Benzodiazepines More Than Just Sedatives? Robert S. Hoffman, MD

Benzodiazepines Chemical Structure –Benzene ring –Diazepine ring Diazepam

The GABA A 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 ω 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)

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 1 st therapy –NTG5.2 –BZ + NTG3.9 p= minutes after 2 nd treatment –NTG4.6 –BZ + NTG1.5 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

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