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Benzodiazepines

Drugs & Medication

Benzodiazepines

Alprazolam | Diazepam | Flunitrazepam | Lorazepam | Midazolam

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The benzodiazepines(pronounced [ˌbenzəʊdaɪˈæzəpiːnz], which are considered 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 physiological and psychological 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. Their chemical structure is based upon diazepine and phenyl groups.

Contents

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 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 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 α1 are associated with sedation whereas those with higher affinity for GABAA receptors containing α2 and/or α3 subunits have good anti-anxiety activity.

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 elimination half-life may greatly vary between individuals, especially the elderly.

The various benzodiazepines and their respective trade-names, half-lives, and primary uses are listed in the following table.

Drug Name Common Brand Names* Elimination Half-Life (h)** [active metabolite] Primary Effects Approximate Equivalent Dose***
Alprazolam Xanax, Xanor, Tafil, Alprox 6-12 hours anxiolytic 0.5 mg
Bromazepam Lexotan, Lexomil, Somalium, Bromam 10-20 hours anxiolytic 5-6 mg
Chlordiazepoxide Librium, Tropium, Risolid, Klopoxid 5-30 hours [36-200 hours] anxiolytic 25 mg
Cinolazepam Gerodorm 9 h sedative ?
Clobazam Frisium, Urbanol 12-60 hours anxiolytic, anticonvulsant 5-20 mg
Clonazepam Klonopin, Klonapin, Rivotril 18-50 hours anxiolytic, anticonvulsant 0.5 mg
Clorazepate Tranxene [36-100 hours] anxiolytic, anticonvulsant 15 mg
Diazepam Valium, Apzepam, Stesolid, Apozepam, Hexalid, Valaxona 20-100 hours [36-200] anxiolytic, hypnotic, anticonvulsant, muscle relaxant 10 mg
Estazolam ProSom 10-24 h hypnotic 1-2 mg
Flunitrazepam Rohypnol, Fluscand, Flunipam, Ronal 18-26 hours [36-200 hours] hypnotic 1 mg
Flurazepam Dalmane [40-250 hours] hypnotic 15-30 mg
Halazepam Paxipam [30-100 hours] anxiolytic 20 mg
Ketazolam Anxon 2 hours anxiolytic 15-30 mg
Loprazolam Dormonoct 6-12 hours hypnotic 1-2 mg
Lorazepam Ativan, Temesta, Lorabenz 10-20 hours anxiolytic 1 mg
Lormetazepam Noctamid, Pronoctan 10-12 hours hypnotic 1-2 mg
Medazepam Nobrium 36-200 hours anxiolytic 10 mg
Midazolam Dormicum, Versed, Hypnovel 3 hours (1.8-6 hours) hypnotic 5-15 mg
Nitrazepam Mogadon, Apodorm, Pacisyn, Dumolid 15-38 hours hypnotic 10 mg
Nordazepam Madar, Stilny 50-120 hours anxiolytic 10 mg
Oxazepam Serax, Serenid, Serepax, Sobril, Oxascand, Alopam, Oxabenz, Oxapax 4-15 hours anxiolytic 20 mg
Pinazepam Domar [40-100 hours] sedative 5-20 mg
Prazepam Centrax [36-200 hours] anxiolytic 10-20 mg
Quazepam Doral 25-100 hours hypnotic 20 mg
Temazepam Restoril, Normison, Euhypnos 8-22 hours hypnotic 15 mg
Tetrazepam Mylostan 3-26 hours Skeletal muscle relaxant ?
Triazolam Halcion, Rilamir 2 hours hypnotic 0.5 mg
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.[1]

Effects/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. It is commonly used in conjunction with opiates.

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. 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.

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 rarely, if ever, occurs as is evidenced by a 20-year study on alprazolam (Xanax®) in the treatment of panic disorder. [2]

Dependence

Long-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:

  • Insomnia
    Rebound REM (or dreaming) sleep
    Anxiety, possible panic attacks
    Tachycardia
    Hypertension
    Depression, possible suicidal ideation
    Tremor
    Perspiration
    Loss of appetite
    Dysphoria

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

  • Convulsions
    Delusions
    Psychosis
    Effects similar to delirium tremens

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, 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. The ability to determine the difference between relapse and rebound is very important during the withdrawal phase.

Abuse Potential

Although benzodiazepines are invaluable in the treatment of anxiety disorders, they have some potential for abuse and may cause dependence or addiction. It is important to distinguish between addiction to and normal physical dependence on benzodiazepines. Intentional abusers of benzodiazepines usually have other substance abuse problems. Benzodiazepines are usually a secondary drug of abuse, used mainly to augment the high received from another drug or to offset the adverse effects of other drugs. Few cases of addiction arise from legitimate use of benzodiazepines. [3]

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 if quantities of the substances ingested are not sufficent 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.

Legal status

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

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.

See also

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.
  • Benzodiazepine Equivalence Table
  • Gerada C, Ashworth M. ABC of mental health. Addiction and dependence--I: Illicit drugs. BMJ 1997;315:297-300. Fulltext. PMID 9274553.
  • O'Brien, CP. "Benzodiazepine use, abuse, and dependence", Journal of Clinical Psychiatry. 2005;66 Suppl 2:28-33. [4]
  • Sternbach LH. The discovery of librium. Agents Actions 1972;2:193-6. PMID 4557348
  • Handbook of Clinical Psychopharmacology for Therapists Fourth Ed. - John D. Preston, Psy.D., ABPP; John H. O'Neal, MD; Mary C. Talaga, R.Ph., Ph.D (for alprazolam 1mg = 10mg diazepam)

External links


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This guide is licensed under the GNU Free Documentation License. It uses material from the Wikipedia.


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