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Chapter: Basic & Clinical Pharmacology : Sedative-Hypnotic Drugs

Pharmacodynamics of Benzodiazepines, Barbiturates, & Newer Hypnotics

A. Molecular Pharmacology of the GABAA Receptor B. Neuropharmacology C. Benzodiazepine Binding Site Ligands D. Organ Level Effects

Pharmacodynamics of Benzodiazepines, Barbiturates, & Newer Hypnotics

A. Molecular Pharmacology of the GABAA Receptor

The benzodiazepines, the barbiturates, zolpidem, zaleplon, eszopi-clone, and many other drugs bind to molecular components of the GABAA receptor in neuronal membranes in the central nervous system. This receptor, which functions as a chloride ion channel, is activated by the inhibitory neurotransmitter GABA .

The GABAA receptor has a pentameric structure assembled from five subunits (each with four membrane-spanning domains) selected from multiple polypeptide classes (α, β, γ, δ, ε, π, ρ, etc). Multiple subunits of several of these classes have been character-ized, among them six different α (eg, α1 through α6), four β, and three γ. A model of the GABAA receptor-chloride ion channel macromolecular complex is shown in Figure 22–6.

A major isoform of the GABAA receptor that is found in many regions of the brain consists of two α1, two β2, and one γ2 subunits. In this isoform, the two binding sites for GABA are located between adjacent α1 and β2 subunits, and the binding pocket for benzodiazepines (the BZ site of the GABAA receptor) is between anα1 and the γ2 subunit. However, GABAA receptors in different areas of the central nervous system consist of various combinations of the essential subunits, and the benzodiazepines bind to many of these, including receptor isoforms containing α2, α3, and α5 subunits.

Barbiturates also bind to multiple isoforms of the GABAA receptor but at different sites from those with which benzodiazepines interact. In contrast to benzodiazepines, zolpidem, zaleplon, and eszopiclone bind more selectively because these drugs interact only with GABAA-receptor isoforms that contain α1 subunits. The heterogeneity of GABAA receptors may constitute the molecular basis for the varied pharmacologic actions of benzodiazepines and related drugs (see Box: GABA Receptor Heterogeneity & Pharmacologic Selectivity).

In contrast to GABA itself, benzodiazepines and other sedative-hypnotics have a low affinity for GABAB receptors, which are acti-vated by the spasmolytic drug baclofen.

B. Neuropharmacology

GABA (γ-aminobutyric acid) is a major inhibitory neurotransmitter in the central nervous system . Electrophysiologic studies have shown that benzodiazepines potentiate GABAergic inhi-bition at all levels of the neuraxis, including the spinal cord, hypo-thalamus, hippocampus, substantia nigra, cerebellar cortex, and cerebral cortex. Benzodiazepines appear to increase the efficiency of GABAergic synaptic inhibition. The benzodiazepines do not substi tute for GABA but appear to enhance GABA’s effects allosterically without directly activating GABAA receptors or opening the associ-ated chloride channels. The enhancement in chloride ion conduc-tance induced by the interaction of benzodiazepines with GABA takes the form of an increase in the frequency of channel-opening events.

Barbiturates also facilitate the actions of GABA at multiple sites in the central nervous system, but—in contrast to benzodiazepines—they appear to increase the duration of the GABA-gated chloride channel openings. At high concentrations, the barbiturates may also be GABA-mimetic, directly activating chloride channels. These effects involve a binding site or sites distinct from the benzodiazepine binding sites. Barbiturates are less selective in their actions than benzodiazepines, because they also depress the actions of the excitatory neurotransmitter glu-tamic acid via binding to the AMPA receptor. Barbiturates also exert nonsynaptic membrane effects in parallel with their effects on GABA and glutamate neurotransmission. This multiplicity of sites of action of barbiturates may be the basis for their ability to induce full surgical anesthesia  and for their more pronounced central depressant effects (which result in their low margin of safety) compared with benzodiazepines and the newer hypnotics.

C. Benzodiazepine Binding Site Ligands

The components of the GABAA receptor-chloride ion channel mac-romolecule that function as benzodiazepine binding sites exhibit heterogeneity (see Box: The Versatility of the Chloride Channel GABA Receptor Complex). Three types of ligand-benzodiazepine receptor interactions have been reported: (1) Agonists facilitate GABA actions, and this occurs at multiple BZ binding sites in the case of the benzodiazepines. As noted above, the nonbenzodiaz-epines zolpidem, zaleplon, and eszopiclone are selective agonists at the BZ sites that contain anα1 subunit. Endogenous agonist ligands for the BZ binding sites have been proposed, because benzodiazepine-like chemicals have been isolated from brain tissue of animals never exposed to these drugs. Nonbenzodiazepine molecules that have affinity for BZ sites on the GABAA receptor have also been detected in human brain. (2) Antagonists are typi-fied by the synthetic benzodiazepine derivative flumazenil, which blocks the actions of benzodiazepines, eszopiclone, zaleplon, and zolpidem but does not antagonize the actions of barbiturates, mep-robamate, or ethanol. Certain endogenous neuropeptides are also capable of blocking the interaction of benzodiazepines with BZ binding sites. (3) Inverse agonists act as negative allosteric modula-tors of GABA-receptor function . Their interaction with BZ sites on the GABAA receptor can produce anxiety and sei-zures, an action that has been demonstrated for several compounds, especially the β-carbolines, eg, n-butyl-β-carboline-3-carboxylate (β-CCB). In addition to their direct actions, these molecules can block the binding and the effects of benzodiazepines.

The physiologic significance of endogenous modulators of GABA functions in the central nervous system remains unclear. To date, it has not been established that the putative endogenous ligands of BZ binding sites play a role in the control of states of anxiety, sleep patterns, or any other characteristic behavioral expression of central nervous system function.

GABA Receptor Heterogeneity & Pharmacologic Selectivity

Studies involving strains of genetically engineered (“knock-out”) rodents have demonstrated that the specific pharmaco-logic actions elicited by benzodiazepines and other drugs that modulate GABA actions are influenced by the composition of the subunits assembled to form the GABA A receptor. Benzodiazepines interact primarily with brain GABAA recep-tors in which the α subunits (isoforms 1, 2, 3, and 5) have a conserved histidine residue in the N-terminal domain. Mice in which a point mutation has been inserted converting histidine to arginine in the α1 subunit show resistance to both the sedative and amnestic effects of benzodiazepines, but anxi-olytic and muscle-relaxing effects are largely unchanged. These animals are also unresponsive to the hypnotic actions of zolpidem and zaleplon, drugs that bind selectively to GABAA receptors containing α1 subunits. In contrast, mice with selec-tive histidine-arginine mutations in the α2 or α3 subunits of GABAA receptors show selective resistance to the antianxiety effects of benzodiazepines. Based on studies of this type, it has been suggested that α1 subunits in GABAA receptors mediate sedation, amnesia, and ataxic effects of benzodiazepines, whereas α2 and α3 subunits are involved in their anxiolytic and muscle-relaxing actions. Other mutation studies have led to suggestions that an α5 subtype is involved in at least some of the memory impairment caused by benzodiazepines. It should be emphasized that these studies involving genetic manipulations of the GABAA receptor utilize rodent models of the anxiolytic and amnestic actions of drugs

The Versatility of the Chloride Channel GABA Receptor Complex

The GABAA-chloride channel macromolecular complex is one of the most versatile drug-responsive machines in the body. In addition to the benzodiazepines, barbiturates, and the newer hypnotics (eg, zolpidem), many other drugs with central nervous system effects can modify the function of this important iono-tropic receptor. These include alcohol and certain intravenous anesthetics (etomidate, propofol) in addition to thiopental. For example, etomidate and propofol  appear to act selectively at GABAA receptors that contain β2 and β3 subunits, the latter suggested to be the most important with respect to the hypnotic and muscle-relaxing actions of these anesthetic agents. The anesthetic steroid alphaxalone is thought to interact with GABAA receptors, and these recep-tors may also be targets for some of the actions of volatile anesthetics (eg, halothane). Most of these agents facilitate or mimic the action of GABA. However, it has not been shown that all these drugs act exclusively by this mechanism. Other drugs used in the management of seizure disorders indirectly influence the activity of the GABAA-chloride channel macro-molecular complex by inhibiting GABA metabolism (eg, vigabatrin) or reuptake of the transmitter (eg, tiagabine). Central nervous system excitatory agents that act on the chloride channel include picrotoxin and bicuculline. These convulsant drugs block the channel directly (picrotoxin) or interfere with GABA binding (bicuculline).

D. Organ Level Effects

1.     Sedation—Benzodiazepines, barbiturates, and most oldersedative-hypnotic drugs exert calming effects with concomitant reduction of anxiety at relatively low doses. In most cases, how-ever, the anxiolytic actions of sedative-hypnotics are accompa-nied by some depressant effects on psychomotor and cognitive functions. In experimental animal models, benzodiazepines and older sedative-hypnotic drugs are able to disinhibit punishment-suppressed behavior. This disinhibition has been equated with antianxiety effects of sedative-hypnotics, and it is not a charac-teristic of all drugs that have sedative effects, eg, the tricyclic antidepressants and antihistamines. However, the disinhibition of previously suppressed behavior may be more related to behav-ioral disinhibitory effects of sedative-hypnotics, including euphoria, impaired judgment, and loss of self-control, which can occur at dosages in the range of those used for management of anxiety. The benzodiazepines also exert dose-dependent antero-grade amnesic effects (inability to remember events occurring during the drug’s duration of action).


2.        Hypnosis—By definition, all of the sedative-hypnoticsinduce sleep if high enough doses are given. The effects of sedative-hypnotics on the stages of sleep depend on several factors, including the specific drug, the dose, and the frequency of its administration. The general effects of benzodiazepines and older sedative-hypnotics on patterns of normal sleep are as fol-lows: (1) the latency of sleep onset is decreased (time to fall asleep); (2) the duration of stage 2 NREM (nonrapid eye move-ment) sleep is increased; (3) the duration of REM sleep is decreased; and (4) the duration of stage 4 NREM slow-wave sleep is decreased. The newer hypnotics all decrease the latency to persistent sleep. Zolpidem decreases REM sleep but has minimal effect on slow-wave sleep. Zaleplon decreases the latency of sleep onset with little effect on total sleep time, NREM, or REM sleep. Eszopiclone increases total sleep time, mainly via increases in stage 2 NREM sleep, and at low doses has little effect on sleep patterns. At the highest recommended dose, eszopiclone decreases REM sleep.

More rapid onset of sleep and prolongation of stage 2 are presumably clinically useful effects. However, the significance of sedative-hypnotic drug effects on REM and slow-wave sleep is not clear. Deliberate interruption of REM sleep causes anxiety and irritability followed by a rebound increase in REM sleep at the end of the experiment. A similar pattern of “REM rebound” can be detected following abrupt cessation of drug treatment with older sedative-hypnotics, especially when drugs with short durations of action (eg, triazolam) are used at high doses. With respect to zolpidem and the other newer hypnotics, there is little evidence of REM rebound when these drugs are discontinued after use of recommended doses. However, rebound insomnia occurs with both zolpidem and zaleplon if used at higher doses. Despite possible reductions in slow-wave sleep, there are no reports of disturbances in the secretion of pituitary or adrenal hormones when either barbiturates or benzodiazepines are used as hypnotics. The use of sedative-hypnotics for more than 1–2 weeks leads to some tolerance to their effects on sleep patterns.

3.     Anesthesia—As shown in Figure 22–1, high doses of certainsedative-hypnotics depress the central nervous system to the point known as stage III of general anesthesia . However, the suitability of a particular agent as an adjunct in anesthesia depends mainly on the physicochemical properties that determine its rapidity of onset and duration of effect. Among the barbiturates, thiopental and methohexital are very lipid-soluble, penetrating brain tissue rapidly following intravenous administra-tion, a characteristic favoring their use for the induction of anes-thesia. Rapid tissue redistribution (not rapid elimination) accounts for the short duration of action of these drugs, a feature useful in recovery from anesthesia.


Benzodiazepines—including diazepam, lorazepam, and midazolam—are used intravenously in anesthesia , often in combination with other agents. Not surprisingly, benzodiazepines given in large doses as adjuncts to general anes-thetics may contribute to a persistent postanesthetic respiratory depression. This is probably related to their relatively long half-lives and the formation of active metabolites. However, if neces-sary, such depressant actions of the benzodiazepines are usually reversible with flumazenil.

4.     Anticonvulsant effects—Many sedative-hypnotics arecapable of inhibiting the development and spread of epileptiform electrical activity in the central nervous system. Some selectivity exists in that some members of the group can exert anticonvulsant effects without marked central nervous system depression (although psychomotor function may be impaired). Several benzodiazepines—including clonazepam, nitrazepam, lorazepam, and diazepam—are sufficiently selective to be clinically useful in the management of seizures . Of the barbiturates, phenobarbital and metharbital (converted to phenobarbital in the body) are effective in the treatment of generalized tonic-clonic seizures, though not the drugs of first choice. Zolpidem, zaleplon, and eszopiclone lack anticonvulsant activity, presumably becauseof their more selective binding than that of benzodiazepines to GABAA receptor isoforms.


5. Muscle relaxation— Some sedative-hypnotics, particularlymembers of the carbamate (eg, meprobamate) and benzodiazepine groups, exert inhibitory effects on polysynaptic reflexes and inter-nuncial transmission and at high doses may also depress transmis-sion at the skeletal neuromuscular junction. Somewhat selective actions of this type that lead to muscle relaxation can be readily demonstrated in animals and have led to claims of usefulness for relaxing contracted voluntary muscle in muscle spasm (see Clinical Pharmacology). Muscle relaxation is not a characteristic action of zolpidem, zaleplon, and eszopiclone.

6.     Effects on respiration and cardiovascular function— Athypnotic doses in healthy patients, the effects of sedative-hypnotics on respiration are comparable to changes during natural sleep. However, even at therapeutic doses, sedative-hypnotics can pro-duce significant respiratory depression in patients with pulmonary disease. Effects on respiration are dose-related, and depression of the medullary respiratory center is the usual cause of death due to overdose of sedative-hypnotics.


At doses up to those causing hypnosis, no significant effects on the cardiovascular system are observed in healthy patients. However, in hypovolemic states, heart failure, and other diseases that impair cardiovascular function, normal doses of sedative-hypnotics may cause cardiovascular depression, probably as a result of actions on the medullary vasomotor centers. At toxic doses, myocardial contractility and vascular tone may both be depressed by central and peripheral effects, leading to circulatory collapse. Respiratory and cardiovascular effects are more marked when sedative-hypnotics are given intravenously.

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