SEDATIVE HYPNOTICS OD


Sedative-hypnotic agents are medications used to treat anxiety, panic disorders, and insomnia.
Medications in this class include barbiturates, benzodiazepines, antihistamines, antidepressants, and other agents with sedating side effects.
This section is limited to a discussion of barbiturates and benzodiazepines.

Barbiturates

Barbiturates are used as sedatives, to induce anesthesia, and to treat epilepsy, including status epilepticus.

They are categorized by their duration of action.

  • Ultrashort-acting (eg, methohexital, thiopental)
  • Short-acting (eg, pentobarbital)
  • Intermediate-acting (eg, amobarbital)
  • Long-acting (eg, phenobarbital)

The magnitude and duration of effect depends on the agent and dose. Chronic exposure often leads to tolerance.

MECHANISM/TOXICITY

  • Bind to GABA-A chloride channel → depression of neuronal firing
  • Depress medullary respiratory centers
  • Inhibit myocardial contractility and conduction

SYMPTOMS/EXAM

  • Mild to moderate intoxication:
    • Lethargy
    • Nystagmus
    • Ataxia
    • Slurred speech (similar to alcohol intoxication)
  • Severe intoxication:
    • Small/midsized pupils
    • Hypothermia
    • Coma
    • Respiratory depression
    • Hypotension
    • Bradycardia
  • Withdrawal Symptoms:
    • Occur within 24 hr of cessation, begins with mild symptoms, which may become severe over next 2 - 8 days.
    • Minor Symptoms:
      • Anxiety, restlessness, depression, insomnia, anorexia, nausea, vomiting
    • Major Symptoms:
      • Psychosis, hallucinations, delirium, generalized seizures, hyperthermia, & cardiovascular collapse.
Severe barbiturate intoxication depressed/decreased:
  • HR
  • BP
  • RR
  • Temperature
  • CNS

DIAGNOSIS

  • Usually based on history of exposure and clinical examination
  • Serum levels may be available for agents used to treat epilepsy (eg, phenobarbital).
  • In overdose, clinically correlate levels, and monitor for peak and decline.

TREATMENT

  • Stabilize airway. Endotracheal intubation in the severely poisoned pt. is commonly required & should be initiated early. Due to potential for Myocardial depression, place 2 large-bore IVs & initialte fluid resuscitation w/ isotonic saline for hypotension.
  • Consider empiric Tx with Narcan &  Thiamine early in management.
  • Dopamine or Norepinephrine may be needed if fluid boluses fail to reverse hypotension.
  • Hypothermia between 30 C (86 F) & 36 C (96.8 F) requires standard rewarming techniques.
  • Gastric lavage if life-threatening ingestion and <60 minutes from ingestion
  • Activated charcoal: helps reduce absorption
    • Awake, Cooperative pt.=  50 - 100 g PO (1g/kg in children)
    • Sedated/Unconscious pt.=  Airway protection, Multi-dose activated charcoal
  • Whole-bowel irrigation if long-acting agents
  • Urinary alkalinization (NOT considered first line Tx)
    • For long-acting barbiturates (eg, phenobarbital, primidone) only
    • Not effective for shorter-acting agents
    • To urine pH of 8.0
  • Hemodialysis, hemoperfusion, & hemodiafiltration:
    • For severely intoxicated patients refractory to above therapy.
    • Only effective for phenobarbital toxicity

DISPOSITION

  • Evidence of toxicity > 6 hr from time of arrival requires hospital admission.
  • Obtain psychiatric consult for intentional overdose.
  • Toxicology or poison center consultation is recommended to assist the management.
Urinary alkalinization is effective for long-acting barbiturates (phenobarbital) only

 

Benzodiazepines

Benzodiazepines are used as sedatives, to induce anesthesia, and to treat epilepsy, including status epilepticus.

They are categorized by their duration of action.

  • Short-acting (eg, midazolam)
  • Intermediate-acting (eg, lorazepam)
  • Long-acting (eg, diazepam)

The shorter-acting agents are more lipophilic, and therefore cross the blood-brain barrier more rapidly (rapid on, rapid off). Half-life is not a good indicator of duration of effect.

Severe toxicity from benzodiazepine exposure is rare unless combined with other agents that have synergistic effects.

Pathophysiology

  • Indirect GABA agonist resulting in CNS inhibition & decr spontaneous reflexes
    • Also has some anticholinergic effects
  • Risk factors for toxicity
    • Elderly, peds, decr renal/hepatic funct, coingestions with other depressants (EtOH)
  • Kinetics
    • Short-acting: alprazolam, midazolam, oxazepam, triazolam
    • Intermediate-acting: estazolam, lorazepam, temazepam
    • Long-acting: chlordiazepoxide, clonazepam, clorazepate, diazepam, flurazepam, prazepam

Symptoms

  • Decr MS, coma (11%), sedation, delirium, HA, weakness, ataxia
  • Slurred speech, psychosis; obtundation usually resolves within 36 hr
  • Mild to moderate intoxication:
    • Lethargy, slurred speech, ataxia
  • Severe intoxication:
    • Coma, respiratory depression, hypotension

Physical Exam

  • Hyporeflexia, resp depression (esp flunitrazepam OD), hypothermia (15%), bradycardia, rhabdo
  • Dilated pupils, incr HR, hypotension (diazepam IV: propylene glycol diluent)

Diagnostic testing

  • Labs
    • Lytes, BUN/Cr, glucose: r/o causes of MS change
    • Tox screen: r/o other coingestions if ind
      • Quantitative benzodiazepine levels not clinically useful
      • Urine drug screens only useful for diazepam congeners
  • EKG
    • Frequent cyclic coingestions

Treatment

  • Priorities include assessment & stabilization of airway, breathing, & circulation.
    IV Access, O2, Cardiac monitor
  • Do NOT induce emesis. Gastric lavage, forced dieresis, enhanced elimination, hemodialysis & hemoperfusion are ineffective and unncecessary.
  • Activated charcoal: (if <1 hour and no significant CNS depression)
    • Adult: 25 - 50 g
    • Children: 1 g/kg
  • Antidote: Flumazenil
    • Benzodiazepine receptor antagonist
    • Dose:
      • Adult: 0.2 mg IV, titrate q 1 min to a max: 3 mg
      • Children: 0.01 - 0.02 mg/kg
    • Duration of effect = 1 hour (recurrent sedation possible)
    • Limited utility in the ED (mostly for reversal of procedural sedation)
    • Contraindications:
      • Overdose of unknown agents.
      • Chronic benzodiazepine use (may induce withdrawal)
      • Co-ingestion of seizure-inducing medication (eg, TCAs)
      • Suspected increased ICP
      • Known seizure disorder

Disposition:

  • Admit to ICU  if Significant alterations of mental status, respiratory depression, hypotension.
  • Psychiatric Consult
Flumazenil contraindications:
Chronic benzodiazepine use Coingestion of seizure inducing meds Suspected ↑ ICP

 

Generic Name Time to Peak Effect
 
Elimin-ation Half-Life (h) Duration of Action Active Metabolite (half-life) Oral Dose Equivalent to Diazepam 10 mg PO
Short Acting
Alprazolam 1-2 h 6-12 4-7 h No 0.5
Midazolam IV 1-2 min 3-6 IV 2 h Yes 5
IM 10-15 min IM 4-6 h
PO 30-60 min PO 4-6 h
Oxazepam 20-30 min 5-10 3-6 h No 20
Tetrazepam 1-3 h 15 6-8 h No 50-100
Triazolam 15-30 min 2-5 6-7 h No 0.25-0.50
Intermediate Acting
Bromazepam 1-3 h 10-20 <12 h Yes 5-6
Cinolazepam 0.5-2.0 h 9 9 h No 40
Estazolam 1 h 10-24 <12 h No 1-2
Flunitrazepam 15-20 min 18-24 4-6 h Yes (36-200 h) 1
Loprazolam 0.5-4.0 h 6-12 <12 h No 1-2
Lorazepam IV 5-20 min 9-16 6-8 h No 1
IM 20-30 min
PO 30-60 min
Lormetazepam 0.5-2.0 h 10-12 <12 h No 1-2
Nimetazepam 15-30 min 14-30 <12 h No 5
Nitrazepam 0.5-5.0 h 16-48 <12 h No 10
Premazepam 2 h 10-13 <12 h No 3.75
Temazepam 80-100 min 9-12 5-20 h No 20
Long Acting
Chlordiazepoxide 2 h 5-30 5-30 h Yes (36-200 h) 25
Clonazepam 20-60 min 20-80 <12 h No 0.5
Clorazepate 1-2 h 48 8-24 h Yes (36-200 h) 15
Cloxazolam 2-5 h 65 18-50 h No 1-2
Diazepam IV 1-5 min 20-50 IV 15-60 min Yes (36-200 h) 10
PO 15-45 min PO 12-24 h
PR 5-45 min --
Flurazepam 30-60 min 2 12 h Yes (50-100 h) 15-30
Flutoprazepam 0.5-2.0 h 60-90 24 h Yes 2-3
Halazepam 1-3 h -- 12-24 h Yes (30-100 h) 20-40
Ketazolam 2.5-3.0 h 30-100 12-24 h Yes (36-200 h) 15-30
Medazepam -- 36-150 10-12 h Yes (36-200 h) 10
Nordazepam 2 h 40-50 12-14 h Yes (50-120 h) 10
Phenazepam 1.5-4.0 h 60 12 h Yes 1
Pinazepam 1-2 h 20-25 12-24 h Yes (40-100 h) 20
Prazepam 2-6 h 40-80 12-24 h Yes (36-200 h) 10-20
Quazepam 0.5-2.0 h 27-41 12-24 h Yes (28-80 h) 20

 

Non-Benzodiazepine Sedatives

Nonbenzodiazepine Sedatives:
Name Protein Binding (%) Volume of Distribution (L/kg) Plasma Half-Life
Buspirone 95 5-6 2-3 h
Carisoprodol 60 Unknown 100 min
Chloral hydrate 35 for trichloroethanol 0.6 4 min for chloral hydrate and 6–10 h for trichloroethanol
Gamma hydroxyl butyric acid 0 0.4 0.3-1 h
Melatonin 61-78 1.8-2.5 40–50 min
Meprobamate 15 0.7 6-7 h
Ramelteon 82 74 1-3 h
Zaleplon 60 1.0-1.5 0.9-1.2 h
Zolpidem 93 0.5-0.7 1.4-4.5 h
Zopiclone and eszopiclone 45 1.3-1.6 3.5-6.5 h

Selected Aspects of Nonbenzodiazepine Overdose:
Agent Features Commonly Seen with Overdose Unique Toxicologic Effects
Buspirone Sedation, GI distress, vomiting, hypotension, priapism & dizziness. Generalized seizures (rare)
Serotonin syndrome (possible)
Carisoprodol Sedation, coma, cardiovascular collapse, pulmonary edema, Myoclonic jerks
Meprobamate Sedation, coma, cardiopulmonary depression Gastric bezoar with prolonged coma
Chloral hydrate Coma Cardiac instability, ventricular arrhythmias, sensitivity to catecholamines, GI distress, hemorrhagic gastritis
Hydroxybutyrate Amnesia, sedation, seizure, coma, cardiac and respiratory depression Steep dose-response curve
Sudden awakening
Melatonin Sedation, headache, dizziness, fatigue,  disorientation None observed
Ramelteon Sedation None observed
Zolpidem Sedation,  vivid dreams, sleep-walking & driving, coma possible Limited experience, vomiting
Zaleplon Sedation, incoordination Limited experience, headache (possible)
Zopiclone and eszopiclone Sedation Limited experience, none observed

 

ED CARE AND DISPOSITION:

  • In general, management for the non-benzodiazepines is supportive. Flumazenil is ineffective for these medications.
  • For ventricular arrhythmias in the setting of chloral hydrate intoxication, IV B-Blocker (e.g. propranolol 1mg IV or 0.01 to 0.1 mg/kg IV in children) are first-line agents.
  • Disposition is largely guided by the degree of symptoms. Have a low threshold for admission of any pt. with altered mental status, abnormal vital signs, or arrhythmias.
  • Consult psychiatric services when appropriate.