1. Anti-Anxiety Medications Brian Ladds, M.D.

2. Anti-Anxiety Medications 1903: first barbiturate introduced in U.S. –e.g., pentobarbital (Nembutal), amobarbital (Amytal) –high abuse potential, lethality in overdose & in withdrawal 1960: first benzodiazepine introduced –e.g., chordiazepoxide (Librium), diazepam (Valium) which is more potent –now ~ 39 benzodiazepines Other med’s are also sedative (or “anxiolytic”)

3. Hypothesis of the Neuro-biology of Anxiety Abnormalities in the gamma-aminobutyric acid (GABA) system Monoamine systems are also involved NE SE

4. Amino Acid Neurotransmitters The most prevalent neurotransmitters (NT) in the brain –synthesized in the brain and well-insulated from fluctuations in serum level Nearly all neurons: –are activated by excitatory amino acid NT –inhibited by inhibitory amino acid NT

5. Amino Acid Neurotransmitters Excitatory amino acid NT: –Glutamate Inhibitory amino acid NT: –GABA –(Glycine) Glutamate and GABA differ by a single carboxyl group

8. Amino Acid Neurotransmitters Actions mediated mostly at ligand-gated ion channel type receptors –rapid, short-lasting alterations in membrane potential (In contrast to many of the receptors for DA, NE, and SE, which are G-protein coupled receptors linked to second messengers)

9. GABA Gamma-Amino Butyric Acid (GABA) –synthesized by glutamic acid decarboxylase (GAD) rate-limiting step –catabolized by GABA transaminase valproate and other medications inhibit this enzyme

10. GABA In the cortex, GABA is localized primarily to intrinsic neurons –local feedback loop –tonic inhibition GABAergic dysfunction is sufficient for seizures In extrapyramidal motor system, GABA efferent projection neurons e.g. striato-nigral pathway: inhibit dopaminergic neurotransmission

12. GABA A Receptor Complex Ligand-gated chloride ion channel –brief current flow, decreasing excitability Distinct sub-units –has a multiplicity of isoforms >5000 possible combinations may permit development of novel drugs that are selective

13. GABA A Receptor Complex 3 functional domains –GABA recognition site –ion channel site –barbiturates prolong channel opening –benzodiazepine receptor site –1 sub-type is the “central receptor” (only in brain) »unclear endogenous ligand –benzo’s increase affinity of GABA for its binding site »inc. frequency of Cl- ion channel opening; influx of Cl- hyperpolarizes neuron, causing inhibition and decreased excitability

14. Benzodiazepine Receptor The benzodiazepine receptor is unique in that it mediates drugs that have opposite effects.

15. Ligands of the Benzodiazepine Receptor Agonists Inverse agonists –decreases Cl- ion channel opening –anxiogenic Antagonists –inhibit agonists and inverse agonists –restores the unmodified state –flumazenil (Mazicon) treatment of benzo overdose

16. Benzodiazepines –anti-convulsants –muscle relaxants (via spinal cord) –sedative-hypnotic –anxiolytic –prevent alcohol withdrawal symptoms e.g., Delirium Tremens “DT’s”

17. Benzodiazepines All BZ’s are equally efficacious –different potencies, therefore different doses Rapid onset of action –Unlike anti-depressants Few side effects –sedation –memory problems –dependence –withdrawal

18. Benzodiazepines Diazepam (Valium) long half-life –less withdrawal but increased sedation Alprazolam (Xanax) short half-life –more withdrawal multiple daily dosing Lorazepam (Ativan) intermediate half-life

20. Anxiolytics Benzodiazepines Barbiturates –higher lethality in overdose Anti-depressants Zolpidem (Ambien) –acts on the GABA receptor complex –used for insomnia Anti-histamines Buspirone (Buspar)

21. Buspirone Novel anxiolytic (for GAD) – non-sedative & non-benzodiazepine –unclear mechanism of action may affect serotonin system in unique ways may affect GABA system in unique ways few side effects –no dependence or withdrawal slow onset of action

22. Summary: Anxiety Low GABA ~ high anxiety (& sz. d/o) BZ -> inc GABA ->inc Cl- -> dec excitability -> less anxiety (& sz d/o) Other neurotransmitters (NE, SE) are also involved, and other medications are efficacious