BenzodiazepinesMore Than Just Sedatives?
Robert S. Hoffman, MD
Benzodiazepines
• Chemical Structure– Benzene ring– Diazepine ring
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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 5.2– BZ + NTG 3.9
• p=0.02
• 5 minutes after 2nd treatment– NTG 4.6– BZ + NTG 1.5
• P=0.005
• 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
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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
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