Drugs, Prolonged QT Interval and Torsades de Pointes

The QT interval of an ECG (electrocardiogram) represents ventricular depolarisation and repolarisation. It is normally less than 440 milliseconds (although this may vary between individuals and by gender).

Torsades de Pointes (TdP) is a form of polymorphic ventricular tachycardia that occurs in patients who have a long QT interval when in normal rhythm (usually sinus rhythm, but sometimes in patients with atrial fibrillation). Prolongation of the QT interval can predispose individuals to this potentially lethal arrhythmia (and less commonly, other arrhythmias) by prolonging repolarisation, which induces early afterdepolarisations and spatial dispersion of refractoriness. The risk of TdP is increased when the QT interval is above 500 milliseconds or increased from the patient’s baseline by at least 60 milliseconds.

Prolongation of the QT interval can be caused by many factors including:

• Congenital long QT syndrome (genetic; generally autosomal dominant disorders)
• Pre-existing cardiac structural disease (such as heart failure and myocardial infarction)
• Bradycardia
• “Stimulant conditions” such as exercise or emotion
• Electrolyte abnormalities (hypokalaemia, hypomagnesaemia and hypocalcaemia)
• Testosterone suppression
• Thyroid disease
• Female gender
• Increasing age, and
• Drugs.

The highest risk population appears to be females between menarche and menopause. Prolongation of the QT interval is quite often asymptomatic and self-limiting but can recur if underlying causes are not corrected. TdP produces no effective cardiac output, therefore if an episode is less than 10 seconds a patient may not notice it, however longer than this may cause a collapse, potentially with loss of consciousness. Seizures may occur due to brain hypoxia. Death may occur if the abnormal rhythm is not terminated within a few minutes, however if it does terminate, the patient will recover consciousness quickly.

Treatment for TdP is slow intravenous injection of magnesium sulphate as well as a drug to shorten the QT interval such as isoprenaline. Electrolyte abnormalities should be corrected and any drugs prolonging the QT interval should be stopped.

Drugs generally lengthen the QT interval via interacting with some of the cardiac membrane ion channels, particularly the potassium channel. The identification of a prolonged QT interval is difficult. It is important to manually measure the interval and not rely on the generated measurement on the ECG, and measure this on a QT nomogram. QRS widening on the ECG may cause prolonged QT, however this is not a risk for TdP (such as in bupropion poisoning).

Drugs that prolong the QT interval are separated into three categories of risk for producing TdP, and quality and quantity of evidence supporting the conclusion:

1. Proven risk of TdP when given therapeutically

Substantial evidence supports the conclusion that these drugs prolong the QT interval and have a risk of TdP when used in therapeutic doses.

• Antiarrhythmics: Amiodarone, Disopyramide, Flecainide and Sotalol;
• Antidepressants: Citalopram and Escitalopram;
• Anti-infectives: Azithromycin, Chloroquine, Clarithromycin, Erythromycin,
  Moxifloxacin and Pentamidine;
• Antipsychotics: Chlorpromazine, Droperidol and Haloperidol;
• Gastrointestinal agents: Cisapride and Domperidone; and
• Miscellaneous: Arsenic Trioxide, Dextropropoxyphene, Methadone and Sevoflurane.

Figure 1. Schematic representation of ECG trace

2. Drugs with conditional risk of TdP

Substantial evidence supports the conclusion that these drugs prolong the QT interval and have a risk of TdP under certain known conditions (e.g. not in therapeutic doses under such conditions as drug interactions or excessive dosing).

• Antidepressants: Fluoxetine, Tricyclic antidepressants, Paroxetine*, Sertraline* (*lower risk than Tricyclic antidepressants);
• Anti-infectives: Ciprofloxacin, Co-Trimoxazole, Fluconazole, Itraconazole, Ketoconazole, Mefloquine and Ritonavir;
• Antipsychotics: Amisulpride; and
• Miscellaneous: Cocaine, Diphenhydramine, Galantamine, Loratadine, Pazopanib, Propranolol, Sevoflurane, Solifenacin and Toremifene.

3. Drugs with possible risk of TdP

Substantial evidence supports the conclusion that these drugs prolong the QT interval but insufficient evidence that they cause TdP.

• Antidepressants: Moclobemide and Venlafaxine;
• Anti-infectives: Atazanavir, Foscarnet and Voriconazole;
• Antipsychotics: Clozapine, Paliperidone, Olanzapine, Quetiapine,
  Risperidone, Sertindole and Ziprasidone;
• Gastrointestinal agents: Dolasetron, Famotidine, Granisetron and Ondansetron; and
• Miscellaneous: Alfuzosin, Amantadine, Dasatinib, Fingolimod, Indapamide,
  Lapatinib, Lithium, Nilotinib, Roxithromycin, Sorafenib, Sunitinib, Tacrolimus,
  Tamoxifen and Vardenafil.

The degree of QT prolongation associated with drug use appears to be related to drug plasma concentration which is affected by dose, frequency, route of administration, and variables that interfere with the pharmacokinetics of the drug.

Therefore, to reduce the risk of TdP in a patient with risk factors for prolonged QT:

• Avoid drugs that prolong QT. If this will reduce treatment efficacy, use a drug which
  is less likely to cause TdP (i.e. one that has little evidence of TdP or needs certain conditions to prolong QT);
• Use the lowest possible dose;
• Use the oral route where possible;
• If given intravenously, give as slowly and as diluted as possible; and
• Reduce pharmacokinetic and pharmacodynamic interactions by avoiding the concomitant use of agents which may prolong the QT interval, drugs that will inhibit the metabolism of drugs that prolong QT interval (i.e. cytochrome P450 inhibitors), or drugs that increase the concentration of these agents.

For example, in a patient with severe community-acquired pneumonia who requires intravenous administration of azithromycin, along with other antibiotics, whilst sputum and blood cultures are pending. Administration of azithromycin in 500mL over three hours is preferable to the more routine administration of 250mL administered over one hour (unless the patient is fluid restricted). If the patient is nauseous, metoclopramide should be used over domperidone.

Although the frequency of TdP is low, it can occur as often as 2-3% with some drugs, and can be fatal. Practical measures can be taken to prevent it by understanding risk factors and negotiating therapy to still provide the best patient outcomes.