K'd-OUT-in-AZ
Bluelighter
I have posted a kind of "similar" thread way back but wanted to post a 2nd Edition with additional information. I would like this info to be shown to newer members who never saw the 1st Edition and those who are very interested in benzodiazepines. This info was obtained from MANY VARIOUS websites (too many I can't remember to thank) and accurate personal knowledge. I have also included some personal experience. Well enough talk, here you go...
Some history of benzodiazepines… Chlordiazepoxide was the first benzodiazepine to be synthesized and its discovery was by pure chance. It was synthesized in the mid 1950's from work on a chemical dye, quinazolone-3-oxides. It was discovered by accident when in 1957 tests revealed that the compound had hypnotic, anxiolytic and muscle relaxant effects. Three years later chlordiazepoxide was marketed as a therapeutic benzodiazepine medication under the brand name Librium. In 1963 diazepam hit the market under the brand name Valium, as a "simplified" version of chlordiazepoxide, primarily to counteract anxiety symptoms. The most positive results were observed among alcoholic patients. Sleep-related problems were treated with Nitrazepam (Mogadon), which was introduced in 1965, Temazepam (Restoril), which was introduced in 1969, and Flurazepam (Dalmane), which was introduced in 1973.
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The molecular mechanisms of Benzodiazepines are well defined in that they enhance the actions of the inhibitory neurotransmitter GABA by binding to specific recognition sites on GABA-a receptors containing six discrete GABA-a (alpha) subunits, GABA alpha1-6. Of those six receptors, benzodiazepines have no affinity for (a 4) and (a 6). Compounds that bind at these modulator sites by enhancing the inhibitory actions of GABA are classified as agonists, those that decrease the actions of GABA are termed inverse agonists whereas compounds that counteract the effects are called antagonists. Flumazenil is a benzodiazepine antagonist that counteracts overdose.
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The benzodiazepines represent a large class of drugs with varying hypnotic, sedative, anxiolytic, anticonvulsant, muscle relaxant and amnesic properties. They are potent anticonvulsants and have life-saving properties in the acute management of status epilepticus. Benzodiazepines are primarily used to treat panic disorder, generalized anxiety disorder, insomnia, seizures, alcohol withdrawals & acute anxiety. They are also indicated to produce amnesia for surgery. There are over 50 known worldwide. These include the variants of the 1,4-benzodiazepines such as the prototype forms diazepam and nordiazepam (also known as nordazepam or N-desmethyl diazepam). Known 3-hydroxy metabolites, namely temazepam, lorazepam and oxazepam, are also registered as benzodiazepines in their own right. The majority of these drugs are excreted as glucuronide conjugates at the 3-hydroxy. Some drugs are metabolized to nordiazepam. These include chlordiazepoxide and clorazepate. 7-Nitro substituted 1,4-benzodiazepines such as
flunitrazepam, nitrazepam, and clonazepam represent a sub-group of drugs that are often abused. These 7-nitro substituted drugs are metabolized by nitroreduction and have no active metabolites. The triazolo ring type benzodiazepines are frequently very potent
and require much lower doses than the older analogs. Some examples include alprazolam, estazolam, and triazolam.
The five various benzodiazepine compounds:
2-Keto Compound
*Includes Diazepam, Flurazepam, Chlordiazepoxide
*All have active metabolites (Most commonly desmethyldiazepam)
*Longest active half-lives (Accumulates from repeated use. Anywhere from 20-200 hours)
3-hydroxy Compound
*Includes Lorazepam, Temazepam, Oxazepam
*No active metabolites
*Intermediate half-lives (generally 8-20 hours)
Triazolo
*Includes Alprazolam, Triazolam, Estazolam
*Few metabolites
*Very short half-lives (anywhere from 3-18 hours)
Imidazo
*Includes Midazolam, Loprazolam and antagonist Flumazenil
*Very potent water-soluble amnesiac sedatives.
*Short to ultra short half-lives (7 hours or less; Flumazenil roughly 15-30 minutes)
7-Nitro Compound
*Includes Clonazepam, Nitrazepam, Flunitrazepam
*No active metabolites. Metabolized by nitroreduction
*Long half-lives (18-50 hours)
The binding properties and action of benzodiazepines depend on the alpha-subunit profile of the hetero-pentameric receptors: whereas the alpha1 subunit is associated with benzodiazepine type I (BZD1) pharmacology and reportedly mediates sedative as well as amnesic actions of benzodiazepines, the alpha2 subunit confers benzodiazepine type II (BZD2) pharmacology and mediates the anxiolytic actions of benzodiazepines.
All benzodiazepine agonists exert five primary effects and they are:
1. Hypnotic
(Prescribed for: short-term management of insomnia)
2. Anxiolytic
(Prescribed for: treatment of anxiety disorders and phobias; prevention of panic attacks)
3. Anti-convulsant/anti-seizure
(Prescribed for: seizure control; management of status epileptics; prevention of panic attacks)
4. Antispasmodic (Muscle relaxant)
(Prescribed for: treatment of muscle spasms, for example, Tetanus or spastic disorders and Restless legs syndrome.
5. Amnesic
Used as sedatives for patients receiving mechanical ventilation, or those in extreme distress or severe pain. Midazolam is the most common and effective for sleep-induced procedures.
Different benzodiazepines exhibit these primary effects to varying degrees. For example, diazepam (Valium) is a relatively powerful hypnotic, whereas the more modern benzodiazepines such as alprazolam (Xanax), lorazepam (Ativan), and clonazepam (Klonopin) are less powerful hypnotics, but are very powerful anxiolytics. Do not assume that because one benzodiazepine makes you sleepier than another that this benzodiazepine is more potent than those that don’t produce sleepiness to the same degree. Often, the reverse is true.
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The pharmacological spectrum of benzodiazepine site ligands, ranging from the therapeutic benefits of hypnosis, anxiolysis, anticonvulsant, and muscle relaxation to the potentially unwanted aspects of impaired motor co-ordination, attention and memory, tolerance and dependence and potentiation of the effects of alcohol, are believed to result from interactions with multiple GABA-A receptor “subunits”.
There are six GABA-a subunits, GABA(a 1), GABA(a 2), GABA(a 3), GABA(a 4), GABA(a 5) and GABA(a 6). Of those six receptors, benzodiazepines have no affinity for (a 4) and (a 6). Most effective anti-anxiety benzodiazepines have affinity to both alpha1 and alpha2 subunits while the more effective hypnotics have higher affinity to just the alpha1 subunit
GABA-A receptor subtype containing:
Alpha1: sedation, amnesiac, alcohol interaction, tolerance
Alpha2: anxiolysis, muscle relaxation
Alpha3: anxiolysis, muscle relaxation
Alpha5: memory, tolerance
The classical benzodiazepine show no selectivity between these GABA-A receptor subtypes and can exhibit the entire spectrum of pharmacological effects, depending on the dose. The “non-benzodiazepines” (zolpidem and zaleplon) show selectivity towards alpha1-containing GABA-A receptors, and these produce a predominant hypnotic pharmacological profile.
The alpha1-containing has been proposed to be responsible for the sedative action; the alpha2 and/or the alpha3 subtypes have been suggested to mediate the anxiolytic activity and the myorelaxation effects, and the alpha5 subtype has been associated with cognition processes.
The anticonvulsant properties of benzodiazepines may be in part or entirely due to binding to voltage-dependent sodium channels rather than benzodiazepine receptors. Sustained repetitive firing seems to be limited by benzodiazepines effect of slowing recovery of sodium channels from inactivation.
Primarily Anxiolytic Benzodiazepines: diazepam, clonazepam, alprazolam, bromazepam, chlordiazepoxide, oxazepam, nordazepam, lorazepam
Primarily (Non-selective) Hypnotic Benzodiazepines: nitrazepam, temazepam, flunitrazepam, lormetazepam, triazolam, estazolam, midazolam
Structural Potency of benzodiazepines
There is already a lot of information about equivalent doses of benzodiazepines on a milligram basis. While this is undoubtedly important for clinical practice, it doesn't give the whole story as to why certain benzodiazepines are much more potent than others.
To do this, the therapeutically equivalent doses in milligrams need to be converted to a molar basis and multiplied by their respective bioavailabilities. This tells us exactly how many molecules of a specific benzodiazepine (that reach the circulation) are needed to achieve a standard anxiolytic level. This arbitrary standard in most publications is the level produced by 10 mg of oral diazepam (Valium).
This thought experiment should reveal the common characteristics of the benzodiazepines that bond strongly to the GABA receptor, and thus require the lowest doses on a micromolar basis.
The potency of benzodiazepines in order from most to least (judging from the molecules on a molar basis):
1. Triazolam (Halcion; hypnotic) 1.31 umol
2. Alprazolam (Xanax; anxiolytic) 1.38 umol
3. Clonazepam (Klonopin; anxiolytic, anticonvulsant) 1.43 umol
4. Flunitrazepam (Rohypnol; hypnotic) 1.60 umol
5. Lorazepam (Ativan; anxioltic, anticonvulsant) 2.65 umol
6. Loprazolam (Dormonoct; hypnotic) 2.90 umol
7. Lormetazepam (Noctamid; hypnotic) 3.58 umol
8. Eszopiclone (Lunesta; non-benzodiazepine hypnotic) 4.24 umol
9. Estazolam (ProSom; hypnotic) 4.73 umol
10. Bromazepam (Lexotan; anxiolytic) 14.61 umol
11. Quazepam (Doral; hypnotic) 17.06 umol
12. Zalepion (Sonata; non-benzodiazepine hypnotic) 19.65 umol
13. Zopiclone (Imovane; non-benzodiazepine hypnotic) 21.22 umol
14. Nitrazepam (Mogadon; hypnotic) 30.48 umol
15. Diazepam (Valium; anxiolytic, anticonvulsant, hypnotic) 32.67 umol
16. Medazepam (Nobrium; anxiolytic) 33.23 umol
17. Nordazepam (Nordaz; anxiolytic) 33.25 umol
18. Clorazepate (Tranxene; anxiolytic) 41.27 umol
19. Prazepam (Centrax; anxiolytic) 41.56 umol
20. Flurazepam (Dulmane; hypnotic) 47.08 umol
21. Halazepam (Paxipam; anxiolytic) 51.03 umol
22. Ketazolam (Anxon; anxiolytic) 53.69 umol
23. Clobazam (Frisium; anxiolytic, anticonvulsant) 59.9 umol
24. Zolpidem (Ambien; non-benzodiazepine hypnotic) 59.9 umol
25. Temazepam (Restoril; hypnotic) 63.9 umol
26. Oxazepam (Serax; anxiolytic) 67 umol
27. Chlordiazepoxide (Librium; anxiolytic, anticonvulsant) 75 umol
Please note that the potency of a benzodiazepine has no correlation with euphoria. For example, among drug abusers, Temazepam is and has always been known as a euphoric benzodiazepine and in fact has been banned in many countries due to its recreational abuse, yet its one of the least potent benzodiazepines (according to its molar basis).
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The benzodiazepine equivalency table is firmly based on clinical experience during switch-over to diazepam at start of withdrawal programs. The following dosages are equivalent to 10mg of Diazepam (oral) rather than each other because not all benzodiazepines have the same properties. This is the most updated and accurate equivalency table:
Alprazolam: 0.5mg
Bromazepam: 5.5mg
Chlordiazepoxide: 25mg
Clobazam: 20mg
Clonazepam: 0.5mg
Clorazepate: 15mg
Diazepam: 10mg
Estazolam: 1.5mg
Flunitrazepam: 1mg
Flurazepam: 22mg
Halazepam: 20mg
Ketazolam: 22mg
Loprazolam: 1.5mg
Lorazepam: 1mg
Lormetazepam: 1.5mg
Medazepam: 10mg
Midazolam (PO): 4.76mg
Nitrazepam: 10mg
Nordazepam: 10mg
Oxazepam: 20mg
Prazepam: 15mg
Quazepam: 20mg
Temazepam: 20mg
Triazolam: 0.5mg
Non-benzodiazepine hypnotics
Zaleplon: 20mg
Zolpidem: 20mg
Zopiclone: 15mg
Eszopiclone 3mg
The Half-life of following benzodiazepines [active metabolite in brackets]
Alprazolam: 6-12 hours
Bromazepam: 10-12 hours
Chlordiazepoxide: 5-30 hours [36-200]
Clobazam: 12-60 hours
Clonazepam: 18-50 hours
Clorazepate: [36-200]
Diazepam: 20-100 hours [36-200]
Estazolam: 10-24 hours
Flunitrazepam: 18-26 hours [36-200]
Flurazepam: [40-250]
Halazepam: [30-100]
Ketazolam: 30-100 hours [36-200]
Loprazolam: 6-12 hours
Lorazepam: 10-20 hours
Lormetazepam: 10-12 hours
Medazepam: [36-200]
Midazolam: 1.5-2.5 hours
Nitrazepam: 15-38 hours
Nordazepam: [36-200]
Oxazepam: 4-15 hours
Prazepam: 10-20 hours [36-200]
Quazepam: 25-100 hours
Temazepam: 8-22 hours
Triazolam: 2 hours
Non-benzodiazepine hypnotics
Zaleplon: 2-3 hours
Zolpidem: 2-3 hours
Zopiclone: 5-6 hours
Eszopiclone 3-4 hours
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• Just from some personal experience of mine regarding how I feel about particular benzodiazepines and their effects. I’m not including the non-benzodiazepines. Could be useful for some. (Differs from person to person):
Alprazolam – Kicks in rapidly and short acting but packs a punch. Has roughly 3-4 hour duration. Better anxiolytic than sedative. Great for panic disorder but not so much generalized anxiety since dosing has to be repeated so often. I personally like it.
Chlordiazepoxide – Isn’t anything special. Very weak in my opinion. Best qualities are its anti-convulsant effects, however not an effective muscle relaxant.
Clobazam – Has moderate anti-convulsant effects but that’s all it is good for. Has got to be the worst benzodiazepine I’ve ever encountered. Very weak anxiolytic and causes very little sedation. 1,5 benzodiazepine.
Clonazepam – A personal favorite. A great long-lasting anxiolytic that makes it very effective for generalized anxiety disorder. Also controls panic attacks although not quick acting. Greatly reduces symptoms of Restless Leg Disorder. Good muscle relaxant, powerful anti-convulsant and produces moderate sedation. Memory impairment in high doses or when combined with alcohol!
Diazepam – Good anxiolytic with sedative qualities. Works well for generalized anxiety disorder. Also controls symptoms of alcohol withdrawals very well. I know from personal experience in rehab. A powerful anti-convulsant and great for muscle relaxation. Has a long-half life despite short duration of effects roughly 4 hours, possibly a little more. Great for tapering, as I am using it now.
Estazolam – Hypnotic that works moderately well for sleep, as it prevented me from waking so many times in sleep but sort of weak with mild to moderate sedation. Takes some time to actually get asleep.
Flurazepam – Moderately potent hypnotic with milder sedation than most hypnotics although was still effective for sleep. Not really euphoric and doesn’t produce a “buzz” like the more potent hypnotics.
Flunitrazepam – A rather powerful hypnotic that produces moderately high sedation. Kept me to sleep but I’d wake early. Has anti-convulsant qualities. Not a powerful anxiolytic.
Lorazepam – Works well for generalized anxiety disorder. Has a subtle sedative-hypnotic effect. Rather weak though in my opinion. Doesn’t work that well for me personally. I need high doses. Some moderate muscle relaxant qualities. Duration of 6-8 hours can be used for sleep.
Midazolam – Water soluble, and I’ve only used the IV route, its a VERY powerful amnesiac. Intense sedation. Not to be used for an anti-anxiety drug due to sedation. Has a really short duration. Once again, never tried it PO.
Nitrazepam – Hypnotic that I find rather effective for sleep, as I don’t wake multiple times in the middle of the night. Induces sedation and has a longer duration than most hypnotics. Personally I rather like it.
Oxazepam – Weak anxioytic and produces moderately low sedation. I don’t find it very effective at all. One of the worst benzodiazepines I’ve encountered with exception of Clobazam. Only good qualities are its moderate muscle relaxant effects.
Temazepam – My favorite benzodiazepine! Very effective hypnotic that produces euphoria. Produces very relaxing sedation. Nice muscle relaxant with anti-convulsant properties. Has one of the longer durations of the sleep inducers. I don’t wake in the middle of the night.
Triazolam – Hypnotic with a very short duration that kicks in really quick. Has the ability to get me asleep but I still wake in the middle of the night and early morning. Can produce a hang over. Can’t remember a thing if I take in higher doses the night before.
Those are pretty much the majority of benzodiazepines that are prescribed in the United States. I’ve tried just about all of them because I suffer from insomnia and anxiety. Eventually their effects wear off and the hypnotics are only good for a short duration of time. Doses have to be upped and upped and then you are taking them daily at these excessive doses just to prevent withdrawals. Benzodiazepines are only good to be taken for a short duration of time or every now and then. If the hypnotics are taken for a certain amount of time, usually after a month or less, they can produce rebound insomnia and anxiety; especially Triazolam that can cause rebound insomnia after only 2 weeks of taking it. Addiction to benzodiazepines is nothing short of horrible. I’ve taken benzodiazepines for nearly 10 years and tapering with Diazepam. Almost finished.
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Some interesting information:
From experience I have found that a medication called Pregabalin (Lyrica) is very helpful during the taper of benzodiazepines. Reduced nearly all symptoms during each taper at therapeutic doses of 450-600mg/daily. Pregabalin is thought to mimic the effects of GABA-A, which may be the reason why it is useful.
Any additional information on benzodiazepines you'd like to contribute, please do!
Some history of benzodiazepines… Chlordiazepoxide was the first benzodiazepine to be synthesized and its discovery was by pure chance. It was synthesized in the mid 1950's from work on a chemical dye, quinazolone-3-oxides. It was discovered by accident when in 1957 tests revealed that the compound had hypnotic, anxiolytic and muscle relaxant effects. Three years later chlordiazepoxide was marketed as a therapeutic benzodiazepine medication under the brand name Librium. In 1963 diazepam hit the market under the brand name Valium, as a "simplified" version of chlordiazepoxide, primarily to counteract anxiety symptoms. The most positive results were observed among alcoholic patients. Sleep-related problems were treated with Nitrazepam (Mogadon), which was introduced in 1965, Temazepam (Restoril), which was introduced in 1969, and Flurazepam (Dalmane), which was introduced in 1973.
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The molecular mechanisms of Benzodiazepines are well defined in that they enhance the actions of the inhibitory neurotransmitter GABA by binding to specific recognition sites on GABA-a receptors containing six discrete GABA-a (alpha) subunits, GABA alpha1-6. Of those six receptors, benzodiazepines have no affinity for (a 4) and (a 6). Compounds that bind at these modulator sites by enhancing the inhibitory actions of GABA are classified as agonists, those that decrease the actions of GABA are termed inverse agonists whereas compounds that counteract the effects are called antagonists. Flumazenil is a benzodiazepine antagonist that counteracts overdose.
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The benzodiazepines represent a large class of drugs with varying hypnotic, sedative, anxiolytic, anticonvulsant, muscle relaxant and amnesic properties. They are potent anticonvulsants and have life-saving properties in the acute management of status epilepticus. Benzodiazepines are primarily used to treat panic disorder, generalized anxiety disorder, insomnia, seizures, alcohol withdrawals & acute anxiety. They are also indicated to produce amnesia for surgery. There are over 50 known worldwide. These include the variants of the 1,4-benzodiazepines such as the prototype forms diazepam and nordiazepam (also known as nordazepam or N-desmethyl diazepam). Known 3-hydroxy metabolites, namely temazepam, lorazepam and oxazepam, are also registered as benzodiazepines in their own right. The majority of these drugs are excreted as glucuronide conjugates at the 3-hydroxy. Some drugs are metabolized to nordiazepam. These include chlordiazepoxide and clorazepate. 7-Nitro substituted 1,4-benzodiazepines such as
flunitrazepam, nitrazepam, and clonazepam represent a sub-group of drugs that are often abused. These 7-nitro substituted drugs are metabolized by nitroreduction and have no active metabolites. The triazolo ring type benzodiazepines are frequently very potent
and require much lower doses than the older analogs. Some examples include alprazolam, estazolam, and triazolam.
The five various benzodiazepine compounds:
2-Keto Compound
*Includes Diazepam, Flurazepam, Chlordiazepoxide
*All have active metabolites (Most commonly desmethyldiazepam)
*Longest active half-lives (Accumulates from repeated use. Anywhere from 20-200 hours)
3-hydroxy Compound
*Includes Lorazepam, Temazepam, Oxazepam
*No active metabolites
*Intermediate half-lives (generally 8-20 hours)
Triazolo
*Includes Alprazolam, Triazolam, Estazolam
*Few metabolites
*Very short half-lives (anywhere from 3-18 hours)
Imidazo
*Includes Midazolam, Loprazolam and antagonist Flumazenil
*Very potent water-soluble amnesiac sedatives.
*Short to ultra short half-lives (7 hours or less; Flumazenil roughly 15-30 minutes)
7-Nitro Compound
*Includes Clonazepam, Nitrazepam, Flunitrazepam
*No active metabolites. Metabolized by nitroreduction
*Long half-lives (18-50 hours)
The binding properties and action of benzodiazepines depend on the alpha-subunit profile of the hetero-pentameric receptors: whereas the alpha1 subunit is associated with benzodiazepine type I (BZD1) pharmacology and reportedly mediates sedative as well as amnesic actions of benzodiazepines, the alpha2 subunit confers benzodiazepine type II (BZD2) pharmacology and mediates the anxiolytic actions of benzodiazepines.
All benzodiazepine agonists exert five primary effects and they are:
1. Hypnotic
(Prescribed for: short-term management of insomnia)
2. Anxiolytic
(Prescribed for: treatment of anxiety disorders and phobias; prevention of panic attacks)
3. Anti-convulsant/anti-seizure
(Prescribed for: seizure control; management of status epileptics; prevention of panic attacks)
4. Antispasmodic (Muscle relaxant)
(Prescribed for: treatment of muscle spasms, for example, Tetanus or spastic disorders and Restless legs syndrome.
5. Amnesic
Used as sedatives for patients receiving mechanical ventilation, or those in extreme distress or severe pain. Midazolam is the most common and effective for sleep-induced procedures.
Different benzodiazepines exhibit these primary effects to varying degrees. For example, diazepam (Valium) is a relatively powerful hypnotic, whereas the more modern benzodiazepines such as alprazolam (Xanax), lorazepam (Ativan), and clonazepam (Klonopin) are less powerful hypnotics, but are very powerful anxiolytics. Do not assume that because one benzodiazepine makes you sleepier than another that this benzodiazepine is more potent than those that don’t produce sleepiness to the same degree. Often, the reverse is true.
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The pharmacological spectrum of benzodiazepine site ligands, ranging from the therapeutic benefits of hypnosis, anxiolysis, anticonvulsant, and muscle relaxation to the potentially unwanted aspects of impaired motor co-ordination, attention and memory, tolerance and dependence and potentiation of the effects of alcohol, are believed to result from interactions with multiple GABA-A receptor “subunits”.
There are six GABA-a subunits, GABA(a 1), GABA(a 2), GABA(a 3), GABA(a 4), GABA(a 5) and GABA(a 6). Of those six receptors, benzodiazepines have no affinity for (a 4) and (a 6). Most effective anti-anxiety benzodiazepines have affinity to both alpha1 and alpha2 subunits while the more effective hypnotics have higher affinity to just the alpha1 subunit
GABA-A receptor subtype containing:
Alpha1: sedation, amnesiac, alcohol interaction, tolerance
Alpha2: anxiolysis, muscle relaxation
Alpha3: anxiolysis, muscle relaxation
Alpha5: memory, tolerance
The classical benzodiazepine show no selectivity between these GABA-A receptor subtypes and can exhibit the entire spectrum of pharmacological effects, depending on the dose. The “non-benzodiazepines” (zolpidem and zaleplon) show selectivity towards alpha1-containing GABA-A receptors, and these produce a predominant hypnotic pharmacological profile.
The alpha1-containing has been proposed to be responsible for the sedative action; the alpha2 and/or the alpha3 subtypes have been suggested to mediate the anxiolytic activity and the myorelaxation effects, and the alpha5 subtype has been associated with cognition processes.
The anticonvulsant properties of benzodiazepines may be in part or entirely due to binding to voltage-dependent sodium channels rather than benzodiazepine receptors. Sustained repetitive firing seems to be limited by benzodiazepines effect of slowing recovery of sodium channels from inactivation.
Primarily Anxiolytic Benzodiazepines: diazepam, clonazepam, alprazolam, bromazepam, chlordiazepoxide, oxazepam, nordazepam, lorazepam
Primarily (Non-selective) Hypnotic Benzodiazepines: nitrazepam, temazepam, flunitrazepam, lormetazepam, triazolam, estazolam, midazolam
Structural Potency of benzodiazepines
There is already a lot of information about equivalent doses of benzodiazepines on a milligram basis. While this is undoubtedly important for clinical practice, it doesn't give the whole story as to why certain benzodiazepines are much more potent than others.
To do this, the therapeutically equivalent doses in milligrams need to be converted to a molar basis and multiplied by their respective bioavailabilities. This tells us exactly how many molecules of a specific benzodiazepine (that reach the circulation) are needed to achieve a standard anxiolytic level. This arbitrary standard in most publications is the level produced by 10 mg of oral diazepam (Valium).
This thought experiment should reveal the common characteristics of the benzodiazepines that bond strongly to the GABA receptor, and thus require the lowest doses on a micromolar basis.
The potency of benzodiazepines in order from most to least (judging from the molecules on a molar basis):
1. Triazolam (Halcion; hypnotic) 1.31 umol
2. Alprazolam (Xanax; anxiolytic) 1.38 umol
3. Clonazepam (Klonopin; anxiolytic, anticonvulsant) 1.43 umol
4. Flunitrazepam (Rohypnol; hypnotic) 1.60 umol
5. Lorazepam (Ativan; anxioltic, anticonvulsant) 2.65 umol
6. Loprazolam (Dormonoct; hypnotic) 2.90 umol
7. Lormetazepam (Noctamid; hypnotic) 3.58 umol
8. Eszopiclone (Lunesta; non-benzodiazepine hypnotic) 4.24 umol
9. Estazolam (ProSom; hypnotic) 4.73 umol
10. Bromazepam (Lexotan; anxiolytic) 14.61 umol
11. Quazepam (Doral; hypnotic) 17.06 umol
12. Zalepion (Sonata; non-benzodiazepine hypnotic) 19.65 umol
13. Zopiclone (Imovane; non-benzodiazepine hypnotic) 21.22 umol
14. Nitrazepam (Mogadon; hypnotic) 30.48 umol
15. Diazepam (Valium; anxiolytic, anticonvulsant, hypnotic) 32.67 umol
16. Medazepam (Nobrium; anxiolytic) 33.23 umol
17. Nordazepam (Nordaz; anxiolytic) 33.25 umol
18. Clorazepate (Tranxene; anxiolytic) 41.27 umol
19. Prazepam (Centrax; anxiolytic) 41.56 umol
20. Flurazepam (Dulmane; hypnotic) 47.08 umol
21. Halazepam (Paxipam; anxiolytic) 51.03 umol
22. Ketazolam (Anxon; anxiolytic) 53.69 umol
23. Clobazam (Frisium; anxiolytic, anticonvulsant) 59.9 umol
24. Zolpidem (Ambien; non-benzodiazepine hypnotic) 59.9 umol
25. Temazepam (Restoril; hypnotic) 63.9 umol
26. Oxazepam (Serax; anxiolytic) 67 umol
27. Chlordiazepoxide (Librium; anxiolytic, anticonvulsant) 75 umol
Please note that the potency of a benzodiazepine has no correlation with euphoria. For example, among drug abusers, Temazepam is and has always been known as a euphoric benzodiazepine and in fact has been banned in many countries due to its recreational abuse, yet its one of the least potent benzodiazepines (according to its molar basis).
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The benzodiazepine equivalency table is firmly based on clinical experience during switch-over to diazepam at start of withdrawal programs. The following dosages are equivalent to 10mg of Diazepam (oral) rather than each other because not all benzodiazepines have the same properties. This is the most updated and accurate equivalency table:
Alprazolam: 0.5mg
Bromazepam: 5.5mg
Chlordiazepoxide: 25mg
Clobazam: 20mg
Clonazepam: 0.5mg
Clorazepate: 15mg
Diazepam: 10mg
Estazolam: 1.5mg
Flunitrazepam: 1mg
Flurazepam: 22mg
Halazepam: 20mg
Ketazolam: 22mg
Loprazolam: 1.5mg
Lorazepam: 1mg
Lormetazepam: 1.5mg
Medazepam: 10mg
Midazolam (PO): 4.76mg
Nitrazepam: 10mg
Nordazepam: 10mg
Oxazepam: 20mg
Prazepam: 15mg
Quazepam: 20mg
Temazepam: 20mg
Triazolam: 0.5mg
Non-benzodiazepine hypnotics
Zaleplon: 20mg
Zolpidem: 20mg
Zopiclone: 15mg
Eszopiclone 3mg
The Half-life of following benzodiazepines [active metabolite in brackets]
Alprazolam: 6-12 hours
Bromazepam: 10-12 hours
Chlordiazepoxide: 5-30 hours [36-200]
Clobazam: 12-60 hours
Clonazepam: 18-50 hours
Clorazepate: [36-200]
Diazepam: 20-100 hours [36-200]
Estazolam: 10-24 hours
Flunitrazepam: 18-26 hours [36-200]
Flurazepam: [40-250]
Halazepam: [30-100]
Ketazolam: 30-100 hours [36-200]
Loprazolam: 6-12 hours
Lorazepam: 10-20 hours
Lormetazepam: 10-12 hours
Medazepam: [36-200]
Midazolam: 1.5-2.5 hours
Nitrazepam: 15-38 hours
Nordazepam: [36-200]
Oxazepam: 4-15 hours
Prazepam: 10-20 hours [36-200]
Quazepam: 25-100 hours
Temazepam: 8-22 hours
Triazolam: 2 hours
Non-benzodiazepine hypnotics
Zaleplon: 2-3 hours
Zolpidem: 2-3 hours
Zopiclone: 5-6 hours
Eszopiclone 3-4 hours
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• Just from some personal experience of mine regarding how I feel about particular benzodiazepines and their effects. I’m not including the non-benzodiazepines. Could be useful for some. (Differs from person to person):
Alprazolam – Kicks in rapidly and short acting but packs a punch. Has roughly 3-4 hour duration. Better anxiolytic than sedative. Great for panic disorder but not so much generalized anxiety since dosing has to be repeated so often. I personally like it.
Chlordiazepoxide – Isn’t anything special. Very weak in my opinion. Best qualities are its anti-convulsant effects, however not an effective muscle relaxant.
Clobazam – Has moderate anti-convulsant effects but that’s all it is good for. Has got to be the worst benzodiazepine I’ve ever encountered. Very weak anxiolytic and causes very little sedation. 1,5 benzodiazepine.
Clonazepam – A personal favorite. A great long-lasting anxiolytic that makes it very effective for generalized anxiety disorder. Also controls panic attacks although not quick acting. Greatly reduces symptoms of Restless Leg Disorder. Good muscle relaxant, powerful anti-convulsant and produces moderate sedation. Memory impairment in high doses or when combined with alcohol!
Diazepam – Good anxiolytic with sedative qualities. Works well for generalized anxiety disorder. Also controls symptoms of alcohol withdrawals very well. I know from personal experience in rehab. A powerful anti-convulsant and great for muscle relaxation. Has a long-half life despite short duration of effects roughly 4 hours, possibly a little more. Great for tapering, as I am using it now.
Estazolam – Hypnotic that works moderately well for sleep, as it prevented me from waking so many times in sleep but sort of weak with mild to moderate sedation. Takes some time to actually get asleep.
Flurazepam – Moderately potent hypnotic with milder sedation than most hypnotics although was still effective for sleep. Not really euphoric and doesn’t produce a “buzz” like the more potent hypnotics.
Flunitrazepam – A rather powerful hypnotic that produces moderately high sedation. Kept me to sleep but I’d wake early. Has anti-convulsant qualities. Not a powerful anxiolytic.
Lorazepam – Works well for generalized anxiety disorder. Has a subtle sedative-hypnotic effect. Rather weak though in my opinion. Doesn’t work that well for me personally. I need high doses. Some moderate muscle relaxant qualities. Duration of 6-8 hours can be used for sleep.
Midazolam – Water soluble, and I’ve only used the IV route, its a VERY powerful amnesiac. Intense sedation. Not to be used for an anti-anxiety drug due to sedation. Has a really short duration. Once again, never tried it PO.
Nitrazepam – Hypnotic that I find rather effective for sleep, as I don’t wake multiple times in the middle of the night. Induces sedation and has a longer duration than most hypnotics. Personally I rather like it.
Oxazepam – Weak anxioytic and produces moderately low sedation. I don’t find it very effective at all. One of the worst benzodiazepines I’ve encountered with exception of Clobazam. Only good qualities are its moderate muscle relaxant effects.
Temazepam – My favorite benzodiazepine! Very effective hypnotic that produces euphoria. Produces very relaxing sedation. Nice muscle relaxant with anti-convulsant properties. Has one of the longer durations of the sleep inducers. I don’t wake in the middle of the night.
Triazolam – Hypnotic with a very short duration that kicks in really quick. Has the ability to get me asleep but I still wake in the middle of the night and early morning. Can produce a hang over. Can’t remember a thing if I take in higher doses the night before.
Those are pretty much the majority of benzodiazepines that are prescribed in the United States. I’ve tried just about all of them because I suffer from insomnia and anxiety. Eventually their effects wear off and the hypnotics are only good for a short duration of time. Doses have to be upped and upped and then you are taking them daily at these excessive doses just to prevent withdrawals. Benzodiazepines are only good to be taken for a short duration of time or every now and then. If the hypnotics are taken for a certain amount of time, usually after a month or less, they can produce rebound insomnia and anxiety; especially Triazolam that can cause rebound insomnia after only 2 weeks of taking it. Addiction to benzodiazepines is nothing short of horrible. I’ve taken benzodiazepines for nearly 10 years and tapering with Diazepam. Almost finished.
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Some interesting information:
From experience I have found that a medication called Pregabalin (Lyrica) is very helpful during the taper of benzodiazepines. Reduced nearly all symptoms during each taper at therapeutic doses of 450-600mg/daily. Pregabalin is thought to mimic the effects of GABA-A, which may be the reason why it is useful.
Any additional information on benzodiazepines you'd like to contribute, please do!
