Weng - Anxiety

Etiology of Anxiety

Overactivation of the Limbic System = Anxiety

• Limbic system: amygdala, hippocampus, hypothalamus, prefrontal cortex, etc

• GABA and 5-HT are crucial

  • Decrease → dysfunction of limbic system → excessive excitation of sympathetic nervous system

• Increased HR, BP, tremors, diaphoresis, RR

• Pt with anxiety disorder have more activity in limbic system

  • hyperactive amygdala: “fear center”

GABA-A Receptor

• When 5-HT binds to receptor = stimulates GABAergic neurons to release GABA

• GABA: inhibitory neurotransmitter, supposed to inhibit limbic system neuron

  • binds to GABA-A, at 2 sites between alpha and beta subunits = trigger chloride channel opening = hyperpolarization

  • reduction of excessive neuron firing = decrease in sympathetic effect

• GABA-A features:

  • pentameric structure

  • chloride ion channel

  • major target of anxiolytic and hypnotic agents

• BZD and newer hypnotic drugs bind to single site btwn alpha and gamma subunits

  • GABA agonists

• Specific subunit that mediates sedation = alpha-1 isoform

Drugs Used to Treat Anxiety

• Reduce by means of sedation and hypnosis

• SSRIs and SNRIs are widely used

  • Mostly mild CNS depressants

  • Drowsiness is most common side effect

• Goals: increase GABA and 5-HT

  • BZDs

  • Barbiturates

  • BZD-like drugs

• SSRI, SNRI, TCAs, Antihistamine, Anticonvulsants, BZD, Misc, Beta-Blocker

BZD (based on half life)

Short acting (1-15 hr)

• Triazolam

• Midazolam

Immediate-acting (15-20 hr) “A LOT”

• Alprazolam (Xanax)

• Oxazepam

• Lorazepam (Ativan)

• Temazepam (Restoril)

Long-acting (>20 hrs) 3CDF

• Chlordiazepoxide

• Clonazepam (Klonopin)

• Diazepam (Valium)

• Flurazepam

• Clorazepate (Tranxene-T)

BZD MOA

• Enhance inhibitory effects of GABA by binding to allosteric site on GABA-A = increase affinity of GABA binding = increase frequency of chloride channel opening

• BZD activity is dependent on GABA bound to GABA-A receptor

• Rapid relief, short-term treatment for acute anxiety

• Causes CNS depression

BZD Side Effects

SE: drowsiness, ataxia, dizziness, decreased alertness and concentration, impairment of motor coordination

• Dose-dependent highly sedating

  • Sedative at low, hypnotic at high

• “LOT” (lorazepam oxazepam temazepam) have less side effects

ALL BZD undergo hepatic metabolism, CYP3A4

Abuse and Overdose

• CIV substance

• shut down of limbic system → anesthetic state, coma

• significant CNS depression → loss of consciousness, bradycardia, hypotension, resp. depression

Flumazenil (Romazicon)

• BZD antidote

• MOA: competitive GABA receptor antagonist

• Reverses BZD overdose

• Administered IV, rapid-onset with short duration of action

  • rapid onset can induce withdrawal symptoms

  • difficult to control

• Can cause adverse effects like seizures and arrhythmias

Buspirone (Buspar)

• MOA: may be due to affinity for 5-HT1A and 5-HT2 receptors

  • no direct interaction with GABAergic

• Non-BZD, non CNS depressant

  • non-sedating antianxiety

C/I: DO NOT USE WITH MAOIS

• Risk of serotonin syndrome

Avoid use in severe liver and kidney impairment

Major substrate of CYP3A4

• decrease dose if used with CYP3A4 inhibitors (diltiazem, itraconazole)

• increase dose if used with CYP3A4 inducers (rifampin)

SE: dizziness, drowsiness, nausea, nervousness, headache, tachycardia, palpitations

Propranolol

MOA: competitive non-selective beta-1 and beta-2 adrenergic receptor blocker

• Low dose used off-label for stage fright and performance anxiety

• Treats physical symptoms of anxiety only

SE: hypotension, bradycardia, arrhythmias, bronchospasms