Toxicity,Sedative-
Hypnotics
中山急诊 姚晨玲
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
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
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
? 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.,
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
? 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
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,
? 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
Treatment of complication
? Pneumonia
? Arrhythmias
? Acute renal failure
Prognosis
prophylaxis
Hypnotics
中山急诊 姚晨玲
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
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
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
? 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.,
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
? 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
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,
? 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
Treatment of complication
? Pneumonia
? Arrhythmias
? Acute renal failure
Prognosis
prophylaxis
