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Clotiazepam
Clotiazepam
Clotiazepam
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Clotiazepam
Clinical data
Trade namesVeratran, Rize, Clozan
AHFS/Drugs.comInternational Drug Names
Routes of
administration		Oral, sublingual, liquid drops
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability~90%
MetabolismHepatic
Elimination half-life4 hours[2]
ExcretionRenal
Identifiers
  • 5-(2-chlorophenyl)-7-ethyl-1-methyl-3H-thieno[2,3-e][1,4]diazepin-2-one
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.046.920 Edit this at Wikidata
Chemical and physical data
FormulaC16H15ClN2OS
Molar mass318.82 g·mol−1
3D model (JSmol)
  • ClC1=C(C2=NCC(N(C)C3=C2C=C(CC)S3)=O)C=CC=C1
  • InChI=1S/C16H15ClN2OS/c1-3-10-8-12-15(11-6-4-5-7-13(11)17)18-9-14(20)19(2)16(12)21-10/h4-8H,3,9H2,1-2H3 checkY
  • Key:CHBRHODLKOZEPZ-UHFFFAOYSA-N checkY
 ☒NcheckY (what is this?)  (verify)
Clotiazepam pills sold in France as Vératran

Clotiazepam[3] (marketed under brand name Clozan, Distensan, Trecalmo, Rize, Rizen and Veratran) is a thienodiazepine drug which is a benzodiazepine analog. The clotiazepam molecule differs from benzodiazepines in that the benzene ring has been replaced by a thiophene ring.[4] It possesses anxiolytic,[5] skeletal muscle relaxant,[6] anticonvulsant, sedative properties.[7] Stage 2 NREM sleep is significantly increased by clotiazepam.[8]

Indications

[edit]

Clotiazepam has been trialed and found to be effective in the short-term management of anxiety.[9] Clotiazepam is also used as a premedicant in minor surgery in France and Japan, where the drug is commercially available under the brand names Veratran and Rize, respectively.[10][11]

Pharmacokinetics

[edit]

A cross-over study in six healthy volunteers (median age 28 years) was conducted using single-dose pharmacokinetics of 5 mg clotiazepam drops, oral tablets, and sublingual tablets. The formulations had similar systemic availability. Compared with oral tablets, the sublingual route gave a lower peak concentration and a delayed peak time, while drops gave a greater maximum concentration with a similar peak time. The use of drops is suggested for a more marked initial effect and the sublingual route for easier administration, especially in the elderly.[12]

Pharmacology

[edit]

Similar to other benzodiazepines clotiazepam has anxiolytic, sedative, hypnotic, amnesic, anticonvulsant and muscle relaxant pharmacological properties.[7] Clotiazepam binds to the benzodiazepine site of the GABAA receptor where it acts as a full agonist; this action results in an enhanced GABA inhibitory effect at the GABAA receptor which results in the pharmacological effects of clotiazepam.[13]

Clotiazepam has a short elimination half-life and is less prone to accumulation after repeated dosing compared to longer-acting benzodiazepine agents. It is metabolised via oxidation.[14] Clotiazepam is metabolised to hydroxy-clotiazepam and desmethyl-clotiazepam. After oral ingestion of a single 5 mg dose of clotiazepam by three healthy volunteers the drug was rapidly absorbed.[15] The elimination half-life of the drug and its metabolites range from 6.5 hours to 18 hours. Clotiazepam is 99 percent bound to plasma protein.[15] In elderly men the elimination half-life is longer and in elderly women the volume of distribution is increased.[16] Individuals with liver impairment have a reduced volume of distribution as well as a reduced total clearance of clotiazepam; renal impairment does not affect the kinetics of clotiazepam.[17]

The dose equivalent to 10 mg diazepam is thought to be between 5 and 10 mg clotiazepam.

Side effects

[edit]

Side effects experienced with this product will resemble those of other benzodiazepines. Drowsiness and asthenia are common side effects.[18] There has been a report of reversible hepatitis caused by clotiazepam.[19]

Abuse

[edit]

Clotiazepam is a recognised drug of abuse.[20]

See also

[edit]

References

[edit]
[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Clotiazepam

View on Grokipedia
from Grokipedia
Clotiazepam is a derivative, chemically distinct from traditional benzodiazepines by incorporating a ring, with the molecular formula C16H15ClN2OS and a molecular weight of 318.8 g/mol. It functions as an , , , and skeletal muscle relaxant, primarily prescribed for the short-term management of anxiety disorders and associated symptoms such as tension and restlessness. Unlike many benzodiazepines, clotiazepam significantly increases stage 2 non-REM sleep without substantially disrupting deeper sleep stages, making it suitable for conditions involving sleep disturbances related to anxiety. Pharmacologically, clotiazepam exerts its effects by binding to the site on GABAA receptors in the , enhancing the inhibitory actions of gamma-aminobutyric acid (GABA) and thereby producing calming effects on neuronal activity. It is rapidly absorbed after , with peak plasma concentrations reached within 1-3 hours, a of 6 to 18 hours, and extensive hepatic followed by renal excretion. The drug is highly protein-bound (about 99%) and has been shown in clinical studies to effectively reduce peak anxiety levels and improve symptoms in patients with generalized anxiety. However, like other agents in its class, it carries risks of , dependence, and withdrawal, necessitating cautious use, particularly in elderly patients where may be altered or those with hepatic impairment. Developed by Mitsubishi Tanabe Pharma Corporation, clotiazepam was first approved in in 1988 and is approved for medical use in several countries, including the , , , and various European nations, but it is not approved by the FDA in the United States or . In , it is classified as a Schedule IV under the , indicating low potential for abuse relative to other drugs. Its varies internationally, with prescription-only requirements in places like (Anlage III for higher doses) and Class C classification in the UK. Clinical evidence also supports its off-label exploration in high doses for intractable auditory hallucinations in chronic , though this remains investigational.

Medical uses

Therapeutic indications

Clotiazepam is primarily indicated for the short-term treatment of anxiety disorders, where it serves as an agent to alleviate symptoms such as excessive worry, tension, and nervousness. It has demonstrated efficacy in managing through clinical trials evaluating its effects on anxiety symptoms in affected patients. It is also indicated for the short-term treatment of and sleep disturbances related to anxiety. In addition, it is used for adjustment disorders characterized by anxiety, particularly in response to stressful life events. As a secondary application, clotiazepam is employed as prior to minor surgical procedures to reduce preoperative anxiety and induce mild , with established use in countries including and where it holds regulatory approval. In , it is administered orally before bedtime or for this purpose, typically in doses of 10 to 15 mg. Studies have supported its role in short surgical , showing comparable effects to other benzodiazepines without excessive . Clotiazepam also finds occasional for muscle relaxation in conditions involving tension-related spasms, leveraging its relaxant properties, though this is not its primary therapeutic focus. Due to the risk of tolerance and dependence associated with benzodiazepines, treatment with clotiazepam is recommended for short-term durations, generally limited to 2-4 weeks, to optimize benefits while minimizing potential adverse outcomes.

Dosage and administration

Clotiazepam is available in several pharmaceutical forms to facilitate , including 5 mg and 10 mg tablets for standard , 5 mg sublingual tablets, and oral solution drops at a concentration where 20 drops are equivalent to 5 mg (approximately 5 mg/mL). The standard dosing regimen for anxiety consists of 5-15 mg per day, administered in divided doses to maintain therapeutic levels given the drug's relatively short elimination . For prior to , a single dose of 10-15 mg is typically given before bedtime or shortly before the procedure. Dosage adjustments are essential for specific populations to minimize risks. In elderly patients, lower initial doses such as 2.5-5 mg are recommended due to age-related changes in , with gradual to avoid excessive . Similarly, patients with hepatic impairment require reduced doses, as studies show decreased clearance and prolonged in , necessitating careful monitoring and starting at the lower end of the range (e.g., 2.5-5 mg). Administration guidelines emphasize route selection based on needs. Sublingual tablets are preferred for elderly individuals to simplify intake and achieve adequate onset without difficulties. Oral drops can provide a more rapid initial effect if quicker absorption is desired. Therapy should involve gradual tapering upon discontinuation to prevent withdrawal symptoms associated with benzodiazepines.

Pharmacology

Pharmacodynamics

Clotiazepam is a that functions as a positive at the GABA_A receptor, binding to the recognition site located at the interface between the α and γ subunits. This binding enhances the affinity of the receptor for the endogenous neurotransmitter γ-aminobutyric acid (), thereby increasing the frequency of opening and promoting chloride ion influx into the neuron. The resulting hyperpolarization inhibits neuronal excitability and reduces the probability of discharge, mediating the drug's overall inhibitory effects in the . As a full at the site on GABA_A receptors, clotiazepam exhibits non-selective binding across various receptor subtypes, potentiating GABA-mediated inhibition without intrinsic activity in the absence of GABA. This action distinguishes it from partial agonists, allowing for robust enhancement of inhibitory at therapeutic doses. The pharmacological profile of clotiazepam includes effects primarily through modulation of GABA_A receptors in the , where it dampens emotional processing and fear responses. and properties arise from actions on receptors in the and , promoting behavioral inhibition and suppressing propagation. effects are attributed to depression of activity via α2-containing GABA_A receptors. Clotiazepam specifically increases the duration of stage 2 non-REM sleep without altering total sleep time, contributing to its utility in managing associated with anxiety. Compared to other benzodiazepines, it demonstrates a low potential for inducing , correlating with reduced abuse liability as classified under DEA Schedule IV.

Pharmacokinetics

Clotiazepam is rapidly absorbed after oral administration, with peak plasma concentrations typically achieved within 1 to 3 hours. Oral, sublingual, and liquid drop formulations exhibit similar systemic , though sublingual tablets produce lower peak concentrations and a delayed time to peak compared to oral tablets, while drops yield higher peak concentrations with a comparable time to peak. This rapid absorption profile supports an within 30 to for oral doses. Following absorption, clotiazepam distributes widely in the body, with a of approximately 2.57 L/kg in healthy individuals. The drug is highly bound to plasma proteins, at about 99%. Clotiazepam undergoes hepatic metabolism primarily via enzymes, including , , CYP2C18, and , to form active metabolites such as hydroxy-clotiazepam and desmethyl-clotiazepam. Elimination of clotiazepam occurs mainly through renal of its metabolites, with the parent compound having an elimination in the range of 6 to 18 hours (reported values of 6.5, 7.0, and 17.8 hours in early studies); the half-lives of its metabolites are similar. This intermediate half-life may lead to some accumulation with repeated dosing. In special populations, pharmacokinetics vary: in elderly patients, increases (especially in women) and clearance may decrease (in men), resulting in higher exposure; in , clearance is reduced and decreased, prolonging effects and requiring dose adjustment.

Chemistry

Chemical structure

Clotiazepam is a derivative characterized by the replacement of the ring found in traditional benzodiazepines with a ring, resulting in the core structure of a fused thiophene-diazepinone system. Its systematic IUPAC name is 5-(2-chlorophenyl)-7-ethyl-1-methyl-3H-thieno[2,3-e][1,4]diazepin-2-one. The molecular formula of clotiazepam is C16H15ClN2OS, with a of 318.82 g/mol. Key structural features include an at the 7-position, a at the N1 position, and a 2-chlorophenyl at the C5 position. These elements are integral to the compound's potency, as the 2-chlorophenyl moiety enhances binding affinity to GABAA receptors similar to other analogs, while the alkyl substitutions at N1 and C7 modulate and duration of action. The ring itself contributes to potential , as it has been linked to idiosyncratic in clinical reports. Physically, clotiazepam appears as an off-white crystalline solid. It has a of 105–106 °C and exhibits low in (approximately 5.37 × 10−3 g/L) but good solubility in organic solvents such as , , , acetone, and (15 mg/mL in DMF and DMSO).

Synthesis

Clotiazepam is synthesized from the starting material 3-(2-chlorobenzoyl)-5-ethyl-2-aminothiophene through a two-step process involving ring formation of the diazepine moiety. In the first key step, the amino group of the derivative undergoes cyclocondensation with ethyl chloroacetate under basic conditions, typically in a such as or at moderate temperatures (around 50–80°C), to form the intermediate 2-(chloroacetamido)-3-(2-chlorobenzoyl)-5-ethyl. This intermediate is then reacted with , often in a like or at to slightly elevated temperatures (20–60°C), to displace the chloro group and facilitate intramolecular cyclization, yielding clotiazepam after purification. Laboratory-scale syntheses of this route generally achieve yields of 50–70%, depending on reaction optimization and purification methods such as or recrystallization. Alternative synthetic routes, including variations that employ glycine ethyl ester derivatives for the initial step or direct ring with preformed diazepine precursors, have been developed and patented by Mitsubishi Tanabe Pharma Corporation to improve scalability and efficiency for industrial production. These methods maintain similar overall yields but may reduce the number of steps or enhance in analog preparation.

Adverse effects

Common side effects

The most common side effects of clotiazepam, consistent with its benzodiazepine-like profile, include drowsiness, asthenia or , , and , which arise primarily from its enhancement of GABA-mediated inhibition in the . These effects are frequently reported in clinical use and may impair daily activities such as driving or operating machinery. Gastrointestinal disturbances, such as mild and dry mouth, occur less frequently but are noted in users of clotiazepam. These symptoms are typically transient and resolve with continued administration or dose adjustment. Cognitive effects, including and impaired concentration, can emerge particularly at higher doses, reflecting the drug's impact on processes. Such impairments are more likely during the initial treatment phase and may affect learning or tasks. Less frequent side effects may include vertigo, , , depression, slurred speech, changes in , , visual disturbances, or incontinence, and changes in salivation. The incidence of these side effects is dose-dependent, with higher doses increasing their likelihood and severity. They are also more pronounced in elderly patients due to age-related reductions in and heightened sensitivity to .

Serious adverse effects

Clotiazepam, like other benzodiazepines, can rarely cause , manifesting as reversible acute with hepatocellular . This idiosyncratic reaction has been documented in case reports, with onset typically occurring after several months of continuous use, such as 7 months in one instance. The condition generally resolves upon drug discontinuation. The ring in clotiazepam's structure is implicated in this hepatotoxic potential, distinguishing it from typical benzodiazepines with a ring. Respiratory depression represents another serious adverse effect of clotiazepam, particularly when administered in high doses or concurrently with other depressants such as opioids or alcohol. This can lead to , hypoxia, and in severe cases, , though it is uncommon at standard therapeutic doses. The risk is heightened in patients with preexisting respiratory conditions, and monitoring is essential to prevent life-threatening complications. Paradoxical reactions occur in less than 1% of individuals treated with benzodiazepines, including clotiazepam, and may include agitation, , , or increased anxiety instead of the expected . These responses are more frequent in elderly patients and children. Discontinuation of the drug usually alleviates these effects promptly. As with other benzodiazepines, extremely rare serious adverse effects may include blood dyscrasias, such as or , and severe allergic reactions like or Stevens-Johnson syndrome, though these have not been specifically documented for clotiazepam. These events necessitate immediate medical intervention if suspected.

Dependence and abuse

Potential for dependence

Clotiazepam, like other benzodiazepines, exhibits rapid development of tolerance to its effects, often within weeks of continuous use, necessitating dose escalation to maintain therapeutic efficacy. This differential tolerance profile arises from adaptive changes in the , particularly the downregulation of GABA_A receptors following chronic exposure, which reduces the drug's ability to enhance GABA-mediated inhibition. Chronic use of clotiazepam leads to physical and , primarily through neuroadaptive alterations that impair normal signaling. Upon abrupt discontinuation, withdrawal symptoms emerge, including anxiety, , tremors, and, in severe cases, seizures; these are typically managed through gradual dose tapering to minimize intensity. The drug's relatively short of approximately 6 to 18 hours, which may be prolonged in the elderly, can exacerbate the onset and severity of withdrawal due to rapid clearance from the body. Key risk factors for developing dependence on clotiazepam include long-term use exceeding four weeks, higher-than-recommended doses, and a personal history of , all of which accelerate tolerance and heighten vulnerability to withdrawal. These factors underscore the importance of short-term prescribing to mitigate dependence potential while preserving clinical benefits.

Abuse liability

Clotiazepam exhibits a low to moderate potential relative to other s, influenced by its short plasma of 6 to 18 hours and limited capacity to produce . As a member of the class, it carries a significant risk for misuse, though this is tempered by its pharmacological profile compared to agents like or that engender stronger reinforcing effects. Internationally, clotiazepam is recognized as a of abuse, reflected in its classification under Schedule IV of the , which denotes substances with low potential for abuse and dependence but still warranting control to prevent diversion. Misuse patterns typically involve diversion from legitimate prescriptions for of anxiety disorders or to potentiate the effects of other substances, such as alcohol or opioids, rather than pursuit of intense recreational highs. Intravenous administration is rare, unlike with select benzodiazepines favored for injection due to , and occurs primarily in polydrug contexts among individuals with histories of substance use disorders. Non-therapeutic use heightens the risk of accidents attributable to profound and impaired psychomotor function, particularly in activities requiring like . It also contributes to polydrug overdoses by exacerbating when combined with other depressants, though fatalities from clotiazepam alone are uncommon. To monitor illicit trade and prevent widespread diversion, clotiazepam is tracked through international psychotropic schedules maintained by the , facilitating global reporting and regulatory oversight.

History

Development

Clotiazepam was developed by Tanabe Seiyaku Co., Ltd. (now part of Mitsubishi Tanabe Pharma Corporation) in during the early 1970s as a analog within the class. This effort focused on replacing the benzene ring of traditional with a ring to create novel compounds with potential therapeutic applications as minor tranquilizers. The rationale for its development stemmed from the need to explore structural modifications that could enhance pharmacological properties, including , , and effects, while maintaining low toxicity. Preclinical studies demonstrated that clotiazepam potentiates narcosis, suppresses aggressive behaviors in animal models, and exhibits activity, confirming its interaction with the GABA_A receptor as a positive that enhances GABA-mediated inhibition. Key milestones included the initial synthesis of the core thieno[2,3-e][1,4]diazepin-2-one structure around 1970, with a priority filing date of , 1970, in , followed by a U.S. on , 1971. These developments positioned clotiazepam as a promising agent for treating , anxiety, tension, and related conditions through targeted modulation of inhibition.

Clinical introduction

Clotiazepam, a derivative, was first approved for medical use in in 1988 by Tanabe Seiyaku (now part of Mitsubishi Tanabe Pharma Corporation) for the treatment of anxiety disorders. This approval marked its initial regulatory entry as an agent, with typical dosing ranging from 5 to 15 mg daily, administered orally in tablet or granule form. Early adoption focused on its rapid onset and short , making it suitable for managing acute anxiety symptoms without significant accumulation upon repeated use. The drug's expansion beyond occurred in the 1980s, with approval in for use as a premedicant in minor surgical procedures, marketed under the brand name Veratran. Its rollout remained limited to select European and Asian markets, reflecting cautious regulatory approaches to benzodiazepine-class drugs. Key clinical trials from the and 1980s demonstrated clotiazepam's efficacy in reducing anxiety symptoms such as restlessness, tension, and somatic complaints in ambulatory patients. Additional research emphasized its favorable safety profile with minimal adverse events at therapeutic doses, supporting its role in short-term anxiety management. Like other benzodiazepines, broader concerns over dependence, tolerance, and long-term risks led to decreased prescriptions class-wide by the late . Despite this, clotiazepam continues to be available in limited markets like and as of 2025, where it is prescribed judiciously for and purposes under strict guidelines.

Society and culture

Clotiazepam is classified as a Schedule IV substance under the 1971 , indicating a low potential for abuse relative to substances in higher schedules, though its international trade and manufacture are monitored by the (INCB). In the United States, clotiazepam is listed as a Schedule IV by the (DEA), subjecting it to strict regulations on possession, distribution, and manufacturing. However, it has not been approved by the (FDA) for marketing in the country. In Canada, clotiazepam is a Schedule IV drug under the Controlled Drugs and Substances Act (CDSA), requiring a prescription for legal possession and use, though it is not commercially available. The legal status varies across other countries. In Brazil, it is classified as a Class B1 psychotropic substance under Portaria SVS/MS No. 344/1998, mandating special controls for prescription and dispensing. In Japan, it is regulated as a psychotropic under the Narcotics and Psychotropics Control Law, available only by prescription. In France, it is a prescription-only medication under national drug control regulations. Within the European Union, classifications differ; for example, it is prescription-only (Anlage III for higher doses) in Germany and Class C (Schedule 4) in the United Kingdom under the Misuse of Drugs Act 1971.

Availability and brand names

Clotiazepam is marketed under several brand names, including Clozan, Distensan, Trecalmo, , Rizen, and Veratran, with generic versions available in select markets. The drug is widely available by prescription in , where it is commonly dispensed as 5 mg and 10 mg tablets from manufacturers such as Sawai Pharmaceutical and Towa Pharmaceutical. In , it is authorized under the brand Veratran in tablet form by Amdipharm . Availability extends to through various suppliers offering licensing and formulations, and to , where it falls under Class B1 regulations permitting controlled prescription access. In contrast, clotiazepam has limited availability or has been withdrawn in the , , and the ; it is not approved for marketing in the or and, despite prior approval in the UK, is no longer actively marketed there. Formulations typically include 5 mg tablets, 10 mg tablets, and 1 mg/mL oral drops (or 10 mg/mL in some preparations). Access to clotiazepam remains restricted in many jurisdictions owing to prescribing guidelines that emphasize short-term use and recommend alternatives such as SSRIs for anxiety management to mitigate risks of dependence.

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