Sedatives Flashcards

1
Q

sedatives

A

relieve anxiety (anxiolytic), cause relaxation
mild CNS depressants

calming

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2
Q

hypnotics

A

similar effects to sedatives but also cause drowsiness and sleep

sleeping

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3
Q

Z-drugs

A

Ambien (zolpidem), zopliclone
orexin antagonists
melatonin agonists
anti-histamines

sleep aids
depress neural activity

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4
Q

sedatives and hypnotics

A

loss of sensory information
GABA receptor = center of pharmacodynamic effects

benzodiazepines and barbiturates

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5
Q

synergism

A

amplified response by 2+ drugs

combined with other depressants
targeting GABA receptor = over depressing of electrical activity

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6
Q

sedatives - clinical use

A

high doses = sedation, sleep
low doses = anxiolysis
mid doses = muscle relaxant

progressively greater depression of electrical activity

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7
Q

hypnotics as sleep aids

A

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

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8
Q

distribution

A

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

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9
Q

longer acting sedatives

A

anticonvulsants (ex. phenobarbital), muscle relaxants, anxiolytics (ex. diazepam - Valium, clonazepam - Klonopin)

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10
Q

shorter acting sedatives

A

anesthetics (thiopental, midazolam, triazolam)
treat insomnia

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11
Q

chemical structure of benzodiazepines

A

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

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12
Q

short to long acting benzodiazepines

A
  1. triazolam
  2. alprazolam
  3. clonazepam
  4. lorazepam
  5. diazepam
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13
Q

administration

A

oral - prescription
rectal
injection - short acting (anesthetics)

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14
Q

metabolism

A

liver - CYP450
some drug metabolism produces active metabolites = prolonged duration of action (diazepam)

decreased in infants, pregnant women, those with liver disease, and elderly

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15
Q

half lives of benzos

A

midazolam t1/2 = 2 hours
diazepam t1/2 = 100 hours

big difference due to structures

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16
Q

elimination

A

4-5 half lives for elimination
3-4 half lives to start eliminating effects

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17
Q

floppy infant syndrome

A

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

18
Q

GABA (A) receptor binding

A

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

19
Q

benzodiazepines

A

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)

20
Q

barbiturates

A

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

21
Q

acute effects of sedatives in the brain

A

reduce muscle tone, impair coordination, increase sedation and sleep (reduced REM sleep)
reduce anxiety
impaired concentration, learning, and memory, can cause bizarre, uninhibited behaviours

22
Q

common side effects

A

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

23
Q

acute effects in the lungs

A

barbiturates: decrease respiratory rate
benzos: do not significantly decrease resp rate (safer)

24
Q

acute effects in the heart

A

barbiturates: slightly lower heart rate
benzos: slightly elevate heart rate

25
dangers associated with sedatives
effects on fetus drug interactions - synergism overdose
26
risk for fetus
rapid entry, increased half life (under-developed liver) increased risk of cleft palate, floppy infant syndrome, withdrawal
27
overdose
treated with flumazenil rare for benzos alone barbiturates have low therapeutic index (increased risk when combined with alcohol - resp rate)
28
flumazenil
GABA antagonist perfect reverser of sedative activities confirms result of in vivo reinforcement - reverses increased dopamine firing
29
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
30
chronic effects of sedatives
daytime fatigue, accidents, depression, violence, and increased overall mortality
31
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
32
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
33
lower abuse potential
in progressive schedules, animals exert less effort for sedatives compared to cocaine or opioids breakpoint is much lower
34
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
35
breakpoint
where reward is no longer worth the effort level stop pushing the lever
36
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
37
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
38
benzo-evoked reinforcement
single unit recordings from neurons in mice midazolam increases VTA dopaminergic firing; decreases VTA GABAergic interneuron firing
39
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
40
GHB prodrugs
gamma-butyrylactone 1,4-butanediol metabolized by body into GHB
41
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
42
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