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Phenothiazine


Phenothiazine

Article Author:
Ariel Kidron
Article Editor:
Hoang Nguyen
Updated:
6/2/2020 2:35:28 PM
For CME on this topic:
Phenothiazine CME
PubMed Link:
Phenothiazine

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, to 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 modality 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% - 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]

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

Phenothiazines can be administered orally through the use of 10 mg to 200 mg capsules at increments of 25 mg, 50 mg, 100 mg, and 200 mg, depending on the case. The standard dosing for Schizophrenia begins at 25 mg and may increase to 75 mg twice per day at the maintenance of 200 mg per day. The maximal allowable dosage is 800 mg per day. The medication can also be administered parenterally with a dosage of 25 mg with an additional dose of 25 mg to 50 mg during the following 4 hours. Similar to the oral route, the maximal parenteral dose caps out at 800 mg per day. The standard oral dose for nausea and vomiting starts at 10 mg and can increase to 25 mg at 4 to 6 hourly increments. If given parenterally, the dosage can begin at 25 mg and can increase to 50 mg at 4 to 6 hourly increments.[2][9]

Adverse Effects

The most common adverse reactions include[10][4][11]:

  • Extrapyramidal symptoms, including dystonia, parkinsonism, akathisia, and tardive dyskinesia.
  • Weight gain
  • Orthostatic hypotension can manifest in 75% of patients that may have 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 who are suffering from extrapyramidal events or are using other medications that elicit those effects should avoid using Phenothiazines as they will significantly increase the effect of those conditions.[12][11]

Monitoring

Patients who have mild QTc elongation or history of blood pressure fluctuations should have close monitoring throughout treatment for the 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 the case of disease resistance, clinicians should consider utilizing either a combination or a different therapy modality. Moreover, the CYP2D6 enzyme has 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][13]

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, the pupil size of less than 3 mm was present in the most severe poisoning cases. Prolonged QTc interval was noted and could receive treatment with diphenylhydantoin. An echocardiogram is a suggested approach for all cases of phenothiazine overdoses.[14]

Treatment methods for phenothiazine overdoses included the administration of 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.[14]

Enhancing Healthcare Team Outcomes

The Phenothiazine overdose report described that 19% of the cases were accidental; therefore, better communication is needed between all members of the healthcare team 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 ranging from primary care physicians to nurses to 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. Appropriate cooperation between all the health professionals is needed to ensure that the patient receives the most effective care at all times with phenothiazine therapy. [Level 5]


References

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[2] Mann SK,Marwaha R, Chlorpromazine 2020 Jan;     [PubMed PMID: 31971720]
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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 : an international journal on programmed cell death. 2020 Feb 8;     [PubMed PMID: 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 neglected tropical diseases. 2020 Mar 13;     [PubMed PMID: 32168320]
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[9] Choi M,Barra ME,Newman K,Sin JH, Safety and Effectiveness of Intravenous Chlorpromazine for Agitation in Critically Ill Patients. Journal of intensive care medicine. 2018 Dec 17;     [PubMed PMID: 30558470]
[10] Tisdale JE, Drug-induced QT interval prolongation and torsades de pointes: Role of the pharmacist in risk assessment, prevention and management. Canadian pharmacists journal : CPJ = Revue des pharmaciens du Canada : RPC. 2016 May;     [PubMed PMID: 27212965]
[11] Feinberg SM,Saadabadi A, Thioridazine 2020 Jan;     [PubMed PMID: 29083818]
[12] Klinger G,Stahl B,Fusar-Poli P,Merlob P, Antipsychotic drugs and breastfeeding. Pediatric endocrinology reviews : PER. 2013 Mar-Apr;     [PubMed PMID: 23724438]
[13] Rivera-Calimlim L, Problems in therapeutic blood monitoring of chlorpromazine. Therapeutic drug monitoring. 1982;     [PubMed PMID: 7041337]
[14] Barry D,Meyskens FL Jr,Becker CE, Phenothiazine poisoning. A review of 48 cases. California medicine. 1973 Jan;     [PubMed PMID: 4405537]