Sedative-Hypnotic Overdose

Goal

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.

Objectives

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;

History

Shakespeare: Not poppy, nor mandragora,Nor all the drowsy syrups of the world,Shall ever medicine thee to that sweet sleepWhich thou owedst yesterday. Othello, act 3, sc 3, I. 330-3.

More Modern History

More Modern History

More Modern History

More Modern History

What a drag it is getting old"Kids are different today,“I hear ev'ry mother sayMother needs something today

to calm her downAnd though she's not really illThere's a little yellow pillShe goes running for the shelter

of a mother's little helperAnd it helps her on her way,

gets her through her busy dayRolling Stones; Aftermath, 1966

Sedative Hypnotic History

Commonly used and misused in the middle to late part of the 20th Century

Several substances no longer commercially produced (methaqualone, ethchlorvynol, glutethamide, etc.)

Most current sedative hypnotic use is primarily focused on benzodiazepines

Epidemiology

Substance Total Major

Death

Long acting barbiturates

2,041 47 0

Benzodiazepines

79,989 306 17

Chloral hydrate 68 2 0

Mowry JB et al: 2012 Annual report of the American Association of Poison Control Centers National Poison Data System (NPDS): 30th Annual report. Clin Tox 2013;51:949-1229.

Classes of Agents

BenzodiazepinesBarbituratesOthers (e.g., Chloral hydrate, zolpidem, meprobamate, propofol)

No longer marketed: Ethchlorvynol, Glutethamide, Methaqualone)

Mechanism of Action

Nearly all sedative hypnotics work at or around the GABA receptor

GABAA receptors have different distributions of subunit families: alpha, beta, gamma, etc.

Nearly all sedative hypnotics bind to GABAA receptors containing the alpha subunit.

Binding at benzodiazepine receptor enhances binding of other GABA agonists to GABAA receptor

Mechanism of Action

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)

Pharmacokinetics

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

Pharmacokinetics

Many agents are metabolized to active metabolites

Most agents are eliminated by the liver (chloral hydrate and meprobamate are renally cleared)

Clinical Effects

SedationSlurred speechPoor attentionComa

Benzodiazepines

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)

Other Clinical Effects

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;346:1253-1254.

Treatment

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!

Decontamination

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

Enhanced Clearance

For severe phenobarbital overdoses, may consider use of multiple dose activated charcoal to enhance drug clearance

Only consider MDAC for those with bowel sounds

Antidote

Flumazenil (Romazicon®) is a benzodiazepine antagonist

Potential for life threatening benzodiazepine withdrawal; however, few cases of severe withdrawal documented

Barbiturates

Short acting vs. long acting

Can produce profound CNS and respiratory depression

Overdoses can lead to “barb bullae”, even in minor overdose

Chloral Hydrate

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

Meprobamate/Carisoprodol

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

Zolpidem/Zaleplon/Zopiclone

The most commonly prescribed sleep medications

Less likelihood to produce dependence than other sedative-hypnotics

Symptoms more than drowsiness are extremely rare

Propofol

Rapidly acting intravenous agent

Postsynaptic GABA agonist

Also stimulates presynaptic release of GABA

NMDA receptor antagonist

Propofol

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)

Propofol Infusion Syndrome

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