Carbamazepine Increases the Risk of Sudden Cardiac Arrest by a Reduction of the Cardiac Sodium Current

Abstract

Aim: To assess the risk of sudden cardiac arrest (SCA) associated with the use of carbamazepine (CBZ) and establish the possible underlying cellular electrophysiological mechanisms.Methods: The SCA risk association with CBZ was studied in general population cohorts using a case–control design (n = 5,473 SCA cases, 21,866 non-SCA controls). Effects of 1–100 µM CBZ on action potentials (APs) and individual membrane currents were determined in isolated rabbit and human cardiomyocytes using the patch clamp technique.Results: CBZ use was associated with increased risk of SCA compared with no use (adjusted odds ratio 1.90 [95% confidence interval: 1.12–3.24]). CBZ reduced the AP upstroke velocity of rabbit and human cardiomyocytes, without prominent changes in other AP parameters. The reduction occurred at ≥30 µM and was frequency-dependent with a more pronounced reduction at high stimulus frequencies. The cardiac sodium current (INa) was reduced at ≥30 μM; this was accompanied by a hyperpolarizing shift in the voltage-dependency of inactivation. The recovery from inactivation was slower, which is consistent with the more pronounced AP upstroke velocity reduction at high stimulus frequencies. The main cardiac K+ and Ca2+ currents were unaffected, except reduction of L-type Ca2+ current by 100 µM CBZ.Conclusion: CBZ use is associated with an increased risk of SCA in the general population. At concentrations of 30 µM and above, CBZ reduces AP upstroke velocity and INa in cardiomyocytes. Since the concentration of 30 µM is well within the therapeutic range (20–40 µM), we conclude that CBZ increases the risk of SCA by a reduction of the cardiac INa.

SCN5A channelopathy: arrhythmia, cardiomyopathy, epilepsy and beyond

“…Hence, the (co-)occurrence of SCN5A mutations in these patients may have contributed to the development of cardiac arrhythmias and potentially SUDEP. However, some of these patients were also treated with anti-epileptic drugs, many of which are in fact sodium channel blockers, which may by themselves, or in co-occurrence with SCN5A variants, decrease peak sodium current and increase the risk for arrhythmias [135,136], thereby providing an additional factor underlying and/or contributing to SUDEP.…”

The Antidepressant Paroxetine Reduces the Cardiac Sodium Current

“…The concentration of 3 µM was chosen because it gave rise to a considerable amount of changes in NaV1.5 current in voltage clamp experiments on HEK-293 cells (Figures 1-3) without too extreme effects that might prevent excitability of cardiomyocytes completely. Figure 4a shows typical AP recordings Many NaV1.5 current inhibitors-including, for example, methylflavonolamine and lidocaine [36], hesperetin [37], eleclazine [38], carbamazepine [39], mexiletine [40], and aripiprazole [41]-generate a shift in steady-state inactivation to more negative potentials (as shown for paroxetine in Figure 2c,d) that is accompanied by a slowing of recovery from inactivation. Under close-to-physiological conditions, i.e., at a potential of −85 mV and 37 °C [35], recovery from inactivation of the sodium current in cardiomyocytes is not fully complete within 1 s, which explains why the maximum AP upstroke velocity at a pacing frequency of 3 Hz is smaller than at 1 Hz under control conditions (Figure 5a, gray lines; Figure 5b, gray bars).…”

The opioid tramadol blocks the cardiac sodium channel Nav1.5 in HEK293 cells

“… 7 At present, this group contains tricyclic antidepressants 19 , 20 and antiepileptic drugs. 21 We hypothesize that this group may also contain opioids and opioid agonists. Indeed, various opioids, including morphine, U-50, 488H, oxycodone, methadone, loperamide, and buprenorphine, inhibit Na v 1.5 channels and/or cardiac AP upstroke velocities.…”