Transcript Benzodiazepines

Benzodiazepines
David Preston
Alexa Sardina
Brett Feig
Ryan Holevinski
Site and Structure of Action
• Site of action is the GABAA receptor
• Structure of GABAA receptor
• Comprised of 5 subunits
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2 α subunits (to which GABA binds)
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2 β subunits (to which barbiturates
bind)
• 1 γ subunit (to which benzodiazepines bind)
Benzodiazepine receptor of
GABAA is heterogeneous
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13 known subunits of the GABAAγ
receptor
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Benzodiazepine-sensitive
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α1, α2, α3, α5
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Benzodiazepine-insensitive
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α4 and α6
Properties of GABAA receptor
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• Myorelaxant, motor-impairing, and
anxiolytic-like properties thought to be
mediated by α2, α3, and/or α5 subunits2
• Benzodiazepines acting on α2, α3, and/or α5
subunits (but NOT α1) have demonstrated
nonsedative, nonamnesic anxiolytic properties2
Properties continued
Anticonvulsant
activity and amnesic
properties are thought
to be mediated by α1
receptors2
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Benzodiazepines and
barbiturates bind more
strongly when GABA is also
bound to the receptor
Properties Continued
• Benzodiazepines increase the affinity
of the receptor for GABA, and thus increase
Cl- conductance and hyperpolarizing current
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Therefore, benzodiazepines are
indirect agonists of the GABA receptor
Location(s) and mechanism of
action on GABAA receptor:
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Appear to act at the limbic, thalamic, and
hypothalamic levels of the CNS
• Neuroanatomically, the amygdala, orbitofrontal
cortex, and insula are associated with the production of
behavioral responses to fearful stimuli and the central
mediation of anxiety and panic
• PET scans demonstrate increased blood flow to the
amygdala concomitant with anxiety responses
• Patients with panic disorders have shown a global
decrease in benzodiazepine binding, largely in the
orbitofrontal cortex and insula
Location and mechanism
Continued
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Increased activity of amygdala function along
with concurrent lowered GABAergic inhibition of
function produces anxiogenic responses
The conclusion is that hypofunctional
GABAA- receptor activity may sensitize the
amygdala to anxiogenic responses
It is thought that the benzodiazepines may
reset the threshold of the amygdala to a more
normal level of responsiveness
Local and Mechanism Cont.
• VTA has been shown as a possible sit
for anxiolytic actions of benzodiazepines
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We know that dopamine neurons
synapse with and are regulated by GABAA
Cl- channels in the VTA
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Flurazepam injections into the VTA
have been shown to block anxious
responses
Location and Therapeutic Index
Location of Action
Therapeutic Effect
Amygdala
Orbitofrontal Cortex
Insula
Alleviate anxiety, agitation, and fear
Cerebral Cortex
Hippocampus
Mental confusion, amnesia, antiepileptic actions
Spinal Cord
Cerebellum
Brain Stem
Mild muscle-relaxing effects
Ventral Tegmental Area
Nucleus Accumbens
Abuse potential, and psychological dependence
Absorbtion distribution,
Metabolism and Excretion
• Well absorbed when taken orally, with peak
plasma concentrations achieved in approx. 1 hour
• Several benzo’s (diazepam, chlordiazepoxide,
chlorazepate, halazepam, prazepam, chlorazepate)
are first biotransformed to pharmacologically
active intermediates
• These intermediates are then degraded and
excreted
• Thus, long-lasting benzo’s are so b/c they
are first degraded to active intermediates, and both
the parent drug and the intermediate are longlasting/acting
Short Acting and the Elderly
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Short-lasting benzo’s are not
converted to active intermediates; they are
metabolized directly into inactive products
• The elderly have a reduced ability to
metabolize long-acting benzo’s (and their
active metabolites)
• Pharmacokinetics are not drastically altered
with the short-acting benzo’s
Pharmacological effects
• Those compounds that bind and enhance the
inhibitory actions of GABA are complete agonists
(Ex) Lorazepam, midazolam, etc.
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• Those compounds that bind with “less than
complete agonist action” are termed partial
agonists
(Ex) Ambien (zolpidem)
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• Those compounds that bind and decrease
the inhibitory actions of GABA are inverse
agonists
Pharmacological effects cont.
• Those compounds that bind and have no
effect on GABA inhibition are antagonists
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Prevent enhancement of GABA effects, but
do NOT reduce the basal conductance of Cl•o
Prevent gating of Cl- channels in spite of the
presence of benzodiazepines
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Flumazenil (a benzodiazepine) binds with
high affinity to the GABAA complex, but illicits
no response
• Rapidly metabolized in the liver, and therefore has
a very short half-life
Receptor Ligands
Uses
• Major indication is for use in treatment of
severely debilitating anxiety (because of their
anxiolytic properties)
• Effective as hypnotics, as they possess
many of the same sedative qualities as barbiturates
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Therefore useful in treatment of insomnia
• Effective muscle relaxants
• Generate anterograde amnesia
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Lorazepam → long-lasting amnesia
• Midazolam → short-lasting amnesia
Uses Cont.
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Useful for panic attacks and phobias
Efficacy may be less than that achieved with SSRI’s
Treatment of alcohol withdrawal
Effective anticonvulsant → useful in treatment of
epilepsy
Advantages:
Rapid onset
Anxiolysis
Low-level side effects
Disadvantages:
Impaired psychomotor performance and alertness
Potential for dependence and abuse
Benzodiazepine Therapy
Side Effects and Toxicity
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At low doses symptoms can include sedation, drowsiness, ataxia,
lethargy, mental confusion, motor and cognitive impairments,
disorientation, slurred speech, amnesia, dementia, etc.
At high doses mental and psychomotor dysfunction can progress
to hypnosis (i.e., pass out)
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Respiration is not seriously depressed, unless benzo is taken
concurrently with another CNS depressant (i.e., alcohol)
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Short-acting agents taken at bedtime can result in both earlymorning wakening and rebound insomnia the following night
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Long-acting agents taken at bedtime can result in daytime
sedation the following day
Cognitive impacts are considerable:
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Inhibition of learning behaviors, academic performance, and
psychomotor functioning common
These symptoms can persist long after treatment is discontinued
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Tolerance and Dependence
• Reputation for causing only a low incidence
of abuse and dependence, however, when taken
for prolonged periods of time, dependence can
develop and result in withdrawal
• Withdrawal symptoms include:
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Return (and possible intensification) of anxiety
state, increases in rebound insomnia, restlessness,
agitation, irritability, etc.
Effects on Pregnancy
• Benzodiazepines (and their metabolites) can
freely cross the placental barrier and accumulate in
fetal circulation
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Administration during the first trimester can
result in fetal abnormalities
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Administration in third trimester (close to
the time of birth) can result in fetal dependence, or
“floppy-infant syndrome”
• Benzodiazepines are also excreted in the
breast milk
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Second-Generation Anxiolytics
• Zolpidem (Ambien)
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General:
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Nonbenzodiazepine
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Structurally unrelated to benzo’s, but acts in
much the same manner
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Binds to (subtype 1) GABAA1 receptors
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Useful for the short-term treatment of
insomnia
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Primarily a sedative (rather than an
anxiolytic)
Pharmacokinetics and Dynamics
and Adverse Effects
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Pharmacokinetics
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Rapidly absorbed in the GI tract following oral administration (75%
reaches plasma)
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Only approx. 20% is metabolized in first-pass metabolism
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Metabolized in the liver and excreted by the kidney’s
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Peak plasma levels reached in approx. 1 hour
Pharmacodynamics
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Produces sedation and promotes good sleep (w/o anxiolytic,
anticonvulsant, or muscle-relaxant effects)
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Memory is affected
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Flumazenil reported to reverse memory impairments and overdoses
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Flumazenil also reported to improve memory and learning, thus
suggesting a possible role of endogenous benzo’s in memory function
Adverse Effects
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Drowsiness, dizziness, and nausea at therapeutic doses
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Severe nausea and vomiting greatly limit overdoses
Agonists of Benzo Receptors
• Zaleplon & Zopiclone
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Nonbenzodiazepine agonist that acts at the
GABAA1 receptors to exert actions similar to benzo’s
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Short half-life
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Only approx. 30% of an orally administered dose
reaches the plasma, and most of that undergoes first-pass
elimination
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Half as potent as zolpidem
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Improves sleep quality w/o rebound insomnia, and
little chance of developing dependency
Partial Agonists
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Full GABA agonists (i.e., benzodiazepines) are effective anxiolytics
use is limited though by their potential for rebound anxiety, physical
dependence, abuse potential, and side effects (i.e., ataxia, sedation, memory
impairment, etc.)
• Partial agonists provide effective anxiolytics without the limiting side effects
o Alpidem
o Partial agonist of GABA1 and GABA3 receptors
o More anxiolytic than full agonists, with less sedation and no interaction with
EtOH
o May induce hepatitis though
o Etizolam
o Potent anxiolytic
• “lower incidence of side effects at comparable efficacy”