Flashcards in Week 5: Anxiolytics Deck (13)
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)
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
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
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
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.
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
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
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
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)
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
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
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