Sedative-hypnotic drugs

Last updated: November 28, 2023

Summarytoggle arrow icon

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.

Overviewtoggle arrow icon

Overview of sedative-hypnotic drugs
Agents Indications Mechanism of action Contraindications Adverse effects
Benzodiazepines Short-acting: midazolam, triazolam
Intermediate-acting: lorazepam, temazepam, oxazepam, lormetazepam, alprazolam
Long-acting: diazepam, chlordiazepoxide, clonazepam, tetrazepam, flurazepam
Nonbenzodiazepines (Z-drugs) Zolpidem, zaleplon, eszopiclone
Barbiturates Ultra-short acting: thiopental, methohexital
Short-acting: pentobarbital, secobarbital
Intermediate-acting: amobarbital, butalbital
Long-acting Phenobarbital
Melatonin agonists Ramelteon
  • Hypersensitivity
Orexin antagonists Suvorexant

Benzodiazepinestoggle arrow icon

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]

Benzo increases the frequenzo of Cl-channel opening.

Effects [3]


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
  • 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]

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]

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]

Nonbenzodiazepine hypnotics (Z-drugs)toggle arrow icon

Agents [4]

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

Mechanism of action [4]

Effects [4]

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


Adverse effects [4]


Barbituratestoggle arrow icon

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

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



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

Accidental intraarterial injection of barbiturates

Barbiturate overdose

Barbiturate dependence


Melatonin agoniststoggle arrow icon


  • Ramelteon
  • Tasimelteon
  • Agomelatine

Ramelteon, tasimelteon, and agomelatine are melatonin receptor agonists.

Mechanism of action


Adverse effects

Contraindications [11]

Orexin antagoniststoggle arrow icon


  • Suvorexant

Mechanism of action

Suvorex-ant is an orexin antagonist.


Adverse effects [12]


Referencestoggle arrow icon

  1. Griffin et al.. Benzodiazepine pharmacology and central nervous system-mediated effects.. Ochsner J. 2013; 13 (2): p.214-23.
  2. Walls R, Hockberger R, Gausche-Hill M. Rosen's Emergency Medicine. Elsevier Health Sciences ; 2018
  3. Soyka M. Treatment of benzodiazepine dependence. N Engl J Med. 2017; 376 (12): p.1147-1157.doi: 10.1056/nejmra1611832 . | Open in Read by QxMD
  4. Brunton L. Goodman and Gilman's The Pharmacological Basis of Therapeutics, 13th Edition. McGraw-Hill Education / Medical ; 2017
  5. DG Dikeos et al.. Sleep Disorders. CRC Press ; 2008
  6. Guina J, Merrill B. Benzodiazepines I: Upping the Care on Downers: The Evidence of Risks, Benefits and Alternatives. J Clin Med. 2018; 7 (2): p.17.doi: 10.3390/jcm7020017 . | Open in Read by QxMD
  7. Mancuso CE et al.. Paradoxical Reactions to Benzodiazepines: Literature Review and Treatment Options. Pharmacotherapy. 2004; 24 (9): p.1177-1185.doi: 10.1592/phco.24.13.1177.38089 . | Open in Read by QxMD
  8. WHO task force. Clinical Guidelines for Withdrawal Management and Treatment of Drug Dependence in Closed Settings. World Health Organization ; 2009
  9. Jacobson LH, Callander GE, Hoyer D. Suvorexant for the treatment of insomnia. Expert Review of Clinical Pharmacology. 2014; 7 (6): p.711-730.doi: 10.1586/17512433.2014.966813 . | Open in Read by QxMD
  10. Schifano et al.. An Insight into Z-Drug Abuse and Dependence: An Examination of Reports to the European Medicines Agency Database of Suspected Adverse Drug Reactions. Int J Neuropsychopharmacol. 2019; 22 (4): p.270-277.doi: 10.1093/ijnp/pyz007 . | Open in Read by QxMD
  11. Barbiturate (Oral Route, Parenteral Route, Rectal Route). Updated: January 1, 2017. Accessed: October 4, 2017.
  12. $ROZEREM (ramelteon) tablets.

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