Benzodiazepine

Benzodiazepine

IUPAC name	5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one
Identifiers
CAS number
PubChem	76175
SMILES	O=C1N([H])c2ccccc2C(c3ccccc3)=NC1
Properties
Molecular formula	C₁₅H₁₂N₂O
Molar mass	236. Alprazolam, also known under the trade names Xanax and Niravam, is a short-acting drug of the Benzodiazepine class used to treat moderate A tablet is a mixture of active substances and Excipients usually in powder form pressed or compacted into a solid IUPAC Nomenclature is a system of naming Chemical compounds and of describing the science of Chemistry in general CAS registry numbers are unique numerical identifiers for Chemical compounds Polymers biological sequences mixtures and Alloys They are also referred to PubChem is a Database of chemical Molecules The system is maintained by the National Center for Biotechnology Information (NCBI a component A chemical formula is a way of expressing information about the Atoms that constitute a particular Chemical compound, and how the relationship between those atoms changes Molar mass, symbol M, is the Mass of one mole of a substance ( Chemical element or Chemical compound) 26858
Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa) Infobox disclaimer and references

The benzodiazepines (pronounced [ˌbɛnzoː. In Chemistry, the standard state of a material is its state at 1 bar (100 Kilopascals exactly daɪˈæzəˌpiːn], often abbreviated to "benzos") are a class of psychoactive drugs with varying hypnotic, sedative, anxiolytic, anticonvulsant, muscle relaxant and amnesic properties, which are mediated by slowing down the central nervous system. A psychoactive drug or psychotropic substance is a Chemical substance that acts primarily upon the Central nervous system where it alters Brain For the state of mind see Hypnosis. Hypnotic drugs induce Sleep (which differentiates them from the Sedative A sedative, or more specifically a sedative-hypnotic, is a substance that depresses the Central nervous system (CNS resulting in calmness relaxation sleepiness An anxiolytic is a drug prescribed for the treatment of Symptoms of Anxiety. The anticonvulsants, also called antiepileptic drugs (abbreviated "AEDs" are a diverse group of pharmaceuticals used in the treatment of epileptic This article refers to skeletal muscle relaxants For information on Smooth muscle relaxants see Antispasmodic. Anterograde amnesia is a loss of Memory of what happens after the event that caused the Amnesia; it is different from Retrograde amnesia, where memories In Vertebrates the central nervous system ( CNS) is the part of the Nervous system which is enclosed in the Meninges. ^[1] Benzodiazepines are useful in treating anxiety, insomnia, agitation, seizures, and muscle spasms, as well as alcohol withdrawal. Anxiety is a physiological and psychological state characterized by Cognitive, Somatic, Emotional and Behavioral components Insomnia is a symptom of a sleeping disorder characterized by persistent difficulty falling asleep or staying asleep despite the opportunity An epileptic seizure is caused by excessive and/or hypersynchronous electrical Neuronal activity and is usually self-limiting A spasm is a sudden involuntary contraction of a Muscle, a group of muscles or a hollow organ, or a similarly sudden Contraction of an Orifice Withdrawal, also known as withdrawal/abstinence syndrome, refers to the characteristic signs and symptoms that appear when a drug that causes Physical dependence is They can also be used before certain medical procedures such as endoscopies or dental work where tension and anxiety are present, and prior to some unpleasant medical procedures in order to induce sedation and amnesia^[2] for the procedure. Endoscopy means looking inside and typically refers to looking inside the body for medical reasons using an instrument called an endoscope. Dentistry' is the "evaluation diagnosis prevention and/or treatment (nonsurgical surgical or related procedures of diseases disorders and/or conditions of the oral cavity Sedation is a Medical procedure involving the administration of Sedative drugs generally to facilitate a medical procedure with Local anaesthesia. Amnesia (from Greek) is a condition in which Memory is disturbed Another use is to counteract anxiety-related symptoms upon initial use of SSRIs and other antidepressants, or as an adjunctive treatment. Anxiety is a physiological and psychological state characterized by Cognitive, Somatic, Emotional and Behavioral components Selective serotonin reuptake inhibitors ( SSRIs) are a class of Antidepressants used in the treatment of depression, Anxiety disorders An antidepressant is a Psychiatric medication used for alleviating major depression or Dysthymia ('milder' depression Recreational stimulant users often use benzodiazepines as a means of "coming down" (see: Drug abuse). Stimulant drugs are Drugs that temporarily increase alertness and awareness Drug abuse has a wide range of definitions related to taking a Psychoactive drug or Performance enhancing drug for a non-therapeutic or non-medical effect Benzodiazepines are also used to treat the panic that can be caused by hallucinogen intoxication. The general group of pharmacological agents commonly known as hallucinogens can be divided into three broad categories Psychedelics, Dissociatives ^[3]

The long-term use of benzodiazapines can cause physical dependence. Physical dependence (or drug dependence) refers to a state resulting from habitual use of a drug where negative physical Withdrawal symptoms result from abrupt discontinuation The use of benzodiazepines should therefore commence only after medical consultation and benzodiazepines should be prescribed the smallest dosage possible to provide an acceptable level of symptom relief. Dependence varies with the benzodiazepine used and with the user. Physical dependence (or drug dependence) refers to a state resulting from habitual use of a drug where negative physical Withdrawal symptoms result from abrupt discontinuation

History

The first benzodiazepine, chlordiazepoxide (Librium) was discovered serendipitously in 1954 by the Austrian scientist Leo Sternbach (1908–2005), working for the pharmaceutical company Hoffmann–La Roche. Chlordiazepoxide (pronounced) is a Sedative / Hypnotic drug which is a Benzodiazepine derivative and is marketed under the trade name Librium Serendipity is the effect by which one accidentally discovers something fortunate especially while looking for something else entirely Dr Leo Henryk Sternbach ( May 7, 1908 &ndash September 28, 2005) was a Polish - Jewish chemist who is credited F Hoffmann–La Roche Ltd is a Swiss global health-care company which operates world-wide under two divisions Pharmaceuticals and Diagnostics. Chlordiazepoxide was synthesised from work on a chemical dye, quinazolone-3-oxides. Initially, he discontinued his work on the compound Ro-5-0690, but he "rediscovered" it in 1957 when an assistant was cleaning up the laboratory. Although initially discouraged by his employer, Sternbach conducted further research that revealed the compound was a very effective tranquilizer. A sedative, or more specifically a sedative-hypnotic, is a substance that depresses the Central nervous system (CNS resulting in calmness relaxation sleepiness Tests revealed that the compound had hypnotic, anxiolytic and muscle relaxant effects. For the state of mind see Hypnosis. Hypnotic drugs induce Sleep (which differentiates them from the Sedative An anxiolytic is a drug prescribed for the treatment of Symptoms of Anxiety. This article refers to skeletal muscle relaxants For information on Smooth muscle relaxants see Antispasmodic. Three years later chlordiazepoxide was marketed as a therapeutic benzodiazepine medication under the brand name Librium. Following chlordiazepoxide in 1963 diazepam hit the market under the brand name Valium, followed by many further benzodiazepine compounds which were introduced over the subsequent years and decades. ^[4]

The original chemical name of chlordiazepoxide was methaminodiazepoxide but it was changed to chlordiazepoxide. Chlordiazepoxide (pronounced) is a Sedative / Hypnotic drug which is a Benzodiazepine derivative and is marketed under the trade name Librium It was marketed under the trade name Librium, derived from the final syllables of equilibrium. In 1959 it was used by over 2,000 physicians and more than 20,000 patients. It was described as "chemically and clinically different from any of the tranquilizers, psychic energizers or other psychotherapeutic drugs now available. " During studies, chlordiazepoxide induced muscle relaxation and a quieting effect on laboratory animals like mice, rats, cats, and dogs. Fear and aggression were eliminated in much smaller doses than those necessary to produce hypnosis. Chlordiazepoxide is similar to phenobarbital in its anticonvulsant properties. Phenobarbital ( INN) or phenobarbitone (former BAN) is a Barbiturate, first marketed as Luminal by Friedr The anticonvulsants, also called antiepileptic drugs (abbreviated "AEDs" are a diverse group of pharmaceuticals used in the treatment of epileptic However, it lacks the hypnotic effects of barbiturates. Barbiturates are drugs that act as central nervous system Depressants and by virtue of this they produce a wide spectrum of effects from mild Sedation Animal tests were conducted in the Boston Zoo and the San Diego Zoo. The San Diego Zoo in Balboa Park, San Diego, California is one of the largest most progressive Zoos in the world with over 4000 animals Forty-two hospital patients admitted for acute and chronic alcoholism, and various psychoses and neuroses were treated with chlordiazepoxide. Psychosis (from the Greek ψυχή "psyche" for mind or soul and -οσις "-osis" for abnormal condition with adjective psychotic This article describes the term in psychology For the experimental metal band see Neurosis (band. In a majority of the patients, anxiety, tension, and motor excitement were "effectively reduced. " The most positive results were observed among alcoholic patients. It was reported that ulcers and dermatologic problems, both of which involve emotional factors, were reduced by chlordiazepoxide. ^[5]

Chlordiazepoxide enabled the treatment of emotional disturbances without a loss of mental acuity or alertness. It assisted persons burdened by compulsive reactions like one that felt compelled to count the slats on venetian blinds upon entering a room. For other uses see Blinds (disambiguation For the desktop theming software see WindowBlinds. ^[6]

Dr. Carl F. Essig of the Addiction Research Center of the National Institute of Mental Health spoke at a symposium on drug abuse at an annual meeting of the American Association for the Advancement of Science, in December 1963. The National Institute of Mental Health ( NIMH) is part of the federal government of the United States and the largest research organization in the world specializing in The American Association for the Advancement of Science (or AAAS) is an organization that promotes cooperation between Scientists defends scientific freedom encourages Year 1963 ( MCMLXIII) was a Common year starting on Tuesday (link will display full calendar of the Gregorian calendar. He named meprobamate, glutethimide, ethinamate, ethchlorvynol, methyprylon, and chlordiazepoxide as drugs whose usefulness can hardly be questioned. Glutethimide is a hypnotic Sedative that was introduced in 1954 as a safe alternative to Barbiturates to treat Insomnia. Ethinamate (Valamin Valmid is a short-acting Sedative-hypnotic Medication used to treat Insomnia. Ethchlorvynol is a Sedative and Hypnotic drug. It has been used to treat Insomnia, but has been largely superseded and is only offered where Methyprylon is a Sedative of the Piperidinedione derivative family However, Essig labeled these newer products as drugs of addiction, like barbiturates, whose habit-forming qualities were more widely-known. He mentioned a 90-day study of chlordiazepoxide, which concluded that the automobile accident rate among 68 users was ten times higher than normal. Participants' daily dosage ranged from 5 to 100 milligrams. ^[7]

In 1963, approval for use was given to diazepam (Valium), a "simplified" version of chlordiazepoxide, primarily to counteract anxiety symptoms. Diazepam (daɪˈæzɨpæm first marketed as Valium by Hoffmann-La Roche, is a Benzodiazepine derivative Drug. Sleep-related problems were treated with nitrazepam (Mogadon), which was introduced in 1965, temazepam (Restoril), which was introduced in 1969, and flurazepam (Dalmane), which was introduced in 1973. Nitrazepam is a type of Benzodiazepine drug It is a hypnotic drug with Sedative and motor impairing properties Anxiolytic, Amnestic Temazepam (marketed under brand names Restoril, Euhypnos, Normison, Remestan, Tenox and Norkotral) is an intermediate-acting Flurazepam (marketed under the brand names Dalmane and Dalmadorm) is a drug which is a Benzodiazepine derivative ^[8]

Common benzodiazepines

For various benzodiazepines and their respective generic and non-US brand-names, half-lives, and primary uses, see list of benzodiazepines. The various Benzodiazepines and their respective trade-names half-lives and primary uses are listed in the following table

The core chemical structure of "classical" benzodiazepine drugs is a fusion between the benzene and diazepine ring systems. Benzene, or benzol, is an organic Chemical compound and a known Carcinogen with the molecular formula C 6 H 6 Diazepine is a seven-membered Heterocyclic compound with two Nitrogen atoms (e Many of these drugs contain the 5-phenyl-1,3-dihydro-1,4-benzodiazepin-2-one substructure (see figure to the above right). In Universal algebra, an (induced substructure or (induced subalgebra is a structure whose domain is a subset of that of a bigger structure and Benzodiazepines are molecularly similar to several groups of drugs, some of which share similar pharmacological properties, including the quinazolinones, hydantoines, succinimides, oxazolidinediones, barbiturates and glutarimides. Quinazoline is a compound made up of two fused six-membered Simple aromatic rings a Benzene ring and a Pyrimidine ring Succinimide is a cyclic Imide with the formula C4H5NO2 It appears as a white or colorless crystalline solid and has a faint odor of sweat The following are oxazolidinediones Paramethadione Trimethadione Ethadione to chemicals for scientifical Barbiturates are drugs that act as central nervous system Depressants and by virtue of this they produce a wide spectrum of effects from mild Sedation ^[9]^[10]

Most benzodiazepines are administered orally; however, administration can also occur intravenously, intramuscularly, sublingually or as a suppository. Intravenous therapy or IV therapy is the giving of Liquid substances directly into a Vein. Intramuscular injection is the injection of a substance directly into a Muscle. A suppository is a drug delivery system that is inserted either into the Rectum (rectal suppository Vagina (vaginal suppository or Urethra (urethral Common benzodiazepines and their primary trade names include:

Hypnotic benzodiazepines

brotizolam (Lendormin)
estazolam (ProSom)
flunitrazepam (Rohypnol; Hypnodorm)
flurazepam (Dalmane)
loprazolam (Dormonoct)
lormetazepam (Loramet)
midazolam (Dormicum; Versed)
nimetazepam (Ermin)
nitrazepam (Mogadon; Alodorm)
temazepam (Restoril; Normison)
triazolam (Halcion)

Anxiolytic benzodiazepines

alprazolam (Xanax)
bromazepam (Lexotan; Lexotanil)
chlordiazepoxide (Librium)
clonazepam (Rivotril; Klonopin)
clorazepate (Tranxene)
diazepam (Valium)
lorazepam (Ativan; Temesta; Tavor)
oxazepam (Serax; Serepax)
prazepam (Centrax; Lysanxia)

A related class of drugs that also work on the benzodiazepine receptors, the nonbenzodiazepines, has recently been introduced. Brotizolam (marketed under brand name Lendormin is a drug which is Thienobenzodiazepine (a Benzodiazepine derivative Estazolam (marketed under the brand names ProSom, Eurodin) is a drug which is a Benzodiazepine derivative. Flunitrazepam (ˌfluːnaɪˈtræzəpæm is a highly potent Hypnotic drug with powerful Sedative, Anxiolytic, Amnestic, and Skeletal Flurazepam (marketed under the brand names Dalmane and Dalmadorm) is a drug which is a Benzodiazepine derivative Loprazolam ( Triazulenone) marketed under the brand names Dormonoct Havlane Sonin Somnovit is a drug which is an imidazole Benzodiazepine derivative Lormetazepam is available as a generic or available under the following trade or brand names ( Noctamid, Ergocalm, Loramet, Dilamet, Sedaben Midazolam (marketed under brand names Dormicum, Flormidal, Versed, Hypnovel and Dormonid, pronounced mɪˈdæzəlæm Nimetazepam (marketed under brand name Erimin) is a powerful Hypnotic drug which is a Benzodiazepine derivative which was first synthesized in Japan Nitrazepam is a type of Benzodiazepine drug It is a hypnotic drug with Sedative and motor impairing properties Anxiolytic, Amnestic Temazepam (marketed under brand names Restoril, Euhypnos, Normison, Remestan, Tenox and Norkotral) is an intermediate-acting Triazolam (marketed under brand names Halcion, Novodorm, Songar) is a Benzodiazepine derivative drug Alprazolam, also known under the trade names Xanax and Niravam, is a short-acting drug of the Benzodiazepine class used to treat moderate Bromazepam (marketed under brand names Calmepam Compendium Creosedin Durazanil Lectopam Lexaurin Lexilium Lexomil Lexotan Lexotanil Normoc Novepam Somalium Lexatin is a drug Chlordiazepoxide (pronounced) is a Sedative / Hypnotic drug which is a Benzodiazepine derivative and is marketed under the trade name Librium Clonazepam (marketed by Roche under the trade-names Klonopin in the United States and Rivotril, Ravotril or Rivatril in Europe South Clorazepate (marketed under the brand names Tranxene and Tranxilium) is a drug which is a Benzodiazepine Diazepam (daɪˈæzɨpæm first marketed as Valium by Hoffmann-La Roche, is a Benzodiazepine derivative Drug. Lorazepam (also known by its brand name Ativan or Temesta) is a Benzodiazepine drug with short to medium duration of action Oxazepam (marketed under brand names Alepam, Murelax, Opamox, Oxascand, Serax, Serepax, Seresta, Sobril Prazepam (marketed under the trade name Centrax, in the US is a Benzodiazepine derivative drug The nonbenzodiazepines are comparatively new drugs whose actions are somewhat similar to those of the Benzodiazepines but are structurally unrelated to the Benzodiazepines ^[11] Nonbenzodiazepines are molecularly distinct from benzodiazepines and have less addictive potential, while still offering benefits very similar to those of benzodiazepines.

Pharmacology

Duration of action

Benzodiazepines are commonly divided into three groups by their half-lives: Short-acting compounds have a half-life of less than 12 hours, and have few residual effects if taken before bedtime, but rebound insomnia may occur and they might cause wake-time anxiety. The biological half-life of a substance is the time it takes for a substance (drug radioactive nuclide or other to lose half of its pharmacologic physiologic or radiologic activity Rebound insomnia is Insomnia that occurs following discontinuation of Sedative substances taken to relieve primary insomnia Intermediate-acting compounds have a half-life of 12–24 hours, may have residual effects in the first half of the day. Rebound insomnia however is more common upon discontinuation of short-acting benzodiazepines. Daytime withdrawal symptoms are also a problem with prolonged usage of short-acting benzodiazepines, including daytime anxiety. Long-acting compounds have a half-life greater than 24 hours. ^[12]^[13] Strong sedative effects typically persist throughout the next day if long-acting preparations are used for insomnia. A sedative, or more specifically a sedative-hypnotic, is a substance that depresses the Central nervous system (CNS resulting in calmness relaxation sleepiness Accumulation of the compounds in the body may occur. The elimination half-life may greatly vary between individuals, especially the elderly. Shorter-acting compounds are usually best for their hypnotic effects, whereas longer-acting compounds are usually better for their anxiolytic effects. For the state of mind see Hypnosis. Hypnotic drugs induce Sleep (which differentiates them from the Sedative An anxiolytic is a drug prescribed for the treatment of Symptoms of Anxiety. Benzodiazepines with shorter half-lives tend to be able to produce tolerance and addiction quicker, as the drug does not last in the system for as long, with resultant interdose withdrawal phenomenon and next-dose craving. Although short-acting drugs are more commonly prescribed for insomnia, there are exceptions to the rules, such as alprazolam being prescribed as an anxiolytic more than a hypnotic, despite possessing a short half-life. Alprazolam, also known under the trade names Xanax and Niravam, is a short-acting drug of the Benzodiazepine class used to treat moderate An anxiolytic is a drug prescribed for the treatment of Symptoms of Anxiety.

Mechanism of action

Benzodiazepines produce a range of effects from depressing to stimulating the central nervous system via modulating the GABA_A receptor, the most prolific inhibitory receptor within the brain. In Vertebrates the central nervous system ( CNS) is the part of the Nervous system which is enclosed in the Meninges. The GABAA receptor is one of two ligand-gated Ion channels responsible for mediating the effects of Gamma-aminobutyric acid (GABA the major The GABA_A receptor is made up from 5 subunits out of a possible 19, and GABA_A receptors made up of different combinations of subunits have different properties, different locations within the brain, and different activities relative to pharmacological and clinical effects.

Benzodiazepines bind at the interface of the α and γ subunits on the GABA _A receptor. Benzodiazepine binding also requires that alpha subunits contain a histidine amino acid residue, (i. Histidine (abbreviated as His or H) is one of the 20 standard Amino acids present in Proteins In the Nutritional sense in e. , α₁, α₂, α₃ and α₅ containing GABA_A receptors). For this reason, benzodiazepines show no affinity for α₄ and α₆ subunits containing GABA_A receptors, which contain an arginine instead of a histidine residue. Arginine (abbreviated as Arg or R) is an α- Amino acid. The L-form is one of the 20 most common natural amino acids Other sites on the GABA_A receptor also bind neurosteroids, barbiturates and certain anesthetics. Neuroactive Steroids (or neurosteroids') rapidly alter Neuronal excitability through interaction with Neurotransmitter[[ligand gated ion channel|-gated Barbiturates are drugs that act as central nervous system Depressants and by virtue of this they produce a wide spectrum of effects from mild Sedation Anesthesia, or anaesthesia (see spelling differences; from Greek grc αν- an-, "without" and grc αἲσθησις ^[14]

In order for GABA_A receptors to be sensitive to the action of benzodiazepines, they need to contain both an α and a γ subunit, where the benzodiazepine binds at the interface. Once bound, the benzodiazepine locks the GABA_A receptor into a conformation where the neurotransmitter GABA has much higher affinity for the GABA_A receptor, increasing the frequency of opening of the associated chloride ion channel and hyperpolarizing the membrane. Ion channels are pore-forming Proteins that help establish and control the small Voltage Gradient across the Plasma membrane of all living This potentiates the inhibitory effect of the available GABA, leading to sedatory and anxiolytic effects. As mentioned above, different benzodiazepines can have different affinities for GABA_A receptors made up of different collection of subunits. For instance, benzodiazepines with high activity at the α₁ are associated with sedation, whereas those with higher affinity for GABA_A receptors containing α₂ and/or α₃ subunits have good anti-anxiety activity. ^[15] Benzodiazepines also bind to glial cell membranes. Glial cells, commonly called neuroglia or simply glia (Greek for "glue" are non- Neuronal cells that provide support and nutrition ^[16]

Benzodiazepines are full agonists at the benzodiazepine receptor producing anxiolytic and sedating properties. An agonist is a term used to describe a type of ligand or drug that binds and alters the activity of a receptor.

Compounds that bind to the benzodiazepine receptor and enhance the GABA receptor function are termed benzodiazepine receptor agonists and display sedative/hypnotic properties. Compounds that, in the absence of agonist, have no apparent activity but that competitively inhibit the binding of agonists to the receptor are called benzodiazepine receptor antagonists. A receptor antagonist is a type of receptor ligand or Drug that does not provoke a biological response itself upon binding to a receptor, but blocks Ligands that decrease GABA function are termed benzodiazepine receptor inverse agonists. In Pharmacology, an inverse agonist is an agent which binds to the same receptor binding-site as an Agonist for that receptor and reverses constitutive Full inverse agonists have potent convulsant activities.

Some compounds lie somewhere between being full agonists or full antagonists, and are termed either partial agonists or partial antagonists. There has been interest in partial agonists for the benzodiazepine receptor with evidence that complete tolerance may not occur with chronic use, with partial agonists demonstrating continued anxiolytic properties with reduced sedation, dependence, and withdrawal problems. ^[17]

The anticonvulsant properties of benzodiazepines may be in part or entirely due to binding to voltage-dependent sodium channels rather than benzodiazepine receptors. Sustained repetitive firing seems to be limited by benzodiazepines effect of slowing recovery of sodium channels from inactivation. ^[18]

Therapeutic uses

Benzodiazepines have a number of therapeutic uses, are well-tolerated, and are very safe and effective drugs in the short term for a wide range of conditions.

Use as anticonvulsants

Benzodiazepines are potent anticonvulsants and have life-saving properties in the acute management of status epilepticus. Clobazam is a drug which is a Benzodiazepine derivative It has been marketed as an Anxiolytic since 1975 and an Anticonvulsant since 1984 Clonazepam (marketed by Roche under the trade-names Klonopin in the United States and Rivotril, Ravotril or Rivatril in Europe South Clorazepate (marketed under the brand names Tranxene and Tranxilium) is a drug which is a Benzodiazepine Diazepam (daɪˈæzɨpæm first marketed as Valium by Hoffmann-La Roche, is a Benzodiazepine derivative Drug. Lorazepam (also known by its brand name Ativan or Temesta) is a Benzodiazepine drug with short to medium duration of action Midazolam (marketed under brand names Dormicum, Flormidal, Versed, Hypnovel and Dormonid, pronounced mɪˈdæzəlæm The anticonvulsants, also called antiepileptic drugs (abbreviated "AEDs" are a diverse group of pharmaceuticals used in the treatment of epileptic Status epilepticus (SE refers to a life-threatening condition in which the Brain is in a state of persistent Seizure. The most commonly-used benzodiazepines for seizure control are lorazepam and diazepam. Lorazepam (also known by its brand name Ativan or Temesta) is a Benzodiazepine drug with short to medium duration of action Diazepam (daɪˈæzɨpæm first marketed as Valium by Hoffmann-La Roche, is a Benzodiazepine derivative Drug. A meta-analysis of 11 clinical trials concluded that lorazepam was superior to diazepam in treating persistent seizures. In Statistics, a meta-analysis combines the results of several studies that address a set of related research hypotheses ^[19] Although diazepam is much longer-acting than lorazepam, lorazepam has a more prolonged anticonvulsant effect. This is because diazepam is very lipid-soluble and highly protein-bound, and has a very large distribution of unbound drug, resulting in diazepam's having only a 20– to 30-minute duration of action against status epilepticus. Lorazepam, however, has a much smaller volume of distribution of unbound drug, which results in a more prolonged duration of action against status epilepticus. Lorazepam can therefore be considered superior to diazepam, at least in the initial stages of treatment of status epilepticus. ^[20]

Use as anxiolytics

Benzodiazepines possess anti-anxiety properties and can be useful for the short-term treatment of severe anxiety. Alprazolam, also known under the trade names Xanax and Niravam, is a short-acting drug of the Benzodiazepine class used to treat moderate Bromazepam (marketed under brand names Calmepam Compendium Creosedin Durazanil Lectopam Lexaurin Lexilium Lexomil Lexotan Lexotanil Normoc Novepam Somalium Lexatin is a drug Chlordiazepoxide (pronounced) is a Sedative / Hypnotic drug which is a Benzodiazepine derivative and is marketed under the trade name Librium Clonazepam (marketed by Roche under the trade-names Klonopin in the United States and Rivotril, Ravotril or Rivatril in Europe South Clorazepate (marketed under the brand names Tranxene and Tranxilium) is a drug which is a Benzodiazepine Diazepam (daɪˈæzɨpæm first marketed as Valium by Hoffmann-La Roche, is a Benzodiazepine derivative Drug. Lorazepam (also known by its brand name Ativan or Temesta) is a Benzodiazepine drug with short to medium duration of action Medazepam is a drug which is a Benzodiazepine derivative It possesses Anxiolytic, Anticonvulsant, Sedative and Skeletal muscle relaxant Nordazepam (marketed under brand names Stilny Madar Vegesan and Calmday also known as nordiazepam and desmethyldiazepam, is a 14-benzodiazepine Oxazepam (marketed under brand names Alepam, Murelax, Opamox, Oxascand, Serax, Serepax, Seresta, Sobril Prazepam (marketed under the trade name Centrax, in the US is a Benzodiazepine derivative drug Benzodiazepines are usually administered orally for the treatment of anxiety; however, occasionally lorazepam or diazepam may be given intravenously for the treatment of panic attacks. Panic attacks are sudden discrete periods of intense anxiety mounting Physiological arousal fear stomach problems and discomfort that are associated with a variety of [1]

A panel of over 50 peer-nominated internationally recognized experts in the pharmacotherapy of anxiety and depression judged the benzodiazepines, especially combined with an antidepressant, as the mainstays of pharmacotherapy for anxiety disorders. ^[21]^[22]^[23]^[24]

Despite increasing focus on the use of antidepressants and other agents for the treatment of anxiety, benzodiazepines have remained a mainstay of anxiolytic pharmacotherapy due to their robust efficacy, rapid onset of therapeutic effect, and generally favorable side effect profile. ^[25] Treatment patterns for psychotropic drugs appear to have remained stable over the past decade, with benzodiazepines being the most commonly used medication for panic disorder. ^[26]

Use for insomnia

Hypnotic benzodiazepines have strong sedative effects, and certain benzodiazepines therefore are often prescribed for the management of insomnia. Brotizolam (marketed under brand name Lendormin is a drug which is Thienobenzodiazepine (a Benzodiazepine derivative Estazolam (marketed under the brand names ProSom, Eurodin) is a drug which is a Benzodiazepine derivative. Flunitrazepam (ˌfluːnaɪˈtræzəpæm is a highly potent Hypnotic drug with powerful Sedative, Anxiolytic, Amnestic, and Skeletal Flurazepam (marketed under the brand names Dalmane and Dalmadorm) is a drug which is a Benzodiazepine derivative Loprazolam ( Triazulenone) marketed under the brand names Dormonoct Havlane Sonin Somnovit is a drug which is an imidazole Benzodiazepine derivative Lormetazepam is available as a generic or available under the following trade or brand names ( Noctamid, Ergocalm, Loramet, Dilamet, Sedaben Midazolam (marketed under brand names Dormicum, Flormidal, Versed, Hypnovel and Dormonid, pronounced mɪˈdæzəlæm Nimetazepam (marketed under brand name Erimin) is a powerful Hypnotic drug which is a Benzodiazepine derivative which was first synthesized in Japan Nitrazepam is a type of Benzodiazepine drug It is a hypnotic drug with Sedative and motor impairing properties Anxiolytic, Amnestic Phenazepam is a Benzodiazepine drug which was developed in Soviet Union and now produced in Russia and some CIS countries Temazepam (marketed under brand names Restoril, Euhypnos, Normison, Remestan, Tenox and Norkotral) is an intermediate-acting Triazolam (marketed under brand names Halcion, Novodorm, Songar) is a Benzodiazepine derivative drug Longer-acting benzodiazepines, such as nitrazepam, have side-effects that may persist into the next day, whereas the more intermediate-acting benzodiazepines (for example, temazepam) may have less "hangover" effects the next day. Temazepam (marketed under brand names Restoril, Euhypnos, Normison, Remestan, Tenox and Norkotral) is an intermediate-acting [2] Benzodiazepine hypnotics should be reserved for short-term courses to treat acute conditions, as tolerance and dependence may occur if these benzodiazepines are taken regularly for more than a few weeks.

Use as a premedication before procedures

Benzodiazepines can be very beneficial as premedication before surgery, especially in those that are anxious. Usually administered a couple of hours before surgery, benzodiazepines will bring about anxiety relief and also produce amnesia. Amnesia can be useful in this situation, as patients will not be able to remember any unpleasantness from surgery. [3] Lorazepam can be utilized in patients who are particularly anxious about dental procedures. [4] Alternatively nitrous oxide can be administered in dental phobia due to its sedative and dissociative effects, its fast onset of action, and its extremely short duration of action. Nitrous oxide, commonly known as " laughing gas," is a Chemical compound with the Chemical formula N 2 O. Dental fear refers to the Fear of Dentistry and of receiving Dental care.

Use in intensive care

Benzodiazepines can be very useful in intensive care to sedate patients receiving mechanical ventilation, or those in extreme distress or severe pain. In Medicine, mechanical ventilation is a method to mechanically assist or replace spontaneous breathing when patients cannot do so on their own Caution should be exercised in this situation due to the occasional scenario of respiratory depression, and benzodiazepine overdose treatment facilities should be available. [5]

The following are some of the criteria for Intensive care unit monitoring[6]

• Age greater than 40 with concomitant medical illness e. g. cardiac disease with failure, ischemia or angina, recent infarction • Severe electrolyte imbalances especially with ECG changes, severe acid base disturbances • Hemodynamic instability • Respiratory insufficiency, hypoxemia and or hypercapnia • Potentially serious infections, including sepsis • GI pathology including pancreatitis, GI bleeding, fulminant hepatic failure, peritonitis • Persistent hyperthermia (Tmax > 39 0 or 1030 F) • Rhabdomyolysis • Renal failure • Prior history of severe Delirium Tremens • Need for IV benzodiazepines or other IV drips to control withdrawal

Use in alcohol dependence

Benzodiazepines have been shown to be safe and effective, particularly for preventing or treating seizures and delirium, and are the preferred agents for treating the symptoms of alcohol withdrawal syndrome^[27]. Chlordiazepoxide (pronounced) is a Sedative / Hypnotic drug which is a Benzodiazepine derivative and is marketed under the trade name Librium Diazepam (daɪˈæzɨpæm first marketed as Valium by Hoffmann-La Roche, is a Benzodiazepine derivative Drug. Lorazepam (also known by its brand name Ativan or Temesta) is a Benzodiazepine drug with short to medium duration of action Oxazepam (marketed under brand names Alepam, Murelax, Opamox, Oxascand, Serax, Serepax, Seresta, Sobril Phenazepam is a Benzodiazepine drug which was developed in Soviet Union and now produced in Russia and some CIS countries An epileptic seizure is caused by excessive and/or hypersynchronous electrical Neuronal activity and is usually self-limiting Delirium is an acute and relatively sudden (developing over hours to days decline in attention-focus perception and Cognition. Alcohol detoxification, or detox, for individuals with Alcohol dependence, is the abrupt cessation of alcohol intake coupled with the substitution of alcohol with The choice of agent is based on pharmacokinetics. Pharmacokinetics (in Greek: “pharmacon” meaning drug and “kinetikos” meaning putting in motion the study of time dependency sometimes abbreviated as “PK” is a The most commonly used benzodiazepines in the management of alcohol withdrawal are Diazepam (Valium) and chlordiazepoxide (Librium), two long-acting agents, and lorazepam (Ativan) and oxazepam (Serax), two intermediate acting agents. The long half-life of diazepam and chlordiazepoxide make withdrawal smoother, and rebound withdrawal symptoms are less likely to occur. The two intermediate-acting agents have excellent records of efficacy. Chlordiazepoxide is the benzodiazepine of choice in uncomplicated alcohol withdrawal^[28]. Chlordiazepoxide (pronounced) is a Sedative / Hypnotic drug which is a Benzodiazepine derivative and is marketed under the trade name Librium Oxazepam is the most commonly used benzodiazepine in managing alcohol withdrawal symptoms. Oxazepam (marketed under brand names Alepam, Murelax, Opamox, Oxascand, Serax, Serepax, Seresta, Sobril It is the benzodiazepine of choice in treating severe alcohol withdrawal symptoms, and it's often used in patients who metabolize medications less effectively, particularly the elderly and those with cirrhosis. Lorazepam is the only benzodiazepine with predictable intramuscular absorption (if intramuscular administration is necessary) and it's the most effective in preventing and controlling seizures. Phenazepam is another benzodiazepine which has been used to treat alcohol withdrawal with excellent efficacy. Phenazepam is a Benzodiazepine drug which was developed in Soviet Union and now produced in Russia and some CIS countries In Russia, it is preferred over diazepam in the management of alcohol withdrawal.

Use in muscular disorders

Benzodiazepines are well known for their strong muscle-relaxing properties, and can be useful in the treatment of muscle spasms, for example, Tetanus or spastic disorders [7] and Restless legs syndrome. Tetanus is a medical condition that is characterized by a prolonged contraction of Skeletal muscle fibres Spazz redirects here This article is about the word For the band see Spazz (band. Restless legs syndrome (RLS Wittmaack-Ekbom's syndrome, or sometimes but inaccurately referred to as Nocturnal myoclonus) is a condition that is characterized Clonazepam has been used with efficacy in the treatment of some forms of Tourette's syndrome (with symptoms more on the side of motor tics, as opposed to vocal tics, although almost any tic can be preceded by, and intensify with stress; therapy for Tourette's syndrome is highly individualized. ) Many people experiencing tremors may be helped with benzodiazepines.

Use in acute mania

Mania, a mood disorder, is a state of extreme mood elevation and is a diagnosable serious psychiatric disorder. Mania (from Greek μανία and that from μαίνομαι - mainomai, "to rage to be furious" is a severe medical condition Mental disorder or mental illness is a psychological or behavioral pattern that occurs in an individual and is thought to cause distress or disability that is not expected as Benzodiazepines can be very useful in the short-term treatment of acute mania, until the effects of Lithium or neuroleptics take effect. Lithium (ˈlɪθiəm is a Chemical element with the symbol Li and Atomic number 3 Antipsychotics are a group of Psychoactive drugs commonly but not exclusively used to treat Psychosis, which is typified by Schizophrenia. Benzodiazepines bring about rapid tranquillisation and sedation of the manic individual, therefore benzodiazepines are a very important tool in the management of mania. Both clonazepam and lorazepam are used for the treatment, with some evidence that clonazepam may be superior in the treatment of acute mania. Clonazepam (marketed by Roche under the trade-names Klonopin in the United States and Rivotril, Ravotril or Rivatril in Europe South Lorazepam (also known by its brand name Ativan or Temesta) is a Benzodiazepine drug with short to medium duration of action ^[29]^[30]

Therapeutic uses in veterinary practice

As in humans, benzodiazepines have a wide range of uses in veterinary practice in the treatment of various disorders and scenarios involving animals. Veterinary medicine the application of medical, diagnostic, and therapeutic principles to companion, domestic, exotic, wildlife

Midazolam and diazepam are utilized for their anesthetic properties in veterinary practice in combination with other general anesthetic drugs such as ketamine. Midazolam (marketed under brand names Dormicum, Flormidal, Versed, Hypnovel and Dormonid, pronounced mɪˈdæzəlæm Veterinary anesthesia is Anesthesia performed on animals (excluding humans performed by a Veterinarian. Ketamine is a drug for use in human and veterinary medicine developed by Parke-Davis (today a part of Pfizer) in 1962 ^[31]^[32]

Midazolam or diazepam can also be used as a sedative anxiolytic to quell anxiety and agitation experienced by animals in veterinary practice, for example, during transport. Midazolam (marketed under brand names Dormicum, Flormidal, Versed, Hypnovel and Dormonid, pronounced mɪˈdæzəlæm Diazepam (daɪˈæzɨpæm first marketed as Valium by Hoffmann-La Roche, is a Benzodiazepine derivative Drug. ^[33]^[34] Diazepam has also been found to have tranquillising effects on various animals tested with the following properties; myorelaxation, stress reduction and aggression inhibition. This article refers to skeletal muscle relaxants For information on Smooth muscle relaxants see Antispasmodic. ^[35]

Benzodiazepines are also commonly used for the control of muscular conditions in animals. Diazepam has been prescribed for the effective treatment and control of tremors by veterinarians in animals. Diazepam (daɪˈæzɨpæm first marketed as Valium by Hoffmann-La Roche, is a Benzodiazepine derivative Drug. A veterinarian ( American English) or a Veterinary surgeon ( British English) often shortened to vet, is a Physician Corticosteroids and or Diazepam have been found to be effective for the control of tremors in veterinarian practice. Corticosteroids are a class of Steroid hormones that are produced in the Adrenal cortex. ^[36]^[37] Diazepam has also been used in to control muscle spasms that were the result of tetanus in cats. A spasm is a sudden involuntary contraction of a Muscle, a group of muscles or a hollow organ, or a similarly sudden Contraction of an Orifice Tetanus is a medical condition that is characterized by a prolonged contraction of Skeletal muscle fibres ^[38]

Benzodiazepines, such as diazepam, are used in the treatment of various forms of epilepsy in dogs. ^[39] Benzodiazepines have potent anticonvulsant properties and are very effective in the short term in managing seizure disorders in animals. The anticonvulsants, also called antiepileptic drugs (abbreviated "AEDs" are a diverse group of pharmaceuticals used in the treatment of epileptic However, with prolonged usage, benzodiazepines tend to lose their anticonvulsant properties. Partial benzodiazepine receptor agonists have shown some promise, with continued efficacy being demonstrated with benzodiazepine receptor partial agonists and also displaying mild withdrawal symptoms upon discontinuation, which may make them superior to benzodiazepines in the long-term management of epilepsy in animals. Efficacy is the capacity to produce a desired size of an effect under Ideal or Optimal conditions An agonist is a term used to describe a type of ligand or drug that binds and alters the activity of a receptor. Epilepsy is a common chronic Neurological disorder that is characterized by recurrent unprovoked seizures. ^[40] Phenobarbital is the drug of choice and potassium bromide is the drug of second choice in the treatment of epilepsy in dogs and diazepam is recommended for the treatment at home of cluster seizures. Potassium bromide ( K[[Bromine Br]] is a salt, widely used as an Anticonvulsant and a Sedative in the late 19th and early 20th centuries ^[41]

Lorazepam has been found to be an effective premedication before general anesthesia in bringing about adequate muscular relaxation for veterinary surgery. Lorazepam (also known by its brand name Ativan or Temesta) is a Benzodiazepine drug with short to medium duration of action Premedication refer to a drug treatment given to a patient before a (surgical or invasive medical procedure In modern medical practice general anaesthesia ( AmE: anesthesia) is a state of total unconsciousness resulting from General anaesthetic drugs Veterinary surgery is Surgery performed on animals by Veterinarians Most veterinarians perform surgery but it is also possible to specialize in surgery by becoming ^[42]

Midazolam can also be used along with other drugs in the sedation and capture of wild animals. Midazolam (marketed under brand names Dormicum, Flormidal, Versed, Hypnovel and Dormonid, pronounced mɪˈdæzəlæm ^[43]

Side-effects

The following list summarises the side effects which may occur from use of benzodiazepines. ^[44]

Drowsiness
Dizziness
stomach upset
Blurred vision
Headache
Confusion
Depression
Impaired coordination
Changes in heart rate
Trembling
Weakness
Amnesia
Hangover effect (grogginess)
Dreaming or nightmares
Chest pain
Vision changes
Jaundice
Paradoxical reactions^[45]

Paradoxical reactions

Severe behavioral changes resulting from benzodiazepines have been reported including mania, schizophrenia, anger, impulsivity, and hypomania. Somnolence (or " drowsiness " is a state of near- Sleep, a strong desire for sleep or sleeping for unusually long periods (c Many different terms are often used to describe what is collectively known as dizziness. In Human anatomy, the stomach is a J-shaped hollow muscular organ of the Gastrointestinal tract involved in the second phase of Digestion, following Blurred vision is an Ocular Symptom. Causes There are many causes of blurred vision including use of Atropine. A headache ( cephalalgia in medical terminology is a condition of pain in the Head; sometimes Neck or upper back pain may also be interpreted Confusion, of a Pathological degree usually refers to loss of orientation (ability to place oneself correctly in the world by time location and personal identity and In the fields of Psychology and Psychiatry, the terms depression or depressed refer to both expected and pathologically chronic or severe Amnesia (from Greek) is a condition in which Memory is disturbed In Medicine, chest pain is a Symptom of a number of serious conditions and is generally considered a Medical emergency. Jaundice, also known as icterus (attributive adjective "icteric" is yellowish discoloration of the Skin, sclerae (whites of the eyes A paradoxical reaction is when medical treatment usually a drug has an opposite effect to an effect normally expected Mania (from Greek μανία and that from μαίνομαι - mainomai, "to rage to be furious" is a severe medical condition Schizophrenia ( from the Greek roots schizein (σχίζειν "to split" and phrēn This article is an expansion of a section entitled '''Hypomania''' from within the main article Bipolar disorder. ^[46] Individuals with borderline personality disorder appear to have a greater risk of experiencing severe behavioral or psychiatric disturbances from benzodiazepines. Borderline personality disorder ( BPD) is a psychiatric diagnosis in the Diagnostic and Statistical Manual of Mental Disorders ( DSM-IV Personality Aggression and violent outbursts can also occur with benzodiazepines, particularly when they are combined with alcohol. Recreational abusers and patients on high-dosage regimes may be at an even greater risk of experiencing paradoxical reactions to benzodiazepines. ^[47] Paradoxical reactions may occur in any individual on commencement of therapy and initial monitoring should take into account the risk of increase in anxiety or suicidal thoughts. A paradoxical reaction is when medical treatment usually a drug has an opposite effect to an effect normally expected ^[45]

When benzodiazepines are used as an adjunct in the treatment of seizures, an increase in dosage of the primary agent may be required. The concomitant administration of benzodiazepines and anti-convulsants may precipitate an increase in certain seizure activity, specifically tonic-clonic seizures.

In a letter to the British Medical Journal, it was reported that a high proportion of parents referred for actual or threatened child abuse were taking drugs at the time, often a combination of benzodiazepines and tricyclic antidepressants. Child abuse is the physical, psychological or sexual maltreatment of children Many mothers described that instead of feeling less anxious or depressed, they became more hostile and openly aggressive towards the child as well as to other family members while consuming tranquilizers. Anxiety is a physiological and psychological state characterized by Cognitive, Somatic, Emotional and Behavioral components The author warned that environmental or social stresses such as difficulty coping with a crying baby combined with the effects of tranquilizers may precipitate a child abuse event. ^[48]

Paradoxical rage reactions from benzodiazepines are thought to be due to partial deterioration from consciousness, generating automatic behaviors, fixation amnesia, and aggressiveness from disinhibition with a possible serotonergic mechanism playing a role. ^[49]

Physical dependence and withdrawal

Main article: Benzodiazepine withdrawal syndrome

Long-term benzodiazepine usage, in general, leads to some form of tolerance and/or dependence with the appearance of a benzodiazepine withdrawal syndrome when the benzodiazepines are stopped or the dose is reduced. Benzodiazepine withdrawal syndrome is caused by stopping benzodiazepines or during dosage reduction of Benzodiazepines. Drug tolerance occurs when a subject's reaction to a Psychoactive drug (such as a painkiller or intoxicant decreases so that larger doses are required to achieve the same effect Physical dependence (or drug dependence) refers to a state resulting from habitual use of a drug where negative physical Withdrawal symptoms result from abrupt discontinuation Benzodiazepine withdrawal syndrome is caused by stopping benzodiazepines or during dosage reduction of Benzodiazepines. However, it is important to distinguish between addiction to and normal physical dependence on benzodiazepines. Intentional abusers of benzodiazepines usually have other substance abuse problems. Benzodiazepines are usually a secondary drug of abuse-used mainly to augment the high received from another drug or to offset the adverse effects of other drugs. F. ^[50]

Regular use of benzodiazepines at prescribed levels for six weeks was found to produce a significant risk of dependence, with resultant withdrawal symptoms appearing on abrupt discontinuation in a study assessing diazepam and buspirone. However, with abrupt withdrawal after six weeks of treatment with buspirone, no withdrawal symptoms developed. ^[51] Various studies have shown between 20–100% of patients prescribed benzodiazepines at therapeutic dosages long term are physically dependent and will experience withdrawal symptoms. ^[52]

Benzodiazepine dependence is a frequent complication when they are prescribed for or taken for longer than four weeks, with physical dependence and withdrawal symptoms being the most common problem, but also occasionally drug-seeking behavior. Withdrawal symptoms include anxiety, perceptual disturbances, distortion of all the senses, dysphoria, and, in rare cases, psychosis, and epileptic seizures. The risk factors for benzodiazepine dependence are long-term use beyond four weeks, use of high doses, and use of potent short-acting benzodiazepines among those with certain pre-existing personality characteristics such as dependent personalities, and those prone to drug abuse. ^[53]

Previously, physical dependence on benzodiazepines was largely thought to occur only in people on high-therapeutic-dose ranges, and low- or normal-dose dependence was not suspected until the 1970s; and it wasn't until the early 1980s that it was confirmed. ^[54] However, low-dose dependence is now a recognized clinical disadvantage of benzodiazepines, and severe withdrawal syndromes can occur from these low doses of benzodiazepines even after gradual dose reduction. ^[55]^[56] Low dose dependence has now been clearly demonstrated in both animal studies and human studies. ^[57]^[58]

In an animal study of four baboons on low-dose benzodiazepine treatment, three out of the four baboons demonstrated physical dependence and developed flumazenil-precipitated withdrawal symptoms after only two weeks of low-dose benzodiazepine treatment. The baboons are African Old World monkeys belonging to the genus Papio, part of the subfamily Cercopithecinae. Physical dependence (or drug dependence) refers to a state resulting from habitual use of a drug where negative physical Withdrawal symptoms result from abrupt discontinuation Flumazenil (also known as flumazepil, code name Ro 15-1788, trade names Anexate, Lanexat, Mazicon, Romazicon Furthermore, the baboons on low-dose therapy did not develop more severe flumazenil-precipitated withdrawal symptoms because low-dose benzodiazepine therapy was continued over a period of 6–10 months, suggesting rapid onset of dependence with benzodiazepines and suggesting that physical dependence was complete after two weeks of chronic, low-dose benzodiazepine treatment. ^[59] In another animal study, physical dependence was demonstrated with withdrawal signs appearing after only seven days of low-dose benzodiazepine treatment, and withdrawal signs appeared after only three days after high-dose treatment, which demonstrated the extremely rapid development of tolerance and dependence on benzodiazepines, at least in baboons. It was also found that previous exposure to benzodiazepines sensitized baboons to the development of physical dependence. ^[60]

In humans, chronic, low-therapeutic-dose dependence was clearly demonstrated using flumazenil to show physical dependence and withdrawal signs. Human beings, humans or man (Origin 1590–1600 L homō man OL hemō the earthly one (see Humus Withdrawal symptoms experienced by the chronic therapeutic low-dose subjects included increased ratings of dizziness, blurred vision, heart pounding, feelings of unreality, pins and needles, nausea, sweatiness, noises louder than usual, jitteriness, things moving, sensitivity to touch. Many different terms are often used to describe what is collectively known as dizziness. Paresthesia (pron /ˌpɛɹɪsˈθiʒə/ paraesthesia in British English, pron Nausea ( Latin: Nausea, Greek:, " Sea-sickness " also called wamble) is the sensation of unease and discomfort ^[61] In another study of 34 low-dose benzodiazepine users, physiological dependence was demonstrated by the appearance of withdrawal symptoms in 100% of those who received flumazenil whereas those receiving placebo experienced no withdrawal signs. Physiology (from Greek grc φύσις physis, "nature origin" and grc -λογία -logia) is the study of the mechanical physical It was also found that those dependent on low doses of benzodiazepines with a history of panic attacks were at an increased risk of suffering panic attacks due to flumazenil precipitated benzodiazepine withdrawal. ^[62] It has been estimated that 30–45% of chronic low dose benzodiazepine users are dependent and it has been recommended that benzodiazepines even at low dosage be prescribed for a maximum of 7–14 days to avoid dependence. ^[63]

Some controversy remains, however, in the medical literature as to the exact nature of low-dose dependence and the difficulty in getting patients to discontinue their benzodiazepines, with some papers attributing the problem to predominantly drug-seeking behavior and drug craving, whereas other papers have found the opposite, attributing the problem to a problem of physical dependence with drug-seeking and craving not being typical of low-dose benzodiazepine users. A controversy or dispute is a commencement of a conflict between statements of accepted fact and a new or unaccepted proposal that disagrees with argues against ^[64]^[65]

Cross tolerance

Benzodiazepines share a similar mechanism of action with various sedative compounds that act by enhancing the GABA_A receptor. Cross tolerance means that one drug will alleviate the withdrawal effects of another. It also means that tolerance of one drug will result in tolerance of another similarly-acting drug. Benzodiazepines are often used for this reason to detoxify alcohol-dependent patients, and can have life-saving properties in preventing and/or treating severe life-threatening withdrawal syndromes from alcohol, such as delirium tremens. Delirium tremens (colloquially the DTs, " the horrors " " the fear "" the shakes "" jazz hands "" However, although benzodiazepines can be very useful in the acute detoxification of alcoholics, benzodiazepines in themselves act as positive reinforcers in alcoholics, by increasing the desire for alcohol. Low doses of benzodiazepines were found to significantly increase the level of alcohol consumed in alcoholics. ^[66] However, alcoholics dependent on benzodiazepines should not be abruptly withdrawn but be very slowly withdrawn from benzodiazepines as over-rapid withdrawal is likely to produce severe anxiety or panic, which is well known for being a relapse risk factor in alcoholics. See (benzodiazepine withdrawal syndrome). Benzodiazepine withdrawal syndrome is caused by stopping benzodiazepines or during dosage reduction of Benzodiazepines.

There is also cross tolerance between alcohol, the benzodiazepines, the barbiturates, and the nonbenzodiazepine drugs, corticosteroids which all act by enhancing the GABA_A receptor's function via modulating the chloride ion channel function of the GABA_A receptor. Barbiturates are drugs that act as central nervous system Depressants and by virtue of this they produce a wide spectrum of effects from mild Sedation The nonbenzodiazepines are comparatively new drugs whose actions are somewhat similar to those of the Benzodiazepines but are structurally unrelated to the Benzodiazepines Corticosteroids are a class of Steroid hormones that are produced in the Adrenal cortex. ^[67]^[68]^[69]^[70] ^[71]

The Committee on the Review of Medicines

The Committee on the Review of Medicines (UK) carried out a review into benzodiazepines due to significant concerns of tolerance, drug dependence, and benzodiazepine withdrawal problems and other adverse effects. Benzodiazepine withdrawal syndrome is caused by stopping benzodiazepines or during dosage reduction of Benzodiazepines. The committee found that benzodiazepines do not have any antidepressant or analgesic properties, and are therefore unsuitable treatments for conditions such as depression, tension headaches, and dysmenorrhoea. An antidepressant is a Psychiatric medication used for alleviating major depression or Dysthymia ('milder' depression Tension headaches, which were renamed tension-type headaches by the International Headache Society in 1988 are the most common type of primary Headaches Dysmenorrhea (or dysmenorrhoea) is a medical condition characterized by severe Uterine Pain during Menstruation. Benzodiazepines are also not beneficial in the treatment of psychosis due to a lack of efficacy. Psychosis (from the Greek ψυχή "psyche" for mind or soul and -οσις "-osis" for abnormal condition with adjective psychotic The committee also recommended against benzodiazepines being used in the treatment of anxiety or insomnia in children. Anxiety is a physiological and psychological state characterized by Cognitive, Somatic, Emotional and Behavioral components Insomnia is a symptom of a sleeping disorder characterized by persistent difficulty falling asleep or staying asleep despite the opportunity The committee was in agreement with the Institute of Medicine (USA) and the conclusions of a study carried out by the White House Office of Drug Policy and the National Institute on Drug Abuse (USA) that there was little evidence that long-term use of benzodiazepine hypnotics are beneficial in the treatment of insomnia due to the development of tolerance. The Institute of Medicine (IOM is one of the United States National Academies, and is a not-for-profit non-governmental American organization chartered in 1970 as a part of the United The White House Office of National Drug Control Policy (ONDCP, a Cabinet level component of the Executive Office of the President of the United States, was established in 1988 The National Institute on Drug Abuse (NIDA is a United States federal-government research institute whose mission is to "lead the Nation in bringing the power of science Benzodiazepines tended to lose their sleep-promoting properties within 3–14 days of continuous use, and, in the treatment of anxiety, the committee found that there was little convincing evidence that benzodiazepines retain efficacy in the treatment of anxiety after 4 months of continuous use due to the development of tolerance.

The committee found that regular use of benzodiazepines may cause dependence characterized by tolerance to the therapeutic effects and the development of benzodiazepine withdrawal syndrome, which includes symptoms such as anxiety, apprehension, tremor, insomnia, nausea, and vomiting upon cessation of benzodiazepine use. Anxiety is a physiological and psychological state characterized by Cognitive, Somatic, Emotional and Behavioral components Fear is an Emotional response to Threats and Danger. It is a basic survival mechanism occurring in response to a specific Stimulus, such as Tremor is an unintentional somewhat rhythmic muscle movement involving to-and-from movements (oscillations of one or more parts of the body Insomnia is a symptom of a sleeping disorder characterized by persistent difficulty falling asleep or staying asleep despite the opportunity Nausea ( Latin: Nausea, Greek:, " Sea-sickness " also called wamble) is the sensation of unease and discomfort Vomiting (also called throwing up, emesis) is the forceful expulsion of the contents of one's Stomach through the Mouth and sometimes the Withdrawal symptoms tended to develop within 24 hours after the cessation of a short-acting benzodiazepine and within 3–10 days after longer acting benzodiazepines. Withdrawal effects could occur, however, after treatment lasting only 2 weeks at therapeutic-dose levels, but with a higher tendency with habitual use beyond 2 weeks and more likely at higher doses. The withdrawal symptoms may appear to be similar to the original condition before treatment. The committee reported that all benzodiazepine therapy should be withdrawn gradually, that therapy be limited to short-term use only and only in carefully-selected patients.

It was noted in the review that alcohol can potentiate the central nervous system depressant effects of benzodiazepines and should be avoided concomitantly. In Vertebrates the central nervous system ( CNS) is the part of the Nervous system which is enclosed in the Meninges. These effects may affect an individual's ability to drive or operate machinery, with the elderly being more prone to these adverse effects. In the neonate, high single doses or repeated low doses have been reported to produce hypotonia, poor sucking, and hypothermia, along with irregularities in the fetal heart. Hypotonia is a condition of abnormally low Muscle tone (the amount of tension or resistance to movement in a muscle often involving reduced muscle strength Hypothermia is a condition in which an organism's temperature drops below that required for normal Metabolism and bodily functions A fetus (or foetus or fœtus) is a developing Mammal or other Viviparous Vertebrate, after the Embryonic stage and Benzodiazepines should also be avoided during lactation. Lactation describes the secretion of Milk from the Mammary glands the process of providing that milk to the young and the period of time that a Mother

Taken together, withdrawal from benzodiazepines should be gradual, as abrupt withdrawal from high doses may cause confusion, toxic psychosis, convulsions, or a condition resembling delirium tremens. Confusion, of a Pathological degree usually refers to loss of orientation (ability to place oneself correctly in the world by time location and personal identity and Psychosis (from the Greek ψυχή "psyche" for mind or soul and -οσις "-osis" for abnormal condition with adjective psychotic An epileptic seizure is caused by excessive and/or hypersynchronous electrical Neuronal activity and is usually self-limiting Delirium tremens (colloquially the DTs, " the horrors " " the fear "" the shakes "" jazz hands "" Abrupt withdrawal from lower doses may cause depression, nervousness, rebound insomnia, irritability, sweating, and diarrhoea. Anxiety is a physiological and psychological state characterized by Cognitive, Somatic, Emotional and Behavioral components Rebound insomnia is Insomnia that occurs following discontinuation of Sedative substances taken to relieve primary insomnia Irritability is an excessive response to stimuli. Irritability takes many forms from the Contraction of a Unicellular organism when touched to complex In Medicine, diarrhea, also spelled diarrhoea (see spelling differences) is frequent loose or liquid Bowel movements Acute diarrhea ^[72]

Withdrawal management

Benzodiazepine withdrawal symptoms occur when benzodiazepine dosage is reduced in people who are physically dependent on benzodiazepines. Benzodiazepine withdrawal syndrome is caused by stopping benzodiazepines or during dosage reduction of Benzodiazepines. Abrupt or over-rapid dosage reduction can produce severe withdrawal symptoms. Withdrawal symptoms can even occur during a very gradual and slow dosage reduction but are usually not serious.

Benzodiazepine withdrawal is best managed by transferring the physically-dependent patient to an equivalent dose of diazepam because it has the longest half-life of all of the benzodiazepines and is available in low-potency, 2-mg tablets, which can be quartered for small dose reductions. ^[73] The speed of benzodiazepine reduction regimes varies from person to person, but is usually 10% every 2–4 weeks. A slow withdrawal, preferably under medical supervision by a physician that is knowledgeable about the benzodiazepine withdrawal syndrome, with the patient in control of dosage reductions coupled with reassurance that withdrawal symptoms are temporary, have been found to produce the highest success rates. Benzodiazepine withdrawal syndrome is caused by stopping benzodiazepines or during dosage reduction of Benzodiazepines. The withdrawal syndrome can usually be avoided or minimized by use of a long half-life benzodiazepine such as diazepam (Valium) or chlordiazepoxide (Librium) and a very gradually tapering off the drug over a period of months, or even up to a year or more, depending on the dosage and degree of dependency of the individual. Diazepam (daɪˈæzɨpæm first marketed as Valium by Hoffmann-La Roche, is a Benzodiazepine derivative Drug. Chlordiazepoxide (pronounced) is a Sedative / Hypnotic drug which is a Benzodiazepine derivative and is marketed under the trade name Librium A slower withdrawal rate significantly reduces the symptoms. In fact, some people feel better and more clear-headed as the dose gradually gets lower, so withdrawal from benzodiazepines is not necessarily an unpleasant event. People that report severe experiences from benzodiazepine withdrawal have almost invariably withdrawn or been withdrawn too quickly. ^[74]

Non-medical use

Benzodiazepines are used/abused recreationally and activate the dopaminergic reward pathways in the central nervous system. ^[75] Misusers of benzodiazepines develop a high degree of tolerance, coupled with dosage escalation, often increasing their dosage to very high levels. Long-term use of benzodiazepines has the potential to cause both physical and psychological dependence, and are at risk of severe withdrawal symptoms. Withdrawal, also known as withdrawal/abstinence syndrome, refers to the characteristic signs and symptoms that appear when a drug that causes Physical dependence is Tolerance and dependence to benzodiazepines develop rapidly with users of benzodiazepines, demonstrating benzodiazepine withdrawal syndrome after as little as 3 weeks of continuous use. Benzodiazepine withdrawal syndrome is caused by stopping benzodiazepines or during dosage reduction of Benzodiazepines. Benzodiazepines, and in particular temazepam, are sometimes used intravenously, which can lead to medical complications including abscesses, cellulitis, thrombophlebitis, arterial puncture, deep vein thrombosis, hepatitis B and C, HIV or AIDS, overdose and gangrene. Temazepam (marketed under brand names Restoril, Euhypnos, Normison, Remestan, Tenox and Norkotral) is an intermediate-acting An abscess (abscessus is a collection of Pus (dead Neutrophils) that has accumulated in a cavity formed by the tissue on the basis of an infectious process Cellulitis is an Infection of the deep Subcutaneous tissue of the Skin. Thrombophlebitis is Phlebitis (vein Inflammation) related to a blood clot or Thrombus. In Medicine, deep vein thrombosis (also known as deep-vein thrombosis or deep venous thrombosis and usually abbreviated as DVT) is the formation Hepatitis (plural hepatitides) implies injury to the Liver characterized by the presence of Inflammatory cells in the tissue of Human immunodeficiency virus ( HIV) is a Lentivirus (a member of the Retrovirus family that can lead to acquired immunodeficiency syndrome The term drug overdose (or simply overdose or OD) describes the Ingestion or application of a Drug or other substance in quantities Please do not add warnings to this page about the pictures Wikipedia is not censored for taste and has a guideline preventing such warnings - WikipediaNo disclaimers in articles

Benzodiazepine use is widespread among amphetamine users, and those that have used amphetamines and benzodiazepines have greater levels of mental health problems, social deterioration, and poorer general health. Benzodiazepine injectors are almost four times more likely to inject using a shared needle than non-benzodiazepine-using injectors. It has been concluded in various studies that benzodiazepine use causes greater levels of risk and psycho-social dysfunction among drug users. ^[76] Those who use stimulants and depressant drugs are more likely to report adverse reactions from stimulant use, more likely to be injecting stimulants, and more likely to have been treated for a drug problem than those using stimulants but not depressant drugs. ^[77]

Once benzodiazepine dependence has been established a clinician should first establish the average daily consumption of benzodiazepines and then convert the patient to an equivalent dose of diazepam before beginning a gradual reduction program, starting initially with 2mg-size reductions. Additional drugs, such as antidepressants like buspirone, β blockers, and carbamazepine, should not be added into the withdrawal program unless there is a specific indication for their use. Buspirone (brand-names Ansial, Ansiced, Anxiron, Axoren, Bespar, BuSpar, Buspimen, Buspinol, BETA is a pure Object-oriented language originating within the "Scandinavian School" in object-orientation where the first object-oriented language Simula Carbamazepine ("CBZ" is an Anticonvulsant and mood stabilizing drug used primarily in the treatment of Epilepsy and Bipolar disorder ^[78]

A six-year study on 51 Vietnam veterans who were drug abusers of either mainly stimulants (11 people), mainly opiates (26 people), or mainly benzodiazepines (14 people), was carried out to assess psychiatric symptoms related to the specific drugs of abuse. Vietnam Era veteran is a phrase used to describe someone who served in the armed forces of participating countries during the Vietnam War. Stimulant drugs are Drugs that temporarily increase alertness and awareness After six years, opiate abusers had little change in psychiatric symptomatology; 5 of the stimulant users had developed psychosis, and 8 of the benzodiazepine users had developed depression. For other uses see Opiate (disambiguation, or for the class of drugs see Opioid. Psychosis (from the Greek ψυχή "psyche" for mind or soul and -οσις "-osis" for abnormal condition with adjective psychotic Therefore, long-term benzodiazepine abuse and dependence seems to carry a negative effect on mental health, with a significant risk of causing depression. Mental health is a term used to describe either a level of cognitive or Emotional wellbeing or an absence of a Mental disorder. ^[79]

Increased mortality was found in drug misusers that also used benzodiazepines against those that did not. Heavy alcohol misuse was also found to increase mortality among multiple-drug users. ^[80]

Neuropsychological function can be permanently affected by abuse of certain hypnotic benzodiazepines (temazepam, nitrazepam, flunitrazepam, and nimetazepam were found to be particularly toxic), with brain damage similar to alcoholic brain damage, as was shown in a 4– to 6-year follow-up study of hypnotic abusers by Borg and others of the Karolinska Institute. Neuropsychology is the applied scientific discipline that studies the structure and function of the Brain related to specific psychological processes and overt behaviors Temazepam (marketed under brand names Restoril, Euhypnos, Normison, Remestan, Tenox and Norkotral) is an intermediate-acting Nitrazepam is a type of Benzodiazepine drug It is a hypnotic drug with Sedative and motor impairing properties Anxiolytic, Amnestic Flunitrazepam (ˌfluːnaɪˈtræzəpæm is a highly potent Hypnotic drug with powerful Sedative, Anxiolytic, Amnestic, and Skeletal Nimetazepam (marketed under brand name Erimin) is a powerful Hypnotic drug which is a Benzodiazepine derivative which was first synthesized in Japan Karolinska Institutet (often translated from Swedish into English as the Karolinska Institute, and in older texts often as the Royal Caroline The CT scan abnormalities showed dilatation of the ventricular system. However, unlike alcoholics, hypnotic abusers showed no evidence of widened cortical sulci. The study concluded that, when cerebral disorder is diagnosed in hypnotic benzodiazepine abusers, it is often permanent. ^[81] An earlier study by Borg et al. found evidence of cerebral disorder in those that exclusively abused hypnotic benzodiazepines, suggesting that cerebral disorder was not the result of other substances of abuse. Anxiolytic benzodiazepines, such as diazepam, clonazepam, alprazolam, bromazepam and lorazepam were not found to have the same toxic properties of most of the hypnotics. An anxiolytic is a drug prescribed for the treatment of Symptoms of Anxiety. ^[82]

Crime

In a survey of police detainees carried out by the Australian Government, both legal and illegal users of benzodiazepines were found to be more likely to have lived on the streets, less likely to have been in full time work, and more likely to have used heroin or methamphetamines in the past 30 days from the date of taking part in the survey. Heroin ( INN: diacetylmorphine, BAN: diamorphine) is a semi-synthetic opioid synthesized from Morphine, a derivative Benzodiazepine users were also more likely to be receiving illegal incomes and more likely to have been arrested or imprisoned in the previous year. Benzodiazepines were sometimes reported to be abused alone, but most often formed part of a poly drug-using problem. Female users of benzodiazepines were more likely than men to be using heroin, whereas male users of benzodiazepines were more likely to report amphetamine use. Benzodiazepine users were more likely than non-users to claim government financial benefits, and benzodiazepine users who were also poly-drug users were the most likely to be claiming government financial benefits. Problem benzodiazepine use can be associated with crime. Those who reported using benzodiazepines alone were found to be in the mid range when compared to other drug using patterns in terms of property crimes and criminal breaches. Of the detainees reporting benzodiazepine use, one in five reported injection use, mostly of illicit temazepam, but some reported injecting prescribed temazepam or more rarely, other benzodiazepines. Temazepam (marketed under brand names Restoril, Euhypnos, Normison, Remestan, Tenox and Norkotral) is an intermediate-acting Injection was a concern in this survey due to increased health risks. The main problems highlighted in this survey were concerns of dependence, the potential for overdose of benzodiazepines in combination with opiates and the health problems associated with injection of benzodiazepines. The most consequential, and by far most commonly-abused benzodiazepine, was temazepam. Temazepam (marketed under brand names Restoril, Euhypnos, Normison, Remestan, Tenox and Norkotral) is an intermediate-acting ^[83] In the U.S. several jurisdictions have reported that benzodiazepine abuse by criminal detainees has surpassed that of opiates. The United States of America —commonly referred to as the ^[84]

Benzodiazepines have also been used as a tool of murder by serial killers, murderers, and as a murder weapon by those with the condition Munchausen syndrome by proxy. Fabricated or induced illness (FII or Factitious disorders, originally and more commonly known as Munchausen syndrome or Munchausen syndrome by ^[85]^[86]^[87] Benzodiazepines have also been used to facilitate rape or robbery crimes, and benzodiazepine dependence has been linked to shoplifting due to the fugue state induced by the drug. A fugue state is a state of mind characterized by abandonment of personal Identity, along with the Memories, Personality and other identifying ^[88]^[89] When benzodiazepines are used for criminal purposes against a victim they are often mixed with food or drink. ^[90] Flunitrazepam, temazepam, and midazolam are the most common benzodiazepines used to facilitate date rape. Flunitrazepam (ˌfluːnaɪˈtræzəpæm is a highly potent Hypnotic drug with powerful Sedative, Anxiolytic, Amnestic, and Skeletal Temazepam (marketed under brand names Restoril, Euhypnos, Normison, Remestan, Tenox and Norkotral) is an intermediate-acting Midazolam (marketed under brand names Dormicum, Flormidal, Versed, Hypnovel and Dormonid, pronounced mɪˈdæzəlæm See also Types of rape The term "date rape" refers to the non-consensual Sexual activity between people who are known to each other either platonically ^[91] Alprazolam has been abused for the purpose of carrying out acts of incest and for the corruption of adolescent girls. Alprazolam, also known under the trade names Xanax and Niravam, is a short-acting drug of the Benzodiazepine class used to treat moderate ^[92] However, alcohol remains the most common drug involved in cases of drug rape. ^[93] Although benzodiazepines and ethanol are the most frequent drugs used in sexual assaults, GHB is another potential date rape drug which has received increased media focus. Sexual assault is any Assault of a sexual nature on another person gamma -Hydroxybutyric acid, 4-hydroxybutanoic acid, GHB, or fantasy is a naturally-occurring substance found in the Central nervous Date rape drug refers to any drug that can be used to assist in the commission of a Sexual assault ( Date rape) ^[94] Some benzodiazepines are more associated with crime than others especially when abused or taken in combination with alcohol. The potent benzodiazepine flunitrazepam (Rohypnol), which has strong amnesia producing effects can cause abusers to become cold blooded and ruthless and also cause feelings of being invincible. Flunitrazepam (ˌfluːnaɪˈtræzəpæm is a highly potent Hypnotic drug with powerful Sedative, Anxiolytic, Amnestic, and Skeletal This has led to some acts of extreme violence to others, often leaving abusers with no recollection of what they have done in their drug-induced state. It has been proposed that criminal and violent acts brought on by benzodiazepine abuse may be related to lowered serotonin levels via enhanced GABAergic effects. ^[95] Flunitrazepam has been implicated as the cause of one serial killers violent rampage, triggering off extreme aggression with anterograde amnesia. Anterograde amnesia is a loss of Memory of what happens after the event that caused the Amnesia; it is different from Retrograde amnesia, where memories ^[96] A study on forensic psychiatric patients who had abused Flunitrazepam at the time of their crimes found that the patients displayed extreme violence, lacked the ability to think clearly and experienced a loss of empathy for their victims while under the influence of flunitrazepam, and it was found that the abuse of alcohol or other drugs in combination with Flunitrazepam compounded the problem. Their behaviour under the influence of Flunitrazepam was in contrast to their normal psychological state. ^[97]

Patients reporting to two emergency rooms in Canada with violence-related injuries were most often found to be intoxicated with alcohol and were significantly more likely to test positive for benzodiazepines (most commonly temazepam) than other groups of individuals, whereas other drugs were found to be insignificant in relation to violent injuries. ^[98]

Overdose

Overdosage of benzodiazepines, particularly when combined with alcohol or opiates, may lead to coma. In Medicine, a coma (from the Greek koma, meaning deep sleep is a profound state of Unconsciousness. ^[99] The antidote for all benzodiazepines is flumazenil (Anexate), a benzodiazepine antagonist, which is occasionally used empirically in patients presenting with unexplained loss of consciousness in an emergency room setting. Flumazenil (also known as flumazepil, code name Ro 15-1788, trade names Anexate, Lanexat, Mazicon, Romazicon As with all overdose situations, the care provider must be aware of the possibility that multiple substances were utilized by the patient. Supportive measures should be put in place prior to administration of any benzodiazepine antagonist in order to protect the patient from both the withdrawal effects and possible complications arising from simultaneous utilization of chemically-unrelated pharmaceutical compounds. A determination of possible deliberate overdose should be considered with appropriate scrutiny, and precautions taken to prevent any attempt by patient to commit further bodily harm. ^[100]^[101]

Flumazenil should be administered only by physicians that are familiar and suitably trained in the use of flumazenil in benzodiazepine overdose. Treating benzodiazepine overdose with flumazenil may reduce the chance of the patient being admitted to intensive care; however, caution should be exercised in the administration of flumazenil. The term drug overdose (or simply overdose or OD) describes the Ingestion or application of a Drug or other substance in quantities Intensive Care Medicine or critical care medicine is a branch of medicine concerned with the provision of Life support or organ support systems in patients The treating physician should bear in mind the possibility of mixed overdoses, especially mixed overdoses of other drugs or substances, as cocktails of drugs are often taken in overdose situations with their own overdose risks.

Patients suspected of overdosing on benzodiazepines that are showing significant impairment of consciousness and respiratory depression and that are likely to need endotracheal intubation and be admitted to intensive care should be considered for flumazenil therapeutic treatment to avoid intubation and artificial ventilation. Consciousness has been defined loosely as a constellation of attributes of Mind such as Subjectivity, Self-awareness, Sentience, and the In Medicine, hypoventilation (also known as respiratory depression) occurs when ventilation is inadequate ( hypo means "below" to perform needed Intensive Care Medicine or critical care medicine is a branch of medicine concerned with the provision of Life support or organ support systems in patients In Medicine, intubation refers to the placement of a tube into an external or internal orifice of the body In Medicine, mechanical ventilation is a method to mechanically assist or replace spontaneous breathing when patients cannot do so on their own The decision to administer flumazenil to a suspected benzodiazepine-overdosed patient should be made after a comprehensive clinical evaluation including a complete clinical and biochemical evaluation of the respiratory status and the patient's ability to protect his or her own airway. Flumazenil, however, should be avoided in patients suspected of taking proconvulsant drugs, e. g. , tricyclic antidepressants, and patients with a history of epilepsy. Tricyclic antidepressants (abbreviation TCAs) are a class of Antidepressant drugs first used in the 1950s Flumazenil should also be avoided in patients that have a physical dependency on benzodiazepines, as flumazenil may precipitate an acute withdrawal syndrome due to rapidly displacing benzodiazepines from the benzodiazepine receptor, thus potentially triggering severe seizures. Flumazenil should be administrated gradually and carefully to avoid any potentially serious adverse reactions associated with flumazenil usage. The minimum effective dose should be given to patients to avoid the common unpleasant psychological effects of flumazenil administration, and also to avoid potentially serious side-effects. Patients may become agitated after awakening from flumazenil and may try to leave the treatment environment. In these cases clinicians should warn the patient that leaving the facility may result in re-sedation. Flumazenil should be used only where full resuscitation equipment is immediately available. ^[102]

Benzodiazepine overdose can either be intentional, accidental, or iatrogenic in nature. The terms iatrogenesis and iatrogenic artifact refer to adverse effects or complications caused by or resulting from medical treatment or advice Flumazenil can reverse all the effects of benzodiazepines due to its specific competitive benzodiazepine receptor antagonist properties. The initial treatment, as well as diagnosis of benzodiazepine overdose, can be achieved via incremental intravenous bolus injections of flumazenil in the range of 0. In medicine a bolus (from Latin bolus, ball is the administration of a Medication, Drug or other compound that is given to raise 1 to 0. 3 mg. These dose ranges are generally well tolerated and effective in the diagnosis and treatment of benzodiazepine overdose. Many benzodiazepines are longer-acting than flumazenil, and therefore there is a significant risk of relapse into coma or respiratory depression as the flumazenil wears off. Additional boluses of flumazenil or else an infusion (0. 3 to 0. 5 mg/h) therefore may need to be given, depending on the half-life of the benzodiazepine. Careful monitoring after flumazenil therapy has been discontinued is warranted in order to avoid relapse of the clinical condition. In neonates and small children, intravenous flumazenil of 10 to 20 μg/kg is an effective dose range for benzodiazepine overdose. In the Metric system, a microgram is 1/1000000 of a Gram (1 × 10-6 or 1/1000 of a milligram is one of the smallest units of weight/mass commonly used Alternative routes of administration are intramuscular, oral (20 to 25 mg three times daily or as required), and rectal, which may be used as alternatives in long-term regimens. Intramuscular injection is the injection of a substance directly into a Muscle. The rectum (from the Latin rectum intestinum, meaning straight intestine) is the final straight portion of the Large intestine in some Mammals Flumazenil can precipitate seizures in patients that have taken mixed overdoses of carbamazepine or tricyclic antidepressants; flumazenil can also precipitate benzodiazepine withdrawal symptoms; however these complications of flumazenil administration can be avoided via a careful flumazenil dose titration. Flumazenil therefore is a relatively safe and very effective treatment of benzodiazepine overdose, provided it is carried out by an experienced and knowledgeable physician in a suitable clinical environment. A physician, medical practitioner or medical doctor who practices Medicine, and is concerned with maintaining or restoring human Health ^[103]

From a research perspective, there are some data suggesting that temazepam may be more frequently involved in drug-related deaths than are some other benzodiazepines. Temazepam (marketed under brand names Restoril, Euhypnos, Normison, Remestan, Tenox and Norkotral) is an intermediate-acting Temazepam produced more sedation than did other benzodiazepines, in overdose situations. Thus, there is some reason to think that temazepam (once taken in overdose) may have greater toxicity than other benzodiazepines. ^[104]

Pregnancy

In the United States the FDA has categorised benzodiazepines into either category D or category X benzodiazepines. ^[105] International statistics show that 3. 5% of women consume psychotropic drugs during pregnancy and of that 3. 5% up to 85% report using benzodiazepines during pregnancy making benzodiazepines the most commonly prescribed psychotropic drug consumed during pregnancy. Approximately 0. 4% of all pregnancies are to women who have used benzodiazepines chronically throughout their pregnancy. ^[106] Neurodevelopmental and clinical symptoms are commonly found in babies exposed to benzodiazepines in utero. Benzodiazepine exposed babies have a low birth weight but catch up to normal babies at an early age but smaller head circumferences found in benzo babies persists. Other adverse effects of benzodiazepines taken during pregnancy are deviating neurodevelopmental and clinical symptoms including craniofacial anomalies, delayed development of pincer grasp, deviations in muscle tone and pattern of movements. Motor impairments in the babies are impeded for up to 1 year after birth. Gross motor development impairments takes 18 months to return to normal but fine motor function impairments persist. ^[107] In addition to the smaller head circumference found in benzodiazepine exposed babies mental retardation and lower intelligence occurs. ^[108]

Elderly

A large cohort study found that benzodiazepine use is associated with a significantly higher incidence of hip fracture. Short half life benzodiazepines are as likely to be associated with hip fracture as long acting benzodiazepines. Hip fractures are a frequent cause of disability and death in the elderly and this has led to efforts to reduce benzodiazepine prescribing in the elderly. ^[109] Still, a law introduced in New York State reducing benzodiazepine use by 60% did not result in a measurable decrease in hip fractures. New York ( is a state in the Mid-Atlantic and Northeastern regions of the United States and is the nation's third most populous ^[110]

Side effects are common in the elderly taking benzodiazepines. Side effects include oversedation, amnestic disorders, confusion, depression, ataxia and pseudodementia. Pseudodementia induced by benzodiazepines in the elderly may be misdiagnosed as "true" dementia. ^[111]

Legal status

All benzodiazepines are Schedule IV in the USA under the Federal Controlled Substances Act, even when not on the market (for example, nitrazepam and bromazepam). The Controlled Substances Act ( CSA) was enacted into law by the Congress of the United States as Title II of the Comprehensive Drug Abuse Prevention and Control The Controlled Substances Act ( CSA) was enacted into law by the Congress of the United States as Title II of the Comprehensive Drug Abuse Prevention and Control In Canada benzodiazepines are also Schedule IV. Country to "Dominion of Canada" or "Canadian Federation" or anything else please read the Talk Page ^[112]

Elsewhere in the world, however, benzodiazepines which are often subject to heavy abuse and addiction are often more strictly regulated or controlled. Temazepam, nimetazepam, and flunitrazepam are the worlds most heavily regulated benzodiazepines.

Flunitrazepam (Rohypnol), Nimetazepam (Erimin), and Temazepam (Restoril; Normison) are treated more severely under International law than other benzodiazepines. Flunitrazepam (ˌfluːnaɪˈtræzəpæm is a highly potent Hypnotic drug with powerful Sedative, Anxiolytic, Amnestic, and Skeletal Nimetazepam (marketed under brand name Erimin) is a powerful Hypnotic drug which is a Benzodiazepine derivative which was first synthesized in Japan Temazepam (marketed under brand names Restoril, Euhypnos, Normison, Remestan, Tenox and Norkotral) is an intermediate-acting For example, in the United States, despite being Schedule IV like any other benzodiazepine, flunitrazepam is not commercially available. The United States of America —commonly referred to as the It also carries tougher Federal penalties for trafficking and possession than other Schedule IV drugs. With the exception of cases involving 5 grams or more of cocaine or morphine, flunitrazepam is the only controlled substance whose first-offense simple possession is a federal felony. Cocaine ( benzoylmethyl ecgonine) is a Crystalline Tropane Alkaloid that is obtained from the leaves of the Coca plant Medical uses Morphine can be used as an analgesic in hospital settings to relieve pain in Myocardial infarction pain in Flunitrazepam (ˌfluːnaɪˈtræzəpæm is a highly potent Hypnotic drug with powerful Sedative, Anxiolytic, Amnestic, and Skeletal A controlled substance is generally a drug or chemical whose manufacture possession and use are regulated by a government Temazepam is the only benzodiazepine which may require specially-coded prescriptions in some states.

Throughout Europe, including the United Kingdom, temazepam and flunitrazepam also carry tougher penalties for trafficking and possession. ^[113] In Ireland, temazepam and flunitrazepam are both Schedule 3 drugs under the Misuse of Drugs (Amendment) Regulations, (1993), while all other benzodiazepines are Schedule 4. As a result of continued abuse, illegal diversion, distrubtion, and clandestine manufacture in Eastern Europe, Germany is currently in the process of possibly taking temazepam off of Anlage 3 (equivalent to Schedule 3 or Class C) of the BtMG (or Betäubungsmittelgesetz, which means Narcotics Act) and placing it under Anlage 2 (equivalent to Schedule 2 or Class B). Eastern Europe is a general term that refers to the Geopolitical region encompassing the easternmost part of the European continent.

In the Netherlands, since October 1993, benzodiazepines are all placed on List 2 of the Opium Law. The Netherlands ( Dutch:, ˈnedərlɑnt is the European part of the Kingdom of the Netherlands, which consists of the Netherlands the Netherlands The Opium Law (or Opium Wet in Dutch is the section of the Dutch Law which covers nearly all psychotropic drugs A prescription is needed for possession of all benzodiazepines.

In Australia, both temazepam and flunitrazepam, in all forms are restricted as Schedule 8 controlled drugs. For a topic outline on this subject see List of basic Australia topics. As Schedule 8 controlled substances, it is illegal to possess either drug without an authority prescription from a registered doctor. The Standard for the Uniform Scheduling of Drugs and Poisons, abbreviated SUSDP, is a document used in the regulation of drugs and poisons in Australia. In New Zealand, temazepam and flunitrazepam are completely illegal to possess and/or traffic. New Zealand is an Island country in the south-western Pacific Ocean comprising two main landmasses (the North Island and the South Island All other benzodiazepines are not illegal to possess for personal use, but distribution/traffic of any benzodiazepine is punishable by law.

In East Asia and Southeast Asia, temazepam and nimetazepam are often heavily controlled and restricted. In certain countries, triazolam, flunitrazepam, flutoprazepam, and midazolam are also restricted or controlled to certain degrees. In Hong Kong for example, temazepam and nimetazepam are regulated under Schedule 1 of Hong Kong's Chapter 134 Dangerous Drugs Ordinance. Hong Kong ( officially the Hong Kong Special Administrative Region, is a territory located on China 's south coast on the Pearl River Delta, and borders Temazepam (marketed under brand names Restoril, Euhypnos, Normison, Remestan, Tenox and Norkotral) is an intermediate-acting Nimetazepam (marketed under brand name Erimin) is a powerful Hypnotic drug which is a Benzodiazepine derivative which was first synthesized in Japan Hong Kong ( officially the Hong Kong Special Administrative Region, is a territory located on China 's south coast on the Pearl River Delta, and borders Triazolam, flunitrazepam, flutoprazepam, and midazolam are regulated under Schedule 2 of Hong Kong's Chapter 134 Dangerous Drugs Ordinance. Triazolam (marketed under brand names Halcion, Novodorm, Songar) is a Benzodiazepine derivative drug Flunitrazepam (ˌfluːnaɪˈtræzəpæm is a highly potent Hypnotic drug with powerful Sedative, Anxiolytic, Amnestic, and Skeletal Flutoprazepam (Restas KB-509 is a drug which is a Benzodiazepine derivative Midazolam (marketed under brand names Dormicum, Flormidal, Versed, Hypnovel and Dormonid, pronounced mɪˈdæzəlæm Hong Kong ( officially the Hong Kong Special Administrative Region, is a territory located on China 's south coast on the Pearl River Delta, and borders Other benzodiazepines are not scheduled or controlled substances.

In Singapore, the Misuse of Drugs Act lists both temazepam and nimetazepam as Class A/Schedule I controlled drugs. Singapore The Misuse of Drugs Act is a national drug control law classifying substances into three categories Classes A B and C The Misuse of Drugs Act is a national drug control law classifying substances into three categories Classes A B and C Flutoprazepam, flunitrazepam, and triazolam are listed as Class C/Schedule II controlled drugs. The Misuse of Drugs Act is a national drug control law classifying substances into three categories Classes A B and C Furthermore, a number of other benzodiazepines are regulated. Regulation of certain benzodiazepines under Schedule III was based on the relative ease by which they may be used to manufacture controlled benzodiazepines. They are as follows: camazepam, clonazepam, diazepam, estazolam, lorazepam, lormetazepam, nitrazepam, oxazepam, and prazepam. Camazepam (marketed under the brand names Albego, Limpidon, and Paxor) is the dimethyl Carbamate Ester of Temazepam, a Clonazepam (marketed by Roche under the trade-names Klonopin in the United States and Rivotril, Ravotril or Rivatril in Europe South Diazepam (daɪˈæzɨpæm first marketed as Valium by Hoffmann-La Roche, is a Benzodiazepine derivative Drug. Estazolam (marketed under the brand names ProSom, Eurodin) is a drug which is a Benzodiazepine derivative. Lorazepam (also known by its brand name Ativan or Temesta) is a Benzodiazepine drug with short to medium duration of action Lormetazepam is available as a generic or available under the following trade or brand names ( Noctamid, Ergocalm, Loramet, Dilamet, Sedaben Nitrazepam is a type of Benzodiazepine drug It is a hypnotic drug with Sedative and motor impairing properties Anxiolytic, Amnestic Oxazepam (marketed under brand names Alepam, Murelax, Opamox, Oxascand, Serax, Serepax, Seresta, Sobril Prazepam (marketed under the trade name Centrax, in the US is a Benzodiazepine derivative drug These benzodiazepines are regulated under Schedule III as controlled equipment, materials or substances useful for manufacturing controlled drugs. The Misuse of Drugs Act is a national drug control law classifying substances into three categories Classes A B and C Restriction of these benzodiazepines is a measure against any clandestine manufacture of anyone of the controlled benzodiazepines, as seen with the growing illicit manufacture and distribution of temazepam in other regions of the world. The illegal drug trade or drug trafficking is a global Black market consisting of the cultivation manufacture distribution and sale of illegal Drugs Other benzodiazepines are not controlled drugs, but are available only by prescription and if used to manufacture any of the controlled benzodiazepines, automatically become Schedule III substances or material. The Misuse of Drugs Act is a national drug control law classifying substances into three categories Classes A B and C

Internationally, temazepam, nimetazepam, and flunitrazepam are Schedule IV drugs under the Convention on Psychotropic Substances. The Convention on Psychotropic Substances is a United Nations Treaty designed to control Psychoactive drugs such as Amphetamines Barbiturates Though they are classed as a Schedule IV internationally, penalties for their possession and/or trafficking are more severe than other Schedule IV drugs, including all other benzodiazepines. Temazepam and nimetazepam continue to be the most widely abused benzodiazepines worldwide. ^[114] ^[115] Seizures of the two drugs by authorities are far higher in number than seizures of all the other benzodiazepines combined, including flunitrazepam. Worldwide, seizures of temazepam and nimetazepam may be comparable in number to seizures of the hypnotic, methaqualone. Methaqualone is a Sedative drug which is similar in effect to Barbiturates a general CNS Depressant. ^[116]^[117]^[118]

Various other countries limit the availability of benzodiazepines legally. Even though it is a commonly-prescribed class of drugs, the Medicare Prescription Drug, Improvement, and Modernization Act specifically states that insurance companies that provide Medicare Part D plans are not allowed to cover benzodiazepines. The Medicare Prescription Drug Improvement and Modernization Act (, also called Medicare Modernization Act or MMA) is a law of the United States which Medicare Part D is a federal program to subsidize the costs of Prescription drugs for Medicare beneficiaries in the United States.

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External links

Benzodiazepine Equivalence Table
Drugs.com - Benzodiazepines (advanced consumer information)
Inchem.org - Benzodiazepines
The Eaton T. Fores Research Center - An Overview of the History, Chemistry, and Pharmacodynamics of Benzodiazepines
Flash animation about how benzodiazepines work (mechanism of action)
Benzodiazepines: How they work and how to withdraw
Addiction: Part I. Benzodiazepines--Side Effects, Abuse Risk and Alternatives

Dictionary

-noun

Any of a class of psychoactive drugs, structured upon diazepine, used in the treatment of anxiety, insomnia and other disorders

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