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Efficacy and safety of benzodiazepines: Mechanisms of action
246
Efficacy and Safety of benzodiazepines: Mechanisms of Action
Kales, A. and Vgontzas, A.N. Pennsylvania State University College of Medicine, Hershey, Pennsylvania, U.S.A. Key words: Benzodiazepines; Adverse Effects; Efficacy; Mechanism of Action Introduction The first benzodiazepines introduced (1,4 benzodiazepines) as anxiolytics and hypnotics, e.g., diazepam and fiurazepam, were similar in pharmacokinetics (relatively slow elimination rate) and pharmacodynamics (relatively low receptor binding affinity/potency). The most frequent side effect of these benzodiazepines was excessive daytime sleepiness, an expected side effect. Late in the 70s, new 1,4 benzodiazepines were introduced, e.g., lorazepam, which were more rapidly eliminated and more potent. Use of these new benzodiazepines was associated with more potent anxiolytic and hypnotic effects, but also with more rapid development of tolerance, significant withdrawal difficulties, i.e., rebound insomnia and anxiety and the adverse reaction of amnesia. In the late 70s and early 80s, a new class of potent and rapidly eliminated benzodiazepines was introduced, the triazolobenzodiazepines. This new class (triazolam and alprazolam) was also different chemically from the classical 1,4 benzodiazepines in that it included a triazolo ring attached to the basic diazepine structure and was promoted for its unique clinical applications. However, it soon became clear from clinical case reports, postmarketing surveillance data and controlled studies that use of triazolobenzodiazepines was associated with frequent and severe CNS and psychiatric adverse reactions in three major categories: amnesia and other cognitive impairments; daytime anxiety, tension and panic and early morning insomnia; and withdrawal difficulties such as rebound insomnia and seizures.
Triazolobenzodiazepines: Unique Profile of Adverse Effects Copelling scientific evidence has been gathered over the last 15 years documenting the frequency and severity of these side effects associated with the use of triazolam (Kales, 1991): (a) Amnesia and other cognitive impairments. Findings supported by: 24 published case reports of 51 patients; Spontaneous Reporting System (SRS) data showing ratios of amnesia for triazolam of 47.5 to 1 and 47.5 to 0 compared to temazepam and flurazepam, respectively; six studies of memory at time of peak drug concentration showing greater memory impairment with triazolam compared to other benzodiazepine hypnotics or placebo and two recent controlled studies showing next-day amnesia with triazolam but not temazepam; FDA analysis of New Drug Application (NDA) data showing significantly more dropouts due to memory impairment with 0,5 mg of triazolam compared to 30 mg of flurazepam (no episodes reported). (b) Hyperexcitability states during drug administration (daytime anxiety, tension and panic and early morning insomnia). Findings supported by: SRS data showing ratios of hyperexcitability for triazolam of 83.8 to 31.9 and 83.8 to 11.1 compared to temazepam and fiurazepam, respectively; 12 case reports; eight controlled studies; and recent FDA analysis of NDA data showing significantly more dropouts due to anxiety with both 0.5 mg and 0.25 mg of triazolam (3-6 times greater) compared to 30 mg of flurazeparn and placebo. (c) Withdrawal difficulties (rebound insomnia and seizures). Findings supported by: SRS data showing ratios of withdrawal difficulties and dependency for triazolam of 23.7 versus 12.0 and 4.2 compared to temazepam or flurazepam, respectively; SRS data indicating a ratio of seizures following withdrawal of triazolam of 37.4:1 compared to temazepam; 12 case reports. In addition, alprazolam has been found to be frequently associated with early development of tolerance, hyperexcitability phenomena during drug administration (interdose rebound anxiety, mania, disinhibition) and severe withdrawal difficulties (panic, seizures). In one large-scale multicenter study, 60% of the patients had either significant increase of the original
247 symptom (panic, anxiety) or new serious withdrawal symptoms, even though the drug was gradually tapered (Abramowitz, 1991). Preliminary analysis of SRS data showed a much higher rate of CNS ADRs for alprazolam versus lorazepam, withdrawal and hyperexcitability being the highest. Mechanism of Action
A thorough review of the pharmacokinetics, pharmacodynamics and the unique properties of triazolobenzodiazepines can account for the serious adverse reactions of these drugs (Kales and Vgontzas, 1990).
Cognitive Impairments We have proposed that triazolam's induced incognitive impairments and symptoms and signs of organic mental disorder are related, in order of importance, to high receptor binding affinity, the unique properties of triazolobenzodiazepines and rapidity of elimination. In contrast, benzodiazepine hypnotics such as temazepam, flurazepam and quazepam are infrequently associated with cognitive impairments. Each of the latter drugs: has relatively low receptor binding affinity; is more slowly eliminated; and, is a 1,4 benzodiazepine that does not have the unique properties specific to a triazolobenzodiazepine.
Hyperexcitability States We have proposed that hyperexcitability states, both during drug administration and withdrawal, are related to at least three mechanisms: (1) rapid elimination; (2) relatively high receptor binding affinity; and (3) unique properties of triazolobenzodiazepines, such as direct effects on the locus coeruleus-noradrenergic system. When all three factors are present, for example, with traizolam, hyperexcitability phenomena are more frequent, immediate and of greater severity. When none of the factors is present, as is the case for both flurazepam and quazepam which are slowly eliminated, have relatively low receptor binding affinity and none of the unique triazoiobenzodiazepine properties, hyperexcitability phenomena are much more infrequent, delayed and mild in severity. When only one factor is present (for example, temazepam is relatively rapidly eliminated but has a low receptor binding affinity), hyperexcitability phenomena are more likely to be less frequent and milder in severity.
Unique Chemical Properties Triazolam, in addition to its ultra-short elimination half-life and high binding affinity, shares some of the unique chemical properties of the triazolobenzodiazepines. For example, triazolobenzodiazepines activate alpha-2 adrenoreceptors, inhibit platelet activating factor 0aAF), and do not appear to have total cross-tolerance with other benzodiazepines. Alpha-2 receptors are mainly located in the brain system and have an inhibiting effect oil the locus coeruleus-noradrenergic (LC-NE) system. Also, PAF activates eorticotropin releasing factor, which in turn has an activating effect on the LC-NE system. Therefore, triazolobenzodiazepines, by activating alpha-2 adrenoreceptors and inhibiting PAF, have a direct suppressant effect on the LC-NE system. It is also likely that the initial dampening or suppression of the LC-NE system is followed by a significant rebound and activation of the LC-NE system, when the drug is rapidly eliminated from the system. This repetitive daily pattern of suppression followed by activation can explain neurochemically (excessive norepinephrine) and neurophysiologically (kindeling phenomenon) many behavioral side effects during interdose withdrawal oftriazolam such as daytime anxiety, panic, mania and hostility. Also, it can explain to some extent the frequent memory impairment caused by triazolam, which has been observed both during the presence as well as during the absence of the drug. The patteru of repeated suppression/activation of the LC-NE system is consistent with the finding that the dose effect curve of NE on memory has an inverted U shape. In other words, too low or too high norepinephrine levels adversely affect memory. Conclusion
In summary, it is proposed that the more frequent and severe adverse reactions with triazolobenzodiazepines are related to an interaction of several factors including rapid elimination, high binding affinity and their unique direct effects on the norepinephrine system. References
Kales, A. An overview of safety problems of triazolam. International Drug Therapy Newsletter 1991;26:25-28. Aramowitz, M. Aplrazolam for panic disorder. Medical Letter 1991;33:30-31.
248 Kales, A. and Vgontzas, A.N. Not all benzodiazepines are alike. In: Stefanis C.N., Rabavilas, A.D. and Soldatos, C.R. (eds.) Psychiatry: A World Perspective - Voi 3, Amsterdam: Elsevier Science Publishers, 1990:379-384.
Newer Hypnotic Drugs V e l a - B u e n o , A. Department of Psychiatry, Autonomous University and Sleep Disorders Center, Madrid, Spain
Key words: Non-benzodiazepine; Zopiclone; Zolpidem Introduction The multidimensional treatment of insomnia includes, when indicated, the adjunctive use of hypnotic drugs (Kales and Kales, 1987). The introduction of benzodiazepines in clinical practice was a major step, given the much larger margin of safety of these drugs as compared to barbiturates. However it has become clear that not all benzodiazepines (especially the triazoiobenzodiazepines) have an adequate benefit-to-risk-ratio (Kales and Vgontzas, 1990). The identification of the binding sites for benzodiazepines led to the understanding of their mechanisms of action. It is now accepted that benzodiazepines exert their pharmacologic activity through the GABA neurotransmitter system, with the GABA receptor, benzodiazepine recognition site, and chloride channels forming a supramolecular complex. The activation of the benzodiazepine receptor increases the affinity of the GABA receptor for GABA, resulting in an increased number of the openings of chloride channels. In recent years several non-benzodiazepine groups of substances with hypnotic and anxiolitic effects have been found to act through the benzodiazepine GABA receptor complex. In this presentation I will briefly overview the hypnotic and safety profile of two such substances, each belonging to a different drug class: zopiclone and zolpidem.
Zopiclone It is the first drug of the new class of compounds known as cyclopyrrolones (Hindmarch and Musch, 1990). It exerts its hypnotic action by binding to the supramolecular complex in a site different from that of benzodiazepines. Zopiclone binds only to central receptors but not to peripheral ones. Zopiclone is rapidly absorbed, reaching a peak plasma concentration between 30 to 100 minutes after oral administration of 7.5 mg. Its distribution is rapid and the elimination half-life of zopiclone and its active N-oxide metabolite ranges between 3.5 and 6.5 hours (mean 5 hours). It has no long-acting metabolites. The hypnotic efficacy of zopiclone has been documented both in sleep laboratory studies as well as in clinical trials. The recommended dose is 7.5 mg. At this dose level the drug has been shown in sleep laboratory studies with insomniac patients to decrease sleep latency, to increase total sleep duration, to diminish the number of awakenings and to increase the sleep efficiency. It has been reported that with zopiclone there is no development of tolerance or rebound insomnia. However some data in the literature suggest the need to assess both phenomena more carefully. Data on the effects of zopicione on sleep stages are controversial. Thus some studies reported no changes or an increase of slow wave sleep, whereas other studies found a decrease. As for the safety profile of the drug, there are limited residual side effects the next day. Also the existing data suggest that there are relatively few behavioral and psychiatric adverse reactions.
Zolpidem It is a compound with an imidazopyridine structure (Sauvanet et al., 1988). Its binding sites are preferentially central; a
Efficacy and Safety of benzodiazepines: Mechanisms of Action
Kales, A. and Vgontzas, A.N. Pennsylvania State University College of Medicine, Hershey, Pennsylvania, U.S.A. Key words: Benzodiazepines; Adverse Effects; Efficacy; Mechanism of Action Introduction The first benzodiazepines introduced (1,4 benzodiazepines) as anxiolytics and hypnotics, e.g., diazepam and fiurazepam, were similar in pharmacokinetics (relatively slow elimination rate) and pharmacodynamics (relatively low receptor binding affinity/potency). The most frequent side effect of these benzodiazepines was excessive daytime sleepiness, an expected side effect. Late in the 70s, new 1,4 benzodiazepines were introduced, e.g., lorazepam, which were more rapidly eliminated and more potent. Use of these new benzodiazepines was associated with more potent anxiolytic and hypnotic effects, but also with more rapid development of tolerance, significant withdrawal difficulties, i.e., rebound insomnia and anxiety and the adverse reaction of amnesia. In the late 70s and early 80s, a new class of potent and rapidly eliminated benzodiazepines was introduced, the triazolobenzodiazepines. This new class (triazolam and alprazolam) was also different chemically from the classical 1,4 benzodiazepines in that it included a triazolo ring attached to the basic diazepine structure and was promoted for its unique clinical applications. However, it soon became clear from clinical case reports, postmarketing surveillance data and controlled studies that use of triazolobenzodiazepines was associated with frequent and severe CNS and psychiatric adverse reactions in three major categories: amnesia and other cognitive impairments; daytime anxiety, tension and panic and early morning insomnia; and withdrawal difficulties such as rebound insomnia and seizures.
Triazolobenzodiazepines: Unique Profile of Adverse Effects Copelling scientific evidence has been gathered over the last 15 years documenting the frequency and severity of these side effects associated with the use of triazolam (Kales, 1991): (a) Amnesia and other cognitive impairments. Findings supported by: 24 published case reports of 51 patients; Spontaneous Reporting System (SRS) data showing ratios of amnesia for triazolam of 47.5 to 1 and 47.5 to 0 compared to temazepam and flurazepam, respectively; six studies of memory at time of peak drug concentration showing greater memory impairment with triazolam compared to other benzodiazepine hypnotics or placebo and two recent controlled studies showing next-day amnesia with triazolam but not temazepam; FDA analysis of New Drug Application (NDA) data showing significantly more dropouts due to memory impairment with 0,5 mg of triazolam compared to 30 mg of flurazepam (no episodes reported). (b) Hyperexcitability states during drug administration (daytime anxiety, tension and panic and early morning insomnia). Findings supported by: SRS data showing ratios of hyperexcitability for triazolam of 83.8 to 31.9 and 83.8 to 11.1 compared to temazepam and fiurazepam, respectively; 12 case reports; eight controlled studies; and recent FDA analysis of NDA data showing significantly more dropouts due to anxiety with both 0.5 mg and 0.25 mg of triazolam (3-6 times greater) compared to 30 mg of flurazeparn and placebo. (c) Withdrawal difficulties (rebound insomnia and seizures). Findings supported by: SRS data showing ratios of withdrawal difficulties and dependency for triazolam of 23.7 versus 12.0 and 4.2 compared to temazepam or flurazepam, respectively; SRS data indicating a ratio of seizures following withdrawal of triazolam of 37.4:1 compared to temazepam; 12 case reports. In addition, alprazolam has been found to be frequently associated with early development of tolerance, hyperexcitability phenomena during drug administration (interdose rebound anxiety, mania, disinhibition) and severe withdrawal difficulties (panic, seizures). In one large-scale multicenter study, 60% of the patients had either significant increase of the original
247 symptom (panic, anxiety) or new serious withdrawal symptoms, even though the drug was gradually tapered (Abramowitz, 1991). Preliminary analysis of SRS data showed a much higher rate of CNS ADRs for alprazolam versus lorazepam, withdrawal and hyperexcitability being the highest. Mechanism of Action
A thorough review of the pharmacokinetics, pharmacodynamics and the unique properties of triazolobenzodiazepines can account for the serious adverse reactions of these drugs (Kales and Vgontzas, 1990).
Cognitive Impairments We have proposed that triazolam's induced incognitive impairments and symptoms and signs of organic mental disorder are related, in order of importance, to high receptor binding affinity, the unique properties of triazolobenzodiazepines and rapidity of elimination. In contrast, benzodiazepine hypnotics such as temazepam, flurazepam and quazepam are infrequently associated with cognitive impairments. Each of the latter drugs: has relatively low receptor binding affinity; is more slowly eliminated; and, is a 1,4 benzodiazepine that does not have the unique properties specific to a triazolobenzodiazepine.
Hyperexcitability States We have proposed that hyperexcitability states, both during drug administration and withdrawal, are related to at least three mechanisms: (1) rapid elimination; (2) relatively high receptor binding affinity; and (3) unique properties of triazolobenzodiazepines, such as direct effects on the locus coeruleus-noradrenergic system. When all three factors are present, for example, with traizolam, hyperexcitability phenomena are more frequent, immediate and of greater severity. When none of the factors is present, as is the case for both flurazepam and quazepam which are slowly eliminated, have relatively low receptor binding affinity and none of the unique triazoiobenzodiazepine properties, hyperexcitability phenomena are much more infrequent, delayed and mild in severity. When only one factor is present (for example, temazepam is relatively rapidly eliminated but has a low receptor binding affinity), hyperexcitability phenomena are more likely to be less frequent and milder in severity.
Unique Chemical Properties Triazolam, in addition to its ultra-short elimination half-life and high binding affinity, shares some of the unique chemical properties of the triazolobenzodiazepines. For example, triazolobenzodiazepines activate alpha-2 adrenoreceptors, inhibit platelet activating factor 0aAF), and do not appear to have total cross-tolerance with other benzodiazepines. Alpha-2 receptors are mainly located in the brain system and have an inhibiting effect oil the locus coeruleus-noradrenergic (LC-NE) system. Also, PAF activates eorticotropin releasing factor, which in turn has an activating effect on the LC-NE system. Therefore, triazolobenzodiazepines, by activating alpha-2 adrenoreceptors and inhibiting PAF, have a direct suppressant effect on the LC-NE system. It is also likely that the initial dampening or suppression of the LC-NE system is followed by a significant rebound and activation of the LC-NE system, when the drug is rapidly eliminated from the system. This repetitive daily pattern of suppression followed by activation can explain neurochemically (excessive norepinephrine) and neurophysiologically (kindeling phenomenon) many behavioral side effects during interdose withdrawal oftriazolam such as daytime anxiety, panic, mania and hostility. Also, it can explain to some extent the frequent memory impairment caused by triazolam, which has been observed both during the presence as well as during the absence of the drug. The patteru of repeated suppression/activation of the LC-NE system is consistent with the finding that the dose effect curve of NE on memory has an inverted U shape. In other words, too low or too high norepinephrine levels adversely affect memory. Conclusion
In summary, it is proposed that the more frequent and severe adverse reactions with triazolobenzodiazepines are related to an interaction of several factors including rapid elimination, high binding affinity and their unique direct effects on the norepinephrine system. References
Kales, A. An overview of safety problems of triazolam. International Drug Therapy Newsletter 1991;26:25-28. Aramowitz, M. Aplrazolam for panic disorder. Medical Letter 1991;33:30-31.
248 Kales, A. and Vgontzas, A.N. Not all benzodiazepines are alike. In: Stefanis C.N., Rabavilas, A.D. and Soldatos, C.R. (eds.) Psychiatry: A World Perspective - Voi 3, Amsterdam: Elsevier Science Publishers, 1990:379-384.
Newer Hypnotic Drugs V e l a - B u e n o , A. Department of Psychiatry, Autonomous University and Sleep Disorders Center, Madrid, Spain
Key words: Non-benzodiazepine; Zopiclone; Zolpidem Introduction The multidimensional treatment of insomnia includes, when indicated, the adjunctive use of hypnotic drugs (Kales and Kales, 1987). The introduction of benzodiazepines in clinical practice was a major step, given the much larger margin of safety of these drugs as compared to barbiturates. However it has become clear that not all benzodiazepines (especially the triazoiobenzodiazepines) have an adequate benefit-to-risk-ratio (Kales and Vgontzas, 1990). The identification of the binding sites for benzodiazepines led to the understanding of their mechanisms of action. It is now accepted that benzodiazepines exert their pharmacologic activity through the GABA neurotransmitter system, with the GABA receptor, benzodiazepine recognition site, and chloride channels forming a supramolecular complex. The activation of the benzodiazepine receptor increases the affinity of the GABA receptor for GABA, resulting in an increased number of the openings of chloride channels. In recent years several non-benzodiazepine groups of substances with hypnotic and anxiolitic effects have been found to act through the benzodiazepine GABA receptor complex. In this presentation I will briefly overview the hypnotic and safety profile of two such substances, each belonging to a different drug class: zopiclone and zolpidem.
Zopiclone It is the first drug of the new class of compounds known as cyclopyrrolones (Hindmarch and Musch, 1990). It exerts its hypnotic action by binding to the supramolecular complex in a site different from that of benzodiazepines. Zopiclone binds only to central receptors but not to peripheral ones. Zopiclone is rapidly absorbed, reaching a peak plasma concentration between 30 to 100 minutes after oral administration of 7.5 mg. Its distribution is rapid and the elimination half-life of zopiclone and its active N-oxide metabolite ranges between 3.5 and 6.5 hours (mean 5 hours). It has no long-acting metabolites. The hypnotic efficacy of zopiclone has been documented both in sleep laboratory studies as well as in clinical trials. The recommended dose is 7.5 mg. At this dose level the drug has been shown in sleep laboratory studies with insomniac patients to decrease sleep latency, to increase total sleep duration, to diminish the number of awakenings and to increase the sleep efficiency. It has been reported that with zopiclone there is no development of tolerance or rebound insomnia. However some data in the literature suggest the need to assess both phenomena more carefully. Data on the effects of zopicione on sleep stages are controversial. Thus some studies reported no changes or an increase of slow wave sleep, whereas other studies found a decrease. As for the safety profile of the drug, there are limited residual side effects the next day. Also the existing data suggest that there are relatively few behavioral and psychiatric adverse reactions.
Zolpidem It is a compound with an imidazopyridine structure (Sauvanet et al., 1988). Its binding sites are preferentially central; a