OF TORSADES DE POINTES

Transcription

1 ELECTROPHYSIOLOGY DRUG INDUCED QT PROLONGATION AND TORSADES DE POINTES CAUSES See end of artile for authors affiliations Correspondene to: Dr Yee Guan Yap, Department of Cardiologial Sienes, St George s Hospital Medial Shool, Cranmer Terrae, London SW17 0RE, UK; ygyap@aol.om I Yee Guan Yap, A John Camm Heart 2003; 89: n 1966, Franois Dessertenne desribed a speifi eletroardiographi form of polymorphi ventriular tahyardia, whih he termed torsades de pointes (TdP). w1 w2 The word torsades refers to an ornamental motif imitating twisted hairs or threads as seen on lassial arhitetural olumns, and pointes referred to points or peaks. w1 w2 In the seminal artile, Dessertenne made no attempt to suggest the mehanism of TdP and, until reently, there has been onsiderable onjeture as to the pathophysiology of this arrhythmia. OF TORSADES DE POINTES Sine the original work by Dessertenne, it has been well reognised that many onditions may ause prolonged or abnormal repolarisation (that is, QT interval prolongation and/or abnormal T or T/U wave morphology), whih is assoiated with TdP. If TdP is rapid or prolonged, it an lead to ventriular fibrillation and sudden ardia death (fig 1). Essentially, TdP may be aused by either ongenital or aquired long QT syndrome (LQTS). In reent years, there has been onsiderable renewed interest in the assessment and understanding of ventriular repolarisation and TdP. There are several reasons for this. Firstly, the loning of ardia ion hannels has improved the understanding of the role of ioni hannels in mediating ardia repolarisation, the pathophysiologial mehanism of LQTS (ongenital and aquired forms), and the pathogenesis of TdP. Seondly, modern moleular tehniques have unravelled the mutations in genes enoding ardia ion hannels that ause long QT syndrome, although the geneti defets in about 50% of patients are still unknown. Thirdly, there has been onsiderable enthusiasm for the development and use of lass III antiarrhythmi drugs, whih prolong repolarisation and ardia refratoriness. Unfortunately, drugs that alter repolarisation have now been reognised to inrease the propensity for TdP. Finally, an inreasing number of drugs, espeially non-ardia drugs, have been reognised to delay ardia repolarisation and to share the ability with lass III antiarrhythmis to ause TdP oasionally. Many of the drugs that were initially known to prolong the QT interval were antiarrhythmis, and quinidine was the most ommonly impliated agent. Surprisingly, many non-ardia drugs have also been reported to ause QT prolongation and/or TdP reently. In a survey in both the UK and Italy, non-ardia drugs that have pro-arrhythmi potential (that is, have an offiial warning on QT prolongation or TdP, or with published data on QT prolongation, ventriular tahyardia, or lass III effet) alone represented 3% and 2% of total presriptions in both ountries, respetively. 1 The danger of drug indued pro-arrhythmia is therefore serious. This issue has been identified as a onsiderable publi health problem and has attrated attention from the drug regulatory authorities. The exat inidene of drug indued TdP in the general population is largely unknown. Most of our understandings of the inidene, risk fators, and drug interation of pro-arrhythmi drugs are derived form epidemiologial studies, anedotal ase reports, linial studies during drug development, and post-marketing surveillane. The awareness of drug indued TdP in the last few years has resulted in an inrease in the number of spontaneous reports. Nevertheless, the absolute total number remains very low, although it has been suggested that the system of spontaneous reporting under-reports the true inidene of serious adverse reations by a fator of at least Between 1983 and Deember 1999, 761 ases of TdP, of whih 34 were fatal, were reported to the World Health Organization Drug Monitoring Centre by the member states. 3 The WHO data provide an insight into the inidene of TdP on the most ommonly reported pro-arrhythmi drugs 3 (table 1). However, suh a reporting system is undermined by the widely variable ontent and linial information between different ountries and soures. It is also ompounded by various fators suh as the patient s underlying disease, whether the adverse drug reation is well known or has not been previously desribed, and the amount of attention paid by the medial ommunity on a speifi adverse drug reation. In this artile, we will review the risk of drug indued QT prolongation and/or TdP Heart: first published as /heart on 31 Otober Downloaded from on 12 November 2018 by guest. Proteted by opyright.

2 1364 MECHANISM OF DRUG INDUCED QT PROLONGATION AND TORSADES DE POINTES At the ellular level, the repolarisation phase of the myoytes is driven predominantly by outward movement of potassium ions. A variety of different K + hannel subtypes are present in the heart. Two important K + urrents partiipating in ventriular repolarisation are the subtypes of the delayed retifier urrent, I Kr ( rapid ) and I Ks ( slow ). Blokade of either of these outward potassium urrents may prolong the ation potential. I Kr is the most suseptible to pharmaologial influene. It is now understood that virtually without exeption, the blokade of I Kr urrent by these drugs is at least in part responsible for their pro-arrhythmi effet. Blokade of the I Kr urrent manifests linially as a prolonged QT interval and the emergene of other T or U wave abnormalities on the surfae ECG. The prolongation of repolarisation may result in subsequent ativation of an inward depolarisation urrent, known as an early afterdepolarisation, whih may promote triggered ativity. When aompanied by the presene of a notably inreased dispersion of repolarisation, this may indue re-entry and provoke Figure 1 (A) Self limiting torsades de pointes (TdP). (B) TdP leading to ventriular fibrillation. TdP, whih is then sustained by further re-entry or spiral wave ativity (fig 2). Suh phenomena are more readily indued in the His-Purkinje network and also from a subset of myoardial ells from the mid ventriular myoardium, known as M ells. 4 Compared to subendoardial or subepiardial ells, M ells show muh more pronouned ation potential prolongation in response to I Kr blokade. 4 This property results in a pronouned dispersion of repolarisation (that is, heterogeneous reovery of exitability), reating a zone of funtional refratoriness in the mid myoardial layer, whih is probably the basis of the re-entry that is sustaining the TdP. There is a harateristi initiating sequene before the onset of TdP, partiularly in the aquired form. The first ventriular omplex of the sequene is usually a ventriular etopi beat or the last beat of a salvo of ventriular premature beats (fig 3). This is then followed by a ompensatory pause terminated by a sinus beat. The sinus beat frequently has a very prolonged QT interval and an exaggerated U wave. A ventriular extrasystole then falls on the exaggerated U wave of the sinus beat and preipitates the Table 1 Twenty most ommonly reported drugs assoiated with torsades de pointes (TdP) between 1983 and Drug TdP (n) Fatal (n) Total (n) TdP/total (%) Sotalol Cisapride Amiodarone Erythromyin Ibutilide Terfenadine Quinidine Clarithromyin Haloperidol Fluoxetine Digoxin Proainamide Terodiline Fluonazole Disopyramide Bepridil Furosemide Thioridazine Fleainide Loratidine TdP (n), total number of adverse drug reation reports whih named TdP assoiated with this drug; Fatal (n): number of adverse drug reation reports whih named TdP with fatal outome; Total (n): total number of adverse drug reation reports for the drug. Heart: first published as /heart on 31 Otober Downloaded from on 12 November 2018 by guest. Proteted by opyright.

3 Figure 2 Arrhythmogenesis of torsades de pointes. VF, ventriular fibrillation. Figure 3 Rhythm strip in a patient with drug indued TdP. Note the typial short-long-short initiating ventriular yle, pause dependent QT prolongation, and abnormal TU wave leading to the lassial twisting of a point of the ardia axis during TdP Heart: first published as /heart on 31 Otober Downloaded from on 12 November 2018 by guest. Proteted by opyright.

4 1366 onset of TdP. It has been suggested that post-pause aentuation of the U wave, if present, may be a better preditor of drug indued TdP than the duration of QT interval. 5 METHOD FOR MEASUREMENT OF QT INTERVAL When measuring the QT interval, the ECG is best reorded at a paper speed of 50 mm/s and at an amplitude of 0.5 mv/m using a multihannel reorder apable of simultaneously reording all 12 leads. A tangent line to the steepest part of the desending portion of the T wave is then drawn. The interept between the tangent line and the isoeletri line is defined as the end of the T wave. w3 The QT interval is measured from the beginning of the QRS omplex to the end of the T wave on a standard ECG. There are no available data on whih lead or leads to use for QT interval measurement. Traditionally, lead II has been used for QT interval measurement beause in this lead, the vetors of repolarisation usually result in a long single wave rather than disrete T and U waves. 6 Generally, QT prolongation is onsidered when the QT interval is greater than 440 ms (men) and 460 ms (women), although arrhythmias are most often assoiated with values of 500 ms or more (table 2). The severity of pro-arrhythmia at a given QT interval varies from drug to drug and from patient to patient. Unfortunately, the extent of QT prolongation and risk of TdP with a given drug may not be linearly related to the dose or plasma onentration of the drug beause patient and metaboli fators are also important (for example, sex, eletrolyte onentrations, et). Furthermore, there is not a simple relation between the degree of drug indued QT prolongation and the likelihood of the development of TdP, whih an oasionally our without any substantial prolongation of the QT interval. The QT interval is influened by heart rate. The RR interval preeding the QT interval should be measured for rate orretion. Several formulae may be used to orret the QT interval for the biophysial effet of heart rate (QT), but none is perfet. The most ommonly used formulae are Frideriia s ube root formula (QT = QT/RR 1/3 ) and Bazett s square root formula (QT = QT/RR 1/2 ). Of the two, Bazett s formula is the more popular, but Frideriia s orretion is preferred beause it is more aurate at the extremes of physiologial heart rate. w4 w5 Apart from heart rate, the duration of the QT interval is also subjet to the tehniques of reording and measurement error of the QT interval, sympathovagal ativity, drugs, geneti abnormalities, eletrolyte disorders, ardia or metaboli diseases, hanges of ardia afterload, and diurnal variation whih an be up to ms. It is important to remember that for every individual there is a different relation between the QT interval and the heart rate. Although the rate2orretion formulae are useful linially, they may not be aurate Table 2 QT values for normal and prolonged QT interval after orretion with Bazett s formula 6 QT values by age group and sex (ms) 1 15 years Adult males Adult females Normal,440,430,450 Borderline Prolonged (top 1%) enough, espeially when assessing the minor hanges of the QT interval indued by drugs. The suggested QT values using the Bazett s formula for diagnosing QT prolongation are outlined in table 1. 7 Newer repolarisation parameters suh as QT dispersion (maximum 2 minimum QT intervals) on the 12 lead surfae ECG, whih is onsidered to be an indiret measure of spatial heterogeneity of repolarisation, may be useful in assessing drug effiay and safety. In one important study, patients who reeived lass 1a antiarrhythmi drugs and developed TdP had signifiantly inreased preordial QT interval dispersion. w6 In ontrast, patients reeiving amiodarone or lass 1a antiarrhythmis without TdP did not have inreased QT dispersion, although the QT interval was notieably prolonged. w6 Thus, spatial heterogeneity/dispersion of the ventriular repolarisation proess may be required in addition to QT prolongation for the genesis of TdP. Although the use of QT dispersion in the assessment of drugs that prolong the QT interval needs further onfirmation, it may provide information about the linial signifiane of QT prolongation. DRUGS THAT CAUSE QT PROLONGATION AND/OR TORSADES DE POINTES The list of drugs that an prolong QT interval and/or ause TdP is extensive (table 3). Antiarrhythmis The early landmark report by Selzer and Wray observed that quinidine use was assoiated with synope and ventriular fibrillation or flutter. w7 In their report, the risk of TdP with quinidine was not neessarily a onsequene of exessive doses of the drug. Others have onfirmed that TdP with lass Ia drugs an our at low therapeuti or subtherapeuti onentrations. w8 Indeed most of the lass Ia drugs, inluding quinidine, disopyramide, and proainamide, are similar in this regard. w9 On the other hand, antiarrhythmi agents suh as sotalol are assoiated with a greater inidene of TdP as the dose inreases. w10 One possible explanation for suh disrepany is that the blokade of sodium hannels by lass Ia drugs suppresses the QT prolonging effet at higher onentrations. Pure I Kr potassium bloking antiarrhythmi drugs suh as d,l,-sotalol prolong the QT interval and indues TdP at an inidene diretly proportionate to their onentration until the potassium urrents are ompletely bloked. w9 The mean effet on QT prolongation by d,l,-sotalol varies from ms at doses from mg/day. It is noteworthy that while lass Ia drugs are strongly onordant in their prodution of TdP, onordane with lass III antiarrhythmi agents is less lear. For example, while both sotalol and amiodarone have the same potent effets on QT prolongation, the inidene of TdP is very low with amiodarone ompared with sotalol. A literature review revealed that the inidene of TdP with amiodarone was only 0.7% in 17 unontrolled studies (2878 patients) between 1982 and 1993, and that no pro-arrhythmia was reported in seven ontrolled studies (1464 patients) between 1987 and Indeed, the evidene from a reent meta-analysis of amiodarone trials showed that amiodarone atually redued the risk of arrhythmi death and resusitated ardia arrest in patients after myoardial infartion or with heart failure. w11 The risk of TdP with amiodarone mainly ours in patients with other o-existing risk fators suh as hypokalaemia or bradyardia. In ontrast, d,l,-sotalol has a 0.3% inidene rate Heart: first published as /heart on 31 Otober Downloaded from on 12 November 2018 by guest. Proteted by opyright.

5 Table 3 Drugs that an prolong QT interval and torsades de pointes (this list is not omprehensive) Antiarrhythmi drugs Calium hannel blokers Psyhiatri drugs Antihistamines Antimirobial and antimalarial drugs Serotonin agonists/antagonists Immunosuppressant Antidiureti hormone Other agents of TdP for a daily dose of 80 mg, whih rises to 3.8% for a daily dose of. 680 mg. w9 The risk is greater in female patients, and patients with redued reatinine learane, ongestive heart failure, or sustained ventriular tahyardia. In the USA, patients initiated or re-initiated on d,l,-sotalol are required to be admitted to hospital for a minimum of three days (on their maintenane dose) in a faility that an provide ardia resusitation, ontinuous eletroardiographi monitoring, and alulations of reatinine learane (that must preede administration of the first dose of d,l,- sotalol), and in the presene of personnel trained in the Type 1A (TdP reported in all) Quinidine (TdP reported) Proainamide (TdP reported) Disopyramide (TdP reported) Ajmaline (TdP reported) Type 1C (inrease QT by prolonging QRS interval) Enainide Fleainide Type 3 (TdP reported in all) Amiodarone Sotalol d-sotalol Bretylium Ibutilide Dofetilide Amakalant Semantilide Prenylamine (TdP reported, withdrawn) Bepridil (TdP reported, withdrawn) Terodiline (TdP reported, withdrawn) Thioridazine (TdP reported) Chlorpromazine (TdP reported) Haloperidol (TdP reported) Droperidol (TdP reported) Amitriptyline Nortriptyline Imipramine (TdP reported) Desipramine (TdP reported) Clomipramine Maprotiline (TdP reported) Doxepin (TdP reported) Lithium (TdP reported) Chloral hydrate Sertindole (TdP reported, withdrawn in the UK) Pimozide (TdP reported) Ziprasidone Terfenadine (TdP reported, withdrawn in the USA) Astemizole (TdP reported) Diphenhydramine (TdP reported) Hydroxyzine Ebastine Loratadine Mizolastine Erythromyin (TdP reported) Clarithromyin (TdP reported) Ketoonazole Pentamidine (TdP reported) Quinine Chloroquine (TdP reported) Halofantrine (TdP reported) Amantadine (TdP reported) Sparfloxain Grepafloxain (TdP reported, withdrawn in the UK and USA) Pentavalent antimonial meglumine Ketanserin (TdP reported) Cisapride (TdP reported, withdrawn in the UK and USA) Tarolimus (TdP reported) Vasopressin (TdP reported) Adenosine Organophosphates Probuol (TdP reported) Papaverine (TdP reported) Coaine management of serious ventriular arrhythmias in order to minimise the risk of TdP. w12 The risk of TdP an be redued by adjustment of the d,l,-sotalol dose aording to reatinine learane and by monitoring the ECG for exessive inreases in the QT interval. d,l,-sotalol is ontraindiated in patients with reatinine learane, 40 ml/min or QT interval. 450 ms. w12 Similar to d,l,-sotalol, dofetilide also exhibits a dose dependent effet on QT prolongation and TdP. The mean QT prolongation with dofetilide varies from 5220 ms at doses of mg twie daily, and the inidene of TdP 1367 Heart: first published as /heart on 31 Otober Downloaded from on 12 November 2018 by guest. Proteted by opyright.

6 1368 ranges from % at doses, 250 mg to. 500 mg. w13 Other new lass III intravenous antiarrhythmis, suh as ibutilide, are equally toxi in induing TdP. In the ibutilide repeat dose study, 8.3% of the patients developed TdP during or soon after the start of two, 10 minute infusions, separated by 10 minutes of ibutilide (1.0 and 0.5 mg or 1.0 and 1.0 mg). w14 Similarly, in patients with atrial fibrillation, intravenous almokalant indued TdP in 6% of the patients. w15 Oral azimilide at doses up to 200 mg/day prolongs the QT interval by 4242%. w16 Several ases of TdP have been reported in assoiation with azimilide use, usually when bradyardia, pauses, or hypokalaemia are present, but the preliminary results from the ALIVE (azimilide post-infartion survival evaluation) study showed that azimilide presribed at 100 mg has a low inidene of TdP even in high risk postmyoardial infartion patients with redued heart rate variability. w17 Antihistamines Sine 1986, ertain non-sedating antihistamines, the so alled seond generation antihistamines (mainly terfenadine and astemizole), have been reported to ause QT prolongation and, in some ases, TdP. 9 w18 These inidents have ourred when the reommended dose has been exeeded, at normal doses with onurrent use of drugs that inhibit hepati ytohrome P450 enzymes (for example, imidazole, antifungals, and marolide antibiotis), impaired liver funtion, or in patients with ongenital long QT syndrome. 9 Like lass III antiarrhythmis, terfenadine and astemizole were found to prolong the monophasi ation potential and QT interval, whih led to the development of early after-depolarisation and TdP through inhibition of the I Kr hannel. w19 As almost all of the non-sedating antihistamines were metabolised via the hepati ytohrome P450 CYP3A4 system, onomitant administration of drugs or food (grapefruit juie) that inhibit the hepati ytohrome P450 or severely ompromise liver funtion may result in the aumulation of the parent drug and ardiotoxiity. w19 Furthermore, o-administration of non-sedating antihistamines with other drugs that prolong the QT interval by the same or other mehanism (for example, antiarrhythmis, antipsyhotis, triyli antidepressants) also inreases their adverse effet on ardia repolarisation. w19 Other drug related fators suh as the physiohemial properties of the antihistamines (for example, diarylalkylamine moiety, quaternisation of diphenhydramine, lipophiliity of the side hain), their metaboli profile, and tissue distribution may also ontribute to the ardia response of antihistamines. Newer non-sedating antihistamines (loratadine, etirizine, arivastine, mizolastine, ebastine, and fexofenadine) ontinue to be introdued into the market. The ardia safety profile of these newer non-sedating antihistamines will require onfirmation. Antihistamines with low or no potential to blok the K + retifiation hannel (for example, I Kr ) hannels are likely to possess ardia safety advantages. The overall evidene so far indiates that the potential to ause TdP is not a lass effet of non-sedating antihistamines; ertain non-sedating antihistamines suh as terfenadine and astemizole have potent pro-arrhythmi risk, whereas others have low risk of (for example, azelastine, mizolastine) or are probably not assoiated with (for example, loratadine, etirizine, ebastine and fexofenadine) QT prolongation, TdP or other ventriular arrhythmias. It should be emphasised that apart from the speifi ontraindiations desribed, the inidene of ardiotoxiity with antihistamines is very low in view of the widespread use of the drugs. 10 Nevertheless, as they are widely presribed for a self limiting, non-fatal disease, the risk attributable must be assessed very arefully. Antimirobials Marolides (erythromyin, larithromyin), fluoroquinolones, antifungals, and antimalarials have been impliated 11 w20223 in predisposing to TdP as a result of QT prolongation. These reports are few and anedotal. Similar to lass III antiarrhythmis and antihistamines, marolides prolong the QT interval and ause dispersion of repolarisation aross the ventriular wall, resulting in the indution of TdP. In the ase of fluoroquinolones, sparfloxain lengthened the duration of the ation potential in a onentration dependent manner, 12 whereas ofloxain and levofloxain did not alter the ation potential duration at a variety of onentrations (1 100 mm). w24 Thus, sparfloxain exerts a pure lass III eletrophysiologial effet whereas levofloxain and ofloxain do not. Clinially, it is not yet known whether sparfloxain will ause any spontaneous TdP, partiularly in low risk patients. Sine the drug was marketed in 1994, there were very few ases of ventriular arrhythmia (three reversible ventriular tahyardias) reported during the European postmarketing surveillane of sparfloxain, all of whih ourred in patients with underlying ardia onditions. 12 Grepafloxain, a new fluoroquinolone available in the UK sine 1998, has reently been withdrawn voluntarily by its distributor beause of its effet on QT prolongation and some reported ases of TdP. The available evidene from prelinial and linial studies suggested that there are signifiant differenes in the poteny to prolong QT interval among the fluoroquinolones, and the risk of arrhythmias varies between drugs 13 (fig 4). Sporadi ases of TdP have been reported in assoiation with most, but not all, fluoroquinolones. As a whole, apart from grepafloxain and possibly sparfloxain, the fluoroquinolones that are urrently on the market or soon to be launhed are safe from the point of view of QT prolongation and TdP, with a frequeny of this adverse event generally ourring at a rate of about one per million presriptions. Antimalarials deserve some attention as they are ommonly presribed worldwide. Quinine, quinidine, and halofantrine are apable of prolonging the QT interval. w25228 Quinine prolongs the QT interval at standard doses, as does halofantrine (60%). Halofantrine indues a dose related prolongation of the QT interval whereas mefloquine has no effet on QT interval. w25 However, the risk of signifiant QT prolongation (. 25% or QT > 0.55 s 1/2 ) was greater if halofantrine was given as a re-treatment following mefloquine failure than as primary treatment. w25 The Committee of Safety of Mediines in the UK reommends that halofantrine should not be given with other drugs that prolong QT interval or to patients with any form of ardia ondition assoiated with QT prolongation. Cardiotoxiity of antimalarials is inreased in patients with aute renal failure, espeially after three days of treatment. w26 Hene, it has been reommended that ECG monitoring should be arried out during quinidine infusion. w26 However, it is interesting to note that pre-treatment ECGs were poorly preditive of QT prolongation during oral treatment of halofantrine, although it may be useful for evaluating patients with pre-existing Heart: first published as /heart on 31 Otober Downloaded from on 12 November 2018 by guest. Proteted by opyright.

7 ardia onditions. w27 This is partly beause the degree of QT prolongation is dependent on the plasma onentration of halofantrine. w28 The antifungal agents ketoonazole and itraonazole prolong the QT interval by bloking the I Kr hannels. w29 w30 Similar to marolide antibiotis, ketoonazole and itraonazole also inhibit the hepati ytohrome P450 CYP3A4 isoenzyme. w29 w30 Therefore, o-administration of ketoonazole or itraonazole with another QT prolonging drug that is metabolised by the ytohrome P450 CYP3A4 isoenzyme, suh as terfenadine, will result in a notably prolonged QT interval and inrease the risk of TdP. w29231 Triyli antidepressants The use of triyli antidepressants (TCAs) has raised some onern about their ardiotoxiity. The effet of TCAs on the QT interval have been investigated, but with mixed results. w32234 Amitriptyline, doxepin, desipramine, imipramine, and lomipramine have been assoiated with a prolonged QT interval, whereas dothiepin has no effet on QT interval. In hildren, onerns about possible TCA assoiated adverse effets were raised after a few ases of sudden death in hildren treated with TCAs. w35 w36 The TCAs impliated were desipramine, lomipramine, and imipramine. These ases of sudden death ourred without aute overdose. A possible mehanism is the fast or slow metabolism of TCA by hepati ytohromes. 14 w37 For example, impaired metabolism aused by a genetially determined slow metaboliser phenotype of ytohrome CYP2D6 is suggested as a possible mehanism for the apparent toxiity of these triyli antidepressants. w37 Co-administration of drugs that an alter the onentrations of both parent drug and metabolites will therefore affet the QT interval. It has been reommended that hildren and adolesents on TCA have an ECG at baseline and after eah dose inrease. w38 Reently, there have been ase reports of abnormal ECG hanges, akin to that observed in patients with Brugada s syndrome, following overdoses of antidepressants and neuroleptis (namely, phenothiazine, amitriptyline, fluoxetine), Figure 4 Effet of various fluoroquinolones on prolonging ation potential duration. Modified and reprodued from Hagiwara and olleagues 13 with permission. w39 w40 and therapeuti doses of trifluoperazine and loxapine, with triyli antidepressants being the most frequently impliated. The ECGs in these patients showed right bundle branh blok and ST segment elevation on the preordial leads, similar to that seen in patients with Brugada s syndrome, following the ingestion of these drugs. These hanges, however, disappeared after the withdrawal of the drugs and ould not be reprodued with the subsequent fleainide tests on these patients. Evidene from ellular studies suggest that, similar to lass I drugs, amitriptyline, phenothiazine, and fluoxetine indue ardia sodium hannel blokade and redue I to ativation, whih may shorten the ation potential durations and indue an intramyoardial eletrial gradient that produes the typial ECG hanges desribed above. However, suh ECG hanges will probably only our upon massive overdose of these drugs as in the ase of these patients, whih may explain why the ECG hanges ould not be reprodued with subsequent fleainide hallenge. Furthermore, it is also possible that these patients may have sublinial dysfuntional sodium hannels that were unmasked by these drugs. Thus, it has been postulated that this ould be another mehanism for drug indued sudden death in patients reeiving hroni treatment with triyli antidepressants and neuroleptis. Nevertheless, further studies are required to investigate this phenomenon. Neuroleptis Neuroleptis have long been assoiated with sudden death and are reported to ause QT prolongation and TdP at therapeuti doses or in overdose (phenothiazines, thioridazine, haloperidol, hlorpromazine, trifluoperazine, periyline, prohlorperazine, and fluphenazine). 15 w41245 Among them, thioridazine was the most potent in ausing QT prolongation and arrhythmia 15 (fig 5). In addition, the linial use of thioridazine has also been known to ause a derease in T wave amplitude, and a prominent U wave in approximately 50% of patients reeiving mg/day of the drug, albeit seldom with linial onsequenes. At toxi 1369 Heart: first published as /heart on 31 Otober Downloaded from on 12 November 2018 by guest. Proteted by opyright.

8 1370 onentrations, thioridazine an ause sinus bradyardia, atrioventiular blok, pronouned QT prolongation, and reurrent ventriular tahyardia and fibrillation. w46 At both w42 w46 therapeuti and toxi doses, thioridazine an indue TdP. In the presene of hypokalaemia, TdP an develop even with a low dose (50 mg daily) of thioridazine. w43 Sertindole is a relatively new atypial antipsyhoti for the treatment of shizophrenia. Its safety and effiay were assessed in three double blind randomised studies in the USA, North Ameria, and Europe. w47 Slight QT prolongation was seen with sertindole in early linial trials although TdP was not reported in these studies. However, 12 unexplained sudden deaths and 23 ases of synope ourred among 1446 patients during the pre-marketing trials of sertindole. w48 A total of 27 deaths assoiated with its use had been reported to the US Food and Drug Administration (FDA) by Although an independent review panel then did not find a ausal relationship between sertindole and these deaths, w49 in 1996 the drug was not approved for marketing in the USA. Nevertheless, sertindole was marketed in Europe. However, in the UK the Committee of Safety of Mediines was notified of 36 suspeted adverse drug reations with a fatal outome by the end of November w50 Not all of these reports were related to sudden ardia death. In addition, 13 reports of serious but non-fatal ardia arrhythmia were also reported in the UK during the same period. Beause of the number of adverse drug events, fatal and non-fatal, reported sine the marketing of sertindole in the UK, it was onsidered that the risks of treatment with this drug outweighed its benefits. The manufaturers of Figure 5 (A) The ECG of a middle aged woman who was otherwise healthy but suffered a ventriular fibrillation ardia arrest while reeiving 20 mg daily of thioridazine. This ECG was reorded immediately after the ardia arrest. Note the prolonged T wave offset resulting in a prolonged QT interval of 619 ms. (B) The ECG of the same patient three days after the withdrawal of thioridazine (QT = 399 ms). sertindole voluntarily suspended its marketing and use from Deember 1998 in the UK, pending further safety evaluations. It is now known that sertindole is a high affinity antagonist of the human ardia I Kr potassium hannel, and this blokade underlies, at least in part, the prolongation of the QT interval observed with this drug. 16 Pimozide is a diphenylpiperidine neurolepti agent with known ardiovasular side effets inluding QT prolongation. w51 TdP has been desribed after aute poisoning. w52 The risk of pimozide ardiotoxiity may be inreased with the onomitant use of drugs that inhibit the ytohrome P450 CYP3A4 isoenzyme for example, larithromyin, ketoonazole, et. w53 Forty reports (16 fatal) of serious ardia reations (predominantly arrhythmias) with pimozide use were reported to Committee of Safety of Mediines between 1971 and 1995, 17 and restrited labelling has now been introdued for pimozide in the UK. Prokinetis Cisapride is gastrointestinal prokineti agent used to treat gastro-oesophageal reflux, gastroparesis, and hildhood hroni intestinal pseudo-obstrution; it is struturally similar to proainamide. In the USA, while isapride was being marketed from 1993 to 1999, the FDA reeived reports on a total of 341 individual patients who had serious adverse ardia effets following the use of isapride: 117 developed QT prolongation; 107 TdP; 16 polymorphi ventriular tahyardia; 27 ventriular tahyardia; 18 ventriular fibrillation; 25 ardia arrest; 16 serious (unspeified) arrhythmia; and 15 sudden death. 18 Eighty (23%) of the 341 patients died. Heart: first published as /heart on 31 Otober Downloaded from on 12 November 2018 by guest. Proteted by opyright.

9 Deaths were diretly or indiretly assoiated with an arrhythmi event. Many of the patients (56%) were also taking an imidazole ompound or a marolide antibioti, whih ould inhibit the P450 CYP3A4 isoenzyme that metabolises isapride and results in inreased serum onentrations. In the UK, sine isapride was first marketed in 1988 the Mediines Control Ageny has reeived reports of 60 serious ardia adverse drug reations, five of whih were fatal. These inluded 24 reations omprising ventriular arrhythmias, sudden unexplained death, ardia arrest, and QT prolongation. w54 Worldwide, there have been 386 reports of serious ventriular arrhythmias assoiated with isapride treatment, 125 of whih were fatal, and 50 reports of sudden unexplained death. In the UK, several relabellings of isapride were required following these inidenes, whih had a limited effet in reduing o-presription of isapride with ontraindiated mediation. Serious ardiovasular reations, inluding fatalities, ontinued to be reported. As a result, the Mediines Control Ageny suspended the produt lienes for isapride in the UK in July 2000 as the risks versus benefits balane was no longer onsidered favourable. Similarly, in the USA, the risk of fatal arrhythmia with isapride was believed to outweigh the benefit for the approved indiation, treatment of noturnal heartburn, leading to the drug s disontinuation there. Cisapride inhibited the I Kr urrent in isolated guinea pig ventriular myoytes in a onentration dependent manner with an IC50 of 15 nmol/l (therapeuti levels, nmol/l). w55 This explained the lengthening of ardia repolarisation observed in patients reeiving linial doses of isapride. Other QT prolonging drugs that have been withdrawn Early reports of TdP assoiated with ardia drugs inriminated not only antiarrhythmis, but antianginal agents suh as bepridil and prenylamine, both of whih have been well doumented to ause TdP. w56 w57 These antianginal agents have now been withdrawn from the market in most regulatory jurisditions. Terodiline, an antispasmodi agent used to treat urinary inontinene, was withdrawn in the UK following 69 reported ases of serious arrhythmias. Fourteen of these patients had sudden death and the remaining 55 patients had non-fatal arrhythmias, inluding 37 with ventriular tahyarrhythmia of whih 24 were aused by TdP. w58 It is now lear that the pro-arrhythmi effet of terodiline is a onsequene of the blokade of I Kr urrent, w59 whih ours in a onentration dependent manner. OTHER FACTORS THAT MAY INCREASE THE PROLONGATION OF VENTRICULAR REPOLARISATION OR PREDICT TORSADES DE POINTES Apart from drugs, other onditions that are likely to ause QT prolongation inlude: organi heart disease (for example, ongenital long QT syndrome, ishaemi heart disease, ongestive heart failure, dilated ardiomyopathy, hypertrophi ardiomyopathy, myoarditis, and Kawasaki syndrome) w60264 metaboli abnormalities (for example, hypokalaemia (by far the most ommon), hypoalaemia, hypomagnesaemia) w65267 w68 w69 bradyardia, atrioventriular and sinoatrial bloks drug related fators (for example, narrow therapeuti window, a multipliity of pharmaologial ations and inhibition and indution of ytohrome P450 enzymes, 19 w70 polypharmay) female preponderane, whih may be aused by sex w71 w72 differenes in speifi ardia ion densities hepati impairment. PREVENTION OF DRUG INDUCED QT PROLONGATION In linial pratie, adverse effets of QT prolonging drugs an be prevented by not exeeding the reommended dose, avoiding their use in patients with pre-existing heart disease or risk fators as mentioned above, previous ventriular arrhythmias, and/or eletrolyte imbalane suh as hypokalaemia. Conomitant administration of drugs that inhibit the ytohrome P450 (for example, imidazole antifungals, marolide antibiotis) or those that an prolong the QT interval or drugs that ause eletrolyte disturbane should be avoided. The serum potassium onentration should be heked regularly as a matter of routine are when the patient is on potassium wasting diuretis. Furthermore, it may be sound linial pratie to perform ECGs routinely before and after an initiation or inrement of dosage of a drug that may prolong the QT interval. If the patient develops TdP, the offending drug should be stopped and eletrolyte abnormalities orreted. Drugs that an prolong the QT interval should ideally be listed and regularly updated in a national drug formulary, whih is not the ase at present. Any adverse event suggestive of ardia arrhythmias should be reported urgently to drug safety authorities and/or drug manufaturers. The management of patients with drug indued TdP inludes identifying and withdrawing the offending drug(s), replenishing the potassium onentration to mmol/l, and infusing intravenous magnesium (1 2 g). In resistant ases, temporary ardia paing may be needed to inrease the heart rate and shorten the QT interval. REGULATORY PERSPECTIVE IN DRUG DEVELOPMENT Apart from antiarrhythmis, many drugs apable of induing TdP are non-ardia and are used for relatively benign onditions. Regulatory authorities in the European Union (EU) are now onerned that the risk should be identified and if possible quantified during the prelinial and linial development of a drug. Currently there are no ontemporary guidelines from other regulatory authorities to address this issue. In 1997, the UK Committee for Proprietary Mediinal Produts (CPMP) adopted a doument entitled Points to onsider: the assessment of the potential for QT interval prolongation by non-ardiovasular mediinal produts. 20 The CPMP guideline doument should be viewed as a strong signal from the publi health authorities that the problem of QT prolongation, espeially by non-ardia drugs, is signifiant and requires areful srutiny. Additional researh and development are needed for any ompound with the potential to prolong the QT interval. The CPMP doument details the neessary prelinial and linial stages required for testing the safety of new ative substanes. CONCLUSION It has been well reognised that a prolonged QT interval (ongenital or aquired) on the surfae ECG is assoiated with an inreased risk of TdP and/or sudden death. By far the most ommon ause of aquired long QT syndrome is drug indued, with antiarrhythmis being the group of drugs most 1371 Heart: first published as /heart on 31 Otober Downloaded from on 12 November 2018 by guest. Proteted by opyright.

10 1372 Drug indued QT prolongation and torsades de pointes: key points Drug indued QT prolongation and torsades de pointes are an inreasing publi health problem The blokade of I Kr potassium urrent by these drugs is responsible for their pro-arrhythmi effet Measurement of QT interval should be orreted for heart rate Antiarrhythmi drugs, non-sedating antihistamines, marolides antibiotis, antifungals, antimalarials, triyli antidepressants, neuroleptis, and prokinetis have all been impliated in ausing QT prolongation and/or torsades de pointes Co-administration of multiple drugs, espeially with other QT prolonging drug(s) and/or hepati ytohrome P450 CYP3A4 isoenzyme inhibitors, must be avoided The risk of QT prolongation is inreased in females, patients with organi heart disease (for example, ongenital long QT syndrome, myoardial infartion, ongestive heart failure, dilated ardiomyopathy, hypertrophi ardiomyopathy, bradyardia), hypokalaemia, and hepati impairment The treatment of drug indued torsades de pointes inludes identifying and withdrawing the offending drug(s), replenishing the potassium onentration to mmol/l, and infusing intravenous magnesium (1 2 g). In resistant ases, temporary ardia paing may be needed ommonly impliated. Sine the 1990s, seven non-ardia drugs marketed in the UK namely, terfenadine, astemizole, isapride, terodiline, halofantrine, sertindole, and pimozide have attrated regulatory attention beause of their propensity to produe QT prolongation, TdP, and/or sudden death. The list of drugs, espeially non-ardia drugs, whih an ause some degree of QT prolongation may ontinue to grow. The risk of TdP is therefore likely to remain a signifiant problem in the future. All physiians and pharmaists, and patients who reeive these drugs, should be made aware of this risk and eduated aordingly, and take preautions to minimise pro-arrhythmia. Prelinial and linial evaluations remain the ornerstone for assessing the arrhythmogeni potential of any new drug before approval. Finally, postmarketing surveillane is also important for monitoring spontaneous adverse ardia effets.... Authors affiliations Y G Yap, A J Camm, Department of Cardiologial Sienes, St George s Hospital Medial Shool, London, UK REFERENCES 1 De Ponti F, Poluzzi E, Montanaro N, et al. QT and psyhotropi drugs. Lanet 2000;356: Wysowski DK, Basanyi J. Cisapride and fatal arrhythmia. N Engl J Med 1996;335: Dapro B. Spetrum of drugs prolonging QT interval and the inidene of torsades de pointes. Eur Heart J 2001;3(suppl K):K A good review providing an insight into the inidene of drug indued TdP. 4 Antzelevith C, Siouri S. Clinial relevane of ardia arrhythmias generated by afterdepolarisation: role of M ells in the generation of U wave, triggered ativity, and torsades de pointes. J Am Coll Cardiol 1994;23: An important study that demonstrated the ellular mehanism of drug indued QT prolongation and TdP. 5 Roden DM. Torsades de pointes. Clin Cardiol 1993;16: Garson A Jr. How to measure the QT interval what is normal? Am J Cardiol 1993;72:14B 16B. A simple guide to measurement of the QT interval for linial use. 7 Moss AJ, Robinson JL. The long QT syndrome: geneti onsideration. Trends Cardiovas Med 1992;2: Hohnloser SH, Klingenheben T, Singh BN. Amiodarone-assoiated proarrhythmi effets. A review with speial referene to torsades de pointes tahyardia. Ann Intern Med 1994;121: Woosley RL, Chen Y, Freiman JP, et al. Mehanism of the ardiotoxi ations of terfenadine. JAMA 1993;269: A good desriptive paper summarising all the earlier ase reports on terfanidine indued arrhythmias and sudden death. This paper highlighted the importane of risk fators and drug2drug interation that predispose to drug indued TdP. 10 Lindquist M, Edwards IR. Risks of non-sedating antihistamines. Lanet 1997;349: Gitler B, Berger LS, Buffa SD. Torsades de pointes indued by erythromyin. Chest 1994;105: Jaillon P, Morganroth J, Brumpt I, Talbot G, and the ardiovasular safety data for sparfloxain. J Antimirob Chemother 1996;37(suppl):A Hagiwara T, Satoh S, Kasai Y, et al. A omparative study of the various fluoroquinolone antibaterial agents on the ardia ation potential in guinea pig right ventriular myoardium. Jpn J Pharmaol 2001;87: Oesterheld J. TCA ardiotoxiity: the latest. J Am Aad Child Adoles Psyhiatry 1996;34: Bukley NA, Whyte Im, Dawson AH. Cardiotoxiity more ommon in thioridazine overdose than with other neuroleptis. J Toxiol Clin Toxiol 1995;33: Rampe D, Murawsky MK, Grau J, et al. The antipsyhoti agent sertindole is a high affinity antagonist of the human ardia potassium hannel HERG. J Pharmaol Exp Ther 1998;286: Committee of Safety of Mediines. Cardia arrhythmias with pimozide (Orap). Current Problems in Pharmaovigilane 1995;21:1. 18 Wysowski DK, Corken A, Gallo-Torres H, et al. Postmarketing reports of QT prolongation and ventriular arrhythmia in assoiation with isapride and Food and Drug Administration regulatory ations. Am J Gastroenterol 2001;96: Zhang M-Q. Chemistry underlying the ardiotoxiity of antihistamines. Curr Med Chem 1997;4: Committee for Proprietary Mediinal Produts. Points to onsider: the assessment of the potential for QT interval prolongation by non-ardiovasular mediinal produts, CPMP/986/96. London: Committee for Proprietary Mediinal Produts, An important doument, this guideline is partiularly useful for the pharmaeutial industry when assessing the pro-arrhythmi toxiity of any new mediinal produt. Additional referenes appear on the Heart website Heart: first published as /heart on 31 Otober Downloaded from on 12 November 2018 by guest. Proteted by opyright.