Insomnia and Sedative-Hypnotics

Case Study: 53-Year-Old Teacher with Insomnia

• A 53-year-old teacher is experiencing difficulty falling asleep and wakes several times a night; this occurs almost nightly and impacts her teaching.
• She drinks decaffeinated coffee in the morning, six cans of diet cola daily, and one glass of wine with dinner.
• She reports experiencing hangover effects from over-the-counter sleep remedies.
• Further history and potential therapeutic measures and prescription drugs for this patient should be considered.

Introduction to Sedative-Hypnotics

• Sedatives (anxiolytics) reduce anxiety and produce calming effects.
• Hypnotics induce and maintain sleep.
• The level of CNS depression varies by drug type and dose.
• The therapeutic goal is to achieve minimal CNS depression needed for effectiveness.

Sedative-Hypnotic Classes

• Benzodiazepines are a class of sedative-hypnotics.
• Short-acting benzodiazepines include triazolam.
• Alprazolamis an intermediate-action benzodiazepine.
• Flurazepam is a long-acting benzodiazepine.
• Barbiturates are another class of sedative-hypnotics.
• Thiopental is an ultra-short-acting barbiturate.
• Secobarbital is a short-acting barbiturate.
• Phenobarbital is a long-acting barbiturate.
• Miscellaneous agents include buspirone, chloral hydrate, eszopiclone, ramelteon, zaleplon, and zolpidem.

Pharmacokinetics: Absorption and Distribution

• Drug lipophilicity impacts absorption and distribution.
• Rapid absorbers include triazolam, diazepam, most barbiturates, and newer hypnotics like eszopiclone, zaleplon, zolpidem and suvorexant.
• Sedative-hypnotics are capable of crossing the placental barrier, which means they can affect the developing fetus during pregnancy. Additionally, these drugs can be found in breast milk, potentially impacting nursing infants..
• Lipid solubility affects the CNS entry rate.

Pharmacokinetics: Biotransformation

• Benzodiazepines are cleared through hepatic metabolism and can have active metabolites, like desmethyldiazepam which has a 40+ hour half-life.
• Barbiturates are mainly metabolized, not excreted unchanged.
• Secobarbital/Pentobarbital have long half-lives of 18-48 hours.
• Phenobarbital has a long half-life of 4-5 days.
• Zolpidem has a peak plasma time of 1-3 hours, is metabolized by CYP3A4, and has a longer half-life in women and elderly patients.
• Zaleplon is metabolized by aldehyde oxidase and CYP3A4; reduced doses are needed for elderly and hepatic patients.
• Eszopiclone is metabolized by CYP3A4 and has a longer half-life in elderly patients.

Factors Affecting Drug Disposition

• Key influences include age, liver function, and enzyme interactions.
• Elderly patients may need dose adjustments.
• In patients with liver disease, the metabolic pathways for many medications, particularly sedative-hypnotics, are impaired, leading to prolonged drug half-lives and potential accumulation that necessitates vigilant monitoring for adverse central nervous system effects.
• Barbiturates can induce enzyme activity, while modern hypnotics do not induce enzymes.
• Special consideration is needed for elderly patients, those with liver disease, long-term users, and patients on multiple medications.
• Clinical implications include individual dose adjustments, monitoring for drug interactions, considering patient-specific factors, and regular assessment of therapeutic response.

Mechanism of Action (MOA) of Sedative-Hypnotics

• Benzodiazepines enhance the inhibitory action of gamma-aminobutyric acid (GABA) by specifically binding to sites on the GABA receptor-chloride ion channel complex, facilitating chloride ion influx and neuronal inhibition.
• This binding leads to conformational changes, opening the chloride ion channel and causing membrane hyperpolarization.
• BZDs increase chloride conductance, counteracting excitatory neurotransmitters.
• Binding of BZD's increase the frequency of channel opening.
• Barbiturates share a mechanism of action (MOA) with benzodiazepines (BZDs) by enhancing GABA receptor activity; however, they uniquely prolong the duration that the chloride ion channel remains open, increasing inhibitory neurotransmission.
• Both benzodiazepines and barbiturates need GABA to function.
• This enhancement of binding affinity is crucial for amplifying the inhibitory effects of GABA, ultimately leading to a more pronounced depressant effect on neuronal activity. The increased interaction promotes heightened chloride ion influx, contributing to overall central nervous system suppression.
• Newer hypnotics, like zolpidem, zaleplon, and eszopiclone, have a more selective binding profile, targeting GABAA receptors with α1 subunits.

BZD Antagonist: Flumazenil

• Flumazenil competitively inhibits the BZD receptor.
• It counteracts the adverse effects of BZDs.
• It is administered intravenously and has a rapid onset and a short duration.

Sedation Effects

• Primary actions include calming effects at low doses and anxiety reduction.
• These depressant effects may manifest as slowed reaction times, impaired coordination, diminished attention span, and reduced problem-solving capabilities, affecting daily activities.
• This phenomenon can lead to impulsive actions and increased risk-taking, as individuals may engage in behaviors they typically avoid due to consequences.
• Potential side effects are Euphoria is a state of intense happiness or elation that can occur as a side effect of sedative-hypnotic medications, particularly benzodiazepines., impaired judgment, and loss of self-control.
• Anterograde amnesia, a significant side effect associated with benzodiazepines, refers to the inability to form new memories after the medication has been administered, impacting daily functioning.

Hypnotic Effects

• General sleep patterns show a notable reduction in REM sleep, which is crucial for cognitive restoration and emotional regulation.
• REM rebound is more common with older sedative-hypnotics and less common with newer agents.
• Tolerance develops after one to two weeks.
• Rebound insomnia is possible with higher doses.
• Zolpidem decreases REM sleep.
• Zaleplon has minimal effect on sleep architecture.
• Eszopiclone increases total sleep time.
• Suvorexant decreases time to persistent sleep and REM sleep but increases total sleep time.

Anesthetic Properties

• Traditional sedative-hypnotics can induce stage III general anesthesia.
• Barbiturates (e.g., thiopental) have a rapid onset due to high lipid solubility and a short duration from tissue redistribution.
• Benzodiazepines are used in anesthesia combinations and carry a risk of prolonged respiratory depression, which is reversible with flumazenil.
• Newer agents like zolpidem, zaleplon, eszopiclone, and suvorexant lack anesthetic activity.

Anticonvulsant Activity

• Active agents include the benzodiazepines clonazepam, nitrazepam, lorazepam, and diazepam.
• Barbiturates with active agents include phenobarbital and metharbital. Newer hypnotics that lack anticonvulsant activity are zolpidem, zaleplon, eszopiclone, and suvorexant.

Muscle Relaxation

• Active muscle relaxants include carbamates (e.g., meprobamate) and benzodiazepines.
• This mechanism effectively disrupts communication within the spinal cord by targeting various neuronal pathways, leading to reduced muscle tone and relaxation. As a result, patients may experience decreased muscle spasms and improved movement control during treatment..
• Zolpidem, zaleplon, eszopiclone, and suvorexant do not have muscle relaxation properties.

Respiratory and Cardiovascular Effects

• Normal doses of sedative-hypnotics have similar effects to natural sleep in healthy patients but carries a risk in those with pulmonary disease.
• High doses can lead to medullary center depression and are a primary cause of overdose death.
• Normal doses have minimal effect in healthy patients but pose a risk in cardiovascular disease.
• Toxic doses can result in depressed myocardial contractility, reduced vascular tone, and potential circulatory collapse.
• Enhanced effects occur with IV administration.
• Suvorexant has no significant respiratory or cardiovascular effects.
• Caution is advised in hypovolemic states, heart failure, and compromised cardiovascular function.

Examples of Benzodiazepines & Trade Names with Indications

• Flurazepam treats insomnia and carries the trade name Dalmadorm.
• Chlordiazepoxide treats general anxiety under the name Librium.
• Lorazepam treats anxiety, insomnia, peri-operative anxiety, and status epilepticus, with trade names Ativan and Tranqipam.
• Clobazam treats anxiety and epilepsy (off-label) and is known as Urbanol.
• Oxazepam treats anxiety and is sold as Serepax/Purata.
• Diazepam treats anxiety, is administered pre-operatively, and is employed in alcohol withdrawal, status epilepticus, and as an adjunct epilepsy and is known as Valium/Pax.
• Alprazolam treats anxiety and is marketed as Xanocor.
• Dipotassium clorazepate treats anxiety and is sold as Tranxene.
• Prazepam treats anxiety and is marketed as Demetrin.
• Bromazepam treats anxiety under the names Lexotan/Brazepan.

Barbiturates

• Phenobarbital is used occasionally to treat seizure disorders.
• Thiopental is administered intravenously to induce anesthesia.

Truth Serum

• Truth serum is psychoactive substances believed to induce a state of enhanced truthfulness or suggestibility.
• Truth serums have been a subject of scientific inquiry since the early 20th century.
• Substances like sodium thiopental, scopolamine, and midazolam have been investigated for their potential to lower inhibitions.
• These drugs may reduce anxiety, fear, and critical thinking, potentially making individuals more susceptible to suggestion or disclosure.

Tolerance and Dependence

• Tolerance is a decreased drug responsiveness after repeated exposure.
• Cross-tolerance occurs between different sedative-hypnotics and ethanol.
• Traditional agents have significant tolerance.
• Zolpidem has tolerance with extended use only.
• Zaleplon shows minimal tolerance after 5-week studies.
• Eszopiclone has minimal tolerance after 6-month studies.
• Psychological aspects of psychological physiological dependence are compulsive misuse potential, anxiety relief, euphoria, sleep promotion.
• Physiological dependence causes withdrawal symptoms, increased anxiety, insomnia, CNS excitability, and potential convulsions.

Clinical Applications of Anxiolytics

• Acute Situations where anxiolytics are used include situational anxiety, medical procedure-related anxiety, and disease-associated anxiety.
• Chronic Conditions that involve treatment with Anxiolytics include generalized anxiety disorder (GAD), panic disorders, and Agoraphobia is an anxiety disorder characterized by intense fear or anxiety about being in situations where escape might be difficult or help unavailable in the event of a panic attack or related embarrassment.

Sleep Disorder Management

• A general principle is to evaluate underlying causes and consider non-pharmacologic approaches, limit duration of drug therapy, and monitor for rebound insomnia.
• Modern approaches with newer hypnotics are less sleep pattern disruption, reduced tolerance risk, and fewer withdrawal symptoms.

Clinical Toxicology concerning Sedative Hypnotics

• Direct Toxic Effects include dose-dependent CNS depression, anterograde amnesia, hangover effects, respiratory depression, and cardiovascular complications.
• Risk Factors include elderly patients, cardiovascular disease, respiratory conditions, hepatic impairment, and polypharmacy.
• Immediate actions required for toxicity management include airway protection, ventilation support, and cardiovascular support.
• Specific interventions include flumazenil for benzodiazepine overdose, hemodialysis/hemoperfusion, and supportive care.

Ramelteon and Tasimelteon

• Ramelteon and Tasimelteon are melatonin receptor agonist hypnotics.
• They target melatonin MT1 and MT2 receptors.
• These receptors are located in suprachiasmatic nuclei.
• They regulate circadian rhythms and Maintain natural sleep-wake cycle.
• Ramelteon is indicated for difficulty falling asleep, reduces sleep latency, preserves sleep architecture, does not cause rebound insomnia, and has minimal withdrawal symptoms.
• Tasimelteon treats non-24-hour sleep-wake disorder with a similar mechanism to ramelteon, targeting circadian rhythm regulation.
• Ramelteon has rapid oral absorption with extensive first-pass metabolism and an active metabolite with a longer half-life (2-5 hours).
• Common adverse effects are dizziness, somnolence, fatigue, and endocrine changes.
• Headache, elevated liver enzymes, nightmares, and abnormal dreams are the most common adverse effects of Tasimelteon.

Buspirone

• Buspirone is selectively anxiolytic, with no sedative or hypnotic effects, has no euphoric properties, and thus has minimal abuse potential.
• It has no direct GABA interaction.
• The primary mechanisms are partial agonism at 5-HT1A receptors and affinity for dopamine D2 receptors.
• Buspirone treats generalized anxiety states but is less effective for panic disorders, with an onset of 3-4 weeks.
• Advantages include no rebound anxiety, no withdrawal symptoms, no sedative-hypnotic interaction, safety for elderly patients, minimal psychomotor impairment, and no effect on driving skills.

Summary of Important Points

• BZDs are indicated for treatment of anxiety disorders, insomnia, muscle spasms, seizure disorders, and spasticity.
• BZDs facilitate GABA binding and increase the frequency with which the chloride channel opens.
• BZDs also decrease the release of GABA, limiting CNS depression magnitude.
• BZDs and other hypnotic drugs reduce sleep latency, reduce early awakenings, and increase total sleep time.
• Barbiturates bind to the GABAA receptor but do not exhibit a ceiling effect. They can cause respiratory depression, coma, and death.
• Barbiturates induce their metabolism.
• Long-term administration of BZDs and barbiturates can lead to tolerance and physical dependence, with abrupt discontinuation which can lead to withdrawal symptoms.
• Zolpidem, zaleplon and eszopiclone are effective, short-acting sedative-hypnotics that have little effect on normal sleep architecture and produce few adverse effects.
• Ramelteon is the first prescription drug that acts on melatonin receptors to treat insomnia.
• Flumazenil is a BZD receptor antagonist that can be used to counteract respiratory depression and other reactions that are usually caused by excessive doses of BZDs.