Barbiturate sedative-hypnotics pharmacologic effects

The chemical structures of some older and less commonly used sedative-hypnotics, including several barbiturates, are shown in Figure 22-3. Glutethimide and meprobamate are of distinctive chemical structure but are practically equivalent to barbiturates in their pharmacologic effects. They are rarely used. The sedative-hypnotic class also includes compounds of simpler chemical structure, including ethanol (see Chapter 23) and chloral hydrate. 

Most sedatives and hypnotics achieve concentrations in breast milk sufficient to produce a pharmacologic effect in some infants. Barbiturates taken in hypnotic doses by the mother can produce lethargy, sedation, and poor suck reflexes in the infant. Chloral hydrate can produce sedation if the infant is fed at peak milk concentrations. Diazepam can have a sedative effect on the nursing infant, but, most importantly, its long half-life can result in significant drug accumulation. 

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. 

Sedative-hypnotic agents are some of the most widely prescribed and used drugs in the developed world. They are also frequently drugs of abuse. Sedative-hypnotics are used to promote sleep, as their name implies, and to reduce anxiety. Their overall effect is to act as CNS depressants. We will consider the two major classes of drugs in this category, the benzodiazepines and the barbiturates. For a detailed discussion of the pharmacology of these agents, see Chamey et al. (2006). 

The barbiturates have a different pharmacological and binding profile from that of the benzodiazepines. They exert a depressant effect on the cerebrospinal axis and depress neuronal activity as well as skeletal muscle, smooth muscle, and cardiac muscle activity. Depending on the compound, dose, and route of administration, the barbiturates can produce different degrees of CNS depression and have found use as sedatives, hypnotics, anticonvulsants, or anesthetics. 

I. Pharmacology. Pentobarbital is a short-acting barbiturate with anticonvulsant as well as sedative-hypnotic properties. It is used as a third-line drug in the treatment of status epilepticus. It may also reduce intracranial pressure in patients with cerebral edema by inducing vasoconstriction. After intravenous administration of a single dose, the onset of effect occurs within about 1 minute and lasts about 15 minutes. Pentobarbital demonstrates a biphasic elimination pattern the half-life of the initial phase is 4 hours, and the terminal phase half-life is 35-50 hours. Effects are prolonged after termination of a continuous infusion. 

---