Sedation and Hypnosis Pharmacology

Sedation and Hypnosis

• Sedative-hypnotic drugs relieve anxiety and encourage sleep.
• Anxiety and sleep disorders are common, leading to widespread prescription of sedative-hypnotics.

General Effects

• Sedatives at lower doses produce calming, anxiolytic effects.
• Hypnotics at higher doses induce sleep and depress the central nervous system (CNS).
• Drugs generally have sedative effects at low doses and hypnotic effects at high doses.

Basic Pharmacology

• Dose-dependent sedation, sleep, anesthesia, and coma are degrees of a single basic effect.
• Hypnosedatives cause a widespread depression of central nervous system Neurons.
• Two main dose-response modalities exist: linear or parabolic.
• Older agents like barbiturates and ethanol show a near-linear dose-response curve, posing risks of respiratory depression and death.
• Benzodiazepines and newer hypnotics display a non-linear dose-response trend, enhancing safety margins.
• Sedative hypnotics may have anticonvulsant effects and can reduce muscle tonus, but are not analgesics and should not be the only treatment for pain.
• Sedative hypnotics should not be used in a painful situation as they are contraindicated, and can cause confusion and agitation.

Classification of Drugs

• Benzodiazepines
• Barbiturates
• Nonbenzodiazepine Hypnotics (“Z Drugs”)
• Melatonin Receptor Agonists
• Orexin (Hypocretin) Receptor Antagonists
• Other drugs

Benzodiazepines

• Benzodiazepines bind to a specific allosteric site on the GABA_A receptor, located between the α and γ subunits.
• By binding to the GABA_A receptor, benzodiazepines increase the receptor's affinity for GABA, boosting the frequency of chloride channel openings.
• They are well absorbed orally due to high lipophilicity, enabling rapid passage across the blood-brain barrier.
• Most are metabolized in the liver, primarily by cytochrome P450 enzymes CYP3A4 and CYP2C19.
• Some metabolize into active metabolites, prolonging their effects; examples include diazepam and chlordiazepoxide.
• Chlorazepate is a pro-drug.
• Lorazepam, oxazepam, and temazepam undergo direct conjugation (glucuronidation) and are not metabolized by CYP enzymes.
• Lorazepam, oxazepam, and temazepam are safer choices for those with hepatic insufficiency.
• Glucuronidation is less affected by liver dysfunction than oxidation.
• Benzodiazepines lacking active metabolites reduce the risk of prolonged sedation and toxicity.
• Diazepam, chlordiazepoxide, alprazolam, and midazolam undergo extensive oxidative metabolism via cytochrome P450, making them unsuitable for patients with liver impairment.
• Benzodiazepines are classified by elimination half-life (ultra-short, short, intermediate, and long-acting), impacting dosing and accumulation risks with chronic use.
• Benzodiazepines bind to a specific site on the GABA-A receptor, enhancing GABA's effect without directly activating the receptor.
• Benzodiazepines increase the frequency of chloride channel openings in the presence of GABA.
• They have a higher safety margin than barbiturates due to their dependence on GABA's presence.

Benzodiazepines: Adverse Effects and Considerations

• Adverse effects include lethargy, confusion, disorientation, impaired motor coordination, ataxia, and nystagmus.
• Symptoms mimicking dementia, paradoxically increased anxiety, dysphoria, hyperactivity, paranoia, and depression may also be observed.
• Tolerance develops to sedative-hypnotic effects but not to amnesia, psychomotor slowing, or ataxia.
• Short-acting agents can lead to physical dependence more quickly.
• Other adverse effects include rebound insomnia and CNS depression.
• Withdrawal symptoms include maximum in 3-7 days after drug discontinuation and can be 2-4 weeks long, depending on drug duration of action.
• Withdrawal symptoms include tremor, anxiety, sleep disturbance, restlessness, sweating, decreased appetite, nausea, vomiting, perception impairment, and intolerance to loud sounds and noise.
• Benzodiazepines are preferred over barbiturates, as they have a lower risk of fatal respiratory depression and improved overall safety.
• Long-term use requires caution due to the potential for tolerance, dependence, and withdrawal.
• Long acting Diazepam may be used for anxiety, muscle relaxation, seizure control, and as a preanesthetic agent due to active metabolites which prolong its effect.
• Ultra-short acting Midazolam, is often used in procedural sedation and as an adjunct in anesthesia.
• Long-acting Chlordiazepoxide, may be used for alcohol withdrawal and anxiety due to active metabolites.
• Alprazolam, is typically used for anxiety disorders and panic attacks.

Barbiturates

• Barbiturates, an older class of sedative-hypnotics, depress central nervous system activity.
• Unlike benzodiazepines, they enhance GABA-A receptor function by prolonging chloride channel opening duration.
• At high concentrations, barbiturates can directly activate the receptor, leading to profound CNS depression, not need GABA to function.
• Barbiturates have a narrow therapeutic index, increasing risk of toxicity.
• Barbiturates have the potential for cumulative effects and respiratory depression, resulting in a preference for safer alternatives.
• Similar to benzodiazepines, barbiturates are well absorbed orally due to high lipophilicity and rapidly cross the blood-brain barrier.
• They rapidly cross the blood-brain barrier and distribute widely into body tissues due to high lipid solubility (redistribution phenomenon).
• Most undergo oxidation via liver enzymes.
• Phenobarbital has a longer half life, whereas thiopental and methohexital are rapidly metabolized and more suitable for anesthesia.
• Barbiturates bind to allosteric sites on the GABA-A receptor within the channel structure, and increase the duration of chloride channel openings when GABA is present.
• Anesthesia induction can be achieved via ultra-short-acting agents like thiopental to rapidly induce anesthesia.
• Sedation and Hypnosis was previously achieved via barbiturates, but that has been since limited by a narrow therapeutic window.
• Phenobarbital continues to be useful for seizure control in refractory epilepsy cases, particularly in pediatric cases.

Barbiturates: Adverse Effects and Considerations

• Adverse effects include tolerance and dependency, shortened REM sleep, rebound insomnia, residual impact, and paradoxical anxiety and excitation.
• Porphyria aggravation, allergic reaction, respiratory depression, myalgia, joint pain, and a lowered pain threshold are also adverse effects.
• Thiopental is an ultra-short-acting barbiturate used for anesthesia induction due to its rapid onset (20 seconds) and short duration (10 minutes).
• Redistribution effect can prolong its half-life up to 24 hours.
• Methohexital is similar to thiopental, and it is used for anesthesia induction with a very short duration of action.
• Phenobarbital is a long-acting barbiturate with anticonvulsant properties used to manage seizures, particularly in children.

Differences Between Benzodiazepines and Barbiturates

Benzodiazepines typically offer:

• Less addiction and tolerance
• Fewer sleep disturbances
• A wider therapeutic range
• Less respiratory/KVS depressant effects and
• No enzyme induction, contrasting with the properties of barbiturates.

Atypical Benzodiazepines ("Z Drugs")

• "Z drugs" are structurally distinct from classic benzodiazepines but act at the benzodiazepine binding site on the GABA-A receptor.
• Examples include zolpidem, zaleplon, zopiclone, and eszopiclone.
• They bind to receptors with a higher affinity for receptor isoforms containing the α1 subunit.
• They provide strong hypnotic effects with less muscle relaxant or anticonvulsant actions, leading to more targeted effects on sleep regulation.
• Pharmacokinetics is similar to benzodiazepines, and have short elimination half-lives like zaleplon, approximately 1 hour, or zolpidem, which has around 2-3.5 hours, which minimizes next-day residual sedation.
• Primarily used as hypnotics for treating insomnia, and are quick acting for rapid sleep onset to minimize hangover effects.
• There are concerns over tolerance, rebound insomnia, and potential risks for dependence with long-term or high-dose use.

Melatonin Receptor Agonists

• Melatonin receptor agonists mimic the action of endogenous melatonin, regulating the sleep-wake cycle.
• Melatonin is the primary hormone regulating the body's biological clock.
• These drugs bind with high affinity to melatonin receptors (MT1 and MT2) in the suprachiasmatic nucleus, the body's master clock in the hypothalamus.
• Activation of receptors regulates circadian rhythms and promotes sleep onset, mimicking melatonin's natural effects.
• Agents undergo extensive first-pass metabolism in the liver.
• Ramelteon is metabolized by CYP1A2 (with contributions from CYP2C9), producing inactive metabolites.
• CYP1A2 inhibitors like fluvoxamine and ciprofloxacin can heighten adverse effects by increasing ramelteon levels.
• Includes ramelteon which is approved for the treatment of insomnia and difficulty falling asleep.
• Tasimelteon is mainly used for circadian rhythm sleep disorders, ex. non-24-hour sleep-wake disorder, and particularly in blind people.
• They have a low potential for abuse and dependence, with minimal tolerance and withdrawal symptoms compared to GABAergic hypnotics.
• Their mechanism more closely mimics physiological sleep regulation, with fewer adverse cognitive and psychomotor effects.
• They are best suited for patients with circadian rhythm disruption rather than generalized CNS depression.

Orexin Receptor Antagonists

• Orexin receptor antagonists are hypnotics that cause sleep by blocking orexin (hypocretin) receptors, which stimulate wakefulness.
• Suvorexant and lemborexant are examples.
• Antagonists block orexin receptors (OX1R and OX2R) in the hypothalamus, playing a key role in maintaining arousal and wakefulness.
• By antagonizing receptors, the drive for wakefulness is lower, facilitating both the initiation and maintenance of sleep.
• Unlike GABAergic drugs, these agents don't broadly depress CNS activity, helping preserve normal sleep architecture and cognitive function.
• These agents have relatively long elimination half-lives (ex. suvorexant's half-life is around 12 hours), this helps maintain sleep, yet requires careful dosing to prevent daytime sedation.
• It is approved mainly for treating insomnia, particularly in patients who have difficulty falling asleep or staying asleep.
• It blocks orexin-mediated wake drive, avoiding broader CNS depression seen with GABAergic hypnotics.
• They tend to preserve sleep architecture, including REM sleep, more effectively than many traditional hypnotics.
• Due to its long half-life, careful dose titration is important to prevent daytime drowsiness.
• They exhibit a low risk for tolerance and dependence compared to older hypnotics.

Other Drugs

• Buspirone is a nonbenzodiazepine anxiolytic used to manage generalized anxiety disorder (GAD).
• Unlike benzodiazepines, buspirone doesn't have significant sedative, muscle relaxant, or anticonvulsant properties.
• It is not associated with cognitive impairment or abuse potential.
• Buspirone acts as a partial agonist at 5-HT1A receptors in the brain, modulating serotonergic neurotransmission.
• It is most effective for chronic anxiety rather than acute anxiety episodes due to its slower onset of action.
• Anxiolytic effects typically take several weeks, so it is not useful for immediate relief of acute anxiety symptoms.
• Chloral hydrate was introduced in the 19th century and widely used for hypnotic and sedative properties in both adults and children.
• Concerns have grown over Chloral hydrate's toxicity and side-effect profile, leading to decreased use in modern clinical practice.
• Chloral hydrate is rapidly converted in the body to trichloroethanol, its active metabolite, which is primarily responsible for its sedative-hypnotic effects.
• The active metabolite enhances inhibitory neurotransmission in the brain, potentiating GABAergic activity that results in sedation and sleep induction.
• It has been used in pediatric populations for sedation in some circumstances.
• Chloral hydrate has a narrow therapeutic index, presenting a small margin between effective and toxic doses.
• Its use has declined largely because of safety concerns, including the risk of overdose, gastrointestinal irritation, and potential for liver toxicity.
• Beta blockers have a weak anxiolytic effect, with propranolol being most commonly used.
• In anxiety disorders, somatic symptoms of sympathetic hyperactivity respond to beta blockers due to peripheral action
• Propranolol increases the anxiolytic efficacy of diazepam
• Clonidine activates presynaptic alpha 2 receptors in central noradrenergic nerve endings and attenuates noradrenergic excess (AUTO RECEPTORS).
• It is used in panic disorder that does not respond to other medications.
• Histamine promotes wakefulness in the brain, thus, antihistamines can be used as sedative hypnotics.
• Doxylamine, diphenhydramine, promethazine, and metapyrilene are examples of antihistamines.