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Newer CNS depressants

Newer CNS depressants. Benzodiazepines, second generation anxiolytics, and antiepileptic drugs. Use of benzodiazepines. Not for chronic anxiety disorders Not for the elderly Not for depression For short-term treatment of stress-related anxiety: Acute situational grief

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Newer CNS depressants

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  1. Newer CNS depressants Benzodiazepines, second generation anxiolytics, and antiepileptic drugs

  2. Use of benzodiazepines • Not for chronic anxiety disorders • Not for the elderly • Not for depression • For short-term treatment of stress-related anxiety: • Acute situational grief • Acute stress reactions • Short-term anxiety-induced insomnia

  3. Pharmacodynamics • GABAA receptor interactions • Benzodiazepine agonists, eg. diazepam • Benzodiazepine antagonists, eg. flumazenil • Chloride ion channels and fast IPSPs • GABAB receptor interactions • Presynaptic for several neurotransmitters • Potassium ion channels and late IPSPs • Baclofen, a muscle relaxant and antispastic

  4. Localized pharmacodynamics • Low-dose antianxiety effects: hippocampus and amygdala • Mental confusion and amnesia: hippocampus and cerebral cortex • Sedative-hypnotic effects: cerebral cortex • Different benzodiazepines have different relative effects, perhaps due to multiple subtypes of GABAA receptors.

  5. Pharmacokinetics • Study administration, absorption and distribution in Julien, pp. 97 - 103 • Metabolism is unusual: • Intermediate metabolites may be psychoactive. • Intermediate metabolites may be long-lasting. • Elderly patients have difficulty metabolizing long-acting benzodiazepines, leading to profound dementia. May take 60 days to clear.

  6. Uses and side effects of benzodiazepines • Panic attacks and phobias • Alcohol withdrawal and abstinence • Antiepileptic • Dose-related side effects: • Drug-induced brain syndrome • Impaired functioning • Amnesia • Severe interactions with alcohol

  7. Benzodiazepine miscellany • Fetal effects have been reported for BDZ taken in the first trimester, but other research disputes the claim. • If abused, BDZs are part of polydrug abuse, complicating flumazenil antagonistic effects • GABAA antagonists may enhance learning by facilitating cortical and hippocampal cholinergic activity • GABAB antagonists may enhance cognition and counter depression

  8. Second generation anxiolytics • Zolpidem (Ambien, 1993): Not a BDZ, it is a specific agonist at GABAA1 receptors. • Rapid uptake and short elimination half-life make it an effective insomnia treatment • Little interference with normal sleep cycle • Safe, and high doses trigger vomiting • High doses produce problems in older people • Flumazenil antagonizes zolpidem

  9. Second generation anxiolytics • Buspirone (BuSpar): A weak agonist of 5-HT1A receptors, so no crossing or synergy with other CNS depressants • Buspirone is also antidepressant • No sedation, little amnesia or confusion • Very slow development of main effect: several weeks tid. • Useful for GAD and anxiety in older people. • Postsynaptic inhibition of adenyl cyclase • Presynaptic inhibition of 5-HT synthesis

  10. Controversial anti-anxiety drugs • Triazolam (Halcion) • Flunitrazepam (Rohypnol) • Illegal in U.S.A. • Produces amnesia • Synergistic with alcohol: “Date-rape drug” • Roughies, roofies, rochas

  11. Future directions in anxiety control • Find partial agonists of BDZ receptors • Abecarnil, used for GAD • Find drugs which act on different receptor subtypes, like Zolpidem • Alpidem acts on GABA A1 and GABA A3 sites • Imidazenil has fewer side effects • Nonhormonal neurosteroids (epalons) as GABAA agonists: Fewer side effects • Serotonin (5HT1A) agonists, like buspirone

  12. Antiepileptic drugs, pp. 55-60 • Identify the three main groups of antiepileptic drugs. • In which group would you place carbamazepine and valproic acid? • Construct a timeline of the drug treatment of seizure disorders, starting with bromide. • How do antiepileptic drugs relate to specific psychological disorders?

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