Definition and Therapeutic Role
Phenothiazine antipsychotics are a class of first-generation (typical) antipsychotic drugs derived from the phenothiazine chemical structure. Introduced in the early 1950s with the discovery of chlorpromazine, this class revolutionized psychiatry by providing effective treatment for psychosis, particularly schizophrenia and bipolar mania. They act mainly by blocking dopamine D2 receptors in the brain’s mesolimbic pathway, reducing psychotic symptoms such as hallucinations and delusions.
These medications are divided into three structural subgroups based on side-chain substitutions, each affecting potency and adverse effect profiles. Although atypical antipsychotics have largely replaced phenothiazines in clinical use due to a more favorable side-effect profile, phenothiazines remain essential, especially in acute psychosis, severe agitation, and intractable nausea or hiccups.
1. Chemical Classification
Phenothiazines are divided based on their side-chain substitutions, affecting their antipsychotic potency and side-effect profile.
A. Aliphatic Side Chain Subclass (Low Potency)
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Chlorpromazine
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Promazine
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Triflupromazine
B. Piperidine Side Chain Subclass (Low to Moderate Potency)
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Thioridazine
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Mesoridazine
C. Piperazine Side Chain Subclass (High Potency)
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Perphenazine
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Trifluoperazine
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Fluphenazine
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Prochlorperazine
2. Mechanism of Action
Phenothiazines act as dopamine D2 receptor antagonists in the mesolimbic pathway, which is primarily responsible for their antipsychotic effects. Additional receptor actions contribute to their adverse effects:
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D2 antagonism (CNS): Reduces psychotic symptoms; causes extrapyramidal symptoms (EPS)
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Muscarinic M1 antagonism: Dry mouth, blurred vision, constipation, urinary retention
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Histamine H1 antagonism: Sedation, weight gain
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Alpha-1 adrenergic antagonism: Orthostatic hypotension, dizziness
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5-HT2A antagonism: Minor role in mood and anxiety symptoms
3. Therapeutic Indications
A. Psychiatric Indications
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Schizophrenia (acute and chronic)
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Schizoaffective disorder
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Acute manic episodes in bipolar disorder
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Psychotic depression (with antidepressants)
B. Non-Psychiatric Indications
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Severe nausea and vomiting (e.g., prochlorperazine)
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Intractable hiccups (e.g., chlorpromazine)
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Preoperative sedation
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Tetanus adjunct therapy
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Delirium and agitation in ICU settings
4. Generic Drug Names and Brand Examples
| Generic Name | Brand Name(s) | Potency | Common Uses |
|---|---|---|---|
| Chlorpromazine | Largactil, Thorazine | Low | Psychosis, nausea, hiccups |
| Thioridazine | Mellaril | Low–moderate | Schizophrenia (withdrawn in many markets due to cardiac risk) |
| Triflupromazine | Vesprin | Low | Rarely used |
| Prochlorperazine | Compazine, Stemetil | Moderate | Antiemetic, psychosis |
| Trifluoperazine | Stelazine | High | Schizophrenia, anxiety |
| Fluphenazine | Modecate, Prolixin | High | Schizophrenia, depot formulations |
| Perphenazine | Trilafon | Moderate–high | Psychosis, severe agitation |
| Mesoridazine | Serentil | Low–moderate | Withdrawn in many countries |
| Promazine | Sparine | Low | Rare use |
5. Pharmacokinetics
| Property | Phenothiazines (general) |
|---|---|
| Bioavailability | Variable, subject to first-pass metabolism |
| Onset of action | Oral: 1–2 hours; IM: 15–30 minutes |
| Half-life | 10–30 hours (oral); depot: several days |
| Metabolism | Hepatic (CYP450, especially CYP2D6, CYP3A4) |
| Excretion | Renal and fecal |
6. Adverse Effects
A. Dopaminergic-Related (D2 Blockade)
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Extrapyramidal symptoms (EPS):
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Acute dystonia
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Akathisia
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Pseudoparkinsonism
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Tardive dyskinesia (late-onset)
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Neuroleptic malignant syndrome (NMS): rare but life-threatening
B. Cardiovascular
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Orthostatic hypotension
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QT interval prolongation
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Ventricular arrhythmias (notably thioridazine)
C. Anticholinergic
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Dry mouth
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Blurred vision
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Constipation
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Urinary retention
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Confusion (especially in elderly)
D. Endocrine
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Hyperprolactinemia (galactorrhea, amenorrhea, gynecomastia)
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Weight gain
E. Sedation
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Dose-dependent, stronger in low-potency agents (e.g., chlorpromazine)
F. Hepatic and Hematologic
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Elevated liver enzymes
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Cholestatic jaundice
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Agranulocytosis (rare)
7. Contraindications
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Comatose states
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Bone marrow suppression
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Pheochromocytoma
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Severe liver disease
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QT prolongation or history of ventricular arrhythmias
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Hypersensitivity to phenothiazines
8. Drug Interactions
| Interacting Agent | Effect |
|---|---|
| CNS depressants (e.g., alcohol, benzodiazepines) | Additive sedation |
| Antihypertensives | Potentiated hypotension |
| Anticholinergics | Enhanced antimuscarinic effects |
| Levodopa | Antagonized by phenothiazines (worsens Parkinsonism) |
| QT-prolonging agents | Increased risk of torsades de pointes |
| CYP2D6 inhibitors/inducers | May alter plasma levels |
9. Monitoring Parameters
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Baseline and periodic ECG (especially with thioridazine or other QT-prolonging meds)
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Liver function tests (LFTs)
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CBC with differential
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Serum prolactin if symptoms of hyperprolactinemia
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AIMS scale for monitoring tardive dyskinesia
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EPS monitoring (regular neurologic exam)
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Vital signs and orthostatic blood pressure
10. Clinical Considerations
Potency and Side Effect Trade-Off
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Low-potency agents (chlorpromazine, thioridazine): more sedation, hypotension, anticholinergic side effects; less EPS
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High-potency agents (fluphenazine, trifluoperazine): more EPS, less sedation
Use in Treatment-Resistant Schizophrenia
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Phenothiazines may still be considered when second-generation agents fail or are poorly tolerated.
Depot Formulations for Non-Adherence
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Fluphenazine decanoate allows monthly dosing in non-compliant patients
Special Populations
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Elderly: increased risk of falls, anticholinergic burden, cognitive impairment
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Children: use with caution; may exacerbate EPS
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Pregnancy: Category C (most); avoid in third trimester unless benefits outweigh risks
11. Summary of Agents by Potency and Use
| Drug | Potency | Common Uses | Notable Risks |
|---|---|---|---|
| Chlorpromazine | Low | Psychosis, hiccups, sedation | Sedation, hypotension, anticholinergic |
| Thioridazine | Low–moderate | Schizophrenia | QT prolongation, retinopathy |
| Fluphenazine | High | Chronic schizophrenia (depot) | EPS, NMS |
| Prochlorperazine | Moderate | Nausea, agitation | Sedation, EPS |
| Trifluoperazine | High | Schizophrenia, anxiety | High EPS rate |
| Perphenazine | Moderate–high | Acute agitation | EPS |
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