Understanding Promethazine and Its Toxicity
Promethazine is a first-generation antihistamine belonging to the phenothiazine family of medications [1.2.3]. It is commonly used to treat allergies, motion sickness, nausea, and vomiting, and for sedation [1.3.3, 1.4.2]. While effective for these conditions, it carries a significant risk of toxicity, especially in overdose or when used improperly. Its toxic effects stem from its actions as a strong anticholinergic agent and its impact on various receptors in the central nervous system (CNS) [1.2.3]. An overdose can lead to a wide array of symptoms, from severe drowsiness and confusion to life-threatening complications like respiratory depression and cardiac arrhythmias [1.3.3, 1.2.1].
Central Nervous System (CNS) Toxicity
The most prominent toxic effects of promethazine involve the central nervous system.
- Sedation and Coma: The main feature of promethazine toxicity is CNS depression, which can range from severe drowsiness to a coma where the individual is unresponsive [1.3.3, 1.2.1]. This sedative effect is amplified when combined with other CNS depressants like alcohol, opioids, or benzodiazepines [1.3.3].
- Delirium and Paradoxical Excitation: While sedation is common, promethazine can also cause paradoxical reactions like agitation, confusion, disorientation, and hallucinations [1.2.1]. Children, in particular, may experience hyperexcitability and nightmares instead of drowsiness [1.3.2, 1.7.3]. A study found that the probability of developing delirium increases with the ingested dose, with a 1-gram dose resulting in a 55% probability [1.11.3].
- Seizures and Movement Disorders: Overdose can lower the seizure threshold and cause convulsions [1.4.1, 1.2.1]. Promethazine can also induce extrapyramidal symptoms (EPS), which are drug-induced movement disorders. These include acute dystonia (involuntary muscle stiffness and spasms, especially in the neck and face), akathisia (an inability to sit still), and pseudoparkinsonism [1.2.3, 1.2.1]. Involuntary tongue movements and tremors are also signs of nervous system toxicity [1.2.1].
Neuroleptic Malignant Syndrome (NMS)
A rare but potentially fatal toxic effect associated with promethazine is Neuroleptic Malignant Syndrome (NMS) [1.4.2]. NMS is a life-threatening reaction characterized by a combination of symptoms:
- High fever (hyperpyrexia) [1.5.1]
- Severe muscle rigidity, sometimes called "lead pipe" rigidity [1.5.1]
- Altered mental status (confusion, delirium, or coma) [1.5.1]
- Autonomic instability (irregular pulse, variable blood pressure, excessive sweating) [1.5.1]
NMS requires immediate discontinuation of the drug and intensive medical treatment [1.5.1, 1.9.2].
Respiratory and Cardiovascular Toxicity
Respiratory Depression One of the most dangerous toxic effects of promethazine is severe respiratory depression, which can be fatal [1.7.3]. This risk is so significant that the FDA has issued a boxed warning against its use in children under two years of age [1.3.3, 1.7.3]. Even in children over two, it must be used with extreme caution and at the lowest effective dose, avoiding other respiratory depressant drugs [1.7.3]. Between 1969 and 2003, there were reports of 22 cases of respiratory depression in children under two, seven of which were fatal [1.7.1].
Cardiovascular Effects Promethazine toxicity can also affect the heart.
- Hypotension: Low blood pressure is a known side effect [1.2.3]. In cases of overdose, severe hypotension may occur, which requires treatment with intravenous fluids and, in some cases, vasopressors like norepinephrine. Epinephrine should not be used as it can paradoxically lower blood pressure further [1.9.1, 1.9.2].
- Cardiac Arrhythmias: Tachycardia (a rapid heartbeat) is a common finding in overdose [1.2.1]. More seriously, promethazine can prolong the QTc interval, an electrical phase of the heartbeat [1.6.2]. A prolonged QTc interval increases the risk of life-threatening arrhythmias like Torsades de Pointes [1.6.2].
Severe Tissue Injury (Injection)
Injectable promethazine carries a black box warning for the risk of severe tissue injury, including gangrene, regardless of the administration route [1.4.2, 1.8.1]. It is a chemical irritant that can cause serious damage if it is injected into an artery or leaks out of the vein into the surrounding tissue (extravasation) [1.8.2]. Complications can include burning pain, swelling, blistering, nerve damage, tissue necrosis (death), and gangrene, sometimes requiring surgical intervention, skin grafts, or even amputation [1.8.4, 1.8.1]. Because of these risks, intramuscular injection is the preferred route over intravenous administration [1.8.2].
Promethazine vs. Diphenhydramine (Benadryl) Toxicity
| Feature | Promethazine | Diphenhydramine (Benadryl) |
|---|---|---|
| Primary Class | Phenothiazine Antihistamine [1.2.3] | Ethanolamine Antihistamine [1.10.1] |
| Black Box Warnings | Yes: Respiratory depression in children <2; Severe tissue injury with injection [1.4.2] | No specific black box warnings mentioned. |
| Risk of NMS | Yes, associated with phenothiazine class [1.4.2] | Not typically associated. |
| Extrapyramidal Symptoms | Higher risk due to dopamine D2 receptor antagonism [1.2.3] | Lower risk. |
| Drug Interactions | Interacts with a high number of drugs (over 750 known) [1.10.1] | Interacts with a high number of drugs (over 450 known) [1.10.1] |
| Half-Life | Longer (around 16 hours for some formulations) [1.10.1] | Shorter (around 9.3 hours) [1.10.1] |
Management of Promethazine Toxicity
There is no specific antidote for promethazine overdose [1.9.2]. Treatment is primarily symptomatic and supportive [1.9.2].
- Airway Support: The first priority is ensuring a patent airway and adequate breathing. In cases of severe CNS or respiratory depression, this may require intubation and mechanical ventilation [1.9.3].
- Decontamination: Activated charcoal may be given if the overdose is recent (within about two hours) to help reduce absorption of the drug from the gut [1.9.2].
- Cardiovascular Support: Hypotension is managed with IV fluids and repositioning. If vasopressors are needed, norepinephrine is preferred over epinephrine [1.9.1]. Continuous ECG monitoring is used to watch for arrhythmias [1.9.3].
- Seizure Control: Seizures may be treated with benzodiazepines like diazepam [1.9.1].
- NMS Treatment: If NMS develops, the drug is stopped immediately, and intensive cooling measures are started, along with medications like dantrolene or bromocriptine [1.5.4, 1.9.2].
For authoritative information, please consult resources like the National Institutes of Health (NIH)
Conclusion
The toxic effects of promethazine are extensive and can be severe, particularly in overdose and in vulnerable populations like young children. Major toxicities include profound central nervous system and respiratory depression, life-threatening Neuroleptic Malignant Syndrome, extrapyramidal symptoms, and cardiovascular complications. The injectable form also carries a risk of severe tissue damage. Due to this significant potential for harm, it is essential that promethazine be used only as directed, at the lowest effective dose, and with full awareness of its potential adverse effects and drug interactions.
