Long-term myocardial toxicity in a patient with tizanidine and etizolam overdose

Abstract

Tizanidine hydrochloride, α2-receptor stimulant, is a central muscle relaxant. Etizolam is a benzodiazepine-based anti-anxiety agent. Both drugs are widely used for the treatment of a variety of muscle pain and frequently used together in Japan. We experienced a case of complicating prolonged myocardial dysfunction in a 56-year-old woman. Six hours after overdose of 48 mg tizanidine and 24 mg etizolam, she showed sinus bradycardia and peripheral vascular resistance decreasing shock. At that time new ST-T depressions were recognized in electrocardiography (ECG); however, structural heart diseases were interpreted as negative by other examinations. Intravenous norepinephrine infusion was useful to maintain the hemodynamic stability. ECG reversed to normal findings on day 14; however, the cardiac nuclear medicine studies on day 30 showed severe fatty metabolic disorder and sympathetic denervation. Non-sustained ventricular tachycardia was detected. Complete recovery of the myocardium damage required one year. For one mechanism, it was suggested that over-stimulation of α2-receptor by tizanidine inhibited the norepinephrine secretion and reuptake at pre-synaptic surface of adipose cell and cardiac sympathetic nerve. We want to suggest that the cardiologist should consider the risk of fatal arrhythmia and long-term myocardium toxicity as the poisoning of the central muscle relaxant and benzodiazepine agent.

<Learning objective: We experienced a case of complicating prolonged myocardial dysfunction in a 56-year-old woman. Six hours after overdose of 48 mg tizanidine and 24 mg etizolam, she showed sinus bradycardia and peripheral vascular resistance decreasing shock. The cardiac nuclear medicine studies on day 30 showed severe fatty metabolic disorder and sympathetic denervation. Non-sustained ventricular tachycardia was detected. Complete recovery of the myocardium damage required one year.>

Introduction

Tizanidine hydrochloride, α2-receptor stimulant, is a central muscle relaxant. This agent is mainly metabolized in the liver by cytochrome enzyme P450 CYP1A2, and it has a T_max of 1 h, C_max of 1.83 ng/mL, and T_1/2 of 1.58 h [1]. Common side effects include drowsiness or liver dysfunction, and adverse effects for the cardiovascular system are hypotension and bradycardia caused by an action analogous to α2 adrenergic stimulation, leading to an inhibition of peripheral norepinephrine (NE) secretion. Etizolam is a benzodiazepine-based anti-anxiety agent. This agent is metabolized by CYP2C9 and CYP3A4, and it has a T_max of 0.8 h, C_max of 27.32 ng/mL, and T_1/2 of 4 h [2]. Disturbance of consciousness is a common side effect in cases of overdose, and adverse effects for the cardiovascular system are hypotension, bradycardia, QT prolongation, and Torsades de pointes. Both drugs are widely used for the treatment of a variety of muscle pain such as low backache, cervical vertebral syndrome, and tension-type headache, and are frequently used together in Japan. However, there are no reports about the prognosis of myocardial toxicity associated with central muscle relaxants or/and the benzodiazepine agents.

Case report

A 56-year-old woman took 48 tablets of tizanidine (1 mg) (treatment dosage: 2–3 mg/day) and 48 tablets of etizolam (0.5 mg) (treatment dosage: 1.5–3 mg/day), after a quarrel with her daughter at home. The family found the patient unconscious after 30 min, and then called the ambulance. At the arrival to hospital, the vitals were as follows: Japan Coma Scale, 300; Glasgow Coma Scale, 1-1-1; pupils, R2/L2; no light reflex; body temperature, 35.0 °C; breathing rate, 16 breaths/min; heart rate, 66 beats/min, regular; blood pressure, 100/60 mmHg; and SpO₂, 99% (3 L nasal oxygen). Blood examination only showed moderate increase of lactate (33 mg/dl). There were no abnormal findings in electrocardiography (ECG), echocardiography, chest X-ray, and head/chest computed tomography scan. She had no history of visitations for psychiatric care and epilepsy. Based on these observations, she was diagnosed as having consciousness disturbance resulting from overdose of tizanidine and etizolam, and admitted to the intensive care unit on artificial respiration support in preparation for the potential risk of apnea.

Six hours after taking the two agents, hypotension (82/46 mmHg) and sinus tachycardia (122 bpm) appeared temporally. One more hour later, she developed hypotension (73/44 mmHg) and heart rate adversely changed to sinus bradycardia (45 bpm). ECG indicated ST depression and negative T wave (Fig. 1A). Ischemic heart diseases, myocarditis, takotsubo-cardiomyopathy, or sepsis-cardiomyopathy were interpreted as negative by the longitudinal laboratory and echocardiography findings, and blood cultures. Swan-Ganz monitoring showed the finding of decreased peripheral vascular resistance [cardiac output/cardiac index 6.5/3.5; systemic vascular resistance (SVR)/SVR index 926/1200; pulmonary capillary wedge pressure 6]. For the treatment, intravenous NE infusion was useful to maintain the hemodynamic stability. On day 3, hemodynamic statuses became stable without NE administration. The respirator was taken off after the patient's conscious level became alert. On day 4, ECG showed the partially normalized T wave (Fig. 1A). In blood concentrations of tizanidine and etizolam, both agents showed maximum level on day 1 and fell below detectable limits on day 5 (Fig. 1B). The patient was discharged on day 6.

Fig. 1.

Electrocardiogram (ECG) and blood level of tizanidine and etizolam. (A) ECG on day 1: normal sinus rhythm, no abnormal finding. ECG on day 2: ST depression and negative T wave at lead I.aVL.II.III.aVF.V3-6. ECG on day 4: normalized T wave at lead I.aVL.V3-4. ECG on day 14: reversed to normal findings. (B) Black square line shows tizanidine (pg/dl) and black circle line shows etizolam (ng/dl). In blood level of drug measurements, both tizanidine and etizolam increased to maximum value on day 1 and fell below detectable limits by day 5.

In the out-patient clinic, ECG reversed to normal findings on day 14 (Fig. 1A). On day 30, cardiac nuclear medicine studies were performed for further work-up. Technetium-99 m-tetrofosmin (^99mTc-TF) was used for myocardial perfusion imaging, ¹²³I-β-methyl-p-iodophenyl-pentadecan-oic acid (¹²³I-BMIPP) for myocardial fatty acid metabolism imaging, and ¹²³I-metaiodobenzylguanadine (¹²³I-MIBG) for cardiac sympathetic functional imaging. The ^99mTc-TF analysis did not show any abnormal findings. The ¹²³I-BMIPP analysis suggested attenuation at the area of posterior and cardiac apex (Fig. 2A). In the ¹²³I-MIBG, early imaging showed little uptake from the postero-inferior to apex with decreased heart/medium (H/M) ratio and increased washout rate (Fig. 2A). Coronary angiography did not show any coronary stenosis and vasospastic changes induced by the acetylcholine infusion. Around the same time, 24-h ambulatory ECG detected non-sustained ventricular tachycardia (22 times, maximum beat: 146 bpm, maximum running: 15 continual ventricular premature complexes) and independent multiple ventricular premature contractions (13,239 beats/day). The nuclear medicine study at 6 months indicated partial recovery without any treatment, but not cured completely and anterior wall showed newly developed attenuation in ¹²³I-BMIPP (Fig. 2B). Full recovery of the myocardium damage required one year (Fig. 2C). The risk of occurrence of fatal arrhythmia decreased with the improvement in nuclear scintigraphy.

Fig. 2.

Findings of the nuclear cardiac medicine study. (A) The images of ¹²³I-β-methyl-p-iodophenyl-pentadecan-oic acid (BMIPP) and ¹²³I-metaiodobenzylguanadine (MIBG) on day 30. The attenuation at the area of posterior and apex suggests the myocardial metabolic disorder of fatty acid. However, the end-diastolic volume (EDV), end-systolic volume (ESV), stroke volume (SV), and ejection fraction (EF) were within normal limits. In the early-image of MIBG, there was little uptake at the postero-inferior to apex. The delayed-image demonstrated a decrease in the heart/medium (H/M) ratio and increase in the washout rate, which suggests the disorder of cardiac sympathetic activity. We have carefully selected the same slice levels of short-axis, long-axis, and horizontal-axis images for the two myocardial SPECT (BMIPP and MIBG). (B) The follow-up BMIPP image showed little attenuation of isotope in the chronic phase after 6 months. The result of MIBG revealed the recovery with accumulation of isotope at the area of posterior and apex except inferior wall. However, anterior shows newly developed attenuation. The H/M ratio and washout rate also recovered within normal range. (C) The follow-up BMIPP and MIBG showed full recovery after 1 year.

Discussion

The clinical findings that should be mentioned specifically are the long-term disorders of myocardial fatty acid metabolism and cardiac sympathetic nerve identified by the nuclear scintigraphy. These results do not support structural heart disease, but instead suggest impaired cardiac dysfunction by drug poisoning.

Generally, the shock and bradycardia would easily develop due to overdose of etizolam with tizanidine. Tizanidine is both structurally and pharmacologically analogous to clonidine (α2 agonist antihypertensive agent) and thus, through stimulation of central α2 receptors, suppresses peripheral sympathetic nerves and catecholamine secretion, creating a hypotensive effect. When blood pressure decreased, the initial response is an increase in heart rate, and the patient may present primarily with tachycardia; however, afterward, the attenuated peripheral sympathetic activity due to α2-adrenoceptor leads to bradycardia [3]. As for the etizolam, it is rare to die because of the oral benzodiazepine agent alone. However, it causes shock, bradycardia, or cardiac arrest when used with alcohol or other central nervous depressants [4]. But there is no report about fatty acid metabolism disorder and sympathetic denervation induced by the etizolam or tizanidine.

The detailed mechanism is unclear about the fatty acid metabolism and sympathetic nerve disorder, but inferred as below. An α2 agonist simulates norepinephrine (NE) in binding to pre-synaptic surface auto receptors, which in turn mediates feedback inhibition of NE release. Another major control mechanism for noradrenergic neurotransmission is termination of signaling by pre-synaptic NE transporter-mediated NE reuptake [5]. Park et al. [6] reported that α2 adrenergic agonists (xylazine and dexmedetomidine) suppress cellular NE transport from their ¹²³I-MIBG uptake experiments. Furthermore, clonidine, lofexidine, tizanidine, and guanabenz significantly inhibited ¹²³I-MIBG uptake at doses of 100 μM.

In addition, NE released in the synapse space acts on an adrenergic β receptor in the surface of adipose cell and promotes lipolysis. However, the α-receptor controls anti-lipolysis, particularly α2-receptor. In one hypothesis, if tizanidine excessively inhibited catecholamine release, free fatty acid might decrease extremely in the blood. Hence, it was thought that heterogeneous distribution of fatty acid was recognized in the myocardium. Dissociation of triglyceride pool might spread among the injured lesion, border zone, and non-injured lesion to prevent the myocardium toxicity [7]. In our case, there were various changes longitudinally in the SPECT images such as the attenuation of postero-inferior wall on day 30 or anterior wall on day 180. It might be potentially explained that fatty acid metabolism caused a variety of localization during a process of restoration. It needs to be elucidated in further studies. The cardiologist should consider the risk of fatal ventricular arrhythmia and long-term myocardium toxicity as a result of poisoning by central muscle relaxant and benzodiazepine-based anti-anxiety agents.

Conflict of interest

There were no grants or financial support. The authors report no conflicts of interest. The authors are responsible for the content and writing of this paper.