Mexazolam
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Product Description
Mexazolam (C₁₈H₁₆Cl₂N₂O₂) is a long-acting oxazolobenzodiazepine pro-drug indicated for the short-term management of anxiety disorders with or without psychoneurotic features. Administered orally at 1–3 mg/day—preferably in three divided doses and at reduced strength in the elderly—it is metabolized mainly by hepatic CYP3A4 and CYP2C11 to active species that confer anxiolytic activity with comparatively modest sedation, ataxia or psychomotor impairment. Randomized, double-blind trials show efficacy equivalent to alprazolam in generalized anxiety disorder, while in-vitro studies identify it as a sensitive CYP3A4 probe substrate whose oxidation is selectively inhibited by lipophilic lactone statins, underscoring the need for cautious co-prescription with drugs that modulate this pathway.
Synthesis and Production
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Synthesis Method: Mexazolam is a synthetic compound. It is derived from oxazolam via chlorination. A key step in its synthesis is the formation of the oxazolidine ring from a 1,4-benzodiazepine-2-one precursor.
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Production Notes: The synthesis involves creating a fused oxazolo-benzodiazepine core structure. Kinetic studies on its analogues highlight the importance of the acid-base equilibrium and the conformational stability (cis/trans isomers) of the oxazolidine ring, which can influence the compound's properties.
Uses and Applications
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Primary Medical Use: Management of anxiety disorders, including those with or without psychoneurotic conditions. It is also used for anxiety associated with psychosomatic disorders.
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Other Applications:
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Treatment of insomnia and indefinite complaints related to anxiety.
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Alleviation of somatic anxiety symptoms such as asthenia, headache, irritability, restlessness, palpitations, and chest tightness.
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Therapeutic Role: Considered a second-line or short-term treatment option for anxiety, not a first-line long-term solution, to minimize risks like dependence. Clinical studies show it is more effective than bromazepam and oxazolam, and at least as effective as alprazolam.
Chemical and Physical Properties
1. Chemical Properties
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Molecular Formula: C₁₈H₁₆Cl₂N₂O₂
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IUPAC Name: 10-chloro-11b-(2-chlorophenyl)-3-methyl-2,3,5,7-tetrahydro-[1,3]oxazolo[3,2-d][1,4]benzodiazepin-6-one
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Molecular Weight: 363.2 g/mol
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CAS Number: 31868-18-5
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XLogP3: 3.7 (Indicates moderate lipophilicity)
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Hydrogen Bond Donor Count: 1
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Hydrogen Bond Acceptor Count: 3
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Rotatable Bond Count: 1
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Topological Polar Surface Area: 41.6 Ų
2. Pharmacological Properties
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Mechanism of Action: Binds to benzodiazepine receptors as a positive allosteric modulator of the GABA-A receptor. This enhances the effect of the inhibitory neurotransmitter GABA, leading to increased chloride ion influx, neuronal hyperpolarization, and central nervous system depression.
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Key Characteristic: It is a prodrug. The parent compound has weak activity and is rapidly metabolized into active metabolites.
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Active Metabolites: Chloronordiazepam (CND or Chlornordiazepam) and Chloroxazepam. These are responsible for its therapeutic effects.
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Pharmacodynamic Fingerprint: The active metabolite chlornordiazepam shows subunit selectivity for GABA-A receptors containing α2 and/or α3 subunits (associated with anxiolysis) over those containing α1 subunits (associated with sedation). This may explain its clinical profile of efficacy with fewer sedative effects compared to other benzodiazepines like alprazolam and bromazepam.
3. Pharmacokinetic Properties
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Absorption: After oral administration, the parent drug is not detected unaltered in blood. The active metabolite chloronordiazepam reaches peak concentration in 1-2 hours.
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Metabolism: Primarily metabolized in the liver via the CYP3A4 pathway. It undergoes two main metabolic pathways: a benzodiazepine-type pathway (producing active metabolites) and a benzophenone-type pathway (producing inactive metabolites).
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Distribution: Active metabolites are >90% protein-bound in plasma. Follows a two-compartment model.
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Half-Life: Biphasic elimination. The parent drug has a short half-life, but the active metabolites are long-acting.
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Initial half-life: ~1.4 hours
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Terminal half-life: ~76 hours
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Excretion: Mainly eliminated in the bile and feces. <10% is excreted as metabolites in the urine. Over 50% of a dose is eliminated as the metabolite chloroxazepam.
4. Physical Properties
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Experimental Property: The Kovats Retention Index (a measure used in gas chromatography) is 2670 under standard non-polar conditions.
Safety and Handling
1. Adverse Effects
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Common Side Effects: Drowsiness, sedation, dizziness, muscle weakness, ataxia (loss of coordination), headache, dry mouth, and fatigue.
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Less Common Effects: Paradoxical reactions (increased anxiety, agitation), amnesia, and dependence with long-term use.
2. Toxicity and Overdose
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Toxicity Summary: Benzodiazepines like mexazolam enhance GABAergic inhibition. Overdose primarily causes CNS depression (drowsiness, confusion, coma) and respiratory depression.
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Acute Effects: Symptoms are an extension of its pharmacological effects. Data on specific lethal doses (e.g., LD50) for mexazolam is not prominently detailed in the provided information.
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Treatment for Overdose:
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General Support: Employ supportive measures, maintain an airway, administer intravenous fluids, and use vasopressors like norepinephrine for hypotension.
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Antidote: Flumazenil is a competitive benzodiazepine receptor antagonist that can reverse CNS depression. Its use is controversial due to contraindications (e.g., in patients with long-term benzodiazepine use or seizure disorders).
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Decontamination: Gastric lavage or activated charcoal are not routinely recommended for pure benzodiazepine overdose but may be considered if other drugs are involved.
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3. Drug Interactions
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CYP3A4 Inhibitors: Metabolism is susceptible to inhibition by drugs that affect the CYP3A4 enzyme.
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HMG-CoA Reductase Inhibitors (Statins): The lactone forms (e.g., simvastatin, lovastatin) inhibit mexazolam's metabolism more strongly than the acid forms (e.g., pravastatin, atorvastatin). Pravastatin shows negligible inhibition.
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CNS Depressants: Concomitant use with alcohol, opioids, or other sedatives can lead to dangerous additive CNS depression.
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Protein Binding: High protein binding suggests a potential for interaction with other highly protein-bound drugs, though this is less common.
4. Warnings and Precautions
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Dependence and Withdrawal: Long-term use can lead to tolerance, physical dependence, and withdrawal symptoms (anxiety, insomnia, tremors, seizures) upon discontinuation. Treatment should be as short as possible.
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Elderly Patients: Increased risk of falls and cognitive impairment. A lower maximum daily dose (1.5 mg) is recommended.
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Contraindications: Not indicated for pediatric patients. Not recommended for breastfeeding mothers (excreted in milk). Safety in human pregnancy is not established.
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Tapering: Abrupt discontinuation should be avoided. A gradual taper is necessary after prolonged use.
5. Regulatory and Handling Information
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Controlled Substance: In many countries, including the United States, it is considered a Schedule IV controlled substance under analogue acts, indicating a potential for abuse and dependence.
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Carcinogenicity: Classified as "No indication of carcinogenicity to humans" by the IARC.