Sedatives

Question 1

sedatives

Answer 1

relieve anxiety (anxiolytic), cause relaxation
mild CNS depressants

calming

Question 2

hypnotics

Answer 2

similar effects to sedatives but also cause drowsiness and sleep

sleeping

Question 3

Z-drugs

Answer 3

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

sleep aids
depress neural activity

Question 4

sedatives and hypnotics

Answer 4

loss of sensory information
GABA receptor = center of pharmacodynamic effects

benzodiazepines and barbiturates

Question 5

synergism

Answer 5

amplified response by 2+ drugs

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

Question 6

sedatives - clinical use

Answer 6

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

progressively greater depression of electrical activity

Question 7

hypnotics as sleep aids

Answer 7

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

Question 8

distribution

Answer 8

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

Question 9

longer acting sedatives

Answer 9

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

Question 10

shorter acting sedatives

Answer 10

anesthetics (thiopental, midazolam, triazolam)
treat insomnia

Question 11

chemical structure of benzodiazepines

Answer 11

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

Question 12

short to long acting benzodiazepines

Answer 12

1. triazolam
2. alprazolam
3. clonazepam
4. lorazepam
5. diazepam

Question 13

administration

Answer 13

oral - prescription
rectal
injection - short acting (anesthetics)

Question 14

metabolism

Answer 14

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

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

Question 15

half lives of benzos

Answer 15

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

big difference due to structures

Question 16

elimination

Answer 16

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

Question 17

floppy infant syndrome

Answer 17

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

Question 18

GABA (A) receptor binding

Answer 18

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

Question 19

benzodiazepines

Answer 19

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)

Question 20

barbiturates

Answer 20

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

Question 21

acute effects of sedatives in the brain

Answer 21

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

Question 22

common side effects

Answer 22

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

Question 23

acute effects in the lungs

Answer 23

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

Question 24

acute effects in the heart

Answer 24

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

Question 25

dangers associated with sedatives

Answer 25

effects on fetus drug interactions - synergism overdose

Question 26

risk for fetus

Answer 26

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

Question 27

overdose

Answer 27

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

Question 28

flumazenil

Answer 28

GABA antagonist perfect reverser of sedative activities confirms result of in vivo reinforcement - reverses increased dopamine firing

Question 29

tolerance

Answer 29

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

Question 30

chronic effects of sedatives

Answer 30

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

Question 31

withdrawal

Answer 31

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

Question 32

dependence

Answer 32

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

Question 33

lower abuse potential

Answer 33

in progressive schedules, animals exert less effort for sedatives compared to cocaine or opioids breakpoint is much lower

Question 34

progressive schedules

Answer 34

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

Question 35

breakpoint

Answer 35

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

Question 36

disinhibition of VTA dopaminergic neurons

Answer 36

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

Question 37

GABA receptors on dopaminergic neurons

Answer 37

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

Question 38

benzo-evoked reinforcement

Answer 38

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

Question 39

Gamma-hydroxybutyric acid

Answer 39

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

Question 40

GHB prodrugs

Answer 40

gamma-butyrylactone 1,4-butanediol metabolized by body into GHB

Question 41

dose dependent effects of GHB

Answer 41

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

Question 42

dose dependent effect of sedatives

Answer 42

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