 At the end of this session, students will be able to identify usual signs and symptoms of sedative-hypnotic overdoses and be able to provide appropriate treatment recommendations for those patients.

 Describe the usual signs and symptoms of sedative-hypnotic overdoses;  List the usual treatments for managing patients with overdoses of benzos/CNS depressants;  Be able to develop an appropriate treatment plan for simulated benzodiazepine, chloral hydrate, and other sedative hypnotic overdose patients;

Shakespeare: Not poppy, nor mandragora, Nor all the drowsy syrups of the world, Shall ever medicine thee to that sweet sleep Which thou owedst yesterday. Othello, act 3, sc 3, I

What a drag it is getting old "Kids are different today,“ I hear ev'ry mother say Mother needs something today to calm her down And though she's not really ill There's a little yellow pill She goes running for the shelter of a mother's little helper And it helps her on her way, gets her through her busy day Rolling Stones; Aftermath, 1966

 Commonly used and misused in the middle to late part of the 20 th Century  Several substances no longer commercially produced (methaqualone, ethchlorvynol, glutethamide, etc.)  Most current sedative hypnotic use is primarily focused on benzodiazepines

SubstanceTotalMajorDeath Long acting barbiturates 2, Benzodiazepines79, Chloral hydrate6820 Mowry JB et al: 2012 Annual report of the American Association of Poison Control Centers National Poison Data System (NPDS): 30 th Annual report. Clin Tox 2013;51:

 Benzodiazepines  Barbiturates  Others (e.g., Chloral hydrate, zolpidem, meprobamate, propofol)  No longer marketed: Ethchlorvynol, Glutethamide, Methaqualone)

 Nearly all sedative hypnotics work at or around the GABA receptor  GABA A receptors have different distributions of subunit families: alpha, beta, gamma, etc.  Nearly all sedative hypnotics bind to GABA A receptors containing the alpha subunit.  Binding at benzodiazepine receptor enhances binding of other GABA agonists to GABA A receptor

 There is variability in binding, depending on the specific agent (e.g., at low doses, benzodiazepines bind primarily at the gamma 2 subunit)  Most sedative hypnotics ALSO bind to other receptors (e.g., propofol also inhibits glutamate mediated NDMA receptors which results in decreased excitatory nerve transmission)

 In general, onset of action is determined by the drugs ability to cross the blood-brain barrier; more lipophilic drugs cross the BBB more readily than less lipophilic drugs  Most agents have very large volumes of distribution; many are protein bound  After initial distribution, many drugs demonstrate complex secondary distribution to other tissues

 Many agents are metabolized to active metabolites  Most agents are eliminated by the liver (chloral hydrate and meprobamate are renally cleared)

 Sedation  Slurred speech  Poor attention  Coma

 Patients commonly experience CNS depression yet GENERALLY maintain adequate vital signs  May see respiratory depression in very large oral overdoses or large intravenous overdoses  Exposure to multiple CNS depressants can enhance depressive effects (e.g., ethanol + alprazolam)

 Large exposures to intravenous formulations may lead to toxic effects from diluents (e.g., propylene glycol in lorazepam).  One study showed that 2/3 of critical care patients receiving > 0.16 mg/kg/hour lorazepam for more than 48 hours developed hyperosmolar metabolic acidosis secondary to propylene glycol in lorazepam Taylor J, Jabbour G, Saggi SJ. Severe hyperosmolar metabolic acidosis due to large doses of intravenous lorazepam. N Engl J Med 2002;346:

 Supportive care (A, B, Cs) will be adequate to treat the vast majority of sedative hypnotic overdoses.  Some agents can produce cardiotoxicity that requires additional treatment  Chloral hydrate may produce ventricular dysrhythmias; sort acting beta blockers (esmolol) may be used in these cases  Don’t pull the plug too soon!

Oral activated charcoal should be considered for all substantial, recent oral sedative hypnotic overdoses.

 For severe phenobarbital overdoses, may consider use of multiple dose activated charcoal to enhance drug clearance  Only consider MDAC for those with bowel sounds

 Flumazenil (Romazicon ® ) is a benzodiazepine antagonist  Potential for life threatening benzodiazepine withdrawal; however, few cases of severe withdrawal documented

 Short acting vs. long acting  Can produce profound CNS and respiratory depression  Overdoses can lead to “barb bullae”, even in minor overdose

 First introduced in 1832  Well absorbed, but irritating to GI tract  Still occasionally used in pediatrics  Therapeutic half life of 4 – 12 hours  Can produce cardiac dysrhythmias due to increased sensitivity of the myocardium to catecholamines  Use beta blockers to treat ventricular tachycardia, ventricular fibrilation

 Commonly used as muscle relaxants  Similar actions to barbiturates at the GABA receptor  Case reports of bezoar formation in large meprobamate overdose leading to prolonged and delayed symptoms  May see profound hypotention

 The most commonly prescribed sleep medications  Less likelihood to produce dependence than other sedative- hypnotics  Symptoms more than drowsiness are extremely rare

 Rapidly acting intravenous agent  Postsynaptic GABA agonist  Also stimulates presynaptic release of GABA  NMDA receptor antagonist

 Produces dose dependent effects:  Profound CNS depression and resp depression  Large doses associated with metabolic acidosis, cardiac dysrhythmias, and skeletal muscle injury (Propofol Infusion Syndrome: PIS)

 Signs of PIS include new onset right bundle branch block and ST segment elevation  More often seen in pediatric patients, those with traumatic brain injuries, respiratory challenges, exogenous catecholamine use, inadequate carbohydrate intake  May be due to disruption of free fatty acid utilization and metabolism  Treatment is to d/c propofol and provide supportive care