1. Preventing a BZD Crisis & Understanding Protracted Withdrawal Syndrome – basic science
Robert B Raffa, PhD

2. Learning Objectives
Review the mechanism of BZD action at central GABAA receptors
Evaluate the implications of peripheral BZD receptors
Relate the existing unknowns about BZDs to uncertainties of prescribing
Question BZD use beyond the knowledge base (i.e., more than 2 – 4 weeks)

3. Disclosure
Dr. Raffa was a previous employee of Johnson & Johnson in analgesics drug-discovery, currently has academic affiliations (Temple University, University of AZ), consults for multiple pharmaceutical companies regarding the discovery and development of opioid and non-opioid analgesics, and is a principal in two (non-opioid) analgesics drug discovery companies: CaRafe Drug Innovation and Neumentum.

4. No drug is perfect
Sola dosis facit venenum Only dose makes a poison – Paracelsus

5. Basic science of BZDs – it dependsW

6. What we know we know very well

7. Ion channel → neuronal TM-ΔV → clinical

8. What we don’t know so well
Down-regulation of BZD receptors and subunits of GABAA receptors (and the receptor mRNA) occur – with concomitant decrease in the responsiveness of GABAA receptors (measured as electrophysiological response, Cl– flux, and functional coupling).
Thus, a patient’s BZD receptors and GABAA response are not the same after more than a few weeks of BZD exposure compared to start of therapy.
Sun et al. (2017) Br Med J 356: j760
Sirdifield et al. (2013) BMC Fam Pract 14:191
Griffi et al. (2013) Ochsner J 13:
Campo-Soria et al. (2006) Br J Pharmacol 148:
Schallek et al. (1979) Adv Pharmacol Chemother 16:45-87
Gielen et al. (2012) J Neurosci 32:
Brett and Pratt (1995) Br J Pharmacol 116:
Jacob et al. (2012) Proc Natl Acad Sci USA 109:
Karlsson et al. (2011) J Gen Physiol 138:
Jacob et al. (2008) Nat Rev Neurosci 9:

9. What we don’t know so well
There is a surprising paucity of information about the receptor binding profile of many of the BZDs at off-target sites. Radioligand binding data are available for BZDs at BZD receptors, but not at other receptors.

10. What we don’t know so well
BZDs potentiate adenosine A2AR-mediated Es
BZDs allosterically modulate 1-adrenoceptor
signaling by inhibiting PDE-4
BZDs possibly are agonists at oxytocin Rs
Salonen et al. (1992) Anesthesiology 76:
Yagi and Onaka (1996) Neurosci Lett 203:49-52
Collado et al. (1998) Br J Pharmacol 123:
Waugh et al. (1999) J Pharmacol Exp Ther 291:
Seubert et al. (2000) Anesthesiology 92:

13. What about the rest of the body??

14. What we don’t know much at all
Peripheral BZD receptors are located in abundance on
mitochondria and immune cells.

15. Just the tip of the iceberg?
Changes in polymorphic expression?
receptors?
metabolism?
Protein synthesis (activation or inhibition
of DNA promotor regions)?
Epigenetic changes?
Nutritional factors?
NO/ONOO– cycle?1
1LaCorte (2018) Med Hypoth 118:59-67

16. Conclusion

17. Alice as pharmacologist
It was all very well to say “Drink me”, but the wise little Alice was not going to do that in a hurry. “No, I’ll look first”, she said, “and see whether it’s marked ‘poison’ or not.”
— Lewis Carroll