Clinically Significant Bradycardia and Hypotension Following Consumption of Betel Leaf in a Patient Treated for Chronic Atrial Fibrillation

Introduction

Betel leaf (Piper betle) is a plant originating in Southeast Asia consumed around the world for religious, recreational, and medicinal purposes.^1-3 Proposed medicinal uses of betel leaves include use as an anti-infective, anti-inflammatory, digestive aid, anti-anxiety at high doses, and a stamina aid at lower doses.^1-3 The leaves are typically chewed alone or consumed as a part of betel quid, a blend of betel nut (Areca catechu), and slaked lime (calcium hydroxide) wrapped in betel leaves.^1,2,4 There are a plethora of studies demonstrating the pharmacologic effects of the active compounds in betel leaf, primarily eugenol and safrole, on in vitro and in vivo models.^1-7 Low concentrations of highly addictive betel leaf have been shown to produce stimulant and euphoric effects in humans, whereas large doses have resulted in sedation.^1,4,5 Adverse systemic effects on the nervous, cardiovascular, gastrointestinal, and endocrine systems have been reported for decades.^4,8,9 Chen et al. ¹⁰ found that the administration of intravenous betel leaf extract led to hypotension and bradycardia in rats. The betel nut, in particular, may be associated with an increase in cardiovascular disease and all-cause mortality. ¹¹ While studies have addressed the potential consequences of betel leaf use, further studies are needed to establish direct effects in humans.

We present a patient case and report of new onset symptomatic bradycardia and hypotension likely associated with post-ingestion of betel leaf in combination with cardiodepressant medications and lessons learned by the healthcare team.

Patient Case

The patient case took place at a 200-bed, non-profit, suburban, community hospital in the United States. A 66-year-old Nigerian woman presented to the emergency department (ED) for evaluation of multiple near syncope episodes. Upon arrival, she complained of mild chest pain, shortness of breath, and generalized weakness. She had a heart rate of 55 bpm and a blood pressure of 121/65 mmHg. Her electrocardiogram revealed atrial fibrillation (AF) with slow ventricular response and nonspecific ST- and T-wave abnormalities. Patient has a history of AF and this was not a new finding. Her potassium and blood sugar were elevated at 5.4 mEq/L and 377 mg/dL. Pertinent lab trends are shown in Table 1 and vital sign trends in Table 2. The patient arrived with multiple medication bottles containing metoprolol succinate and extended-release verapamil. Of note, the patient was initially interviewed by two student pharmacists and subsequently interviewed by the ED pharmacist to obtain a thorough home medication reconciliation and assess compliance. She stated she had taken her medication as prescribed earlier that morning and has been on the same doses for several months. The patient also reported that she is compliant with her prescribed medication and endorsed a thorough understanding of her medication. Compliance with her prescribed medications was verified by review of recent fill history data at her pharmacy. After initial evaluation by the ED pharmacist, she disclosed she had also taken several betel leaves that she grinds up and puts in a smoothie in combination with garlic for general health purposes. Patient stated that this is an infrequent practice but that she did consume a betel leaf smoothie prior to feeling poorly and deciding to come to the ED. She was not able to give a clear frequency of consuming betel leaf and it was assessed that this was not a commonly practiced activity. Patient was further questioned about other herbal or over the counter medications and stated she did not take anything else. Over the next several hours, her heart rate fell into the 30 s with a low blood pressure of 71/31 mm Hg. She received 2 L of normal saline and was admitted to the critical care unit (CCU) for overnight observation over concern for hypotension and symptomatic bradycardia. The patient weighed 89.4 kg with a body mass index (BMI) of 33.8 kg/m². Her pertinent past medical history included type 2 diabetes mellitus, asthma, obesity, hypertension, and hypothyroidism. Of note, she was not currently treated for hypothyroidism and her thyroid stimulating hormone (TSH) was normal at 1.32 mIU/ml, ruling out myxedema coma or acute hypothyroidism as an explanation for her hemodynamic changes. The patient has a documented history of AF and near syncopal episodes requiring hospitalization 3 years prior but no other documented hospital encounters for cardiovascular reasons. Her family history included stroke in her father and dementia in her mother. Her home medication list consisted of spironolactone 50 mg PO daily, metoprolol succinate 50 mg PO in the morning and 25 mg at bedtime, and verapamil ER 240 mg PO twice daily. She reported allergies to hydrocodone, ibuprofen, and lidocaine. She denied the use of tobacco, alcohol, and recreational drugs. Upon admission, her home medications including metoprolol, verapamil, and spironolactone were held. Intravenous fluids were continued, and she received atropine .4 mg IV as needed for symptomatic bradycardia. Approximately 18 h following admission, her vital signs were stable, and her admitting labs had returned to baseline. At that time, verapamil 80 mg IR was administered and well tolerated by the patient. Verapamil ER 240 mg once daily and metoprolol succinate 50 mg daily were then ordered which is a reduction from patient’s home dose. She remained stable and was prepped for discharge with a recommendation to continue her home medications at a reduced dose and to follow-up with her primary care provider. There were no clear indications of counseling on betel leaf consumption in the discharge summary.

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Table 1.

Pertinent Lab Trends.

Laboratory value (facility reference range)	Presentation Day 1 12:33	Day of discharge Day 2 04:46
Potassium (3.55–.1 mEq/L)	5.4 mEq/L	3.8 mEq/L
BUN (9–20 mg/dL)	20 mg/dL	16 mg/dL
SCr (.66–1.25 mg/dL)	.99 mg/dL	.70 mg/dL
Glucose (70–110 mg/dL)	377 mg/dL	90 mg/dL
AST (15–46 units/L)	172 units/L	94 units/L
ALT (0–49 units/L)	177 units/L	193 units/L
Alkaline phosphatase (38–126 units/L)	52 units/L	51 units/L
Albumin (3.5–5 g/dL)	3.4 g/dL	3.4 g/dL
Total bilirubin (.2–1.3 mg/dL)	.7 mg/dL	.3 mg/dL
TSH (.3–3 mIU/ml)		1.32 mIU/mL
PT/INR (.89–1.18)	13.2/0.99

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Table 2.

Vital Sign Trends.

	Initial Day 1 12:26	ED Day 1 15:20	Admission day 1 20:00	Day 2 am Day 2 04:00	Discharge Day 2 12:00
Temperature (°F)	97.5	97.7	98.3	98.5	98.0
Blood pressure (mmHg)	121/65	77/46	94/46	156/76	132/67
Heart rate (bpm)	55	37	42	102	98
Oxygen saturation (%)	96	98	98	95	97

Abbreviation: ED, emergency department.

Discussion

Historically consumed in Asian counties, betel leaf is being increasingly used in the United States, Canada, Middle East, and European countries for various health purposes. ¹ Despite its widespread use, there is little established evidence of its physiologic effects in the settings of acute toxicity, concomitant comorbidities, or prescription medications. This patient case presented a novel cause-and-effect relationship between betel leaf consumption and automatic dysfunction. The negative outcome experienced by our patient contributes to existing knowledge of the potential consequences associated with betel leaf.

Available reports suggest that betel nut, when consumed as a part of betel quid, can cause acute toxic symptoms if taken at increased quantities, leading to dyspnea, tachypnea, palpitations, hypotension, chest tightness, dizziness, abdominal colic, and even myocardial infarction and coma. ⁴ In the majority of cases, the effects of acute toxicity are transient, and patients have a timely recovery. ⁴ Due to the nature of consumption being chewing of leaves or drinking, relative doses or amounts of betel leaf have not been described in terms of toxicity. Additionally, the time to recovery from betel leaf consumption is not well described in the limited literature available. While there are no case reports regarding betel leaf alone, numerous studies have extracted chemical constituents shown to precipitate systemic effects in animal and human models. Important isolated elements of betel leaf comprise eugenol and safrole.^6,12,13 Eugenol, a phenolic compound, demonstrated toxic effects in rats when consumed at high doses including somnolence, altered sleep time, increased respirations, and dyspnea. ¹⁴ Lahlou et al. ¹⁵ showed that intravenous treatment of rats with eugenol induces dose-dependent hypotension and bradycardia. Isomers of eugenol have also been shown to induce highly reactive oxygen species in humans leading to cytotoxicity observed in the liver, lung, and nervous systems. ¹⁶ Essential oils produced from betel leaf have shown cardiac and respiratory depressant effects mainly attributed to the presence of high-dose eugenol. ¹³ Similarly, betel leaf’s major constituent safrole has displayed somnolence in rats when consumed at toxic doses. ¹⁷ Safrole is found to be a potent inhibitor of human cytochrome P450 metabolizing enzymes in the liver including CYP1A2, CYP2A6, and CYP2E1 and with relatively less potency, CYP2D6 and CYP3A4. ¹⁷ Safrole and eugenol may play a role in the development of acute hepatoxicity and chronic liver cirrhosis.^17-19

A Naranjo Scale score was calculated based on the case with a result of 5, indicating that betel leaf consumption in this case is probable. The reaction seen could have been due to direct toxicity or indirect drug interactions with concurrent medications. Based on evidence regarding the systemic effects of betel leaf, it is reasonable to conclude that the potential for clinically significant adverse effects and drug interactions is prevalent. Systemic activity and alterations in metabolizing enzymes can lead to pronounced additive and altered pharmacokinetic effects of other medications. It is likely that the hemodynamic instability experienced by our patient is explained by two noteworthy mechanisms. The patient ingested “several” betel leaves that may have resulted in large quantities of eugenol and safrole, although this cannot be confirmed due to the limited data on relative amounts of these compounds in the leaves, the state of the leaves when consumed (fresh vs dried), and the specific number of leaves consumed. High-dose eugenol may have resulted in additive cardiodepressant effects of her home medications including extended-release verapamil and metoprolol succinate. In addition, the metabolism of verapamil, a major substrate of CYP3A4 and minor substrate of CYP1A2 and CYP2E1, may have been altered by safrole’s activity at the same cytochrome P450 metabolizing enzymes. ²⁰ Inhibition of the metabolism of verapamil may have led to an increase in serum concentration and cardiac depressant effects including bradycardia and hypotension. Betel leaf’s activity at the liver may explain the patients transiently elevated liver enzymes although there were no clinical findings suggestive of acute liver injury. While the consumption of betel leaves in this case is a probable cause of the reaction either by direct toxicity or drug interaction with current medications, it is possible that the use of metoprolol and verapamil as a combination by itself could have caused the reaction or that the patient could have taken an extra dose of either. The patient did report appropriate knowledge of her medications and did not endorse taking extra medication. Additionally, compliance was confirmed by prescription fill history via an electronic insurance claims database, although this is limited information. Patient had underlying AF and reported hypothyroidism, but these were ruled out as causes of her reaction. While the patient is at risk for bradycardia and hypotension due to her medication regimen, the temporal nature of this reaction following betel leaf consumption makes this at least a plausible contributing factor to her presentation.

This patient case also demonstrated the importance of the pharmacist’s role in the ED in identifying potentially life-threatening drug interactions. In the physician’s original evaluation, betel leaf use was not reported by the patient. Complementary and alternative medication (CAM) information is rarely obtained during initial medication reconciliations. A study conducted by Gardiner et al. ²¹ found that less than 10% of patients were asked, disclosed, and had documented CAM in their chart. Additionally, while various medical personnel conduct medication reconciliation interviews, literature shows that pharmacists in comparison to other medical professionals provide the most detailed and accurate medication reconciliation reports.^22,23 Upon a follow-up evaluation by the ED pharmacist, our patient disclosed her use of betel leaf earlier that morning. In this case, the use of betel leaf potentially caused a clinically significant interaction that led to an overnight CCU admission. Failure to obtain a complete medication history in this patient may have led to misdiagnosis or inappropriate dose reductions in her home medications possibly precipitating further complications. It is important to recognize that hospitalized and elderly patients may be at higher risk of drug–dietary supplement (DS) interactions due to an increase in chronic conditions and concomitant medications. ²¹ It is also of note that non-disclosure of CAM use is higher in minorities and may significantly differ among patient populations. ²¹ For instance, betel leaf is commonly used among African and South Asian populations. ¹ By being aware of cultural aspects of patient care, the relative cultural perceptions of CAM outside of the native culture, and the risks associated with CAM, healthcare providers can be more vigilant and effective in identifying meaningful drug interactions such as the one depicted in this patient case. Finally, the importance of medication counseling extends to CAM and the potential interactions and adverse events associated with them alone and in combination with traditional medications. This is another essential role for the pharmacist in patient care.

Conclusion

Betel leaf intrinsically contains chemicals that have been documented to cause central and autonomic nervous system alterations. The patient’s clinical presentation and hospital course are consistent with available reports of acute toxicity of betel nut and betel quid. Following removal of betel leaf and subsequent re-introduction of lower doses of home medication, the patient stabilized and discharged. In this presented case, we saw an intriguing patient who presented with seemingly unprovoked hemodynamic instability. Initially, it was considered that the patient may have taken too much of her home medications, despite asserting that she takes them as prescribed. Upon disclosure that she had ingested several betel leaves due to the medication reconciliation interview conducted by the ED pharmacist and student pharmacists, the healthcare team was able to shift our focus to the possibility of acute toxicity.

This patient case adds to existing evidence that betel leaf can have significant systemic effects which could result in adverse events when used in combination with cardiodepressant medications. It also highlights the importance of obtaining a comprehensive and accurate medication reconciliation and pharmacists and pharmacy extenders are well positioned to provide this service. Including discussion on CAM during a medication reconciliation interview is essential as the use of CAM is growing across all cultures. Healthcare providers should be aware of the culture aspects of health care and possible implications of CAM. By holistically understanding the patient and their approaches to health, potentially life-threatening interactions can be identified, corrected, and prevented. Finally, patient counseling on CAM is an important component of the patient care process but should be done with appropriate cultural understanding and sensitivity.