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Introduction: Propofol is an anesthetic agent commonly used in emergency department (ED) procedural sedation. It is often preferred in orthopedic procedures because of its muscle-relaxing properties. Rarely, however, it can induce agitation and muscle hypertonicity.Case Report: A 58-year-old man presented to the ED with a left ankle fracture-dislocation. Propofol was used to facilitate procedural sedation, but the patient became mildly agitated. Ketamine was used to achieve full induction, after which propofol was used again to facilitate muscle relaxation. Near the end of the procedure, the patient had opisthotonos and masseter spasm requiring bag-valve-mask ventilation and subsequent intubation. This reaction was ultimately attributed to adverse effects of the propofol.Conclusion: While propofol is generally well tolerated, it can potentially cause agitation, hypertonicity, and other side effects such as muscle spasms and seizure-like activity. Acknowledging and preparing for these risks can potentially improve patient outcomes.

Methaqualone, a quinazolinone marketed commercially as Quaalude, is a central nervous system depressant that was used clinically as a sedative-hypnotic, then became a notorious recreational drug in the 1960s-80s. Due to its high abuse potential, medical use of methaqualone was eventually prohibited, yet it persists as a globally abused substance. Methaqualone principally targets GABAA receptors, which are the major inhibitory neurotransmitter-gated ion channels in the brain. The restricted status and limited accessibility of methaqualone have contributed to its pharmacology being understudied. Here, we use cryo-EM to localize the GABAA receptor binding sites of methaqualone and its more potent derivative, PPTQ, to the same intersubunit transmembrane sites targeted by the general anesthetics propofol and etomidate. Both methaqualone and PPTQ insert more deeply into subunit interfaces than the previously-characterized modulators. Binding of quinazolinones to this site results in widening of the extracellular half of the ion-conducting pore, following a trend among positive allosteric modulators in destabilizing the hydrophobic activation gate in the pore as a mechanism for receptor potentiation. These insights shed light on the underexplored pharmacology of quinazolinones and further elucidate the molecular mechanisms of allosteric GABAA receptor modulation through transmembrane binding sites.