Drug Effects, Electrolyte Abnormalities, and Metabolic Disturbances

Drugs Used to Treat Cardiac Arrhythmias

Numerous drugs, both “cardiac” and “noncardiac,” can affect the ECG. These changes may be mediated by direct effects on the electrical properties of pacemaker cells, the specialized conduction system (atrioventricular [AV] node and His–Purkinje network), and atrial or ventricular myocytes themselves. Drugs that alter autonomic nervous system activity (vagal and/or sympathetic) may also have important direct and indirect effects on pacemaker activity and conduction/recovery properties.

Cardiologists often use a shorthand classification system when referring to drugs primarily used to treat arrhythmias ( Box 11.1 ). The original (class I-IV) system has been revised to accommodate new additions to the roster of drugs used to treat arrhythmias and to overcome some limitations of the earlier classification scheme. A modified/simplified version of the latest classification scheme is as follows:

• Class 0 drugs block the hyperpolarization-activated, cyclic nucleotide-gated (HCN) channel, which mediates pacemaker (I _f ) currents (I _f stands for the so-called funny current). This action reduces the rate of depolarization of sinoatrial pacemaker cells and lowers heart rate. The sole currently available member of this class is ivabradine.

• Class 1 drugs have a sodium channel blocking action, so they may prolong the QRS duration. The class 1 drugs are subdivided into A, B, C, and most recently D ^a

  a Class 1D drugs (e.g., ranolazine) affect the late sodium channel current and cause a reduction in early after-depolarization- induced triggered activity, despite prolonging the QT interval. However, ranolazine, as of May 2022, is U.S. Food and Drug Administration (FDA)-approved only for adjunctive treatment of chronic angina.

  groups. Class 1A drugs, such as procainamide, quinidine, and disopyramide, also prolong repolarization via potassium channel blocking effects. Therefore they may prolong the QT(U) interval, leading to increased risk of torsades de pointes and sudden cardiac arrest (see 16 , 21 ). Class 1B drugs include lidocaine and mexiletine. Class IC drugs, such as flecainide and propafenone, used to treat atrial fibrillation and other supraventricular tachycardias, are the most likely to produce clinically important widening of the QRS complex (intraventricular conduction delays) because of their highly potent sodium channel blocking effects.

All “antiarrhythmic” class 1 (sodium channel blocking) drugs, along with many other pharmaceutical agents, may paradoxically induce or promote the occurrence of life-threatening ventricular arrhythmias in part by altering basic electrical properties of myocardial cells. These often unexpected, paradoxically proarrhythmic drug effects, are of major clinical importance, as discussed further in 16, 21 .

Prolongation of the QT(U) interval, with the attendant life-threatening risk of torsades de pointes ( Chapter 16 ), a major example of ventricular proarrhythmia, can also occur with class 3 drugs, notably ibutilide, dofetilide, sotalol (which also has beta-blocking effects), amiodarone (with beta-blocking, among multiple other effects), and dronedarone ( Fig. 11.1 ). This QT(U) prolongation effect is also related to blocking of potassium channel function with prolongation of myocardial cellular repolarization.

Beta blockers ( class 2 ) and certain calcium channel blockers ( class 4 ) depress the sinus node and AV node so that bradycardias may occur, ranging from mild to severe. Drug combinations (e.g., metoprolol and diltiazem) may produce marked sinus node slowing or AV nodal block, especially in older adults. Carvedilol has both beta-adrenergic and alpha-adrenergic (vasodilatory) effects, making hypotension a particular risk.

Limitations of this classification scheme include failure to account for drugs with “mixed” effects (e.g., amiodarone and sotalol) and the fact that important drugs, such as adenosine and digoxin, do not fit in. Instead, these drugs are separately categorized. Perhaps most important, as noted, is that the term antiarrhythmic agent does not take into account the potentially life-threatening proarrhythmic effects of many of these drugs (see 16, 21 ). The major and large topic of the toxic effects of digoxin and related cardiac glycosides is discussed separately in Chapter 20 .

Psychotropic and Related Drugs

Psychotropic drugs (e.g., phenothiazines and tricyclic antidepressants) can markedly alter the ECG and in toxic doses can induce syncope or cardiac arrest because of a ventricular tachyarrhythmia or asystole. They may also prolong the QRS interval, causing a bundle branch block-like pattern, or they may lengthen repolarization (long QT[U] intervals), predisposing patients to develop torsades de pointes. Fig. 11.2 presents the classic ECG findings of tricyclic antidepressant overdose with the characteristic triad of a prolonged QRS and QT interval, along with sinus tachycardia.

A variety of drugs used in psychiatric practice can prolong the QT interval, predisposing to torsades de pointes–type ventricular tachycardia. These drugs include methadone and the so-called atypical or second-generation psychotropic agents (e.g., risperidone and quetiapine). This topic is discussed further in Chapter 16 as part of the important clinical subject of acquired long QT syndromes.

Lithium carbonate, used in the treatment of bipolar disease, may cause sinus node pacemaker automaticity dysfunction or sinus exit block, resulting in severe bradycardia ( Chapter 13 ).

Donepezil, rivastigmine, and galantamine, used in the management of Alzheimer’s disease, may induce or worsen bradyarrhythmias because of their anticholinesterase effects that enhance the action of acetylcholine on the sinus and AV nodes. The risk of severe bradyarrhythmias with this class of drugs appears to be augmented by concomitant therapy with beta blockers.