J1307870
Special edition: Drug therapy management of arrhythmia
Drug-induced QT prolongation
syndrome and treatment thereof
Yoshiaki Keneko (Associate Professor, Organ pathology internal medicine, Department of Medicine
and Biological Science, Graduate School of Medicine, Gunma University)
G11/ Pharmaceuticals Monthly/ (ISSN: 0016-5980) ; ()/
55 (8) 1369-1373/(2013.8)
Reference documents: 2
[Drug name:*indicate drugs in scope for safety]
* flecainide
* bepridil
pilsicainide
K
[Keywords]
Side effects
[Side-effect syndrome] MeDRA/J V16.0 (LLT) [PT]
QT prolongation syndrome (10024803) [QT prolongation syndrome; 10024803]
Torsade de pointes (10044067) [Torsade de pointes; 10044066]
Special edition: Drug therapy management of arrhythmia
J1307870
Drug-induced QT prolongation syndrome and treatment thereof
Yoshiaki Keneko
Drug-induced QT prolongation syndrome is a condition which causes dangerous arrhythmia
called torsades de pointes by causing QT prolongation by administration of certain drugs. The
causal drugs include not only anti-arrhythmia drugs but also non-cardiovascular drugs such as
antibacterial drugs, antifungal drugs, antidepressants, antihistamines, gastrointestinal drugs,
and anesthetics. Also, excessive drug administration, hepatic/renal function abnormalities and
drug-drug interactions increase the blood concentration of certain drugs, and may result in QT
prolongation. In recent years, studies have found that genetic factors such as abnormalities of
genes encoding K channels are the background to this syndrome, in the same way as in the
congenital QT prolongation syndrome. In diagnosis, it is important to first diagnose the patient
with torsades de pointes on ECG, and in treatment, it is important to discontinue the causal
drug, to treat risk factors, and particularly to avoid bradycardia.
Keywords: QT prolongation, arrhythmia-inducing actions, drugs, torsades de pointes
Introduction
Drug-induced QT prolongation syndrome is a side-effect of general drugs which causes severe
arrhythmia, and in the worst case it can lead to death. It is an important issue not only for medical
staff involved in actual administration of drugs to patients, such as doctors, pharmacists, and
nurses, but also for local administrative health organizations and for medical governance on a
national level. The present paper aims to provide an overview of this disease from the basics, with
the expectation that most readers are pharmacists.
What is a QT interval and QT prolongation?
A normal electrocardiogram waveform of a single heartbeat continues from the P wave reflecting
stimulation of the atrium, to the QRS wave reflecting stimulation of the ventricle (depolarization),
and, further, a T wave reflecting the process of recovery from stimulation (repolarization) (Figure
1). A QT interval is the interval from the Q wave until the end of the T-wave, and it corresponds to
the repolarization time of the cardiac muscle. Also, since the QT interval changes depending on
the heart rate (RR interval), there is no absolute normal value. Due to this, QT prolongation is
determined through QTc, which is the QT corrected using the Bazett formula [QTc (msec) = QT
(msec) / RR (sec)], and in general, a QTc of 0.45 or greater in males or 0.46 in females is assessed
as QT prolongation.
Figure 1 QT interval on a normal electrocardiogram (arrow)
Associate Professor, Organ pathology internal medicine, Department of Medicine and Biological Science, Graduate School of Medicine, Gunma University
Pharmaceuticals Monthly 2013.8 (Vol.55 No. 8) – 101 (1369)
Special edition Drug therapy management of arrhythmia
Onset of continually elevated U-wave following the recovery period (arrow)
Figure 2 Frequently-seen torsade de pointes
What is QT prolongation syndrome?
QT prolongation syndrome is a pathological state occurring in the frequency of atrial contraction
characterized by QT prolongation due to some cause accompanied by torsade de pointes (Figure
2). Torsade de pointes in French means "twisted axis", and literally means that the QRS wave form
changes into a type of polymorphic ventricular tachycardia. It is abbreviated and often referred to
as “TdP”. TdP often stops naturally; however, there are also cases of progression to ventricular
fibrillation, which is fatal arrhythmia, and sudden death occurring. From a clinical point of view,
there is a major distinction between congenital QT prolongation syndrome, which is QT
prolongation with a genetic cause, and acquired (secondary) QT prolongation syndrome caused by
non-genetic factors. Congenital cases are relatively rare; however, acquired cases are not
uncommon in everyday treatment and diagnosis. The congenital abnormality is an abnormality of
the genes mainly encoding K channels and sometimes encoding Na channels, which are ion
channels involved in electrical stimulation of cardiac muscle. However, the cause of the majority of
acquired cases is due to drugs which are explained in the present a paper, followed by
hypokalemia and hypomagnesaemia. In rare cases the cause is bradycardia itself.
What drugs cause drug-induced QT prolongation syndrome?
On a cardiac cellular level, drug-induced QT prolongation is mainly caused by prolonged action
potential duration resulting from prolongation of repolarization due to inhibition of faster
elements (Ikr) within the delayed-rectifier potassium current. There are various types of drugs
which may cause QT prolongation - in addition to anti-arrhythmia agents such as Class Ia or III
drugs, as well as antibacterial agents, antifungal agents, antidepressants, antihistamines,
gastrointestinal drugs, and anesthetics, and there is no relationship with the effects of such drugs
1)
. (The main drugs are shown in Table 1. For further details, please refer to
http://www.torsades.org/). Of patients administered these specified drugs, drug-induced QT
prolongation syndrome occurs in patients who also have QT prolongation exacerbation risk factors,
as shown in Table 2, and in particular such patients have a high frequency of complications
electrolyte abnormalities such as hypokalemia, heart failure, and bradycardia2). Of these,
particular attention should be paid to 1. patients with genetic factors predisposing them to QT
prolongation, and 2. the possibility of QT prolongation occurring due to elevated blood drug
concentration levels through the administration of excessive drugs with hepatic or renal function
abnormalities, or with coadministration of drugs which cause QT prolongation together with
drugs which inhibit enzymes metabolizing such drugs (such as cytochrome P450) (shown in Table 3.
For further information, refer to http://www.drug-interactions.com/.) Genetic factors which have
been clarified at present are, similarly to those with congenital QT prolongation syndrome,
abnormalities in genes encoding K channels, and they have also been reports that genetic
abnormalities have been identified in 10 to 15% of drug-induced QT prolongation syndrome cases.
However, since the degree of such functional abnormalities is mild relative to congenital cases, QT
prolongation does not occur if it is not induced, but QT prolongation occurs with drugs which may
induce it, and TdP may occur. It appears that it is not possible to give a prognosis of the risk of the
present condition occurring in patients with no past history of it.
102 (1370) - Pharmaceuticals Monthly 2013.8 (Vol. 55 No. 8)
Drug-induced QT prolongation syndrome and treatment
Table 1 Drugs causing QT prolongation (names in brackets are product names)
1) Class I
Disopyramide (Rythmodan)
Cibenzoline succinate (Cibenol)
Procainamide hydrochloride (Amisalin)
Quinidine sulfate (Quinidine sulfate)
2) Class III
Amiodarone hydrochloride (Ancaron)
Sotalol hydrochloride (Sotacor)
3) Class IV
Bepridil hydrochloride (Bepricor)
2. Antibiotic substances, synthetic antibiotic agents, and chemotherapy drugs
Erythromycin (Erythrocin)
Clarithromycin (Klaricid, Clarith)
Amoxicillin (Sawacillin)
Midecamycin
Levofloxacin (Cravit)
Moxifloxacin (Avelox)
Sparfloxacin (Spara
Prulifloxacin (Sword
Linezolid (Zyvox
Miconazole (Florid
Fluconazole (Diflucan, Prodif
Pentamidine isethionate (Benambax)
Trimethoprim-sulfamethoxazole combination (ST combination, Baktar, Bactramin)
3. Antianxiety agents, antidepressants, anti-manic agents, antipsychotics, and anaesthetics
Etizolam (Depas)
Imipramine hydrochloride (Ludiomil
Trazodone hydrochloride (Reslin
Lithium carbonate (Limas
Chlorpromazine hydrochloride (Wintermin, Contomin
Pimozide (Orap)
Nortriptyline hydrochloride (Noritren)
Droperidol (Droleptan)
Droperidol - entanyl citrate (Thalamonal)
4. H1 blockers
Terfenadine (Triludan)
Diphenhydramine (Restamin)
Promethazine hydrochloride (Pyrethia)
Hydroxyzine hydrochloride (Atarax)
5. Anti-ulcer drugs
Omeprazole (Omepral)
Mosapride citrate (Gasmotin)
Ranitidine hydrochloride (Zantac)
Famotidine (Gaster)
Cimetidine (Tagamet)
Domperidone (Nauzelin)
6. Anti-tumor drugs
Daunorubicin hydrochloride (Daunomycin)
Doxifluridine (Furtulon)
Mitoxantrone hydrochloride (Novantrone)
Amrubicin hydrochloride (Calsed)
7. Others
Probucol (Sinlestal, Lorelco)
Cisapride (Acenalin)
How is drug-induced QT prolongation syndrome diagnosed and treated?
Many patients in which TdP occurs for the first time go for a diagnosis when they observe that
they have dizziness or syncopal attack.
Table 2 (Drug induced QT prolongation syndrome risk factors)
∙
Female
∙
Hypokalemia
∙
Bradycardia
∙
Recently defibrillated AF cases by a drug which particularly causes QT prolongation
∙
Congestive heart failure
∙
Digitalis therapy
∙
Elevated blood concentration
∙
Intravenous bolus of drugs
∙
Prolongation of baseline QT interval
∙
Potential QT prolongation syndrome
∙
Genetic polymorphisms encoding ion channels
∙
Severe hypomagnesaemia
Pharmaceuticals Monthly 2013.8 (Vol.55 No. 8) – 101 (1371)
Special edition: Drug therapy management of arrhythmia
Table 3 (Drugs causing QT prolongation due to drug-drug interactions)
Drug causing QT prolongation
(Product name)
Anti-arrhythmic agents
Quinidine sulfate (quinidine
sulfate)
Quinidine sulfate (quinidine
sulfate)
Antibacterial drug
Erythromycin (Erythrocin)
Antifungal drugs
Itraconazole (Itrizole)
Miconazole(Florid F)
HIV protease inhibitors
Amprenavir (Prose)
Saquinavir mesilate (Invirase)
Code administered drugs
inhibiting cytochrome P-450
enzymes (Product name)
Inhibited cytochrome P-450
enzymes
Itraconazole (Itrizole)
3A4
Miconazole(Florid D)
3A, 2C9
Pimozide (Orap)
Disopyramide (Rythmodan)
3A
Pimozide (Orap)
Quinidine sulfate (quinidine
sulfate)
Pimozide (Orap)
Quinidine sulfate (quinidine
sulfate)
3A4
Pimozide (Orap)
Pimozide (Orap)
3A4
3A4
3A4
Combining these in coadministration is prohibited.
When they do so, it is important to accurately diagnose patients with TdP accompanying QT
prolongation syndrome based on QT prolongation and recovery periods directly prior to the onset
of TdP observed on ECG (Figure 2), as well as based on elevated U-waves accompanying such
observations. Polymorphic ventricular tachycardia with no TdP characteristics on ECG may not be
TdP.
Subsequently, drug-induced QT prolongation syndrome should be suspected, and an interview
should be held on the patient's medical history, including the drug history, and if the patient is
taking any drugs which may cause QT prolongation, they should be discontinued immediately.
Moreover, whether the patient has risks of QT prolongation such as electrolyte abnormalities such
as hypokalemia, bradycardia, or heart failure should be checked, and such risks should be treated
as much as possible.
For cases which frequently have TdP, the following methods are useful for the purpose of reducing
the recovery period which exacerbates TdP, directly prior to TdP onset: 1. temporary pacing, or 2.
increasing the heart rate through continuous intravenous infusion of isoproterenol. Also,
intravenous administration of magnesium sulfate (1-2g) is efficacious; however, it is necessary to
pay attention to bradycardia and hypotension due to a calcium channel blockage effect.
Case:
A case of TdP onset upon hypokalemia during the oral administration of bepridil, an antiarrhythmic agent
Case: A 61-year-old male
Chief complaint: Loss of consciousness
Past history: Hypothyroidism and hypertension
Current history: At the age of 60, the patient had onset of paroxysmal atrial fibrillation. Upon
initial diagnosis, pilsicainide was administered; however, due to efficacy reasons, it was switched
to flecainide (200 mg/day), and bepridil (100 mg/day) was added. Half a year thereafter, the
patient suffered a loss of consciousness during breakfast, and was taken by ambulance to hospital.
Progress: At the time of hospitalization, consciousness was clear, and a fever of 38 to less than 39
degrees Celsius was observed. Serum potassium was 2.9 mEQ/L and hypokalemia was observed.
ECG found sinus rhythm, HR was 62 bpm, and prominent QT prolongation was observed (Figure 3).
Further, frequent TdP was found in the long-short excitation order (Figure 2). The two antiarrhythmia drugs were discontinued and a potassium supplement was given. On the following day,
serum potassium level and QT normalized and TdP disappeared. When looking at the ECG
progression from the time directly after administration of bepridil until the onset of TdP, only mild
QT prolongation was observed until one week prior to the onset following the administration;
however, prominent prolongation at the time of onset and a negative U-wave were observed.
Since the blood concentration of bepridil did not reach the treatment range, it was considered
that the TdP onset was due to QT prolongation which was additively caused due to the
complication of hypokalemia accompanying fever.
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Drug-induced QT prolongation syndrome and treatment thereof
Prominent QT prolongation (QT/QTc: 640/653ms) was observed
In closing
Drug-induced QT prolongation syndrome is rarely caused by the single administration of a certain
drug, but rather is caused through the additive effects of other risk factors; therefore, at present,
it may be difficult to forecast its onset. The important thing is accurate electrocardiological TdP
diagnosis, and we assume that such diagnosis will not lead to incorrect decisions in subsequent
treatment.
References
.
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