Benzodiazepines

1
Benzodiazepines

• David Preston
• Alexa Sardina
• Brett Feig
• Ryan Holevinski

2
Site and Structure of Action

• Site of action is the GABAA receptor
• Structure of GABAA receptor
• -         Comprised of 5 subunits
• o       2 a subunits (to which GABA binds)
• o       2 ß subunits (to which barbiturates bind)
• 1 ? subunit (to which benzodiazepines bind)

3
 Benzodiazepine receptor of GABAA is
heterogeneous

• o       13 known subunits of the GABAA? receptor
•       Benzodiazepine-sensitive
•         a1, a2, a3, a5
•       Benzodiazepine-insensitive
•         a4 and a6

4
Properties of GABAA receptor

• Myorelaxant, motor-impairing, and anxiolytic-like
  properties thought to be mediated by a2, a3,
  and/or a5 subunits2

-        

• Benzodiazepines acting on a2, a3, and/or a5
  subunits (but NOT a1) have demonstrated
• nonsedative, nonamnesic anxiolytic properties2

5
Properties continued

•      Anticonvulsant activity and amnesic
  properties are thought to be mediated by a1
  receptors2
• Benzodiazepines and barbiturates bind more
  strongly when GABA is also bound to the receptor

6
Properties Continued

• -         Benzodiazepines increase the affinity
  of the receptor for GABA, and thus increase Cl-
  conductance and hyperpolarizing current
• o       Therefore, benzodiazepines are indirect
  agonists of the GABA receptor

7
Location(s) and mechanism of action on GABAA
receptor

• -         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

8
Location and mechanism Continued

• 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

9
Local and Mechanism Cont.

• -         VTA has been shown as a possible sit
  for anxiolytic actions of benzodiazepines
• o       We know that dopamine neurons synapse
  with and are regulated by GABAA Cl- channels in
  the VTA
• o       Flurazepam injections into the VTA have
  been shown to block anxious responses

10
Location and Therapeutic Index
11
Absorbtion distribution, Metabolism and Excretion

• Well absorbed when taken orally, with peak plasma
  concentrations achieved in approx. 1 hour
• Several benzos (diazepam, chlordiazepoxide,
  chlorazepate, halazepam, prazepam, chlorazepate)
  are first biotransformed to pharmacologically
  active intermediates
• These intermediates are then degraded and
  excreted
• -         Thus, long-lasting benzos are so b/c
  they are first degraded to active intermediates,
  and both the parent drug and the intermediate are
  long-lasting/acting

12
Short Acting and the Elderly

• o       Short-lasting benzos are not converted
  to active intermediates they are metabolized
  directly into inactive products
• -         The elderly have a reduced ability to
  metabolize long-acting benzos (and their active
  metabolites)
• Pharmacokinetics are not drastically altered with
  the short-acting benzos

13
Pharmacological effects

• -         Those compounds that bind and enhance
  the inhibitory actions of GABA are complete
  agonists
• o       (Ex) Lorazepam, midazolam, etc.
• -         Those compounds that bind with less
  than complete agonist action are termed partial
  agonists
• o       (Ex) Ambien (zolpidem)
• -         Those compounds that bind and decrease
  the inhibitory actions of GABA are inverse
  agonists

14
Pharmacological effects cont.

• -         Those compounds that bind and have no
  effect on GABA inhibition are antagonists
• o       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
• o       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

15
Receptor Ligands
16
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
• o       Therefore useful in treatment of insomnia
• -         Effective muscle relaxants
• -         Generate anterograde amnesia
• o       Lorazepam ? long-lasting amnesia
• Midazolam ? short-lasting amnesia

17
Uses Cont.

•        Useful for panic attacks and phobias
•      Efficacy may be less than that achieved with
  SSRIs
•         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

18
Benzodiazepine Therapy
19
Side Effects and Toxicity

• -         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)
• o       Respiration is not seriously depressed,
  unless benzo is taken concurrently with another
  CNS depressant (i.e., alcohol)
• o       Short-acting agents taken at bedtime can
  result in both early-morning wakening and rebound
  insomnia the following night
• o       Long-acting agents taken at bedtime can
  result in daytime sedation the following day
• -         Cognitive impacts are considerable
• o       Inhibition of learning behaviors,
  academic performance, and psychomotor functioning
  common
• These symptoms can persist long after treatment
  is discontinued

20
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
•      Return (and possible intensification) of
  anxiety state, increases in rebound insomnia,
  restlessness, agitation, irritability, etc. 

21
Effects on Pregnancy

• -         Benzodiazepines (and their metabolites)
  can freely cross the placental barrier and
  accumulate in fetal circulation
• o       Administration during the first trimester
  can result in fetal abnormalities
• o       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
•  

22
Second-Generation Anxiolytics

• Zolpidem (Ambien)
•  
•       General
•         Nonbenzodiazepine
•        Structurally unrelated to benzos, but
  acts in much the same manner
•          Binds to (subtype 1) GABAA1 receptors
•         Useful for the short-term treatment of
  insomnia
•      Primarily a sedative (rather than an
  anxiolytic)

23
Pharmacokinetics and Dynamicsand Adverse Effects

•      Pharmacokinetics
•         Rapidly absorbed in the GI tract
  following oral administration (75 reaches
  plasma)
•         Only approx. 20 is metabolized in
  first-pass metabolism
• o       Metabolized in the liver and excreted by
  the kidneys
•         Peak plasma levels reached in approx. 1
  hour
•      Pharmacodynamics
•         Produces sedation and promotes good
  sleep (w/o anxiolytic, anticonvulsant, or
  muscle-relaxant effects)
•         Memory is affected
•         Flumazenil reported to reverse memory
  impairments and overdoses
• o       Flumazenil also reported to improve
  memory and learning, thus suggesting a possible
  role of endogenous benzos in memory function
•       Adverse Effects
•         Drowsiness, dizziness, and nausea at
  therapeutic doses
• o       Severe nausea and vomiting greatly limit
  overdoses

24
Agonists of Benzo Receptors

• Zaleplon Zopiclone
•         Nonbenzodiazepine agonist that
  acts at the GABAA1 receptors to exert actions
  similar to benzos
•         Short half-life
•         Only approx. 30 of an orally
  administered dose reaches the plasma, and most of
  that undergoes first-pass elimination
• o       Half as potent as zolpidem
•         Improves sleep quality w/o rebound
  insomnia, and little chance of developing
  dependency

25
Partial Agonists

• 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
• Alpidem
• Partial agonist of GABA1 and GABA3 receptors
• More anxiolytic than full agonists, with less
  sedation and no interaction with EtOH
• May induce hepatitis though
• Etizolam
• Potent anxiolytic
• lower incidence of side effects at comparable
  efficacy