Symptoms
Drug-induced prolongation of the QT interval can rarely lead to severe arrhythmias. This is polymorphic ventricular tachycardia, known as torsade de pointes arrhythmia. It can be seen on the ECG as a wave-like structure. Due to the dysfunction, the heart cannot maintain blood pressure and can only pump insufficient blood and oxygen to the brain. This results in malaise, dizziness, palpitations and a sudden loss of consciousness (syncope). If the heart does not find its normal rhythm spontaneously or by external action, arrhythmia can lead to sudden cardiac death.
Causes
The QT interval refers to the time in milliseconds that elapses on the ECG between the onset of the QRS complex and the end of the T wave. During this interval, the ventricles are de- and repolarized. The heart muscle contracts and relaxes again. The cause of a prolongation of the QT interval is a prolongation of repolarization (= T-wave). Hundreds of agents from different drug groups can prolong the QT interval. These include, for example (selection):
| Antiarrhythmic drugs | Amiodarone, quinidine, dofetilide, flecainide, sotalol |
| Antiemetics | Domperidone, ondansetron |
| Antihistamines | Astemizole, mizolastine, terfenadine |
| Antiinfectives | Quinolones, clarithromycin, cotrimoxazole, grepafloxicin |
| Antifungals | Fluconazole, ketoconazole |
| Antimalarials | Quinine, chloroquine, halofantrine |
| Neuroleptics and antidepressants | Amisulpride, amitriptyline, citalopram, escitalopram, haloperidol, imipramine, lithium, risperidone, thioridazine |
| Opioids | Fentanyl, methadone, pethidine |
| Prokinetics | Cisapride |
HERG potassium channel
The deeper cause of drug-induced QT interval prolongation is often blockade of the voltage-gated hERG (human ether-a-go-go-related gene) potassium channel. This potassium channel transports potassium ions into the extracellular space and is involved in repolarization of cells in the heart muscle. When the potassium channel is blocked, the action potential is prolonged. Because the QT interval is dependent on heart rate, QTc time is used, which is corrected using heart rate (c = corrected). Several drugs had to be withdrawn from the market due to QT prolongation. Today, new agents are systematically screened for cardiotoxicity at every stage of drug development.
Risk factors
Important: Not every prolongation of the QT interval leads to cardiac arrhythmias! The QT interval is used as a surrogate marker for the cardiotoxicity of a drug. The risk for clinically relevant symptoms increases when several critical agents are combined. A hazard exists in the case of overdose or drug-drug interactions. When an agent that prolongs the QT interval and is metabolized by CYP450 isozymes is combined with a CYP inhibitor, plasma concentrations may increase and the effect may be enhanced. Other risk factors include (selection):
- Heredity (genetic predisposition), congenital long-QT syndrome (LQTS).
- Female gender
- Age
- Electrolyte disorders (hypokalemia, hypomagnesemia, hypocalcemia), taking diuretics.
- Heart disease, for example, untreated heart failure.
- Relevant bradycardia (< 50 heartbeats / minute).
- Hypothyroidism
- CYP450 polymorphisms
- Anorexia
- Renal insufficiency without dose adjustment
- High drug dose
- Hypothermia
Diagnosis
Diagnosis is made in medical treatment on the basis of clinical symptoms, patient history and by means of ECG.
Treatment
Torsade de pointes ventricular tachycardia is a medical emergency that requires prompt medical attention (including electrical cardioversion, correction of electrolyte disturbances, discontinuation of the drug).
