Barbiturates Notes

Barbiturates

Overview

Barbiturates are drugs synthesized from barbituric acid, historically used for anxiety, sleep problems, and seizures, but now largely replaced by benzodiazepines. Examples include Phenobarbital, Barbituric acid, Sodium thiopental, and Primidone.

History

  • First synthesized in 1864 by Adolf von Baeyer.
  • Introduced as hypnotics in 1904 (Barbital) and 1912 (Phenobarbital).
  • Later used as antiepileptics and anesthetics.
  • Usage declined from the 1960s due to recognized dependence and overdose risks.

Mechanism of Action

  • Primarily target GABAA receptors as allosteric modulators, enhancing Cl- influx and hyperpolarization.
  • At high concentrations, they can directly activate GABAA receptors.
  • Binding site is not fully known but structural modeling suggests pockets within the pore.

Classification

Barbiturates are classified by duration of action, which is influenced by lipophilicity:

  • Ultra-short acting: (e.g., Thiopentone) - Immediate effect, 30 minutes duration, anesthesia induction.
  • Short acting: (e.g., Methohexital) - 10-15 minutes to take effect, 3-4 hours duration, sedative/hypnotic.
  • Intermediate acting: (e.g., Pentobarbital) - 1 hour to take effect, 6-8 hours duration, sedative/hypnotic.
  • Long acting: (e.g., Phenobarbital) - 1 hour to take effect, 6-12 hours duration, anticonvulsant.

Clinical Uses

  • Historically used as hypnotics and sedatives.
  • Currently used as general anesthetics, anticonvulsants, and in treatment of migraines or cluster headaches.

Side Effects

  • Respiratory depression
  • Reduced cardiac output
  • Impaired judgment
  • Increased pain perception and irritability
  • Tolerance and dependence

Dose Dependency

  • Low dose: sedative, hypnotic.
  • High dose: anesthetic, coma.
  • No ceiling effect; higher doses can be deadly.

Brain Region Sensitivity

  • Cortex: Most sensitive, regulates cognition and consciousness.
  • Brain stem: Least sensitive, regulates life-sustaining reflexes.

Barbiturates vs. Benzodiazepines

  • Barbiturates act throughout the CNS.
  • Benzodiazepines are more target/region selective, exhibiting a ceiling effect.

Off-Target Effects

  • Can act on other Cys-loop receptors (Acetylcholine, Glycine, Dopamine).
  • Induce Cytochrome P450 enzymes, affecting drug metabolism.

Addiction

  • Increase GABA, which reduces the reward signal in the brain.

Truth Serums

  • Barbiturates like Sodium amytal and Pentothal sodium were used for their truth-telling effects but induce suggestibility with poor reliability.

Epilepsy

  • Barbiturates are used to treat seizures, which are caused by unsynchronized and excessive neuronal activity.

Sleep

  • Barbiturates repress REM sleep and can cause REM rebound upon discontinuation, leading to increased dreaming, restlessness and anxiety.
  • Chronic use alters GABAA subunit expression as a homeostatic response.