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