Benzodiazepine

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In pharmacology, benzodiazepines (BZD) are a class of medications that are "a group of two-ring heterocyclic compounds consisting of a benzene ring fused to a diazepine ring."[1] All benzodiazepines affect specific benzodiazepine receptors and modulate gamma-aminobutyric acid. Specific benzodiazepines also affect other neurotransmitters (e.g., clonazepam and alprazolam affect serotonin). Receptor relationships are quite complex and are discussed further below.

Uses include the treatment of anxiety disorders and alcohol withdrawal syndrome. Some are used as anticonvulsants and to treat musculoskeletal spasticity.

Selected benzodiazepines[2]
Half life Examples
ultra-short  
short (< 6 hrs) brotizolam
midazolam
triazolam
intermediate (6 - 24 hrs) alprazolam
bromazepam
estazolam
flunitrazepam
loprazolam
lorazepam
lormetazepam
nimetazepam
oxazepam
temazepam
long (> 24 hrs) clonazepam
chlordiazepoxide
diazepam
flurazepam
nitrazepam
quazepam

History

The first benzodiazepine, chlordiazepoxide (Librium) was discovered serendipitously in 1954 by the Austrian scientist Leo Sternbach (1908–2005), working for the pharmaceutical company Hoffmann–La Roche. Chlordiazepoxide was synthesised from work on a chemical dye, quinazolone-3-oxides. 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. Tests revealed that the compound had hypnotic, anxiolytic and muscle relaxant effects. Three years later chlordiazepoxide was marketed as a therapeutic benzodiazepine medication under the brand name Librium. Following chlordiazepoxide in 1963 diazepam hit the market under the brand name Valium, followed by many further benzodiazepine compounds which were introduced over the subsequent years and decades.[3]

The original chemical name of chlordiazepoxide was methaminodiazepoxide but it was changed to chlordiazepoxide. It was marketed under the trade name Librium, derived from the final syllables of equilibrium. In 1959 it was used by over 2,000 physicians and more than 20,000 patients. It was described as "chemically and clinically different from any of the tranquilizers, psychic energizers or other psychotherapeutic drugs now available." During studies, chlordiazepoxide induced muscle relaxation and a quieting effect on laboratory animals like mice, rats, cats, and dogs. Fear and aggression were eliminated in much smaller doses than those necessary to produce hypnosis. Chlordiazepoxide is similar to phenobarbital in its anticonvulsant properties. However, it lacks the hypnotic effects of barbiturates. Animal tests were conducted in the Boston Zoo and the San Diego Zoo. Forty-two hospital patients admitted for acute and chronic alcoholism, and various psychoses and neuroses were treated with chlordiazepoxide. In a majority of the patients, anxiety, tension, and motor excitement were "effectively reduced." The most positive results were observed among alcoholic patients. It was reported that ulcers and dermatologic problems, both of which involve emotional factors, were reduced by chlordiazepoxide.[4]

Chlordiazepoxide enabled the treatment of emotional disturbances without a loss of mental acuity or alertness. It assisted persons burdened by compulsive reactions like one that felt compelled to count the slats on venetian blinds upon entering a room.[5]

Dr. Carl F. Essig of the Addiction Research Center of the National Institute of Mental Health spoke at a symposium on drug abuse at an annual meeting of the American Association for the Advancement of Science, in December 1963. He named meprobamate, glutethimide, ethinamate, ethchlorvynol, methyprylon, and chlordiazepoxide as drugs whose usefulness can hardly be questioned. However, Essig labeled these newer products as drugs of addiction, like barbiturates, whose habit-forming qualities were more widely-known. He mentioned a 90-day study of chlordiazepoxide, which concluded that the automobile accident rate among 68 users was ten times higher than normal. Participants' daily dosage ranged from 5 to 100 milligrams.[6]

In 1963, approval for use was given to diazepam (Valium), a "simplified" version of chlordiazepoxide, primarily to counteract anxiety symptoms. Sleep-related problems were treated with nitrazepam (Mogadon), which was introduced in 1965, temazepam (Restoril), which was introduced in 1969, and flurazepam (Dalmane), which was introduced in 1973.[7]

Receptors

Part of the confusion in the receptors they affect come from the observation that what had previously been considered the GABAA-benzodiazepine-Cl- channel complex receptor has numerous sub-receptors, in five classes (α, β, γ, δ, ρ) with at least 16 subtypes. Benzodiazepine receptor type 1, for example, involves binding to α1, β2 and γ2.[8] The interactions among GABA, benzodiazepines, and some other classes of drugs are even more complex, in that binding to one receptor type affects other receptors. For example, certain bindings to benzodiazepine receptors will increase the rate of opening of the GABAA receptor,[9] potentiating the effect of both endogenous GABA and GABA released by direct GABA agonists such as baclofen.

There can be synergism in the use of various drugs that affect GABA. In musculoskeletal spasticity, as in multiple sclerosis or various disorders of spinal nerves, the first antispasticity drug prescribed is usually the GABA agonist baclofen, but it may be supplemented the BZD diazepam; diazepam can also be used as an alternative. In one study, the GABA agonists baclofen and muscimol were potentiated pain relief in rats when combined with the benzodiazepine diazepam. [10]

Clinical use

Anxiety

Benzodiazepines possess anti-anxiety properties and can be useful for the short-term treatment of severe anxiety. Benzodiazepines are usually administered orally for the treatment of anxiety; however, occasionally lorazepam or diazepam may be given intravenously for the treatment of panic attacks. A panel of over 50 peer-nominated internationally recognized experts in the pharmacotherapy of anxiety and depression judged the benzodiazepines, especially combined with an antidepressant, as the mainstays of pharmacotherapy for anxiety disorders.[11][12][13][14]

Despite increasing focus on the use of antidepressants and other agents for the treatment of anxiety, benzodiazepines have remained a mainstay of anxiolytic pharmacotherapy due to their robust efficacy, rapid onset of therapeutic effect, and generally favorable side effect profile.[25] Treatment patterns for psychotropic drugs appear to have remained stable over the past decade, with benzodiazepines being the most commonly used medication for panic disorder.[15]

Convulsive disorders

Benzodiazepines are potent anticonvulsants and have life-saving properties in the acute management of status epilepticus. The most commonly-used benzodiazepines for seizure control are lorazepam and diazepam. A meta-analysis of 11 clinical trials concluded that lorazepam was superior to diazepam in treating persistent seizures.[16] Although diazepam is much longer-acting than lorazepam, lorazepam has a more prolonged anticonvulsant effect. This is because diazepam is very lipid-soluble and highly protein-bound, and has a very large distribution of unbound drug, resulting in diazepam's having only a 20– to 30-minute duration of action against status epilepticus. Lorazepam, however, has a much smaller volume of distribution of unbound drug, which results in a more prolonged duration of action against status epilepticus. Lorazepam can therefore be considered superior to diazepam, at least in the initial stages of treatment of status epilepticus.[17]

Insomnia

Hypnotic benzodiazepines have strong sedative effects, and certain benzodiazepines therefore are often prescribed for the management of insomnia. Longer-acting benzodiazepines, such as nitrazepam, have side-effects that may persist into the next day, whereas the more intermediate-acting benzodiazepines (for example, temazepam) may have less "hangover" effects the next day.[18] Benzodiazepine hypnotics should be reserved for short-term courses to treat acute conditions, as tolerance and dependence may occur if these benzodiazepines are taken regularly for more than a few weeks.

Toxicity and abuse

A large cohort study found that in primary care, "anxiolytic and hypnotic drugs were associated with significantly increased risk of mortality over a seven year period, after adjusting for a range of potential confounders". [19]

References

  1. Anonymous (2015), Benzodiazepine (English). Medical Subject Headings. U.S. National Library of Medicine.
  2. Charney Dennis S, Mihic S. J, Harris R. A, "Chapter 16. Hypnotics and Sedatives" (Chapter). Brunton LL, Lazo JS, Parker KL: Goodman & Gilman's The Pharmacological Basis of Therapeutics, 11e:.
  3. Cooper, Jack R; Floyd E. Bloom, Robert H. Roth (15). The Complete Story of the Benzodiazepines, seventh (in Eng), USA: Oxford University Press. ISBN 0195103998.
  4. Help For Mental Ills (Reports on Tests of Synthetic Drug Say The Results are Positive), New York Times, February 28, 1960, Page E9.
  5. Makers Worried On Tranquilizers, New York Times, August 28, 1960, Page F1.
  6. Warning Is Issued On Tranquilizers, New York Times, December 30, 1963, Page 23.
  7. Sternbach LH (1972). "The discovery of librium". Agents Actions 2 (4): 193-6. PMID 4557348.
  8. Ross J. Baldessarini (1996), Chapter 18, Drugs and the treatment of Psychiatric Disorders: Psychosis and Anxiety, in Joel G. Hardman et al., Goodman and Gilman's The Pharmacological Basis of Therapeutics (Ninth Edition ed.), McGraw-Hill, ISBN 0070262667 pp. 421-434
  9. Robin Mantooth (28 January 2010), Toxicity, Benzodiazepine, eMedicine
  10. Kaoru Hara et al. (May 2004), "The Interaction Between Gamma-Aminobutyric Acid Agonists and Diltiazem in Visceral Antinociception in Rats", Anesthesia and Analgesia 98 (5): 1380-1384, DOI:01.ANE.0000107935.84035.48 10.1213/​ 01.ANE.0000107935.84035.48
  11. Uhlenhuth EH, Balter MB, Ban TA, Yang K (1999). "International study of expert judgment on therapeutic use of benzodiazepines and other psychotherapeutic medications: VI. Trends in recommendations for the pharmacotherapy of anxiety disorders, 1992-1997". Depress Anxiety 9 (3): 107–16. PMID 10356648.
  12. Uhlenhuth EH, Balter MB, Ban TA, Yang K (1995). "International study of expert judgement on therapeutic use of benzodiazepines and other psychotherapeutic medications: II. Pharmacotherapy of anxiety disorders". J Affect Disord 35 (4): 153–62. PMID 8749980.
  13. Uhlenhuth EH, Balter MB, Ban TA, Yang K (1999). "Trends in recommendations for the pharmacotherapy of anxiety disorders by an international expert panel, 1992-1997". Eur Neuropsychopharmacol 9 Suppl 6: S393–8. PMID 10622685.
  14. Uhlenhuth EH, Balter MB, Ban TA, Yang K (1999). "International study of expert judgment on therapeutic use of benzodiazepines and other psychotherapeutic medications: IV. Therapeutic dose dependence and abuse liability of benzodiazepines in the long-term treatment of anxiety disorders". J Clin Psychopharmacol 19 (6 Suppl 2): 23S–29S. PMID 10587281.
  15. Bruce SE, Vasile RG, Goisman RM, et al (2003). "Are benzodiazepines still the medication of choice for patients with panic disorder with or without agoraphobia?". Am J Psychiatry 160 (8): 1432–8. PMID 12900305.
  16. Prasad K; Krishnan PR, Al-Roomi K, Sequeira R. (Jun 2007). "Anticonvulsant therapy for status epilepticus.". British journal of clinical pharmacology. 63 (6): 640-7. doi:10.1002/14651858.CD003723.pub2. PMID 17439538.
  17. Treiman DM. (1989). "Pharmacokinetics and clinical use of benzodiazepines in the management of status epilepticus.". Epilepsia. 30 (2): 4-10. PMID 2670537.
  18. Hypnotics at British National Formulary. Accessed 10 May 2012.
  19. Weich S, Pearce HL, Croft P, Singh S, Crome I, Bashford J et al. (2014). "Effect of anxiolytic and hypnotic drug prescriptions on mortality hazards: retrospective cohort study.". BMJ 348: g1996. DOI:10.1136/bmj.g1996. PMID 24647164. PMC PMC3959619. Research Blogging.