Anxiolytics pharmacological properties

From the examination of structure-activity relationships, it has been concluded that a phenyl moiety at C-6 as well as a 4-hydroxypiperidine side-chain attached to C-3 of the pyridazine system is essential for anticonvulsant activity in this class of compounds [184], Compounds (54) and (55) have been found to have similar anticonvulsant profiles in animals (mice, rats and baboons) [165, and literature cited therein] and to represent potent broad-spectrum antiepileptic drugs. Their potency with regard to antagonizing seizures (induced by electro-shock or various chemicals) has been compared with standard anticonvulsants like carbamazepine and phenobarbitone [185, 186], A quantitative electroencephalographic analysis of (55) has been published [187]. From in vitro studies it has been concluded that the anticonvulsant activities of these compounds are not mediated by an enhancement of GABAergic transmission or by an interaction with benzodiazepine receptor sites [ 165,186,187], On the other hand, in vivo experiments showed that (54), at anticonvulsant doses, increases the affinity of flunitrazepam for its central receptor site [ 186], Investigations of (54) and (55) in a behavioural test predictive of antianxiety activity revealed a marked difference in the pharmacological profiles of these structurally closely related compounds the dichloro compound SR 41378 (55) has also been found to possess anxiolytic (anticonflict) properties [165],... 

A further discussion of the pharmacological properties of the anxiolytic drugs is given in Chapter 9. 

Goa KL, Ward A Buspirone a preliminary review of its pharmacological properties and therapeutic efficacy as an anxiolytic. Drugs 32 114-129, 1986... 

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. 

Opening with the history of kava, this book proceeds to describe the botany, cultivation, harvesting and economic aspects of kava. A major part of the book is then devoted to the chemical and pharmacological properties of the kavalactones, the psychoactive constituents of kava that are reported to have sedative, anxiolytic, analgesic, local anesthetic, anticonvulsant, and neuroprotective properties. The medical and clinical studies that provide evidence for the therapeutic benefits are balanced with an assessment of the known adverse effects and interactions and the recently reported cases of severe liver toxicity in which kava has been implicated. 

Some of this classification is not pure in that agents in some subcategories have multiple pharmacological properties that are frequently of clinical usefulness and not necessarily related to psychotropic effects. For example, some of the minor tranquilizers include members that have excellent skeletal muscle relaxant properties several are used as antiepileptics (e.g., diazepam). The diphenylmethane derivative hydroxyzine is a particularly good example of multiple pharmacology. In addition to its anxiolytic (antianxiety) property, it also exhibits the following clinically significant assets antihistaminic, adrenolytic, antiemetic, antispasmodic, hypothermic, and sedative effects. 

With an understanding of the mechanisms and metabolic reactions of these drugs, newer drug design concepts were applied in later synthetic phases. It is not surprising that compounds were developed in which certain pharmacologic properties became elevated or subdued (but never eliminated). Flurazepam (No. 7, Table 12-8), nitrazepam (No. 13), and triazolam (No. 22) became widely used as hypnotics clonazepam (No. 3) is used almost exclusively as an anticonvulsant, while diazepam (No. 6), clorazepate (No. 4), lorazepate (No. 19), prazepam (No. 16), and aprazolam (No. 19) are marketed primarily as anxiolytics. 

Doxepin [1668-19-5] (38), unlike other commercially available tricyclics, has an oxygen atom in the bridge between the two aromatic rings. It is marketed as a cis—trans mixture (1 5) of isomers, both of which are active. This close relative of amitriptyline (33) has both sedative and anxiolytic properties associated with its antidepressant profile. Maprotiline [10262-69-8] (39) and amoxapine [14028-44-5] (40) are pharmacologically, although not chemically, similar to the tricycHc secondary amines. Clomipramine [303-49-1] (41) has similar pharmacological and antidepressant efficacy. However, clomipramine is approved by the U.S. FDA only for the treatment of obsessive—compulsive disorder. Representative brands of tricycHc antidepressants marketed in the United States are Hsted in Table 2. 

Imipramine, a TCA, was the first pharmacological agent noted to treat panic disorder (Klein 1964). Other TCAs, notably clomipramine, have also been found to have significant anxiolytic properties (den Boer et al. 1990 Modigh 1992). Studies of ethnic differences in the pharmacokinetics of the TCAs in... 

In principle, all drugs with damping action on the central nervous system could be used as anxiolytics or hypnotics, but the pharmacological and/or pharmacokinetic properties of most compounds are not appropriate for their therapeutic use ... 

Buspirone has selective anxiolytic effects, and its pharmacologic characteristics are different from those of other drugs described in this chapter. Buspirone relieves anxiety without causing marked sedative, hypnotic, or euphoric effects. Unlike benzodiazepines, the drug has no anticonvulsant or muscle relaxant properties. Buspirone does not interact directly with GABAergic systems. It may exert its anxiolytic effects by acting as a partial agonist at brain 5-HTia receptors, but it also has affinity for brain dopamine D2 receptors. Buspirone-treated patients show no... 

Diazepam, lorazepam, and midazolam are used for preanesthetic medication and as adjuvants during surgical procedures performed under local anesthesia. As a result of their sedative, anxiolytic, and amnestic properties, and their ability to control acute agitation, these compounds are considered to be the drugs of choice for premedication. (The basic pharmacology of benzodiazepines is discussed in Chapter 22.) Diazepam and lorazepam are not water-soluble, and their intravenous use necessitates nonaqueous vehicles, which cause pain and local irritation. Midazolam is water-soluble and is the benzodiazepine of choice for parenteral administration. It is important that the drug becomes lipid-soluble at physiologic pH and can readily cross the blood-brain barrier to produce its central effects. 

It is generally accepted that the pharmacology of benzodiazepine derivatives is identical qualitatively but varies quantitatively. In other words, the sedative, hypnotic, anticonvulsant, muscle relaxant, and anxiolytic properties reside to various degrees in all of them. Nevertheless, they do exhibit pharmacological specificity, making it necessary to select a particular drug for its desired therapeutic effect. 

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