Benzodiazepines
More Than Just Sedatives?
Robert S. Hoffman, MD
Benzodiazepines
O
• Chemical Structure
Me
– Benzene ring
– Diazepine ring
N
N
Ph
Cl
Diazepam
The GABAA Receptor
• Comprised of 5
subunits (most
common)
– 2 α subunits
– 2 β subunits
– 1 γ subunit
• Many subtypes
– 170,000 possible
combinations due to
splice variants
Two Central Bz Receptors
• Differ in location and effect
– BZ1 (ω1)
• Sensory and motor area
• Sedative, hypnotic
– BZ2 (ω2)
• Subcortical and limbic areas
• Anxiolytic, anticonvulsant
• Both increase Cl conductance to
hyperpolarize the cell
BZ Receptor Requirements
• Must have a γ subunit to recognize
benzodiazepines
• α subunits define the receptor type
– α1 isoform is found in the BZ1 receptor
– BZ2 receptors have the α2, α3 or α5 isoforms
• Zolpidem has high affinity for α1,
intermediate affinity for α2 and α3 and low
affinity for α5
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
Peripheral Benzodiazepine
Receptors
• Also known as PBRs or ω3 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)
PBRs
• Heterotrimer composed of:
– An isoquinoline binding protein
• The actual 18 kDa receptor
– A voltage-dependent anion channel (VDAC)
– An adenine nucleotide transporter (ANT)
Papadopoulos
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
Housekeeping gene
Mitochondrial Permeability
Transition Pore
Do PBRs Have A Role in
Poisoning?
Vasoconstriction and Nitrates
• 12 patients were given cocaine during
routine cardiac catheterization
– Brogan WC: J Am Coll Cardiol 1991;18:581-6
• Normal arteries constricted 22%
• Diseased arteries constricted 45%
(p<0.02)
• All vessels responded to sublingual
nitroglycerin
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
Am J Emerg Med 2003;21:39-42
• 37 patients
• Randomized
– NTG plus lorazepam
– Lorazepam alone
• Therapy repeated if needed
• Outcome on a simple chest pain score
Results
• CP score at 5 minutes after 1st therapy
– NTG
– BZ + NTG
5.2
3.9
• p=0.02
• 5 minutes after 2nd treatment
– NTG
– BZ + NTG
• P=0.005
4.6
1.5
• 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
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?
Trial of SSR180575: a novel PBR agonist
Rat model of ischemia / reperfusion
Following ligation of rabbit coronary arteries
Chloroquine
• Popular drug in
overdose
• Sudden
cardiovascular
compromise
• High case fatality rate
• Protocol included
– Intubation
– High dose epinephrine
– Diazepam 2 mg/kg over 30 minutes
Controlled trial of diazepam in chloroquine poisoned pigs
Chloroquine
O
Me
N
N
Ph
Cl
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
Thoughts
• The cardiotoxicity of chloroquine might be
partially related to overstimulation of PBRs
– High dose diazepam may be used to displace
chloroquine from PBRs
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