Pharm Lecture 4 Benzo

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Benzodiazepines Overall enhance the

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inhibitory tone of the
central nervous system

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Benzodiazepines Need to exert (in varying degrees) 5
pharmacologicic effects

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– Anxiolysis
– Seda2on
– Anticonvulsant actions
– Spinal cord‐mediated skeletal muscle relaxation
– Anterograde amnesia

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Alcohol
– Probably goes back

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to Neolithic period

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Genesis 9:20‐ bible

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stated ‘Noah began farming and
planted a vineyard. He drank of the wine and became
drunk’

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Bromides
2 types
cause that results in

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Sodium Bromide or Potassium Bromide
– Organic substances that have sedative actions,
hypnotic actions and antiepileptic actions
– Causes dependency and accumulation results in
Bromism

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Barbiturates -
Barbituric acid synthesized by

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Bayer in 1864. Not
pharmacologically active

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1903 Fischer and Von Mehring synthesized

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diethyl
barbuturic acid: or Veronal

barbuturic acid: or Veronal
• Called hypnotics: caused sleep at night and drowsiness and
relaxation when taken in the day
• Very slow onset and slow metabolism
• The search began for a faster onset and metabolism with same
hypnotic properties

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release of Quaalude

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1959 the release of Quaalude
• Searching for an antimalarial drug
• Combined with benadryl and released as a the first nonbarbiturate
sedative and “non‐addictive”
– Substitute for thalidamide in Great Britain
– Removed from market in late 1970

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Miltown‐meprobamate
– Safer than

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barbiturates but still many problems
with over‐intoxication and sedation
• Later found to be physically and psychologically
addictive
• All but off the market by early 1970s.
• Was the forerunner of benzodiazepines

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1st benzo released in

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1954

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benzo fyi

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• Released in 1960 as Librium
– Valium 1963
– Mogodon 1965
– Dalmane 1973
– Xanax 1980
– By mid 1970s 8000 tons sold yearly
– By the end of the 1970s the most widely
prescribed medications in the world
• Today about 3 dozen benzos available over
2000 have been synthesized

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5 farm effects of benzo

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• Seda2on
• Anxiolysis
• An2convulsant ac2ons
• Spinal cord mediated skeletal muscle
relaxation
– Not adequate for surgical conditions
• Anterograde amnesia
– Greater than sedative effects

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Site of Action

GABA Composed of

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– Composed of multivariant combinations of 5
subunits
• 2 alpha subunits
• 2 Beta subunits
• 1 gamma subunit

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Main inhibitory neurotransmiaer in the SNS

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GABA

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GABA Found

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Found throughout the brain stem, thalamus,
hypothalamus, basal forebrain, cortex and spinal
column

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Neuron at rest
Res2ng Membrane Poten2al

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‐65mV

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Excited Neuron

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– RMP = ‐45 mV
– Cell depolarizes

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Inhibited neuron

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– RMP: ‐70 mV
– The RMP is more negative
than normal which makes it
harder to reach threshold and
depolarize

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Benzodiazepines interact with

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the alpha subunits
on the GABA receptor

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GABA the differences in effects comes from

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GABA
– Benzodiazepines interact with the alpha subunits
on the GABA receptor
– Because there are different types of alpha
subunits (alpha1 and alpha2), it is thought that
the differences in effects comes from differences
in interactions with the different subunits
• Alpha 1: sedative effects
• Alpha 2: anxiolytic effects

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GABA
Alpha 1: produces

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sedative effects

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GABA
Alpha 2: produces

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anxiolytic effects

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gaba
Act on receptors in

how

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the CNS

Does not activate the receptor
– Facilitates the actions of GABA
• Gamma‐aminobutyric acid
– Causes a drug induced increased affinity of the GABA receptor for GABA
• Opens chloride channel
• Producing hyperpolarization of the postsynaptic cell membrane
• Rendering postsynaptic neurons more resistant to excitation

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Sedative effects of benzos r/t binding of the

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alpha1 subunit at receptors sites.

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alpha1 subunit at receptors sites Present in 3 areas

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cerebral cortex, cerebellar cortex,
and thalamus

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Anxiolytic effects of benzos r/t binding of the

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alpha2 subunit at receptor sites.

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Anxiolytic effects of benzos r/t binding of the alpha2 subunit at receptor sites.
found in

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hippocampus and amygdala

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Responsible for the anticonvulsant effects

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Anxiolytic effects of benzos r/t binding of the
alpha2 subunit

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Responsible for drowsiness d/t effects on the Reticular Activating System

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Anxiolytic effects of benzos r/t binding of the
alpha2 subunit at receptor sites

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Receptor affinity determines potency
– With respect to sedative effects only
3 greatest to least

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Lorazapam > Midazolam > Diazepam

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The % of receptor occupancy determines effect

• _______ receptor occupancy for anxioly2c effect
• ______ receptor occupancy seda2on
• _____ receptor occupancy unconsciousness

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20%

30‐50%

60%

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Lorzepam, Midazolam,
Diazepam
– Chemical structure
• Contain

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benzene ring fused to a
seven‐member diazepine ring

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benzo soluability

bound to

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– All are lipid soluble
– Highly pound to plasma proteins
especially albumin

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May lead to increased
sensitivity and increased side
effects (3 disease processes)

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Hypoalbuminemia, CRF or
cirrhosis

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– Water soluble preparation
– Lipid soluble at physiologic pH
– 2‐3 times as potent as diazepam
• Related to receptor affinity

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Midazolam

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2‐3 times as potent as diazepam

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Midazolam

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Midazolam
– Pharmacokinetics
• Absorption:

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Rapid from GI tract
» Substantial first pass effect

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Midazolam
Distribution

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– Prompt passage across the blood‐brain barrier
– Slow effect‐site equilibration time
– High protein binding (96‐98%)
– Short durattion of action – lipid solubility and redistribution to
inactive sites

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Midazolam
– Pharmacokinetics
• Metabolism

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Metabolized by hepatic and small intestine oxidative
hydroxylation (CY P450

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Midazolam Active metabolite :

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1‐hydroxymidazolam

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1‐hydroxymidazolam

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» Half the activity of midazolam
» Rapidly conjugated to 1‐hydroxymidazolam glucoronide
» Cleared by the kidneys

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Midazolam Slowed in the presence of other drugs 5

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» Cimetidine, erythromycin, CCB, antifungal drugs
» Fentanyl

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Midazolam Elimination
– Half life

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1‐4 hours

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Midazolam elderly

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May be doubled in elderly
» Decrease hepatic blood flow
» Decreased enzyme activity
» Increased volume of distribution

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Midazolam
– Pharmacodynamics
• CNS effects 5

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– Decreases CMRO2 and cerebral blood flow
– Cerebral vasomotor responsiveness is preserved
– Does not protect against increased ICP with laryngoscopy
– Unable to produce isoelectric line (ceiling effect)

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Midazolam
– Pharmacodynamics
As a sedative
– Two times as potent as

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diazepam

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Midazolam Amnestic effects

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Amnestic effects more potent than sedative effects

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Midazolam Potency increased in the

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elderly and those with CNS depression

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Midazolam Onset

Duration of sedation

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30‐sec to 1 min

15‐ 80 minutes

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Midazolam
Effects are greater when ____________ are administered with midazolam

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narcotics

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Midazolam Induction dose

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.2‐.35 mg/kg

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Midazolam
– Pharmacodynamics
• Respiratory effects

Greater in patients with

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Dose dependent decreases in ventilation
» Similar to Diazepam
» Greater in patients with COPD

COPD

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Studies on healthy patients show effects from small amount of
ventilatory depression to no ventilatory depression unless combined
with

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opioids

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Midazolam
Cardiovascular

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– Minimal CV effects in sedative dose
– May decrease BP in hypovolemic patients
– May cause respiratory depression d/t decreased hypoxic drive: more pronounced in those with lung disease.

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Lorazepam soluability

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White powder insoluble in water

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Lorazepam Absorp2on

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Slower onset of action because it is less lipid soluble and
therefore has a slower entrance into the CNS

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Metabolism Lorazepam
Elimination half time

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is 10 to 20 hours

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Lorazepam Metabolized by

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hepatic glucoronidation (slower than
oxidation)

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Lorazepam Metabolites

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are inactive
Not entirely dependent on hepatic enzymes

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Lorazepam Excretion

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Bythe kidneys
– Vd and elimination half time increased in obese patients
– Elimination half life twice that of midazolam

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Lorazepam As a sedative

comparative

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As a sedative 2‐3 times more potent than midazolam,
5‐6 times more potent than diazepam.

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Lorazepam
Amnestic potency ______ times that of midazolam

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4

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Lorazepam Slower onset d/t

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d/t lower lipid solubility

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Lorazepam
Onset, peak, duration

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Onset in 1‐2 minutes, peak 20‐30 minutes, sedation
duration 6‐10 hours

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Diazepam
– Dissolved in

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propylene glycol

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Diazepam
soluble

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Insoluble in water

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Diazepam

If diluted with water, may become

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cloudy, but
potency unaltered.

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Diazepam
– Pharmacokinetics
• Absorption

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Rapid from GI aser oral administration

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Diazepam
Distribution

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– Peak after 1 hour
– Redistribution to inactive tissue
– Large VD
– Protein binding

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Diazepam
– Pharmacokinetics
• Metabolism

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– In the liver
– By oxidative pathway (N‐demethyla2on)

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Diazepam Metabolites

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» Desmethyldiazepam‐ slightly less potent than Diazepam.
Accounts for return of drowsiness that manifests 6‐8
hours later
» Oxazepam
» Temazepam

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Diazepam Elimiation half time

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21‐37 hours

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Diazepam Increased up ____________ in people who have liver failure

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5 times

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Diazepam
– Pharmacodynamics
• CNS

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– Half the potency of midazolam
– One sixth the potency of lorazepam
– Amnestic potency is greater than sedation

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Diazepam Respiratory

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– Miniman depressant effects on ventilation (dose dependent)
– Less respiratory depression than with midazolam

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Diazepam CV

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– Minimal decreases in BP, CO, SVR
– Myocardial depression
» May lead to hypotension in patients who are
hemodynamically unstable

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Oxazepam

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– DOA shorter than diazepam
– Useful in treatment of insomnia

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Alprazolam

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Significant anxiety reducing effects

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Clonazepam

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Effective in the control and prevention of seizures

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Temazepam
Triazolam

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Treatment of insomnia

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Benzodiazepine Antagonist

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Flumazenil

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Flumazenil class

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Competative antagonist

Reverses the effects of benzodiazepines
• Cardiopulmonary depressant effects
• Excessive sedation

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Flumazenil Dose:

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• 0.2 mg (8‐15 mcg/kg)

– Reverses effects within 2 minutes
– Failure to respond to IV doses of more than 5 mg
means excessive sedation/CP depression is from
other cause