Sedative-hypnotic drugs

Sedative-hypnotics are a class of drugs that cause a dose-dependent depression of the CNS function, inducing sedation, sleep, and unconsciousness with increasing dose. Agents in this class of drugs include benzodiazepines and Z-drugs, barbiturates, and melatonin agonists. Most of the 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, drowsiness, somnolence, and respiratory depression. Long-term use of sedative-hypnotics is associated with a risk of dependence.

Lorazepam, Oxazepam, and Temazepam are preferred in those who drink a LOT because they are not metabolized by the liver and therefore safe in alcoholic liver disease.

Remember ATOM for benzodiazepines with a short half-life: Alprazolam, Triazolam, Oxazepam, and Midazolam.

Mechanism of action

• 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
• Decreases the duration of N3 phase in REM sleep, thereby reducing the occurrence of sleepwalking and night terrors

Benzo increases the frequenzo of Cl-channel opening.

Side effects

General adverse effects

• Anterograde amnesia
• Addictive potential
• Drug tolerance
• Drowsiness, sleepiness, or dizziness
• Blunted affect
• ↑ Appetite
• Hangover effect
• Paradoxical excitability ^[2]
  • Manifests with symptoms such as increased talkativeness, excessive movement, anxiety, irritability, and aggression
  • Occurs most frequently in older and pediatric patients
  • Risk factors include substance use and preexisting psychiatric conditions (e.g., anxiety disorders, personality disorders).
  • Treatment involves discontinuing the causative drug.

Benzodiazepine overdose

• Clinical features
  • CNS depression
    • Lethargy, somnolence
    • Respiratory depression
      • Intensifies drastically when combined with other respiratory depressants like alcohol or barbiturates
      • Benzodiazepines have a wider margin of safety than barbiturates and, consequently, a lower risk of coma and respiratory depression.
  • Mild hypotension
  • Hypotonia and hyporeflexia
  • Ataxia
  • Slurred speech
• Diagnostics: Routine urine screening for benzodiazepine metabolites (e.g., oxazepam, nordiazepam) is not required.
• Differential diagnosis: other substances that lead to a sedative‑hypnotic toxidrome after an overdose (e.g., alcohol, barbiturates, and anticonvulsants such as phenytoin)
• Treatment
  • Supportive therapy
    • Single dose of activated charcoal if the patient is fully conscious and presents within 30 minutes of overdose
    • Airway obstruction, respiratory depression, and ↓ oxygen saturation: consider endotracheal intubation (see “Airway management and ventilation”)
    • Hypotension: fluid resuscitation
    • Extracorporeal removal (e.g., hemodialysis, plasmapheresis) is not recommended.
  • 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)
    • Use of flumazenil for benzodiazepine overdose is not recommended due to risk of seizures (flumazenil induces a state of acute benzodiazepine withdrawal).

Most cases of benzodiazepine overdose occur in patients who are 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 co-ingestion of alcohol, opioids, barbiturates, first-generation antihistamines (e.g., diphenhydramine) or other respiratory or CNS depressants.

Benzodiazepine dependence ^[3]

• Rebound phenomenon: reemergence of symptoms (e.g., depression, insomnia, and anxiety) that were previously absent or controlled by benzodiazepine therapy when the medication is discontinued for a few days
• Withdrawal symptoms
  • Autonomic nervous system
    • Sweating
    • Nausea, vomiting, and anorexia
    • Hypertension
  • Neurological
    • Seizures
    • Tremors
    • Memory impairment
  • Psychiatric
    • Depressive moods
    • Insomnia
    • Withdrawal psychosis with optic and auditory hallucinations
• Treatment
  • Nonpharmacological measures: psychotherapy, inpatient care
  • Pharmacological measures
    • Dose tapering
    • Seizure prophylaxis (e.g., carbamazepine)
    • Catatonic excitement: antipsychotics (e.g., haloperidol)

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

Contraindications for benzodiazepines ^[4]

• Hypersensitivity to benzodiazepines
• Neuromuscular diseases (e.g., myasthenia gravis): worsening of myasthenic symptoms
• Narrow-angle glaucoma
• Respiratory depression (COPD, respiratory failure)
• Drug dependence (alcohol, illicit drug, or prescription medication use)
• Pregnancy (except for the management of eclampsia following unsuccessful magnesium sulfate therapy): ↑ risk of floppy infant syndrome (hypotonia)

Agents

• Zolpidem (imidazopyridine): half-life up to 4.5 hours
• Zaleplon (pyrazolopyrimidine): half-life ∼ 1 hour
• Eszopiclone: half-life ∼ 6 hours

Indication

• Sleep disorders (especially with difficulty falling asleep)

Mechanism of action

• 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

• Good sedative and 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).

Side effects

• Ataxia
• Headaches
• Confusion
• Hangover effect (less common than in other sedative-hypnotic drugs)
  • Psychomotor depression
  • Amnesia
  • Sleepiness
  • Impaired cognitive functions
• In the case of overdose
  • Symptoms are similar to those of benzodiazepine toxicity.
  • Can be treated with flumazenil as with benzodiazepines
• Development of drug tolerance and dependence
  • Significantly lower risk than with benzodiazepines, but should not be underestimated
  • 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).

Contraindications

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

Agents and indications ^[5]

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).

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 in the brain
• Additional, non-GABA-dependent, mechanisms of action
  • ↓ Glutamate signaling
  • Membrane effects similar to those of inhalational anesthetics
• High lipid solubility of barbiturates leads to their:
  • 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 (from low to higher dose)
  • Sedative
  • Hypnotic
  • Inducing general anesthesia
• ↓ Intracranial pressure due to reduced cerebral blood flow
• Antiepileptic
• Little to no analgesic or muscle relaxant effects

Adverse effects

• Hypotension (dose-dependent): See “Barbiturate overdose.”
• Respiratory depression; and/or apnea (dose-dependent): Barbiturates have a narrower margin of safety than benzodiazepines.
• Dependence
• Cytochrome P450 induction → variety of possible drug interactions
• CNS depression, especially when used with other CNS depressants (e.g., benzodiazepines, alcohol)
• Laryngospasm, bronchospasm (due to histamine release)
• Myoclonus
• Painful injection

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 (possibly fatal)
  • Barbiturate blisters
• 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

• Withdrawal symptoms
  • Delirium
  • Severe hypotension, possibly cardiovascular collapse

Contraindications

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

• Agents: ramelteon, tasimelteon, agomelatine
• Mechanism of action: activation of MT1 and MT2 receptors in suprachiasmatic nuclei of the hypothalamus → quicker sleep onset
• Indications
  • Insomnia (particularly in delayed-onset sleep)
  • Circadian rhythm disorders
• Adverse effects
  • Headache
  • Dizziness
  • Fatigue
  • Nausea
  • Arthralgias
  • Angioedema (rare)
  • Do not cause dependence
• Interactions: CYP1A2 inhibitors (e.g., fluvoxamine) increase blood concentration.

Ramelteon, tasimelteon, and agomelatine are melatonin receptor agonists.

• Agents: suvorexant
• Mechanism of action: antagonism of orexin (hypocretin) receptors
• Indications: insomnia disorder
• Adverse effects ^[6]
  • Sleep disturbances: abnormal dreams, nightmares, sleep terrors
  • CNS depression (e.g., somnolence)
  • Dependency (limited)
  • Headache
  • Suicidal thoughts
• Contraindications
  • Liver disease
  • Narcolepsy
• Interactions: Suvorexant should not be taken together with CYP3A4 inhibiting drugs.

Suvorex-ant is an orexin antagonist.