Flashcards in Week 5: Anxiolytics Deck (13)
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1
What are the areas of the brain affected by generalized anxiety disorder?
-passive activity: have increased metabolic rates in occipital, temporal, and frontal lobes, and in cerebellum and thalamus
-vigilance tasks: increased activity in basal ganglia
-overall: hyperactive brain circuits in GAD
Role of other parts of brain
-amygdala=anxiety way station that mediates incoming stimuli from environment (form thalamus and sensory cortex) and stored experience (frontal cortex and hippocampus)
2
What is involved in the panic response pathway in the periphery (descending pathways)?
-Sympathetic nervous system response
-ANS sends impulses from CNS to peripheral organs
3
What brain circuits are implicated in GAD?
-hypofunction of serotonergic neurons arising from dorsal rap he nucleus and GABAergic neurons--> lack of inhibitory effect on GAD pathway
-overactivity of noradrenergic neurons from locus coeruleus-->excessive excitation
4
What is the importance of GABAergic and serotonergic (5-HT) modulation of CNS activity?
-GABAergic neuron activity decreased in GAD
-5-HT neuron activity in prefrontal cortex, basal ganglia, and limbic region reduced in GAD
-GABA=main inhibitory neurotransmitter in CNS
-Serotonergic nuclei found in rostral and caudal raphe nuclei
5
What are the 3 main classes of anxiolytics?
-anxiolytics cause CNS depression=reduced activity
1. Benzodiazepines (BZs)- e.g. Valium
2. Barbiturates - not used much anymore
3. Buspirone and SSRI/SNRI - 1st line treatment for anxiety disorders, act on serotonin/norepineprhine reuptake.
6
How do GABA neurotransmission work?
-bind to receptor site on Cl- channel
-Cl- channels open and Cl- flow inward-->hyper polarization
-increases intracellular negative charge and reduces probability of firing
-Specific subunits in GABA A receptors confer functional diversity on the receptor
-GABAergic synapses confined to neural tissues
7
What is the mechanism of action of BZ?
-BZ receptor agonists increase the affinity of GABA to its receptor
-causes allosteric modification of the receptor that allows for Cl- to flow in per unit time
-excitability of target neurons is decreased
8
What is the mechanism of action of 5-HT1a receptor agonist (Buspirone)?
-5-HT1A receptors have inhibitor effect on neurotransmission when bound by an agonist
-Buspirone is a serotonin mimic
-Buspirone is an agonist of 5-HT1a
-5-HT1a receptors activate K+ channels via G proteins and allows K+ outflow to hyper polarize the cells and reduce excitability
-there are 5-HT1a receptors on pre synaptic neuron that reduces serotonin release also
9
What is the mechanism of action of SSRIs (5-HT reuptake inhibition)?
-increase 5-HT concentration at the synapse and acts on pre and post synaptic 5-HT1a receptors
-result is similar to Buspirone (activation of K+ channels-->K+ outflow and hyper polarization)
10
What is the dose dependent effect of BZs and barbiturates?
-increase in dose higher than needed of hypnosis may lead to a state of general anesthesia
-higher doses, sedative-hypnotics may depress respiratory and vasomotor centers in the medulla, leading to coma and death
11
Describe the influence of metabolism on duration of action of BZ?
-Most BZs are metabolized
-metabolites are inactive, polarity and water solubility increases and speeds up excretion
-Some older BZs are metabolized to active compounds, e.g. Clorazepate
-active metabolites of Diazepam have CNS depressant actions, extends half life to days
12
What are the advantages of SSRIs over BZs for long-term treatment?
-physiological dependence occurs in susceptible individuals with BZ and barbiturates (not buspirone of SSRIs)
-acquired tolerance develops with BZ and barbiturates
-BZs actions are lost within 2 weeks (dose increases, increases chance of overdose)
-physical dependence and withdrawal syndrome including rebound anxiety and insomnia with BZ and barbiturates
13
