QT-Interval Prolongation Associated with Supratherapeutic Guanfacine Concentration: A Case Report

Abstract

Introduction

Guanfacine, an alpha-2 adrenergic agonist, is used to treat attention deficit hyperactivity disorder (ADHD). Although cardiovascular effects including hypotension and bradycardia are common adverse effects of guanfacine, the effect of guanfacine on QT intervals remains unclear. The association between the serum concentration of guanfacine and its toxicity has also not been fully investigated.

Case Report

This is a case of a 21-year-old woman with ADHD who developed repeated presyncope 1 day before admission. She was taking 3 mg of extended-release guanfacine and 50 mg of sertraline. On admission, she had bradycardia and hypotension. An electrocardiogram (ECG) showed a QT interval of 0.68 s and a QTcF interval of 0.648 s. The QT intervals were manually measured and corrected by the Fridericia formula (QTcF = QT/RR^1/3). Although she denied taking an overdose of guanfacine and other drugs, we suspected guanfacine toxicity. The serum guanfacine concentration was 13.0 ng/mL on admission and decreased to 3.2 ng/mL on day 1 and 0.4 ng/mL on day 2. Changes in QTcF intervals and her vital signs correlated with serum guanfacine concentrations.

Conclusion

Supratherapeutic serum guanfacine concentrations may induce QT prolongation.

Introduction

Guanfacine is a selective alpha-2-adrenergic agonist that was initially approved as an antihypertensive agent and is now used for the treatment of attention deficit hyperactivity disorder (ADHD). Adverse effects such as drowsiness, bradycardia, and hypotension may occur, but serious effects such as coma and circulatory and respiratory depression are very rare [1, 2]. However, as guanfacine prescriptions for patients with ADHD increase, serious complications have been increasingly reported [1]. Although QT prolongation due to guanfacine may be one of potentially critical adverse effects, the impact of guanfacine on QT interval has not been clarified [3, 4]. In addition, there have been few reports showing an association between the serum concentration of guanfacine and its toxicity including its effect on QT prolongation. To our knowledge, we present the first case of bradycardia, hypotension, and QT prolongation in a patient who was prescribed 3 mg of extended-release guanfacine daily, indicating an association between serum guanfacine concentration and QT intervals.

Case Report

A 21-year-old woman (body weight of 53.0 kg) with ADHD presented to our emergency department with repeated presyncope. Since the day before admission, she had many near-syncopal episodes on standing up and was unable to walk as usual due to lightheadedness. She had started treatment with 1 mg of extended-release guanfacine 54 days before admission, and the dose was increased from 2 to 3 mg 26 days before admission. She had also been taking 50 mg of sertraline, 1 mg of flunitrazepam, and 10 mg of bepotastine besilate daily. She had never experienced syncope and convulsion, and there was no family history of sudden cardiac death and QT prolongation. An electrocardiogram (ECG) at 6 months before admission showed normal QT intervals: QT of 0.36 s and QTcF of 0.404 s (Fig. 1A). The QT intervals were manually measured and corrected by the Fridericia formula (QT/RR^1/3 = QTcF). On arrival, her initial vital signs were as follows: heart rate, 52 beats per minute; blood pressure, 74/28 mm Hg; oxygen saturation, 97% on room air; and temperature, 36.5 °C. Physical examination revealed 2-mm pupils with normal light reflexes and no paralysis. In addition, she did not have spontaneous and positional nystagmus, hearing loss, double vision, visual loss, slurred speech, numbness of the face or body, and incoordination in her extremities. Blood examination showed potassium of 4.1 mmEq/L, magnesium of 1.8 mg/dL (normal range 1.9–2.5), calcium of 9.2 mg/dL (normal range 8.8–10.1), lactic acid of 2.3 mmol/L, creatinine of 0.46 mg/dL, and troponin T of 0.038 ng/dL. An ECG showed a QT interval of 0.68 s and a QTcF interval of 0.648 s (Figs. 1B and 2). Although she denied taking an overdose of guanfacine or sertraline, we suspected drug-induced hypotension, bradycardia, and QT prolongation. After fluid resuscitation and intravenous administration of 1 g of magnesium sulfate, she was admitted for monitoring ECG and her symptoms. Her heart rate and blood pressure gradually increased to 71 beats per minute and 93/64 mm Hg, and QT prolongation also improved on day 2 (Fig. 2). Transthoracic echocardiography showed normal cardiac anatomy and ventricular function. Symptoms improved, and she was discharged on day 2. There were no reports of recurrent symptoms after discharge. An ECG 1 month after discharge, when she was taking sertraline and bepotastine, showed a QT interval of 0.36 s and a QTcF interval of 0.381 s (Fig. 1C).

Fig. 1.

(A) At 6 months before admission, (B) on admission, and (C) 1 month after discharge.

Fig. 2.

The QT interval was manually measured and corrected by the Fridericia formula. The interval between measurements of serum guanfacine concentration on admission and on day 1 was 18 h, and the interval between measurements on day 1 and on day 2 was 26 h.

Measurements using a high-performance liquid chromatograph/tandem mass spectrometer (1260 infinity LC system and 6420 Triple Quad Mass spectrometer (Agilent Technologies, Palo Alto, CA, USA)) showed that the serum concentrations of guanfacine were 13.0 ng/mL (therapeutic range 1–10), 3.2 ng/mL, and 0.4 ng/mL on admission, on day 1, and on day 2, respectively (Fig. 2). Supratherapeutic guanfacine concentrations have been associated with bradycardia and orthostatic hypotension [5, 6]. In addition, the serum concentration of sertraline on admission was below the detection sensitivity. Finally, based on her clinical course and results of pharmacological analysis, we made a diagnosis of guanfacine toxicity. Consent for publication of this case was obtained and provided to the journal in accordance with JMT policy.

Discussion

To our knowledge, this is the first case of QT prolongation associated with a supratherapeutic serum guanfacine concentration, with normalization of the QT interval seen with a falling serum concentration. This association is supported by the fact that the prolonged QT intervals on admission gradually improved in accordance with a decrease in serum guanfacine concentration.

Guanfacine acts as both a central and a peripheral alpha-adrenergic agonist and can reduce sympathetic influence on the heart and the peripheral vascular resistance, leading to hypotension and bradycardia. In addition, activation of alpha-adrenergic receptors in the locus coeruleus causes miosis and central nervous system and respiratory depression. Although central alpha-adrenergic activation is usually predominant, paradoxical hypertension may occur transiently, in the distributive phase of overdose due to non-specific peripheral alpha-1 receptor stimulation [7]. In contrast, the hypotensive effects of guanfacine begin approximately 8 to 12 h post-ingestion, resulting from central alpha-2 stimulation once the drug is distributed to the brain [8]. Our patient had typical clinical signs of guanfacine toxicity, and hypotension responded to intravenous fluid therapy alone.

It is generally accepted that guanfacine has no effect on QT intervals with therapeutic dosing; if it does have an effect, changes in QT intervals may not be clinically significant [3]. In contrast, previously, a prolonged QT has been observed after a reported guanfacine overdose; however, the authors did not report serum guanfacine concentrations [9]. In our case, we suspected a guanfacine overdose based on symptoms due to guanfacine toxicity (i.e., hypotension and bradycardia) and supratherapeutic serum guanfacine concentration on admission, although she denied taking an overdose of guanfacine. Based on information on serum guanfacine concentrations and the time of measurement, we can calculate the elimination half-life using a plotted graph that is exponential with the decay curve [10]. Assuming a single guanfacine overdose with no prior intake, we calculated the elimination half-life to be approximately 9 h. However, due to the extended-release nature of the formulation, it is not possible to back-extrapolate a peak concentration accurately. Given these considerations, it is highly likely her serum concentration was much higher at the time of symptom onset 24 h prior to presentation, which resulted in a strong effect on the sympathetic nervous system, leading to bradycardia, hypotension, and QT prolongation [5, 6]. In addition, it is noteworthy that the QT interval was prolonged despite a decrease in serum guanfacine concentrations to the therapeutic levels on day 1. We hypothesize that, in cases of guanfacine overdose, resolution of QT prolongation may lag behind a falling serum concentration, in a similar way to the prolonged postural hypotension often seen after overdose [8]. Possible reasons for an elevated serum concentration of guanfacine other than an overdose, including drug-drug interaction, drug-food interaction, and impairments of metabolic pathways, were considered. The possibility of drug and food interactions such as CYP3A4-inhibiting drugs, high-fat meals, and grapefruit was extremely low based on a detailed medical history. In addition, our patient had no hepatic or renal dysfunction. Thus, we considered that unexpected causes other than an overdose were unlikely to lead to a supratherapeutic serum guanfacine concentration.

In our case, QT prolongation might have been caused by another drug (i.e., sertraline or bepotastine). However, a previous ECG and a post-discharge ECG, when our patient had been taking sertraline and bepotastine, showed normal QT intervals, and pharmacological analysis revealed that the serum sertraline concentration on admission was below the detectable limit. Thus, the possibility that sertraline or bepotastine caused the QT prolongation was extremely low. In addition, other possible causes of QT prolongation may be potential channelopathies such as long-QT syndrome. However, our patient did not experience syncope or convulsion, and there was no family history of sudden cardiac death and long-QT syndrome. T waves before, after, and on admission may not be specific changes in long-QT syndrome [11]. Based on the clinical course of our case and ECG changes before and after taking guanfacine, we postulate that guanfacine may have been responsible for the QT prolongation.

Conclusions

A supratherapeutic serum guanfacine concentration was associated with QT prolongation in this 21 year old patient with presyncopal symptoms. Since the number of prescriptions for guanfacine continue to increase worldwide, evaluating the potential association of guanfacine with QT-interval conduction disturbances is needed.

Sources of Funding

None.

Data Availability

This is a case report, all data are in the manuscript.

Declarations

Ethical Approval

Consent for publication of this case was obtained and provided to the journal in accordance with JMT policy.

Conflicts of Interest

None.