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Activation of 5-HT1A and 5-HT2A receptors
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Agonism of the mu-opioid receptor
Generation of oxalic acid
Inhibition of glutamate action at NMDA receptors
Positive allosteric modulation of the GABA-A receptor
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This patient presents with depressed mental status (somnolence, slurred speech) and normal vital signs without abnormal findings on physical exam, indicative of the sedative-hypnotic syndrome. In this patient with a history of panic disorder (suggestive of benzodiazepine treatment), this syndrome is most likely caused by an overdose of benzodiazepines, which are positive allosteric modulators of the GABA-A receptor. The sedative-hypnotic syndrome is often described as a “coma with normal vitals,” referring to the finding of depressed mental status with a normal physical exam. Although patients appear to have depressed mental status, they are typically easily rousable and can provide a sufficient history. Causative agents include benzodiazepines, which positively modulate the GABA-A receptor to increase the frequency of channel opening to chloride ions. Diagnostic work-up should specifically rule out co-ingestants such as alcohol or opioids. With isolated benzodiazepine ingestion, respiratory depression is not typically seen (although dose-dependent). Treatment of isolated benzodiazepine overdose is supportive, with special attention to respiratory function. Griffin et al. review the pharmacology of benzodiazepines and their central nervous system effects. They discuss how these agents have a depressive effect on patients. They recommend that benzodiazepines should be used cautiously in the elderly and patients with comorbid lung, liver, or kidney dysfunction. Incorrect Answers: Answer 1: Activation of 5-HT1A and 5-HT2A receptors describes serotonin syndrome, which can be caused by serotonergic drugs like selective serotonin reuptake inhibitors (SSRIs) used in the treatment of depression. Patients would have vital sign abnormalities such as tachycardia, hyperthermia, and hypertension as well as clonus on physical exam. Treatment is with benzodiazepines. Answer 2: Agonism of the mu-opioid receptor describes the action of opioids. Opioid overdose presents with altered mental status, respiratory depression, and miosis. This patient has a normal respiratory rate. Initial treatment would be with naloxone. Answer 3: The generation of oxalic acid describes ethylene glycol ingestion. While ethylene glycol ingestion can cause sedative-hypnotic syndrome as well as nephropathy due to oxalic acid toxicity, it would increase the serum osmolality gap, calculated as serum osmolality gap = measured osmolality – (2 * [Na+]) – ([glucose] / 18) – ([urea] / 2.8). Treatment is with fomepizole. Answer 4: Inhibition of glutamate action at NMDA receptors describes the action of ethanol, which is also a GABA receptor agonist. Ethanol ingestion can cause the sedative-hypnotic syndrome; however, ethanol is also an unmeasured osmolyte that would increase the osmolal gap. Treatment is supportive. Bullet Summary: Benzodiazepine overdose can cause the sedative-hypnotic syndrome via its action as a positive allosteric modulator of GABA-A receptors.
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