Benzodiazepine

The benzodiazepines (pronounced ˌbenzəʊdaɪˈæzəpiːns, also known ^* as minor tranquilizers) 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 GABA_A, the activation of which dampens higher neuronal activity. They began to be widely prescribed for stress-related ailments in the 1960s and 1970s. Their chemical structure is based upon diazepine and benzyl groups.

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 of the compounds in the body 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). The elimination half life may greatly vary between individuals, especially the elderly.

How Supplied

Drug Name	Common Brand Names*	Elimination Half-Life (hrs) metabolite**	Primary Effects	Approximate Equivalent Dose***
Alprazolam	Xanax, Xanor	6-12 hours	anxiolytic	0.5mg
Bromazepam	Lexotan, Lexomil, Somalium	10-20 hours	anxiolytic	5-6mg
Chlordiazepoxide	Librium, Tropium	5-30 hours hours	anxiolytic	25mg
Clobazam	Frisium	12-60 hours	anxiolytic, anticonvulsant	20mg
Clonazepam	Klonopin, Klonapin, Rivotril	18-50 hours	anxiolytic, anticonvulsant	0.5mg
Clorazepate	Tranxene	hours	anxiolytic, anticonvulsant	15mg
Diazepam	Valium, Apzepam, Stesolid	20-100 hours ^*	anxiolytic	10mg
Estazolam	ProSom	10-24 hours	hypnotic	1-2mg
Flunitrazepam	Rohypnol, Fluscand	18-26 hours hours	hypnotic	1mg
Flurazepam	Dalmane	hours	hypnotic	15-30mg
Halazepam	Paxipam	hours	anxiolytic	20mg
Ketazolam	Anxon	2 hours	anxiolytic	15-30mg
Loprazolam	Dormonoct	6-12 hours	hypnotic	1-2mg
Lorazepam	Ativan, Temesta	10-20 hours	anxiolytic	1mg
Lormetazepam	Noctamid	10-12 hours	hypnotic	1-2mg
Medazepam	Nobrium	36-200 hours	anxiolytic	10mg
Midazolam	Versed, Hypnovel	3 hours (1.8-6 hours)	anxiolytic	?
Nitrazepam	Mogadon, Apodorm	15-38 hours	hypnotic	10mg
Nordazepam	Madar, Stilny	50-120 hours	anxiolytic	?
Oxazepam	Serax, Serenid, Serepax, Sobril, Oxascand	4-15 hours	anxiolytic	20mg
Prazepam	Centrax	hours	anxiolytic	10-20mg
Quazepam	Doral	25-100 hours	hypnotic	20mg
Temazepam	Restoril, Normison, Euhypnos	8-22 hours	hypnotic	20mg
Tetrazepam	Mylostan	3-26 hours	Skeletal muscle relaxant	?
Triazolam	Halcion	2 hours	hypnotic	0.5mg
DMCM	?	?	anxiogenic, convulsant	not used therapeutically

*Not all trade names are listed. Click on drug name to see a more conclusive list.
**The duration of apparent action is usually considerably less than the half-life. With most benzodiazepines, noticeable effects usually wear off within a few hours. Nevertheless, as long as the drug is present it will exert subtle effects within the body. These effects may become apparent during continued use or may appear as withdrawal symptoms when dosage is reduced or the drug is stopped.
***Equivalent doses are based on clinical experience but may vary between individuals.

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.

Tolerance

Tolerance develops to many of the therapeutic effects of benzodiazepines rapidly with daily or frequent use. Unlike tolerance to other drugs such as opioids, stimulants, and nicotine, tolerance to benzodiazepines can put the patient at risk for experiencing an iatrogenic syndrome, consisting of a spectrum of side effects that can be worse than their original condition. This is why current established guidelines restrict benzodiazepine treatment to a maximum of 2-4 weeks use. Typically, tolerance to the hypnotic effects occurs within days and the anxiolytic effects usually do not persist beyond a few months. After that, the dosage may need to be increased on a regular basis to minimize the numerous unpleasant symptoms that can emerge during long-term (>4 weeks) benzodiazepine use. Eventually the patient can reach a point where increasing the dose is ineffective in relieving the side effects caused by the drug. This is why it is important for physicians to adhere to the established guidelines of 2-4 weeks maximum (including a taper). Tolerance to benzodiazepines can cause a wide range of symptoms related to nervous system dysfunction to emerge, many of these symptoms are identical to benzodiazepine withdrawal symptoms. It is important for physicians not to misinterpret benzodiazepine tolerance symptoms as a separate disease. This can result in misdiagnosis and inappropriate treatment. These symptoms may include:

Abdominal pain and discomfort
Agitation
Dizziness
Flu-like symptoms
Tremor
Agoraphobia
Depersonalization
Depression
Irrational fear and paranoid thoughts
Lack of concentration and confusion
Rapid mood changes

Abuse and dependence

Long-term benzodiazepine usage generally leads to some form of tolerance and/or dependence. Benzodiazepines are considered to be moderately to highly addictive. Withdrawal symptoms may include:

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 by a professional who is knowledgeable about the long-term effects of benzodiazepines. It is important to note that the withdrawal syndrome from long-term benzodiazepine use, even at low doses, can be extremely severe and debilitating, lasting months to years. This can usually be avoided or minimized by very gradually tapering off of the drug over a period of many months.

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.

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®), which is occasionally used empirically in patients presenting with unexplained loss of consciousness in an emergency room setting.

Legal status

Nearly all medically-used benzodiazepines are Schedule IV in the USA under the Federal Controlled Substances Act.

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 required 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 and flurazepam (Dalmane®), which was introduced in 1973.

Pharmacology

Benzodiazepines produce their variety of effects by modulating the GABA_A receptor, the most prolific inhibitory receptor within the brain. The GABA_A receptor is made up from 5 subunits out of a possible 19, and GABA_A 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 GABA_A 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 GABA_A receptor into a conformation where the neurotransmitter GABA has much higher affinity for the GABA_A 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 GABA_A 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 GABA_A receptors containing α₂ and/or α₃ subunits have good anti-anxiety activity.

References

Ashton H. Benzodiazepines: How They Work And How to Withdraw. 2002 Aug. Fulltext.
Atack JR. Anxioselective compounds acting at the GABA(A) receptor benzodiazepine binding site. Current drug targets. CNS and neurological disorders. 2003 Aug;2(4):213-32.
Gerada C, Ashworth M. ABC of mental health. Addiction and dependence--I: Illicit drugs. BMJ 1997;315:297-300. Fulltext. PMID 9274553.
Sternbach LH. The discovery of librium. Agents Actions 1972;2:193-6. PMID 4557348

External links

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