Pharmacology of Promethazine

Introduction/Overview

Promethazine is a phenothiazine derivative with a multifaceted pharmacological profile, primarily recognized for its potent antihistaminic and antiemetic properties. First synthesized in the 1940s, it has maintained a significant, though increasingly nuanced, role in clinical medicine for over seven decades. Its utility spans several therapeutic areas, including allergy management, nausea and vomiting control, sedation, and motion sickness prophylaxis. However, its use is tempered by a well-documented adverse effect profile, particularly concerning extrapyramidal symptoms and respiratory depression in specific populations. A thorough understanding of its pharmacology is essential for medical and pharmacy students to ensure its safe and effective application within modern therapeutic paradigms where newer, often more selective, agents are also available.

Learning Objectives

Upon completion of this chapter, the reader should be able to:

• Describe the chemical classification of promethazine and its relationship to pharmacodynamic activity.
• Explain the primary and secondary mechanisms of action, including receptor affinity profiles and downstream cellular effects.
• Outline the pharmacokinetic properties of promethazine, including absorption, distribution, metabolism, and elimination pathways.
• Identify the approved therapeutic indications, common off-label uses, and the associated clinical evidence.
• Analyze the major adverse effects, contraindications, and drug interactions, with particular attention to high-risk populations and black box warnings.

Classification

Promethazine belongs to a specific subclass of pharmacological agents, and its classification informs both its therapeutic effects and its adverse reaction profile.

Drug Classes and Categories

Promethazine is categorized primarily as a first-generation or classical antihistamine. More specifically, it is an H₁ receptor inverse agonist. Its chemical lineage places it within the phenothiazine class, sharing a core tricyclic structure with antipsychotic agents like chlorpromazine. This structural similarity confers additional pharmacodynamic properties beyond simple H₁ blockade. Consequently, promethazine is also classified therapeutically as an antiemetic, a sedative-hypnotic, and an anticholinergic agent. Its official therapeutic categories according to standard drug compendia include antihistamines, antiemetics, and sedatives.

Chemical Classification

Chemically, promethazine is a phenothiazine derivative. Its systematic name is (RS)-N,N-dimethyl-1-(10H-phenothiazin-10-yl)propan-2-amine. The molecule consists of a tricyclic phenothiazine nucleus, which is essential for interacting with various neuroreceptor sites, linked to an isopropylamine side chain. This side chain is characteristic of the “alkylamine” subclass of H₁ antihistamines, which also includes agents like chlorpheniramine. Unlike many antipsychotic phenothiazines that have a piperazine or aliphatic side chain, the isopropylamine group contributes to promethazine’s pronounced antihistaminic and sedative effects with a relatively lower, though still present, potential for antipsychotic and extrapyramidal activity. The compound is typically administered as the hydrochloride salt, which is highly water-soluble.

Mechanism of Action

The therapeutic and adverse effects of promethazine arise from its interaction with multiple receptor systems in the central and peripheral nervous systems. Its action is best described as pleiotropic.

Detailed Pharmacodynamics

The primary mechanism of action is competitive antagonism, or more accurately, inverse agonism, at histamine H₁ receptors. In the inverse agonist model, promethazine stabilizes the inactive conformation of the H₁ receptor, producing a functional effect opposite to that of histamine even in its absence. This action is responsible for its efficacy in allergic conditions, as it prevents histamine-mediated vasodilation, increased capillary permeability, and bronchoconstriction. Within the central nervous system, antagonism of H₁ receptors in the hypothalamus and brainstem is a major contributor to its sedative and antiemetic effects, particularly against stimuli processed by the vestibular apparatus and chemoreceptor trigger zone (CTZ).

Receptor Interactions

Promethazine exhibits significant affinity for several receptor classes beyond the H₁ receptor, a consequence of its phenothiazine structure. Its receptor profile includes:

• Muscarinic Acetylcholine Receptors (mAChRs): Promethazine acts as a competitive antagonist at muscarinic receptors, particularly the M₁ to M₅ subtypes. This anticholinergic activity contributes to its antiemetic effect (by blocking pathways in the vomiting center), its inhibition of secretions, and side effects like dry mouth, blurred vision, urinary retention, and constipation.
• Dopamine D₂ Receptors: The drug possesses moderate antagonistic activity at dopaminergic D₂ receptors, especially in the CTZ. This action is central to its efficacy in treating nausea and vomiting from diverse causes, including chemotherapy, radiation, and opioids. However, this dopamine blockade also underlies the risk of acute dystonias and other extrapyramidal symptoms, particularly at higher doses.
• Alpha-1 Adrenergic Receptors (α₁-ARs): Antagonism of α₁-adrenoceptors can lead to peripheral vasodilation and orthostatic hypotension, which may be pronounced, especially with intravenous administration.
• Serotonin Receptors (5-HT): Some activity at serotonin receptors, particularly 5-HT₂, may contribute to its sedative and antiemetic properties, though this is not its primary mode of action.

The relative potency at these various receptors dictates the net clinical effect. Promethazine’s strong H₁ and mAChR blockade, coupled with moderate D₂ blockade, defines its characteristic profile distinct from more selective antiemetics.

Molecular and Cellular Mechanisms

At the molecular level, promethazine’s receptor antagonism inhibits second messenger systems. H₁ receptor blockade prevents the G_q-protein-mediated activation of phospholipase C, thereby reducing the production of inositol trisphosphate (IP₃) and diacylglycerol (DAG). This cascade normally leads to intracellular calcium mobilization and protein kinase C activation, events central to the inflammatory and allergic response. Muscarinic receptor antagonism inhibits G_i or G_q coupled pathways, depending on the subtype. Dopamine D₂ receptor antagonism in the CTZ inhibits the G_i-mediated inhibition of adenylyl cyclase, altering neuronal firing and vomiting reflexes. Furthermore, promethazine’s ability to penetrate the blood-brain barrier readily is due to its high lipophilicity, allowing these central receptor effects to manifest prominently.

Pharmacokinetics

The absorption, distribution, metabolism, and excretion of promethazine influence its dosing regimens, onset and duration of action, and potential for drug interactions.

Absorption

Promethazine is well absorbed from the gastrointestinal tract following oral administration. However, it undergoes significant first-pass metabolism in the liver, resulting in an oral bioavailability estimated to be approximately 25%. The onset of action after oral administration typically occurs within 20 to 30 minutes. When administered via intramuscular injection, absorption is more reliable and rapid, with effects often noticeable within 20 minutes. Rectal suppository formulations are also available and provide an alternative route when oral intake is not feasible, with bioavailability comparable to or slightly less than the oral route. Intravenous administration, while used, is not a recommended route due to the high risk of severe tissue injury, including gangrene, and profound hypotension.

Distribution

Promethazine is widely distributed throughout body tissues due to its high lipophilicity. It readily crosses the blood-brain barrier, accounting for its pronounced central nervous system effects. It also crosses the placental barrier and is excreted into breast milk. The volume of distribution (V_d) is large, often reported to be in the range of 10 to 30 L/kg, indicating extensive tissue binding. The drug is highly bound to plasma proteins, primarily albumin and α₁-acid glycoprotein, with protein binding exceeding 90%.

Metabolism

Hepatic metabolism is extensive and serves as the primary route of elimination. The major pathways involve cytochrome P450 enzymes, with CYP2D6 and CYP2B6 playing prominent roles. Primary metabolic reactions include sulfoxidation, N-demethylation, and glucuronide conjugation. The N-demethylation produces the active metabolite, desmethylpromethazine (norpromethazine), which retains some pharmacological activity, primarily as an H₁ antagonist. This metabolite may contribute to the drug’s prolonged effects. The sulfoxide metabolite is generally considered inactive. Genetic polymorphisms in CYP2D6 can lead to variability in metabolic rates, potentially affecting both efficacy and toxicity in individual patients.

Excretion

Elimination occurs predominantly via the kidneys, but only a small fraction of the administered dose is excreted unchanged in urine (less than 5%). The majority is eliminated as various conjugated and unconjugated metabolites. A small portion may be excreted in the feces via biliary elimination. The clearance of promethazine is relatively high, but due to its large volume of distribution, its elimination is rate-limited by redistribution from tissues.

Half-life and Dosing Considerations

The elimination half-life (t_1/2) of promethazine is relatively long and variable, generally reported to be between 10 to 16 hours in adults. The half-life of the active desmethyl metabolite may be even longer. This prolonged half-life supports its use in twice-daily or even once-daily dosing for indications like allergy prophylaxis. For acute indications like nausea, dosing is typically every 4 to 6 hours as needed. The relationship between dose and plasma concentration is not linear due to saturable first-pass metabolism; increasing the oral dose can lead to a disproportionate rise in systemic exposure. Dosing must be adjusted in the elderly and in patients with significant hepatic impairment, as discussed in later sections.

Therapeutic Uses/Clinical Applications

Promethazine is employed for a range of conditions, leveraging its antihistaminic, antiemetic, and sedative properties. Its use requires careful risk-benefit analysis.

Approved Indications

Regulatory-approved indications for promethazine include:

• Allergic Conditions: Management of allergic rhinitis, allergic conjunctivitis, and mild allergic skin reactions (e.g., urticaria). It is effective in reducing symptoms like sneezing, rhinorrhea, pruritus, and lacrimation.
• Nausea and Vomiting: Treatment and prevention of nausea and vomiting associated with anesthesia, surgery, and various medical conditions. Its efficacy in chemotherapy-induced nausea and vomiting (CINV) is limited to low-emetogenic risk regimens, having been largely superseded by 5-HT₃ antagonists and neurokinin-1 (NK₁) receptor antagonists for moderate to high emetic risk.
• Motion Sickness: Prophylaxis and treatment of nausea, vomiting, and dizziness associated with motion sickness. It is often administered 30 to 60 minutes before travel.
• Sedation: Preoperative, postoperative, or procedural sedation. It is also used as a sedative-hypnotic for occasional insomnia, though this use has declined due to concerns about tolerance, hangover effects, and safety.
• Adjunct to Analgesics: Used in combination with opioids, such as in “Phenergan with Codeine” formulations, to potentiate the analgesic and sedative effects. This combination may also mitigate opioid-induced nausea.

Off-Label Uses

Several off-label applications are common in clinical practice, though with varying levels of supporting evidence:

• Acute Migraine: Often administered parenterally in emergency settings alongside other agents (e.g., a non-steroidal anti-inflammatory drug and a dopamine antagonist like metoclopramide) for its antiemetic, sedative, and possible headache-modulating effects.
• Vertigo and Labyrinthitis: Used to manage vertigo associated with vestibular disorders, primarily for its central anticholinergic and sedative properties.
• Anxiety and Agitation: Occasionally used for short-term management of anxiety or agitation, particularly in hospital settings, though it is not a first-line agent due to its side effect profile.
• Pruritus: Management of pruritus from various causes, including cholestasis and uremia, due to its central H₁ antagonism and sedative effect.

Adverse Effects

The adverse effect profile of promethazine is broad, reflecting its multi-receptor pharmacology. Effects range from common and bothersome to rare and life-threatening.

Common Side Effects

The most frequently encountered adverse effects are extensions of its pharmacologic activity and are often dose-related. These include:

• Central Nervous System: Sedation, drowsiness, fatigue, dizziness, and impaired cognitive and motor performance are almost universal, especially upon initiation of therapy. Confusion and disorientation may occur, particularly in the elderly.
• Anticholinergic Effects: Dry mouth (xerostomia), blurred vision due to cycloplegia and mydriasis, constipation, urinary retention, and tachycardia.
• Gastrointestinal: Mild gastrointestinal upset.
• Cardiovascular: Mild orthostatic hypotension, palpitations, and reflex tachycardia.

Serious/Rare Adverse Reactions

More severe reactions necessitate caution and often contraindicate further use:

• Extrapyramidal Symptoms (EPS): Acute dystonic reactions (e.g., torticollis, opisthotonos, oculogyric crisis), akathisia, parkinsonism, and tardive dyskinesia can occur due to dopamine D₂ receptor blockade. These are more common with high doses, parenteral administration, and in younger patients.
• Neuroleptic Malignant Syndrome (NMS): A rare but potentially fatal idiosyncratic reaction characterized by hyperthermia, muscle rigidity, autonomic instability, and altered mental status. Although more associated with typical antipsychotics, it has been reported with promethazine.
• Respiratory Depression: Promethazine can cause dose-related respiratory depression, particularly when combined with other central nervous system depressants like opioids, benzodiazepines, or alcohol. This risk is significantly elevated in children under two years of age, leading to a specific contraindication.
• Severe Tissue Injury: Intravenous or inadvertent intra-arterial administration can cause severe chemical irritation, leading to phlebitis, tissue necrosis, and gangrene, potentially necessitating amputation. This has led to strong warnings against IV use.
• Hematologic Effects: Rare instances of leukopenia, agranulocytosis, and thrombocytopenia have been reported, consistent with its phenothiazine class.
• Seizures: May lower the seizure threshold, posing a risk in patients with seizure disorders.
• Cardiac Arrhythmias: Prolongation of the QT interval on the electrocardiogram, potentially leading to torsades de pointes, has been observed, particularly with overdose or in susceptible individuals.

Black Box Warnings

Promethazine carries a prominent boxed warning from the U.S. Food and Drug Administration (FDA):

• Use in Children Under 2 Years: Promethazine is contraindicated for use in children less than two years of age due to the potential for fatal respiratory depression. The risk is heightened in children with conditions that may compromise respiration, such as sleep apnea or upper respiratory infections.
• Caution in Children 2 Years and Older: The drug should be used with extreme caution in children two years of age and older, and the lowest effective dose should be administered. Concomitant use with other respiratory depressants must be avoided.
• Injection Site Tissue Damage: A second boxed warning emphasizes that promethazine injection must be administered by deep intramuscular injection only. Subcutaneous administration is contraindicated, and intravenous administration should be avoided due to the risk of severe chemical irritation and gangrene.

Drug Interactions

Promethazine’s pharmacodynamic and pharmacokinetic properties create the potential for numerous clinically significant drug interactions.

Major Drug-Drug Interactions

Interactions can be categorized as pharmacodynamic (additive or synergistic effects) or pharmacokinetic (altered metabolism).

• Central Nervous System Depressants: Additive or supra-additive sedation, respiratory depression, and psychomotor impairment can occur when promethazine is combined with opioids (e.g., morphine, codeine), benzodiazepines (e.g., diazepam), barbiturates, sedating antidepressants, general anesthetics, and alcohol. Dose reductions of one or both agents are typically required.
• Anticholinergic Agents: Concurrent use with other drugs possessing antimuscarinic activity (e.g., tricyclic antidepressants, first-generation antihistamines, antiparkinsonian agents like benztropine, and some antipsychotics) can lead to an anticholinergic toxidrome, characterized by hyperthermia, delirium, ileus, urinary retention, and tachycardia.
• Dopamine Agonists: Promethazine may antagonize the therapeutic effects of dopamine agonists used in Parkinson’s disease, such as levodopa, pramipexole, and ropinirole.
• Enzyme Inhibitors and Inducers: Strong inhibitors of CYP2D6 (e.g., fluoxetine, paroxetine, quinidine) may increase promethazine plasma concentrations, potentially elevating the risk of adverse effects. Conversely, inducers of CYP enzymes (e.g., rifampin, carbamazepine, phenytoin) may reduce its efficacy.
• QTc-Prolonging Agents: Concomitant use with other drugs known to prolong the QT interval (e.g., class IA and III antiarrhythmics, certain antibiotics like macrolides and fluoroquinolones, some antipsychotics) may increase the risk of life-threatening cardiac arrhythmias, including torsades de pointes.
• Monoamine Oxidase Inhibitors (MAOIs): Concurrent use is generally contraindicated due to theoretical risks of exaggerated anticholinergic effects and potential hypertensive crises, though this interaction is more firmly established for other phenothiazines.

Contraindications

Absolute contraindications to promethazine use include:

• Known hypersensitivity to promethazine, other phenothiazines, or any component of the formulation.
• Age less than two years.
• Comatose states or significantly depressed level of consciousness from any cause (e.g., CNS depressant overdose).
• Subcutaneous or intra-arterial administration of the injectable form.
• Concurrent use with or recent use (within 14 days) of MAOIs, due to potential drug interaction.

Special Considerations

The use of promethazine requires tailored approaches in specific patient populations due to altered pharmacokinetics, pharmacodynamics, or increased susceptibility to adverse effects.

Use in Pregnancy and Lactation

Pregnancy (FDA Category C): Animal reproduction studies have shown adverse effects, and there are no adequate and well-controlled studies in pregnant women. Promethazine crosses the placenta. It may be used during pregnancy if clearly needed, such as for severe hyperemesis gravidarum unresponsive to other therapies, but the potential benefits must justify the potential risks to the fetus. Use near term may be associated with neonatal anticholinergic effects or withdrawal symptoms.

Lactation: Promethazine is excreted into human breast milk in low concentrations. Due to the potential for serious adverse reactions in nursing infants, including sedation, irritability, and feeding difficulties, a decision should be made to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. If used, the infant should be monitored for signs of sedation and anticholinergic effects.

Pediatric and Geriatric Considerations

Pediatric: As noted, it is contraindicated in children under two years. In older children, it must be used cautiously at the lowest effective dose. Children may be more susceptible to paradoxical reactions (excitement, nightmares, hallucinations) and to dystonic reactions. Dosage is typically based on body weight or body surface area.

Geriatric: Patients aged 65 years and older are particularly sensitive to the anticholinergic, sedative, and hypotensive effects of promethazine. Age-related decreases in hepatic and renal function may also lead to prolonged elimination. These factors increase the risk of confusion, falls, urinary retention, and constipation. A lower starting dose is strongly recommended, and routine use for insomnia or chronic conditions is generally discouraged. The Beers Criteria, a guideline for medication use in older adults, lists promethazine as a medication to avoid due to its high anticholinergic burden and associated risks.

Renal and Hepatic Impairment

Renal Impairment: Since only a small fraction of the parent drug is renally excreted, dosage adjustment in mild to moderate renal impairment is not typically required. However, caution is advised in severe renal impairment (creatinine clearance less than 30 mL/min) due to potential accumulation of active metabolites and increased susceptibility to adverse effects. Monitoring for enhanced sedation and anticholinergic effects is prudent.

Hepatic Impairment: Promethazine is extensively metabolized by the liver. In patients with hepatic impairment (e.g., cirrhosis), first-pass metabolism may be reduced, leading to significantly increased bioavailability and systemic exposure after oral doses. The elimination half-life may also be prolonged. Promethazine should be used with great caution in this population, starting with a substantially reduced dose and titrating slowly. It may be contraindicated in severe hepatic failure.

Summary/Key Points

Promethazine is a prototypical first-generation phenothiazine antihistamine with a complex pharmacology rooted in its multi-receptor antagonism.

Bullet Point Summary

• Promethazine is chemically classified as a phenothiazine derivative with an alkylamine side chain, conferring potent H₁ inverse agonism, anticholinergic, and moderate dopamine D₂ antagonistic activities.
• Its primary mechanisms involve blockade of central and peripheral H₁ receptors (for allergy and sedation), muscarinic receptors (for antiemesis and side effects), and dopamine D₂ receptors in the CTZ (for antiemesis).
• Pharmacokinetically, it is well-absorbed but undergoes significant first-pass metabolism, has a large volume of distribution, a long half-life (10-16 hours), and is eliminated hepatically via CYP2D6 and other enzymes.
• Approved uses include allergic conditions, nausea/vomiting, motion sickness, sedation, and as an analgesic adjunct. Off-label uses include migraine and vertigo management.
• The adverse effect profile is extensive, featuring sedation, anticholinergic effects, extrapyramidal symptoms, respiratory depression (especially in young children), and risk of tissue injury from improper injection.
• It carries a black box warning against use in children under two years and against subcutaneous or intravenous injection due to risks of fatal respiratory depression and gangrene, respectively.
• Major drug interactions occur with other CNS depressants, anticholinergics, and QT-prolonging agents. It is contraindicated with MAOIs and in comatose patients.
• Special caution is required in the elderly, who are highly sensitive to its effects, and in patients with hepatic impairment, who may require dose reduction. Use in pregnancy and lactation requires careful risk-benefit assessment.

Clinical Pearls

• Promethazine should not be considered a first-line antiemetic for chemotherapy-induced nausea and vomiting; 5-HT₃ antagonists and NK₁ receptor antagonists are preferred for moderate to high emetic risk.
• For allergic conditions, second-generation non-sedating antihistamines (e.g., loratadine, cetirizine) are generally preferred for daytime use due to their improved safety profile regarding sedation.
• The intramuscular formulation must be administered via deep injection into a large muscle mass (e.g., gluteus maximus). Aspiration prior to injection is necessary to avoid intravascular administration.
• Patients should be counseled extensively about the risks of sedation and impaired cognitive function, advising against driving or operating heavy machinery until their individual response is known.
• In the emergency department setting for migraine, a common and effective “migraine cocktail” may include intravenous fluids, a non-steroidal anti-inflammatory drug (e.g., ketorolac), metoclopramide, and diphenhydramine (to prevent metoclopramide-induced akathisia). Promethazine can be used in place of metoclopramide, providing both antiemetic and sedative effects.
• The anticholinergic burden of promethazine contributes significantly to its toxicity in the elderly, increasing the risk of cognitive decline, falls, and functional impairment. Its routine use in this population should be avoided.

References

1. Whalen K, Finkel R, Panavelil TA. Lippincott Illustrated Reviews: Pharmacology. 7th ed. Philadelphia: Wolters Kluwer; 2019.
2. Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale's Pharmacology. 9th ed. Edinburgh: Elsevier; 2020.
3. Katzung BG, Vanderah TW. Basic & Clinical Pharmacology. 15th ed. New York: McGraw-Hill Education; 2021.
4. Brunton LL, Hilal-Dandan R, Knollmann BC. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 14th ed. New York: McGraw-Hill Education; 2023.
5. Trevor AJ, Katzung BG, Kruidering-Hall M. Katzung & Trevor's Pharmacology: Examination & Board Review. 13th ed. New York: McGraw-Hill Education; 2022.
6. Golan DE, Armstrong EJ, Armstrong AW. Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy. 4th ed. Philadelphia: Wolters Kluwer; 2017.
7. Whalen K, Finkel R, Panavelil TA. Lippincott Illustrated Reviews: Pharmacology. 7th ed. Philadelphia: Wolters Kluwer; 2019.
8. Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale's Pharmacology. 9th ed. Edinburgh: Elsevier; 2020.