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8. Psychopharmacology > Benzodiazepines > Flashcards

Benzodiazepines Flashcards

1
Q

what receptor do benzodiazepines bind to

A

GABA-A ligand-gated chloride channel complex

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2
Q

what is the mechanism of action of benzodiazepines

A

binds to GABA-A–> enhances the inhibitory effects of GABA-regulated channels

INHIBITS neuronal activity presumably in AMYGDALA-centered fear circuits to provide therapeutic benefits in anxiety disorders

inhibitory actions in CEREBRAL CORTEX may provide therapeutic benefits in seizure disorders

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3
Q

how many GABA receptor subtypes are there

A

3–> A, B, C

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4
Q

what is the function of the GABA-A receptor subtype

A

gatekeeper for the chloride channel–> chloride goes into the cell, polarizing the action potential AWAY from activation

action is inihibitory in the amygdala and frontal cortex

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5
Q

the GABA-A receptor is allosterically modulated by which compounds

A

benzos

alcohol

Z drugs

barbiturates

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6
Q

list the four MAIN indications for benzodiazepines

A

anxiety disorder

anxiety disorder associated with depressive symptoms

initial treatment of status epilepticus (

preanesthetic

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7
Q

list other indications for benzodiazepines

A

insomnia

muscle spasm

alcohol withdrawal psychosis

headache

panic disorder

acute mania (adj)

acute psychosis (adj)

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8
Q

how quickly might someone notice benefit from benzodiazepines

A

some immediate relief with first dosing is common

can take several weeks for maximal therapeutic benefit with daily dosing

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9
Q

what is the usual starting dose and the typical range of the following benzodiazepine:

lorazepam

A

start–> 0.5mg

typical daily dosing–> 1-2mg /day

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10
Q

what is the usual starting dose and the typical range of the following benzodiazepine:

clonazepam

A

start–> 0.5mg

typical daily dosing–> 0.5-2mg /day

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11
Q

what is the usual starting dose and the typical range of the following benzodiazepine:

diazepam

A

start–> 2-10 mg

typical daily dosing –> 4-40mg/day

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12
Q

can you use benzodiazepines if kidney/liver function is present

A

monitor functioning if impairment is present

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13
Q

list common side effects of benzodiazepines

A

sedation

fatigue

depression

decreased cognitive processing

anterograde amnesia

dizziness

ataxia/visuospatial and visuomotor deficits

slurred speech

weakness

tolerance/dependence

rebound anxiety

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14
Q

in which patients should you not prescribe benzodiazepines (non-psychiatric reason)

A

those with occupational risks i.e truck drivers, pilots–> higher likelihood of crashes (OR 1.6 on any benzo)

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15
Q

list rare side effects from benzodiazepines

A

hallucinations

hypotension

paradoxical agitation

respiratory depression (esp. when Rx along with CNS depressants)

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16
Q

what medication can counter benzodiazepine overdose

A

flumazenil

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17
Q

what does benzodiazepine overdose look like

A

hypotension

rare respiratory depression

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18
Q

in which patients is the risk of tolerance/dependence to benzodiazepines higher

A

treatment periods over 12 weeks

those with polysubstance abuse

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19
Q

what CYP interactions does the following medication have:

lorazepam

A

none

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20
Q

what CYP interactions does the following medication have:

clonazepam

A

3A4 (major substrate)

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21
Q

what CYP interactions does the following medication have:

diazepam

A

3A4 (major substrate), 2C19 (major substrate)

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22
Q

is lorazepam safe in end stage kidney disease

A

no–> not recommended

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23
Q

which benzo should be used with caution in liver impairment

A

diazepam

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24
Q

what is the half life of lorazepam

A

10-20 hours

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25
Q

what is the half life of clonazepam

A

30-40 hours

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26
Q

what is the half life of diazepam

A

20-50 hours

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27
Q

what determines duration of action in benzodiazepines

A

distribution (not as much by elimination half life)
–> ie diazepam has long half life but is highly lipid soluble so actually has relatively SHORT duration of action as will distribute fairly quickly

marked inter-individual variation

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28
Q

how are benzos metabolized

A

hepatic oxidation, reduction and conjugation

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29
Q

how long will someone notice benefits for insomnia from benzos

A

about 14 days

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30
Q

what is the risk of rapid withdrawal of benzodiazepines

A

seizure

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31
Q

what is the recommended tapering protocol to get someone off benzos if they have been on them a long time

A

rec. taper length is 6-12 months (10% per month)

first half of taper usually much easier than second half

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32
Q

list 3 of the strongest predictors of benzo withdrawal severity

A
  1. high baseline neuroticism
  2. female sex
  3. mild to mod alcohol use

*these are more predictive than daily dose or half life of the benzo

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33
Q

you should evaluate patient for what medical disorder before prescribign benzos

A

OSA–> benzos can worsen OSA

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34
Q

how might you reconsider benzo use in the pediatric population

A

lower dosing range

higher risk of SEs

(same for geri)

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35
Q

which benzo is NOT recommended for use during pregnancy

A

lorazepam–> especially during first trimester

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36
Q

what are some of the considerations for benzo use during pregnancy

A

possible increased risk of birth defects when benzos taken during pregnancy

infants whose mothers received benzos late in pregnancy may experience withdrawal effects

neonatal FLACCIDITY has been reported in mothers who took benzo during pregnancy

some drug found in mother’s breast milk

effects on infant that have been observed: feeding difficulties, sedation, weight loss

*risk category D–> positive evidence of risk to human fetus/ benefits may still justify use

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37
Q

list indications for clonazepam

A

REM sleep behaviour disorder

akathesia

2nd line panic disorder and GAD

38
Q

how quickly does clonazepam act

A

slow onset

39
Q

list indications for lorazepam

A

EtOH/benzo withdrawal

akathesia

agitation

seizure

catatonia

2nd line panic disorder and GAD

40
Q

which benzos can be given IM

A

lorazepam and midazolam

41
Q

how is lorazepam excreted

A

renally–> so does not accumulate in liver failure

(same as oxazepam and temazepam)

42
Q

how quickly does lorazepam act

A

intermediate onset

43
Q

indications for alprazolam

A

2nd line panic disorder and GAD

44
Q

how quickly does alprazolam act

A

intermediate onset

45
Q

what is the max dose for lorazepam

A

10mg/day

30mg/day in catatonia

46
Q

what is the max dose of alprazolam per day

A

8mg/day

47
Q

what is the max dose of diazepam per day

A

40m /day

48
Q

what is the max dose of clonazepam per day

A

4mg/day

49
Q

indications for diazepam

A

EtOH/benzo withdrawal

2nd line panic disorder

50
Q

how quickly does diazepam work

A

rapid onset

*careful in liver failure (increases half life from 50 hours to 500 hours)

51
Q

what is the starting dose of midazolam

A

0.2mg/kg

52
Q

indications for midazolam

A

anesthesia

palliative sedation

seizure

53
Q

how quickly does midazolam work? what is its half life?

A

very rapid onset

half life 3 hours

54
Q

what is the max daily dose of chlordiazepoxide

A

300mg/day (start at 25mg)

55
Q

indications for chlordiazepoxide

A

mild to mod EtOH benzo withdrawal

56
Q

what receptor does zopiclone/zolpidem act on

A

GABA-A receptor

57
Q

what is the starting dose and max dose of zopiclone

A

start 3.75mg

max 7.5 mg

58
Q

what are the starting and max doses of zolpidem

A

start 5-6.25mg

max 10mg

59
Q

side effects for zolpidem

A

complex sleep behaviours

sedation

nausea

headache

60
Q

side effects for zopiclone

A

sedation

headache

nausea

61
Q

how do the Z drugs affect sleep

A

reduce sleep latency

62
Q

what is sodium oxybate

A

a GHB and GABA-B receptor agonist

63
Q

what are indications for sodium oxybate

A

daytime sleepiness and cataplexy caused by narcolepsy

64
Q

indications for Z drugs

A

insomnia

65
Q

side effects of sodium oxybate

A

confusion

N/V

sedation

edema

respiratory depression

psychosis

suicidality

66
Q

what general effects do benzodiazepines have

A

sedative-hypnotic

anxiolytic

anticonvulsant

muscle relaxant

67
Q

describe benzodiazepine protein binding affinity

A

70-909% protein bound

*but distribute RAPIDLY to CNS

68
Q

how do benzodiazepines cross the blood brain barrier

A

via passive diffusion

therefore, rate of CNS distribution correlates with lipophilicity

69
Q

which are the two most lipophilic benzodiazepines

A

diazepam and midazolam

thus have fastest onset of action

70
Q

list 3 benzodiazepines that do not go through CPY450 metabolism

A

lorazepam

oxazepam

temazepam

“the LOT benzos”

71
Q

which benzos are metabolized through glucoronidation

A

the LOT benzodiazepines (loraz, oxaz, temaz)

we care because glucoronidation is better preserved in liver failure so these benzodiazepines are better for liver failure

72
Q

are benzodiazepines agonists?

A

technically no–> they are positive allosteric modulators (PAMs) which act on GABA-A

73
Q

apart from GABA-A, where else does clonazepam act

A

partial serotonin agonist

74
Q

what are the “ATOM” benzos

A

Alprazolam

Triazolam

Oxazepam

Midazolam

75
Q

what do the ATOM benzos have in common

A

all have rapid onset and are short acting

increases risk of abuse, misuse, addiction

76
Q

how long does it take for tolerance and withdrawal to develop on benzos

A

minimum 4 weeks treatment

*psychological dependence can develop at any point during treatment

77
Q

why should you be careful prescribing benzos to the elderly

A

significantly increases risk for confusion, delirium, cognitive impairment in the elderly

78
Q

how do benzos cause respiratory depression

A

two actions:

  1. depress central respiratory drive and chemoreceptor responsiveness to hypercapnia
  2. midaz has been shown to depress the hypoxic ventilatory response
79
Q

how do benzos affect REM sleep

A

decreases amount of REM sleep

80
Q

what is the typical benzo taper

A

10-20% every 1-2 weeks

81
Q

what common antidepressants affect metabolism of some benzos

A

fluoxetine, fluvoxamine, sertraline

decrease metabolism and increase plasma levels of benzos metabolized by the CYP system (i.e alprazolam… any of them but the LOT benzos)

82
Q

how quickly does benzo withdrawal begin after cessation of the agent

A

depends on the agent

i.e short acting benzos like triazolam may precipitate withdrawal within hours after being stopped

83
Q

how quickly might lorazepam withdrawal develop

A

can develop within 6-8 hours of med cessation

will peak in intensity on second day and improve by day 4-5

84
Q

when might diazepam withdrawal syndrome start

A

has long acting metabolites and thus may not produce withdrawal symptoms for 1-2 days (or up to a week) and sx may not peak until the second week after med discontinuation

85
Q

can benzo withdrawal be life threatening

A

yes–similar to EtOH withdrawal

can progress to a life threatening delirium

86
Q

list risk factors for benzo withdrawal syndrome

A

longer substance use

higher dosages
—–> these factors increase risk for severe withdrawal
i.e doses of diazepam 40mg or more are more likely to produce withdrawal symptoms
doses of diazepam 100mg or above are more likely to be followed by withdrawal seizures or delirium

*note that withdrawal has also been reported with low doses when taken daily for several months

87
Q

list symptoms of benzo withdrawal

A

autonomic hyperactivity (sweating, pulse above 100)

hand tremor

insomnia

N/V

transient visual/tactile/auditory hallucinations or illusions

psychomotor agitation

anxiety

grand mal seizures

88
Q

what % of people undergoing UNtreated benzo withdrawal will have a grand mal seizure

A

20-30%

89
Q

what tools can be used to monitor benzo withdrawal

A

CIWA-Ar or PAWSS (same as alcohol)

90
Q

what is thought to be the pathophysiology behind benzo withdrawal symptoms

A

imbalance between GABA (decreased) and glutamate (increased)

8. Psychopharmacology (21 decks)

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