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 theNeuro-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 Cl- hyperpolarizes neuron, causing inhibition and decreased excitability

Benzodiazepine Receptor

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

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

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