Benzodiazepine

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The benzodiazepines (pronounced [ˌbenzəʊdaɪˈæzəpiːnz], or "benzos" for short) are a class of psychoactive drugs considered as minor tranquilizers with varying hypnotic, sedative, anxiolytic, anticonvulsant, muscle relaxant and amnesic properties, which are brought on by slowing down the central nervous system. This makes benzodiazepines useful in treating anxiety, insomnia, agitation, seizures, and muscle spasms, as well as alcohol withdrawal. They can also be used before certain medical procedures such as endoscopies, dental work, or other medical procedures where tension and anxiety are present, and prior to some unpleasant medical procedures in order to induce amnesia for the procedure. Another use is to counteract anxiety-related symptoms upon initial use of SSRIs and other antidepressants, or as an adjunctive treatment. Recreational stimulant users often use benzodiazepines as a means of "coming down".

All benzodiazepines have an addictive potential. Use of benzodiazepines should only commence after medical consultation and prescribed the smallest dosage possible to provide an acceptable level of symptom relief. Dependence varies for the benzodiazepine used, with some reporting Alprazolam dependence in as little as three days.

Contents 1 Common Benzodiazepines 2 Duration of action 3 Pharmacology 4 Side effects 5 Tolerance 6 Cross Tolerance 7 Dependence 8 Intoxication 9 Legal status 10 History 11 References 12 External links

[edit] Common Benzodiazepines

Most benzodiazepines are oral; however, administration can also occur intravenously, intramuscularly, or as a suppository. Well-known benzodiazepines and their primary trade names include Alprazolam (Xanax), Bromazepam (Lexomil), Diazepam (Valium), Lorazepam (Ativan), Clonazepam (Klonopin), Temazepam (Restoril), Oxazepam (Serax), Flunitrazepam (Rohypnol), Triazolam (Halcion), Chlordiazepoxide (Librium), Flurazepam (Dalmane), and Nitrazepam (Mogadon).

A related class of drugs, the nonbenzodiazepines, has recently been introduced. These drugs have benefits very similar to benzodiazepines, but with less addictive potential.

[edit] Duration of action

Benzodiazepines 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.

[edit] Pharmacology

Their 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 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 hyperpolarizing 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.

[edit] 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.

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.

[edit] 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 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. However, patients should be aware that this could lead to a cycle of increasing doses and worsening side-effects. In addition, as dosage is increased, the potential for addiction becomes greater.

[edit] Cross Tolerance

Benzodiazepines share a similar mechanism of action to various sedative compounds which act via enhancing the GABA_A 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 GABA_A receptor's function via modulating the chloride ion channel function of the GABA_A receptor.

[edit] 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 can occur when benzodiazepine dosage is reduced. Abrupt or over rapid dosage reduction can produce severe or withdrawal symptoms. Withdrawal symptoms can even occur during a very gradual and slow dosage reduction but are rarely serious. The withdrawal symptoms may include:

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

An abrupt or over rapid discontinuation of benzodiazepines may result in a more serious and very unpleasant withdrawal syndrome that may additionally result in:

• Convulsions, which may result in death 3 4
• Catatonia, which may result in death 5
• 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 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 as many as 18 months after which symptoms start to decline in severity. In some people the withdrawal syndrome can persist as a sub-acute syndrome with gradually improving symptoms over a period of many months and even 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 and can often lead to a misdiagnosis. For this reason, many experts agree that after withdrawal from long term or even fairly short term use of benzodiazepine drugs, at least six months should have elapsed prior to re-evaluating the symptoms and updating a diagnosis.

[edit] 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 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.

[edit] 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.

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.

[edit] 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.

[edit] 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. [1]
• 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)
• Ashton CH Toxicity and Adverse Consequences of Benzodiazepine Use, Psychiatric Annals Volume 25: pp158-165 March 1995 Fulltext
• Ashton CH, Benzodiazepine Withdrawal: Outcome in 50 Patients, British Journal of Addiction (1987) 82, 655-671 FullText
• COMMITTEE ON SAFETY OF MEDICINES, BENZODIAZEPINES, DEPENDENCE AND WITHDRAWAL SYMPTOMS, UK Government Bulletin to Prescribing Doctors, January 1988 FullText
• Lader MH, Morton SV. A pilot study of the effects of flumazenil on symptoms persisting after benzodiazepine withdrawal, Journal of Psychopharmacology 6(3) (1992) 357-363 FullText
• Rosebush PI, Mazurek MF. Catatonia after benzodiazepine withdrawal. J Clin Psychopharmacol. 1996 Aug;16(4):315-9. Pubmed
• Metten P, Crabbe JC. Genetic determinants of severity of acute withdrawal from diazepam in mice: commonality with ethanol and pentobarbital. Pharmacol Biochem Behav. 1999 Jul;63(3):473-9. Pubmed
• Haque W, Watson DJ, Bryant SG. Death following suspected alprazolam withdrawal seizures: a case report. Tex Med. 1990 Jan;86(1):44-7. Pubmed

[edit] External links

• 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
• Benzodiazepines: How they work and how to withdraw
• Genetic link to the severity of withdrawal