Sedatives Flashcards
sedatives
relieve anxiety (anxiolytic), cause relaxation
mild CNS depressants
calming
hypnotics
similar effects to sedatives but also cause drowsiness and sleep
sleeping
Z-drugs
Ambien (zolpidem), zopliclone
orexin antagonists
melatonin agonists
anti-histamines
sleep aids
depress neural activity
sedatives and hypnotics
loss of sensory information
GABA receptor = center of pharmacodynamic effects
benzodiazepines and barbiturates
synergism
amplified response by 2+ drugs
combined with other depressants
targeting GABA receptor = over depressing of electrical activity
sedatives - clinical use
high doses = sedation, sleep
low doses = anxiolysis
mid doses = muscle relaxant
progressively greater depression of electrical activity
hypnotics as sleep aids
GABA and adenosine = promote sleep
benzos → fall asleep faster, increase total sleep time, decrease nighttime awakenings
but decrease REM sleep
Z-drugs → produce sleep rhythm closer to natural sleep; depress activity in alert regions of brain but can’t shut off impulses that coordinate behavioural responses → risk of MVC, sleep-walking
distribution
lipophilic drugs
faster onset due to rapid distribution
highly bound to plasma proteins
cross placenta = effects in pregnancy
benzos are less lipid soluble = absorbed slower, slower onset of action
longer acting sedatives
anticonvulsants (ex. phenobarbital), muscle relaxants, anxiolytics (ex. diazepam - Valium, clonazepam - Klonopin)
shorter acting sedatives
anesthetics (thiopental, midazolam, triazolam)
treat insomnia
chemical structure of benzodiazepines
azepine ring structure + benzene = benzodiazepine
triazole ring added to azepine ring = higher potency
- better binding kinetics = greater affinity for GABA target *increases number of responses → increased chance of side effects
number of functional groups decreases from short acting to long acting
charges → better enzymatic interactions, easily access bonds = faster metabolism
short to long acting benzodiazepines
- triazolam
- alprazolam
- clonazepam
- lorazepam
- diazepam
administration
oral - prescription
rectal
injection - short acting (anesthetics)
metabolism
liver - CYP450
some drug metabolism produces active metabolites = prolonged duration of action (diazepam)
decreased in infants, pregnant women, those with liver disease, and elderly
half lives of benzos
midazolam t1/2 = 2 hours
diazepam t1/2 = 100 hours
big difference due to structures
elimination
4-5 half lives for elimination
3-4 half lives to start eliminating effects
floppy infant syndrome
use in pregnancy can cause reduced muscle tone in baby
→ inability to nurse (no swallowing/sucking reflex)
slower liver system - blood benzo levels can reach 2x mother’s
GABA (A) receptor binding
five subunits arranged around a chloride conducting pore
different regions have different subunit compositions
Cl- flow into cell = hyperpolarization → decreases electrical activity
GABA binds between alpha and beta subunits
benzodiazepines
allosteric modulators
bind to site between alpha and gamma subunits on GABA (A) receptor → increases frequency of chloride channel openings
receptors in limbic system, reticular activating system, cortex
no binding sites on receptors in brainstem (control of respiration)
barbiturates
activators
general effect on GABA receptors
binding to site between alpha and beta subunits enhances affinity of receptor for GABA = increases duration of time that chloride channel is open → prolonged hyperpolarization = neuronal inhibition
do not rely on presence of GABA to trigger effect = can turn on receptor in absence of GABA
acute effects of sedatives in the brain
reduce muscle tone, impair coordination, increase sedation and sleep (reduced REM sleep)
reduce anxiety
impaired concentration, learning, and memory, can cause bizarre, uninhibited behaviours
common side effects
drowsiness, lethargy, dizziness, confusion, reduced libido, diminished concentration, incoordination, impairment of driving skills
at slightly elevated doses: prevent consolidation of short-term memories → alpha subunit containing receptors in hippocampus
acute effects in the lungs
barbiturates: decrease respiratory rate
benzos: do not significantly decrease resp rate (safer)
acute effects in the heart
barbiturates: slightly lower heart rate
benzos: slightly elevate heart rate