• Clinical science

Sedative-hypnotic drugs

Summary

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, with the exception of 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.

Benzodiazepines

Agents and indications [1][2][3]

Duration of action Pharmacological agent

Indications

Potential for dependence

Short

  • Procedural sedation
  • Anesthesia induction
  • Sleep-onset insomnia
  • Very high
Intermediate
  • High to very high
Long
  • High

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.

ATOM” is the acronym for benzodiazepines with a short half-life: Alprazolam, Triazolam, Oxazepam, and Midazolam.

Mechanism of action [1]

  • Benzodiazepines are indirect GABAA agonists that bind to GABAA receptors affinity of GABA to bind to GABAA receptors GABA action↑ opening frequency of chloride channelshyperpolarization of the postsynaptic neuronal membrane → decreased neuronal excitability
  • Decreases the amount of REM sleep in the sleep cycle

Side effects [4][1]

General adverse effects

Benzodiazepine overdose

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, 1st generation antihistamines (e.g., diphenhydramine) or other respiratory or CNS depressants!

Benzodiazepine dependence [6][7]

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

Contraindications [8]

Benzodiazepine-like substances (Z-drugs)

Agents

Indication

Sleep disorders (especially with difficulty falling asleep)

Mechanism of action [1]

  • Similar to benzodiazepines
  • Show selectivity for GABAA receptors containing α1 subunits
  • Less of an effect on sleep architecture compared to benzodiazepines

Effects

Z-drugs make you sleepy (Zzz...).

Side effects

  • Ataxia
  • Headaches
  • Confusion
  • The hangover effect and the rebound phenomenon are very rarely seen.
  • In the case of overdose: symptoms are similar to those seen in benzodiazepine toxicity
  • Development of drug tolerance: significantly lower than with benzodiazepines but must be considered
    • 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)

References:[1][9]

Barbiturates

Agents and indications

Duration of action Pharmacological agent

Indications

Ultra-short (15 minutes–3 hours)

Short (3–6 hours)
  • Pentobarbital
  • Secobarbital
Intermediate (6–12 hours)
  • Amobarbital
  • Butalbital
Long (12–24 hours)

Barbiturates are no longer used for the long-term treatment of insomnia or sedation. They have been replaced by more effective drugs with fewer side effects.

Mechanism of action [1]

  • 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
  • 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
  • Decreased intracranial pressure due to reduced cerebral blood flow
  • Antiepileptic
  • Little to no analgesic or muscle relaxant effects

Side effects

Barbiturate overdose

Contraindications

References:[10][11][12]

Melatonin agonists

  • Agents: ramelteon, tasimelteon, agomelatine
  • Indications
  • Mechanism of action: activation of MT1 and MT2 receptors; in suprachiasmatic nuclei of the hypothalamusenchanced sleep onset
  • Metabolism: hepatic (CYP1A2); CYP1A2 inhibitors (e.g., fluvoxamine) increase blood concentration
  • Side effects

References:[4]