Benzodiazepines
![Picture](/uploads/9/2/6/8/92684994/leo-sternbach.jpeg?202)
Discovery of Benzodiazepines
Benzodiazepines - commonly referred to as Benzos - were discovered in the 1950s by Leo Sternbach, one of the top 25 most influential Americans of the 20th century, according to U.S. News & World Reports [11]. Sternbach, a Croatian Jew who was educated in Poland, was able to leave Europe and immigrated to America with the help of his employers, F. Hoffman - La Roche Ltd.. Sternbach had been instructed by F. Hoffman - La Roche to mimic Wallace Pharmaceutical’s anxiolytic (anti-anxiety) drug, meprobamate (“Miltown”), in a way that would get around their patent but would not greatly change the effects of the drug. However, Sternbach did not like the idea of copying another man’s drug. Rather, he went off one of his own hunches and began working with compounds that he had studied as potential dyes earlier in his life. His exploits proved fruitless at first, but Sternbach kept working on the project under the radar of his employers, who had told him to scrap it all and move onto something else. As is the case for most success stories, after many months of working with the dyes under the radar, Sternbach discovered the first benzodiazepine, chlordiazepoxide (Librium). He begun testing the drug on mice and found that it was successful; however, he was not meant to be working on the drug at all, so he sat on his finding for six months, before presenting it to Roche’s chief of Pharmacology as something they had stumbled across during a lab cleanup. The drug went on the market in 1960 but three years later it was succeeded by Valium -another benzodiazepine discovered by Sternbach [9]. Valium was the most prescribed drug in the United States from 1969 to 1982. Interestingly, Sternbach’s total profit on each drug was $1, although the company did offer him a $10,000 prize for the discovery of a drug that was significantly profitable [11].
Benzodiazepines - commonly referred to as Benzos - were discovered in the 1950s by Leo Sternbach, one of the top 25 most influential Americans of the 20th century, according to U.S. News & World Reports [11]. Sternbach, a Croatian Jew who was educated in Poland, was able to leave Europe and immigrated to America with the help of his employers, F. Hoffman - La Roche Ltd.. Sternbach had been instructed by F. Hoffman - La Roche to mimic Wallace Pharmaceutical’s anxiolytic (anti-anxiety) drug, meprobamate (“Miltown”), in a way that would get around their patent but would not greatly change the effects of the drug. However, Sternbach did not like the idea of copying another man’s drug. Rather, he went off one of his own hunches and began working with compounds that he had studied as potential dyes earlier in his life. His exploits proved fruitless at first, but Sternbach kept working on the project under the radar of his employers, who had told him to scrap it all and move onto something else. As is the case for most success stories, after many months of working with the dyes under the radar, Sternbach discovered the first benzodiazepine, chlordiazepoxide (Librium). He begun testing the drug on mice and found that it was successful; however, he was not meant to be working on the drug at all, so he sat on his finding for six months, before presenting it to Roche’s chief of Pharmacology as something they had stumbled across during a lab cleanup. The drug went on the market in 1960 but three years later it was succeeded by Valium -another benzodiazepine discovered by Sternbach [9]. Valium was the most prescribed drug in the United States from 1969 to 1982. Interestingly, Sternbach’s total profit on each drug was $1, although the company did offer him a $10,000 prize for the discovery of a drug that was significantly profitable [11].
The Basics of Benzodiazepines
Benzodiazepines are a class of agents that work on the central nervous system and can be used as sedatives, hypnotics, anxiolytics, anticonvulsants and muscle relaxants. Right off the bat we can see some important characteristics of benzodiazepines. They are often used for emergency medical treatment for anxiety disorders due to the fact that the therapeutic effects of the drugs have such a rapid onset. Additionally, although they are also commonly used for long-term treatment of generalized anxiety disorder, they are less satisfactory in this regard. Individuals often try to avoid using benzodiazepines for long-term treatment, because, in addition to causing sedation, they induce tolerance and withdrawal symptoms, and they have rather high potential for abuse. The addictive nature of these drugs has led researchers to seek other drugs in order to treat anxiety disorders, and patients should be careful when taking benzodiazepines for extended periods of time [4].
As it was discussed earlier, benzodiazepines are a class of agents, which means the term refers to a variety of drugs that each have a slightly different function. We are focused on benzodiazepines as a treatment of generalized anxiety disorder, so it is important for us to focus on those that are long-acting. If you have not taken a science class in a while, or you are not familiar with the terminology, you may be asking yourself what it means for a drug to be long-acting. Benzodiazepines are available on a spectrum from short-acting to long-acting, which refers to the half-life of the drug, as measured by how long it takes for half the drug to be eliminated from your body.
Benzodiazepines are a class of agents that work on the central nervous system and can be used as sedatives, hypnotics, anxiolytics, anticonvulsants and muscle relaxants. Right off the bat we can see some important characteristics of benzodiazepines. They are often used for emergency medical treatment for anxiety disorders due to the fact that the therapeutic effects of the drugs have such a rapid onset. Additionally, although they are also commonly used for long-term treatment of generalized anxiety disorder, they are less satisfactory in this regard. Individuals often try to avoid using benzodiazepines for long-term treatment, because, in addition to causing sedation, they induce tolerance and withdrawal symptoms, and they have rather high potential for abuse. The addictive nature of these drugs has led researchers to seek other drugs in order to treat anxiety disorders, and patients should be careful when taking benzodiazepines for extended periods of time [4].
As it was discussed earlier, benzodiazepines are a class of agents, which means the term refers to a variety of drugs that each have a slightly different function. We are focused on benzodiazepines as a treatment of generalized anxiety disorder, so it is important for us to focus on those that are long-acting. If you have not taken a science class in a while, or you are not familiar with the terminology, you may be asking yourself what it means for a drug to be long-acting. Benzodiazepines are available on a spectrum from short-acting to long-acting, which refers to the half-life of the drug, as measured by how long it takes for half the drug to be eliminated from your body.
Pharmacokinetics
Long-acting benzodiazepines usually have half-lives that exceed 24 hours and contain pharmacologically active metabolites (typically desmethyldiazepam). This poses an issue for patients that are using benzodiazepines as a long-term treatment, because the drug begins to accumulate in the body after multiple doses. Furthermore, this is of particular concern for the elderly and patients with liver disease, because they will suffer from impaired clearance of the drug and, therefore, an increase in accumulation. On the other hand, benzodiazepines that are intermediate and short-acting have half-life values between 5 and 24 hours, and it is uncommon for them to contain metabolites. Naturally, these drugs have less of a tendency to accumulate in the patient’s system as they have shorter half-lives and no metabolites. Additionally, their metabolic clearance is not as strongly influenced by age or liver disease, so there is less of a risk for accumulation of the drug. Lastly, ultrashort-acting benzodiazepines have a half-life of less than five hours, which means they are essentially non-accumulating [7].
After reading about the worries of accumulation, you may be wondering why we prefer to use long-acting benzodiazepines for treatment if patients are at a higher risk of having the drug accumulate in their bodies? Unfortunately, when considering what drug a patient should be prescribed, one needs to take into account both the function and the practicality for the patient. With regard to practicality, it is difficult for patients if the drug’s positive effects wear off before the end of the day, forcing them to have to take medication multiple times a day. Long-acting drugs are therefore preferred, as the patient can take one dose in the morning and not have to worry about fluctuations in their mood or a recurrence of their symptoms. Due to the major differences between benzodiazepine derivatives in pharmacokinetic terms, it is of utmost importance that the physician chooses not only a particular drug, but also the dose, the interval between doses and the route of administration. All of these points are necessary for the desired effect to be had and sustained for an appropriate amount of time without the consequences of drug accumulation. If these pharmacokinetic decisions are made appropriately, the pharmacologic properties of the derivatives are actually quite similar [6].
Long-acting benzodiazepines usually have half-lives that exceed 24 hours and contain pharmacologically active metabolites (typically desmethyldiazepam). This poses an issue for patients that are using benzodiazepines as a long-term treatment, because the drug begins to accumulate in the body after multiple doses. Furthermore, this is of particular concern for the elderly and patients with liver disease, because they will suffer from impaired clearance of the drug and, therefore, an increase in accumulation. On the other hand, benzodiazepines that are intermediate and short-acting have half-life values between 5 and 24 hours, and it is uncommon for them to contain metabolites. Naturally, these drugs have less of a tendency to accumulate in the patient’s system as they have shorter half-lives and no metabolites. Additionally, their metabolic clearance is not as strongly influenced by age or liver disease, so there is less of a risk for accumulation of the drug. Lastly, ultrashort-acting benzodiazepines have a half-life of less than five hours, which means they are essentially non-accumulating [7].
After reading about the worries of accumulation, you may be wondering why we prefer to use long-acting benzodiazepines for treatment if patients are at a higher risk of having the drug accumulate in their bodies? Unfortunately, when considering what drug a patient should be prescribed, one needs to take into account both the function and the practicality for the patient. With regard to practicality, it is difficult for patients if the drug’s positive effects wear off before the end of the day, forcing them to have to take medication multiple times a day. Long-acting drugs are therefore preferred, as the patient can take one dose in the morning and not have to worry about fluctuations in their mood or a recurrence of their symptoms. Due to the major differences between benzodiazepine derivatives in pharmacokinetic terms, it is of utmost importance that the physician chooses not only a particular drug, but also the dose, the interval between doses and the route of administration. All of these points are necessary for the desired effect to be had and sustained for an appropriate amount of time without the consequences of drug accumulation. If these pharmacokinetic decisions are made appropriately, the pharmacologic properties of the derivatives are actually quite similar [6].
![Picture](/uploads/9/2/6/8/92684994/benzodiazepine-structure.gif?247)
Chemistry
Benzodiazepines have a chemical structure that is common in a variety of molecules that differ by the presence of different substituents (small chemical groups attached at the edges of the molecules, see R groups in figure 2). Additionally, there are many molecules that do not have the typical benzodiazepine chemical structure; however, they still have the same properties, mechanisms of action and effects of benzodiazepines [1]. Benzodiazepines are organic bases (meaning they are made up of mostly carbon) that get their name due to their core structure, a benzene ring fused to a seven-membered 1,4 diazepine ring (see figure 2 with nitrogen included). Almost all derivatives also have a 5-aryl substituent ring (see figure 2 with the R2'). The different substituents that make each derivative unique can attach to any of the 3 rings; however, they typically attach to position 7 of the benzene ring, positions 1, 2, 3 and 4 of the diazepine ring, and position 2’ of the 5-aryl substituent ring [10]. Additionally, there are general rules for the substituents (extra chemical groups) that make it a benzodiazepine. R1 should be an electron-attracting group, and other substituents should not be attached to any of the carbons on that ring. R2 and R3 can be varied, but activity is decreased if the lactam oxygen (oxygen in a four member nitrogen ring) is replaced by sulfur. Furthermore, the phenyl group (benzene ring with a substituent) is necessary for activity and halogen (noble gas) substituents are preferred in the ortho position (adjacent to the R group) [12]. These various substituents and side chains are the determinants of the potency, duration of action, metabolite activity, and rate of elimination for specific benzodiazepine derivatives.
Benzodiazepines have a chemical structure that is common in a variety of molecules that differ by the presence of different substituents (small chemical groups attached at the edges of the molecules, see R groups in figure 2). Additionally, there are many molecules that do not have the typical benzodiazepine chemical structure; however, they still have the same properties, mechanisms of action and effects of benzodiazepines [1]. Benzodiazepines are organic bases (meaning they are made up of mostly carbon) that get their name due to their core structure, a benzene ring fused to a seven-membered 1,4 diazepine ring (see figure 2 with nitrogen included). Almost all derivatives also have a 5-aryl substituent ring (see figure 2 with the R2'). The different substituents that make each derivative unique can attach to any of the 3 rings; however, they typically attach to position 7 of the benzene ring, positions 1, 2, 3 and 4 of the diazepine ring, and position 2’ of the 5-aryl substituent ring [10]. Additionally, there are general rules for the substituents (extra chemical groups) that make it a benzodiazepine. R1 should be an electron-attracting group, and other substituents should not be attached to any of the carbons on that ring. R2 and R3 can be varied, but activity is decreased if the lactam oxygen (oxygen in a four member nitrogen ring) is replaced by sulfur. Furthermore, the phenyl group (benzene ring with a substituent) is necessary for activity and halogen (noble gas) substituents are preferred in the ortho position (adjacent to the R group) [12]. These various substituents and side chains are the determinants of the potency, duration of action, metabolite activity, and rate of elimination for specific benzodiazepine derivatives.
Effect on GABA
Gamma-aminobutyric acid (GABA) is the chief inhibitory neurotransmitter of the central nervous system. The benzodiazepine receptor is an important part of the GABA-A receptor, which is a chloride ion channel, and it is the job of the benzodiazepines to augment these inhibitory neurons. Using electrophysiological studies scientists have been able to determine that benzodiazepines increase the frequency of channel opening in response to GABA, which leads to an increase in chloride conductance of the neuronal membrane. This increase effectively short-circuits responses to depolarizing inputs. Benzodiazepine receptor agonists (molecules that aid Benzodiazepine binding) increase the affinity of GABA to its receptor, which causes the postsynaptic cell to be hyperpolarized. Ultimately, this leads to a heightened response and a corresponding reduction in excitability [12]. Interestingly, benzodiazepines bind to a specific site on the GABA receptor, but they do not stimulate it directly. The term for this is an indirect agonist. They make the GABA receptor more efficient by increasing the frequency with which the chlorine channel opens when GABA binds to its own site on the receptor, rather than directly stimulating the receptor themselves. This impact on GABA is very important in treating anxiety. Anxiety consists of excessive worrying over things that are, in fact, rather minor in degree, and it presents itself with increased activity of the sympathetic nervous system. Therefore, the inhibitive nature of GABA is effective in treating patients excessive over-concern that interferes with their daily lives [5]. |
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Animation of Effects on GABA
The Youtube video below was posted by the user "pharmedutainment". Although it is titled as a mechanism of action with regards to sedation, it is an informative animation on the effects that benzodiazepines have on the GABA-A receptor. The video goes on to show the effects of barbituates as well, which is covered in a different section of our website! [23]
The Youtube video below was posted by the user "pharmedutainment". Although it is titled as a mechanism of action with regards to sedation, it is an informative animation on the effects that benzodiazepines have on the GABA-A receptor. The video goes on to show the effects of barbituates as well, which is covered in a different section of our website! [23]
Anatomy
The gastrointestinal (GI) tract is the tube that extends from the mouth to the anus, and its function is controlled by the esophagus, stomach, and small and large intenstines. When benzodiazepines are taken orally, they are rapidly absorbed through the GI tract. Furthermore, most benzodiazepines are highly lipophilic and protein bound, which means they have a tendency to combine with or dissolve in lipids or fats, and they are more likely to bind with proteins within the blood plasma, which causes less effective diffusion. Finally, the metabolism of benzodiazepines is primarily hepatic, which means they are digested within the liver [15]. Now that we have covered a basic background on how benzodiazepines are absorbed and digested, let’s take a look at where they take effect in the brain. Ultimately, pinning down a single region of the brain that is affected by benzodiazepines is impossible due to their role with GABA. As we said before, GABA is the chief inhibitory neurotransmitter of the central nervous system, so its impact on the brain is global. That being said, there are some areas that we should highlight. Anxiety disorders often go hand in hand with increased activity of the amygdala. With that in mind, it should not come as a surprise that the amygdala has a relatively high concentration of GABA-A receptors - the target of benzodiazepines. Paulus et al. (2005) performed a study where patients were given Lorazepam - a benzodiazepine derivative - and they were asked to look at emotional faces. They found that the administration of Lorazepam led to a decrease in activation of not only the amygdala, but also the insula when subjects looked at the emotional faces [4]. |
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Limitations and Side Effects
The side effects of benzodiazepines vary widely depending on the specific benzodiazepine being taken, the dose, and the individual. Possible side effects for low to moderate doses include, but are not limited to [3]:
Possible side effects for high doses include those mentioned above, as well as [3]:
Flumazenil is a nonspecific competitive benzodiazepine antagonist (meaning it reduces benzopiazepine binding all over the brain by acting where benzo's normally act) that is commonly referred to as the antidote of benzodiazepine overdose. This is highly controversial, as overdoses are rarely fatal. Administration of flumazenil in patients who have developed a tolerance to benzodiazepines, whether through chronic use or abuse, are at great risk of withdrawal seizures that may cause more damage than the overdose itself. Furthermore, it does not consistently reverse respiratory depression. Many believe the risks of flumazenil when given to patients with benzodiazepine tolerance outweighs the believed benefits of avoiding the need for later procedures. On the other hand, it appears to be a safe and effective drug for reversing the effects of benzodiazepine overdose in patients that are not chronic users [15].
Some common concerns for physicians and patients when dealing with benzodiazepines are tolerance, dependence, withdrawal and addiction. These four potential issues are all interrelated and part of the main warning given to patients that are prescribed benzodiazepines for long-term use. It typically takes upwards of 6 months for patients to develop tolerance to benzodiazepines. This can be dealt with by talking to your prescriber and having them increase the dosage in small increments, or by supplementing the original prescription with another benzodiazepine. Patients typically develop tolerance to the milder effects of the drug, which include sedation and impairment of motor coordination; however, tolerance to any of the effects could potentially occur. Additionally, some patients may experience cross-tolerance between benzodiazepines and other drugs such as alcohol or barbiturates. This means that a patient that has become tolerant to certain effects that are shared between the two drugs, will also be tolerant to those effects when given the other drug [3].
It is difficult to measure the exact prevalence of benzodiazepine dependence due to the limitations on the definition of dependent; however, we do know that there are millions of individuals worldwide that have been on benzodiazepines for more than 5 years [2]. For this reason, it is fair for us to assume that many of these individuals have developed some form of dependence. Dependence leads into withdrawal, as the patient must have a dependency in order to suffer from withdrawal symptoms. Naturally, withdrawal symptoms are more severe when the individual has become accustomed to a relatively high dose. Symptoms are augmented by stopping use abruptly, so it is common for physicians to recommend that users only reduce their use gradually. Once the patient reaches a point that they are using a relatively low dose, then they can discontinue use without serious discomfort from withdrawals.
Recreational benzodiazepine abuse is another growing problem worldwide due to the addictive nature of the drug. When taken simultaneously with other drugs - especially opiates - Benzodiazepines increase the effect obtained from the illicit drug. This makes them a commonly abused drug and very popular among polydrug users. Furthermore, benzodiazepines are often used to alleviate withdrawal symptoms for addicts that are trying to quit other drugs. Benzodiazepines are very useful in this regard as they lessen the withdrawals experienced from quitting another drug. Unfortunately, the issue that arises from this use of the drug is that the individual who is trying to quit abusing alcohol, may end up becoming addicted to benzodiazepines [2].
The side effects of benzodiazepines vary widely depending on the specific benzodiazepine being taken, the dose, and the individual. Possible side effects for low to moderate doses include, but are not limited to [3]:
- Impaired motor coordination
- Drowsiness, lethargy, fatigue
- Impaired thinking and memory
- Confusion
- Depression
- Altered vision
- Slurred speech, stuttering
- Vertigo
- Tremors
- Respiratory depression
- Nausea, constipation, dry mouth, abdominal discomfort, loss of appetite, vomiting, diarrhea
Possible side effects for high doses include those mentioned above, as well as [3]:
- Slowed reflexes
- Mood swings
- Hostile and erratic behavior
- Euphoria
- Muscle weakness, lack of coordination
Flumazenil is a nonspecific competitive benzodiazepine antagonist (meaning it reduces benzopiazepine binding all over the brain by acting where benzo's normally act) that is commonly referred to as the antidote of benzodiazepine overdose. This is highly controversial, as overdoses are rarely fatal. Administration of flumazenil in patients who have developed a tolerance to benzodiazepines, whether through chronic use or abuse, are at great risk of withdrawal seizures that may cause more damage than the overdose itself. Furthermore, it does not consistently reverse respiratory depression. Many believe the risks of flumazenil when given to patients with benzodiazepine tolerance outweighs the believed benefits of avoiding the need for later procedures. On the other hand, it appears to be a safe and effective drug for reversing the effects of benzodiazepine overdose in patients that are not chronic users [15].
Some common concerns for physicians and patients when dealing with benzodiazepines are tolerance, dependence, withdrawal and addiction. These four potential issues are all interrelated and part of the main warning given to patients that are prescribed benzodiazepines for long-term use. It typically takes upwards of 6 months for patients to develop tolerance to benzodiazepines. This can be dealt with by talking to your prescriber and having them increase the dosage in small increments, or by supplementing the original prescription with another benzodiazepine. Patients typically develop tolerance to the milder effects of the drug, which include sedation and impairment of motor coordination; however, tolerance to any of the effects could potentially occur. Additionally, some patients may experience cross-tolerance between benzodiazepines and other drugs such as alcohol or barbiturates. This means that a patient that has become tolerant to certain effects that are shared between the two drugs, will also be tolerant to those effects when given the other drug [3].
It is difficult to measure the exact prevalence of benzodiazepine dependence due to the limitations on the definition of dependent; however, we do know that there are millions of individuals worldwide that have been on benzodiazepines for more than 5 years [2]. For this reason, it is fair for us to assume that many of these individuals have developed some form of dependence. Dependence leads into withdrawal, as the patient must have a dependency in order to suffer from withdrawal symptoms. Naturally, withdrawal symptoms are more severe when the individual has become accustomed to a relatively high dose. Symptoms are augmented by stopping use abruptly, so it is common for physicians to recommend that users only reduce their use gradually. Once the patient reaches a point that they are using a relatively low dose, then they can discontinue use without serious discomfort from withdrawals.
Recreational benzodiazepine abuse is another growing problem worldwide due to the addictive nature of the drug. When taken simultaneously with other drugs - especially opiates - Benzodiazepines increase the effect obtained from the illicit drug. This makes them a commonly abused drug and very popular among polydrug users. Furthermore, benzodiazepines are often used to alleviate withdrawal symptoms for addicts that are trying to quit other drugs. Benzodiazepines are very useful in this regard as they lessen the withdrawals experienced from quitting another drug. Unfortunately, the issue that arises from this use of the drug is that the individual who is trying to quit abusing alcohol, may end up becoming addicted to benzodiazepines [2].
References
[1] Allain, P. "Benzodiazepines." Benzodiazepines - Pharmacorama. Pharmacorama Charter, 19 Aug. 2016. Web. 10 Nov. 2016.
[2] Ashton, Heather. "Benzodiazepines: How They Work & How to Withdraw." Benzo. Institute of Neuroscience, Aug. 2002. Web. 10 Nov. 2016.
[3] "Benzodiazepines" CESAR. University of Maryland, 29 Oct. 2013. Web. 10 Nov. 2016.
[4] Carlson, Neil R. Foundations of Behavioral Neuroscience. Boston: Pearson, 2014. Print.
[5] Dubuc, Bruno. "The Brain From Top To Bottom." The Brain From Top To Bottom. McGill University, n.d. Web. 10 Nov. 2016.
[6] Greenblatt, David J., and Richard I. Shader. "Benzodiazepines — NEJM." New England Journal of Medicine. New England Journal of Medicine, 7 Nov. 1974. Web. 10 Nov. 2016.
[7] Greenblatt, Dj, Ri Shader, M. Divoll, and Js Harmatz. "Benzodiazepines: A Summary of Pharmacokinetic Properties." British Journal of Clinical Pharmacology 11.S1 (1981): 11-16. National Institute of Health. Web. 10 Nov. 2016.
[8] Guzman, Flavio. "Benzodiazepines Mechanism of Action." CME at Pharmacology Corner. Pharmacology Corner, May 2016. Web. 10 Nov. 2016.
[9] Johnson, Linda A. "Roche Closing NJ Site in 2013, Cutting Jobs." US News. US News & World Report L.P., 26 June 2012. Web. 10 Nov. 2016.
[10] Juergens, Steven M. "Understanding Benzodiazepines." Benzodiazepine Use CSAM-ASAM. University of Washington. Web. 10 Nov. 2016.
[11] Maugh, Thomas H., II. "Leo Sternbach, 97; Invented Valium, Many Other Drugs." Los Angeles Times. Los Angeles Times, 01 Oct. 2005. Web. 10 Nov. 2016.
[12] Nogrady, Thomas, and Donald F. Weaver. Medicinal Chemistry: A Molecular and Biochemical Approach. New York, NY: Oxford UP, 2005. Print.
[13] Paulus, MP, SF Tapert, and MA Schuckit. "Neural Activation Patterns of Methamphetamine-dependent Subjects during Decision Making Predict Relapse." Archives of General Psychiatry. U.S. National Library of Medicine, July 2005. Web. 10 Nov. 2016.
[14] Winslow, Terese. "Gastrointestinal Tract - National Library of Medicine - PubMed Health." National Center for Biotechnology Information. U.S. National Library of Medicine, 2005. Web. 10 Nov. 2016.
Image References:
[16] Ashton, Heather. "Benzodiazepines: How They Work & How to Withdraw." Benzo. Institute of Neuroscience, Aug. 2002. Web. 10 Nov. 2016.
[17] "Brain Imaging Produces New Insights into Autism-Anxiety Connection." Autism Speaks. N.p., 15 May 2015. Web. 20 Nov. 2016.
[18] Carlson, Neil R. Foundations of Behavioral Neuroscience. Boston: Pearson, 2014. Print.
[19] "Flumazenil." Wikipedia. Wikimedia Foundation, n.d. Web. 20 Nov. 2016.
[20] Greenblatt, David J., and Richard I. Shader. "Benzodiazepines — NEJM." New England Journal of Medicine. New England Journal of Medicine, 7 Nov. 1974. Web. 10 Nov. 2016.
[21] "Image Bank." Image Bank | Progress In Mind. CNS Forum, n.d. Web. 20 Nov. 2016.
[22] "Leo Sternbach." Baceleb. N.p., 15 Apr. 2015. Web. 20 Nov. 2016.
[23] Pharmedutainment. "Sedative Drugs Mechanism of Action (Benzodiazepines and Barbiturates)." YouTube. YouTube, 29 Mar. 2016. Web. 20 Nov. 2016.
[1] Allain, P. "Benzodiazepines." Benzodiazepines - Pharmacorama. Pharmacorama Charter, 19 Aug. 2016. Web. 10 Nov. 2016.
[2] Ashton, Heather. "Benzodiazepines: How They Work & How to Withdraw." Benzo. Institute of Neuroscience, Aug. 2002. Web. 10 Nov. 2016.
[3] "Benzodiazepines" CESAR. University of Maryland, 29 Oct. 2013. Web. 10 Nov. 2016.
[4] Carlson, Neil R. Foundations of Behavioral Neuroscience. Boston: Pearson, 2014. Print.
[5] Dubuc, Bruno. "The Brain From Top To Bottom." The Brain From Top To Bottom. McGill University, n.d. Web. 10 Nov. 2016.
[6] Greenblatt, David J., and Richard I. Shader. "Benzodiazepines — NEJM." New England Journal of Medicine. New England Journal of Medicine, 7 Nov. 1974. Web. 10 Nov. 2016.
[7] Greenblatt, Dj, Ri Shader, M. Divoll, and Js Harmatz. "Benzodiazepines: A Summary of Pharmacokinetic Properties." British Journal of Clinical Pharmacology 11.S1 (1981): 11-16. National Institute of Health. Web. 10 Nov. 2016.
[8] Guzman, Flavio. "Benzodiazepines Mechanism of Action." CME at Pharmacology Corner. Pharmacology Corner, May 2016. Web. 10 Nov. 2016.
[9] Johnson, Linda A. "Roche Closing NJ Site in 2013, Cutting Jobs." US News. US News & World Report L.P., 26 June 2012. Web. 10 Nov. 2016.
[10] Juergens, Steven M. "Understanding Benzodiazepines." Benzodiazepine Use CSAM-ASAM. University of Washington. Web. 10 Nov. 2016.
[11] Maugh, Thomas H., II. "Leo Sternbach, 97; Invented Valium, Many Other Drugs." Los Angeles Times. Los Angeles Times, 01 Oct. 2005. Web. 10 Nov. 2016.
[12] Nogrady, Thomas, and Donald F. Weaver. Medicinal Chemistry: A Molecular and Biochemical Approach. New York, NY: Oxford UP, 2005. Print.
[13] Paulus, MP, SF Tapert, and MA Schuckit. "Neural Activation Patterns of Methamphetamine-dependent Subjects during Decision Making Predict Relapse." Archives of General Psychiatry. U.S. National Library of Medicine, July 2005. Web. 10 Nov. 2016.
[14] Winslow, Terese. "Gastrointestinal Tract - National Library of Medicine - PubMed Health." National Center for Biotechnology Information. U.S. National Library of Medicine, 2005. Web. 10 Nov. 2016.
Image References:
[16] Ashton, Heather. "Benzodiazepines: How They Work & How to Withdraw." Benzo. Institute of Neuroscience, Aug. 2002. Web. 10 Nov. 2016.
[17] "Brain Imaging Produces New Insights into Autism-Anxiety Connection." Autism Speaks. N.p., 15 May 2015. Web. 20 Nov. 2016.
[18] Carlson, Neil R. Foundations of Behavioral Neuroscience. Boston: Pearson, 2014. Print.
[19] "Flumazenil." Wikipedia. Wikimedia Foundation, n.d. Web. 20 Nov. 2016.
[20] Greenblatt, David J., and Richard I. Shader. "Benzodiazepines — NEJM." New England Journal of Medicine. New England Journal of Medicine, 7 Nov. 1974. Web. 10 Nov. 2016.
[21] "Image Bank." Image Bank | Progress In Mind. CNS Forum, n.d. Web. 20 Nov. 2016.
[22] "Leo Sternbach." Baceleb. N.p., 15 Apr. 2015. Web. 20 Nov. 2016.
[23] Pharmedutainment. "Sedative Drugs Mechanism of Action (Benzodiazepines and Barbiturates)." YouTube. YouTube, 29 Mar. 2016. Web. 20 Nov. 2016.