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

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)

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.

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

Basic science of BZDs – it depends W

What we know we know very well

Ion channel → neuronal TM-ΔV → clinical

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 13:214-223 Campo-Soria et al. (2006) Br J Pharmacol 148:984-990 Schallek et al. (1979) Adv Pharmacol Chemother 16:45-87 Gielen et al. (2012) J Neurosci 32:5707-5715 Brett and Pratt (1995) Br J Pharmacol 116:2375-2384 Jacob et al. (2012) Proc Natl Acad Sci USA 109:18595-18600 Karlsson et al. (2011) J Gen Physiol 138:609-626 Jacob et al. (2008) Nat Rev Neurosci 9:331-343

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.

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 76:1004-1011 Yagi and Onaka (1996) Neurosci Lett 203:49-52 Collado et al. (1998) Br J Pharmacol 123:1047-1054 Waugh et al. (1999) J Pharmacol Exp Ther 291:1164-1171 Seubert et al. (2000) Anesthesiology 92:567-577

What about the rest of the body??

What we don’t know much at all Peripheral BZD receptors are located in abundance on mitochondria and immune cells. http://jnm.snmjournals.org/content/53/2/330

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

Conclusion

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