Anxiety Flashcards
Basic Neural Information
DA = comes from the VTA + substantia nigra
Presents to diff regions of the brain (striatum + cortex)
Ion channels
- nAChR
- glutamate
- GABA
GPCRs -> ACh, DA, + NA
Anxiety
Normal human emotion -> adaptive function
Deals with the perception of a threat, but response = out of proportion to the perceived threat
Unfocused feelings of fear impact normal activities -> need for treatment
- Perceive the world, remember past experiences, understand it + interpret the situation
- involves many parts of the brain
- 1st = accumulation of knowledge thru sensory systems
- > most sensations (except smell) = relayed through dorsal thalamus
- > distributed to primary cortex + relayed to the assoc cortex for interpretation + colouring
-ENVIRONMENT MAY IMPACT ANXIETY
Anxiety Disorders
Generalized anxiety OCD panic disorder acute stressor disorder separation anxiety social phobia specific phobia
Anxiety Treatment
symptoms = often assoc with depression (neurochem disorders = sim, might share chemical basis)
Stage fright - beta blocker (1st action
- SNS activation in anxiety (NA = inc HR)
- block b1 receptor (ex. metoprolol) = dec HR
Acute Tx - Benzodiazepines
Chronic Tx - SSRIs or SNRIs
Benzodiazepines
Acute tx for anxiety
-influences GABAa receptor
GABA = aa (made during protein synthesis)
-housed in vesicles within GABA neurons
GABAa Receptor
- Cl- channel, hyperpolarizes cell, inhibits AP gen
- Dec RMP + maintains inhibitory state
- Made of 5 subunits (2a, b, y, s) - 4 TM domains
- diff combos of subunits = diff complexity & specificity of diff GABA receptors all over the body
Benzodiazepines
-bind allosterically to GABAa receptor (diff subunit)
-facilitate GABA binding (0 competition between GABA binding)
Tx. - anxiety, insomnia, agitation, seizures, muscle spasms, OH WD, + surgeries
- Each has diff properties…
- open longer (this is the mechanism Dr. Beye talked about), bind diff molecules, inc frequency of opening
Examples of Benzodiazepines
Alprazolam - anxiety & agoraphobia Chlordiazepoxide - anxiety & OH WD Clonezepam - seizures + mania Clorazepate - anxiety + seizures Oxazepam - anxiety + OH WD Lorazepam - anxiety + OH WD + pre-anesthetic med
Side Effects of Benzodiazepines
Paradoxical effects (inc anxiety & panic attacks)
Irritability, aggression + behavioural disinhibition
Cranio-facial defects in pregnant women
Cognitive impairment - anterograde amnesia (date-rape drug)
Medullary depression @ high doses
High risk of falling in the elderly
Liver metabolism
Bad to mix with OH
Impaired psychomotor activities
Addiction + Dangerous
Action of of Benzodiazepines
Anxiolysis + sedation muscle relaxant/anticonvulsant hypnosis dec onset t to sleep inc sleep duration dec REM sleep oftentimes = has metabolites that are still active (high t1/2)
Metabolism of of Benzodiazepines
subunit isoforms = diff effects from diff BZs
metabolized by CYP 3A4 in liver
-> conjugation (glucuronidation)
-Should use other drugs for ppl with liver disease or in elderly (shorter t1/2) - d/t lots of active metabolites
Interactions of of Benzodiazepines
CNS depressants (OH, barbituates, opioids) - respiratory depression -either d/t high TD but combo = bad OR high dose = unfavourable side effects
Clarithromycin
- tx. dental infection
- prolonged + increased sedation
Cimetidine, Contraceptives, Fluoxetine, erythromycin
-increased CNS effects
Grapefruit juice
-increase t1/2
Tobacco
-decs [BZ} in blood (some, not all)
Flumazenil
BZ antagonist (blocks binding of BZ) Precipitates WD symptoms
SSRIs/SNRIs
Chronic tx for anixety - block reuptake of serotonin
-2nd gen = less toxic + safer than 1st gen
GOAL: to increase serotonin/NA in cleft
- both serotonin & NA = packaged into vesicles
- 5HT acts on GPCRs + ion channels
- DA + NA = mainly on GPCRs (2o messengers, cAMP + Ca2+)
NET + SERT = uptake tx’ers on presynaptic neurons
- close in structure (reason why some drugs act on both)
- slow tx
- depends on changes changes in mem potential/ion perm
- formed by 2 set of 6 TM domains (12 TM tot.)
Inhibition of SERT (SSRIs)
- inc serotonin in cleft
- inc stimulation of 5HT1a & 5HT7 autoreceptors on cell bodies of Ralphe nucleus & 5HT1d autoreceptors on serotonergic terminals
- reduces 5HT synthesis + release
- gradual down-regulation + desensitization of autoreceptors
- down-regulation of postsynaptic 5HT2a on postsynaptic neurons
Inhibition of SERT + NET (SNRIs)
- inc serotonin + NA in cleft
- inc stimulation of 5HT1a on cell bodies of Ralphe nucleus & 5HT1d autoreceptors on serotonergic terminals (negative feedback)
- reduces 5HT synthesis + release
- gradual down-regulation + desensitization of autoreceptors
- down-regulation of postsynaptic 5HT2a on postsynaptic neurons
- also down-regulation of SERT & NET (dec NT clearance, inc transmission)
Prozac
SSRI
-dec side effects b/c higher selective
Why does it take several weeks for an SSRI/SNRI affect?
CNS = responds to changes in environment
- very plastic/elastic response
- tries to maintain homeostasis
- will internalize receptors, change PK & PD of drugs to limit response
- takes time to alter homeostasis levels
