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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 – e.g., chordiazepoxide (Librium), diazepam (Valium) which is more potent – now ~ 39 benzodiazepines • Other med’s are also sedative (or “anxiolytic”) Hypothesis of the Neuro-biology of Anxiety • Abnormalities in the gamma-aminobutyric acid (GABA) system • Monoamine systems are also involved • NE • SE 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 Amino Acid Neurotransmitters • Excitatory amino acid NT: – Glutamate • Inhibitory amino acid NT: – GABA – (Glycine) • Glutamate and GABA differ by a single carboxyl group 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) 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 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 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 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 Clhyperpolarizes neuron, causing inhibition and decreased excitability Benzodiazepine Receptor • The benzodiazepine receptor is unique in that it mediates drugs that have opposite effects. 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 Benzodiazepines • Benzodiazepines – – – – – anti-convulsants muscle relaxants (via spinal cord) sedative-hypnotic anxiolytic prevent alcohol withdrawal symptoms • e.g., Delirium Tremens “DT’s” 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 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 Anxiolytics • Benzodiazepines • Barbiturates – higher lethality in overdose • Anti-depressants • Zolpidem (Ambien) – acts on the GABA receptor complex – used for insomnia • Anti-histamines • Buspirone (Buspar) 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 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