Prazepam
Encyclopedia
Prazepam is a benzodiazepine
derivative
drug
developed by Warner-Lambert in the 1960s. It possesses anxiolytic
, anticonvulsant
, sedative
and skeletal muscle relaxant properties. Prazepam is a prodrug
for desmethyldiazepam which is an active metabolite
of prazepam. Desmethyldiazepam is responsible for the therapeutic effects of prazepam.
Prazepam is marketed for anxiolytic
use under the trade names Centrac, Centrax, Demetrin, Lysanxia, Mono Demetrin, Pozapam, Prasepine, Prazene, Reapam and Trepidan.
. After short term therapy the dose is usually gradually tapered off to reduce or avoid any withdrawal
or rebound effects. Desmethyldiazepam, an active metabolite
, has a very long half life of 29 to 224 hours which contributes to the therapeutic effects of prazepam.
may occur with symptoms such as tremulousness, dysphoria
, psychomotor agitation
, tachycardia
and sweating
. In severe cases hallucinations, psychosis
and seizures can occur. Withdrawal
related psychosis is generally unresponsive to antipsychotic mediations. The risk and severity of the withdrawal syndrome increases the higher the dose and the longer prazepam is taken for. Tolerance, dependence and withdrawal problems may be less severe than with other benzodiazepines such as diazepam
. It may be because tolerance is slower to develop with prazepam than with other benzodiazepines. Abrupt or over-rapid discontinuation of prazepam after long term use even at low dosage may result in a protracted withdrawal syndrome.
Benzodiazepines can induce serious problems of addiction
which is one of the main reasons for their use being restricted to short term use. A survey in Senegal
found that the majority of doctors believed that their training in this area was generally poor. Recommendations for national authorities to take urgent action regarding the rational use of benzodiazepines. Another study in Dakar
found that almost one fifth of doctors ignored prescribing guidelines regarding short term use of benzodiazepines and almost three quarters of doctors regarded their training and knowledge of benzodiazepines to be inadequate. More training regarding benzodiazepines has been recommended for doctors.
function in the brain. Prazepam like other benzodiazepines has anticonvulsant
properties but its anticonvulsant properties are not as potent as other benzodiazepines when tested in animal studies.
. Prazepam is a prodrug
for descyclopropylmethylprazepam/desmethyldiazepam (also known as norprazepam or nordiazepam) which is responsible for most of the therapeutic activity of prazepam rather than prazepam itself.
. Alcohol
in combination with prazepam increases the adverse effects, particularly performance impairing side effects and drowsiness.
Prazepam is available under different trade names in the following countries; Austria
: Demetrin, Belgium
: Lysanxia, France
: Lysanxia, Germany
: Demetrin; Mono Demetrin, Greece
: Centrac, Ireland
: Centrax, Italy
: Prazene; Trepidan, Macedonia: Demetrin, Prazepam, Netherlands
: Reapam, Portugal
: Demetrin, South Africa
: Demetrin, Switzerland
: Demetrin, Thailand
: Pozapam; Prasepine.
and ataxia
. Hypotonia
may also occur in severe cases. Overdoses in children typically result in more severe symptoms of overdose.
in that it has a substituent on the nitrogen
atom in the first position of the benzodiazepine
system. This drug is made according to a scheme very similar to that of diazepam. It is derived from the same initial 2-amino-5-chlorobenzophenone, which undergoes acylation by cyclopropancarboxylic acid chloride. The resulting 2-cyclopropylcarbonylamino-5-chlorobenzophenone is reduced by lithium aluminum hydride into 2-cyclopropylmethylamino-5-chlorobenzhydrol, and the resulting product is oxidized by manganese dioxide into 2-cyclopropylmethylamino-5-chlorobenzophenone. This is acylated by phthalimidoacetic acid chloride. The phthalimide protecting group
in the resulting product is removed by treatment with hydrazine
, during which an intramolecular
reaction of imino formation occurs under the conditions of synthesis, leading to the formation of the desired product, prazepam.
In the second, simpler scheme, synthesis begins with 7-chloro-5-phenyl-2,3-dihydro-1H-
1,4-benzodiazepin-2-one, which is alkylated by cyclopropylmethylbromide in the presence of sodium hydride
into prazepam.
Benzodiazepine
A benzodiazepine is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring...
derivative
Derivative (chemistry)
In chemistry, a derivative is a compound that is derived from a similar compound by some chemical or physical process. In the past it was also used to mean a compound that can be imagined to arise from another compound, if one atom is replaced with another atom or group of atoms, but modern...
drug
Drug
A drug, broadly speaking, is any substance that, when absorbed into the body of a living organism, alters normal bodily function. There is no single, precise definition, as there are different meanings in drug control law, government regulations, medicine, and colloquial usage.In pharmacology, a...
developed by Warner-Lambert in the 1960s. It possesses anxiolytic
Anxiolytic
An anxiolytic is a drug used for the treatment of anxiety, and its related psychological and physical symptoms...
, anticonvulsant
Anticonvulsant
The anticonvulsants are a diverse group of pharmaceuticals used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of bipolar disorder, since many seem to act as mood stabilizers, and in the treatment of neuropathic pain. The goal of an...
, sedative
Sedative
A sedative or tranquilizer is a substance that induces sedation by reducing irritability or excitement....
and skeletal muscle relaxant properties. Prazepam is a prodrug
Prodrug
A prodrug is a pharmacological substance administered in an inactive form. Once administered, the prodrug is metabolised in vivo into an active metabolite, a process termed bioactivation. The rationale behind the use of a prodrug is generally for absorption, distribution, metabolism, and...
for desmethyldiazepam which is an active metabolite
Active metabolite
- Prodrugs :Sometimes drugs are formulated deliberately so they will break down inside the body to form the active drug, these are called prodrugs. The reason for this may be because the drug is more stable during manufacture and storage as the prodrug form, or because the prodrug is better...
of prazepam. Desmethyldiazepam is responsible for the therapeutic effects of prazepam.
Prazepam is marketed for anxiolytic
Anxiolytic
An anxiolytic is a drug used for the treatment of anxiety, and its related psychological and physical symptoms...
use under the trade names Centrac, Centrax, Demetrin, Lysanxia, Mono Demetrin, Pozapam, Prasepine, Prazene, Reapam and Trepidan.
Indications
Prazepam is indicated for the short term treatment of anxietyAnxiety
Anxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...
. After short term therapy the dose is usually gradually tapered off to reduce or avoid any withdrawal
Withdrawal
Withdrawal can refer to any sort of separation, but is most commonly used to describe the group of symptoms that occurs upon the abrupt discontinuation/separation or a decrease in dosage of the intake of medications, recreational drugs, and alcohol...
or rebound effects. Desmethyldiazepam, an active metabolite
Active metabolite
- Prodrugs :Sometimes drugs are formulated deliberately so they will break down inside the body to form the active drug, these are called prodrugs. The reason for this may be because the drug is more stable during manufacture and storage as the prodrug form, or because the prodrug is better...
, has a very long half life of 29 to 224 hours which contributes to the therapeutic effects of prazepam.
Side effects
Side effects of prazepam are less profound than with other benzodiazepines. Excessive drowsiness and with longer term use drug dependence are the most common side effects of prazepam. Side effects such as fatigue or "feeling spacey" can also occur but less commonly than with other benzodiazepines. Other side effects include feebleness, clumsiness, lethargic, clouded thinking and mental slowness.Tolerance, dependence and withdrawal
Tolerance and dependence can develop with long term use of prazepam and upon cessation or reduction in dosage a benzodiazepine withdrawal syndromeBenzodiazepine withdrawal syndrome
Benzodiazepine withdrawal syndrome—often abbreviated to benzo withdrawal—is the cluster of symptoms which appear when a person who has taken benzodiazepines long term and has developed benzodiazepine dependence stops taking benzodiazepine drug or during dosage reductions...
may occur with symptoms such as tremulousness, dysphoria
Dysphoria
Dysphoria is medically recognized as a mental and emotional condition in which a person experiences intense feelings of depression, discontent and indifference to the world around them.Mood disorders can induce dysphoria, often with a heightened risk of suicide, especially in...
, psychomotor agitation
Psychomotor agitation
Psychomotor agitation is a series of unintentional and purposeless motions that stem from mental tension and anxiety of an individual. This includes pacing around a room, wringing one's hands, pulling off clothing and putting it back on and other similar actions...
, tachycardia
Tachycardia
Tachycardia comes from the Greek words tachys and kardia . Tachycardia typically refers to a heart rate that exceeds the normal range for a resting heart rate...
and sweating
Sweating
Perspiration is the production of a fluid consisting primarily of water as well as various dissolved solids , that is excreted by the sweat glands in the skin of mammals...
. In severe cases hallucinations, psychosis
Psychosis
Psychosis means abnormal condition of the mind, and is a generic psychiatric term for a mental state often described as involving a "loss of contact with reality"...
and seizures can occur. Withdrawal
Withdrawal
Withdrawal can refer to any sort of separation, but is most commonly used to describe the group of symptoms that occurs upon the abrupt discontinuation/separation or a decrease in dosage of the intake of medications, recreational drugs, and alcohol...
related psychosis is generally unresponsive to antipsychotic mediations. The risk and severity of the withdrawal syndrome increases the higher the dose and the longer prazepam is taken for. Tolerance, dependence and withdrawal problems may be less severe than with other benzodiazepines such as diazepam
Diazepam
Diazepam , first marketed as Valium by Hoffmann-La Roche is a benzodiazepine drug. Diazepam is also marketed in Australia as Antenex. It is commonly used for treating anxiety, insomnia, seizures including status epilepticus, muscle spasms , restless legs syndrome, alcohol withdrawal,...
. It may be because tolerance is slower to develop with prazepam than with other benzodiazepines. Abrupt or over-rapid discontinuation of prazepam after long term use even at low dosage may result in a protracted withdrawal syndrome.
Benzodiazepines can induce serious problems of addiction
Substance dependence
The section about substance dependence in the Diagnostic and Statistical Manual of Mental Disorders does not use the word addiction at all. It explains:...
which is one of the main reasons for their use being restricted to short term use. A survey in Senegal
Senegal
Senegal , officially the Republic of Senegal , is a country in western Africa. It owes its name to the Sénégal River that borders it to the east and north...
found that the majority of doctors believed that their training in this area was generally poor. Recommendations for national authorities to take urgent action regarding the rational use of benzodiazepines. Another study in Dakar
Dakar
Dakar is the capital city and largest city of Senegal. It is located on the Cap-Vert Peninsula on the Atlantic coast and is the westernmost city on the African mainland...
found that almost one fifth of doctors ignored prescribing guidelines regarding short term use of benzodiazepines and almost three quarters of doctors regarded their training and knowledge of benzodiazepines to be inadequate. More training regarding benzodiazepines has been recommended for doctors.
Contraindications and special caution
Benzodiazepines require special precaution if used in the elderly, during pregnancy, in children, alcohol or drug-dependent individuals and individuals with comorbid psychiatric disorders.Mechanism of action
Prazepam exerts its therapeutic effects primarily via modulating the benzodiazepine receptor which in turn enhances GABAGabâ
Gabâ or gabaa, for the people in many parts of the Philippines), is the concept of a non-human and non-divine, imminent retribution. A sort of negative karma, it is generally seen as an evil effect on a person because of their wrongdoings or transgressions...
function in the brain. Prazepam like other benzodiazepines has anticonvulsant
Anticonvulsant
The anticonvulsants are a diverse group of pharmaceuticals used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of bipolar disorder, since many seem to act as mood stabilizers, and in the treatment of neuropathic pain. The goal of an...
properties but its anticonvulsant properties are not as potent as other benzodiazepines when tested in animal studies.
Pharmacokinetics
Prazepam is metabolised into descyclopropylmethylprazepam (also known as desmethyldiazepam) and 3-hydroxyprazepam which is further metabolised into oxazepamOxazepam
Oxazepam , is a drug which is a short to intermediate acting 3-hydroxy benzodiazepine derivative...
. Prazepam is a prodrug
Prodrug
A prodrug is a pharmacological substance administered in an inactive form. Once administered, the prodrug is metabolised in vivo into an active metabolite, a process termed bioactivation. The rationale behind the use of a prodrug is generally for absorption, distribution, metabolism, and...
for descyclopropylmethylprazepam/desmethyldiazepam (also known as norprazepam or nordiazepam) which is responsible for most of the therapeutic activity of prazepam rather than prazepam itself.
Interactions
Prazepam may interact with cimetidineCimetidine
Cimetidine INN is a histamine H2-receptor antagonist that inhibits the production of acid in the stomach. It is largely used in the treatment of heartburn and peptic ulcers. It is marketed by GlaxoSmithKline under the trade name Tagamet...
. Alcohol
Ethanol
Ethanol, also called ethyl alcohol, pure alcohol, grain alcohol, or drinking alcohol, is a volatile, flammable, colorless liquid. It is a psychoactive drug and one of the oldest recreational drugs. Best known as the type of alcohol found in alcoholic beverages, it is also used in thermometers, as a...
in combination with prazepam increases the adverse effects, particularly performance impairing side effects and drowsiness.
Trade names
Austria
Austria , officially the Republic of Austria , is a landlocked country of roughly 8.4 million people in Central Europe. It is bordered by the Czech Republic and Germany to the north, Slovakia and Hungary to the east, Slovenia and Italy to the south, and Switzerland and Liechtenstein to the...
: Demetrin, Belgium
Belgium
Belgium , officially the Kingdom of Belgium, is a federal state in Western Europe. It is a founding member of the European Union and hosts the EU's headquarters, and those of several other major international organisations such as NATO.Belgium is also a member of, or affiliated to, many...
: Lysanxia, France
France
The French Republic , The French Republic , The French Republic , (commonly known as France , is a unitary semi-presidential republic in Western Europe with several overseas territories and islands located on other continents and in the Indian, Pacific, and Atlantic oceans. Metropolitan France...
: Lysanxia, Germany
Germany
Germany , officially the Federal Republic of Germany , is a federal parliamentary republic in Europe. The country consists of 16 states while the capital and largest city is Berlin. Germany covers an area of 357,021 km2 and has a largely temperate seasonal climate...
: Demetrin; Mono Demetrin, Greece
Greece
Greece , officially the Hellenic Republic , and historically Hellas or the Republic of Greece in English, is a country in southeastern Europe....
: Centrac, Ireland
Ireland
Ireland is an island to the northwest of continental Europe. It is the third-largest island in Europe and the twentieth-largest island on Earth...
: Centrax, Italy
Italy
Italy , officially the Italian Republic languages]] under the European Charter for Regional or Minority Languages. In each of these, Italy's official name is as follows:;;;;;;;;), is a unitary parliamentary republic in South-Central Europe. To the north it borders France, Switzerland, Austria and...
: Prazene; Trepidan, Macedonia: Demetrin, Prazepam, Netherlands
Netherlands
The Netherlands is a constituent country of the Kingdom of the Netherlands, located mainly in North-West Europe and with several islands in the Caribbean. Mainland Netherlands borders the North Sea to the north and west, Belgium to the south, and Germany to the east, and shares maritime borders...
: Reapam, Portugal
Portugal
Portugal , officially the Portuguese Republic is a country situated in southwestern Europe on the Iberian Peninsula. Portugal is the westernmost country of Europe, and is bordered by the Atlantic Ocean to the West and South and by Spain to the North and East. The Atlantic archipelagos of the...
: Demetrin, South Africa
South Africa
The Republic of South Africa is a country in southern Africa. Located at the southern tip of Africa, it is divided into nine provinces, with of coastline on the Atlantic and Indian oceans...
: Demetrin, Switzerland
Switzerland
Switzerland name of one of the Swiss cantons. ; ; ; or ), in its full name the Swiss Confederation , is a federal republic consisting of 26 cantons, with Bern as the seat of the federal authorities. The country is situated in Western Europe,Or Central Europe depending on the definition....
: Demetrin, Thailand
Thailand
Thailand , officially the Kingdom of Thailand , formerly known as Siam , is a country located at the centre of the Indochina peninsula and Southeast Asia. It is bordered to the north by Burma and Laos, to the east by Laos and Cambodia, to the south by the Gulf of Thailand and Malaysia, and to the...
: Pozapam; Prasepine.
Overdose
The symptoms of an overdose of prazepam include sleepiness, agitationPsychomotor agitation
Psychomotor agitation is a series of unintentional and purposeless motions that stem from mental tension and anxiety of an individual. This includes pacing around a room, wringing one's hands, pulling off clothing and putting it back on and other similar actions...
and ataxia
Ataxia
Ataxia is a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum...
. Hypotonia
Hypotonia
Hypotonia is a state of low muscle tone , often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but a potential manifestation of many different diseases and disorders that affect motor nerve control by the brain or muscle strength...
may also occur in severe cases. Overdoses in children typically result in more severe symptoms of overdose.
Abuse potential
Prazepam like other benzodiazepines has abuse potential and can be habit forming. However, its abuse potential may be lower than other benzodiazepines because it has a slow onset of action.Toxicity
Animal studies have found prazepam taken during pregnancy results in delayed growth and reproductive abnormalities.Chemistry
Prazepam, 7-chloro-1-(cyclopropylmethyl)-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one, differs from diazepamDiazepam
Diazepam , first marketed as Valium by Hoffmann-La Roche is a benzodiazepine drug. Diazepam is also marketed in Australia as Antenex. It is commonly used for treating anxiety, insomnia, seizures including status epilepticus, muscle spasms , restless legs syndrome, alcohol withdrawal,...
in that it has a substituent on the nitrogen
Nitrogen
Nitrogen is a chemical element that has the symbol N, atomic number of 7 and atomic mass 14.00674 u. Elemental nitrogen is a colorless, odorless, tasteless, and mostly inert diatomic gas at standard conditions, constituting 78.08% by volume of Earth's atmosphere...
atom in the first position of the benzodiazepine
Benzodiazepine
A benzodiazepine is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring...
system. This drug is made according to a scheme very similar to that of diazepam. It is derived from the same initial 2-amino-5-chlorobenzophenone, which undergoes acylation by cyclopropancarboxylic acid chloride. The resulting 2-cyclopropylcarbonylamino-5-chlorobenzophenone is reduced by lithium aluminum hydride into 2-cyclopropylmethylamino-5-chlorobenzhydrol, and the resulting product is oxidized by manganese dioxide into 2-cyclopropylmethylamino-5-chlorobenzophenone. This is acylated by phthalimidoacetic acid chloride. The phthalimide protecting group
Protecting group
A protecting group or protective group is introduced into a molecule by chemical modification of a functional group in order to obtain chemoselectivity in a subsequent chemical reaction...
in the resulting product is removed by treatment with hydrazine
Hydrazine
Hydrazine is an inorganic compound with the formula N2H4. It is a colourless flammable liquid with an ammonia-like odor. Hydrazine is highly toxic and dangerously unstable unless handled in solution. Approximately 260,000 tons are manufactured annually...
, during which an intramolecular
Intramolecular
Intramolecular in chemistry describes a process or characteristic limited within the structure of a single molecule, a property or phenomenon limited to the extent of a single molecule.- Examples :...
reaction of imino formation occurs under the conditions of synthesis, leading to the formation of the desired product, prazepam.
- I. Pattison, F.H. McMillan, (1965).
- Warner-Lambert Pharmaceutical Company, (1965).
In the second, simpler scheme, synthesis begins with 7-chloro-5-phenyl-2,3-dihydro-1H-
1,4-benzodiazepin-2-one, which is alkylated by cyclopropylmethylbromide in the presence of sodium hydride
Sodium hydride
Sodium hydride is the chemical compound with the empirical formula NaH. It is primarily used as a strong base in organic synthesis. NaH is representative of the saline hydrides, meaning it is a salt-like hydride, composed of Na+ and H− ions, in contrast to the more molecular hydrides such as...
into prazepam.
- H.M. Wuest, (1965).
- S. Inaba, T. Hirohashi, H. Yamamoto, Chem. Pharm. Bull., 17, 1263 (1969).
See also
- BenzodiazepineBenzodiazepineA benzodiazepine is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring...
- Benzodiazepine dependenceBenzodiazepine dependenceBenzodiazepine dependence or benzodiazepine addiction is a condition during which a person is dependent on benzodiazepine drugs. Dependence can be either a psychological dependence, physical dependence, or a combination of the two...
- Long-term effects of benzodiazepines