Anxiolytics and anxiety Flashcards
1
Q
Generation of anxiety
A
- Generalized anxiety disorder (GAD) patients have hyperactive brain circuits (occipital, temporal and frontal lobes, and in cerebellum, thalamus, and periaqueductal gray)
- The most important of these circuits is in the amygdala since it is the source of fear and panic
- The amygdala mediates incoming stimuli from the environment (from thalamus and sensory cortex) and stored experiences (frontal cortex and hippocampus)
2
Q
Hypoactive neurotransmitter circuits in GAD
A
- Reduced functioning of GABAergic neurons (widely distributed in CNS) and serotonergic (5HT) neurons (arising from the dorsal raphe nucleus) are primarily responsible for GAD
- Thus, there is a hyperactivity within the brain, primarily of noradrenergic neurons
3
Q
Areas of inhibitory innervation in GAD
A
- Hypofunctioning GABA neurons contributing to GAD found everywhere in CNS
- The hypofunctioning 5HT neurons contributing to GAD arise in raphe nucleus and innervate the pre-frontal cortex and basal ganglia
- Activity of descending 5HT neurons to brainstem is unaffected
4
Q
Anxiolytics vs sedatives
A
- Anxiolytics and antidepressants work in the amygdala, limbic system, and frontal cortex to reduce CNS activity (does not cause drowsiness) and anxiety
- Sedatives: relax and induce drowsiness
- Hyponotics: induce drowsiness and encourage sleep
- Barbiturates/benzodiazepines can be sedatives and (if high dose) hypnotics
- SSRIs and benzo’s are also anxiolytics
5
Q
Anxiolytic drugs
A
- Benzo’s (valium) are used for acute phase of anxiety, have a short time of onset (15-60 min)
- SSRIs (selective serotonin reuptake inhibitors) are the 1st line of Rx for anxiety (especially long term)
- SSRIs are much more benign than benzo’s, but their time of onset is 3 weeks to 2 months
- 5HT1A agonists: Buspirone, causes activation of 5HT1A receptors, K efflux and thus hyper polarization (same overall effect as SSRIs)
6
Q
Mechanism of action of benzo’s
A
- BZs augment the effect of GABA neurons, by binding to a specific allosteric site of the GABA(A) receptor
- By binding to this site, the BZ cause a change in conformation that lets the GABAA bind to GABA more effectively and frequently (increase receptor affinity)
- When GABA binds to GABAA there is an inward flow of Cl through the receptor (ionotropic) into the cell and it is hyper polarized
- Overall this causes CNS depression b/c there are more GABAA receptors binding to GABA w/ BZs
7
Q
Subunits of different GABA receptors
A
- BZs, barbiturates, and nonBZs (hypnotics) all work on the GABAA receptor (just bind to different sites/subunits)
- The GABAA receptor can contain any combination of 5 isoforms of the following subunits: alpha, beta, gamma, delta, and rho
- The specific subunits in the GABAA receptor confer functional diversity of the receptor
- For example, for BZs to be functional the receptor must have a gamma subunit
8
Q
BZs vs barbituates
A
- Barbiturates are agonists of GABAA receptor
- BZs are not agonists of GABAA, they are allosteric modulators of the receptor (increase the frequency and affinity of GABA binding)
- Giving a pt BZs will reduce the concentration of GABA needed to activate the receptor, but will not increase the net effect of the receptor (no affect on current)
- But giving a pt barbiturates not only decreases the GABA concentration required for GABAA activation, it also increases the current of Cl generated in the postsynaptic cell
9
Q
5HT receptors and reuptake
A
- Postsynaptic 5HT receptors (5HT1A) activate K channels via G proteins and cAMP
- This causes K efflux and results in hypopolarization
- SSRIs inhibit the reuptake transporter for serotonin (SERT), causing an elevated serotonin level in the synapse
- The overall effect of SSRIs is to increase serotonergic activity (inhibition) and thus reduce CNS activity
10
Q
Dose-dependent affects of BZs
A
- At high doses (higher than doses for hypnotic effects) there may be general anesthesia
- At even higher doses they may depress respiratory and vasomotor centers in medulla and lead to coma/death
- Most metabolites for BZs (and all metabolites of SSRIs) are pharmacologically inactive
- The BZs that produce active metabolites cause the T1/2 to be extended hours-days (due to the action of the metabolites)
11
Q
Advantages of SSRIs over BZs for long-term Rx
A
- Chronic use of BZs leads to adaptive changes, psychological dependence, acquired tolerance (not w/ SSRIs)
- Chance of overdose w/ BZs especially w/ the ones that produce active metabolites (much less chance w/ SSRIs)
- There are physical dependence and withdrawal symptoms (rebound anxiety, insomnia) w/ BZs (but not w/ SSRIs)
- Withdrawal of BZs less severe when slow elimination or metabolites that are active (masks withdrawal symptoms)
12
Q
Anxiety
A
- An emotion that is different from fear in that the location of danger is intra-psychic for anxiety (outside the body for fear)
- Fear and anxiety use the same physiological pathways
- Anxiety is a healthy emotion that informs us about our surrounding and helps us respond accordingly
13
Q
Pathological anxiety
A
- Results when anxiety becomes too high or frequent
- Inhibits normal functioning, is very closetful, and causes suffering
- Leads to psychological problems, avoidance, underperformance, impaired self-care, contributes to medical illness (#1 risk factor for stroke), increased suicidal ideation
- 50-80% of pts w/ anxiety disorder will eventually have major depression d/o
- Genetic contribution to anxiety d/o is 25%
14
Q
Manifestations of anxiety
A
- Can manifest differently for each person and at different times
- Anxiety Sx and Sx’s from other medical conditions can look identical
- Physical and psychological Sx’s can originate from either psychological and/or biological causes
15
Q
Anxiety pathways
A
- Skeletal muscle, smooth muscle, and cognitive pathways
- The degree of severity of each pathway: skeletal < smooth < cognitive
