Monograph of Promethazine

Introduction

Promethazine is a first‑generation phenothiazine antihistamine that has been employed clinically for several decades as an antiemetic, sedative, and anti‑allergic agent. Its primary pharmacologic actions involve antagonism of histamine H1 receptors, inhibition of dopamine D2 receptors, and modulation of muscarinic acetylcholine receptors. The compound is available in oral, intramuscular, and intravenous formulations, and is frequently combined with other agents such as diphenhydramine or phenobarbital in multi‑component preparations.

Historically, the development of phenothiazine derivatives began in the 1950s, with promethazine emerging as one of the earliest antihistamines introduced to the United States market. Over time, its therapeutic profile expanded to include anti‑nausea, anti‑emetic, and sedative indications, especially in perioperative and palliative care settings. Contemporary use continues to emphasize its efficacy in controlling nausea, vomiting, and anxiety, while recognizing its side‑effect potential, notably anticholinergic toxicity and respiratory depression in susceptible populations.

Learning objectives for this chapter include:

• To delineate the physicochemical properties and pharmacokinetic parameters of promethazine.
• To articulate the pharmacodynamic mechanisms underlying its therapeutic effects.
• To evaluate clinical scenarios where promethazine is indicated or contraindicated.
• To interpret dosing regimens and adjust therapy in special populations.
• To identify potential drug‑drug interactions and adverse event profiles.

Fundamental Principles

Core Concepts and Definitions

Promethazine is defined as a 4‑phenyl-1,2,4‑triazolo‑5‑phenothiazine derivative. It is classified pharmacologically as a non‑selective H1 antagonist with significant antimuscarinic, antihistaminic, and dopaminergic blockade. The drug’s lipophilicity facilitates rapid penetration across the blood‑brain barrier, contributing to its central sedative and antiemetic properties.

Theoretical Foundations

The therapeutic actions of promethazine are best understood through receptor pharmacology. Competitive antagonism at H1 receptors reduces histamine‑mediated vasodilation and pruritus. D2 antagonism disrupts the vomiting center in the medulla, thereby mitigating nausea. Antimuscarinic activity attenuates cholinergic tone, which can alleviate gastrointestinal motility disturbances. These mechanisms collectively account for the drug’s broad clinical utility.

Key Terminology

• Half‑life (t_1/2) – The period required for plasma concentration to decrease by 50 %.
• C_max – Peak plasma concentration following administration.
• Clearance (Cl) – Volume of plasma from which the drug is completely removed per unit time.
• Volume of distribution (V_d) – Apparent space in the body occupied by the drug.
• Bioavailability (F) – Fraction of administered dose reaching systemic circulation.

Detailed Explanation

Pharmacokinetics

Absorption

Oral promethazine is absorbed rapidly, with peak plasma levels typically attained within 30 minutes to 2 hours. The absorption rate is influenced by gastrointestinal pH, food intake, and concomitant medications that alter gastric motility. Intramuscular and intravenous routes bypass first‑pass metabolism, leading to higher bioavailability (F ≈ 100 %) compared with oral administration (F ≈ 50–60 %).

Distribution

Due to high lipophilicity, the drug demonstrates a large V_d (≈ 10–15 L/kg). The distribution is widespread, with notable penetration into the central nervous system and ocular tissues. Protein binding is moderate (~ 80 %), primarily to albumin, which may alter free drug concentrations in hypo‑albuminemic patients.

Metabolism

Promethazine undergoes hepatic biotransformation predominantly via cytochrome P450 isoenzymes, chiefly CYP2D6 and CYP3A4. Oxidative dealkylation leads to inactive metabolites such as 4‑hydroxy‑promethazine, which are subsequently conjugated with glucuronic acid and excreted. Genetic polymorphisms in CYP2D6 can result in variable clearance rates among individuals.

Excretion

Renal excretion accounts for approximately 30 % of the dose, whereas biliary excretion contributes the remaining 70 %. The primary elimination pathway is via urine and feces as glucuronide conjugates. The overall elimination half‑life ranges from 5 to 10 hours in healthy adults but may extend to 15–20 hours in the elderly or in patients with hepatic impairment.

Pharmacokinetic Equations

Clearance can be expressed as:

Cl = Dose ÷ AUC

where AUC denotes the area under the plasma concentration–time curve. The concentration at any time t can be modeled by the first‑order elimination equation:

C(t) = C₀ × e^-kt

with k representing the elimination rate constant, k = ln(2) ÷ t_1/2.

Pharmacodynamics

Receptor Antagonism

Promethazine’s affinity for H1 receptors (K_i ≈ 0.1 µM) allows significant blockade at therapeutic concentrations. The drug also exhibits moderate affinity for D2 receptors (K_i ≈ 1–2 µM), contributing to antiemetic activity. Antimuscarinic potency is lower (K_i ≈ 10 µM) but clinically relevant in high doses or in sensitive patients.

Functional Outcomes

The central sedative effect is mediated by H1 blockade within the locus coeruleus and vestibular nuclei. Antiemetic efficacy results from suppression of the chemoreceptor trigger zone and vomiting center. Antihistaminic action reduces allergic symptoms, while antimuscarinic activity lessens gastrointestinal motility and secretions.

Factors Affecting Pharmacologic Response

• Age – Reduced hepatic clearance and altered renal function in the elderly can prolong drug action.
• Genetic Polymorphisms – CYP2D6 poor metabolizers may experience increased exposure.
• Concomitant Medications – Drugs that inhibit CYP3A4 (e.g., ketoconazole) can elevate promethazine levels.
• Gastrointestinal Motility – Reduced motility can delay absorption.
• Renal Function – Impaired clearance may necessitate dose adjustment.

Clinical Significance

Therapeutic Indications

Promethazine is primarily indicated for:

• Pre‑operative and post‑operative nausea and vomiting.
• Acute and chronic motion sickness.
• Anxiety and agitation associated with various medical conditions.
• Allergic reactions presenting with pruritus and urticaria, particularly when rapid relief is required.

Dosage Forms and Regimens

Common formulations include 12.5 mg tablets, 25 mg oral solutions, 25 mg intramuscular injections, and 25 mg intravenous solutions. Standard adult dosing for antiemetic purposes is 25 mg orally 2–3 times daily or 25 mg intramuscularly as needed. In elderly or renal/hepatic impairment, dose reduction to 12.5 mg is advisable.

Adverse Effects and Contraindications

Promethazine is associated with anticholinergic side effects such as dry mouth, blurred vision, and urinary retention. Central nervous system depression can lead to sedation, respiratory depression, and, rarely, paradoxical agitation. In pediatric populations, the risk of severe respiratory depression is heightened, leading to contraindication in infants and young children for certain indications.

Contraindications include:

• Known hypersensitivity to phenothiazines.
• History of seizures or prolonged QT interval.
• Presence of narrow‑angle glaucoma or severe hepatic dysfunction.

Drug–Drug Interactions

Promethazine can potentiate the sedative effects of CNS depressants such as alcohol, benzodiazepines, and opioids. Concurrent use with anticholinergic agents may exacerbate dry‑mouth and urinary retention. CYP3A4 inhibitors (e.g., erythromycin) may increase plasma concentrations, whereas CYP3A4 inducers (e.g., rifampin) may reduce efficacy.

Clinical Applications / Examples

Case Scenario 1: Post‑Operative Nausea in an Elderly Patient

A 78‑year‑old woman undergoes laparoscopic cholecystectomy. Post‑operatively, she reports nausea and mild vomiting. Her baseline renal function is normal, but hepatic function shows mild elevation of transaminases. An oral dose of 12.5 mg promethazine is administered, followed by 12.5 mg 6 hours later. The patient’s nausea resolves within 2 hours, and no adverse events occur. This illustrates dose adjustment based on age and hepatic function.

Case Scenario 2: Acute Motion Sickness in a Pediatric Patient

A 10‑year‑old boy experiences severe motion sickness during a car ride. The parents administer 12.5 mg promethazine orally. The child remains alert, and symptoms improve within 30 minutes. The dosage is within the recommended pediatric range, and monitoring for sedation is advised.

Case Scenario 3: Antihistamine Rescue for Severe Urticaria

A 45‑year‑old man presents with anaphylactic urticaria following a bee sting. Due to the urgency, a 25 mg intramuscular dose of promethazine is administered concurrently with epinephrine. The patient experiences rapid relief of pruritus after 10 minutes, while epinephrine addresses systemic allergic manifestations. This demonstrates the utility of promethazine as a rapid antihistamine in emergency settings.

Problem‑Solving Approach for Dose Adjustment

1. Assess patient age, weight, hepatic and renal status.
2. Determine therapeutic indication and required potency.
3. Select appropriate formulation (oral vs intramuscular vs intravenous).
4. Calculate initial dose using standard adult guidelines, then adjust proportionally for special populations.
5. Monitor for therapeutic response and adverse events, modifying dose as necessary.

Summary / Key Points

• Promethazine is a first‑generation phenothiazine antihistamine with H1, D2, and antimuscarinic activity.
• Rapid absorption and high lipophilicity enable effective central nervous system penetration.
• Standard adult dosing for antiemetic use is 25 mg orally or intramuscularly, with dose reductions for elderly, hepatic impairment, or renal dysfunction.
• Key adverse effects include anticholinergic symptoms and CNS depression; careful monitoring is required, especially in vulnerable populations.
• Drug interactions primarily involve CNS depressants and CYP3A4 modulators.
• Clinical applications span postoperative nausea, motion sickness, anxiety, and emergency antihistamine rescue.
• Familiarity with pharmacokinetic parameters (t_1/2, C_max, Cl, V_d) facilitates rational dosing and therapeutic drug monitoring.

References

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