1. Chemical Dependence Process

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

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

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

5. Pharmacokinetics u Study administration, absorption and distribution in textbook. u Metabolism is unusual: u Intermediate metabolites may be psychoactive. u Intermediate metabolites may be long-lasting. u 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 u Panic attacks and phobias: alprazolam (Xanax) u Alcohol withdrawal and abstinence u Antiepileptic u Dose-related side effects: u Drug-induced brain syndrome u Impaired functioning u Amnesia u Severe interactions with alcohol

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

8. Second generation anxiolytics u Zolpidem (Ambien, 1993): Not a BDZ, it is a specific agonist at GABA A1 receptors. u Rapid uptake and short elimination half-life make it an effective insomnia treatment u Little interference with normal sleep cycle u Safe, and high doses trigger vomiting u High doses produce problems in older people u Flumazenil antagonizes zolpidem

9. Second generation anxiolytics u Buspirone (BuSpar): A weak agonist of 5-HT 1A receptors, so no crossing or synergy with other CNS depressants u Buspirone is also antidepressant u No sedation, little amnesia or confusion u Very slow development of main effect: several weeks tid. Minimal abuse, withdrawal symptoms. u Useful for GAD and anxiety in older people. u Postsynaptic inhibition of adenyl cyclase u Presynaptic inhibition of 5-HT synthesis u Remember grapefruit juice effect on buspirone

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

11. Future directions in anxiety control u Find partial agonists of BDZ receptors u Abecarnil, used for GAD u Find drugs which act on different receptor subtypes, like Zolpidem u Alpidem acts on GABA A1 and GABA A3 sites u Imidazenil has fewer side effects u Nonhormonal neurosteroids (epalons) as GABA A agonists: GanaxoloneGanaxolone u Serotonin (5HT 1A ) agonists, like buspirone: gepirone, alnespirone, ipsapirone

12. Antiepileptic drugs u Epileptic seizures, foci/lesions, and kindling u Sodium channel blocking u carbamazepine, phenytoin (Dilantin) u lamotrigine, valproate/valproic acid u GABA agonism u reduce metabolism of GABA u facilitate GABA release: gabapentin u Enhance GABA action: benzodiazepines, valproic acid

13. Other uses of antiepileptics u Kindling may be part of a set of psychiatric disorders characterized by impulse control difficulty. u Bipolar Disorder and mania u Conduct Disorder u Borderline Personality Disorder u Panic Disorder u Intermittent Explosive Disorder u Antiepileptic drugs are sometimes helpful.

14. Antiepileptic drugs u Identify the three main groups of antiepileptic drugs. u In which group would you place carbamazepine and valproic acid? u Construct a timeline of the drug treatment of seizure disorders, starting with bromide. u How do antiepileptic drugs relate to specific psychological disorders? u http://www.pslgroup.com/dg/2d9a6.htm http://www.pslgroup.com/dg/2d9a6.htm