Promethazine

Promethazine can be synthesized through several methods. One common synthetic route involves the reaction of diethylamine with epoxypropane to obtain 1-diethylamino-2-propanol. This intermediate is then reacted with thionyl chloride and toluene to produce 1-diethylamino-2-chloropropane. Finally, 1-diethylamino-2-chloropropane is reacted with phenothiazine to yield crude this compound, which is purified and salified with hydrochloric acid to obtain this compound hydrochloride .

Industrial production methods often involve crystallization and salification processes to achieve high purity and yield. For example, this compound base can be prepared and then converted to this compound hydrochloride by crystallization using dry hydrogen chloride gas .

General Reactivity

Promethazine can neutralize acids in exothermic reactions, leading to the formation of salts and water . It may be incompatible with various compounds such as isocyanates, halogenated organics, peroxides, phenols (acidic), epoxides, anhydrides, and acid halides .

Reactions with Acids and Bases

This compound can react with acids to form salts . this compound hydrochloride, a common salt form, is produced by the reaction of this compound with hydrochloric acid . This salt is water-soluble and is used in many pharmaceutical formulations .

Incompatibility with Absorbents

Certain mineral-based and clay-based absorbents may react with this compound, indicating a need for caution when handling spills or disposing of the chemical .

Degradation

This compound is sensitive to light and can degrade in aqueous solutions when exposed to heat and light, especially in the presence of air or oxygen . The degradation is accelerated by iron(III) and copper(III) ions .

Reactions with Strong Reducing Agents

When combined with strong reducing agents like hydrides, this compound can generate flammable or toxic gases .

Oxidation

This compound slowly oxidizes when exposed to air, which can cause it to turn blue . This oxidation can affect the stability and efficacy of this compound in pharmaceutical preparations .

Drug Interactions

This compound can interact with other drugs, potentially leading to adverse effects. For example, it may interact negatively with Midodrine, a medication used to control severe motion sickness . Excessive this compound relative to a narcotic may lead to restlessness and motor hyperactivity in patients experiencing pain .

Thermal Decomposition

When heated to decomposition, this compound hydrochloride emits toxic fumes, including hydrochloric acid, sulfur oxides, and nitrogen oxides .

Metabolism

This compound is predominantly metabolized to this compound sulfoxide, with minor metabolites including desmethylthis compound and a hydroxy metabolite . Hydroxylation of this compound is mainly mediated by the CYP2D6 enzyme .

Adverse Reactions and Overdose

Overdoses of this compound can result in central nervous system and cardiovascular depression, hypotension, and respiratory depression . Other symptoms include unconsciousness, hyperreflexia, and gastrointestinal issues . Treatment typically involves symptomatic and supportive measures, such as administering activated charcoal and maintaining controlled ventilation . Some reports have associated the use of this compound with hallucinations .

Contraindications

This compound is contraindicated for use in treating lower respiratory tract symptoms and in individuals with a known hypersensitivity or idiosyncratic reaction to this compound or other phenothiazines .

Pharmacological Profile

Promethazine acts primarily as an antagonist at the H1 receptor, providing antihistaminic effects. It also exhibits moderate anticholinergic properties and has been shown to block sodium channels, contributing to its local anesthetic effects. The compound's mechanism of action includes inhibition of various neurotransmitter receptors, which underlies its diverse therapeutic applications.

Clinical Applications

• Allergic Conditions
  • Indications : Seasonal allergic rhinitis, allergic conjunctivitis, urticaria, and angioedema.
  • Mechanism : By blocking H1 receptors, this compound alleviates symptoms such as itching and inflammation.
• Nausea and Vomiting
  • Indications : Used as an antiemetic for nausea associated with chemotherapy, anesthesia, and postoperative care.
  • Efficacy : Studies show that this compound effectively reduces nausea severity when administered before triggering events .
• Motion Sickness
  • Indications : Prophylactic treatment for motion sickness.
  • Administration : Most effective when taken 30 minutes to 1 hour prior to travel .
• Sedation
  • Indications : Used in preoperative settings to induce sedation.
  • Considerations : Dosing must be carefully managed due to potential side effects like respiratory depression .
• Cough Relief
  • Formulations : Often combined with codeine in cough syrups for symptomatic relief of upper respiratory conditions.
  • Cautions : Use in pediatric populations is controversial due to safety concerns .

Table 1: Summary of Clinical Applications of this compound

Case Study 1: Efficacy in Chemotherapy-Induced Nausea

A clinical trial involving 200 patients undergoing chemotherapy demonstrated that those receiving this compound reported a 40% reduction in nausea compared to a placebo group. The study highlighted the drug's effectiveness as an antiemetic when administered before chemotherapy sessions .

Case Study 2: Pediatric Use and Safety Concerns

A retrospective analysis of pediatric emergency visits revealed that this compound was implicated in several adverse events, including respiratory depression in children under two years old. This prompted further investigation into its safety profile in younger populations .

Promethazine exerts its effects by antagonizing multiple receptors, including histamine H1, post-synaptic mesolimbic dopamine, alpha-adrenergic, muscarinic, and NMDA receptors . Its antihistamine action is primarily responsible for treating allergic reactions, while antagonism of muscarinic and NMDA receptors contributes to its sedative and antiemetic effects .

Structural and Functional Comparisons with Phenothiazines

Structural Modifications and Therapeutic Divergence

Promethazine shares the phenothiazine core with compounds like chlorpromazine (antipsychotic) and thioridazine (antipsychotic/antitubercular). Key structural differences include:

• This compound: Aliphatic dimethylaminoisopropyl side chain, favoring H1 receptor antagonism .
• Chlorpromazine : Piperazine side chain, enhancing dopamine D2 receptor affinity for antipsychotic effects .
• Thioridazine : Piperidine side chain with sulfur substitution, enabling antitubercular activity .

Table 1: Structural and Functional Differences Among Phenothiazines

Pharmacodynamic Comparisons with Antihistamines

Efficacy in Allergic Responses

• Wheal Inhibition : In a double-blind study, this compound showed 52% wheal inhibition at 4 hours, compared to 80% for fexofenadine and 99% for olopatadine. Olopatadine’s longer duration (8 hours) and higher efficacy highlight its superiority for acute allergies .
• Sedation : this compound caused significant sedation (vs. placebo and fexofenadine) at 3–7 hours post-dose, limiting its use in alertness-critical settings .

Table 2: Antihistamine Efficacy and Side Effects

Enzyme Inhibition Profile

This compound and diphenhydramine preferentially inhibit pseudocholinesterase, contributing to antimuscarinic effects. This contrasts with newer antihistamines (e.g., loratadine) lacking significant enzyme interaction .

Therapeutic Efficacy in Clinical Settings

Vertigo Management

• This compound vs. Betahistine : In a randomized trial, betahistine reduced vertigo symptoms faster (2–3 hours vs. 4 hours for this compound) with fewer side effects .

Sedation in Medical Procedures

• Dental Sedation : Midazolam outperformed this compound in efficacy, but this compound showed comparable safety in cross-over trials .
• Pediatric Sedation : Combining this compound with chloral hydrate reduced vomiting (14% vs. 48% with chloral hydrate alone) but increased sedation .

Antifungal Activity

This compound exhibits in vitro antifungal effects against Candida tropicalis biofilms, a unique property absent in most antihistamines. Further studies are needed to validate clinical relevance .

Promethazine is a phenothiazine derivative primarily recognized for its antihistaminic properties, but it also exhibits a range of biological activities that make it a subject of extensive research. This article explores the diverse biological activities of this compound, including its mechanisms of action, therapeutic applications, and potential for repurposing in various medical conditions.

This compound functions as an antagonist at several receptor sites, including:

• Histamine H1 Receptors : Its primary action as an antihistamine helps alleviate allergic reactions and symptoms of motion sickness.
• Dopamine Receptors : It acts on mesolimbic dopamine receptors, contributing to its antiemetic effects.
• Muscarinic and NMDA Receptors : These actions enhance its sedative properties and may play a role in reducing anxiety and tension.

This compound's complex pharmacological profile allows it to be effective in treating various conditions, including nausea, vomiting, and sedation .

Antimicrobial and Antiparasitic Properties

Recent studies have highlighted this compound's potential beyond traditional antihistaminic use:

• Antifungal Activity : this compound has shown effectiveness against Candida tropicalis, inhibiting biofilm formation and reducing the minimum inhibitory concentration (MIC) for azole antifungals. It was found to decrease cell size and membrane integrity in fungal cells, indicating cytotoxic effects .
• Antiparasitic Effects : In vitro studies demonstrated that this compound affects the motility and viability of schistosomes, causing significant tegumental damage. The compound exhibited a 50% lethal concentration (LC50) indicating its potential use in treating parasitic infections .

Biofilm Inhibition

This compound has been investigated for its ability to inhibit biofilm formation in various pathogens:

• A study on Burkholderia thailandensis revealed that this compound significantly reduced biofilm biomass and lipase activity in a concentration-dependent manner. This suggests a potential role in combating infections associated with biofilms .

Clinical Applications

This compound is widely used in clinical settings for several indications:

• Nausea and Vomiting : Its efficacy in managing nausea related to surgery or chemotherapy is well-documented. A study indicated that the combination of this compound with opioids resulted in a significant reduction in opioid usage post-surgery .
• Sedation : Due to its sedative properties, this compound is often used preoperatively to calm patients.
• Chronic Pain Management : Research has shown that this compound is frequently detected in urine samples of chronic pain patients, indicating its use as an adjunctive therapy in pain management .

Case Studies and Research Findings

• Case Study on Overdose Effects : A study examined the clinical effects of this compound overdose, highlighting symptoms such as CNS depression and delirium. This underscores the importance of monitoring dosages carefully due to potential severe side effects .
• Repurposing for Melioidosis : Research into melioidosis treatment indicated that this compound could be repurposed to inhibit biofilm formation in Burkholderia pseudomallei, demonstrating its versatility as an antimicrobial agent .

Summary Table of Biological Activities

Basic Research Questions

Q. What are the critical safety protocols for handling promethazine in laboratory settings?

this compound requires strict exposure controls due to its acute toxicity (oral, dermal, and inhalation hazards). Key measures include:

• Ventilation : Use fume hoods or local exhaust systems to minimize inhalation risks .
• Personal Protective Equipment (PPE) : Wear impermeable gloves (tested for chemical compatibility), eye protection, and lab coats. Respiratory protection (e.g., FFP3 masks) is required for prolonged exposure .
• Storage : Keep containers tightly sealed in dry, well-ventilated areas away from food/feed .
• Waste disposal : Follow institutional guidelines for hazardous waste, as this compound is classified under GHS Category 4 toxicity .

Q. How should researchers design experiments to evaluate this compound’s sedative or antihistaminergic effects in preclinical models?

• Model selection : Rodents (e.g., mice) are commonly used for sedation studies. For example, the tail-flick test or rotarod assay can quantify sedation duration .
• Dosage optimization : Reference prior studies (e.g., 6.25–12.5 mg/kg in rats for teratogenicity assessments) .
• Controls : Include vehicle controls and active comparators (e.g., diphenhydramine) to isolate this compound-specific effects .
• Data collection : Monitor vital signs (respiration rate, locomotor activity) and use blinded scoring to reduce bias .

Advanced Research Questions

Q. What methodologies are recommended for optimizing this compound synthesis to improve yield and purity?

• Reagent selection : Use high-purity starting materials (e.g., phenothiazine derivatives) and catalysts (e.g., HCl for hydrochloride salt formation) .
• Process optimization : Employ factorial design (e.g., 2³ factorial experiments) to test variables like temperature, reaction time, and solvent ratios (see Table 1 in for formulation examples) .
• Analytical validation : Confirm purity via HPLC (≥98%) and characterize intermediates using NMR/FTIR .

Q. How can researchers resolve contradictions in clinical trial data on this compound’s efficacy for anaphylaxis prophylaxis?

• Case study : A double-blind RCT found this compound ineffective against early anaphylactic reactions in Bothrops envenomation (22 untied pairs, p > 0.05) .
• Contradiction analysis :

• Receptor specificity : this compound blocks H1 but not H2 receptors, which may limit its efficacy in systemic anaphylaxis .
• Timing and dosage : Ensure plasma concentrations peak before antigen exposure (e.g., administer 15–20 minutes prior) .
• Alternative hypotheses : Test combinations with H2 antagonists (e.g., ranitidine) to address receptor coverage gaps .

Q. What advanced analytical techniques are suitable for detecting this compound in biological matrices?

• Surface-enhanced Raman spectroscopy (SERS) : Offers high sensitivity (nanomolar detection limits) for this compound in bodily fluids. Use gold/silver nanoparticle substrates to enhance signal .
• LC-MS/MS : Validate methods with deuterated internal standards (e.g., this compound-d6) to correct for matrix effects .
• Quality control : Include calibration curves (1–100 ng/mL) and spike-recovery tests (≥85%) to ensure reproducibility .

Q. How do pharmacological interactions between this compound and CNS depressants influence experimental outcomes?

• Mechanistic studies : this compound potentiates GABAergic agents (e.g., sodium oxybate) by enhancing sedation in mice (e.g., 50% reduction in wakefulness at 10 mg/kg) .
• Dose-response curves : Co-administer this compound with opioids (e.g., codeine) to quantify synergistic respiratory depression using plethysmography .
• Statistical modeling : Apply isobolographic analysis to distinguish additive vs. synergistic effects .

Q. Methodological Best Practices

Q. How can researchers ensure reproducibility in this compound studies?

• Material documentation : Report CAS numbers (e.g., 60-87-7), purity grades, and suppliers (e.g., Key Organics, Cayman Chemical) .
• Protocol transparency : Share step-by-step methods (e.g., synthesis steps , animal dosing schedules ) in supplementary materials.
• Data archiving : Use repositories like Zenodo to deposit raw datasets (e.g., HPLC chromatograms, survival curves) .

Q. What strategies address discrepancies between preclinical and clinical pharmacokinetic data for this compound?

• Species-specific metabolism : Mice exhibit faster hepatic clearance than humans; use allometric scaling to adjust doses .
• In vitro-in vivo correlation (IVIVC) : Compare this compound’s plasma protein binding (80% in humans) with rodent models .
• Population PK modeling : Incorporate covariates (e.g., age, CYP2D6 polymorphism) to predict inter-individual variability .