Sedative-hypnotic drugs

Sedative-hypnotics are a class of drugs that depress CNS function, inducing sedation, sleep, and unconsciousness with increasing dose. Agents in this drug class include benzodiazepines, nonbenzodiazepine hypnotics (Z-drugs), barbiturates, and melatonin agonists. Most sedative-hypnotic drugs affect GABAergic transmission, increasing the inhibition of neuronal excitability, except for melatonin agonists, which act on hypothalamic melatonin receptors. Sedative-hypnotic drugs are used as anxiolytics, sedatives, muscle relaxants, anesthetics, and anticonvulsants. Common side effects result from excessive CNS depression and include confusion, somnolence, and respiratory depression. Long-term use of sedative-hypnotics is associated with a risk of tolerance and withdrawal.

Agents ^[1]

• Short-acting: (half-life 1–12 hours): midazolam, triazolam
• Intermediate-acting: (half-life 12–40 hours): lorazepam; , temazepam, oxazepam, lormetazepam, alprazolam
• Long-acting: (half-life > 40 hours): diazepam, chlordiazepoxide, clonazepam, tetrazepam, flurazepam

Mechanism of action ^[2]

• Benzodiazepines are indirect GABA_A receptor agonists; that bind to GABA-A receptors → ↑ affinity of GABA to bind to GABA_A receptors → ↑ GABA action → ↑ opening frequency of chloride channels → hyperpolarization of the postsynaptic neuronal membrane → ↓ neuronal excitability
• Benzodiazepines decrease the duration of N3 phase in NREM sleep, thereby reducing the occurrence of sleepwalking and night terrors

Benzo increases the frequenzo of Cl-channel opening.

Effects ^[3]

• Anxiolysis
• Sedation
• Hypnotic action
• Muscle relaxation
• Anticonvulsant action
• Amnesia

Indications

• Anxiety disorders: chlordiazepoxide, diazepam, clonazepam, lorazepam, oxazepam, alprazolam
• Insomnia: flurazepam, temazepam, triazolam, lormetazepam
• Alcohol withdrawal: chlordiazepoxide, diazepam, oxazepam
• Seizures and status epilepticus : diazepam, lorazepam, midazolam, clonazepam
• Preoperative and procedural sedation: diazepam, lorazepam, midazolam
• Other indications include skeletal muscle spasticity, catatonia, eclampsia, sleepwalking, night terrors, and chemotherapy-induced nausea and vomiting.

Lorazepam, Oxazepam, and Temazepam are preferred for individuals who drink a LOT (have alcoholic liver disease), because hepatic dysfunction does not have a strong effect on their metabolism. All benzodiazepines are metabolized by the liver, but these three undergo biotransformation through glucuronidation, not CYP450 activation, and are less affected by liver disease. ^[4]

Adverse effects ^[2][3][4]

General adverse effects

• Anterograde amnesia
• Confusion
• Blunted affect
• Residual sedation: sedative effects (e.g., drowsiness) persist beyond the intended time span ^[5]
• Reduced coordination
• Increased risk of injury (especially with benzodiazepine use in older adults) ^[6]
• Paradoxical reactions to benzodiazepines ^[7]
  • Includes restlessness, irritability, impulsivity, and disinhibition.
  • Risk groups: older adults and children, individuals with a history of a substance use disorder or another psychiatric condition.
  • Treatment: discontinuation of the drug
• Rebound phenomenon
  • Reemergence of symptoms (e.g., depression, insomnia, and anxiety) upon discontinuation of benzodiazepine therapy, often with increased intensity
  • Especially common in the treatment of sleep disorders
• Risk of overdose
• Tolerance and withdrawal; short-acting agents are associated with a higher risk of dependence ^[3]
• Risk of developing substance use disorder
• Interactions: cytochrome P450 induction

In older adults, benzodiazepines should be used with extreme caution because they can worsen cognitive impairment, increase the risk of falls, and lead to paradoxical reactions.

Benzodiazepine overdose ^[6]

• Clinical features
  • Symptoms
    • Lethargy, somnolence
    • Respiratory depression
      • Due to a decrease in central respiratory drive and upper airway muscle tone
      • Intensifies drastically when combined with other respiratory depressants such as alcohol or barbiturates
      • Benzodiazepines have a wider margin of safety than barbiturates and, consequently, a lower risk of coma and respiratory depression.
    • Ataxia
    • Hypotonia and hyporeflexia
    • Slurred speech
    • Mild hypotension
  • Focused toxicological history and physical examination
• Diagnostics
  • General diagnostic testing (see “Approach to the poisoned patient”) should be done depending on clinical findings, including:
    • Point of care glucose to rule out hypoglycemia
    • Serum testing for coingestion of other substances (e.g., acetaminophen and ethanol serum values)
    • ECG to evaluate for arrhythmia (with additional screening for arrythmia-inducing toxic substances, if necessary)
  • Urine drug screening is not useful in diagnosing benzodiazepine overdose. ^[2]
• Differential diagnosis
  • Overdose or poisoning from other sedative-hypnotic or anticonvulsant agents (e.g., alcohol, barbiturates, phenytoin)
  • Opioid overdose
  • Stroke or other neurological disorders
• Treatment
  • Supportive therapy according to overdose severity ^[2]
    • Airway obstruction, respiratory depression, and decreased oxygen saturation: consider endotracheal intubation (see “Airway management and ventilation”)
    • Hypotension: fluid resuscitation
    • Consider a trial of naloxone when opioid overdose is suspected.
    • Activated charcoal, hemodialysis, and whole bowel irrigation are not effective treatment options. ^[2]
    • See “Approach to the poisoned patient.”
  • Antidote: flumazenil
    • Mechanism of action: competitive antagonism at GABA receptor
    • Indications
      • Severe respiratory depression
      • Overdose in benzodiazepine-naive patients (e.g., accidental ingestion in children, periprocedural oversedation with benzodiazepines)
    • Due to the risk of seizures, the use of flumazenil is contraindicated under the following circumstances:
      • Chronic benzodiazepine use
      • Underlying seizure disorder
      • Suspected coingestion of proconvulsive substances (e.g., amphetamines, bupropion, methotrexate, clozapine)

Benzodiazepine overdose most commonly occurs in patients on chronic benzodiazepine therapy. Flumazenil can precipitate withdrawal symptoms and seizures in patients with benzodiazepine dependence.

Benzodiazepine overdose is very rarely life-threatening unless associated with the coingestion of alcohol, opioids, barbiturates, first-generation antihistamines (e.g., diphenhydramine), or other respiratory or CNS depressants.

Benzodiazepine dependence ^[3]

• Definition: The physical adaptation to sustained use of a substance with the development of tolerance and withdrawal.
• Withdrawal symptoms
  • Autonomic nervous system
    • Diaphoresis
    • Nausea, vomiting, and anorexia
    • Tachycardia
    • Hypertension
  • Neurological
    • Seizures
    • Tremors
    • Memory impairment
  • Psychiatric
    • Anxiety
    • Depressive mood
    • Insomnia
    • Withdrawal psychosis with transient optic, auditory, or tactile hallucinations
• Treatment ^[8]
  • Dose tapering
    • Withdrawal management should be done in an inpatient setting.
    • Switch from multiple agents to one, preferably diazepam.
    • Discontinue gradually over a period of 4–8 weeks.
    • Reduce dose no more than once a week
  • Seizure prophylaxis (e.g., carbamazepine)
  • Acute seizure management

Prolonged benzodiazepine use causes dependence and, potentially, substance use disorder. Treatment involves cognitive-behavioral therapy and psychosocial interventions to facilitate withdrawal and continued abstinence (i.e., psychoeducation, motivational interviewing, cognitive-behavioral therapy).

Benzodiazepine dependence can already develop after a few weeks of use. Therefore, benzodiazepines should only be prescribed when strongly indicated.

Benzodiazepine dependence in pregnant individuals may lead to withdrawal symptoms in the newborn.

Contraindications for benzodiazepines ^[4][6]

• Hypersensitivity to benzodiazepines
• Narrow-angle glaucoma
• Respiratory depression (COPD, respiratory failure)
• Myasthenia gravis
• History of a substance use disorder (e.g., alcohol, recreational drugs, prescription medications), except in the treatment of acute alcohol or sedative-hypnotic withdrawal
• Pregnancy (except for the management of eclampsia following unsuccessful magnesium sulfate therapy) ^[4]

Agents ^[4]

• Zolpidem (imidazopyridine): half-life ∼ 2 hours
• Zaleplon (pyrazolopyrimidine): half-life ∼ 1 hour
• Eszopiclone: half-life ∼ 6 hours

Mechanism of action ^[4]

• Similar to benzodiazepines
• Selectivity for GABA_A receptors with α1 subunits (corresponding to the BZ₁ subtype)
• Short-acting due to fast metabolization by liver enzymes

Effects ^[4]

• Sedation
• Hypnotic action
• Less effect on sleep architecture than benzodiazepines
• Less effective than benzodiazepines as an anticonvulsant and an anxiolytic

Z-drugs give you the Zzzz's (make you sleepy).

Indications

• Insomnia

Adverse effects ^[4]

• Ataxia
• Headaches
• Confusion
• Psychomotor depression
• Amnesia
• Residual sedation
• Impaired cognitive functions
• Risk of overdose
  • Symptoms are similar to those of benzodiazepine overdose.
  • Can be treated with flumazenil as with benzodiazepines
• Tolerance and withdrawal ^[9]
  • Risk profile is similar to that of benzodiazepines
  • After long-term use, the daily dose should be tapered gradually (there is a risk of developing withdrawal symptoms and memory impairment upon sudden cessation of therapy).
• Risk of developing substance use disorder

Contraindications

• Similar to contraindications for benzodiazepines (see the corresponding section above)

Agents ^[10]

• Ultra-short acting: (half-life 15 minutes–3 hours): thiopental, methohexital
• Short-acting: (half-life 3–6 hours): pentobarbital, secobarbital
• Intermediate-acting (half-life 6–12 hours): amobarbital, butalbital
• Long-acting: (half-life 12–24 hours): phenobarbital, primidone

Mechanism of action

• Bind to GABA_A receptors; → ↑ duration of the GABA-gated chloride channel opening → ↑ intracellular Cl^--flow → hyperpolarization of postsynaptic neurons → ↓ neuronal excitability
• Additional, non-GABA-dependent, mechanisms of action
  • ↓ Glutamate signaling
  • Membrane effects similar to those of inhalational anesthetics
• High lipid solubility of barbiturates leads to:
  • Rapid onset of action
  • Accumulation in skeletal and adipose tissue → prolonged duration of action

Benzodiazepines increase the frequency of chloride channel opening, whereas barbiDURATes increase the DURATion of chloride channel opening.

Effects

• Dose-dependent effects
  • Low dose: sedative
  • Medium dose: hypnotic
  • High dose: general anesthetic
• Decreased intracranial pressure due to reduced cerebral blood flow
• Antiepileptic
• Little to no analgesic or muscle relaxant effects

Indications

• Ultra-short acting
  • General anesthesia (see “Intravenous anesthetics”)
  • Status epilepticus
  • Sedation; for electroconvulsive therapy (methohexital)
  • Reduction of intracranial pressure for brain edema following trauma or surgery
• Short-acting and intermediate-acting
  • Preanesthetic sedation
  • Short-term treatment for insomnia or anxiety disorders
  • Tension-type headache
• Long-acting
  • Generalized-onset and focal-onset seizures (see “Anticonvulsant drugs”)
  • Phenobarbital
    • Status epilepticus
    • Neonatal seizures
    • Preanesthetic sedation
    • Alcohol withdrawal
    • Gilbert syndrome (to reduce hyperbilirubinemia)
  • Primidone: essential tremor

Barbiturates are no longer used for sedation or long-term treatment of insomnia due to their low safety margin. They have been replaced by more effective drugs with fewer side effects (e.g., benzodiazepines).

Adverse effects

• Hypotension (dose-dependent)
• Respiratory depression; and/or apnea (dose-dependent): Barbiturates have a narrower margin of safety than benzodiazepines.
• Tolerance and withdrawal
• CNS depression, especially when used with other CNS depressants (e.g., benzodiazepines, alcohol)
• Toxicity
• Laryngospasm, bronchospasm (due to histamine release)
• Myoclonus
• Interactions: cytochrome P450 induction (leads to a variety of possible drug interactions)

Accidental intraarterial injection of barbiturates

• Etiology: incorrect injection of barbiturates
• Clinical features: tissue necrosis; gangrene (through vessel injury, spasm, and thrombosis)
• Treatment
  • Intraarterial dilution with NaCl 0.9% and injection of heparin to prevent thrombosis
  • Termination of vessel spasm
    • Intraarterial administration of 5–10 mL of 1% lidocaine
    • Axillary plexus or stellate ganglion block to block sympathetic nerve fibers that uphold the vessel spasm

Barbiturate overdose

• Clinical features
  • Impaired consciousness, coma
  • Respiratory failure
  • Cardiovascular depression (potentially fatal)
• Management: mainly supportive as there is no specific antidote
  • Monitoring
  • Secure airways, maintain adequate oxygenation, and provide respiratory assistance, if necessary.
  • Fluid resuscitation to maintain blood pressure
  • ECG: Monitor for arrhythmia.
  • ABG: Monitor for metabolic acidosis and increase levels of serum lactic acid.
  • In cases of suspected alcohol intoxication, measure the alcohol and barbiturate levels in serum.
  • Sodium bicarbonate (NaHCO₃): urine alkalinization and forced diuresis

Barbiturate dependence

• The physical adaptation to sustained use of barbiturates with the development of tolerance and withdrawal.
• Withdrawal symptoms
  • CNS stimulation (e.g., insomnia, irritability)
  • Autonomic dysfunction (e.g., tachycardia, diarrhea)
  • Dysphoria, delirium
  • Tremors, seizures
  • Life-threatening cardiovascular dysfunction

Contraindications

• Porphyria
• Severe anemia
• Myasthenia gravis
• Addison disease
• Liver or kidney disease
• Thyroid disorders
• Asthma

Agents

• Ramelteon
• Tasimelteon
• Agomelatine

Ramelteon, tasimelteon, and agomelatine are melatonin receptor agonists.

Mechanism of action

• Activation of MT1 and MT2 receptors in suprachiasmatic nuclei of the hypothalamus → quicker sleep onset
• Do not cause dependence

Indications

• Insomnia, especially in older adults
• Circadian rhythm disorders

Adverse effects

• Headache
• Dizziness
• Fatigue
• Nausea
• Arthralgias
• Angioedema (rare)
• Interactions: CYP1A2 inhibitors (e.g., fluvoxamine) increase blood concentration.

Contraindications ^[11]

• Hypersensitivity reactions

Agents

• Suvorexant

Mechanism of action

• Antagonism of orexin (hypocretin) receptors → inhibits the binding of neuropeptides orexin A and B → ↓ wakefulness and arousal

Suvorex-ant is an orexin antagonist.

Indications

• Insomnia

Adverse effects ^[12]

• Headache
• Sleep disturbances: abnormal dreams, nightmares, sleep terrors
• CNS depression (e.g., somnolence)
• Tolerance and withdrawal (rare)
• Suicidal ideation
• Interactions: CYP3A4 inhibitors

Contraindications

• Liver disease
• Narcolepsy