ANXIOLYTICS & HYPNOTICS Flashcards
anxiety
an unpleasant emotional state characterized by fearfulness / distressing physical symptoms
CNS: worry, fear, obsession, rumination
PNS: sweating, tremors, tachycardia, vomiting
often connected with phobias, PTSD, OCD
basis of anxiety
hypoactive (inactive) GABA receptors
inappropriate upregulation of CNS serotonergic neurons
overactivity of adrenergic neurons (cns/pns)
what strongly innervates the hippocampus
serotonergic neurons
what are anxiolytics
drugs that provide relief from symptoms of anxiety
what are some anxiolytics
- BENZODIAZEPINES - allosteric agonists on GABAa
- modulators of SEROTONIN transmission
(either increase /decrease) - B- ADRENERGIC receptor ANTAGONISTS
(physical symptoms - b1 affect the heart)
BENZODIAZEPINES
DIAZEPAM . anxiolytic, hypnotic, anticonvulsant . IV GE . muscle relaxant = short-term treatment
drug bings allosterically to GABAa R - increase binding of GABA to its normal binding site
=MORE FREQUENT opening of Cl- channels
=enhancement of inhibitory GABA response
hypnotic
sleep-inducing
what are benzodiazepines
allosteric agonists - bind to GABA R at a site distinct from binding site
= locks GABA b.s into confirmation where GABA can bind
inverse agonists (B-carboline)- lock GABA b.s into form that doesn’t favour GABA binding
side effects of benzodiazepines
- tolerance
- physical dependance = rebound anxiety WORSE!
- sedative effects
- retrograde(before onset)/anterograde(while) AMNESIA
- psychomotor effects (loss of coordination)
how is diazepam metabolized into an active compound
by C450 enzyme
Diazepam (half-life 1-3 days)
» NORDAZEPAM (half-life 2-7 days)
half-life doubled in elderly = slower metabolism
serotonin 5-HT has both excitatory/inhibitory functions
*chemical mediator in both CNS (behavioral effects)
PNS (vasoconstriction/dilation, platelet aggregation)
larger differences in receptor expression
5-HT1A receptor
The 5-HT1A receptor = subtype of serotonin receptor located in presynaptic and postsynaptic regions
Activation of this receptor has been involved in the mechanism of action of anxiolytic, antidepressant and antipsychotic medications
SSRI’s
Selective serotonin reuptake inhibitors (SSRIs)
= increase serotonin in synapse
describe serotonin neurotransmission
Gs - stimulate adenylate cyclase = increase cAMP
Gi - inhibit adenylate cyclase = decrease cAMP
Gq - direct activator of protein kinase C
modulators of serotonin transmission F
FLUOXETINE
. SSRI
. blocks SERT: prevents 5-HT uptake = increases serotonin in synaptic cleft
. treatment for chronic anxiety/depression
side effects:
sexual, anxiety, headache, insomnia, sedation
modulators of serotonin transmission B
BUSPIRONE
. used for short/long term treatment of anxiety
. partial agonist at postsynaptic 5-HT1A
. full agonist at presynaptic autoinhibitory receptors
= Reduces activity of CNS serotonergic pathways
= antagonist of dopamine D2 receptors
side effects:
. no sedative/loss of coordination/ little risk of physical dependence
. doesn’t treat PNS symptoms
B1- ADRENERGIC RECEPTOR ANTAGONISTS
PROPRANOLOL
. treats PNS symptoms of axiety
. competitive inhibitor of B-adrenergic receptors
side effects:
well-tolerated (// cardiac insufficiency, hypoglycemia, bradycardia, asthma)
- treats high BP as a result of decreasing HR
BARBIUATES
GABA enhancers (bind different site to benzodiazepines)
. promote INCREASED DURATION of Cl- channel opening
. LOW TI (suppress CNS)
. serious problems with tolerance/dependence
NOT used
other drugs to treat anxiety
monamine oxidase inhibitors (MAOI)
tricyclic antidepressants (TCAs)
future drugs: more selective 5-HT modulators
CRF antagonists = decrease cortisol
comparison of anxiolytics
Benzodiazepines . fast onset -immediate symptom relief . produce tolerance/dependence . sedative/amnesic side effects . high potential for abuse
Fluoxetine/ Buspirone . slow onset . most effective for general anxiety . few serious side effects . treat comorbid depression
B-adrenergic anatagonists
. treat physical symptoms
. non-sedating/ few side effects
sleep disorders
- insomnia - state of wakefulness during normal sleep time
- hypersomnia - excessive sleep
- Narcolepsy - sudden periods of deep sleep that occur during normal wake hours
describe stages of normal sleep
- NonREM sleep = Serotonin + GABA
- REM sleep = ACh + NE
normal sleep = repeated patterns of REM/NonREM sleep
treatment of insomnia
- BENZODIAZEPINES
- decrease time taken to enter sleep
- increase duration of sleep
- inhibit REM sleep
(habituation/dependance - not for long-term)
other anti-insomnia drugs
- ZOLPIDEM - non-benzodiazepine GABA R agonist
. no effect on REM sleep / ineffective as anxiolytic
. therapeutic effect long lasting
. psychological dependence (hallucinations) - barbituates - reduces REM sleep - not used
- choral hydrate - rarely used ^
- Antihistamines - dry mouth
- THC - decreases sleep latency + REM sleep
2 modulators of serotonin transmission
fluoxetine
buspirone
