Continuing Education Activity

Phenothiazines are a class of first-generation heterocyclic anti-psychotic medications, which display antagonistic activity towards dopamine receptors and recently have been shown to have potential anti-neoplastic properties. This activity illustrates the indications, action, and contraindications for phenothiazine as a valuable agent in treating and managing severe mental disorders such as schizophrenia, cancer, and other manifestations of psychosis. Also, this activity will highlight the mechanism of action, adverse event profile, and other key factors such as pharmacodynamics and relevant interactions pertinent for members of the interprofessional healthcare team charged with the care of patients with schizophrenia and other related conditions.

Objectives:

• Identify the mechanism of action of phenothiazines.
• Describe the potential adverse events associated with phenothiazine therapy.
• Outline the typical presentation of a patient with phenothiazine toxicity.
• Explain the significance of enhancing care coordination between interprofessional healthcare workers as it directly pertains to improving care delivery to patients suffering from phenothiazine toxicity.

Indications

Phenothiazines are a group of nitrogen and sulfur-containing heterocyclic compounds, labeled as the first-generation typical antipsychotic medications used for the treatment of schizophrenia, bipolar disorders, control nausea and vomiting, and other psychotic disorders with delusional manifestations. Phenothiazines were synthesized in 1883 and served as the first commercial antipsychotic therapy in the USA during the 1950s.[1][2][3]

In cases of schizophrenia that are resistant to therapy, clinicians can use phenothiazines in combination along with second-generation antipsychotics such as clozapine. However, this combination therapy exposes the patient to multiple antipsychotic medications and may increase the risk of serious side effects, so this approach is preferable in later stages of treatment. Patients who undertook pharmacological therapy as an avenue of treatment showcased an 18% to 32% relapse, while patients that did not elect to incorporate pharmacological therapy showcased 60% to 80% relapse in their symptoms. Phenothiazines produce the most optimal results when combined with non-pharmacological psychotherapeutic therapy, such as narrative, meta-cognitive, and mindfulness therapy.[4]

Also, recent studies have investigated the anti-cancer properties of phenothiazines in glioblastoma as it produced an arrest in the G1 cycle of cancer cells, pointing to a reduction in cyclins stimulating DNA replication along with an increase in Cycline inhibiting compounds.[5]

Furthermore, phenothiazines have shown anti-helminths properties such as Trypanosoma brucei by inhibiting trypanothione reductase and causing cell cycle abnormalities. Specifically, a decrease in the S phase, an accumulation of the parasite in the G2 phase, and a lack of nucleus creation in the parasite.[6]

This review will primarily focus on phenothiazines as antipsychotic medications.

Mechanism of Action

The precise mechanism of action exhibited by phenothiazines is not entirely known. Yet, phenothiazines act primarily through inhibiting the dopamine receptor at the mesolimbic pathway with a selective activity at the D2 receptor. This inhibition antagonizes the hyperactivity of dopamine at the synapse and reduces positive symptoms such as delusions and hallucinations associated with schizophrenia.[4][7][8]

Administration

As antipsychotics, phenothiazines fall into three different groups: aliphatic compounds, piperidines, and piperazines. Examples of specific agents in each class follow:

Aliphatic compounds:

• Chlorpromazine - available in 10 mg, 25 mg, 50 mg, 100 mg, and 200 mg tablets. Injectable formulation 25 mg/mL.[9]

Piperidines:

• Thioridazine - The branded version was discontinued because of cardiac adverse events. Generic versions are still available in the USA, but it is seldom used.[10][10]

Piperazines:

• Fluphenazine - available in 1 mg, 2.5 mg, 5 mg, and 10 mg tablets, as a solution as 2.5 mg mL or 5 mg/5 mL, and a 2.5 mg/5 mL injection.[11]
• Prochlorperazine - available as 5 mg and 10 mg tablets, as an injection 5 mg/mL, and in 25 mg suppositories. It is more commonly used for migraines and as an antiemetic.[12][13]

Adverse Effects

The most common adverse reactions include[14][4][15]:

• Extrapyramidal symptoms, including dystonia, parkinsonism, akathisia, and tardive dyskinesia.
• Weight gain
• Orthostatic hypotension can manifest in 75% of patients with potentially increased risk due to diabetes and pre-existing cardiovascular disorders.
• QTc prolongation
• Pseudoparkinsonism most often occurring in women or older patients.
• Seizures
• Delirium
• Psychosis

Rare adverse events:

• Neuroleptic malignant syndrome
• Retinitis pigmentosa
• Cataracts
• Dermatological allergic reactions
• Poikilothermia
• Agranulocytosis

Common less severe adverse events:

• Urinary hesitancy and retention
• Dry mouth,
• Dry eyes
• Sedation
• Pruritus
• Photosensitivity
• Constipation

Contraindications

Phenothiazines selectively inhibit the D2 receptor; thus, any medications that act through this mechanism of action should be contraindicated, like levodopa or cabergoline. Dementia-related psychosis is contraindicated as it can increase the risk of death as secondary to a cardiovascular or infectious effect. Also, patients who have a history of QTc elongation, hypotension, abnormal lymphoid count, or that are currently using other medications that elongate the QTc interval extenuate hypotension like beta-blockers, and or affect their lymphoid count should not receive phenothiazines. Furthermore, patients suffering from extrapyramidal events or using other medications that elicit those effects should avoid using phenothiazines as they will significantly increase the effects of those conditions.[16][15]

Monitoring

Patients who have mild QTc elongation or a history of blood pressure fluctuations should have close monitoring throughout treatment regarding the potential development of orthostatic hypotension and QTc interval that exceeds 500 msec. This monitoring is achievable through an echocardiogram and blood pressure measurements. Additionally, the clinician should monitor patients in the first seven days of treatment for efficacy. In instances of resistant disease, clinicians should consider utilizing either a combination or a different therapy modality. Moreover, the CYP2D6 enzyme has been shown to metabolize phenothiazines, and patients possessing reduced amounts of the enzyme require monitoring throughout treatment for increased toxicity. Patients should continue taking phenothiazines for 12 months after the remission of their first psychotic episode to reduce the relapse of symptoms.[4][17]

Approximately 10% to 30% of patients taking phenothiazines don't display improvement in their symptoms after several rounds of administration, while 30% to 60% showcase partial or not sufficient improvement in their symptoms following usage. It is crucial to monitor these patients for the efficacy of the medications and to undertake a different form of treatment if the results are not satisfactory.[4]

Toxicity

A review of 48 hospital-admitted phenothiazine toxicities with concentrations of 200 mg to 500 mg per patient has listed common reactions such as hypothermia, tachycardia, tachypnea, and decreased diastolic blood pressure. A tendency towards obtundation can present in cases where other drugs were also involved. Furthermore, a pupil size of less than 3 mm was present in the most severe poisoning cases. Prolonged QTc interval was noted, and patients were treated with diphenylhydantoin. An echocardiogram is a suggested approach for all cases of phenothiazine overdoses.[18]

Treatment methods for phenothiazine overdoses included administering ipecac, gastric lavage, intravenous diphenhydramine, and intravenous hydration to reverse extrapyramidal symptoms and absorption. No fatalities occurred, and 50% of the patients were discharged following 24 hours, while the other 50% stayed for an average duration of 3.4 days. Potentially serious complications were present in 71% of the patients who stayed longer than 24 hours; however, all of those patients recovered.[18]

Enhancing Healthcare Team Outcomes

A report on phenothiazine overdose showed that 19% of the cases were accidental; therefore, better communication is needed between all interprofessional healthcare team members to relay the appropriate dosing information to the patients and prevent medical errors. Phenothiazines may initially be administered to patients following a consultation with a neurologist or psychiatrist. Yet, other healthcare professionals, including primary care clinicians, nurses, pharmacists, and emergency medical technicians, may play a vital role in the continued care of the patient. Emergency medical technicians and nurses monitor the patient and may have valuable input on any adverse events or the efficacy of the medications. Primary care physicians may review dosing information and reinforce the dosing regimen and compliance. Pharmacists can also verify dosing and perform medication reconciliation to check for drug-drug interactions and further reinforce patient counseling regarding dosing and adverse effects. Appropriate cooperation between all interprofessional team members is essential to ensure that the patient receives the most effective care at all times with phenothiazine therapy. [Level 5]

Review Questions

• Access free multiple choice questions on this topic.
• Comment on this article.

References

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5.

Omoruyi SI, Ekpo OE, Semenya DM, Jardine A, Prince S. Exploitation of a novel phenothiazine derivative for its anti-cancer activities in malignant glioblastoma. Apoptosis. 2020 Apr;25(3-4):261-274. [PubMed: 32036474]

6.

Walsh ME, Naudzius EM, Diaz SJ, Wismar TW, Martchenko Shilman M, Schulz D. Identification of clinically approved small molecules that inhibit growth and affect transcript levels of developmentally regulated genes in the African trypanosome. PLoS Negl Trop Dis. 2020 Mar;14(3):e0007790. [PMC free article: PMC7094864] [PubMed: 32168320]

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Jaszczyszyn A, Gąsiorowski K, Świątek P, Malinka W, Cieślik-Boczula K, Petrus J, Czarnik-Matusewicz B. Chemical structure of phenothiazines and their biological activity. Pharmacol Rep. 2012;64(1):16-23. [PubMed: 22580516]

10.

Purhonen M, Koponen H, Tiihonen J, Tanskanen A. Outcome of patients after market withdrawal of thioridazine: a retrospective analysis in a nationwide cohort. Pharmacoepidemiol Drug Saf. 2012 Nov;21(11):1227-31. [PubMed: 22941581]

11.

Matar HE, Almerie MQ, Sampson SJ. Fluphenazine (oral) versus placebo for schizophrenia. Cochrane Database Syst Rev. 2018 Jun 12;6(6):CD006352. [PMC free article: PMC6513420] [PubMed: 29893410]

12.

Drugs for Migraine. Med Lett Drugs Ther. 2020 Oct 05;62(1608):153-160. [PubMed: 33434187]

13.

Kow CS, Hasan SS. Prochlorperazine for nausea and vomiting accompanied COVID-19. J Gastroenterol Hepatol. 2021 Feb;36(2):524-525. [PubMed: 33068035]

14.

Tisdale JE. Drug-induced QT interval prolongation and torsades de pointes: Role of the pharmacist in risk assessment, prevention and management. Can Pharm J (Ott). 2016 May;149(3):139-52. [PMC free article: PMC4860751] [PubMed: 27212965]

15.

Feinberg SM, Fariba KA, Saadabadi A. StatPearls [Internet]. StatPearls Publishing; Treasure Island (FL): Feb 6, 2023. Thioridazine. [PubMed: 29083818]

16.

Klinger G, Stahl B, Fusar-Poli P, Merlob P. Antipsychotic drugs and breastfeeding. Pediatr Endocrinol Rev. 2013 Mar-Apr;10(3):308-17. [PubMed: 23724438]

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Rivera-Calimlim L. Problems in therapeutic blood monitoring of chlorpromazine. Ther Drug Monit. 1982;4(1):41-9. [PubMed: 7041337]

18.

Barry D, Meyskens FL, Becker CE. Phenothiazine poisoning. A review of 48 cases. Calif Med. 1973 Jan;118(1):1-5. [PMC free article: PMC1454993] [PubMed: 4405537]

Disclosure: Ariel Kidron declares no relevant financial relationships with ineligible companies.

Disclosure: Hoang Nguyen declares no relevant financial relationships with ineligible companies.