Benzodiazepines More Than Just Sedatives

1
BenzodiazepinesMore Than Just Sedatives?

• Robert S. Hoffman, MD

2
Benzodiazepines

• Chemical Structure
• Benzene ring
• Diazepine ring

Diazepam
3
The GABAA Receptor

• Comprised of 5 subunits (most common)
• 2 a subunits
• 2 ß subunits
• 1 ? subunit
• Many subtypes
• 170,000 possible combinations due to splice
  variants

4
(No Transcript)
5
Two Central Bz Receptors

• Differ in location and effect
• BZ1 (?1)
• Sensory and motor area
• Sedative, hypnotic
• BZ2 (?2)
• Subcortical and limbic areas
• Anxiolytic, anticonvulsant
• Both increase Cl conductance to hyperpolarize
  the cell

6
BZ Receptor Requirements

• Must have a ? subunit to recognize
  benzodiazepines
• a subunits define the receptor type
• a1 isoform is found in the BZ1 receptor
• BZ2 receptors have the a2, a3 or a5 isoforms
• Zolpidem has high affinity for a1, intermediate
  affinity for a2 and a3 and low affinity for a5

7
GABA Effects

• Popularity for a wide variety of indications
• Sedative
• Muscle relaxant
• Amnestic
• Anticonvulsant
• Used as antidotes for a variety of poisons and
  withdrawal syndromes

8
Peripheral Benzodiazepine Receptors

• Also known as PBRs or ?3 receptors
• Defined in the 1970s to describe high affinity
  binding sites for BZs outside of the CNS
• PBRs also
• Have high affinity for structurally dissimilar
  compounds
• Can be found on microglia of the CNS
• New name - translocator protein (18 kDa)

9
PBRs

• Heterotrimer composed of
• An isoquinoline binding protein
• The actual 18 kDa receptor
• A voltage-dependent anion channel (VDAC)
• An adenine nucleotide transporter (ANT)

10
Papadopoulos
11
Are PBRs Real?

• Highly conserved in nature
• Found in
• Bacteria
• Plants
• Animals
• In humans and mammals
• Found in many tissues
• Concentrated in adrenal glands,heart, kidney,
  brain
• Diffusely in mitochondria

12
Housekeeping gene
13
(No Transcript)
14
Mitochondrial Permeability Transition Pore
15
Do PBRs Have A Role in Poisoning?
16
(No Transcript)
17
(No Transcript)
18
Vasoconstriction and Nitrates

• 12 patients were given cocaine during routine
  cardiac catheterization
• Brogan WC J Am Coll Cardiol 199118581-6
• Normal arteries constricted 22
• Diseased arteries constricted 45 (plt0.02)
• All vessels responded to sublingual nitroglycerin

19
(No Transcript)
20
(No Transcript)
21
Benzodiazepines

• 40 patients with cocaine chest pain
• Randomized to receive
• NTG (13)
• Diazepam (12)
• Both (15)
• Therapy repeated every 5 minutes until resolution
  of pain

22
(No Transcript)
23
Am J Emerg Med 20032139-42
24

• 37 patients
• Randomized
• NTG plus lorazepam
• Lorazepam alone
• Therapy repeated if needed
• Outcome on a simple chest pain score

25
Results

• CP score at 5 minutes after 1st therapy
• NTG 5.2
• BZ NTG 3.9
• p0.02
• 5 minutes after 2nd treatment
• NTG 4.6
• BZ NTG 1.5
• P0.005

26

• Role of benzodiazepines not necessarily sedation
• Most patients with cocaine chest pain usually
  have
• Normal blood pressure
• Normal pulse
• Absence of adrenergic findings
• Pupils, sweat, etc

27
Role of PBRs

• Benzoylecgonine
• Principle metabolite of cocaine
• Not very psychoactive
• Good vasoconstrictor
• Calcium channel mediated
• PRB binding inhibits norepinephrine induced
  vasoconstriction
• Calcium channel blockade?

28
(No Transcript)
29
(No Transcript)
30
Trial of SSR180575 a novel PBR agonist Rat model
of ischemia / reperfusion
31
(No Transcript)
32
Following ligation of rabbit coronary arteries
33
Chloroquine

• Popular drug in overdose
• Sudden cardiovascular compromise
• High case fatality rate

34

• Protocol included
• Intubation
• High dose epinephrine
• Diazepam 2 mg/kg over 30 minutes

35
Controlled trial of diazepam in chloroquine
poisoned pigs
36
(No Transcript)
37
(No Transcript)
38
Chloroquine
39
Thoughts

• High dose benzodiazepines typically used in
  sympathomimetic overdose and withdrawal may have
  additional benefits beyond sedation
• In patients with cocaine associated chest pain
  benzodiazepines may reduce vasospasm and prevent
  cell death following myocardial ischemia

40
Thoughts

• The cardiotoxicity of chloroquine might be
  partially related to overstimulation of PBRs
• High dose diazepam may be used to displace
  chloroquine from PBRs

41
Summary

• PBRs are probably responsible for many
  housekeeping cellular functions
• Modulation of PBRs may prove useful in a variety
  of conditions including poisoning
• There is tremendous opportunity for research