Severe Hypertension on the Background of Buspirone Use

Abstract

Drug-induced hypertension, though rare, often presents diagnostic challenges, particularly when the causative drug is not typically associated with hypertension. We describe a case involving a 55-year-old woman who presented with anxiety, confusion, and significantly high blood pressure unresponsive to standard treatments. Despite increasing medication doses, her blood pressure remained poorly controlled, leading to an investigation for secondary causes. Elevated plasma and urinary catecholamines were found. It was determined that the recent initiation of buspirone for anxiety was the cause. Discontinuation of buspirone normalized her catecholamine levels and improved blood pressure control. This case underscores the importance of considering drug-induced hypertension, particularly in instances of abrupt and severe blood pressure elevation, where elevated catecholamine levels may suggest conditions such as pheochromocytoma. It highlights the necessity for healthcare practitioners to be vigilant regarding the uncommon side effects of commonly prescribed medications, thereby ensuring accurate diagnosis and appropriate management.

Introduction

Buspirone, an FDA-approved anxiolytic, is rarely reported as a cause of secondary hypertension. Proposed mechanisms include its metabolite’s action, direct alpha adrenergic stimulation, or catecholamine release from nerve endings.^1,2 Elevated norepinephrine levels due to buspirone can mimic pheochromocytoma, presenting as sustained or paroxysmal hypertension. ³ This case highlights the importance of careful medication review in diagnosing and managing iatrogenic hypertension. It emphasizes how recognizing the side effects of commonly prescribed drugs can help distinguish between drug-induced hypertension and conditions like pheochromocytoma.

Case Presentation

A 55-year-old woman with a medical history significant for hypertension, hyperlipidemia, anxiety, and marijuana use disorder presented to the emergency room directly from her doctor’s office exhibiting symptoms of anxiety, confusion, night terrors, and night sweats persisting for 1 month. Additionally, her systolic blood pressure readings at home had consistently exceeded 200 mmHg. She was using prescribed metoprolol XR 200 mg and lisinopril 40 mg once daily, along with clonidine, rosuvastatin, ropinirole, progesterone, apremilast, duloxetine, bupropion, as needed rizatriptan and buspirone 10 mg 3 times daily. Her physical exam findings were unremarkable.

Upon admission, the patient was afebrile, displaying extremely high blood pressure readings (277/134 mmHg), with a normal heart rate (68 bpm), respiratory rate (16 breaths per minute), and oxygen saturation within the normal range. Initial laboratory investigations revealed unremarkable results, as outlined in Table 1.

Table 1.

Pertinent Laboratory Work-Up on Initial and Subsequent Presentations.

Pertinent laboratory work-up
Parameter	Result	Normal range
At initial presentation (blood pressure (BP): 277/134-180/122 mmHg)
Hemoglobin (g/dl)	15.4	12-16
White cell count (×103/µl)	8.41	4-11
Platelets (×103/µl)	296	130-400
Potassium (mmol/l)	3.8	3.5-5.3
Magnesium (mg/dl)	2.1	1.8-2.4
Creatinine (mg/dl)	0.87	0.5-1.02
Calcium (mg/dl)	9.7	8.5-10.1
TSH (mlU/l)	1.740	0.35-3.7
Urinalysis	1+ protein	—
Urine toxicology	positive cannabinoids	—
At subsequent visits (BP: 148-196/96-100 mmHg)
Plasma renin (ng/ml/h)	4.91	0.25-5.82
Plasma aldosterone (ng/dl)	8	<21
Plasma renin/aldosterone	1.6	0.9-28.9
Total plasma metanephrines (pg/ml)	495	<205
Free plasma normetanephrine (pg/ml)	442	<148
Plasma catecholamines (pg/ml)	Total: 1857	Total: 424-1125
	Dopamine: 81	Dopamine: <20
	Norepinephrine: 1776	Norepinephrine: 214-1109
24 hrs urine catecholamines (µg)	Dopamine: 503	52-240
24 hrs urine metanephrines (µg)	Total: 857	Total: 224-832
	Normetanephrines: 962	Normetanephrines: 962
CT angiogram of the abdomen and pelvis	No evidence of renal artery stenosis as shown in Figure 1	—
Transthoracic echocardiogram	Left ventricular ejection fraction: 55%-60%, trace tricuspid regurgitation, mild thickening of mitral valve leaflets	—
CT head	No acute abnormality	—
14 days after stopping buspirone (BP: 114-132/70-80 mm Hg)
24 h urine catecholamines (µg)	Dopamine: 204	52-240
24 h urine metanephrines (µg)	Total: 680	Total: 224-832
	Normetanephrines: 579	Normetanephrines: 962

Figure 1.

No evidence of renal artery stenosis on CT angiogram of the abdomen and pelvis.

Following administration of anxiolytic and clonidine in the emergency room, the patient did not exhibit any response. Subsequently, intravenous hydralazine was initiated, resulting in a gradual improvement in blood pressure. During observation following admission, while offering symptomatic management for severe headache, it was suspected that the patient had a high baseline systolic blood pressure ranging between 170 and 180 mmHg. Considering the worsening confusion and night terrors, a decision was made to switch from metoprolol to carvedilol at a dosage of 25 mg twice daily, while maintaining the same dose of lisinopril. Additionally, due to concerns regarding rebound hypertension, clonidine was discontinued.

At the outpatient follow-up after 10 days, there was a downward trend in blood pressure readings, although they remained above the target range. Subsequent to persistently elevated blood pressures over the following 2 weeks, despite escalation of antihypertensive medications, an investigation into secondary causes was initiated, as detailed in Table 1. The patient’s workup revealed elevated levels of plasma dopamine, norepinephrine, total catecholamines, and free plasma metanephrines, while renin and aldosterone levels remained within normal limits. Abdominal ultrasound revealed right renal artery stenosis, though subsequent CT angiogram did not suggest significant renal artery stenosis.

Considering the elevated catecholamines and metanephrines, buspirone was discontinued. Subsequent testing after a 14-day interval exhibited improvement. Although the patient’s blood pressure decreased, it necessitated continued management with multiple antihypertensive medications.

Discussion

Hypertension stands as one of the most prevalent health concerns in developed nations, impacting approximately 30% of the adult population in the United States, with its prevalence surging to 65% among individuals aged 60 to 69 years. ⁴ On a global scale, 1 in every 4 individuals grapples with hypertension, with suboptimal blood pressure levels persisting as the leading risk factor for all-cause mortality worldwide, as per findings from the Global Burden of Disease study. ⁵ Given its modifiable nature, the proper assessment and treatment of hypertension hold profound potential to mitigate the risk of major cardiovascular events by 20% to 25%. ⁶ This notion gained significant traction following the adjustment of systolic blood pressure (SBP) targets from 140 to 130 mm Hg in the 2017 ACC/AHA hypertension guidelines. This shift prompted a cohort study involving 1457 participants in 2020, revealing a 53% increased risk of atherosclerotic cardiovascular disease (ASCVD) with every 10 mmHg elevation in SBP. ⁷

Hypertension, characterized by systolic blood pressure (SBP) exceeding 130 mmHg and/or diastolic blood pressure (DBP) surpassing 80 mmHg, can manifest either as essential or secondary hypertension. ⁵ Secondary hypertension, stemming from an underlying and potentially reversible cause, accounts for 5% to 10% of hypertension cases. Noteworthy triggers include onset before the age of 30, sudden exacerbation of hypertension with inadequate response to treatment, or disproportionate end-organ damage relative to the severity and duration of hypertension, warranting thorough investigation. ⁵ Its prevalence among individuals aged 18 to 40 years can reach up to 30%. ⁸ Common culprits of secondary hypertension encompass renal parenchymal disease, renal artery stenosis, and primary hyperaldosteronism. However, drug-induced hypertension often eludes diagnosis despite its significance. ⁹ Various medications can incite secondary hypertension through diverse mechanisms, ⁹ with our focal point being buspirone—an FDA-approved anxiolytic rarely associated with hypertension.

Buspirone, primarily utilized in managing generalized anxiety disorder, is recognized for its common central nervous system (CNS) side effects such as dizziness, lightheadedness, headache, and nervousness, alongside several less frequent adverse reactions. ¹⁰ Among these, buspirone-induced hypertension is exceedingly rare, accounting for less than 1% of reported cases. It is postulated that buspirone elevates blood pressure in a dose-dependent manner via its metabolite 1 to 2 pyrimidinyl piperazine, which acts as an α2-adrenoceptor antagonist. ¹ Additionally, it appears to activate the sympathetic nervous system, either by releasing catecholamines from free nerve endings or through direct activation of alpha-1 adrenergic receptors. ² Studies examining the catecholamine surge induced by buspirone have demonstrated significant increases in noradrenaline, dopamine, and free serotonin levels shortly after administration, reflecting heightened peripheral neural sympathetic activity but not adrenal sympathetic activity. ¹¹ A similar case reported in 1985 involved a patient presenting with severe uncontrolled hypertension, concurrent buspirone use, and positive metanephrines in urine. It was hypothesized that buspirone may interfere with urinary catecholamine assays, as evidenced by negative assays following discontinuation, although blood pressure improvement was not documented. ¹² In such instances, persistent hypertension induced by norepinephrine release can mimic the sustained hypertension observed in pheochromocytoma, stemming from either a norepinephrine-releasing tumor or axon nerve endings. ¹³ Hence, it is prudent to investigate any drug-related causes of elevated plasma and urine catecholamines and subsequent hypertension before initiating extensive pheochromocytoma workup. Moreover, evidence suggests that in patients with catecholamine-induced hypertension, sustained elevation is associated with lower circulating concentrations, predominantly featuring norepinephrine, ³ aligning with our patient’s presentation.

Our case illustrates the presentation of a young female with pre-existing hypertension, who experienced a sudden, severe, and persistent increase in blood pressure following the recent initiation of buspirone. As part of the diagnostic process to rule out secondary causes of hypertension, elevated catecholamine levels were identified, which subsequently normalized upon discontinuation of the offending medication. Following this intervention, notable improvements in blood pressure were observed. This case underscores the significance of considering secondary hypertension, particularly drug-induced hypertension, which can be effectively managed through a meticulous review of the patient’s medical history and thorough evaluation of their medication profile. By promptly identifying and addressing the underlying cause of hypertension, unnecessary and costly investigations for other secondary causes can be avoided, leading to potential reductions in healthcare-related expenses.