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Neuro Week 6 > ICL 5.1: Sedatives & Hypnotics > Flashcards

ICL 5.1: Sedatives & Hypnotics Flashcards

1
Q

what is chronic insomnia?

A

the persistence of symptoms at least 3 days a week for more than a month at a time

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2
Q

what conditions can cause secondary insomnia?

A
  1. depression
  2. pain
  3. restless leg syndrome
  4. obstructive sleep apnea
  5. prostate
  6. gastroesophogeal reflux disease
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3
Q

what things can cause sleep disorders?

A
  1. psychological factors
  2. sleep apnea (respiratory impairment)
  3. myoclonus
  4. idiopathic
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4
Q

what things are considered good sleep hygiene habits?

A
  1. minimize use of caffeine, cigarettes, stimulants and other medications
  2. recognize that alcohol may cause fragmentation of sleep – it stimulates GABA(A) and it’s an antagonist for NMDA
  3. maintain regular sleep schedule
  4. exercise regularly, not too close to bedtime
  5. avoid napping (after 2 p.m.)
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5
Q

which 6 neurotransmitters play a role in the neurochemistry of sleep?

A
  1. acetylcholine
  2. histamine
  3. adenosine
  4. norepinephrine
  5. serotonin
  6. melatonin
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6
Q

how does acetylcholine play a role in the neurochemistry of sleep?

A

midbrain nuclei (pedunculopontine and dorsolateral tegmental) release acetylcholine

acetylcholine enhances sleep (parasympathetic tone)

it may also help entrain circadian rhythm**

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7
Q

how does histamine play a role in the neurochemistry of sleep?

A

histamine is important for wakefulness!!

histamine neurons are located in the tuberomammillary nucleus (TMN)

the neuropeptide orexin A induces wakefulness through activation of histamine pathways – so they work together to keep you awake!

so drowsiness is associated with H1 antagonists aka anti-histamines! that’s why sometimes people with allergies taking medications can have a hard time sleeping

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8
Q

how does adenosine play a role in the neurochemistry of sleep?

A

adenosine promotes sleep through regulation of activity in midbrain cholinergic pathways

caffeine inhibits adenosine receptor activity (nonselective antagonist), promoting wakefulness

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9
Q

how does norepinephrine play a role in the neurochemistry of sleep?

A

locus coeruleus activation in the pons is associated with wakefulness

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10
Q

how does serotonin play a role in the neurochemistry of sleep?

A

raphe neurons (source of serotonin) can facilitate sleep

role of serotonin is complicated because of the involvement of multiple receptor subtypes

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11
Q

how does melatonin play a role in the neurochemistry of sleep?

A

melatonin promotes sleep and regulates sleep wake cycle

it’s chemically related to serotonin (5-HT).

melatonin receptors are located in the suprachiasmatic nucleus (SCN) of the hypothalamus.

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12
Q

what parts of the brain are involved in waking up?

A

cells in the locus coeruleus (norepinephrine) and raphe nucleus (serotonin) increase their activity in anticipation of awakening, increasing excitability of cortical neurons and suppressing brain rhythms

that’s why lesions of the brainstem can cause sleep and coma (“ascending reticular activating system”)

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13
Q

what parts of the brain are involved falling asleep/non-REM sleep?

A

decrease in firing of many brainstem neurons, increased firing in some cholinergic neurons

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14
Q

what parts of the brain are involved in REM sleep?

A

locus coeruleus (noradrenergic) and raphe nuclei (serotonergic) are silent, but cholinergic neurons in the pons are highly active

spinal motor neurons are inhibited!!

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15
Q

what are the various categories of sedative drugs that can be used?

A
  1. barbiturates
  2. non-barbiturate sedative-hypnotic: chloral hydrate
  3. benzodiazepines
  4. non-benzodiazepine
  5. other anxiolytics

benzodiazepines are just an anesthetic unless they are mixed with alcohol or other drugs then they can lead to medullary depression and coma

on the otherhand, barbiturates can cause medullary depression and coma all on their own if they are abused

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16
Q

what are the 5 therapeutic uses of benzodiazepines?

A
  1. sedation
  2. anxiolytic
  3. anesthesia
  4. anticonvulsants
  5. muscle relation
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17
Q

what are the anxiolytic effects of benzodiazepines?

A

benzodiazepines are approved to treat anxiety states however some older benzodiazepines may make it worse

anxiety states are generally treated with antidepressants like SSRIs (fluoxetine)

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18
Q

what is the MOA of benzodiazepines?

A

they facilitate GABA action at GABA(A) receptors

GABA(A) receptors are coupled to Cl- channels and there will be hyperpolarization due to Cl- influx

GABA(B) receptors are insensitive to benzodiazepines and barbiturates

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19
Q

what is the relationship between mechanisms of action for benzodiazepines and barbiturates?**

A

benzodiazepines are allosteric activators of GABA binding; they ↑ frequency of Cl- channel opening in response to GABA at GABA(A)

barbiturates are also allosteric activators at GABA(A) but instead they increase the open time of Cl- channels –> this means that barbiturates can stimulate GABA receptors directly in the absence of GABA while benzodiazepines can’t!

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20
Q

how are benzodiazepines metabolized in the body?

A

most long-acting drugs are dealkylated to active metabolites which have long half-lives

oxazepam (Serax®) and Lorazepam (Ativan®) are inactive metabolites because they are metabolized directly to glucuronides

dealkylation and hydroxylation is decreased in elderly, people with cirrhosis, and acute hepatitis; glucuronidation is unaffected –> so you shouldn’t prescribe drugs that get metabolized via dealkylation or hydroxylation in those patients

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21
Q

what are the adverse effects of benzodiazepines?

A
  1. extension of CNS depressant effects = drowsiness, dizziness, ataxia, paradoxical excitement in elderly
  2. CNS effects enhanced when taken with other drugs like ethanol, barbiturates, or antihistamines!!!
  3. can produce anterograde amnesia**
  4. rebound insomnia/anxiety
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22
Q

what are the withdrawal signs seen with benzodiazepines?

A
  1. rebound anxiety
  2. insomnia
  1. dizziness, headache, confusion, altered taste
  2. tinitus
  3. palpitations
  4. poor concentration, seizures, irritability

symptoms are more intense for benzodiazepines with short duration of action

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23
Q

what medications are used as benzodiazepine substitutions or during benzodiazepine detox?

A
  1. B-blockers
  2. antidepressants
  3. enhancing GABA activity with partial agonists or anticonvulsants
  4. flumazenil is a GABA(A) antagonist –> it reverses the effect of BDZ**

for detox, do the loading dose at 40% of the daily dose then decrease by 10% each day

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24
Q

what are benzodiazepine ligands?

A

agonists at the benzodiazepine binding site of GABA(A) receptors that display sedative/hypnotic and anxiolytic activity

ex. diazepam
ex. flurazepam

25
Q

what is the MOA of flumazenil?**

A

it’s an antagonist at benzodiazepine binding sites

so it inhibits binding of benzodiazepine agonists like diazepam and flurazepam which have sedative activity

so this is what is used when people are overdosing on benzodiazepines!

however, it has NO direct effect on Cl- influx!

26
Q

what is the MOA of a benzodiazepine inverse agonist?

A

it decreases chloride influx and blocks the effects of ethanol

it provides support for the effects of alcohol being mediated by enhancing GABAA receptor activity

ex. Ro-15-4513

27
Q

what is the chemical effect of benzodiazepine agonists, antagonists, and inverse agonists?

A

agonists = increased Cl- influx

antagonists = no effect on Cl- influx, they just inhibit binding of benzodiazepine agonists

inverse agonists = decreased Cl- influx

28
Q

what is the toxicity of benzodiazepines?

A

low toxicity

but in combination with other things, especially alcohol, they can be fatal

29
Q

what drug can be used to block adverse effects of benzodiazepines?

A

flumazenil

flumazenil is a benzodiazepine antagonist that can be used to block adverse effects of benzodiazepines

like if someone goes in with a BDZ overdose, you can use flumazenil to treat since it’s an antagonist

30
Q

what are the non-benzodiazepine sedatives?

A
  1. zolpidem (ambien)
  2. zaleplon (sonata)
  3. eszopiclone (lunesta)

these are all non-BDZ that bind to BDZ site on GABA receptors that are used to treat insomnia

31
Q

what is zolpidem? what is the MOA of zolpidem?

A

aka Ambien!!

it’s a non-benzodiazepine that binds to the BDZ site on GABA receptors

it’s used for insomnia, anti-convulsive, muscle relaxing

no withdrawal effects; minimal rebound insomnia

adverse effects = morning sedation

32
Q

what is zaleplon? what is the MOA of zaleplon?

A

aka Sonata

it’s a non-benzodiazepine that binds to the BDZ site on GABA receptors

fast onset, short duration when compared with zolpidem

it decreases the latency of sleep onset with little effect on total sleep time

33
Q

what are the adverse effects of zaleplon?

A
  1. anterograde amesia**
  2. morning sedation
  3. transient visual illusions with higher dose
34
Q

what is eszopiclone? what is the MOA of eszopiclone?

A

it’s a non-benzodiazepine that binds to the BDZ site on GABA receptors

rapid onset action and it increases the total sleep time!

adverse effects = morning sedation

35
Q

what is the MOA of ramelteon?

A

aka Rozerem

it’s a melatonin receptor agonists that binds and has action in the suprachiasmatic nucleus

36
Q

what are the adverse effects of ramelteon?

A
  1. morning sedation
  2. elevates prolactin levels and should be avoided in patients with depression*

must use SSRIs instead

37
Q

what is the MOA of barbiturates?

A

they facilitate GABA action on the GABA(A) receptors by increasing GABA affinity and prolonging duration of chloride (Cl-) channel opening

they have a DIRECT effect on GABA(A) receptors to open Cl- channels

barbiturates block glutamate receptor-mediated excitation at low doses and block K+ and Na+ channels at higher doses

38
Q

what is the MOA of thiopental?

A

a barbiturate that also inhibits GABA transaminase which is the enzyme responsible for inactivation of GABA

since it’s a barbiturate it also
facilitates GABA action on the GABA(A) receptors by increasing GABA affinity and prolonging duration of chloride (Cl-) channel opening

39
Q

what are the 3 therapeutic uses of barbiturates?

A
  1. anxiolytic
  2. hypnotic
  3. neurology
40
Q

what are the anxiolytic uses of barbiturates?

A

used as a pre-anesthetic to reduce anxiety

usefulness is limited by low selectivity

there’s substantial drowsiness and ataxia

41
Q

what are the neurological uses of barbiturates?

A
  1. useful in acute seizures arising from disease or poisoning

drowsiness, ataxia and respiratory depression still problematic

  1. decrease cerebral edema associated with surgery or head injury
42
Q

what happens when there’s a barbiturate overdose?

A

the lethal dose of a barbiturate depends on the specific barbiturate pharmacokinetics but usually you will see:

  1. pupillary constriction or hypoxic paralytic dilatation
  2. coma, profound depression of respiration due to the effect of the drug and hypoxia on medullary centers
  3. pulmonary edema
  4. renal failure
43
Q

how do you treat a barbiturate overdose?

A
  1. remove the drug from the stomach via lavage or apomorphine to induce vomiting
  2. artificial ventilation
  3. hemodialysis
44
Q

do barbiturates cause dependence?

A

barbiturates produce both psychological and physiological dependence

chronic use induces GABAA receptor down-regulation

45
Q

what are the effects of chloral hydrate on the body?

A

it’s a sedative that’s neither a benzodiazepine nor barbiturate

but it has general pharmacological features similar to barbiturates:

  1. produce CNS depression
  2. produce psychological and physical dependency
  3. effective as hypnotics for short periods of time
46
Q

how is chloral hydrate metabolized in the body?

A

alcohol dehydrogenase

47
Q

what is the toxicity of chloral hydrate?

A

low toxicity – relatively wide safety margin

irritating to the GI tract though

48
Q

are barbiturates or chloral hydrate better at improving sleep?

A

chloral hydrate is superior to barbiturates with respect to modifying sleep patterns, REM rebound

when combined with ethanol, chloral hydrate rapidly and effectively promotes sleep

it slows ethanol metabolism thereby enhancing effects of ethanol

49
Q

what are orexin-A and orexin-B?

A

they are neuropeptides produced in the lateral hypothalamus that:

1 stimulate tuberomammilary neurons

  1. elevate histamine levels
  2. promote wakefulness, regulate arousal
  3. play a role in regulating food intake
50
Q

which neurotransmitters are related to narcolepsy?

A

orexin-A and orexin-B

hypocretin-1 and hypocretin-2 are critical in narcolepsy

narcolepsy patients have fewer orexin neurons and decreased levels of orexin-A

51
Q

what is narcolepsy?

A

sleep/waking disturbance, often characterized by collapse into sleep state (REM-like) triggered by strong emotional expression

52
Q

what is canine narcolepsy?

A

canine narcolepsy is caused by a genetic mutation in the hypocretin receptors

research shows that there’s few hypocretin-positive neurons in the hypothalamus or narcoleptic animals

53
Q

what happens in mice when there’s no OX1 vs. OX2 receptors?

A

orexin peptide knockout mice have severe sleepiness

lack of OX1 receptor → normal

lack of OX2 receptor → sleepiness, no cataplexy (paralysis)

disruption of both receptors → marked sleepiness and cataplexy

54
Q

what are OX1 and OX2 antagonists used to treat?

A

data suggest OX1 and OX2 antagonists might be useful in treating sleep disorders

orexin antagonists increase sleep in rodents

55
Q

what is propranolol?

A

β1-adrenergic receptor antagonist

useful in the treatment of stage fright because it decreases symptoms like sweating, elevated heart rate and bP

56
Q

what is hydroxyzine?

A

it’s an antihistamine used to help with insomnia

limited cognitive impairment but potentially adverse effects on fetus

57
Q

what is the MOA of buspirone?

A

it’s a partial serotonin 5-HT1A agonist and a weak dopaminergic D2 mixed agonist/antagonist

it inhibits serotonin release via stimulation of serotonin autoreceptors

used for insomnia and also has anxiolytic activity

58
Q

what are the side effects of buspirone?

A

CNS = dizziness, insomnia, headache

peripheral = nausea, tachycardia, myalgia, paresthesia, skin rash

59
Q

Which of the following is most likely to result from treatment with moderate-high doses of diazepam?

A. alleviation of the symptoms of major depression

B. agitation and possible hyperreflexia with abrupt discontinuance after chronic use

C. improved performance on tests of psychomotor function

D. retrograde amnesia

A

A. alleviation of the symptoms of major depression

Neuro Week 6 (8 decks)

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