Benzodiazepines selection considerations

The major uses of individual barbiturates are listed in Table 16-3, mostly uses involving CNS actions of these drugs. As with the benzodiazepines, selection of particular barbiturates for a given therapeutic indication is based primarily on pharmacokinetic considerations. 

Specific factors to consider are both psychiatric and physical contraindications. For example, bupropion is contraindicated in a depressed patient with a history of seizures due to the increased risk of recurrence while on this agent. Conversely, it may be an appropriate choice for a bipolar disorder with intermittent depressive episodes that is otherwise under good control with standard mood stabilizers. This consideration is based on the limited data suggesting that bupropion is less likely to induce a manic switch in comparison with standard heterocyclic antidepressants. Another example is the avoidance of benzodiazepines for the treatment of panic disorder in a patient with a history of alcohol or sedative-hypnotic abuse due to the increased risk of misuse or dependency. In this situation, a selective serotonin reuptake inhibitor (SSRI) may be more appropriate. 

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. 

All benzodiazepines are equally effective anxiolytics, and consideration of pharmacokinetic properties and the patient s clinical situation will assist in the selection of the most appropriate agent. Pharmacokinetic differences vary, and the clinician must monitor response to the initial treatment regimen after 2 to 4 weeks. ... 

Advances in the molecular biology and pharmacology of the neurotransmitter, GABA, have established there is considerable heterogeneity in GA-BAa receptors, the receptors known to be modulated by all the clinically effective benzodiazepine anxiolytics. The consequent surge of activity to find anxiolytic agents which are more selective and possess fewer side-effects than the early benzodiazepines has led to the synthesis of a variety of novel structures. One such series of pyrido[l,2-a]benzimidazoles is described in Chapter 4. 

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