Heart (Cardiovascular Events)
Corrected QT Interval Prolongation, Torsades de Pointes (TdP) , and
Ventricular Fibrillation resulting in Angina, Heart Failure,
Cardiomyopathy, Stroke or Transient Ischemic Attack, Chest Pain or
Shortness of Breath with Activity and Sudden Death.
It has been shown that the radical in position 5 of the
fluoroquinolone ring is responsible for QTc prolongation. The methyl
group at position 5 is associated with the prolongation of the QTc
interval found with Sparfloxcacin. An amino group at position 5 is
associated with the prolongation of the QTc interval found with
Grepafloxacin. A proton (H) at this position is associated with the
QTc prolongation found with Ciprofloxacin, Gatifloxacin,
Gemifloxacin, Moxifloxacin and Levofloxacin.
During preclinical animal toxicological assessment, all quinolones so
far adequately investigated have proved to prolong the QT interval.
Almost every quinolone investigated, however partially, provides some
evidence of effects on cardiac conduction and some are associated
with `clinically significant' events. It is perhaps the latter
phraseology which stimulates controversy as, taken alone,
prolongation of the QTc is rarely considered to be a `clinically
significiant' event, during the drug trials, by the investigators.
The QT interval is that ECG measurement which describes the period
between onset of ventricular depolarization and the end of the
repolarization process. It varies with heart rate. Prolongation of
the rate-corrected QT interval (QTc) is recognized to be associated
with various malignant tachy-arrhythmias and specifically with
torsade de pointes. When sufficiently prolonged they may precipitate
torsade de pointes (TdP) which, if transient, may present with
syncope and, if not, may cause sudden death.
Hence the risk of sudden death as a result of fluoroquinolone
therapy, as a result of TdP is to be considered a class effect. The
fluoroquinolones induce Corrected QT Interval Prolongation and the
resultant TdP by blocking the cardiac voltage-gated potassium
channels, particularly the rapid component (IKr) of the delayed
rectifier potassium current (IK). By doing so, fluoroquinolones
prolong the QT interval, a process that even if subdued may lead to
the occurrence of arrhythmia (irregular heartbeat).
Untreated arrhythmia may result in the inducement of acute myocardial
infarction (heart attack). In addition, they have the potential to
interact with other drugs that prolong the QTc interval. As such
heart patients who are taking other drugs should not carelessly be
prescribed a fluoroquinolone without taking such drugs into
consideration.
It has been shown that the higher the fluoroquinolone dose and serum
AUCs, the higher the QT prolongation risk and subsequently the risk
of TdP which may result in angina, heart failure, cardiomyopathy,
stroke or transient ischemic attack, chest pain or shortness of
breath with activity and sudden death.
Research has clearly indicated that the calcium signals are affected
by the fluoroquinolones as a consequence of reduction of
mitochondrial DNA content in Jurkat cells. All fluoroquinolones have
the capacity to block HERG (the human-ether-a-go-go gene),
responsible for the IKr, and subsequently for prolonged QT and TdP.
Hence the prolongation of the QTc interval would be considered to be
a class effect of the fluoroquinolones. The blockade of the human
cardiac K(+) channel HERG underlies such clinical findings.
Prolongation of the QT interval, which may lead to potentially life-
threatening ventricular arrhythmias such as torsades de pointes, is
one such example of the cardiovascular events associated with the
fluoroquinolones.
Drugs such as Sparfloxcacin and Grepafloxacin have been removed from
the market in the United States, in part because of their potential
for such dramatic QTc interval prolongation. However it is to be
noted that Moxifloxacin (recently approved by the FDA in spite of
these cardiovascular events) has the usual adverse effects of
fluoroquinolones, but carries a far greater risk of QT prolongation
than Ciprofloxacin, Levofloxacin and Ofloxacin.
As such the known mechanisms of action for the cardiovascular events
found with the fluoroquinolones (which are to be considered a class
effect) are the reduction of mitochondrial DNA content in Jurkat
cells, blocking of HERG (the human-ether-a-go-go gene)responsible for
the Ikr, and interference with the calcium signals. As noted earlier
it is the radical in position 5 of the fluoroquinolone ring that is
responsible for QTc prolongation and the subsequent TdP, which may
result in the sudden death of the patient.
However, the fluoroquinolones effect on potassium and magnesium
excretion and whether it somehow is additive with other drugs that
produces increased loss of electrolytes through the kidneys, has not
been studied. Thus the reduction of available potassium and magnesium
may also prove to be a contributory factor as well.
It is to noted that the FDA, in 2004, mandated warnings be added to
all of the package inserts for all the drugs found within this class
as it relates to these cardiovascular events. However, such warnings
are diluted for the drugs currently in use and greatly expanded upon
with the drugs that are available either as a generic or off patent
and rarely utilized anymore. (such as Nalidixic Acid).
It may be several more years before such revised package inserts
become readily available. Such events are rarely reported in the
elderly population as the physician just assumes that since they are
elderly such spontaneous heart attacks and strokes are resultant of
old age and these cardiovascular adverse reactions associated with
the fluoroquinolones are rarely, if ever, considered to be a
contributory or sole factor in the sudden death of the patient.
Proarrhythmia as a class
effect of quinolones: increased dispersion of repolarization and triangulation
of action potential predict torsades de pointes.
Antibiotic Treatment Does Not Reduce Risk of Secondary Cardiac Events
RAXAR:Warning on Label Omits Deaths
http://www.latimes.com/news/nation/reports/fda/lat_raxar001220.htm
Heart problems were mentioned in fine print, but not key dosage
data. By DAVID WILLMAN, Times Staff Writer
Quinolone-induced QT interval prolongation: a not-so-unexpected class effect
Torsades de pointes associated with fluoroquinolones.
Quotes from a
recent FDA hearing regarding approval of Moxifloxacin (Avelox) a fluoroquinolone
RAXAR:Warning on Label Omits Deaths
Cardiotoxicity of fluoroquinolones
Rates of Torsades de
Pointes Associated with Ciprofloxacin, Ofloxacin, Levofloxacin,
Gatifloxacin, and Moxifloxacin RAXAR:Warning on Label Omits Deaths
Heart problems were mentioned in fine print,
but not key dosage data. By DAVID WILLMAN, Times Staff Writer
Wednesday, December 20, 2000 |
Torsades de pointes associated with
fluoroquinolones: importance of concomitant risk factors.
Fluconazole- and levofloxacin-induced torsades
de pointes in an intensive care unit patient.
Prolongation of QT interval is probably a class
effect of fluoroquinolones
Bradycardic syncope in 2 patients who recently
began gatifloxacin treatment. The following citations have no abstract. Full text can be
obtained by contacting either the author or the publication cited:
Gatifloxacin-induced QTc prolongation and ventricular tachycardia. Additional Research from PubMed/Medline
Heart (36)
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Richard Frothingham, M.D.
http://www.latimes.com/news/nation/reports/fda/lat_raxar001220.htm
18 May 2000
Nicholson WJ, Buxton AE, Tammaro D.
Gatifloxacin-Associated Corrected QT Interval
Prolongation, Torsades de Pointes, and Ventricular Fibrillation in
Patients with Known Risk Factors
Joseph S. Bertino, Jr.,1 Robert C. Owens, Jr.,2 Timothy D. Carnes,3
and Paul B. Iannini4
Moxifloxacin: new preparation. A me-too with
more cardiac risks.
[No authors listed]
Lannini PB, Circiumaru I.
Department of Medicine, Danbury Hospital, Connecticut 06810, USA.
Paul.iannini@danhosp.org
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10
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11
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12
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13
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14
Bertino JS Jr, Owens RC Jr, Carnes TD, Iannini PB.Gatifloxacin-associated
corrected QT interval prolongation, torsades de pointes, and ventricular
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15
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16
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17
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18
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19
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20
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21
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22
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23
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24
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25
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27
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28
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31
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32
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33
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34
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35
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