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Pmcol 305 > Sedatives > Flashcards

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
Q

dangers associated with sedatives

A

effects on fetus
drug interactions - synergism
overdose

26
Q

risk for fetus

A

rapid entry, increased half life (under-developed liver)
increased risk of cleft palate, floppy infant syndrome, withdrawal

27
Q

overdose

A

treated with flumazenil
rare for benzos alone
barbiturates have low therapeutic index (increased risk when combined with alcohol - resp rate)

28
Q

flumazenil

A

GABA antagonist
perfect reverser of sedative activities

confirms result of in vivo reinforcement - reverses increased dopamine firing

29
Q

tolerance

A

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
Q

chronic effects of sedatives

A

daytime fatigue, accidents, depression, violence, and increased overall mortality

31
Q

withdrawal

A

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
Q

dependence

A

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
Q

lower abuse potential

A

in progressive schedules, animals exert less effort for sedatives compared to cocaine or opioids

breakpoint is much lower

34
Q

progressive schedules

A

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
Q

breakpoint

A

where reward is no longer worth the effort level
stop pushing the lever

36
Q

disinhibition of VTA dopaminergic neurons

A

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
Q

GABA receptors on dopaminergic neurons

A

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
Q

benzo-evoked reinforcement

A

single unit recordings from neurons in mice
midazolam increases VTA dopaminergic firing; decreases VTA GABAergic interneuron firing

39
Q

Gamma-hydroxybutyric acid

A

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
Q

GHB prodrugs

A

gamma-butyrylactone
1,4-butanediol

metabolized by body into GHB

41
Q

dose dependent effects of GHB

A

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
Q

dose dependent effect of sedatives

A

low = less depressed electrical activity
- sedative, slurred speech, ataxia + incoordinated muscle movements
high = more affected brain regions (basal ganglia)
- drowsiness, anesthetic

Pmcol 305 (18 decks)

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