Atarax 25mg

Descripción Del Producto

1. Classification and Chemical Overview

Atarax 25mg is a licensed branded and generic oral solid-dose pharmaceutical preparation containing hydroxyzine hydrochloride (originally developed by Union Chimique Belge [UCB] and distributed extensively across the United Kingdom and international jurisdictions). Chemically designated as $(\pm)\text{-2-(2-\{4-[(4-chlorophenyl)(phenyl)methyl]piperazin-1-yl\}ethoxy)ethan-1-ol dihydrochloride}$, hydroxyzine is a synthetic first-generation antihistamine belonging to the diphenylmethylpiperazine chemical subclass. Structurally, it consists of a central piperazine ring substituted at position 1 with a bulky, lipophilic diphenylmethyl (benzhydryl) moiety carrying a para-chloro substituent, and substituted at position 4 with a 2-(2-hydroxyethoxy)ethyl side chain. This amphiphilic molecular configuration confers lipophilicity sufficient to traverse the blood-brain barrier readily, while its terminal primary alcohol group serves as the metabolic substrate for enzymatic oxidation into its major active, peripherally restricted metabolite, cetirizine. Its empirical formula as a dihydrochloride salt is $\text{C}_{21}\text{H}_{27}\text{ClN}_2\text{O}_2\cdot 2\text{HCl}$, yielding an average molecular weight of $447.83\text{ g/mol}$ (hydroxyzine free base: $374.90\text{ g/mol}$).

Standard solid oral presentations of Atarax 25mg in the United Kingdom appear as round, biconvex, white film-coated tablets featuring a central score line on one face to permit division into equal halves ($12.5\text{ mg}$) for dose titration. Non-active pharmaceutical excipients within the tablet core typically include lactose monohydrate, microcrystalline cellulose, colloidal anhydrous silica, magnesium stearate, and a film-coating matrix comprising hypromellose (E464), macrogol 400, and titanium dioxide (E171).

Within the United Kingdom regulatory framework:

• Medicinal Classification: Categorized as a Prescription Only Medicine (POM) governed by the Human Medicines Regulations 2012.

• Controlled Drug Scheduling: Hydroxyzine is not a controlled substance under the Misuse of Drugs Act 1971 or the Misuse of Drugs Regulations 2001.

• NHS Formulary Positioning: Catalogued in the British National Formulary (BNF) and listed on the NHS Drug Tariff, reimbursable via standard NHS prescription forms (FP10) across primary and secondary care.

• MHRA Drug Safety Alerts and Dose Capping: Following a major European Medicines Agency (EMA) safety review concluded in 2015, the Medicines and Healthcare products Regulatory Agency (MHRA) issued definitive safety directives restricting hydroxyzine dosing. Due to concentration-dependent blockade of cardiac potassium channels and the associated risk of QT-interval prolongation and ventricular dysrhythmias, the maximum adult daily dose is strictly capped at $100\text{ mg/day}$ (and capped at $50\text{ mg/day}$ in the elderly).

In clinical toxicology and community addiction medicine, Atarax 25mg carries recognized diversion liabilities. While it possesses minimal direct recreational value when ingested alone, it is frequently diverted and misused as a potentiating agent:

• Co-administered with weak opioids (e.g., codeine, dihydrocodeine) or strong opioids (e.g., methadone, oxycodone) to amplify central somnolence and euphoric sedation while suppressing opioid-mediated histaminergic pruritus and nausea.

• Diverted as an alternative sedating antihistamine in “lean” / “purple drank” concoctions when promethazine is unavailable.

• Sourced from unregulated online pharmacies or grey-market channels without prior cardiac screening or baseline ECG risk assessment.

2. Mechanism of Action and Pharmacodynamics

The pharmacodynamic profile of hydroxyzine is characterized by potent inverse agonism at histamine $H_1$ receptors, balanced by selective central serotonergic antagonism and low-to-moderate affinity for muscarinic, dopaminergic, and adrenergic receptors:

• Histamine $H_1$ Receptor Inverse Agonism:

  • Hydroxyzine acts as a high-affinity, competitive inverse agonist at human peripheral and central histamine $H_1$ receptors ($K_i \approx 2\text{ nM}$).

  • Peripheral Activity: In cutaneous and bronchial tissues, it prevents histamine-mediated endothelial nitric oxide release, blunting post-capillary venule permeability, suppressing axon-reflex flare, and eliminating histamine-induced wheal formation and pruritus.

  • Central Sedative and Anti-Anxiety Actions: Because of its lipophilicity, hydroxyzine crosses the blood-brain barrier to occupy $H_1$ receptors on postsynaptic neurons across the tuberomammillary nucleus, ascending reticular activating system, and cerebral cortex. By blocking physiological histaminergic arousal signaling, it produces dose-dependent somnolence, muscle relaxation, and sedation.

• Serotonin 5-$\text{HT}_{2\text{A}}$ Receptor Antagonism:

  • Unlike most other classical first-generation antihistamines (such as diphenhydramine or chlorphenamine), hydroxyzine displays meaningful affinity as an antagonist at the human serotonin $5\text{-HT}_{2\text{A}}$ receptor ($K_i \approx 50\text{ to }100\text{ nM}$).

  • This antagonism modulates downstream cortico-limbic serotonergic signaling, providing a distinct, non-benzodiazepine anxiolytic effect without directly stimulating the $\text{GABA}_A$ receptor complex.

• Ancillary Receptor Interactions:

  • Muscarinic Acetylcholine Receptors: Exhibits weak antimuscarinic (anticholinergic) properties ($K_i \approx 100\text{ to }1,000\text{ nM}$). While dry mouth occurs clinically, severe anticholinergic delirium and urinary retention are substantially less pronounced than with ethanolamines (diphenhydramine) or phenothiazines (promethazine).

  • $\alpha_1$-Adrenoceptors and Dopamine $D_2$ Receptors: Displays low-to-negligible affinity for $\alpha_1$-adrenergic and $D_2$ dopamine receptors at therapeutic doses, minimizing extrapyramidal symptoms or profound orthostatic hypotension.

• Cardiac Electrophysiological Modulation (hERG Channel Blockade):

  • Hydroxyzine and its primary active metabolite cetirizine interact with cardiac ion channels; however, hydroxyzine itself is a potent blocker of the human Ether-à-go-go-Related Gene (hERG / $K_v11.1$) voltage-gated potassium channel.

  • Suppression of the rapid delayed rectifier potassium current ($I_{Kr}$) delays myocardial ventricular repolarization, causing concentration-dependent prolongation of the QT/QTc interval and predisposing vulnerable individuals to torsades de pointes (TdP).

3. Approved UK Clinical Indications and Therapeutic Scope

Hydroxyzine hydrochloride 25mg holds specific, licensed indications within the British National Formulary (BNF) and National Institute for Health and Care Excellence (NICE) guidelines:

• Pruritus Associated with Urticaria and Dermatological Conditions (Licensed UK Indication):

  • Indicated for the symptomatic relief of acute or chronic pruritus in conditions such as chronic idiopathic urticaria, atopic eczema, contact dermatitis, and pruritic dermatoses.

  • Adult Dosing: Initially $25\text{ mg}$ at bedtime, titrating if necessary up to $25\text{ mg}$ three to four times daily (maximum daily ceiling: $100\text{ mg/day}$).

  • Elderly Dosing: Capped strictly at a maximum of $50\text{ mg/day}$ (starting at $12.5\text{ to }25\text{ mg/day}$), due to prolonged drug clearance and elevated susceptibility to cardiac conduction delays.

• Anxiety in Adults (Licensed UK Indication):

  • Indicated for the short-term symptomatic treatment of acute anxiety states in adults aged 18 years and older (e.g., situational anxiety, generalized anxiety flares, or pre-operative tension).

  • Adult Dosing: $50\text{ to }100\text{ mg/day}$ administered in divided doses (e.g., $25\text{ mg}$ twice daily or $25\text{ mg}$ in the morning and $50\text{ mg}$ at bedtime).

  • Duration Restrictions: Clinical prescribing standards mandate that therapy should be limited to the shortest possible duration (ideally not exceeding a few weeks) to avoid progressive tolerance to sedative actions and reduce cumulative cardiac exposure.

• NICE Guidance Positioning:

  • Under NICE Guideline CG113 (Generalized anxiety disorder), hydroxyzine is not recommended as a first-line therapy for the routine long-term maintenance of generalized anxiety disorder. Gold-standard pharmacological management remains selective serotonin reuptake inhibitors (SSRIs) and serotonin-noradrenaline reuptake inhibitors (SNRIs), paired with Cognitive Behavioural Therapy (CBT).

  • Hydroxyzine is positioned as a non-addictive, second- or third-line bridging agent for short-term anxiolysis, particularly in patients with a history of substance use disorder where benzodiazepine scheduling is strictly contraindicated.

• Premedication in Surgical and Anaesthetic Practice:

  • Administered as an oral pre-medication ($50\text{ to }100\text{ mg}$) 1 to 2 hours prior to surgical procedures to secure preoperative anxiolysis, reduce procedural emesis, and provide mild antihistaminic sedation.

In non-medical, recreational, or unauthorized settings:

• Misused at supratherapeutic doses ($150\text{ to }300+\text{ mg}$) for sedative detachment.

• Combined with alcohol or benzodiazepines to amplify sedation.

• Co-ingested with prescription or illicit opioids to augment peak “nodding” euphoric sedation while suppressing histamine-induced flushing and nausea.

4. Pharmacokinetic Profile and Metabolic Fate

The pharmacokinetic profile of Atarax 25mg is defined by rapid oral absorption, extensive tissue distribution, hepatic oxidation via alcohol dehydrogenase and CYP pathways, and active metabolite generation:

Hepatic Biotransformation and the Cetirizine Paradigm

1. Carboxylic Acid Oxidation (The Dominant Pathway): The primary biotransformation route of hydroxyzine does not involve cytochrome P450 enzymes. Instead, cytosolic alcohol dehydrogenases y aldehyde dehydrogenases oxidize the terminal primary alcohol of the ethoxyethoxyethanol chain, generating the active carboxylic acid metabolite cetirizine (accounting for $\sim 50\text{ to }60\%$ of total metabolic disposition).

   • Pharmacodynamic Shift: Cetirizine is a zwitterion with low lipophilicity that poorly penetrates the blood-brain barrier. While parent hydroxyzine drives central anxiolysis, sedation, and cardiac hERG channel blockade, circulating cetirizine provides extended, non-sedating peripheral antihistaminic actions.

2. Minor Cytochrome Pathways: Secondary Phase I routes catalyzed by CYP3A4 y CYP3A5 mediate $N$-dealkylation, generating $N$-dealkylated metabolites (e.g., $p$-chlorobenzhydrylpiperazine), while CYP2D6 contributes to minor phenolic ring hydroxylation.

3. Hepatic and Renal Clearance Alterations:

   • In patients with hepatic impairment (cirrhosis), the elimination half-life of parent hydroxyzine is prolonged up to $30\text{ to }40\text{ hours}$, and systemic exposure ($AUC$) increases up to 3-fold.

   • In moderate-to-severe renal impairment (eGFR $<50\text{ mL/min/1.73 m}^2$), the clearance of active cetirizine is blunted, leading to secondary accumulation.

5. Physiological Effects and Adverse Event Spectrum

Therapeutic administration stabilizes mast cells, alleviates pruritus, and dampens autonomic and psychomotor anxiety. However, central nervous system depression and cardiac electrophysiological interference generate a distinct adverse event profile:

• Central Nervous System and Neuropsychiatric Toxicity (Very Common, $\ge 1/10$):

  • Daytime Somnolence and Sedation: The most prevalent adverse effect, observed in up to $40\%$ of patients upon initiation. Often exhibits partial tolerance after several days of continuous therapy.

  • Fatigue, asthenia, dizziness, and cognitive clouding (impaired attention, slowed mental processing speed).

  • Paradoxical Central Excitation: Restlessness, psychomotor agitation, insomnia, tremors, and hallucinations (disproportionately documented in pediatric poisoning or elderly populations).

  • Anterograde psychomotor impairment: Delayed reaction times, incoordination, and elevated risk of mechanical falls in elderly individuals.

• Anticholinergic and Autonomic Manifestations (Common, $1/100$ to $<1/10$):

  • Xerostomia (dry mouth; very common), thickening of bronchial secretions, and nasal dryness.

  • Blurred vision secondary to cycloplegia (loss of accommodation).

  • Constipation, epigastric discomfort, and nausea.

  • Urinary hesitation and acute urinary retention (specifically in patients with baseline bladder-outflow compromise).

• Severe, Emergent and Life-Threatening Hazards (Critical Safety Alerts):

  • Cardiac Conduction Delays and Lethal Ventricular Dysrhythmias:

    • hERG Blockade and QTc Prolongation: Hydroxyzine causes concentration-dependent prolongation of the ventricular repolarization phase (QTc interval).

    • Torsades de Pointes (TdP): In patients receiving supratherapeutic doses, or in those with pre-existing risk factors (hypokalaemia, congenital long QT syndrome, co-prescribed QTc-prolonging drugs), prolonged repolarization can degenerate into polymorphic ventricular tachycardia (Torsades de Pointes), leading to syncope, ventricular fibrillation, and sudden cardiac arrest.

  • Synergistic Depressant Poisoning and Central Apnea: Co-ingestion of hydroxyzine with alcohol, opioids, or benzodiazepines produces marked synergistic central nervous system depression. Hydroxyzine blunts compensatory arousal mechanisms; when paired with opioids, it magnifies medullary ventilatory drive failure, precipitating coma, severe hypoxemia, and fatal asphyxiation.

  • Severe Cutaneous Adverse Reactions (SCARs): Acute Generalized Exanthematous Pustulosis (AGEP)—characterized by the rapid eruption of numerous sterile non-follicular pustules over an erythematous base accompanied by pyrexia—is a recognized, life-threatening class effect of hydroxyzine requiring immediate drug withdrawal. Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) occur rarely.

  • Convulsive Seizures: In massive overdose ($>500\text{ mg}$), severe $H_1$ antagonism combined with metabolic shifts can lower the cortical seizure threshold, triggering generalized tonic-clonic convulsions.

6. Contraindications, Drug Interactions, and Clinical Precautions

Prescribing, administering, or toxicologically evaluating Atarax 25mg mandates strict adherence to MHRA cardiovascular safety restrictions, renal and hepatic dose adjustments, and metabolic interaction screening:

• Contraindications:

  • Known Acquired or Congenital Long QT Syndrome: Absolute Contraindication. Any pre-existing baseline QTc prolongation (males $>450\text{ ms}$, females $>470\text{ ms}$) or family history of sudden cardiac death.

  • High-Risk Cardiovascular Conditions: Absolute contraindication in patients with significant bradycardia ($<50\text{ bpm}$), severe uncompensated heart failure, recent myocardial infarction, or severe uncorrected electrolyte disturbances (hypokalaemia, hypomagnesaemia).

  • Concurrent QTc-Prolonging Medications: Co-administration with other drugs known to prolong the QT interval (e.g., amiodarone, sotalol, quinidine, erythromycin, clarithromycin, ciprofloxacin, haloperidol, quetiapine, citalopram, escitalopram, methadone) is strictly contraindicated.

  • Closed-Angle Glaucoma: Absolute contraindication; antimuscarinic-induced pupillary dilation can precipitate acute pupillary block and sudden, blinding elevations in intraocular pressure.

  • Bladder Outflow Obstruction: Contraindicated in severe prostatic hyperplasia or bladder neck stenosis due to the risk of precipitating acute urinary retention.

  • Porphyria: Contraindicated; hydroxyzine is considered porphyrinogenic in acute hepatic porphyrias.

  • Pregnancy and Breastfeeding: Contraindicated during pregnancy (teratogenic risk signals in animal models; crosses the placenta, causing neonatal hypotonia, tremor, and withdrawal-like CNS symptoms); strictly contraindicated during lactation (active drug distributes into maternal breast milk, presenting severe risks of infant apnea and somnolence).

  • Hypersensitivity: Hypersensitivity to hydroxyzine, cetirizine, levocetirizine, other piperazine derivatives (e.g., cyclizine), or formulation excipients.

• Drug Interactions:

  • QTc-Prolonging Drugs (Highest-Tier Pharmacodynamic Hazard): Concurrent prescription with Class IA / III antiarrhythmics, antipsychotics, fluoroquinolones, macrolides, or methadone exponentially elevates the hazard of fatal Torsades de Pointes.

  • Central Nervous System Depressants (Alcohol, Benzodiazepines, Z-drugs, Barbiturates): Produces marked, additive psychomotor impairment, severe somnolence, and blunted cognitive processing.

  • Opioid Analgesics (e.g., Morphine, Oxycodone, Dihydrocodeine, Fentanyl): Marked synergistic sedation and respiratory depression. While occasionally co-prescribed in palliative care, combination use requires dose reductions and close monitoring.

  • Cytochrome P450 Inhibitors (e.g., Ketoconazole, Itraconazole, Fluconazole, Cimetidine): Inhibiting CYP3A4-mediated minor pathways increases circulating parent hydroxyzine levels, heightening cardiac dysrhythmia risks.

  • Anticholinergic Agents (e.g., TCAs, Atropine, Oxybutynin): Additive antimuscarinic toxicity, increasing the incidence of severe constipation, paralytic ileus, hyperthermia, and acute urinary retention.

• Clinical Precautions and Emergency Overdose Management (“Red Flags”):

  • MHRA Dose Capping Protocol:

    • Adult maximum: $100\text{ mg in 24 hours}$.

    • Elderly maximum: $50\text{ mg in 24 hours}$.

    • Hepatic or renal impairment: Dose must be reduced by $50\%$ ($12.5\text{ to }25\text{ mg}$ daily).

  • Acute Overdose Resuscitation Protocol: Patients presenting following significant hydroxyzine overdose ($>200\text{ to }500+\text{ mg}$) exhibit severe somnolence, tachycardia, hypotension, dilated pupils, tremor, seizures, and QTc prolongation:

    • Airway and Oxygenation: Prioritize airway patency, position in the recovery position, administer supplemental oxygen, and provide bag-valve-mask or mechanical ventilation if central hypoventilation or profound coma supervenes.

    • Continuous ECG Telemetry: Continuous 12-lead ECG monitoring is mandatory for a minimum of 12 to 24 hours. The primary concern is QTc prolongation and the precipitation of Torsades de Pointes (TdP).

    • Management of Torsades de Pointes (TdP): If ventricular dysrhythmias or TdP emerge, administer intravenous magnesium sulphate ($2\text{ g}$ IV over 10 to 15 minutes, repeatable). Overdrive pacing or isoprenaline infusions should be considered for refractory bradycardia-dependent TdP. Unsynchronized electrical defibrillation is required for sustained, pulseless ventricular tachycardia.

    • Seizure Control: Terminate generalized convulsions immediately using intravenous benzodiazepines (e.g., IV diazepam $10\text{ mg}$ or lorazepam $2\text{ to }4\text{ mg}$).

    • Hemodialysis Ineffectiveness: Due to hydroxyzine’s massive volume of distribution ($>16\text{ L/kg}$) and high plasma protein binding, hemodialysis, hemoperfusion, and forced diuresis are completely ineffective for accelerating drug elimination.

  • Driving and Operating Machinery: Hydroxyzine impairs mental alertness and reaction speed. In accordance with the Road Traffic Act 1988, patients must be warned against driving or operating machinery until they are certain the medication does not impair their psychomotor function.

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