Benzodiazepines: Difference between revisions

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It is worth noting that [[Benzodiazepine#Discontinuation|the sudden discontinuation of benzodiazepines]] can be potentially dangerous or life-threatening for individuals that develop a physical dependence on them after using them regularly for extended periods of time, which can result in potentially fatal seizures.<ref>A fatal case of benzodiazepine withdrawal. (PubMed.gov / NCBI) | http://www.ncbi.nlm.nih.gov/pubmed/19465812</ref> For this reason, it is highly recommended to [[taper]] one's dose by gradually lowering the amount taken each day for a prolonged period of time instead of stopping one's usage abruptly.<ref>Canadian Guideline for Safe and Effective Use of Opioids for Chronic Non-Cancer Pain - Appendix B-6: Benzodiazepine Tapering | http://nationalpaincentre.mcmaster.ca/opioid/cgop_b_app_b06.html</ref>

==History==

[[File:Chlordiazepoxide structure.svg|thumb|250px|right|alt=Chemical structure diagram of a benzene ring fused to a diazepine ring. Cl is attached to the benzene; N, H, CH3, and O are attached to the diazepine.|The molecular structure of chlordiazepoxide, the first benzodiazepine. It was marketed by Hoffmann–La Roche from 1960 branded as ''Librium''.]]

The first benzodiazepine, chlordiazepoxide (''Librium''), was synthesized in 1955 by Leo Sternbach while working at Hoffmann–La Roche on the development of tranquilizers. The pharmacological properties of the compounds prepared initially were disappointing, and Sternbach abandoned the project.

Two years later, in April 1957, co-worker Earl Reeder noticed a "nicely crystalline" compound left over from the discontinued project while spring-cleaning in the lab. This compound, later named chlordiazepoxide, had not been tested in 1955 because of Sternbach's focus on other issues. Expecting pharmacology results to be negative, and hoping to publish the chemistry-related findings, researchers submitted it for a standard battery of animal tests.

However, the compound showed very strong [[sedative]], [[anticonvulsant]], and [[muscle relaxant]] effects. These impressive clinical findings led to its speedy introduction throughout the world in 1960 under the brand name ''Librium''.<ref name="pmid34039">{{cite journal | author = Sternbach LH | title = The benzodiazepine story | journal = Journal of Medicinal Chemistry | volume = 22 | issue = 1 | pages = 1–7 | year = 1979 | pmid = 34039 | doi = 10.1021/jm00187a001 | quote = During this cleanup operation, my co-worker, Earl Reeder, drew my attention to a few hundred milligrams of two products, a nicely crystalline base and its hydrochloride. Both the base, which had been prepared by treating the quinazoline N-oxide 11 with methylamine, and its hydrochloride had been made sometime in 1955. The products were not submitted for pharmacological testing at that time because of our involvement with other problems }}</ref><ref name="Miller-Gold">{{cite journal |vauthors=Miller NS, Gold MS | title = Benzodiazepines: reconsidered | journal = Adv Alcohol Subst Abuse | volume = 8 | issue = 3–4 | pages = 67–84 | year = 1990 | pmid = 1971487 | doi = 10.1300/J251v08n03_06 }}</ref> Following chlordiazepoxide, [[diazepam]] marketed by Hoffmann–La Roche under the brand name ''Valium'' in 1963, and for a while the two were the most commercially successful drugs. The introduction of benzodiazepines led to a decrease in the prescription of [[barbiturate]]s, and by the 1970s they had largely replaced the older drugs for sedative and [[hypnotic]] uses.<ref name="isbn0-19-517668-5">{{cite book |author=Shorter E |title=A Historical Dictionary of Psychiatry |publisher=Oxford University Press |year=2005 |chapter=Benzodiazepines |pages=41–2 |isbn=0-19-517668-5 }}</ref>

==Society and culture==

The new group of drugs was initially greeted with optimism by the medical profession, but gradually concerns arose; in particular, the risk of dependence became evident in the 1980s. Benzodiazepines have a unique history in that they were responsible for the largest-ever class-action lawsuit against drug manufacturers in the United Kingdom, involving 14,000 patients and 1,800 law firms that alleged the manufacturers knew of the dependence potential but intentionally withheld this information from doctors.

At the same time, 117 general practitioners and 50 health authorities were sued by patients to recover damages for the harmful effects of dependence and withdrawal. This led some doctors to require a signed consent form from their patients and to recommend that all patients be adequately warned of the risks of dependence and withdrawal before starting treatment with benzodiazepines.<ref>{{cite journal | author = King MB | title = Is there still a role for benzodiazepines in general practice? | journal = Br J Gen Pract | volume = 42 | issue = 358 | pages = 202–5 | year = 1992 | pmid = 1389432 | pmc = 1372025 }}</ref> The court case against the drug manufacturers never reached a verdict; legal aid had been withdrawn and there were allegations that the consultant psychiatrists, the expert witnesses, had a conflict of interest. This litigation led to changes in the British law, making class action lawsuits more difficult.<ref name="urlHouse of Commons">{{cite web |url=http://www.publications.parliament.uk/pa/cm199899/cmselect/cmhealth/549/99072723.htm |title=Memorandum by Dr Reg Peart |author=Peart R |date=1999-06-01 |work=Minutes of Evidence |publisher=Select Committee on Health, House of Commons, UK Parliament |accessdate=2009-05-27 }}</ref>

Although antidepressants with anxiolytic properties have been introduced, and there is increasing awareness of the adverse effects of benzodiazepines, prescriptions for short-term anxiety relief have not significantly dropped.<ref name=pmid18671662>{{cite journal | author = Lader M | title = Effectiveness of benzodiazepines: do they work or not? | journal = Expert Rev Neurother | volume = 8 | issue = 8 | pages = 1189–91 | year = 2008 | pmid = 18671662 | doi = 10.1586/14737175.8.8.1189 | type = PDF }}</ref> For treatment of insomnia, benzodiazepines are now less popular than nonbenzodiazepines, which include [[zolpidem]], zaleplon and [[zopiclone|eszopiclone]].<ref>{{cite journal | author = Jufe GS | title = [New hypnotics: perspectives from sleep physiology] | journal = Vertex | volume = 18 | issue = 74 | pages = 294–9 | date = Jul–Aug 2007 | pmid = 18265473 }}</ref> Nonbenzodiazepines are molecularly distinct, but nonetheless, they work on the same benzodiazepine receptors and produce similar sedative effects.<ref name=wake>{{cite journal | author = Lemmer B | title = The sleep–wake cycle and sleeping pills | journal = Physiol Behav | volume = 90 | issue = 2–3 | pages = 285–93 | year = 2007 | pmid = 17049955 | doi = 10.1016/j.physbeh.2006.09.006 }}</ref>

==Chemistry==

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|{{effects/physical|

*'''[[Effect::Sedation]]''' - In terms of energy level alterations, these substances have the potential to be extremely sedating and this often results in an overwhelmingly lethargic state. At higher levels, this causes users to suddenly feel as if they are extremely sleep deprived and have not slept for days, forcing them to sit down and generally feel as if they are constantly on the verge of passing out instead of engaging in physical activities. This sense of sleep deprivation increases proportional to dosage and eventually becomes powerful enough to force a person into complete unconsciousness.

*'''[[Effect::Muscle relaxation]]'''

*'''[[Effect::Physical euphoria]]'''

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*'''[[Effect::Respiratory depression]]'''

*'''[[Effect::Dizziness]]'''

*'''[[Effect::Sedation]]''' - In terms of energy level alterations, these drugs have the potential to be extremely sedating and this often results in an overwhelmingly lethargic state. At higher levels, this causes users to suddenly feel as if they are extremely sleep deprived and have not slept for days, forcing them to sit down and generally feel as if they are constantly on the verge of passing out instead of engaging in physical activities. This sense of sleep deprivation increases proportional to dosage and eventually becomes powerful enough to force a person into complete unconsciousness.

}}

@@ Line 7: / Line 7: @@
 It is worth noting that [[Benzodiazepine#Discontinuation|the sudden discontinuation of benzodiazepines]] can be potentially dangerous or life-threatening for individuals that develop a physical dependence on them after using them regularly for extended periods of time, which can result in potentially fatal seizures.<ref>A fatal case of benzodiazepine withdrawal. (PubMed.gov / NCBI) | http://www.ncbi.nlm.nih.gov/pubmed/19465812</ref> For this reason, it is highly recommended to [[taper]] one's dose by gradually lowering the amount taken each day for a prolonged period of time instead of stopping one's usage abruptly.<ref>Canadian Guideline for Safe and Effective Use of Opioids for Chronic Non-Cancer Pain - Appendix B-6: Benzodiazepine Tapering | http://nationalpaincentre.mcmaster.ca/opioid/cgop_b_app_b06.html</ref>
+==History==
+[[File:Chlordiazepoxide structure.svg|thumb|250px|right|alt=Chemical structure diagram of a benzene ring fused to a diazepine ring. Cl is attached to the benzene; N, H, CH3, and O are attached to the diazepine.|The molecular structure of chlordiazepoxide, the first benzodiazepine. It was marketed by Hoffmann–La Roche from 1960 branded as ''Librium''.]]
+The first benzodiazepine, chlordiazepoxide (''Librium''), was synthesized in 1955 by Leo Sternbach while working at Hoffmann–La Roche on the development of tranquilizers. The pharmacological properties of the compounds prepared initially were disappointing, and Sternbach abandoned the project.
+Two years later, in April 1957, co-worker Earl Reeder noticed a "nicely crystalline" compound left over from the discontinued project while spring-cleaning in the lab. This compound, later named chlordiazepoxide, had not been tested in 1955 because of Sternbach's focus on other issues. Expecting pharmacology results to be negative, and hoping to publish the chemistry-related findings, researchers submitted it for a standard battery of animal tests.
+However, the compound showed very strong [[sedative]], [[anticonvulsant]], and [[muscle relaxant]] effects. These impressive clinical findings led to its speedy introduction throughout the world in 1960 under the brand name ''Librium''.<ref name="pmid34039">{{cite journal | author = Sternbach LH | title = The benzodiazepine story | journal = Journal of Medicinal Chemistry | volume = 22 | issue = 1 | pages = 1–7 | year = 1979 | pmid = 34039 | doi = 10.1021/jm00187a001 | quote = During this cleanup operation, my co-worker, Earl Reeder, drew my attention to a few hundred milligrams of two products, a nicely crystalline base and its hydrochloride. Both the base, which had been prepared by treating the quinazoline N-oxide 11 with methylamine, and its hydrochloride had been made sometime in 1955. The products were not submitted for pharmacological testing at that time because of our involvement with other problems }}</ref><ref name="Miller-Gold">{{cite journal |vauthors=Miller NS, Gold MS | title = Benzodiazepines: reconsidered | journal = Adv Alcohol Subst Abuse | volume = 8 | issue = 3–4 | pages = 67–84 | year = 1990 | pmid = 1971487 | doi = 10.1300/J251v08n03_06 }}</ref> Following chlordiazepoxide, [[diazepam]] marketed by Hoffmann–La Roche under the brand name ''Valium'' in 1963, and for a while the two were the most commercially successful drugs. The introduction of benzodiazepines led to a decrease in the prescription of [[barbiturate]]s, and by the 1970s they had largely replaced the older drugs for sedative and [[hypnotic]] uses.<ref name="isbn0-19-517668-5">{{cite book |author=Shorter E |title=A Historical Dictionary of Psychiatry |publisher=Oxford University Press |year=2005 |chapter=Benzodiazepines |pages=41–2 |isbn=0-19-517668-5 }}</ref>
+==Society and culture==
+The new group of drugs was initially greeted with optimism by the medical profession, but gradually concerns arose; in particular, the risk of dependence became evident in the 1980s. Benzodiazepines have a unique history in that they were responsible for the largest-ever class-action lawsuit against drug manufacturers in the United Kingdom, involving 14,000 patients and 1,800 law firms that alleged the manufacturers knew of the dependence potential but intentionally withheld this information from doctors.
+At the same time, 117 general practitioners and 50 health authorities were sued by patients to recover damages for the harmful effects of dependence and withdrawal. This led some doctors to require a signed consent form from their patients and to recommend that all patients be adequately warned of the risks of dependence and withdrawal before starting treatment with benzodiazepines.<ref>{{cite journal | author = King MB | title = Is there still a role for benzodiazepines in general practice? | journal = Br J Gen Pract | volume = 42 | issue = 358 | pages = 202–5 | year = 1992 | pmid = 1389432 | pmc = 1372025 }}</ref> The court case against the drug manufacturers never reached a verdict; legal aid had been withdrawn and there were allegations that the consultant psychiatrists, the expert witnesses, had a conflict of interest. This litigation led to changes in the British law, making class action lawsuits more difficult.<ref name="urlHouse of Commons">{{cite web |url=http://www.publications.parliament.uk/pa/cm199899/cmselect/cmhealth/549/99072723.htm |title=Memorandum by Dr Reg Peart |author=Peart R |date=1999-06-01 |work=Minutes of Evidence |publisher=Select Committee on Health, House of Commons, UK Parliament |accessdate=2009-05-27 }}</ref>
+Although antidepressants with anxiolytic properties have been introduced, and there is increasing awareness of the adverse effects of benzodiazepines, prescriptions for short-term anxiety relief have not significantly dropped.<ref name=pmid18671662>{{cite journal | author = Lader M | title = Effectiveness of benzodiazepines: do they work or not? | journal = Expert Rev Neurother | volume = 8 | issue = 8 | pages = 1189–91 | year = 2008 | pmid = 18671662 | doi = 10.1586/14737175.8.8.1189 | type =  PDF }}</ref> For treatment of insomnia, benzodiazepines are now less popular than nonbenzodiazepines, which include [[zolpidem]], zaleplon and [[zopiclone|eszopiclone]].<ref>{{cite journal | author = Jufe GS | title = [New hypnotics: perspectives from sleep physiology] | journal = Vertex | volume = 18 | issue = 74 | pages = 294–9 | date = Jul–Aug 2007 | pmid = 18265473 }}</ref> Nonbenzodiazepines are molecularly distinct, but nonetheless, they work on the same benzodiazepine receptors and produce similar sedative effects.<ref name=wake>{{cite journal | author = Lemmer B | title = The sleep–wake cycle and sleeping pills | journal = Physiol Behav | volume = 90 | issue = 2–3 | pages = 285–93 | year = 2007 | pmid = 17049955 | doi = 10.1016/j.physbeh.2006.09.006 }}</ref>
 ==Chemistry==
@@ Line 23: / Line 39: @@
 |{{effects/physical|
+*'''[[Effect::Sedation]]''' -  In terms of energy level alterations, these substances have the potential to be extremely sedating and this often results in an overwhelmingly lethargic state. At higher levels, this causes users to suddenly feel as if they are extremely sleep deprived and have not slept for days, forcing them to sit down and generally feel as if they are constantly on the verge of passing out instead of engaging in physical activities. This sense of sleep deprivation increases proportional to dosage and eventually becomes powerful enough to force a person into complete unconsciousness.
 *'''[[Effect::Muscle relaxation]]'''
 *'''[[Effect::Physical euphoria]]'''
@@ Line 30: / Line 46: @@
 *'''[[Effect::Respiratory depression]]'''
 *'''[[Effect::Dizziness]]'''
-*'''[[Effect::Sedation]]''' -  In terms of energy level alterations, these drugs have the potential to be extremely sedating and this often results in an overwhelmingly lethargic state. At higher levels, this causes users to suddenly feel as if they are extremely sleep deprived and have not slept for days, forcing them to sit down and generally feel as if they are constantly on the verge of passing out instead of engaging in physical activities. This sense of sleep deprivation increases proportional to dosage and eventually becomes powerful enough to force a person into complete unconsciousness.
 }}