through the His–Purkinje system is coupled to mechanical contraction of the heart’s
ventricular muscles. The electrical generation and conduction system of the heart
is analogous to excitable membranes elsewhere in the body and is focused around the
sequential opening of voltage-gated Na+channels, producing an action potential, with
additional ionic contributions from K+and Ca^2 +channels.
Any disturbance in the generation or conduction of impulses within the heart’s elec-
trical system leads to abnormalities of heartbeat called arrhythmias. Arrhythmias do not
themselves constitute a disease, but rather are symptomatically indicative of some
underlying pathology within the heart. Over 80% of people with myocardial infarctions
experience arrhythmias; almost 50% of people undergoing general anesthesia will like-
wise experience arrhythmias. Arrhythmias are caused by abnormal pacemaker activity
or abnormal impulse propagation and manifest themselves as too slow a heart rate
(bradycardia [<60 bpm]), too fast a heart rate (tachycardia [100–220 bpm], flutter
[220–350 bpm], fibrillation [>350 bpm]), or loss of regular rhythm (e.g.,premature
ventricular contractions; PVCs). Atrial fibrillation is not life threatening, so long as the AV
node does not transmit the rapid stimulus rate from the atria to the ventricles; but if the
rapid rate is successfully transmitted to the ventricles, the resulting ventricular fibrillation
is rapidly fatal. Any arrhythmia that functionally decouples the heart’s electrical-
mechanical pump efficiency, such as ventricular fibrillation, has the capacity to be lethal.
Drug-based treatment of arrhythmias is targeted against the generation and propagation
of aberrant electrical activity within the heart’s conduction system. Understandably, such
drugs target the voltage-gated ion channels, particularly the voltage-gated Na+channel.
Drug design of therapeutics for the treatment of arrhythmias is centered about four
classes of compounds:
- Class I—“membrane stabilizing drugs” to reduce cardiac electrical excitability:
molecules that are sodium channel blockers, usually based on local anesthetic
molecular structure - Class II—“sympathoplegic drugs” that reduce heart responsiveness to sympathetic
autonomic nervous system excitation: molecules that reduce adrenergic stimulation
of the heart, usually β-adrenergic blocking agents - Class III—drugs that prolong the action potential duration: molecules that either
block outward K+currents or augment inward Na+currents - Class IV—drugs that slow cardiac electrical conduction: molecules that block cardiac
Ca^2 +channel currents
Classes I, III, and IV all involve transmembrane ion channels; Classes I and III involve
Na+channels. Class I compounds are designed to block cardiac Na+channels in a voltage-
dependentmanner, similar to local anesthetics. Not surprisingly, many of these Class I
agents are either local anesthetics or are structurally based on local anesthetics. Class I
compounds include procainamide (7.15), disopyramide (7.16), amiodarone (7.17), lido-
caine (7.5), tocainide (7.18), mexiletine (7.19), and flecainide (7.20). The majority of
these compounds possess two or three of the fundamental structural building blocks
found within local anesthetics. Propranolol (7.21) is the prototypic Class II agent. Class III
compounds include molecules that block outward K+channels, such as sotalol (7.22)
and dofetilide (7.23), and molecules that enhance an inward Na+current, such as
420 MEDICINAL CHEMISTRY