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Diazepam International Programme on Chemical Safety Poisons Information Monograph 181 Pharmaceutical This mongraph is harmonised with the Group monograph on Benzodiazepines (PIM G008).Diazepam ATC classification indexPsycholeptics (N05)/Anxiolytics (N05B)/Benzodiazepine derivatives (N05BA)methyl diazepinone;diacepin;La III;Ro 5-2807;1.4.1 CAS number439-14-51.4.2 Other numbersRTECS DF1575000Diazepam as the only active substance: Diazeplex, Diazepam, Relanium, Stesolid, Valium, Others. Combination products: Aneurol, Ansium, Calmaven, Diaceplex, Edym Sedante, Gobanal, Pacium, Pertranquil, Reladon, Tepazepam, Tropargal, Vincosedan.Central nervous system, causing depression of respiration and consciousness.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 justified.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.Synthetic 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 diazepam.Chemical name 7-Chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin- 2-one Alternative 7-Chloro-1-methyl-5-phenyl-3H-1,4-benzodiazepin-2(1H)-oneMolecular formula C₁₆H₁₃ClN₂O Molecular weight 284.763.3.1 ColourWhite or yellow3.3.2 State/FormSolid-crystals3.3.3 DescriptionMelting 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 (Reynolds, 1993). 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.3.4.1 Shelf-life of the substance5 years (oral tablets) 3 years, (parenteral formulation)3.4.2 Storage conditionsStore in air-tight containers. Protect from light (Reynolds, 1993).4.1.1 Indications4.1.2 DescriptionAnxiety 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. Insomnia 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 include: CNS stimulants (e.g. cocaine, amphetamines) Drug-induced seizures -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., 1988) -Physostigmine (Klemm, 1983) -Pyrethroids (Gammon, 1982).4.2.1 AdultsOral Anxiolytic mg to 30 mg daily, in 2 or 3 divided doses. Hypnotic to 30 mg as a single dose. Muscle spasm 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 doseRectal 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.Parenteral 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.Tetanus 100 to 300 µg/kg intravenously (repeated every 1 to 4 hours)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.Status epilepticus 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 be instituted.Continuous infusion for ICU patients 3 to 10 mg/kg over 24 hours.4.2.2 ChildrenOral 40 to 200 µg/kg of bodyweight (Initial dose), which can be repeated as tolerated up to 4 times daily.Rectal Suppositories 40 to 200 µg/kg of bodyweight, which can be repeated as tolerated up to 4 times daily. Rectal solution For the treatment of seizures, 5 mg (1 to 3 years of age). May be repeated after 5 to 10 minutes.Parenteral Sedative or Muscle relaxant 200 µg/kg of bodyweight intravenously. Status epilepticus 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 parenteral formulation. 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 Myasthenia gravis Close angle glaucoma Poisoning by other CNS depressants Breast feeding Geriatric patients Severe liver failure Pregnancy (USPC, 1989)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 models. 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, 1991).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; Reynolds, 1993). 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., 1987). 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 venous irritation. 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.Oral 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 bioavailability close to 1.0. (Mandelli et al., 1978).Parenteral Intramuscular 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). Intravenous 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, 1993).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.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).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.7.1.1 ToxicodynamicsThe 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 system. 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).7.1.2 PharmacodynamicsThe 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., 1979). 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 disorders.7.2.1 Human data7.2.1.1 AdultsThere 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.7.2.1.2 ChildrenAs 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., 1989).7.2.2 Relevant animal dataAcute LD50 (oral) rat 1200 mg/kg LD50 (oral) dog 1000 mg/kg LD50 (oral) mice 700 mg/kg (Clarke, 1978)Sub-chronic dosing 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 is unclear.7.2.3 Relevant in vitro dataNo 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, 1990).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 al.(1979).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).Metabolic interactions 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, 1993). 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: Cimetidine Oral contraceptives Disulfiram Erythromycin Isoniazid Probenicid Propranolol Fluvoxamine Imipramine Fluoxetine CiprofloxacinAgents inducing diazepam metabolism: Rifampin Phenytoin Carbamazepine Phenobarbital Cigarette smoking (Gilman et al., 1990; Plon & Gottschalk, 1988; Reynolds, 1993; USPC, 1989; Lemberger et al., 1988; Perucca et al., 1994; Okiyama et al., 1987).Dynamic interaction 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 involved. Diazepam can decrease the efficacy of L-dopa used for the treatment of Parkinsonism. The effect is reversible (Reynolds, 1993). The anticonvulsant action of diazepam antagonizes the pro- convulsant activity of certain agents, including cocaine and strychnine.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 frequently. 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 al., 1978). 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 weeks.8.1.1 Sampling and specimen collection8.1.1.1 Toxicological analyses8.1.1.2 Biomedical analyses8.1.1.3 Arterial blood gas analysis8.1.1.4 Haematological analyses8.1.1.5 Other (unspecified) analyses8.1.2 Storage of laboratory samples and specimens8.1.2.1 Toxicological analyses8.1.2.2 Biomedical analyses8.1.2.3 Arterial blood gas analysis8.1.2.4 Haematological analyses8.1.2.5 Other (unspecified) analyses8.1.3 Transport of laboratory samples and specimens8.1.3.1 Toxicological analyses8.1.3.2 Biomedical analyses8.1.3.3 Arterial blood gas analysis8.1.3.4 Haematological analyses8.1.3.5 Other (unspecified) analyses8.2.1 Tests on toxic ingredient(s) of material8.2.1.1 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 specimens8.2.2.1 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 analyses8.3.1 Biochemical analysis8.3.1.1 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 fluids8.3.2 Arterial blood gas analyses8.3.3 Haematological analyses"Basic analyses" "Dedicated analyses" "Optional analyses"8.3.4 Interpretation of biomedical investigationsSample 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.9.1.1 IngestionThe 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 collapse9.1.2 InhalationNot relevant.9.1.3 Skin exposureNo data.9.1.4 Eye contactNo data.9.1.5 Parenteral exposureOverdose 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 Other9.2.1 IngestionToxic 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 InhalationNo data.9.2.3 Skin exposureNo data.9.2.4 Eye contactNo data.9.2.5 Parenteral exposureThe chronic parenteral administration of benzodiazepines may produce thrombophlebitis and tissue irritation, in addition to the usual symptoms (Greenblat & Koch-Weser, 1973).9.2.6 OtherNo data.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.9.4.1 CardiovascularHypotension, 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 RespiratoryRespiratory 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 Neurological9.4.3.1 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 system9.4.3.3 Autonomic nervous system9.4.3.4 Skeletal and smooth muscle9.4.4 GastrointestinalOral 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 HepaticA case of cholestatic jaundice due focal hepatic necrosis was associated with the administration of diazepam (Tedesco & Mills, 1982).9.4.6 Urinary9.4.6.1 RenalVesical hypotonia and urinary retention has been reported in association with diazepam poisoning (Chadduck et al., 1973).9.4.6.2 Other9.4.7 Endocrine and reproductive systemsGalactorrhoea 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 DermatologicalBullae 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 effectsBrown opacification of the lens occurred in 2 patients who used diazepam for several years (Pau Braune, 1985).9.4.10 HaematologicalNo data.9.4.11 ImmunologicalAllergic reaction as above (see 9.4.8).9.4.12 Metabolic9.4.12.1 Acid-base disturbancesNo direct disturbances have been described.9.4.12.2 Fluid and electrolyte disturbancesNo direct disturbances have been described.9.4.12.3 Others9.4.13 Allergic reactionsHypersensitivity 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 effectsHypothermia was reported in 15% of cases in one series. (Martin, 1985; Hojer et al., 1989).9.4.15 Special risksPregnancy 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).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).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.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 given orally.Methods of enhancing elimination are not indicated.10.5.1 AdultsFlumazenil, 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 ChildrenThe 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).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.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. 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Guy's Hospital Reports, London, 123:13-25.Author Dr Pere Munne Urgencias (Toxicologia) Hospital Clinic Emergency Department 170 Villarroel Street 08036 Barcelona Spain Tel: 34-3-4546000 Fax: 34-3-4546691 Date: April 1990 Peer Review: Strasbourg, France, April 1990 Adelaide, Australia, April 1991 Dr. Wm Watson, August, 1996 INTOX - 9, Cardiff, Wales, September, 1996 This monograph has been harmonised with the Group Monograph (G008) on Benzodiazepines: 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. 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