Phenothiazine

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]