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Toxicity, Sedative-
Hypnotics
复旦大学
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
Background
acute sedative-hypnotics poisoning
withdrawal syndrome
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Etiology
Benzodiazepines (BZD)
• Long acting (half life >30h):
chlordiazepoxide (利眠宁)
diazepam(地西泮、安定)
flurazepam (氟安定)
• Short acting (half life 6-30h):
alprazolam(阿普唑仑)
• Ultrashort acting :
triazolam(三唑仑)
Etiology
Barbiturates
Ultrashort acting
Methohexital (Brevital甲己炔巴比妥)
thiopental (Pentothal硫喷妥那)
Short acting
pentobarbital (Nembutal戊巴比妥)
secobarbital (Seconal司可巴比妥)
Intermediate acting
Amobarbital (Amytal异戊巴比妥)
butalbital (Fioricet, Fiorinal异丁巴比妥)
Long acting
Phenobarbital (Luminal鲁米那)
Nonbarbiturate, nonbenzodiazepine
sedative-hypnotics (NBNB)
Chloral hydrate (水合氯醛)
Ethchlorvynol (乙氯维诺)
Glutethimide (导眠能)
Methyprylon (甲乙哌酮)
Meprobamate (眠尔通)
Etiology
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一、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
Pathogenesis
Pathogenesis
2、Pharmacokinetics of Barbiturates
Barbiturates with low lipid solubility are excreted
in the unchanged form by the kidneys. ie
phenobarbital(苯巴比妥).
Barbiturates with high lipid solubility are
metabolized to more polar compounds in the
liver before being excreted via the kidneys. ie
thiopental (硫喷妥).
3、Pharmacokinetics of NBNB
Most NBNB are extensively metabolized by the liver
Pathogenesis
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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
二、 The mechanism of action
Pathogenesis
BZD
GABA
chloride channel
Cl- Cl-
++ + + +-
-
---
hyperpolarization
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.
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
Clinical
Clinical
Glutethimide (Doriden)
Loss of brainstem reflexes
Flaccidity
Anticholinergic effects
Delayed gastric emptying
May cause hyperthermia or heatstroke
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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
Clinical
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).
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
Lab Studies
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Diagnosis
History
Symptom and sign
serum drug concentrations
Differentials
Toxicity, Alcohols
Hypoglycemia
Diabetic Ketoacidosis
Neoplasms, Brain
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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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.
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.
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
Treatment
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Treatment of complication
Pneumonia
Arrhythmias
Acute renal failure
Prognosis
prophylaxis