EXAM 4 Sedatives Dr. Pond

Question 1

What is the difference between sedatives and hypnotics?

Answer 1

Sedative reduces anxiety (anxiolytic

Hypnotics reduce the onset and improve the maintenance of sleep

-a d can drug can be used as a sedative at a low dose, and as a hypnotic at a higher dose

Question 2

Which drugs have a linear relationship between the dose and sedative-hypnotic effect

Answer 2

Barbiturates: the higher the dose, the more it goes from a sedative to a hypnotic -> up to coma and death

Benzos is not as linear and safer

Question 3

Which areas of the brain are involved in causing anxiety?

Answer 3

-Amygdala - associated with fear
-Hippocampus - mood, emotion, memory

so when experiencing something that caused fear that memory context becomes activated too

Question 4

Which structure communicates with both

Answer 4

Raphe nuclei: contain serotonergic cell bodies in the brain stem

->connected to the Brainstem, hypothalamus and vagus

->causing physical symptoms:
-increased respiration
-increase in NE (fight or flight)
-activation of HPA axis -> cortisol
-increase in BP and HR

Question 5

What is required for benzos to have sedative-hypnotic activity?

Answer 5

a substituent at postion 7

ex: nitrazepam, clonazepam (Klonidin), temazepam (Restoril)

Question 6

Which benzo produces profound anterograde
amnesia when used with alcohol?

Answer 6

Flunitrazepam “Roofies”

Question 7

How are benzos metabolized?

Answer 7

-Metabolized via microsomal enzymes in the liver
-glucuronidation only
-Liver is the only means of elimination

Question 8

Which benzo has the shortest onset?

Answer 8

Diazepam
-but long half-life (20-50hr)

Question 9

Which benzos have a slow onset?

Answer 9

Temazepam
Oxazepam

Question 10

Which benzos form metabolites?

Answer 10

-Chlordiazepoxide
-Diazepam

others don’t have active metabolites

Question 11

Which benzos have low risk of withdrawal?

Answer 11

-long half-life -> it stays arround and tapres itself
-actvite metabolites

-Diazepam

high risk: Chlordiazepoxide, Alpralzolam, Lorazepam, Oxazepam

Question 12

Benzos with short-half-life

Answer 12

Lorazepam
Oxazepam
Temazepam

Question 13

Which benzos are metabolized by phase II glucuronidation only?

Answer 13

-Lorazepam
-Oxazepam
-Temazepam

Question 14

What type of channel is the GABA(A) receptor?

Answer 14

ion-channel: Cl(-)

Question 15

Which subunits of the GABA(A) receptor are targets?

Answer 15

α subunit: GABA

ß subunit: Benzos

must include at least 1 γ2 subunit (most abundant
in limbic and neocortical regions – emotions, memory)

Question 16

What is the role of Flumazenil?

Answer 16

-Benzodaizepine antagonist

-Used for reversing CNS depression (benzo overdose)

Question 17

What is the MOA of ß Carbolines?

Answer 17

inverse agonist of GABA(A) receptors

-bind to GABA(A) but have the opposite effect
->excitatory: can cause anxiety and seizures

Question 18

What is the MOA of Buspirone (Buspar)?

Answer 18

Pre- and postsynaptically: INHIBITORY

5-HT1A Full agonist at Raphe Nucleus

5-HT1A partial agonist at the Hippocampus and Amygdala

Question 19

What is the role of Barbiturates in therapy?

Answer 19

-anesthesia induction
-seizures
-inducing coma after head trauma

Question 20

What to be cautious about with barbiturates

Answer 20

-low therapeutic index
-high abuse potential and physical dependence

-tolerance to sedative but not toxic effects
-often used for suicide

Question 21

MOA of barbiturates

Answer 21

-Interact with all types of GABA(A) receptors

-GABA(A-R) agonist at high concentrations

-AMPA-R antagonist: activated by glutamate, excitatory

Question 22

MOA of Partial allosteric modulators PAMs

Answer 22

Zolpidem (Ambien)
Zaleplon (Sonata)
Eszopiclone (Lunesta)

-Similar to benzodiazepines but only bind to GABA(A) receptor isoforms with α1subunits

-predominantly used in insomnia

Question 23

Which of the PAMs have the shortest half-life?

Answer 23

Zaleplon: 1hr

-Zolpidem: half life ~ 2 hrs
-Eszopiclone: half life 6 hr

Question 24

Where is Melatonin produced?

Answer 24

Pineal Gland
promotes sleep -> binding MT1, MT2 receptors

Question 25

Where is Orexin produced?

Answer 25

Lateral Hypothalamus

Orexin A and Orexin B
promotes wakefulness -> binding OX1R, OX2R

Question 26

MOA of Ramelteon (Rozerem)

Answer 26

MT1 and MT2 agonist
-helps with falling asleep
-forms active metabolites

ADE:
dizziness, drowsiness, fatigue, nausea

Question 27

MOA of Tasmelteon (Hetlioz)

Answer 27

-Melatonin receptor agonist (MT2 > MT1)
-used for non-24 hr sleep/wake cycle
-metabolites have minimal activity

ADE:
-headache, dream disorder
-UTIs, upper respiratory infections
-alanine aminotransferase levels may be elevated

Question 28

What are the Orexin receptor antagonist

Answer 28

[orexant]

-Suvorexant
-lemborexant
-daridorexant

Question 29

What type of receptors are Orexin A and Orexin B?

Answer 29

metabotropic
found pre and postsynaptically

Question 30

Which drug is used for narcolepsy and cataplexy?

Answer 30

Sodium oxybate (Xyrem)

Question 31

MOA of Sodium oxybate (Xyrem)

Answer 31

-Weak agonist at GABAB receptors, high affinity for GHB receptor

-Gamma hydroxybutyrate (GHB) salt

ADE:
-dizziness, somnolence
-CNS/respiratory depression & abuse!
-tremor
-N/V
-urinary incontinence,
-confusion, sleep-walking
-depression/suicide risk