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)|| |
|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 
- 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
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 
- 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 floppy infant syndrome (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 barbiturate levels in serum. , measure the alcohol and
- 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.
Ramelteon, tasimelteon, and agomelatine are melatonin receptor agonists.
- 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.