58 - Pathophysiology of anxiety and sleep disorders Flashcards
- ___ - calms anxiety, decreases excitement and activity, does not produce drowsiness, or impair performance
- ____ - anti-anxiety, relieves anxiety without sleep or sedation (not all anxiolytics are sedatives)
- ___ - induces sleep, implies restful, refreshing sleep
- ___ - actuall means “sleep producing, no refers to opiods or illegal drugs
- sedative
- anxiolytic
- hypnotic
- narcotic
Sleep Physiology
stages of sleep
- wakefulness
- NREM - ___ wave sleep
- REM sleep - similar to ___ in EEG
NREM slee
- stage 1: ___
- stage 2: ___ sleep
- stage 3: ___ increase, ___ decrease
- stage 4: ___ waves
sleep deprivations
- ___ sleep
- ___ sleep
- REM
- slow
- awake
- dosing
- unequivocal
- voltage, frequency
- delta
- total
- delta
factors that regulate sleep
- age: decreases with age due to changes of ___ formation
- sleep history : rebound of ___ sleep
- ___ ingestion: acute and withdrawal produce rebound effects
- circadian rhythms: normal sleep cycle
- reticular
- REM
- drug
biological regulators of sleep
neurotransmitters (almost all)
- catecholamines (epinephrine, norepinephrine, and dopamnie)
- serotonin
- histamine
- ACh
- ___ (main target for current medications)
neuromodulators
- growth hormone prolactin
- cortisol
- melatonin - hormone of darkness
- endogenous peptides
GABA
GABA A receptor comprised of __ subunits from several polypeptide classes
5
GABA A Receptor/Chloride Ion Channel Complex
orthosteric site: GABA (a1 and B2)
allosteric sites
- benzodiazepine site ( ___ and ___ )
- barbiturates
- ethanol
- glucocorticoids
channel pore - picrotoxin
most common: 2a1, 2B2, 1y2 (43% of CNS GABA A receptors)
a1, y2
Ligands Acting at the BZD receptor
- BZDs facilitate ___ action ( e.g. __ __ - __ ) increase ___ , and require intact GABA systems
- Non-BZDs (Z-hypnotics) - ___ (Ambien) , ___ (Sonata), ___ (Lunesta) - ___ receptors of ___
- BZD antagonists: ___ (Romazicon), overdose treatment
- inverse BZD agonists: B carbolines
- GABA, a1-5, frequency
- zolpidem, zaleplon, eszopiclone, BZ1, a1
- flumazenil
Modulation of the GABA A receptor
- BZDs - increase ___ of channel opening
- barbiturates (Bbt) - increase ___ of channel opening, and ___ effects on GABA A at high doses
- alcohol - enhances actions of GABA at receptor
- GABA channel bloockers: picrotoxin
- etomidate and propofol (Diprovan “milk of amnesia”) ___ and ___ subunit containing receptors
- neurosteroids (e.g. progesterone and deoxycortisone) for treating depression etc
- frequency
- duration, direct
- B2, B3
chemistry and metabolism - BZDs
SAR
- __ position ___ is the source of active metabolites
- annealating the __ - __ bond with an electron rich ring (triazole or imidazole) yields ___ affinity and ___ t1/2
- 1, alkylation
- 1-2, high, decreased
metabolism of diazepam (long t1/2)
diazepam undergoes ___ and then ___ to become oxazepam
- ___ t1/2
- N-dealkylation, hydroxylation
- long
Benzodiazepines with intermediate and Rapid elimination rates
intermediate: H = ___ (Serax) and Cl = ___ (Ativan)
intermediate/rapid: H = ___ (Xanax) and Cl = ___ (Halcion)
- oxazepam, lorazepam
- alprazolam, triazolam
PK - slow elimination rates
all have active ___
___ (Librium) - 1st BZD, used as anxiolytic for alcohol withdrawal, accumulation of metabolites
___ (Valium) - prototypical BZD, used as an anxiolytic for alcohol withdrawal and treatment for ___ , accumulation of metabolites
___ (Dalman) - used as hypnotic, accumulation of metabolites
___ (Tranxene) - used as an anxiolytic, for alcohol withdrawal, and for treatment of ___ , accumulation of metabolites
___ (Doral) - used as a hypnotic, accumulation of metabolites
metabolites
- chlordiazepoxide
- diazepam
- flurazepam
- clorazepate
- quazepam
PK - intermediate elimination rates
___ (Xanax) - withdrawal symptoms can present if abrupt d/c, used as an anxiolytic and anesthetic
___ (Ativan) - used an anxiolytc and hypnotic
___ (Klonopin) - tolerance may develop woth prolonged use, used as an ___
___ (Serax) - used as an anxiolytic and for alcohol withdrawal
___ (Restoril) - used as a short term hypnotic
- alprazolam
- lorazepam
- clonazepam, anticonvulsant
- oxazepam
- temazepam
PK - rapid elimination rates
___ (Versed) - rapid anesthesia
___ (Halcion d/c’ed) - used as short term hypnotic
- midazolam
- triazolam
biotransformation and therapeutics - BZD usage
slow elimination
- accumulation
- ___ metabolites
- drowsiness and sedation
- useful in patietns who “wake up”
intermediate to rapid elimination
- preferable in patients with ___ problems
- preferable in ___ patients
- drugs that alter liver enzymes
- rapid ___
- rebound ___
- active
- hepatic
- elderly
- tolerance
- insomnia
general considerations
- readily absorbed (can be ___ by food)
- have ___ metabolites or are converted to active forms
- increased ___ solubility will increase speed of delivery to brain
- redistribution to highly perused tissue may ___ duration of action
- cross placental barrier and are detected in breast milk
- extensive protein binding, but not clinically significant
- delayed
- active
- lipid
- decrease
dose response curves: BDZ vs Bbt
drug A is ___
drug B is ___
Bbt
BDZ
PCOL Properties - BDZ
anxiolytic
sleep
- reduce sleep latency
- increase total sleep time
- increase stage 2
- decrease ___
- decrease stage ___ and ___
- tolerance and rebound to ___ and ___
___ activity
muscle relaxant
cardiovascular and respiratory depression (major issue when combined with other agents)
anterograde amnesia
unable to recall events that occurred
- REM
- 3, 4
- delta, REM
anticonvulsant
Toxicology
SE are ___ dependent
- sedations: confusion, ataxia, daytime sedations
- ___ develops with longer acting agents
- weakness, headache, vertigo, nausea, paradoxical effects
Precautions and interactions
- other sedatives, ___
- pregnancy and breast feeding
Drug dependence and abuse
- abuse potential is ___ than Bbt
- small “kick” - often when in combo with other drugs
dose
- tolerance
- alcohol
- lower
benzodiazepine antagonist
___ (Romazicon)
- treat ___ overdose
initial dose: 0.2 mg IV over 30 seconds
if desired consciousness is not obtained, increase to 0.3 mg IV over 30 seconds
Max total cumulative dose: 3 mg, usual range 1-3 mg
SE
- induced convulsions*
- panic attacks*
- agitation
- confusion
- N/V
- headache
*for pts who developed dependence
flumazenil
- BZD
-
non-BZD
Z-hypnotics - act at BZD binding site ( ___ receptor )
___ (Ambien)
- ___ term treatment of insomnia
- with difficulty of sleep ___
- Ambien CR for sleep maintenance
___ (Sonata)
- ___ term treatment of insomnia (7-10 days)
- rapid acting, rapidly eliminated
- little ___ or ___
___ (Lunesta)
- ___ enatiomer of zopiclone (50x greater affinity)
- treatment of ___ (approved for ___ term use)
BZ1
Zolpidem
- short
- onset
Zaleplon
- short
- tolerance, dependence
eszopiclone
- active
- insomnia, long
Z-Hypnotic - Common Features
metabolism - CYP ___ to some extent
overdose treatment: ___ (Romazicon)
SE
- daytime drowsiness, dizziness, ataxia, N/V
- cause less negative effects on sleep patterns vs ___
- sleep driving/cooking/eating/sex (warn patient)
- 3A4
- flumazenil
- BZD
illicit use of sedative-hypnotics that target the BZD binding site
BZD
___ (C-IV)
- not availabe in US
- “roofies”
- DEA recommends changing to C-I
- anterograde amnesia
___ (C-IV)
- research for social deficits in autism
Non-BZD
Zolpidem (C-IV)
- Ambien
- A-minus, Zombie Pills
- dangerous for sexual assault
Flunitrazepam
Clonazepam
Bbt
long acting ( ___ )
- ___ (Luminal)
- mephobarbital (Mebaral)
short to intermediate acting (sedative-hypnotics)
- amobarbital (Amytal)
- butabarbital (Butisol sodium)
- ___ (Nembutal)
- secobarbital (Seconal)
- aprobarbital (Alurate)
ultra-short acting (IV ___ )
- thiopental (Pentothal)
- methohexital (Brevital Sodium)
- Thiamylal (Surital)
anticonvulsants
- phenobarbital
- pentobarbital
anesthetics
Pharmacology - Bbt
sleep physiology - comparable to BZD
- decrease ___
- slow ___ sleep
CV depression at high doses
___ depression leading to death
enzyme interactions
- compete for CYPS for metabolism
- enzyme induction
- REM
- deep
- respiratory
PCOL -Bbt
anticonvulsant
idiosyncratic excitement and ___
dependence and ___
abuse
withdrawal
overdose
after effect
- ___
- accumuation
pain
tolerance
hangover
PK - Bbt
duration of action - inversely proportional to ___ solubility
decrease of activities - metabolic transformations and redistribution
ultra-short and short-acting - determined by ___
anesthetics - determined by ___ solubility an rapid ___
long t1/2 - accumulation
- lipid
- redistribution
- lipid, redistribution
compare Bbt, BZD, and Z-hypnotics
Bbt - bind to all GABA A __ __-__ ; increase the ___ of channel opening; and ___ effect on GABA A channel (high doses); higher risk
BZD - bind to all GABA A __ __- __ ; increase ___ of GABA A channel opening; medium risk
Z-hypnotics: bind to GABA A ___ receptors of ___ ; increase ___ of GABA A channel opening; lower risk
**the use and limitation of flumazenil88
- a1-5, duration, direct
- a1-5, frequency
- BZ1, a1, frequency
