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Feinberg Psych Module 2022 > 95b - Sedatives and Hypnotics > Flashcards

95b - Sedatives and Hypnotics Flashcards

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1
Q

Can benzos on their own be deadly?

In what situations?

A

Yes

Anyone with a breathing disorder (OSA, COPD)

Usually, the biggest danger of benzos is mixing with other drugs and/or alcohol -> respiratory depression

Hypnotic and sedative doses are usually pretty safe on their own

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2
Q

Dealkylation of which kinds of benzodiazepines results in a long-acting metabolite?

Which enzyme is the dealkylate-er?

What are the implications?

A

-azepams are dealkylated by CYP2C19

This metabolite is long-acting and will hang out for awhile, especially in anyone with slower liver metabolism

Avoid the -azepams* in anyone taking multiple drugs that could have deathly synergy, the elderly, and anyone who might have impaired hepatic function

*Except the LOTs: They are okay

(Lorazepam, oxazepam, temazepam)

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3
Q

How are the -zazoles metabolized?

A
  • Phase I: CYP3A4
  • Phase II: Glucuronidation
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4
Q

Are the benzos or -zazoles better agents for insomnia?

Why?

A

-zazoles

  • They increase sleep quantity AND normalize sleep architecture (including slow wave and REM sleep)
    • vs. benzos, which suppress slow wave and REM sleep
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5
Q

Which benzos are safest for use by elderyly patients?

A

the LOTs

  • Lorazepam
  • Oxazepam
  • Temazepam

These are pre-lubed and can go directly to glucuronidation; no active metabolites are produced

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6
Q

Which benzodiazepine would you use to treat a patient with alcohol withdrawal and liver disese?

A

One of the LOTs (Lorazepam, Oxazepam)

Metabolites will not accumulate

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7
Q

How does melatonin induce sleep?

A

When there is no light hitting the SCN…

  • Melatonin is synthesized and released from the pineal gland
  • Melatonin acts on the SCN via MT1 receptors to inhibit neurons in the SCN
    • MT1 receptors activation activates K+ channels, resulting in membrane hyperpolarization
    • Also inhibits Ca2+ channels and decreases cAMP, but to a lesser degree
  • ​This induces sleep
    • Melatonin assists darkness in inhibiting the SCN?
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8
Q

What is the action of penicillin on the GABAA receptor?

A

At high doses, penicillin is an uncompetitive inhibitor at the GABAA receptor

  • Blocks the channel after its been opened by GABA
  • Results in seizures
  • Newborns, people with renal impairment are susceptible
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9
Q

What si the difference in structure between the -azepams and
-azolams?

A
  • -azepam: Diazepine ring with 2 benzenes
  • -azolam: has extra 5-membered ring
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10
Q

How do benzodiazepines affect the action of the GABAA receptor?

A

Increase the frequencey of Cl- channel opening

Requires endogenous GABA

(Vs. barbituates, which increase the duration of opening and can activate the receptor without endogenous GABA)

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11
Q

What is the pharmacological target of sedative-hypnotics?

A

GABAA receptors

(The GABAA receptors is a ligand-gated Cl- channel)

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12
Q

Which receptors do the -zazoles act on?

Where do they bind?

A

Benzodiazepine receptor

Bind to omega1 sites on BDZ1 receptors

  • These only exist when gamma subunits are next to alpha1 subunits
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13
Q

How do the -zazoles affect sleep?

A
  • Reduce sleep latency
  • Fewer awakenings
  • Do not suppress slow wave or REM sleep!
    • vs. Benzos that do suppress slow wave and REM

These characteristics make the -zazoles good for treating sleep disorders!

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14
Q

What is the effect of combining ethanol and benzos?

A

Life-threatening synergy ->

Respiratory and cardiac depression

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15
Q

How do scopolamine/other antimuscarinics affect sleep?

A
  • Decrease sleep latency
  • Decrease # of awakening
  • Increase slow wave sleep
  • Decrease REM sleep

Same as diphenhydramine

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16
Q

How does light influence melatonin production?

A

Light inhibits melatonin synthesis by stimulating GABAA receptors in the PVN

  • Light -> Retina -> Suprachiasmatic nucleus (SCN) -> GABAA receptors in the PVN

Darkness removes this inhibition

  • Melatonin is synthesized and released from the pineal gland
  • Acts on the SCN via MT1 receptors to inhibit neurons in the SCN
    • ​This induces sleep
17
Q

Describe the interaction between the SCN and the VLPO

A
  • Light -> Retina -> SCN
  • The SCN feeds the subparaventricular zone (SPZ)
  • The SPZ feeds the dorsomedial hypothalamus (DMH)
  • The DMH inhibits the VLPO and stimulates orexin neurons

Basically, when the SCN is stimulated by light orexin is released (wakefulness!) and the VLPO is inhibited (no sleepiness!)

18
Q

When activated:

[MT1/MT2] receptors induce a phase shift and can re-set the circaidan clock

[MT1/MT2] receptors control sleepiness

A

When activated:

MT2 receptors induce a phase shift and can re-set the circaidan clock

MT1 receptors control sleepiness

Note:

Ramelteon binds the MT1 receptor

Tasimelteon binds the MT2 receptor

Melatonin binds both equally

19
Q

How are the -azepams metabolized?

A
  • Dealkylation by CYP2C19
    • Produces a long acting active metabolite
    • Can cause problems if other drugs are involved bc it hangs out for so long!
  • Hydroxylation by CYP3A4
    • Produces an intermediate-acting metabolite similar to the LOTs
    • Remember, the LOTs are “pre-lubed” - ready for glucuronidation
  • Glucuronidation
20
Q

Where do benzodiazepines bind to the GABAA recpetor?

A

Junction of the alpha and gamma subunits

This is called either BDZ1 or BDZ2, depending on which kind of GABAA receptor it is

  • BDZ1 = alpha1 and gamma1
  • BDZ2 = alpha2 and gamma2
21
Q

What is the difference between a sedativve and a hypnotic?

A
  • Sedative
    • Reduces the excitatory response -> calmness
  • Hypnotic
    • Causes drowsiness and sleep

Sedative-hypnotic produces calmness at low doses, sleep at high doses

(anesthesia, coma, death at even higher doses)

22
Q

How does diphenhydramine/other antihistamines affect sleep?

A
  • Decrease sleep latency
  • Decrease # of awakenings
  • Increase slow wave sleep
  • Decrease REM sleep

Same as scopolamine

23
Q

What are the therapeutic uses of ramelteon?

A

Treat sleep-onset insomnia

Will not reduce number of awakenings

Not good for non-24h sleep/wake disorder (use tasimelteon for this)

24
Q

Describe the melatonin prduction pathway

How is it influenced by light?

A
  • Paraventricular nucleus (PVN) of the hypothalamus sends axons to the spinal cord
  • Preganglionic sympathetics from the spinal cord synapse in the sympathetic cervical ganglion
  • Postganglionic sympathetics go to the pineal gland
  • NE is released onto B1 receptors
  • Increased melatonin synthesis

Light inhibits melatonin synthesis by stimulating GABAA receptors in the PVN

  • Light -> Retina -> SCN -> GABAA receptors in the PVN
25
Q

How does alcohol affect sleep?

A
  • Some normalization of sleep
  • Suppression of REM sleep in the first 1/2 of the sleep period
  • Increases slow wave sleep
  • Effects on sleep latency, awakenings is variable
26
Q

What are the drugs of choice for sleep?

A

-zazoles

zaleplon, zolpidem, eszopiclone

They bind to the benzodiazepine receptor, but are NOT benzos

  • -zazoles normalize both sleep duration AND sleep architecture
    • vs. benzos, which inhibit slow wave and REM sleep
27
Q

Which drug is a benzodiazepine antagonist that can help reverse the effect in case of overdose?

A

Flumazenil

28
Q

How is ramelteon metabolized?

A

CYP1A2

29
Q

What are the indications for tasimelteon?

A

Non 24h sleep-wake disorder

but v expensive :(

30
Q

Ramelteon has affinity for [MT1 receptors/MT2 receptors]

Tasimeltion has affinity for [MT1 receptors/MT2 receptors]

Melatonin has affinity for [MT1 receptors/MT2 receptors]

A

Ramelteon has affinity for MT1 receptors

Tasimeltion has affinity for MT2 receptors

Melatonin has affinity for Both

31
Q

What is the mechanism of action of suvorexant?

What is it used for?

A

Suvorexant is an orexin receptor antagonist

  • Orexins are wakefulness neuropeptides
    • Blocking orexin signaling = inactivation of wakefulness
    • All arousal amine cell bodies have orexin receptors (5HT, NE, ACh, DA)

Used to treat insomnia - improves sleep duration and maintenence

Drawback = long half-life

32
Q

List some of the clinical uses of benzodiazepines

A
  • Anxiety/aggression
  • Severe anxiety w/panic
  • Sedationa and amnesia during medical procedures
  • Anticonvulsants
  • Muscle spasm
  • Alcohol withdrawal

But shoudl not be used long term - tolerance and dependence can build!

Often used as a bridge until SSRIs can kick in

33
Q

Which benzodiazepines do not produce active metabolites when they are metabolized?

A

The LOTs

Lorazepam, oxazepam, temazepam

They are glucuronidated directly = no active metabolites

Feinberg Psych Module 2022 (37 decks)

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