Benzodiazepine pharmacological properties

Secobarbital exhibits the same pharmacologic properties as other members of the barbiturate class. Most nonmedical use is with short-acting barbiturates, such as secobarbital. Although there may be considerable tolerance to the sedative and intoxicating effects of the drug, the lethal dose is not much greater in addicted than in normal persons. Tolerance does not develop to the respiratory effect. The combination of alcohol and barbiturates may lead to fatalities because of their combined respiratory depressive effects. Similar outcomes may occur with the benzodiazepines. Severe withdrawal symptoms in epileptic patients may include grand mal seizures and delirium. 

Benzodiazepines have similar pharmacological properties and are used in anxiety and insomnia. The choice of which benzodiazepine to use usually lies with the pharmacodynamic and pharmacokinetic properties, which vary across the class. For example, diazepam, flurazepam and nitrazepam have a prolonged duration of action whereas lorazepam and temazepam have a shorter duration of action. 

Pharmacology Zolpidem is a nonbenzodiazepine hypnotic. While zolpidem is a hypnotic agent with a chemical structure unrelated to benzodiazepines, barbiturates, or other drugs with known hypnotic properties, it interacts with a GABA-BZ receptor complex and shares some of the pharmacological properties of the benzodiazepines. 

Zolpidem (Ambien) and zaleplon (Sonata) are structurally unrelated to the benzodiazepines, but both drugs share pharmacological properties with the benzodiazepines. They bind to benzodiazepine receptors and facilitate GABA-mediated inhibition. 

Allain H, Rahola JG (1996) Switching to zolpidem in patients habituated to long-term benzodiazepine use. In H Freeman, AJ Puech, T Roth (eds) Zolpidem an update of its pharmacological properties and therapeutic place in the management of insomnia. Elsevier, Paris, 176-182... 

Historically the first sedative hypnotics to be introduced were the bromides in the mid 19th century, shortly followed by chloral hydrate, paraldehyde and urethane. It was not until the early years of this century that the first barbiturate, sodium barbitone, was developed and this was shortly followed by over 50 analogues, all with essentially similar pharmacological properties. The major breakthrough in the development of selective, relatively non-toxic sedative hypnotics followed the introduction of chlordiazepoxide in 1961. Most of the benzodiazepines in current use have been selected for their high anxiolytic potency relative to their central depressant effects. Because of their considerable safety, the benzodiazepines have now largely replaced the barbiturates and the alcohols, such as chloral hydrate and trichloroethanol, as the drugs of choice in the treatment of insomnia. 

The pharmacological properties of these drugs are dealt with in Chapter 5, and therefore only their propensity to cause physical and psychological dependence is considered here. Because of their lack of efficacy, and particularly because of their toxicity, barbiturates should never be used now as anxiolytic or sedative drugs. For this reason, emphasis is placed here on the benzodiazepines, which are not only effective but also relatively safe. Nevertheless, problems have arisen regarding their ability to cause dependence, and so this aspect of their pharmacology must be considered. 

The imine groups of benzodiazepines can participate in cycloaddition reactions to form both mono- and bis-adducts. In this way 3-, 4-, 5-, and 6-membered rings have been annelated to the diazepine rings. Much of this work has been motivated by the observation that a number of annelated benzodiazepines have interesting pharmacological properties (78MI2). 

The title compound, MJ-13805, gepirone 38, possessing pharmacological properties indicative of auxiolytic activity in man, distinct from the activities of classical benzodiazepine auxiolytics21,22, has been deuterium labelled23 according to a general synthetic route, illustrated by equation 6. It permits one to obtain in a similar manner the 3H4... 

Brogden RN, Goa KL. Flumazenil. A reappraisal of its pharmacological properties and therapeutic efficacy as a benzodiazepine antagonist. Drugs 1991 42(6) 1061-89. 

Benzodiazepines and 3//-1,5-benzodiazepines are important classes of compounds because of their interesting pharmacological properties. They show anticonvulsant, antianxiety, analgesic, sedative, antidepressive, hypnotic, antiinflammatory activity and also potent inhibitor of HIV-1 reverse transcriptase. Besides their biological relevance, benzodiazepines have also found application as dyes for acrylic fibers [163]. 

The antianxiety effects of chlordiazepoxide (165) were described in 1960 and this compound was followed by diazepam (135). These two drugs have captured 75% of the market for sedatives in the USA. Other benzodiazepines used as antianxiety agents include oxazepam (166 R = H), a metabolite of diazepam that is better tolerated, lorazepam (166 R = Cl) and potassium clorazepate (167). Prazepam is the iV-cyclopropylmethyl analogue of diazepam. The benzodiazepines have other therapeutic applications, many being used for inducing sleep, diazepam and nitrazepam are anticonvulsants and flurazepam (168) is both an antianxiety agent and a potent hypnotic. Thieno- and pyrazolo-1,4-diazepinones isosteric with diazepam have similar pharmacological properties (B-81 Ml 10604). 

As part of a systematic search for benzodiazepines exhibiting unusual pharmacological properties, scientists at Hoffman-La Roche synthesized a number of novel azido-substituted benzodiazepine derivatives [291]. The introduction of an azido group in the 7-position of 5-phenyl-1,4-benzodiazepines afforded a series of compounds (225)-(231) which included the 7-azido analogues of diazepam and oxazepam (228) and (229). The azido pharmacophore endowed potency and a spectrum of biological activity comparable with the corresponding 7-halo and 7-nitro analogues, and far superior to the 7-amino derivatives. All of the azides prepared were... 

Many of the pharmacological properties of barbiturates and benzodiazepines, including their therapeutic actions and their tolerance and dependence, are associated with their effects on GABAergic neurotransmission in the CNS. GABA (10) is a major inhibitory neuro-... 

Derivatives of /V-alkylbenzophenones and peptidoamino-benzophenones undergo hydrolysis, with subsequent intramolecular condensation that results in the formation of the 1,4-benzodiazepine hypnotics. A number of such compounds, e.g. rilmazafone (140), were suggested to have more beneficial pharmacological properties in comparison to standard benzodiazepines. Rilmazafone is a ring-opened derivative of 1,4-benzodiazepine (Scheme 25) and was developed in Japan... 

The importance of l,4-benzodiazepine-2,5-diones (BZDs) has increased due to their valuable pharmacological properties in the treatment of cancer, AIDS, hypertension, inflammation, pain, muscle tension, and depression. The green reaction of isatoic anhydrides with a-amino acids in the presence of the IL l-butyl-3-methyli-midazolium bromide gave 1,4- benzodiazepine-2,5-diones in excellent yields with no catalyst (Equation 4.45). The reaction work-up is simple and the IL was easily separated from the reaction and reused. The methodology was fairly general and numerous cyclic and acyclic a-amino acids were used to produce 1,4-benzodiaze-pine-2,5-diones [87]. 

The pharmacological properties of meprobamate resemble those of the benzodiazepines in a number of ways. Meprobamate can release suppressed behaviors in experimental animals at doses that cause little impairment of locomotor activity, and although it can cause widespread depression of the CNS, it cannot produce anesthesia. However, ingestion of large doses of meprobamate alone can cause severe or even fatal respiratory depression, hypotension, shock, and heart failure. Meprobamate appears to have a mild analgesic effect in patients with musculoskeletal pain, and it enhances the analgesic effects of other drugs. 

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