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
dangers associated with sedatives
effects on fetus
drug interactions - synergism
overdose
risk for fetus
rapid entry, increased half life (under-developed liver)
increased risk of cleft palate, floppy infant syndrome, withdrawal
overdose
treated with flumazenil
rare for benzos alone
barbiturates have low therapeutic index (increased risk when combined with alcohol - resp rate)
flumazenil
GABA antagonist
perfect reverser of sedative activities
confirms result of in vivo reinforcement - reverses increased dopamine firing
tolerance
receptor subunit composition shifts to alter neuron sensitivity
sedative + hypnotic effects = days to weeks
anxiolytic effects = 3-4 months
does not develop for respiratory depression
benzos are known for producing tolerance
chronic effects of sedatives
daytime fatigue, accidents, depression, violence, and increased overall mortality
withdrawal
worse with short acting drugs
high dose intermittent use → peak and elimination cycle strengthens cellular adaptations = stronger response with more frequent administration
hyperexcitability
insomnia, anxiety, tremor, headache, confusion, and difficulty concentrating
dependence
physical and psychological
benzos are less addictive than barbiturates - slower onset, slower distribution to the brain; targeted pharmacodynamic effects; can’t activate GABA receptors on their own
lower abuse potential
in progressive schedules, animals exert less effort for sedatives compared to cocaine or opioids
breakpoint is much lower
progressive schedules
increasing response requirement to get delivery over successive succession → how many times lever push is required for hit increases
assesses motivation (effort level) to get drug
drug seeking behaviour
breakpoint
where reward is no longer worth the effort level
stop pushing the lever
disinhibition of VTA dopaminergic neurons
mechanism of reinforcement; increase dopamine release in nucleus accumbens
GABA release sets threshold for activating DA neurons
benzos bind to GABA receptors on GABA interneurons in VTA → inhibition of GABA = inhibition of DA (disinhibition)
= dopaminergic neuron increases rate of firing = increase release of dopamine
GABA receptors on dopaminergic neurons
triggering would cause hyperpolarization of cells = oppose reinforcing mechanism
disinhibition happens first
sensitivity of GABA receptors on interneurons
= triggered before GABA receptors on DA neurons
benzo-evoked reinforcement
single unit recordings from neurons in mice
midazolam increases VTA dopaminergic firing; decreases VTA GABAergic interneuron firing
Gamma-hydroxybutyric acid
GHB
neurotransmitter + illegal drug
naturally occurring in body = difficult to trace intoxication
GABA (B) receptor agonist
Gi/o linked, inhibits Ca2+ channels, activates GIRK
precursor of GABA, Glu, and Gly
GHB prodrugs
gamma-butyrylactone
1,4-butanediol
metabolized by body into GHB
dose dependent effects of GHB
affects dopamine, acetylcholine, serotonin, opioids
sensation is similar to alcohol inebriation
low doses of GHB have a stimulatory effect: stimulates release of excitatory glutamate
high doses - binds to GABA (B) receptors and can cause sedation
can lead to suppressed respiration, convulsions, coma, and death
dose dependent effect of sedatives
low = less depressed electrical activity
- sedative, slurred speech, ataxia + incoordinated muscle movements
high = more affected brain regions (basal ganglia)
- drowsiness, anesthetic
