Sedatives and Hypnotics - Comprehensive Notes

Sedatives and Hypnotics

Categories of Neuro Drugs

• Sedative: Exerts a calming effect.

• Hypnotic: Sleep-inducing.

• Anticonvulsant: Acts to inhibit seizures.

• Anxiolytics and Antidepressants: Reduces anxiety and/or depression.

• Antipsychotic (Neuroleptics): Tranquilizers used in the treatment of psychotic disorders.

• Mood Stabilizer: Anti-manic agents, often described as those with both anti-manic and antidepressant actions.

Commonality Among Categories

• All 7 categories (Anxiolytics, Antipsychotics, Antidepressants, Sedatives, Hypnotics, Anticonvulsants, Mood Stabilizers) have some level of commonality.

• Examples of drugs that fall into these categories include: Barbiturates, Benzodiazepines, SSRIs, Gabapentin, and Quetiapine.

GABA Antagonist

• Hemlock water dropwort is a GABA antagonist but not a sedative.

• Historical context: In pre-Roman Sardinia, elderly people unable to support themselves were intoxicated with the sardonic herb (Oenanthe) and killed. The facial muscular contraction induced by the herb mimicked a smile, giving rise to the term "risus sardonicus" to indicate a sinister smile.

Excitatory and Inhibitory Synaptic Transmission

• Illustrations depict presynaptic and postsynaptic neuron interactions, showing excitatory postsynaptic potentials (EPSP) and inhibitory postsynaptic potentials (IPSP).

GABA Receptors

• Directly Hyperpolarizing: Target of many sedative/hypnotics.

• Indirectly Hyperpolarizing (via K+ channel): Target of Baclofen, a muscle relaxant.

GABA A Receptors

• Ligand gated, chloride permeable ion channels.

• Many different subunits: 19 homologous subunit gene products: 6$\alpha$, 4$\beta$, 3$\gamma$, 2$\rho$, $\delta$, $\epsilon$, $\Theta$ and $\pi$.

• Most common receptor subtype in mammalian tissue contains $\alpha1$, $\beta2$, and $\gamma2$ subunits.

• $\alpha2$, $\beta2$, and $\gamma$ is the next most common, although homomeric receptors also exist.

• Receptors containing $\alpha$,$\beta$,X are 2:2:1 stoichiometry.

• Receptors containing $\alpha$,$\beta$ only are 2:3 stoichiometry.

• All must contain an $\alpha$ subunit + other subunits.

Single Channel Recordings of GABA A Receptors

• Benzodiazepines: Increase channel opening probability, enhancing GABAergic signaling.

• Barbiturates: Increase channel opening duration.

Barbiturates

• Sedative/ hypnotic/ anesthesia inducing agent/ anticonvulsant.

• Positive allosteric modulators of GABA A receptors (mean open time).

• Commonly used barbiturates include: Pentobarbital, Butobarbital, Phenobarbital, Sodium thiopental.

• Uses:

  • Pentobarbital or sodium thiopental is used in the induction of general anesthesia.

  • Phenobarbital and Pentobarbital are used in some cases of epilepsy.

  • Sedation and hypnosis to calm the patient and induce sleep.

Barbiturates – PK and Classes

• Barbiturates are often classified according to speed of onset and duration of action.

• Ultrashort-acting barbiturates: Commonly used for anesthesia due to their short duration of action, allowing for greater control.

• Short/intermediate-acting: Employed for anesthetic purposes, insomnia (hypnotics), and anxiolytics.

• Long-acting barbiturates (e.g., phenobarbital): Used almost exclusively as anticonvulsants, with rare prescriptions for daytime sedation. Phenobarbital has a half-life of roughly 80 hours.

Fastest vs Slowest Barbiturates

• Thiopental: High lipid solubility. Rapid action makes it a viable choice for anesthesia induction, but painful side effects and risk of overdose have led to its replacement (e.g., propofol).

• Phenobarbital: Lowest lipid solubility, lowest plasma binding, lowest brain protein binding, the longest delay in onset of activity, and the longest duration of action. Plasma half-life of 53 to 118 hours (mean: 79 hours). Metabolized primarily by the liver, and most metabolic products are excreted in the urine.

Barbiturates – Lethality and Antidote

• Lethal overdose is due to barbiturate’s ability to act as a direct agonist at higher concentrations.

• $LD_{50}$ varies, but typically 10x full hypnotic dose at once will lead to severe poisoning. The effects occur sooner if taken with alcohol or other CNS depressants.

• Antidotes:

  • Low doses: bicuculline (competitive antagonist).

  • High doses: picrotoxin (noncompetitive antagonist).

Benzodiazepines

• Sedative/ hypnotic/ anticonvulsant/ muscle relaxant.

• Positive allosteric modulators of GABA A receptors (probability of opening).

• Commonly used BZDs include:

  • Diazepam (Valium) – sedation and anxiety.

  • Alprazolam (Xanax) – sedation and anxiety.

  • Temazepam (Restoril) – sleep aid.

  • Midazolam (Versed) – pretreatment for procedures – sedation, anxiolysis, and amnesia, treatment of status epilepticus.

• Rarely used as maintenance therapies due to tolerance and addictive properties.

• Show strong muscle-relaxing properties and can be useful in the treatment of muscle spasms, although tolerance often develops to their muscle relaxant effects.

Benzodiazepines - Safety

• Benzodiazepines are relatively safe because the lethal dose is over 1000-fold greater than the typical therapeutic dose.

Effects of BZDs Modulated by Different GABA Receptor Subtypes

• Knockin mutant mouse experiment: Resulting mice were resistant to the effects of BZDs and showed protection from the sedating, amnestic, and anticonvulsant properties of BZDs, but NOT the anxiolytic, motor impairing, and ethanol-potentiating effects.

“Benzodiazepine Receptor”

• The BZ binding site is located at the interface of an $\alpha$ and a $\gamma$ subunit.

• BZD pharmacology is determined by the specific $\alpha$- and $\gamma$-subunit isoforms that are present in the receptor oligomer. The incorporation of the $\alpha4$ or $\alpha6$ subunit in the receptor, for example, bestows insensitivity to diazepam and other classical BZDs.

Different BZDs Receptors

• Type I BZD receptor: Contains the $\alpha1$ isoform. Highly concentrated in the cortex, thalamus, and cerebellum, responsible for the BZDs' sedative effects and anterograde amnesia and for some of the anticonvulsive effects of diazepam. Sixty percent of GABA-A receptors contain the $\alpha1$ subunit.

• Type II BZD receptors: Contain the $\alpha2/3/5$ isoform and mediate the anxiolytic and, to a large extent, the myorelaxant effects of BZDs. These are concentrated in areas such as the limbic system, motor neurons, and the spinal cord. The anxiolytic effects of BZDs are believed to be mediated through receptors located in the limbic system, and myorelaxant properties are mediated via $\alpha2$-containing receptors in the spinal cord and motor neurons.

• More differences are thought to exist and reflect the different properties of various BZD drugs.

BZD Drawbacks

• Although BZDs do not induce pharmacokinetic tolerance, they DO still cause pharmacodynamic tolerance (downregulation of receptors over time).

• Tolerance develops to hypnotic and myorelaxant effects within days to weeks and to anticonvulsant and anxiolytic effects within weeks to months.

• Withdrawal of dose can lead to rebound symptoms (return of original symptoms, but often more severe) and physical withdrawal symptoms such as depression, suicidal behavior, psychosis, seizures, and delirium tremens.

Benzodiazepine Metabolism

• Pharmacokinetics are driven by metabolite activity.

• Table lists common benzodiazepines, their half-lives, and speeds of onset.

• Examples: Alprazolam, Lorazepam, Diazepam, Temazepam, Chlordiazepoxide, Clonazepam.

Structural Analysis of Binding Sites on GABA Receptors

• Phenobarbital-binding sites: The atomic model of TMD viewed down the channel axis from the synaptic perspective. The boxes highlight phenobarbital sites with the ligands shown as spheres.

• The effect of mutation at the 15′ position of different subunits on the potentiation of GABA activation by phenobarbital.

Binding Sites of Benzodiazepines and Their Mechanism of Action

• Occupancy of four sites by diazepam results in global stabilization compared to the complex with GABA alone, and especially compared to the complex with GABA and flumazenil

• Z-slices in the TMD of cryo-EM density maps for the receptor in complex with GABA plus flumazenil (a), GABA alone (b) and GABA plus diazepam (c). Boxes in c highlight diazepam (salmon) TMD sites. This illustrates the large interfacial gap in the complex with GABA plus flumazenil, the smaller gap in the complex with GABA alone, and the absence of a gap in the complex with GABA plus diazepam

Flumazenil

• Competitive inhibitor for BZD binding to GABA-A receptor.

• Many benzodiazepines (e.g., midazolam) have longer half-lives than flumazenil, so repeat doses may be required to prevent symptoms of overdosage re-occurring once the initial dose of flumazenil wears off.

• Subjects who are physically dependent on benzodiazepines may suffer benzodiazepine withdrawal symptoms, including seizure, upon rapid administration of flumazenil.

Hypnotic Agents

• Medications used to induce or maintain sleep; often target wake-arousal systems in the brain.

Wake-Arousal Systems – Sites of Drug Action

• Neurotransmitters involved: 5HT, NE, ACh, Hist, Orexin.

• Targets: $\alpha2$ agonists, antihistamines, Orexin antagonists, Trazodone, GABAergic PAMs.

"Z" Drugs

• Similar MOA to BZDs (but structurally unrelated – also to each other).

• Positive allosteric modulators of GABA A receptors (probability of opening).

• In contrast to BZDs, which non-selectively bind to and activate all BZ receptor subtypes, Z drugs show preference for the $\alpha1$ containing receptors subunits which may explain the relative absence of myorelaxant and anticonvulsant effects, as well as the relative preservation of deep sleep (stages 3 and 4) in human studies of zolpidem at hypnotic doses.

• Examples:

  • Zolpidem (Ambien).

  • Eszopiclone (Lunesta); additional activity in $\alpha2$ and $\alpha3$ containing receptors.

  • Zaleplon (Sonata); shorter half-life, therefore fewer hangover effects.

Z-Drugs: Specifics

• Zolpidem: Mediates its effects largely through activation of the $\alpha1$-containing GABAA (BZ1) receptor, though it has some agonist activity at $\alpha2$ and $\alpha3$ subunits, and very little at the $\alpha5$ subunit; therefore, zolpidem is considered a potent sedative and hypnotic with minimal anxiolytic efficacy.

• Zopiclone: Shows preferential agonist activity at the $\alpha1$ subunit of the GABAA receptor, and its duration of action is the longest of the Z-drugs, comparable to short-acting BZDs – useful in both induction and maintenance of sleep. Eszopiclone (S-enantiomer) has greater efficacy at the $\alpha2$ and $\alpha3$ subunits. The addition of the R-enantiomer augments efficacy at the $\alpha1$ subunit, leading to increased sedation and residual effects.

• Zaleplon: Has unique receptor and pharmacokinetic properties, potentially increasing its utility in select sleep disorders. Zaleplon exerts its effects through selective binding at BZ1 receptors ($\alpha1$ subunit); it has low affinity and potency at $\alpha2$ and $\alpha3$ subunits. It is an ultra-short-acting Z-drug that reduces sleep latency and can be taken after trying but failing to fall asleep. Zaleplon can also be taken for middle-of-the-night awakening.

Sedatives and Hypnotics

Categories of Neuro Drugs

• Sedative: A substance that exerts a calming effect by reducing excitability, irritability, or excitement.

• Hypnotic: A sleep-inducing agent that promotes or enhances sleep.

• Anticonvulsant: A medication that inhibits seizures by reducing the excessive electrical activity in the brain.

• Anxiolytics and Antidepressants: Medications that reduce anxiety and/or alleviate symptoms of depression.

• Antipsychotic (Neuroleptics): Tranquilizers used to manage psychotic disorders such as schizophrenia by reducing hallucinations and delusions.

• Mood Stabilizer: Agents that stabilize mood, primarily used to treat bipolar disorder by preventing manic and depressive episodes; often described as having both anti-manic and antidepressant actions.

Commonality Among Categories

• All 7 categories (Anxiolytics, Antipsychotics, Antidepressants, Sedatives, Hypnotics, Anticonvulsants, Mood Stabilizers) share some level of commonality, often through their effects on neurotransmitter systems in the brain.

• Examples of drugs that fall into these categories include: Barbiturates, Benzodiazepines, SSRIs, Gabapentin, and Quetiapine, each acting on different neurotransmitter systems to achieve their therapeutic effects.

GABA Antagonist

• Hemlock water dropwort contains compounds that act as GABA antagonists but is not used as a sedative due to its toxicity.

• Historical context: In pre-Roman Sardinia, elderly people unable to support themselves were intoxicated with the sardonic herb (Oenanthe), which contains GABA antagonists, and killed. The facial muscular contraction induced by the herb mimicked a smile, giving rise to the term "risus sardonicus" to indicate a sinister smile.

Excitatory and Inhibitory Synaptic Transmission

• Illustrations depict presynaptic and postsynaptic neuron interactions, showing excitatory postsynaptic potentials (EPSP), which depolarize the postsynaptic neuron, and inhibitory postsynaptic potentials (IPSP), which hyperpolarize the postsynaptic neuron, reducing the likelihood of an action potential.

GABA Receptors

• Directly Hyperpolarizing: These are the target of many sedative/hypnotics, which enhance GABA's action to increase chloride ion flow into the neuron, causing hyperpolarization.

• Indirectly Hyperpolarizing (via K+ channel): Target of Baclofen, a muscle relaxant that activates GABAB receptors, leading to increased potassium ion flow out of the neuron, resulting in hyperpolarization and reduced muscle excitability.

GABA A Receptors

• Ligand-gated, chloride-permeable ion channels that mediate fast inhibitory synaptic transmission in the central nervous system.

• Many different subunits: 19 homologous subunit gene products: 6 $\alpha$, 4 $\beta$, 3 $\gamma$, 2 $\rho$, $\delta$, $\epsilon$, $\Theta$ and $\pi$, each contributing to the receptor's pharmacology and regional distribution.

• Most common receptor subtype in mammalian tissue contains $\alpha1$, $\beta2$, and $\gamma2$ subunits, which are primary targets for benzodiazepines and Z-drugs.

• $\alpha2$, $\beta2$, and $\gamma$ is the next most common, although homomeric receptors also exist, providing diversity in receptor function.

• Receptors containing $\alpha$,$\beta$,X are 2:2:1 stoichiometry, indicating the structural arrangement of subunits.

• Receptors containing $\alpha$,$\beta$ only are 2:3 stoichiometry.

• All must contain an $\alpha$ subunit + other subunits, highlighting the essential role of $\alpha$ subunits in receptor assembly and function.

Single Channel Recordings of GABA A Receptors

• Benzodiazepines: Increase channel opening probability, enhancing GABAergic signaling by allowing chloride ions to flow more frequently, increasing neuronal inhibition.

• Barbiturates: Increase channel opening duration, prolonging the time that chloride ions flow through the channel, leading to a greater inhibitory effect.

Barbiturates

• Sedative/ hypnotic/ anesthesia inducing agent/ anticonvulsant, acting as central nervous system depressants.

• Positive allosteric modulators of GABA A receptors (mean open time), enhancing GABA's effects by increasing the duration of chloride channel opening.

• Commonly used barbiturates include: Pentobarbital, Butobarbital, Phenobarbital, Sodium thiopental, each with varying durations of action and uses.

• Uses:

  • Pentobarbital or sodium thiopental is used in the induction of general anesthesia due to their rapid onset and short duration of action.

  • Phenobarbital and Pentobarbital are used in some cases of epilepsy to control seizures, particularly in status epilepticus.

  • Sedation and hypnosis to calm the patient and induce sleep, though less commonly used today due to safer alternatives.

Barbiturates – PK and Classes

• Barbiturates are often classified according to speed of onset and duration of action, influencing their clinical applications.

• Ultrashort-acting barbiturates: Commonly used for anesthesia due to their short duration of action, allowing for greater control over the level of anesthesia.

• Short/intermediate-acting: Employed for anesthetic purposes, insomnia (hypnotics), and anxiolytics, though less common due to the risk of dependence and safer alternatives.

• Long-acting barbiturates (e.g., phenobarbital): Used almost exclusively as anticonvulsants, with rare prescriptions for daytime sedation. Phenobarbital has a half-life of roughly 80 hours, allowing for once-daily dosing.

Fastest vs Slowest Barbiturates

• Thiopental: High lipid solubility allows rapid action, making it a viable choice for anesthesia induction, but painful side effects and risk of overdose have led to its replacement (e.g., propofol).

• Phenobarbital: Lowest lipid solubility, lowest plasma binding, lowest brain protein binding, the longest delay in onset of activity, and the longest duration of action. Plasma half-life of 53 to 118 hours (mean: 79 hours). Metabolized primarily by the liver, and most metabolic products are excreted in the urine.

Barbiturates – Lethality and Antidote

• Lethal overdose is due to barbiturate’s ability to act as a direct agonist at higher concentrations, opening chloride channels independently of GABA.

• $LD_{50}$ varies, but typically 10x full hypnotic dose at once will lead to severe poisoning. The effects occur sooner if taken with alcohol or other CNS depressants due to additive CNS depression.

• Antidotes:

  • Low doses: bicuculline (competitive antagonist) can block the GABA receptor, reversing some effects.

  • High doses: picrotoxin (noncompetitive antagonist) can block the chloride channel, reducing the effects of barbiturates.

Benzodiazepines

• Sedative/ hypnotic/ anticonvulsant/ muscle relaxant, widely used for anxiety, insomnia, and seizures.

• Positive allosteric modulators of GABA A receptors (probability of opening), enhancing GABA's effects by increasing the frequency of chloride channel opening.

• Commonly used BZDs include:

  • Diazepam (Valium) – sedation and anxiety, known for its long half-life and rapid onset.

  • Alprazolam (Xanax) – sedation and anxiety, a short-acting BZD with a high potential for dependence.

  • Temazepam (Restoril) – sleep aid, primarily used for insomnia due to its hypnotic effects.

  • Midazolam (Versed) – pretreatment for procedures – sedation, anxiolysis, and amnesia, treatment of status epilepticus due to its rapid onset and short duration.

• Rarely used as maintenance therapies due to tolerance and addictive properties, which limit their long-term use.

• Show strong muscle-relaxing properties and can be useful in the treatment of muscle spasms, although tolerance often develops to their muscle relaxant effects.

Benzodiazepines - Safety

• Benzodiazepines are relatively safe because the lethal dose is over 1000-fold greater than the typical therapeutic dose, reducing the risk of fatal overdose compared to barbiturates.

Effects of BZDs Modulated by Different GABA Receptor Subtypes

• Knockin mutant mouse experiment: Resulting mice were resistant to the effects of BZDs and showed protection from the sedating, amnestic, and anticonvulsant properties of BZDs, but NOT the anxiolytic, motor impairing, and ethanol-potentiating effects, demonstrating the involvement of specific GABA receptor subtypes in mediating different effects of BZDs.

“Benzodiazepine Receptor”

• The BZ binding site is located at the interface of an $\alpha$ and a $\gamma$ subunit, highlighting the importance of subunit composition in determining drug binding.

• BZD pharmacology is determined by the specific $\alpha$- and $\gamma$-subunit isoforms that are present in the receptor oligomer. The incorporation of the $\alpha4$ or $\alpha6$ subunit in the receptor, for example, bestows insensitivity to diazepam and other classical BZDs, limiting their effectiveness.

Different BZDs Receptors

• Type I BZD receptor: Contains the $\alpha1$ isoform. Highly concentrated in the cortex, thalamus, and cerebellum, responsible for the BZDs' sedative effects and anterograde amnesia and for some of the anticonvulsive effects of diazepam. Sixty percent of GABA-A receptors contain the $\alpha1$ subunit.

• Type II BZD receptors: Contain the $\alpha2/3/5$ isoform and mediate the anxiolytic and, to a large extent, the myorelaxant effects of BZDs. These are concentrated in areas such as the limbic system, motor neurons, and the spinal cord. The anxiolytic effects of BZDs are believed to be mediated through receptors located in the limbic system, and myorelaxant properties are mediated via $\alpha2$-containing receptors in the spinal cord and motor neurons.

• More differences are thought to exist and reflect the different properties of various BZD drugs, contributing to the diverse clinical effects of different BZDs.

BZD Drawbacks

• Although BZDs do not induce pharmacokinetic tolerance (changes in drug metabolism), they DO still cause pharmacodynamic tolerance (downregulation of receptors over time), reducing their effectiveness.

• Tolerance develops to hypnotic and myorelaxant effects within days to weeks and to anticonvulsant and anxiolytic effects within weeks to months, requiring dose adjustments or alternative treatments.

• Withdrawal of dose can lead to rebound symptoms (return of original symptoms, but often more severe) and physical withdrawal symptoms such as depression, suicidal behavior, psychosis, seizures, and delirium tremens, necessitating slow tapering of the dose during discontinuation.

Benzodiazepine Metabolism

• Pharmacokinetics are driven by metabolite activity, where active metabolites can prolong the effects of the parent drug.

• Table lists common benzodiazepines, their half-lives, and speeds of onset, providing insight into their duration of action and clinical applications.

• Examples: Alprazolam, Lorazepam, Diazepam, Temazepam, Chlordiazepoxide, Clonazepam, each with different pharmacokinetic profiles.

Structural Analysis of Binding Sites on GABA Receptors

• Phenobarbital-binding sites: The atomic model of TMD viewed down the channel axis from the synaptic perspective. The boxes highlight phenobarbital sites with the ligands shown as spheres.

• The effect of mutation at the 15′ position of different subunits on the potentiation of GABA activation by phenobarbital, illustrating the importance of specific amino acids in drug binding and receptor modulation.

Binding Sites of Benzodiazepines and Their Mechanism of Action

• Occupancy of four sites by diazepam results in global stabilization compared to the complex with GABA alone, and especially compared to the complex with GABA and flumazenil, enhancing GABAergic neurotransmission.

• Z-slices in the TMD of cryo-EM density maps for the receptor in complex with GABA plus flumazenil (a), GABA alone (b) and GABA plus diazepam (c). Boxes in c highlight diazepam (salmon) TMD sites. This illustrates the large interfacial gap in the complex with GABA plus flumazenil, the smaller gap in the complex with GABA alone, and the absence of a gap in the complex with GABA plus diazepam, showing how diazepam stabilizes the GABA A receptor.

Flumazenil

• Competitive inhibitor for BZD binding to GABA-A receptor, used to reverse the effects of benzodiazepine overdose.

• Many benzodiazepines (e.g., midazolam) have longer half-lives than flumazenil, so repeat doses may be required to prevent symptoms of overdosage re-occurring once the initial dose of flumazenil wears off.

• Subjects who are physically dependent on benzodiazepines may suffer benzodiazepine withdrawal symptoms, including seizure, upon rapid administration of flumazenil, necessitating careful monitoring and gradual withdrawal strategies.

Hypnotic Agents

• Medications used to induce or maintain sleep; often target wake-arousal systems in the brain by modulating neurotransmitter activity.

Wake-Arousal Systems – Sites of Drug Action

• Neurotransmitters involved: 5HT, NE, ACh, Hist, Orexin, playing critical roles in regulating sleep and wakefulness.

• Targets: $\alpha2$ agonists, antihistamines, Orexin antagonists, Trazodone, GABAergic PAMs, each acting on different neurotransmitter systems to promote sleep.

"Z" Drugs

• Similar MOA to BZDs (but structurally unrelated – also to each other), selectively targeting GABA A receptors to induce sleep.

• Positive allosteric modulators of GABA A receptors (probability of opening), enhancing GABA's effects by increasing the frequency of chloride channel opening.

• In contrast to BZDs, which non-selectively bind to and activate all BZ receptor subtypes, Z drugs show preference for the $\alpha1$ containing receptors subunits which may explain the relative absence of myorelaxant and anticonvulsant effects, as well as the relative preservation of deep sleep (stages 3 and 4) in human studies of zolpidem at hypnotic doses.

• Examples:

  • Zolpidem (Ambien).

  • Eszopiclone (Lunesta); additional activity in $\alpha2$ and $\alpha3$ containing receptors.

  • Zaleplon (Sonata); shorter half-life, therefore fewer hangover effects.

Z-Drugs: Specifics

• Zolpidem: Mediates its effects largely through activation of the $\alpha1$-containing GABAA (BZ1) receptor, though it has some agonist activity at $\alpha2$ and $\alpha3$ subunits, and very little at the $\alpha5$ subunit; therefore, zolpidem is considered a potent sedative and hypnotic with minimal anxiolytic efficacy.

• Zopiclone: Shows preferential agonist activity at the $\alpha1$ subunit of the GABAA receptor, and its duration of action is the longest of the Z-drugs, comparable to short-acting BZDs – useful in both induction and maintenance of sleep. Eszopiclone (S-enantiomer) has greater efficacy at the $\alpha2$ and $\alpha3$ subunits. The addition of the R-enantiomer augments efficacy at the $\alpha1$ subunit, leading to increased sedation and residual effects.

• Zaleplon: Has unique receptor and pharmacokinetic properties, potentially increasing its utility in select sleep disorders. Zaleplon exerts its effects through selective binding at BZ1 receptors ($\alpha1$ subunit); it has low affinity and potency at $\alpha2$ and $\alpha3$ subunits. It is an ultra-short-acting Z-drug that reduces sleep latency and can be taken after trying but failing to fall asleep. Zaleplon can also be taken for middle-of-the-night awakening.