| 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|
| 2.1 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|
| 4.1 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 ENTRY|
| 5.1 Oral|
| 5.2 Inhalation|
| 5.3 Dermal|
| 5.4 Eye|
| 5.5 Parenteral|
| 5.6 Other|
| 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|
| 188.8.131.52 Adults|
| 184.108.40.206 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|
| 220.127.116.11 Toxicological analyses|
| 18.104.22.168 Biomedical analyses|
| 22.214.171.124 Arterial blood gas analysis|
| 126.96.36.199 Haematological analyses|
| 188.8.131.52 Other (unspecified) analyses|
| 8.1.2 Storage of laboratory samples and specimens|
| 184.108.40.206 Toxicological analyses|
| 220.127.116.11 Biomedical analyses|
| 18.104.22.168 Arterial blood gas analysis|
| 22.214.171.124 Haematological analyses|
| 126.96.36.199 Other (unspecified) analyses|
| 8.1.3 Transport of laboratory samples and specimens|
| 188.8.131.52 Toxicological analyses|
| 184.108.40.206 Biomedical analyses|
| 220.127.116.11 Arterial blood gas analysis|
| 18.104.22.168 Haematological analyses|
| 22.214.171.124 Other (unspecified) analyses|
| 8.2 Toxicological Analyses and Their Interpretation|
| 8.2.1 Tests on toxic ingredient(s) of material|
| 126.96.36.199 Simple Qualitative Test(s)|
| 188.8.131.52 Advanced Qualitative Confirmation Test(s)|
| 184.108.40.206 Simple Quantitative Method(s)|
| 220.127.116.11 Advanced Quantitative Method(s)|
| 8.2.2 Tests for biological specimens|
| 18.104.22.168 Simple Qualitative Test(s)|
| 22.214.171.124 Advanced Qualitative Confirmation Test(s)|
| 126.96.36.199 Simple Quantitative Method(s)|
| 188.8.131.52 Advanced Quantitative Method(s)|
| 184.108.40.206 Other Dedicated Method(s)|
| 8.2.3 Interpretation of toxicological analyses|
| 8.3 Biomedical investigations and their interpretation|
| 8.3.1 Biochemical analysis|
| 220.127.116.11 Blood, plasma or serum|
| 18.104.22.168 Urine|
| 22.214.171.124 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|
| 126.96.36.199 Central nervous system (CNS)|
| 188.8.131.52 Peripheral nervous system|
| 184.108.40.206 Autonomic nervous system|
| 220.127.116.11 Skeletal and smooth muscle|
| 9.4.4 Gastrointestinal|
| 9.4.5 Hepatic|
| 9.4.6 Urinary|
| 18.104.22.168 Renal|
| 22.214.171.124 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|
| 126.96.36.199 Acid-base disturbances|
| 188.8.131.52 Fluid and electrolyte disturbances|
| 184.108.40.206 Others|
| 9.4.13 Allergic reactions|
| 9.4.14 Other clinical effects|
| 9.4.15 Special risks|
| 9.5 Other|
| 9.6 Summary|
| 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|
|14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES)|
International Programme on Chemical Safety
Poisons Information Monograph 181
This mongraph is harmonised with the Group monograph on
Benzodiazepines (PIM G008).
ATC classification index
Psycholeptics (N05)/ Anxiolytics (N05B)/
Benzodiazepine derivatives (N05BA)
methyl diazepinone; diacepin;
La III; Ro 5-2807;
1.4 Identification numbers
1.4.1 CAS number
1.4.2 Other numbers
1.5 Main brand names, main trade names
Diazepam as the only active substance:
Diazeplex, Diazepam, Relanium, Stesolid, Valium, Others.
Aneurol, Ansium, Calmaven, Diaceplex, Edym Sedante, Gobanal,
Pacium, Pertranquil, Reladon, Tepazepam, Tropargal,
1.6 Main manufacturers, main importers
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 other
manifestations 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.
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
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
A method for the synthesis of diazepam has been
described(Sternbach et al, 1961). Benzoyl chloride reacts
with p-chloroaniline to produce 2-amino-5-chlorobenzophenone.
This is converted to the oxime with hydroxylamine. After
cyclization with chloroacetyl chloride and ring enlargement
with alkali treatment, 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-
benzodiazepin-2-one-4-oxide is reduced and methylatedto
3.2 Chemical structure
Molecular formula C16H13ClN2O
Molecular weight 284.76
3.3 Physical properties
White or yellow
Melting point 131.5 to 134.5 C.
Odourless, slightly bitter taste
The solubility of diazepam as per the British
Pharmacopoeia is very slightly soluble in water,
soluble in alcohol and freely soluble in chloroform
The solubility of diazepam as per the United States
Pharmacopeia is soluble 1 in 16 of ethyl alcohol, 1 in
2 of chloroform, and 1 in 39 of ether; practically
insoluble in water (Reynolds, 1993).
The pH is neutral.
3.4 Other characteristics
3.4.1 Shelf-life of the substance
5 years (oral tablets)
3 years, (parenteral formulation)
3.4.2 Storage conditions
Store in air-tight containers. Protect from
light (Reynolds, 1993).
Seizures, status epilepticus
Symptoms of drug withdrawal associated with the
chronic abuse of ethanol, benzodiazepines,
barbiturates, and other CNS depressants.
Skeletal muscle spasticity and acute muscular spasms,
including tetanus and cerebral palsy.
Anxiety and/or desire for producing amnesia prior to
surgery, dental, and endoscopic procedures
Conscious sedation for short anesthesia, alone or in
combination with an opioid.
Continuous infusion for sedation or seizures in the
intensive care setting
Treatment of toxicity, based on the literature, can
CNS stimulants (e.g. cocaine, amphetamines)
-Sarin, VX, Soman, and potentially organophosphate
pesticides (in conjunction with atropine and oximes)
(Gupta, 1984; McDonough et al., 1989)
-Lindane (Griffith & Woolley, 1989)
-Chloroquine (Havens et al., 1988; Riou et al.,
-Physostigmine (Klemm, 1983)
-Pyrethroids (Gammon, 1982).
4.2 Therapeutic dosage
mg to 30 mg daily, in 2 or 3 divided doses.
to 30 mg as a single dose.
to 15 mg daily in divided doses. In severe spasticity
associated with cerebral palsy, doses may be increased
gradually up to 60 mg daily
Premedication or sedation in surgery, dentistry to 20
mg as a single dose
Given as suppositories at the same doses used orally.
The oral solution can be administered rectally, and
has been used as treatment of seizures primarily in
children. The rectal solution is administered as a
single dose of 10 mg, followed by another dose 5
minutes later if there is no response in adults and
children more than 3 years of age.
Severe anxiety or acute muscle spasm
Intravenous doses of 2 to 5 mg should be administered
at intervals of at least 10 min until the desired
effect is achieved. The dose should be administered
at a rate of less than 5 mg per minute.
100 to 300 µg/kg intravenously (repeated every 1 to 4
Premedication or sedation in surgery, dentistry
2 to 10 mg intravenous doses, repeated at intervals of
at least 5 to 10 minutes, until adequate sedation
and/or anxiolysis is achieved.
5 to 10 mg intravenous doses. May be repeated every 5
to 10 minutes until termination of seizures. A maximum
dose of 40 to 60 mg is used. If this dose is
ineffective, other anticonvulsant drug therapy should
Continuous infusion for ICU patients
3 to 10 mg/kg over 24 hours.
40 to 200 µg/kg of bodyweight (Initial dose), which
can be repeated as tolerated up to 4 times daily.
40 to 200 µg/kg of bodyweight, which can be repeated
as tolerated up to 4 times daily.
For the treatment of seizures, 5 mg (1 to 3 years of
age). May be repeated after 5 to 10 minutes.
Sedative or Muscle relaxant
200 µg/kg of bodyweight intravenously.
200 to 300 µg/kg of bodyweight intravenously. May
berepeated after 5 to 10 minutes if required.
(USPC, 1989; Reynolds, 1993)
The primary absolute contraindication is an allergy to
diazepam or other benzodiazepines, or the constituents of the
There are relative contraindications, which require more
careful monitoring of patients after receiving diazepam, and
stronger consideration of alternative drug therapy. In these
patients, the initial dose should be decreased:
Chronic obstructive respiratory disease
Neonates and infants up to 6 months of age
Close angle glaucoma
Poisoning by other CNS depressants
Severe liver failure
5. ROUTES OF ENTRY
This is the most frequent route of diazepam
administration for therapeutic use as well as accidental
poisonings, intentional overdoses, and abuse.
The administration of diazepam solution into the lungs
via an endotracheal tube has been demonstrated to produce
therapeutic serum diazepam concentrations in animal
Histologic examination of the lung demonstrated pneumonitis.
These results suggest adequate absorption, however, the
increased pulmonary toxicity indicates that this route should
not be used in clinical practice (Rusli et al., 1987).
Diazepam is absorbed through the skin, however, this
route of administration is not used clinically (Hori,
No data available.
The preferred route of parenteral administration is
intravenous. Indications include severe anxiety, excitation,
alcohol and drug withdrawal syndrome, and seizures. The
intramuscular route of diazepam administration should be
avoided because absorption is erratic, and may be
significantly delayed. The benzodiazepine lorazepam is more
consistently absorbed from muscle, and should be used if
intramuscular administration is required (USPC 1989;
The intraosseous infusion of diazepam has been described as
efficacious in the critically ill child, however, this route
of administration is not commonly used (McNamara et al.,
Parenteral diazepam is irritating, and intravenous
administration should be into a large peripheral vein. The
rate of administration should be no faster than 5 mg per
minute, and be followed by a saline flush to decrease local
Significant adverse effects of intravenous diazepam include
coma, hypotension, bradycardia, and respiratory failure. Such
effects usually occur in the setting of rapid administration,
administration of excessive doses, or administration to high-
risk patients (the elderly, infants, patients with chronic
respiratory disease) (USPC 1989; Reynolds, 1993).
Administration of diazepam rectally as either
suppositories or solution results in good absorption. This
route of administration is primarily used in convulsing
children with no route of parenteral access.
6.1 Absorption by route of exposure
Diazepam is absorbed rapidly following oral administration;
with peak plasma concentrations generally being achieved
within 1.0 hour (range 0.08 to 2.5 hours). (Greenblatt et
al., 1988). The absorption rate is slowed by food and
antacids. Absorption is almost complete with
close to 1.0. (Mandelli et al., 1978).
Absorption is poor and erratic after intramuscular injection;
plasma levels attained are equal to 60% of those reached
after the same oral dose (Hillestad et al., 1974). The use of
intramuscular diazepam has been described, however, this
route should only be considered when other routes of
administration or benzodiazepines are not available (USPC,
1989; Reynolds, 1993; Vale & Scott, 1974).
Blood concentrations of 400 ng/mL and 1,200 ng/mL were
measured 15 minutes after intravenous bolus doses of 10 and
20 mg, respectively (Hillestead et al., 1974). Chronic
administration of daily doses ranging from 2 mg to 30 mg
result in plasma diazepam concentrations of 20 ng/mL to 1,010
ng/mL, and concentrations of desmethyldiazepam, an active
metabolite, of 55 ng/mL to 1,765 ng/mL (Reynolds,
6.2 Distribution by route of exposure
The volume of distribution has been calculated to range
from 0.7 to 2.6 L/kg. (Mandelli et al, 1978; Baselt & Cravey,
1989) In human volunteers, the plasma protein binding of
diazepam is greater than 95% (Klotz et al., 1976a; Mandelli
et al., 1978). The concentration in the CSF appears to
approximately correlate with the plasma free fraction (Kanto
et al., 1975). Patients with low serum albumin concentrations
may have greater CNS effects secondary to an increased free
fraction of diazepam.
Following intravenous administration, diazepam concentrations
can be described by a 2 compartment kinetic model. An initial
rapid decline in serum concentrations associated with
distribution into tissue, is followed by a slower decline
reflecting the terminal elimination half-life.
Due to its high lipid solubility diazepam passes rapidly into
the brain, and other well perfused organs, and is afterwards
redistributed to muscle and adipose tissue. Enterohepatic
circulation is minimal. Diazepam crosses the placental
barrier to the fetus and is present in breast milk.
6.3 Biological half-life by route of exposure
The terminal elimination half-life of diazepam ranges
from approximately 24 hours to more than two days. With
chronic dosing, steady state concentrations of diazepam are
achieved between 5 days to 2 weeks. The half-life is
prolonged in the elderly and in patients with cirrhosis or
hepatitis. It is shortened in patients taking drugs which
induce hepatic enzymes, included anticonvulsants. The active
metabolite desmethyldiazepam has a longer half-life than
diazepam, and takes longer to reach steady state
concentrations. (Klotz et al, 1976a; Mandelli et al, 1978;
Klotz et al.,1975; Andreasen et al., 1976).
A sample of 48 healthy male volunteers ranging in age from 18
to 44 years demonstrated variable pharmacokinetic parameters.
This demonstrates the need for further understanding of the
variables which determine diazepam absorption, distribution,
metabolism, and elimination (Greenblatt et al., 1989).
Diazepam is primarily metabolized by hepatic enzymes,
with very little unchanged drug eliminated in the urine. The
hepatic cytochrome enzyme isozyme responsible for S-
mephenytoin hydroxylation polymorphism is most likely the
hepatic enzyme species responsible for diazepam metabolism
(Perucca et al., 1994) Hepatic n-demthylation results in the
formation of the active metabolite desmethyldiazepam (also
known as nordiazepam). This metabolite is hydroxylated to
form oxazepam, which is conjugated to oxazepam glucuronide. A
minor active metabolite is temazepam. The main active
substances found in blood are diazepam and desmethyldiazepam,
because oxazepam and temazepam are conjugated and excreted at
almost the same rate as they are generated (Greenblatt et
al., 1988; Baselt & Cravey, 1989).
6.5 Elimination and excretion
A two-compartment open model is usually used to describe
elimination kinetics of diazepam and plasma clearance of 26
to 35 mL/min after a single intravenous dose has been
reported (Klotz et al., 1975; Andreasen et al., 1976; Klotz
et al., 1976a). Urinary excretion of diazepam is primarily in
the form of sulphate and glucuronide conjugates, and accounts
for the majority of the ingested dose (Mandelli et al., 1978;
Baselt & Cravey, 1986; Gilman et al., 1990) There is some
evidence that the disposition of diazepam is slowed by
chronic dosing and by plasma desmethyldiazepam levels (Klotz
et al., 1976b).
There is some evidence for species differences in biliary
excretion. However, studies by Klotz et al. (1975; 1976a,b)
suggest that biliary excretion of diazepam is probably
clinically unimportant in man.
7. PHARMACOLOGY AND TOXICOLOGY
7.1 Mode of action
The toxic and therapeutic effects of diazepam
are a result of its effect on CNS GABA activity. GABA
(gamma-aminobutyric acid) is an important inhibitory
neurotransmitter which mediates pre- and post-synaptic
inhibition in all regions of the central nervous
Diazepam and the other benzodiazepines appear to
either enhance or facilitate GABA activity by binding
to the benzodiazepine receptor, which is part of a
complex including an aminobutyric acid receptor,
benzodiazepine receptor, and barbiturate receptor.
Binding at the complex results in increased CNS
inhibition by GABA. The anticonvulsant and other
effects of diazepam are believed to be produced by a
similar mechanism, possibly involving various subtypes
of the receptor (Gilman et al., 1990).
The pharmacodynamic effects of diazepam are
also produced primarily by its actions with the result
being enhancement of the inhibitory effects of GABA on
the CNS. Two different zones have been described for
the benzodiazepine binding at receptor sites (Squires
et al., 1979) and they have been classified as type I
(chloride independent) and type II (chloride
dependent. Type I receptor stimulation is believed to
be responsible for anxiolysis, and Type II receptors
responsible for sedation and ataxia (Klepner et al.,
Skeletal muscle relaxation is most likely secondary to
the CNS effects of diazepam, and may also involve
inhibition of a presynaptic neural conduction at GABA
mediated sites in the spinal chord. It is unclear how
diazepam produces amnesia. Similar to other sedative
hypnotic drugs, preanesthetic doses of diazepam
produce anterograde amnesia in the presence of
therapeutic concentrations of diazepam, probably by
impairing the establishment of the memory trace in the
CNS (Gilman et al., 1990) It has been suggested that
diazepam may have some anticholinergic effects,
however, these are not clearly defined, and not
generally of clinical importance. (Goodman & Gilman,
1986; USPC, 1989). Grade IV come has, however, been
reversed by physostigmine in a case of severe
nitrazepam poisoning, confirmed by drug screening.
The serum nitrazepam concentration was 6 µmol/L
(Jacobsen & Kjeldsen, 1979).
Tolerance to its anticonvulsant effects of diazepam
generally develop within the first 6 to 12 months of
therapy, which result in loss of anticonvulsant
effects. For this reason diazepam is not commonly
utilised for the chronic treatment of seizure
7.2.1 Human data
There is no specific dose associated
with death. In the few documented fatal
cases doses have not been known with
certainty and other factors complicated the
clinical presentation (Cardauns & Iffland,
1973). In a survey of 914 benzodiazepine
related deaths in North America, only 2 cases
were associated with diazepam alone, in the
remainder other drugs were present which
either contributed to or caused death (Finkle
et al., 1979). After the intentional
ingestion of doses of 450 to 500 mg, and 2000
mg in two cases, patients recovered without
specific therapy within 24 to 48 hours
(Greenblatt et al., 1978).
Toxicity associated with rapid intravenous
injection is not dose related, and may occur
at therapeutic doses.
As with adults, no specific diazepam
dose is associated with severe toxicity. A
range of 4 to 5 mg/kg has been described as
producing clinical toxicity. (Arcas Cruz,
1985). Cases involving the ingestion of 20
mg to 150 mg have resulted in complete
recovery (Clark, 1978).
The neonate is very sensitive to the effects
of benzodiazepine (Briggs et al.,
7.2.2 Relevant animal data
LD50 (oral) rat 1200 mg/kg
LD50 (oral) dog 1000 mg/kg
LD50 (oral) mice 700 mg/kg
A number of repeated dose studies have been carried
out. In general, toxic effects have not been
remarkable. In a three-month study in rats and a six-
month study in dogs, some increase in liver size was
seen, together with an increase in blood cholesterol;
in the dogs an elevation of plasma alanine
aminotransferase activity was observed (Scrollini et
al., 1975). The clinical significance of these data
7.2.3 Relevant in vitro data
No data available.
While it was suggested that diazepam may be associated
with increased frequency of tumours in some animal models,
this has not been confirmed. De la Iglesia et al. (1981)
found no increase in tumour frequency after feeding diazepam,
75 mg/kg/day, to rats and mice for 104 and 80 weeks,
respectively. There is no evidence of carcinogencity in
humans. (Reynolds, 1993) A suggestion that benzodiazepine
ingestion is associated with an increased risk of breast
cancer has been disproved by additional studies (Kaufman,
There is a some evidence that diazepam and other
benzodiazepines are teratogenic in humans, increasing the
risk of congenital malformations when ingested by the mother
during the first trimester of pregnancy (Reynolds, 1993;
USPC, 1989; Briggs et al., 1986).
Diazepam has been reported to have mutagenic activity in
the Salmonella typhimurium tester train TA100 in the Ames
test (Batzinger et al., 1978), and to be genotoxic in a mouse
bone marrow micronucleus test (Das & Kar, 1986). Little or
no effect was seen in an assay for chromosomal abberations,
performed in Chinese hamster cells in vitro, by Matsuoka et
Synergistic effects of CNS depression is observed when
diazepam is ingested together with ethanol and other CNS
depressant drugs. CNS depressant co-ingestants are very
common, and virtually always present if coma greater than
Grade II is present (Jatlow et al., 1979).
Diazepam does not induce or inhibit hepatic enzyme activity,
and does not alter the metabolism of other agents. There is
also no evidence of autoinduction or inhibition which would
significantly alter its own metabolism with chronic therapy
(Reynolds, 1993). There is a report suggesting that diazepam
therapy may alter digoxin serum concentrations (Reynolds,
As diazepam is primarily dependent on hepatic metabolism for
elimination, numerous agents which either induce or inhibit
hepatic cytochrome P450 pathways or conjugation can alter the
rate of diazepam metabolism. With many interactions it is
not clear whether the interaction is maintained with chronic
therapy. These interactions would be expected to be most
significant with chronic diazepam therapy, and their clinical
significance is variable. The following lists includes most
of the reported interactions (however, the possibility of
interactions between diazepam and any substance known to
alter hepatic metabolism should be considered).
Agents inhibiting diazepam metabolism:
Agents inducing diazepam metabolism:
(Gilman et al., 1990; Plon & Gottschalk, 1988; Reynolds,
1993; USPC, 1989; Lemberger et al., 1988; Perucca et al.,
1994; Okiyama et al., 1987).
The major dynamic interactions with diazepam involve the
synergistic increase in CNS depression (including central
respiratory depression and hemodynamic depression) associated
with other CNS depressant agents, including ethanol, non-
benzodiazepine sedative hypnotics, barbiturates, drugs with
CNS anticholinergic effects such as the antihistamines and
tricyclic antidepressants, and opioids. These interactions
increase synergistically the CNS depression, respiratory
depression, and hemodynamic depression produced by each agent
Diazepam can decrease the efficacy of L-dopa used for the
treatment of Parkinsonism. The effect is reversible
The anticonvulsant action of diazepam antagonizes the pro-
convulsant activity of certain agents, including cocaine and
7.7 Main adverse effects
The primary adverse effects are secondary to the
pharmacologic action of enhanced CNS GABA activity. Cognitive
and psychomotor abilities may be impaired at therapeutic
doses. Additional adverse effects include dizziness and
prolonged reaction time, motor incoordination, ataxia, mental
confusion, dysarthria, anterograde amnesia, somnolence,
vertigo, and fatigue. Dysarthria and dystonia occur much less
Paradoxical reactions of CNS hyperactivity occur rarely and
manifest primarily as aggressive behaviour, irritability, and
anxiety. Intravenous injection can produce local phlebitis
and thrombophlebitis. Intra-articular injection may produce
arterial necrosis. Diazepam and other benzodiazepines can
cause physical and psychological dependence when administered
at high doses for prolonged periods of time (Hollister et
al., 1961; 1963; 1981; Hollister, 1988).
A withdrawal syndrome has been described after continuous
ingestion of 30 to 45 mg per day of diazepam for
approximately 6 weeks or longer. Symptoms are generally
minimal initially, and increase in severity over the first 5
to 9 days after diazepam ingestion is stopped. (Pevnick et
The clinical manifestations of the withdrawal syndrome are
similar to those associated with withdrawal of other sedative
hypnotic and CNS depressants drugs. The long half-life and
presence of active metabolites result in delayed onset of
symptoms. The symptoms include anxiety, insomnia,
irritability, confusion, anorexia, nausea and vomiting,
tremors, hypotension, hyperthermia, and muscular spasm.
Severe withdrawal symptoms include seizures and death. The
treatment to prevent withdrawal and minimize any symptoms is
to slowly reduce the dose of diazepam over 2 to 4
8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS
8.1 Material sampling plan
8.1.1 Sampling and specimen collection
220.127.116.11 Toxicological analyses
18.104.22.168 Biomedical analyses
22.214.171.124 Arterial blood gas analysis
126.96.36.199 Haematological analyses
188.8.131.52 Other (unspecified) analyses
8.1.2 Storage of laboratory samples and specimens
184.108.40.206 Toxicological analyses
220.127.116.11 Biomedical analyses
18.104.22.168 Arterial blood gas analysis
22.214.171.124 Haematological analyses
126.96.36.199 Other (unspecified) analyses
8.1.3 Transport of laboratory samples and specimens
188.8.131.52 Toxicological analyses
184.108.40.206 Biomedical analyses
220.127.116.11 Arterial blood gas analysis
18.104.22.168 Haematological analyses
22.214.171.124 Other (unspecified) analyses
8.2 Toxicological Analyses and Their Interpretation
8.2.1 Tests on toxic ingredient(s) of material
126.96.36.199 Simple Qualitative Test(s)
188.8.131.52 Advanced Qualitative Confirmation Test(s)
184.108.40.206 Simple Quantitative Method(s)
220.127.116.11 Advanced Quantitative Method(s)
8.2.2 Tests for biological specimens
18.104.22.168 Simple Qualitative Test(s)
22.214.171.124 Advanced Qualitative Confirmation Test(s)
126.96.36.199 Simple Quantitative Method(s)
188.8.131.52 Advanced Quantitative Method(s)
184.108.40.206 Other Dedicated Method(s)
8.2.3 Interpretation of toxicological analyses
8.3 Biomedical investigations and their interpretation
8.3.1 Biochemical analysis
220.127.116.11 Blood, plasma or serum
18.104.22.168 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
8.5 Overall interpretation of all toxicological analyses and
For toxicological analyses: whole blood 10 mL; urine 25 mL
and gastric contents 25 mL.
Blood gases, serum electrolytes, blood glucose and hepatic
enzymes when necessary in severe cases.
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.
9. CLINICAL EFFECTS
9.1 Acute poisoning
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
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
Coma Grade II: Depressed level of consciousness, no
response to painful stimuli
Deep tendon reflexes and vital signs
Coma Grade III: Depressed level of consciousness, no
response to painful stimuli
Deep tendon reflexes absent. Vital
Coma Grade IV: Coma grade III plus respiratory and
9.1.3 Skin exposure
9.1.4 Eye contact
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
9.2 Chronic poisoning
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
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.
9.2.3 Skin exposure
9.2.4 Eye contact
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).
9.3 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
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.
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).
22.214.171.124 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
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;
The muscle relaxation caused by
benzodiazepines is of CNS origin and
manifests as dysarthria, incoordination and
difficulty standing and walking.
126.96.36.199 Peripheral nervous system
188.8.131.52 Autonomic nervous system
184.108.40.206 Skeletal and smooth muscle
Oral benzodiazepine poisoning will produce
minimal effects on the gastrointestinal tract (GI)
tract but can occasionally cause nausea or vomiting
(Shader & Dimascio, 1970).
A case of cholestatic jaundice due focal
hepatic necrosis was associated with the
administration of diazepam (Tedesco & Mills,
Vesical hypotonia and urinary
retention has been reported in association
with diazepam poisoning (Chadduck et al.,
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).
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,
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
Allergic reaction as above (see 9.4.8).
220.127.116.11 Acid-base disturbances
No direct disturbances have been
18.104.22.168 Fluid and electrolyte disturbances
No direct disturbances have been
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.,
9.4.15 Special risks
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,
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).
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,
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;
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.
Benzodiazepines, particularly temazepam, have been abused
both orally and intravenously (Stark et al., 1987; Woods,
1987; Funderburk et al, 1988)
The amnesic effects of benzodiazepines have been used for
criminal purposes with medicolegal consequences (Ferner,
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
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.
Gastric lavage is not routinely indicated following
benzodiazepine overdose. Emesis is contraindicated because of
the potential for CNS depression. Activated charcoal can be
10.4 Enhanced elimination
Methods of enhancing elimination are not
10.5 Antidote treatment
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.,
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).
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.,
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
11. ILLUSTRATIVE CASES
11.1 Case reports from literature
A 61 year old women ingested between 450 and 500 mg of
diazepam approximately 8 hours before presentation. She had
been treated with imipramine for depression, though there was
no evidence of coingestion of imipramine. She did not
respond to the administration of naloxone or 50% Dextrose in
water intravenously, and responded only to noxious physical
stimuli. Her blood pressure was 110/80 mmHg, heart rate was
75 to 80 per minute, and respiratory rate was 20 per min.
Arterial blood gases were normal, as were other laboratory
tests. She was observed, and other than a mild episode of
hypotension which resolved without treatment, her recovery
was uneventful. She was fully alert and responsive 1 day
after admission (Greenblatt et al., 1978).
A 28 year old man ingested 2,000 mg diazepam approximately 10
hours before presentation. He had a blood pressure of 110/60
mmHg, heart rate of 68 per minute, and spontaneous
respirations of 16 per minute. He was responsive to verbal
stimuli, and oriented to person, place and time. He was
observed, and fully alert 2 days after admission (Greenblatt
et al., 1978).
A healthy young male known to use diazepam was admitted two
hours after ingestion of 1 gram of diazepam. Upon admission
he felt tired, otherwise the clinical examination and
standard laboratory evaluation was normal. The serum
diazepam concentration was 18.6 µmol/L. The patient
recovered uneventfully (Jacobsen et al., 1979).
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