Definition and Therapeutic Relevance
Phenothiazine antiemetics are a subclass of the broader phenothiazine chemical class, originally developed as antipsychotics, but later recognized for their potent anti-nausea and anti-vomiting (antiemetic) properties. Their antiemetic activity is primarily mediated through dopamine D2 receptor antagonism in the chemoreceptor trigger zone (CTZ) located in the area postrema of the medulla. Some members also exhibit anticholinergic and antihistaminic properties, which further contribute to their effectiveness in nausea control.
This group is widely used in clinical practice for managing nausea and vomiting of various etiologies, including postoperative nausea, chemotherapy-induced nausea, migraine-associated nausea, vertigo, and motion sickness. They are especially effective in non-cytotoxic drug-induced nausea and gastrointestinal causes.
1. Mechanism of Action
Phenothiazine antiemetics exert their effects mainly through:
A. Dopamine D2 Receptor Antagonism
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Inhibition of D2 receptors in the chemoreceptor trigger zone (CTZ) in the brainstem
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Suppresses central signals triggering emesis
B. Anticholinergic (Muscarinic) Effects
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Suppression of nausea pathways via muscarinic receptor blockade, especially in vestibular system (motion sickness)
C. Antihistaminic (H1 Receptor) Effects
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Reduction of nausea from inner ear disturbances and vestibular disorders (e.g., vertigo)
D. Alpha-1 Adrenergic Antagonism
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May contribute to hypotension and sedation side effects
These mechanisms make phenothiazines especially effective for nausea of central origin and vestibular origin, but they are less effective in controlling delayed chemotherapy-induced nausea, where serotonin and NK1 antagonists are preferred.
2. Generic Drug Names and Brand Names
| Generic Name | Brand Name(s) | Route(s) of Administration | Clinical Use |
|---|---|---|---|
| Prochlorperazine | Compazine, Stemetil | Oral, IM, IV, rectal | Nausea (all causes), migraine, vertigo |
| Promethazine | Phenergan | Oral, IM, IV, rectal | Motion sickness, pregnancy-related N/V |
| Chlorpromazine | Thorazine, Largactil | Oral, IM, IV | Severe N/V, hiccups, psychiatric uses |
| Triflupromazine | Vesprin (discontinued in many markets) | Oral, IM | Less commonly used |
| Thiethylperazine | Torecan (available in select countries) | Oral, IM, rectal | Vertigo, nausea |
| Perphenazine | Trilafon | Oral, IM | Primarily antipsychotic, also antiemetic |
3. Therapeutic Indications
Phenothiazine antiemetics are indicated in the management of a variety of conditions involving nausea and vomiting:
A. Approved Uses
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Nausea and vomiting due to:
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Migraine
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Postoperative states
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Gastroenteritis
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Radiation sickness
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Drug toxicity
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Uremia
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Motion sickness (especially promethazine)
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Pregnancy-induced nausea and vomiting (promethazine as Category C/D—used cautiously)
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Vertigo and Ménière’s disease
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Severe intractable hiccups (chlorpromazine)
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Psychogenic vomiting (prochlorperazine)
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Adjunct in migraine treatment (especially prochlorperazine)
B. Off-Label Uses
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Nausea during palliative care
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Adjunct for antipsychotic-induced nausea
4. Pharmacokinetics
| Property | General Profile (Phenothiazines) |
|---|---|
| Absorption | Variable oral bioavailability due to first-pass metabolism |
| Peak plasma levels | 1–2 hours (oral); 15–30 minutes (IM) |
| Half-life | 4–20 hours depending on agent |
| Metabolism | Primarily hepatic (CYP2D6, CYP3A4) |
| Excretion | Renal and fecal routes |
5. Adverse Effects
Phenothiazines are associated with both dose-dependent toxicities and receptor-mediated side effects. The risk varies by agent and dose.
A. Central Nervous System
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Sedation (common with promethazine and chlorpromazine)
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Dizziness
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Extrapyramidal symptoms (EPS):
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Acute dystonia
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Pseudoparkinsonism
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Akathisia
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Tardive dyskinesia (with prolonged use)
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Neuroleptic Malignant Syndrome (NMS) (rare)
B. Autonomic Effects
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Orthostatic hypotension (α1 antagonism)
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Dry mouth, blurred vision, constipation, urinary retention (anticholinergic effects)
C. Cardiovascular
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QT interval prolongation (especially with prochlorperazine and chlorpromazine)
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Arrhythmias
D. Hematologic
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Rare agranulocytosis, leukopenia
E. Dermatologic
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Photosensitivity reactions
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Skin rashes
F. Local Reactions
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Tissue necrosis with IV promethazine (boxed warning)
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Use deep IM route for parenteral promethazine
6. Contraindications
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Hypersensitivity to phenothiazines
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Comatose or CNS-depressed states
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Children under 2 years (especially with promethazine)
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Parkinson’s disease (risk of exacerbating symptoms)
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Severe hypotension or cardiovascular disease
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Prolonged QT syndrome
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History of neuroleptic malignant syndrome
7. Drug Interactions
| Interacting Agent | Effect |
|---|---|
| CNS depressants (alcohol, opioids, benzodiazepines) | Additive sedation or respiratory depression |
| Anticholinergics (e.g., atropine) | Potentiation of antimuscarinic effects |
| QT-prolonging agents (e.g., amiodarone, fluoroquinolones) | Increased risk of torsades de pointes |
| Levodopa | Antagonism of dopaminergic effects (may worsen Parkinsonism) |
| CYP2D6 inhibitors (e.g., fluoxetine, paroxetine) | May increase plasma levels and side effects |
8. Special Clinical Considerations
A. Pediatric Use
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Promethazine is contraindicated in children <2 years due to fatal respiratory depression
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Use caution with older children and adolescents due to EPS risk
B. Pregnancy
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Promethazine is often used off-label for hyperemesis gravidarum
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Category C or D, depending on agent and gestational age
C. Elderly
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Higher sensitivity to orthostatic hypotension, EPS, and cognitive impairment
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Consider alternatives in geriatric populations unless necessary
D. Route Selection
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Oral and rectal: common for ambulatory patients
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IV/IM: for acute severe vomiting (e.g., chemotherapy-induced)
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Deep IM preferred over IV for promethazine to avoid tissue damage
9. Summary of Key Phenothiazine Antiemetics
| Drug | Primary Use | Notable Properties |
|---|---|---|
| Prochlorperazine | General antiemetic, migraine-related N/V | Moderate EPS risk, used in ER and palliative care |
| Promethazine | Motion sickness, pregnancy N/V | Sedating, antihistaminic, anticholinergic |
| Chlorpromazine | Severe nausea, intractable hiccups | Strong sedative, used less due to side effects |
| Triflupromazine | Rarely used | Similar to chlorpromazine |
| Thiethylperazine | Vertigo, vestibular disorders | Available in select markets |
10. Alternatives and Comparison
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Serotonin 5-HT3 antagonists (e.g., ondansetron):
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Superior for chemotherapy-induced nausea
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Minimal EPS risk
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NK1 receptor antagonists (e.g., aprepitant):
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Used in highly emetogenic chemotherapy
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Antihistamines (e.g., meclizine):
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Preferred for motion sickness with fewer CNS effects
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Dopamine antagonists (e.g., metoclopramide):
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Similar to phenothiazines but more commonly used for gastroparesis
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