| 독성 요약 | IDENTIFICATION: Diazepam is classified as a psycholeptic, anxiolytic benzodiazepine derivative. Diazepam is a crystalline solid. Diazepam is very slightly soluble in water, soluble in alcohol and freely soluble in chloroform. Indications: Treatment of anxiety disorders, seizures and 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. Treatment of 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. HUMAN EXPOSURE: Main risks and target organs: Central nervous system, causing depression of respiration and consciousness. 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 apnea 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. Contraindications: 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 diseaseneonates and infants up to 6 months of agemyasthenia gravis patients, close angle glaucoma, poisoning by other CNS depressantsbreast feedinggeriatric patients, patients with severe liver failure and pregnancy. Routes of entry: Oral: This is the most frequent route of diazepam administration for therapeutic use as well as accidental poisonings, intentional overdoses, and abuse. Inhalation: 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. Dermal: Diazepam is absorbed through the skin, however, this route of administration is not used clinically. Parenteral: 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. 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) Other: 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. Absorption by route of exposure: Oral: Diazepam is absorbed rapidly following oral administrationwith peak plasma concentrations generally being achieved within 1.0 hour (range 0.08 to 2.5 hours). The absorption rate is slowed by food and antacids. Absorption is almost complete with bioavailability. Parenteral: Intramuscular: Absorption is poor and erratic after intramuscular injectionplasma levels attained are equal to 60% of those reached after the same oral dose. 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. 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 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. Distribution by route of exposure: In human volunteers, the plasma protein binding of diazepam is greater than 95%. The concentration in the CSF appears to approximately correlate with the plasma free fraction. 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. 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. Metabolism: 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. Hepatic n-demethylation 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. Elimination and excretion: A two-compartment open model is usually used to describe elimination kinetics of diazepam, after a single intravenous dose has been determined. Urinary excretion of diazepam is primarily in the form of sulphate and glucuronide conjugates, and accounts for the majority of the ingested dose. There is some evidence that the disposition of diazepam is slowed by chronic dosing and by plasma desmethyldiazepam levels. There is some evidence for species differences in biliary excretion. Studies suggest that biliary excretion of diazepam is probably clinically unimportant in man. Mode of action: Toxicodynamics: 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 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. Pharmacodynamics: 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 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. 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. 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. The neonate is very sensitive to the effects of benzodiazepine. Teratogenicity: 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. Metabolic interactions: Diazepam does not induce or inhibit hepatic enzyme activity, and does not alter the metabolism of other agents. 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. Agents inhibiting diazepam metabolism: Cimetidine, oral contraceptives, disulfiram, erythromycin, isoniazid, probenecid, propranolol, fluvoxamine, imipramine, fluoxetine and ciprofloxacin. Agents inducing diazepam metabolism: Rifampin, phenytoin, carbamazepine and phenobarbital. 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. 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. 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. ANIMAL/PLANT STUDIES: 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 cholesterolin the dogs an elevation of plasma alanine aminotransferase activity was observed. There was no increase in tumour frequency after feeding diazepam to rats and mice for 104 and 80 weeks, respectively. There is no evidence of carcinogenicity in humans. Mutagenicity: Diazepam has been reported to have mutagenic activity in the Salmonella typhimurium tester train TA100 in the Ames test, and to be genotoxic in a mouse bone marrow micronucleus test. Little or no effect was seen in an assay for chromosomal aberrations, performed in Chinese hamster cells in vitro.Diazepam OverdoseBenzodiazepines bind nonspecifically to benzodiazepine receptors which mediate sleep, affects muscle relaxation, anticonvulsant activity, motor coordination, and memory. As benzodiazepine receptors are thought to be coupled to gamma-aminobutyric acid-A (GABA<sub>A</sub>) receptors, this enhances the effects of GABA by increasing GABA affinity for the GABA receptor. Binding of GABA to the site opens the chloride channel, resulting in a hyperpolarized cell membrane that prevents further excitation of the cell. |
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