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)
- Secobarbital (sleep-inducing hypnotic)
Ultra-short barbiturates (20mins)
- Thiobarbital (anaesthesia)
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.