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Common BenzodiazepinesFor various benzodiazepines and their respective generic and non-US trade-names, half-lives, and primary uses, see list of benzodiazepines.
A related class of drugs, the nonbenzodiazepines, has recently been introduced. These drugs have benefits very similar to benzodiazepines, but with less addictive potential. Duration of actionBenzodiazepines are commonly divided into three groups by their half-lives: Short-acting compounds act for less than six 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 an effect for 6-10 hours, may have mild residual effects but rebound insomnia is not common. Long-acting compounds have strong sedative effects that persist. 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 an addiction quicker as the drug does not last in the system for as long. There are exceptions to the rules, such as Alprazolam being prescribed as an anxiolytic more than a hypnotic, despite possessing a short half-life. PharmacologyTheir chemical structure is based upon diazepine and phenyl groups. Benzodiazepines produce their variety of effects by depressing the central nervous system and by modulating the GABAA receptor, the most prolific inhibitory receptor within the brain. The GABAA receptor is made up from 5 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 benzodiazepines.
Side effectsThe 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 choice for longer term treatment in the elderly due to its stronger amnesic effects potentially aggravating forgetfulness and confusion. But then lorazepam may be a better choice for short term treatment of a younger, non-drinking patient as it is relatively less sedating. Benzodiazepines have replaced the barbiturates because they have a lower abuse potential and relatively lower adverse reactions (chiefly, death is a relatively common result in barbiturate overdoses) and interactions. Still, drowsiness, ataxia, confusion, vertigo, impaired judgement, and a number of other effects are common. 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. 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. Paradoxical reactions may occur to any individual on commencement of therapy and initial monitoring should take into account the risk of increase in anxiety or suicidal thoughts. 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. ToleranceTolerance 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. There is little evidence of continued anxiolytic properties from benzodiazepines after four months of continuous use other than the suppresion of withdrawal signs. However there are studies which dispute this and find continued anxiolytic benefits after 20 years of continued usage as was the finding of one study on the effects of long term Alprazolam (Xanax®) use for panic disorder [1]. 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 [2]. A possible explaination 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. Cross ToleranceBenzodiazepines 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 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. DependenceLong-term benzodiazepine usage generally leads to some form of tolerance and/or dependence. It is estimated that up to 50 percent of patients prescribed diazepam for 6 months at therapeutic dosages are physically dependent. Withdrawal symptoms due to abrupt discontinuation 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. Onset of the withdrawal syndrome from long half-life benzodiazepines might be delayed for up to 3 weeks, although withdrawal from short-acting benzodiazepines often presents early usually within 24 hours. The acute benzodiazepine withdrawal syndrome generally lasts for about 3 weeks to 3 months after which symptoms start to decline in severity. However in a minority of people perhaps 10 - 15% the withdrawal syndrome can persist as a sub-acute syndrome with gradually improving symptoms over a period of months and very occasionally years. The severity and length of the withdrawal syndrome is likely determined by various factors including rate of tapering, length of use of benzodiazepines and dosage size and possibly genetic factors 6. Detoxification of a benzodiazepine dependent individual is often carried out using an equivalent dose of diazepam to the benzodiazepine the individual is dependent on and by reducing in steps of 10% every 2 - 4 weeks depending on the severity of the dependency and the patient's response to reductions. Some people experience little or no withdrawal when stopping long term benzodiazepine usage. It is not known for sure why there is such a variation between patients but recent research in animals suggests that withdrawal from sedative hypnotic drugs may be influenced by a genetic component. Some of the withdrawal symptoms are identical to the symptoms for which the medication was originally prescribed. The ability to determine the difference between relapse and rebound is very important during the withdrawal phase. IntoxicationOverdosage of benzodiazepines, particularly when combined with alcohol, may lead to coma, but does not cause severe biochemical disturbances and therefore carries a relatively good prognosis if quantities of the substances ingested are not sufficient to cause death. 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. Legal statusNearly all medically-used benzodiazepines are Schedule IV in the USA under the Federal Controlled Substances Act. In Canada benzodiazepines are also Schedule IV. 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 around $4 for persons on low-income. Flunitrazepam (Rohypnol) is treated more severely under Federal law than other benzodiazepines. For example, despite being Schedule IV like any other benzodiazepine, it 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 crack, flunitrazepam is the only controlled substance in which first-offense simple possession is a federal felony. 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. HistoryThe 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 and flurazepam (Dalmane®), which was introduced in 1973. References
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