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]

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]

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]

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

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]