# A Look at the Importance of Chirality in Drug Activity: Some Significative Examples
## 2 Drugs Acting on the Cardiovascular System  
### Antiarrhythmics  
Antiarrhythmics draws have been differently classified [50]. According to the Vaughan Williams classification, class I, including drugs acting on sodium channels, is subdivided into three subclasses: class IA (quimidine, procanamide, and disopyramide), class IB (lidocaine, procanidine, medicine, and diphenylhydantoin), and class IC (flecainide, propdenone, and moricizine). Class II are the \(\beta\)-adrenergic blocking agents; class III (amiodarone, breyllium, dottelike, azimilide, and ibutilide) includes drugs that block the potassium channels. Finally, drugs that block calcium influx, during the various phases of the action potential prolong repolarization, are grouped as class IV agents (diliazem, verapamil). Most of these drugs are chiral, including quinidine (**1**, Table 1) and disopyramide (**2**), mexiletine (**3**) and tocainide (**4**), fleacinide (**5**), propdenone (**6**), and sotalol and ibutilide (**7**). Class IB antiarrhythmics mexiletine and tocainide have been widely studied for their chirality. (\(R\))-mexiletine has shown higher activity than the racemate [51, 52]. In particular, some metabolites of mexiletine were described and sometimes they showed a higher activity than the parent compound, as was the case for _meta_-hydroxymexiletine [53]. The same stereoselectivity pattern observed for mexiletine was found for this metabolite: the (\(R\))-enantiomer was the eutomer on arrhythmia, showing a negative inotropism higher than the one displayed by mexiletine [54, 55]. Class IB antiarrhythmics have been demonstrated to act on the Nav1.4 voltage-gated sodium channel that is present in skeletal muscle; thus, these compounds also exert antimyotonic activity, i.e., activity towards myotonias, diseases of the skeletal muscle characterized by skeletal muscle stiffness. Some analogues of these drugs are more active than the parent compounds and have been studied both in their racemic and enantiomeric forms [56, 57]. Ivabradine (**8**) is a contemporary antiarrhythmic compound that promotes only HCN\({}_{4}\) channel inhibition [58] and was first authorized by the European Medicines Agency (EMA) in 2005 for stable angina treatment, then, in 2015, it was approved by the FDA. It is extensively used in heart failure in patients for whom the \(\beta\)-blockers are contraindicated, or in combination with a \(\beta\)-blocker, as well as a calcium channel blocker, in the cases in which the \(\beta\)-blockers or calcium channel blockers alone are not able to control the disease. It is commercialized as a pure soluble (\(S\))-enantiomer under different brand names, with no in vivo racemization [59, 60]. However, the higher toxicity of (\(S\))-ivabradine than its enantiomer towards the marine bacterium _Vibrio fischeri_ has been recently demonstrated [61].  
\begin{table}
\begin{tabular}{c c c} \hline \hline
**Structure** & **Name** & **Number of Compounds** \\ \hline _Antiarrhythmic drugs_ & & \\ \hline \hline \end{tabular}
\end{table}
Table 1: Structures of chiral drugs in therapy.  
\begin{table}
\begin{tabular}{c c c} \hline
**Structure** & **Name** & **Number of Compounds** \\ \hline _Drugs acting on CNS_ & & \\ \hline \end{tabular}
\end{table}
Table 1: Cont.  
\begin{table}
\begin{tabular}{c c c} \hline \hline
**Structure** & **Name** & **Number of Compounds** \\ \hline
**N** & **COOH** & **Etodolac** & **32** \\
**H** & **Etodolac** & **32** \\ \hline _Antitubaterials_ & & \\ \hline \hline \end{tabular}
\end{table}
Table 1: Cont.  
\begin{table}
\begin{tabular}{c c c} \hline \hline
**Structure** & **Name** & **Number of Compounds** \\ \hline _Selective Serotonin Reuptake Inhibitors_ & & \\ \hline \hline \end{tabular}
\end{table}
Table 1: Cont.