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`Published in final edited formas:
`Curr Pharm Des. 2004 . 10(20): 2463-2475,
`
`Cardiovascular Side Effects of New Antidepressants and
`Antipsychotics: New Drugs, old Concerns?
`
`Pal Pacher!:2:" and Valeria Kecskemeti2”
`1 National Institutes ofHealth, National Institute on Alcohol Abuse & Alcoholism, Laboratory Physiologic
`Studies, Bethesda,MD 20892-8115, USA
`
`2Department ofPharmacology and Pharinacotherapy, Semmelweis University ofMedicine, Faculty of
`Medicines, Budapest Hungary
`
`Abstract
`
`The cardiovasculartoxicity of older generation of tricyclic antidepressants (e.g. imipramine,
`desipramine, amitriptyline, clomipramine) and neuroleptics (e.g. haloperidol, droperidol,
`thioridazine, pimozide) is well established. These drugs inhibit cardiovascular Na*, Ca?” and K~
`channels oficn leading to life-threatening arrhythmia.
`
`To overcomethe toxicity of old generation of antidepressants and antipsychotics, selective serotonin
`reuptake inhibitor antidepressants (SSRIs: fluoxetine, fluvoxamine, paroxetine, sertraline,
`citalopram, venlafaxin) and several newantipsychotics (c.g. clozapine, olanzapine, risperidone,
`sertindolc,. aripiprazole. ziprasidone, quetiapine) were introduced during the past decade. Although
`these new compoundsare not more effective in treating psychiatric disorders than older medications,
`they gained incredible popularity since they have been reported to have fewer and more benign side
`effect profile (including cardiovascular) than predecessors.
`
`Surprisingly. an increasing numberofcase reports have demonstrated that the use of SSRIs and new
`antipsychotics (c.g. clozapine, olanzapine, risperidone, sertindole, aripiprazole, ziprasidone,
`quetiapine) is associated with cases of arrhythmias, prolonged QTc interval on electrocardiogram
`(ECG) and orthostatic hypotensionin patients lacking cardiovascular disorders, raising new concerns
`about the putative cardiovascularsafety of these compounds. In agreementwith these clinical reports
`these new compounds indeed showmarked cardiovascular depressant effects in different mammalian
`and humancardiovascular preparations by inhibiting cardiac and vascular Na‘, Ca?* and K*
`channels. Taken together, these results suggest that the newgeneration of antidepressants and
`antipsychotics also have clinically important cardiac as well as vascular effects. Clinicians should
`be more vigilant about these potential adverse reactions and ECG control maybe suggested during
`therapy. especially in patients with cardiovascular disorders.
`
`The primarygoal ofthis reviewis to shed light on the recently observed clinically important
`cardiovascular effects of newantidepressants and antipsychotics and discuss the mechanism beyond
`this phenomenon.
`
`*Address Corresspondanceto these authors at the Department of Pharmacologyand Pharmacotherapy, Semmelweis University, Faculty
`of Medicine, Nagyvaradtér 4, P-O.Box 370, Budapest H 1445, Hungary, Tel: 36-1-2102930/6265; Fax: 36-1-2104412; E-mail:
`keesval(@pharma.sote.hu and NationalInstitutes of Health, NIAAA,Park Bldg., Rm. 445, 12420 Parklawn Drive, MSC-8$115, Bethesda,
`MD2 20892-8115 USA;Tel: 301-496-6777; Fax: 301-480-0257, E-mails: ppacher@lycos.com.
`
`1
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`Exhibit 2055
`Slayback v. Sumitomo
`IPR2020-01053
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`IPR2020-01053
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`Pacher and Keeskemeti
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`Keywords
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`Page 2
`
`antidepressants; neuroleptics; antipsychotics, QT prolongation; arrhythmia; cardiac ion channels;
`repolarization
`
`INTRODUCTION
`
`Cardiovascular mortality in psychiatric patients is high. Reports of sudden unexplained death
`in those taking psychotropic drugs, including neuroleptics and antidepressants, have raised the
`concern that part of this excess maybe duc to drug-induced arrhythmias, since manyof these
`drugs have cardiac electrophysiological effects similar to those of quinidine. Indeed, it has
`recently been established that old generation of antidepressants (tricyclic antidepressants
`(TCAs) and antipsychotics (c.g. haloperidol, droperidol, thioridazine, pimozide) can be
`associated with increased risk of cardiac arrhythmias and sudden death [reviewed in 1-7),
`
`In contrast, newgeneration of selective serotonin reuptake inhibitor antidepressants (SSRIs:
`fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram, venlafaxin) and several new
`antipsychotics (e.g. clozapine, olanzapine, risperidone, sertindole, aripiprazole, ziprasidone,
`quetiapine risperidal) are considered to be free from the cardiotoxicity of their predecessors.
`However, there are increasing numberof case reports on various arrhythmias and syncope
`associated with the use of these new compounds [reviewedin: 3, 5-9) . Inadditionrecentstudies
`have demonstrated that the new SSRIs and antipsychotics also exert potent cardiovascular
`depressanteffects in various mammalian and human cardiovascular preparations byinhibiting
`cardiac and vascular Na’. Ca?’ and K* channels. This reviewis concerned with the
`cardiovascular effects of newantidepressants and antipsychotics.
`
`1. CARDIOVASCULAR EFFECTS OF ANTIDEPRES-SANTS
`
`1.1. Clinical Evidence
`
`1.1.1. Cardiovascular Effects of Tricyclic Antidepressants (TCAs)—The
`cardiovascular effects and toxicity of tricyclic antidepressants have been well documentedin
`depressed patients without pre-existing cardiac disease | 1,3, 10-11 |. The most common
`manifestation of such effect is the slowing ofintraventricular conduction, manifested by
`prolonged PR, QRSand QTintervals on the standard ECG,and othostatic hypotension j2-
`5}. The prolonged conduction can be dangerous in overdose and depressed patients with
`preexisting conduction defect and in paticnts who have already been treated with a classI
`(Na*-channel blocking) antiarrhythmic agent jl6-I 71. In overdose, delayed conduction may
`result ina complete heart block or ventricular reentry arrhythmias. Any of these complications,
`or a combinationof both, maylead to death [8-2 |. Depressed patients with conduction
`disease, particularly bundle branchblock, being treated with TCAsat therapeutic plasma levels,
`are at a higherrisk of developing symptomatic AV block than those of free from conduction
`disorders jlO-17). Tricyclic antidepressants have also been found to exert I/A class
`antiarrhythmic effects (2 I ~23), Children seemto beespecially vulnerable to cardiotoxic effects
`of high doses of tricyclic compounds, Death has occurred in children after accidental or
`deliberate overdose with only a few hundred milligrams of drug (24). Sincetricyclic
`antidepressants can cause orthostatic hypotension. induce arrhythmiaat higher doses ortissue
`concentrations, and interact unpredictably with other drugs, as do the serotonin-reuptake
`inhibitors, they must be used with great cautionin patients with cardiac disease [! I .
`
`1.1.2. Cardiovascular Effects of Selective Serotonin ReuptakeInhibitors (SSRIs)
`—The most human clinical studies with SSRIs like fluoxetine, fluvoxamin, paroxetine,
`sertaline and citalopram showedsignificant advantages over TCAsin producing fewer
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`cardiotonic, anticholinergic and antihistaminergic side effects in the treatment of major
`depressive disorders [reviewed in-3}. These newercompoundsexhibited lowerrisk ofinchicg
`hypotension and a higher margin ofsafety in acute overdose thantricyclics [reviewedin -3}.
`However,it is interesting to note that the results of some animalstudies were not always so
`clear cut. For example, early preclinical studies in cats with the highly selectiveom
`reuptake inhibitor, citalopram, showed TCA-like cardiac effects at high doses|25), and the
`developmentof citalopram was delayed byreports ofcarters in dogs, eventually
`attributed to a species-specific metabolite not found in humans (2 |.
`
`The SSRI drug,ofthat the mostinformation is available, is fluoxetine [77] used for oral
`administration;it is chemically unrelated to tricyclic, tetracyclic antidepressantagents. Several
`clinical studies showed that comparedto tricyclic antidepressants, fluoxetine causes
`significantly fewereinen antihistaminergic and cardiovascularside effects
`[reviewed in: 3, 8-9|. However, even with fluoxetine one must be cautious in the conclusions
`drawnbecausethe patients that have been carefully studied are, in general, depressed patients
`free ofcardiovasculardisease, endoonly verylimited informationis available in paticnts having
`cardiovascular disease as well (28-31). The SSRIs do have cardiac effects, the best
`demonstrated of those being a mild bradycardia observed during chronic treatment with
`fluoxetine, fluvoxamin, paroxetine [reviewed in 3,88). This usually amountsto onlya fewbeats
`per minute butit is the opposite ofthe tachycardia that has beenassociated with tricyclic ies
`Analysing large number of ECG recordings from citalopram-treated patients Enemark |~32)
`reported that citalopram-treatment also reduced the heart rate. This reduction occurred within
`the first week of the treatment without further reduction later. In a small group of citalopram-
`treated patients (3—4%) with normalheart rate at baseline bradycardia was developed.
`Furthermore, citalopram treatment was associated with a non-specific, insignificant
`prolongation of QTinterval irrespective of age. In younger groupof the paticntsa statistically
`significant decrease in T-wave amplitude was also demonstrated [- 2). Moreover.there are
`increasing numberofcase reports on dyshyoa and syncope associated with fluoxetine and
`another SSRIs treatment and overdose ps 58}. A multicenter case-control study has shown
`that in the elderly the consumption of noe wassignificantly associated with an excess
`risk ofsyncope and orthostatic hypotension >91. A penton blood pressure lowering effect
`of fluoxetine was reported in DOCA-hypertensive rats (6!1, The authors suggested that a
`central action of fluoxetine on vasomotorcenter maybe responsible for the reduction of blood
`pressure, but the possible direct cardiac and/or vascular effects of fluoxetine were not excluded
`or determined.Interestingly, several recent studies have provided evidence that fluoxetine and
`citalopram directly inhibit Ca?* entry into vascular and intestinal smooth musclesresulting in
`vasodilation = intestinal relaxation, effects, which could be ofsignificant therapeutic
`importance. (° 1-64|. Surprisinglyresults from recently published retrospective studies show
`that the use of new SSRIs,similarly e the old TCAs,increasesthe risk offalls and hip fracture
`among elderly people [reviewed in 1.
`
`1.2, Cellular Electrophysiological Effects
`
`Electrophysiological studies (using a broad range ofin vitro models) demonstrated that both
`antidepressants and antipsychotics exerted their cardiac actions by modifying the different
`cardiac ionic currents during the action potential (Fig. 1).
`
`1.2.1. Cellular Electrophysiological Effects of TCAs—Inclectrophysiological studies
`on isolated mammalian multicellular cardiac preparations and single myocytes, TCAs, such as
`imipramine, chlorimipramine amitriptyline, desipramine, dibenzepin, lofepramine and
`
`amoxapine, were demonstrated to reduce the maximum velocity ofCopokatagiona of
`the action potential, an indirect indexof the fast inward sodium current, Ina.| 65-6
`Furthermore, imipramine also blocks the outward delayed rectifier K* current (Ix) is the
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`inward slow Ca2* (Icq) currents in eulncsapis ventricular myocytes and transient outward
`K* current (Ito) in rabbit atrial cells {7°
`]. These direct membraneeffects explain a variety
`ofcharacteristic ECG abnormalitieslike prolongation of PQ. QRS, and QT,and cardiac adverse
`effects including tachyarrhythmias, heart block, oae nae failure, observed during
`tricyclic antidepressants treatment and overdose ji. 3 10-14, 19). The effects of imipramine
`onaction potential Suetion (APD) showimportant species peetcr In bovine ventricular
`[75 and Purkinje fibers |65|, guinea-pig papillary muscles {7 7 and isolated vee
`myocytes | /70) imipramine shortened the APD, whereas in rabbit andratatrial fibers [78“79
`it lengthened the APD. Thedifferenteffects of imipramine on APD can be explained bythe
`important differences in the ionic currents responsible for the snares among animal
`species. In guinea-pig ventricular myocytes where |, is relativelylittle (’4), the APDis
`controlled bythe interaction oeeen inward (Ix and I¢q) and outwardes (x and Tx)).
`Imipramine decreased the Ix, [8 ly, Ix andIg, but did not modify the Ix, (70» 75 |. The reduction
`of the APD in bovineaepues pig ventricular preparations could be an mainly by
`inhibition ofIca j5, 70
`1]. In contrast, in rat, rabbit and human atria (o4 80, 82) gand rat
`ventricular myocytesthe Ix is negligible and ],, appears to be the most important outward
`K’ current responsible for action potential repolarization. Thus the reduction ofI, could
`explain the prolongation of the APD observed in above-mentioned species. More recently
`several antidepressants with different chemical structures (imipramine, amitriptyline,
`naianeesine, maprotiline and trazodone) were reported to block transient outward K~ current
`(Ito) é3).
`
`1.2.2. Cellular Electrophysiological Effects of SSRIs
`
`1.2.2.1. Effects of SSRIs on Cardiac Action Potentials (APs) In vitro: Wepreviously
`demonstrated that fluoxetine elicited a concentration dependent depression of the amplitude
`ofaction potential (APA), overshoot (OS) and the maximumrateofrise of depolarization phase
`(Vmax) in multicellular ventricular kc
`tions of rats, rabbits and dogs without changing the
`resting membrane potential (RP) [s4- 5}. The significant threshold concentrations were more
`or less similar (3—10 4M)in various species (including the most sensitive isolated canine
`myocytes). Fluoxctine caused a nearlysimilar shortening of the duration of ventricular action
`potential (APD)in three species (guinea pig. rabbit, canine), but not in rats. Fluoxetine caused
`a concentration-dependentdecreasein force of contractionin rat right ventricular papillary
`muscle with a calculated [C59 value of 9.86 uM. Citalopramsimilarly to fluoxetine elicited a
`concentration-dependent (10-100 1M)reduction of Vmax, decrease ofAPA, OS and
`shortening of APA in guinea-pig ventricular papillary muscle (86). Fluoxetine and citalopram
`produced a dose-dependent decrease of V max (an indirect indicator of the fast Na’ channel
`activity), which suggests that they inhibited the activation of fast Na* channels and exhibited
`class | anti-arrhythmic effects. A possible explanation of the decrease in APA and OS and
`shortening ofthe early part of repolarization (APDso) can be the inhibition of the calcium
`current (I¢q). This latter mechanism mayalso be responsible for the negative inotropic effect
`of fluoxetine. The inhibitory effect of fluoxetine on peak Ca?* current wasprovenin voltage
`clamped canine ventricular myocytes by ICs value of 5.4 1M. This effect may cause
`lengthening ofatrioventricular conduction. Considering its Na* and Ca?* currents inhibitory
`action, fluoxetine mayhave antiarrhythmic as well as pro-arrhythmic properties (due to
`impairementof atrioventricular or intraventricular conduction). As far as the different effects
`of fluoxetine on rat ventricular APD are concerned, these can be explained bythe unique ion
`regulation characteristic to ventricular repolarization phase of rat markedlydifferent from that
`ofother mammalian species [87]. Similar cardiac clectrophysiological effects with venlafaxine
`were observedin guinea-pig cardiac myocytes (88). Thesedirect cardiac effects of fluoxetine
`and citalopramare similar to those found byus for TCA clomipramine (8) and previously
`reported for the tri- and tetracyclic antidepressants |” ].
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`1.2.2.2. Effects of SSRIs on Cardiac lon Channels: Previous and recent studies demonstrated
`that fluoxetine and other SSRIs —aiantagonistic properties on celaeee
`ion channels in different tissues ps4
`6). The ICsg values of SSRIs for Na*, Ca?* and
`K* channels of mainly cardiac tissues are summarized in Table 1. Fluoxetine inhibited L-type
`of Ca?*(Cay?*) currentin both rat and canine ventricular myocytes, be itspotency was twice
`as high in rat (C59 2.8 uM) than in caninesyonyite (IC59 5.4 uM) (34> 99), It is interesting
`to note that sertraline also inhibited the Ca; 2° current in rat myocytesandits inhibitoryactivity
`(I1Csg= 2.3 4M)wassimilarto that of fluoxetine, while citalopram inhibited Ca;?* current of
`guinea-pig myocytes at much higher concentration (100 wM) [25> 195). These data provide
`evidence that inhibition of cardiac Cay2* current could play an importantrole in reducing
`cardiac contractility, heart rate and atrio-ventricularconduction. The proposed mechanism may
`explain the prolonged PRinterval, AV block, hypotension, which are commoncardiovascular
`complications of fluoxetine therapy.
`
`Fluoxetine and citalopram have a highaporn (ICsg=3.1, 1.5 and 3.97 yM,
`respectively) on HERG potassium channel (9+
`5]. The Auman ether-a-go-go-related gence,
`HERG, is believed to encodethe protein, which underlies the rapid componentof the delayed
`rectifier K* current Ix,. HERG encoded I x, plays an important part in the repolarization of the
`cardiac action potential. Pharmacological inhibition ofeither heterologously expressed HERG
`or native Ix, would thus be expectedto correlate with ventricular action potential prolongation
`and associated prolongation of the QTc interval on ECG. Thus the HERGcurrent inhibition
`byfluoxetine and citalopram may give an explanation for the arrhythmogenic side effects
`(ventricular tachycardias) of these drugs. It is very important to note that this current inhibition
`can occurat nearly therapeutic levels of these drugs, thus this effect should be considered
`during the therapy.
`
`SSRIs also exhibit potent inhibitoryeffects on various voltage-dependent ion channels in non-
`cardiac tissues. Some of these effects are summarized in the Table 1, but the detailed description
`is beyond the scopeofthis review.
`
`The inhibitory concentrations of SSRIs on cardiac APs and ion current were in the upper range
`of the therapeutic plasma levels p107 |. However, it is difficult to relate in vivo plasma
`concentrations to én viiro concentrations as pharmacokinetic properties (tissue accumulation,
`metabolites) of the drug must also be considered. Undercertain conditions (c.g. incase of drug
`interactions or reduced metabolism in elderly) the plasma concentration of SSRIs can reach
`even higherlevels. Thus, a significant inhibition of various cardiovascular ion channels by
`SSRIs mayoccurin patients chronicallytreated with these compounds,resulting in certain pro-
`or arrhythmiceffects. [reviewed in ~].
`
`2. CARDIOVASCULAR EFFECTS OF NEUROLEPTICS
`
`2.1, Clinical Evidence
`
`The aim ofthis part of the reviewis to organise the available evidences on cardiac/
`cardiovascularside effects; proarrhythmic potential of antipsychotic drugs andto discusstheir
`actions on cardiac ion currents as proposed explanationoftheir proarrhythmic effects.
`
`Antipsychotic drugs represent a chemically various group of compounds. Antipsychotic drugs
`canbe classified typical (older drugs acting on dopamine Dj, D>, adrenergic a). muscarinic
`cholinergic, 5-HT> and histamine H)-receptors and associated with different side effects) and
`atypical (newerdrugs inhibiting mainly both D2 and 5-HT2,receptors and have a higher
`efficacy and fewerside effects) groups. Amongatypical antipsychotics clozapine shows
`marked esgee fromthe others binding more to Dy, 5-HTand a, receptors than to D2
`receptor. jo8). Aripiprazole is a first memberof a newclass of atypical antipsychotics have
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`also unique properties showing a combinedipartialagonist activity at Dz and 5-HT|,, receptors
`with an antagonism at 5-HT2,receptors !
`Vy
`
`Antipsychotic drugs have long been knownto be associated with risk of cardiac arrhythmia
`and cardiac arrest. These arrhythmias are often reflected as changes in the electrocardiogram
`(ECG),prolongation of the QT interval, ventricular tachycardias, torsades de pointes (TdP).
`TdPisa potentially life-threatening ventricular tachyarrhythmia thatis associated with sy ncope
`and sudden death. TdP is characterized by a twisting morphology of the QRS complex around
`the isoelectric baseline and can occur in congenital and acquired form induced byvarious
`
`cardiac and non-cardiac drugs. Among antipsychotics taleperel, dro1gees pimozide,
`sertindole,thioridazine were foundto cause definitively TdP pil 2-118).
`Several other
`antipsychotics includingtypical (chlorpromazine, fluphenazine, vente.
`ocienen Ree, sultopride)| 119-12 ] (quetiapine, olanzapine, risperidone,
`ziprasidone)| 122-127 | have beenreported to prolong the corrected OT interval (corrected for
`heart rate)(QTc). Both an Australian and a Finnish study ofneuroleptic poisoning demonstrated
`that thioridazine caused the moet frequently tachycardia, prolonged QTc. widened QRS,
`arrhythmias and sudden death (220, 28). Thioridazine and Spero:wear found to be
`associated with prolongation of QTc even at dosage used for therapy [2| and basedonthis
`studythe indications ofthioridazine were cyge and droperidol was voluntarily
`discontinued by the manufacturer in UK pil4), Pimozide, sultopiride and droperidole also
`prolong QTc ehpeat have been associated with TdP and sudden death, but far fewerdata
`areavailable jl2
`30), The high-potency drug ena can prolong QTc interval, causes
`TdP and sudden death at normal therapeuticdoses [*” I), but the frequency by which these
`effects occuris less than with thioridazine | 1288). Similar cardiovascular risks of traditional
`antipsychotics used at therapeutic dosage were published in the USA i-a retrospective study
`investigating 481.744 persons (aged 15-84 years, from 1988 to 1993) [}32}.
`
`The newatypical antipsychotics have greater efficacy and fewerside effects than older
`neuroleptics and with the exceptions of sertindole and ziprasidone they have not caused
`consistentoesignificant lengthening ofQT or sudden cardiac death at therapeutic
`concentrations il
`3]. Sertindole has becn provento be associated with a QT prolongation
`at therapeutic concentrations it 17, 124) and bothincreasing evidence of unexplained sudden
`cardiac death and serious arrhythmias found by the Committee on Safety ofMedicine imane
`United Kingdomresulted in a voluntary withdrawal of the drug by the manufacturer ps4).
`Albeit the known correlation between schizophrenia and increased cardiovascular mortalityit
`ma oe to estimate the sudden death due to particular neuroleptics at therapeutic doses
`| 135, 1 36), Clozapine beyond the well-known agranulocytosisrisk, is being associated with
`myocarditis, cardiomyopathyand arrhythmogenesis risk 137. 138 He also reduced measures
`of heart rate variability associated with parasympathetic control jl24]. In the study of
`overdoses, clozapine overdose was associated with sinus tachycardia (more than 66% ofthe
`patients) anaesit the case of risperidone overdose more than 66% ofthe patients were
`asyReet (39. However,there are data suggesting that risperidone could cause sudden
`death pl25}. Neither olanzapine nor quetiapine had been implicated in cases of TdP or sudden
`death.
`
`Ziprasidoneis a newatypical drug with less side effects and in comparison with olanzapine
`and risperidone it does not appear to cause weight gain, hyperlipidemia and hyperglycaemia
`
`(12 rolongs the QT interval more than haloperidol, olanzapine, quetiapine and risperidone
`27). Althoughit was not associated with cardiac events during premarketing trials the
`ene ofunexpected life-threatening arrhythmias can not be excluded when the drug
`
`enters widespread use.
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`2.2. Mechanism of the Lengthening of QTInterval
`
`The QTinterval includes both depolarization and repolarization. Q waverepresents the onset
`of ventricular depolarization, while T waveis the sign of the repolarization. Because the QT
`interval shortens with increasing heart rates, it is usually corrected for heart rate (QTc).
`Depolarization ofventricularcells is the result ofa rapid influx of sodium ions through selective
`Na’ channel and its duration measured by the QRS interval. Repolarization involves calcium,
`sodium, and different potassium channels. Whereas the participation of these ion channels in
`the repolarization is highly dependent on species, mainly potassium channels are responsible
`for this parameter. Concerning the specificity of QT prolongation as a markerof an effect on
`cardiac repolarisation, it should be kept in mind that the duration of the QT interval maybe
`affected byboth the velocity of repolarisation and ventricular conduction velocity. Class I
`antiarrhythmics as sodium channel blockers, decrease ventricular aia velocity, cause
`widening of QRS complexand therefore lengthen the QT interval (491. Similar action can be
`observedin the case of tricyclic antidepressants which by blocking Na” as well K* channels
`widen both the QRS and the QTc. The potassium channels (among them I,) are most often
`involved in drug-induced QT prolongation and TdP. Drug!Lacking the IKrchannel can induce
`QTprolongation and TdP and sometimes sudden death ji+ y. However. there is no close
`correlation between QTc interval prolongation and occurrence of TdP. Notall drugs that
`prolong the QTc interval produce TdP. Amiodarone,a class III antiarrhythmic drug, produces
`marked prolongation of QTc interval but docs not evoke TdP. The calcium-channel blocker
`verapamil has been alown to prolong QTinterval in a mannerthatis linearly correlatedto its
`spc concentration [!42} but there are fewdescribed casesofverapamil-induced TdP
`it 43), Noclear-cut dose-dependencycanalso be observed for QT prolongation or occurrence
`of TdP. In some cases the QT prolongation and occurrence of TdP is dose dependentbut these
`parameters can also be observed at normal plasma levels ofdrugs, too ji44). Inthe latter several
`factors (hypokalaemia/magnesaemia, mutation of K* channels) reducing the repolarization
`eh=a given subject greatly increase the proarrhythmic potential of relatively low plasma
`level [?>
`‘].
`
`The link between the lengthening of QT interval and TdP is seemingly very complex and
`affected byseveral factors including electrolyte imbalance, age, gender, disease (myocardial
`ischemia, infarction, hypertension, hypothyroidism, diabetes, renal or hepatic dysfunction) and
`concomitant medications.
`
`2.3. Cellular Electrophysiological Effects of Neuroleptics
`Most ofantipsychotics are generally lengthenthe action potential duration (APD)and inhibit
`the rapid componentof the delayed rectifier current (I,,) but some of the typical antipsychotics
`including ipo andpagent, beyond their inhibitory effect on K~ current inhibit
`also Na* and Ca?* channels (8 1). Such effects could be antiarrhythmic orcardiotoxic,
`depending on the health (e.g. post myocardial infarct) of the myocardium. Thenet effect on
`APDofantipsychotics depend on the overall balance between inward and outward currents
`during the plateau phase of AP andtheir relative sensitivity to the particular agent in question.
`Table 2. summarizes the inhibitory potencyof antipsychotic drugs on K“(Ik. Ito. Ik. HERG)
`and other ion (Na”, Ca") currents. In humanIx,is carried by the humanether-a-go-go (HERG)
`K* channel, which can be expressed in homologousand heterologouscells in orderto assess
`the potency (ICs9) of a drug in inhibiting this channel. Haloperidol and droperidol prolong
`APDinguinea-pig ventricular myocytes and inhibit Ix, and HERG with ICs9 values of 20
`nM-1.36 uMand 32.2 1M,respectively and the effects of haloperidol on eS are overfive
`aoeenty times more potent than its effects on Iy, and Icy), respectively (3!» 145-146, 150,
`63}. Thioridazine also lengthened APD in guinea-pig ventricular myory-ae potently
`inhibited I, and HERG (IC«q values of 1.25 uM, 191 nMand | yM) [!47-
`!49), Comparative
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`Curr Pharm Des. Author manuscript, available in PMC 2008 August 1.
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`Pacher and Keeskemeti
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`study showed that neweratypical antipsychotic ziprasidone, olaseapine, risperidone block
`HERGandIx; ina more orless similar concentration range (}
`if
`
`Figures (2 and 3) showthat risperidone concentration-dependently increased APDin both
`guinea-pig ventricular muscle (Fig. 2A) and canine ventricular myocytes (Fig. 3B). This effect
`was most prominent on terminal phase of repolarization (APDog) (with ECso values of 0.29
`uM and 0.48 iM in guinea pig and canine myocytes,respectively) (Fig. 3C) and showed reverse
`tate dependence (Fig. 2B). Haloperidol had similar effect on APD (Fig. 2C) but reduced also
`the maximum velocityofdepolarization (V,,,,)(indirect indicator ofNa* channelactivity)(Fig.
`2D) while risperidone was ineffective on this parameter. We found thatrisperidone
`concentration-dependently inhibited Ix, with an IC59 of 0.92 4M and practically had no effect
`on the other K‘ currents(1, with ICs >10 wM,Ixy with ICsg >100 uM) [!51}. Similareffects
`of re on both APD andIx,in rabbit ventricular myocardium and myocytes were
`observed | 152lwme lowerICsgvalues (167 and 261 nM, respectively) were found in HERG
`channelbyothers | 147, 155),
`
`Sertindole was found to be a high affinity antagonist of the human cardiac K' channel HERG
`(ICsg= 3 and 14 nM)but wasless active at blocking other K* currents (Kv 1.5, Ijo with
`ICso=2.1 and 10 uM, respectively) [147. 148, 153],
`pimozide potentlyinhibited cardiagHERGK*channel (IC59 values of 18 and 174 nM) ie
`oe the inhibitory action onHERGchannel sertindole and pimozide also blocked the
`30), increased the risk of TdP pls4 and also blocked Ica; in rat ventricular myocytes[ 56|.
`human brain K* channelerg3. Sertindole blockeder;ef 3 channel currents with an ICs9 of 43
`nM, while pimozide had an ICs9 value of 103 nM il 7]. It was suggested that this inhibition
`of erg3 related K* channels in the brain might contribute to their cfficacy/side effect profiles.
`
`Comparing the HERG channel inhibitory activity of seven antipsychotics drugs (olanzapine,
`pimozide. quetiapine. risperidone, sertindole. thioridazine, ziprasidone)to their binding
`affinities for Dy and 5-HT}, receptors the following selectivity rank was found: olanzepine >
`risperidone > ziprasidone > thioridazine > pimozide > sertindole. Sertindole and pimozide had
`the highest HERG channelinhibitory activity, while the lowest inhibitory activity can be
`observed in the case of olanzapine and quetiapine. These results also showedthatsertindole,
`pimozide, thioridazine displayed little or no selectivity for dopamine Dz or 5-HT2, receptors
`relative to their HERG channelaffinities, and olanzapine had the greatestselectivity for
`dopamine D, and 5-HT>, receptor binding compared to the HERG channel. In the case of
`quetiapine the selectivity was not calculated due to its lack of affinity for the dopamine D>
`recepm,Esamainien the relationship between plasma levels and QT prolongation for these
`drugs ji27 the authors also found a good correlation between ae)ang oftotal plasma drug
`concentration to HERG ICs, and their QTc prolongation effect i+7. Based uponthis in
`vilro results drug’s selectivity (between their target receptoraffinity and their HERG channel
`ICs value) seems to be a predictive factor for appearance ofQT prolongation in clinic. Itwould
`be expected that olanzepine and risperidone, displaying highselectivity, would havethe least
`potential to produce QT prolongationin clinical settings.
`
`However,it is widely accepted that most QT prolonging drugsinhibit Ix, but the potency of
`drug-induced block of Ix, does not showa clear correlation with the risk of QT prolongation
`and moran ofTdP.In isolated feline hearts haloperidol prolongs QT interval more than
`sertindole pi59}. while sertindole is 10-300 times more potent as a blocker ofHERGthan
`haloperidole (Table 2). In addition, some aoeeee that thioridazine and chlorpromazine
`have similar potenciesfor inhibition of HERG pis8) and in stepwise regression analysis of 495
`beyctentpatients thioridazine wasassociatedwithQT prolongation, butchlorpromazine was
`not| 128|. These d