Benzodiazepines

The benzodiazepines are a class of drugs with sedative/hypnotic, anxiolytic, anticonvulsant, amnestic and muscle relaxant properties. Benzodiazepines are often used for short-term relief of severe, disabling anxiety or insomnia. Long-term use can be problematic due to the development of tolerance and dependency. They are believed to act on the GABA receptor GABAA, the activation of which dampens higher neuronal activity. They began to be widely prescribed for stress-related ailments in the 1960s and 1970s.

Members
Benzodiazepines are commonly divided into three groups: 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 may occur.

The various benzodiazepines are listed in order of the shortest acting to the longest acting (by the approximate elimination half-life of the drug), however this time may greatly vary between persons.


 * Triazolam (Halcion&reg;) - 2 hours
 * Midazolam (Versed&reg;, Hypnovel&reg;) - 3 hours (1.8-6 hours)
 * Oxazepam (Serax&reg;) - 4-15 hours
 * Chlordiazepoxide (Librium&reg;) - 5-25 hours
 * Alprazolam (Xanax&reg;) - 6-12 hours
 * Temazepam (Restoril&reg;) 8-20 hours
 * Lorazepam (Ativan&reg;) 10-20 hours
 * Loprazolam (Dormonoct&reg;) 10-20 hours
 * Bromazepam (Lexotan&reg;) 10-20 hours
 * Estazolam (ProSom&reg;) 10-24 hours
 * Clobazam (Frisium&reg;) 18 hours
 * Flunitrazepam (Rohypnol&reg;) 18-26 hours. Withdrawn from the market in some countries; considered a "date-rape drug"
 * Clonazepam (Klonopin&reg;, Rivotril&reg;) 18-50 hours
 * Nitrazepam (Mogadon&reg;) 20-40 hours
 * Quazepam (Doral&reg;) 25-100 hours
 * Clorazepate (Tranxene&reg;) 36-100 hours
 * Medazepam (Nobrium&reg;) 36-150 hours
 * Nordazepam (Madar&reg;, Stilny&reg;) 50-120 hours
 * Prazepam (Centrax&reg;) 36-200 hours
 * Diazepam (Valium&reg;) 36-200 hours
 * Flurazepam (Dalmane&reg;) 40-250 hours

Uses
Benzodiazepines are used in many situations, depending on the pharmacokinetics of each of the constituent drugs. The main use of the short-acting benzodiazepines is in insomnia, while anxiety responds better to medium- to long-acting substances that will be required all day.

Midazolam is mostly used as an intravenous injection for sedation before surgical procedures or for emergency intubation.

Effects
All benzodiazepines have the following, predictable effects, though some may be relatively stronger anxiolytics and others relatively stronger amnesics. Each effect is more likely to occur at higher doses. Selecting the right type of benzodiazepine for a particular patient and then prescribing it at the minimum effective dose will lessen the likelihood of adverse effects.


 * Anxiolytic (reduce anxiety).
 * Anticonvulsant (used against epileptic seizures).
 * Antispasmodic (muscle relaxant).
 * Sedative / hypnotic ("sleeping tablet" effect).
 * Amnesic (producing anterograde amnesia).

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 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. The effects of long-acting benzodiazepines can also linger over to the following day.

Abuse and dependence
Long-term benzodiazepine usage generally leads to some form of tolerance and/or dependence. As a Schedule IV drug, benzodiazepines are considered moderately addictive. Withdrawal symptoms include:


 * Insomnia
 * Anxiety, possible panic attacks
 * Depression, possible suicidal ideation
 * Tremor
 * Perspiration
 * Loss of appetite
 * Delusions

An abrupt discontinuation of benzodiazepines may result in a severe and very unpleasant withdrawal syndrome that may additionally result in:


 * Convulsions
 * Confusion
 * Psychosis
 * Effects similar to delirium tremens

Hence, every person on long-term or high dosage of any benzodiazepine should be carefully weaned off the drug, preferably under medical supervision.

Onset of the withdrawal syndrome might be delayed, and it might be delayed longer than the barbiturate withdrawal syndrome, although withdrawal from short-acting benzodiazepines often presents early.

Some of the withdrawal symptoms are identical to the symptoms for which the medication was originally prescribed. Benzodiazepines are valued by many patients for their ability to ameliorate existing conditions, while benzodiazepine dependency can cause them.

As it happens, benzodiazepines are the largest group of recreationally used drugs as well (Gerada & Ashforth 1997). Users typically take large doses of benzodiazepines orally, intravenously, or by snorting crushed tablets up the nose. This results in a "high" resembling alcoholic intoxication, and intravenous doses, especially of so called "high potency" benzodiazepines (eg. clonazepam, lorazepam, alprazolam), often results in a euphoric "rush".

Intoxication
Overdosage 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. The antidote for all benzodiazepines is flumazenil (Annexate&reg;), which is occasionally used empirically in patients presenting with unexplained loss of consciousness in an emergency room setting.

Legal status
All medically-used benzodiazepines are Schedule IV in the USA under the Federal Controlled Substances Act.

Flunitrazepam 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 required to cover benzodiazepines

History
The first benzodiazepine, chlordiazepoxide (Librium&reg;) 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&reg;) - a simplified version of Librium - primarily to counteract anxiety symptoms. Sleep-related problems were treated nitrazepam (Mogadon&reg;), which was introduced in 1965 and flurazepam (Dalmane&reg;), which was introduced in 1973.

Pharmacology
Benzodiazepines produce their variety of effects 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.

In order for GABAA receptors to be sensitive to the action of benzodiazepines they need to contain an &alpha; and a &gamma; 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 hyperpolarising the membrane. 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 &alpha;1 are associated with sedation whereas those with higher affinity for GABAA receptors containing &alpha;2 and/or &alpha;3 subunits have good anti-anxiety activity.