What are phenothiazines, their indications, dosing, major side effects, contraindications, and alternative antipsychotic options?

Phenothiazines: Clinical Overview

What Are Phenothiazines?

Phenothiazines are dopamine D2 receptor antagonists that function as typical (first-generation) antipsychotics, with varying potency levels determining their clinical applications and side effect profiles. 1

• High-potency phenothiazines (e.g., perphenazine, fluphenazine, trifluoperazine) are primarily used for psychiatric conditions including schizophrenia, psychosis, and mania in bipolar disorder 1, 2
• Low/mid-potency phenothiazines (e.g., chlorpromazine, prochlorperazine) are used for both psychiatric conditions and antiemetic purposes, including nausea, vomiting, and refractory gastroparesis 2, 1

Primary Clinical Indications

Psychiatric Uses

• Control of delusions, hallucinations, severe psychomotor agitation, and combativeness in conditions like schizophrenia and Alzheimer's disease 2
• These agents should be considered second-line therapy after atypical antipsychotics fail or are not tolerated 2

Non-Psychiatric Uses

• Antiemetic therapy for nausea and vomiting, particularly in gastroparesis and palliative care settings 2
• Prochlorperazine and chlorpromazine are specifically used for refractory nausea, though they have not been formally studied in controlled trials for gastroparesis 2

Dosing Guidelines

For Nausea/Vomiting (Gastroparesis)

• Prochlorperazine: 5-10 mg four times daily 2
• Chlorpromazine: 10-25 mg three to four times daily 2

For Palliative Sedation

• Levomepromazine: Start 12.5-25 mg, with continuous infusion of 50-75 mg; can titrate up to 300 mg/day 2
• Chlorpromazine: IV/IM 12.5 mg every 4-12 hours, or 3-5 mg/hour IV; rectal 25-100 mg every 4-12 hours 2

For Behavioral Disturbances in Alzheimer's Disease

• Dosing varies by specific agent; use the lowest effective dose 2

Major Side Effects and Safety Concerns

Extrapyramidal Symptoms (EPS)

Phenothiazines carry significant risk of extrapyramidal symptoms, including acute dystonia, parkinsonism, and irreversible tardive dyskinesia, which can develop in 50% of elderly patients after 2 years of continuous use. 2

• Acute dystonia (including oculogyric crisis and neck stiffness) occurs most commonly in young males and within the first days to weeks of treatment 3
• High-potency agents like fluphenazine carry substantially greater dystonia risk than low-potency agents 3
• Immediate treatment: Benztropine 1-2 mg IM/IV or diphenhydramine 25-50 mg IM/IV provides rapid relief within minutes 3

Anticholinergic Effects

• Orthostatic hypotension, dry mouth, constipation, urinary retention, confusion, and blurred vision 2
• The cumulative anticholinergic burden must be assessed, as adding anticholinergic agents (like benztropine) to phenothiazines with inherent anticholinergic properties may potentiate adverse effects 4

Cardiovascular Effects

• QT prolongation with risk of torsades de pointes 2
• Orthostatic hypotension requiring careful monitoring 2

Paradoxical Reactions

• Paradoxical agitation can occur, particularly in elderly patients 2

Black Box Warning

• All antipsychotics, including phenothiazines, increase mortality in elderly patients with dementia (FDA black box warning) 5
• Increased risk of cerebrovascular events (stroke, TIA) in this population 5

Contraindications and Precautions

Absolute Contraindications for Anticholinergic Management

• Glaucoma, benign prostatic hypertrophy, or current anticholinergic drug intoxication when considering anticholinergic agents for EPS management 3

Use with Extreme Caution

• Tachycardia, cardiac decompensation, coronary insufficiency, or cardiac arrhythmias 4
• Gastrointestinal obstruction or stenosing peptic ulcer disease 4
• Prostatic hypertrophy or bladder outlet obstruction 4
• Myasthenia gravis 4

Special Populations

• Elderly patients with dementia: Discuss risks versus benefits with family before initiating; attempt gradual reduction after 3-6 months of symptomatic control 5
• Young males: Highest risk for acute dystonia; consider prophylactic anticholinergics when using high-potency agents 3

Alternative Antipsychotic Options

Atypical (second-generation) antipsychotics should be prioritized over phenothiazines due to diminished risk of extrapyramidal symptoms and tardive dyskinesia. 2

Preferred Atypical Agents

For Alzheimer's Disease/Dementia

• Risperidone: Start 0.25 mg at bedtime; maximum 2-3 mg/day in divided doses (EPS may occur at ≥2 mg/day) 2
• Olanzapine: Start 2.5 mg at bedtime; maximum 10 mg/day in divided doses; generally well tolerated 2
• Quetiapine: Start 12.5 mg twice daily; maximum 200 mg twice daily; more sedating with risk of orthostatic hypotension 2, 5

For Nausea/Vomiting

• 5-HT3 antagonists (ondansetron 4-8 mg 2-3 times daily, granisetron 1 mg twice daily) are preferred first-line agents 2
• NK-1 receptor antagonists (aprepitant 80 mg/day) for refractory nausea 2

Non-Antipsychotic Alternatives for Agitation

• Trazodone: 25 mg/day initially, up to 200-400 mg/day in divided doses 2
• Divalproex sodium: 125 mg twice daily, titrate to therapeutic level (40-90 mcg/mL); generally better tolerated than other mood stabilizers 2

Critical Clinical Pitfalls

• Avoid routine prophylactic anticholinergics: Only use antiparkinsonian agents when EPS actually occurs, not preventatively, except in high-risk patients (young males on high-potency agents with prior dystonic reactions) 4, 3
• Do not dismiss dystonic reactions as benign: These are highly distressing and represent a common reason for treatment discontinuation, increasing relapse risk 3
• Monitor for laryngeal dystonia: This represents a life-threatening emergency requiring immediate anticholinergic treatment 3
• Reassess underlying antipsychotic regimen: If dystonic reactions are frequent or severe, change the medication rather than relying on chronic anticholinergic therapy 4
• Avoid benztropine or trihexyphenidyl when managing haloperidol-induced EPS in favor of dose reduction or switching agents 2
• Reevaluate need after 3-6 months: Attempt gradual dose reduction to determine lowest effective maintenance dose; discontinuation should be gradual over more than 1 month to avoid withdrawal 5