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Benzodiazepine

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Benzodiazepines
Chemical structure diagram of a benzene ring fused to a diazepine ring. Another benzene ring is attached to the bottom of the diazepine ring via a single line. Attached to the first benzene ring is a side chain labeled R7; to the second, a side chain labeled R2'; and attached to the diazepine ring, two side chains labeled R1 and R2.
The core structure of benzodiazepines. "R" labels denote common locations of side chains, which give different benzodiazepines their unique properties.

The benzodiazepine (Template:Pron-en, often abbreviated to "benzo") class of psychoactive drugs has varying sedative, hypnotic (sleep inducing), anxiolytic (antianxiety), anticonvulsant, muscle relaxant and amnesic properties.[1] These properties make benzodiazepines useful in treating anxiety, insomnia, agitation, seizures, muscle spasms, alcohol withdrawal and for medical or dental procedures.[2] Benzodiazepines vary in their elimination half-life, being categorized as either short-acting, intermediate-acting or long-acting. Short- and intermediate-acting benzodiazepines are preferred for the treatment of insomnia whilst longer-acting benzodiazepines are preferred for the treatment of anxiety.[3]

The first benzodiazepine, chlordiazepoxide (Librium), was discovered accidentally by Leo Sternbach; it was introduced to the market in 1960 and was quickly followed by diazepam (Valium). The therapeutic properties are mediated by enhancing the effect of the inhibitory neurotransmitter GABA at GABAA receptors, which results in a depressant effect on the central nervous system.[4] After their introduction they largely replaced barbiturates as the most commonly prescribed sedative hypnotics. Benzodiazepines, in turn, are beginning to be replaced by the nonbenzodiazepines, especially for treatment of insomnia.[5]

Benzodiazepines are generally safe and effective in the short term, although cognitive impairments or paradoxical effects such as aggression or behavioral disinhibition occasionally occur. They are also major drugs of abuse.[6] Their use in the longer term is not recommended due to their propensity to cause tolerance, physical dependence, addiction and a withdrawal syndrome upon cessation of use.[7][8] Long-term use of benzodiazepines also tends to cause or worsen sleep problems, cognitive deficits, depression, anxiety and panic attacks.[9][10] The elderly are at an increased risk of suffering from both short- and long-term adverse effects.[9][11]

Benzodiazepines taken during pregnancy can cause withdrawal symptoms in the newborn. There is controversy concerning the safety of benzodiazepines in pregnancy; while they are not major teratogens, uncertainty remains whether they cause major malformations in a small number of babies and whether neurobehavioural effects occur as result of prenatal exposure.[12] Benzodiazepines are often taken in overdoses but rarely cause fatalities and are much less toxic than their predecessors the barbiturates.[13] When they are combined with other central nervous system depressants such as alcohol and opiates, the potential for toxicity increases. This is particularly problematic in the drug misusing community.[14][15]

History

The molecular structure of chlordiazepoxide, discovered by Leo Sternbach which gave birth to the benzodiazepine drug class

The first benzodiazepine, chlordiazepoxide (Librium), was synthesized in 1955 by Leo Sternbach while working at Hoffmann–La Roche on the development of tranquilizers. Pharmacological properties of many compounds prepared initially were disappointing and Sternbach abandoned the project. Two years later, in April 1957 during a spring cleaning in the lab, his co-worker, Earl Reeder noticed a "nicely crystalline" compound left over from the discontinued project. This compound, which later was named chlordiazepoxide, had not been tested in 1955 because of Sternbach's "involvement with other problems". Expecting the pharmacology results to be negative and then hoping to publish the chemistry part of their work, researchers submitted it for a standard battery of animal tests. Unexpectedly, the compound showed very strong sedative, anticonvulsant and muscle relaxant effects. The impressive clinical results led to its speedy introduction in 1960 throughout the world under the brand name Librium.[16][17] Following chlordiazepoxide, diazepam hit the market in 1963 under the brand name Valium and for a while both were the two most commercially successful drugs. The introduction of benzodiazepines led to a fall in barbiturate sedative hypnotics prescriptions and by the 1970s they had largely replaced the older drugs.[4]

The new group of drugs was initially greeted with hope and optimism by the medical profession but gradually concerns emerged, in particular the risk of dependence came to be realized in the 1980s leading them to be regarded unpopularly. Benzodiazepines have a unique history, in that they were responsible for the largest ever class action lawsuit in the United Kingdom, involving 14,000 patients and 1,800 law firms against the drugs manufacturers, alleging that they knew of the dependence potential but intentionally withheld this information from doctors. At the same time there were 117 general practitioners and 50 health authorities also being sued by patients to recover damages they incurred as a result of dependence and withdrawal. This led to some doctors requiring a signed consent form from their patients and recommendations that all patients are adequately warned of the dependence and withdrawal problems before starting benzodiazepines.[18] The court case against the drug manufacturers never reached conclusion, collapsing due to legal aid being withdrawn and allegations of conflicts of interest of consultant psychiatrists who were case experts. The litigation led to changes in the British law making class action law suits more difficult.[19]

Although antidepressants with anxiolytic properties have been introduced and there is increasing awareness of the adverse effects of benzodiazepines there has not been any significant change in prescribing levels for short term anxiety relief.[7] A newer class of drugs called the nonbenzodiazepines (also sometimes referred to as Z-drugs) are now beginning to replace the benzodiazepines, in the treatment of insomnia.[5][20] Although they are molecularly distinct, nonbenzodiazepines work on benzodiazepine receptors.[21]

Therapeutic uses

See also: List of benzodiazepines
Injectable midazolam in 1 mg/ml and 5 mg/ml strengths.

Benzodiazepines possess sedative, hypnotic, anxiolytic, anticonvulsant, muscle relaxant and amnesic actions,[1][2] which are useful in a variety of indications such as alcohol dependence, seizures, anxiety, panic, agitation and insomnia. Most are administered orally; however, they can also be given intravenously, intramuscularly or rectally.[22] Benzodiazepines are well-tolerated and are generally safe and effective drugs in the short-term for a wide range of conditions.[23][24] Tolerance can develop to their effects and there is also a risk of dependence and a withdrawal syndrome when discontinued. These factors combined with other possible secondary effects after prolonged use such as psychomotor, cognitive or memory impairments, limit their long term applicability.[25][26]

Alcohol withdrawal

Benzodiazepines are the preferred choice in the management of alcohol withdrawal syndrome, particularly for preventing or treating seizures and delirium.[27] The most commonly used are diazepam (Valium) and chlordiazepoxide (Librium). Their long half-life makes withdrawal smoother and rebound symptoms less likely to occur. Oxazepam or lorazepam are often used in patients at risk of drug accumulation, particularly the elderly and those with cirrhosis because of their shorter half life. Lorazepam is the only benzodiazepine with predictable intramuscular absorption and it is the most effective in preventing and controlling acute seizures.[28] However, the shorter acting drugs may be less effective than longer acting ones in reducing alcohol withdrawal symptoms and may lead to break through seizures. They are thus not recommended for outpatient detoxification. Rebound effects are more likely with short-acting benzodiazepines especially if they are not tapered after alcohol detoxification.[29][30]

Seizures

Prolonged convulsive epileptic seizures are a medical emergency that can usually be dealt with effectively by administering fast-acting benzodiazepines, which are potent anticonvulsants. In a hospital environment, intravenous lorazepam and diazepam are first-line choices, with a preference for lorazepam due to its longer duration of action. In the community, intravenous administration is not practical and so rectal diazepam or (more recently) buccal midazolam are used, with a preference for midazolam as its administration is easier and more socially acceptable.[31][32]

When benzodiazepines were first introduced they were enthusiastically adopted for treating all forms of epilepsy. However, drowsiness and tolerance become problems with continued use and none are now considered first-line choices for long-term epilepsy therapy.[33] Clobazam is widely used by specialist epilepsy clinics worldwide (but it is not available in the US) and clonazepam is popular in France.[33] In the UK, both clobazam and clonazepam are second-line choices for treating many forms of epilepsy.[34] Clobazam also has a useful role for very short-term seizure prophylaxis and in catamenial epilepsy.[33] Discontinuation after long term use in epilepsy requires additional caution because of the risks of rebound seizures. Therefore, the dose is slowly tapered over a period of up to six months or longer.[32]

Anxiety, panic and agitation

As they possess anti-anxiety properties, benzodiazepines can be useful for the short-term treatment of severe anxiety.[35] Their use beyond two to four weeks is not recommended in clinical guidelines. Tolerance and a physical dependence develops rapidly with withdrawal symptoms including rebound anxiety occuring after six weeks or more of use.[36] Benzodiazepines continue to be prescribed long term for anxiety disorders, despite certain antidepressants and the anticonvulsant drug pregabalin being recommended as first line treatment options.[37]

They are usually administered orally; however, very occasionally lorazepam or diazepam may be given intravenously for the treatment of panic attacks.[22] Benzodiazepines are also used to treat the acute panic caused by hallucinogen intoxication[38] and occasionally prescribed long-term for panic disorder.[23][24] There are no controlled clinical trials to demonstrate whether efficacy is maintained and not lost due to tolerance. Limited data from longitudinal studies have suggested benefit from long term use in panic disorder.[39] Long-term use of benzodiazepines for panic disorder with or without agoraphobia is an unlicensed indication and does not have a good outcome and is therefore not recommended. Psychological therapies such as Cognitive Behavioural Therapy are recommended as a first line therapy but benzodiazepine use has been found to interfere with therapeutic gains from these therapies.[36]

Benzodiazepines can sometimes be effective in the short-term treatment of psychiatric emergencies such as acute psychosis such as schizophrenia or mania, bringing about rapid tranquillization and sedation until the effects of lithium or neuroleptics (antipsychotics) take effect. Lorazepam is most commonly used but clonazepam is also sometimes prescribed.[40][41] They are also used to calm the acutely agitated individual and can if required, be given via an intramuscular injection.[42]

Insomnia

Some benzodiazepines are prescribed for the short-term management of severe or debilitating insomnia. Longer-acting benzodiazepines, such as nitrazepam or quazepam, have side-effects that may persist into the next day, whereas the more intermediate-acting ones (for example, temazepam or loprazolam) may have less "hangover" effects. Drawbacks of benzodiazepines including worsening of sleep quality such as increased light sleep and decreased deep sleep as well as tolerance and dependence and rebound effects.[43][44] They are preferably prescribed for only a few days at the lowest effective dose and avoided altogether wherever possible in the elderly. It has been argued that long term use of hypnotics and overprescribing of these drugs represents an unjustifiable risk to the individual and to public health.[45]

Other indications

Benzodiazepines are often used for a wide range of conditions. Some of the most notable indications are summarised below.

They can be very useful in intensive care to sedate patients receiving mechanical ventilation, or those in extreme distress or severe pain. Caution is exercised in this situation due to the occasional scenario of respiratory depression and it is recommended that benzodiazepine overdose treatment facilities should be available.[46]

They are also effective as premedication a couple of hours before surgery. They bring about anxiety relief and also produce amnesia; which can be useful in this situation, as patients will not be able to remember any unpleasantness from the procedure.[46] Diazepam or temazepam can be utilized in patients who are particularly anxious about dental procedures for example those with dental phobia.[46]

Benzodiazepines are well known for their strong muscle-relaxing properties and can be useful in the treatment of muscle spasms due to a wide range of causes.[22] Some examples include the treatment of tetanus[47] and stiff person syndrome which is a neurological disorder characterized by severe muscle stiffness.[48][49]

Side effects

See also: Long-term effects of benzodiazepines and Paradoxical reaction § Benzodiazepines

The most common side effects of benzodiazepines are related to their sedating and muscle-relaxing action. They include drowsiness, dizziness and decreased alertness and concentration. Lack of coordination may result in ataxia, falls and injuries, particularly in the elderly.[50][51] Another result is impairment of driving skills and increased risk of road traffic accidents.[52][53] Decreased libido and erection problems are a common side effect. An emergence of depression and paradoxical side reactions of disinhibition may occur. Hypotension and suppressed breathing may be encountered with intravenous use.[50][51] Less common side effects include nausea and changes in appetite, blurred vision, confusion, euphoria, depersonalization and nightmares. Cases of liver toxicity have been described but are very rare.[22][54]

Paradoxical reactions, such as aggression, violence, impulsivity, irritability and suicidal behavior sometimes occur. These reactions have been explained as consequences of disinhibition, that is loss of control over socially unacceptable behavior.[55] Paradoxical reactions are rare in the general population, with an incidence rate below 1% and similar to placebo.[56] However, they occur with greater frequency in recreational abusers, individuals with borderline personality disorder, children and patients on high-dosage regimes.[55][57] In these groups, impulse control problems are perhaps the most important risk factor for disinhibition; learning disabilities, neurological disorders are also significant risks. Most reports of disinhibition involve high doses of high-potency benzodiazepines.[56]

Long-term use of benzodiazepines can cause a number of adverse effects which can include sleep problems, depression, anxiety and panic attacks as well as agoraphobia.[9][10] Benzodiazepines adversely affect cognition; long-term administration affects sensory processing, psychomotor speed, nonverbal memory, visuospatial ability and several other cognitive domains and after benzodiazepines are withdrawn, cognitive function improves but does not return to ordinary levels.[58]

Withdrawal syndrome

Main articles: Benzodiazepine dependence and Benzodiazepine withdrawal syndrome
Diazepam 2 mg and 5 mg diazepam tablets, which are commonly used in the treatment of benzodiazepine withdrawal.

Tolerance, dependence and withdrawal

Discontinuation of benzodiazepines or abrupt reduction of the dose, even after a relatively short course of treatment (three to four weeks), may result in two groups of symptoms—rebound and withdrawal. Rebound symptoms are the return of the symptoms for which the patient was treated but worse than before.[59] The withdrawal syndrome from benzodiazepines from mild and short lasting to severe and prolonged. Withdrawal of benzodiazepines generally leads to improved physical and mental health particularly in the elderly. Some long term users do report however, continued benefit from taking benzodiazepines but this may be the result of suppression of withdrawal effects.[11]

Tolerance occurs rapidly to the sleep inducing effects of benzodiazepines but takes several months to develop to the anxiolytic effects. The anticonvulsant and muscle relaxant effects last for a few weeks before tolerance occurs in most individuals. Tolerance results in a change in the desensitisation of GABA receptors and an increased sensitisation of the excitatory neurotransmitter system, glutamate such as NMDA glutamate receptors. These changes occur as a result of the body trying to overcome the drugs effects. Other changes which occur are the reduction of the number of GABA receptors (internalisation) as well as possibly long term changes in gene transcription coding of brain cells. The differing speed at which tolerance occurs to the therapeutic effects of benzodiazepines can be explained by the speed of changes in the range of neurotransmitter systems and sub systems which are altered by chronic benzodiazepine use. The various neurotransmitter systems and subsystems may reverse tolerance at different speeds thus explaining the prolonged nature of some withdrawal symptoms. As a result of a physical dependence which develops due to tolerance a characteristic benzodiazepine withdrawal syndrome often occurs after removal of the drug or a reduction in dosage.[11] Symptom severity is worse with the use of high doses, or with benzodiazepines of high potency or short half life. Other cross tolerant sedative hypnotics, such as barbiturates or alcohol increase the risk of benzodiazepine dependence.[60]

Withdrawal symptoms and management

Chlordiazepoxide 5 mg capsules which are sometimes used as an alternative to diazepam for benzodiazepine withdrawal. Like diazepam it has a long elimination half life and long acting active metabolites.

Withdrawal symptoms are new symptoms that occur when the benzodiazepine is stopped. Insomnia, gastric problems, tremors, agitation, fearfulness and muscle spasm are the most frequent.[59] The less frequent effects are irritability, sweating, depersonalization, derealization, hypersensitivity to stimuli, depression, suicidal behavior, psychosis, seizures and delirium tremens.[61] Severe symptoms usually occur as a result of abrupt or over-rapid withdrawal. Abrupt withdrawal can be dangerous, therefore a gradual reduction regime is recommended.[8]

Symptoms may also occur during a gradual dosage reduction but are typically less severe and may persist as part of a protracted withdrawal syndrome for months after cessation of benzodiazepines.[62] Approximately 10% of patients will experience a notable protracted withdrawal syndrome which can persist for many months or in some cases a year or longer. Protracted symptoms tend to resemble those seen during the first couple of months of withdrawal but usually are of a sub acute and gradually declining level of severity. It is not known definitively whether such symptoms persisting long after withdrawal are related to true pharmacological withdrawal or whether they are due to neuronal damage as result of chronic use or withdrawal. Nevertheless, such symptoms do gradually lessen over time, eventually disappearing altogether.[10]

Benzodiazepines have a reputation amongst patients and doctors for causing a severe and traumatic withdrawal, however, this is in large part due to the withdrawal process being poorly managed. Over-rapid withdrawal from benzodiazepines increases the severity of the withdrawal syndrome and increases the failure rate. A slow and gradual withdrawal customised to the individual and if indicated psychological support is the most effective way of managing the withdrawal. The opinion on the time needed to complete ranges from four weeks to several years. Aiming for within six months has been suggested,[8] but due to factors such as dosage and type of benzodiazepine, reasons for prescription, lifestyle, personality, environmental stresses and amount of available support a year or more to withdraw may be needed.[22][11]

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 tablets, which can be quartered for smaller doses.[63] A further benefit is that it is available in liquid form which allows for even smaller reductions.[8] Chlordiazepoxide which also has a long half life and long acting active metabolites can be used as an alternative.[63][64] Nonbenzodiazepines are contraindicated during benzodiazepine withdrawal as they are cross tolerant with benzodiazepines and can induce dependence.[11] Alcohol is also cross tolerant with benzodiazepines and more toxic and thus caution is needed to avoid replacing one dependence with another. Fluoroquinolone antibiotics displace benzodiazepines from their binding site and interact with the GABA system and if possible are best avoided during withdrawal as they may aggravate withdrawal symptoms.[63]

Contraindications

Because of their muscle relaxant action, benzodiazepines may cause respiratory depression in susceptible individuals. For that reason, they are contraindicated in people with myasthenia gravis, sleep apnea, bronchitis and COPD.[65][50] Caution is required when benzodiazepines are used in people with personality disorders or mental retardation because of frequent paradoxical reactions.[65][50] In major depression they may precipitate suicidal tendencies.[66] Individuals with a history of alcohol, opioid and barbiturate abuse should generally avoid benzodiazepines as there is a risk of life-threatening interactions with these drugs.[67]

Pregnancy

See also: Effects of benzodiazepines on newborns
Benzodiazepines taken during pregnancy has adverse effects on the baby. Abrupt withdrawal in benzodiazepine dependent pregnant women may result in spontaneous abortions and provoke suicidal ideation.

In the United States, the Food and Drug Administration has categorized benzodiazepines into either category D or X meaning potential for harm in the unborn has been demonstrated.[68]

Exposure to benzodiazepines during pregnancy is associated with a slightly increased, from 0.06 to 0.07%, risk of cleft palate in newborns. This however, is controversial: some studies find no association with benzodiazepines and cleft palate. Their use by expectant mothers shortly before the delivery may result in a floppy infant syndrome, with the newborns suffering from hypotonia, hypothermia, lethargy and breathing and feeding difficulties. Neurobehavioural abnormalities such as growth restriction, dysmorphism, mental and physical and psychomotor retardation has been correlated with prenatal benzodiazepine exposure but the data is conflicting and controversial.[12][69] Cases of neonatal withdrawal syndrome have been described in infants chronically exposed to benzodiazepines in utero. For benzodiazepines this syndrome may be hard to recognize as it starts several days after delivery, for example, as late as 21 day for chlordiazepoxide. The symptoms include tremors, hypertonia, hyperreflexia, hyperactivity and vomiting and may last for up to three to six months.[12][70] Tapering down the dose during pregnancy may lessen its severity. If used in pregnancy, benzodiazepines with a better and longer safety record, such as diazepam or chlordiazepoxide, are recommended over potentially more harmful benzodiazepines, such as alprazolam or triazolam. Using the lowest effective dose for the shortest period of time, minimizes the risks to the unborn child.[71]

Elderly

Adverse effects of benzodiazepines are increased in the elderly. These adverse effects are often mistaken for the effects of old age.

The benefits are least and the risks are the greatest in the elderly.[72] The elderly are at an increased risk of dependence and more sensitive to the adverse effects such as memory problems, daytime sedation, impaired motor coordination and increased risk of motor vehicle accidents and falls.[73] Chronic effects of benzodiazepines and benzodiazepine dependence in the elderly can resemble dementia, depression or anxiety syndromes, which worsens over time. The success of gradual-tapering benzodiazepines is as great in the elderly as in younger people. Benzodiazepines should be prescribed to the elderly only with caution and only for a short period at low doses. The short-acting drugs, such as oxazepam, alprazolam and triazolam, have been recommended in such cases.[74]

The current chronic use of benzodiazepines has been associated with increased risk of cognitive impairment but its relationship with dementia remains inconclusive.[75] The association of a past history of benzodiazepine use and cognitive decline is unclear, with some studies reporting a lower risk of cognitive decline in former users, some finding no association and some indicating an increased risk of cognitive decline.[76]

Benzodiazepines are sometimes prescribed to treat behavioral symptoms of dementia. However, similarly to antidepressants and antipsychotics also used for this indication, their balance of risks and benefits may be unfavorable.[77][78]

Pharmacology

Benzodiazepines share a similar chemical structure and their effects in humans are mainly produced by the allosteric modification of a specific kind of neurotransmitter receptor, the GABAA receptor, which increases the conductance of this inhibitory channel.[79] Other less important mechanisms of action are also known.[80][81]

Chemistry

Left: Core structure of 1,4-benzodiazepine. Right: 5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one forms the skeleton of many of the most common benzodiazepine pharmaceuticals, such as diazepam (7-chloro-1-methyl substituted).

The term benzodiazepine is the chemical name for the central ring system (see figure to the right) which is a fusion between the benzene and diazepine ring systems.[82] Benzodiazepine drugs are substituted 1,4-benzodiazepines, although the chemical term can refer to many other compounds which do not have useful pharmacological properties. Many of the pharmacological active "classical" benzodiazepine drugs contain the 5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one substructure (see figure to the right).

Under Hantzsch–Widman nomenclature, a diazepine is a heterocycle with two nitrogen atoms, five carbon atom and the maximum possible number of cumulative double bonds. The "benzo" prefix indicates the benzene ring fused onto the diazepine ring.[82]

Different benzodiazepine drugs have different side groups attached to this central structure. The different side groups affect the binding of the molecule to the GABAA receptor and so modulate the pharmacological properties.[79]

Mechanism of action

Benzodiazepines work by increasing the efficiency of a natural brain chemical, GABA, to decrease the excitability of certain types of brain cells called neurons. This reduces the communication between neurons and therefore has a calming effect on many of the functions of the brain.

Schematic diagram of the (α1)2(β2)2(γ2) GABAA receptor protein complex which depicts the five subunits that form the protein, the chloride (Cl-) ion channel pore at the center, the two GABA active binding sites at the α1 and β2 interfaces and the benzodiazepine (BZD) allosteric binding site at the α1 and γ2 interface.

GABA controls the excitability of neurons through binding to the GABAA receptor.[79] The GABAA receptor is a protein complex located in the synapses of neurons. All GABAA receptors contain an ion channel that conducts chloride ions across neuronal cell membranes and two binding sites for the neurotransmitter gamma-aminobutyric acid (GABA) while a subset of GABAA receptor complexes also contain a single binding site for benzodiazepines. Binding of benzodiazepines to this receptor complex promotes binding of GABA which in turn increases the conduction of chloride ions across the neuronal cell membrane. This increased conductance raises the membrane potential of the neuron which results in inhibition of neuronal firing. In addition, different GABAA receptor subtypes have varying tissue distributions within the brain and therefore control distinct neuronal circuits. Hence activation of different GABAA receptor subtypes by benzodiazepines may result in distinct pharmacological actions.[83] Depending on which specific neurons are affected and how strongly they are inhibited, a spectrum of effects can result from administration of benzodiazepines. Mild and selective inhibition of neuronal firing by benzodiazepines may result in an anti-anxiety effect whereas progressively stronger and more widespread inhibition results in a sedative/hypnotic effect and ultimately sleep.

The subset of GABAA receptors that also bind benzodiazepines are referred to as benzodiazepine receptors (BzR). The GABAA receptor is a heteromer composed of five subunits, most commonly two α's, two β's and one γ (α2β2γ). For each subunit, many subtypes exist (α1-6, β1-3 and γ1-3). GABAA receptors that are made up of different combinations of subunit subtypes have different properties, different distributions in the brain and different activities relative to pharmacological and clinical effects.[84] Benzodiazepines bind at the interface of the α and γ subunits on the GABAA receptor. Binding also requires that alpha subunits contain a histidine amino acid residue, (i.e., α1, α2, α3 and α5 containing GABAA receptors). For this reason, benzodiazepines show no affinity for GABAA receptors containing α4 and α6 subunits, which contain an arginine instead of a histidine residue.[85]

Once bound to the benzodiazepine receptor the benzodiazepine ligand locks the benzodiazepine receptor into a conformation in which it has a much higher affinity for the GABA neurotransmitter. This increases the frequency of opening of the associated chloride ion channel and hyperpolarizes the membrane of the associated neuron. This potentiates the inhibitory effect of the available GABA, leading to sedatory and anxiolytic effects. Furthermore, different benzodiazepines can have different affinities for BzRs made up of different collection of subunits. For instance, those with high activity at the α1 (temazepam, triazolam, nitrazepam, etc) are associated with stronger hypnotic effects, whereas those with higher affinity for GABAA receptors containing α2 and/or α3 subunits (diazepam, clonazepam, bromazepam, etc) have good anti-anxiety activity.[86]

The benzodiazepine class of drugs also interact with peripheral benzodiazepine receptors. Peripheral benzodiazepine receptors are present in peripheral nervous system tissues, glial cells and to a lesser extent the central nervous system.[87] These peripheral receptors are not structurally related nor coupled to GABAA receptors. They modulate the immune system and are involved in the body response to injury.[80][88] Benzodiazepines also function as weak adenosine reuptake inhibitors. It has been suggested that some of their anticonvulsant, anxiolytic and muscle relaxant effects may be in part mediated by this action.[81]

Pharmacokinetics

A benzodiazepine can be placed into one of three groups by its elimination half-life, or time it takes for the body to eliminate half of the dose:[3]

Short-acting compounds have a half-life of 1–8 hours. They have few residual effects if taken before bedtime, rebound insomnia may occur upon discontinuation and they might cause day time withdrawal symptoms such as next day rebound anxiety with prolonged usage. Examples are brotizolam, midazolam and triazolam.

Intermediate-acting compounds have a half-life of 8–40 hours. They may have some residual effects in the first half of the day if used as a hypnotic. Rebound insomnia, however, is more common upon discontinuation of intermediate-acting benzodiazepines than longer acting benzodiazepines. Examples are estazolam, flunitrazepam, lormetazepam, nitrazepam and temazepam.

Long-acting compounds have a half-life of 40–200 hours. They have a risk of accumulation in the elderly and in individuals with severely impaired liver function, but they have a reduced severity of rebound effects and withdrawal. Examples are flurazepam and quazepam.

Interactions

Individual benzodiazepines may have different interactions with certain drugs. Depending on their metabolism pathway, benzodiazepines can be roughly divided into two groups. The largest group consists of those that are metabolized by cytochrome P450 (CYP450) enzymes and possess significant potential for interactions with other drugs. The other group comprises those that are metabolized through glucuronidation, such as lorazepam, oxazepam and temazepam and generally have few drug interactions.[65]

Many drugs, including oral contraceptives, some antibiotics, antidepressants and antifungal agents, inhibit cytochrome enzymes in the liver. They reduce the rate of elimination of the benzodiazepines that are metabolized by CYP450, leading to possibly excessive drug accumulation and increased side effects. Conversely, drugs that induce cytochrome P450 enzymes, such as St John's wort, the antibiotic rifampicin and the anticonvulsants carbamazepine and phenytoin, accelerate elimination of many benzodiazepines and decrease their action.[89][67]

Taking benzodiazepines with alcohol, opioids and other central nervous system depressants potentiates their action. This often results in increased sedation, impaired motor coordination, suppressed breathing and other adverse effects that may potentially be lethal.[89][67] Antacids may slow down absorption of some benzodiazepines; however, this effect is marginal and inconsistent.[67]

Overdose

Main article: Benzodiazepine overdose
The use of Flumazenil is controversial following benzodiazepine overdose.

Whilst benzodiazepines are much safer in overdose than their predecessors the barbiturates they still can cause problems in overdose.[13] Taken alone, they rarely cause severe complications in overdose;[90] statistics in England showed that benzodiazepines were responsible for 3.8% of all deaths by poisoning from a single drug.[14] However, combining these drugs with alcohol or opiates markedly raises the toxicity.[91][15] The elderly are more sensitive to the side effects of benzodiazepines and poisoning may even occur from their long-term use.[92] The various benzodiazepines differ in their toxicity; alprazolam appears to be most toxic in overdose and when used with other drugs.[93]

A reversal agent for benzodiazepines exists, flumazenil (Anexate). Its use as an antidote in an overdose however is controversial.[94] Numerous contraindications to its use exist. It is contraindicated in patients who are on long term benzodiazepines, those who have ingested a substance that lowers the seizure threshold or may cause an arrhythmia and in those with abnormal vital signs.[95] One study found that only 10% of the patient population presenting with a benzodiazepine overdose are suitable candidates for treatment with flumazenil.[96]

Drug misuse

Main articles: Benzodiazepine drug misuse and Drug-related crime
Alprazolam "Bars" 2 mg tablets

Benzodiazepines are considered major drugs of abuse.[6] Internationally, benzodiazepines are categorized as Schedule IV controlled drugs, apart from flunitrazepam which is a Schedule III drug under the Convention on Psychotropic Substances.[97] Some variation in drug scheduling exists in individual countries, for example in the United Kingdom midazolam and temazepam are Schedule III controlled drugs.[98][99]

Benzodiazepines are used recreationally and by problematic drug misusers. Mortality is higher among poly-drug misusers that also use benzodiazepines. Heavy alcohol use also increases mortality among poly-drug users.[14]

Dependence and tolerance, often coupled with dosage escalation, to benzodiazepines can develop rapidly among drug misusers; withdrawal syndrome may appear after as little as three weeks of continuous use. Long-term use has the potential to cause both physical and psychological dependence and severe withdrawal symptoms. Benzodiazepines and in particular temazepam, are sometimes used intravenously, which if done incorrectly or in an unsterile manner, can lead to medical complications including abscesses, cellulitis, thrombophlebitis, arterial puncture, deep vein thrombosis and gangrene. Sharing syringes and needles for this purpose also brings up the possibility of transmission of hepatitis, AIDS and other diseases. Benzodiazepines are also misused intranasally which may have additional health consequences. Once benzodiazepine dependence has been established, a clinician usually converts the patient to an equivalent dose of diazepam before beginning a gradual reduction program.[100]

A 1999–2005 Australian police survey of detainees reported preliminary findings that self-reported users of benzodiazepines were less likely than non-user detainees to work full-time and more likely to receive government benefits, use methamphetamine or heroin and be arrested or imprisoned.[101] Benzodiazepines are also sometimes used for criminal purposes; they serve to incapacitate a victim in cases of drug assisted rape or robbery.[102]

Veterinary use

Benzodiazepines are used in veterinary practice in the treatment of various disorders and conditions. As in humans, they are used in the first-line management of seizures, status epilepticus and tetanus and also as maintenance therapy in epilepsy (particularly in cats).[103][104][105] They are also widely used in small and large animals (including horses, swine, cattle and exotic and wild animals) for their anxiolytic and sedative effects, as premedication before surgery, for induction of anesthesia and as adjuncts to anesthesia.[103][106]

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Further reading

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