Clorazepate, sold under the brand name Tranxene among others, is a

benzodiazepine Benzodiazepines (BZD, BDZ, BZs), sometimes called "benzos", are a class of depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed to treat conditions such as anxiety disorders, ...

medication. It possesses

anxiolytic An anxiolytic (; also antipanic or antianxiety agent) is a medication or other intervention that reduces anxiety. This effect is in contrast to anxiogenic agents which increase anxiety. Anxiolytic medications are used for the treatment of anxiet ...

anticonvulsant Anticonvulsants (also known as antiepileptic drugs or recently as antiseizure drugs) are a diverse group of pharmacological agents used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of ...

sedative A sedative or tranquilliser is a substance that induces sedation by reducing irritability or excitement. They are CNS depressants and interact with brain activity causing its deceleration. Various kinds of sedatives can be distinguished, but ...

hypnotic Hypnotic (from Greek ''Hypnos'', sleep), or soporific drugs, commonly known as sleeping pills, are a class of (and umbrella term for) psychoactive drugs whose primary function is to induce sleep (or surgical anesthesiaWhen used in anesthesia ...

, and

skeletal muscle relaxant A muscle relaxant is a drug that affects skeletal muscle function and decreases the muscle tone. It may be used to alleviate symptoms such as muscle spasms, pain, and hyperreflexia. The term "muscle relaxant" is used to refer to two major therapeu ...

properties. Clorazepate is an unusually long-lasting benzodiazepine and serves as a majoritive

prodrug A prodrug is a medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be used to improve how the dru ...

for the equally long-lasting

desmethyldiazepam Nordazepam (INN; marketed under brand names Nordaz, Stilny, Madar, Vegesan, and Calmday; also known as nordiazepam, desoxydemoxepam, and desmethyldiazepam) is a 1,4-benzodiazepine derivative. Like other benzodiazepine derivatives, it has amnesi ...

, which is rapidly produced as an

active metabolite An active metabolite is an active form of a drug after it has been processed by the body. Metabolites of drugs An active metabolite results when a drug is metabolized by the body into a modified form which continues to produce effects in the body ...

. Desmethyldiazepam is responsible for most of the therapeutic effects of clorazepate. It was patented in 1965 and approved for medical use in 1967.

Medical uses

Clorazepate is used in the treatment of

anxiety disorder Anxiety disorders are a cluster of mental disorders characterized by significant and uncontrollable feelings of anxiety and fear such that a person's social, occupational, and personal function are significantly impaired. Anxiety may cause phy ...

s and

insomnia Insomnia, also known as sleeplessness, is a sleep disorder in which people have trouble sleeping. They may have difficulty falling asleep, or staying asleep as long as desired. Insomnia is typically followed by daytime sleepiness, low energy, ...

. It may also be prescribed as an

muscle relaxant A muscle relaxant is a drug that affects skeletal muscle function and decreases the muscle tone. It may be used to alleviate symptoms such as muscle spasms, pain, and hyperreflexia. The term "muscle relaxant" is used to refer to two major therap ...

. It is also used as a premedication. Clorazepate is prescribed principally in the treatment of

alcohol withdrawal Alcohol withdrawal syndrome (AWS) is a set of symptoms that can occur following a reduction in alcohol use after a period of excessive use. Symptoms typically include anxiety, shakiness, sweating, vomiting, fast heart rate, and a mild fever. M ...

and

epilepsy Epilepsy is a group of non-communicable neurological disorders characterized by recurrent epileptic seizures. Epileptic seizures can vary from brief and nearly undetectable periods to long periods of vigorous shaking due to abnormal electrica ...

, although it is also a useful

because of its long half-life. The normal starting dosage range of Clorazepate is 15 to 60 mg per day. The drug is to be taken two to four times per day. Dosages as high as 90 to 120 mg per day may be used in the treatment of acute alcohol withdrawal. In the United States and Canada, Clorazepate is available in 3.75, 7.5, and 15 mg capsules or tablets. In Europe, tablet formations are 5 mg, 10 mg, 20 mg and 50 mg. Clorazepate SD (controlled release) is available and may have a reduced incidence of adverse effects. The sustained-release formulation of clorazepate has some advantages in that, if a dose is missed, less profound fluctuations in blood plasma levels occur, which may be helpful to some people with epilepsy at risk of break-through seizures.

Adverse effects

Adverse effects of clorazepate include

tolerance Tolerance or toleration is the state of tolerating, or putting up with, conditionally. Economics, business, and politics * Toleration Party, a historic political party active in Connecticut * Tolerant Systems, the former name of Veritas Software ...

, dependence, withdrawal reactions, cognitive impairment,

confusion In medicine, confusion is the quality or state of being bewildered or unclear. The term "acute mental confusion"

, anterograde amnesia, falls in the elderly,

ataxia Ataxia is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in eye movements. Ataxia is a clinical manifestation indicating dysfunction of ...

, hangover effects, and drowsiness. It is unclear whether cognitive deficits resulting from the

long-term use of benzodiazepines The effects of long-term benzodiazepine use include drug dependence and neurotoxicity as well as the possibility of adverse effects on cognitive function, physical health, and mental health. Long-term use is sometimes described as use not shorter ...

return to normal or persist indefinitely after withdrawal from benzodiazepines. Benzodiazepines are also known to cause or worsen depression.

Paradoxical effects A paradoxical reaction (or paradoxical effect) is an effect of a chemical substance, such as a medical drug, that is opposite to what would usually be expected. An example of a paradoxical reaction is pain caused by a pain relief medication. Parad ...

including excitement and paradoxical worsening of seizures can sometimes result from the use of benzodiazepines. Children, the elderly, individuals with a history of

alcohol use disorder Alcoholism is, broadly, any drinking of alcohol that results in significant mental or physical health problems. Because there is disagreement on the definition of the word ''alcoholism'', it is not a recognized diagnostic entity. Predomin ...

or a history of aggressive behavior and anger are at greater risk of developing paradoxical reactions to benzodiazepines. In September 2020, the U.S.

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...

(FDA) required the

boxed warning In the United States, a boxed warning (sometimes "black box warning", colloquially) is a type of warning that appears on the package insert for certain prescription drugs, so called because the U.S. Food and Drug Administration specifies that i ...

be updated for all benzodiazepine medicines to describe the risks of non-medical use, addiction, physical dependence, and withdrawal reactions consistently across all the medicines in the class.

Tolerance, dependence and withdrawal

Delirium Delirium (also known as acute confusional state) is an organically caused decline from a previous baseline of mental function that develops over a short period of time, typically hours to days. Delirium is a syndrome encompassing disturbances ...

has been noted from discontinuation from clorazepate. A

benzodiazepine dependence Benzodiazepine dependence defines a situation in which one has developed one or more of either tolerance, withdrawal symptoms, drug seeking behaviors, such as continued use despite harmful effects, and maladaptive pattern of substance use, accord ...

occurs in approximately one third of patients who take benzodiazepines for longer than 4 weeks, which is characterised by a withdrawal syndrome upon dose reduction. When used for

seizure An epileptic seizure, informally known as a seizure, is a period of symptoms due to abnormally excessive or synchronous neuronal activity in the brain. Outward effects vary from uncontrolled shaking movements involving much of the body with lo ...

control, tolerance may manifest itself with an increased rate of seizures as well an increased risk of withdrawal seizures. In humans, tolerance to the anticonvulsant effects of clorazepate occurs frequently with regular use. Due to the development of tolerance, benzodiazepines are, in general, not considered appropriate for the long-term management of epilepsy; increasing the dose may result only in the developing of tolerance to the higher dose combined with worsened adverse effects. Cross-tolerance occurs between benzodiazepines, meaning that, if individuals are tolerant to one benzodiazepine, they will display a tolerance to equivalent doses of other benzodiazepines. Withdrawal symptoms from benzodiazepines include a worsening of pre-existing symptoms as well as the appearance of new symptoms that were not pre-existing. The withdrawal symptoms may range from mild anxiety and insomnia to severe withdrawal symptoms such as

seizures An epileptic seizure, informally known as a seizure, is a period of symptoms due to abnormally excessive or synchronous neuronal activity in the brain. Outward effects vary from uncontrolled shaking movements involving much of the body with lo ...

and

psychosis Psychosis is a condition of the mind that results in difficulties determining what is real and what is not real. Symptoms may include delusions and hallucinations, among other features. Additional symptoms are incoherent speech and behavi ...

. Withdrawal symptoms can be difficult in some cases to differentiate between pre-existing symptoms and withdrawal symptoms. Use of high doses, long-term use and abrupt or over-rapid withdrawal increases increase the severity of withdrawal syndrome. However, tolerance to the

of clorazepate may occur more slowly than with other benzodiazepines. Regular use of benzodiazepines causes the development of dependence characterised by tolerance to the therapeutic effects of benzodiazepines and the development of the

benzodiazepine withdrawal syndrome Benzodiazepine withdrawal syndrome often abbreviated to benzo withdrawal or BZD withdrawal is the cluster of signs and symptoms that may emerge when a person who has been taking benzodiazepines, either medically or recreationally develops a p ...

including symptoms such as

anxiety Anxiety is an emotion which is characterized by an unpleasant state of inner turmoil and includes feelings of dread over anticipated events. Anxiety is different than fear in that the former is defined as the anticipation of a future threat wh ...

, apprehension,

tremor A tremor is an involuntary, somewhat rhythmic, muscle contraction and relaxation involving oscillations or twitching movements of one or more body parts. It is the most common of all involuntary movements and can affect the hands, arms, eyes, f ...

nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of th ...

, and

vomiting Vomiting (also known as emesis and throwing up) is the involuntary, forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose. Vomiting can be the result of ailments like food poisoning, gastroenter ...

upon cessation of benzodiazepine use. Withdrawal from benzodiazepines should be gradual as abrupt withdrawal from high doses of benzodiazepines may cause

confusion In medicine, confusion is the quality or state of being bewildered or unclear. The term "acute mental confusion"

, toxic psychosis,

convulsions A convulsion is a medical condition where the body muscles contract and relax rapidly and repeatedly, resulting in uncontrolled shaking. Because epileptic seizures typically include convulsions, the term ''convulsion'' is sometimes used as a ...

, or a condition resembling

delirium tremens Delirium tremens (DTs) is a rapid onset of confusion usually caused by withdrawal from alcohol. When it occurs, it is often three days into the withdrawal symptoms and lasts for two to three days. Physical effects may include shaking, shiver ...

. Abrupt withdrawal from lower doses may cause depression,

nervousness Nervous may refer to: * nervousness * Nervous system, a network of cells in an animal's body that coordinates movement and the senses ** Nervous tissue, the cells of the nervous system that work in aggregate to transmit signals Music * "Nervous" ...

rebound insomnia The rebound effect, or rebound phenomenon, is the emergence or re-emergence of symptoms that were either absent or controlled while taking a medication, but appear when that same medication is discontinued, or reduced in dosage. In the case of re ...

irritability Irritability (also called as crankiness) is the excitatory ability that living organisms have to respond to changes in their environment. The term is used for both the physiological reaction to stimuli and for the pathological, abnormal or excessi ...

sweating Perspiration, also known as sweating, is the production of fluids secreted by the sweat glands in the skin of mammals. Two types of sweat glands can be found in humans: eccrine glands and apocrine glands. The eccrine sweat glands are distri ...

, and

diarrhea Diarrhea, also spelled diarrhoea, is the condition of having at least three loose, liquid, or watery bowel movements each day. It often lasts for a few days and can result in dehydration due to fluid loss. Signs of dehydration often begin w ...

Interactions

All

s or

s e.g. other

barbiturate Barbiturates are a class of depressant drugs that are chemically derived from barbituric acid. They are effective when used medically as anxiolytics, hypnotics, and anticonvulsants, but have physical and psychological addiction potential a ...

antiepileptic Anticonvulsants (also known as antiepileptic drugs or recently as antiseizure drugs) are a diverse group of pharmacological agents used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of b ...

drugs,

alcohol Alcohol most commonly refers to: * Alcohol (chemistry), an organic compound in which a hydroxyl group is bound to a carbon atom * Alcohol (drug), an intoxicant found in alcoholic drinks Alcohol may also refer to: Chemicals * Ethanol, one of sev ...

antihistamine Antihistamines are drugs which treat allergic rhinitis, common cold, influenza, and other allergies. Typically, people take antihistamines as an inexpensive, generic (not patented) drug that can be bought without a prescription and provide ...

opioid Opioids are substances that act on opioid receptors to produce morphine-like effects. Medically they are primarily used for pain relief, including anesthesia. Other medical uses include suppression of diarrhea, replacement therapy for opioid use ...

neuroleptic Antipsychotics, also known as neuroleptics, are a class of psychotropic medication primarily used to manage psychosis (including delusions, hallucinations, paranoia or disordered thought), principally in schizophrenia but also in a range of oth ...

s, sleep aids are likely to magnify the effects of clorazepate on the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...

. Drugs that may interact with clorazepate include,

digoxin Digoxin (better known as Digitalis), sold under the brand name Lanoxin among others, is a medication used to treat various heart conditions. Most frequently it is used for atrial fibrillation, atrial flutter, and heart failure. Digoxin is o ...

disulfiram Disulfiram is a medication used to support the treatment of chronic alcoholism by producing an acute sensitivity to ethanol (drinking alcohol). Disulfiram works by inhibiting the enzyme acetaldehyde dehydrogenase, causing many of the effects o ...

fluoxetine Fluoxetine, sold under the brand names Prozac and Sarafem, among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It is used for the treatment of major depressive disorder, obsessive–compulsive diso ...

, isoniazid,

ketoconazole Ketoconazole, sold under the brand name Nizoral among others, is an antiandrogen and antifungal medication used to treat a number of fungal infections. Applied to the skin it is used for fungal skin infections such as tinea, cutaneous ca ...

levodopa -DOPA, also known as levodopa and -3,4-dihydroxyphenylalanine, is an amino acid that is made and used as part of the normal biology of some plants and animals, including humans. Humans, as well as a portion of the other animals that utilize -DOPA ...

metoprolol Metoprolol, sold under the brand name Lopressor, among others, is a selective β1 receptor blocker medication. It is used to treat high blood pressure, chest pain due to poor blood flow to the heart, and a number of conditions involving an a ...

, hormonal contraceptives, probenecid,

propranolol Propranolol, sold under the brand name Inderal among others, is a medication of the beta blocker class. It is used to treat high blood pressure, a number of types of irregular heart rate, thyrotoxicosis, capillary hemangiomas, performance an ...

, rifampin,

theophylline Theophylline, also known as 1,3-dimethylxanthine, is a phosphodiesterase inhibiting drug used in therapy for respiratory diseases such as chronic obstructive pulmonary disease (COPD) and asthma under a variety of brand names. As a member of the ...

, valproic acid.

Selective serotonin reuptake inhibitor Selective serotonin reuptake inhibitors (SSRIs) are a class of drugs that are typically used as antidepressants in the treatment of major depressive disorder, anxiety disorders, and other psychological conditions. SSRIs increase the extracellul ...

cimetidine Cimetidine, sold under the brand name Tagamet among others, is a histamine H2 receptor antagonist that inhibits stomach acid production. It is mainly used in the treatment of heartburn and peptic ulcers. The development of longer-acting H2 r ...

macrolide The Macrolides are a class of natural products that consist of a large macrocyclic lactone ring to which one or more deoxy sugars, usually cladinose and desosamine, may be attached. The lactone rings are usually 14-, 15-, or 16-membered. Ma ...

antibiotics and antimycotics inhibit the metabolism of benzodiazepines and may result in increased plasma levels with resultant enhancement of adverse effects.

Phenytoin Phenytoin (PHT), sold under the brand name Dilantin among others, is an anti-seizure medication. It is useful for the prevention of tonic-clonic seizures (also known as grand mal seizures) and focal seizures, but not absence seizures. The in ...

phenobarbital Phenobarbital, also known as phenobarbitone or phenobarb, sold under the brand name Luminal among others, is a medication of the barbiturate type. It is recommended by the World Health Organization (WHO) for the treatment of certain types of ep ...

, and

carbamazepine Carbamazepine (CBZ), sold under the trade name Tegretol among others, is an anticonvulsant medication used primarily in the treatment of epilepsy and neuropathic pain. It is used as an adjunctive treatment in schizophrenia along with other m ...

have the opposite effect, with coadministration leading to increased metabolism and decreased therapeutic effects of clorazepate.

Contraindications and special caution

Benzodiazepines require special precaution if used in the elderly, children, alcohol- or drug-dependent individuals and individuals with

comorbid In medicine, comorbidity - from Latin morbus ("sickness"), co ("together"), -ity (as if - several sicknesses together) - is the presence of one or more additional conditions often co-occurring (that is, concomitant or concurrent) with a primary ...

psychiatric disorders A mental disorder, also referred to as a mental illness or psychiatric disorder, is a behavioral or mental pattern that causes significant distress or impairment of personal functioning. Such features may be persistent, relapsing and remitt ...

. Clorazepate if used late in pregnancy, the third trimester, causes a definite risk of severe

in the neonate with symptoms including

hypotonia Hypotonia is a state of low muscle tone (the amount of tension or resistance to stretch in a muscle), often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but a potential manifestation of many different diseases ...

, and reluctance to suck, to apnoeic spells,

cyanosis Cyanosis is the change of body tissue color to a bluish-purple hue as a result of having decreased amounts of oxygen bound to the hemoglobin in the red blood cells of the capillary bed. Body tissues that show cyanosis are usually in locations ...

, and impaired

metabolic Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cell ...

responses to cold stress.

Floppy infant syndrome Hypotonia is a state of low muscle tone (the amount of tension or resistance to stretch in a muscle), often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but a potential manifestation of many different diseases a ...

and sedation in the newborn may also occur. Symptoms of floppy infant syndrome and the neonatal benzodiazepine withdrawal syndrome have been reported to persist from hours to months after birth. Special precaution is required when using clorazepate in the elderly because the elderly metabolise clorazepate more slowly, which may result in excessive drug accumulation. Additionally the elderly are more sensitive to the adverse effects of benzodiazepines compared to younger individuals even when blood plasma levels are the same. Use of benzodiazepines in the elderly is only recommended for 2 weeks and it is also recommended that half of the usual daily dose is prescribed.

Pharmacology

Clorazepate is a "classical" benzodiazepine. Other classical benzodiazepines include chlordiazepoxide,

diazepam Diazepam, first marketed as Valium, is a medicine of the benzodiazepine family that acts as an anxiolytic. It is commonly used to treat a range of conditions, including anxiety, seizures, alcohol withdrawal syndrome, muscle spasms, insomnia, ...

, clonazepam, oxazepam,

lorazepam Lorazepam, sold under the brand name Ativan among others, is a benzodiazepine medication. It is used to treat anxiety disorders, trouble sleeping, severe agitation, active seizures including status epilepticus, alcohol withdrawal, and che ...

, nitrazepam,

bromazepam Bromazepam, sold under many brand names, is a benzodiazepine. It is mainly an anti-anxiety agent with similar side effects to diazepam (Valium). In addition to being used to treat anxiety or panic states, bromazepam may be used as a premedicant p ...

and flurazepam. Clorazepate is a long-acting benzodiazepine drug. Clorazepate produces the

desmethyl-diazepam, which is a

partial agonist In pharmacology, partial agonists are drugs that bind to and activate a given receptor, but have only partial efficacy at the receptor relative to a full agonist. They may also be considered ligands which display both agonistic and antagonis ...

of the GABA_A receptor and has a half life of 20 – 179 hours; a small amount of desmethyldiazepam is further metabolised into oxazepam. Clorazepate exerts its pharmacological properties via increasing the opening frequency of the chloride ion channel of GABA_A receptors. This effect of benzodiazepines requires the presence of the neurotransmitter GABA and results in enhanced inhibitory effects of the neurotransmitter GABA acting on GABA_A receptors. Clorazepate, like other benzodiazepines, is widely distributed and is highly bound to plasma proteins; clorazepate also crosses readily over the

placenta The placenta is a temporary embryonic and later fetal organ that begins developing from the blastocyst shortly after implantation. It plays critical roles in facilitating nutrient, gas and waste exchange between the physically separate mate ...

and into breast milk. Peak plasma levels of the

desmethyl-diazepam are seen between 30 minutes and 2 hours after oral administration of clorazepate. Clorazepate is completely metabolised to desmethyl-diazepam in the gastrointestinal tract and thus the pharmacological properties of clorazepate are largely due to desmethyldiazepam.

Chemistry

Clorazepate is used in the form of a dipotassium

salt Salt is a mineral composed primarily of sodium chloride (NaCl), a chemical compound belonging to the larger class of salts; salt in the form of a natural crystalline mineral is known as rock salt or halite. Salt is present in vast quant ...

. It is unusual among benzodiazepines in that it is freely soluble in water. Clorazepate can be synthesized starting from 2-amino-5-chlorobenzonitrile, which upon reaction with

phenylmagnesium bromide Phenylmagnesium bromide, with the simplified formula , is a magnesium-containing organometallic compound. It is commercially available as a solution in diethyl ether or tetrahydrofuran (THF). Phenylmagnesium bromide is a Grignard reagent. It is ...

is transformed into 2-amino-5-chlorbenzophenone imine.J. Schmitt, P. Comoy, M. Subsequent, G. Callet, I. Le Meur, T. Clim, M. Brunaud, J. Mereir, J. Salle, G. Siou, Chim. Ther., 4, 239 (1969) Reacting this with aminomalonic ester gives a heterocyclization product, 7-chloro-1,3-dihydro-3-carbethoxy-5-phenyl-2''H''-benzodiazepin-2-one. Upon hydrolysis using an alcoholic solution of

potassium hydroxide Potassium hydroxide is an inorganic compound with the formula K OH, and is commonly called caustic potash. Along with sodium hydroxide (NaOH), KOH is a prototypical strong base. It has many industrial and niche applications, most of which exp ...

forms a dipotassium salt, chlorazepate. Chlorazepate synthesis

Legal status

In the United States, clorazepate is listed under Schedule IV of the

Controlled Substances Act The Controlled Substances Act (CSA) is the statute establishing federal U.S. drug policy under which the manufacture, importation, possession, use, and distribution of certain substances is regulated. It was passed by the 91st United States ...

References

External links

Rx-List.com - Clorazepate

{{GABAAR PAMs Benzodiazepines Chloroarenes GABAA receptor positive allosteric modulators Hypnotics Lactams