Polypharmacy-related Shock Symptoms and Complications Associated with Phenothiazine (2024)

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Abstract

This report describes a case of shock symptoms in a 72-year-old woman with epilepsy who had been in a state of polypharmacy, taking multiple antipsychotic drugs. After receiving a normal dose of periciazine, she exhibited impaired consciousness, hypothermia, and hypotension and was admitted to hospital. Despite poor response to vasopressors, conservative treatment led to gradual improvement. Subsequent pharmaco*kinetic analysis showed non-toxic blood concentrations of periciazine, suggesting that even small doses of phenothiazines could result in toxic symptoms. This case highlights the importance of monitoring for adverse reactions when prescribing multiple antipsychotic drugs, particularly in older polypharmacy patients.

Keywords: phenothiazine, drug intoxication, blood concentration, adrenergic reversal, polypharmacy

Introduction

Phenothiazines belong to a category of antipsychotic drugs, with chlorpromazine and periciazine (also known as pericyazine or propericiazine) serving as notable examples. The mechanism underlying addiction entails cardiotoxicity through the selective inhibition of potassium channels and diverse impacts arising from receptor blockade (1-3). Given that hemodialysis or perfusion appear to yield limited efficacy, the primary approach to management remains systemic (4). Many antipsychotic drugs, phenothiazines included, are metabolized by cytochrome p450 (CYP). Age-related metabolic decline is associated with reduced expression of CYP, which has been associated with unexpected symptoms caused by drug interactions, especially during polypharmacy, which is defined as the regular use of five or more drugs (5). This report describes a case involving shock-like symptoms, potentially stemming from phenothiazine intoxication in an elderly patient undergoing polypharmacy, wherein the intoxication likely resulted from an inadvertent, minimal dose.

Case Report

The 72-year-old woman, residing in a case facility, had been receiving various medications for conditions such as cerebellar infarction sequelae, hypertension, hypothyroidism, gastroesophageal reflux disease, dyslipidemia, constipation, and osteoporosis. These prescriptions were managed at a nearby internal medicine clinic. Additionally, she had been treated for refractory epilepsy for 20 years at a psychiatric department, taking multiple medications including antipsychotics, leading to a state of polypharmacy (Table 1). Additionally, she had been diagnosed with chronic hyponatremia (Na: 119-135 mEq/L) for over 10 years. She was also being regularly monitored for a suspected antipsychotic-induced syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Her medication had not been changed in the past two years, and facility staff were administering her medication, and no errors had been reported. The patient retainedbasic communication skills and walking ability. She had not exhibited any problematic behaviors, was not prone to frequent falls, and had no reported instances of polydipsia.

On the day when phenothiazine toxicity symptoms emerged, a staff member had mistakenly administered 10 mg of periciazine and 1 mg of biperiden hydrochloride to the patient at dinner. The medication should have been administered to another resident. The patient was followed up by facility staff and 2 h later, she developed hypothermia (34°C), impaired consciousness, and unmeasurable blood pressure. She was urgently transported to our hospital.

Upon arrival, physical examination revealed a Glasgow Coma Scale of 9/15 (E2V2M5). Notably, her body temperature was 34.0°C; blood pressure, 52/40 mmHg; heart rate, 60 beats/min (bpm); and oxygen saturation, 96% at 5 L/min mask ventilation employing the nasal airway. Her pupils were excessively constricted (2 mm/2 mm), and peripheral coldness was evident. However, her neck was supple, and other physical examination findings were unremarkable.

Her admission laboratory data (Table 2) revealed low serum sodium (114 mEq/L) and low blood osmolality (152 mOSM/L). However, we noted a discrepancy between the calculated and measured osmotic pressures, indicating an osmotic pressure difference exceeding -100 mOSM/L. Although the exact cause remains unknown, this discrepancy could be attributed to inaccurate blood osmolality measurements. Her urinary osmolality was 158 mOSM/L, revealing that her urine was not maximally diluted. Additionally, her urine sodium concentration was 57 mEq/L, showing no decline. These laboratoy findings suggest manifestation of SIADH, likely linked to drug effects, particularly the patient's existing antipsychotic regimen or her use of periciazine (6).

A 12-lead electrocardiogram displayed a sinus rhythm, maintaining a heart rate of 72 bpm. However, the QT interval, adjusted for heart rate, was significantly prolonged at 0.516 s (Fig. 1). Subsequent echocardiography showed reduced cardiac contractility (ejection fraction ＜50%) and a collapsed inferior vena cava. Computed tomography scan of the head, chest, and abdomen revealed no organic abnormalities that could elucidate the underlying cause of altered consciousness.

In light of physical examination findings, including prolonged QT interval, impaired consciousness, hypotension, hypothermia, and constricted pupils (Fig. 2), the working diognosis leaned towards phenothiazine intoxication, even though periciazine was administered as a usual single dose. Notably, dehydration and hyponatremia may have contributed to the patient's medical condition. Consequently, we administered systemic management, involving rehydration and careful electrolyte management, until the drug had been metabolized.

Controlled warming was performed to restore her temperature. The patient's marked hypotension was treated with extracellular fluid, albumin, and colloidal solutions. Despite these interventions, her blood pressure exhibited minimal improvement, prompting a substantial fluid replacement of 7 L within 2 h. Additionally, boosting agents including 0.2 γ noradrenaline, 11 γ dopamine, and 3 γ dobutamine were administered. Her blood pressure slowly improved to around 80/60 mmHg after 2 h, and diuresis was also observed. Therefore, infusion volume was reduced to approximately 100 mL/h. Eight hours after the patient's arrival, her blood pressure finally exceeded 100/70 mmHg, and her temperature returned to the 36°C range.

Twelve hours after treatment, her consciousness had improved, pupil diameter expanded to 3 mm/3 mm, QT internal became less prolonged, and serum sodium normalized (Na: 134 mEq/L). Therefore, her prescribed antipsychotic medications were reinstated. As blood pressure improved, fluid replacement decreased. The three vasopressors were gradually tapered and eventually stopped on the second day.

The blood concentration of periciazine was measured in collabolation with the Clinical Pharmacology Center, Jichi Medical University Hospital, using a liquid chromatograph triple quadrupole mass spectrometer (LCMS-8050 System, Shimadzu, Kyoto, Japan) (Supplementary material). Subsequently, it was revealed that the patient's initial blood concentration of periciazine upon admission was 7.032 ng/mL, which is not usually considered high. This concentration gradually declined over time, measuring 3.424 ng/mL at 2 h and 1.994 ng/mL at 16 h after admission (Fig. 3). This decrease in concentration corresponded to the progressive improvement in her symptoms.

On the third day, she began eating food and resumed all medications, including antihypertensive drugs on the fourth day. She was discharged on the sixth day. Her condition reverted to her pre-hospitalization state, with the same medication regimen and serum sodium level (125-133 mEq/L) as before. A year after discharge, her condition remained favorable.

Discussion

Here, we describe a case illustrating shock symptoms potentially stemming from phenothiazine intoxication in an older female patient undergoing polypharmacy. The clinical course and symptoms detailed here suggest that even small phenothiazine doses could induce intoxication. Caution should be exercised when administering phenothiazine, even standard doses, to older adults or those on multiple medications.

Phenothiazines can elicit various symptoms via their pharmacological mechanisms. These derivatives exert blocking effects on dopamine D2, histamine H1, muscarinic, and α1-adrenergic receptors (2,3). Resultant clinical manifestations include malignant syndrome due to dopamine D2 receptor blockade, impaired consciousness due to histamine H1 receptor blockade and muscarinic receptor blockade, mydriasis, and hypotension due to enhanced α1-adrenergic receptor blockade (4). Additionally, phenothiazines inhibit myocardial cell membrane potassium channels, restraining potassium efflux thereby extending the refractory period of myocardial cells and potentially culminating in lethal arrhythmias such as ventricular fibrillation, ventricular tachycardia, and Torsade de Pointes (1,7).

Most phenothiazines are swiftly absorbed through the gastrointestinal tract, undergo hepatic metabolism, and are excreted in the bile and urine. Blood concentrations typically peak 2-4 h after oral intake (8). Phenothiazines are highly liposoluble, with substantial distribution volumes and high protein binding rates. Techniques such as hemodialysis or perfusion to hasten elimination are thus ineffective, and systemic management is pivotal in addressing phenothiazine poisoning.

In this case, the patient had low blood pressure at admission. Her blood pressure remained low despite extensive fluid replacement and administering pressor agents. This might be linked to adrenergic reversal, a phenomenon arising when intravenous adrenaline is administered after an α1-receptor antagonist, such as phenothiazine, resulting in a blood pressure-lowering effect due to insufficient α activation and remaining β activation (9). The patient's blood pressure gradually improved 2 h after admission, approximately 4 h after inadvertent periciazine administration. Her overall condition also improved. Although periciazine has a long half-life of approximately 8 h, its peak concentration is achieved at 1.8 h, after which the concentration starts to decline (10). Considering this, the α-receptor antagonist effect of periciazine likely waned as its concentration decreased, rendering the patient more responsive to antihypertensive agents, yielding gradual circulatory improvement.

Retrospectively determining the appropriateness of adrenaline administration is challenging in this scenario. Vasopressin, due to its mechanism of action, may have been more effective. Previous reports have suggested the use of direct α1 agonists for control (4), including the continuous administration of phenylephrine, which may have been more effective without causing adrenaline reversal. However, there's few reports on these interventions for phenothiazine intoxication, and their efficacy remains uncertain. Based on the phenothiazine poisoning literature (11,12), supportive care such as norepinephrine usage is pivotal for systemic maintenance, and their use should be considered when necessary.

In this case, the patient showed intoxication symptoms surpassing expectations despite misadministration of a standard dose. These symptoms are suspected to have been caused by an increase in blood concentration of periciazine due to interactions with other drugs. Most phenothiazine derivatives, including periciazine, undergo hepatic metabolism. Although the involvement of CYPs in periciazine metabolism remains unknown, the metabolism of chlorpromazine, a similarly acting drug, does involve CYPs, and we suspect that periciazine metabolism may also involve CYPs (13,14). Additionally, the patient was originally administered multiple drugs, many with hepatic metabolism (15-30) (Fig. 4). Despite searching the literature, clear data on antipsychotic-drug interactions, particularly for phenothiazines (31), remain elusive. However, psychotropic drugs have been reported to cause intoxication even at normal doses when CYP2D6 activity is diminished (32). Although this patient did not have congenitally decreased CYP2D6 activity, she was concurrently using multiple drugs, which may have resulted in a relatively reduced CYP2D6 activity.

Although the toxic range of periciazine has not been described, this patient's blood levels were not significantly different from those of a normal adult male receiving 10 mg of periciazine (10). However, her return to consciousness coincided with the decrease in blood concentration of periciazine, suggesting that periciazine toxicity contributed to her symptoms.

Intoxication can be defined as damage to an organism arising from the interaction of a foreign chemical (toxin) with a biological system (33). Interestingly, the definition of intoxication does not include blood concentrations. Despite a lack of comparable cases on psychotropic toxicity, instances of adverse symptoms due to lead intoxication have been reported even at minute blood levels below the toxic range (34). Thus, diagnosing intoxication should be based on more than just blood levels. Given the expansive distribution volume of phenothiazine derivatives, the drug could have remained in the body beyond the concentration measured in the blood, resulting in excessive symptoms in older adults, especially those with poor circulation and increased body fat.

Other differentials should also be considered in this case. Notably, the patient was in a state of polypharmacy, and the misadministration of phenothiazines may have enhanced the effects of other drugs and complicated her clinical course. The patient was receiving milnacipran hydrochloride, a serotonin-norepinephrine reuptake inhibitor, which may have attenuated catecholamine effects. Additionally, calcium and angiotensin II receptor blockers may have contributed to the persistent hypotension. Haloperidol, clonazepam, and bromazepam can cause impaired consciousness. Chronic hyponatremia can also contribute to decreased circulating blood volume, persistent hypotension, and impaired consciousness. The coincidence of these factors with oral phenothiazine administration may have led to a clinical course similar to that of phenothiazine poisoning. However, this hypothesis does not explain the hypothermia and the prolonged QT interval. In this case, it is highly possible that the pathophysiology of phenothiazine poisoning was superimposed. Demonstrating these hypotheses remains challening, which is a limitation of this case report.

Importantly, the patient was an older adult at high risk for adverse drug reactions (35) and that she was in a state of polypharmacy, which likely influenced her clinical course. Polypharmacy increases the risk of adverse drug interactions and interactions with comorbidities, and is a major contributing factor to adverse drug events in the elderly (5). This case highlights the need for caution when administering phenothiazines to older adults or those on multiple medications, even at standard doses, and highlights the problem of polypharmacy.

The authors state that they have no Conflict of Interest (COI).

Supplementary Material

References