Clinical and Case Study Article Drug-induced proarrhythmia: Discussion and considerations for clinical practice Ralph J. Klotzbaugh, FNP-BC, PhD1, Alejandra Martin, PA-C2, & John Rick Turner, PhD, DSc3 ABSTRACT The clinical practice of pharmaceutical medicine includes contributions from physicians, pharmacists, nurse prac- titioners, and physician assistants. Drug safety considerations are of considerable importance. This article discusses drug-induced proarrhythmia, with a specific focus on Torsade de Pointes (Torsade), a polymorphic ventricular tachycardia that typically occurs in self-limiting bursts that can lead to dizziness, palpitations, syncope, and seizures, but on rare occasions can progress to ventricular fibrillation and sudden cardiac death. A dedicated clinical phar- macology study conducted during a drug’s clinical development program has assessed its propensity to induce Torsade using prolongation of the QT interval as seen on the surface electrocardiogram (ECG) as a biomarker. Identification of QT-interval prolongation does not necessarily prevent a drug from receiving marketing approval if its overall benefit-risk balance is favorable, but, if approved, a warning is placed in its Prescribing Information. This article explains why drugs can have a proarrhythmic propensity and concludes with a case presentation. Keywords: Delayed depolarization; hERG cardiac ionic current; QT-interval prolongation. Journal of the American Association of Nurse Practitioners 32 (2020) 128–135, © 2020 American Association of Nurse Practitioners DOI# 10.1097/JXX.0000000000000348 Introduction rare polymorphic ventricular arrhythmia that typically This article discusses the important role of clinicians in the occurs in self-limiting bursts that can lead to symptoms of anticipation, identification, and treatment of one particular dizziness, palpitations, syncope, and seizures, but the one cardiac occurrence in the practice of pharmaceutical that can occasionally progress to ventricular fibrillation medicine, namely the polymorphic ventricular tachycardia and sudden cardiac death. As shown in Figure 1,theelec- Torsade de Pointes (Torsade). Although drugs from diverse trocardiogram (ECG) waveform of Torsade is very different pharmacological classes can lead to multiple types of from that seen during normal sinus rhythm. It is charac- arrhythmias, the focus is on Torsade as many drugs pro- terized by rapid, irregular QRS complexes that appear to long the cardiac repolarization period, a phenomenon twist around the isoelectric baseline. associated with Torsade. The mechanism of action of re- Torsade can result from inherited condition called long polarization prolongation is discussed in due course. QT syndrome (LQTS), and of importance in the practice of Sudden death caused by drug-induced arrhythmia has pharmaceutical medicine, it can also be drug induced by a been described as one of the most feared complications in wide range of drugs and drug classes. In both cases, Tor- fi medicine (Link, Yan, & Kowey, 2010). Torsade was rst de- sade is associated with prolongation of the QT interval, the scribed by Dessertenne (Dessertenne, 1966: see also time between the onset of the QRS complex and the offset Bubien, 1999, for discussion in the nursing literature). It is a of the T wave, as seen on the surface ECG. Figure 2 presents a stylistic representation of the QT interval and QT-interval prolongation. For each cardiac cycle, ventric- JAANP and JAAPA have arranged to publish this article simultaneously ular depolarization is reflected in the QRS waveform, in their February 2020 issues. Although the two articles may have whereas ventricular repolarization is reflected in the T minor style differences, they are essentially the same. wave. Delayed ventricular repolarization is manifest as 1 University of New Mexico College of Nursing, Albuquerque, New prolongation of the QT interval (Turner et al., 2018). Mexico, 2Goodwin Community Health Center, Somersworth, New Hampshire, 3Cardiovascular Center of Excellence, Durham, North In recent years, a dedicated clinical pharmacology Carolina study has been conducted for each new drug under de- Correspondence: Ralph J. Klotzbaugh, FNP-BC, PhD, College of velopment to assess its propensity to induce Torsade using Nursing, University of New Mexico, Albuquerque, NM 87131. Tel: 6077611800; E-mail: [email protected] QT-interval prolongation as a biomarker. When Received: 17 June 2019; revised: 12 September 2019; accepted submitting a New Drug Application to the US Food and Drug 17 September 2019 Administration and similar documents to regulatory 128 February 2020 · Volume 32 · Number 2 Journal of the American Association of Nurse Practitioners © 2020 American Association of Nurse Practitioners. Unauthorized reproduction of this article is prohibited. R. J. Klotzbaugh et al. practitioners and physician assistants. Table 1 provides a summary of key take-home messages. Inherited long QT syndrome Although drug-induced (acquired) QT prolongation is the primary focus of this article, it is important to be familiar with inherited (congenital) LQTS. In clinical medicine, QT prolongation is of concern because it is the defining phe- Figure 1. An electrocardiogram showing an episode of notypic characteristic of a constellation of LQTSs that have torsade. been associated with Torsade and sudden death (Fernandez-Falgueras,´ Sarquella-Brugada, Brugada, Bru- agencies in other geographic jurisdictions, the results of gada, & Campuzano, 2017). Of specific interest in the pres- this study are included in the sponsor’s application dos- ent context is long QT syndrome 2 (LQT2), discussed shortly. sier. Identification of QT-interval prolongation does not As noted previously, QT-interval prolongation is a necessarily prevent a drug from receiving marketing ap- manifestation of delayed ventricular repolarization. Both proval if its overall benefit-risk balance is favorable, but, if depolarization and repolarization are governed by the approved, a warning is placed in the drug’s Prescribing flow of ionic currents through cardiac ion channels. Ion Information (Turner, Karnad, Cabell, & Kothari, 2017). channels, which occur in multiple biological systems, are When prescribing, dispensing, and administering such a structured transmembrane protein complexes that are drug to a patient, health care professionals need to con- embedded in cell plasma membranes. Multiple subunits sider this information in conjunction with the patient’s within these complexes organize to form a trans- likelihood of receiving required therapeutic benefitandhis membrane (central) pore through which ionic currents or her susceptibility for Torsade. This susceptibility is flow across cell membranes. Multiple cardiac ionic cur- influenced by biological risk factors including advanced age rents influence both depolarization and repolarization. and female sex, concurrent clinical characteristics including Ikr, a repolarizing current, is of direct relevance here. hypocalcemia, hypokalemia, and hypomagnesemia, and LQT2 is seen when an individual’s genetic inheritance concomitant medications that also prolong the QT interval. includes an abnormal variant of the human ether-a-go- Monitoring patients’ ECGs and calcium, sodium, and mag- go–related gene (hERG) that encodes a protein compris- nesium electrolyte levels in hospital settings is also im- ing the subunit forming the central pore of the cardiac portant (Turner et al., 2018). potassium ion channel (known as the hERG channel) This article explains why drugs can have a proar- through which Ikr flows. Abnormal variants of hERG lead rhythmic propensity, discusses the origins and nature of to a cascade of consequences as follows: loss of function the regulatory landscape that governs current pre- of the expressed ion channels, reduced Ikr flowing marketing assessments, provides examples of resulting through them, reduced net repolarizing influence, Prescribing Information warnings, and presents a sce- delayed repolarization, QT-interval prolongation, and nario illustrating clinical practice implications for nurse sometimes proarrhythmia, that is, the potential genera- tion of a new arrhythmia or the worsening of an existing arrhythmia (Turner & Durham, 2009). Drug-induced QT prolongation Ion channels have various defining characteristics. One, just discussed, is that abnormal variants of genes encoding them can cause specific arrhythmias. Another is that their activi- ties can be affected by drugs. (Murray & Granner, 2006). In the case of the hERG channel, drugs can lead to a reduction in function. This results in a cascade of consequences— reduced Ikr, reduced net repolarizing influence, delayed re- polarization, QT-interval prolongation, and sometimes proarrhythmia—that are in many ways similar to those resulting from abnormal variants of hERG and the resultant inherited LQT2. Given this similarity, hERG channel blockade hasbecomeasignificant scientific, clinical, and regulatory Figure 2. Stylistic representation of the QT interval and QT- concern during the past three decades (Turner et al., 2018). A interval prolongation. brief summary is provided in the following section. Journal of the American Association of Nurse Practitioners February 2020 · Volume 32 · Number 2 129 © 2020 American Association of Nurse Practitioners. Unauthorized reproduction of this article is prohibited. Clinical and Case Study Article Drug-induced proarrhythmia Table 1. Key points for clinicians Clinicians play a key role in the practice of pharmaceutical