Azapirones
Introduction and History
The need was critical for a drug that was effective in treating Generalized Anxiety Disorder (GAD) without any negative side effects and without the potential for abuse and addiction that often comes along with popularly used medications such as benzodiazepines and barbiturates. This need was made even more pertinent by the rising number of people that abuse and/or have become addicted to these medications and other prescription drugs.
In 1972, a team at Mead Johnson was the first to discover buspirone, a type of azapirone, and got a patent for it in 1975. However, it wasn’t until 1986 that Bristol-Myers Squibb, a split-off organization of Mead Johnson, received approval from the FDA for buspirone as a treatment medication for GAD. In 2001, the patent from the FDA expired, but buspirone can now be found as a generic drug. Buspirone has minimal side effects, and no potential for abuse and addiction, while still remaining effective in treating GAD. Other azapriones are currently being developed and tested for their effectiveness in treating GAD, but buspirone is the only current medication used to treat GAD.
The need was critical for a drug that was effective in treating Generalized Anxiety Disorder (GAD) without any negative side effects and without the potential for abuse and addiction that often comes along with popularly used medications such as benzodiazepines and barbiturates. This need was made even more pertinent by the rising number of people that abuse and/or have become addicted to these medications and other prescription drugs.
In 1972, a team at Mead Johnson was the first to discover buspirone, a type of azapirone, and got a patent for it in 1975. However, it wasn’t until 1986 that Bristol-Myers Squibb, a split-off organization of Mead Johnson, received approval from the FDA for buspirone as a treatment medication for GAD. In 2001, the patent from the FDA expired, but buspirone can now be found as a generic drug. Buspirone has minimal side effects, and no potential for abuse and addiction, while still remaining effective in treating GAD. Other azapriones are currently being developed and tested for their effectiveness in treating GAD, but buspirone is the only current medication used to treat GAD.
![Picture](/uploads/9/2/6/8/92684994/screen-shot-2016-12-04-at-11-30-32-pm.png?334)
Comparison with Benzodiazepines
Because of the numerous and dangerous side effects of benzodiazepines, such as the addictive nature of the drug, potential for abuse, and the ability to develop a tolerance and dependency, as well as the ability of benzodiazepines to interfere with motor and cognitive functioning, buspirone is often compared to it as an alternative medication because buspirone lacks these dangerous side effects.
When compared to diazepam, a benzodiazepine, and a placebo, busprione showed similar levels of effectivness when treating GAD as showed in Figure 1 to the right. (see reference 8 of [3]). Also, through double-blind, placebo-controlled clinical trials, buspirone was shown to be effective in treating GAD, along with benzodiazepines [9][11]. However, buspirone showed significantly less side effects when compared to benzodiazepines. It remarkably showed side effects similar to that of the placebo. Buspirone did not impair sleep patterns, wakefulness during daytime, or memory. It did not produce any muscle relaxation or sedation. It also didn’t impair psychomotor performance, the coordination of sensory and cognitive processes with motor activity. Eison et al. (1986) showed that in rats, the amount of buspirone that was needed to produce a 50% decrease in spontaneous motor activity is thirteen times greater than that of diazepam. Which speaks to buspirone's lack of a sedative nature. It also didn’t produce any muscular weakness in rats and mice, which shows that buspirone lacks muscle relaxant properties.
Newton et. al (1986) showed that the most reported side effects of buspirone out of 17 clinical trials were dizziness (12%), drowsiness (10%), nausea (8%), headache (6%), nervousness (5%), fatigue (4%), insomnia (3%), lightheadedness (3%), dry mouth (3%) and excitement (2%). There is no difference in the side effects between young and old patients who take buspirone [8], it lacks the potential for abuse [5][8][3], has little to no effect with alcohol, has little to no sedative effects and is safe in high doses [6]. There is no documented deaths caused by an overdose of buspirone alone [8]. Buspirone also shows no useful properties for helping with panic attacks, obsessions, compulsions, PTSD, drug abuse or benzodiazepine withdrawal [6].
Robinson and Rickels (2013) showed that after 40 months in a long term follow up that compared buspirone and clorazepate, another benzodiazepine, none of the patients who were treated with buspirone needed anxiolytic medication while 50% of patients treated with clorazepate still needed to take it or another benzodiazepine. This finding could be explained by Panesar et. al., which showed that in rats, long term usage of buspirone actually reduced the amount of serotonin binding sites in the frontal cortex. If buspirone limits the amount of serotonin recept0rs over time, it may cause a decreased amount of anxiety and thus eliminates the need to continue medication for an extended period of time.
This also lends to the ability of buspirone to treat GAD while also leaving no chance for pill dependency. Along those same lines, patients who suddenly stopped the use of buspirone did not show anxiety caused by a withdrawal from the drug, which is a common predictor of dependence, unlike benzodiazepines, because buspirone doesn’t contain any addictive properties.
However, buspirone isn’t the perfect drug. When compared to benzodiazepines, it may take several weeks for buspirone to show its effect on anxiety, which can perturb doctors or patients from wanting to use buspirone. Also, people who have taken benzodiazepines in the past may not respond as well to buspirone compared to people who have not. However, Robinson and Rickels (2013) showed that patients who haven’t taken benzodiazepines for more than six months show a response to the effects of buspirone similar to people who have never taken benzodiazepines at all.
Because of the numerous and dangerous side effects of benzodiazepines, such as the addictive nature of the drug, potential for abuse, and the ability to develop a tolerance and dependency, as well as the ability of benzodiazepines to interfere with motor and cognitive functioning, buspirone is often compared to it as an alternative medication because buspirone lacks these dangerous side effects.
When compared to diazepam, a benzodiazepine, and a placebo, busprione showed similar levels of effectivness when treating GAD as showed in Figure 1 to the right. (see reference 8 of [3]). Also, through double-blind, placebo-controlled clinical trials, buspirone was shown to be effective in treating GAD, along with benzodiazepines [9][11]. However, buspirone showed significantly less side effects when compared to benzodiazepines. It remarkably showed side effects similar to that of the placebo. Buspirone did not impair sleep patterns, wakefulness during daytime, or memory. It did not produce any muscle relaxation or sedation. It also didn’t impair psychomotor performance, the coordination of sensory and cognitive processes with motor activity. Eison et al. (1986) showed that in rats, the amount of buspirone that was needed to produce a 50% decrease in spontaneous motor activity is thirteen times greater than that of diazepam. Which speaks to buspirone's lack of a sedative nature. It also didn’t produce any muscular weakness in rats and mice, which shows that buspirone lacks muscle relaxant properties.
Newton et. al (1986) showed that the most reported side effects of buspirone out of 17 clinical trials were dizziness (12%), drowsiness (10%), nausea (8%), headache (6%), nervousness (5%), fatigue (4%), insomnia (3%), lightheadedness (3%), dry mouth (3%) and excitement (2%). There is no difference in the side effects between young and old patients who take buspirone [8], it lacks the potential for abuse [5][8][3], has little to no effect with alcohol, has little to no sedative effects and is safe in high doses [6]. There is no documented deaths caused by an overdose of buspirone alone [8]. Buspirone also shows no useful properties for helping with panic attacks, obsessions, compulsions, PTSD, drug abuse or benzodiazepine withdrawal [6].
Robinson and Rickels (2013) showed that after 40 months in a long term follow up that compared buspirone and clorazepate, another benzodiazepine, none of the patients who were treated with buspirone needed anxiolytic medication while 50% of patients treated with clorazepate still needed to take it or another benzodiazepine. This finding could be explained by Panesar et. al., which showed that in rats, long term usage of buspirone actually reduced the amount of serotonin binding sites in the frontal cortex. If buspirone limits the amount of serotonin recept0rs over time, it may cause a decreased amount of anxiety and thus eliminates the need to continue medication for an extended period of time.
This also lends to the ability of buspirone to treat GAD while also leaving no chance for pill dependency. Along those same lines, patients who suddenly stopped the use of buspirone did not show anxiety caused by a withdrawal from the drug, which is a common predictor of dependence, unlike benzodiazepines, because buspirone doesn’t contain any addictive properties.
However, buspirone isn’t the perfect drug. When compared to benzodiazepines, it may take several weeks for buspirone to show its effect on anxiety, which can perturb doctors or patients from wanting to use buspirone. Also, people who have taken benzodiazepines in the past may not respond as well to buspirone compared to people who have not. However, Robinson and Rickels (2013) showed that patients who haven’t taken benzodiazepines for more than six months show a response to the effects of buspirone similar to people who have never taken benzodiazepines at all.
![Picture](/uploads/9/2/6/8/92684994/buspirone-synthesis-svg.png?533)
Chemistry [2] (Disclaimer: Chemistry jargon included)
The complete chemical name for buspirone is 8-[4-[4-(2-pyrimidinyl)-l-piperazinyl]butyl]-8-azaspiro[4.5]-decane-7,9-dione hydrochloride. It is a dibasic heterocyclic piperazinyl pyrimidine derivative. This just means that the chemical structure of buspirone has two replaceable hydrogen atoms, has two different elements within the ring system, has a radical or cation based off of piperazine, and is a pyrimidine derivative. Buspirone is water soluble and is also lipophilic, which means that it combines with or dissolves in fats or lipids, which are abundant within the body. Its physical appearance comes in the form of white crystals and has a unique molecular structure which is different than any other anti-anxiety medications.
The complete chemical name for buspirone is 8-[4-[4-(2-pyrimidinyl)-l-piperazinyl]butyl]-8-azaspiro[4.5]-decane-7,9-dione hydrochloride. It is a dibasic heterocyclic piperazinyl pyrimidine derivative. This just means that the chemical structure of buspirone has two replaceable hydrogen atoms, has two different elements within the ring system, has a radical or cation based off of piperazine, and is a pyrimidine derivative. Buspirone is water soluble and is also lipophilic, which means that it combines with or dissolves in fats or lipids, which are abundant within the body. Its physical appearance comes in the form of white crystals and has a unique molecular structure which is different than any other anti-anxiety medications.
![Picture](/uploads/9/2/6/8/92684994/screen-shot-2016-12-04-at-11-22-44-pm.png?359)
Psychopharmacology
When compared to other GAD medications, the specific mechanisms in which azapirones, and especially buspirone, act within the body are still relatively unknown due to the complexity and uniqueness in which buspirone acts within the central nervous system.
When compared to other GAD medications, the specific mechanisms in which azapirones, and especially buspirone, act within the body are still relatively unknown due to the complexity and uniqueness in which buspirone acts within the central nervous system.
![Picture](/uploads/9/2/6/8/92684994/screen-shot-2016-12-05-at-6-29-19-pm.png?415)
Since buspirone is the only current azapirone used to clinically treat GAD, more is known about its mechanisms of action within the brain than other azapirones. However, Taylor and Moon (1991) reviewed 4 types of azapirones (buspirone, gepirone, ipsapirone, and tandospirone) and how they interact with the brain. From in vitro and anatomical studies, azapirones act as a partial agonist to the serotonin 5-HT1A receptors of the brain while having a high affinity to these receptors. This means that the azapirone molecules are highly attracted to the serotonin 5-HT1A receptors. When they bind there, the activation of the serotonin 5-HT1A receptors causes the neuron to not fire and reduces the amount of serotonin in the brain. Animal models also showed that the interaction that azapirones have upon serotonin is connected to the ability of azapirones to treat anxiety. When serotonergic pathways in the animal’s brains were lesioned, azapirones no longer showed any influence on reducing anxiety.
![Picture](/uploads/9/2/6/8/92684994/screen-shot-2016-12-05-at-6-29-32-pm.png?396)
Panesar et. al. gave a better understanding of how buspirone interacts with the serotonin 5-HT1A receptor. They came to the conclusion that buspirone is a full agonist in presynaptic 5-HT1A receptors, which again inhibits the production of 5-HT neurons and stops the firing of the neuron. They also showed that buspirone was a partial agonist in postsynaptic 5-HT1A receptors in the hippocampus and cortex. As a partial agonist, this means that buspirone binds to these receptors and allows the nueron to fire, but only with partial effectiveness.
![Picture](/uploads/9/2/6/8/92684994/screen-shot-2016-12-05-at-6-29-45-pm.png?483)
Also, buspirone was shown to be a full agonist for presynaptic 5-HT1A receptors, which inhibits the firing of the 5-HT neurons of the brain in the raphe nuclei, specifically the dorsal raphe nucleus [4][8]. This makes sense because raphe nuclei are critical for the release of serotonin to the rest of the brain.
Taylor and Moon (1991) showed that azapirones were shown to be most active within the limbic system 0f the brain, specifically the amygdala, lateral septum, entorhinal cortex, and hippocampal formation, all of which are high in serotonin 5-HT1A receptors. Within the hippocampus, activity of buspirone, gepirone, and ipsapirone in the pyramidal cells showed these azapirones acting as partial agonist at some of the serotonin receptors.
Taylor and Moon (1991) showed that azapirones were shown to be most active within the limbic system 0f the brain, specifically the amygdala, lateral septum, entorhinal cortex, and hippocampal formation, all of which are high in serotonin 5-HT1A receptors. Within the hippocampus, activity of buspirone, gepirone, and ipsapirone in the pyramidal cells showed these azapirones acting as partial agonist at some of the serotonin receptors.
![Picture](/uploads/9/2/6/8/92684994/screen-shot-2016-12-05-at-6-28-47-pm.png?447)
The exact mechanism of action for buspirone upon the serotonin 5-HT1A receptors is still unknown, but Loan and Politis (2012) gives a possible solution to this problem. When bound by an agonist, the serotonin 5-HT1A receptors produce an inhibitory effect on neurotransmission. The serotonin 5-HT1A receptors are coupled to inhibitory G-proteins, which acts as a secondary messenger. So when buspirone binds, the G-proteins are released. The G-proteins in turn bind to adenylate cyclase, which is an enzyme within the body has important regulatory functions within all cells, and inhibits its functioning. This then prevents the conversion of ATP to cAMP within the cell, which blocks the transduction of neuronal signals from one neuron to another and in turn initiates the signaling mechanisms of another secondary mechanism. This inhibits cell depolarization (rapid loss of the difference of the charge between the inside and the outside of the cell), which doesn’t allow the cell to fire. This process ultimately reducing the amount of serotonin in the central nervous system, and ultimately helping relieve a person’s anxiety.
However, buspirone also interacts with chemical receptors, other than the serotonin 5-HT1A receptors, within the brain. Due to the complexity of this issue, it is still not completely certain what this exact interaction is. Ortiz et. al (1987) shed some light on this and found that in a living organism (in vivo), buspirone does not bind to benzodiazepine receptors and outside of a living organism (in vitro), like in a test tube or petri dish, buspirone also doesn’t bind to benzodiazepine receptors as well as GABA, adrenergic, muscarinic, serotonergic type 2, opiate, adenosine, glutamate, glycine and histamine receptors.
There is some evidence that buspirone interacts with the systems that produce dopamine and GABA and in a different way in which benzodiazepines do. It is also thought that buspirone has some effect on the systems that produce norepinephrine. It appears that buspirone has a low affinity as an antagonist for dopamine D2 autoreceptors [4] while also specifically blocking presynaptic dopamine receptors [3]. Through electrophysiologic studies, Eison and Temple Jr. (1986) showed that buspirone increased the rate of firing for dopamine neurones in the midbrain, which increases the amount of dopamine in the brain. It also increases the amount of dopamine metabolites, which are necessary for metabolism, and the synthetic enzyme tyrosine hydroxylase, which is important for the production of dopamine. However, there was no effect of buspirone on tyrosine hydroxylase in the frontal cortex.
With GABA, not as much is known on how buspirone affects this system, but in the substantia nigra structure of the brain, buspirone blocks the inhibitory effects of GABA upon dopamine neurons, which leads to an increase of firing for these dopamine neurons [3]. This shows that buspirone does have some sort of GABA antagonist-like component.
However, buspirone also interacts with chemical receptors, other than the serotonin 5-HT1A receptors, within the brain. Due to the complexity of this issue, it is still not completely certain what this exact interaction is. Ortiz et. al (1987) shed some light on this and found that in a living organism (in vivo), buspirone does not bind to benzodiazepine receptors and outside of a living organism (in vitro), like in a test tube or petri dish, buspirone also doesn’t bind to benzodiazepine receptors as well as GABA, adrenergic, muscarinic, serotonergic type 2, opiate, adenosine, glutamate, glycine and histamine receptors.
There is some evidence that buspirone interacts with the systems that produce dopamine and GABA and in a different way in which benzodiazepines do. It is also thought that buspirone has some effect on the systems that produce norepinephrine. It appears that buspirone has a low affinity as an antagonist for dopamine D2 autoreceptors [4] while also specifically blocking presynaptic dopamine receptors [3]. Through electrophysiologic studies, Eison and Temple Jr. (1986) showed that buspirone increased the rate of firing for dopamine neurones in the midbrain, which increases the amount of dopamine in the brain. It also increases the amount of dopamine metabolites, which are necessary for metabolism, and the synthetic enzyme tyrosine hydroxylase, which is important for the production of dopamine. However, there was no effect of buspirone on tyrosine hydroxylase in the frontal cortex.
With GABA, not as much is known on how buspirone affects this system, but in the substantia nigra structure of the brain, buspirone blocks the inhibitory effects of GABA upon dopamine neurons, which leads to an increase of firing for these dopamine neurons [3]. This shows that buspirone does have some sort of GABA antagonist-like component.
Dosages
Dosages of buspirone range from 5mg to 30mg, based off the discretion of the prescribing physician and there is no difference between young or old patients in terms of dosages [2]. It is important to note that if ingested, buspirone is rapidly and practically completely absorbed through the intestinal tract [4][6]. It also easily crosses the blood-brain barrier in order to enter the brain, which is ideal for a drug that treats GAD [6]. It’s also important to note that it has a quick first pass metabolism [4][6][8]. This means that a large concentration of the drug is lost during the process of absorption. This may play role for why buspirone is slow acting.
Dosages of buspirone range from 5mg to 30mg, based off the discretion of the prescribing physician and there is no difference between young or old patients in terms of dosages [2]. It is important to note that if ingested, buspirone is rapidly and practically completely absorbed through the intestinal tract [4][6]. It also easily crosses the blood-brain barrier in order to enter the brain, which is ideal for a drug that treats GAD [6]. It’s also important to note that it has a quick first pass metabolism [4][6][8]. This means that a large concentration of the drug is lost during the process of absorption. This may play role for why buspirone is slow acting.
Conclusion
With continued treatment of buspirone, symptoms of GAD will begin to subside. It also is extremely valuable because it lacks any potential for abuse or addiction. Buspirone is a safe alternative and fulfills the niche of helping people with GAD who have had a history of drug abuse. Also, the way in which buspirone interacts with various chemicals and neurotransmitters, especially serotonin and dopamine, within the brain helps to give some understanding on what causes GAD from a chemical sense and how to treat it.
With continued treatment of buspirone, symptoms of GAD will begin to subside. It also is extremely valuable because it lacks any potential for abuse or addiction. Buspirone is a safe alternative and fulfills the niche of helping people with GAD who have had a history of drug abuse. Also, the way in which buspirone interacts with various chemicals and neurotransmitters, especially serotonin and dopamine, within the brain helps to give some understanding on what causes GAD from a chemical sense and how to treat it.
References
[1] Allen L.E., Ferguson H.C., Kissel J.W. "Psychosedative agents. 2. 8-(4-Substituted 1-piperazinylalkyl)-8-azaspiro(4.5)decane-7,9-diones". Journal of Medicinal Chemistry. 15.5 (1972): 477–9.
[2] "Buspirone (Rx)." BuSpar (buspirone) Dosing, Indications, Interactions, Adverse Effects, and More. Medscape, n.d. Web. 04 Dec. 2016.
[3] Eison, Arlene S., M.A., and Davis L. Temple, Jr., Ph.D. "Buspirone: Review of Its Pharmacology and Current Perspectives on Its Mechanism of Action." The American Journal of Medicine 80.3 (1986): 1-9. Web.
]4] Loane, C., and M. Politis. "Buspirone: What Is It All About?" Brain Research 1461 (2012): 111-18. Elsevier Ltd. Web.
[5] Newton R.E., J.D. Maruncyz, M.T. Alderdice, et. al. “Review of the side effect profile of buspirone. Am J Med 80 (1986): 17-21. Print.
[6] Ortiz, Aurelio, Robert Pohl, and Samuel Gershon. "Azaspirodecanediones in Generalized Anxiety Disorder: Buspirone." Journal of Affective Disorders 13.2 (1987): 131-43. Elsevier Ltd. Web.
[7] Panesar, Kiran, Flavio Guzman M.D., et. al."5-HT1A Receptors in Psychopharmacology." Clinical Psychopharmacology Education. Psychopharmacology Institute, n.d. Web. 04 Dec. 2016.
[8] Robinson, David S., M.D., and Karl Rickels, M.D. "Chapter 14. Buspirone." Essentials of Clinical Psychopharmacology (2013): 207-16. Web.
[9] Taylor, D.P. "Buspirone, a new approach to the treatment of anxiety." FASEB Journal 2 (1988): 2445-452. Print.
[10] Taylor, D.P., and S.L. Moon. "Buspirone and Related Compounds as Alternative Anxiolytics." Neuropeptides 19 (1991): 15-19. Churchill Livingston. Web.
[11] Taylor, D.P. “Serotonin agents in anxiety.” Annals of the New York Academy of Sciences (1990), in press.
[1] Allen L.E., Ferguson H.C., Kissel J.W. "Psychosedative agents. 2. 8-(4-Substituted 1-piperazinylalkyl)-8-azaspiro(4.5)decane-7,9-diones". Journal of Medicinal Chemistry. 15.5 (1972): 477–9.
[2] "Buspirone (Rx)." BuSpar (buspirone) Dosing, Indications, Interactions, Adverse Effects, and More. Medscape, n.d. Web. 04 Dec. 2016.
[3] Eison, Arlene S., M.A., and Davis L. Temple, Jr., Ph.D. "Buspirone: Review of Its Pharmacology and Current Perspectives on Its Mechanism of Action." The American Journal of Medicine 80.3 (1986): 1-9. Web.
]4] Loane, C., and M. Politis. "Buspirone: What Is It All About?" Brain Research 1461 (2012): 111-18. Elsevier Ltd. Web.
[5] Newton R.E., J.D. Maruncyz, M.T. Alderdice, et. al. “Review of the side effect profile of buspirone. Am J Med 80 (1986): 17-21. Print.
[6] Ortiz, Aurelio, Robert Pohl, and Samuel Gershon. "Azaspirodecanediones in Generalized Anxiety Disorder: Buspirone." Journal of Affective Disorders 13.2 (1987): 131-43. Elsevier Ltd. Web.
[7] Panesar, Kiran, Flavio Guzman M.D., et. al."5-HT1A Receptors in Psychopharmacology." Clinical Psychopharmacology Education. Psychopharmacology Institute, n.d. Web. 04 Dec. 2016.
[8] Robinson, David S., M.D., and Karl Rickels, M.D. "Chapter 14. Buspirone." Essentials of Clinical Psychopharmacology (2013): 207-16. Web.
[9] Taylor, D.P. "Buspirone, a new approach to the treatment of anxiety." FASEB Journal 2 (1988): 2445-452. Print.
[10] Taylor, D.P., and S.L. Moon. "Buspirone and Related Compounds as Alternative Anxiolytics." Neuropeptides 19 (1991): 15-19. Churchill Livingston. Web.
[11] Taylor, D.P. “Serotonin agents in anxiety.” Annals of the New York Academy of Sciences (1990), in press.