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==Pharmacokinetics== |
==Pharmacokinetics== |
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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:<ref>{{cite book |author= Dikeos DG, Theleritis CG, Soldatos CR |chapter= Benzodiazepines: effects on sleep |pages=220–2 |title= Sleep Disorders: Diagnosis and Therapeutics |editor= Pandi-Perumal SR, Verster JC, Monti JM, Lader M, Langer SZ (eds.) |publisher=Informa Healthcare |year=2008 |isbn=0-415-43818-7}}</ref> |
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Benzodiazepines are commonly divided into three groups by their [[Biological half-life|half-lives]]:<ref name="pmid6133528">{{cite journal | author = Greenblatt DJ, Shader RI, Divoll M, Harmatz JS | title = Benzodiazepines: a summary of pharmacokinetic properties | journal = Br J Clin Pharmacol | volume = 11 |issue= Suppl 1 | pages = 11S–16S | year = 1981 | pmid = 6133528 | pmc = 1401650 | url = http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1401650&blobtype=pdf |format= PDF }}</ref><ref name="pmid2251629">{{cite journal | author = Summers RS, Schutte A, Summers B | title = Benzodiazepine use in a small community hospital. Appropriate prescribing or not? | journal = S Afr Med J | volume = 78 | issue = 12 | pages = 721–5 | year = 1990 | pmid = 2251629 }}</ref> |
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Short-acting compounds have a half-life of |
Short-acting compounds have a half-life of 1–8 hours. They have few residual effects if taken before bedtime, but [[rebound insomnia]] may occur and they might cause wake-time anxiety. Daytime withdrawal symptoms are also a problem with prolonged usage, including daytime anxiety. Examples are [[brotizolam]], [[midazolam]], and [[triazolam]]. |
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Intermediate-acting compounds |
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]]. |
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Long-acting compounds have a half-life |
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]]. |
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==Overdose== |
==Overdose== |
Revision as of 08:13, 12 June 2009
Benzodiazepines |
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The benzodiazepine (Template:Pron-en) 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][3] 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. Longer-acting benzodiazepines are preferred for the treatment of anxiety.[4]
The first of its kind, chlordiazepoxide (Librium), was discovered accidentally by Leo Sternbach; it was introduced to the market in 1960 and 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.[5] Because they are much safer, benzodiazepines largely replaced barbiturates as the most commonly prescribed sedative hypnotics. However, they are now beginning to be replaced in turn by the nonbenzodiazepines, especially for treatment of insomnia.[6]
Benzodiazepines are generally safe and effective in the short-term, although cognitive impairments or paradoxical effects such as aggression or behavioral disinhibition occasionally occur. 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. They are also major drugs of abuse.[7][8][9] Other drawbacks from long term use include their propensity to cause or worsen sleep problems, cognitive deficits, depression, anxiety and panic attacks as well as agoraphobia.[10][11][12] The elderly are at an increased risk of suffering from the adverse effects.[10][13]
There is controversy concerning their safety in pregnancy; while they are not major teratogens, uncertainty remains whether they cause major malformations in a small number of babies. Taken during gestation, they can however cause neonatal withdrawal effects.[14][15] Benzodiazepines are often taken in overdoses, but because they are much less toxic than their predecessors the barbiturates, overdoses rarely are fatal.[16] When they are combined with other central nervous system depressants such as alcohol or opiates, however, the potential for overdose greatly increases. This is particularly problematic in the drug misusing community.[17][18]
History
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.[19][5] 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 benzodiazepine sedative hypnotics led to a fall in barbiturate prescriptions and by the 1970s they had largely replaced the older drugs.[20]
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.[21] 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.[22]
A newer class of drugs called the nonbenzodiazepines (also sometimes referred to as Z-drugs) are now beginning to replace the benzodiazepines, particularly in the treatment of insomnia. Although they are molecularly distinct, nonbenzodiazepines work on benzodiazepine receptors.[6][23][24]
Therapeutic uses
Benzodiazepines possess sedative, hypnotic, anxiolytic, anticonvulsant, muscle relaxant and amnesic actions,[1] 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.[25] Benzodiazepines are well-tolerated and are generally safe and effective drugs in the short-term for a wide range of conditions.[26][27] Tolerance can develop to their effects, and there is also a risk of dependence and a withdrawal syndrome when retired. These factors combined with other possible secondary effects after prolonged use such as psychomotor, cognitive or memory impairments, limit their long term applicability.[28][29][30]
Alcohol dependence
Benzodiazepines are the preferred choice in the management of alcohol withdrawal syndrome, particularly for preventing or treating seizures and delirium.[31] 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.[32] 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. The patient is also more prone to rebound if they are not tapered after alcohol detoxification.[33][34]
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.[35][36]
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.[37] Clobazam is widely used by specialist epilepsy clinics worldwide (but it is not available in the US), and clonazepam is popular in France.[37] In the UK, both clobazam and clonazepam are second-line choices for treating many forms of epilepsy.[38] Clobazam also has a useful role for very short-term seizure prophylaxis and in catamenial epilepsy.[37] 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.[36]
Anxiety, panic and agitation
As they possess anti-anxiety properties, benzodiazepines can be useful for the short-term treatment of severe anxiety.[39] Benzodiazepines are often prescribed long term for anxiety disorders, despite certain antidepressants and the anticonvulsant drug pregabalin being recommended as first line treatment options. Their effectiveness is questioned for this indication and is not recommended by current guidelines.[40] They are usually administered orally; however, very occasionally lorazepam or diazepam may be given intravenously for the treatment of panic attacks. Benzodiazepines are also used to treat the acute panic caused by hallucinogen intoxication,[41] and occasionally prescribed for panic disorder.[26][27] 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.[42]
Benzodiazepines can be very useful in the short-term treatment of acute psychosis such as schizophrenia or mania, bringing about rapid tranquillization and sedation until the effects of lithium or neuroleptics (antipsychotics) take effect. They are also used to calm the acutely agitated individual in a psychiatric emergency and may, if required, be given via an intramuscular injection. Lorazepam is most commonly used but clonazepam is also sometimes prescribed.[43][44][45]
Insomnia
Hypnotic benzodiazepines are prescribed for the short-term management of severe or debilitating insomnia. They have strong sedative effects, are typically the most rapid-acting and have strong receptor affinity. 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. 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.[46]
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.[47]
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.[47] Diazepam or temazepam can be utilized in patients who are particularly anxious about dental procedures for example those with dental phobia.[47]
Benzodiazepines are well known for their strong muscle-relaxing properties and can be useful in the treatment of muscle spasms caused by tetanus.[48] Stiff person syndrome which is a neurological disorder characterized by severe muscle stiffness can also be treated.[49][50]
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 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.[51]
Oral contraceptives, some antibiotics, antidepressants, antifungal agents and other drugs inhibit cytochrome enzymes in the liver. They reduce the rate of elimination of many benzodiazepines leading to possibly excessive drug accumulation and increased side effects. St John's wort, the antibiotic rifampicin and the anticonvulsants carbamazepine and phenytoin induce cytochrome P450 enzymes, accelerate elimination of many benzodiazepines and decrease their action.[52][53]
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.[52][53] Antacids may slow down absorption of some benzodiazepines; however, this effect is marginal and inconsistent.[53]
Side effects
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.[54][55] Another result is impairment of driving skills and increased risk of road traffic accidents.[56][57] Benzodiazepines adversely affect cognition; they interfere with the formation and consolidation of memories of the new material and may induce complete anterograde amnesia. Decreased libido and erection problems are a common side effect. An emergence of depression and paradoxical side reactions of disinhibition have been observed. Hypotension and suppressed breathing may be encountered with intravenous use.[54][55] Less common side effects include nausea and changes in appetite, blurred vision, confusion, euphoria, dissociation, depersonalization and nightmares. Cases of liver toxicity have been described but are very rare.[25][58][59][9]
Numerous cases of paradoxical reactions, such as aggression, violence, impulsivity, irritability and suicidal behavior have been described in the literature. These reactions have been explained as consequences of disinhibition, that is loss of control over socially unacceptable behavior.[60] Recreational abusers, individuals with borderline personality disorder, children and patients on high-dosage regimes are at a greater risk of experiencing these side effects.[60][61] The frequency of paradoxical reactions to benzodiazepines is uncertain. A review of 45 controlled trials found no difference in their incidence between patients given triazolam, flurazepam and placebo. Another review estimated that the incidence of aggressive reactions to the administration of benzodiazepines is similar to placebo and below 1%. On the other hand, in controlled trials and case series for alprazolam, paradoxical reactions were observed in 10-20% of the cases.[62] In several trials oxazepam demonstrated a lower rate of disinhibition reactions than other benzodiazepines.[54][62][63]
Withdrawal syndrome
Long-term usage, in general, leads to some form of tolerance and/or dependence with the appearance of a withdrawal syndrome when the use of benzodiazepines is stopped or reduced. Discontinuation of benzodiazepines, even after a relatively short course of treatment (three to four weeks), may result in a withdrawal syndrome. Benzodiazepine withdrawal symptoms occur when the dosage is reduced in people who are physically dependent with severe symptoms occurring during abrupt or over-rapid dosage reduction. Symptoms may also occur during a gradual dosage reduction but are typically less severe or may persist as part of a protracted withdrawal syndrome for months after cessation of benzodiazepines.[64]
Withdrawal effects may linger up to a year after cessation of benzodiazepines and include anxiety, irritability, sweating, tremor, sleep disorders, depersonalization, derealization, hypersensitivity to stimuli, abnormal sensation of movement and less commonly depression, suicidal behavior, psychosis, seizures and delirium tremens.[65] Approximately 10% of patients will experience a notable protracted withdrawal syndrome. Protracted symptoms tend to resemble those seen during the first couple of months of withdrawal but usually are of a sub acute 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.[12] Use of high doses (or high potency benzodiazepines) and those with a shorter half life increases symptoms severity. Other cross tolerant sedative hypnotics, such as barbiturates or alcohol increase the risk of benzodiazepine dependence.[66]
Abrupt withdrawal can be hazardous, therefore a gradual reduction regime is recommended. The opinion on the time needed to complete ranges from four weeks to several years. Aiming for within six months has been suggested.[8] Factors affecting withdrawal rate include severity of physical dependence, dose and length of use, type of benzodiazepine used, social and environmental factors as well as psychological and possibly genetic factors. Thus the rate of reduction can vary significantly and needs to be individually customized.[67] 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 .[67] 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.[67][68] The speed of withdrawal is usually done in 10% of daily dose stepped reductions over a period of months or even up to a year. The use of long half-life drugs and the slow tapering usually permit withdrawal syndrome to be avoided or reduced. A slow withdrawal, under medical supervision by a physician that is knowledgeable about the syndrome, with the patient in control of dosage reductions coupled with reassurance that symptoms are temporary, has been found to produce the highest success rates. People that report severe experiences have almost invariably withdrawn too quickly.[67]
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.[51][54][52] Caution is required when benzodiazepines are used in people with personality disorders or mental retardation because of frequent paradoxical reactions. In major depression they may precipitate suicidal tendencies and are sometimes used for suicidal overdoses.[51][54][69] 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.[53]
Long-term use of benzodiazepines in pregnant or breast feeding women is not recommended because of the side effects like neonatal withdrawal syndrome.[70]
Pregnancy
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.[71]
Use of benzodiazepines may result in a neonatal withdrawal syndrome, including irritability, hyperactivity, disturbed sleep pattern, high-pitched crying, tremor, vomiting, diarrhea, weight loss and failure to gain weight.[72] Other neonatal withdrawal symptoms include; hypertonia, hyperreflexia, restlessness, abnormal sleep patterns, jerking of the extremities, bradycardia, cyanosis, suckling difficulties, apnea, risk of aspiration of feeds and growth retardation. The syndrome may last from a few days to several months. Tapering down the dose during pregnancy may lessen its severity. If used in pregnancy, benzodiazepines which have 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.[73]
Elderly
The benefits are least and the risks are the greatest in the elderly.[74] The toxicity is increased with the coadministration of other central nervous system depressants or from long term use of benzodiazepines.[75] The elderly are at an increased risk of dependence and more sensitive to the adverse effects such as cognitive impairment, including memory problems, daytime sedation, impaired motor coordination, increased risk of motor vehicle accidents and falls. 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.[76]
Drug induced dementia may affect up to 10 percent of patients attending memory clinics. Most often the drugs implicated include the benzodiazepines, antihypertensives and anticholinergic drugs.[77] A past history of benzodiazepine use and withdrawal may also predict dementia but the literature is conflicting and inconclusive.[78][79]
Up to 10% of hospital admissions are because of benzodiazepines. Similarly whilst sometimes prescribed to treat behavioral symptoms in dementia there is little evidence demonstrating their effectiveness and limited information on their safety.[80][81]
Pharmacology
Benzodiazepines share a similar chemical structure;[82] while 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.[83] Other less important mechanisms of action are also known.[84][85]
Chemistry
The core chemical structure of "classical" benzodiazepine drugs is a fusion between the benzene and diazepine ring systems. Many of these drugs contain the 5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one substructure (see figure to the right).[82] Benzodiazepines are structurally similar to several groups of drugs, some of which share similar pharmacological properties, including the quinazolinones, hydantoins, succinimides, oxazolidinediones, barbiturates and glutarimides.[86][87][88][89]
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.
GABA controls the excitability of neurons through binding to the GABAA receptor.[83] 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.[90] 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.[91] 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.[92]
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.[93]
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. 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.[84][94][95] 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.[85]
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:[96]
Short-acting compounds have a half-life of 1–8 hours. They have few residual effects if taken before bedtime, but rebound insomnia may occur and they might cause wake-time anxiety. Daytime withdrawal symptoms are also a problem with prolonged usage, including daytime anxiety. 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.
Overdose
Taken alone, benzodiazepines rarely cause severe complications in overdose,[97] and deaths after hospital admission are rare.[98] However, combining these drugs with alcohol or opiates markedly raises the toxicity.[99] The various benzodiazepines differ in their toxicity; alprazolam appears to be most toxic in overdose and when used with other drugs.[100]
A reversal agent for benzodiazepines exists, flumazenil (Anexate). Its use as an antidote in an overdose however is controversial.[101] 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.[102] One study found that only 10% of the patient population presenting with a benzodiazepine overdose are suitable candidates for treatment with flumazenil.[103]
Drug misuse
Internationally, benzodiazepines are categorized as Schedule IV controlled drugs, apart from flunitrazepam which is a Schedule III drug under the Convention on Psychotropic Substances.[104] Some variation in drug scheduling exists in individual countries, for example in the United Kingdom midazolam and temazepam are Schedule III controlled drugs.[105][106]
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.[17]
Dependence and tolerance, often coupled with dosage escalation, to benzodiazepines develops rapidly among drug misusers; withdrawal syndrome can 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 of transmission of hepatitis, AIDS, and other diseases. Benzodiazepines are also sometimes 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.[107]
A police survey of arrestees found that benzodiazepine misuse is also associated with drug-related crime such as property crime, increased methamphetamine and heroin misuse. Unemployed and receipt of government financial benefits was also found to be higher in benzodiazepine misusers.[108] Benzodiazepines are also sometimes used for criminal purposes; they serve to incapacitate a victim in cases of drug assisted rape or robbery.[109]
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).[110][111][112] 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.[110][113]
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Further reading
- Ashton CH (2002). "Benzodiazepines: how they work & how to withdraw". The Ashton Manual. benzo.org.uk. Retrieved 2009-06-09.
- Ashton CH (2007). "Benzodiazepine equivalence table". benzo.org.uk. Retrieved 2009-06-09.
- Fruchtengarten L (1998). "Benzodiazepines". PIM G008. International Programme on Chemical Safety (IPCS) INCHEM. Retrieved 2009-06-09.
- Longo LP, Johnson B (2000). "Addiction: part I. Benzodiazepines—side effects, abuse risk and alternatives". Am Fam Physician. 61 (7): 2121–8. PMID 10779253.
- "The complete story of the benzodiazepines". The Eaton T. Fores Research Center. 2005. Retrieved 2009-06-09.
- "Benzodiazepines advanced consumer information". Drugs.com. 2005-02-24. Retrieved 2009-06-09.