Presentazione di PowerPoint - Area-c54

QT lungo
Flavio Ribichini
Cardiologia
Università di Verona
1
01/10/2010
Referto ECG: ritmo sinusale, QT lungo
2
01/10/2010
Principi di base dell’ECG
L'amperometro è uno strumento
per la misura dell'intensità di
corrente elettrica, che percorre una
sezione di un conduttore
Il galvanometro è uno strumento
che traduce una corrente elettrica
in una torsione meccanica.
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01/10/2010
ECG
L'elettrocardiogramma
(ECG) è la registrazione
dell'attività elettrica del
cuore che si verifica nel
ciclo cardiaco.
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01/10/2010
ECG
’
Ciclo depolarizzazione
ripolarizzazione
il prolungamento QT é correlato al blocco dei canali del
potassio, questi riducono la corrente di ripolarizzazione in
uscita e prolungano la durata del potenziale d’azione e
l’intervallo QT.
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01/10/2010
E il QT lungo?
INTERVALLO QT: è la
distanza tra la prima
deflessione del QRS e la
fine dell’onda T.
IL QTc misura la durata
(tempo) diviso la radice
dell’intervallo RR in sec
Nota: il QT viene misurato in msec,
L’intervallo RR in sec,
quindi il QTc è una standardizzazione
della durata del QT per la FC
(idealmente a 60bpm)
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01/10/2010
Valori di normalità del QT
Un intervallo QT non corretto oltre 500
msec è usualmente considerato
patologico
8
01/10/2010
ECG normale: esercizio 1
1quadratino
piccolo 40 msec
1 quadrato grande
200 msec
1 quadrato grande e
3 piccoli:
200+120=320 msec
9
01/10/2010
Esercizio 2
3 quadrati
grandi da
200 msec
+
1quadratino
piccolo 40
msec
10
01/10/2010
Esercizio 3
3 quadrati
grandi =
600 msec
11
01/10/2010
L’inizio del problema…
Numerosi sono i meccanismi con cui gli antipsicotici alterano
la conduzione cardiaca, quasi sempre gli antipsicotici
antagonizzano la componente rapida del canale del
potassio Ikr.
Il canale del potassio IKr è codificato dal gene umano HERG
(human Ether-à-go-go Related Gene) e studi di tranfezione di
cellule del gene HERG mostrano un antagonismo diretto di
alcune sostanze tra cui aloperidolo (Suessbrich 1997)
sertindolo (Rampe D.1998) clozapina (Tie H 2000),
tioridazina e clorpromazina (Tie H 2001). Questo è il
meccanismo maggiormente implicato nell’allungamento del
QT (William J 2006)
Il blocco del recettore IKr risulta dose dipendente (Drolet
1999, Tie H 2000)
Alcuni antipsicotici sembrano interferire anche con i canali del
sodio e del calcio (Shader 1999)
L’inizio del problema…
http://www.agenziafarmaco.it/sites/default/files/bif0703120.pdf
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01/10/2010
Non è chiaro l’effetto sul QTc a bassi dosaggi (5 mg die) o a
dosaggi moderati (5-20 mg die) (Fulop 1987, Czekalla 1961)
Segnalato allungamento del QTc e torsioni di punta per alti
dosaggi per os (>20 mg die) (Kriwisky 1990, Metzger 1993) o
in caso di sovradosaggio (Henderson 1991)
Alti dosaggi (>50 mg die) per via endovenosa si associano ad
un allungamento del QTc con casi descrtitti di torsioni di punta
(Lawrence 1997, O’Brien 1999)
Per dosaggi endovenosi da 5-25 mg sono segnalati aumenti
del QTc a valori superiori a 500 ms (Hatta 2000)
Per somministrazione intramuscolare di una dose di 7.5 mg
seguita da dose di 10 mg è segnalato un aumento medio del
QTc di 15 ms.(Miceli JL 2002)
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01/10/2010
Concetti pratici…
1.
La dose e la via di somministrazione ha un’importanza
nella possibile tossicità?
2.
E’ da preferire/evitare una via parenterale ad una via
orale?
3.
L’effetto degli antipsicotici sul QT è sinergico?
4.
Lo è anche con i farmaci antiaritmici?
15
01/10/2010
Concetti pratici…
1.
La dose e la via di somministrazione hanno
un’importanza nella possibile tossicità?
SI, la dose e le somministrazioni parenterali aumentano la
biodisponibilità di questi farmaci e quindi possono
causare un maggior blocco dei canali del K e maggior
allungamento del QT.
L’effetto è comunque molto modesto
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01/10/2010
Abstract BACKGROUND: Antipsychotic agents have been associated with a prolonged QT interval. Data on
the effects of ziprasidone and haloperidol on the QTc interval are lacking. OBJECTIVE: This study aimed to
Abstract
characterize the effects of 2 high-dose intramuscular injections of ziprasidone and haloperidol on the
STUDY
OBJECTIVE:
ToMETHODS:
characterizeThis
the randomized,
effect of oral ziprasidone
and haloperidol
on the corrected
QT
QTc interval
at T(max).
single-blind study
enrolled patients
with
(QTc)
interval under
steady-state conditions.
Design.
Prospective,
randomized,
open-label,
parallel-group
schizophrenia
or schizoaffective
disorder in whom
long-term
antipsychotic
therapy
was indicated.
Patients
study.
were randomized to receive 2 high-dose intramuscular injections of ziprasidone (20 and 30 mg) or
haloperidolInpatient
(7.5 andclinical
10 mg)research
separated
by 4 Patients
hours. The
primaryadults
outcome
was the
SETTING:
facility.
Fifty-nine
(agemeasure
range 25-59
yrs)mean
with change
from baselineor
in schizoaffective
QTc at the T(max)
of each
injection.
dose
administration
was followed
by serial ECG
schizophrenia
disorder
who
had no Each
clinically
significant
abnormality
on electrocardiogram
and blood
samplingIntervention.
for pharmacokinetic
determinations.
Twelve-lead
ECG dataand
were
obtained immediately
(ECG)
at screening.
During period
1 (days -10
to -4), antipsychotic
anticholinergic
drugs
before
and
at
predetermined
times
after
injections.
ECG
tracings
were
read
by
a
blinded
central
reader.
were tapered. On the first day (day -3) of period 2, the drugs were discontinued, and placebo was given for
Blood
were obtained
immediately
before
injections.
estimates
CIs for
the
nextsamples
3 days (days
-2 to 0). On
the last day
(day and
0) ofafter
period
2, serialPoint
baseline
ECGs and
were95%
collected.
mean QTc
and
changes
from
baseline
in QTc escalating
were estimated.
No between-group
tests to
were
During
period
3 (days
1-16),
patients
received
oral doses
of ziprasidonehypothesis
and haloperidol
reach
conducted.
the assessments
tolerability
and safety
profile, patients
underwent
physical antipsychotic
examination,
steady
state.For
Period
4 (days 17-19)ofallowed
for study
drug washout
and initiation
of outpatient
includingsafety
measurement
of vital
signs,
laboratory
therapy;
assessments
were
alsoclinical
performed
duringevaluation,
this period.and monitoring for adverse events (AEs)
using
spontaneous
reporting.
RESULTS:
A
total
of
59
patients
to treatment,
andor58plasma
received
MEASUREMENTS AND RESULTS: At each steady-state dose were
level, assigned
three ECGs
and a serum
study medication
(ziprasidone,
31 patients;
haloperidol,
27; age
range,
21-72 years;
79%
male).
After the
sample
were collected
at the predicted
time of
peak exposure
to the
administered
drug.
Point
estimates
and
firstconfidence
injection, mean
(95%
CI)were
changes
from baseline
wereQTc
4.6 interval
msec (0.4-8.9)
withand
ziprasidone
(n =
95%
intervals
(CIs)
determined
for the mean
at baseline
for the mean
25) andfrom
6.0 baseline
msec (1.4-10.5)
haloperidol
(n dose
= 24).level.
AfterMean
the second
injection,
these values
were
change
in QTc atwith
each
steady-state
changes
from baseline
in the QTc
12.8
msec
(6.7-18.8)
and
14.7
msec
(10.2-19.2),
respectively.
Mild
and
transient
changes
in
heart
interval (msec) for ziprasidone were 4.5 (95% CI 1.9-7.1), 19.5 (95% CI 15.5-23.4), and 22.5 (95% CI rate
15.7and
blood
pressure
were
observed
with
both
treatments.
None
of
the
patients
had
a
QTc
interval
>480
29.4) for steady-state doses of 40, 160, and 320 mg/day, respectively; for haloperidol, -1.2 (95% CI -4.1msec.
patients
in the ziprasidone
group
experienced
QTc prolongation
>450
(457
and
msec)
1.7),
6.6Two
(95%
CI 1.6-11.7),
and 7.2 (95%
CI 1.4-13.1)
for steady-state
doses
of msec
2.5, 15,
and
30 454
mg/day.
and QTc no
changes
exceeded
60 msec
(62experienced
and 76 msec)
relative
to the
time-matched
baseline
Although
patientthat
in either
treatment
group
a QTc
interval
of 450
msec or greater,
thevalues.
QTc
With
haloperidol,
QTc
interval
values
were
<450
msec
with
no
changes
>60
msec.
Treatment-emergent
AEs
interval increased 30 msec or more in 11 and 17 ziprasidone-treated patients at 160 and 320 mg/day,
were
reported
in
29
of
31
patients
(93.5%)
in
the
ziprasidone
group
and
25
of
27
patients
(92.6%)
in
the
respectively, and in 3 and 5 haloperidol-treated patients at 15 and 30 mg/day, respectively. Most treatmenthaloperidol
group;drug
mostreactions
events were
mildinorintensity,
moderate
severity.
Frequently
emergent
adverse
wereofmild
and
none were
severe.reported AEs were
somnolence (90.3% and 81.5%, respectively), dizziness (22.6% and 7.4%), anxiety (16.1% and 7.4%),
CONCLUSION:
QTc interval
ziprasidoneand haloperidol-treated
patients
increased
with
dose.
extrapyramidal The
symptoms
(6.5% in
and
33.3%), agitation
(6.5% and 18.5%),
and insomnia
(0%
and
14.8%).
Treatment with high doses of ziprasidone or haloperidol did not result in any patient experiencing a
CONCLUSIONS:
Inmsec
this study
of the effects of high-dose ziprasidone and haloperidol in patients with
QTc
interval of 450
or greater.
schizophrenic disorder, none of the patients had a QTc interval >480 msec, and changes from baseline
Pharmacotherapy.
Feb;30(2):127-35.
of Oral
Ziprasidone
Oral Haloperidol
on QTc
QTc interval were2010
clinically
modest withEffects
both drugs.
Both
drugs wereand
generally
well tolerated.
interval in patients with Schizophrenia or Schizoaffective disorder. Miceli JJ, Tensfeldt TG, Shiovitz T,
Clin Ther.
Mar;32(3):472-91.
Effects of high-dose ziprasidone and haloperidol on the QTc interval
Anziano
R, 2010
O'Gorman
C, Harrigan RH.
after intramuscular administration: a randomized, single-blind, parallel-group study in patients with
schizophrenia or schizoaffective disorder. Miceli JJ, Tensfeldt TG, Shiovitz T, Anziano RJ, O'Gorman C, 17
Harrigan RH.
01/10/2010
Concetti pratici…

E’ da preferire/evitare una via IM ad una via IV?
Una minor biodisponibilità del farmaco riduce il rischio di
tossicità nelle somministrazioni estemporanee in PS.
Rischio che permane comunque modesto.

18
01/10/2010
J Hosp Med. 2010 Apr;5(4):E8-16.
The FDA extended warning for intravenous haloperidol and torsades de pointes: how should institutions
respond?
Meyer-Massetti C, Cheng CM, Sharpe BA, Meier CR, Guglielmo BJ.
Department
Clinical
School of Pharmacy, University of California San Francisco, Medication
Expert OpinofDrug
Saf.Pharmacy,
2003 Nov;2(6):543-7.
Outcomes
Center,
San
Francisco,
California,
USA. carla.meyer@unibas.ch
Torsade de
pointes
associated
with
the administration
of intravenous haloperidol:a review of the literature
Abstract
and practical guidelines for use.
BACKGROUND:
In September
2007, the Food and Drug Administration (FDA) strengthened label
Hassaballa HA, Balk
RA.
warnings
intravenous
haloperidol
regarding
QT prolongation
(QTP) Medical
and torsades
pointes
Division offor
Pulmonary
and (IV)
Critical
Care Medicine,
Rush-Presbyterian
St Luke's
Center,de
1653
West
(TdP)
in
response
to
adverse
event
reports.
Considering
the
widespread
use
of
IV
haloperidol
in
the
Congress Parkway, Chicago, IL 60612, USA.
management of acute delirium, the specific FDA recommendation of continuous electrocardiogram (ECG)
Abstract in this setting has been associated with some controversy. We reviewed the evidence for the
monitoring
Haloperidol
theprovide
most commonly
medication
for the treatment
of delirium and psychosis in the
FDA
warningisand
a potentialused
medical
center response
to this warning.
critically ill patient.
Whilst
generally
considered to be
safe, haloperidol
has by
been
associated
with a
METHODS:
Cases of
intravenous
haloperidol-related
QTP/TdP
were identified
searching
PubMed,
number
of
important
cardiovascular
side
effects.
The
major
toxicities
include
hypotension,
cardiac
EMBASE, and Scopus databases (January 1823 to April 2009) and all FDA MedWatch reports of
arrhythmias and prolongation
the corrected
QT (QTc)
interval.
In particular, torsade de pointes, a
haloperidol-associated
adverseofevents
(November
1997 to
April 2008).
polymorphic ventricular tachyarrhythmia, has been associated with both intravenous and oral haloperidol
RESULTS:
A total
of management
70 of IV haloperidol-associated
QTPconsists
and/or TdP
were identified.
were 54
reports
administration.
The
of torsade de pointes
of discontinuation
of There
the possible
offending
ofagent(s),
TdP; 42 correction
of these events
were reportedly
preceded
by QTP. When
post-eventsulfate
QTc data
reported,
of electrolyte
abnormalities,
administration
of magnesium
and,were
if necessary,
QTc
was prolonged
>450 msec
in 96% ofshould
cases.be
Three
patients
experienced
cardiac arrest.ofSixtyoverdrive
pacing. Although
clinicians
aware
of this
potentiallysudden
lethal complication
eight
patients
(97%)
had
additional
risk
factors
for
TdP/prolonged
QT,
most
commonly
of to
intravenous haloperidol therapy, it should not deter clinicians from using intravenous receipt
haloperidol
concomitant
proarrhythmic
agents. Patients
experiencing
TdP QTc.
received a cumulative dose of 5 mg to
treat acute agitation
in the critically
ill patient
with a normal
645 mg, patients with QTP alone received a cumulative dose of 2 mg to 1540 mg.
CONCLUSIONS: While administration of IV haloperidol can be associated with QTP/TdP, this complication
most often took place in the setting of concomitant risk factors. Importantly, the available data suggest
that a total cumulative dose of IV haloperidol of <2 mg can safely be administered without ongoing
electrocardiographic monitoring in patients without concomitant risk factors.
19
01/10/2010
Concetti pratici…
Ann GenL’effetto
Psychiatry. 2005della
Jan 25;4(1):1.

politerapia
con antipsicotici sul QT è
QT interval prolongation related to psychoactive drug treatment: a comparison of monotherapy versus polytherapy.
Sala M, Vicentini A, Brambilla P, Montomoli C, Jogia JR, Caverzasi E, Bonzano A, Piccinelli M, Barale F, De Ferrari GM.
Department of Health Sciences-Section of Psychiatry, IRCCS Policlinico S, Matteo, University of Pavia, School of Medicine,
Pavia, Italy. michelasalacap@yahoo.it.
Abstract

BACKGROUND: Several antipsychotic agents are known to prolong the QT interval in a dose dependent manner. Corrected
QT interval (QTc) exceeding a threshold value of 450 ms may be associated with an increased risk of life threatening
arrhythmias. Antipsychotic agents are often given in combination with other psychotropic drugs, such as antidepressants, that
may also contribute to QT prolongation. This observational study compares the effects observed on QT interval between
antipsychotic monotherapy and psychoactive polytherapy, which included an additional antidepressant or lithium treatment.
METHOD: We examined two groups of hospitalized women with Schizophrenia, Bipolar Disorder and Schizoaffective
Disorder in a naturalistic setting. Group 1 was composed of nineteen hospitalized women treated with antipsychotic
monotherapy (either haloperidol, olanzapine, risperidone or clozapine) and Group 2 was composed of nineteen hospitalized
women treated with an antipsychotic (either haloperidol, olanzapine, risperidone or quetiapine) with an additional
antidepressant (citalopram, escitalopram, sertraline, paroxetine, fluvoxamine, mirtazapine, venlafaxine or clomipramine) or
lithium. An Electrocardiogram (ECG) was carried out before the beginning of the treatment for both groups and at a second
time after four days of therapy at full dosage, when blood was also drawn for determination of serum levels of the
antipsychotic.Statistical analysis included repeated measures ANOVA, Fisher Exact Test and Indipendent T Test.
RESULTS: Mean QTc intervals significantly increased in Group 2 (24 +/- 21 ms) however this was not the case in Group 1 (-1
+/- 30 ms) (Repeated measures ANOVA p < 0,01). Furthermore we found a significant difference in the number of patients
who exceeded the threshold of borderline QTc interval value (450 ms) between the two groups, with seven patients
in Group 2 (38%) compared to one patient in Group 1 (7%) (Fisher Exact Text, p < 0,05).
CONCLUSIONS: No significant prolongation of the QT interval was found following monotherapy with an
antipsychotic agent, while combination of these drugs with antidepressants caused a significant QT prolongation.
Careful monitoring of the QT interval is suggested in patients taking a combined treatment of antipsychotic and
antidepressant agents.
sinergico?
SI, sono potenzialmente sinergici sull’allungamento del
QT e quindi questi pazienti meritano più attenzione
20
01/10/2010
Concetti pratici…
1.
Lo è anche con i farmaci antiaritmici?
2.
Assolutamente SI, i farmaci antiaritmici di classe terza
allungano il QT per loro stesso meccanismo d’azione
21
01/10/2010
Definizione della Sindrome del QT lungo
La sindrome da QT lungo (LQTS) è un
eterogeneo gruppo di disturbi congeniti o
acquisiti dei canali ionici coinvolti nella
ripolarizzazione.
E’ caratterizzata da un prolungamento
dell’intervallo QT all’ECG di superficie e dalla
conseguente predisposizione a sviluppare
sincope e morte cardiaca improvvisa (SCD)
per causa aritmica.
Nella maggior parte dei casi l’exitus è
provocato da tachicardie ventricolari polimorfe
maligne chiamate “torsades de pointes” (TdP).
W. Hurst, Il cuore, capitolo 31, 1068-1070, 11 edizione,
22
01/10/2010
Fattori di rischio per il QT lungo
Legati al paziente :
• Sindrome congenita del QT lungo
• Sesso femminile
• Bradicardia significativa, storia di
aritmie sintomatiche o altre
malattie cardiache
• Bilancio elettrolitico alterato
• Alterate funzioni renale o epatica
• Ipotirodismo
23
01/10/2010
Classificazione
Esistono diverse forme di LQTS:
congenite: canalopatie
(poche), interesse cardiologico
acquisite: iatrogene (molte),
interesse cardiologico e psichiatrico
24
01/10/2010
È con il QT lungo cosa succede?
L’allungamento dell’intervallo QT
può esacerbare una Triggered
activity, ossia la comparsa di
“post-potenziali" tipicamente
precoci.
Questi sono anormale oscillazioni
del potenziale di membrana che
seguono un potenziale d’azione. A
differenza dell’automaticità, i postpotenziali dipendono dal
precedente potenziale d’azione (il
"trigger") e l’aritmia che ne risulta
mantiene una relazione con esso.
25
01/10/2010
Torsione di punta, e adesso?
O termina o innesca un rientro che
determina un fibrillazione ventricolare con
exitus del paziente se non defibrillata.
26
01/10/2010
Quanto è grande il problema?
Un QT marcatamente prolungato, spesso accompagnato da
torsioni di punta, può accadere nell’1-10% dei pazienti che
ricevono farmaci antiaritmici noti per prolungare il QT, ma è
molto più raro nei pazienti che ricevono farmaci “non
cardiovascolari “ che potenzialmente prolungano il QT.
ACC/AHA/ESC 2006 guidelines for management of patients with
ventricular arrhythmias and the prevention of sudden cardiac death
Il problema è principalmente correlato a farmaci cardiologici
che prolungano il QT per loro stesso meccanismo d’azione,
questi farmaci andrebbero iniziati in ambiente ospedaliero con
monitoraggio ECG
27
01/10/2010
Problema limitato in psichiatria
Abstract BACKGROUND: Antipsychotic agents have been associated with a prolonged QT interval. Data on
the effects of ziprasidone and haloperidol on the QTc interval are lacking. OBJECTIVE: This study aimed to
Abstract
characterize the effects of 2 high-dose intramuscular injections of ziprasidone and haloperidol on the QTc
Although
haloperidol
(HAL) is ansingle-blind
effective medication
that
is often
to or
Abstract
interval atintravenous
T(max). METHODS:
This randomized,
study enrolled
patients
withprescribed
schizophrenia
treat
agitation, several
instances
of torsade
pointes
or QT
prolonged
QT
interval were
have
been
schizoaffective
disorder
in
whomdrugs
long-term
therapy
wasinterval
indicated.
Patients
randomized
to
BACKGROUND:
Psychotropic
haveantipsychotic
thede
potential
for
prolongation,
the
reported.
To
investigate
the
association
between
intravenous
HAL
and
QT
prolongation
and
receive
2
high-dose
intramuscular
injections
of
ziprasidone
(20
and
30
mg)
or
haloperidol
(7.5
and
10
mg)
frequency is not known. The aim of this study was to monitor the occurrence of QT interval
separated
by 4 hours. The
outcome measure
was the mean
change from baseline
in QTc
at the
between
intravenous
HALprimary
andpopulation
ventricular
tachyarrhythmia,
a cross-sectional
cohort
study
was
prolongation
in
a
non-selected
of
patients
treated
with
psychotropic
drugs
with
T(max) of each
injection. Each
dose administration
wasintervals
followed by
serial
and blood sampling
for
performed
that
included
measuring
corrected QT
(QTc)
onECG
an emergency
basis before
proarrhythmic
potential.
pharmacokinetic
Twelve-lead
ECG electrocardiographic
data were obtained immediately
before and
at
intravenous
HALdeterminations.
and continuously
monitoring
(ECG) findings
after
predetermined
times after injections.
ECG
tracings were
read by a wards
blinded at
central
reader. Blood of
samples
METHODS:
InHAL.
consecutive
patients
hospitalized
at psychotic
the Department
intravenous
During abefore
2-month
period,
47 patients
received
intravenous
injections
toand
were
obtained
immediately
and
after
injections.
Point
estimates
and
95%
CIs
for
mean
QTc
Psychiatry
treated
with
antipsychotic
and
antidepressant
drugs
with
known
or
unexplored
control
psychotic
disruptive
According
to clinical practice,
patients
were
divided as
changes
frompotential
baseline
in
QTc behavior.
wereECG
estimated.
No between-group
hypothesis
tests were
conducted.
the
proarrhythmic
a
12-lead
was
recorded
(50
mm/s,
20
mm/mV)
on
therapy;
theFor
QT
follows.
The
FZ-alone
group
was
treated
with
intravenous
flunitrazepam
(FZ),
and
the
FZ-plusassessments of tolerability and safety profile, patients underwent physical examination, including
interval
was measured
manually,
according
to Bazett
andfor
Fridericia.
QTc
intervals
HAL
group
received
intravenous
FZ followed
by intravenous
HAL.
Although
difference
inofthe
measurement
of vital signs,
clinicalcorrected
laboratory
evaluation,
and
monitoring
adversethe
events
(AEs) using
470
ms QTc
(females)
and 450
ms intravenous
(males)
considered
borderline,
intervals
were
spontaneous
reporting.
RESULTS:
A totalwere
of 59
patients
were
assigned
tolonger
treatment,
58 received
mean
immediately
after
FZ
between
the
two groups
wasQTc
notand
significant,
thestudy
considered
medication
(ziprasidone,
patients;
haloperidol,
27;
agelonger
range, 21-72
years;
male). Aftergroup
the first
mean
QTcpathologic.
after
8 hours in31the
FZ-plus-HAL
group
was
than that
in 79%
the FZ-alone
(p
injection,
mean
(95%
CI)
changes
from
baseline
were
4.6
msec
(0.4-8.9)
with
ziprasidone
(n
=
25)
and
6.0
RESULTS:
ECGspatients
were recorded
in 452 patients
males,
43+/-16
< 0.001). Four
in the FZ-plus-HAL
group(187
hadfemales,
a QTc of265
more
thanaged
500 msec
after 8
msec
(1.4-10.5)
with
haloperidol
(n
=
24).
After
the
second
injection,
these
values
were
12.8
msec
(6.7-18.8)
years).
Using
Bazett'sincorrection,
abnormal
QTc values differed
were observed
only
intwo
2%groups
of the (t
whole
hours.
The
change
QTc
during
8
hours
significantly
between
the
= 2.64,
and 14.7 msec (10.2-19.2), respectively. Mild and transient changes in heart rate and blood pressure were
group
and
in
1.8%
of
the
patients
treated
with
drugs
associated
with
QT
prolongation
(the
p observed
> 0.05). with
Furthermore,
the change
QTc
was had
moderately
correlated
with Two
the dose
of in the
both treatments.
None ofin
the
patients
a QTc interval
>480 msec.
patients
greatest
QTc value
is
ms inQTc
female
and 480
ms
in male).
With
Fridericia's
correction,
there
intravenous
HAL, experienced
as490
evidenced
byprolongation
a coefficient
of msec
correlation
of454
0.48
(p < and
0.001).
However,
ziprasidone
group
>450
(457 and
msec)
QTc changes
that
was
only
1
case
of
borderline
QTc
in
the
whole
group
(the
greatest
QTc
value
is
450
ms
in
both
ventricular
wasrelative
not detected
among 307
patients
within
1-year period,
exceeded 60tachyarrhythmia
msec (62 and 76 msec)
to the time-matched
baseline
values.
With ahaloperidol,
QTc
sex
groups).
interval values
werewas
<450continuously
msec with no monitored
changes >60for
msec.
Treatment-emergent
AEs were reported
29 of
although
the ECG
at least
8 hours after intravenous
HAL. in
The
31
patients
(93.5%)
in
the
ziprasidone
group
and
25
of
27
patients
(92.6%)
in
the
haloperidol
group;
most
modest nature ofOur
QTc2-year
prolongation
the apparent
of ventricular
tachyarrhythmia
CONCLUSIONS:
real-life and
experience
showsabsence
that occurrence
of QTc
prolongation in
events
were
of
mild
or
moderate
severity.
Frequently
reported
AEs
were
somnolence
(90.3%
and 81.5%,
under continuous
ECG monitoring
indicate
that QTc prolongation
associated
with intravenous
present
psychiatric
patients
is
low.
Values
associated
with
high
risk
of
arrhythmias
respectively), dizziness (22.6% and 7.4%), anxiety (16.1% and 7.4%), extrapyramidal symptoms (6.5% and
HAL
is not
necessarily
dangerous.
However,
an and
emergency
clinicians
cannot
(QTc>500
ms)
were
notand
observed.
This
mightinbe
to thesituation,
recent changes
of spectrum
33.3%), agitation
(6.5%
18.5%), and
insomnia
(0%related
14.8%).CONCLUSIONS:
In this
study of theof
exclude
patients
predisposed
torsade
de pointes,
such
as those
with
inherited
ionofchannel
antipsychotic
therapy
used, the to
general
trend
topatients
use lower
and
increasing
awareness
effects of
high-dose
ziprasidone
and
haloperidol
in
withdoses,
schizophrenic
disorder,
none
the patients
disorders.
Therefore,
clinicians
should
be aware
of theonassociation
between
intravenous
Clin
2010
Mar;32(3):472-91.
Effects
of high-dose
ziprasidone
and haloperidol
the
QTcinterval
interval after
intramuscular
administration:
aHAL
randomized,
about
the
drug-induced
long
QT
syndrome.
hadTher.
a QTc
interval
>480
msec,
and
changes
from
baseline
QTc
were
clinically
modest
with
single-blind,
parallel-group
study
in
patients
with
schizophrenia
or
schizoaffective
disorder.
Miceli
JJ,
Tensfeldt
TG,
Shiovitz
T,
Anziano
RJ,
O'Gorman
C,
and
QTRH.
prolongation.
both
Both drugs were generally well tolerated.
Harrigandrugs.
J Clin Psychopharmacol. 2001 Jun;21(3):257-61.The association between intravenous haloperidol and prolonged QT interval. Hatta K, Takahashi
T, Nakamura H, Yamashiro H, Asukai N, Matsuzaki I, Yonezawa Y. Department of Psychiatry, Tokyo Metropolitan Bokuto General Hospital, Japan.
hattak8s@cd.mbn.or.jp
28
Int J Cardiol. 2007 May 2;117(3):329-32. Epub 2006 Jul 24. Monitoring of QT interval in patients treated with psychotropic
drugs. Novotny T, Florianova A, Ceskova E, Weislamplova M, Palensky V, Tomanova J, Sisakova M, Toman O, Spinar J.01/10/2010
Farmaci che frequentemente prolungano il QT
ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the
prevention of sudden cardiac death
29
01/10/2010
ALOPERIDOLO
antagonista dopaminergico non
selettivo
+
antagonista a-adrenergico
30
01/10/2010
AMIODARONE
Effetto principale:
- blocco canali IKr (correnti del potassio rapide) e corrente IKs
(correnti del potassio lente).
- Altri effetti sono blocco dei canali per il sodio (classe Ia), del
calcio e fungere da beta-bloccante (classe II).
Meccanismo: Il blocco dei canali per i potassio comporta una
incapacità da parte della cellula miocardica di ritornare nei tempi
fisiologici al potenziale di riposo; in particolare, viene ad essere
prolungato il periodo refrattario, condizione che comporta un
impedimento elettrico nella genesi di nuovi potenziale d'azione
nelle cellule con bassa soglia di eccitabilità, con conseguente
marcato effetto anti-aritmico. tale fenomeno è testimoniato nella
pratica clinica dal prolungamento dell'intervallo QT.
31
01/10/2010
SOTALOLO
Beta bloccante non selettivo
+
Bloccante canali del potassio
32
01/10/2010
Farmaci con rischio di TDP
www.torsades.org
33
01/10/2010
Nella pratica clinica:
Un paziente “vero” della cardiologia, UCIC,
rianimazione o medicina generale…
Anziano con infezione respiratoria, in FA cronica, con
agitazione psicomotoria (notturna).
E’ sotto cordarone (FA), ha iniziato la claritromicina
da tre giorni, e nella notte diamo il Serenase iv…
Curr Drug Saf. 2010 Jan;5(1):97-104. QT alterations in psychopharmacology: proven candidates and
suspects. Alvarez PA, Pahissa J. Department of Internal Medicine, CEMIC, Buenos Aires, Argentina.
palvarez@cemic.edu.ar
Abstract
Nuovi farmaci confronti
Psychotropics are among the most common causes of drug induced acquired long QT
syndrome. Blockage of Human ether-a-go-go-related gene (HERG) potassium channel by
psychoactive drugs appears to be related to this adverse effect. Antipsychotics such as
haloperidol, thioridazine, sertindole, pimozide, risperidone, ziprasidone, quetiapine,
olanzapine and antidepressants such as amitriptyline, imipramine, doxepin, trazadone,
fluoxetine depress the delayed rectifier potassium current (IKr) in a dose dependent
manner in experimental models. The frequency of QTc prolongation (more than 456 ms)
in psychiatric patients is estimated to be 8%. Age over 65 years, tricyclic antidepressants
(TCA), thioridazine, droperidol, olanzapine, and higher antipsychotic doses were predictors of
significant QTc prolongation. In large epidemiological controlled studies a dose dependent
increased risk of sudden death has been identified in current users of antipsychotics
(conventional and atypical) and of TCA. Thioridazine and haloperidol shared a similar
relative risk of SCD. Lower doses of risperidone had a higher relative risk than
haloperidol for cardiac arrest and ventricular arrhythmia. No increased risk was identified in
current users of selective serotonin reuptake inhibitors (SSRI). Cases of TdP have been
reported with thioridazine, haloperidol, ziprazidone, olanzapine and TCA. Evidence of QTc
prolongation with sertindole is significant and this drug has not been approved by the
Food and Drugs Administration (FDA). A large trial is ongoing to evaluate the cardiac risk
profile of ziprazidone and olanzapine. Selective serotonin reuptake inhibitors have been
associated with QTc prolongation but no cases of TdP have been reported with the use of these
agents. There are no reported cases of lithium induced TdP. Risk factors for drug induced LQT
syndrome and TdP include: female gender, concomitant cardiovascular disease, substance
abuse, drug interactions, bradychardia, electrolyte disorders, anorexia nervosa, and congenital
Long QT syndrome. Careful selection of the psychotropic and identification of patient's risk
35
factors for QTc prolongation is applicable in current clinical practice.
01/10/2010
Raccomandazioni specifiche del AIFA
Sull’utilizzo di:
Serenase
Droperidolo
Primozide
Raccomandazioni
ACC/AHA/ESC 2006 guidelines for management of patients with
ventricular arrhythmias and the prevention of sudden cardiac death
37
01/10/2010
Il mio paziente ha il QT lungo,
cosa faccio?
1- sospensione dei farmaci implicati nell’allungamento del tratto QT;
2- il mantenimento di livelli di concentrazione di K+ plasmatici tra 4 – 4,5
mmol/L;
3- la somministrazione di 1 – 2 g di solfato magnesio EV, con possibilità di
aumentare la dose e la velocità d’infusione in base alla gravità del quadro
clinico;
4- in caso di refrattarietà al trattamento e di concomitante bradicardia, può
essere d’aiuto il “pacing cardiaco temporaneo” o l’isoproterenolo.
38
01/10/2010
LINEE GUIDA PER IL TRATTAMENTO CON
FARMACI A POTENZIALE RISCHIO DI
ALLUNGAMENTO DEL QTC



Pazienti a basso rischio (QTc basale 0.41 sec): non
necessitano di ECG dopo l’introduzione di un singolo antipsicotico
in monoterapia. Necessario ECG di controllo per farmaci associati
all’antipsicotico con potenziale aumento del QT
Pazienti borderline (QTc 0.42-0.44.sec): sono a basso rischio di
aritmia. Necessitano di un ECG dopo la prima dose e allo steady
state. Se QTc >450 ms ridurre i dosaggi o cambiare con un
farmaco meno a rischio. ECG di controllo per polifarmacoterapie.
Pazienti ad alto rischio (QTc >0.45 sec) Sono ad alto rischio di
aritmie necessitano di un ECG dopo la prima dose e allo steady
state. Se QTc >500 ms cambiare con farmaco meno a rischio.
ECG di controllo per polifarmacoterapie. Monitoraggio degli
elettroliti
Moss AJ, Zareba W, Benhorin J, et al. ISHNE guidelines for electrocardiographic evaluation of drug-related QT prolongation
and other alterations in ventricular repolarization: Task force summary. A report of the Task Force of the International
Society for Holter and Noninvasive Electrocardiology (ISHNE), Committee on Ventricular Repolarization. Ann Noninvasive
Electrocardiol 2001;6:333–341
Approccio clinico e strumentale in base al
livello di rischio.
Livello di
rischio
Definizione
Screening
ECG
Follow-up
ECG
Consulenza
cardiologica
Monitoraggio
sec. Holter
Molto
basso
Maschi senza
fattori di rischio
Non
necessario
Non
necessario
Non
necessaria
Non necessario
Basso
Donne senza fattori
di rischio
Non
necessario
Non
necessario
Non
necessaria
Non necessario
Medio
Patologie cardiache
Consigliabile
Consigliabile
Consigliabile
Non necessario
Alto
Interazioni tra
farmaci
Necessario
Necessario
Necessaria
Discutibile
Molto alto
Storia di LQTS
Obbligatorio
Obbligatorio
Obbligatoria
Obbligatorio
Viskin S. Long QT syndrome caused by non-cardiac drugs.
Progress in Cardiovascular Disease. 2003; 45:415-427.
Il farmaco che sto dando
prolunga il QT?
www.qtdrugs.org
www.torsades.org
Su questi siti si trova una lista
sempre aggiornata dei
farmaci che possono
prolungare il QT
41
01/10/2010
E il QT corto?
La sindrome del QT breve è una patologia
ereditaria a carattere autosomico dominante
Si caratterizza per la presenza sull’ecg di
base di un intervallo QT spiccatamente
breve ed una propensione a sviluppare
aritmie ipercinetiche a livello atriale e/o
ventricolare in assenza di anomalie
strutturali cardiache
42
01/10/2010
ECG QT corto
• Intervallo QT breve,
genericamente ≤ 300 ms, che non
cambia in maniera significativa
con il ritmo cardiaco.
• Si possono notare in oltre onde
T alte ed appuntite.
• Alcuni individui possono anche
presentare fibrillazione atriale
sottostante.
43
01/10/2010
Basi genetiche
Basi genetiche della Short QT Syndrome
Wilde AAM e Coll. Heart 2005;91:1352-1358
Le mutazioni nei geni KCNH2, KCNJ2 e
KCNQ1. Questi geni codificano le proteinecanale di membrana del K.
44
01/10/2010
Trattamento
Al momento l’unica azione terapeutica efficace
per i soggetti affetti da sindrome del QT breve
è l’impianto di un defibrillatore automatico.
Trattamento mediante AICD
• L’unica “copertura” sicuramente efficace nei
pazienti considerati ad alto rischio, in rapporto
anche alla difficile valutazione della efficacia
farmacologica
• Sono stati segnalati diversi casi di “Shock
inappropriato da doppio conteggio includente
una onda T di elevato voltaggio
45
01/10/2010
Trattamento
Un suggerimento da cardiologo:
Provate a dare l’aloperidolo…. magari si
allunga il QT e risparmiamo un defi…!
Commenti conclusivi

Il QT lungo esiste nella misura in cui lo si misura. L’occhio del cardiologo
quasi non vede un QT <500msec, mentre l’elettrocardiografo misura
variazioni anche “impercettibili” che spesso corrispondono
all’allungamento massimo che questi farmaci possono causare (40msc)
sono sempre poi un quadratino da 1 mm…

Gli effetti cardiotossici avvengono quasi sempre in pazienti cardiopatici,
con farmaci antiaritmici, in politerapia o con disturbi elettrolitici.

Quando vi arriva un referto ECG con diagnosi di QT lungo, spesso è già
soppesato dal cardiologo. Il significato è = sospendi il farmaco.

Non sottovalutare il QT lungo, ma valutalo insieme al cardiologo.

Le dimostrazioni del nesso tra l’allungamento del QT e la morte cardiaca
sono note ma l’incidenza (NNT - NNH) è poco conosciuta poiché molto
bassa. Infatti, le torsioni di punta da antipsicotico sono molto molto rare.
01/10/2010
47
La riflessione di un cardiologo
Il possibile rischio cardiologico conferito da questi farmaci
è comunque MINORE del sicuro effetto dei fattori di
rischio convenzionali tra i quali il fumo, sedentarietà, il
sovrappeso e l’ipertensione o della sindrome
metabolica spesso presenti nei pazienti psichiatrici.
01/10/2010
Grazie dell’attenzione
49
01/10/2010