History of Respiratory Stimulants

Abstract

The interest in substances that stimulate respiration has waxed and waned throughout the years, intensifying following the introduction of a new class of drugs that causes respiratory depression, and diminishing when antidotes or better drug alternatives are found. Examples include the opioids––deaths increasing during overprescribing, diminishing with wider availability of the opioid receptor antagonist naloxone, increasing again during COVID-19; the barbiturates––until largely supplanted by the benzodiazepines; propofol; and other central nervous system depressants. Unfortunately, two new troubling phenomena force a reconsideration of the status-quo: (1) overdoses due to highly potent opioids such as fentanyl, and even more-potent licit and illicit fentanyl analogs, and (2) overdose due to polysubstance use (the combination of an opioid plus one or more non-opioid drug, such as a benzodiazepine, sedating antidepressant, skeletal muscle relaxant, or various other agents). Since these now represent the majority of cases, new solutions are again needed. An interest in respiratory stimulants has been revived. This interest can be informed by a short review of the history of this interesting class of medications. We present a short history of the trajectory of advances toward more selective and safer respiratory stimulants.

Prevalence and blood concentrations of benzodiazepines and opioids in opioid‐positive death investigations in Ontario, Canada, from 2017 to 2021

“…As polysubstance overdoses are becoming increasingly more common, the effectiveness of naloxone in reversing the overdose may be limited. Naloxone is only effective in treating opioid overdoses, with no effects against benzodiazepines, meaning that naloxone's life-saving potential is diminished in polysubstance overdoses [27,28]. Despite this, its use is advised in such situations as it can effectively reduce opioid-induced respiratory depression and improve the chances of survival by temporarily removing the effects of the opioid [28][29][30].…”

Anti-Strychnine Immunoconjugate Reduces the Effects of Strychnine-Induced Toxicity in Mice

“…The polycyclic indoline alkaloid strychnine is a noxious secondary metabolite predominantly isolated from the seeds of the Strychnos nux-vomica tree indigenous to India, southeastern Asia, and Australia. Since the initial discovery of strychnine in 1818, numerous attempts have been made to effectively utilize this structurally complex small molecule as a treatment for a variety of medical conditions. − However, strychnine has remained notorious for its distinctive manifestation of toxicity in humans (oral LD 50 ∼ 1–2 mg/kg, approximately 70–150 mg) and other lower-order vertebrate species . Strychnine is a competitive antagonist of glycine-gated chloride channels in the spinal cord, causing visually striking and severely painful seizure-like contractions of the skeletal and respiratory muscles.…”