Can dantrolene be used in the treatment of cardioglycosides poisonings?

The Na+/K+-ATPase pump plays an essential role in the membrane potential. This pump is electrogenic as it transports three sodium ions out of the cell for every two potassium ions entering the cell [1].

Cardiac glycosides induce an increase in intracellular sodium concentration by inhibiting Na+/K+-ATPase [2]. Therefore, cardioactive steroids can increase the intracellular sodium concentration [3]. As intracellular sodium increases, the concentration gradient, which drives sodium through the exchanger into the cell, is reduced; this decreases exchanger activity, thereby reducing the movement of calcium out of the cell and leading to an increase in intracellular calcium concentration through the effect of the Na⁺‐Ca²⁺ exchanger [2,4,5]. Within the heart, the increased intracellular calcium allows the sarcoplasmic reticulum to release more calcium [6]. In this way, additional calcium is available for binding to troponin C, which increases contractility (inotropy) [2]. Cardioglycosides can also increase vagal efferent activity to the heart through mechanisms that are not entirely understood. This parasympathomimetic behavior of digitalis reduces the firing rate of the sinoatrial node (decreases heart rate, negative chronotropy) and reduces the speed of electrical impulses through the atrioventricular node (negative dromotropy), and voltage-gated Na+ channels can be blocked [4,5,7]. Other actions, including Na+-K+-ATPase endocytosis and activation of intracellular signal transduction mechanisms are also documented [4,5].

Expert Opinion

Dantrolene sodium, a ryanodine receptor (RYR) antagonist, is very well-known in anesthesiology [8]. The RYR is one of two main channels for calcium release; the other receptor is inositol-1,4,5-trisphosphate [9]. Since the 1980s, dantrolene has been used extensively to treat malignant hyperthermia (MH) and, more recently, neuroleptic malignant syndrome, spasticity, heatstroke, and ecstasy intoxication [9]. Dantrolene sodium (1-[[[5-(4-nitrophenyl)-2-furanyl]-methylene]amino]-2,4-imidazolidinedione sodium salt), a hydantoin derivative, inhibits RYRs. These receptors are expressed on both the endoplasmic reticulum (ER) and SR surfaces [9]. RYRs release Ca^{2 +} ubiquitously from ER and SR intracellular stores [9]. In mammalian tissues, three distinct RYR isoforms have been identified. RYR1 is expressed mainly in the skeletal muscle on the SR terminal cisternae; RYR2 is expressed primarily in cardiac muscle; and RYR3 is expressed in most tissues at low levels. However, it is most commonly present in the brain [7–9]. Dantrolene directly affects RYR1 and RYR3 to inhibit the extent of calmodulin (CaM) channel activation and decrease the sensitivity of Ca2 switch to the channel [9]. Membrane depolarization in the cardiac muscle causes the opening of Cav1.2 L-type calcium channels from extracellular space, contributing to the influx of Ca^{2 +}. RYR2 is stimulated as a result of Ca^{2 +} afflux, and Ca^{2 +} is released from the SR [9]. Dantrolene decreases intracellular calcium in muscles and the heart [10]. According to the recent study, calmodulin (CaM) bound to the ryanodine receptor (RyR2) with constitution a large pool of total CaM in cardiac myocytes, but the affinity of CaM-RyR2 decreases under pathological conditions, including angiotensin II (AngII) or phenylephrine (PE) with nuclear accumulation of CaM by dissociating from RyR2 and translocating to the nucleus [11].

Another animal study shows that dantrolene also protects against heart failure and arrhythmias caused by the spontaneous release of Ca2 in single channels with the necessity of CaM to inhibit RyR1 and RyR2 [12].

A recent study suggests that dantrolene exerts antiarrhythmic effects and preserves inotropy in HF cardiomyocytes by reducing the incidence of diastolic Ca^{2 +} sparks, increasing the Ca^{2 +} intra-SR threshold at which spontaneous Ca^{2 +} waves occur, and decreasing the loss of Ca^{2 +} from the SR [10]. Another study has demonstrated the antiarrhythmic (tachyarrhythmia and ventricular fibrllation) potential of dantrolene in a dose-dependent manner [13]. In another study [14], dantrolene increased systemic vascular resistance, decreased cardiac index in a dose-dependent manner with no significant effect on atrioventricular conduction. According to recent studies, the impacts of dantrolene on type 2 RyR (RyR2) in cardiac cells can be considered. Ryanodex (dantrolene sodium) for Injectable Suspension (250 mg/vial) is a novel dantrolene sodium (50 mg/mL after reconstitution) nanoparticle suspension approved for the treatment of malignant hyperthermia. In all pharmacokinetic (PK) and safety attributes, Ryanodex is equivalent to conventional dantrolene, except for higher Cmax & shorter Tmax, obtained by more rapid dantrolene administration with this novel formulation that would make administration in an acute overdose situation much more accessible [15].

Digoxin immune Fab (Digifab) is the most common antidote for reversing the signs and symptoms of digoxin toxicity, which it achieves by binding to circulating digoxin to develop a complex molecule that cannot be absorbed by body tissue. This complex molecule is excreted through urine [16]. This drug was labeled as category C for pregnancy; it should be administered cautiously to patients with known hypersensitivity to sheep products because the drug is created from sheep antibodies. Several adverse effects, including symptoms of rebound cardiac failure, atrial fibrillation, and hypokalemia, are considered [16]. As the drug is either nonexistent or extremely expensive in underdeveloped and developing countries and because of the disadvantages mentioned above, alternatives are needed to treat digitalis toxicity [17].

In conclusion, with cardiac glycoside poisoning, there is an increase in myocytes’ calcium cytoplasm; by contrast, dantrolene prevents the escape of Ca^{2 +} into the cytoplasm from the sarcoplasmic reticulum and decreases the calcium in the cytoplasm. Since Dantrolene is a US Food and Drug Administration approved medication, the new dantrolene sodium particulate can be given in small volume and has a physiologic potential to treat cardioglycosides poisoning. We suggest an animal model followed by a clinical trial to assess dantrolene’s safety and clinical efficacy in treating cardioglycosides poisoning.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

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Funding

This paper was not funded.