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Anti-Anxiety Medications

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

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Anti-Anxiety Medications

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  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 theNeuro-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

  6. 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)

  7. 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

  8. 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

  9. GABAA 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

  10. GABAA 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

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

  12. Ligands of theBenzodiazepine 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

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

  14. 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

  15. 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

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

  17. 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

  18. 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

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