Cinolazepam
| 1. NAME |
| 1.1 Substance |
| 1.2 Group |
| 1.3 Synonyms |
| 1.4 Identification numbers |
| 1.4.1 CAS number |
| 1.4.2 Other numbers |
| 1.5 Main brand names, main trade names |
| 1.6 Main manufacturers, main importers |
| 2. SUMMARY |
| 2.1 Main risks and target organs |
| 2.2 Summary of clinical effects |
| 2.3 Diagnosis |
| 2.4 First aid measures and management principles |
| 3. PHYSICO-CHEMICAL PROPERTIES |
| 3.1 Origin of the substance |
| 3.2 Chemical structure |
| 3.3 Physical properties |
| 3.3.1 Colour |
| 3.3.2 State/Form |
| 3.3.3 Description |
| 3.4 Other characteristics |
| 3.4.1 Shelf-life of the substance |
| 3.4.2 Storage conditions |
| 4. USES |
| 4.1 Indications |
| 4.1.1 Indications |
| 4.1.2 Description |
| 4.2 Therapeutic dosage |
| 4.2.1 Adults |
| 4.2.2 Children |
| 4.3 Contraindications |
| 5. ROUTES OF EXPOSURE |
| 5.1 Oral |
| 5.2 Inhalation |
| 5.3 Dermal |
| 5.4 Eye |
| 5.5 Parenteral |
| 5.6 Other |
| 6. KINETICS |
| 6.1 Absorption by route of exposure |
| 6.2 Distribution by route of exposure |
| 6.3 Biological half-life by route of exposure |
| 6.4 Metabolism |
| 6.5 Elimination and excretion |
| 7. PHARMACOLOGY AND TOXICOLOGY |
| 7.1 Mode of action |
| 7.1.1 Toxicodynamics |
| 7.1.2 Pharmacodynamics |
| 7.2 Toxicity |
| 7.2.1 Human data |
| 7.2.1.1 Adults |
| 7.2.1.2 Children |
| 7.2.2 Relevant animal data |
| 7.2.3 Relevant in vitro data |
| 7.3 Carcinogenicity |
| 7.4 Teratogenicity |
| 7.5 Mutagenicity |
| 7.6 Interactions |
| 7.7 Main adverse effects |
| 8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS |
| 8.1 Material sampling plan |
| 8.1.1 Sampling and specimen collection |
| 8.1.1.1 Toxicological analyses |
| 8.1.1.2 Biomedical analyses |
| 8.1.1.3 Arterial blood gas analysis |
| 8.1.1.4 Haematological analyses |
| 8.1.1.5 Other (unspecified) analyses |
| 8.1.2 Storage of laboratory samples and specimens |
| 8.1.2.1 Toxicological analyses |
| 8.1.2.2 Biomedical analyses |
| 8.1.2.3 Arterial blood gas analysis |
| 8.1.2.4 Haematological analyses |
| 8.1.2.5 Other (unspecified) analyses |
| 8.1.3 Transport of laboratory samples and specimens |
| 8.1.3.1 Toxicological analyses |
| 8.1.3.2 Biomedical analyses |
| 8.1.3.3 Arterial blood gas analysis |
| 8.1.3.4 Haematological analyses |
| 8.1.3.5 Other (unspecified) analyses |
| 8.2 Toxicological Analyses and Their Interpretation |
| 8.2.1 Tests on toxic ingredient(s) of material |
| 8.2.1.1 Simple Qualitative Test(s) |
| 8.2.1.2 Advanced Qualitative Confirmation Test(s) |
| 8.2.1.3 Simple Quantitative Method(s) |
| 8.2.1.4 Advanced Quantitative Method(s) |
| 8.2.2 Tests for biological specimens |
| 8.2.2.1 Simple Qualitative Test(s) |
| 8.2.2.2 Advanced Qualitative Confirmation Test(s) |
| 8.2.2.3 Simple Quantitative Method(s) |
| 8.2.2.4 Advanced Quantitative Method(s) |
| 8.2.2.5 Other Dedicated Method(s) |
| 8.2.3 Interpretation of toxicological analyses |
| 8.3 Biomedical investigations and their interpretation |
| 8.3.1 Biochemical analysis |
| 8.3.1.1 Blood, plasma or serum |
| 8.3.1.2 Urine |
| 8.3.1.3 Other fluids |
| 8.3.2 Arterial blood gas analyses |
| 8.3.3 Haematological analyses |
| 8.3.4 Interpretation of biomedical investigations |
| 8.4 Other biomedical (diagnostic) investigations and their interpretation |
| 8.5 Overall interpretation of all toxicological analyses and toxicological investigations |
| 8.6 References |
| 9. CLINICAL EFFECTS |
| 9.1 Acute poisoning |
| 9.1.1 Ingestion |
| 9.1.2 Inhalation |
| 9.1.3 Skin exposure |
| 9.1.4 Eye contact |
| 9.1.5 Parenteral exposure |
| 9.1.6 Other |
| 9.2 Chronic poisoning |
| 9.2.1 Ingestion |
| 9.2.2 Inhalation |
| 9.2.3 Skin exposure |
| 9.2.4 Eye contact |
| 9.2.5 Parenteral exposure |
| 9.2.6 Other |
| 9.3 Course, prognosis, cause of death |
| 9.4 Systematic description of clinical effects |
| 9.4.1 Cardiovascular |
| 9.4.2 Respiratory |
| 9.4.3 Neurological |
| 9.4.3.1 Central nervous system (CNS) |
| 9.4.3.2 Peripheral nervous system |
| 9.4.3.3 Autonomic nervous system |
| 9.4.3.4 Skeletal and smooth muscle |
| 9.4.4 Gastrointestinal |
| 9.4.5 Hepatic |
| 9.4.6 Urinary |
| 9.4.6.1 Renal |
| 9.4.6.2 Other |
| 9.4.7 Endocrine and reproductive systems |
| 9.4.8 Dermatological |
| 9.4.9 Eye, ear, nose, throat: local effects |
| 9.4.10 Haematological |
| 9.4.11 Immunological |
| 9.4.12 Metabolic |
| 9.4.12.1 Acid-base disturbances |
| 9.4.12.2 Fluid and electrolyte disturbances |
| 9.4.12.3 Others |
| 9.4.13 Allergic reactions |
| 9.4.14 Other clinical effects |
| 9.4.15 Special risks |
| 9.5 Other |
| 9.6 Summary |
| 10. MANAGEMENT |
| 10.1 General principles |
| 10.2 Life supportive procedures and symptomatic/specific treatment |
| 10.3 Decontamination |
| 10.4 Enhanced elimination |
| 10.5 Antidote treatment |
| 10.5.1 Adults |
| 10.5.2 Children |
| 10.6 Management discussion |
| 11. ILLUSTRATIVE CASES |
| 11.1 Case reports from literature |
| 12. Additional information |
| 12.1 Specific preventive measures |
| 12.2 Other |
| 13. REFERENCES |
| 14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES) |
Cinolazepam
International Programme on Chemical Safety
Poisons Information Monograph 920
Pharmaceutical
This monograph does not contain all of the sections completed. This
mongraph is harmonised with the Group monograph on Benzodiazepines
(PIM G008).
1. NAME
1.1 Substance
Cinolazepam
1.2 Group
ATC classification index
Psycholeptics (N05)/ Anxiolytics (N05B)/
Benzodiazepine derivatives (N05BA)
1.3 Synonyms
OX-373
1.4 Identification numbers
1.4.1 CAS number
75696-02-5
1.4.2 Other numbers
1.5 Main brand names, main trade names
Gerodorm
1.6 Main manufacturers, main importers
2. SUMMARY
2.1 Main risks and target organs
Central nervous system, causing depression of
respiration and consciousness.
2.2 Summary of clinical effects
Central nervous system (CNS) depression and coma, or
paradoxical excitation, but deaths are rare when
benzodiazepines are taken alone. Deep coma and
othermanifestations of severe CNS depression are rare.
Sedation, somnolence, diplopia, dysarthria, ataxia and
intellectual impairment are the most common adverse effects
of benzodiazepines. Overdose in adults frequently involves
co-ingestion of other CNS depressants, which act
synergistically to increase toxicity. Elderly and very young
children are more susceptible to the CNS depressant action.
Intravenous administration of even therapeutic doses of
benzodiazepines may produce apnoea and hypotension.
Dependence may develop with regular use of benzodiazepines,
even in therapeutic doses for short periods. If
benzodiazepines are discontinued abruptly after regular use,
withdrawal symptoms may develop. The amnesia produced by
benzodiazepines can have medico-legal consequences.
2.3 Diagnosis
The clinical diagnosis is based upon the history of
benzodiazepine overdose and the presence of the clinical
signs of benzodiazepine intoxication.
Benzodiazepines can be detected or measured in blood and
urine using standard analytical methods. This information may
confirm the diagnosis but is not useful in the clinical
management of the patient.
A clinical response to flumazenil, a specific benzodiazepine
antagonist, also confirms the diagnosis of benzodiazepine
overdose, but administration of this drug is rarely
justified.
2.4 First aid measures and management principles
Most benzodiazepine poisonings require only clinical
observation and supportive care. It should be remembered that
benzodiazepine ingestions by adults commonly involve co-
ingestion of other CNS depressants and other drugs. Activated
charcoal normally provides adequate gastrointestinal
decontamination. Gastric lavage is not routinely indicated.
Emesis is contraindicated. The use of flumazenil is reserved
for cases with severe respiratory or cardiovascular
complications and should not replace the basic management of
the airway and respiration. The routine use of flumazenil is
contraindicated because of potential complications, including
seizures. Renal and extracorporeal methods of enhanced
elimination are not effective.
3. PHYSICO-CHEMICAL PROPERTIES
3.1 Origin of the substance
3.2 Chemical structure
Chemical Name:
7-Chloro-5-(2-fluorophenyl)-2,3-dihydro-3-hydroxy-2-oxo-
-1H-1,4-benzodiazepine-1-propionitrile.
Molecular Formula: C18H13ClFN3O2
Molecular Weight: 357.8
3.3 Physical properties
3.3.1 Colour
3.3.2 State/Form
3.3.3 Description
3.4 Other characteristics
3.4.1 Shelf-life of the substance
3.4.2 Storage conditions
4. USES
4.1 Indications
4.1.1 Indications
4.1.2 Description
4.2 Therapeutic dosage
4.2.1 Adults
4.2.2 Children
4.3 Contraindications
5. ROUTES OF EXPOSURE
5.1 Oral
5.2 Inhalation
5.3 Dermal
5.4 Eye
5.5 Parenteral
5.6 Other
6. KINETICS
6.1 Absorption by route of exposure
6.2 Distribution by route of exposure
6.3 Biological half-life by route of exposure
6.4 Metabolism
6.5 Elimination and excretion
7. PHARMACOLOGY AND TOXICOLOGY
7.1 Mode of action
7.1.1 Toxicodynamics
7.1.2 Pharmacodynamics
7.2 Toxicity
7.2.1 Human data
7.2.1.1 Adults
7.2.1.2 Children
7.2.2 Relevant animal data
7.2.3 Relevant in vitro data
7.3 Carcinogenicity
7.4 Teratogenicity
7.5 Mutagenicity
7.6 Interactions
7.7 Main adverse effects
8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS
8.1 Material sampling plan
8.1.1 Sampling and specimen collection
8.1.1.1 Toxicological analyses
8.1.1.2 Biomedical analyses
8.1.1.3 Arterial blood gas analysis
8.1.1.4 Haematological analyses
8.1.1.5 Other (unspecified) analyses
8.1.2 Storage of laboratory samples and specimens
8.1.2.1 Toxicological analyses
8.1.2.2 Biomedical analyses
8.1.2.3 Arterial blood gas analysis
8.1.2.4 Haematological analyses
8.1.2.5 Other (unspecified) analyses
8.1.3 Transport of laboratory samples and specimens
8.1.3.1 Toxicological analyses
8.1.3.2 Biomedical analyses
8.1.3.3 Arterial blood gas analysis
8.1.3.4 Haematological analyses
8.1.3.5 Other (unspecified) analyses
8.2 Toxicological Analyses and Their Interpretation
8.2.1 Tests on toxic ingredient(s) of material
8.2.1.1 Simple Qualitative Test(s)
8.2.1.2 Advanced Qualitative Confirmation Test(s)
8.2.1.3 Simple Quantitative Method(s)
8.2.1.4 Advanced Quantitative Method(s)
8.2.2 Tests for biological specimens
8.2.2.1 Simple Qualitative Test(s)
8.2.2.2 Advanced Qualitative Confirmation Test(s)
8.2.2.3 Simple Quantitative Method(s)
8.2.2.4 Advanced Quantitative Method(s)
8.2.2.5 Other Dedicated Method(s)
8.2.3 Interpretation of toxicological analyses
8.3 Biomedical investigations and their interpretation
8.3.1 Biochemical analysis
8.3.1.1 Blood, plasma or serum
"Basic analyses"
"Dedicated analyses"
"Optional analyses"
8.3.1.2 Urine
"Basic analyses"
"Dedicated analyses"
"Optional analyses"
8.3.1.3 Other fluids
8.3.2 Arterial blood gas analyses
8.3.3 Haematological analyses
"Basic analyses"
"Dedicated analyses"
"Optional analyses"
8.3.4 Interpretation of biomedical investigations
8.4 Other biomedical (diagnostic) investigations and their
interpretation
8.5 Overall interpretation of all toxicological analyses and
toxicological investigations
Sample collection
For toxicological analyses: whole blood 10 mL; urine 25 mL
and gastric contents 25 mL.
Biomedical analysis
Blood gases, serum electrolytes, blood glucose and hepatic
enzymes when necessary in severe cases.
Toxicological analysis
Qualitative testing for benzodiazepines is helpful to confirm
their presence, but quantitative levels are not clinically
useful. More advanced analyses are not necessary for the
treatment of the poisoned patient due the lack of correlation
between blood concentrations and clinical severity (Jatlow et
al., 1979; MacCormick et al., 1985; Minder, 1989).
TLC and EMIT: These provide data on the presence of
benzodiazepines, their metabolites and possible associations
with other drugs.
GC or HPLC: These permit identification and quantification of
the benzodiazepine which caused the poisoning and its
metabolites in blood and urine.
8.6 References
9. CLINICAL EFFECTS
9.1 Acute poisoning
9.1.1 Ingestion
The onset of impairment of consciousness is
relatively rapid in benzodiazepine poisoning. Onset
is more rapid following larger doses and with agents
of shorter duration of action. The most common and
initial symptom is somnolence. This may progress to
coma Grade I or Grade II (see below) following very
large ingestions.
Reed Classification of Coma (Reed et al., 1952)
Coma Grade I: Depressed level of consciousness,
response to painful stimuli
Deep tendon reflexes and vital signs
intact
Coma Grade II: Depressed level of consciousness, no
response to painful stimuli
Deep tendon reflexes and vital signs
intact
Coma Grade III: Depressed level of consciousness, no
response to painful stimuli
Deep tendon reflexes absent. Vital
signs intact
Coma Grade IV: Coma grade III plus respiratory and
circulatory collapse
9.1.2 Inhalation
Not relevant.
9.1.3 Skin exposure
No data.
9.1.4 Eye contact
No data.
9.1.5 Parenteral exposure
Overdose by the intravenous route results in
symptoms similar to those associated with ingestion,
but they appear immediately after the infusion, and
the progression of central nervous system (CNS)
depression is more rapid. Acute intentional poisoning
by this route is uncommon and most cases are
iatrogenic. Rapid intravenous infusion may cause
hypotension, respiratory depression and
apnoea.
9.1.6 Other
9.2 Chronic poisoning
9.2.1 Ingestion
Toxic effects associated with chronic exposure
are secondary to the presence of the drug and
metabolites and include depressed mental status,
ataxia, vertigo, dizziness, fatigue, impaired motor
co-ordination, confusion, disorientation and
anterograde amnesia. Paradoxical effects of
psychomotor excitation, delirium and aggressiveness
also occur. These chronic effects are more common in
the elderly, children and patients with renal or
hepatic disease.
Administration of therapeutic doses of benzodiazepines
for 6 weeks or longer can result in physical
dependence, characterized by a withdrawal syndrome
when the drug is discontinued. With larger doses, the
physical dependence develops more rapidly.
9.2.2 Inhalation
No data.
9.2.3 Skin exposure
No data.
9.2.4 Eye contact
No data.
9.2.5 Parenteral exposure
The chronic parenteral administration of
benzodiazepines may produce thrombophlebitis and
tissue irritation, in addition to the usual symptoms
(Greenblat & Koch-Weser, 1973).
9.2.6 Other
No data.
9.3 Course, prognosis, cause of death
Benzodiazepines are relatively safe drugs even in
overdose. The clinical course is determined by the
progression of the neurological symptoms. Deep coma or other
manifestations of severe central nervous system (CNS)
depression are rare with benzodiazepines alone. Concomitant
ingestion of other CNS depressants may result in a more
severe CNS depression of longer duration.
The therapeutic index of the benzodiazepines is high and the
mortality rate associated with poisoning due to
benzodiazepines alone is very low. Complications in severe
poisoning include respiratory depression and aspiration
pneumonia. Death is due to respiratory arrest.
9.4 Systematic description of clinical effects
9.4.1 Cardiovascular
Hypotension, bradycardia and tachycardia have
been reported with overdose (Greenblatt et al., 1977;
Meredith & Vale 1985). Hypotension is more frequent
when benzodiazepines are ingested in association with
other drugs (Hojer et al., 1989). Rapid intravenous
injection is also associated with hypotension.
9.4.2 Respiratory
Respiratory depression may occur in
benzodiazepine overdose and the severity depends on
dose ingested, amount absorbed, type of benzodiazepine
and co-ingestants. Respiratory depression requiring
ventilatory support has occurred in benzodiazepine
overdoses (Sullivan, 1989; Hojer et al.,1989). The
dose-response for respiratory depression varies
between individuals. Respiratory depression or
respiratory arrest may rarely occur with therapeutic
doses. Benzodiazepines may affect the control of
ventilation during sleep and may worsen sleep apnoea
or other sleep-related breathing disorders, especially
in patients with chronic obstructive pulmonary disease
or cardiac failure (Guilleminault, 1990).
9.4.3 Neurological
9.4.3.1 Central nervous system (CNS)
CNS depression is less marked than
that produced by other CNS depressant agents
(Meredith & Vale, 1985). Even in large
overdoses, benzodiazepines usually produce
only mild symptoms and this distinguishes
them from other sedative-hypnotic agents.
Sedation, somnolence, weakness, diplopia,
dysarthria, ataxia and intellectual
impairment are the most common neurological
effects. The clinical effects of severe
poisoning are sleepiness, ataxia and coma
Grade I to Grade II (Reed). The presence of
more severe coma suggests the possibility of
co-ingested drugs. Certain of the newer
short-acting benzodiazepines (temazepam,
alprazolam and triazolam) have been
associated with several fatalities and it is
possible that they may have greater acute
toxicity (Forrest et al., 1986). The elderly
and very young children are more susceptible
to the CNS depressant action of
benzodiazepines.
The benzodiazepines may cause paradoxical CNS
effects, including excitement, delirium and
hallucinations. Triazolam has been reported
to produce delirium, toxic psychosis, memory
impairment and transient global amnesia
(Shader & Dimascio, 1970; Bixler et al,
1991). Flurazepam has been associated with
nightmares and hallucinations.
There are a few reports of extrapyramidal
symptoms and dyskinesias in patients taking
benzodiazepines (Kaplan & Murkafsky, 1978;
Sandyk, 1986).
The muscle relaxation caused by
benzodiazepines is of CNS origin and
manifests as dysarthria, incoordination and
difficulty standing and walking.
9.4.3.2 Peripheral nervous system
9.4.3.3 Autonomic nervous system
9.4.3.4 Skeletal and smooth muscle
9.4.4 Gastrointestinal
Oral benzodiazepine poisoning will produce
minimal effects on the gastrointestinal tract (GI)
tract but can occasionally cause nausea or vomiting
(Shader & Dimascio, 1970).
9.4.5 Hepatic
A case of cholestatic jaundice due focal
hepatic necrosis was associated with the
administration of diazepam (Tedesco & Mills,
1982).
9.4.6 Urinary
9.4.6.1 Renal
Vesical hypotonia and urinary
retention has been reported in association
with diazepam poisoning (Chadduck et al.,
1973).
9.4.6.2 Other
9.4.7 Endocrine and reproductive systems
Galactorrhoea with normal serum prolactin
concentrations has been noted in 4 women taking
benzodiazepines (Kleinberg et al., 1977).
Gynaecomastia has been reported in men taking high
doses of diazepam (Moerck & Majelung, 1979). Raised
serum concentrations of oestrodiol were observed in
men taking diazepam 10 to 20 mg daily for 2 weeks
(Arguelles & Rosner, 1975).
9.4.8 Dermatological
Bullae have been reported following overdose
with nitrazepam and oxazepam (Ridley, 1971; Moshkowitz
et al., 1990).
Allergic skin reactions were attributed to diazepam at
a rate of 0.4 per 1000 patients (Brigby,
1986).
9.4.9 Eye, ear, nose, throat: local effects
Brown opacification of the lens occurred in 2
patients who used diazepam for several years (Pau
Braune, 1985).
9.4.10 Haematological
No data.
9.4.11 Immunological
Allergic reaction as above (see 9.4.8).
9.4.12 Metabolic
9.4.12.1 Acid-base disturbances
No direct disturbances have been
described.
9.4.12.2 Fluid and electrolyte disturbances
No direct disturbances have been
described.
9.4.12.3 Others
9.4.13 Allergic reactions
Hypersensitivity reactions including
anaphylaxis are very rare (Brigby, 1986). Reactions
have been attributed to the vehicle used for some
parenteral diazepam formulations (Huttel et al.,
1980). There is also a report of a type I
hypersensitivity reaction to a lipid emulsion of
diazepam (Deardon, 1987).
9.4.14 Other clinical effects
Hypothermia was reported in 15% of cases in
one series. (Martin, 1985; Hojer et al.,
1989).
9.4.15 Special risks
Pregnancy
Passage of benzodiazepines across the placenta depends
on the degree of protein binding in mother and fetus,
which is influenced by factors such as stage of
pregnancy and plasma concentrations of free fatty
acids in mother and fetus (Lee et al., 1982). Adverse
effects may persist in the neonate for several days
after birth because of immature drug metabolising
enzymes. Competition between diazepam and bilirubin
for protein binding sites could result in
hyperbilirubinemia in the neonate (Notarianni,
1990).
The abuse of benzodiazepines by pregnant women can
cause withdrawal syndrome in the neonate. The
administration of benzodiazepines during childbirth
can produce hypotonia, hyporeflexia, hypothermia and
respiratory depression in the newborn.
Benzodiazepines have been used in pregnant patients
and early reports associated diazepam and
chlordiazepoxide with some fetal malformations, but
these were not supported by later studies (Laegreid et
al., 1987; McElhatton, 1994).
Breast feeding
Benzodiazepines are excreted in breast milk in
significant amounts and may result in lethargy and
poor feeding in neonates. Benzodiazepines should be
avoided in nursing mothers (Brodie, 1981; Reynolds,
1996).
9.5 Other
Dependence and withdrawal
Benzodiazepines have a significant potential for abuse and
can cause physical and psychological dependence. Abrupt
cessation after prolonged use causes a withdrawal syndrome
(Ashton, 1989). The mechanism of dependence is probably
related to functional deficiency of GABA activity.
Withdrawal symptoms include anxiety, insomnia, headache,
dizziness, tinnitus, anorexia, vomiting, nausea, tremor,
weakness, perspiration, irritability, hypersensitivity to
visual and auditory stimuli, palpitations, tachycardia and
postural hypotension. In severe and rare cases of withdrawal
from high doses, patients may develop affective disorders or
motor dysfunction: seizures, psychosis, agitation, confusion,
and hallucinations (Einarson, 1981; Hindmarch et al, 1990;
Reynolds, 1996).
The time of onset of the withdrawal syndrome depends on the
half-life of the drug and its active metabolites; the
symptoms occur earlier and may be more severe with short-
acting benzodiazepines. Others risk factors for withdrawal
syndrome include prolonged use of the drug, higher dosage and
abrupt cessation of the drug.
Abuse
Benzodiazepines, particularly temazepam, have been abused
both orally and intravenously (Stark et al., 1987; Woods,
1987; Funderburk et al, 1988)
Criminal uses
The amnesic effects of benzodiazepines have been used for
criminal purposes with medicolegal consequences (Ferner,
1996).
9.6 Summary
10. MANAGEMENT
10.1 General principles
Most benzodiazepine poisonings require only clinical
observation and supportive care. It should be remembered that
benzodiazepine ingestions by adults commonly include other
drugs and other CNS depressants. Activated charcoal normally
provides adequate gastrointestinal decontamination. Gastric
lavage is not routinely indicated. Emesis is contraindicated.
The use of flumazenil is reserved for cases with severe
respiratory or cardiovascular complications and should not
replace the basic management of the airway and respiration.
Renal and extracorporeal elimination methods are not
effective.
10.2 Life supportive procedures and symptomatic/specific treatment
The patient should be evaluated to determine adequacy
of airway, breathing and circulation. Continue clinical
observation until evidence of toxicity has resolved.
Intravenous access should be available for administration of
fluid. Endotracheal intubation, assisted ventilation and
supplemental oxygen may be required on rare occasions, more
commonly when benzodiazepines are ingested in large amounts
or with other CNS depressants.
10.3 Decontamination
Gastric lavage is not routinely indicated following
benzodiazepine overdose. Emesis is contraindicated because of
the potential for CNS depression. Activated charcoal can be
given orally.
10.4 Enhanced elimination
Methods of enhancing elimination are not
indicated.
10.5 Antidote treatment
10.5.1 Adults
Flumazenil, a specific benzodiazepine
antagonist at central GABA-ergic receptors is
available. Although it effectively reverses the CNS
effects of benzodiazepine overdose, its use in
clinical practice is rarely indicated.
Use of Flumazenil is specifically contraindicated when
there is history of co-ingestion of tricyclic
antidepressants or other drugs capable of producing
seizures (including aminophylline and cocaine),
benzodiazepine dependence, or in patients taking
benzodiazepines as an anticonvulsant agent. In such
situations, administration of Flumazenil may
precipitate seizures (Lopez, 1990; Mordel et al.,
1992).
Adverse effects associated with Flumazenil include
hypertension, tachycardia, anxiety, nausea, vomiting
and benzodiazepine withdrawal syndrome.
The initial intravenous dose of 0.3 to 1.0 mg may be
followed by further doses if necessary. The absence of
clinical response to 2 mg of flumazenil within 5 to 10
minutes indicates that benzodiazepine poisoning is not
the major cause of CNS depression or coma.
The patient regains consciousness within 15 to 30
seconds after injection of flumazenil, but since it is
metabolised more rapidly than the benzodiazepines,
recurrence of toxicity and CNS depression can occur
and the patient should be carefully monitored after
initial response to flumazenil therapy. If toxicity
recurs, further bolus doses may be administered or an
infusion commenced at a dose of 0.3 to 1.0 mg/hour
(Meredith et al., 1993).
10.5.2 Children
The initial intravenous dose of 0.1 mg should
be repeated each minute until the child is awake.
Continuous intravenous infusion should be administered
at a rate of 0.1 to 0.2 mg/hour (Meredith et al.,
1993).
10.6 Management discussion
Most benzodiazepine poisonings require only clinical
observation and supportive care. Flumazenil is the specific
antagonist of the effects of benzodiazepines, but the routine
use for the treatment of benzodiazepine overdosage is not
recommended. The use of Flumazenil should only be considered
where severe CNS depression is observed. This situation
rarely occurs, except in cases of mixed ingestion. The
administration of flumazenil may improve respiratory and
cardiovascular function enough to decrease the need for
intubation and mechanical ventilation, but should never
replace basic management principles.
Flumazenil is an imidazobenzodiazepine and has been shown to
reverse the sedative, anti-convulsant and muscle-relaxant
effects of benzodiazepines. In controlled clinical trials,
flumazenil significantly antagonizes benzodiazepine-induced
coma arising from anaesthesia or acute overdose. However, the
use of flumazenil has not been shown to reduce mortality or
sequelae in such cases.
The administration of flumazenil is more effective in
reversing the effects of benzodiazepines when they are the
only drugs producing CNS toxicity. Flumazenil does not
reverse the CNS depressant effects of non-benzodiazepine
drugs, including alcohol. The diagnostic use of flumazenil in
patients presenting with coma of unknown origin can be
justified by its high therapeutic index and the fact that
this may limit the use of other diagnostic procedures (CT
scan, lumbar puncture, etc).
Flumazenil is a relatively expensive drug and this may also
influence its use, especially in areas with limited
resources.
11. ILLUSTRATIVE CASES
11.1 Case reports from literature
12. Additional information
12.1 Specific preventive measures
12.2 Other
13. REFERENCES
Arguelles AE, & Rosner J. (1975) Diazepam and plasma
testosterone levels. Lancet, ii: 607.
Ashton CH (1989) Drug-induced stupor and coma: some physical signs
and their pharmacological basis. Adverse drug React Acute
Poisoning Rev, 8: 1-59.
Bixler EO, Kales A, Manfredi RL, Vgontzas AN, Tyson KL, & Kales JD
(1991) Next-day memory impairment with triazolam use. Lancet, 337:
827-831.
Brigby M. (1986) Drug induced cutaneous reactions. JAMA, 256:
3358-63.
Brodie RR, Chasseaud LF & Taylor T (1981) Concentrations of N-
descyclopropylmethyl-prazepam in whole-blood, plasma and milk
after administration of prazepam to humans. Biopharm Drug Dispos,
2: 59-68.
Chadduck WM, Loar CR & Denton IC. (1973) Vesical hypotonicity with
diazepam. J Urol, 109: 1005-1007.
Deardon DJ. (1987) Acute hypersensivity to IV Diazulmuls. Br J
Anaesth, 59: 391.
Einarson TR (1981) Oxazepam withdrawal convulsions. Drug Intell
Clin Pharm, 15: 487.
Ellenhorn, M. (1996) Medical Toxicology. 2nd Ed., Elsevier.
Ferner RE (1996) Forensic Pharmacology, 1st Ed. Oxford University
Press, Oxford.
Forrest ARW, Marsh I, Bradshaw C & Braich SK (1986) Fatal
temazepam overdoses (letter). Lancet, 2: 226.
Funderburk FR, Griffiths RR, McLeod DR, Bigelow GE, Mackenzie A,
Liebson IA & Newmeth-Coslett R (1988) Relative abuse liability of
lorazepam and diazepam: an evaluation in "recreational" drug
users. Drug Alcohol Depend, 22: 215-222.
Greenblatt DJ, Allen MD, Noel BJ et al (1977) Acute overdose with
benzodiazepine derivatives. Clin Pharm Ther, 21: 497-513.
Guilleminault C. (1990) Benzodiazepines, bresthing and sleep. Am J
Med, 88 (suppl 3A): 25S - 28S.
Hindmarch I, Beaumont G, Brandon S, & Leonard, B. (1990)
Benzodiazepines Current Concepts, John Wiley & Sons Ltd, UK.
Hojer J, Baehrendtz S & Gustafsson L. (1989) Benzodiazepine
poisoning: experience of 702 admissions to an intensive care unit
during a 14-year period. J Intern Med, 226: 117-122.
Huttel MS, Schou Olesen A & Stofferson E (1980) Complement-
mediated reactions to diazepam with Cremophor as solvent. Br J
Anaesth, 52: 77-9.
Hyams SW & Keroub C (1977) Glaucoma due to diazepam. Am J
Psychiatry, 134: 477-479.
Kaplan SR, & Murkofsky C (1978) Oral-buccal dyskinesic synptoms
associated with low dose benzodiazepine treatment. Am J
Psychiatry, 135: 1558-1559.
Kleinberg DL, Noel GL & Frantz AG (1977) Galactorrhea a study of
235 cases. N Eng J Med 296: 589-600.
Laegreid L, Olegard R, & Wahlstrom J (1987) Abnormalities in
children exposed to benzodiazepines in utero. Lancet, 1:108-
109.
Lee JN, Chen SS, Richens A, Menabawey m & Chard T (1982) Serum
protein binding of diazepam in maternal and foetal serum during
pregnancy. Br J Clin Pharmacol, 14: 551-4.
Lopez A & Rebollo J (1990) Benzodiazepine withdrawal syndrome
after a benzodiazepine antagonist. Crit Care Med, 18:1480-
1481.
Martin SM (1985) The effect of diazepam on body temperature change
in humans during cold exposure. J Clin Pharmacol, 25: 611-
613.
McCormick SR, Nielsen J & Jatlow PI (1985) Alprazolam overdose:
clinical findings and serum concentrations in two cases. J Clin
Psychiatr, 46:247-248.
McElhatton PR. (1994) The effects of benzodiazepines use during
pregnancy and lactation. Reprod Toxicol, 8: 461-75.
Meredith TJ, Jacobsen D, Haines JA, Berger JC (1993) IPCS/CEC
Evaluation of Antidotes Series, Vol1, Naloxone, flumazenil and
dantrolene as antidotes, 1st ed. Cambridge University Press,
Cambridge.
Meredith TJ, & Vale JA (1985) Poisoning due to psychotropic
agents. Adverse Drug React Acute Poison Rev, 4: 83-122.
Minder EI (1989) Toxicity in a case of acute and massive overdose
of chlordiazepoxide and its correlation to blood concentration.
Clin Toxicol, 27: 117-127.
Moerck HJ, Majelung G (1979) Gynaecomastia and diazepam
abuse.Lancet, i: 1344-5.
Mordel A, Winkler E, Almog S, Tirosh M & Ezra D (1992) Seizures
after flumazenil administration in a case of combined
benzodiazepine and tricyclic antidepressant overdose. Crit Care
Med, 12: 1733-1734.
Notarianni LJ. (1990) Plasma protein binding of drugs in pregnancy
and neonates. Clin Pharnacokinet, 18: 20-36.
Pau Braune H (1985) [Eyes effect of diazepam.] Klin Monatsbl
Augenheilkd, 187: 219-20 (in German).
Reed C E, Driggs M F, & Foote CC (1952) Acute barbiturate
intoxication. A study of 300 cases based on a physiologic system
of classification of the severity of intoxication. Ann Intern Med,
37: 390-396.
Reynolds J (1996) Martindale, The Extra Pharmacopeia. 30th ed. The
Pharmaceutical Press, London, 699-744.
Ridley CM (1971) Bullous lesions in nitrazepan overdosage. Br Med
J, 3: 28-29.
Sandyk R (1986) Orofacial diskynesias associated with lorazepam
therapy. Clin Pharm, 5: 419-21.
Shader RI & Dimascio A (1970) Psychotropic drug side effects, 1st
ed. Willians & Wilkins, Baltimore.
Stark C, Sykes R & Mullin P (1987) Temazepam abuse (letter).
Lancet, 2: 802-803.
Sullivan RJ Jr (1989) Respiratory depression requiring ventilatory
support following 0.5 mg of Triazolam. J Am Geriatr, Soc 37: 450-
452.
Tedesco FJ, & Mills LR. (1982) Diazepam hepatites. Dig Dis Sci 27:
470-2.
14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE
ADDRESS(ES)
Author: Dr Ligia Fruchtengarten
Poison Control Centre of Sao Paulo - Brazil
Hospital Municipal Dr Arthur Ribeiro de Saboya -
Coperpas 12
FAX / Phone: 55 11 2755311
E-mail: lfruchtengarten@originet.com.br
Mailing Address: Hospital Municipal Dr Arthur Ribeiro de Saboya -
Coperpas 12
Centro de Controle de Intoxicaçoes de Sao Paulo
Av Francisco de Paula Quintanilha Ribeiro, 860
04330 - 020 Sao Paulo - SP - Brazil.
Date: July 1997
Peer Review: INTOX 10 Meeting, Rio de Janeiro, Brazil,
September 1997.
R. Ferner, L. Murray (Chairperson), M-O.
Rambourg, A. Nantel, N. Ben Salah, M. Mathieu-
Nolf, A.Borges.
Review 1998: Lindsay Murray
Queen Elizabeth II Medical Centre
Perth, Western Australia.
Editor: Dr M.Ruse, April 1998