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Chapter 6: Intravenous Sedative–Hypnotics

Aaron Freeman; Ken B. Johnson

HISTORY OF DEVELOPMENT

Sedative–hypnotics are a relatively new class of anesthetics, beginning with the introduction of sodium thiopental in the early 1930s. Since then, several ­sedative–hypnotics have been introduced (Table 6–1), with more in the drug development pipeline, such as remimazolam, fospropofol, and isomers of etomidate. Goals of these modified drugs include fast metabolism and breakdown as well as creating “soft” drugs with safer profiles. A major goal in developing methoxycarbonyl-etomidate is the removal of adrenocortical suppression by modifying the pyrrole ring in etomidate. Fospropofol is water-soluble as opposed to propofol, which is administered as an oil–water emulsion. In 2008, fospropofol was approved by the US Food and Drug Administration, although many clinical trials are still underway for specific uses of the drug.1

Table 6–1History of sedative–hypnotics.
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Table 6–1 History of sedative–hypnotics.
Drug Year of Discovery Year of First Clinical Use Details
Sodium thiopental 1930 1934 Popular for many years for the induction of anesthesia. However, the use in the United States as part of a 3-drug cocktail for lethal injection of death row inmates caused the major supplier to stop sales to the United States. This has limited availability of the drug.
Benzodiazepines 1955 1957 Well known for positive drug effects that include sedation, anticonvulsant properties, and muscle relaxation. However, dependence and withdrawal symptoms have limited their use.
Ketamine 1962 1970 After approval was a popular battlefield anesthetic. However, unpleasant awakening/dissociation has limited use. Illicit use led to classification as a Schedule III controlled substance.
Etomidate 1964 1972 Used for sedation in the intensive care unit until studies showed increased mortality rates due to adrenocortical suppression and inhibition of protein synthesis.4
Propofol 1973 1983 (current formulation) Negative side effects of various formulations led to the current lipid emulsion form. Propensity for bacterial growth led to the addition of EDTA or sodium metabisulfite to prevent bacterial growth. The drug is very popular for induction of anesthesia due to quick action and elimination along with a decrease in intracranial pressure, decreased metabolism of oxygen by the brain and anticonvulsant effects.5
Dexmedetomidine 1970s 1999 The D-steroisomer of medetomidine was used for years as an α2-receptor agonist in veterinary medicine. The drug was approved by the FDA for use in humans in 1999.

EDTA, ethylenediaminetetraacetic acid; FDA, US Food and Drug Administration.

MECHANISM OF ACTION AND DRUG EFFECTS

Most sedative–hypnotics work via the γ-aminobutyric acid (GABA) receptor complex by enhancing the effect of GABA (Figure 6–1), the major inhibitory neurotransmitter in the central nervous system. GABA receptors are transmembrane, made up of 5 subunits (2 α, 2 β, 1 γ), with a central pore. There are several types of each subunit, leading to a variety of slightly different GABA receptors. Overall, there are 2 types: type A, a chloride channel, and type B, a potassium channel. Type ...

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