Sodium Channel Blockade

TCA-induced cardiotoxicity is the single most important factor contributing to patient mortality. Life-threatening cardiotoxicity results from TCA-induced inhibition of sodium influx through voltage-dependent sodium channels. Inhibition of fast sodium channels in His-Purkinje cells leads to delayed depolarization and conduction abnormalities.4 Impaired sodium entry into myocardial tissue leads to decreased contractility. Sodium channel blockade is often referred to synonymously as membrane stabilizing, quinidine-like, or local anesthetic effect. Sodium channel blockade results in a prolongation of phase 0 of the action potential, which becomes more pronounced with rapid heart rates, hyponatremia, and acidosis. This effect expresses itself on the electrocardiograph (ECG) as prolongation of PR and QRS intervals and right-axis deviation (RAD) of the terminal 40 ms. The RAD is most pronounced in the terminal 40 ms of limb leads, as demonstrated on ECG by a terminal R wave in lead aVR and an S wave in lead I. Rapid influx of sodium is necessary for the release of intracellular calcium stores and subsequent myocardial contractility. Some of the negative chronotropic effect of sodium channel blockade can be attenuated by the sinus tachycardia secondary to antimuscarinic activity. Bradycardia is particularly worrisome when accompanied by QRS complex widening because it indicates profound sodium channel blockade. Local changes in electrical conduction can predispose to ventricular dysrhythmias by establishing reentry loops. In summary, severe sodium channel blockade culminates in depressed myocardial contractility, various types of heart blocks, RAD, hypotension, wide QRS, and cardiac ectopy.

Sodium channel blockade can be overcome in part by serum alkalinization (pH 7.50-7.55) and increasing the serum sodium concentration. In humans, intravenous sodium bicarbonate (NaHCO3) is thought to be more effective than either hyperventilation (alkalinizes blood) or sodium chloride (increases Na +) in treating TCA cardiotoxicity. One explanation for the greater effectiveness of NaHCO 3 is that it produces both blood alkalinization and increased serum sodium concentration. The mechanism by which blood alkalinization partially reverses sodium channel blockade remains unknown, but it does not appear to be related to enhancement of plasma TCA serum protein binding. It may decrease the overall inhibition to sodium ion influx. Recent animal data suggest that hypertonic saline (7.5% NaCl) may be more efficacious than sodium bicarbonate or hyperventilation in reversing TCA cardiotoxicity. 5 Whether this finding also will be applicable to humans is currently unknown. Hypertonic saline is believed to act primarily by increasing the extracellular sodium concentration gradient, thus favoring the inward movement of sodium ions.

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