Sleep Rx Flashcards
There are two ascending arousal pathways. What’s the first?
The cholinergic cell groups in the upper pons( the PPT and LDT) activate the thalamus
What’s the 2nd AAS pathway?
2nd pathway: monoamine, histaminergic, GABAergic activates cortex to process thalamic inputs
What mediates the very rapid transition between sleep and awake state?
Orexin containing neurons in the hypothalamus. These neurons provide a link between the limbic system, energy homeostasis, the brain stem, and other system
How do orexin neurons promote wakefullness?
Orexin neurons promote wakefulness through monoaminergic nuclei that are wake-active
Stimulation of dopaminergic centers by orexins modulate what system?
The reward systems (VTA)
Stimulation of neuropeptide Y by orexin does what?
Increases food intake
How does the suprachiasmatic nucleus send input to orexin neurons?
Via the dorsomedial hypothalamus
Goals of insomnia Rx?
Improvement in nighttime and daytime Sx
What are some of the FDA concerns regarding the development of insomnia drugs?
Daytime somnolence, especially while driving. Unconscious nighttime activity, suicidal ideation, and other narcolepsy assoc events like sleep paralysis, hypnagogic hallucinations, and mild cataplexy
What are some key points regarding the Rx of insomnia?
Most drugs are used off label. 75% of the drugs are anti-depressants, only a handful are actually approved for insomnia, and lots of ppl treat themselves with OTC and herbal supplements (1st gen anti histamines and melatonin)
Which drugs are approved for Rx of insomnia?
Benzodizepines, BNZ receptor agonists, and melatonin receptor agonists
All of the drugs used to Rx insomnia act through effects on the GABA receptors in the CNS except for?
Ramelteon: which acts upon the melatonin receptor
What is thought to be responsible for the sedative, anti convulsant, anxiolytic, and myorelaxant drug properties?
Subunit modulation of the GABA-A receptor chloride channel
At normal clinical doses do any of the Rx’s work in place of endogenous GABA in opening the channel?
No. It is critical to appreciate that each of these drug classes modifies the response pattern of the GABA receptor to endogenous ligand.
Why have barbiturates been largely replaced by BNZ and BRA’s?
Clinical safety
What do BNZ and BRA require to act?
GABA-they allosterically modify the receptor response to GABA (shift the dose response curve to the left)
Why are barbiturates lethal at high doses?
B/c they fnc like GABA itself
What schedule are the BNZ’s and BRA’s?
Schedule IV
ADE’s of BNZs?
Sedation, cognitive impairment, and rebound insomnia (esp with short acting drugs)
What are withdrawal Sx of BNZs?
Anxiety, irritability, restlessness, obstructive sleep apnea, severe ventilatory impairment. Taper withdrawal
What subunit of the GABA receptor do BNZs bind?
alpha
What are the 3 different subgroups of the GABA-A receptor?
BZ-1=sedative and amnesic
BZ-2=anxiolysis
BZ-3=myorelaxation and anticonvulsant (supraclinical doses)
Which subgroups do BNZ’s and BRA’s effect?
BNZ’s: effect all three
BRA’s: BZ-1
BNZ’s duration of action?
Complex mech. of elimination, but all lead to conjugation and renal excretion. Some drugs have many steps to reach glucoronidation (diazepam=long t1/2) but others go straight to glucoronidation (lorazepam and estazolam=short t1/2)
