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.
|Overview of sedative-hypnotic drugs|
|Agents||Indications||Mechanism of action||Adverse effects||Contraindications||Interactions|
|Benzodiazepines||Short-acting (midazolam, triazolam, alprazolam , oxazepam )|| |
|Intermediate-acting (temazepam, lormetazepam, lorazepam)|| |
|Long-acting (diazepam, clonazepam, chlordiazepoxide, tetrazepam, flurazepam)|| |
|Benzodiazepine-like substances (Z-drugs; e.g., zolpidem, zaleplon, eszopiclon)|| || |
|Barbiturates||Ultra-short acting (i.e., 15 minutes–3 hours; e.g., thiopental)|
|Short-acting (i.e., 3–6 hours; e.g., pentobarbital)|
|Intermediate-acting (i.e., 6–12 hours; e.g., amobarbital)|
|Long-acting (i.e., 12–24 hour)||Phenobarbital|| |
|Melatonin agonists (e.g., ramelteon)|| |
|Orexin antagonists (e.g., suvorexant)|
Mechanism of action
- Benzodiazepines are indirect GABAA receptor agonists; that bind to GABA-A receptors → ↑ affinity of GABA to bind to GABAA 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.
General adverse effects
- Anterograde amnesia
- Addictive potential
- Drug tolerance
- Drowsiness, sleepiness, or dizziness
- Blunted affect
- ↑ Appetite
- Hangover effect
Paradoxical excitability 
- A rare, atypical response to medication characterized by symptoms opposite to the expected effects, including disinhibition, impulsivity, restlessness, and irritability
- Occurs most commonly with benzodiazepine use in older adults and children, but may also occur with other drugs (e.g., barbiturates, antipsychotics) and in other age groups
- Risk factors include substance use and preexisting psychiatric disorders characterized by agitation or excitability (e.g., anxiety disorders, personality disorders).
- Treatment involves discontinuation of the drug.
- CNS depression
- Mild hypotension
- Hypotonia and hyporeflexia
- 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)
- 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 “ ”).
- Extracorporeal removal (e.g., hemodialysis, plasmapheresis) is not recommended.
- Mechanism of action: competitive antagonism at GABA receptor
- Use of flumazenil for benzodiazepine overdose is not recommended due to risk of seizures (flumazenil induces a state of acute benzodiazepine withdrawal).
- Supportive therapy
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 
- 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
Contraindications for benzodiazepines 
- 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 infantile hypotonia
- Zolpidem (imidazopyridine): half-life up to 4.5 hours
- Zaleplon (pyrazolopyrimidine): half-life ∼ 1 hour
- Eszopiclone: half-life ∼ 6 hours
- Sleep disorders (especially with difficulty falling asleep)
Mechanism of action
- Similar to benzodiazepines
- Selectivity for GABAA receptors with α1 subunits (corresponding to the BZ1 subtype)
- Short-acting due to fast metabolization by liver enzymes
- 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).
Hangover effect (less common than in other sedative-hypnotic drugs)
- Psychomotor depression
- Impaired cognitive functions
- In the case of overdose
- Development of drug tolerance and dependence
- Similar to contraindications for benzodiazepines (see the corresponding section above)
Agents and indications 
|Overview of barbiturates and their indications|
|Duration of action||Pharmacological agent|| |
Ultra-short (15 minutes–3 hours)
|Short (3–6 hours)|| |
|Intermediate (6–12 hours)|| |
|Long (12–24 hours)|
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 GABAA 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
High lipid solubility of barbiturates leads to their:
- Rapid onset of action
- Accumulation in skeletal and adipose tissue → prolonged duration of action
Dose-dependent effects (from low to higher dose)
- Inducing general anesthesia
- ↓ Intracranial pressure due to reduced cerebral blood flow
- Little to no analgesic or muscle relaxant effects
- Hypotension (dose-dependent): See “.”
- Respiratory depression; and/or apnea (dose-dependent): Barbiturates have a narrower margin of safety than benzodiazepines.
- 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)
- Painful injection
Accidental intraarterial injection of barbiturates
- Etiology: incorrect injection of barbiturates
- Clinical features: tissue necrosis; gangrene (through vessel injury, spasm, and thrombosis)
- Clinical features
Management: mainly supportive as there is no specific antidote
- 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 and barbiturate levels in serum. , measure the
- Sodium bicarbonate(NaHCO3): urine alkalinization and forced diuresis
- Agents: ramelteon, tasimelteon, agomelatine
- Mechanism of action: activation of MT1 and MT2 receptors in suprachiasmatic nuclei of the hypothalamus → quicker sleep onset
- Adverse effects
- Interactions: CYP1A2 inhibitors (e.g., fluvoxamine) increase blood concentration.
- Agents: suvorexant
- Mechanism of action: antagonism of orexin (hypocretin) receptors
- Indications: insomnia disorder
- Adverse effects 
- Interactions: Suvorexant should not be taken together with CYP3A4 inhibiting drugs.
Suvorex-ant is an orexin antagonist.