Toxicity, Sedative-Hypnotics ???? ???

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Toxicity, Sedative-Hypnotics ???? ???
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Background

• Sedative-hypnotics are a group of drugs that
  cause CNS depression.
• Benzodiazepines (BZD)
• barbiturates
• nonbarbiturate nonbenzodiazepine
  sedative-hypnotics (NBNB)

the most commonly used agents
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Background

• acute sedative-hypnotics poisoning
• withdrawal syndrome

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Etiology

• Benzodiazepines (BZD)
• Long acting (half life gt30h)
• chlordiazepoxide (???)
• diazepam(??????)
• flurazepam (???)
• Short acting (half life 6-30h)
• alprazolam(????)
• Ultrashort acting
• triazolam(???)

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Etiology

• Barbiturates
• Ultrashort acting
• Methohexital (Brevital??????)
• thiopental (Pentothal????)
• Short acting
• pentobarbital (Nembutal????)
• secobarbital (Seconal?????)
• Intermediate acting
• Amobarbital (Amytal?????)
• butalbital (Fioricet, Fiorinal?????)
• Long acting
• Phenobarbital (Luminal???)

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Etiology

• Nonbarbiturate, nonbenzodiazepine
  sedative-hypnotics (NBNB)
• Chloral hydrate (????)
• Ethchlorvynol (????)
• Glutethimide (???)
• Methyprylon (????)
• Meprobamate (???)

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Pathogenesis

• ??Pharmacokinetics
• 1?Pharmacokinetics of the BZD
• Most BZD are extensively metabolized by the
  liver.
• Some are metabolized to products which are
  active
• and may have a much longer half life than the
  parent
• drug.
• The major route of metabolism is
  N-demethylation.
• in the elderly
• Cimetidine

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Pathogenesis

• 2?Pharmacokinetics of Barbiturates
• Barbiturates with low lipid solubility are
  excreted in the unchanged form by the kidneys. ie
  phenobarbital(????).
• Barbiturates with high lipid solubility are
  metabolized to more polar compounds in the liver
  before being excreted via the kidneys. ie
  thiopental (???).

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Pathogenesis

• 3?Pharmacokinetics of NBNB
• Most NBNB are extensively metabolized by the
  liver

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Pathogenesis
?? The mechanism of action

• BZD
• In the CNS, benzodiazepines exert their
  clinical effect by enhancing the activity of the
  inhibitory neurotransmitter GABA.
• (The clinical effects of GABA release and
  GABA-gated chloride channels include sleep
  induction and excitement inhibition)
• Barbiturates
• in prolongation of the duration of opening of
  GABA-gated chloride channels, leading to
  hyperpolarization of the membrane and suppression
  of neurotransmission. ?
• NBNB
• similar to the action of Barbiturates

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Cl-
Cl-

---
--

hyperpolarization
BZD
GABA
chloride channel
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Clinical

• Benzodiazepine
• blurred vision, dizziness, confusion,
  drowsiness, anxiety, agitation, and
  unresponsiveness or coma.
• BZD overdose in itself is remarkably safe. most
  patients with benzodiazepine overdose can be
  managed in the ED and released home after
  appropriate care.
• When combined with other sedatives (most
  frequently alcohol), patients with benzodiazepine
  overdose can present with profoundly depressed
  levels of consciousness. .
•  

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Clinical

• Barbiturates
• Mild intoxication is characterized by ataxia,
  incoordination, nystagmus, slurred speech, and
  altered level of consciousness.
• Moderate poisoning leads to respiratory
  depression and hyporeflexia.
• Severe poisoning leads to flaccid areflexic coma,
  apnea, and hypotension.
• Occasionally, hyperreflexia, rigidity, clonus,
  and Babinski signs are present.
• Miosis is common, but mydriasis may be present
  with certain agents.
• Generally, 10 times the hypnotic dose
  produces severe toxicity.

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Clinical

• Chloral hydrate
• Mild intoxication is characterized by ataxia,
  lethargy
• Severe poisoning leads to stupor, coma, pinpoint
  pupils, hypotension, slow or rapid and shallow
  respiration, hypothermia, areflexia, and muscle
  flaccidity.
• Arrhythmias

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Clinical

• Glutethimide (Doriden)
• Loss of brainstem reflexes
• Flaccidity
• Anticholinergic effects
• Delayed gastric emptying
• May cause hyperthermia or heatstroke

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Clinical

• Methaqualone (Quaalude)
• Resembles barbiturate poisoning
• Has more pronounced motor problems (eg, ataxia)
  and is known as wallbanger because of this
  phenomenon.
• Can lead to severe muscular hypertonicity and
  seizures

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Lab Studies

• Obtain a complete blood count (CBC), arterial
  blood gas (ABG), glucose, chemistry,
• Imaging Studies
• Obtain an abdominal x-ray. Chloral hydrate is
  radiopaque.
• Other Tests
• Obtain an electrocardiogram (ECG) Co-ingested
  drugs may have direct cardiac effects (eg,
  tricyclic antidepressants). 

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Lab Studies

• Quantitative serum drug concentrations are
  recommended for patients with serious toxicity
• Barbiturates For short-acting drugs, the lethal
  dose is 3 g or a serum concentration higher than
  3.5 mg/dL. For long-acting drugs, the lethal dose
  is 5-10 g or a concentration higher than 8 mg/dL.
• Chloral hydrate The lethal dose is 10 g and a
  concentration higher than 100 mg/mL is toxic

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Diagnosis

• History
• Symptom and sign
• serum drug concentrations

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Differentials

• Toxicity, Alcohols
• Hypoglycemia
• Diabetic Ketoacidosis
• Neoplasms, Brain

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Treatment

• Emergency Department Care
• Establish ABCs, obtain IV access, provide oxygen
• Ensure adequate airway and ventilation. Do
  endotracheal intubation if necessary.
• Fluid resuscitation and anti-shock
• Naloxone is recommended to the patients with
  comma.

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Treatment

• Prevention of absorption
• Gastric lavage may be performed if the patient
  presents obtunded within 2hour of ingestion
• Activated charcoal is recommended for
  sedative-hypnotic overdoses. Multi-dose activated
  charcoal (20-50 g q4h) is recommended for
  overdoses with barbiturates, glutethimide, and
  meprobamate.

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Treatment

• Elimination enhancement
• Alkaline diuresis enhances elimination of
  phenobarbital and other long-acting barbiturates.
  It is recommended for all symptomatic patients
  with long-acting barbiturate toxicity.
• Consider hemodialysis or hemoperfusion in
  glutethimide, methyprylon, phenobarbital,
  meprobamate, and chloral hydrate poisoning.

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Treatment

• Detoxicant Flumazenil
• Flumazenil competitively and reversibly binds
  benzodiazepine receptors (ie, GABA).
• The use of flumazenil for suspected
  benzodiazepine overdoses is controversial. If
  used, it should be administered slowly (0.2
  mg/min up to 3-5 mg) because large doses cause
  agitation and withdrawal.
• This drug is contraindicated in patients with
  increased intracranial pressure (ICP) or closed
  head injury (CHI), those with a history of
  epilepsy, or those known to have ingested a
  tricyclic antidepressant (TCA) agent

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Treatment of complication

• Pneumonia
• Arrhythmias
• Acute renal failure

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Prognosis prophylaxis