Drugs for Insomnia

Question 1

Cell groups from the PPT and LDT that activate the thalamus use what neurotransmitter?

Answer 1

Ach

Question 2

What is the role of orexin?

Answer 2

controls transition from sleep to awake states

Question 3

What is the function of GABA in wakefulness?

Answer 3

GABA functions as a negative regulator of these ascending pathways and also functions as an inhibitor of the neuronal activity in the cortex.

Question 4

What are the goals for treatment of insomnia?

Answer 4

improve nighttime and daytime symptoms

Question 5

What are the only FDA approved drug classes for insomnia?

Answer 5

Benzodiazepines
Benzodiazepine receptor agonists
Melatonin receptor agonist

Question 6

What is the MOA of benzodiazepines and benzodiazepine receptor agonists in the treatment of insomnia?

Answer 6

Endogenous GABA opens the channel and these drugs structurally reconfigure the open pore

Question 7

What is the MOA of antidepressants in the off-label treatment of insomnia?

Answer 7

sedation due to anti-histaminergic effect centered in the tuberomammillary nucleus

Question 8

What is the MOA of OTC 1st generation antihistamines in the treatment of insomnia?

Answer 8

sedation due to anti-histaminergic effect centered in the tuberomammillary nucleus

Question 9

List the benzodiazepines used in the treatment of insomnia.

Answer 9

Estazolam 
Flurazepam
Quazepam
Temazepam
Triazolam

Question 10

Which benzodiazepine is known for its short half-life?

Answer 10

estazolam

Question 11

True or false: all benzodiazepines bind to the GABA receptor at DISTINCT sites.

Answer 11

TRUE

Question 12

Which alpha-subunits do benzodiazepines bind to on the GABA receptor?

Answer 12

BZ-1
BZ-2
BZ-3

Question 13

What is the role of BZ-1 alpha subunit?

Answer 13

sedation

Question 14

What is the role of BZ-2 alpha subunit?

Answer 14

anxiolysis

Question 15

What is the role of BZ-3 alpha subunit?

Answer 15

myorelaxation and anticonvulsant

Question 16

List the benzodiazepine receptor agonists used in the treatment of insomnia.

Answer 16

Zolpidem
Zaleplon
Eczopiclone

Question 17

Which alpha subunits do benzodiazepine receptor agonists bind to?

Answer 17

BZ-1

Question 18

What is interesting about the pharmacokinetic parameters of benzodiazepines and benzodiazepine receptor agonists?

Answer 18

Allosteric modulators, so left-shift in the dose response curve to endogenous GABA. Have a “ceiling effect”.

Question 19

True or false: elimination half-life of benzodiazepines have a close relation to the time course of pharmacological effect.

Answer 19

FALSE: Formation of active metabolites makes it where the elimination half-life of a parent drug may have little relation to the time course of pharmacological effect

Question 20

Which drugs are offered with a “quick release, slow release” co-formulation?

Answer 20

benzodiazepine receptor agonists

Question 21

Which drug for insomnia has a rapid action with sublingual and oral spray?

Answer 21

zolpidem

Question 22

Which drug for insomnia has sex-related differences in metabolism? (women slower than men)

Answer 22

zolpidem (REDUCE DOSE OF ZOLPIDEM in WOMEN due to increased risk of next-day impairment)

Question 23

What is ramelteon?

Answer 23

melatonin receptor agonist

Question 24

What receptors does ramelteon bind to?

Answer 24

MT1 and MT2 (GPCRs)

Question 25

What does binding of ramelteon to MT1 do?

Answer 25

Binding to MT1 attenuates suprachiasmatic nucleus activity and induces sleep

Question 26

What does binding of ramelteon to MT2 do?

Answer 26

MT2 binding maintains circadian rhythm.

Question 27

How is ramelteon metabolized?

Answer 27

CYPS in the liver

Question 28

List the antidepressants used to treat insomnia.

Answer 28

Doxepin Mirtazapine Trazodone

Question 29

MOA: M block, NE reuptake block, 5-HT reuptake block. Primarily antihistamine at low doses

Answer 29

Doxepin

Question 30

MOA: 5-HT reuptake block

Answer 30

trazodone

Question 31

MOA: Significant alpha-2 antagonism reinforcing NE and 5-HT release

Answer 31

mirtazapine

Question 32

List the 1st generation antihistamines used in the treatment of insomnia.

Answer 32

Diphenhydramine | Doxylamine

Question 33

MOA of 1st generation antihistamines in treatment of insomnia.

Answer 33

H1 antagonism and anticholinergic effects

Question 34

What is Suvorexant?

Answer 34

it was an orexin receptor antagonist (that gave problems with next-day sedation so it was rejected by the FDA)

Question 35

What are the major FDA concerns with drugs to treat insomnia?

Answer 35

* Persistent CNS-debilitating effects the day after consuming the drug * Unrecognized physical activity at night * Suicidal Ideation * Narcolepsy-associated events

Question 36

List the benzodiazepine that is NOT CYP metabolized.

Answer 36

Temazepam

Question 37

List the benzodiazepines that are CYP3A4 metabolized.

Answer 37

Estazolam Flurazepam Triazolam

Question 38

List the benzodiazepine that is CYP 2B6>3A4.

Answer 38

Quazepam

Question 39

What drug should be used with caution in Asians due to some CYP ethnic variabilities?

Answer 39

Zaleplon

Question 40

What is the most widely prescribed hypnotic in USA and the only drug approved for middle-of the night awakening?

Answer 40

Zolpidem

Question 41

What drug class is absolutely contraindicated in pregnancy (CAT X)?

Answer 41

Benzodiazepines

Question 42

What benzodiazepines do you have to worry about accumulation with?

Answer 42

Flurazepam | Quazepam

Question 43

Which benzodiazepine undergoes rapid inactivation?

Answer 43

Triazolam

Question 44

What drugs should be used with caution in hepatic disease, COPD, depression, driving, and closed angle glaucoma?

Answer 44

Benzodiazepines | Benzodiazepine receptor agonists

Question 45

What drug types do Benzodiazepines and Benzodiazepine receptor agonists have reactions with?

Answer 45

CNS drugs | CYP-metabolized drugs

Question 46

TOXICITY: sedation, cognitive impairment, rebound insomnia (especially with short/intermediate-acting dugs) and can lead to physical dependence and withdrawal (with severe ventilatory impairment*)

Answer 46

Benzodiazepines | Benzodiazepine receptor agonists

Question 47

What is the CYP specificity of Ramelteon

Answer 47

metabolized by 1A2>2C9 and 3A4

Question 48

TOXICITY: SEDATION major; suicidal ideation; psychotic episodes

Answer 48

Antidepressants

Question 49

TOXICITY: Few AEs (HA, somnolence, nausea, insomnia, and nasopharyngitis and URTI with long-term use)

Answer 49

ramelteon

Question 50

True or false: remelteon is not a scheduled drug, so there is NO abuse potential or respiratory depression.

Answer 50

TRUE

Question 51

What are some side effects seen with 1st generation antihistamines?

Answer 51

Sedation and xerostomia, blurred vision, urinary retention, increased intraocular pressure.

Question 52

What is the only way in which benzodiazepines can be lethal?

Answer 52

Only lethal when consumed with quantities of alcohol

Question 53

Which drug class should be used with caution in the elderly and those with narrow-angle glaucoma?

Answer 53

1st generation antihistamines

Question 54

Which drug class should be used with caution in those with pre-existing suicidal thoughts or psychotic disorders?

Answer 54

antidepressants

Question 55

In which drug class does rapid tolerance develop?

Answer 55

1st generation antihistamines

Question 56

Which drug is used to reverse the effect of BNZ and BzRAs?

Answer 56

Flumazenil (GABA inhibitor)

Question 57

What are the potential side effects of flumazenil?

Answer 57

seizures and symptoms of withdrawal as well as dysphoria, agitation, and possible increased adverse effects due to the abrupt awakening