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L a u r a S i m -S e l l e y
8 2 7 -0 4 6 4
ljsimsel@hsc.vcu.edu
Highest dose
hypnosis
anesthesia
coma
death
Mechanism of Action
III. Classes
A. Benzodiazepines
Receptor
Ionotropic receptor composed of 5 subunits (pentamer) that assemble to
form a Cl- channel
Subunit diversity (8 classes with multiple isoforms = at least 18 subunits)
Benzodiazepine drugs
3. Mechanism:
a. Benzodiazepine (BZ) site: potentiates GABA
actions
Anxiety:
Alprazolam (Xanax )
Chlordiazepoxide (Librium )
Chlorazepate (Tranxene )
Midazolam (Versed )
oral
intermediate
short-acting
short-acting
Anxiety, sedation:
Diazepam (Valium )
Lorazepam (Ativan )
Insomnia:
Estazolam (Prosom )
Flurazepam (Dalmane )
Quazepam (Doral )
Temazepam (Restoril )
Triazolam (Halcion)
oral, i.v.
oral, i.v.
long-acting
intermediate
oral
oral
intermediate
long-acting
long-acting
intermediate
short-acting
concentrations of GABA
Safety probably results from binding properties:
benzodiazepines do not have an effect on their
own, but require GABA
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b. Drug Classification
Agonist: positive allosteric modulator that facilitates GABA actions by increasing Clconductance, shifts GABA concentration-response curve to left
Includes clinically useful benzodiazepines and endogenous agonist (endozepines)
Full agonist: produces maximal effect (i.e. diazepam)
Partial agonist: less than maximal effect (i.e. alpidem)
produce anti-anxiety effects with less sedation
e. Muscle relaxation
f. Alcohol Withdrawal Syndrome
g. Conscious sedation: i.v. diazepam, lorazepam, midazolam, produce muscle
relaxation and anterograde amnesia
Antagonist: flumazenil (Romazicon): has no effect on its own but blocks effects of
agonist/inverse agonist
Blocks benzodiazepines and zolpidem, but does not affect barbitu rates or
ethanol
Also endogenous compound (diazepam binding inhibitor (DBI))
Therapeutic uses: management of BZ overdose and reversal of sedative
effects produced by BZ during diagnostic/therapeutic procedures
Side Effects: agitation, confusion, dizziness, may precipitate withdrawal
Parenteral use associated with increased respiratory depression when used for
conscious sedation: monitor respiration and cardiovascular function
Parenteral diazepam can produce thrombophlebitis (due to vehicle for infusion:
polypropylene glycol); midazolam is water soluble therefore doesnt have this
effect
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Categories:
1. transient insomnia: <3 days, usually emotional or situational stressor
treatment: sleep hygiene, low dose hypnotics for 2-3 nights
note: use prior to event (i.e. exam) may impair performance
long half life: patients with significant daytime anxiety who can tolerant
some sedation
To discontinue use after >2 weeks taper rather than withdraw
if using short half life BZ, switch to long half life BZ, then taper
may not have difficulty with zopiclone
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angle glaucoma (may be used with wide -angle glaucoma: more common type)
E. GI: cramps, pain
F. Reproduction: Sedative-hypnotics cross the placental barrier and are detectable
in breast milk
1st trimester: congenital malformations
Pre-delivery: large doses may produce hypothermia, hypotonia and mild
respiratory depression in neonate
6. Chronic Administration
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c. Overdose: rare
Treatment:
Emesis
Flumazenil (Romazicon): antagonist
i.v. administration (extensive 1st pass metabolism means that
effective oral dose can produce headache and dizziness)
may be incomplete reversal of respiratory depression; *note this
b. Dependence
Psychological dependence: most sedative-hypnotics are schedule III or IV
because of abuse liability due to anxiolysis, euphoria and disinhibition
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C. Barbiturates
*Due to their relative safety, benzodiazepines have largely replaced older
sedative-hypnotics (i.e. barbiturates)
Barbiturates: lack specificity in CNS, lower therapeutic index, frequent
tolerance, greater abuse liability, more drug interactions, no antagonist
1. Classes
a. ultrashort: <60 min
thiopental (Pentothal), methohexital (Brevital)
used as i.v. anesthetics
lipophilic = rapid onset of CNS effects, short duration of actions
b. short to intermediate
secobarbital (Seconal), pentobarbital (Nembutal)
oral or i.v. sedative hypnotic
c. long-acting
phenobarbital, mephobarbital (Mebaral), barbital
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6. Tolerance
3-4 fold for hypnosis, less for lethality
cross dependence with other sedative hypnotics
pharmacodynamic (major) and pharmacokinetic (minor)
more tolerance two sedative and hypnotic effects than anticonvulsant and lethal
effects (i.e. therapeutic index decreases with tolerance)
7. Dependence and withdrawal
withdrawal: excitability, convulsions, delirium
also abuse potential
8. Contraindications
hepatic porphyria (defect in hemoglobin breakdown)
pulmonary disease
sensitivity
9. Drug interactions
CNS depression
additive CNS depression: most commonly ethanol
enzyme induction
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