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PHARMACEUTICAL LIBRARY

Barbiturates

Barbiturates

Such drugs induce general depression of the CNS at all level in a dose-dependent fashion.

Therapeutic uses of barbiturates:

  • Treatment of anxiety (replaced by benzodiazepines);
  • Treatment of insomnia (replaced by benzodiazepines);
  • Used as anticonvulsant;
  • Used for general anaesthesia (thopental).

Long acting barbiturates (6hrs)

Slow metabolism and slow excretion – at low doses they are used as anticonvulsant agents.

Intermediate-acting barbiturates (3-5 hrs)

Short acting barbiturates (2hrs)

Ultra-short barbiturates (20mins)

Mechanism of action of barbiturates: they bind an allosteric site on the alpha-subunit of the GABAa receptor. They enhance, extend and or mimic the GABA action (hyperpolarization). The Chlorine channel is open for a longer time. At very high concentration are able to open the channel also without GABA (for this reason they are very toxic. Metabolism of barbiturates: mainly happens in the liver by CYP450.

Structure of barbiturates: Barbituric acid (Malonic acid + Urea): barbituric acid has been synthesized in 1863 by Adolf von Bayer. Tautomeric forms of barbituric acid are the active ones. Barbiturates are can have a lactam (e.g monolaactam) or a lactim (e.g. dilactim, all-lactim), where the oxydrlic group is important for the interaction with the receptor.

Structure-activity relationships (SARs) of barbiturates:

  • Substitution with S: increase the onset of action and decrease the time of action; while substitution with two 2 S does not induce any activity.
  • Substitution with –CH3: increase the potency and the onset but reduces the time of action; Substitution with –CH3 in position 3 and induce no activity.
  • Double substitution: in position 5 double substitution is needed; substitution with a polar group lead to any activity, while increasing the length of the substituent (5-10 C atoms) increase the time of action and reduces the onset.
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