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Management of Sodium-Channel Blocker Poisoning: the Role of Hypertonic Sodium Salts

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Management of Sodium-Channel Blocker Poisoning: the Role of Hypertonic Sodium Salts European Review for Medical and Pharmacological Sciences 2010; 14: 25-30 Management of sodium-channel blocker poisoning: the role of hypertonic sodium salts A. DI GRANDE, C. GIUFFRIDA*, G. NARBONE, C. LE MOLI, F. NIGRO, A. DI MAURO, G. PIRRONE, V. TABITA, B. ALONGI U.O.C. di Medicina e Chirurgia d’Accettazione e d’Urgenza, Az. Osp. S. Elia, Caltanissetta (Italy) *U.O.C. di Medicina e Chirurgia d’Accettazione e d’Urgenza, Az. Osp. Piemonte, Messina (Italy) Abstract. – Sodium-channel blockers act Sodium salts increase serum pH and extracel- by slowing sodium influx into myocytes through lular concentration of the ion with displacement voltage gated channels. Many substances have sodium-channel block- of the drug from its receptor sites, and can be ad- 4 ing properties and many others show this effect ministered as therapeutic agents . when taken in overdose. Despite this theoretical assumption, conflict- Sodium-channel blocker poisoning, associat- ing results have been presented and optimal treat- ed with a high death rate, is characterized by a ment has not been established. variety of clinical presentation, depending on the The aim of this paper is to analyze the electro- pharmaceutical agent involved. physiological bases of sodium-channel blocker Sodium bicarbonate or lactate, increasing serum pH and extracellular concentration of the poisoning and the evidences in regard to the ther- ion, displace the drug from its receptor sites and apeutic use of hypertonic sodium salts in the can be used for the treatment of cardiac toxicity in treatment of the myocardial toxicity. the setting of sodium-channel blocker poisoning. In spite of this theoretical assumption, the role played by hypertonic sodium salts is not well elucidated and conflicting results have been reported. Electrophysiology Authors review the pathophysiologic mecha- nisms of sodium-channel blocker poisoning and Ionic movement across the cell membrane cre- the evidences in literature concerning the effica- ates the cardiac action potential. The membrane cy of hypertonic sodium salts in the treatment of is not permeable to the ions and in the different the related toxicity. phases of the action potential are involved specif- Key Words: ic voltage gated channels that control inward and outward currents5. Sodium channel blockers, Poisoning, Sodium bicar- The function of the voltage-gated sodium chan- bonate, Sodium lactate, Class IC drugs, Tricyclic anti- nels was fully elucidated by Hodgkin and Katz6 in depressant. 1949, in a classic study performed on the great ax- on of the squid. In the heart, they play a role in the depolarization of sodium-dependent myocardial cells (atria, ventricles and His-Purkinje fibers) that Introduction occurs with a conformational change (activated state), rapid opening of the channel and the subse- Sodium-channel poisoning is a potentially life- quent massive sodium influx (phase 0). threatening condition characterized by a variety This state is followed by other two additional of clinical presentation depending on the phar- changes in the conformation of the channel that maceutical agent involved1,2. becomes first inactivated (inactivated state), and Many substances have sodium-channel block- then capable of activating again (resting state)5. ing properties, but tricyclic antidepressants and Unlike sodium-dependent myocardial cells, Vaughan Williams class IC antiarrhythmic agents very little Na+ influx occurs instead during the remain the most common causes of sodium- phase 0 of calcium-dependent cells, such as channel blocker poisoning3. sinoatrial and atrioventricular nodes. Corresponding Author: Aulo Di Grande, MD; e-mail: [email protected] 25 A. Di Grande, C. Giuffrida, G. Narbone, C. Le Moli, F. Nigro, et al. Heart rate modulates the conformational In contrast, class IC antiarrhythmic drugs and changes, increasing tachycardia the number of other agents devoid of these properties are far channels in active and inactive states per unit more likely cause of bradyarrhythmias, such as time1. junctional or ventricular escape and eventual Sodium-channel blockers bind to the trans- asystole12,13. membrane channels and reduce the number avail- As mentioned above, tachyarrhythmias, pre- able for the depolarization, with a delay of the venting complete repolarization, increase the phase 0 and a slowing in the conduction of atria, number of channels in active and inactive states ventricles and His-Purkinje fibers: this effect has per unit time, with a decline in the Vmax (upslope been described as quinidine-like effect, in refer- of phase 0 of a myocardial cell). ence to the antiarrhythmic drug7,8. This phenomena is further enhanced in the face In calcium-dependent cells, a slowed depolar- of sodium-channel blockade because more bind- ization during phase 4 is the main electrophysio- ing sites are offered to the drug, as reflected in an logical effect1,9. increase of QRS lengthening at faster heart rates7. The reduction of intracellular sodium concen- The structural similarity between Na+ and K+ tration due to the blockade of sodium channels channels can explain the prolonged repolariza- results in a decrease of sodium-calcium exchange tion observed with some sodium-channel block- and a fall in intracellular calcium, effect that ex- ers (i.e. tricyclic antidepressants, IA antiarrhyt- plains the potential decrease in myocardial con- mic drugs, phenothiazines). tractility. The lengthening of QT interval, due to an im- At high doses, some sodium channel blockers pairment of outward K+ currents, is a potential (i.e. lidocaine, quinidine) block calcium channels trigger for the occurrence of torsades de pointes, directly. uncommon in poisoning with agents having anti- colinergic properties for the protective role played by the increase in heart rate14-16. A rightward axis shift in the terminal 40 ms of Electrocardiographic the QRS axis is a sensitive (83%) and specific Manifestations of Sodium-Channel (63%) marker for tricyclic toxicity. Blockers Poisoning This alteration is detected as a negative de- flection of the final portion of QRS complex on The principal alteration on the electrocardio- lead I [a deep S wave] and a positive deflection gram is a QRS complex widening; rarely, the of the terminal portion of lead aVr (a large R QRS complexes may take the pattern of bundle wave)17. branch blocks10. In severe poisonings, the QRS widening be- comes so profound that a differential diagnosis between supraventricular and ventricular rhythms Clinical Features of Sodium-Channel can be impossible. Blocker Poisoning A slowing of the intraventricular conduction and a unidirectional conduction block create the Sodium-channel blocker poisoning is not char- development of a re-entrant circuit, with possible acterized by a specific symptomatology. onset of ventricular tachycardia that can degener- Anticholinergic properties produce agitation, ate into ventricular fibrillation11. respiratory depression, tachycardia, mydriasis, Sinus bradycardia results from the slowing in anhydrosis, depressed gastrointestinal motility the depolarization of sinoatrial node, but with and urinary retention. sodium-channel blocker agents having anti- At high concentration most sodium-channel cholinergic and/or adrenergic effects (i.e. tri- blockers show proconvulsant activity due to a va- cyclic antidepressants), sinus tachycardia is very riety of mechanisms: inhibition of the GABA common. system (i.e. lidocaine), activation of a sodium In these cases, when bradycardia occurs, it ouabain-sensitive current (i.e. enaminones), stim- is an indication that Na+ channels blockade is ulation of 5-TH2C receptors (i.e. cocaine, so profound that the increase in heart rate in mepryicaine, tricyclic antidepressants), H1 re- response to muscarinic antagonism is not pos- ceptors antagonism and neuronal noradrenaline sible1. activating effect [i.e. imipramine)18-21. 26 Management of sodium-channel blocker poisoning: the role of hypertonic sodium salts Hypertension, tachycardia and diaphoresis, ef- Molecular Mechanism fects of adrenergic stimulation, characterize co- Molecular mechanism by which hypertonic caine intoxication22. sodium salts reverse Na+ channel blockade is not Myocardial depression, often associated with clear and can include changes in diastolic poten- vasodilation (i.e. quinidine, tricyclic antidepres- tial, in action potential duration (APD), in ion- sants, phenothiazines), results in severe hypoten- ized Ca++ and in the direct interaction between sion. drug and receptor26. Block of K+ efflux (i.e. chloroquine, quinine, First evidences emphasized the role of alkalin- disopyramide) produces hypoglycaemia by in- ization, that decreases the free concentration of sulin release23,24. the drug, but following studies demonstrated that Severe poisonings, apart from the substance the effect is independent of protein binding27,28. involved, are characterized by coma and pro- The dissociation of the blocking agent from found respiratory depression. the channel could be related to the rise in Na+ concentration [mass effect], and this would ex- plain the assumed benefits of hypertonic saline solution reported in literature29-31. Hypertonic Sodium Salts in Electrostatic repulsion has been postulated to the Management of Sodium-Channel explain the reduction in Na+ channel drug-block- + Blockers Poisoning ing action when (Na )0 is increased, and changes + in the magnitude of INa as result of altered (Na )0 Hypertonic sodium salts, bicarbonate or lac- have been thought to be important26.
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