Sodium channel blockade

The amide local anaesthetic lidocaine may also be used as an antianhythmic for ventricular tachycardia and exra-systoles after injection into the blood circulation. Drugs with high lipid solubility such as bupivacaine cannot be used for these purposes because their prolonged binding to the channel may induce dysrhythmias or asystolic heart failure [3]. Systemically applied lidocaine has also been used successfully in some cases of neuropathic pain syndromes [4]. Here, electrical activity in the peripheral nervous system is reduced by used-dependent but incomplete sodium channel blockade. 

The typical form of proarrhythmia caused by the type Ic antiarrhythmic drugs is a rapid, sustained, monomorphic VT with a characteristic sinusoidal QRS pattern that is often resistant to resuscitation with cardioversion or overdrive pacing. Some clinicians have had success with IV lidocaine (competes for the sodium channel receptor) or sodium bicarbonate (reverses the excessive sodium channel blockade). 

Antiarrhythmics Vaughn Williams Classification Class I Sodium Channel Blockade... 

Ma, Y., Peters, N.S. and Henry, J.A. (2006) al-Acid glycoprotein reverses cocaine-induced sodium channel blockade in cardiac myocytes. Toxicology, 220, 46-50. 

Figure 5.6 Sodium channel blockade by local anaesthetic drug, mechanism of action. L, local anaesthetic free base L+, ionised local anaesthetic ECF, extracellular fluid Memb, axonal cell membrane.

Arrhythmias are caused by abnormal pacemaker activity or abnormal impulse propagation. Thus, the aim of therapy of the arrhythmias is to reduce ectopic pacemaker activity and modify conduction or refractoriness in reentry circuits to disable circus movement. The major mechanisms currently available for accomplishing these goals are (1) sodium channel blockade, (2) blockade of sympathetic autonomic effects in the heart, (3) prolongation of the effective refractory period, and (4) calcium channel blockade. 

Class 1 action is sodium channel blockade. Subclasses of this action reflect effects on the action potential duration (APD) and the kinetics of sodium channel blockade. Drugs with class 1A action prolong the APD and dissociate from the channel with intermediate kinetics drugs with class IB action shorten the APD in some tissues of the heart and dissociate from the channel with rapid kinetics and drugs with class 1C action have minimal effects on the APD and dissociate from the channel with slow kinetics. 

Quinidine has actions similar to those of procainamide it slows the upstroke of the action potential and conduction, and prolongs the QRS duration of the ECG, by blockade of sodium channels. The drug also prolongs the action potential duration by blockade of several potassium channels. Its toxic cardiac effects include excessive QT interval prolongation and induction of torsade de pointes arrhythmia. Toxic concentrations of quinidine also produce excessive sodium channel blockade with slowed conduction throughout the heart. 

Miiller A, Dhein S Sodium channel blockade enhances dispersion of the cardiac action potential duration. A computer simulation study. Basic Res Cardiol 1993 88 11-15. 

A medium throughput approach to evaluating sodium channel activity is the measurement of sodium flux across cell membranes [103]. In these experiments, a tracer that permeates the channel and is easily quantifiable is used to analyze sodium influx. Traditionally, radioactive tracers such as 22Na+ or [14C]guanidinium have been used. Alternatively, Li+ can be used as a tracer and analyzed by atomic absorption spectrometry. Sodium flux assays can be used to test approximately 105 compounds per year. They offer a robust readout of channel activity, but lack voltage control and temporal resolution. To examine sodium channel blockade by measuring sodium flux,... 

Class I sodium channel blockade. These drugs restrict the rapid inflow of sodium during phase 0 and thus slow the maximum rate of depolarisation. Another term for this property is membrane stabilising activity it may contribute to stopping arrh5dhmias by limiting the responsiveness to excitation of cardiac cells. The class may be subclassified as follows ... 

CLASS IA (sodium channel blockade with lengthened refractoriness)... 

Priori SG, Napolitano C, Terrence L, et al. Incomplete penetrance and variable response to sodium channel blockade in Brugada s syndrome. Eur Heart J1999 20(Suppl) 465A. 

Carbamazepine Sodium channel blockade Hepatic, may induce own metabolism Dizziness, ataxia Drug-drug interactions due to ability to induce and inhibit metabolism of other drugs... 

The activity of the local anesthetics is enhanced by increased extraneuronal pH and by coadministration of a vasoconstrictor (e.g. epinephrine (adrenaline)) or hyaluronidase. Sodium channel blockade is pH dependent, increasing when the pH is alkaline, and can be reduced in disease conditions associated with acid pH (e.g. inflammation). The addition of bicarbonate (e.g. to lidocaine) speeds up the onset and prolongs the duration of action. If bicarbonate is added to... 

Carbamazepine is both an important anticonvulsant in therapeutic doses and a powerful proconvulsant in overdose. The therapeutic anticonvulsant mechanism is primarily related to blockade of presynaptic voltage-gated sodium channels. Blockade of the sodium channels is believed to inhibit the release of synaptic glutamate and possibly other neurotransmitters. Carbamazepine is also a powerful inhibitor of the muscurinic and nicotinic acetylcholine receptors, N-methyl-D-aspartate (NMDA) receptors and the central nervous system (CNS) adenosine receptors. In addition, carbamazepine is structurally related to the cyclic antidepressant impramine and in massive overdose may affect cardiac sodium channels. 

Propoxyphene is an agonist of opioid fi receptors. It is this opioid effect that is responsible for the central nervous system and respiratory depression seen in overdose. Both propoxyphene and norpropoxyphene are potent blockers of myocardial sodium channels, an effect identical to type lA antidysrhythmic agents. This myocardial sodium channel blockade may result in prolongation of the electrocardiogram QRS complex, arrhythmias, and cardiovascular depression seen in propoxyphene poisoning. 

Type I antiarrhythmics possess rate dependence i.e., sodium channel blockade and slowed conduction are greatest at fast heart rates and least during bradycardia. For slow on/off drugs, sodium channel blockade is evident at normal rates (60 to 100 beats per minute), but for fast on/off agents, slowed conduction is apparent only at rapid rates of stimnlation. 

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