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`Published in final edited fomi as:
`(‘urr Phnrm Dev. 2004 ; l0(20): 2463—2475.
`
`Cardiovascular Side Effects of New Antidepressants and
`
`Antipsychotics: New Drugs, old Concerns?
`
`Pal Pacher1»2-' and Valeria Kecskemetiz.
`1.\'ali'(mal Institutes o/‘Healrh. National Institute on . llcohal .tlbuse dis Alcoholism. Laboratory Physiologic
`Studies. Bethesda. MD 20892-8115.
`(ASL-l
`
`ZDepnrtmem ofl’harmacologv and Pharmacotherapt'. .S‘emmelwcls Universnjv QfMedtcme. Focultv of
`illcdtcmes. Budapest Hungan'
`
`Abstract
`
`The cardiovascular toxicity of older generation of tricyclic antidepressants (cg. imipramine.
`desipraminc. amiiriptvline. clomipraminc) and neurolcptics (e. g. halopcridol. droperidol.
`thioridazinc. pimozidc) is well established. These drugs inhibit cardiovascular Na‘. Caz‘ and K”
`channels often leading to life-threatening an'hythmia.
`
`To overcome the toxicity of old generation of antidepressants and antipsychoties. selective serotonin
`reuptake inhibitor antidepressants (SSRls: fluoxctine. fluvoxamine. paroxetine. sertraline.
`citalopram. maintain) and several new antipsychotics (cg. clompinc. olanzapine. rispcridone.
`scrtindole. aripiprazolc. ziprasidonc. quctiapinc) were introduced during the past decade. Although
`these new compounds are 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 number of case reports have demonstrated that the use of SSRls and new
`antipsyehoties (e.g. clompinc. olanzapinc. rispen‘done. sertindolc. an'piprazolc. ziprasidonc.
`quetiapine) is associated with cases of arrirythmias. prolonged QTc interval on electrocardiogram
`(ECG) and orthostalie hypotcnsion in patients lacking cardiovasculardisorders. raising new eoucems
`about the putative cardiovascular safety of these compounds. In agreement with these clinical reports
`these new compounds indeed show marked cardiovascular depressant effects in different mammalian
`and human cardiovascular preparations by inhibiting cardiac and vascular Na’. Caz‘ and K‘
`channels. Taken togetherl these results suggest that the new generation of antidepressants and
`antipsyehotics also have clinically important cardiac as well as vascular effects. Clinicians should
`be more vigilant about these potential adverse reactions and ECG control may be suggested during
`therapy. especially in patients with cardiovascular disorders.
`
`The primary goal of this review is to shed light on the recently observed clinically important
`cardiovascular efl‘ects of new antidepressants and antipa'ehotics and discuss the mechanism beyond
`this phenomenon.
`
`‘Address Corresspondancc tothesc authors at the Department of l’ltannacolog)’ and Phannaeothcrnpv. Scmmclweis University. Faculty
`of Medicine. Nagyvaratl ier 4. PI) Hot 370. Budapest H 1445. Hungary. 'l'el’ 364-2 "129106265; Fax: 36- l-2104-ll2'. l‘Z-mail:
`kecsval/(iphatmasotehu and National institutes ol'llealth. NMAA. Park Bldg. Rm. 445. l2420 Parklnwn Drive. MSC-Sl lS. Bethesda.
`MDZ 20892-8l15 USA. Tel. 301-496-6777. Fax. 301-480-0257; E-Iuails. ppachcrffillvcusicmn.
`
`Exhibit 2055
`Slayback v. Sumitomo
`|PR2020—01053
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`Exhibit 2055
`Slayback v. Sumitomo
`IPR2020-01053
`
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`Keywords
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`Page 2
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`antidepressants: neuroleptics; antipsy chotics; QT prolongation; arrhythmia; cardiac ion channels;
`repolarization
`
`INTRODUCTION
`
`Cardiovascular mortality in pagchiatric patients is high. Reports of sudden unexplained death
`in those taking psychotropic drugs. including neuroleptics and antidepressants. have raised the
`concern that pan of this excess may be due to dnig-induced arrhythmias. since many of these
`drugs have cardiac electrophysiologieal effects similar to those of quinidine. Indeed. it has
`recently been established that old generation of antidepressants (tricyclic antidepressants
`(TCAs) and antipsychotics (cg. halopcridol. dropcridol. thioridazinc. pimozidc) can be
`associated with increased risk of cardiac arrirythmias arid sudden death [reviewed in 1'7].
`
`In contrast. new generation of selective serotonin rcuptake inhibitor antidepressants (SSRls:
`fluoxetine. flnvoxamine. paroxetine. sertraline. citalopram. venlafaxin) and several new
`antipsycltotics (cg. clompinc. olanrapinc. rispcridonc. scrtindolc. aripipramlc. xiprasidone.
`quetiapine risperidal) are considered to be Free from the cardioloxicity of their predecessors.
`However. there are increasing number of case reports on various arrh) thmias and syncope
`associated with the use of these new compounds [reviewed in: 3- 5'9]. In addition recent Studies
`have demonstrated that the new SSRls and antipsychoties also exert potent cardiovascular
`depressant effects in various mammalian and human cardiovascular preparations by inhibiting
`cardiac and vascular Na . Caz' and K" channels. This review is concerned with the
`cardiovascular effects of new antidepressants and antipsychotics.
`
`1. CARDIOVASCULAR EFFECTS OF ANTIDEPRES-SANTS
`
`1.1. Clinical Evidence
`
`1.1.1. Cardiovascular Effects of Tricyclic Antidepressants (TCAsl—The
`cardiovascular effects and toxicity of tricyclic antidepressants have been well documented in
`depressed patients without pro-existing cardiac disease |L 3- 10‘Ill. The most common
`manifestation of such effect is the slowing of intraventricular conduction manifested by
`prolonged PR. QRS and QT intervals on the standard ECG. and ethostatic hypotension '12—
`5]. The prolonged conduction can be dangerous in overdose and depressed patients with
`preexisting conduction defect and in patients who have already been treated with a class I
`(Na-channel blocking) antiarrhythmic agent [I64 7]. In overdose. delayed conduction may
`result in a complete heart block or ventricrtlar reertt
`‘ arrhythmias. Any of these complications.
`or a combination of both. may lead to death [18—2 |. Depressed patients with conductiotr
`disease. particularly bundle branchblock. being treated with TCAs at therapeutic plasma levels.
`are at a higher risk of developing symptomatic AV block titan those of free from conduction
`disorders [16—17]. Tricvclie antidepressants have also been found to exert l/A class
`antiarrhythmic effects |2 I “23]. Children scent to beespecially vulnerable to cardiotoxic effects
`of high doses of tricyclic compounds. Death has occuned in children after accidental or
`deliberate overdose with only a few hundred milligrams of drug [24]. Since tricyclic
`antidepressants can cause orthostatic hypotension. induce arrhythmia at higher doses or tissue
`concentrations. and interact unpredictably with other drugs. as do the serotonin-ten ta_ke
`inhibitors. they must be used with great caution in patients with cardiac disease [I "I j].
`
`1 .1 .2. Cardiovascular Effects of Selective Serotonin Reuptake Inhibitors (SSRIs)
`—The most human clinical studies with 551215 like fluoxetine. fluvoxamin. paroxetine.
`senaline and citalopram showed significant advantages over TCAs in producing fewer
`
`L'm'r Phann Dar. Author manuscnpt; available tn PMC 2008 August I.
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`cardiotoxic. anticholinergic and antihistaminergic side efi'ects in the treatment of major
`depressive disorders [reviewed in 3]. These newer compounds exhibited lower risk of inducing
`hypotension arid a higher margin of safety in acute overdose than tricyclics [reviewed in 3I.
`However, it is interesting to note that the results of some animal studies were not always so
`clear cut. For example. early preclinical studies in cats with the highly selective serotonin
`reuptakc inhibitor. citalopram. showed TCA-like cardiac effects at high doses [2’]. and the
`development of citalopram was delayed by reports of eardiotoxicitv in dogs. eventually
`attributed to a species-specific metabolite not found in humans [26].
`
`The SSRl drug. ofthat the most information is available. is fluoxetine [27] used for oral
`administration: it is chemically unrelated to trieyclic. tetracyclic antidepressant agents Several
`clinical studies showed that compared to tricyclic antidepressants. fluoxetine causes
`significantly fewer anti-eholinergic. antihistaminergic and cardiovascular side effects
`[reviewed in: 3- 8‘9]. However. even with fluoxetine one must be cautious in the conclusions
`drawn because the patients that have been carefully studied are. in general. depressed patients
`frec of cardiovascular disease. and only very limited information is available in patients having
`cardiovascular disease as well [28-31]. The SSRls do have cardiac effects, the best
`demonstrated of those being a mild bradycan‘lia observed during chronic treatment with
`fluoxetine. fluvoxamin. paroxetine [reviewed iii 3- 8|. This usually amounts to only a few beats
`per minute but it is the opposite of the tachycardia that has becnassociatcd with tricyclic dfirugs.
`Analysing large number of ECG recordings from citalopram-treated patients Enemark [32]
`reported that eitalopram-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 normal heart rate at baseline biadycardia was developed.
`Furthermore. citalopram treatment was associated with a non-specific. insignificant
`prolongation of QT interval irrespective of age. In younger group of the patients a statistically
`significant decrease in T-wave amplitude was also demonstrated [32]. Moreover. there are
`increasing number of case reports on dysrhythmia and syncope associated with fluoxetine and
`another SSRIs treatment and overdose [33—58]. A multicenterease-control study has shown
`that in the elderly the consumption of fluoxetine was significantly associated with an excess
`risk of syncope and orthostatic hypotension [59]. A significant blood pressure lowering effect
`of fluoxetine was reported in DOCA-hypertensive rats [60]. The authors suggested that a
`central action of fluoxetine on vasomotor center may be responsible for the reduction of blood
`pressure. but the possible direct cardiac and/orvascular effects of fluoxetinc were not excluded
`or determined. lnteresti ugly. several recent studies have provided evidence that fluoxetine and
`citalopram directly inhibit Caz’ entry into vascular and intestinal smooth muscles resulting in
`vasodilation and intestinal relaxation. effects. which could be of significant therapeutic
`importance [61‘64]. Surprisingly results from recently published retrospective studies show
`that the use of new SSRls. similarly to the old TCAs. increases the risk of falls and hip fracture
`among elderly people [reviewed in 9].
`
`1.2. Cellular Electrophysiological Effects
`
`Electrophysiological studies (using a broad range of in vitro models) demonstrated that both
`antidepressants and antipsychotics exerted their cardiac actions by modifying the different
`cardiac ionic currents during the action potential (Fig, l).
`
`1.2.1. Cellular Electrophysiological Effects of TCAs—ln electrophysiological studies
`on isolated mammalian inulticellular cardiac preparations and single myocytes. TC As. such as
`imipramine. chlorimipramine amitriptyline. desipramine. diben'zepin. lofepraminc and
`amoxapine. were demonstrated to reduce the maximum velocity of depolarization ngax) of
`the action potential. an indirect index of the fast inward sodium current. 1M. [63”
`l.
`Furthermore. imipramine also blocks the outward delayed rectifier 14' current (1K) and the
`
`(‘m'r Phann Des. Author manuscnpt; available in PMC 2008 August I.
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`inward slow Caz‘ (ICa) currents in guinea-fig ventricrrlar myocytes and transient outward
`K ‘ crrrrent (lto) in rabbit atrial cells [70"7 ]. These direct membrane effects explain a variety
`ofcharacteristic ECG abnormalities like prolongalion of PQ. QRS. and QT. and cardiac adverse
`effects including tachyarrlrythmias. heart block. congestive heart failure. observed during
`tricyclic antidepressants treatment and overdose [L ’~ 10—H~ 19]. The effects of imipramine
`on action potential duration (APD) show important species de
`ndcnce. In bovine ventricular
`[75] and Purkinje fibers [65]. guinea-pig papillary muscles [7 "771 and isolated ventricular
`myocytes I70] imipramine shortened the APD. whereas in rabbit and rat atrial fibers l’ 849|
`it lengthened the APD. The dichrent effects of imipramine on APD can be explained by the
`
`important differences in the ionic currents responsible for the repolarization among animal
`species. In guinea-pig ventricular myocytes where Ito is relatively little [’4]. the APD is
`controlled by the interaction between inward (INa and lea) and outward currents (it; and [1.41).
`lmipramine decreased the INa [8 l ]. l}; and 1C, but did not modify the “(I I70~ 75]. The reduction
`of the APD in bovine and uinca pig ventricular preparations could be explained mainly by
`inhibition of [ca [65‘ 70- 7 - 77]. In contrast. in rat. rabbit and human atria [64- 80- 82| and rat
`ventricular myocytes the [K is negligible and 1m appears to be the most important outward
`K' current responsible for action potential repolarization. Thus the reduction of I“, could
`explain the prolongation of the APD observed in above-mentioned species. More recently
`several antidepressants with different chemical structures (imipraminc. amitriptyline.
`mianserinc. maprotilinc and trazodonc) were reported to block transient outward K' current
`(to) I73].
`
`1.2.2. Cellular Electrophysiological Effects of SSRls
`
`1.2.2.1. Effects of SSRIs on Cardiac Action Potentials Al’s In titro: We previously
`demonstrated that fluoxetine elicited a concentration dependent depression of the amplitude
`ofaction potential (APA). overshoot (OS) and the maximum rate of rise of depolarization phase
`(me) in multieellular vcntriculargprc _
`tions of rats. rabbits and dogs without changing the
`resting membrane potential (RP) l 4' DJ. The significant threshold concentrations were more
`or less similar (3-10 M) in various species (including the most sensitive isolated canine
`myocytes). Fluoxctinc caused a nearly similar shortening of the duration of ventricular action
`potential (APD) in three species (guinea pig. rabbit. canine). btrt not in rats. Fluoxetine caused
`a concentration-depc ndent decrease in force of contraction in rat right ventricular papillary
`muscle with a calculated IC50 value of 9.86 pM. Citalopram similarly to fluoxetine elicited a
`concentration-dependent (IO—100 pM) reduction of Vmax. decrease of APA. OS and
`shortening of APA in guinea-pig ventricular papillary muscle [86]. Fluoxetine and citaloprarn
`produced a dose-dependent decrease of V "m- (an indirect indicator of the fast Na’ channel
`activity). which suggests that they inhibited the activation of fast Na’ channels and exhibited
`class I anti-arrhythmic effects. A possible explanation of the decrease in APA and OS and
`shortening of the early part of repolari7ation (APDsu) can be the inhibition of the calcium
`cunent (ICa)- This latter mechanism may also be responsible for the negative inotmpic effect
`of fluoxetine. The inhibitory effect offluoxetine on peak Caz‘ current was proverr in voltage
`clamped canine ventricular myocytes by lC5o value of 5.4 rtM. This effect may cause
`lengthening of atrioventricular conduction. Considering its Na+ and Caz’ currents inhibitory
`action. fluoxetine may have antiarrirythmic as well as pro-arrhythmic properties (due to
`impairement of atrioventricular or intraventricular conduction). As far as the difl’ereut effects
`of fluoxetine on rat ventricular APD are concerned. these can be explained by the unique ion
`regulation characteristic to ventricular repolarization phase of rat markedly dilfercnt from that
`ofother mammalian species [87L Similareardiac electrophysiologieal effects with venlafaxine
`were observed in guinea-pig cardiac myocytcs [88]. These direct cardiac effects of fluoxetine
`and citalopram are similar to those found by trs for TCA clonripraminc [ml and previously
`reported for the tri- and tetracyclic antidepressants I3].
`
`(‘m'r Phann Der. Author manuscnpt; available tn PMC 2008 August I.
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`l.2,2.2= Effect; of 55R]; on gammy. lgn glhgnnclg; Previous and recent studies demonstrated
`that fltroxctirre and other SSRls possess ggtcnt antagonistic properties on voltage-dependent
`ion channels irt different lissrres [84—8i
`406]. The leo values of SSRls for Na’. Ca2+ artd
`K‘ channels of mainly cardiac tisstrcs are summarized in Table l. Flttoxetirre irtlribited L-type
`of Ca2‘(CaL2") current in both rat and canine ventricular myocytes. but itspotency was twice
`as high in rat (ch0 2.8 uM) Linn in canine myocytes (IC50 5.4 uM) [84~ 93]. It is interesting
`to note that sertraline also inhibited the CaLZ' current in rat myocytcs and its inhibitory activity
`(ngo= 2.3 M1) was similar to that of fluoxetine. while citaloprarn inhibited Cal,” current of
`guinea-pig myocytcs at much higher concentration (100 W) [93* 103]. These data provide
`evidence that inhibition of cardiac CaLz’ current could play an important role in reducing
`cardiac contractility. heart rate and attic-ventricularconduction The proposed mechanism may
`explain the prolortged PR interval. AV block. hypotension. which are common cardiovascular
`corrrplicatiotts ol' lluoxetine therapy
`
`Fluoxetine and citalopram have a high inhibitoryopotency (le0=3. l. 1.5 and 3.97 M.
`respectively) on HERG potassium channel [94‘
`5I. The human ether-a-go-go-relatea’ gene.
`HERG. is believed to encode the protein. which underlies the rapid component of the delayed
`reclifich ' cunertt [Kr HERG encoded l K, plays art important pan in the repola flame" of the
`cardiac action potential. Pharmacological irthibition of either lteterologously expressed HERG
`or native I“, would thus be expected to correlate with ventricularaction potential prolongation
`and associated prolongation of the QTe interval on ECG. Thus the HERG current inhibition
`by fluoxetine 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 occur at nearly therapeutic levels of these drugs. tlttrs this ctfect should be considered
`during the therapy.
`
`SSRls also exhibit potent inhibitory effects on various voltage-dependent ion channels in non-
`cardiac tissues. Some of these effectsare summarized in the Table l. butthe detailed description
`is beyond the scope of this review.
`
`The inlubitory concentrations of SSRIs on cardiac APs and ion current were in the upper range
`of the therapeutic plasma levels [107|. However. it is difficult to relate m wvo plasma
`concentrations to in vitro concentrations as pharmacokinetic properties (tissue accumulation.
`metabolites) of the drug must also be considered. Under certain conditions (e. g. in case of drug
`interactions or reduced metabolism in elderly) the plasma concentration of SSRls can reach
`even higher levels. Thus. a significant inhibition of variotts cardiovascular ion channels by
`SSRls may occur in patients chronically treated with these conrpounds. resulting itt certain pro-
`or arrhythmic effects. [reviewed irt J].
`
`2. CARDIOVASCULAR EFFECTS OF NEUROLEPTICS
`
`2.1. Clinical Evidence
`
`The aim of this part of the review is to organise the available evidences on cardiac!
`cardiovascular side effects; proarrhythmic potential of antipsyehotic drugs and to discuss their
`actions on cardiac ion currents as proposed explanation of their proarrhythmic ctTcets.
`
`Antipsychotic dmgs represent a chemically various group of compounds. Antipsychotic drugs
`can be classified typical (older drugs acting on dopamine D1. 02. adrcncrgic a]. muscarinic
`cholinergic. 5-HT; and histamine H I -rcccptors and associated with dilfercnt side effects) and
`atypical (newer drugs inhibiting mainly both D2 and 5-HT“ receptors and have a higher
`efficacy and fewer side effects) groups. Among atypical antipsychotics clo7apine shows
`marked difference from the others binding tnore to D4. 5-HT; and (11 receptors than to D2
`receptor. [108]. Aripiprazole is a first member of a rcw class of atypical antipsychotics have
`
`(‘m'r Phann Des. Author manusenpt; available tn PMC 2008 August I.
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`Page 6
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`also unique properties showing a combined artial agonist activity at D; and 5-HT” receptors
`with an antagonism at 5-HT“ receptors II 9‘1”].
`
`Antipsychotic drugs have long been known to 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 dc pointcs (TdP).
`TdP is a potentially life-threatening ventricular tachyarrhythmia that is associated with syncope
`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 by various
`cardiac and non-cardiac drugs. Among antipsychotics haIOpen'dol. drogreridol. pimozide.
`sertindole. thioridazine were found to cause definitively TdP [1 12—1 1
`]. Several other
`antipsychotics including typical (chlorpromazine. flu henazine. mesoridazine.
`prochlorperazine. trifluperazine. sultopn‘dc) [”9“12 I (quetiapinc. olanzapine. risperidone.
`ziprasidonc) I 122—127] have been reported to prolong the corrected QT interval (corrected for
`heart rathQTc). Both an Australian and a Finnish study ofneurolcptic poisoning demonstrated
`that thion'dazine caused the most in ucntly tachycardia. prolonged QTc. widened QRS.
`arrhythmias and sudden death [120 28]. Thioridazine and droperidole were found to be
`associated with prolongation of QTc even at dosage used for therapy [‘29] and based on this
`study the indications of thioridazine were restricted and droperidol was voluntarily
`discontinued by the manufacturer in UK [1 14]. Pimozide. sultopin'de and droperidole also
`prolong QTc interval and have been associated with TdP and sudden death. but far fewer data
`are available I12 L 130l. The high-potency drug halopgridole can prolong QTc interval. muses
`TdP and sudden death at normal therapeutic doses | J 1|. but the frequency by which these
`effects occur is less than with thioridazine [[28]. Similar cardiovascular risks of traditional
`antipsychotics used at therapeutic dosage were published in the USA in a retrospective study
`investigating 431.744 persons (aged 15—84 years. from 1988 to 1993) ['32].
`
`The new atypical antipsychotics have greater efficacy and fewer side effects than older
`neurolcptics and with the exceptions of sertindolc and ziprasidonc they lave not caused
`consistent statistical] ' significant lengthening of QT or sudden cardiac death at therapeutic
`concentrations [1 I 3-
`3 3I. Scrtindolc has been proven to be associated with a QT prolongation
`at therapeutic concentratiorts [1 17‘ 12‘1’], and both increasing evidence of unexplained sudden
`cardiac death and serious arrhythmias found by the Committee on Safety of Medicine in the
`United Kingdom resulted in a voluntary withdrawal of the dmg by the manufacturer [134].
`Albeit the known correlation between schizophrenia and increased cardiovascular mortality it
`ma difficult to estimate the sudden death due to particular neuroleptics at therapeutic doses
`| l 5- 136]. Clozapine beyond the well-known agranulocytosis risk. is being associated with
`myocarditis. cardiomyopathy and arrhythmogenesis risk “37- '38 . It also reduced measures
`of heart rate variability associated with parasympathetic control [1 4I. In the study of
`overdoses, clozapine overdose was associated with sinus tachycardia (more titan 66% of the
`patients) however. in the case of risperidone overdose more than 66% of the patients were
`asymptomatic [139]. However. there are data suggesting that risperidone could cause sudden
`death [125]. Neither olan'lapine nor quetiapine had been implicated in cases of TdP or sudden
`death.
`
`Ziprasidone is a new atypical dnig with less side effects and in comparison with olanrapine
`and risperidone it does not appear to cause weight gain. hyperlipidemia and hyperglycaemia
`but‘prolongs the QT interval more than haloperidol. olanyapine. quetiapine and risperidone
`[12 ]. Although it was not associated with cardiac events dtrring premarketing trials the
`appearance of unexpected life-threatening arrhythrnias can not be excluded when the drug
`enters widespread use.
`
`Curr Pharm Des. Author manusenpt available in PMC 2008 August I.
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`2.2. Mechanism of the Lengthening of QT Interval
`
`The QT interval includes both depolari/ation and repolarization. Q wave represents tlte onset
`of ventricular depolarilation. while T wave is the sign of the repolarilation. Because the QT
`interval shortens with increasing heart rates. it is usually corrected for heart rate (QTc).
`Depolanration ofventricular cells 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. Conccming the specificity of QT pmlongtion as a marker of an effect on
`cardiac repolarisation it should be kept in mind that the duration of the QT interval may be
`affected by both the velocity of rcpolarisation and ventricular conduction velocity. Class I
`antiarrhytlunics as sodium channel blockers. decrease ventricular conduction velocity. cause
`widening of QRS complex and therefore lengthen the QT interval [140]. Similar action can be
`observed in 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 dmg-indueed QT prolongation and TdP. Drug blocking the IKrchannel can induce
`QT prolongation and TdP and sometimes sudden death [1“]. However. there is no close
`correlation between QTc interval prolongation and occurrence of TdP. Not all drugs that
`prolong the QTc interval produce TdP. Amiodaronc. a class III antiarrhythmic drug. produces
`marked prolongation of QTc interval but does not evoke TdP. The calcium-channel blocker
`verapamil has been shown to prolong QT interval in a manner that is linearly correlated to its
`plasma concentration [”2] but there are few described cases of verapamil-induced TdP
`[”3]. No clear-cut dose-dependency can also be observed for QT prolongation or occurrence
`of TdP. In some cases the QT prolongation and occurrence of TdP is dose dependent but these
`parameters can also be observed at normal plasma levels ofdrugs. too [”4]. lnthe latter several
`factors (hypokalaemia/magnesaemia. mutation of K ' channels) reducing the repolarization
`resent;of]a given subject greatly increase the proarrhythmic potential of relatively low plasma
`level I
`~
`].
`
`The link between the lengthening of QT interval and TdP is seemingly very complex and
`affected by several factors including electrolyte imbalance. age. gender. disease (myocardial
`isehemia. infarction. hypertension. hypothyroidism. diabetes. renal or hepatic dysfunction) and
`concomitant medications.
`
`2.3. Cellular Electrophysiological Effects of Neuroleptics
`
`Most of antipsycliotics are generally lengthen the action potential duration (APD) and inhibit
`the rapid component of the delayed reeti fier current (IKr) but sonre of the typical antipsychotics
`including chlorpromaaine and haloperidol. beyond their inhibitory effect on K‘ current inhibit
`also Na‘ and Caz’ channels [8 1]. Such effects could be antiarrhythmic or cardiotoxic.
`depending on the health (cg. post myocardial infarct) of the myocardium. The net effect on
`APD of antipsychotics depend on the overall balance between inward and outward cunents
`during the plateau phase of AP and their relative sensitivity to the particular agent in question
`Table 2. summarizes the inhibitory potency of antipsychotic dmgs on K71“. 1m. 1“. HERG)
`and other ion (Na". Ca2 ’) currents. In human [in is carried by the human cthcr-a-go-go (HERG)
`K’ channel. which can be expressed in homologous and heterologous cells in order to assess
`the potency (leo) of a dnrg in inhibiting this channel. Haloperidol and droperidol prolong
`APD in guinea-pig ventricular myocytes and inhibit 1K, and HERG with lC5o values of 20
`nM-l .36 pM and 32.2 trM. respectively and the effects of haloperidol on HERG are over five
`or twenty times more potent than its effects on IN, and ICal ,. respectively [31- ”3‘ 1 46‘ 150-
`l63 ]. Thioridazine also lengthened APD in guinea-pig ventricular myocytes and potently
`inhibited in and HERG (1c50 values of 1.25 “M. 191 nM and 1 MA) I 14 /~ “9]. Comparative
`
`(‘m'r Phann Des. Author manuscnpt; available in PMC 2008 August I.
`
`

`

`Pitcher Md Keeskemeti
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`Page 8
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`study showed that newer atypical antipsychotic 7iprasidone. olan7apine. risperidone block
`HERG and 1);, in a more or less similar concentration range [”8].
`
`Figures (2 and 3) show tint risperidone concentration-dependently increased APD in both
`guinea-pig ventricular muscle (Fig. 2A) and canine ventricular myocytcs (Fig. 3B). This effect
`was most prominent on tcm'linal phase of rcpolarization (APDgo) (with ECso values of 0.29
`M and 0.48 M in guinea pigand canine myocytes. respectively) (Fig. 3C) and showed reverse
`rate dependence (Fig. 28). Halopcridol had similar effect on APD (Fig. 2C) btit reduced also
`the maximum velocity of depolarization (Vnmxindirect indicator ofNa+ channel activity)(Fig.
`2D) while rispen'done was ineffective on this parameter. We found that risperidone
`concentration-dependently inhibited 1Kr with an 1C50 of 0.92 M and practically had no effect
`on the otherK‘ currents (1.0 with 1c,0 >10 nM. 1K. with lcj0 >100 nM) [151|. Similar effects
`of risperidoge on both APD and 1K, in rabbit ventricular myocardium and myocytes were
`observed [132]. while_lower 1C50 values ( 167 and 261 nM. respectively) were found in HERG
`channel by others [14“ 155].
`
`Sertindole was found to be a high affinity antagonist of the human cardiac K‘ channel HERG
`(1cm: 3 and [4 nM) but was less active at blocl5ing other K’ currents (Kv 1.5. I“, with
`ngo=2.l and 10 nM. respectively) [1473 148~ ”3].
`
`Pimozide potently inhibited cardiac HERG K’ channel (1c50 values of 18 and 174 nm ([47-
`150]. increased the risk of Ta? [154] and also blocked [Cu], in rat ventricular myocytes [ >6I.
`Beyond the inhibitory action on HERG channel sertindole and pimozide also blocked the
`human brain K+ channel erg3. Sertindole blocked or 3. channel currents with an [C50 of 43
`nM. while pimozidc had an 1C50 value of 103 nM |1 l]. it was suggested that this inhibition
`of crg3 related K+ channels in the brain might contribute to their efficacy/side effect profiles.
`
`Comparing the HERG channel inhibitory activity of seven antipsychotics dnlgs (olanzapine.
`pimozidc. quetiapine. n‘speridonc. sertindole. thioridazinc. zipmsidonc) to their binding
`affinities for D2 and 5-HT“ receptors the following selectivity rank was found: olanchine >
`risperidonc > ziprasidonc > thioridazinc > pimozidc > sertindole. Sertindole and pimozidc had
`the highest HERO channel inhibitory activity. while the lowest inhibitory activity can be
`observed in the case of olarwapine and qnetiapine. These results also showed that sertindole.
`pimozide. thioridazinc displayed little or no selectivity for dopamine D2 or 5-HT“ receptors
`relative to their I-IERG channel affnlities, and olanzapine had the greatest selectivity for
`dopamine D; and 5-HT2A 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 D2
`receptor. Examining the relationship between plasma levels and QT prolongation for these
`drugs |127| the authors also found a good correlation between the ratio of total plasma dmg
`concentration to HERG ngu and their QTc prolongation effect [“7]. Based upon this in
`vilro results drug‘s selectivity (between their target receptor affinity and their HERO cinnnel
`[€50 value) seems to be a predic