Sedatives and Hypnotics

Question 1

Which 3 have actions on GABA neurotransmission?

Answer 1

barbiturates, benzodiazepines, z-drugs

Question 2

Sedative

Answer 2

reduces anxiety and produces a calming effect

Question 3

Hypnotic

Answer 3

produces drowsiness; aids sleep onset or maintenance

Question 4

sedative-hypnotics

Answer 4

drugs that can produce sedation at lower doses and can produce hypnosis at higher doses

Question 5

CNS depressant

Answer 5

produces a net shift toward inhibitory neurotransmission (e.g. drugs that act at GABA(a) receptors are DNS depressants

Question 6

To what receptor do barbiturates bind and what is the normal function of that receptor?

Answer 6

-GABA(a) receptor at multiple sites (alpha or beta subunits)
-they act as positive allosteric modulators of GABA(a), increasing the duration of chloride ion channel opening when GABA binds
-antagonist at glutamate AMPA receptors
-primary GABA(a) receptor agonist (only at high concentrations)

Question 7

To what receptor do benzodiazepines bind and what is the normal function of that receptor?

Answer 7

-can only bind to GABA(a) receptor at a single site (those that have an alpha next to a gamma subunit)
-positive allosteric modulators of GABA(a) but they increase the frequency of channel openings (opens at lower GABA conc)

Question 8

What receptor does flumazenil target?

Answer 8

GABA(a)
-acts as a competitive GABA(a) antagonist because it occupies the benzodiazepine and z-drug binding sites without producing an effect
-reverses CNS depression, respiratory depression and amnesia caused by benzos and z-drugs

Question 9

Z drugs and their binding site

Answer 9

-hypnotic agents prescribed for insomnia
-binds selectively to alpha 1 GABA(a) receptor subunit; increase chloride ion conductance
-more selective than benzos therefore limited range of effects

Question 10

2 clinical uses for barbiturates

Answer 10

antiepileptics and anesthetics

Question 11

6 clinical uses for benzodiazepines

Answer 11

antiepileptics
anesthetics
muscle relaxants
alcohol withdrawal
anxiety (short-term)
insomnia (short-term)

Question 12

ramelteon (drug type, indication, receptor binding site)

Answer 12

-unscheduled hypnotic for long-term use in insomnia
-melatonin 1/2 receptor agonist

Question 13

buspirone (drug type, indication, receptor binding site)

Answer 13

-serotonin (5-HT 1A) receptor agonist which is a GPCR (no effect on GABAa receptors)
-sedative used for generalized anxiety disorder

Question 14

Why are barbiturates most dangerous in overdose?

Answer 14

1. Linear dose-response progresses to coma, death
2. Tolerance develops to sedative and hypnotic effects, but not lethal effects (narrows TI)
3. No antidote exists; treatment limited to supportive measure (e.g. mechanical ventilation)

Question 15

Which 3 potentiate effects (interact with) of other CNS depressants?

Answer 15

Barbiturates, Benzos, and Z-drugs

Question 16

Which tends to have many active metabolites?

Answer 16

Benzos

Question 17

Which have highest and lowest risk of dependence?

Answer 17

Highest: barbiturates
Lowest: Z-drugs

Question 18

Why have z-drugs replaced benzos as treatment for sleep disorders?

Answer 18

Carry less risk of dependence and withdrawal

Question 19

What other 4 effects besides sedation are produced at the lowest dose?

Answer 19

anxiolysis, anti-convulsant, muscle-relaxant, disinhibition

Question 20

Which has the highest risk of PK drug interaction due to its enzyme induction/inhibition properties?

Answer 20

barbiturates

Question 21

2 clinical uses for barbiturates

Answer 21

antiepileptics
anesthetics

Question 22

For the drugs with both sedative and hypnotic properties (barbiturates & benzodiazepines), name a major physicochemical property that affects time to onset of action, and a property that affects duration of action (see slides on benzodiazepines).

Answer 22

Barbiturates time to onset of action and duration of action is driven primarily by lipophilicity. Benzodiazepines time to action is determined mainly by lipophilicity and onset is determined by whether the benzodiazepines have active metabolites.

Question 23

Which 3 have potential for abuse (i.e. are scheduled substances)?

Answer 23

Barbiturates, Benzodiazepines, and Z-drugs