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Benzodiazepines More Than Just Sedatives?

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

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Benzodiazepines More Than Just Sedatives?

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  1. BenzodiazepinesMore Than Just Sedatives? Robert S. Hoffman, MD

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

  3. 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

  4. 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

  5. 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

  6. 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

  7. 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)

  8. PBRs • Heterotrimer composed of: • An isoquinoline binding protein • The actual 18 kDa receptor • A voltage-dependent anion channel (VDAC) • An adenine nucleotide transporter (ANT)

  9. Papadopoulos

  10. 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

  11. Housekeeping gene

  12. Mitochondrial Permeability Transition Pore

  13. Do PBRs Have A Role in Poisoning?

  14. 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

  15. 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

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

  17. 37 patients • Randomized • NTG plus lorazepam • Lorazepam alone • Therapy repeated if needed • Outcome on a simple chest pain score

  18. 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

  19. 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

  20. 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?

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

  22. Following ligation of rabbit coronary arteries

  23. Popular drug in overdose Sudden cardiovascular compromise High case fatality rate Chloroquine

  24. Protocol included • Intubation • High dose epinephrine • Diazepam 2 mg/kg over 30 minutes

  25. Controlled trial of diazepam in chloroquine poisoned pigs

  26. Chloroquine

  27. 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

  28. Thoughts • The cardiotoxicity of chloroquine might be partially related to overstimulation of PBRs • High dose diazepam may be used to displace chloroquine from PBRs

  29. 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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