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This information is provided as an addendum to the Q&A: What is the QT-Prolonging effect of Epinephrine on Patients Taking SSRIs?

What is the QT interval

QT interval is the time period on the EKG from the start of the QRS wave to the end of the T wave. It is determined from a 12-lead EKG tracing. Then a corrected QT time is calculated (QTc). This represents the repolarization time of the ventricular myocardium. Repolarization in the myocardium acts through potassium channels. Thus, drugs that affect myocardial potassium channels will affect the QT interval.

What is prolonged QT and long QT

A prolonged QT is defined as a QTc time of greater than 440msec. A long Qt is defined as a QTc time of greater than 500msec. The significance of increased QT interval is the increased risk of Torsades de Pointes (TdP). TdP is a fatal arrhythmia similar to ventricular fibrillation and is a differential diagnosis of sudden death in any individual with an either congenital or acquired prolonged or long QT. The risk of TdP rises exponentially by 5-7% for each 10msec increase in QT.

Which drugs cause prolonged QT

The drugs associated with the most significant QT prolongation are class IC (sotalol) and III (flecanide, propafenone) antiarrhythmics. Fortunately none of the above would be commonly used in our outpatient population.

The commonly used drugs that have QT prolonging effects that can be present in the outpatient dental setting are:

  • Antihistamines
  • Macrolide antibiotics
  • Fluoroquinolone antibiotics
  • Anticholinergics
  • Antidepressants
  • Antipsychotics

What are SSRIs

Selective Serotonin Receptor Inhibitors are the preferred drugs for treatment of mild to moderate depression. They are also the first line drugs for panic disorder and obsessive-compulsive disorder.

While older SSRIs solely act by inhibiting serotonin reuptake, newer agents act on both serotonin and norepinephrine reuptake inhibition. Prozac is the tradename for fluoxetine, which was the first SSRI released on the market.

SSRIs have differing side effect profile that is individualized to each patient, thus it is standard practice to try different classes of SSRIs to determine which is most effective with the least amount of side effect.

It has been shown that psychotropic medications increase QTc by inhibiting potassium channels.

What are the QT prolonging SSRIs

Of interest regarding increased QTc are venlafaxine, citalopram, and fluoxetine. Of these three however, only citalopram is reported in literature to show clinically significant cardiotoxicity.

The newer agents have only minor effects on QTc. These are paroxetine, sertraline, fluvoxamine, reboxetine, and duloxetine. In addition, drugs that cause greater than 5msec increase in QTc are often removed from further development.

Although the new agents offer greater safety, this is only true when used as a single drug to treat the illness (i.e. monotherapy). Once more than one antipsychotic or antidepressants (i.e. polypharmacy) come into the picture, QTc can be significantly increased.

How does epinephrine affect QTc

The direct effect of epinephrine on QTc and TdP is difficult to show. Stress as a surrogate marker for endogenous catecholamines is difficult to measure and quantify. Add in that epinephrine in dentistry is not used intravascularly, its effect becomes further difficult to objectively examine. What is known is that epinephrine seems to significantly (by over 30msec) increase QTc from baseline. This was determined from a cohort of adult patients undergoing major non-cardiac surgery under general anesthesia. The patients in this study also had known coronary artery disease or had at least 3 risk factors (Hypertension, Hyperlipidemia, Smoking, Diabetes, Family history, Stroke). All patients had significantly increased QTc post-surgery which corrected by the next two days. Thus we can only conclude that in patients with already diminished heart function, endogenous catecholamines regardless of cause will increase QTc. Of note is that, the one patient that experienced TdP, the QTc was increased by 29msec.

Non-drug factors associated with prolonged QT

Several patient physiologic factors are associated with prolonged QT. These are:

1. Heart disease

  • Congestive Heart Failure
  • Left Ventricular dysfunction
  • Coronary Artery Disease
  • Myocardial hypertrophy
  • Myocardial ischemia

2. Female sex
3. Age over 65
4. Electrolyte disturbance

  • Hypokalemia
  • Hypomagnesemia

5. Bradycardia
6. Congenital Long QTc (LQTc) syndrome
7. Stress and hypothermia

In a review of 77 cases of TdP in setting of a QT prolonging drug, 85% of the cases also included the above risk factors. Heart disease was present in 77% of cases, female sex in 69% of cases, age over 65 in 54% of cases, and hypokalemia in 30% of cases.

References

  1. Moss AJ, Schwartz PJ, Crampton RS, Tzivoni D, Locati EH, MacCluer J, et al. The long QT syndrome. Prospective longitudinal study of 328 families. Circulation 1991;84(3):1136-44.
  2. Nagele P, Pal S, Brown F, Blood J, Miller JP, Johnston J. Postoperative QT interval prolongation in patients undergoing noncardiac surgery under general anesthesia. Anesthesiology 2012;117(2):321-8.
  3. Kongsamut S, Kang J, Chen XL, Roehr J, Rampe D. A comparison of the receptor binding and HERG channel affinities for a series of antipsychotic drugs. Eur J Pharmacol 2002;450(1):37-41.
  4. Wenzel-Seifert K, Wittmann M, Haen E. QTc prolongation by psychotropic drugs and the risk of Torsade de Pointes. Dtsch Arztebl Int 2011;108(41):687-93.
  5. Sala M, Vicentini A, Brambilla P, Montomoli C, Jogia JR, Caverzasi E, et al. QT interval prolongation related to psychoactive drug treatment: a comparison of monotherapy versus polytherapy. Ann Gen Psychiatry 2005;4(1):1.
  6. Letsas KP, Efremidis M, Kounas SP, Pappas LK, Gavrielatos G, Alexanian IP, et al. Clinical characteristics of patients with drug-induced QT interval prolongation and torsade de pointes: identification of risk factors. Clin Res Cardiol 2009;98(4):208-12.
  7. Astrom-Lilja C, Odeberg JM, Ekman E, Hagg S. Drug-induced torsades de pointes: a review of the Swedish pharmacovigilance database. Pharmacoepidemiol Drug Saf 2008;17(6):587-92.