Promethazine
1. Drug Name
Generic Name: Promethazine
Brand Names: Phenergan, Promethegan, and others
2. Drug Classification
Class: Antihistamine
Subclass: First-generation H1 receptor antagonist, Anti-emetic, Sedative
Other Classifications: Anticholinergic, Antidopaminergic
3. Mechanism of Action
Histamine H1 Receptor Antagonism: Promethazine primarily exerts its effects by blocking the H1 receptors, which are responsible for allergic reactions like itching, swelling, and sneezing. By inhibiting histamine binding to H1 receptors, it alleviates these symptoms.
Anticholinergic Effects: As a first-generation antihistamine, promethazine also has significant anticholinergic effects. It blocks acetylcholine receptors, which contributes to dry mouth, blurred vision, and urinary retention.
Dopamine Antagonism: Promethazine also blocks dopamine receptors in the brain, particularly in the chemoreceptor trigger zone (CTZ) in the medulla, which helps prevent nausea and vomiting.
CNS Depression: Promethazine has sedative effects due to its ability to cross the blood-brain barrier and block histamine in the central nervous system (CNS), leading to drowsiness and calmness.
4. Pharmacokinetics
Absorption:
Bioavailability: Approximately 25-30% after oral administration. Intravenous and intramuscular forms have higher bioavailability.
Onset of Action: Oral administration typically results in onset of effects within 20 minutes, while the peak effect is observed at around 2 hours.
Distribution:
Volume of Distribution (Vd): Promethazine has a high Vd, indicating it is extensively distributed in tissues.
Protein Binding: It is about 90-99% protein-bound, primarily to albumin.
Metabolism:
Liver Metabolism: Promethazine is metabolized in the liver by cytochrome P450 enzymes (primarily CYP2D6 and CYP3A4), producing various metabolites.
Excretion:
Half-life (t½): The terminal half-life of promethazine is approximately 10-19 hours, which can be prolonged in patients with hepatic impairment.
Excretion: The drug is excreted predominantly through urine, with a small fraction in the feces.
Special Considerations:
Renal/Hepatic Impairment: Promethazine should be used with caution in patients with hepatic or renal dysfunction due to slowed metabolism and excretion, which can lead to increased drug levels and risk of side effects.
Age Considerations: Elderly patients may be more susceptible to the sedative and anticholinergic effects of promethazine, requiring dose adjustments.
5. Indications
Primary Indications:
Allergic Conditions: Promethazine is used for treating allergic reactions such as allergic rhinitis, hay fever, urticaria (hives), and conjunctivitis.
Motion Sickness: It is effective in preventing and treating nausea, vomiting, and dizziness associated with motion sickness.
Nausea and Vomiting: Promethazine is used to treat nausea and vomiting of various origins, including post-operative nausea and nausea from chemotherapy.
Sedation: Due to its sedative properties, promethazine is used as a preoperative sedative and in some cases for sleep disturbances.
Cough: It is used in combination with other drugs in cough syrups for symptomatic relief of cough.
Off-label Uses:
Insomnia: Due to its sedative effects, it is sometimes used off-label for short-term management of sleep disturbances.
Post-operative nausea and vomiting (PONV): Promethazine is often used in combination with other antiemetics for the prevention and treatment of nausea and vomiting after surgery.
Special Populations:
Pediatrics: Promethazine can be used in children aged 2 years and older for allergy relief and motion sickness. The dose should be adjusted for age and weight.
Geriatrics: Use with caution in elderly patients due to increased risk of sedation, confusion, and anticholinergic effects, including urinary retention and dry mouth.
6. Dosage and Administration
Adult Dosing:
Allergic Conditions: 25 mg orally at bedtime or every 4-6 hours as needed.
Motion Sickness: 25 mg orally 30-60 minutes before travel, and then every 4-6 hours as needed.
Nausea and Vomiting: 12.5-25 mg orally, IM, or IV every 4-6 hours as needed.
Preoperative Sedation: 25-50 mg orally or IM, given 1-2 hours before surgery.
Pediatric Dosing:
Allergic Conditions:
Children aged 2 to 6 years: 6.25 mg every 4-6 hours (maximum 25 mg per day).
Children aged 6 to 12 years: 12.5-25 mg every 4-6 hours (maximum 50 mg per day).
Children aged 12 years and older: Same as adult dosing.
Motion Sickness: Same as for allergic conditions.
Renal/Hepatic Impairment: Dose adjustments may be necessary in patients with renal or hepatic dysfunction, as they may have reduced drug clearance.
7. Contraindications
Absolute Contraindications:
Hypersensitivity: Known hypersensitivity to promethazine or any of its components.
Comatose States: Promethazine should not be used in patients who are comatose or in a state of acute alcohol intoxication.
Lower Respiratory Tract Symptoms: Should not be used in children under 2 years for cough or colds due to the risk of respiratory depression.
Relative Contraindications:
Severe Liver Disease: Use with caution in patients with severe liver dysfunction due to altered drug metabolism and the increased risk of toxicity.
Glaucoma: Caution is advised in patients with narrow-angle glaucoma due to its anticholinergic effects.
Prostatic Hypertrophy: Promethazine should be used with caution in men with prostatic hypertrophy as it can worsen urinary retention.
8. Warnings and Precautions
CNS Depression: Promethazine can cause significant sedation, drowsiness, and impair coordination. Patients should avoid activities requiring full alertness, such as driving or operating heavy machinery.
Anticholinergic Effects: The drug has anticholinergic properties, which can lead to dry mouth, blurred vision, constipation, and urinary retention. These effects are especially pronounced in elderly individuals.
Severe Respiratory Depression in Children: Use in children under 2 years of age is contraindicated due to the risk of fatal respiratory depression.
Hypotension: Promethazine may cause hypotension, especially when administered intravenously, and should be used cautiously in patients with cardiovascular disease.
Prolonged QT Interval: High doses or intravenous administration may prolong the QT interval, which can lead to arrhythmias. Careful monitoring is advised.
9. Adverse Effects
Common Adverse Effects:
Sedation and Drowsiness: Due to its central H1 antagonism and anticholinergic properties.
Dry Mouth: Common, especially with long-term use.
Dizziness: Particularly in the elderly and those who are sensitive to sedative effects.
Less Common but Clinically Significant:
Blurred Vision: Due to the anticholinergic effect.
Urinary Retention: Commonly seen in older patients or those with prostate problems.
Rare/Serious Adverse Reactions:
Severe Allergic Reactions: Anaphylaxis, angioedema, and anaphylactic shock are rare but possible.
Respiratory Depression: Especially in children under 2 years of age.
Neuroleptic Malignant Syndrome (NMS): Although rare, NMS can occur with dopaminergic antagonists like promethazine. Symptoms include hyperthermia, muscle rigidity, altered mental status, and autonomic dysregulation.
10. Drug Interactions
CNS Depressants: Promethazine increases the sedative effects of other CNS depressants, such as alcohol, benzodiazepines, barbiturates, and opiates.
MAO Inhibitors (MAOIs): Promethazine may interact with MAOIs and increase the risk of adverse effects, including hypertensive crises or central nervous system toxicity.
Anticholinergic Drugs: Combining promethazine with other anticholinergic agents (e.g., atropine, tricyclic antidepressants) can enhance the anticholinergic effects, leading to increased risk of dry mouth, urinary retention, and confusion.
11. Clinical Pharmacology
Pharmacodynamic Profile: Promethazine’s primary actions are through histamine receptor antagonism and dopamine receptor blockade. It reduces allergic symptoms and prevents nausea and vomiting by inhibiting dopamine’s effect on the CTZ.
Additional Effects: Its sedative effects are useful in managing insomnia or preoperative anxiety, while its anticholinergic effects can be beneficial for patients with motion sickness.
12. Special Populations
Pregnancy: Category C. While there are no well-controlled studies in pregnant women, promethazine is often used when benefits outweigh the risks. It is generally considered safe for short-term use during pregnancy.
Lactation: Excreted in breast milk; use with caution during breastfeeding as it may cause drowsiness in the infant.
Pediatrics: Used in children over 2 years of age for conditions like allergies, motion sickness, and nausea.
Geriatrics: Elderly individuals are more likely to experience side effects like sedation, confusion, and anticholinergic effects, necessitating lower doses and close monitoring.
13. Therapeutic Uses
Primary: Treatment of allergic conditions (e.g., rhinitis, urticaria), motion sickness, nausea, and vomiting, as well as a sedative and adjunct in preoperative settings.
Off-label: Management of insomnia, short-term use in anxiety, and treatment of post-operative nausea and vomiting.
Clinical Trials: Studies have shown that promethazine is effective in preventing motion sickness and reducing the severity of nausea and vomiting in various settings, including post-operative care.
14. Monitoring and Follow-Up
Symptom Monitoring: Monitor for signs of excessive sedation or anticholinergic effects, especially in elderly patients.
Respiratory Monitoring: In children, particularly those under 2 years, monitoring for respiratory depression is essential.
Cardiovascular Monitoring: In patients with pre-existing heart conditions, monitoring for hypotension or arrhythmias is recommended.
15. Overdose Management
Symptoms of Overdose: Overdose symptoms may include excessive sedation, dry mouth, blurred vision, urinary retention, confusion, seizures, and respiratory depression.
Management: Overdose management is symptomatic, with activated charcoal used within 1 hour of ingestion. Seizures should be treated with anticonvulsants, and respiratory depression may require intubation and mechanical ventilation.
16. Patient Counseling Information
Administration: Advise patients to take promethazine with food or milk to reduce gastrointestinal irritation.
Avoid Alcohol: Patients should avoid alcohol or any other CNS depressants, as they can enhance sedative effects and increase the risk of side effects.
Caution with Activities: Inform patients about the sedative effects and recommend avoiding activities requiring full mental alertness (e.g., driving or operating heavy machinery).
Inform about Side Effects: Patients should be aware of potential side effects, such as dry mouth, blurred vision, and drowsiness, and be instructed to report any severe reactions promptly.