Drugs & Medication

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 1 Pharmacology 2 Members 3 Effects/Uses 4 Side effects 5 Tolerance 6 Dependence 7 Abuse Potential 8 Intoxication 9 Legal status 10 History 11 See also 12 References 13 External links

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.

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

• Sedative
• Hypnotic
• Psychoactive drug

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

• Benzo.org.uk - Benzodiazepine addiction and withdrawal
• Drugs.com - Benzodiazepines (advanced consumer information)
• Inchem.org - Benzodiazepines
• The Eaton T. Fores Research Center - An Overview of the History, Chemistry, and Pharmacodynamics of Benzodiazepines