Block 2 Lecture 3 -- Anxiolytic and Hypnotic Drugs Flashcards
What is anxiety?
inappropriate worry in absence of a true threat that significantly impairs QoL.
Sxs of OCDs.
obsession
thoughts of murder + sex
hallucinations
fear to use public toilets
Sxs of social phobias.
fear of excessive humiliation
“ public speaking
“ public toilets
Sxs of mixed anxiety and depressive disorder.
- anxiety
- inner tension, depression
- aggressiveness
Sxs of panic disorder.
- fear of dying
- fear of going
- chest pain + SOB
How is GAD treated?
1st: CBT
2nd: anti-depressant
3rd: anti-depressant combos
What are the FDA-approved anti-depressants available for GAD treatment?
1st: SSRIs
– es/citalopram, paroxetine, fluoxetine
– +NET: duloxetine, venlafaxine
2nd: buspirone
also: hydroxyzine
also: combos, anti-convulsants
short-term: BZDs
What is hydroxyzine?
h1 antagonist
When is buspirone used in GAD?
2nd line as adjunct to SSRI or as monotherapy
Describe the onset of SSRIs
2-4 weeks
What happens if a GAD patient fails the 1st-line anti-depressant?
try another anti-depressant
What is agoraphobia?
avoidance of triggers evoking panic
How are agoraphobia and other anxiety disorders treated?
similar to GAD when chronic
- anti-depressants (1+), buspar, combos
- BZDs for exacerbations or agoraphobia
- beta-blockers for acute panic
What drugs may cause secondary anxiety disorders?
1) NET/DAT-active anti-depressants
2) sympathomimetics
3) thyroid hormone
4) stimulants
What might anxiety disorders be secondary to?
1) medical conditions
2) drugs
3) drug withdrawal
For what conditions are barbs indicated?
1) induction of anesthesia
2) epilepsy
3) severe tension/migraine HA
MoA of barbs:
APLs of GABAa
- increase duration of channel opening
- synergistic with EtOH, BZDs, Z drugs, opioids
How does one become tolerant to barbs?
1) rapid PK (1a2, 2c9, 2c19, 3a4)
2) slow PD (decrease GABA # and change composition)
Why are barb withdrawals life-threatening?
convulsions
How are barbs categorized?
duration of action
ultra-short acting barbs:
methohexital
thiopental
What are ultra-short-acting barbs indicated for?
1) induction of anesthesia
2) terminal anesthesia
What are the intermediate-acting barbs?
1) pentobarbital
2) butalbital
What are the long-acting barbs?
phenobarbital
How is phenobarb used?
long-acting barb for anti-convulsant
How is butalbital used?
included with ASA/APAP and caffeine
– w/ codeine for tension HA
What is the old lethal injection cocktail?
sodium thiopental, pancuronium br, KCl
What is the newer lethal injection cocktail?
hi-dose Na thiopental or pentobarbital
Where are alpha-1 containing GABAa receptors located?
most abundant, most widely distributed
– also in VTA and HT
(hypnotic, anticonvulsant, amnestic, addiction)
Where are alpha-2 containing GABAa receptors located?
limbic, cortex, striatum (anxiolytic properties when agonized)
Where are alpha-3/5 containing GABAa receptors located?
spinal cord (muscle relaxant properties when agonized)
What is the MoA of BZDs?
non-selectively interact with a1/2/3/5 subunits of GABAa receptors
- increase affinity for GABA
- increase frequency of channel opening
Why don’t BZDs cause fatal respiratory depression?
do not directly open Cl channel
How long should BZDs be used?
DNE 2-4 weeks or past acute exacerbation
What co-morbidites can be problematic with BZD use especially if used w/ EtOH or opiates?
liver disease
respiratory issues (sleep apnea included)
child
Describe metabolism of BZDs.
- no enzyme induction
- catabolized by 3a4 and c19
- active metabolites may be GABAa APLs
What enzyme does grapefruit juice inhibit?
3a4
What factors of BZD selection should be selected for longer-acting effects?
active mets
lipid soluble
What are sxs of BZD withdrawal?
due to downregulation of GABA…
– anxiety, muscle cramping/twitching, psychosis, panic, ANS sxs, convulsions
What are the longer-acting BZDs?
- clonazepam (longer t1/2)
- chlordiazepoxie (active mets but low potency)
- diazepam (long t1/2 + active mets)
What are the ultra-rapid-acting BZDs?
midazolam
lorazepam
How is midazolam used?
anesthetic
How is clonazepam used?
anxiolytic, anti-convulsant
How is alprazolam used?
anxiolytic, agoraphobia
What BZDs are used for sleep?
1) flurazepam
2) temazepam
3) triazolam
What other drugs act on the BZD-binding site?
1) flumazenil
2) flunitrazepam
What is flumazenil?
BZD-binding site antagonist
– IV admin for BZD overdose
What is flunitrazepam?
rapid-onset APL of GABAa via the BZD-binding site
– date-rape
What are non-barb, non-BZD anxiolytic sedatives?
1) buspirone!
What is the MoA for buspar?
5ht1a partial agonist
Where is 5HT1a dense?
amygdala and limbic regions
What is the main use for buspar?
GAD
- no efficacy for acute panic
- not as efficacious as SSRIs for other anxiety-related disorders
Describe metabolism of buspar.
3a4
– caution MAOI or SSRI
What are the advantages of buspar?
fewer ADRs and less sedation
Describe the ADRs of buspar.
n/v, dizziness, ha
What are the disadvantages of buspar?
– 2-4 week onset
How is non-rem sleep regulated?
raphe (5-HT) and NTS (NE and autonomics)
How is REM sleep regulated?
cholinergic regions of forebrain and midbrain
What are the primary complaints of primary sleep disorder?
1) getting to sleep
2) staying asleep
3) waking up too early
4) sleeping at wrong time
What are dyssomnias?
primary insomnia, primary hypersomnia, narcolepsy, jet lag, shift-work disorder, sleep apnea, non-24
What are parasomnias?
nightmares, night terrors, sleepwalking, bruxism
What sedative drugs are used for primary sleep disorders?
1) trazodone
2) TCAs
3) clonidine
4) CNS-acting muscle relaxants
MoA of trazodone.
5ht1a partial agonist; 5ht2a antagonist; SSRI
What are the general categories of drugs used for sleep disorders?
1) sedatives
2) BZDs
3) Z-drugs
4) melatonin and MTr agonists
5) OXr antagonists
What effects do BZDs have on sleep?
1) quicker induction
2) quicker time to REM
3) decreased awakenings
4) more sleep (greatest increase in stage 2 non-rem)
5) decreased total REM
What are ADRs of BZDs used for sleep?
- risk for hangover
- rapid-onset = abuse
- rebound insomnia
- rebound REM sleep
What is the MoA of Z-drugs?
a1-selective-GABAa (HT sleep center); bind BZD site
What are Z-drugs used for?
effective for sleep induction and maintenance only
How do Z-drugs differ?
half-life
What is the shorter-acting Z drug?
zalepon (sonata) shorter –1hr– than zolpidem (ambien)–2hr–
What are the MTr agonists?
ramelteon
tasimelteon
What is the MoA for ramelteon?
Mt1/Mt2 receptor agonist
Which MTr is thought to be more important for sleep?
MT2
Describe the MTr.
Gi coupled, dense in circadian regions of HT
What are the advantages of ramelteon?
1) non-scheduled
2) does not disturb REM
3) 30-min onset with 2 hr t1/2
Describe metabolism of ramelteon.
30 min onset
2 hour half-life
1a2 metabolism
What are ADRs of MTr agonists?
HA, sedation, fatigue, N/V
How does tasimelteon differ from ramelteon?
1) $$
2) more M2-selective
3) 1a2 and 3a4
What are OXr antagonists?
suvorexant
What are orexins?
wake-promoting peptides synthesized by orexin neurons
Describe OX1/OX2 receptors.
Gs GPCRs on wake-active neurons; localized to lateral and posterior HT
Why is suvorexant scheduled?
anorectic (abuse potential)
What concentration of EtOH is the legal limit?
17 mM
How does EtOH work at 1mM?
potentiation of delta-subunit GABAa receptors
How does EtOH work at 10 mM?
GlyR potentiation
inhibition of a7 nAChR, NMDAr, vgCA channels
How does EtOH work at 50 mM?
1) potentiation of GABAa, a4-nAChR, NMDAr, 5ht3
2) inhibition of AMPA and kainate
EtoH MoA:
1) indirect intx with target proteins
- - membrane fluidization
- - lateral membrane pressures
- - replaces H2O at lipid-protein surfaces
2) direct interaction with allosteric/orthosteric receptor sites
- - low affinity
