultsUnder conventional voltage-clamp, WT IhERG peaked at 0-+10 mV, whilst for T618I IhERG maximal current was right-ward shifted to ∼ +40 mV. Voltage-dependent activation and inactivation of T618I IhERG were positively shifted (respectively by +15 and ∼ +25 mV) compared to WT IhERG. The IhERG ‘window’ was increased for T618I compared to WT hERG. Under ventricular AP clamp, maximal repolarising WT IhERG occurred at ∼ -30 mV, whilst for T618I hERG peak IhERG occurred earlier during AP repolarisation, at ∼ +5 mV. Under conventional voltage clamp, half-maximal inhibitory concentrations (IC50) for inhibition of IhERG tails by quinidine, disopyramide, D-sotalol and flecainide for T618I hERG ranged between 1.4 and 3.2 fold that for WT hERG. Under action potential voltage clamp, T618I IC50s ranged from 1.2 to 2.0 fold the corresponding IC50 values for WT hERG.ConclusionsThe T618I mutation produces a more modest effect on repolarising IhERG than reported previously for the N588K-hERG variant 1 SQTS mutation. All drugs studied here appear substantially to retain their ability to inhibit IhERG in the setting of the SQTS-linked T618I mutation.

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“…D-sotalol had similar prolonging effects on the action potentials of rabbit ventricular myocytes driven at 0.2 to 1 Hz and a slightly reduced effect at 2 Hz [23]. In vivo studies on anaesthetised dog hearts and in vitro studies with guinea-pig cardiomyocytes showed no reverse use dependency with D-sotalol over a wide range of frequency, 0.5 -3.5 Hz [24]. On the ferret ventricle, D-sotalol had similar prolonging effects on action potentials at 2 and 4 Hz and on the atria, slightly lesser effects at 4 Hz than at 2 Hz [11].…”

Section: Use and Reverse Use Dependencymentioning

confidence: 56%

“…A high concentration of D-sotalol (5 x 10 -5 M) showed reverse use dependence on guinea-pig ventricular myocardium [24]. Even if reverse use dependence is observed with D-sotalol, the slow offset kinetics of D-sotalol may preserve the anti-arrhythmic action for some time during a sudden increase in heart rate [24].…”

Section: Use and Reverse Use Dependencymentioning

confidence: 96%

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D-Sotalol: death by the SWORD or deserving of further consideration for clinical use?

Doggrell¹,

Brown²

2000

Expert Opinion on Investigational Drugs

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D-Sotalol is the dextro-rotatory isomer of sotalol and a class III anti-arrhythmic. D-Sotalol prolongs cardiac repolarisation by inhibiting the fast component of the delayed outward rectifying potassium channel. In animal studies, D-sotalol has been shown to be more effective in prolonging atrial, rather than ventricular, action potentials, suggesting that D-sotalol may be more effective against supra-ventricular than ventricular arrhythmias. Furthermore, in animal studies, D-sotalol induces after-depolarisations, which are predictors of pro-arrhythmic activity. D-Sotalol shows little or no reverse use dependence in animal and humans and has slow offset kinetics. This suggests that, in addition to being a preventative treatment for arrhythmias, D-sotalol may be effective at the start or during arrhythmia. As D-sotalol does not block the slow component of the delayed outward rectifying potassium channel, which is activated by the sympathetic nervous system, D-sotalol will not protect against sympathetic hyperactivity. D-Sotalol also has no effect on the K(ATP) channel, which is activated in ischaemia to shorten the action potential. Thus D-sotalol is less effective in ischaemia. Anti-arrhythmic activity with D-sotalol has been demonstrated in dog models of ventricular tachycardia and sudden death. Arrhythmias with D-sotalol have been demonstrated in an ischaemic guinea-pig ventricle model in the absence of action potentials. D-Sotalol is a weak beta-adrenoceptor antagonist and may also be a positive inotrope. In humans, D-sotalol has 100% systemic oral bioavailability, a terminal half-life of 7.2 h and is mainly excreted unchanged in the urine. Preliminary, mainly hospital-based, clinical trials showed that D-sotalol was effective in a variety of supraventricular and ventricular arrhythmias. However, a large clinical trial of D-sotalol as a preventative treatment for arrhythmias and sudden death after myocardial infarction, the SWORD trial, was terminated early because of increased mortality with D-sotalol. The group at greatest risk was those with a remote myocardial infarction and relatively good left ventricular function, the group that showed the lowest mortality when untreated. It is assumed that excessive prolongation of the action potential leading to pro-arrhythmia with D-sotalol, underlies the increased risk of death. However, there is little objective evidence in the SWORD trial to support this. Obviously D-sotalol should not be used in humans with a remote myocardial infarction and relatively good left ventricular function. D-Sotalol could still be considered for short-term hospital use in resistant arrhythmias and for longer-term use to prevent atrial fibrillation in those with remote myocardial infarction and poor left ventricular function.

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Rate Dependence of Antiarrhythmic and Proarrhythmic Properties of Class I and Class III Antiarrhythmic Drugs

Cited by 13 publications

References 26 publications

Anticonvulsant treatment of asphyxiated newborns under hypothermia with lidocaine: efficacy, safety and dosing

Anticonvulsant treatment of asphyxiated newborns under hypothermia with lidocaine: efficacy, safety and dosing

Action Potential Clamp and Pharmacology of the Variant 1 Short QT Syndrome T618I hERG K+ Channel

D-Sotalol: death by the SWORD or deserving of further consideration for clinical use?

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