Acyclovir-induced sinus bradycardia: a case report and literature review

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Abstract

Introduction

Acyclovir is an antiviral medication with activity against herpes simplex viruses 1 and 2 (HSV-1 and -2) and varicella zoster virus (VZV). Intravenous acyclovir is indicated for use in patients with severe VZV infection, e.g., patients with ocular or neurologic or disseminated disease, or patients with severe HSV infection, e.g., patients with encephalitis/meningitis [1]. Intracellularly, acyclovir is converted into acyclovir triphosphate by viral thymidine kinase within infected cells. Acyclovir triphosphate acts as an analog of deoxyguanosine triphosphate. When incorporated into the growing viral DNA chain, chain termination ensues because this analog lacks the 3’ hydroxyl group that is necessary for incorporation of the next nucleotide [2].

The half-life of acyclovir in patients with normal renal function is approximately 2 to 3 hours [2,3]. Acyclovir is well tolerated in most patients; however, renal and neurologic toxicities may occur [2]. Common side effects of acyclovir treatment include mild injection site reactions, gastrointestinal complaints such as abdominal pain, polydipsia, anorexia, nausea, vomiting, or generalized fatigue. Rare side effects may include changes in vision, jaundice, myalgias, ataxia, and tachycardia [4].

Case report

A 50-year-old female presented to our emergency department (ED) with headache, blurred vision, and painful vesicular lesions in the left T4 dermatome. Her significant past medical history included a mood disorder treated with fluoxetine and rheumatoid arthritis treated with risankizumab, an anti-interleukin 23A monoclonal antibody. Prior to presentation, the patient was evaluated by her family physician and prescribed valacyclovir. Due to worsening pain, spread of the vesicular rash throughout the T4 dermatome, and a burning sensation that developed in her left temporal scalp without rash, she presented to our ED for further evaluation.

Initial vital signs were: a blood pressure of 109/58 mmHg, heart rate of 83 beats/min, respiratory rate of 18 breaths/min, oxygen saturation of 97% on room air, and a temperature of 37.1 C. Physical examination revealed normal cardiac sounds with no extra heart sounds or murmurs; good air entry bilaterally without adventitial sounds; and a soft, non-tender, and non-distended abdomen. Neurological examination was unremarkable with no visual field defects and full extraocular eye movements. The pupillary examination results were normal.

Skin examination revealed fluid-filled vesicles on the left hemithorax and dorsal aspect at the level of the T4 dermatome. No vesicles or rash were identified in the scalp on careful examination.

Laboratory investigations revealed a normal white blood cell count, hemoglobin level, and platelet count. The creatinine level was 74 μmol/L with an eGFR of 81 mL/min/1.73 m². A polymerase chain reaction test for severe acute respiratory syndrome coronavirus 2 using a nasopharyngeal swab was negative. Chest X-ray and a non-contrast computed tomography scan of the head were unremarkable.

Lumbar puncture was performed. The cerebrospinal fluid (CSF) had a nucleated cell count of 1 × 10⁶/L, an erythrocyte count of 1 × 10⁶/L, a protein level of 0.26 g/L, and a glucose level of 3.0 mmol/L. CSF Gram stain and culture were negative. CSF VZV, HSV-1, and HSV-2 polymerase chain reaction tests were negative.

This 60-kg patient was started on empiric intravenous (IV) acyclovir via peripheral IV at the standard dose for suspected disseminated VZV infection of 10 mg/kg IV every 8 hours until disseminated infection was excluded. Risankizumab was withheld.

On admission day 1, approximately 12 hours after the initiation of acyclovir, the patient’s vital signs were stable with occasional episodes of mild bradycardia (Table 1). However, on day 3 of acyclovir treatment, the patient’s vital signs and electrocardiogram revealed a sinus bradycardia of 35 beats/min. The patient was placed on telemetry. The baseline rhythm remained at an average of 46 beats/min throughout the day with occasional increases to 70 beats/min. Due to the possibility of acyclovir-induced bradycardia, IV acyclovir was discontinued and valacyclovir was reinitiated.

Table 1

Blood pressure, heart rate, and medications administered from day 0 to 9

The patient’s heart rate normalized over the next 2 days with near-complete resolution on day 2 post-IV acyclovir discontinuation and complete resolution by day 3. No other factors were identified to explain the sinus bradycardia. We recommended that the patient receive VZV vaccination in a year.

Discussion

A literature review was performed to identify other cases of acyclovir-induced sinus bradycardia. The MEDLINE search strategy used was: (acyclovir.mp OR Acyclovir/) AND (bradycardi*.mp OR Bradycardia/). Seven articles were identified, two of which included patients who developed sinus bradycardia following acyclovir treatment [5,6]. Table 2 outlines these two case reports that discuss sinus bradycardia as a rare side effect of acyclovir. Our case report is the third.

Table 2

Case reports of sinus bradycardia as a rare side effect of acyclovir

The other two case reports, one by Wolters et al. [5] and the other by Gill et al. [6], are cases of bradycardia attributed to IV acyclovir therapy. The patients described were treated with IV acyclovir for dermatomal zoster and aseptic meningitis, respectively. Our patient’s age was identical to the patient described in the report of Wolters et al. [5]. Ours is the first female case report of acyclovir-induced bradycardia. Because neither patient weight nor renal function test results were included in the other two case reports, we are unable to assess the appropriateness of acyclovir dosing in those cases.

The pathophysiology of acyclovir-induced sinus bradycardia has not been described. A study in halothane-anesthetized dogs describes several effects that acyclovir may have on heart function [7]. Interestingly, although the authors describe bradycardia as a potential side effect in the clinical setting, no change in heart rate was found in these experimental models. However, acyclovir was found to decrease peripheral vascular resistance with a subsequent decrease in blood pressure. From these findings, the authors hypothesized that acyclovir may act on rapid delayed rectifier channels (I_Kr) and could potentially induce Ca²⁺ overload with subsequent early depolarization. This may contribute to a small increase in the risk of reentrant arrhythmia [8].

As valacyclovir is a prodrug of acyclovir, we were interested in the different reaction to this drug as the patient improved on valacyclovir despite the active drug being theoretically identical. We performed a similar literature search for valacyclovir and identified an article describing a patient with valacyclovir-induced neurotoxicity who presented with drowsiness and disorientation. He was subsequently found to have sinus bradycardia on routine electrocardiography in the ED [7]. Therefore, a report of valacyclovir-induced sinus bradycardia also exists; and the reason for our patient’s improvement with valacyclovir is unclear.

Following thorough investigation and review of laboratory and imaging results and medication changes, we could not find an alternative explanation for the patient’s sinus bradycardia. The patient had neither a history of bradycardia nor a history of cardiac disease, and no cardiac disease risk factors were identified. The only other medication administered during the time of the patient’s sinus bradycardia was dexamethasone (Table 1). We reviewed an article on dexamethasone-induced bradycardia [9] and concluded that our patient’s sinus bradycardia was unlikely to be associated with IV dexamethasone therapy. This conclusion is based on the expectation that bradycardia would have occurred closer to the administration of the first dose of dexamethasone and resolved more rapidly than was observed in our patient.

Ours is the third reported case of acyclovir-induced bradycardia. Switching this patient from IV acyclovir to valacyclovir corrected the arrhythmia. Clinicians should consider IV acyclovir as a cause of de novo sinus bradycardia. Further research may identify mechanisms of acyclovir-induced arrhythmia.

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