Benzodiazepines (BZD , BZs ), sometimes called "benzos ", are a class of psychoactive drugs whose chemicals Its main structure is the fusion of benzene rings and diazepine rings. The first drug, chlordiazepoxide (Librium), was discovered accidentally by Leo Sternbach in 1955, and was available in 1960 by Hoffmann-La Roche, who, since 1963, also marketed benzodiazepine diazepam (Valium). In 1977, benzodiazepines globally were the most commonly prescribed drugs. They are in a family of drugs commonly known as minor tranquillizers.
Benzodiazepines enhance the effects of gamma-aminobutyric acid (GABA) neurotransmitters on the GABA receptor A , producing tranquilizers, hypnotics (inducing sleep), anxiolytics (anti-anxiety), anticonvulsants, and muscle relaxants properties. High doses of many short-acting benzodiazepines can also cause anterograde amnesia and dissociation. These properties make benzodiazepine useful in treating anxiety, insomnia, agitation, seizures, muscle spasms, withdrawal of alcohol and as premedication for medical or dental procedures. Benzodiazepines are categorized as short, intermediate, or long acting. Short and medium-term benzodiazepines are preferred for the treatment of insomnia; longer-acting benzodiazepines are recommended for the treatment of anxiety.
Benzodiazepines are generally considered safe and effective for short-term use, although cognitive impairment and paradoxical effects such as aggression or disinhibition behavior occasionally occur. A small number of people can have paradoxical reactions such as agitation or panic that worsen. Benzodiazepines are also associated with an increased risk of suicide. Long-term use is controversial due to concerns about adverse psychological and physical effects, decreased effectiveness, and physical dependence and withdrawal. As a result of adverse effects associated with long-term use of benzodiazepines, withdrawal from benzodiazepines often leads to improved physical and mental health. Parents are at an increased risk of short-term and long-term side effects, and as a result, all benzodiazepines are listed in the Beer List of drugs not suitable for older adults.
There is controversy about the safety of benzodiazepines in pregnancy. Although they are not a large teratogen, uncertainty remains about whether they cause the crevice ceiling in a small number of infants and whether neurobehavioural effects occur as a result of prenatal exposure; they are known to cause withdrawal symptoms in newborns. Benzodiazepines can be taken with an overdose and can cause deep unconsciousness. However, they are less toxic than their predecessors, barbiturates, and death are rare when benzodiazepines are the only drug taken. When combined with other central nervous system (CNS) depressants such as alcoholic beverages and opioids, the potential for fatal toxicity and overdose increases. Benzodiazepines are commonly abused and used in conjunction with other drug abuse.
Video Benzodiazepine
Medical use
Benzodiazepines have sedative, hypnotic, anxiolytic, anticonvulsant, muscle relaxants, and amnesia, which are useful in various indications such as alcohol dependence, seizures, anxiety disorders, panic, agitation, and insomnia. Mostly given orally; However, they can also be given intravenously, intramuscularly, or rectally. In general, benzodiazepine is well tolerated and is a safe and effective drug in the short term for various conditions. Tolerance can develop into its effects and there is also the risk of dependence, and after the withdrawal of the withdrawal syndrome can occur. These factors, combined with other secondary effects that may be after long-term use such as psychomotor, cognitive, or memory disorders, limit their long-term application. The effects of long-term use or abuse include a tendency to cause or worsen cognitive deficits, depression, and anxiety. The College of Physicians and Surgeons of British Columbia recommends stopping the use of benzodiazepines in those who use opioids and those who have used them over the long term. Benzodiazepines can have poor health outcomes, and these findings support clinical and regulatory efforts to reduce use, especially in combination with non-benzodiazepine receptor agonists.
Panic disorder
Because of the effectiveness, tolerability, and rapid onset of anxiolytic action, benzodiazepines are often used for the treatment of anxiety associated with panic disorder. However, there is disagreement among expert agencies regarding the long-term use of benzodiazepines for panic disorder. Views range from those who argue that benzodiazepines are not effective over the long term and that they should be reserved for treatment-resistant cases for those who consider they are effective in the long term as selective serotonin reuptake inhibitors.
The American Psychiatric Association's Guidelines (APA) note that, in general, benzodiazepines are well tolerated, and their use for early treatment for panic disorder is strongly supported by a variety of controlled trials. APA states that there is not enough evidence to recommend a panic disorder treatment that already exists above the others. Treatment options between benzodiazepines, SSRIs, serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, and psychotherapy should be based on patient history, preferences, and other individual characteristics. Selective serotonin reuptake inhibitors tend to be the best choice of pharmacotherapy for many patients with panic disorder, but benzodiazepines are also frequently used, and some studies show that these drugs are still used with greater frequency than SSRIs. One of the advantages of benzodiazepines is that they relieve anxiety symptoms much more rapidly than antidepressants, and therefore may be preferred in patients who control rapid symptoms is essential. However, this advantage is offset by the possibility of developing a benzodiazepine dependency. APA does not recommend benzodiazepine for people with symptoms of depression or recent history of substance abuse. The APA guidelines state that, in general, pharmacotherapy panic disorder should be continued for at least a year, and clinical experience supports ongoing benzodiazepine treatment to prevent recurrence. Although major concerns about tolerance and withdrawal of benzodiazepines have increased, there is no evidence for significant dose escalation in patients using long-term benzodiazepines. For many such patients, stable doses of benzodiazepines retain their efficacy for several years.
The guidelines issued by the UK-based National Institute for Health and Clinical Excellence (NICE) conduct a systematic review using different methodologies and come to different conclusions. They questioned the accuracy of the placebo-controlled study. And, based on the findings of a placebo-controlled study, they do not recommend the use of benzodiazepines after two to four weeks, as tolerance and physical dependence develop rapidly, with withdrawal symptoms including rebound anxiety that occurs after six weeks or more of use. However, benzodiazepines are still prescribed for long-term treatment of anxiety disorders, although specific antidepressants and psychological therapy are recommended as a first-line treatment option with pregabalin anticonvulsant drugs indicated as second or third line treatment and are suitable for the long term. use of the term. NICE states that long-term use of benzodiazepines for panic disorder with or without agoraphobia is indicated without permission, has no long-term efficacy, and therefore, is not recommended by clinical guidelines. Psychological therapy such as cognitive behavioral therapy is recommended as first-line therapy for panic disorder; the use of benzodiazepines has been found to interfere with the therapeutic benefits of this therapy.
Benzodiazepines are usually given orally; However, sometimes lorazepam or diazepam may be given intravenously for the treatment of panic attacks.
General anxiety disorder
Benzodiazepines have a strong efficacy in the short-term management of generalized anxiety disorder (GAD), but are not proven to be effective in generating overall long-term improvement. According to the National Institute for Health and Clinical Excellence (NICE), benzodiazepines may be used in the management of GAD immediately, if necessary. However, they are usually not given more than 2-4 weeks. The only NICE recommendation for long-term management of GAD is antidepressants.
Likewise, the Canadian Psychiatric Association (CPA) recommends benzodiazepine alprazolam, bromazepam, lorazepam, and diazepam only as second-line options, if treatment with two different antidepressants is unsuccessful. Although they are second-line agents, benzodiazepines can be used for a limited time to relieve severe anxiety and agitation. The CPA guidelines note that after 4-6 weeks the effects of benzodiazepines may decrease to placebo levels, and that benzodiazepines are less effective than antidepressants in reducing ruminative concerns, the GAD core symptoms. However, in some cases, prolonged treatment with benzodiazepines in addition to antidepressants may be warranted.
2015 reviews find a greater effect with the drug than speech therapy. Drugs with benefits include serotonin-noradrenaline reuptake inhibitors, benzodiazepines, and selective serotonin reuptake inhibitors.
Insomnia
Benzodiazepines may be useful for the treatment of short-term insomnia. Its use beyond 2 to 4 weeks is not recommended because of the risk of dependence. The Drug Safety Committee report recommends that where long-term use of benzodiazepines for insomnia is indicated, treatment should be intermittent where possible. It is preferred that benzodiazepines are intermittently taken and at the lowest effective dose. They fix sleep-related problems by shortening the time spent in bed before falling asleep, lengthening bedtime, and, in general, reducing awareness. However, they worsen the quality of sleep by improving light sleep and reducing restful sleep. Other disadvantages of hypnotics, including benzodiazepines, are the possible tolerances for their effects, rebound insomnia, and decreased slow-wave sleep and withdrawal periods characterized by rebound insomnia and anxiety and agitation periods prolonged.
The list of approved benzodiazepines for the treatment of insomnia is quite similar in most countries, but which benzodiazepines are officially designated as first-line hypnotics prescribed for the treatment of insomnia varies across countries. Again-acting benzodiazepines such as nitrazepam and diazepam have residual effects that can persist into the next day and, in general, are not recommended.
Since the release of nonbenzodiazepines in 1992 in response to safety concerns, individuals with insomnia and other sleep disorders have been increasingly prescribed nonbenzodiazepine (2.3% in 1993 to 13.7% of Americans in 2010), less frequently prescribed benzodiazepines (23.5 % in 1993 to 10.8% in 2010). It is unclear whether the new nonbenzodiazepine (Z-drug) hypnotics are better than short-acting benzodiazepines. The efficacy of both groups of drugs is similar. According to the US Agency for Healthcare Research and Quality, indirect comparisons suggest that the side effects of benzodiazepines may be about twice as frequent as nonbenzodiazepine. Some experts recommend the use of nonbenzodiazepine as a long-term treatment of insomnia. However, the UK National Institute for Health and Clinical Excellence found no convincing evidence to support Z-drugs. NICE reviews indicate that Z-drug short-acting is inappropriately compared in clinical trials with long-acting benzodiazepines. There have been no trials comparing short-acting Z-drugs with appropriate short-acting benzodiazepines. Based on this, NICE recommends choosing hypnosis based on patient costs and preferences.
Older adults should not use benzodiazepines to treat insomnia unless other treatments fail. When benzodiazepines are used, patients, their caregivers, and their doctors should discuss the increased risk of harm, including evidence that shows twice the incidence of traffic crashes among patients who drive, and fall and hip fractures for older patients.
Seizures
Prolonged convulsive epilepsy seizures are medical emergencies that can usually be dealt with effectively with the rapid administration of benzodiazepines, which are potent anticonvulsants. In the hospital setting, intravenous clonazepam, lorazepam, and diazepam are first-line options, clonazepam due to stronger and stronger anticonvulsant action, diazepam because of its faster onset and lorazepam for longer duration of action. In the community, intravenous administration is impractical and rectal diazepam or (later) midazolam buccal is used, with preference for midazolam because its administration is easier and more socially acceptable.
When benzodiazepines were first introduced, they were enthusiastically adopted to treat all forms of epilepsy. However, drowsiness and tolerance are problematic with ongoing use and none are now considered first-line options for long-term epilepsy therapy. Clobazam is widely used by specialist epilepsy clinics around the world and popular clonazepam in the Netherlands, Belgium and France. Clobazam is approved for use in the United States in 2011. In the UK, both clobazam and clonazepam are second-line options for treating various forms of epilepsy. Clobazam also has a useful role for the prophylaxis of short-term seizures and in catamenial epilepsy. Termination after prolonged use in epilepsy requires additional attention because of the risk of rebound seizures. Therefore, the dose slowly tapered for a period of up to six months or longer.
Alcohol withdrawal
Chlordiazepoxide is the most commonly used benzodiazepine for alcohol detoxification, but diazepam can be used as an alternative. Both are used in detoxification of individuals who are motivated to stop drinking, and are prescribed for a short period of time to reduce the risk of developing tolerance and dependence on the benzodiazepine drug itself. Benzodiazepines with longer half-lives make detoxification more tolerable, and harmful (and potentially lethal) alcohol withdrawal effects are less likely. On the other hand, short-acting benzodiazepines may cause breakthrough seizures, and therefore, are not recommended for detoxification in ambulatory settings. Oxazepam and lorazepam are often used in patients at risk of drug accumulation, in particular, parents and those with cirrhosis, as they are metabolized differently from other benzodiazepines, via conjugation.
Benzodiazepines are the preferred choice in the management of alcohol withdrawal syndromes, in particular, for the prevention and treatment of dangerous complications of seizures and subjugation of severe delirium. Lorazepam is the only benzodiazepine with predictable intramuscular absorption and it is the most effective in preventing and controlling acute seizures.
Anxiety
Benzodiazepines are sometimes used in the treatment of acute anxiety, because they carry fast symptom relief and are marked or moderate in most individuals; however, they are not recommended after 2-4 weeks of use because of the risk of tolerance and dependence and the lack of long-term effectiveness. As for insomnia, they can also be used irregularly/"as needed", as in cases where the word anxiety is at its worst. Compared with other pharmacological treatments, benzodiazepines are twice as likely to cause a recurrence of underlying conditions after discontinuation. Psychological therapy and other pharmacological therapies are recommended for long-term treatment of generalized anxiety disorders. Antidepressants have higher remission rates and, in general, are safe and effective in the short and long term.
Other indications
Benzodiazepines are often prescribed for a variety of conditions:
- They can be very useful in intensive care to calm patients who receive mechanical ventilation or those who are under extreme pressure. Attention is made in this situation because of occasional occurrence of respiratory depression, and it is recommended that overdose treatment facilities of benzodiazepine should be available.
- Benzodiazepines are effective as a drug given several hours before surgery to reduce anxiety. They also produce amnesia, which can be useful, because patients may not remember the discomfort of the procedure. They are also used in patients with dental phobia as well as some eye procedures such as refractive surgery; although such use is controversial and is only recommended for those who are very anxious. Midazolam is the most commonly prescribed for this use due to its strong sedative action and rapid recovery time, as well as its water solubility, which reduces pain when injected. Diazepam and lorazepam are sometimes used. Lorazepam specifically characterizes the properties of amnesia that might make it more effective when amnesia is the desired effect.
- Benzodiazepines are notorious for their strong properties for muscle relaxation and can be useful in the treatment of muscle spasms, although tolerance often develops into a muscle relaxant effect. Baclofen or tizanidine is sometimes used as an alternative to benzodiazepines. Tizanidine has been found to have superior tolerability compared to diazepam and baclofen.
- Benzodiazepines are also used to treat acute panic induced by hallucinogenic intoxication. Benzodiazepines are also used to soothe highly anxious individuals and can, if needed, be administered by intramuscular injection. They can sometimes be effective in short-term treatment of psychiatric emergencies such as acute psychosis as in schizophrenia or mania, leading to rapid sedation and sedation until lithium or neuroleptic effects (antipsychotics) have an effect. Lorazepam is most commonly used but clonazepam is sometimes prescribed for acute psychosis or mania; Their long-term use is not recommended because of the risk of dependence. Further research investigates the use of benzodiazepines only and in combination with antipsychotic drugs to treat acute psychosis is necessary.
- Clonazepam, benzodiazepine is used to treat various forms of parasomnia. Impaired eye movement behavior quickly responds well to low doses of clonazepam. Restless leg syndrome can be treated using clonazepam as a third-line treatment option because the use of clonazepam is still under investigation.
- Benzodiazepines are sometimes used for obsessive-compulsive disorder (OCD), although it is generally believed to be ineffective for these indications. Effectiveness, however, is found in one small study. Benzodiazepines may be considered as treatment options in cases that are resistant to treatment.
- Antipsychotics are generally first-line treatment for delirium; however, when delirium is caused by alcohol or sedative cessation of hypnosis, benzodiazepines are the first-line treatment.
- There is some evidence that low doses of benzodiazepines reduce the adverse effects of electroconvulsive therapy.
Maps Benzodiazepine
Contraindications
Because of their muscle relaxant action, benzodiazepines can cause respiratory depression in susceptible individuals. For that reason, they are contraindicated in patients with myasthenia gravis, sleep apnea, bronchitis, and COPD. Care is needed when benzodiazepines are used in people with personality disorders or intellectual disabilities because of frequent paradoxical reactions. In severe depression, they can trigger suicidal tendencies and are sometimes used for overdose of suicide. Individuals with a history of alcohol abuse, opioids and barbiturates should avoid benzodiazepines, as there is a risk of life-threatening interactions with these drugs.
Pregnancy
In the United States, the Food and Drug Administration has categorized benzodiazepines into categories D or X which means potential harm to unborn babies has been demonstrated.
Exposure to benzodiazepines during pregnancy has been associated with a slight increase (from 0.06-0.07%) risk of cleft palate in newborns, a controversial conclusion since some studies have found no association between benzodiazepines and cleft palates. Its use by pregnant women shortly before delivery can cause floppy baby syndrome, with newborns suffering from hypotonia, hypothermia, lethargy, and difficulty in breathing and eating. The case of neonatal withdrawal syndrome has been described in infants who are chronically exposed to benzodiazepines in the uterus. This syndrome may be difficult to recognize, since it begins several days after delivery, for example, at least 21 days for chlordiazepoxide. The symptoms include tremor, hypon, hyperreflexia, hyperactivity, and vomiting and can last up to three to six months. Streamline the dose during pregnancy can reduce the severity. If used in pregnancy, they benzodiazepines with better and longer safety records, such as diazepam or chlordiazepoxide, are recommended for potentially more benzodiazepines, such as temazepam or triazolam. Using the lowest effective dose for the shortest period of time minimizes the risk to the fetus.
Elderly
Benzodiazepine benefits the least and the greatest risk in the elderly. Parents are at increased risk of dependence and more sensitive to adverse effects such as memory problems, daytime sedation, motor coordination disorders, and increased risk of motor vehicle accidents and falls, and an increased risk of hip fractures. Long-term effects of benzodiazepines and benzodiazepine dependence in the elderly may resemble dementia, depression, or anxiety syndrome, and worsen over time. The adverse effects on cognition can be misinterpreted as the effects of old age. The benefits of withdrawal include increased cognition, alertness, mobility, decreased risk of incontinence, and decreased risk of falls and fractures. The success of a gradual decrease in benzodiazepines is as great in the elderly as in younger people. Benzodiazepines should be prescribed for the elderly only with caution and only for a short time with low doses. Short to intermediate-acting benzodiazepines are preferred in the elderly such as oxazepam and temazepam. High potency of benzodiazepine alprazolam and triazolam and long-acting benzodiazepines are not recommended in the elderly because of the adverse side effects. Nonbenzodiazepines such as zaleplon and zolpidem and low doses of sedating antidepressants are sometimes used as an alternative to benzodiazepines.
Long-term use of benzodiazepines has been associated with an increased risk of cognitive impairment, but its association with dementia remains unconvincing. The association between the history of benzodiazepine use and cognitive decline is unclear, with some studies reporting a lower cognitive impairment risk in previous users, some finding no association and some showing an increased risk of cognitive impairment.
Benzodiazepines are sometimes prescribed to treat symptoms of dementia behavior. However, like antidepressants, they have little evidence of effectiveness, although antipsychotics have shown some benefits. The effects of cognitive impairment from benzodiazepines that often occur in older people can also aggravate dementia.
Adverse effects
The most common side effects of benzodiazepines are linked to their sedative and muscle-relaxing action. They include drowsiness, dizziness, and decreased alertness and concentration. Lack of coordination can result in falling and injury, in particular, in the elderly. Another result is the deterioration of driving skills and the possible increase in road traffic accidents. Decreased libido and erection problems are common side effects. Depression and disinhibition may appear. Hypotension and suppressed breath (hypoventilation) can be found with intravenous use. Less common side effects include nausea and appetite changes, blurred vision, confusion, euphoria, depersonalization and nightmares. Cases of liver toxicity have been described but are very rare.
Long-term effects of benzodiazepine use may include cognitive impairment as well as affective and behavioral problems. Feelings of turmoil, difficulty in constructively thinking, loss of sex drive, agoraphobia and social phobia, increase anxiety and depression, lose interest in pursuit and interest, and an inability to experience or express feelings can also occur. However, not everyone is having trouble with long-term use. In addition, self-perception, the environment and changing relationships can occur.
Compared to other hypnotic sedatives, hospital visits involving benzodiazepines are 66% more likely than poor health outcomes. These include hospitalization, patient transfer, or death, and visits involving a combination of benzodiazepines and non-benzodiapine receptor agonists nearly four times increase the likelihood of a serious health outcome.
Cognitive effects
Short-term use of benzodiazepines adversely affects many areas of cognition, the most important being that it interferes with the formation and consolidation of new material memory and may lead to complete anterograde amnesia. However, the researchers argued otherwise about long-term administration effects. One view is that many of the short-term effects continue into the long run and may even worsen, and are not resolved after stopping the use of benzodiazepines. Another view suggests that cognitive deficits in chronic benzodiazepine users only occur for short periods after dosing, or that anxiety disorders are the cause of this deficit.
While less definitive studies, the previous outlook received support from 2004 meta-analysis of 13 small studies. This meta-analysis found that long-term benzodiazepine use was associated with moderate to large adverse effects in all areas of cognition, with visuospatial memory being the most frequently detected disorder. Some other disorders reported are decreased IQ, visiomotor coordination, information processing, verbal learning and concentration. The meta-analysts and reviewers later noted that the application of this meta-analysis was limited because subjects were drawn mostly from the withdrawal clinics; joint drugs, alcohol use, and psychiatric disorders are not defined; and several studies including performing cognitive measurements during the withdrawal period.
Paradoxical Effects
Paradoxical reactions, such as increased seizures in epilepsy, aggression, violence, impulsivity, irritability and suicidal behavior occasionally occur. These reactions have been described as a consequence of disinhibition and loss of control over unacceptable social behavior. Paradoxical reactions are rare in the general population, with an incidence rate below 1% and similar to placebo. However, they occur with greater frequency in recreational users, individuals with impaired personality thresholds, children, and patients in high-dose regimens. In these groups, impulse control problems may be the most important risk factors for disinhibition; learning disabilities and neurological disorders are also significant risks. Most reports about disinhibition involve high doses of high-potency benzodiazepines. Paradoxical effects may also appear after the use of chronic benzodiazepines.
Exacerbate long-term psychiatric symptoms
While benzodiazepines may have short-term benefits for anxiety, sleep and agitation in some patients, long-term use (ie, more than 2-4 weeks) may lead to worsening of symptoms intended for treatment. Potential explanations include exacerbating cognitive problems that are already common in anxiety disorders, causing or aggravating depression and suicide, disrupting sleep architecture by inhibiting deep sleep stage, withdrawal symptoms or rebound symptoms between doses mimicking or worsening anxiety or underlying sleep disorders, inhibiting the benefits of psychotherapy by inhibiting memory consolidation and reducing fear extinction, and reducing overcoming trauma/stress and increasing susceptibility to stress in the future. Anxiety, insomnia, and irritability may increase temporarily during withdrawal, but psychiatric symptoms after termination are usually less than when taking benzodiazepines. Fortunately, for those with benzodiazepine-induced problems, functioning significantly increases within 1 year of discontinuation.
Improvement disorder
Tolerance
The main problem of chronic use of benzodiazepines is the development of tolerance and dependence. Tolerance manifests itself as a diminishing and rapidly growing pharmacological effect on tranquilizers, hypnotics, anticonvulsants, and muscle relaxants of benzodiazepines. Tolerance to anti-anxiety effects develops more slowly with little evidence of continued effectiveness after four to six months of ongoing use. In general, tolerance to the effects of amnesia does not occur. However, controversy exists for tolerance of anxiolytic effects with some evidence that benzodiazepines retain efficacy and challenge evidence from systematic review of the literature that tolerance is common and some evidence that anxiety may worsen with long-term use. The question of tolerance for the effects of amnesia from benzodiazepines is also unclear. Some evidence suggests that partial tolerance develops, and that, "memory impairment is confined to narrow windows within 90 minutes after each dose".
The main disadvantages of benzodiazepines that are tolerant to therapeutic effects develop relatively quickly while many adverse effects persist. Tolerance develops into hypnotic and myorelexant effects within days to weeks, and the anticonvulsant and anxiolytic effects in weeks to months. Therefore, benzodiazepines are unlikely to be effective in long-term care for sleep and anxiety. While the effects of BZD therapy are lost with tolerance, depression and impulsivity with a high risk of suicide generally persist. Several studies have confirmed that long-term benzodiazepines did not differ significantly from placebo for sleep or anxiety. This may explain why patients usually increase doses over time and many end up taking more than one type of benzodiazepine after losing its first effectiveness. Moreover, since tolerance to the sedative effects of benzodiazepines develops faster than tolerance to the effects of brainstem depressants, those who take more benzodiazepines to achieve the desired effect may suffer from sudden respiratory depression, hypotension or death. Most patients with anxiety disorder and PTSD have symptoms that persist for at least several months, making tolerance to the therapeutic effect a problem for them and necessitating the need for more effective long-term care (eg, psychotherapy, serotonergic antidepressants).
Symptoms and withdrawal management
Termination of benzodiazepines or sudden dose reductions, even after relatively short treatment (three to four weeks), may cause two sets of symptoms - rebound and withdrawal. The symptoms of rebound are the return of symptoms in which the patient is treated but worse than before. Withdrawal symptoms are a new symptom that occurs when benzodiazepine is stopped. They are a major sign of physical dependence.
The most common withdrawal symptoms of benzodiazepines are insomnia, gastric problems, tremors, agitation, fear, and muscle spasms. Less frequent effects are irritability, sweating, depersonalization, derealization, hypersensitivity to stimuli, depression, suicidal behavior, psychosis, seizures, and delirium tremens. Severe symptoms usually occur as a result of sudden or over-rapid withdrawal. A sudden withdrawal can be dangerous, therefore a gradual reduction regimen is recommended.
Symptoms may also occur during gradual dose reduction, but are usually less severe and may persist as part of a prolonged withdrawal syndrome for months after the cessation of benzodiazepines. Approximately 10% of patients have prominent prolonged withdrawal syndrome, which can persist for months or in some cases a year or more. Prolonged symptoms tend to resemble those seen during the first few months of withdrawal but usually sub-acute severity. Such symptoms gradually diminish with time, eventually disappearing altogether.
Benzodiazepines have a reputation with patients and doctors for causing severe and traumatic withdrawals; However, this is mostly due to poorly managed withdrawal processes. Excessive withdrawal from benzodiazepines increases the severity of the withdrawal syndrome and increases the failure rate. Slow and gradual withdrawals are tailored to the individual and, if indicated, psychological support is the most effective way to manage withdrawals. Opinions about the time it takes to complete the withdrawal range from four weeks to several years. A goal of less than six months has been suggested, but due to factors such as dosage and benzodiazepine type, the reasons for prescription, lifestyle, personality, environmental stress, and the amount of support available, a year or more may be required to resign.
Better withdrawal is managed by transferring physically dependent patients to equivalent doses of diazepam because it has the longest half of all benzodiazepines, metabolized into long-acting active metabolites and available in low-potency tablets, which can be subdivided for smaller doses. A further benefit is that it is available in liquid form, which allows for a smaller reduction. Chlordiazepoxide, which also has long and active long half-active metabolites, can be used as an alternative.
Nonbenzodiazepine is contraindicated during withdrawal of benzodiazepines because they are cross-tolerant with benzodiazepines and may cause dependence. Alcohol is also cross-resistant with benzodiazepines and more toxic and therefore caution is required to avoid substituting one dependency with another. During withdrawal, fluoroquinolone-based antibiotics should be avoided where possible; they replace benzodiazepines from the binding sites and reduce GABA function and, as such, may exacerbate withdrawal symptoms. Antipsychotics are not recommended for withdrawal of benzodiazepines (or other CNS depressant withdrawal conditions), especially clozapine, olanzapine or low potency phenothiazines, eg. chlorpromazine because they lower the seizure threshold and may exacerbate the withdrawal effect; if used very carefully is required.
Withdrawal from long-term benzodiazepines is beneficial to most individuals. Benzodiazepine withdrawal from long-term users, in general, leads to improved physical and mental health especially in the elderly; Although some long-term users report on the sustained benefits of consuming benzodiazepines, this may be the result of suppression of withdrawal effects.
Controversial association
Beyond the established relationship between benzodiazepines and psychomotor disorders resulting in motor vehicle accidents and falling leads to fractures; research in the 2000s and 2010s has enhanced the association between benzodiazepines (and Z-Drugs) and others, as has not been proven, side effects including dementia, cancer, infections, pancreatitis, and exacerbations of respiratory diseases.
Dementia
Numerous studies have drawn links between long-term benzodiazepine use and neuro-degenerative diseases, especially Alzheimer's disease. However, most of these studies have been retrospective and observational in that it limits the belief in causal conclusions. Expert criticism from this research body has consistently speculated that associations may be due to protopathic biases or confounding by indications, in which individuals experience early stages of dementia (or who have previously been diagnosed) prescribed benzodiazepines to manage agitation and behavioral disorders. Further evidence of a large prospective study of long duration of follow-up along with neuro-pharmacological studies is needed to confirm or refute this relationship.
Infection
Several observational studies have detected a significant association between benzodiazepines and respiratory infections such as pneumonia where others do not. A large meta-analysis of randomized, pre-marketing controlled trials on pharmacologically related Z-Drugs showed a small increase in the risk of infection as well. The immunodeficiency effects of benzodiazepine action on GABA-A receptors have been postulated from studies in animals.
Cancer
A meta-analysis of observational studies has determined the association between the use of benzodiazepines and cancer, although the risks in different agents and different cancers vary significantly. Moreover, most of these studies can not control the confounding variables that might affect relationships such as lifestyle exposures (ie tobacco, alcohol). In terms of evidence of experimental basic science, analyzes of carcinogenesis and genotoxicity data for various benzodiazepines have suggested a small possibility of carcinogenesis for small amounts of benzodiazepines. A large randomized, controlled, controlled trial with appropriate follow-up in addition to further pharmacological/toxicological examinations is needed to confirm these preliminary findings.
Pancreatitis
Evidence showing a link between benzodiazepines (and Z-Drugs) and pancreatic inflammation is very rare and limited to some observational studies from Taiwan. Critics of confounding can be applied to these findings as with other controversial associations above. Further well-designed studies of other populations as well as reasonable biological mechanisms are needed to confirm this relationship.
Overdose
Although benzodiazepines are much safer in overdose than their predecessors, barbiturates, they can still lead to overdose problems. Taken alone, they rarely cause severe complications in overdose; statistics in the UK show that benzodiazepines are responsible for 3.8% of all deaths due to poisoning from one drug. However, combining these drugs with alcohol, opiates or tricyclic antidepressants significantly increases toxicity. Parents are more sensitive to the side effects of benzodiazepines, and poisoning can even occur from their long-term use. Various benzodiazepines differ in their toxicity; temazepam appears most toxic in overdose and when used with other drugs. Symptoms of a benzodiazepine overdose may include; drowsiness, slurred speech, nystagmus, hypotension, ataxia, coma, respiratory depression, and cardiorespiratory arrest.
An inverting agent for benzodiazepines exists, flumazenil (Anexate). Its use as an antidote is not recommended routinely because of the high risk of recedation and seizures. In a double-blind, placebo-controlled trial of 326 people, 4 had serious side effects and 61% became resedated after the use of flumazenil. Many contraindications to its use exist. This is contraindicated in people with a history of long-term use of benzodiazepines, those who consume substances that lower the seizure threshold or may cause arrhythmias, and in those with abnormal vital signs. One study found that only 10% of people who came with an overdose of benzodiazepine were suitable candidates for treatment with flumazenil.
Interactions
Individual benzodiazepines may have different interactions with certain drugs. Depending on their metabolic pathway, benzodiazepines can be divided into two groups. The largest group consists of those who are metabolized by the cytochrome P450 (CYP450) enzyme and have significant potential for interactions with other drugs. Other groups consist of those metabolized through glucuronidation, such as lorazepam, oxazepam, and temazepam, and, in general, have little drug interactions.
Many drugs, including oral contraceptives, some antibiotics, antidepressants, and antifungal agents, inhibit cytochrome enzymes in the liver. They reduce the elimination rate of benzodiazepines metabolized by CYP450, leading to excessive drug accumulation and increased side effects. In contrast, drugs that induce P450 cytochrome enzymes, such as St. John's wort, rifampicin antibiotics, and anticonvulsant carbamazepine and phenytoin, accelerate the elimination of many benzodiazepines and decrease their action. Taking benzodiazepines with alcohol, opioids and other central nervous system depressors potentiates their actions. This often results in increased sedation, impaired motor coordination, shortness of breath, and other potentially lethal adverse effects. Antacids may slow the absorption of some benzodiazepines; However, these effects are marginal and inconsistent.
Pharmacology
Action mechanism
Benzodiazepines work by increasing the natural brain chemical efficiency, GABA, to reduce neuronal stimulation. It reduces communication between neurons and, therefore, has a calming effect on many brain functions.
GABA controls the stimulation of neurons by binding to the GABA receptor A . GABA A receptor is a protein complex located in the synapses of neurons. All GABA recipes A contain ion channels conducting chloride ions across nerve cell membranes and two binding sites for gamma-aminobutyric acid (GABA) neurotransmitters, while a subset of GABA A receptor complexes also contains a single binding site for benzodiazepines. Binding to benzodiazepines to this receptor complex does not alter GABA binding. Unlike other positive allosteric modulators that increase ligand bonds, benzodiazepine binding acts as a positive allosteric modulator by increasing total chloride ion conduction across nerve cell membranes when GABA is attached to its receptor. This increase in chloride ion influ- sid causes hyperpolarization of neuronal membrane potential. As a result, the difference between break potential and threshold potential increases and firing is less likely. Different subtypes of GABA A receptors have varying distributions in different regions of the brain and, therefore, control different neuronal circuits. Therefore, activation of various subtypes of GABA receptor A by benzodiazepines may result in different pharmacological actions. In terms of the mechanism of action of benzodiazepines, their similarity is too great to separate them into individual categories such as anxiolytics or hypnotics. For example, hypnotics given in low doses produce an anxiety-relieving effect, whereas benzodiazepine is marketed as an anti-anxiety drug at higher doses inducing sleep.
Part of the GABA receptor A which also binds benzodiazepines is referred to as benzodiazepine receptor (BzR). GABA A receptor is a heteromer consisting of five subunits, the most common being two ? , two ? , and one ? (? 2 ? 2 ?). For each subunit, many subtypes exist (? 1-6 , 1-3 , and? 1-3 ). The GABA A receptor consisting of different subtype subunit combinations has different properties, different distribution in brain and different activity relative to pharmacological and clinical effects. Benzodiazepin binding on the interface? and? subunit on recipe GABA A . Binding also requires that the alpha subunits contain the amino acid residues of histidine, ( ie , 1 , 2 , 3 , and 5 containing GABA recipes A ). For this reason, benzodiazepines show no affinity for GABA receptors A containing subunits 4 and? 6 with arginine instead of histidine residue. Once bound to a benzodiazepine receptor, the benzodiazepine ligand locks the benzodiazepine receptor into a conformation in which it has a greater affinity for GABA neurotransmitters. This increases the frequency of opening of the associated chloride ion channels and hyperpolarizes the membranes of the associated neurons. The inhibitory effect of GABA available is potentiation, leading to sedative and anxiolytic effects. For example, high activity ligands in
Benzodiazepine group drugs also interact with peripheral benzodiazepine receptors. Peripheral benzodiazepine receptors are present in peripheral nervous system tissues, glial cells, and at lower levels of the central nervous system. These peripheral receptors are not structurally related or are combined with GABA receptors A . They modulate the immune system and engage in the body's response to injury. Benzodiazepines also serve as weak adenosine reuptake inhibitors. It has been suggested that some of their anticonvulsant, ansiolytic, and muscle relaxant effects may be partially mediated by this action.
Pharmacokinetics
Benzodiazepines can be placed into one of three groups with part-time elimination, or the time it takes the body to remove half of the dose. Some benzodiazepines have long-acting active metabolites, such as diazepam and chlordiazepoxide, which are metabolized into desmethyldiazepam. Desmethyldiazepam has a half-life of 36-200 hours, and flurazepam, with the main active metabolite of desalkylflurazepam, with a half-life of 40-250 hours. This long working metabolism is a partial agonist.
- The short-acting compound has a median half-life of 1-12 hours. They have some residual effects if taken before bed, rebound insomnia can occur after discontinuation, and they may cause daytime withdrawal symptoms like anxiety rebound the next day with prolonged use. Examples are brotizolam, midazolam, and triazolam.
- The intermediate-acting compound has a median half-life of 12-40 hours. They may have some residual effects during the first half of the day if used as hypnosis. Insomnia rebound, however, is more common after interruption of benzodiazepine intermediate-acting drugs than benzodiazepines that work longer. Examples are alprazolam, estazolam, flunitrazepam, clonazepam, lormetazepam, lorazepam, nitrazepam, and temazepam.
- The long compound in action has a half-life of 40-250 hours. They have an accumulated risk in the elderly and in individuals with severe liver dysfunction, but they have the severity of reduction in rebound effects and withdrawal. Examples are diazepam, clorazepate, chlordiazepoxide, and flurazepam.
Chemistry
Benzodiazepines have the same chemical structure, and their effects on humans are primarily generated by allosteric modification of certain types of neurotransmitter receptors, GABA receptors A , which increases the overall conductance of this inhibitory channel; this results in a variety of therapeutic effects as well as the adverse effects of benzodiazepines. Other less important mechanisms of action are also known.
The term benzodiazepine is the chemical name for the heterocyclic ring system (see image on the right), which is a mixture of benzene and diazepine ring system. Based on the nomenclature of Hantzsch-Widman, diazepine is a heterocycle with two nitrogen atoms, five carbon atoms and possibly a cumulative double bond. The "benzo" prefix shows the benzene ring fused with the diazepine ring.
The benzodiazepine drug is a substitute of 1,4-benzodiazepines, although the chemical term may refer to many other compounds that have no useful pharmacological properties. Different benzodiazepine drugs have different side groups attached to this central structure. Different groups influence the binding of molecules to GABA recipes A and modulate pharmacological properties. Many pharmacologically active "benzodiazepine" drugs contain 5-phenyl-1 H -benzo [ e ] [1,4] diazepin-2 (3 H ) - one substructure (see picture on right). Benzodiazepines have been found to mimic structurally reversing proteins, allowing them with their biological activity in many cases.
Nonbenzodiazepine also binds to the binding of benzodiazepines to GABA receptors A and has the same pharmacological properties. While nonbenzodiazepine is structurally defined as unrelated to benzodiazepines, the two classes of drugs have general pharmacofora (see figure on lower right), which explains its binding to the general receptor site.
General type
- The 2-keto compound:
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- clorazepate, diazepam, flurazepam, halazepam, prazepam, and others.
- 3-hydroxy compound:
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- lorazepam, lormetazepam, oxazepam, temazepam
- 7-nitro compound:
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- clonazepam, flunitrazepam, nimetazepam, nitrazepam
- Triazolo compound:
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- adinazolam, alprazolam, estazolam, triazolam
- Imidazo compound
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- climazolam, loprazolam, midazolam
History
The first benzodiazepine, chlordiazepoxide ( Librium ), was synthesized in 1955 by Leo Sternbach while working at Hoffmann-La Roche on the development of tranquilizers. The pharmacological properties of the prepared compound were initially disappointing, and Sternbach left the project. Two years later, in April 1957, a co-worker of Earl Reeder noticed the remaining "sweet crystals" of the paused project during spring cleaning in the laboratory. This compound, later named chlordiazepoxide, had not been tested in 1955 because of Sternbach's focus on other issues. Expecting negative pharmacological results, and hoping to publish chemical-related findings, the researchers sent them for standard animal tests. However, the compound exhibits a very strong sedative effect, anticonvulsant, and muscle relaxation. This impressive clinical find led to a rapid worldwide introduction in 1960 under the brand name Librium . Following chlordiazepoxide, diazepam was marketed by Hoffmann-La Roche under the brand name Valium in 1963, and for a time both were the most commercially successful drugs. The introduction of benzodiazepines led to a decline in barbiturate recipes, and by the 1970s they had replaced most of the older drugs for the use of sedatives and hypnosis.
The new drug group was initially greeted with optimism by the medical profession, but gradually raised concerns; in particular, the risk of dependence became apparent in the 1980s. Benzodiazepines have a unique history because they are responsible for the largest class action lawsuit against drugmakers in the UK, involving 14,000 patients and 1,800 law firms that accuse producers of knowing the potential for dependence but deliberately withholding this information from doctors.. At the same time, 117 general practitioners and 50 health authorities were sued by patients to recover damages from harmful effects of dependence and withdrawal. This led some doctors to require a signed consent form from their patients and to recommend that all patients be adequately warned about the risk of dependence and withdrawal before starting treatment with benzodiazepines. Court cases against drug manufacturers have never reached a verdict; legal aid has been withdrawn and there are allegations that psychiatrist consultants, expert witnesses, have a conflict of interest. This litigation led to a change in British law, making class action more difficult.
Although antidepressants with anxiolytic properties have been introduced, and there is an increased awareness of the adverse effects of benzodiazepines, prescriptions for short-term anxiety relief did not decrease significantly. For the treatment of insomnia, benzodiazepines are now less popular than nonbenzodiazepines, which include zolpidem, zaleplon and eszopiclone. Nonbenzodiazepines are molecularly different, but even so, they act on the same benzodiazepine receptor and produce similar sedative effects.
Society and culture
Legal status
In the United States, benzodiazepines are drug Schedule IV under the Federal Controlled Substances Act, even when not on the market (eg, nitrazepam and bromazepam). Flunitrazepam is subject to more stringent regulations in certain countries and temazepam recipes require special coded bearings in certain countries.
In Canada, benzodiazepine ownership is legal for personal use. All benzodiazepines are categorized as Schedule IV substances under the Drug and Controlled Medicines Act. Since 2000, benzodiazepines have been classified as targeted substances , which means that additional regulation exists primarily affecting pharmacist notes. Since about 2014, Health Canada, the Canadian Medical Association and the College of Provincial Doctors and Surgeons have issued increasingly stringent guidelines for prescription of benzodiazepines, especially for the elderly (eg the British Columbia School of Physicians and Surgeons). Unfortunately, many of these guides are not publicly available.
In the UK, benzodiazepines are Class-controlled drugs, carrying a maximum sentence of 7 years in prison, unlimited fines or both for possession and a maximum penalty of 14 years in imprisonment of unlimited fine or both to supply benzodiazepines to others.
In the Netherlands, since October 1993, benzodiazepines, including formulations containing less than 20 mg of temazepam, are all placed on List 2 of the Opium Act. It takes a prescription to have all benzodiazepines. Temazepam formulations containing 20 mg or more of the drugs are placed on List 1, requiring the physician to write prescriptions in the List 1 format.
In East Asia and Southeast Asia, temazepam and nimetazepam are often controlled and restricted. In certain countries, triazolam, flunitrazepam, flutoprazepam and midazolam are also restricted or controlled to a certain degree. In Hong Kong, all benzodiazepines are set out under Schedule 1 of Chapter 132 of the Hong Kong Dangerous Drug Act. Previously only brotizolam, flunitrazepam and triazolam were classified as dangerous drugs.
Internationally, benzodiazepines are categorized as drug controlled Schedule IV, in addition to flunitrazepam, which is a drug Schedule III under the Convention on Psychotropic Substances.
Use of recreation
Benzodiazepines are considered to be the main drug of abuse. Abuse of Benzodiazepines is largely confined to individuals who abuse other drugs, ie drug abusers. In the international arena, benzodiazepines are categorized as drug controlled Schedule IV by INCB, apart from flunitrazepam, which is a drug Schedule III under the Psychotropic Substance Convention. Some variations in drug scheduling exist in each country; for example, in the UK, midazolam and temazepam are drug controlled Schedule III.
British law requires that temazepam (but not midazolam) be kept in safe custody. Safe custody requirements ensure that pharmacists and doctors who store temazepam stock must keep it in a secure double layer steel vault and keep a written list, which must be tied and contain separate entries for temazepam and should be written in ink without using a correction fluid (although the registers written is not needed for temazepam in the UK). Disposal of stock expiry shall be witnessed by the designated inspector (either a police officer or an authorized official of the local health service). Abuse of Benzodiazepine ranges from occasional binges at large doses, to high doses of chronic and compulsive drug abuse.
Benzodiazepines are used recreationally and by drug abusers with problems. Mortality is higher among mixed drug addicts who also use benzodiazepines. The use of heavy alcohol also increases death among drug users. Dependence and tolerance, often accompanied by dose escalation, until benzodiazepines can develop rapidly among drug users; Withdrawal syndrome can appear after at least three weeks of continuous use. Long-term use has the potential to cause physical and psychological dependence and severe withdrawal symptoms such as depression, anxiety (often up to the point of panic attack), and agoraphobia. Benzodiazepines and, in particular, temazepam are sometimes used intravenously, which, if done incorrectly or in a non-sterile manner, can cause medical complications including abscesses, cellulitis, thrombophlebitis, arterial puncture, deep venous thrombosis, and gangrene. Sharing needles and needles for this purpose also raises the possibility of transmission of hepatitis, HIV, and other diseases. Benzodiazepines are also abused intranasally, which may have additional health consequences. Once the benzodiazepine dependency has been established, a doctor usually converts the patient to an equivalent dose of diazepam before initiating a gradual reduction program.
A 1999-2005 Australian police survey of detainees reported preliminary findings that self-reported benzodiazepine users were less likely than non-user prisoners to work full-time and were more likely to receive government benefits, use shabu or heroin, and be arrested or imprisoned. Benzodiazepines are sometimes used for criminal purposes; they serve to paralyze a victim in cases of drug-assisted rape or robbery.
Overall, anecdotal evidence suggests that temazepam may be the most habitual (addictive) benzodiazepine. Abuse of Temazepam achieves epidemic proportions in some parts of the world, in particular, in Europe and Australia, and is a major drug abuse in many Southeast Asian countries. This has led authorities from different countries to place temazepam under more stringent legal status. Some countries, such as Sweden, prohibit the drug directly. Temazepam also has certain pharmacokinetic properties of absorption, distribution, elimination, and cleansing which makes it easier to misuse than many other benzodiazepines.
Veterinary use
Benzodiazepines are used in veterinary practice in the treatment of various disorders and conditions. As in humans, they are used in the management of first-line seizures, status epilepticus, and tetanus, and as maintenance therapy in epilepsy (especially in cats). They are widely used in small and large animals (including horses, pigs, cattle and exotic and wild animals) for their anxiolytic and sedative effects, as pre-treatment prior to surgery, for induction of anesthesia and in addition to anesthesia.
References
External links
- National Institute on Drug Abuse: "NIDA for Teens: Prescription Drugs Depression". * Ashton CH (2002). Benzodiazepines: how does it work & amp; interesting way (aka The Ashton Manual) . The Ashton Manual . Retrieved 2009-06-09 .
Source of the article : Wikipedia
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