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Sedatives and Hypnotics


GENERAL CHARACTERISTICS

Sedative/hypnotics are a diverse class of central nervous system (CNS) depressants with addictive liability and a wide range of therapeutic functions. Benzodiazepines are the most widely prescribed medication among sedative/hypnotics, and they are also the most widely prescribed class of all psychotropic medications. At any given time, approximately 5% of all adults in the United States have been prescribed benzodiazepines.

CHEMICAL STRUCTURE AND NEUROBIOLOGY

Pharmacodynamics

The primary receptor target for all sedative/hypnotic medications is the γ-aminobutyric acid (GABA) receptor. Here we review key features of GABA receptor functioning relevant for understanding the various sedative/hypnotics’ biological actions.

The two primary GABA receptors are GABA-A and GABA-B. The GABA-A receptor is an ionotropic , ligand-gated ion channel made up of five subunits that are arranged around a central pore. The five subunits are classified into alpha (1–6), beta (1–3), gamma (1–3), delta, and epsilon. The most commonly encountered GABA-A receptor structure has two alpha, two beta, and one gamma subunit. When GABA binds to the receptor, there is a conformational change leading to an influx of chloride and hyperpolarization of the cell membrane.

The six different isoforms of the GABA-A alpha subunit that can be expressed mediate different biological effects:

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    Alpha-1 subunit mediates sleep/amnestic effects.

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    Alpha-2 to -3 subunits mediate anxiolytic/muscle relaxant effects.

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    Alpha-1 to -3 subunits mediate anticonvulsant activity.

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    Alpha-5 subunit mediates effects of benzodiazepines.

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    Alpha-4 and -6 are insensitive to benzodiazepines.

In contrast to GABA-A receptor, the GABA-B receptor is metabotropic, and the receptor is separate from the ion channel. The binding of GABA leads to activation of second-messenger G-proteins and opening of the ion channels.

The primary mechanism of all sedative/hypnotics is through their GABAergic actions; knowing which subunits these drugs bind to can help predict their effects.

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    Benzodiazepines : Bind GABA-A receptors at the interface between the alpha and gamma-2 subunits with roughly the same affinities for alpha-1 to -3 and -5 subunits, and increase the frequency of channel opening; they are indirect agonists and positive allosteric modulators.

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    Barbiturates : Bind GABA-A receptors at the interface of subunits at sites distinct from benzodiazepines and increase duration of channel opening; they are indirect agonists and positive allosteric modulators. Unlike benzodiazepines, barbiturates also block isoxazolepropionic acid (AMPA) kainate glutamatergic receptors.

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    Ethanol : Binds GABA-A receptors; ethanol is also a positive allosteric modulator similar to benzodiazepines and barbiturates; the precise molecular target on GABA-A receptors is not fully known.

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    Z-drugs, a.k.a. nonbenzodiazepines (e.g., zaleplon, zolpidem, eszopiclone, zopiclone): Bind GABA-A at the same sites as benzodiazepines. Z-drugs have greatest effect at alpha-1 subunits and weaker activity at alpha-2 and -3 subunits, lending to its potent hypnotic effects and lesser anxiolytic effects.

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    Gamma-hydroxy-butyrate (GHB): GABA-B receptor agonist used for narcolepsy.

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    Baclofen : GABA-B receptor agonist used for muscle spasticity.

Know This:

Z-drugs have greatest activity at the alpha-1 receptors; benzodiazepines have greatest activity at the alpha-1 through -3 and -5 subunits. Because Z-drugs primarily bind to the alpha-1 subunit of the GABA-A receptor, they have limited anxiolytic and anticonvulsant activity.

Z-drugs are cross-tolerant for alcohol but less so than benzodiazepines and barbiturates.

Pharmacokinetics

The pharmacokinetic effects of the various sedative/hypnotics can help to predict their effectiveness, duration of action, and differential liabilities for addiction. In general, medications with faster onsets of action are considered more addictive.

Onset and Duration of Action

The structure of prototypical sedative/hypnotics is shown in Fig. 5.1 . To predict the actions of benzodiazepines, you should know the relative potency, lipophilicity, and elimination half-life.

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    Potency refers to the number of milligrams to obtain a given action; for example, alprazolam 1 mg is considered equivalent to diazepam 10 mg, indicating that alprazolam has a higher potency. Approximate dose equivalencies for commonly used benzodiazepines are shown in Table 5.1 .

    Table 5.1
    Commonly Used Benzodiazepines, Approximate Half-Lives and Equipotent Dosages
    Benzodiazepines Elimination Half-Life (hr) Active Metabolite Dose Equivalency (mg) a
    Triazolam 2–5 Inactive 0.5
    Lorazepam 10–14 Inactive 1
    Temazepam 8–15 Inactive 10
    Alprazolam 11–15 Inactive 0.5
    Chlordiazepoxide 5–30 Active b 10
    Clonazepam 18–50 Inactive 0.25–0.5
    Oxazepam 5–15 Inactive 15–30
    Diazepam 50–100 Active b 5

    a These doses are approximate equipotencies and are not recommended for initiation or for conversion between medications.

    b The active metabolites of diazepam are oxazepam, temazepam, and desmethyldiazepam; those of chlordiazepoxide are oxazepam and desmethyldiazepam. The presence of these active metabolites contributes to these compounds’ longer half-lives.

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    Elimination half-life: The half-lives of commonly used benzodiazepines are also shown in Table 5.1 . Benzodiazepines with longer half-lives can be dosed less frequently.

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    Lipophilicity: The more lipophilic a benzodiazepine is, the more quickly it will both enter and leave the CNS. High-lipophilicity benzodiazepines have a more rapid onset and include diazepam and alprazolam; low-lipophilicity benzodiazepines include lorazepam and chlordiazepoxide.

Fig. 5.1, Structure of prototypical sedative/hypnotics. Benzodiazepines are composed of a benzene ring fused to a seven-membered diazepine ring; modification of the R-groups can change the compound’s characteristics. Barbituric acid is the parent compound for all barbiturates. Zolpidem is shown as a prototypical nonbenzodiazepine or Z-drug.

Knowing just the elimination half-life of a benzodiazepine is not a good predictor of how quickly or how long a patient will feel the medication’s effect: you must also consider its lipophilicity and potency. For example, although the half-life of alprazolam is 11 to 15 hours, patients typically experience the acute anxiolytic effects of alprazolam for approximately 2 to 4 hours; this is because alprazolam is highly lipophilic and both enters and leaves the CNS rapidly. The same principles regarding lipophilicity and elimination half-life apply to other sedatives/hypnotics. Concerning barbiturates, the compound with the fastest onset of action is sodium thiopental, which is highly lipophilic and used for anesthesia. It has an onset of action of less than 1 minute and a duration of action between 5 and 10 minutes.

Metabolism

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    Benzodiazepines are generally metabolized by CYP3A4 oxidation followed by glucuronide conjugation. The exceptions to this are the “LOT” (lorazepam, oxazepam, and temazepam) benzodiazepines, which undergo only glucuronidation and have no active metabolites. For this reason, they are preferred in patients with hepatic impairment or to avoid drug–drug interactions. Many of the common benzodiazepines are metabolized to oxazepam (diazepam, clorazepate, chlordiazepoxide, and temazepam). Alprazolam, lorazepam, and clonazepam do not share this metabolic pathway.

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    Barbiturates are generally metabolized by CYP3A4, 3A5, and 3A7; they also induce CYP2D6, 2C9, and 3A4 and can, therefore, decrease serum levels of medications metabolized by these enzymes.

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    Zolpidem and zopiclone are metabolized by CYP3A4; zaleplon is metabolized by aldehyde oxidase. There are significant sex differences in the metabolism of zolpidem. In 2003, the U.S. Food and Drug Administration (FDA) required lower recommended doses of zolpidem for women to reduce the risk of next-day activities that require alertness, such as driving. Men metabolize the standard 10-mg formulation approximately twice as quickly as women; females have also been found to have higher peak concentration of zolpidem than men.

Know This:

Most benzodiazepines are metabolized by CYP3A4 enzymes. Any medication that induces or inhibits CYP3A4 (e.g., ketoconazole, macrolides, oral contraceptives) may, therefore, affect drug levels. Exceptions to this are lorazepam, oxazepam, and temazepam, which do not undergo metabolism by CYP enzymes.

Lorazepam and diazepam are prepared in solutions with propylene glycol when administered intravenously. There have been cases of iatrogenic propylene glycol toxicity with repeated administration of intravenous benzodiazepines.

TOXICOLOGY TESTING

Toxicology testing for benzodiazepines is covered more extensively in Chapter 12. Recall that the standard toxicology test for benzodiazepines detects the presence of compounds that are metabolized to oxazepam—this includes diazepam, chlordiazepoxide, clorazepate, and temazepam. Several of the very commonly prescribed benzodiazepines (clonazepam, alprazolam, and lorazepam) have a different metabolic pathway and are frequently missed by standard toxicology tests.

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