Sedatives/Hypnotics

Question 1

SSRIs and SNRIs

Answer 1

SSRIs: escitalopram, paroxetine, sertraline

SNRIs: duloxetine, venlafaxine

• theorized to activate stress-adapting pathways
• reduces somatic anxiety symptoms and general distress from the symptoms
• 1st line for chronic mgmt of GAD, particularly w comorbid depression
• requires 2-4 weeks for response
• side effects: diarrhea, n/v, impotence, insomnia, weight gain, headache, diaphoresis

Question 2

5-HT1A Agonist

Answer 2

• buspirone
• NOT GABA-ergic
• partial 5HT agonist but also has affinity for D2 receptors
• selective anxiolytic without causing sedation, hypnosis, or euphoria
• 2nd line agent for chronic GAD mgmt
• lack of suitability for comorbid disorders
• requires 2< weeks for effect
• side effects: GI, transient drowsiness/dizziness
• interacts with inducers and inhibitors of CYP3A4 as well as MAO inhibitors

Question 3

Anticonvulsant

Answer 3

• Pregabalin
• GABAergic agent that doesn’t interact with GABA-R itself.
• potentiates actions of GABA in 2 ways:
  1. Increases PRESYNAPTIC GABA release by binding a2d subunit of voltage-gated Ca channels and altering calcium influx
  2. Increasing GABA biosynthesis by modulating the actions glutamate decarb and branched chain aminotransferase.
• 2nd line agent for chronic GAD mgmt
• idiosyncratic adverse effects: peripheral edema, thrombocytopenia

Question 4

Tricyclic

Answer 4

• Imipramine
• acts like an SNRI
• 2ns line agent for chronic GAD mgmt
• blocks histamine, muscarinic/cholinergic, and alpha adrenergic
• antihistamine: sedation/sleepiness
• antichol: dry mouth, const, diplopia, tachy
• andiadrenergic: orthostatic hypotension
• serious tox: seizures, tachy, cardiac arrest

Question 5

Antihistamine

Answer 5

• hydroxyzine
• H1 antihistamine that also acts as strong 5-HT antagonist
• similar anxiolytic effects as buspar and benzos
• ALTERNATIVE agent for tx of GAD
• doesn’t tx comorbidities
• sedative for dental procedures
• antihistamine effects: sedation/sleepiness
• antichol effects: dry mouth, const, diplopia
• antidopa: extrapyramidal symptoms (dyskinesias/tremors)
• overdose—> hallucinations, prolonged QT/torsades des pointes

Question 6

Atypical Antipsychotic

Answer 6

• quetiapine
• 5-HT2 antagonist
• earlier onset of action
• ALTERNATIVE tx for GAD
• orthostatic hypotension, dry mouth, const, tachy, extrapyramidal symptoms

Question 7

Benzo Hypnotics

Answer 7

• estazolam, flurazepam, quazepam, temazepam, triazolam
• decreases sleep latency (time to sleep) and the # of awakenings
• used for sleep disorders characterized by difficulty in falling asleep
• hypnotic doses are higher than anxiolytic doses
• should be used acutely, not a chronic tx; tolerance can develop within a month
• rebound insomnia can occur with abrupt cessation

Question 8

Non-Benzo GABA-ergic hypnotics

Answer 8

• zolpidem, zaleplon, eszopiclone
• more selective than benzos with regard to GABA-R isoform
• zolpidem and eszopiclone increase total sleep time while zaleplon does not
• reduced potential for amnesic effects and day-after psychomotor depression
• also acute tx, same indication for benzos (difficulty in falling asleep)
• adverse effects: somnolence, dizziness, HA, GI, myalgia, risk of dependence
• less intense rebound insomnia upon cessation

Question 9

Melatonin Receptor Agonist

Answer 9

• ramelteon, tasimelteon
• no GABA-ergic activity
• decreases sleep latency and increases sleep period, no rebound insomnia or risk of dependence
• can cause endocrine changes (decreased T and increased PRL) with ramelteon
• with tasimelteon, can get abnormal dreams, and UTIs

Question 10

Orexin Receptor Antagonist

Answer 10

• suvorexant
• no GABA-ergic activity in the brain
• decreases sleep latency and increases sleep periods
• can cause day-after somnolence, sleep driving, and risk of dependence. Also has amnesic effects

Question 11

GABAa Receptor Antagonist

Answer 11

• flumazenil
• competitive antagonist at benzo binding site on GABA-R
• also competes with non-benzo GABA-ergic hypnotics like zolpidem, zaleplon, and eszopiclone
• typically requires re-administration due to short t1/2
• adverse rxs include agitation and confusion + precipitating drug withdrawal in cases of drug dependence