Post by Deleted on Apr 19, 2011 0:00:00 GMT -5
Paradoxical reactions –benzodiazepines
If you take such a drug you expect that it will calm and relax you.
Some of us experience what is called paradoxical reactions towards benzodiazepines.
Carol Paton mentions the following symptoms in her article:
“In the majority of recipients, benzodiazepines have a calming effect but in a minority they can cause paradoxical reactions (also called disinhibitory reactions) characterised by acute excitement and an altered mental state: increased anxiety, vivid dreams, hyperactivity, sexual disinhibition, hostility and rage…”
“Paradoxical reactions have been described for many drugs that interact with the GABA receptors. Diverse classes of sedatives and general anesthetic agents including
barbiturates, volatile anesthetics, and etomidate are believed to mediate their effect, to some extent, through GABA-A receptors. (Robin)
What I have observed in our quinolone scene is that in some cases not only drugs caused such reactions, but herbs or other plants, which are able to calm down the nervous system, too. I remember one person had problems after he took cava cava and another person after she had an herbal sleeping tea. Therefore if you make such an unexpected experience, please stop taking it and maybe speak with your doctor about it.
I found no explanations in the literature directly connected with the expression “paradoxical reactions”, but I found some interesting informations, which may help to explain it:
- If a transporter named KCC2 is lowered, symptoms like anxiety and excitotoxicty can happen. I think this can play a role in some of us. Please read the article about the KCC2 in the section with “small parts from articles”.
- Since the discovery of benzodiazepines it is known that some substances, which connect at the GABA receptor, are able to cause extreme anxiety. These substances are called invert agonists and for example beta- carbolines belong to that class.
- If you had in the past often problems with drugs, then you may have genetic changes in the CYP450 detoxification system. These are enzymes, which you need to metabolize foods, drugs, chemicals and some substances produced by the body.
You can find a CYP450 Drug Interaction Table at medicine.iupui.edu/clinpharm/ddis/table.asp
- The GABA receptor and the TRPV1 receptor are activated through the same substances like phenols, which can be found in many plants.
My theory is that the threshold for activation of the TRPV1 is so much lowered that this receptor, which is responsible for pain and inflammation, is easier activated than the “calming” GABA receptor. This leads to an activation of the NMDA receptor and to an upregulation /excitotoxicty of the nervous system and likely to a decrease in the KCC2 activity.
This list will help you to find out, which foods you may not be able to tolerate.
en.wikipedia.org/wiki/List_of_phytochemicals_in_food
- In a study by Benson et al the pharmacology of recombinant GABA receptors in rats was tested and they have altered the genes to make some GABA receptors insensitive to diazepam.
The receptor responded normally to GABA but was unaffected by diazepam. (Robin)
This may be interesting for persons, who only have problems with diazepam.
---------------------------------------------------------------------------------------------------------
Short parts from articles
The KCC2 transporter
A transporter, which shall mainly extrude Cl from the cell, may be decreased and that can lead to anxiety. It is said that stress is able to lower it. I controlled, if oxidative stress is able to decrease it, too and I found an article, where this was mentioned. Through this we get the connection towards the quinolones, because they are able to produce oxidative stress (see Goswami 2006).
Please read the following article below about the KCC2 transporter.
www.medicine.ucalgary.ca/about/bains/stressprotein
New and unexpected mechanism identifies how the brain responds to stress
Posted: March 2, 2009
Switching off a protein causes the brakes to fail in our natural ability to respond to stress.
Chronic stress takes a physical and emotional toll on our bodies and scientists are working on piecing together a medical puzzle to understand how we respond to stress at the cellular level in the brain. Being able to quickly and successfully respond to stress is essential for survival.
Using a rat model, Jaideep Bains, PhD, a University of Calgary scientist and his team of researchers at the Hotchkiss Brain Institute have discovered that neurons in the hypothalamus, the brain’s command centre for stress responses, interpret ‘off’ chemical signals as ‘on’ chemical signals when stress is perceived. “It’s as if the brakes in your car are now acting to speed up the vehicle, rather than slow it down.” says Bains.
This unexpected finding is being published in the March 1st online edition of Nature Neuroscience.
Normally, neurons receive different chemical signals that tell them to either switch on or switch off. The off signal or brake only works if the levels of chloride ion in the cells are maintained at a low level.
This is accomplished by a protein, known as KCC2. What Bains and colleagues have shown is that stress turns down the activity of KCC2, thus removing the ability of the brake, a chemical known as GABA, to work properly. A loss of the brain’s ability to slow down may explain some of the harmful, emotional consequences of stress.
… “I was fascinated when I learned of this work. It has not been clear till now how the neuroendocrine stress response was activated by external stressors. Bains’ work shows a complex, yet elegant solution, involving a switch from inhibition to excitation.” says Jane Stewart, PhD a behavioural neuroscientist from Concordia University, “these findings may lead to a better understanding of the changes in sensitivity to stress that result from chronic exposure.”
www.millipore.com/catalogue/item/....cid=biocompar e
Studies in mice have shown that KCC2 reduces GABA's inhibitory signaling, resulting in motor defects, epilepsy, and anxiety-like behavior.
ethesis.helsinki.fi/julkaisut/bio/bioja/vk/tornberg/abstract.html
…Pharmacological analysis of KCC2-deficient mice revealed reduced sensititivity to diazepam but normal gaboxadol-induced sedation, neurosteroid hypnosis and alcohol-induced motor impairment. … (Tornberg 2006)
www.jneurosci.org/cgi/content/abstract/27/7/1642
Oxidative stress (H2O2) and the induction of seizure activity (BDNF) and hyperexcitability (0 Mg2+) resulted in a rapid dephosphorylation of KCC2 that preceded the decreases in KCC2 protein or mRNA expression. Dephosphorylation of KCC2 is correlated with a reduction of transport activity and a decrease in [Cl–]i, as well as a reduction in KCC2 surface expression. Manipulation of KCC2 tyrosine phosphorylation resulted in altered neuronal viability in response to in vitro oxidative stress. During continued neuronal stress, a second phase of functional KCC2 downregulation occurs that corresponds to decreases in KCC2 protein expression levels. We propose that neuronal stress induces a rapid loss of tyrosine phosphorylation of KCC2 that results in translocation of the protein and functional loss of transport activity. (Wake et al. 2007)
aac.asm.org/cgi/content/short/50/3/949
Involvement of Reactive Oxygen Species in the Action of Fluoroquinolones
The present study demonstrates the role of reactive oxygen species in the antibacterial action of fluoroquinolones. This statement is supported by the observation that known ROS scavengers, such as glutathione and ascorbic acid, gave protection to E. coli MG1655 against ciprofloxacin. (Goswami et al. 2006)
Benzodiazepines:
Benzodiazepines - depressions
www.benzo.org.uk/manual/bzcha03.htm
Severe depression may result from biochemical changes in the brain induced by benzodiazepines. Benzodiazepines are known to decrease the activity of serotonin and norepinephrine (noradrenaline), neurotransmitters believed to be closely involved in depression. (Ashton)
Frequency of occurrence of paradoxical reactions:
Carol Patton writes:…In a placebo-controlled study of alprazolam in the treatment of panic disorder, 13.7% of patients randomised to alprazolam experienced paradoxical reactions compared with none given placebo (O'Sullivan et al, 1994). In a further study of the efficacy of alprazolam in borderline personality disorder, 58% of patients randomised to alprazolam experienced paradoxical reactions compared with 8% with placebo (Gardner & Cowdrey, 1985)...
Christian Robin mentions in his article the following:
“In 1980, Litchfield4 reported a review
of 16,000 cases of intravenous use of diazepam in
dental practices. He concluded that 29% of patients had
minor adverse reactions. These were talkativeness, crying,
loss of inhibitions, excitement, and rage. The incidence
of these reactions was more frequent with higher
dosage and in younger patients (3- to 19-years old).”
Literature:
Carol Paton
Benzodiazepines and disinhibition: a review
The Psychiatrist (2002) 26: 460-462. doi: 10.1192/pb.26.12.460
pb.rcpsych.org/cgi/content/full/26/12/460
Christian Robin, DMD, and Norman Trieger, DMD, MD
Paradoxical Reactions to Benzodiazepines in
Intravenous Sedation: A Report of 2 Cases and
Review of the Literature
Janne Tornberg
Generation and Characterization of the Cation-Chloride Cotransporter KCC2 Hypomorphic Mouse. 2006
ethesis.helsinki.fi/julkaisut/bio/bioja/vk/tornberg/abstract.html
Hiroaki Wake, Miho Watanabe, Andrew J. Moorhouse, Takashi Kanematsu, Shoko Horibe, Noriyuki Matsukawa, Kiyofumi Asai, Kosei Ojika, Masato Hirata, and Junichi Nabekura
Early Changes in KCC2 Phosphorylation in Response to Neuronal Stress Result in Functional Downregulation
The Journal of Neuroscience, February 14, 2007, 27(7):1642-1650; doi:10.1523/JNEUROSCI.3104-06.2007
www.jneurosci.org/cgi/content/abstract/27/7/1642
M. Goswami, S. H. Mangoli, and N. Jawali*
Involvement of Reactive Oxygen Species in the Action of Ciprofloxacin against Escherichia coli
Antimicrobial Agents and Chemotherapy, March 2006, p. 949-954, Vol. 50, No. 3
0066-4804/06
aac.asm.org/cgi/content/short/50/3/949
Professor C Heather Ashton
BENZODIAZEPINES: HOW THEY WORK AND HOW TO WITHDRAW
www.benzo.org.uk/manual/bzcha03.htm
If you take such a drug you expect that it will calm and relax you.
Some of us experience what is called paradoxical reactions towards benzodiazepines.
Carol Paton mentions the following symptoms in her article:
“In the majority of recipients, benzodiazepines have a calming effect but in a minority they can cause paradoxical reactions (also called disinhibitory reactions) characterised by acute excitement and an altered mental state: increased anxiety, vivid dreams, hyperactivity, sexual disinhibition, hostility and rage…”
“Paradoxical reactions have been described for many drugs that interact with the GABA receptors. Diverse classes of sedatives and general anesthetic agents including
barbiturates, volatile anesthetics, and etomidate are believed to mediate their effect, to some extent, through GABA-A receptors. (Robin)
What I have observed in our quinolone scene is that in some cases not only drugs caused such reactions, but herbs or other plants, which are able to calm down the nervous system, too. I remember one person had problems after he took cava cava and another person after she had an herbal sleeping tea. Therefore if you make such an unexpected experience, please stop taking it and maybe speak with your doctor about it.
I found no explanations in the literature directly connected with the expression “paradoxical reactions”, but I found some interesting informations, which may help to explain it:
- If a transporter named KCC2 is lowered, symptoms like anxiety and excitotoxicty can happen. I think this can play a role in some of us. Please read the article about the KCC2 in the section with “small parts from articles”.
- Since the discovery of benzodiazepines it is known that some substances, which connect at the GABA receptor, are able to cause extreme anxiety. These substances are called invert agonists and for example beta- carbolines belong to that class.
- If you had in the past often problems with drugs, then you may have genetic changes in the CYP450 detoxification system. These are enzymes, which you need to metabolize foods, drugs, chemicals and some substances produced by the body.
You can find a CYP450 Drug Interaction Table at medicine.iupui.edu/clinpharm/ddis/table.asp
- The GABA receptor and the TRPV1 receptor are activated through the same substances like phenols, which can be found in many plants.
My theory is that the threshold for activation of the TRPV1 is so much lowered that this receptor, which is responsible for pain and inflammation, is easier activated than the “calming” GABA receptor. This leads to an activation of the NMDA receptor and to an upregulation /excitotoxicty of the nervous system and likely to a decrease in the KCC2 activity.
This list will help you to find out, which foods you may not be able to tolerate.
en.wikipedia.org/wiki/List_of_phytochemicals_in_food
- In a study by Benson et al the pharmacology of recombinant GABA receptors in rats was tested and they have altered the genes to make some GABA receptors insensitive to diazepam.
The receptor responded normally to GABA but was unaffected by diazepam. (Robin)
This may be interesting for persons, who only have problems with diazepam.
---------------------------------------------------------------------------------------------------------
Short parts from articles
The KCC2 transporter
A transporter, which shall mainly extrude Cl from the cell, may be decreased and that can lead to anxiety. It is said that stress is able to lower it. I controlled, if oxidative stress is able to decrease it, too and I found an article, where this was mentioned. Through this we get the connection towards the quinolones, because they are able to produce oxidative stress (see Goswami 2006).
Please read the following article below about the KCC2 transporter.
www.medicine.ucalgary.ca/about/bains/stressprotein
New and unexpected mechanism identifies how the brain responds to stress
Posted: March 2, 2009
Switching off a protein causes the brakes to fail in our natural ability to respond to stress.
Chronic stress takes a physical and emotional toll on our bodies and scientists are working on piecing together a medical puzzle to understand how we respond to stress at the cellular level in the brain. Being able to quickly and successfully respond to stress is essential for survival.
Using a rat model, Jaideep Bains, PhD, a University of Calgary scientist and his team of researchers at the Hotchkiss Brain Institute have discovered that neurons in the hypothalamus, the brain’s command centre for stress responses, interpret ‘off’ chemical signals as ‘on’ chemical signals when stress is perceived. “It’s as if the brakes in your car are now acting to speed up the vehicle, rather than slow it down.” says Bains.
This unexpected finding is being published in the March 1st online edition of Nature Neuroscience.
Normally, neurons receive different chemical signals that tell them to either switch on or switch off. The off signal or brake only works if the levels of chloride ion in the cells are maintained at a low level.
This is accomplished by a protein, known as KCC2. What Bains and colleagues have shown is that stress turns down the activity of KCC2, thus removing the ability of the brake, a chemical known as GABA, to work properly. A loss of the brain’s ability to slow down may explain some of the harmful, emotional consequences of stress.
… “I was fascinated when I learned of this work. It has not been clear till now how the neuroendocrine stress response was activated by external stressors. Bains’ work shows a complex, yet elegant solution, involving a switch from inhibition to excitation.” says Jane Stewart, PhD a behavioural neuroscientist from Concordia University, “these findings may lead to a better understanding of the changes in sensitivity to stress that result from chronic exposure.”
www.millipore.com/catalogue/item/....cid=biocompar e
Studies in mice have shown that KCC2 reduces GABA's inhibitory signaling, resulting in motor defects, epilepsy, and anxiety-like behavior.
ethesis.helsinki.fi/julkaisut/bio/bioja/vk/tornberg/abstract.html
…Pharmacological analysis of KCC2-deficient mice revealed reduced sensititivity to diazepam but normal gaboxadol-induced sedation, neurosteroid hypnosis and alcohol-induced motor impairment. … (Tornberg 2006)
www.jneurosci.org/cgi/content/abstract/27/7/1642
Oxidative stress (H2O2) and the induction of seizure activity (BDNF) and hyperexcitability (0 Mg2+) resulted in a rapid dephosphorylation of KCC2 that preceded the decreases in KCC2 protein or mRNA expression. Dephosphorylation of KCC2 is correlated with a reduction of transport activity and a decrease in [Cl–]i, as well as a reduction in KCC2 surface expression. Manipulation of KCC2 tyrosine phosphorylation resulted in altered neuronal viability in response to in vitro oxidative stress. During continued neuronal stress, a second phase of functional KCC2 downregulation occurs that corresponds to decreases in KCC2 protein expression levels. We propose that neuronal stress induces a rapid loss of tyrosine phosphorylation of KCC2 that results in translocation of the protein and functional loss of transport activity. (Wake et al. 2007)
aac.asm.org/cgi/content/short/50/3/949
Involvement of Reactive Oxygen Species in the Action of Fluoroquinolones
The present study demonstrates the role of reactive oxygen species in the antibacterial action of fluoroquinolones. This statement is supported by the observation that known ROS scavengers, such as glutathione and ascorbic acid, gave protection to E. coli MG1655 against ciprofloxacin. (Goswami et al. 2006)
Benzodiazepines:
Benzodiazepines - depressions
www.benzo.org.uk/manual/bzcha03.htm
Severe depression may result from biochemical changes in the brain induced by benzodiazepines. Benzodiazepines are known to decrease the activity of serotonin and norepinephrine (noradrenaline), neurotransmitters believed to be closely involved in depression. (Ashton)
Frequency of occurrence of paradoxical reactions:
Carol Patton writes:…In a placebo-controlled study of alprazolam in the treatment of panic disorder, 13.7% of patients randomised to alprazolam experienced paradoxical reactions compared with none given placebo (O'Sullivan et al, 1994). In a further study of the efficacy of alprazolam in borderline personality disorder, 58% of patients randomised to alprazolam experienced paradoxical reactions compared with 8% with placebo (Gardner & Cowdrey, 1985)...
Christian Robin mentions in his article the following:
“In 1980, Litchfield4 reported a review
of 16,000 cases of intravenous use of diazepam in
dental practices. He concluded that 29% of patients had
minor adverse reactions. These were talkativeness, crying,
loss of inhibitions, excitement, and rage. The incidence
of these reactions was more frequent with higher
dosage and in younger patients (3- to 19-years old).”
Literature:
Carol Paton
Benzodiazepines and disinhibition: a review
The Psychiatrist (2002) 26: 460-462. doi: 10.1192/pb.26.12.460
pb.rcpsych.org/cgi/content/full/26/12/460
Christian Robin, DMD, and Norman Trieger, DMD, MD
Paradoxical Reactions to Benzodiazepines in
Intravenous Sedation: A Report of 2 Cases and
Review of the Literature
Janne Tornberg
Generation and Characterization of the Cation-Chloride Cotransporter KCC2 Hypomorphic Mouse. 2006
ethesis.helsinki.fi/julkaisut/bio/bioja/vk/tornberg/abstract.html
Hiroaki Wake, Miho Watanabe, Andrew J. Moorhouse, Takashi Kanematsu, Shoko Horibe, Noriyuki Matsukawa, Kiyofumi Asai, Kosei Ojika, Masato Hirata, and Junichi Nabekura
Early Changes in KCC2 Phosphorylation in Response to Neuronal Stress Result in Functional Downregulation
The Journal of Neuroscience, February 14, 2007, 27(7):1642-1650; doi:10.1523/JNEUROSCI.3104-06.2007
www.jneurosci.org/cgi/content/abstract/27/7/1642
M. Goswami, S. H. Mangoli, and N. Jawali*
Involvement of Reactive Oxygen Species in the Action of Ciprofloxacin against Escherichia coli
Antimicrobial Agents and Chemotherapy, March 2006, p. 949-954, Vol. 50, No. 3
0066-4804/06
aac.asm.org/cgi/content/short/50/3/949
Professor C Heather Ashton
BENZODIAZEPINES: HOW THEY WORK AND HOW TO WITHDRAW
www.benzo.org.uk/manual/bzcha03.htm