The benzodiazepines are the most widely prescribed sedative/hypnotic drugs and over 20 congeners are marketed. Because of the huge variation in potency, doses range from 1 to 200 mg. Intravenous abuse of liquid encapsulated forms (e.g., temazepam) occurs, but the usual route is oral.
Pharmacological Effects
The most prominent effects of benzodiazepines on the CNS are sedation, hypnosis, decreased anxiety, and anticonvulsant activity. There are virtually no effects on the peripheral tissues even in overdose.
Toxic Effects
Chronic abuse leads to blurred vision, confusion, slow reflexes, slurred speech, and hypotension. Benzodiazepines are relatively safe drugs in overdose, and deaths are usually the result of concomitant ingestion of ethanol or other drugs.
Assay Technology
Benzodiazepines are extensively metabolized by the liver by processes of N-dealkylation and hydroxylation. Only trace amounts of the parent compounds appear in the urine. Hydroxylated metabolites of benzodiazepines and those with a hydroxyl group in the C3 position are conjugated to glucuronic acid; these conjugates account for the major proportion of the dose eliminated in the urine.
The diversity of ring substituents and metabolites is immense, and no immunoassay yet devised can claim to cover all members of the group. The compromise has been to raise antibodies toward the most common metabolites encountered (in particular, oxazepam and nordiazepam), and hope that there is sufficient cross-reactivity toward other products to widen the scope of the assay. Where the therapeutic dose is very low, as in the case of the so-called “date-rape” drug flunitrazepam, immunoassays often give false positives. Hydrolyzing samples with β-glucuronidase can increase detection rates, and some manufacturers incorporate this enzyme in the reagent. For some low-dose benzodiazepines such as alprazolam and triazolam, further improvement can be made by lowering the cutoff level. A comprehensive account of the problems of benzodiazepine detection by immunoassays can be found in Fraser and Meatherall (1996).
The EMIT d.a.u. benzodiazepine assay detects primarily those drugs that have oxazepam glucuronide as a major urinary metabolite. More recent benzodiazepine drugs such as alprazolam and midazolam are also readily detected by this assay. A positive result is based on a response greater than that of a 300 ng/mL oxazepam calibrator (see Table 10).
TABLE 10. Concentrations of Benzodiazepine Compounds Showing a Positive Response in the EMIT d.a.u. Benzodiazepine Assay. Cross-Reactivity Data Relative to Oxazepam Are Listed in Table 11
CompoundConcentration (ng/mL)Chlordiazepoxide3000Clonazepam2000Demoxepam2000Desalkyflurazepam2000N-desmethyldizepam2000Diazepam2000Flunitrazepam2000Flurazepam2000Lorazepam3000Nitrazepam2000Oxazepam300
Cross-reactivity data relative to oxazepam are listed in Table 11.
TABLE 11. Relative Cross-Reactivity of Benzodiazepine Derivatives to Oxazepam in the EMIT d.a.u. Benzodiazepine Assay
CompoundRelative Cross-Reactivity∗Chlordiazepoxide0.03–0.33Clidinium bromide0.07Clonazepam0.15Clorazepate0.25Demoxepam0.15N-desalkylflurazepam0.14–1.00Diazepam0.15–0.63Flurazepam>0.01–0.23Hydroxyethylflurazepam>0.13-Hydroxydesalkyl-flurazepam0.50Lorazepam>0.01–0.23Medazepam0.06Nitrazepam0.15–0.35Norchlordiazepoxide0.17Nordiazepam0.15–1.11Oxazepam1.00Temazepam (3-hydroxydiazepam)0.45
∗Relative cross-reactivity is defined as the test concentration of oxazepam divided by the concentration of cross-reacting compound required to give an equal response.The EMIT assay is unlikely to detect the use of flurazepam, flunitrazepam, or triazolam because of poor cross-reactivity and low concentrations of the urinary metabolites.
False-positive results have occurred in samples containing the nonsteroidal anti-inflammatory drug, oxaprozin, but no major interference from other non-benzodiazepine drugs has been reported.
The CEDIA assays have greater expected rate differences between the zero and cutoff calibrators than, say, EMIT II. This gives better discrimination between blank urine samples and those with drugs at cutoff concentrations. The high sensitivity (HS) protocol benzodiazepine assay also improves the rate of positive detection by an enhancement of the sensitivity toward benzodiazepine glucuronides. Cross-reactivity data for the CEDIA benzodiazepine assay are listed in Table 12. False-positive results have been noted in samples containing metabolites of the antidepressant drug sertraline, but changing the antibodies has now eliminated the problem. In other reports, some interference was noted in samples containing the antihistamine embramine and more recently the nonsteroidal anti-inflammatory drug, oxaprozin, has been shown to cause false positives.
TABLE 12. Cross-Reactivity of Benzodiazepines in the CEDIA Benzodiazepine Assay
CompoundCross-Reactivity (%)Nitrazepam100Alprazolam205Bromazepam110Chlordiazepoxide13Clobazem62Clonazepam140Diazepam247Flunitrazepam135Flurazepam190Lorazepam122Medazepam135Oxazepam107Nordiazepam210Temazepam144Triazolam191
The Abuscreen OnLine benzodiazepine system is very sensitive and is claimed to detect at least 6 ng/mL of nordiazepam. Manufacturers have been criticized in the past for publishing cross-reactivity data only for the parent drugs, but no such accusation can apply with this assay where a long list of benzodiazepines have been evaluated together with, in many cases, their metabolites. See Table 13.
TABLE 13. Cross-Reactivity of Benzodiazepine Compounds in the Abuscreen OnLine Benzodiazepine Assay
CompoundConcentration Equivalent to 100 ng/mL NordiazepamCross-Reactivity (%)Alprazolam11289α-Hydroxyprazolam114884-Hydroxyprazolam11686Bromazepam13574Chlordiazepoxide17258Desmethylchlordiazepoxide17956Clonazepam16760Demoxepam12878Diazepam11885Oxazepam13972N-Methyloxazepam12779Flunitrazepam18255Desmethylflunitrazepam169593-Hydroxyflunitrazepam38526Flurazepam16461Desalkylflurazepam17557Didesethylflurazepam12580Hydroxyethylfiurazepam12381Lorazepam16959Medazepam34529Desmethylmedazepam28635Midazolam13029Nitrazepam133757-Acetamidonitrazepam62.5000.27-Aminonitrazepam18953Pinazepam12779Prazepam13972Triazolam12779α -Hydroxytriazolam115874-Hydroxytriazolam19651
No interference from other drugs has been reported.
The Concateno benzodiazepines microplate EIA is designed for use on serum or whole blood and can give a semiquantitative result. The calibrators consist of a protein matrix with temazepam at concentrations of 0, 1, 10, and 100 ng/mL (for a description of the kit see Amphetamines). No major interferences have been reported and a list of benzodiazepine cross-reactivity data is given in Table 14.
TABLE 14. Cross-Reactivity of Benzodiazepines in the Concateno Microplate Benzodiazepine Assay
CompoundConcentration (ng/mL)Cross-Reactivity (%)Temazepam1, 10, 100100Alprazolam1100104010060Nordiazepam1, 1010100510002Oxazepam1051000.55001.0Triazolam100210000.410,0000.08Nitrazepam100210000.410,0000.7Diazepam111010100100Flunitrazepam10, 100510002Clobazam10501002110006.5
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Drugs and Behavior, Psychiatry of
R.M. Julien, in International Encyclopedia of the Social & Behavioral Sciences, 2001
(a)
Development of the barbiturates as sedative-hypnotic drugs. Recognition of their toxicity and abuse potential led to identification and development of the benzodiazepines as safer agents for the treatment of anxiety states and insomnia.
(b)Development of the phenothiazines for the treatment of schizophrenia. Recognition of the therapeutic limitations and toxicities of these drugs led to development of the atypical antipsychotics in the 1980s and 1990s.
(c)Development of several classes of antidepressant drugs effective in the treatment of major depression and dysthymia. These included the monoamine oxidase inhibitors and the tricyclic antidepressants. This was followed in the 1980s and 1990s by development of less toxic antidepressants such as the serotonin-specific reuptake inhibitors and ‘dual action’ antidepressants. As the twenty-first century begins, additional classes of safer and even less toxic antidepressants are being introduced. These include a specific norepinephrine reuptake inhibitor, COMT-inhibitors, a selective, reversible MAO-inhibitor, a neurokinin-1 receptor antagonist, and ‘natural’ products such as St. John's wort and DHEA (an adrenal androgen).
(d)Identification of the therapeutic efficacy of lithium in the treatment of bipolar illness. In the 1990s, safer and less toxic alternatives were developed. These included at least 6 different antiepileptic drugs, atypical antipsychotic drugs, and ‘natural’ products such as omega-3 fatty acids.
(e)Identification of the usefulness of certain of the antidepressant drugs and atypical antipsychotics in the treatment of specific anxiety disorders (e.g., post-traumatic stress disorder (PTSD), phobias, panic disorder, and obsessive-compulsive disorder), and behavioral disorders with associated symptoms of agitation, aggression, and violence.
(f)Development of psychostimulant agents effective in the treatment of childhood, adolescent, and adult attention-deficit/hyperactivity disorder (ADHD), Alzheimer's disease, narcolepsy, and other disorders of attention, thought, and memory.
(g)Development of drugs useful in the treatment of Parkinson's disease. Here we include dopamine replacement agents, dopamine receptor agonists, and a variety of other drugs that have improved the lives of individuals suffering from this disorder.
(h)Development of new anesthetic agents, allowing for the provision of safe anesthesia in patients in any state of health, debility, or surgical requirement. Such agents include ketamine, etomidate, non-toxic inhalation agents, and ultrashort-acting narcotics and muscle relaxants.
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Porous catalytic systems in the synthesis of bioactive heterocycles and related compounds
Elena Pérez-Mayoral, Antonio J. López-Peinado, in Green Synthetic Approaches for Biologically Relevant Heterocycles (Second Edition), 2021
4.3.2.3 Seven-membered ring heterocycles
Although seven-membered ring heterocycles are a class of heterocyclic compounds infrequent in the nature, benzodiazepines exhibit important biological activities and are widely used as pharmaceuticals.
4.3.2.3.1 Benzodiazepines
Benzodiazepines are often bioactive compounds, widely used as anticonvulsants, antianxiety, hypnotic agents, analgesics, antidepressives, and antiinflammatory drugs (Fig. 4.21) [228]. For instance, 1,5-benzodiazepines are useful precursors for the synthesis of some benzodiazepine derivatives with pharmacological properties such as triaxolo-, triazolo-, oxadiazolo-, oxazino-, or furano-benzodiazepines. In particular, the application of these compounds has been also extended to various diseases such as cancer, viral infection, and cardiovascular disorders.
Figure 4.21. Core structure of benzodiazepines. R refers to side chains that give benzodiazepines their exclusive properties.
4.3.2.3.2 Ring closure reactions
Tajbakhsh et al. described the synthesis of 1,5-benzodiazepines from o-phenylenediamine and ketones over natural zeolites [229]. The authors used a new Heulandite (HEU) type of natural zeolite and the synthetic zeolites HZSM-5 and HY as catalysts. HY and HEU proved to be more efficient catalysts than the HZSM-5 zeolite due to the greater number of Lewis acid sites and the weak acidic sites found in both HY and HEU catalysts. It seems that weak Lewis acid sites favor the progress of the reaction and enhance the catalytic performance. These zeolite catalysts could be reused up to five times without significant loss of activity. Additional studies have been more recently published by Jeganathan and Pitchumani claiming the protocol simplicity and nontoxicity, low cost, and recyclability of this type of eco-friendly catalysts [230].
Fazaeli and Aliyan reported the synthesis of 1,5-benzodiazepine derivatives using Keggin-type polyoxometalates, H3PW12O40, and H3PMo12O40 (HTP and HMP, respectively) supported on clays (KSF and K10 montmorillonite) as heterogeneous catalysts (Scheme 4.59) [231]. The material with the best catalytic activity was HTP/KSF in the optimal conditions of reaction. The catalyst could be recycled decreasing gradually the yields after two cycles of reaction. Recently, Yadav and Yadav carried out the condensation reaction between o-phenylenediamine and acetophenone over a variety of heteropolyacid nanocatalysts [232]. The most active catalyst was Cs2.5H0.5PW12O40/K-10 at 20% wt.%/wt.%, this material was active and reusable for at least four runs.
Scheme 4.59. Synthesis of benzodiazepines.
Mesoporous materials such as H-MCM-22 have also been used as effective catalysts in the condensation reaction between o-phenylenediamine and symmetrical and unsymmetrical ketones in acetonitrile at room temperature, in shorter reaction times [233]. The authors studied in detail the effect of the catalyst and the catalyst concentration on the reaction. The catalyst presented a high activity for this reaction compared to other catalysts in the literature, showing 65%–87% isolated yield of the corresponding 1,5-benzodiazepine derivative.
Corma et al. carried out the one-pot synthesis of substituted 1,5-benzodiazepines from substituted nitroaromatics and ketones, under solvent-free conditions, through cascade reactions in the presence of hydrogen [234]. For that purpose, the authors used bifunctional solid catalysts, Pt/TiO2-MCM-41 and Au/TiO2-MCM-41, composed of a chemoselective hydrogenation functional group. This group was able to reduce the nitro group to a diamino group, followed by the catalytic cyclocondensation of the formed o-phenylenediamine with the corresponding ketone.
Vinu et al. were the first in reported the synthesis of 1,5-benzodiazepine through a condensation reaction between o-phenylenediamine and ketones in acetonitrile, at room temperature, over AlKIT-5 catalysts [235]. Aluminum-supported mesoporous KIT-5 materials (AlKIT-5) proved to be highly active catalysts due to their high acidity, high surface area, large pore volume, and cage type 3D porous structure. These catalysts could also be recycled without a significant loss of activity.
Much more recently, different MIL-100(M) (where M is V3+, Al3+, Fe3+, and Cr3+) have been proposed as recyclable and efficient catalysts involved in the cyclocondensation of o-phenylenediamine with acetone demonstrating that the metal nature in MIL-100(M) influence the reaction rate [236].
Alternatively, to the porous catalyst mentioned above, we have recently proposed new series of bifunctional carbon-based catalysts incorporating both types of acid active sites, Lewis or/and Brönsted acids, which incorporate zirconia (Zr) or sulfated zirconia (SZr) over the carbon surface, active in the synthesis of benzodiazepines (Scheme 4.60) [237]. Our studies confirmed that the combination of porous structure of carbon supports and the acid character of supported Zr or SZr allows a much more sustainable synthesis of benzodiazepine from o-phenylenediamine and acetone, providing high activity and selectivity. These carbon-based catalysts represent a more efficient alternative to zeolites or mesoporous silica catalysts above mentioned or even Fe-containing intercalated montmorillonites recently reported [238].
Scheme 4.60. Synthesis of benzodiazepine 1 from o-phenylenediamine 2 and acetone 3 at 50°C.
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Chloral Hydrate
Stephen Erhorn, in xPharm: The Comprehensive Pharmacology Reference, 2007
Introduction
Chloral hydrate has been used in human and veterinary medicine as a sedative and hypnotic drug since the mid-19th century. Chloral hydrate's effects are primarily caused by its active metabolite trichloroethanol. Chloral hydrate is primarily a hypnotic and has little or no analgesic effect. In candidates for surgery, it is a satisfactory preoperative sedative that allays anxiety and induces sleep without depressing respiratory or cough reflexes. In postoperative care and control of pain, it is a valuable adjunct to opiates and analgesics. However, it generally has been replaced by agents with better pharmacokinetic and pharmacodynamic profiles. The major route of exposure of the general public is from drinking water, as trichloroethanol, are formed when drinking water is disinfected with chlorine (Chloral betaine is a prodrug and is reduced to chloral hydrate following ingestion into the stomach, which has the same actions and uses as chloral hydrate).