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Benzodiazepine

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Alprazolam 2mg tablets

The benzodiazepines (pronounced [ˌbenzəʊdaɪˈæzəpiːnz], or "benzos" for short) are a class of psychoactive drugs considered as minor tranquilizers with varying hypnotic, sedative, anxiolytic, anticonvulsant, muscle relaxant and amnesic properties, which are brought on by slowing down the central nervous system. This makes benzodiazepines useful in treating anxiety, insomnia, agitation, seizures, and muscle spasms, as well as alcohol withdrawal. They can also be used before certain medical procedures such as endoscopies, dental work, or other medical procedures where tension and anxiety are present, and prior to some unpleasant medical procedures in order to induce amnesia for the procedure. Another use is to counteract anxiety-related symptoms upon initial use of SSRIs and other antidepressants, or as an adjunctive treatment. Recreational stimulant users often use benzodiazepines as a means of "coming down" (see: Drug abuse).[1]

All benzodiazepines have an addictive potential. Use of benzodiazepines should only commence after medical consultation and prescribed the smallest dosage possible to provide an acceptable level of symptom relief. Dependence varies for the benzodiazepine used, with some reporting alprazolam dependence in as little as three days.

Common benzodiazepines

For various benzodiazepines and their respective generic and non-US trade-names, half-lives, and primary uses, see list of benzodiazepines.

Most benzodiazepines are administered orally; however, administration can also occur intravenously, intramuscularly, or as a suppository. Well-known benzodiazepines and their primary trade names include Alprazolam (Xanax), Bromazepam (Lexomil), Diazepam (Valium), Lorazepam (Ativan), Clonazepam (Klonopin), Temazepam (Restoril), Oxazepam (Serax), Flunitrazepam (Rohypnol), Triazolam (Halcion), Chlordiazepoxide (Librium), Flurazepam (Dalmane), Estazolam (ProSom), and Nitrazepam (Mogadon).

A related class of drugs, the nonbenzodiazepines, which are molecularly distinct from the benzodiazepine molecule, has recently been introduced which also work on benzodiazepine receptors.[2] These drugs have benefits very similar to benzodiazepines, but with less addictive potential.

Duration of action

Benzodiazepines are commonly divided into three groups by their half-lives: Short-acting compounds have a half life of less than 12 hours and have few residual effects if taken before bedtime, but rebound insomnia may occur and they might cause wake-time anxiety. Intermediate-acting compounds have a half life of 12-24 hours, may have residual effects in the first half of the day. Rebound insomnia however is more common upon discontinuation of short acting benzodiazepines. Day time withdrawal symptoms is also a problem with prolonged usage of short acting benzodiazepines, including day time anxiety. Long-acting compounds have a half life greater than 24 hours.[3] Strong sedative effects typically persist throughout the next day if long acting preparations are used for insomnia. Accumulation of the compounds in the body may occur. The elimination half-life may greatly vary between individuals, especially the elderly. Shorter-acting compounds are usually best for their hypnotic effects, whilst longer-acting compounds are usually better for their anxiolytic effects. Benzodiazepines with shorter half-lives tend to be able to produce tolerance and addiction quicker as the drug does not last in the system for as long, with resultant interdose withdrawal phenomenon and next dose craving.[4] Although short acting drugs are more commonly prescribed for insomnia there are exceptions to the rules, such as alprazolam being prescribed as an anxiolytic more than a hypnotic, despite possessing a short half-life.

Pharmacology

Their chemical structure is based upon diazepine and phenyl groups. Benzodiazepines produce their variety of effects by depressing the central nervous system via modulating the GABAA receptor, the most prolific inhibitory receptor within the brain. The GABAA receptor is made up from 6 subunits out of a possible 19, and GABAA receptors made up of different combinations of subunits have different properties, different locations within the brain and importantly, different activities in regards to pharmacological and clinical effects.

Classical benzodiazepines show high affinity and bind unselectively to alpha1, alpha2, alpha3 and alpha5 subunits on the GABAA receptor but lack affinity for the alpha4 and alpha6 subunits. Benzodiazepines bind only to alpha subunits which contain a histidine protein, eg. alpha1, alpha2, alpha3 and alpha5 containing GABAA receptors. For this reason benzodiazepines show no affinity for alpha4 and alpha6 subunits containing GABAA receptors, which contain an arginine protein instead of a histidine protein. Other locations on the GABAA receptor also bind neurosteroids, barbiturates and some anesthetics.[5]

In order for GABAA receptors to be sensitive to the action of benzodiazepines they need to contain an α and a γ subunit, where the benzodiazepine binds. Once bound, the benzodiazepine locks the GABAA receptor into a conformation where the neurotransmitter GABA has much higher affinity for the GABAA receptor, increasing the frequency of opening of the associated chloride ion channel and depolarizing the neuron. This potentiates the inhibitory effect of the available GABA leading to sedatory and anxiolytic effects. As mentioned, different benzodiazepines can have different affinities for GABAA receptors made up of different collection of subunits. For instance, benzodiazepines with high activity at the α1 are associated with sedation whereas those with higher affinity for GABAA receptors containing α2 and/or α3 subunits have good anti-anxiety activity.[6]

Benzodiazepines are full agonists at the benzodiazepine receptor producing anxiolytic and sedating properties therapeutically. However, with regular or chronic use the risk of physical dependence increases with demonstratable withdrawal symptoms upon discontinuation or dosage reduction. Benzodiazepines also have abuse potential. The benzodiazepine receptor is a modulatory site for the GABA receptor. Compounds which bind to the benzodiazepine receptor and enhance the GABA receptor function are termed benzodiazepine receptor agonists, compounds which decrease GABA function are termed benzodiazepine receptor inverse agonists and compounds that have no direct effects on GABA function are called benzodiazepine receptor antagonist.

Some compounds lie somewhere between being full agonists or full antagonists and are termed either partial agonists or partial antagonists. There has been interest in partial agonists for the benzodiazepine receptor with evidence that complete tolerance may not occur with chronic use, with partial agonists demonstrating continued anxiolytic properties with reduced sedation, dependence and withdrawal problems.[7]

Side effects

The side effects are predictable as they are intrinsic effects of the drug class of benzodiazepines. Knowing the relative effects of benzodiazepine types will help clinicians prescribe the most appropriate type. For example, lorazepam may not be best treatment choice for the elderly due to its stronger amnesic effects and thus greater potential for aggravating forgetfulness and confusion. But then lorazepam is a good choice for the acute treatment of status epilepticus due to its potent anticonvulsant properties.

Benzodiazepines have largely replaced the barbiturates, mainly because benzodiazepines are much safer in terms of overdose. Prior to the introduction of benzodiazepines, barbiturate overdose was of significant concern to both the medical community and the general public. Still, drowsiness, ataxia, confusion, vertigo, impaired judgement, and a number of other effects are common.

The concern is also that - even though they are relative non-toxic in themselves - benzodiazepines may facilitate suicide by other drugs or means, through disinhibition. However benzodiazepines when combined with other central nervous system depressants such as opiates or alcohol the risk of overdose and death increases significantly due to synergistic CNS, respiratory and cardiovascular system depression. The elderly, alcoholics and those with underlying medical conditions eg respiratory disease or personality disorder are at increased risk for both acute adverse reactions and problems arising from long term use, including dependence, confusion, memory impairment or overdose.[8] Paradoxical reactions may occur in any individual on commencement of therapy and initial monitoring should take into account the risk of increase in anxiety or suicidal thoughts.[9]

Benzodiazepines may impair the ability to drive vehicles and to operate machinery. The impairment is worsened by consumption of alcohol, because both act as central nervous system depressants. In fact, consuming any benzodiazepine with alcohol can result in a potentially fatal overdose. The effects of long-acting benzodiazepines can also linger over to the following day.

Benzodiazepines can cause a wide range of significant behavioural disturbances and cognitive impairment. Cognitive deficits including concentration and memory processing problems is a well known adverse effect of benzodiazepines and occurs at prescribed dose levels. The degree of cognitive impairment will depend on the dose used, individual tolerance level to the drug, with the elderly being more vulnerable to cognitive impairments from benzodiazepines.

Amnesia can be a side effect of benzodiazepines and can be utilised in a therapeutic setting to reduce unpleasant memories from investigatory medical procedures eg. endoscopies. Unfortunately the amnesic and sedating properties have found flavour with criminals as a date rape drug. All benzodiazepines can be used as date rape drugs, but flunitrazepam (Rohypnol), clonazepam (Klonopin), midazolam (Versed) and temazepam (Restoril) are the most commonly used.

Severe behavioural changes resulting from benzodiazepines have been reported including mania, schizophrenia, anger, impulsivity and hypomania.[10] Individuals with borderline personality disorder appear to have a greater risk of experiencing severe behavioural or psychiatric disturbances from benzodiazepines. Aggression and violent outbursts can also occur with benzodiazepines particularly when they are combined with alcohol. Recreational abusers and patients on high dosage regimes may be at an even greater risk of experiencing paradoxical reactions to benzodiazepines.[11] Paradoxical reactions may occur in any individual on commencement of therapy and initial monitoring should take into account the risk of increase in anxiety or suicidal thoughts.[12]

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

In long term and high dosage therapy, periodic liver function tests should be administered and the dosage of any benzodiazepine should be carefully titrated in patients with impaired hepatic function and renal clearance. While liver damage may be limited when these drugs are prescribed at the recommended dosage, the possibility of such harm should be considered in all individuals; especially individuals utilizing other medications including over the counter analgesics and/or alcohol.

For a full list of side effects pertaining to a specific drug, individuals in the United States should read the patient information, prescriber guide, or manufacturers information as published in the PDR or other such manuals.

Tolerance

Tolerance develops to many of the therapeutic effects of benzodiazepines rapidly with daily or frequent use. Generally, tolerance to the hypnotic and sedative effects occurs within days; however, tolerance to the anxiolytic effects of benzodiazepines takes longer to develop. According to a 1988 report published by the Committee on Safety of Medicines, there is little evidence of continued anxiolytic properties from benzodiazepines after four months of continuous use other than the suppression of withdrawal signs and recommended that prescriptions of benzodiazepines be limited to 2 - 4 weeks only.[13] There is also evidence that long term use may actually worsen anxiety in some people with or without prior psychiatric history as was found in a study of 50 patients.[14] A possible explanation for increased anxiety from chronic use of benzodiazepines is that it is a side effect of tolerance with increasing doses required to suppress withdrawal effects. However, patients should be aware that this could lead to a cycle of increasing doses and worsening side effects. In addition, as dosage is increased, the potential for addiction becomes greater.

Cross tolerance

Benzodiazepines share a similar mechanism of action to various sedative compounds which act via enhancing the GABAA receptor. Cross tolerance typically means that one drug will alleviate the withdrawal effects of another. It also means that taking of one drug will result in a decreased pharmacological effect of another similar acting drug. Benzodiazepines are often used for this reason to detoxify alcohol dependent patients and can have life saving properties in preventing and/or treating severe life threatening withdrawal syndromes from alcohol such as delirium tremens.

There is also cross tolerance between alcohol, the benzodiazepines, the barbiturates and the nonbenzodiazepine drugs which all also act via enhancing the GABAA receptor's function via modulating the chloride ion channel function of the GABAA receptor.[15][16][17]

Dependence

Long-term benzodiazepine usage generally leads to some form of tolerance and/or dependence. Regular use of benzodiazepines at prescribed levels for 6 weeks was found to produce a significant risk of dependence with resultant withdrawal symptoms appearing on abrupt discontinuation in a study assessing diazepam and buspirone, but after abrupt withdrawal after 6 weeks of treatment with buspirone no withdrawal symptoms developed.[18] Various studies have shown between 20-100% of patients prescribed benzodiazepines at therapeutic dosages long term are physically dependent and will experience withdrawal symptoms.[19]

Benzodiazepine dependence is a frequent complication when benzodiazepines are prescribed for or taken for longer than 4 weeks with physical dependence and withdrawal symptoms being the most common problem, but also occasionally drug seeking behaviour. Withdrawal symptoms include, anxiety, perceptual disturbances, distortion of all the senses, dysphoria and in rare cases psychosis and epileptic seizures. The risk factors for benzodiazepine dependence are as follows; long term use beyond 4 weeks, use of high doses, use of potent short acting benzodiazepines or those with certain pre-existing personality characteristics such as dependent personalities and those prone to drug abuse.[20]

Withdrawal symptoms can occur when benzodiazepine dosage is reduced. Abrupt or over-rapid dosage reduction can produce severe withdrawal symptoms. Withdrawal symptoms can even occur during a very gradual and slow dosage reduction but are rarely serious. The withdrawal symptoms may include:

An abrupt or over-rapid discontinuation of benzodiazepines may result in a more serious and very unpleasant withdrawal syndrome that may additionally result in:

Hence, every person on long-term or high dosage of any benzodiazepine should be slowly and carefully weaned off the drug, preferably under medical supervision by a physician who is knowledgeable about the benzodiazepine withdrawal syndrome. This can usually be avoided or minimized by use of a long half-life benzodiazepine and very gradually tapering off the drug over a period of many weeks or even months.

Withdrawal

Main article: Benzodiazepine withdrawal syndrome

Benzodiazepine withdrawal syndrome is the symptoms seen when a patient who has taken the drug for a period of time stops taking the drug. Benzodiazepine withdrawal is best managed by transferring the physically dependent patient onto an equivalent dose of diazepam because it has the longest half life of all of the benzodiazepines and is available in low potency 2 mg tablets which can be quartered for small dose reductions.[25][26] The speed that benzodiazepine reduction regimes should be carried out at vary from person to person but usually is between 10% every 2-4 weeks. A slow withdrawal with the patient in control of dosage reductions coupled with reassurance that withdrawal symptoms are temporary have been found to produce the highest success rates.

There is strong anecdotal evidence that a slow withdrawal rate significantly reduces the risk of a protracted and or severe withdrawal state. About 10 - 15% of people who come off benzodiazepines develop protracted withdrawal syndrome. There is no known cure for protracted benzodiazepine withdrawal syndrome. Flumazenil in a placebo controlled study seemed to bring about temporary relief, although the author Lader et.al noted that further research is required in this area.[26][27][28]

Common withdrawal symptoms include:

A slower withdrawal rate mitigates the symptoms.

Abuse

Abuse of benzodiazepines is probably greater than the abuse of illicit drugs. Misusers of benzodiazepines develop a high degree of tolerance, coupled with dosage escalation, with misusers often increasing their dosage to very high doses. High dose misusers often develop a high degree of tolerance and dependence and are at risk of severe withdrawal syndromes. Tolerance and dependence on benzodiazepines develops rapidly with users of benzodiazepines demonstrating the benzodiazepine withdrawal syndrome after as little as 3 weeks of continuous use. Benzodiazepines are sometimes abused intravenously which can lead to medical complications including abscess, cellulitis, thrombophlebitis, arterial puncture, deep vein thrombosis, hepatitis B and C, HIV or AIDS, overdose and gangrene.

Once benzodiazepine dependence has been established a clinician should first establish the average daily consumption of benzodiazepines and then convert the patient to an equivalent dose of diazepam before beginning a gradual reduction program, starting initially with 2 mg sized reductions. Additional drugs such as antidepressants like buspirone, β blockers or carbamazepine, should not be added into the withdrawal program unless there is a specific indication for their use.[30]

Crime

In a survey of police detainees carried out by the Australian Government, both legal and illegal users of benzodiazepines were found to be more likely to have lived on the streets, less likely to have been in full time work and more likely to have used heroin or methamphetamines in the past 30 days from the date of taking part in the survey. Benzodiazepine users were also more likely to be receiving illegal incomes and more likely to have been arrested or imprisoned in the previous year.

Benzodiazepines were sometimes reported to be abused alone but most often formed part of a poly drug using problem. Female users of benzodiazepines were more likely than men to be using heroin whereas male users of benzodiazepines were more likely to report amphetamine use. Benzodiazepine users were more likely than non users to claim government financial benefits and benzodiazepine users who were also poly drug users were the most likely to be claiming government financial benefits.

Problem benzodiazepine use can be associated with crime. Those who reported using benzodiazepines alone were found to be in the mid range when compared to other drug using patterns in terms of property crimes and criminal breaches. Of the detainees reporting benzodiazepine use, one in five reported injection use, mostly of illicit benzodiazepines but some reported injecting prescribed benzodiazepines. Injection was a concern in this survey due to increased health risks. The main problems highlighted in this survey were concerns of dependence, the potential for overdose of benzodiazepines in combination with opiates and the health problems associated with injection of benzodiazepines.[31]

Intoxication

Overdosage of benzodiazepines, particularly when combined with alcohol or opiates may lead to coma.[32] The antidote for all benzodiazepines is flumazenil (Annexate®), a benzodiazepine antagonist, which is occasionally used empirically in patients presenting with unexplained loss of consciousness in an emergency room setting. As with all overdose situations, the care provider must be aware of the possibility that multiple substances were utilized by the patient. Supportive measures should be put in place prior to administration of any benzodiazepine antagonist in order to protect the patient from both the withdrawal effects and possible complications arising from simultaneous utilization of chemically unrelated pharmaceutical compounds. A determination of possible deliberate overdose should be considered with appropriate scrutiny and precautions taken to prevent any attempt by patient to commit further bodily harm.[33][34]

All medically-used benzodiazepines are Schedule IV in the USA under the Federal Controlled Substances Act. In Canada benzodiazepines are also Schedule IV.[35]

Australian law allows qualified medical practitioners to prescribe most benzodiazepines to patients, however repeat prescriptions are normally not allowed. Most are subsidised under Medicare, costing around $10, or $AU4.90 for persons on low-income.

Flunitrazepam (Rohypnol) and Temazepam (Restoril) are treated more severely under Federal law than other benzodiazepines. For example, despite being Schedule IV like any other benzodiazepine, flunitrazepam is not commercially available in the United States. It also carries tougher Federal penalties for trafficking and possession than other Schedule IV drugs. With the exception of cases involving 5 grams or more of cocaine or morphine, flunitrazepam is the only controlled substance in which first-offense simple possession is a federal felony. In Europe, especially in the United Kingdom, temazepam and flunitrazepam also carry tougher penalties for trafficking and possession.[36] Similar laws apply for the trafficking and possession of temazepam in Australia and in some parts of Asia. In the United States, some states require specially coded prescriptions for temazepam.

Various other countries limit the availability of benzodiazepines legally. Even though it is a commonly prescribed class of drugs, the Medicare Prescription Drug, Improvement, and Modernization Act specifically states that insurance companies that provide Medicare Part D plans are not allowed to cover benzodiazepines.

History

The first benzodiazepine, chlordiazepoxide (Librium®) was discovered serendipitously in 1954 by the Austrian scientist Dr Leo Sternbach (1908-2005), working for the pharmaceutical company Hoffmann–La Roche. Initially, he discontinued his work on the compound Ro-5-0690, but he "rediscovered" it in 1957 when an assistant was cleaning up the laboratory. Although initially discouraged by his employer, Sternbach conducted further research that revealed the compound was a very effective tranquilizer.

In 1963 approval for use was given to diazepam (Valium®) - a simplified version of Librium - primarily to counteract anxiety symptoms. Sleep-related problems were treated with nitrazepam (Mogadon®), which was introduced in 1965, temazepam (Restoril®), which was introduced in 1969, and flurazepam (Dalmane®), which was introduced in 1973.[37]

See also

References

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