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

2. Benzodiazepines Chemical Structure –Benzene ring –Diazepine ring Diazepam

3. 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

5. 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

6. 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

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 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)

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

14. Mitochondrial Permeability Transition Pore

15. Do PBRs Have A Role in Poisoning?

18. 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

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

23. Am J Emerg Med 2003;21:39-42

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 1 st therapy –NTG5.2 –BZ + NTG3.9 p=0.02 5 minutes after 2 nd treatment –NTG4.6 –BZ + NTG1.5 P=0.005

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?

30. Trial of SSR180575: a novel PBR agonist Rat model of ischemia / reperfusion

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

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