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CBD for Sleep and Insomnia
CBD, or cannabidiol, offers a range of benefits, including helping treat sleep problems, such as insomnia. Gain a deeper understanding of CBD and how it provides relief from insomnia. With this knowledge, you should find yourself getting a better night’s rest regularly. Some of the Top CBD Products for Sleep and Insomnia With all of the above information in mind, it is time to take a look at some of the best CBD products to help with your insomnia and sleeping problems. The following products are highly rated. Understanding CBD Before you can understand how CBD helps with sleep issues and insomnia, you need to have a better grasp of what it is. Cannabidiol is one of the cannabinoids found in cannabis plants. There are more than 100 cannabinoids, all of which occur naturally in cannabis. CBD is among the cannabinoids that provide the strongest benefits for those who consume cannabis or byproducts of it. Cannabidiol is linked to reducing chronic pain, preventing seizures, helping with sleep problems, and relieving nausea. It can even help reduce the symptoms associated with cancer. Not Psychoactive One of the most important things to know about CBD is that this cannabinoid is not psychoactive. In other words, you will not get high from taking CBD, and it should not interfere with your mental state in your daily life. Compared to THC The major psychoactive cannabinoid in cannabis is THC. It is the compound that produces the high associated with smoking marijuana. The Entourage Effect Many CBD products contain just CBD without any THC. Those products are ideal for people who take regular drug tests. Numerous CBD products also contain low levels of THC. These products can give you a positive result on a drug test, so keep that in mind when selecting a CBD product. The benefit of choosing a CBD product with THC is the entourage effect. It means that when you combine THC and CBD, it enhances the effects of the CBD. In other words, you should experience greater relief from insomnia or pain if you take a product with both CBD and THC than if you took one with just CBD. Extracting CBD CBD can be extracted from hemp or cannabis plants. Many extraction methods involve solvents that will separate the cannabinoids from the seeds and stalks. The process always removes the solvent to leave the CBD oil behind specifically. There are also some mechanical methods. CBD Is Legal While cannabis is not legal in many jurisdictions, CBD is in most. The caveat here is that the legal CBD must have no THC in some states. In other states, the THC levels must be under 0.03 percent. Remember that cannabis is illegal at the federal level, but many states have legalized it. Some of those only legalized medical marijuana, while others also legalized recreational use. Keep in mind that CBD can come from hemp or cannabis plants. The hemp-based CBD will be legal everywhere, assuming it does not have THC. Cannabis-based CBD has varying legality depending on the state. To avoid breaking the law when using CBD for your insomnia or sleep issues, take a few minutes to check your local regulations first. CBD products without THC should be legal, but products that also have THC might not be legal. Understanding Insomnia To better understand how CBD treats insomnia and other sleep disorders, familiarize yourself with the complications of insomnia. Those with insomnia have trouble falling asleep or staying asleep. They may also wake up earlier than they want and be unable to fall back asleep. Symptoms In addition to either having difficulty falling asleep and waking up in the night or too early in the morning, there are other symptoms of insomnia. These can include not feeling rested in the morning, being sleepless or tired during the day, anxiety, depression, irritability, trouble focusing, increased errors, and concerns about sleep. These combined symptoms can significantly impact your daily life. Suggested Prevention Many of the prevention methods for stopping insomnia can work well with CBD. These include keeping a consistent sleep and wake schedule, staying active, avoiding naps, avoiding caffeine and alcohol, and making a bedtime ritual. You could even include CBD in that bedtime ritual to further promote relaxation. The Problem with Traditional Insomnia Treatments There are a few issues with traditional treatments for insomnia, including pharmaceutical drugs. Many of these come with side effects, such as drowsiness. Some experts even argue that many sleeping pills are less effective than most people hope and have higher risks. Most people who use sleep medications feel confused, forgetful, drowsy, or confused the following day. There are also limitations on how long you can take sleep medications without side effects and limits on activities, such as combining them with alcohol or other medicine. There are also types of cognitive-behavioral therapy that can help with insomnia. However, these treatments require long-term effort and do not provide relief immediately. By contrast, CBD should help with quality sleep right away. How CBD Helps with Sleep There is early evidence confirming that cannabidiol does help with sleep. A study from January 2019 found promise in using CBD for treating short-term sleeping problems. There are a few factors that allow CBD to help people fall asleep and get better sleep. It Is Easier to Sleep Without Pain or Anxiety One of the ways that CBD promotes sleep is by relieving pain and providing anti-anxiety effects. Many people struggle to fall asleep and stay asleep because their pain keeps them up — or their worried thoughts do. By reducing pain or anxiety, CBD removes a major obstacle preventing a good night’s rest. A study from January 2019 looked at the role of CBD in anxiety and sleep, showing a positive correlation. The results indicated that patients who had anxiety or poor sleep reported a decrease in both or either when taking 25 milligrams of CBD each day. It May Interact with Brain Receptors A review from 2017 from Current Psychiatry Reports suggests that CBD may directly affect your sleep. This would happen by its interactions with brain receptors in charge of the body’s sleep and waking cycles. CBD Affects Sleep Cycles Back in 2014, research indicated that CBD could improve REM sleep. This study looked at patients with REM sleep behavior disorder (RBD), which tends to come with nightmares and poor sleep. In people who also have Parkinson’s disease, the study found improvements to RBD symptoms from taking CBD. Due to the small sample size, more research is necessary. Another study from 2017 similarly found potential in using CBD to treat RBD. The Role of Endocannabinoids Experts indicate that CBD also promotes good sleep quality via its interactions with the endocannabinoid system. The endocannabinoid system is responsible for ensuring our body remains in homeostasis. With the body in homeostasis, it becomes easier to fall asleep. CBD also prevents the breakdown of anandamide, a major endocannabinoid. The increase in circulation of this natural endocannabinoid helps return to your baseline more quickly, including after a stressful situation. This, in turn, makes sleeping easier. CBD Can Promote Wakefulness There is also research indicating that consuming CBD can promote wakefulness. This comes from a 2014 review that looked at research involving animals and humans. The authors found a connection between CBD and wakefulness, but they could not always pinpoint the reason. CBD May Help with Sleep Apnea A recent study found that CBD may even help with other sleep issues, such as sleep apnea. The researchers found that a drug containing CBD and purified delta-9-THC was effective. Those with higher doses of this drug, dronabinol, had reduced signs of sleepiness and reduced occurrences of hypopnea and apnea episodes. Although more research is necessary, this shows CBD has the potential to offer an alternative to CPAP masks and machines that most people with sleep apnea must use. How Much CBD to Take for Sleep Problems Everyone is different when it comes to the amount of CBD that they should take. As such, you will need to experiment before you find the ideal dose for you. Most experts agree that it is best to start small with CBD and work up to a higher dose if you do not notice results. Most people will want to start by trying 10 to 20 milligrams of CBD. Taking too little CBD may mean that you will not notice any improvements to your sleep. Taking too much could lead to grogginess when you wake up or mild side effects. Safety of Taking CBD There are minimal side effects of CBD, and few people notice any negative reactions. You may experience minor side effects, such as changes to your weight, changes in appetite, drowsiness, or diarrhea. Long-Term Safety Unfortunately, experts still have not completed enough research to confirm that CBD is safe for long term use. Despite this, it is almost surely safe because people have used it for centuries. Based on anecdotal evidence, CBD should be safe in the long term. We just do not have solid research to back this up yet. Talk to Your Doctor First Treat CBD as you would any other medication, and discuss it with your doctor before you start using it. This will ensure that it does not interact negatively with any of your existing conditions or medications. Your doctor can let you know if early research shows you should avoid CBD due to a medication or condition. These contraindications are rare, so most people will get approval from their doctor to take CBD. Choose a Safe Product To stay safe while taking CBD, you also need to choose your product carefully. The FDA considers CBD a supplement. As such, the FDA does not regulate it. This means that you must complete your own research to ensure that your chosen product does not include harmful ingredients. You can do this by looking for both third-party independent testing and a certificate of analysis. Most reputable CBD manufacturers will gladly share these lab results with you. Many have them easily available on their websites, while some require customers to send them an email requesting the information. If a company does not share any lab testing with customers, do not buy from it. There will be no way to confirm the product you buy does not contain harmful ingredients. Types of CBD Products for Insomnia or Sleep If you want to try taking CBD to improve your sleep, you will have the choice of several forms. Vape concentrates let you inhale the CBD. This method delivers quick results that do not last as long as other methods. Oils or tinctures involve consuming drops of the oil orally. This takes a little longer than vapes to deliver results but lasts longer. Capsules and pills will take slightly longer for the effects to begin, as your body must digest the pill. This method is relatively long-lasting and offers a high level of convenience. Gummies and other edibles will produce the longest-lasting results but also require the longest to take effect. They are also easy to dose. Using tinctures or oils is ideal for those who need to take unusual doses and want accuracy with dosing. Vaping is ideal for those who want immediate results. Gummies, pills, and capsules are perfect for those who want transportability, convenient dosing, and long-lasting results. Conclusion Insomnia and other sleep problems have the potential to significantly impact your daily life, causing tiredness and an inability to focus. CBD offers a natural alternative to traditional treatments. Most people who use CBD for sleep do not experience any side effects. CBD products are non-psychoactive unless they contain THC. This lets those with insomnia take advantage of this treatment option without worrying about failing a drug test or feeling high in the morning. You can take CBD before bed in various forms, with capsules, soft gels, and tinctures among the most common options. You can also use vape pens with CBD oil or chew CBD gummies before bed. With the help of CBD, it should become easier to fall asleep and stay asleep, leaving you well-rested and with enough energy to take on the day. Pregnancy and sleep Getting sleep during pregnancy is an interesting predicament, especially as the baby gets larger or in the case of multiples. Pregnant women often struggle to get comfortable due to the baby’s activity, their need to use the washroom regularly, physical issues, and the growing pressure from the uterus. Most women have heard they should try and get at least eight hours of sleep each night, if not more, from their doctors during their prenatal appointments. However, it is not always possible. What can be done to help? There are many options that can help pregnant women sleep more comfortably. What Are the Most Common Causes of Less Sleep for Most Pregnant Women? Several things can lead to sleep problems for pregnant women. For those who like to lie on their stomachs or backs, the change in sleep positions can be a difficult one to undertake. It is recommended that all pregnant women sleep on their sides for several reasons once they begin the second trimester. First, the weight of the growing uterus can be painful when sleeping on the back. It can cause backaches, trouble with digestion, and even result in the woman feeling dizzy. Second, as the baby grows, its weight can also limit blood flow to the uterus itself, as well as the lower extremities. The pressure cuts off the blood flow from the vena cava. This vein returns blood from the lower extremities back to the heart. These circulation issues can not only be painful but also leave the baby struggling to receive the proper amount of blood and nutrients that it needs to grow. Doctors often tell pregnant women that occasionally lying on their backs is fine, but not for extended periods. Another cause of lost sleep for many pregnant women is the need to use the washroom so regularly. As pregnancy progresses, the growing uterus puts much pressure on the bladder. It can cause women to need to use the washroom every hour or two all day and all night long. If pregnant women are getting their optimal amounts of water, which is roughly around 100 ounces per day, then using the washroom frequently becomes natural. The foods a woman chooses to eat can also impact her ability to sleep at night. Nearly any food can lead to heartburn toward the end of the pregnancy since the stomach is pushed up to make room for the growing baby. It creates a very acidic environment and can cause issues with heartburn no matter what or how often a woman eats. Many babies also tend to be more active during the nighttime hours. It is possible that when the mother stops moving around, the baby is no longer rocked into a sleepy state. The calm allows the baby to wake up and move, which often involves kicks and elbows to various ribs and internal organs. It can make sleeping a struggle for many pregnant women, plus it is often a time she wants to connect with her unborn child. Carrying around a growing baby is also exhausting for the pregnant woman. It can lead to more naps becoming necessary during the day. When a pregnant woman naps during the day, it can make her unable to sleep at night. While taking sleep where she can get it may feel like the right thing to do, it can also impact a woman’s ability to sleep at night and perpetuate the problem. Aches and pains of varying degrees are common during pregnancy. These issues can lead to trouble sleeping for many pregnant women. It could be that her breasts or back are sore, or that her stomach is in pain due to feeling nauseated. These are normal feelings during pregnancy, but they often interrupt sleep. If it becomes difficult to handle, women should speak with their doctors about how to manage their symptoms. There are ways of being able to decrease soreness or nausea, but they may require medical advice to be sure they are safe to use during pregnancy. Can Pregnant Women Struggle With Insomnia? Some pregnant women struggle with insomnia for a short time during their pregnancies, while others have it throughout nearly their entire pregnancy. It can be due to simply not being able to get comfortable, fears or anxiety about the baby or impending birth, or the physical changes that she goes through as the pregnancy progresses. For most women, insomnia passes once the baby is born, if not sooner. However, for others, medical steps may need to be taken to help the mother get as much sleep as possible during pregnancy. Does Changing Sleeping Positions Help Women Get More Sleep? The way a pregnant woman sleeps can go a long way toward helping her sleep. However, some people are not used to sleeping on their sides at all before pregnancy. Getting used to these new sleep positions can take time, but it can be done. One thing nearly all pregnant women may want to stock up on is a vast array of small, supple pillows or a professional pregnancy pillow to prop up the different parts of their bodies. It helps provide support as the uterus grows and keep the woman’s body in an ideal position to get the most sleep possible. It can be a pillow under the small of her back, plus one under her belly. There should also be one between her knees, as it helps to keep the spine straighter as she sleeps. What Is the Best Sleep Position for a Pregnant Woman? If a pregnant woman can get comfortable lying on her left side, this is how she should sleep. The reason that experts and doctors suggest the left is because it allows for the greatest levels of circulation. The back puts pressure on the vena cava, and lying on the stomach becomes impossible once a baby reaches a certain size, so the side is the only option. While the right side is not a bad option, the left allows for greater circulation and blood flow to the mother’s legs and to the placenta that is feeding the baby. Learning How to Sleep Well During Pregnancy Luckily for pregnant women everywhere, there are many ways of getting better sleep. The specific treatment that helps each woman varies, depending on what specifically keeps her awake at night. Here are some of the most effective ways of learning how to sleep well during pregnancy: Limit anything with sugar or caffeine during pregnancy. If the pregnant woman must have her daily cup of coffee, opting for decaf or low-caffeine coffee options are best. Avoid drinking anything 2-3 hours before bedtime each evening, so the bladder is as empty as possible at bedtime. Eat small meals throughout the day, so the last meal is smaller. It can minimize the effects of heartburn, especially in the latter stages of pregnancy. Pregnant women can try and lay still for an hour or so before bed. That way, the baby gets its active time out before her trying to go to sleep. Avoiding naps can help a pregnant woman feel more tired in the evening, but that is not always possible. If a nap is necessary, it should be completed no later than 4-6 hours before bedtime so that the woman can get tired enough for bed at that time. A pregnant woman who stays active sleeps better at night as well. It allows for increased circulation, tired muscles, and an easier delivery over those who are sedentary during pregnancy. Getting into a comfortable position before trying to go to sleep can help. It minimizes tossing and turning and allows for a smoother transition into a sleepy state. Pregnant women who cannot sleep should get up and move around for a while before trying again. By lying in bed, the body can be trained to believe that it does not need to sleep. Making sure to avoid electronic devices, such as computers and smartphones, for one hour before bed can also make falling asleep more likely when a pregnant woman can go to sleep. Keeping the same bedtime routine can lull the body into sleep. It should be at the same basic time each night, with the same basic routine. It helps the body instantly recognize what time it is, and allow it to happen more quickly than without the routine. Conclusion Getting a solid number of hours of sleep each night is important, both for the pregnant mother and her developing unborn child. It allows both of their bodies to keep up with all the changes that are taking place. Growing a human being is exhausting, and sleep allows for all parties to be at their best level of functionality possible. By sleeping with the right support, limiting what they drink before bed, and being careful with their diet, pregnant women can go from struggling to sleep to sleeping peacefully in no time.


Camazepam

1. NAME
   1.1 Substance
   1.2 Group
   1.3 Synonyms
   1.4 Identification numbers
      1.4.1 CAS number
      1.4.2 Other numbers
   1.5 Main brand names, main trade names
   1.6 Main manufacturers, main importers
2. SUMMARY
   2.1 Main risks and target organs
   2.2 Summary of clinical effects
   2.3 Diagnosis
   2.4 First aid measures and management principles
3. PHYSICO-CHEMICAL PROPERTIES
   3.1 Origin of the substance
   3.2 Chemical structure
   3.3 Physical properties
      3.3.1 Colour
      3.3.2 State/Form
      3.3.3 Description
   3.4 Other characteristics
      3.4.1 Shelf-life of the substance
      3.4.2 Storage conditions
4. USES
   4.1 Indications
      4.1.1 Indications
      4.1.2 Description
   4.2 Therapeutic dosage
      4.2.1 Adults
      4.2.2 Children
   4.3 Contraindications
5. ROUTES OF EXPOSURE
   5.1 Oral
   5.2 Inhalation
   5.3 Dermal
   5.4 Eye
   5.5 Parenteral
   5.6 Other
6. KINETICS
   6.1 Absorption by route of exposure
   6.2 Distribution by route of exposure
   6.3 Biological half-life by route of exposure
   6.4 Metabolism
   6.5 Elimination and excretion
7. PHARMACOLOGY AND TOXICOLOGY
   7.1 Mode of action
      7.1.1 Toxicodynamics
      7.1.2 Pharmacodynamics
   7.2 Toxicity
      7.2.1 Human data
         7.2.1.1 Adults
         7.2.1.2 Children
      7.2.2 Relevant animal data
      7.2.3 Relevant in vitro data
   7.3 Carcinogenicity
   7.4 Teratogenicity
   7.5 Mutagenicity
   7.6 Interactions
   7.7 Main adverse effects
8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS
   8.1 Material sampling plan
      8.1.1 Sampling and specimen collection
         8.1.1.1 Toxicological analyses
         8.1.1.2 Biomedical analyses
         8.1.1.3 Arterial blood gas analysis
         8.1.1.4 Haematological analyses
         8.1.1.5 Other (unspecified) analyses
      8.1.2 Storage of laboratory samples and specimens
         8.1.2.1 Toxicological analyses
         8.1.2.2 Biomedical analyses
         8.1.2.3 Arterial blood gas analysis
         8.1.2.4 Haematological analyses
         8.1.2.5 Other (unspecified) analyses
      8.1.3 Transport of laboratory samples and specimens
         8.1.3.1 Toxicological analyses
         8.1.3.2 Biomedical analyses
         8.1.3.3 Arterial blood gas analysis
         8.1.3.4 Haematological analyses
         8.1.3.5 Other (unspecified) analyses
   8.2 Toxicological Analyses and Their Interpretation
      8.2.1 Tests on toxic ingredient(s) of material
         8.2.1.1 Simple Qualitative Test(s)
         8.2.1.2 Advanced Qualitative Confirmation Test(s)
         8.2.1.3 Simple Quantitative Method(s)
         8.2.1.4 Advanced Quantitative Method(s)
      8.2.2 Tests for biological specimens
         8.2.2.1 Simple Qualitative Test(s)
         8.2.2.2 Advanced Qualitative Confirmation Test(s)
         8.2.2.3 Simple Quantitative Method(s)
         8.2.2.4 Advanced Quantitative Method(s)
         8.2.2.5 Other Dedicated Method(s)
      8.2.3 Interpretation of toxicological analyses
   8.3 Biomedical investigations and their interpretation
      8.3.1 Biochemical analysis
         8.3.1.1 Blood, plasma or serum
         8.3.1.2 Urine
         8.3.1.3 Other fluids
      8.3.2 Arterial blood gas analyses
      8.3.3 Haematological analyses
      8.3.4 Interpretation of biomedical investigations
   8.4 Other biomedical (diagnostic) investigations and their interpretation
   8.5 Overall interpretation of all toxicological analyses and toxicological investigations
   8.6 References
9. CLINICAL EFFECTS
   9.1 Acute poisoning
      9.1.1 Ingestion
      9.1.2 Inhalation
      9.1.3 Skin exposure
      9.1.4 Eye contact
      9.1.5 Parenteral exposure
      9.1.6 Other
   9.2 Chronic poisoning
      9.2.1 Ingestion
      9.2.2 Inhalation
      9.2.3 Skin exposure
      9.2.4 Eye contact
      9.2.5 Parenteral exposure
      9.2.6 Other
   9.3 Course, prognosis, cause of death
   9.4 Systematic description of clinical effects
      9.4.1 Cardiovascular
      9.4.2 Respiratory
      9.4.3 Neurological
         9.4.3.1 Central nervous system (CNS)
         9.4.3.2 Peripheral nervous system
         9.4.3.3 Autonomic nervous system
         9.4.3.4 Skeletal and smooth muscle
      9.4.4 Gastrointestinal
      9.4.5 Hepatic
      9.4.6 Urinary
         9.4.6.1 Renal
         9.4.6.2 Other
      9.4.7 Endocrine and reproductive systems
      9.4.8 Dermatological
      9.4.9 Eye, ear, nose, throat: local effects
      9.4.10 Haematological
      9.4.11 Immunological
      9.4.12 Metabolic
         9.4.12.1 Acid-base disturbances
         9.4.12.2 Fluid and electrolyte disturbances
         9.4.12.3 Others
      9.4.13 Allergic reactions
      9.4.14 Other clinical effects
      9.4.15 Special risks
   9.5 Other
   9.6 Summary
10. MANAGEMENT
   10.1 General principles
   10.2 Life supportive procedures and symptomatic/specific treatment
   10.3 Decontamination
   10.4 Enhanced elimination
   10.5 Antidote treatment
      10.5.1 Adults
      10.5.2 Children
   10.6 Management discussion
11. ILLUSTRATIVE CASES
   11.1 Case reports from literature
12. Additional information
   12.1 Specific preventive measures
   12.2 Other
13. REFERENCES
14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES)



    Camazepam

    International Programme on Chemical Safety
    Poisons Information Monograph 283
    Pharmaceutical

    This monograph does not contain all of the sections completed. This
    mongraph is harmonised with the Group monograph on Benzodiazepines
    (PIM G008).

    1.  NAME

        1.1  Substance

             Camazepam

        1.2  Group

             ATC classification index

             Psycholeptics(N05)/  Anxiolytics (N05B)/
             Benzodiazepine derivatives (N05BA)

        1.3  Synonyms

             SB-5833

        1.4  Identification numbers

             1.4.1  CAS number

             1.4.2  Other numbers

        1.5  Main brand names, main trade names

        1.6  Main manufacturers, main importers

    2.  SUMMARY

        2.1  Main risks and target organs

             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.

        2.3  Diagnosis

             The clinical diagnosis is based upon the history of
             benzodiazepine overdose and the presence of the clinical
             signs of benzodiazepine intoxication.
             Benzodiazepines can be detected or measured in blood and
             urine using standard analytical methods. This information may
             confirm the diagnosis but is not useful in the clinical
             management of the patient.
             A clinical response to flumazenil, a specific benzodiazepine
             antagonist, also confirms the diagnosis of benzodiazepine
             overdose, but administration of this drug is rarely
             justified.

        2.4  First aid measures and management principles

             Most benzodiazepine poisonings require only clinical
             observation and supportive care. It should be remembered that
             benzodiazepine ingestions by adults commonly involve co-
             ingestion of other CNS depressants and other drugs. Activated
             charcoal normally provides adequate gastrointestinal
             decontamination. Gastric lavage is not routinely indicated.
             Emesis is contraindicated. The use of flumazenil is reserved
             for cases with severe respiratory or cardiovascular
             complications and should not replace the basic management of
             the airway and respiration. The routine use of flumazenil is
             contraindicated because of potential complications, including
             seizures.  Renal and extracorporeal methods of enhanced
             elimination are not effective.

    3.  PHYSICO-CHEMICAL PROPERTIES

        3.1  Origin of the substance

        3.2  Chemical structure

             Chemical name:
             Dimethylcarbamic acid 7-chloro-2,3-dihydro-1-methyl-2-oxo-5-
             phenyl-1H-1,4-benzodiazepin-3-yl ester;
    

             Alternatives
             7-chloro-1,3-dihydro-3-hydroxy-1-methyl-5-phenyl-2H-1,4-
             benzodiazepin-2-one dimethylcarbamate (ester);
    
             7-chloro-1,3-dihydro-3-(N,N-dimethylcarbamoyl)-1-methyl-5-
             phenyl-2H-1,4-benzodiazepin-2-one;
    
             Molecular formula: C19H18ClN3O3
    
             Molecular  weight: 371.82.

        3.3  Physical properties

             3.3.1  Colour

                    White

             3.3.2  State/Form

                    Solid-crystals

             3.3.3  Description

                    Melting point: 173-174 degC. 
                    Soluble in alcohol; moderately soluble in water.

        3.4  Other characteristics

             3.4.1  Shelf-life of the substance

             3.4.2  Storage conditions

    4.  USES

        4.1  Indications
             4.1.1  Indications
             4.1.2  Description
        4.2  Therapeutic dosage
             4.2.1  Adults
             4.2.2  Children
        4.3  Contraindications

    5.  ROUTES OF EXPOSURE

        5.1  Oral
        5.2  Inhalation
        5.3  Dermal
        5.4  Eye
        5.5  Parenteral
        5.6  Other

    6.  KINETICS

        6.1  Absorption by route of exposure
        6.2  Distribution by route of exposure
        6.3  Biological half-life by route of exposure
        6.4  Metabolism
        6.5  Elimination and excretion

    7.  PHARMACOLOGY AND TOXICOLOGY

        7.1  Mode of action
             7.1.1  Toxicodynamics
             7.1.2  Pharmacodynamics
        7.2  Toxicity
             7.2.1  Human data
                    7.2.1.1  Adults
                    7.2.1.2  Children
             7.2.2  Relevant animal data
             7.2.3  Relevant in vitro data
        7.3  Carcinogenicity
        7.4  Teratogenicity
        7.5  Mutagenicity
        7.6  Interactions
        7.7  Main adverse effects

    8.  TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS

        8.1  Material sampling plan
             8.1.1  Sampling and specimen collection
                    8.1.1.1  Toxicological analyses
                    8.1.1.2  Biomedical analyses
                    8.1.1.3  Arterial blood gas analysis
                    8.1.1.4  Haematological analyses
                    8.1.1.5  Other (unspecified) analyses
             8.1.2  Storage of laboratory samples and specimens
                    8.1.2.1  Toxicological analyses
                    8.1.2.2  Biomedical analyses
                    8.1.2.3  Arterial blood gas analysis
                    8.1.2.4  Haematological analyses
                    8.1.2.5  Other (unspecified) analyses
             8.1.3  Transport of laboratory samples and specimens
                    8.1.3.1  Toxicological analyses
                    8.1.3.2  Biomedical analyses
                    8.1.3.3  Arterial blood gas analysis
                    8.1.3.4  Haematological analyses
                    8.1.3.5  Other (unspecified) analyses
        8.2  Toxicological Analyses and Their Interpretation
             8.2.1  Tests on toxic ingredient(s) of material
                    8.2.1.1  Simple Qualitative Test(s)
                    8.2.1.2  Advanced Qualitative Confirmation  Test(s)
                    8.2.1.3  Simple Quantitative Method(s)
                    8.2.1.4  Advanced Quantitative Method(s)

             8.2.2  Tests for biological specimens
                    8.2.2.1  Simple Qualitative Test(s)
                    8.2.2.2  Advanced Qualitative Confirmation  Test(s)
                    8.2.2.3  Simple Quantitative Method(s)
                    8.2.2.4  Advanced Quantitative Method(s)
                    8.2.2.5  Other Dedicated Method(s)
             8.2.3  Interpretation of toxicological analyses
        8.3  Biomedical investigations and their interpretation
             8.3.1  Biochemical analysis
                    8.3.1.1  Blood, plasma or serum
                             "Basic analyses"
                             "Dedicated analyses"
                             "Optional analyses"
                    8.3.1.2  Urine
                             "Basic analyses"
                             "Dedicated analyses"
                             "Optional analyses"
                    8.3.1.3  Other fluids
             8.3.2  Arterial blood gas analyses
             8.3.3  Haematological analyses
                    "Basic analyses"
                    "Dedicated analyses"
                    "Optional analyses"
             8.3.4  Interpretation of biomedical investigations

        8.4  Other biomedical (diagnostic) investigations and their
             interpretation

        8.5  Overall interpretation of all toxicological analyses and
             toxicological investigations

             Sample collection
             For toxicological analyses: whole blood 10 mL; urine 25 mL
             and gastric contents 25 mL.
    
             Biomedical analysis
             Blood gases, serum electrolytes, blood glucose and hepatic
             enzymes when necessary in severe cases.
    
             Toxicological analysis
             Qualitative testing for benzodiazepines is helpful to confirm
             their presence, but quantitative levels are not clinically
             useful. More advanced analyses are not necessary for the
             treatment of the poisoned patient due the lack of correlation
             between blood concentrations and clinical severity (Jatlow et
             al., 1979; MacCormick et al., 1985; Minder, 1989).
    
             TLC and EMIT: These provide data on the presence of
             benzodiazepines, their metabolites and possible associations
             with other drugs.
    

             GC or HPLC: These permit identification and quantification of
             the benzodiazepine which caused the poisoning and its
             metabolites in blood and urine.

        8.6  References

    9.  CLINICAL EFFECTS

        9.1  Acute poisoning

             9.1.1  Ingestion

                    The onset of impairment of consciousness is
                    relatively rapid in benzodiazepine poisoning.  Onset
                    is more rapid following larger doses and with agents
                    of shorter duration of action. The most common and
                    initial symptom is somnolence.  This may progress to
                    coma Grade I or Grade II (see below) following very
                    large ingestions.
    
                    Reed Classification of Coma (Reed et al., 1952)
    
                    Coma Grade I:   Depressed level of consciousness,
                                    response to  painful stimuli
                                    Deep tendon reflexes and vital signs
                                    intact
    
                    Coma Grade II:  Depressed level of consciousness, no
                                    response to painful stimuli
                                    Deep tendon reflexes and vital signs
                                    intact
    
                    Coma Grade III: Depressed level of consciousness, no
                                    response to painful stimuli
                                    Deep tendon reflexes absent. Vital
                                    signs intact
    
                    Coma Grade IV:  Coma grade III plus respiratory and
                                    circulatory collapse

             9.1.2  Inhalation

                    Not relevant.

             9.1.3  Skin exposure

                    No data.

             9.1.4  Eye contact

                    No data.

             9.1.5  Parenteral exposure

                    Overdose by the intravenous route results in
                    symptoms similar to those associated with ingestion,
                    but they appear immediately after the infusion, and
                    the progression of central nervous system (CNS)
                    depression is more rapid. Acute intentional poisoning
                    by this route is uncommon and most cases are
                    iatrogenic. Rapid intravenous infusion may cause
                    hypotension, respiratory depression and
                    apnoea.

             9.1.6  Other

        9.2  Chronic poisoning

             9.2.1  Ingestion

                    Toxic effects associated with chronic exposure
                    are secondary to the presence of the drug and
                    metabolites and include depressed mental status,
                    ataxia, vertigo, dizziness, fatigue, impaired motor
                    co-ordination, confusion, disorientation and
                    anterograde amnesia. Paradoxical effects of
                    psychomotor excitation, delirium and aggressiveness
                    also occur. These chronic effects are more common in
                    the elderly, children and patients with renal or
                    hepatic disease.
    
                    Administration of therapeutic doses of benzodiazepines
                    for 6 weeks or longer can result in physical
                    dependence, characterized by a withdrawal syndrome
                    when the drug is discontinued. With larger doses, the
                    physical dependence develops more rapidly.

             9.2.2  Inhalation

                    No data.

             9.2.3  Skin exposure

                    No data.

             9.2.4  Eye contact

                    No data.

             9.2.5  Parenteral exposure

                    The chronic parenteral administration of
                    benzodiazepines may produce thrombophlebitis and
                    tissue irritation, in addition to the usual symptoms
                    (Greenblat & Koch-Weser, 1973).

             9.2.6  Other

                    No data.

        9.3  Course, prognosis, cause of death

             Benzodiazepines are relatively safe drugs even in
             overdose. The clinical course is determined by the
             progression of the neurological symptoms. Deep coma or other
             manifestations of severe central nervous system (CNS)
             depression are rare with benzodiazepines alone.  Concomitant
             ingestion of other CNS depressants may result in a more
             severe CNS depression of longer duration.
    
             The therapeutic index of the benzodiazepines is high and the
             mortality rate associated with poisoning due to
             benzodiazepines alone is very low. Complications in severe
             poisoning include respiratory depression and aspiration
             pneumonia. Death is due to respiratory arrest.

        9.4  Systematic description of clinical effects

             9.4.1  Cardiovascular

                    Hypotension, bradycardia and tachycardia have
                    been reported with overdose (Greenblatt et al., 1977;
                    Meredith & Vale 1985). Hypotension is more frequent
                    when benzodiazepines are ingested in association with
                    other drugs (Hojer et al., 1989). Rapid intravenous
                    injection is also associated with hypotension.

             9.4.2  Respiratory

                    Respiratory depression may occur in
                    benzodiazepine overdose and the severity depends on
                    dose ingested, amount absorbed, type of benzodiazepine
                    and co-ingestants. Respiratory depression requiring
                    ventilatory support has occurred in benzodiazepine
                    overdoses (Sullivan, 1989; Hojer et al.,1989). The
                    dose-response for respiratory depression varies
                    between individuals.  Respiratory depression or
                    respiratory arrest may rarely occur with therapeutic
                    doses. Benzodiazepines may affect the control of
                    ventilation during sleep and may worsen sleep apnoea
                    or other sleep-related breathing disorders, especially
                    in patients with chronic obstructive pulmonary disease
                    or cardiac failure (Guilleminault, 1990).

             9.4.3  Neurological

                    9.4.3.1  Central nervous system (CNS)

                             CNS depression is less marked than
                             that produced by other CNS depressant agents
                             (Meredith & Vale, 1985). Even in large
                             overdoses, benzodiazepines usually produce
                             only mild symptoms and this distinguishes
                             them from other sedative-hypnotic agents.
                             Sedation, somnolence, weakness, diplopia,
                             dysarthria, ataxia and intellectual
                             impairment are the most common neurological
                             effects. The clinical effects of severe
                             poisoning are sleepiness, ataxia and coma
                             Grade I to Grade II (Reed). The presence of
                             more severe coma suggests the possibility of
                             co-ingested drugs. Certain of the newer
                             short-acting benzodiazepines (temazepam,
                             alprazolam and triazolam) have been
                             associated with several fatalities and it is
                             possible that they may have greater acute
                             toxicity (Forrest et al., 1986). The elderly
                             and very young children are more susceptible
                             to the CNS depressant action of
                             benzodiazepines.
                             The benzodiazepines may cause paradoxical CNS
                             effects, including excitement, delirium and
                             hallucinations. Triazolam has been reported
                             to produce delirium, toxic psychosis, memory
                             impairment and transient global amnesia
                             (Shader & Dimascio, 1970; Bixler et al,
                             1991). Flurazepam has been associated with
                             nightmares and hallucinations.
                             There are a few reports of extrapyramidal
                             symptoms and dyskinesias in patients taking
                             benzodiazepines (Kaplan & Murkafsky, 1978;
                             Sandyk, 1986).
                             The muscle relaxation caused by
                             benzodiazepines is of CNS origin and
                             manifests as dysarthria, incoordination and
                             difficulty standing and walking.

                    9.4.3.2  Peripheral nervous system

                    9.4.3.3  Autonomic nervous system

                    9.4.3.4  Skeletal and smooth muscle

             9.4.4  Gastrointestinal

                    Oral benzodiazepine poisoning will produce
                    minimal effects on the gastrointestinal tract (GI)
                    tract but can occasionally cause nausea or vomiting
                    (Shader & Dimascio, 1970).

             9.4.5  Hepatic

                    A case of cholestatic jaundice due focal
                    hepatic necrosis was associated with the
                    administration of diazepam (Tedesco & Mills,
                    1982).

             9.4.6  Urinary

                    9.4.6.1  Renal

                             Vesical hypotonia and urinary
                             retention has been reported in association
                             with diazepam poisoning (Chadduck et al.,
                             1973).

                    9.4.6.2  Other

             9.4.7  Endocrine and reproductive systems

                    Galactorrhoea with normal serum prolactin
                    concentrations has been noted in 4 women taking
                    benzodiazepines (Kleinberg et al., 1977).
                    Gynaecomastia has been reported in men taking high
                    doses of diazepam (Moerck & Majelung, 1979). Raised
                    serum concentrations of oestrodiol were observed in
                    men taking diazepam 10 to 20 mg daily for 2 weeks
                    (Arguelles & Rosner, 1975).

             9.4.8  Dermatological

                    Bullae have been reported following overdose
                    with nitrazepam and oxazepam (Ridley, 1971; Moshkowitz
                    et al., 1990).
                    Allergic skin reactions were attributed to diazepam at
                    a rate of 0.4 per 1000 patients (Brigby,
                    1986).

             9.4.9  Eye, ear, nose, throat: local effects

                    Brown opacification of the lens occurred in 2
                    patients who used diazepam for several years (Pau
                    Braune, 1985).

             9.4.10 Haematological

                    No data.

             9.4.11 Immunological

                    Allergic reaction as above (see
                    9.4.8).

             9.4.12 Metabolic

                    9.4.12.1 Acid-base disturbances

                             No direct disturbances have been
                             described.

                    9.4.12.2 Fluid and electrolyte disturbances

                             No direct disturbances have been
                             described.

                    9.4.12.3 Others

             9.4.13 Allergic reactions

                    Hypersensitivity reactions including
                    anaphylaxis are very rare (Brigby, 1986). Reactions
                    have been attributed to the vehicle used for some
                    parenteral diazepam formulations (Huttel et al.,
                    1980). There is also a report of a type I
                    hypersensitivity reaction to a lipid emulsion of
                    diazepam (Deardon, 1987).

             9.4.14 Other clinical effects

                    Hypothermia was reported in 15% of cases in
                    one series. (Martin, 1985; Hojer et al.,
                    1989).

             9.4.15 Special risks

                    Pregnancy
                    Passage of benzodiazepines across the placenta depends
                    on the degree of protein binding in mother and fetus,
                    which is influenced by factors such as stage of
                    pregnancy and plasma concentrations of free fatty
                    acids in mother and fetus (Lee et al., 1982). Adverse
                    effects may persist in the neonate for several days
                    after birth because of immature drug metabolising
                    enzymes. Competition between diazepam and bilirubin
                    for protein binding sites could result in
                    hyperbilirubinemia in the neonate (Notarianni,
                    1990).

                    The abuse of benzodiazepines by pregnant women can
                    cause withdrawal syndrome in the neonate. The
                    administration of benzodiazepines during childbirth
                    can produce hypotonia, hyporeflexia, hypothermia and
                    respiratory depression in the newborn.
                    Benzodiazepines have been used in pregnant patients
                    and early reports associated diazepam and
                    chlordiazepoxide with some fetal malformations, but
                    these were not supported by later studies (Laegreid et
                    al., 1987; McElhatton, 1994).
    
                    Breast feeding
                    Benzodiazepines are excreted in breast milk in
                    significant amounts and may result in lethargy and
                    poor feeding in neonates.  Benzodiazepines should be
                    avoided in nursing mothers (Brodie, 1981; Reynolds,
                    1996).

        9.5  Other

             Dependence and withdrawal
             Benzodiazepines have a significant potential for abuse and
             can cause physical and psychological dependence. Abrupt
             cessation after prolonged use causes a withdrawal syndrome
             (Ashton, 1989). The mechanism of dependence is probably
             related to functional deficiency of GABA activity.
             Withdrawal symptoms include anxiety, insomnia, headache,
             dizziness, tinnitus, anorexia, vomiting, nausea, tremor,
             weakness, perspiration, irritability, hypersensitivity to
             visual and auditory stimuli, palpitations, tachycardia and
             postural hypotension. In severe and rare cases of withdrawal
             from high doses, patients may develop affective disorders or
             motor dysfunction: seizures, psychosis, agitation, confusion,
             and hallucinations (Einarson, 1981; Hindmarch et al, 1990;
             Reynolds, 1996).
             The time of onset of the withdrawal syndrome depends on the
             half-life of the drug and its active metabolites; the
             symptoms occur earlier and may be more severe with short-
             acting benzodiazepines. Others risk factors for withdrawal
             syndrome include prolonged use of the drug, higher dosage and
             abrupt cessation of the drug.
    
             Abuse
             Benzodiazepines, particularly temazepam, have been abused
             both orally and intravenously (Stark et al., 1987; Woods,
             1987; Funderburk et al, 1988)
    
             Criminal uses
             The amnesic effects of benzodiazepines have been used for
             criminal purposes with medicolegal consequences (Ferner,
             1996).

        9.6  Summary

    10. MANAGEMENT

        10.1 General principles

             Most benzodiazepine poisonings require only clinical
             observation and supportive care. It should be remembered that
             benzodiazepine ingestions by adults commonly include other
             drugs and other CNS depressants. Activated charcoal normally
             provides adequate gastrointestinal decontamination. Gastric
             lavage is not routinely indicated. Emesis is contraindicated.
             The use of flumazenil is reserved for cases with severe
             respiratory or cardiovascular complications and should not
             replace the basic management of the airway and respiration.
             Renal and extracorporeal elimination methods are not
             effective.

        10.2 Life supportive procedures and symptomatic/specific treatment

             The patient should be evaluated to determine adequacy
             of airway, breathing and circulation. Continue clinical
             observation until evidence of toxicity has resolved.
             Intravenous access should be available for administration of
             fluid. Endotracheal intubation, assisted ventilation and
             supplemental oxygen may be required on rare occasions, more
             commonly when benzodiazepines are ingested in large amounts
             or with other CNS depressants.

        10.3 Decontamination

             Gastric lavage is not routinely indicated following
             benzodiazepine overdose. Emesis is contraindicated because of
             the potential for CNS depression. Activated charcoal can be
             given orally.

        10.4 Enhanced elimination

             Methods of enhancing elimination are not indicated.

        10.5 Antidote treatment

             10.5.1 Adults

                    Flumazenil, a specific benzodiazepine
                    antagonist at central GABA-ergic receptors is
                    available. Although it effectively reverses the CNS
                    effects of benzodiazepine overdose, its use in
                    clinical practice is rarely indicated.
                    Use of Flumazenil is specifically contraindicated when
                    there is history of co-ingestion of tricyclic

             antidepressants or other drugs capable of producing seizures
             (including aminophylline and cocaine), benzodiazepine
             dependence, or in patients taking benzodiazepines as an
             anticonvulsant agent. In such situations, administration of
             Flumazenil may precipitate seizures (Lopez, 1990; Mordel et
             al., 1992).
                    Adverse effects associated with Flumazenil include
                    hypertension, tachycardia, anxiety, nausea, vomiting
                    and benzodiazepine withdrawal syndrome.
                    The initial intravenous dose of 0.3 to 1.0 mg may be
                    followed by further doses if necessary. The absence of
                    clinical response to 2 mg of flumazenil within 5 to 10
                    minutes indicates that benzodiazepine poisoning is not
                    the major cause of CNS depression or coma.
                    The patient regains consciousness within 15 to 30
                    seconds after injection of flumazenil, but since it is
                    metabolised more rapidly than the benzodiazepines,
                    recurrence of toxicity and CNS depression can occur
                    and the patient should be carefully monitored after
                    initial response to flumazenil therapy.  If toxicity
                    recurs, further bolus doses may be administered or an
                    infusion commenced at a dose of 0.3 to 1.0 mg/hour
                    (Meredith et al., 1993).

             10.5.2 Children

                    The initial intravenous dose of 0.1 mg should
                    be repeated each minute until the child is awake.
                    Continuous intravenous infusion should be administered
                    at a rate of 0.1 to 0.2 mg/hour (Meredith et al.,
                    1993).

        10.6 Management discussion

             Most benzodiazepine poisonings require only clinical
             observation and supportive care. Flumazenil is the specific
             antagonist of the effects of benzodiazepines, but the routine
             use for the treatment of benzodiazepine overdosage is not
             recommended. The use of Flumazenil should only be considered
             where severe CNS depression is observed. This situation
             rarely occurs, except in cases of mixed ingestion. The
             administration of flumazenil may improve respiratory and
             cardiovascular function enough to decrease the need for
             intubation and mechanical ventilation, but should never
             replace basic management principles.
             Flumazenil is an imidazobenzodiazepine and has been shown to
             reverse the sedative, anti-convulsant and muscle-relaxant
             effects of benzodiazepines. In controlled clinical trials,
             flumazenil significantly antagonizes benzodiazepine-induced
             coma arising from anaesthesia or acute overdose. However, the
             use of flumazenil has not been shown to reduce mortality or
             sequelae in such cases.

             The administration of flumazenil is more effective in
             reversing the effects of benzodiazepines when they are the
             only drugs producing CNS toxicity. Flumazenil does not
             reverse the CNS depressant effects of non-benzodiazepine
             drugs, including alcohol. The diagnostic use of flumazenil in
             patients presenting with coma of unknown origin can be
             justified by its high therapeutic index and the fact that
             this may limit the use of other diagnostic procedures (CT
             scan, lumbar puncture, etc).
             Flumazenil is a relatively expensive drug and this may also
             influence its use, especially in areas with limited
             resources.

    11. ILLUSTRATIVE CASES

        11.1 Case reports from literature

    12. Additional information

        12.1 Specific preventive measures

        12.2 Other

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        Ashton CH (1989) Drug-induced stupor and coma: some physical signs
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        Bixler EO, Kales A, Manfredi RL, Vgontzas AN, Tyson KL, & Kales JD
        (1991)  Next-day memory impairment with triazolam use.  Lancet,
        337: 827-831.
    
        Brigby M. (1986) Drug induced cutaneous reactions. JAMA, 256:
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        Brodie RR, Chasseaud LF & Taylor T (1981) Concentrations of N-
        descyclopropylmethyl-prazepam in whole-blood, plasma and milk
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        Chadduck WM, Loar CR & Denton IC. (1973)  Vesical hypotonicity
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        Deardon DJ. (1987) Acute hypersensivity to IV Diazulmuls. Br J
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        Einarson TR (1981) Oxazepam withdrawal convulsions.  Drug Intell
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        Ellenhorn, M. (1996) Medical Toxicology. 2nd Ed., Elsevier.
    
        Ferner RE (1996) Forensic Pharmacology, 1st Ed. Oxford University
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        Forrest ARW, Marsh I, Bradshaw C & Braich SK (1986) Fatal
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        Funderburk FR, Griffiths RR, McLeod DR, Bigelow GE, Mackenzie A,
        Liebson IA & Newmeth-Coslett R (1988) Relative abuse liability of
        lorazepam and diazepam:  an evaluation in "recreational" drug
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        Greenblatt DJ, Allen MD, Noel BJ et al (1977) Acute overdose with
        benzodiazepine derivatives.  Clin Pharm Ther,  21: 497-513.
    
        Guilleminault C. (1990)  Benzodiazepines, bresthing and sleep.  Am
        J Med, 88 (suppl 3A): 25S - 28S.
    
        Hindmarch I, Beaumont G, Brandon S, & Leonard, B. (1990) 
        Benzodiazepines Current Concepts, John Wiley & Sons Ltd, UK.
    
        Hojer J, Baehrendtz S & Gustafsson L. (1989) Benzodiazepine
        poisoning: experience of 702 admissions to an intensive care unit
        during a 14-year period.  J Intern Med, 226: 117-122.
    
        Huttel MS, Schou Olesen A & Stofferson E (1980) Complement-
        mediated reactions to diazepam with Cremophor as solvent. Br J
        Anaesth,  52:  77-9.
    
        Hyams SW & Keroub C (1977) Glaucoma due to diazepam. Am J
        Psychiatry, 134: 477-479.
    
        Kaplan SR, & Murkofsky C (1978) Oral-buccal dyskinesic synptoms
        associated with low dose benzodiazepine treatment. Am J
        Psychiatry, 135: 1558-1559.
    
        Kleinberg DL, Noel GL & Frantz AG (1977) Galactorrhea a study of
        235 cases. N Eng J Med  296: 589-600.
    
        Laegreid L, Olegard R, & Wahlstrom J (1987) Abnormalities in
        children exposed to benzodiazepines in utero.  Lancet, 1:
        108-109.
    
        Lee JN, Chen SS, Richens A, Menabawey m & Chard T (1982) Serum
        protein binding of diazepam in maternal and foetal serum during
        pregnancy. Br J Clin Pharmacol, 14: 551-4.
    
        Lopez A & Rebollo J (1990) Benzodiazepine withdrawal syndrome
        after a benzodiazepine antagonist.  Crit Care Med, 18:
        1480-1481.
    

        Martin SM (1985) The effect of diazepam on body temperature change
        in humans during cold exposure. J Clin Pharmacol,  25: 611-
        613.
    
        McCormick SR, Nielsen J & Jatlow PI (1985) Alprazolam overdose:
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        Psychiatr,  46:247-248.
    
        McElhatton PR. (1994) The effects of benzodiazepines use during
        pregnancy and lactation. Reprod Toxicol,  8: 461-75.
    
        Meredith TJ, Jacobsen D, Haines JA, Berger JC (1993) IPCS/CEC
        Evaluation of Antidotes Series, Vol1, Naloxone, flumazenil and
        dantrolene as antidotes, 1st ed. Cambridge University Press,
        Cambridge.
    
        Meredith TJ, & Vale JA (1985) Poisoning due to psychotropic
        agents. Adverse Drug React Acute Poison Rev,  4: 83-122.
    
        Minder EI (1989) Toxicity in a case of acute and massive overdose
        of chlordiazepoxide and its correlation to blood concentration. 
        Clin Toxicol,  27: 117-127.
    
        Moerck HJ, Majelung G (1979) Gynaecomastia and diazepam abuse.
        Lancet, i: 1344-5.
    
        Mordel A, Winkler E, Almog S, Tirosh M & Ezra D (1992) Seizures
        after flumazenil administration in a case of combined
        benzodiazepine and tricyclic antidepressant overdose. Crit Care
        Med,  12: 1733-1734.
    
        Notarianni LJ. (1990) Plasma protein binding of drugs in pregnancy
        and neonates. Clin Pharnacokinet, 18: 20-36.
    
        Pau Braune H (1985) [Eyes effect of diazepam.] Klin Monatsbl
        Augenheilkd, 187: 219-20 (in German).
    
        Reed C E, Driggs M F, & Foote CC (1952) Acute barbiturate
        intoxication. A study of 300 cases based on a physiologic system
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        37: 390-396.
    
        Reynolds J (1996) Martindale, The Extra Pharmacopeia. 30th ed. The
        Pharmaceutical Press, London, 699-744.
    
        Ridley CM (1971)  Bullous lesions in nitrazepan overdosage. Br Med
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        Sandyk R (1986) Orofacial diskynesias associated with lorazepam
        therapy. Clin Pharm,  5: 419-21.
    
        Shader RI & Dimascio A (1970) Psychotropic drug side effects, 1st
        ed. Willians & Wilkins, Baltimore.
    

        Stark C, Sykes R & Mullin P (1987)  Temazepam abuse (letter).
        Lancet,  2:802-803.
    
        Sullivan RJ Jr (1989) Respiratory depression requiring ventilatory
        support following 0.5 mg of Triazolam. J Am Geriatr,  Soc  37:
        450-452.
    
        Tedesco FJ, & Mills LR. (1982) Diazepam hepatites. Dig Dis Sci 27:
        470-2.

    14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE
        ADDRESS(ES)

        Author:           Dr Ligia Fruchtengarten
                          Poison Control Centre of Sao Paulo  -  Brazil
                          Hospital Municipal Dr Arthur Ribeiro de Saboya -
                          Coperpas 12
                          FAX / Phone:   55  11  2755311
                          E-mail:   lfruchtengarten@originet.com.br
    
        Mailing Address:  Hospital Municipal Dr Arthur Ribeiro de Saboya -
                          Coperpas 12
                          Centro de Controle de Intoxicaoes de Sao Paulo
                          Av Francisco de Paula Quintanilha Ribeiro, 860
                          04330 - 020   Sao Paulo  -  SP  -  Brazil.
    
        Date:             July 1997
    
        Peer Review:      INTOX 10 Meeting, Rio de Janeiro, Brazil,
                          September 1997.
                          R. Ferner, L. Murray (Chairperson), M-O.
                          Rambourg, A. Nantel,  N. Ben Salah, M. Mathieu-
                          Nolf, A.Borges.
    
        Review 1998:      Lindsay Murray
                          Queen Elizabeth II Medical Centre
                          Perth, Western Australia.
    
        Editor:           Dr M.Ruse, April 1998
    


Estazolam 1. NAME 1.1 Substance 1.2 Group 1.3 Synonyms 1.4 Identification numbers 1.4.1 CAS number 1.4.2 Other numbers 1.5 Main brand names, main trade names 1.6 Main manufacturers, main importers 2. SUMMARY 2.1 Main risks and target organs 2.2 Summary of clinical effects 2.3 Diagnosis 2.4 First aid measures and management principles 3. PHYSICO-CHEMICAL PROPERTIES 3.1 Origin of the substance 3.2 Chemical structure 3.3 Physical properties 3.3.1 Colour 3.3.2 State/Form 3.3.3 Description 3.4 Other characteristics 3.4.1 Shelf-life of the substance 3.4.2 Storage conditions 4. USES 4.1 Indications 4.1.1 Indications 4.1.2 Description 4.2 Therapeutic dosage 4.2.1 Adults 4.2.2 Children 4.3 Contraindications 5. ROUTES OF EXPOSURE 5.1 Oral 5.2 Inhalation 5.3 Dermal 5.4 Eye 5.5 Parenteral 5.6 Other 6. KINETICS 6.1 Absorption by route of exposure 6.2 Distribution by route of exposure 6.3 Biological half-life by route of exposure 6.4 Metabolism 6.5 Elimination and excretion 7. PHARMACOLOGY AND TOXICOLOGY 7.1 Mode of action 7.1.1 Toxicodynamics 7.1.2 Pharmacodynamics 7.2 Toxicity 7.2.1 Human data 7.2.1.1 Adults 7.2.1.2 Children 7.2.2 Relevant animal data 7.2.3 Relevant in vitro data 7.3 Carcinogenicity 7.4 Teratogenicity 7.5 Mutagenicity 7.6 Interactions 7.7 Main adverse effects 8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS 8.1 Material sampling plan 8.1.1 Sampling and specimen collection 8.1.1.1 Toxicological analyses 8.1.1.2 Biomedical analyses 8.1.1.3 Arterial blood gas analysis 8.1.1.4 Haematological analyses 8.1.1.5 Other (unspecified) analyses 8.1.2 Storage of laboratory samples and specimens 8.1.2.1 Toxicological analyses 8.1.2.2 Biomedical analyses 8.1.2.3 Arterial blood gas analysis 8.1.2.4 Haematological analyses 8.1.2.5 Other (unspecified) analyses 8.1.3 Transport of laboratory samples and specimens 8.1.3.1 Toxicological analyses 8.1.3.2 Biomedical analyses 8.1.3.3 Arterial blood gas analysis 8.1.3.4 Haematological analyses 8.1.3.5 Other (unspecified) analyses 8.2 Toxicological Analyses and Their Interpretation 8.2.1 Tests on toxic ingredient(s) of material 8.2.1.1 Simple Qualitative Test(s) 8.2.1.2 Advanced Qualitative Confirmation Test(s) 8.2.1.3 Simple Quantitative Method(s) 8.2.1.4 Advanced Quantitative Method(s) 8.2.2 Tests for biological specimens 8.2.2.1 Simple Qualitative Test(s) 8.2.2.2 Advanced Qualitative Confirmation Test(s) 8.2.2.3 Simple Quantitative Method(s) 8.2.2.4 Advanced Quantitative Method(s) 8.2.2.5 Other Dedicated Method(s) 8.2.3 Interpretation of toxicological analyses 8.3 Biomedical investigations and their interpretation 8.3.1 Biochemical analysis 8.3.1.1 Blood, plasma or serum 8.3.1.2 Urine 8.3.1.3 Other fluids 8.3.2 Arterial blood gas analyses 8.3.3 Haematological analyses 8.3.4 Interpretation of biomedical investigations 8.4 Other biomedical (diagnostic) investigations and their interpretation 8.5 Overall interpretation of all toxicological analyses and toxicological investigations 8.6 References 9. CLINICAL EFFECTS 9.1 Acute poisoning 9.1.1 Ingestion 9.1.2 Inhalation 9.1.3 Skin exposure 9.1.4 Eye contact 9.1.5 Parenteral exposure 9.1.6 Other 9.2 Chronic poisoning 9.2.1 Ingestion 9.2.2 Inhalation 9.2.3 Skin exposure 9.2.4 Eye contact 9.2.5 Parenteral exposure 9.2.6 Other 9.3 Course, prognosis, cause of death 9.4 Systematic description of clinical effects 9.4.1 Cardiovascular 9.4.2 Respiratory 9.4.3 Neurological 9.4.3.1 Central nervous system (CNS) 9.4.3.2 Peripheral nervous system 9.4.3.3 Autonomic nervous system 9.4.3.4 Skeletal and smooth muscle 9.4.4 Gastrointestinal 9.4.5 Hepatic 9.4.6 Urinary 9.4.6.1 Renal 9.4.6.2 Other 9.4.7 Endocrine and reproductive systems 9.4.8 Dermatological 9.4.9 Eye, ear, nose, throat: local effects 9.4.10 Haematological 9.4.11 Immunological 9.4.12 Metabolic 9.4.12.1 Acid-base disturbances 9.4.12.2 Fluid and electrolyte disturbances 9.4.12.3 Others 9.4.13 Allergic reactions 9.4.14 Other clinical effects 9.4.15 Special risks 9.5 Other 9.6 Summary 10. MANAGEMENT 10.1 General principles 10.2 Life supportive procedures and symptomatic/specific treatment 10.3 Decontamination 10.4 Enhanced elimination 10.5 Antidote treatment 10.5.1 Adults 10.5.2 Children 10.6 Management discussion 11. ILLUSTRATIVE CASES 11.1 Case reports from literature 12. Additional information 12.1 Specific preventive measures 12.2 Other 13. REFERENCES 14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES) Estazolam International Programme on Chemical Safety Poisons Information Monograph 925 Pharmaceutical This monograph does not contain all of the sections completed. This mongraph is harmonised with the Group monograph on Benzodiazepines (PIM G008). 1. NAME 1.1 Substance Estazolam 1.2 Group ATC classification index Psycholeptics (N05)/ Anxiolytics (N05B)/ Benzodiazepine derivatives (N05BA) 1.3 Synonyms Abbott-47631; D-40TA 1.4 Identification numbers 1.4.1 CAS number 29975-16-4 1.4.2 Other numbers 1.5 Main brand names, main trade names Esilgan; Eurodin; Nuctalon; ProSom; Prosom 1.6 Main manufacturers, main importers 2. SUMMARY 2.1 Main risks and target organs Central nervous system, causing depression of respiration and consciousness. 2.2 Summary of clinical effects Central nervous system (CNS) depression and coma, or paradoxical excitation, but deaths are rare when benzodiazepines are taken alone. Deep coma and 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. 2.3 Diagnosis The clinical diagnosis is based upon the history of benzodiazepine overdose and the presence of the clinical signs of benzodiazepine intoxication. Benzodiazepines can be detected or measured in blood and urine using standard analytical methods. This information may confirm the diagnosis but is not useful in the clinical management of the patient. A clinical response to flumazenil, a specific benzodiazepine antagonist, also confirms the diagnosis of benzodiazepine overdose, but administration of this drug is rarely justified. 2.4 First aid measures and management principles Most benzodiazepine poisonings require only clinical observation and supportive care. It should be remembered that benzodiazepine ingestions by adults commonly involve co- ingestion of other CNS depressants and other drugs. Activated charcoal normally provides adequate gastrointestinal decontamination. Gastric lavage is not routinely indicated. Emesis is contraindicated. The use of flumazenil is reserved for cases with severe respiratory or cardiovascular complications and should not replace the basic management of the airway and respiration. The routine use of flumazenil is contraindicated because of potential complications, including seizures. Renal and extracorporeal methods of enhanced elimination are not effective. 3. PHYSICO-CHEMICAL PROPERTIES 3.1 Origin of the substance 3.2 Chemical structure Chemical Name: 8-Chloro-6-phenyl-4H-1,2,4-triazolo(4,3-a)-1,4- benzodiazepine. Molecular Formula: C16H11ClN4 Molecular Weight: 294.7 3.3 Physical properties 3.3.1 Colour 3.3.2 State/Form 3.3.3 Description 3.4 Other characteristics 3.4.1 Shelf-life of the substance 3.4.2 Storage conditions 4. USES 4.1 Indications 4.1.1 Indications 4.1.2 Description 4.2 Therapeutic dosage 4.2.1 Adults 4.2.2 Children 4.3 Contraindications 5. ROUTES OF EXPOSURE 5.1 Oral 5.2 Inhalation 5.3 Dermal 5.4 Eye 5.5 Parenteral 5.6 Other 6. KINETICS 6.1 Absorption by route of exposure 6.2 Distribution by route of exposure 6.3 Biological half-life by route of exposure 6.4 Metabolism 6.5 Elimination and excretion 7. PHARMACOLOGY AND TOXICOLOGY 7.1 Mode of action 7.1.1 Toxicodynamics 7.1.2 Pharmacodynamics 7.2 Toxicity 7.2.1 Human data 7.2.1.1 Adults 7.2.1.2 Children 7.2.2 Relevant animal data 7.2.3 Relevant in vitro data 7.3 Carcinogenicity 7.4 Teratogenicity 7.5 Mutagenicity 7.6 Interactions 7.7 Main adverse effects 8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS 8.1 Material sampling plan 8.1.1 Sampling and specimen collection 8.1.1.1 Toxicological analyses 8.1.1.2 Biomedical analyses 8.1.1.3 Arterial blood gas analysis 8.1.1.4 Haematological analyses 8.1.1.5 Other (unspecified) analyses 8.1.2 Storage of laboratory samples and specimens 8.1.2.1 Toxicological analyses 8.1.2.2 Biomedical analyses 8.1.2.3 Arterial blood gas analysis 8.1.2.4 Haematological analyses 8.1.2.5 Other (unspecified) analyses 8.1.3 Transport of laboratory samples and specimens 8.1.3.1 Toxicological analyses 8.1.3.2 Biomedical analyses 8.1.3.3 Arterial blood gas analysis 8.1.3.4 Haematological analyses 8.1.3.5 Other (unspecified) analyses 8.2 Toxicological Analyses and Their Interpretation 8.2.1 Tests on toxic ingredient(s) of material 8.2.1.1 Simple Qualitative Test(s) 8.2.1.2 Advanced Qualitative Confirmation Test(s) 8.2.1.3 Simple Quantitative Method(s) 8.2.1.4 Advanced Quantitative Method(s) 8.2.2 Tests for biological specimens 8.2.2.1 Simple Qualitative Test(s) 8.2.2.2 Advanced Qualitative Confirmation Test(s) 8.2.2.3 Simple Quantitative Method(s) 8.2.2.4 Advanced Quantitative Method(s) 8.2.2.5 Other Dedicated Method(s) 8.2.3 Interpretation of toxicological analyses 8.3 Biomedical investigations and their interpretation 8.3.1 Biochemical analysis 8.3.1.1 Blood, plasma or serum "Basic analyses" "Dedicated analyses" "Optional analyses" 8.3.1.2 Urine "Basic analyses" "Dedicated analyses" "Optional analyses" 8.3.1.3 Other fluids 8.3.2 Arterial blood gas analyses 8.3.3 Haematological analyses "Basic analyses" "Dedicated analyses" "Optional analyses" 8.3.4 Interpretation of biomedical investigations 8.4 Other biomedical (diagnostic) investigations and their interpretation 8.5 Overall interpretation of all toxicological analyses and toxicological investigations Sample collection For toxicological analyses: whole blood 10 mL; urine 25 mL and gastric contents 25 mL. Biomedical analysis Blood gases, serum electrolytes, blood glucose and hepatic enzymes when necessary in severe cases. Toxicological analysis Qualitative testing for benzodiazepines is helpful to confirm their presence, but quantitative levels are not clinically useful. More advanced analyses are not necessary for the treatment of the poisoned patient due the lack of correlation between blood concentrations and clinical severity (Jatlow et al., 1979; MacCormick et al., 1985; Minder, 1989). TLC and EMIT: These provide data on the presence of benzodiazepines, their metabolites and possible associations with other drugs. GC or HPLC: These permit identification and quantification of the benzodiazepine which caused the poisoning and its metabolites in blood and urine. 8.6 References 9. CLINICAL EFFECTS 9.1 Acute poisoning 9.1.1 Ingestion The onset of impairment of consciousness is relatively rapid in benzodiazepine poisoning. Onset is more rapid following larger doses and with agents of shorter duration of action. The most common and initial symptom is somnolence. This may progress to coma Grade I or Grade II (see below) following very large ingestions. Reed Classification of Coma (Reed et al., 1952) Coma Grade I: Depressed level of consciousness, response to painful stimuli Deep tendon reflexes and vital signs intact Coma Grade II: Depressed level of consciousness, no response to painful stimuli Deep tendon reflexes and vital signs intact Coma Grade III: Depressed level of consciousness, no response to painful stimuli Deep tendon reflexes absent. Vital signs intact Coma Grade IV: Coma grade III plus respiratory and circulatory collapse 9.1.2 Inhalation Not relevant. 9.1.3 Skin exposure No data. 9.1.4 Eye contact No data. 9.1.5 Parenteral exposure Overdose by the intravenous route results in symptoms similar to those associated with ingestion, but they appear immediately after the infusion, and the progression of central nervous system (CNS) depression is more rapid. Acute intentional poisoning by this route is uncommon and most cases are iatrogenic. Rapid intravenous infusion may cause hypotension, respiratory depression and apnoea. 9.1.6 Other 9.2 Chronic poisoning 9.2.1 Ingestion Toxic effects associated with chronic exposure are secondary to the presence of the drug and metabolites and include depressed mental status, ataxia, vertigo, dizziness, fatigue, impaired motor co-ordination, confusion, disorientation and anterograde amnesia. Paradoxical effects of psychomotor excitation, delirium and aggressiveness also occur. These chronic effects are more common in the elderly, children and patients with renal or hepatic disease. Administration of therapeutic doses of benzodiazepines for 6 weeks or longer can result in physical dependence, characterized by a withdrawal syndrome when the drug is discontinued. With larger doses, the physical dependence develops more rapidly. 9.2.2 Inhalation No data. 9.2.3 Skin exposure No data. 9.2.4 Eye contact No data. 9.2.5 Parenteral exposure The chronic parenteral administration of benzodiazepines may produce thrombophlebitis and tissue irritation, in addition to the usual symptoms (Greenblat & Koch-Weser, 1973). 9.2.6 Other No data. 9.3 Course, prognosis, cause of death Benzodiazepines are relatively safe drugs even in overdose. The clinical course is determined by the progression of the neurological symptoms. Deep coma or other manifestations of severe central nervous system (CNS) depression are rare with benzodiazepines alone. Concomitant ingestion of other CNS depressants may result in a more severe CNS depression of longer duration. The therapeutic index of the benzodiazepines is high and the mortality rate associated with poisoning due to benzodiazepines alone is very low. Complications in severe poisoning include respiratory depression and aspiration pneumonia. Death is due to respiratory arrest. 9.4 Systematic description of clinical effects 9.4.1 Cardiovascular Hypotension, bradycardia and tachycardia have been reported with overdose (Greenblatt et al., 1977; Meredith & Vale 1985). Hypotension is more frequent when benzodiazepines are ingested in association with other drugs (Hojer et al., 1989). Rapid intravenous injection is also associated with hypotension. 9.4.2 Respiratory Respiratory depression may occur in benzodiazepine overdose and the severity depends on dose ingested, amount absorbed, type of benzodiazepine and co-ingestants. Respiratory depression requiring ventilatory support has occurred in benzodiazepine overdoses (Sullivan, 1989; Hojer et al.,1989). The dose-response for respiratory depression varies between individuals. Respiratory depression or respiratory arrest may rarely occur with therapeutic doses. Benzodiazepines may affect the control of ventilation during sleep and may worsen sleep apnoea or other sleep-related breathing disorders, especially in patients with chronic obstructive pulmonary disease or cardiac failure (Guilleminault, 1990). 9.4.3 Neurological 9.4.3.1 Central nervous system (CNS) CNS depression is less marked than that produced by other CNS depressant agents (Meredith & Vale, 1985). Even in large overdoses, benzodiazepines usually produce only mild symptoms and this distinguishes them from other sedative-hypnotic agents. Sedation, somnolence, weakness, diplopia, dysarthria, ataxia and intellectual impairment are the most common neurological effects. The clinical effects of severe poisoning are sleepiness, ataxia and coma Grade I to Grade II (Reed). The presence of more severe coma suggests the possibility of co-ingested drugs. Certain of the newer short-acting benzodiazepines (temazepam, alprazolam and triazolam) have been associated with several fatalities and it is possible that they may have greater acute toxicity (Forrest et al., 1986). The elderly and very young children are more susceptible to the CNS depressant action of benzodiazepines. The benzodiazepines may cause paradoxical CNS effects, including excitement, delirium and hallucinations. Triazolam has been reported to produce delirium, toxic psychosis, memory impairment and transient global amnesia (Shader & Dimascio, 1970; Bixler et al, 1991). Flurazepam has been associated with nightmares and hallucinations. There are a few reports of extrapyramidal symptoms and dyskinesias in patients taking benzodiazepines (Kaplan & Murkafsky, 1978; Sandyk, 1986). The muscle relaxation caused by benzodiazepines is of CNS origin and manifests as dysarthria, incoordination and difficulty standing and walking. 9.4.3.2 Peripheral nervous system 9.4.3.3 Autonomic nervous system 9.4.3.4 Skeletal and smooth muscle 9.4.4 Gastrointestinal Oral benzodiazepine poisoning will produce minimal effects on the gastrointestinal tract (GI) tract but can occasionally cause nausea or vomiting (Shader & Dimascio, 1970). 9.4.5 Hepatic A case of cholestatic jaundice due focal hepatic necrosis was associated with the administration of diazepam (Tedesco & Mills, 1982). 9.4.6 Urinary 9.4.6.1 Renal Vesical hypotonia and urinary retention has been reported in association with diazepam poisoning (Chadduck et al., 1973). 9.4.6.2 Other 9.4.7 Endocrine and reproductive systems Galactorrhoea with normal serum prolactin concentrations has been noted in 4 women taking benzodiazepines (Kleinberg et al., 1977). Gynaecomastia has been reported in men taking high doses of diazepam (Moerck & Majelung, 1979). Raised serum concentrations of oestrodiol were observed in men taking diazepam 10 to 20 mg daily for 2 weeks (Arguelles & Rosner, 1975). 9.4.8 Dermatological Bullae have been reported following overdose with nitrazepam and oxazepam (Ridley, 1971; Moshkowitz et al., 1990). Allergic skin reactions were attributed to diazepam at a rate of 0.4 per 1000 patients (Brigby, 1986). 9.4.9 Eye, ear, nose, throat: local effects Brown opacification of the lens occurred in 2 patients who used diazepam for several years (Pau Braune, 1985). 9.4.10 Haematological No data. 9.4.11 Immunological Allergic reaction as above (see 9.4.8). 9.4.12 Metabolic 9.4.12.1 Acid-base disturbances No direct disturbances have been described. 9.4.12.2 Fluid and electrolyte disturbances No direct disturbances have been described. 9.4.12.3 Others 9.4.13 Allergic reactions Hypersensitivity reactions including anaphylaxis are very rare (Brigby, 1986). Reactions have been attributed to the vehicle used for some parenteral diazepam formulations (Huttel et al., 1980). There is also a report of a type I hypersensitivity reaction to a lipid emulsion of diazepam (Deardon, 1987). 9.4.14 Other clinical effects Hypothermia was reported in 15% of cases in one series. (Martin, 1985; Hojer et al., 1989). 9.4.15 Special risks Pregnancy Passage of benzodiazepines across the placenta depends on the degree of protein binding in mother and fetus, which is influenced by factors such as stage of pregnancy and plasma concentrations of free fatty acids in mother and fetus (Lee et al., 1982). Adverse effects may persist in the neonate for several days after birth because of immature drug metabolising enzymes. Competition between diazepam and bilirubin for protein binding sites could result in hyperbilirubinemia in the neonate (Notarianni, 1990). The abuse of benzodiazepines by pregnant women can cause withdrawal syndrome in the neonate. The administration of benzodiazepines during childbirth can produce hypotonia, hyporeflexia, hypothermia and respiratory depression in the newborn. Benzodiazepines have been used in pregnant patients and early reports associated diazepam and chlordiazepoxide with some fetal malformations, but these were not supported by later studies (Laegreid et al., 1987; McElhatton, 1994). Breast feeding Benzodiazepines are excreted in breast milk in significant amounts and may result in lethargy and poor feeding in neonates. Benzodiazepines should be avoided in nursing mothers (Brodie, 1981; Reynolds, 1996). 9.5 Other Dependence and withdrawal Benzodiazepines have a significant potential for abuse and can cause physical and psychological dependence. Abrupt cessation after prolonged use causes a withdrawal syndrome (Ashton, 1989). The mechanism of dependence is probably related to functional deficiency of GABA activity. Withdrawal symptoms include anxiety, insomnia, headache, dizziness, tinnitus, anorexia, vomiting, nausea, tremor, weakness, perspiration, irritability, hypersensitivity to visual and auditory stimuli, palpitations, tachycardia and postural hypotension. In severe and rare cases of withdrawal from high doses, patients may develop affective disorders or motor dysfunction: seizures, psychosis, agitation, confusion, and hallucinations (Einarson, 1981; Hindmarch et al, 1990; Reynolds, 1996). The time of onset of the withdrawal syndrome depends on the half-life of the drug and its active metabolites; the symptoms occur earlier and may be more severe with short- acting benzodiazepines. Others risk factors for withdrawal syndrome include prolonged use of the drug, higher dosage and abrupt cessation of the drug. Abuse Benzodiazepines, particularly temazepam, have been abused both orally and intravenously (Stark et al., 1987; Woods, 1987; Funderburk et al, 1988) Criminal uses The amnesic effects of benzodiazepines have been used for criminal purposes with medicolegal consequences (Ferner, 1996). 9.6 Summary 10. MANAGEMENT 10.1 General principles Most benzodiazepine poisonings require only clinical observation and supportive care. It should be remembered that benzodiazepine ingestions by adults commonly include other drugs and other CNS depressants. Activated charcoal normally provides adequate gastrointestinal decontamination. Gastric lavage is not routinely indicated. Emesis is contraindicated. The use of flumazenil is reserved for cases with severe respiratory or cardiovascular complications and should not replace the basic management of the airway and respiration. Renal and extracorporeal elimination methods are not effective. 10.2 Life supportive procedures and symptomatic/specific treatment The patient should be evaluated to determine adequacy of airway, breathing and circulation. Continue clinical observation until evidence of toxicity has resolved. Intravenous access should be available for administration of fluid. Endotracheal intubation, assisted ventilation and supplemental oxygen may be required on rare occasions, more commonly when benzodiazepines are ingested in large amounts or with other CNS depressants. 10.3 Decontamination Gastric lavage is not routinely indicated following benzodiazepine overdose. Emesis is contraindicated because of the potential for CNS depression. Activated charcoal can be given orally. 10.4 Enhanced elimination Methods of enhancing elimination are not indicated. 10.5 Antidote treatment 10.5.1 Adults Flumazenil, a specific benzodiazepine antagonist at central GABA-ergic receptors is available. Although it effectively reverses the CNS effects of benzodiazepine overdose, its use in clinical practice is rarely indicated. Use of Flumazenil is specifically contraindicated when there is history of co-ingestion of tricyclic antidepressants or other drugs capable of producing seizures (including aminophylline and cocaine), benzodiazepine dependence, or in patients taking benzodiazepines as an anticonvulsant agent. In such situations, administration of Flumazenil may precipitate seizures (Lopez, 1990; Mordel et al., 1992). Adverse effects associated with Flumazenil include hypertension, tachycardia, anxiety, nausea, vomiting and benzodiazepine withdrawal syndrome. The initial intravenous dose of 0.3 to 1.0 mg may be followed by further doses if necessary. The absence of clinical response to 2 mg of flumazenil within 5 to 10 minutes indicates that benzodiazepine poisoning is not the major cause of CNS depression or coma. The patient regains consciousness within 15 to 30 seconds after injection of flumazenil, but since it is metabolised more rapidly than the benzodiazepines, recurrence of toxicity and CNS depression can occur and the patient should be carefully monitored after initial response to flumazenil therapy. If toxicity recurs, further bolus doses may be administered or an infusion commenced at a dose of 0.3 to 1.0 mg/hour (Meredith et al., 1993). 10.5.2 Children The initial intravenous dose of 0.1 mg should be repeated each minute until the child is awake. Continuous intravenous infusion should be administered at a rate of 0.1 to 0.2 mg/hour (Meredith et al., 1993). 10.6 Management discussion Most benzodiazepine poisonings require only clinical observation and supportive care. Flumazenil is the specific antagonist of the effects of benzodiazepines, but the routine use for the treatment of benzodiazepine overdosage is not recommended. The use of Flumazenil should only be considered where severe CNS depression is observed. This situation rarely occurs, except in cases of mixed ingestion. The administration of flumazenil may improve respiratory and cardiovascular function enough to decrease the need for intubation and mechanical ventilation, but should never replace basic management principles. Flumazenil is an imidazobenzodiazepine and has been shown to reverse the sedative, anti-convulsant and muscle-relaxant effects of benzodiazepines. In controlled clinical trials, flumazenil significantly antagonizes benzodiazepine-induced coma arising from anaesthesia or acute overdose. However, the use of flumazenil has not been shown to reduce mortality or sequelae in such cases. The administration of flumazenil is more effective in reversing the effects of benzodiazepines when they are the only drugs producing CNS toxicity. Flumazenil does not reverse the CNS depressant effects of non-benzodiazepine drugs, including alcohol. The diagnostic use of flumazenil in patients presenting with coma of unknown origin can be justified by its high therapeutic index and the fact that this may limit the use of other diagnostic procedures (CT scan, lumbar puncture, etc). Flumazenil is a relatively expensive drug and this may also influence its use, especially in areas with limited resources. 11. ILLUSTRATIVE CASES 11.1 Case reports from literature 12. Additional information 12.1 Specific preventive measures 12.2 Other 13. REFERENCES Arguelles AE, & Rosner J. (1975) Diazepam and plasma testosterone levels. Lancet, ii: 607. Ashton CH (1989) Drug-induced stupor and coma: some physical signs and their pharmacological basis. Adverse drug React Acute Poisoning Rev, 8: 1-59. Bixler EO, Kales A, Manfredi RL, Vgontzas AN, Tyson KL, & Kales JD (1991) Next-day memory impairment with triazolam use. Lancet, 337: 827-831. Brigby M. (1986) Drug induced cutaneous reactions. JAMA, 256: 3358-63. Brodie RR, Chasseaud LF & Taylor T (1981) Concentrations of N- descyclopropylmethyl-prazepam in whole-blood, plasma and milk after administration of prazepam to humans. Biopharm Drug Dispos, 2: 59-68. Chadduck WM, Loar CR & Denton IC. (1973) Vesical hypotonicity with diazepam. J Urol, 109: 1005-1007. Deardon DJ. (1987) Acute hypersensivity to IV Diazulmuls. Br J Anaesth, 59: 391. Einarson TR (1981) Oxazepam withdrawal convulsions. Drug Intell Clin Pharm, 15: 487. Ellenhorn, M. (1996) Medical Toxicology. 2nd Ed., Elsevier. Ferner RE (1996) Forensic Pharmacology, 1st Ed. Oxford University Press, Oxford. Forrest ARW, Marsh I, Bradshaw C & Braich SK (1986) Fatal temazepam overdoses (letter). Lancet, 2: 226. Funderburk FR, Griffiths RR, McLeod DR, Bigelow GE, Mackenzie A, Liebson IA & Newmeth-Coslett R (1988) Relative abuse liability of lorazepam and diazepam: an evaluation in "recreational" drug users. Drug Alcohol Depend, 22: 215-222. Greenblatt DJ, Allen MD, Noel BJ et al (1977) Acute overdose with benzodiazepine derivatives. Clin Pharm Ther, 21: 497-513. Guilleminault C. (1990) Benzodiazepines, bresthing and sleep. Am J Med, 88 (suppl 3A): 25S - 28S. Hindmarch I, Beaumont G, Brandon S, & Leonard, B. (1990) Benzodiazepines Current Concepts, John Wiley & Sons Ltd, UK. Hojer J, Baehrendtz S & Gustafsson L. (1989) Benzodiazepine poisoning: experience of 702 admissions to an intensive care unit during a 14-year period. J Intern Med, 226: 117-122. Huttel MS, Schou Olesen A & Stofferson E (1980) Complement- mediated reactions to diazepam with Cremophor as solvent. Br J Anaesth, 52: 77-9. Hyams SW & Keroub C (1977) Glaucoma due to diazepam. Am J Psychiatry, 134: 477-479. Kaplan SR, & Murkofsky C (1978) Oral-buccal dyskinesic synptoms associated with low dose benzodiazepine treatment. Am J Psychiatry, 135: 1558-1559. Kleinberg DL, Noel GL & Frantz AG (1977) Galactorrhea a study of 235 cases. N Eng J Med 296: 589-600. Laegreid L, Olegard R, & Wahlstrom J (1987) Abnormalities in children exposed to benzodiazepines in utero. Lancet, 1:108- 109. Lee JN, Chen SS, Richens A, Menabawey m & Chard T (1982) Serum protein binding of diazepam in maternal and foetal serum during pregnancy. Br J Clin Pharmacol, 14: 551-4. Lopez A & Rebollo J (1990) Benzodiazepine withdrawal syndrome after a benzodiazepine antagonist. Crit Care Med, 18:1480- 1481. Martin SM (1985) The effect of diazepam on body temperature change in humans during cold exposure. J Clin Pharmacol, 25: 611- 613. McCormick SR, Nielsen J & Jatlow PI (1985) Alprazolam overdose: clinical findings and serum concentrations in two cases. J Clin Psychiatr, 46:247-248. McElhatton PR. (1994) The effects of benzodiazepines use during pregnancy and lactation. Reprod Toxicol, 8: 461-75. Meredith TJ, Jacobsen D, Haines JA, Berger JC (1993) IPCS/CEC Evaluation of Antidotes Series, Vol1, Naloxone, flumazenil and dantrolene as antidotes, 1st ed. Cambridge University Press, Cambridge. Meredith TJ, & Vale JA (1985) Poisoning due to psychotropic agents. Adverse Drug React Acute Poison Rev, 4: 83-122. Minder EI (1989) Toxicity in a case of acute and massive overdose of chlordiazepoxide and its correlation to blood concentration. Clin Toxicol, 27: 117-127. Moerck HJ, Majelung G (1979) Gynaecomastia and diazepam abuse. Lancet, i: 1344-5. Mordel A, Winkler E, Almog S, Tirosh M & Ezra D (1992) Seizures after flumazenil administration in a case of combined benzodiazepine and tricyclic antidepressant overdose. Crit Care Med, 12: 1733-1734. Notarianni LJ. (1990) Plasma protein binding of drugs in pregnancy and neonates. Clin Pharnacokinet, 18: 20-36. Pau Braune H (1985) [Eyes effect of diazepam.] Klin Monatsbl Augenheilkd, 187: 219-20 (in German). Reed C E, Driggs M F, & Foote CC (1952) Acute barbiturate intoxication. A study of 300 cases based on a physiologic system of classification of the severity of intoxication. Ann Intern Med, 37: 390-396. Reynolds J (1996) Martindale, The Extra Pharmacopeia. 30th ed. The Pharmaceutical Press, London, 699-744. Ridley CM (1971) Bullous lesions in nitrazepan overdosage. Br Med J, 3: 28-29. Sandyk R (1986) Orofacial diskynesias associated with lorazepam therapy. Clin Pharm, 5: 419-21. Shader RI & Dimascio A (1970) Psychotropic drug side effects, 1st ed. Willians & Wilkins, Baltimore. Stark C, Sykes R & Mullin P (1987) Temazepam abuse (letter). Lancet, 2:802-803. Sullivan RJ Jr (1989) Respiratory depression requiring ventilatory support following 0.5 mg of Triazolam. J Am Geriatr, Soc 37: 450-452. Tedesco FJ, & Mills LR. (1982) Diazepam hepatites. Dig Dis Sci 27: 470-2. 14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES) Author: Dr Ligia Fruchtengarten Poison Control Centre of Sao Paulo - Brazil Hospital Municipal Dr Arthur Ribeiro de Saboya - Coperpas 12 FAX / Phone: 55 11 2755311 E-mail: lfruchtengarten@originet.com.br Mailing Address: Hospital Municipal Dr Arthur Ribeiro de Saboya - Coperpas 12 Centro de Controle de Intoxicaçoes de Sao Paulo Av Francisco de Paula Quintanilha Ribeiro, 860 04330 - 020 Sao Paulo - SP - Brazil. Date: July 1997 Peer Review: INTOX 10 Meeting, Rio de Janeiro, Brazil, September 1997. R. Ferner, L. Murray (Chairperson), M-O. Rambourg, A. Nantel, N. Ben Salah, M. Mathieu- Nolf, A.Borges. Review 1998: Lindsay Murray Queen Elizabeth II Medical Centre Perth, Western Australia. Editor: Dr M.Ruse, April 1998 See Also: Estazolam (IARC Summary & Evaluation, Volume 66, 1996) ESTAZOLAM (Group 3) For definition of Groups, see Preamble Evaluation. VOL.: 66 (1996) (p. 105) CAS No.: 29975-16-4 Chem. Abstr. Name: 8-Chloro-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine 5. Summary of Data Reported and Evaluation 5.1 Exposure data Estazolam is a triazolobenzodiazepine used since the 1970s for short-term management of insomnia. 5.2 Human carcinogenicity data No data were available to the Working Group. 5.3 Animal carcinogenicity data Estazolam was tested for carcinogenicity in one experiment in mice and one experiment in rats by oral administration in the diet. No increase in the incidence of tumours was found. 5.4 Other relevant data Estazolam is rapidly and almost completely absorbed in humans. It is extensively metabolized to at least 11 metabolites and excreted mainly in the urine. The elimination half-life is 14-19 h. Metabolism is extensive in various animal species. Rabbits and dogs excrete the metabolites principally in urine, while in mice, rats and guinea-pigs the excretion is mainly in faeces. Some metabolites are species-specific. There were no data available on reproductive effects of estazolam. The data available on genetic effects were negative. 5.5 Evaluation There is inadequate evidencein humans for the carcinogenicity of estazolam. There is evidence suggesting a lack of carcinogenicity in experimental animals for estazolam. Overall evaluation Estazolam is not classifiable as to its carcinogenicity to humans (Group 3). For definition of the italicized terms, see Preamble Evaluation Synonyms A 47631 Abbott 47631 Bay k 4200 Cannoc D 40TA Deprinocte Domnamid Esilgan Eurodin Hypnomat Julodin Kainever Nemurel Noctal Nuctalon ProSom Sedarest Somnatrol Tasedan U 33737 Last updated 22/05/97 See Also: Estazolam (PIM 925) Flunitrazepam 1. NAME 1.1 Substance 1.2 Group 1.3 Synonyms 1.4 Identification numbers 1.4.1 CAS number 1.4.2 Other numbers 1.5 Main brand names, main trade names 1.6 Main manufacturers, main importers 2. SUMMARY 2.1 Main risks and target organs 2.2 Summary of clinical effects 2.3 Diagnosis 2.4 First aid measures and management principles 3. PHYSICO-CHEMICAL PROPERTIES 3.1 Origin of the substance 3.2 Chemical structure 3.3 Physical properties 3.3.1 Colour 3.3.2 State/Form 3.3.3 Description 3.4 Other characteristics 3.4.1 Shelf-life of the substance 3.4.2 Storage conditions 4. USES 4.1 Indications 4.1.1 Indications 4.1.2 Description 4.2 Therapeutic dosage 4.2.1 Adults 4.2.2 Children 4.3 Contraindications 5. ROUTES OF EXPOSURE 5.1 Oral 5.2 Inhalation 5.3 Dermal 5.4 Eye 5.5 Parenteral 5.6 Other 6. KINETICS 6.1 Absorption by route of exposure 6.2 Distribution by route of exposure 6.3 Biological half-life by route of exposure 6.4 Metabolism 6.5 Elimination and excretion 7. PHARMACOLOGY AND TOXICOLOGY 7.1 Mode of action 7.1.1 Toxicodynamics 7.1.2 Pharmacodynamics 7.2 Toxicity 7.2.1 Human data 7.2.1.1 Adults 7.2.1.2 Children 7.2.2 Relevant animal data 7.2.3 Relevant in vitro data 7.3 Carcinogenicity 7.4 Teratogenicity 7.5 Mutagenicity 7.6 Interactions 7.7 Main adverse effects 8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS 8.1 Material sampling plan 8.1.1 Sampling and specimen collection 8.1.1.1 Toxicological analyses 8.1.1.2 Biomedical analyses 8.1.1.3 Arterial blood gas analysis 8.1.1.4 Haematological analyses 8.1.1.5 Other (unspecified) analyses 8.1.2 Storage of laboratory samples and specimens 8.1.2.1 Toxicological analyses 8.1.2.2 Biomedical analyses 8.1.2.3 Arterial blood gas analysis 8.1.2.4 Haematological analyses 8.1.2.5 Other (unspecified) analyses 8.1.3 Transport of laboratory samples and specimens 8.1.3.1 Toxicological analyses 8.1.3.2 Biomedical analyses 8.1.3.3 Arterial blood gas analysis 8.1.3.4 Haematological analyses 8.1.3.5 Other (unspecified) analyses 8.2 Toxicological Analyses and Their Interpretation 8.2.1 Tests on toxic ingredient(s) of material 8.2.1.1 Simple Qualitative Test(s) 8.2.1.2 Advanced Qualitative Confirmation Test(s) 8.2.1.3 Simple Quantitative Method(s) 8.2.1.4 Advanced Quantitative Method(s) 8.2.2 Tests for biological specimens 8.2.2.1 Simple Qualitative Test(s) 8.2.2.2 Advanced Qualitative Confirmation Test(s) 8.2.2.3 Simple Quantitative Method(s) 8.2.2.4 Advanced Quantitative Method(s) 8.2.2.5 Other Dedicated Method(s) 8.2.3 Interpretation of toxicological analyses 8.3 Biomedical investigations and their interpretation 8.3.1 Biochemical analysis 8.3.1.1 Blood, plasma or serum 8.3.1.2 Urine 8.3.1.3 Other fluids 8.3.2 Arterial blood gas analyses 8.3.3 Haematological analyses 8.3.4 Interpretation of biomedical investigations 8.4 Other biomedical (diagnostic) investigations and their interpretation 8.5 Overall interpretation of all toxicological analyses and toxicological investigations 8.6 References 9. CLINICAL EFFECTS 9.1 Acute poisoning 9.1.1 Ingestion 9.1.2 Inhalation 9.1.3 Skin exposure 9.1.4 Eye contact 9.1.5 Parenteral exposure 9.1.6 Other 9.2 Chronic poisoning 9.2.1 Ingestion 9.2.2 Inhalation 9.2.3 Skin exposure 9.2.4 Eye contact 9.2.5 Parenteral exposure 9.2.6 Other 9.3 Course, prognosis, cause of death 9.4 Systematic description of clinical effects 9.4.1 Cardiovascular 9.4.2 Respiratory 9.4.3 Neurological 9.4.3.1 Central nervous system (CNS) 9.4.3.2 Peripheral nervous system 9.4.3.3 Autonomic nervous system 9.4.3.4 Skeletal and smooth muscle 9.4.4 Gastrointestinal 9.4.5 Hepatic 9.4.6 Urinary 9.4.6.1 Renal 9.4.6.2 Other 9.4.7 Endocrine and reproductive systems 9.4.8 Dermatological 9.4.9 Eye, ear, nose, throat: local effects 9.4.10 Haematological 9.4.11 Immunological 9.4.12 Metabolic 9.4.12.1 Acid-base disturbances 9.4.12.2 Fluid and electrolyte disturbances 9.4.12.3 Others 9.4.13 Allergic reactions 9.4.14 Other clinical effects 9.4.15 Special risks 9.5 Other 9.6 Summary 10. MANAGEMENT 10.1 General principles 10.2 Life supportive procedures and symptomatic/specific treatment 10.3 Decontamination 10.4 Enhanced elimination 10.5 Antidote treatment 10.5.1 Adults 10.5.2 Children 10.6 Management discussion 11. ILLUSTRATIVE CASES 11.1 Case reports from literature 12. Additional information 12.1 Specific preventive measures 12.2 Other 13. REFERENCES 14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES) Flunitrazepam International Programme on Chemical Safety Poisons Information Monograph 021 Pharmaceutical This monograph does not contain all of the sections completed. This mongraph is harmonised with the Group monograph on Benzodiazepines (PIM G008). 1. NAME 1.1 Substance Flunitrazepam 1.2 Group ATC classification index Psycholeptics (N05)/Anxiolytics (N05B)/ Benzodiazepine derivatives (N05BA) 1.3 Synonyms Flunitrazepamum; Ro-5-4200 1.4 Identification numbers 1.4.1 CAS number 1622-62-4 1.4.2 Other numbers 1.5 Main brand names, main trade names Darkene; Flunipam; Hypnocalm; Hypnodorm; Hypnor; Narcozep; Noriel; Rohipnol; Rohypnol; Roipnol; Somnubene; Valsera 1.6 Main manufacturers, main importers 2. SUMMARY 2.1 Main risks and target organs Central nervous system, causing depression of respiration and consciousness. 2.2 Summary of clinical effects Central nervous system (CNS) depression and coma, or paradoxical excitation, but deaths are rare when benzodiazepines are taken alone. Deep coma and 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. 2.3 Diagnosis The clinical diagnosis is based upon the history of benzodiazepine overdose and the presence of the clinical signs of benzodiazepine intoxication. Benzodiazepines can be detected or measured in blood and urine using standard analytical methods. This information may confirm the diagnosis but is not useful in the clinical management of the patient. A clinical response to flumazenil, a specific benzodiazepine antagonist, also confirms the diagnosis of benzodiazepine overdose, but administration of this drug is rarely justified. 2.4 First aid measures and management principles Most benzodiazepine poisonings require only clinical observation and supportive care. It should be remembered that benzodiazepine ingestions by adults commonly involve co- ingestion of other CNS depressants and other drugs. Activated charcoal normally provides adequate gastrointestinal decontamination. Gastric lavage is not routinely indicated. Emesis is contraindicated. The use of flumazenil is reserved for cases with severe respiratory or cardiovascular complications and should not replace the basic management of the airway and respiration. The routine use of flumazenil is contraindicated because of potential complications, including seizures. Renal and extracorporeal methods of enhanced elimination are not effective. 3. PHYSICO-CHEMICAL PROPERTIES 3.1 Origin of the substance 3.2 Chemical structure Chemical Name: 5-(2-Fluorophenyl)-1,3-dihydro-1-methyl-7-nitro- -1,4-benzodiazepin-2-one Molecular Formula: C16H12FN3O3 Molecular Weight: 313.3 3.3 Physical properties 3.3.1 Colour White or yellowish 3.3.2 State/Form Solid-crystals 3.3.3 Description Virtually insoluble in water; slightly soluble in alcohol and ether; soluble in acetone (Reynolds, 1996). 3.4 Other characteristics 3.4.1 Shelf-life of the substance 3.4.2 Storage conditions Protect from light (Reynolds, 1996). 4. USES 4.1 Indications 4.1.1 Indications 4.1.2 Description 4.2 Therapeutic dosage 4.2.1 Adults 4.2.2 Children 4.3 Contraindications 5. ROUTES OF EXPOSURE 5.1 Oral 5.2 Inhalation 5.3 Dermal 5.4 Eye 5.5 Parenteral 5.6 Other 6. KINETICS 6.1 Absorption by route of exposure 6.2 Distribution by route of exposure 6.3 Biological half-life by route of exposure 6.4 Metabolism 6.5 Elimination and excretion 7. PHARMACOLOGY AND TOXICOLOGY 7.1 Mode of action 7.1.1 Toxicodynamics 7.1.2 Pharmacodynamics 7.2 Toxicity 7.2.1 Human data 7.2.1.1 Adults 7.2.1.2 Children 7.2.2 Relevant animal data 7.2.3 Relevant in vitro data 7.3 Carcinogenicity 7.4 Teratogenicity 7.5 Mutagenicity 7.6 Interactions 7.7 Main adverse effects 8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS 8.1 Material sampling plan 8.1.1 Sampling and specimen collection 8.1.1.1 Toxicological analyses 8.1.1.2 Biomedical analyses 8.1.1.3 Arterial blood gas analysis 8.1.1.4 Haematological analyses 8.1.1.5 Other (unspecified) analyses 8.1.2 Storage of laboratory samples and specimens 8.1.2.1 Toxicological analyses 8.1.2.2 Biomedical analyses 8.1.2.3 Arterial blood gas analysis 8.1.2.4 Haematological analyses 8.1.2.5 Other (unspecified) analyses 8.1.3 Transport of laboratory samples and specimens 8.1.3.1 Toxicological analyses 8.1.3.2 Biomedical analyses 8.1.3.3 Arterial blood gas analysis 8.1.3.4 Haematological analyses 8.1.3.5 Other (unspecified) analyses 8.2 Toxicological Analyses and Their Interpretation 8.2.1 Tests on toxic ingredient(s) of material 8.2.1.1 Simple Qualitative Test(s) 8.2.1.2 Advanced Qualitative Confirmation Test(s) 8.2.1.3 Simple Quantitative Method(s) 8.2.1.4 Advanced Quantitative Method(s) 8.2.2 Tests for biological specimens 8.2.2.1 Simple Qualitative Test(s) 8.2.2.2 Advanced Qualitative Confirmation Test(s) 8.2.2.3 Simple Quantitative Method(s) 8.2.2.4 Advanced Quantitative Method(s) 8.2.2.5 Other Dedicated Method(s) 8.2.3 Interpretation of toxicological analyses 8.3 Biomedical investigations and their interpretation 8.3.1 Biochemical analysis 8.3.1.1 Blood, plasma or serum "Basic analyses" "Dedicated analyses" "Optional analyses" 8.3.1.2 Urine "Basic analyses" "Dedicated analyses" "Optional analyses" 8.3.1.3 Other fluids 8.3.2 Arterial blood gas analyses 8.3.3 Haematological analyses "Basic analyses" "Dedicated analyses" "Optional analyses" 8.3.4 Interpretation of biomedical investigations 8.4 Other biomedical (diagnostic) investigations and their interpretation 8.5 Overall interpretation of all toxicological analyses and toxicological investigations Sample collection For toxicological analyses: whole blood 10 mL; urine 25 mL and gastric contents 25 mL. Biomedical analysis Blood gases, serum electrolytes, blood glucose and hepatic enzymes when necessary in severe cases. Toxicological analysis Qualitative testing for benzodiazepines is helpful to confirm their presence, but quantitative levels are not clinically useful. More advanced analyses are not necessary for the treatment of the poisoned patient due the lack of correlation between blood concentrations and clinical severity (Jatlow et al., 1979; MacCormick et al., 1985; Minder, 1989). TLC and EMIT: These provide data on the presence of benzodiazepines, their metabolites and possible associations with other drugs. GC or HPLC: These permit identification and quantification of the benzodiazepine which caused the poisoning and its metabolites in blood and urine. 8.6 References 9. CLINICAL EFFECTS 9.1 Acute poisoning 9.1.1 Ingestion The onset of impairment of consciousness is relatively rapid in benzodiazepine poisoning. Onset is more rapid following larger doses and with agents of shorter duration of action. The most common and initial symptom is somnolence. This may progress to coma Grade I or Grade II (see below) following very large ingestions. Reed Classification of Coma (Reed et al., 1952) Coma Grade I: Depressed level of consciousness, response to painful stimuli Deep tendon reflexes and vital signs intact Coma Grade II: Depressed level of consciousness, no response to painful stimuli Deep tendon reflexes and vital signs intact Coma Grade III: Depressed level of consciousness, no response to painful stimuli Deep tendon reflexes absent. Vital signs intact Coma Grade IV: Coma grade III plus respiratory and circulatory collapse 9.1.2 Inhalation Not relevant. 9.1.3 Skin exposure No data. 9.1.4 Eye contact No data. 9.1.5 Parenteral exposure Overdose by the intravenous route results in symptoms similar to those associated with ingestion, but they appear immediately after the infusion, and the progression of central nervous system (CNS) depression is more rapid. Acute intentional poisoning by this route is uncommon and most cases are iatrogenic. Rapid intravenous infusion may cause hypotension, respiratory depression and apnoea. 9.1.6 Other 9.2 Chronic poisoning 9.2.1 Ingestion Toxic effects associated with chronic exposure are secondary to the presence of the drug and metabolites and include depressed mental status, ataxia, vertigo, dizziness, fatigue, impaired motor co-ordination, confusion, disorientation and anterograde amnesia. Paradoxical effects of psychomotor excitation, delirium and aggressiveness also occur. These chronic effects are more common in the elderly, children and patients with renal or hepatic disease. Administration of therapeutic doses of benzodiazepines for 6 weeks or longer can result in physical dependence, characterized by a withdrawal syndrome when the drug is discontinued. With larger doses, the physical dependence develops more rapidly. 9.2.2 Inhalation No data. 9.2.3 Skin exposure No data. 9.2.4 Eye contact No data. 9.2.5 Parenteral exposure The chronic parenteral administration of benzodiazepines may produce thrombophlebitis and tissue irritation, in addition to the usual symptoms (Greenblat & Koch-Weser, 1973). 9.2.6 Other No data. 9.3 Course, prognosis, cause of death Benzodiazepines are relatively safe drugs even in overdose. The clinical course is determined by the progression of the neurological symptoms. Deep coma or other manifestations of severe central nervous system (CNS) depression are rare with benzodiazepines alone. Concomitant ingestion of other CNS depressants may result in a more severe CNS depression of longer duration. The therapeutic index of the benzodiazepines is high and the mortality rate associated with poisoning due to benzodiazepines alone is very low. Complications in severe poisoning include respiratory depression and aspiration pneumonia. Death is due to respiratory arrest. 9.4 Systematic description of clinical effects 9.4.1 Cardiovascular Hypotension, bradycardia and tachycardia have been reported with overdose (Greenblatt et al., 1977; Meredith & Vale 1985). Hypotension is more frequent when benzodiazepines are ingested in association with other drugs (Hojer et al., 1989). Rapid intravenous injection is also associated with hypotension. 9.4.2 Respiratory Respiratory depression may occur in benzodiazepine overdose and the severity depends on dose ingested, amount absorbed, type of benzodiazepine and co-ingestants. Respiratory depression requiring ventilatory support has occurred in benzodiazepine overdoses (Sullivan, 1989; Hojer et al.,1989). The dose-response for respiratory depression varies between individuals. Respiratory depression or respiratory arrest may rarely occur with therapeutic doses. Benzodiazepines may affect the control of ventilation during sleep and may worsen sleep apnoea or other sleep-related breathing disorders, especially in patients with chronic obstructive pulmonary disease or cardiac failure (Guilleminault, 1990). 9.4.3 Neurological 9.4.3.1 Central nervous system (CNS) CNS depression is less marked than that produced by other CNS depressant agents (Meredith & Vale, 1985). Even in large overdoses, benzodiazepines usually produce only mild symptoms and this distinguishes them from other sedative-hypnotic agents. Sedation, somnolence, weakness, diplopia, dysarthria, ataxia and intellectual impairment are the most common neurological effects. The clinical effects of severe poisoning are sleepiness, ataxia and coma Grade I to Grade II (Reed). The presence of more severe coma suggests the possibility of co-ingested drugs. Certain of the newer short-acting benzodiazepines (temazepam, alprazolam and triazolam) have been associated with several fatalities and it is possible that they may have greater acute toxicity (Forrest et al., 1986). The elderly and very young children are more susceptible to the CNS depressant action of benzodiazepines. The benzodiazepines may cause paradoxical CNS effects, including excitement, delirium and hallucinations. Triazolam has been reported to produce delirium, toxic psychosis, memory impairment and transient global amnesia (Shader & Dimascio, 1970; Bixler et al, 1991). Flurazepam has been associated with nightmares and hallucinations. There are a few reports of extrapyramidal symptoms and dyskinesias in patients taking benzodiazepines (Kaplan & Murkafsky, 1978; Sandyk, 1986). The muscle relaxation caused by benzodiazepines is of CNS origin and manifests as dysarthria, incoordination and difficulty standing and walking. 9.4.3.2 Peripheral nervous system 9.4.3.3 Autonomic nervous system 9.4.3.4 Skeletal and smooth muscle 9.4.4 Gastrointestinal Oral benzodiazepine poisoning will produce minimal effects on the gastrointestinal tract (GI) tract but can occasionally cause nausea or vomiting (Shader & Dimascio, 1970). 9.4.5 Hepatic A case of cholestatic jaundice due focal hepatic necrosis was associated with the administration of diazepam (Tedesco & Mills, 1982). 9.4.6 Urinary 9.4.6.1 Renal Vesical hypotonia and urinary retention has been reported in association with diazepam poisoning (Chadduck et al., 1973). 9.4.6.2 Other 9.4.7 Endocrine and reproductive systems Galactorrhoea with normal serum prolactin concentrations has been noted in 4 women taking benzodiazepines (Kleinberg et al., 1977). Gynaecomastia has been reported in men taking high doses of diazepam (Moerck & Majelung, 1979). Raised serum concentrations of oestrodiol were observed in men taking diazepam 10 to 20 mg daily for 2 weeks (Arguelles & Rosner, 1975). 9.4.8 Dermatological Bullae have been reported following overdose with nitrazepam and oxazepam (Ridley, 1971; Moshkowitz et al., 1990). Allergic skin reactions were attributed to diazepam at a rate of 0.4 per 1000 patients (Brigby, 1986). 9.4.9 Eye, ear, nose, throat: local effects Brown opacification of the lens occurred in 2 patients who used diazepam for several years (Pau Braune, 1985). 9.4.10 Haematological No data. 9.4.11 Immunological Allergic reaction as above (see 9.4.8). 9.4.12 Metabolic 9.4.12.1 Acid-base disturbances No direct disturbances have been described. 9.4.12.2 Fluid and electrolyte disturbances No direct disturbances have been described. 9.4.12.3 Others 9.4.13 Allergic reactions Hypersensitivity reactions including anaphylaxis are very rare (Brigby, 1986). Reactions have been attributed to the vehicle used for some parenteral diazepam formulations (Huttel et al., 1980). There is also a report of a type I hypersensitivity reaction to a lipid emulsion of diazepam (Deardon, 1987). 9.4.14 Other clinical effects Hypothermia was reported in 15% of cases in one series. (Martin, 1985; Hojer et al., 1989). 9.4.15 Special risks Pregnancy Passage of benzodiazepines across the placenta depends on the degree of protein binding in mother and fetus, which is influenced by factors such as stage of pregnancy and plasma concentrations of free fatty acids in mother and fetus (Lee et al., 1982). Adverse effects may persist in the neonate for several days after birth because of immature drug metabolising enzymes. Competition between diazepam and bilirubin for protein binding sites could result in hyperbilirubinemia in the neonate (Notarianni, 1990). The abuse of benzodiazepines by pregnant women can cause withdrawal syndrome in the neonate. The administration of benzodiazepines during childbirth can produce hypotonia, hyporeflexia, hypothermia and respiratory depression in the newborn. Benzodiazepines have been used in pregnant patients and early reports associated diazepam and chlordiazepoxide with some fetal malformations, but these were not supported by later studies (Laegreid et al., 1987; McElhatton, 1994). Breast feeding Benzodiazepines are excreted in breast milk in significant amounts and may result in lethargy and poor feeding in neonates. Benzodiazepines should be avoided in nursing mothers (Brodie, 1981; Reynolds, 1996). 9.5 Other Dependence and withdrawal Benzodiazepines have a significant potential for abuse and can cause physical and psychological dependence. Abrupt cessation after prolonged use causes a withdrawal syndrome (Ashton, 1989). The mechanism of dependence is probably related to functional deficiency of GABA activity. Withdrawal symptoms include anxiety, insomnia, headache, dizziness, tinnitus, anorexia, vomiting, nausea, tremor, weakness, perspiration, irritability, hypersensitivity to visual and auditory stimuli, palpitations, tachycardia and postural hypotension. In severe and rare cases of withdrawal from high doses, patients may develop affective disorders or motor dysfunction: seizures, psychosis, agitation, confusion, and hallucinations (Einarson, 1981; Hindmarch et al, 1990; Reynolds, 1996). The time of onset of the withdrawal syndrome depends on the half-life of the drug and its active metabolites; the symptoms occur earlier and may be more severe with short- acting benzodiazepines. Others risk factors for withdrawal syndrome include prolonged use of the drug, higher dosage and abrupt cessation of the drug. Abuse Benzodiazepines, particularly temazepam, have been abused both orally and intravenously (Stark et al., 1987; Woods, 1987; Funderburk et al, 1988) Criminal uses The amnesic effects of benzodiazepines have been used for criminal purposes with medicolegal consequences (Ferner, 1996). 9.6 Summary 10. MANAGEMENT 10.1 General principles Most benzodiazepine poisonings require only clinical observation and supportive care. It should be remembered that benzodiazepine ingestions by adults commonly include other drugs and other CNS depressants. Activated charcoal normally provides adequate gastrointestinal decontamination. Gastric lavage is not routinely indicated. Emesis is contraindicated. The use of flumazenil is reserved for cases with severe respiratory or cardiovascular complications and should not replace the basic management of the airway and respiration. Renal and extracorporeal elimination methods are not effective. 10.2 Life supportive procedures and symptomatic/specific treatment The patient should be evaluated to determine adequacy of airway, breathing and circulation. Continue clinical observation until evidence of toxicity has resolved. Intravenous access should be available for administration of fluid. Endotracheal intubation, assisted ventilation and supplemental oxygen may be required on rare occasions, more commonly when benzodiazepines are ingested in large amounts or with other CNS depressants. 10.3 Decontamination Gastric lavage is not routinely indicated following benzodiazepine overdose. Emesis is contraindicated because of the potential for CNS depression. Activated charcoal can be given orally. 10.4 Enhanced elimination Methods of enhancing elimination are not indicated. 10.5 Antidote treatment 10.5.1 Adults Flumazenil, a specific benzodiazepine antagonist at central GABA-ergic receptors is available. Although it effectively reverses the CNS effects of benzodiazepine overdose, its use in clinical practice is rarely indicated. Use of Flumazenil is specifically contraindicated when there is history of co-ingestion of tricyclic antidepressants or other drugs capable of producing seizures (including aminophylline and cocaine), benzodiazepine dependence, or in patients taking benzodiazepines as an anticonvulsant agent. In such situations, administration of Flumazenil may precipitate seizures (Lopez, 1990; Mordel et al., 1992). Adverse effects associated with Flumazenil include hypertension, tachycardia, anxiety, nausea, vomiting and benzodiazepine withdrawal syndrome. The initial intravenous dose of 0.3 to 1.0 mg may be followed by further doses if necessary. The absence of clinical response to 2 mg of flumazenil within 5 to 10 minutes indicates that benzodiazepine poisoning is not the major cause of CNS depression or coma. The patient regains consciousness within 15 to 30 seconds after injection of flumazenil, but since it is metabolised more rapidly than the benzodiazepines, recurrence of toxicity and CNS depression can occur and the patient should be carefully monitored after initial response to flumazenil therapy. If toxicity recurs, further bolus doses may be administered or an infusion commenced at a dose of 0.3 to 1.0 mg/hour (Meredith et al., 1993). 10.5.2 Children The initial intravenous dose of 0.1 mg should be repeated each minute until the child is awake. Continuous intravenous infusion should be administered at a rate of 0.1 to 0.2 mg/hour (Meredith et al., 1993). 10.6 Management discussion Most benzodiazepine poisonings require only clinical observation and supportive care. Flumazenil is the specific antagonist of the effects of benzodiazepines, but the routine use for the treatment of benzodiazepine overdosage is not recommended. The use of Flumazenil should only be considered where severe CNS depression is observed. This situation rarely occurs, except in cases of mixed ingestion. The administration of flumazenil may improve respiratory and cardiovascular function enough to decrease the need for intubation and mechanical ventilation, but should never replace basic management principles. Flumazenil is an imidazobenzodiazepine and has been shown to reverse the sedative, anti-convulsant and muscle-relaxant effects of benzodiazepines. In controlled clinical trials, flumazenil significantly antagonizes benzodiazepine-induced coma arising from anaesthesia or acute overdose. However, the use of flumazenil has not been shown to reduce mortality or sequelae in such cases. The administration of flumazenil is more effective in reversing the effects of benzodiazepines when they are the only drugs producing CNS toxicity. Flumazenil does not reverse the CNS depressant effects of non-benzodiazepine drugs, including alcohol. The diagnostic use of flumazenil in patients presenting with coma of unknown origin can be justified by its high therapeutic index and the fact that this may limit the use of other diagnostic procedures (CT scan, lumbar puncture, etc). Flumazenil is a relatively expensive drug and this may also influence its use, especially in areas with limited resources. 11. ILLUSTRATIVE CASES 11.1 Case reports from literature 12. Additional information 12.1 Specific preventive measures 12.2 Other 13. REFERENCES Arguelles AE, & Rosner J. (1975) Diazepam and plasma testosterone levels. Lancet, ii: 607. Ashton CH (1989) Drug-induced stupor and coma: some physical signs and their pharmacological basis. Adverse drug React Acute Poisoning Rev, 8: 1-59. Bixler EO, Kales A, Manfredi RL, Vgontzas AN, Tyson KL, & Kales JD (1991) Next-day memory impairment with triazolam use. Lancet, 337: 827-831. Brigby M. (1986) Drug induced cutaneous reactions. JAMA, 256: 3358-63. Brodie RR, Chasseaud LF & Taylor T (1981) Concentrations of N- descyclopropylmethyl-prazepam in whole-blood, plasma and milk after administration of prazepam to humans. Biopharm Drug Dispos, 2: 59-68. Chadduck WM, Loar CR & Denton IC. (1973) Vesical hypotonicity with diazepam. J Urol, 109: 1005-1007. Deardon DJ. (1987) Acute hypersensivity to IV Diazulmuls. Br J Anaesth, 59: 391. Einarson TR (1981) Oxazepam withdrawal convulsions. Drug Intell Clin Pharm, 15: 487. Ellenhorn, M. (1996) Medical Toxicology. 2nd Ed., Elsevier. Ferner RE (1996) Forensic Pharmacology, 1st Ed. Oxford University Press, Oxford. Forrest ARW, Marsh I, Bradshaw C & Braich SK (1986) Fatal temazepam overdoses (letter). Lancet, 2: 226. Funderburk FR, Griffiths RR, McLeod DR, Bigelow GE, Mackenzie A, Liebson IA & Newmeth-Coslett R (1988) Relative abuse liability of lorazepam and diazepam: an evaluation in "recreational" drug users. Drug Alcohol Depend, 22: 215-222. Greenblatt DJ, Allen MD, Noel BJ et al (1977) Acute overdose with benzodiazepine derivatives. Clin Pharm Ther, 21: 497-513. Guilleminault C. (1990) Benzodiazepines, bresthing and sleep. Am J Med, 88 (suppl 3A): 25S - 28S. Hindmarch I, Beaumont G, Brandon S, & Leonard, B. (1990) Benzodiazepines Current Concepts, John Wiley & Sons Ltd, UK. Hojer J, Baehrendtz S & Gustafsson L. (1989) Benzodiazepine poisoning: experience of 702 admissions to an intensive care unit during a 14-year period. J Intern Med, 226: 117-122. Huttel MS, Schou Olesen A & Stofferson E (1980) Complement- mediated reactions to diazepam with Cremophor as solvent. Br J Anaesth, 52: 77-9. Hyams SW & Keroub C (1977) Glaucoma due to diazepam. Am J Psychiatry, 134: 477-479. Kaplan SR, & Murkofsky C (1978) Oral-buccal dyskinesic synptoms associated with low dose benzodiazepine treatment. Am J Psychiatry, 135: 1558-1559. Kleinberg DL, Noel GL & Frantz AG (1977) Galactorrhea a study of 235 cases. N Eng J Med 296: 589-600. Laegreid L, Olegard R, & Wahlstrom J (1987) Abnormalities in children exposed to benzodiazepines in utero. Lancet, 1:108-109. Lee JN, Chen SS, Richens A, Menabawey m & Chard T (1982) Serum protein binding of diazepam in maternal and foetal serum during pregnancy. Br J Clin Pharmacol, 14: 551-4. Lopez A & Rebollo J (1990) Benzodiazepine withdrawal syndrome after a benzodiazepine antagonist. Crit Care Med, 18:1480-1481. Martin SM (1985) The effect of diazepam on body temperature change in humans during cold exposure. J Clin Pharmacol, 25: 611-613. McCormick SR, Nielsen J & Jatlow PI (1985) Alprazolam overdose: clinical findings and serum concentrations in two cases. J Clin Psychiatr, 46:247-248. McElhatton PR. (1994) The effects of benzodiazepines use during pregnancy and lactation. Reprod Toxicol, 8: 461-75. Meredith TJ, Jacobsen D, Haines JA, Berger JC (1993) IPCS/CEC Evaluation of Antidotes Series, Vol1, Naloxone, flumazenil and dantrolene as antidotes, 1st ed. Cambridge University Press, Cambridge. Meredith TJ, & Vale JA (1985) Poisoning due to psychotropic agents. Adverse Drug React Acute Poison Rev, 4: 83-122. Minder EI (1989) Toxicity in a case of acute and massive overdose of chlordiazepoxide and its correlation to blood concentration. Clin Toxicol, 27: 117-127. Moerck HJ, Majelung G (1979) Gynaecomastia and diazepam abuse. Lancet, i: 1344-5. Mordel A, Winkler E, Almog S, Tirosh M & Ezra D (1992) Seizures after flumazenil administration in a case of combined benzodiazepine and tricyclic antidepressant overdose. Crit Care Med, 12: 1733-1734. Notarianni LJ. (1990) Plasma protein binding of drugs in pregnancy and neonates. Clin Pharnacokinet, 18: 20-36. Pau Braune H (1985) [Eyes effect of diazepam.] Klin Monatsbl Augenheilkd, 187: 219-20 (in German). Reed C E, Driggs M F, & Foote CC (1952) Acute barbiturate intoxication. A study of 300 cases based on a physiologic system of classification of the severity of intoxication. Ann Intern Med, 37: 390-396. Reynolds J (1996) Martindale, The Extra Pharmacopeia. 30th ed. The Pharmaceutical Press, London, 699-744. Ridley CM (1971) Bullous lesions in nitrazepan overdosage. Br Med J, 3: 28-29. Sandyk R (1986) Orofacial diskynesias associated with lorazepam therapy. Clin Pharm, 5: 419-21. Shader RI & Dimascio A (1970) Psychotropic drug side effects, 1st ed. Willians & Wilkins, Baltimore. Stark C, Sykes R & Mullin P (1987) Temazepam abuse (letter). Lancet, 2: 802-803. Sullivan RJ Jr (1989) Respiratory depression requiring ventilatory support following 0.5 mg of Triazolam. J Am Geriatr, Soc 37: 450-452. Tedesco FJ, & Mills LR. (1982) Diazepam hepatites. Dig Dis Sci 27: 470-2. 14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES) Author: Dr Ligia Fruchtengarten Poison Control Centre of Sao Paulo - Brazil Hospital Municipal Dr Arthur Ribeiro de Saboya - Coperpas 12 FAX / Phone: 55 11 2755311 E-mail: lfruchtengarten@originet.com.br Mailing Address: Hospital Municipal Dr Arthur Ribeiro de Saboya - Coperpas 12 Centro de Controle de Intoxicaçoes de Sao Paulo Av Francisco de Paula Quintanilha Ribeiro, 860 04330 - 020 Sao Paulo - SP - Brazil. Date: July 1997 Peer Review: INTOX 10 Meeting, Rio de Janeiro, Brazil, September 1997. R. Ferner, L. Murray (Chairperson), M-O. Rambourg, A. Nantel, N. Ben Salah, M. Mathieu-Nolf, A.Borges. Review 1998: Lindsay Murray Queen Elizabeth II Medical Centre Perth, Western Australia. Editor: Dr M.Ruse, April 1998 Flurazepam 1. NAME 1.1 Substance 1.2 Group 1.3 Synonyms 1.4 Identification numbers 1.4.1 CAS number 1.4.2 Other numbers 1.5 Main brand names, main trade names 1.6 Main manufacturers, main importers 2. SUMMARY 2.1 Main risks and target organs 2.2 Summary of clinical effects 2.3 Diagnosis 2.4 First aid measures and management principles 3. PHYSICO-CHEMICAL PROPERTIES 3.1 Origin of the substance 3.2 Chemical structure 3.3 Physical properties 3.3.1 Colour 3.3.2 State/Form 3.3.3 Description 3.4 Other characteristics 3.4.1 Shelf-life of the substance 3.4.2 Storage conditions 4. USES 4.1 Indications 4.1.1 Indications 4.1.2 Description 4.2 Therapeutic dosage 4.2.1 Adults 4.2.2 Children 4.3 Contraindications 5. ROUTES OF EXPOSURE 5.1 Oral 5.2 Inhalation 5.3 Dermal 5.4 Eye 5.5 Parenteral 5.6 Other 6. KINETICS 6.1 Absorption by route of exposure 6.2 Distribution by route of exposure 6.3 Biological half-life by route of exposure 6.4 Metabolism 6.5 Elimination and excretion 7. PHARMACOLOGY AND TOXICOLOGY 7.1 Mode of action 7.1.1 Toxicodynamics 7.1.2 Pharmacodynamics 7.2 Toxicity 7.2.1 Human data 7.2.1.1 Adults 7.2.1.2 Children 7.2.2 Relevant animal data 7.2.3 Relevant in vitro data 7.3 Carcinogenicity 7.4 Teratogenicity 7.5 Mutagenicity 7.6 Interactions 7.7 Main adverse effects 8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS 8.1 Material sampling plan 8.1.1 Sampling and specimen collection 8.1.1.1 Toxicological analyses 8.1.1.2 Biomedical analyses 8.1.1.3 Arterial blood gas analysis 8.1.1.4 Haematological analyses 8.1.1.5 Other (unspecified) analyses 8.1.2 Storage of laboratory samples and specimens 8.1.2.1 Toxicological analyses 8.1.2.2 Biomedical analyses 8.1.2.3 Arterial blood gas analysis 8.1.2.4 Haematological analyses 8.1.2.5 Other (unspecified) analyses 8.1.3 Transport of laboratory samples and specimens 8.1.3.1 Toxicological analyses 8.1.3.2 Biomedical analyses 8.1.3.3 Arterial blood gas analysis 8.1.3.4 Haematological analyses 8.1.3.5 Other (unspecified) analyses 8.2 Toxicological Analyses and Their Interpretation 8.2.1 Tests on toxic ingredient(s) of material 8.2.1.1 Simple Qualitative Test(s) 8.2.1.2 Advanced Qualitative Confirmation Test(s) 8.2.1.3 Simple Quantitative Method(s) 8.2.1.4 Advanced Quantitative Method(s) 8.2.2 Tests for biological specimens 8.2.2.1 Simple Qualitative Test(s) 8.2.2.2 Advanced Qualitative Confirmation Test(s) 8.2.2.3 Simple Quantitative Method(s) 8.2.2.4 Advanced Quantitative Method(s) 8.2.2.5 Other Dedicated Method(s) 8.2.3 Interpretation of toxicological analyses 8.3 Biomedical investigations and their interpretation 8.3.1 Biochemical analysis 8.3.1.1 Blood, plasma or serum 8.3.1.2 Urine 8.3.1.3 Other fluids 8.3.2 Arterial blood gas analyses 8.3.3 Haematological analyses 8.3.4 Interpretation of biomedical investigations 8.4 Other biomedical (diagnostic) investigations and their interpretation 8.5 Overall interpretation of all toxicological analyses and toxicological investigations 8.6 References 9. CLINICAL EFFECTS 9.1 Acute poisoning 9.1.1 Ingestion 9.1.2 Inhalation 9.1.3 Skin exposure 9.1.4 Eye contact 9.1.5 Parenteral exposure 9.1.6 Other 9.2 Chronic poisoning 9.2.1 Ingestion 9.2.2 Inhalation 9.2.3 Skin exposure 9.2.4 Eye contact 9.2.5 Parenteral exposure 9.2.6 Other 9.3 Course, prognosis, cause of death 9.4 Systematic description of clinical effects 9.4.1 Cardiovascular 9.4.2 Respiratory 9.4.3 Neurological 9.4.3.1 Central nervous system (CNS) 9.4.3.2 Peripheral nervous system 9.4.3.3 Autonomic nervous system 9.4.3.4 Skeletal and smooth muscle 9.4.4 Gastrointestinal 9.4.5 Hepatic 9.4.6 Urinary 9.4.6.1 Renal 9.4.6.2 Other 9.4.7 Endocrine and reproductive systems 9.4.8 Dermatological 9.4.9 Eye, ear, nose, throat: local effects 9.4.10 Haematological 9.4.11 Immunological 9.4.12 Metabolic 9.4.12.1 Acid-base disturbances 9.4.12.2 Fluid and electrolyte disturbances 9.4.12.3 Others 9.4.13 Allergic reactions 9.4.14 Other clinical effects 9.4.15 Special risks 9.5 Other 9.6 Summary 10. MANAGEMENT 10.1 General principles 10.2 Life supportive procedures and symptomatic/specific treatment 10.3 Decontamination 10.4 Enhanced elimination 10.5 Antidote treatment 10.5.1 Adults 10.5.2 Children 10.6 Management discussion 11. ILLUSTRATIVE CASES 11.1 Case reports from literature 12. Additional information 12.1 Specific preventive measures 12.2 Other 13. REFERENCES 14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES) Flurazepam International Programme on Chemical Safety Poisons Information Monograph 640 Pharmaceutical This monograph does not contain all of the sections completed. This mongraph is harmonised with the Group monograph on Benzodiazepines (PIM G008). 1. NAME 1.1 Substance Flurazepam 1.2 Group ATC classification index Psycholeptics (N05)/ Anxiolytics (N05B)/ Benzodiazepine derivatives (N05BA) 1.3 Synonyms Flurazepam Hydrochloride (Flurazepam dihydrochloride); NSC-78559 (Flurazepam dihydrochloride); Ro-5-6901 (Flurazepam dihydrochloride) Flurazepami Monohydrochloridum (Flurazepam monohydrochloride) 1.4 Identification numbers 1.4.1 CAS number 17617-23-1 1.4.2 Other numbers Flurazepam dihydrochloride CAS Number: 1172-18-5 Flurazepam monohydrochloride CAS Number: 36105-20-1 1.5 Main brand names, main trade names Flurazepam monohydrochloride Dalmadorm; Dalmane; Dalmane; Felison; Flunox; Flurazepam Capsules BP 1993; Paxane; Somnol; Valdorm Flurazepam dihydrochloride Dalmadorm; Dalmane; Dormodor; Flurazepam Hydrochloride Capsules USP 23; Irdal; Midorm AR; Novoflupam; Remdue 1.6 Main manufacturers, main importers 2. SUMMARY 2.1 Main risks and target organs Central nervous system, causing depression of respiration and consciousness. 2.2 Summary of clinical effects Central nervous system (CNS) depression and coma, or paradoxical excitation, but deaths are rare when benzodiazepines are taken alone. Deep coma and 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. 2.3 Diagnosis The clinical diagnosis is based upon the history of benzodiazepine overdose and the presence of the clinical signs of benzodiazepine intoxication. Benzodiazepines can be detected or measured in blood and urine using standard analytical methods. This information may confirm the diagnosis but is not useful in the clinical management of the patient. A clinical response to flumazenil, a specific benzodiazepine antagonist, also confirms the diagnosis of benzodiazepine overdose, but administration of this drug is rarely justified. 2.4 First aid measures and management principles Most benzodiazepine poisonings require only clinical observation and supportive care. It should be remembered that benzodiazepine ingestions by adults commonly involve co- ingestion of other CNS depressants and other drugs. Activated charcoal normally provides adequate gastrointestinal decontamination. Gastric lavage is not routinely indicated. Emesis is contraindicated. The use of flumazenil is reserved for cases with severe respiratory or cardiovascular complications and should not replace the basic management of the airway and respiration. The routine use of flumazenil is contraindicated because of potential complications, including seizures. Renal and extracorporeal methods of enhanced elimination are not effective. 3. PHYSICO-CHEMICAL PROPERTIES 3.1 Origin of the substance 3.2 Chemical structure Flurazepam Chemical Name: 7-Chloro-1-(2-diethylaminoethyl)-5-(2-fluorophenyl)-1,3- -dihydro- -1,4-benzodiazepin-2-one Molecular Formula: C21H23ClFN3O Molecular weight 387.88. Flurazepam monohydrochloride Chemical Name: 7-Chloro-1-(2-diethylaminoethyl)-5-(2-fluorophenyl)-1,3- -dihydro- -1,4-benzodiazepin-2-one hydrochloride. Molecular Formula: C21H23ClFN3O, HCl Molecular Weight: 424.3 Flurazepam dihydrochloride Chemical Name: 7-Chloro-1-(2-diethylaminoethyl)-5-(2-fluorophenyl)-1,3- -dihydro- -1,4-benzodiazepin-2-one dihydrochloride. Molecular Formula: C21H23ClFN3O, 2HCl Molecular Weight: 460.8 3.3 Physical properties 3.3.1 Colour 3.3.2 State/Form 3.3.3 Description Flurazepam monohydrochloride Flurazepam monohydrochloride is a white or almost white crystalline powder. It is extremally soluble in water; freely soluble in alcohol; practically insoluble in ether. A 5% solution of flurazepam monohydrochloride in water has a pH of 5.0 to 6.0. 32.8 mg of flurazepam monohydrochloride is approximately equivalent to 30 mg of flurazepam. (Reynolds, 1996). Flurazepam dihydrochloride Flurazepam dihydrochloride is an off-white to yellow crystalline powder. It is odourless or almost odourless. 30 mg of flurazepam dihydrochloride is approximately equivalent to 25.3 mg of flurazepam. Soluble 1 in 2 of water, 1 in 4 of alcohol, 1 in 90 of chloroform, 1 in 3 of methyl alcohol, 1 in 69 of isopropyl alcohol, and 1 in 5000 of ether and of petroleum spirit. A solution in water is acid to litmus. (Reynolds, 1996). 3.4 Other characteristics 3.4.1 Shelf-life of the substance 3.4.2 Storage conditions Store in airtight containers and protect from light (Reynolds, 1996). 4. USES 4.1 Indications 4.1.1 Indications 4.1.2 Description 4.2 Therapeutic dosage 4.2.1 Adults 4.2.2 Children 4.3 Contraindications 5. ROUTES OF EXPOSURE 5.1 Oral 5.2 Inhalation 5.3 Dermal 5.4 Eye 5.5 Parenteral 5.6 Other 6. KINETICS 6.1 Absorption by route of exposure 6.2 Distribution by route of exposure 6.3 Biological half-life by route of exposure 6.4 Metabolism 6.5 Elimination and excretion 7. PHARMACOLOGY AND TOXICOLOGY 7.1 Mode of action 7.1.1 Toxicodynamics 7.1.2 Pharmacodynamics 7.2 Toxicity 7.2.1 Human data 7.2.1.1 Adults 7.2.1.2 Children 7.2.2 Relevant animal data 7.2.3 Relevant in vitro data 7.3 Carcinogenicity 7.4 Teratogenicity 7.5 Mutagenicity 7.6 Interactions 7.7 Main adverse effects 8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS 8.1 Material sampling plan 8.1.1 Sampling and specimen collection 8.1.1.1 Toxicological analyses 8.1.1.2 Biomedical analyses 8.1.1.3 Arterial blood gas analysis 8.1.1.4 Haematological analyses 8.1.1.5 Other (unspecified) analyses 8.1.2 Storage of laboratory samples and specimens 8.1.2.1 Toxicological analyses 8.1.2.2 Biomedical analyses 8.1.2.3 Arterial blood gas analysis 8.1.2.4 Haematological analyses 8.1.2.5 Other (unspecified) analyses 8.1.3 Transport of laboratory samples and specimens 8.1.3.1 Toxicological analyses 8.1.3.2 Biomedical analyses 8.1.3.3 Arterial blood gas analysis 8.1.3.4 Haematological analyses 8.1.3.5 Other (unspecified) analyses 8.2 Toxicological Analyses and Their Interpretation 8.2.1 Tests on toxic ingredient(s) of material 8.2.1.1 Simple Qualitative Test(s) 8.2.1.2 Advanced Qualitative Confirmation Test(s) 8.2.1.3 Simple Quantitative Method(s) 8.2.1.4 Advanced Quantitative Method(s) 8.2.2 Tests for biological specimens 8.2.2.1 Simple Qualitative Test(s) 8.2.2.2 Advanced Qualitative Confirmation Test(s) 8.2.2.3 Simple Quantitative Method(s) 8.2.2.4 Advanced Quantitative Method(s) 8.2.2.5 Other Dedicated Method(s) 8.2.3 Interpretation of toxicological analyses 8.3 Biomedical investigations and their interpretation 8.3.1 Biochemical analysis 8.3.1.1 Blood, plasma or serum "Basic analyses" "Dedicated analyses" "Optional analyses" 8.3.1.2 Urine "Basic analyses" "Dedicated analyses" "Optional analyses" 8.3.1.3 Other fluids 8.3.2 Arterial blood gas analyses 8.3.3 Haematological analyses "Basic analyses" "Dedicated analyses" "Optional analyses" 8.3.4 Interpretation of biomedical investigations 8.4 Other biomedical (diagnostic) investigations and their interpretation 8.5 Overall interpretation of all toxicological analyses and toxicological investigations Sample collection For toxicological analyses: whole blood 10 mL; urine 25 mL and gastric contents 25 mL. Biomedical analysis Blood gases, serum electrolytes, blood glucose and hepatic enzymes when necessary in severe cases. Toxicological analysis Qualitative testing for benzodiazepines is helpful to confirm their presence, but quantitative levels are not clinically useful. More advanced analyses are not necessary for the treatment of the poisoned patient due the lack of correlation between blood concentrations and clinical severity (Jatlow et al., 1979; MacCormick et al., 1985; Minder, 1989). TLC and EMIT: These provide data on the presence of benzodiazepines, their metabolites and possible associations with other drugs. GC or HPLC: These permit identification and quantification of the benzodiazepine which caused the poisoning and its metabolites in blood and urine. 8.6 References 9. CLINICAL EFFECTS 9.1 Acute poisoning 9.1.1 Ingestion The onset of impairment of consciousness is relatively rapid in benzodiazepine poisoning. Onset is more rapid following larger doses and with agents of shorter duration of action. The most common and initial symptom is somnolence. This may progress to coma Grade I or Grade II (see below) following very large ingestions. Reed Classification of Coma (Reed et al., 1952) Coma Grade I: Depressed level of consciousness, response to painful stimuli Deep tendon reflexes and vital signs intact Coma Grade II: Depressed level of consciousness, no response to painful stimuli Deep tendon reflexes and vital signs intact Coma Grade III: Depressed level of consciousness, no response to painful stimuli Deep tendon reflexes absent. Vital signs intact Coma Grade IV: Coma grade III plus respiratory and circulatory collapse 9.1.2 Inhalation Not relevant. 9.1.3 Skin exposure No data. 9.1.4 Eye contact No data. 9.1.5 Parenteral exposure Overdose by the intravenous route results in symptoms similar to those associated with ingestion, but they appear immediately after the infusion, and the progression of central nervous system (CNS) depression is more rapid. Acute intentional poisoning by this route is uncommon and most cases are iatrogenic. Rapid intravenous infusion may cause hypotension, respiratory depression and apnoea. 9.1.6 Other 9.2 Chronic poisoning 9.2.1 Ingestion Toxic effects associated with chronic exposure are secondary to the presence of the drug and metabolites and include depressed mental status, ataxia, vertigo, dizziness, fatigue, impaired motor co-ordination, confusion, disorientation and anterograde amnesia. Paradoxical effects of psychomotor excitation, delirium and aggressiveness also occur. These chronic effects are more common in the elderly, children and patients with renal or hepatic disease. Administration of therapeutic doses of benzodiazepines for 6 weeks or longer can result in physical dependence, characterized by a withdrawal syndrome when the drug is discontinued. With larger doses, the physical dependence develops more rapidly. 9.2.2 Inhalation No data. 9.2.3 Skin exposure No data. 9.2.4 Eye contact No data. 9.2.5 Parenteral exposure The chronic parenteral administration of benzodiazepines may produce thrombophlebitis and tissue irritation, in addition to the usual symptoms (Greenblat & Koch-Weser, 1973). 9.2.6 Other No data. 9.3 Course, prognosis, cause of death Benzodiazepines are relatively safe drugs even in overdose. The clinical course is determined by the progression of the neurological symptoms. Deep coma or other manifestations of severe central nervous system (CNS) depression are rare with benzodiazepines alone. Concomitant ingestion of other CNS depressants may result in a more severe CNS depression of longer duration. The therapeutic index of the benzodiazepines is high and the mortality rate associated with poisoning due to benzodiazepines alone is very low. Complications in severe poisoning include respiratory depression and aspiration pneumonia. Death is due to respiratory arrest. 9.4 Systematic description of clinical effects 9.4.1 Cardiovascular Hypotension, bradycardia and tachycardia have been reported with overdose (Greenblatt et al., 1977; Meredith & Vale 1985). Hypotension is more frequent when benzodiazepines are ingested in association with other drugs (Hojer et al., 1989). Rapid intravenous injection is also associated with hypotension. 9.4.2 Respiratory Respiratory depression may occur in benzodiazepine overdose and the severity depends on dose ingested, amount absorbed, type of benzodiazepine and co-ingestants. Respiratory depression requiring ventilatory support has occurred in benzodiazepine overdoses (Sullivan, 1989; Hojer et al.,1989). The dose-response for respiratory depression varies between individuals. Respiratory depression or respiratory arrest may rarely occur with therapeutic doses. Benzodiazepines may affect the control of ventilation during sleep and may worsen sleep apnoea or other sleep-related breathing disorders, especially in patients with chronic obstructive pulmonary disease or cardiac failure (Guilleminault, 1990). 9.4.3 Neurological 9.4.3.1 Central nervous system (CNS) CNS depression is less marked than that produced by other CNS depressant agents (Meredith & Vale, 1985). Even in large overdoses, benzodiazepines usually produce only mild symptoms and this distinguishes them from other sedative-hypnotic agents. Sedation, somnolence, weakness, diplopia, dysarthria, ataxia and intellectual impairment are the most common neurological effects. The clinical effects of severe poisoning are sleepiness, ataxia and coma Grade I to Grade II (Reed). The presence of more severe coma suggests the possibility of co-ingested drugs. Certain of the newer short-acting benzodiazepines (temazepam, alprazolam and triazolam) have been associated with several fatalities and it is possible that they may have greater acute toxicity (Forrest et al., 1986). The elderly and very young children are more susceptible to the CNS depressant action of benzodiazepines. The benzodiazepines may cause paradoxical CNS effects, including excitement, delirium and hallucinations. Triazolam has been reported to produce delirium, toxic psychosis, memory impairment and transient global amnesia (Shader & Dimascio, 1970; Bixler et al, 1991). Flurazepam has been associated with nightmares and hallucinations. There are a few reports of extrapyramidal symptoms and dyskinesias in patients taking benzodiazepines (Kaplan & Murkafsky, 1978; Sandyk, 1986). The muscle relaxation caused by benzodiazepines is of CNS origin and manifests as dysarthria, incoordination and difficulty standing and walking. 9.4.3.2 Peripheral nervous system 9.4.3.3 Autonomic nervous system 9.4.3.4 Skeletal and smooth muscle 9.4.4 Gastrointestinal Oral benzodiazepine poisoning will produce minimal effects on the gastrointestinal tract (GI) tract but can occasionally cause nausea or vomiting (Shader & Dimascio, 1970). 9.4.5 Hepatic A case of cholestatic jaundice due focal hepatic necrosis was associated with the administration of diazepam (Tedesco & Mills, 1982). 9.4.6 Urinary 9.4.6.1 Renal Vesical hypotonia and urinary retention has been reported in association with diazepam poisoning (Chadduck et al., 1973). 9.4.6.2 Other 9.4.7 Endocrine and reproductive systems Galactorrhoea with normal serum prolactin concentrations has been noted in 4 women taking benzodiazepines (Kleinberg et al., 1977). Gynaecomastia has been reported in men taking high doses of diazepam (Moerck & Majelung, 1979). Raised serum concentrations of oestrodiol were observed in men taking diazepam 10 to 20 mg daily for 2 weeks (Arguelles & Rosner, 1975). 9.4.8 Dermatological Bullae have been reported following overdose with nitrazepam and oxazepam (Ridley, 1971; Moshkowitz et al., 1990). Allergic skin reactions were attributed to diazepam at a rate of 0.4 per 1000 patients (Brigby, 1986). 9.4.9 Eye, ear, nose, throat: local effects Brown opacification of the lens occurred in 2 patients who used diazepam for several years (Pau Braune, 1985). 9.4.10 Haematological No data. 9.4.11 Immunological Allergic reaction as above (see 9.4.8). 9.4.12 Metabolic 9.4.12.1 Acid-base disturbances No direct disturbances have been described. 9.4.12.2 Fluid and electrolyte disturbances No direct disturbances have been described. 9.4.12.3 Others 9.4.13 Allergic reactions Hypersensitivity reactions including anaphylaxis are very rare (Brigby, 1986). Reactions have been attributed to the vehicle used for some parenteral diazepam formulations (Huttel et al., 1980). There is also a report of a type I hypersensitivity reaction to a lipid emulsion of diazepam (Deardon, 1987). 9.4.14 Other clinical effects Hypothermia was reported in 15% of cases in one series. (Martin, 1985; Hojer et al., 1989). 9.4.15 Special risks Pregnancy Passage of benzodiazepines across the placenta depends on the degree of protein binding in mother and fetus, which is influenced by factors such as stage of pregnancy and plasma concentrations of free fatty acids in mother and fetus (Lee et al., 1982). Adverse effects may persist in the neonate for several days after birth because of immature drug metabolising enzymes. Competition between diazepam and bilirubin for protein binding sites could result in hyperbilirubinemia in the neonate (Notarianni, 1990). The abuse of benzodiazepines by pregnant women can cause withdrawal syndrome in the neonate. The administration of benzodiazepines during childbirth can produce hypotonia, hyporeflexia, hypothermia and respiratory depression in the newborn. Benzodiazepines have been used in pregnant patients and early reports associated diazepam and chlordiazepoxide with some fetal malformations, but these were not supported by later studies (Laegreid et al., 1987; McElhatton, 1994). Breast feeding Benzodiazepines are excreted in breast milk in significant amounts and may result in lethargy and poor feeding in neonates. Benzodiazepines should be avoided in nursing mothers (Brodie, 1981; Reynolds, 1996). 9.5 Other Dependence and withdrawal Benzodiazepines have a significant potential for abuse and can cause physical and psychological dependence. Abrupt cessation after prolonged use causes a withdrawal syndrome (Ashton, 1989). The mechanism of dependence is probably related to functional deficiency of GABA activity. Withdrawal symptoms include anxiety, insomnia, headache, dizziness, tinnitus, anorexia, vomiting, nausea, tremor, weakness, perspiration, irritability, hypersensitivity to visual and auditory stimuli, palpitations, tachycardia and postural hypotension. In severe and rare cases of withdrawal from high doses, patients may develop affective disorders or motor dysfunction: seizures, psychosis, agitation, confusion, and hallucinations (Einarson, 1981; Hindmarch et al, 1990; Reynolds, 1996). The time of onset of the withdrawal syndrome depends on the half-life of the drug and its active metabolites; the symptoms occur earlier and may be more severe with short- acting benzodiazepines. Others risk factors for withdrawal syndrome include prolonged use of the drug, higher dosage and abrupt cessation of the drug. Abuse Benzodiazepines, particularly temazepam, have been abused both orally and intravenously (Stark et al., 1987; Woods, 1987; Funderburk et al, 1988) Criminal uses The amnesic effects of benzodiazepines have been used for criminal purposes with medicolegal consequences (Ferner, 1996). 9.6 Summary 10. MANAGEMENT 10.1 General principles Most benzodiazepine poisonings require only clinical observation and supportive care. It should be remembered that benzodiazepine ingestions by adults commonly include other drugs and other CNS depressants. Activated charcoal normally provides adequate gastrointestinal decontamination. Gastric lavage is not routinely indicated. Emesis is contraindicated. The use of flumazenil is reserved for cases with severe respiratory or cardiovascular complications and should not replace the basic management of the airway and respiration. Renal and extracorporeal elimination methods are not effective. 10.2 Life supportive procedures and symptomatic/specific treatment The patient should be evaluated to determine adequacy of airway, breathing and circulation. Continue clinical observation until evidence of toxicity has resolved. Intravenous access should be available for administration of fluid. Endotracheal intubation, assisted ventilation and supplemental oxygen may be required on rare occasions, more commonly when benzodiazepines are ingested in large amounts or with other CNS depressants. 10.3 Decontamination Gastric lavage is not routinely indicated following benzodiazepine overdose. Emesis is contraindicated because of the potential for CNS depression. Activated charcoal can be given orally. 10.4 Enhanced elimination Methods of enhancing elimination are not indicated. 10.5 Antidote treatment 10.5.1 Adults Flumazenil, a specific benzodiazepine antagonist at central GABA-ergic receptors is available. Although it effectively reverses the CNS effects of benzodiazepine overdose, its use in clinical practice is rarely indicated. Use of Flumazenil is specifically contraindicated when there is history of co-ingestion of tricyclic antidepressants or other drugs capable of producing seizures (including aminophylline and cocaine), benzodiazepine dependence, or in patients taking benzodiazepines as an anticonvulsant agent. In such situations, administration of Flumazenil may precipitate seizures (Lopez, 1990; Mordel et al., 1992). Adverse effects associated with Flumazenil include hypertension, tachycardia, anxiety, nausea, vomiting and benzodiazepine withdrawal syndrome. The initial intravenous dose of 0.3 to 1.0 mg may be followed by further doses if necessary. The absence of clinical response to 2 mg of flumazenil within 5 to 10 minutes indicates that benzodiazepine poisoning is not the major cause of CNS depression or coma. The patient regains consciousness within 15 to 30 seconds after injection of flumazenil, but since it is metabolised more rapidly than the benzodiazepines, recurrence of toxicity and CNS depression can occur and the patient should be carefully monitored after initial response to flumazenil therapy. If toxicity recurs, further bolus doses may be administered or an infusion commenced at a dose of 0.3 to 1.0 mg/hour (Meredith et al., 1993). 10.5.2 Children The initial intravenous dose of 0.1 mg should be repeated each minute until the child is awake. Continuous intravenous infusion should be administered at a rate of 0.1 to 0.2 mg/hour (Meredith et al., 1993). 10.6 Management discussion Most benzodiazepine poisonings require only clinical observation and supportive care. Flumazenil is the specific antagonist of the effects of benzodiazepines, but the routine use for the treatment of benzodiazepine overdosage is not recommended. The use of Flumazenil should only be considered where severe CNS depression is observed. This situation rarely occurs, except in cases of mixed ingestion. The administration of flumazenil may improve respiratory and cardiovascular function enough to decrease the need for intubation and mechanical ventilation, but should never replace basic management principles. Flumazenil is an imidazobenzodiazepine and has been shown to reverse the sedative, anti-convulsant and muscle-relaxant effects of benzodiazepines. In controlled clinical trials, flumazenil significantly antagonizes benzodiazepine-induced coma arising from anaesthesia or acute overdose. However, the use of flumazenil has not been shown to reduce mortality or sequelae in such cases. The administration of flumazenil is more effective in reversing the effects of benzodiazepines when they are the only drugs producing CNS toxicity. Flumazenil does not reverse the CNS depressant effects of non-benzodiazepine drugs, including alcohol. The diagnostic use of flumazenil in patients presenting with coma of unknown origin can be justified by its high therapeutic index and the fact that this may limit the use of other diagnostic procedures (CT scan, lumbar puncture, etc). Flumazenil is a relatively expensive drug and this may also influence its use, especially in areas with limited resources. 11. ILLUSTRATIVE CASES 11.1 Case reports from literature 12. Additional information 12.1 Specific preventive measures 12.2 Other 13. REFERENCES Arguelles AE, & Rosner J. (1975) Diazepam and plasma testosterone levels. Lancet, ii: 607. Ashton CH (1989) Drug-induced stupor and coma: some physical signs and their pharmacological basis. Adverse drug React Acute Poisoning Rev, 8: 1-59. Bixler EO, Kales A, Manfredi RL, Vgontzas AN, Tyson KL, & Kales JD (1991) Next-day memory impairment with triazolam use. Lancet, 337: 827-831. Brigby M. (1986) Drug induced cutaneous reactions. JAMA, 256: 3358-63. Brodie RR, Chasseaud LF & Taylor T (1981) Concentrations of N- descyclopropylmethyl-prazepam in whole-blood, plasma and milk after administration of prazepam to humans. Biopharm Drug Dispos, 2: 59-68. Chadduck WM, Loar CR & Denton IC. (1973) Vesical hypotonicity with diazepam. J Urol, 109: 1005-1007. Deardon DJ. (1987) Acute hypersensivity to IV Diazulmuls. Br J Anaesth, 59: 391. Einarson TR (1981) Oxazepam withdrawal convulsions. Drug Intell Clin Pharm, 15: 487. Ellenhorn, M. (1996) Medical Toxicology. 2nd Ed., Elsevier. Ferner RE (1996) Forensic Pharmacology, 1st Ed. Oxford University Press, Oxford. Forrest ARW, Marsh I, Bradshaw C & Braich SK (1986) Fatal temazepam overdoses (letter). Lancet, 2: 226. Funderburk FR, Griffiths RR, McLeod DR, Bigelow GE, Mackenzie A, Liebson IA & Newmeth-Coslett R (1988) Relative abuse liability of lorazepam and diazepam: an evaluation in "recreational" drug users. Drug Alcohol Depend, 22: 215-222. Greenblatt DJ, Allen MD, Noel BJ et al (1977) Acute overdose with benzodiazepine derivatives. Clin Pharm Ther, 21: 497-513. Guilleminault C. (1990) Benzodiazepines, bresthing and sleep. Am J Med, 88 (suppl 3A): 25S - 28S. Hindmarch I, Beaumont G, Brandon S, & Leonard, B. (1990) Benzodiazepines Current Concepts, John Wiley & Sons Ltd, UK. Hojer J, Baehrendtz S & Gustafsson L. (1989) Benzodiazepine poisoning: experience of 702 admissions to an intensive care unit during a 14-year period. J Intern Med, 226: 117-122. Huttel MS, Schou Olesen A & Stofferson E (1980) Complement- mediated reactions to diazepam with Cremophor as solvent. Br J Anaesth, 52: 77-9. Hyams SW & Keroub C (1977) Glaucoma due to diazepam. Am J Psychiatry, 134: 477-479. Kaplan SR, & Murkofsky C (1978) Oral-buccal dyskinesic synptoms associated with low dose benzodiazepine treatment. Am J Psychiatry, 135: 1558-1559. Kleinberg DL, Noel GL & Frantz AG (1977) Galactorrhea a study of 235 cases. N Eng J Med 296: 589-600. Laegreid L, Olegard R, & Wahlstrom J (1987) Abnormalities in children exposed to benzodiazepines in utero. Lancet, 1:108- 109. Lee JN, Chen SS, Richens A, Menabawey m & Chard T (1982) Serum protein binding of diazepam in maternal and foetal serum during pregnancy. Br J Clin Pharmacol, 14: 551-4. Lopez A & Rebollo J (1990) Benzodiazepine withdrawal syndrome after a benzodiazepine antagonist. Crit Care Med, 18:1480- 1481. Martin SM (1985) The effect of diazepam on body temperature change in humans during cold exposure. J Clin Pharmacol, 25: 611-613. McCormick SR, Nielsen J & Jatlow PI (1985) Alprazolam overdose: clinical findings and serum concentrations in two cases. J Clin Psychiatr, 46:247-248. McElhatton PR. (1994) The effects of benzodiazepines use during pregnancy and lactation. Reprod Toxicol, 8: 461-75. Meredith TJ, Jacobsen D, Haines JA, Berger JC (1993) IPCS/CEC Evaluation of Antidotes Series, Vol1, Naloxone, flumazenil and dantrolene as antidotes, 1st ed. Cambridge University Press, Cambridge. Meredith TJ, & Vale JA (1985) Poisoning due to psychotropic agents. Adverse Drug React Acute Poison Rev, 4: 83-122. Minder EI (1989) Toxicity in a case of acute and massive overdose of chlordiazepoxide and its correlation to blood concentration. Clin Toxicol, 27: 117-127. Moerck HJ, Majelung G (1979) Gynaecomastia and diazepam abuse. Lancet, i: 1344-5. Mordel A, Winkler E, Almog S, Tirosh M & Ezra D (1992) Seizures after flumazenil administration in a case of combined benzodiazepine and tricyclic antidepressant overdose. Crit Care Med, 12: 1733-1734. Notarianni LJ. (1990) Plasma protein binding of drugs in pregnancy and neonates. Clin Pharnacokinet, 18: 20-36. Pau Braune H (1985) [Eyes effect of diazepam.] Klin Monatsbl Augenheilkd, 187: 219-20 (in German). Reed C E, Driggs M F, & Foote CC (1952) Acute barbiturate intoxication. A study of 300 cases based on a physiologic system of classification of the severity of intoxication. Ann Intern Med, 37: 390-396. Reynolds J (1996) Martindale, The Extra Pharmacopeia. 30th ed. The Pharmaceutical Press, London, 699-744. Ridley CM (1971) Bullous lesions in nitrazepan overdosage. Br Med J, 3: 28-29. Sandyk R (1986) Orofacial diskynesias associated with lorazepam therapy. Clin Pharm, 5: 419-21. Shader RI & Dimascio A (1970) Psychotropic drug side effects, 1st ed. Willians & Wilkins, Baltimore. Stark C, Sykes R & Mullin P (1987) Temazepam abuse (letter). Lancet, 2:802-803. Sullivan RJ Jr (1989) Respiratory depression requiring ventilatory support following 0.5 mg of Triazolam. J Am Geriatr, Soc 37: 450-452. Tedesco FJ, & Mills LR. (1982) Diazepam hepatites. Dig Dis Sci 27: 470-2. 14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES) Author: Dr Ligia Fruchtengarten Poison Control Centre of Sao Paulo - Brazil Hospital Municipal Dr Arthur Ribeiro de Saboya - Coperpas 12 FAX / Phone: 55 11 2755311 E-mail: lfruchtengarten@originet.com.br Mailing Address: Hospital Municipal Dr Arthur Ribeiro de Saboya - Coperpas 12 Centro de Controle de Intoxicaçoes de Sao Paulo Av Francisco de Paula Quintanilha Ribeiro, 860 04330 - 020 Sao Paulo - SP - Brazil. Date: July 1997 Peer Review: INTOX 10 Meeting, Rio de Janeiro, Brazil, September 1997. R. Ferner, L. Murray (Chairperson), M-O. Rambourg, A. Nantel, N. Ben Salah, M. Mathieu- Nolf, A.Borges. Review 1998: Lindsay Murray Queen Elizabeth II Medical Centre Perth, Western Australia. Editor: Dr M.Ruse, April 1998 Glutethimide 1. NAME 1.1 Substance 1.2 Group 1.3 Synonyms 1.4 Identification numbers 1.4.1 CAS number 1.4.2 Other numbers 1.5 Main brand names, main trade names 1.6 Main manufacturers, main importers 2. SUMMARY 2.1 Main risks and target organs 2.2 Summary of clinical effects 2.3 Diagnosis 2.4 First aid measures and management principles 3. PHYSICO-CHEMICAL PROPERTIES 3.1 Origin of the substance 3.2 Chemical structure 3.3 Physical properties 3.3.1 Colour 3.3.2 State/form 3.3.3 Description 3.4 Other characteristics 3.4.1 Shelf-life of the substance 3.4.2 Storage conditions 4. USES 4.1 Indications 4.1.1 Indications 4.1.2 Description 4.2 Therapeutic dosage 4.2.1 Adults 4.2.2 Children 4.3 Contraindications 5. ROUTES OF ENTRY 5.1 Oral 5.2 Inhalation 5.3 Dermal 5.4 Eye 5.5 Parenteral 5.6 Other 6. KINETICS 6.1 Absorption by route of exposure 6.2 Distribution by route of exposure 6.3 Biological half-life by route of exposure 6.4 Metabolism 6.5 Elimination by route of exposure 7. PHARMACOLOGY AND TOXICOLOGY 7.1 Mode of action 7.1.1 Toxicodynamics 7.1.2 Pharmacodynamics 7.2 Toxicity 7.2.1 Human data 7.2.1.1 Adults 7.2.1.2 Children 7.2.2 Relevant animal data 7.2.3 Relevant in vitro data 7.3 Carcinogenicity 7.4 Teratogenicity 7.5 Mutagenicity 7.6 Interactions 7.7 Main adverse effects 8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS 8.1 Material sampling plan 8.1.1 Sampling and specimen collection 8.1.1.1 Toxicological analyses 8.1.1.2 Biomedical analyses 8.1.1.3 Arterial blood gas analysis 8.1.1.4 Haematological analyses 8.1.1.5 Other (unspecified) analyses 8.1.2 Storage of laboratory samples and specimens 8.1.2.1 Toxicological analyses 8.1.2.2 Biomedical analyses 8.1.2.3 Arterial blood gas analysis 8.1.2.4 Haematological analyses 8.1.2.5 Other (unspecified) analyses 8.1.3 Transport of laboratory samples and specimens 8.1.3.1 Toxicological analyses 8.1.3.2 Biomedical analyses 8.1.3.3 Arterial blood gas analysis 8.1.3.4 Haematological analyses 8.1.3.5 Other (unspecified) analyses 8.2 Toxicological analyses and their interpretation 8.2.1 Tests on toxic ingredient(s) of material 8.2.1.1 Simple qualitative test(s) 8.2.1.2 Advanced qualitative confirmation test(s) 8.2.1.3 Simple quantitative method(s) 8.2.1.4 Advanced quantitative method(s) 8.2.2 Tests for biological specimens 8.2.2.1 Simple qualitative test(s) 8.2.2.2 Advanced Qualitative Confirmation Test(s) 8.2.2.3 Simple Quantitative Method(s) 8.2.2.4 Advanced quantitative method(s) 8.2.2.5 Other dedicated method(s) 8.2.3 Interpretation of toxicological analyses 8.3 Biomedical investigations and their interpretation 8.3.1 Biochemical analysis 8.3.1.1 Blood, plasma or serum 8.3.1.2 Urine 8.3.1.3 Other fluids 8.3.2 Arterial blood gas analyses 8.3.3 Haematological analyses 8.3.4 Interpretation of biomedical investigations 8.3.5 Interpretation of biological investigations 8.4 Other biomedical (diagnostic) investigations and their interpretation 8.5 Overall Interpretation of all toxicological analyses and toxicological investigations 9. CLINICAL EFFECTS 9.1 Acute poisoning 9.1.1 Ingestion 9.1.2 Inhalation 9.1.3 Skin exposure 9.1.4 Eye contact 9.1.5 Parenteral exposure 9.1.6 Other 9.2 Chronic poisoning 9.2.1 Ingestion 9.2.2 Inhalation 9.2.3 Skin exposure 9.2.4 Eye contact 9.2.5 Parenteral exposure 9.2.6 Other 9.3 Course, prognosis, cause of death 9.4 Systematic description of clinical effects 9.4.1 Cardiovascular 9.4.2 Respiratory 9.4.3 Neurological 9.4.3.1 Central Nervous System (CNS) 9.4.3.2 Peripheral nervous system 9.4.3.3 Autonomic nervous system 9.4.3.4 Skeletal and smooth muscle 9.4.4 Gastrointestinal 9.4.5 Hepatic 9.4.6 Urinary 9.4.6.1 Renal 9.4.6.2 Other 9.4.7 Endocrine and reproductive systems 9.4.8 Dermatological 9.4.9 Eye, ear, nose, throat: local effects 9.4.10 Haematological 9.4.11 Immunological 9.4.12 Metabolic 9.4.12.1 Acid-base disturbances 9.4.12.2 Fluid and electrolyte disturbances 9.4.12.3 Others 9.4.13 Allergic reactions 9.4.14 Other clinical effects 9.4.15 Special risks 9.5 Other 9.6 Summary 10. MANAGEMENT 10.1 General principles 10.2 Life supportive procedures and symptomatic/specific treatment 10.3 Decontamination 10.4 Enhanced elimination 10.5 Antidote treatment 10.5.1 Adults 10.5.2 Children 10.6 Management discussion 11. ILLUSTRATIVE CASES 11.1 Case reports from literature 12. ADDITIONAL INFORMATION 12.1 Specific preventive measures 12.2 Other 13. REFERENCES 14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES) GLUTETHIMIDE International Programme on Chemical Safety Poisons Information Monograph 246 Pharmaceutical 1. NAME 1.1 Substance Glutethimide 1.2 Group Minor psychotherapeutic, piperidinedione sedative and hypnotic 1.3 Synonyms 2-ethyl-2-phenylglutarimide; 3-ethyl-3-phenyl-2,6-piperidinedione; Alpha-ethyl-alpha-phenyl glutarimide. 1.4 Identification numbers 1.4.1 CAS number 77-21-4 1.4.2 Other numbers No data available. 1.5 Main brand names, main trade names Doridene, Doriden, Dorimide, Glimid, Elrodorm. 1.6 Main manufacturers, main importers 2. SUMMARY 2.1 Main risks and target organs The main target organ is the central nervous system causing coma with fluctuations in depth, and various degrees of hypotension. Anticholinergic effects often occur. 2.2 Summary of clinical effects At lower doses, acute intoxication may cause somnolence, ataxia, tonic muscle spasms and abnormal reflexes. In severe intoxication, hypotension, hypothermia, shock, coma, respiratory depression and acidosis may occur. Effects on other organs are usually secondary to coma and shock. 2.3 Diagnosis Diagnosis is based mainly on the history of the patient and clinical features observed (see 2.2) and also on toxicological analyses. Serum glutethimide is rarely measured since it is poorly correlated with the clinical manifestation of the acute poisoning and requires the use of advanced analytical techniques. 2.4 First aid measures and management principles If ingestion is recent and the patient is still fully conscious with a normal pharyngeal reflex, induce vomiting. The obtunded, comatose patient should be intubated before gastric lavage is performed. Stomach emptying more than four hours after ingestion is probably ineffective. Give activated charcoal. Administer a cathartic. Respiratory depression presents the greatest risk to the patient. Ensure that oxygenation is adequate. Optimize airway position of the patient, perform endotracheal intubation and assist ventilation in severe cases. Blood gases should be monitored in patients with patients with respiratory failure. Pneumonia must be treated with appropriate antibiotics. Open and maintain an intravenous route. Give adequate fluids to maintain diuresis of 2.5 to 3 L/day. Catheterize bladder. Severe hypotension should be treated with fluid replenishment (dopamine or other vasoactive drugs might be needed). In comatose patients, especially with signs of shock, renal function should be monitored (renal output, plasma urea and creatinine, electrolytes, acid-base balance). Pre-renal uraemia occurs rarely but must be taken into consideration. Cerebral oedema (papilloedema) may require treatment with mannitol. Enhanced elimination procedures are not recommended: forced diuresis is ineffective, and the efficacy of haemodialysis (even using oil as dialysis fluid) and of haemoperfusion has not been satisfactory proved. Glutethimide is often ingested with other toxic substances: mixed poisoning with codeine or paracetamol must always be considered, especially in drug addicts. Glutethimide is habit forming. 3. PHYSICO-CHEMICAL PROPERTIES 3.1 Origin of the substance Synthetic. 3.2 Chemical structure STRUCTURAL FORMULA 1 Chemical names: 2 ethyl-2-phenylglutarimide alpha-ethyl-alpha-phenyl glutarimide 3-ethyl-3-phenylpiperidine-2,6-dione Molecular weight: 217.26 Molecular formula: C13H15NO2 (Conversion of traditional units into SI: multiply the value in mg/L by 4.603 to get the result in micromol per litre.) 3.3 Physical properties 3.3.1 Colour Colourless or white. 3.3.2 State/form 3.3.3 Description Odourless and colourless crystals or white crystalline powder, practically insoluble in water, soluble one in five of ethanol, one in less than one chloroform and one in 12 of ether, freely soluble in acetone and ethyl acetate, soluble in methyl alcohol (Reynolds, 1989). Stability: at pH 5 the chemical half life was 28.3 years at 25°C and 1.02 months at pH 8, the decomposition being due to hydrolysis. 3.4 Other characteristics 3.4.1 Shelf-life of the substance 3.4.2 Storage conditions Store in well closed, airtight containers, protected from humidity and light (Wesolowski et al., 1968). 4. USES 4.1 Indications 4.1.1 Indications 4.1.2 Description Used as an hypnotic in insomnia but rarely as a sedative, glutethimide was initially believed to be almost free from side effects (Banen & Resnik, 1973). However, further experience of its toxicity and because its dependence liability (Sramek & Klajawal, 198l; Shamoian, 1975), glutethimide has been banned in many countries and many companies have stopped production. 4.2 Therapeutic dosage 4.2.1 Adults The usual oral adult dose is 250 - 500 mg at bedtime (Reynolds, 1989). 4.2.2 Children It is not recommended for paediatric use (Reynolds, 1989). 4.3 Contraindications Glutethimide is contraindicated in porphyria. Due to its anti-muscarinic action, it should be given with great care to patients with closed-angle glaucoma, prostatic hypertrophy or urinary tract obstruction, and certain cardiac arrhythmias. Alcohol enhances absorption and the hypnotic effects of glutethimide. Like barbiturates, glutethimide induces microsomal hepatic enzymes and enhances the metabolism of coumarin anticoagulants and other drugs, lowering their plasma concentrations. Chronic administration of glutethimide may also enhance vitamin D metabolism (Reynolds, 1989). 5. ROUTES OF ENTRY 5.1 Oral This is the only likely route of administration in man. 5.2 Inhalation Unknown. 5.3 Dermal Unknown. 5.4 Eye Unknown. 5.5 Parenteral Unknown. 5.6 Other Unknown. 6. KINETICS 6.1 Absorption by route of exposure Oral: In six healthy volunteers given a dose of 500 mg, absorption was irregular and peak plasma concentrations occurred over one to six hours. However, in four of the six subjects absorption was biphasic (Curry et al., 1971). Erratic absorption may be due to the poor solubility of glutethimide in water. The onset of sedation usually occurs in 15 to 30 minutes (Baum et al., 1965). Parenteral: following intraperitoneal administration of 70 mg/kg studies in the rat, most of drug was found in the brain and spinal cord and other fat-containing tissues after 20 minutes (Keberle et al., 1962). 6.2 Distribution by route of exposure Oral: following oral administration of 500 mg of glutethimide to healthy subjects, peak plasma concentrations of 2.85 to 7.05 ìg/mL were achieved within two to six hours. Plasma protein binding of glutethimide was about 50%. Mean glutethimide concentrations in the breast milk of 13 nursing mothers given 500 mg were: 0.27, 0.22, 0.12 and 0.04 ìg/mL at 8, 12, 16 and 23 hours, respectively, but levels were undetectable in one-third of the samples (Curry et al., 1971). Glutethimide is highly lipophilic and rapidly concentrates in brain and adipose tissue (Hansen & Fischer, 1974). 6.3 Biological half-life by route of exposure Oral: The elimination half-life is 10 to 12 hours (Kastrup, 1987) but may increase in severe poisoning (Maher, 1970). In six healthy subjects, initial half-lives after ingestion of 500 mg were 2.7 to 4.3 hours and subsequent half-lives ranged from 5.1 to 22 hours (Curry et al., 1971). 6.4 Metabolism Glutethimide is partially metabolized by hydroxylation into 4-hydroxy-2-ethyl-2-phenylglutarimide. In the mouse, this appears to be twice as potent as the parent compound in mice and is believed to contribute to prolonged coma following overdosage (Hansen et al., 1975). Hydroxylated metabolites are conjugated and excreted mainly in the urine but also in bile (Keberle et al., 1962). 6.5 Elimination by route of exposure Oral: glutethimide is inactivated by conjugation and the metabolites are excreted in urine, only 2% of the parent substance is excreted in urine, up to 2% of the dose has been reported to be found in the faeces (Curry et al., 1971). 7. PHARMACOLOGY AND TOXICOLOGY 7.1 Mode of action 7.1.1 Toxicodynamics 7.1.2 Pharmacodynamics Glutethimide directly blocks electron transfer in cellular respiration (Reynolds, 1989). 7.2 Toxicity 7.2.1 Human data 7.2.1.1 Adults In adults, death has been reported after 5 g. The usual lethal dose is 10 to 20 g, although survival after a dose of 28 g has been reported (Skoutakis & Acchiardo, 1982). 7.2.1.2 Children One 500 mg tablet may produce severe toxicity in a small child (Sramek & Klajawal, 1981). 7.2.2 Relevant animal data Not relevant. 7.2.3 Relevant in vitro data Not relevant. 7.3 Carcinogenicity Unknown. 7.4 Teratogenicity There is no evidence of teratogenicity from therapeutic use (Keberle et al., 1962). 7.5 Mutagenicity Unknown. 7.6 Interactions The effects of glutethimide are additive with those of benzodiazepines, barbiturates, codeine and other CNS depressants. Concomitant administration of antidepressants, antiparkinsonian drugs or other anticholinergic agents may cause additive anticholinergic effects such as urinary retention, exacerbation of glaucoma, or adynamic ileus. Ethanol enhances the effects of glutethimide. Glutethimide induces the hepatic metabolism of some drugs, such as dicoumarol derivatives, the dose of drugs taken concomitantly may require adjustment (Hansten & Horn, 1989). 7.7 Main adverse effects Common adverse effects are as follows: nausea, headache, hangover, blurred vision, occasional skin rashes, blood disorders (megaloblastic anaemia) (Pearson, 1965). Osteomalacia (Greenwood et al., 1973) peripheral neuropathy and cerebral impairment (Nover, 1967) after prolonged use may also occur. Glutethimide is a drug of abuse and may cause dependence. 8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS 8.1 Material sampling plan 8.1.1 Sampling and specimen collection 8.1.1.1 Toxicological analyses Toxic ingredient: suspect materials e.g. tablets, liquids In case of ingestion: Vomitus: total amount Gastric aspirate: total amount (or gastric lavage: first portion: 100 mL) Blood without additives: 10 mL Urine: random specimen: 50 mL 8.1.1.2 Biomedical analyses Plasma (lithium heparin as anticoagulant) or serum and urine for standard biochemical analyses. 8.1.1.3 Arterial blood gas analysis Heparinized arterial blood sample (in severe cases). 8.1.1.4 Haematological analyses Not necessary. 8.1.1.5 Other (unspecified) analyses No further materials. 8.1.2 Storage of laboratory samples and specimens 8.1.2.1 Toxicological analyses Store separated serum in refrigerator (4°C). 8.1.2.2 Biomedical analyses No special requirements, but as usually performed. 8.1.2.3 Arterial blood gas analysis No special requirements, but as usually performed. 8.1.2.4 Haematological analyses Not applicable. 8.1.2.5 Other (unspecified) analyses Acute glutethimide poisoning is not associated with specific biochemical effects other than changes secondary to coma, respiratory failure and shock. Routine analyses for assessing the patient's general clinical condition are necessary. Chronic glutethimide abuse may lead to conditions such as megaloblastic anaemia (Pearson, 1965) or osteomalacia (Greenwood et al., 1973). Bone marrow biopsy, calcium/phosphate studies and serum phosphatase determinations may be necessary. 8.1.3 Transport of laboratory samples and specimens 8.1.3.1 Toxicological analyses 8.1.3.2 Biomedical analyses In acute glutethimide poisoning, an isoelectric encephalogram may not indicate brain death or a fatal prognosis (Huttenlocher, 1963). 8.1.3.3 Arterial blood gas analysis 8.1.3.4 Haematological analyses 8.1.3.5 Other (unspecified) analyses 8.2 Toxicological analyses and their interpretation 8.2.1 Tests on toxic ingredient(s) of material 8.2.1.1 Simple qualitative test(s) The presence of glutethimide in materials can be inferred by a number of simple colour tests. Details of the reagents and procedures for these tests can be found in Moffat et al. (1986). Results of colour tests must be taken as presumptive only, since many other drugs give similar reactions, and the limitations of each are given where these are known. Koppanyi-Zwikker test. Dissolve approximately 1 mg of the material in 1 mL ethanol. Add 1 drop of 1% cobalt nitrate in ethanol, followed by 10 µL pyrrolidine. A violet reaction is given by compounds which have >C=O and >NH groups adjacent within a ring (i.e. by glutethimide and by barbiturates). Note that hydrochloride salts give a blue colour before addition of pyrrolidine. Liebermann's test. To 1 mg of material on a white tile, add 2 drops 0.1% sodium nitrite in concentrated sulphuric acid. A red colour is produced by glutethimide, and by phenobarbital, but not by other barbiturates. Since many substances give a red colour with sulphuric acid, all positive materials should be re-tested with sulphuric acid. Mercurous nitrate test. To freshly prepared saturated mercurous nitrate add solid sodium bicarbonate until effervescence ceases and the precipitate becomes yellow. Shake before use, and use within 1 hour. Dissolve a small amount of test material in a minimum of ethanol, and add one drop of reagent. A dark grey / black colour within 2 minutes is given by ring imides or sulphonamides with an additional ring. The barbiturate reaction is quicker and more intense than that of glutethimide. UV spectrophotometry gives rather more specificity. Dissolve a portion of material in ethanol to achieve an appropriate instrument response. If necessary, centrifuge or filter the mixture and analyse the clear supernatant. The spectrum in ethanol gives deltamax at 252 nm, 258 nm (A| = 18) and 264 nm. Glutethimide is unstable at alkaline pH, due to hydrolysis of the glutarimide ring. Adjustment of the pH to >11 (e.g. by addition of 4M NaOH or ammonium hydroxide) to the ethanolic solution of glutethimide results in a characteristic decline in absorbance at 230 - 235 nm over a time period of some 20 minutes. Immunoassays for barbiturates (e.g. TDx [Abbott Laboratories, Abbott Park, Illinois 60064 USA] or EMIT [Syva-Behring Diagnostics, Cupertino, California 95014 USA]) do not usually have sufficient cross-reactivity to respond to glutethimide. However, cross-reactivity varies between manufacturers, and for polyclonal assays, between lot numbers of the same kit. More than 25 mg/L glutethimide is usually required to obtain a positive result, corresponding to a cross reactivity of less than 1%. Since the concentration in a suspect material is likely to exceed this concentration by several-fold, it is always worth testing the cross-reactivity of available kit by the addition of known amounts of glutethimide to drug free urine. Once the cut-off concentration has been determined in this way, the test substance dissolved in drug free urine can then be examined. Thin layer chromatography is highly appropriate for identification of glutethimide, and may be either an in-house system or a commercially-available system such as Toxi-Lab [Ansys Inc, Irvine, California 92718, USA]. The material can be dissolved in an organic solvent such as methanol or dichloromethane and applied directly to the plate. Using silica plates without modifiers and standard systems, the Rf of glutethimide is 0.75 on methanol / concentrated ammonia (100: 1.2), and 0.62 on ethyl acetate / methanol / ammonia (85:15:6). Several locating reagents can be used. Mercurous nitrate reagent is the most specific, and gives a dark grey response with a sensitivity of approximately 10 ng. However, the purple response produced by mercuric chloride-diphenylcarbazone reagent, and the positive reaction to Dragendorff or acidified iodoplatinate are also useful but are less characteristic (Moffat et al., 1986). 8.2.1.2 Advanced qualitative confirmation test(s) Gas chromatography can be used after dissolving the material in a small amount of organic solvent (e.g. 10 mg in 10 mL methanol). The Retention index for glutethimide is 1836 on OV1, SE30, DB5 or similar phases. Isothermal analysis may be performed at about 220°C, without the need for derivatization. Flame ionization detection gives adequate sensitivity (2 to 5 ng on column), and nitrogen-phosphorus detection gives additional selectivity (see for example Gold et al., 1974; Hansen & Fischer, 1974; Flanagan & Berry, 1977). Mass spectrometry can be applied to the gas chromatographic identification of glutethimide in suspect materials. Characteristic fragmentation is achieved without the need for derivatization, and the most abundant ions are m/z 189, 132, 117, 160 and 217 (Kennedy et al., 1978). HPLC may be used to identify glutethimide, and most published methods involve reverse phase chromatography with UV detection. Dissolve a small amount of the suspect material in the mobile phase, and filter if necessary to obtain a clear supernatant. Kabra et al. (1978) used a C18 column with a mobile phase of acetonitrile / phosphate buffer (300 µL 1M KH2PO4 and 50 µL 0.9 M phosphoric acid in 1800 mL water) [215:785]. Using isocratic elution at 50°C glutethimide was detected at 195 nm with a relative retention of 0.55 to the internal standard methylphenytoin. Svinarov & Dotchev (1989) used a C8 column with a mobile phase of acetonitrile / water (1:4), performing isocratic elution at ambient temperature. Glutethimide was detected at 208 nm with a relative retention of 1.57 to the internal standard tolylphenobarbital. Additional confirmation of identity may be obtained by performing a full scan analysis on the appropriate portion of the HPLC effluent. 8.2.1.3 Simple quantitative method(s) Direct quantitative spectrophotometric analysis of glutethimide has been described. The decline in absorbance in alkaline solution at 233 nm due to hydrolysis of the glutarimide ring directly correlates with the amount of glutethimide present. The test is performed by dissolving a small amount of material in chloroform. Five volumes of the test solution are mixed with one volume of 3M NaOH solution. Absorbance at 233 nm is measured at one and five minutes after addition of the alkali. Alternatively, the difference in absorbance at 233 nm at time zero and 20 minutes (by which time the degradation will be completed) can be used. Quantitation is performed by comparison to the analysis of known amounts of glutethimide prepared similarly. If a scanning spectrophotometer is available, this test can be combined effectively with the Broughton method for barbiturate determination by following the differential absorbance of pH 9.5 and pH 13 sample extracts over the wavelength range 220 to 320 nm (Dain & Trainer, 1970). 8.2.1.4 Advanced quantitative method(s) Gas chromatography can be used after dissolving the material in a small amount of organic solvent (e.g. 10 mg in 10 mL methanol). The retention index for glutethimide is 1836 on OV1, SE30, DB5 or similar phases. Isothermal analysis may be performed at about 220°C, without the need for derivatization. Flame ionization detection gives adequate sensitivity (2 to 5 ng), although nitrogen-phosphorus detection gives additional selectivity. Quantitation is performed by addition of an internal standard (e.g. p-dimethylaminobenzaldehyde, piperidone, p-hydroxybenzophenone or a non-prescription barbiturate) and direct comparison to known amounts of glutethimide subjected to similar dilution. Using mass spectrometry detection quantification of glutethimide in materials is achieved in SIM mode (using m/z 189; qualifier m/z 160) without the need for derivatization (Kennedy et al., 1978). HPLC may be used to quantify glutethimide in residues, and most published methods involve reverse phase chromatography with UV detection. The material should be dissolved in mobile phase (e.g. 10 mg in 10 mL) and filtered to provide a clear supernatant if necessary. Kabra et al. (1978) used a C18 column with a mobile phase of acetonitrile / phosphate buffer (300 µL 1M KH2PO4 and 50 µL 0.9 M phosphoric acid in 1800 mL water) [215:785]. Using isocratic elution at 50°C glutethimide was detected at 195 nm with a relative retention of 0.55 to the internal standard methylphenytoin. Svinarov & Dotchev (1989) used a C8 column with a mobile phase of acetonitrile / water (1:4), performing isocratic elution at ambient temperature. Glutethimide was detected at 208 nm with a relative retention of 1.57 to the internal standard tolylphenobarbital. Quantitation is achieved by comparison to known amounts of glutethimide subjected to similar dilution. 8.2.2 Tests for biological specimens 8.2.2.1 Simple qualitative test(s) Commonly-available immunoassay kits for barbiturate detection do not have sufficient cross-reactivity to respond to glutethimide or its metabolites in biological specimens: sensitivity is usually less than 25 mg/L, which is less than 1% cross reactivity (see under 8.2.1.1 above). Direct UV methods may be applied to the detection of glutethimide in gastric contents, but are not useful for the analysis of other fluids. Dilute a portion of gastric contents in ethanol to achieve an appropriate instrument response. The spectrum in ethanol gives deltamax at 252 nm, 258 nm (A| = 18) and 264 nm. Glutethimide and its common metabolites are unstable in alkaline solution (pH>11) due to hydrolysis of the glutarimide ring. For the spectrophotometric identification of glutethimide in urine or serum, the drug must first be extracted from the matrix at neutral pH into a polar solvent (e.g. dichloromethane, ethyl acetate) to maximize response from the metabolites. After solvent evaporation, the residue is taken up in water. The pH is adjusted to 13 by the addition of one part of 3M NaOH solution to five parts of test solution. Absorbance at 233 nm is monitored, where a characteristic decline over a time period of some 20 minutes will be observed. If a scanning spectrophotometer is available, this test can be combined effectively with the Broughton method for barbiturate determination by following the differential absorbance of pH 9.5 and pH 13 sample extracts over the wavelength range 220 to 320 nm (Dain & Trainer, 1970). Thin layer chromatography can then be used after extraction from the samples (urine or gastric contents - 10 to 20 mL) into an organic solvent at pH 5 to 7 (glutethimide is unstable under alkaline conditions). The use of a polar extraction solvent (e.g. dichloromethane, ethyl acetate) ensures good recovery of glutethimide and a number of metabolites, whereas the use of a non-polar solvent (e.g. hexane, petroleum ether) excludes virtually all the metabolites from the extraction. Concentration of the extract may be performed by evaporation of the solvent. Thin layer chromatography may be either an in-house system or a commercially-available system such as Toxi-Lab [Ansys Inc, Irvine, California 92718, USA]. Using silica plates without modifiers and standard solvent systems, the Rf is 0.75 on methanol / concentrated ammonia (100: 1.2), and 0.62 on ethyl acetate / methanol / ammonia (85:15:6) (Moffat et al., 1986). Chromatograms of urine samples extracted with polar solvents typically show up to six distinctive spots when eluted in cyclohexane / ethanol (80:20). Rf values on this system are: glutethimide 0.53; 4-hydroxyglutethimide 0.42; other metabolites at 0.05, 0.13, 0.30 and 0.38 (Sunshine et al., 1969). Several locating reagents can be used. Mercurous nitrate reagent is the most specific, and gives a dark grey response with a sensitivity in the region of 1 mg/L in the original sample (50 ng on plate). However, the purple response produced by mercuric chloride-diphenylcarbazone reagent, and the positive reaction to Dragendorff or acidified iodoplatinate are also useful but are less sensitive and less characteristic (Moffat et al., 1986). 8.2.2.2 Advanced Qualitative Confirmation Test(s) Gas chromatography can be used after extraction into an organic solvent from a pH adjusted to 4 to 7 using a phosphate buffer. The use of a polar solvent (e.g. dichloromethane or ethyl acetate) ensures good recovery of glutethimide and metabolites, whereas the use of a non-polar solvent (e.g. hexane or petroleum ether) excludes the extraction of up to 90% of the metabolites. The recovery of metabolites from urine can be greatly enhanced by incubation of the sample with glucuronidase prior to extraction (e.g. at pH5 for one hour at 50°C). Isothermal analysis may be performed at about 220°C, without the need for derivatization. Urine extracted with polar solvents typically show up to six peaks in addition to glutethimide: two elute before, and four elute after glutethimide. The major urinary metabolites are immediately adjacent to the glutethimide peak. The retention index for glutethimide is 1836 on OV1, SE30, DB5 or similar phases; the major metabolites 4-hydroxyglutethimide and 2-phenylglutarimide run at 1875 and 1778 respectively. Flame ionization detection gives adequate sensitivity (2 to 5 ng), and nitrogen-phosphorus detection gives additional selectivity, but does not give improved sensitivity. Mass spectrophotometric detection can be applied to the gas chromatographic detection of glutethimide and several metabolites in plasma and urine. Characteristic fragmentation of glutethimide, 2-phenylglutarimide and desethylglutethimide is achieved without the need for derivatization, although the hydroxylated metabolites are chromatographed as trifluoroacetate derivatives (Kennedy et al., 1978). HPLC may be used to identify glutethimide, and most published methods involve reverse phase chromatography with UV detection, and do not discuss analysis of urine specimens. The drug must first be extracted from the specimen, and the precipitation of plasma with an equal volume of acetonitrile as described by Kabra et al. (1978) is easily performed and reliable. Kabra et al. (1978) used a C18 column with a mobile phase of acetonitrile / phosphate buffer (300 µL 1M KH2PO4 and 50 µL 0.9 M phosphoric acid in 1800 mL water) [215:785]. Using isocratic elution at 50°C glutethimide was detected at 195 nm with a relative retention of 0.55 to the internal standard methylphenytoin. Svinarov & Dotchev (1989) used a C8 column with a mobile phase of acetonitrile / water (1:4), performing isocratic elution at ambient temperature. Glutethimide was detected at 208 nm with a relative retention of 1.57 to the internal standard tolylphenobarbital. Neither method shows chromatograms from specimens taken following glutethimide ingestion, nor give mention of glutethimide metabolites. Additional confirmation of identity may be obtained by performing a full scan analysis on the appropriate portion of the HPLC effluent or incorporating a diode array detector. 8.2.2.3 Simple Quantitative Method(s) Quantitative spectrophotometric analysis of glutethimide in biological fluids has been described. The analysis is based on the observation that the decline in absorbance in alkaline solution at 230 nm, due to hydrolysis of the glutarimide ring directly correlates with the amount of glutethimide present. The test is performed by extracting the drug from the matrix at neutral pH (at pH 5.5 the recovery of barbiturates and glutethimide is higher, but this introduces the possibility of co-extraction of salicylates which will interfere with the absorption spectrum). Care should be taken to select a non-polar solvent such as hexane or petroleum ether, as the use of a polar solvent co-extracts glutethimide metabolites which will interfere with the analysis and produce falsely elevated results, particularly in the later stages of intoxication. Some methods which use dichloromethane as extraction solvent employ a washing step with NaOH to remove co-extracted metabolites, but it is thought that contact with the alkali initiates the degradation process and makes the timing of the assay critical. The extract is evaporated to dryness and the residue is taken up in water (methods which use ethanol as the reconstitution solvent suffer interference from the dissolution of fatty deposits from serum). Five volumes of the test solution are mixed with one volume of 3M NaOH solution. Absorbance at 233 nm is measured at one and five minutes after addition of the alkali. Alternatively, the difference in absorbance at 233 nm at time zero and 20 minutes (by which time the degradation will be completed) can be used. Quantitation is performed by comparison to the analysis of known amounts of glutethimide prepared in a similar matrix and extracted similarly. (Dain & Trainer, 1970). A modification of this procedure is given by Finkle (1975). If a scanning spectrophotometer is available, this test can be combined effectively with the Broughton method for barbiturate determination by following the differential absorbance of pH 9.5 and pH 13 sample extracts over the wavelength range 220 to 320 nm (Dain & Trainer, 1970). 8.2.2.4 Advanced quantitative method(s) Gas chromatography methods for quantitation of glutethimide and its major metabolites in serum have been described. In general, most of the methods which have been described for screening of barbiturates and hypnotics in serum can be applied to the analysis of glutethimide. However, all of the published dedicated gas chromatography methods for glutethimide pre-date the use of capillary columns which offer superior separation over standard packed columns and improved sensitivity for polar metabolites. After the addition of a suitable internal standard (e.g. p-dimethylaminobenzaldehyde, piperidone, p-hydroxybenzophenone or a non-prescription barbiturate), the drug is extracted into an organic solvent from a pH adjusted to 4 to 7 using a phosphate buffer. If non-polar solvents such as hexane are used, metabolites will not be extracted: the use of polar solvents (e.g. dichloromethane or ethyl acetate) ensures that metabolites are also extracted. Gold et al. (1974) report the presence of up to six metabolites in sera from poisoned patients, only three of which were present in significant quantities. Chromatography can be performed isothermally at about 220°C, on a number of common packed column phases (OV1, SE30, OV225, Carbowax 20M, PolyA-103) without the need for derivatization: DB5 is a useful capillary column equivalent. The retention index for glutethimide is 1836 on OV1, SE30, DB5 or similar phases; the major metabolites 4-hydroxyglutethimide and 2-phenylglutarimide run at 1875 and 1778 respectively. Flame ionization detection gives adequate sensitivity (2 to 5 ng), and nitrogen-phosphorus detection gives additional selectivity, but does not improve sensitivity. Quantitative analysis can be performed by comparison to known amounts of glutethimide dissolved in aqueous solution or preferably plasma / serum and extracted similarly. Using 0.2 mL of serum a sensitivity of 1 mg/L should easily be achieved. For example see the methods described by Gold et al., 1974; Hansen & Fischer, 1974; Flanagan & Berry, 1977. When analysing plasma using a packed column and FID, care should be taken to exclude interference from co-eluting endogenous fatty acids. The use of a capillary column or a more selective detector (nitrogen-phosphorus) alleviates this problem. Mass Spectrometry in SIM mode has been used with gas chromatography for quantification of glutethimide and its metabolites in plasma and urine. Glutethimide, 2-phenylglutarimide and dehydroglutethimide are quantified directly, while the hydroxylated metabolites are chromatographed following derivatization with trifluoroacetic anhydride (Kennedy et al., 1978). HPLC methods are described for quantitative analysis of glutethimide in plasma. Most published methods involve reverse phase chromatography with UV detection, and give a sensitivity of 1 mg/L using a 100 µL sample volume. The drug must first be extracted from the specimen, and the precipitation of plasma with an equal volume of acetonitrile as described by Kabra et al. (1978) is easily performed and reliable. Kabra et al. (1978) used a C18 column with a mobile phase of acetonitrile / phosphate buffer (300 µL 1M KH2PO4 and 50 µL 0.9 M phosphoric acid in 1800 mL water) [215:785]. Using isocratic elution at 50°C glutethimide was detected at 195 nm with a relative retention of 0.55 to the internal standard methylphenytoin. Svinarov & Dotchev (1989) used a C8 column with a mobile phase of acetonitrile / water (1:4), performing isocratic elution at ambient temperature. Glutethimide was detected at 208 nm with a relative retention of 1.57 to the internal standard tolylphenobarbital. Neither method shows chromatograms of specimens taken following glutethimide ingestion, nor gives mention of glutethimide metabolites. Analysis of patient samples by HPLC must therefore be undertaken with due attention to the possibility of interference from co-extracted metabolites. Quantitation is performed by comparison to samples of drug free plasma to which known amounts of glutethimide have been added and treated similarly. 8.2.2.5 Other dedicated method(s) Not applicable. 8.2.3 Interpretation of toxicological analyses There is considerable variation in individual response to a given plasma glutethimide concentration. Contribution to the overall clinical picture can be made by co-ingested medications, the amount of toxic metabolites produced, the degree of tissue distribution, underlying medical conditions, presence of infective agents etc. As a guide, the following table shows typical concentrations of glutethimide in serum. mg/L µmol/L After single oral dose (1 to 6 hours) 3 - 7 14 - 32 Steady-state in therapy <4 <18 Toxicity apparent (coma, convulsions, pulmonary oedema) 10 46 Potentially fatal (deep coma, sudden apnoea) 30 138 After therapeutic doses, peak concentrations of the active metabolite 4-hydroxyglutethimide are in the range 4 to 6 mg/L at about 24 hours. After overdose, 4-hydroxyglutethimide accumulates in plasma, rising to several times the concentration of the parent compound, and peaking on the second day, where after it declines in parallel to glutethimide. There is disagreement over whether fluctuations in 4-hydroxyglutethimide may be responsible for, or contribute to the cyclical and prolonged coma seen after overdose (Gold et al., 1974; Hansen et al., 1975; Curry et al., 1987). There are insufficient data to determine the clinical significance of the concentrations of the other active metabolites 2-phenylglutarimide and the gamma-butyrolactone derivative. 8.3 Biomedical investigations and their interpretation 8.3.1 Biochemical analysis 8.3.1.1 Blood, plasma or serum Sodium, potassium, chloride Alanine aminotransferase, aspartate transaminase Glucose, urea, creatinine 8.3.1.2 Urine Not applicable. 8.3.1.3 Other fluids No dedicated test. 8.3.2 Arterial blood gas analyses pH, pCO2, pO2, HCO3- concentration, base excess, O2-saturation. 8.3.3 Haematological analyses Not applicable. 8.3.4 Interpretation of biomedical investigations Not applicable. 8.3.5 Interpretation of biological investigations Acute glutethimide poisoning is not associated with specific biochemical effects other than changes secondary to coma, respiratory failure and shock. Routine analyses for assessing the patient's general clinical condition are necessary. 8.4 Other biomedical (diagnostic) investigations and their interpretation 8.5 Overall Interpretation of all toxicological analyses and toxicological investigations There are no special precautions to be taken for sample collection for biomedical or toxicological analyses. Acute glutethimide poisoning is not associated with specific biochemical effects other than changes secondary to coma, respiratory failure and shock. Routine analyses for assessing the patient's general clinical condition are necessary. Presumptive tests on toxic ingredients of materials can be performed by colourimetric, spectrophotometric or thin layer chromatographic techniques. Gas chromatography of glutethimide (flame ionization detection) is not difficult, and is much more specific. Specific identification of the causative agent as glutethimide in cases of hypnotic intoxication is useful since the clinical course of glutethimide poisoning is more complicated, and its management is more difficult, than that of the barbiturates. Measurement of serum concentrations of glutethimide may be useful in cases where coma is prolonged or symptoms are particularly severe. Measurement of glutethimide in biological materials is possible after extraction into an organic solvent, and metabolites will be co-extracted if polar solvents are used. Metabolites (particularly 4-hydroxyglutethimide) are seen by most advanced techniques. Qualitative analysis is most easily performed by thin layer chromatography. Gas chromatography allows for both qualitative and quantitative analysis, and derivatization is not required; flame ionization detection gives adequate sensitivity for most applications. Gas chromatography / mass spectrometry has been used where confirmatory testing is required. HPLC has not been widely used. Typical concentrations of glutethimide in serum are: mg/L µmol/L After single oral dose (1 to 6 hours) 3 - 7 14 - 32 Steady-state in therapy <4 <18 Toxicity apparent (coma, convulsions, pulmonary oedema) 10 46 Potentially fatal (deep coma, sudden apnoea) 30 138 The metabolite 4-hydroxyglutethimide may contribute to the clinical and toxic effects of glutethimide, but there are insufficient data to determine the clinical significance of the concentrations of the metabolites 4-hydroxyglutethimide, 2-phenylglutarimide and gamma-butyrolactone, all of which have known pharmacological activity. 9. CLINICAL EFFECTS 9.1 Acute poisoning 9.1.1 Ingestion Ingestion is the only route by which acute poisoning may occur. Mild intoxication with small doses results in somnolence, ataxia, tonic muscle spasms, abnormal reflexes. In severe intoxication coma, hypotension, hypothermia, shock, respiratory depression and cerebral oedema may occur. Signs from other organs and systems are usually secondary to coma and shock. 9.1.2 Inhalation Unknown. 9.1.3 Skin exposure Unknown. 9.1.4 Eye contact Unknown. 9.1.5 Parenteral exposure Unknown. 9.1.6 Other Unknown. 9.2 Chronic poisoning 9.2.1 Ingestion Ingestion is the only route of glutethimide administration in humans. Prolonged use of the drug may cause peripheral neuropathy (Nover, 1967), hypocalcaemia (Ober et al., 1981) and osteomalacia (Greenwood et al., 1973). Acute abstinence syndrome following glutethimide withdrawal has been described (Johnson & Van Buren, 1962). Chronic ingestion of high doses is associated with impaired memory, inability to concentrate, ataxia, tremors, hyporeflexia, slurring of speech, and convulsions (Reynolds, 1989). 9.2.2 Inhalation Unknown. 9.2.3 Skin exposure Unknown. 9.2.4 Eye contact Unknown. 9.2.5 Parenteral exposure Unknown. 9.2.6 Other Unknown. 9.3 Course, prognosis, cause of death Any acute poisoning without loss of consciousness may be regarded as mild and the patient is not at risk. The occurrence of coma, hypotension, hypothermia, shock, respiratory depression and complications such as pneumonia mean that glutethimide poisoning is potentially serious. However, death is unusual provided the patient is admitted to intensive care when needed. Cerebral oedema may be fatal (Wright & Roscoe, 1970). 9.4 Systematic description of clinical effects 9.4.1 Cardiovascular Hypotension, shock and tachycardia have been observed. Unexplained dysrhythmias may be due to the antimuscarinic effects of the drug or low plasma calcium concentrations (Wright & Roscoe, 1970, Chazan & Garella, 1971). 9.4.2 Respiratory Respiratory depression with intermittent apnea and or arrest may occur in very severe cases. Pneumonia due to aspiration and pulmonary oedema have been reported (Wright & Roscoe, 1970, Chazan & Garella, 1971). 9.4.3 Neurological 9.4.3.1 Central Nervous System (CNS) Various degrees of CNS depression may occur, ranging from lethargy to deep coma. Cerebral oedema, intracranial haemorrhage, tonic muscle spasms and hyperreflexia may occur. Truncal ataxia has been reported in acute glutethimide intoxication in children (Huttenlocher, 1963). 9.4.3.2 Peripheral nervous system Peripheral neuropathy and diplopia has been reported following chronic use. 9.4.3.3 Autonomic nervous system Glutethimide has antimuscarinic/anticholinergic activity, tachycardia, dryness of mouth, mydriasis, irritability, urinary retention and constipation. 9.4.3.4 Skeletal and smooth muscle Tonic muscle spasm and paralytic ileus (adynamic ileus) may also be observed. 9.4.4 Gastrointestinal Gastrointestinal atony due to parasympatholytic activity may occur (Chazan & Garella, 1971). 9.4.5 Hepatic No direct effects are known. 9.4.6 Urinary 9.4.6.1 Renal With the exception of possible pre-renal uraemia due to severe hypotension, no other renal effects occur (Wright & Roscoe, 1970; Chartier, 1983). 9.4.6.2 Other Urinary retention may occur due to the anticholinergic effect of glutethimide. 9.4.7 Endocrine and reproductive systems No data available. 9.4.8 Dermatological Bullous changes resembling those seen in barbiturate poisoning (Burdon & Cade, 1979) and erythematous vesicles (Leavell et al., 1972) have been described. 9.4.9 Eye, ear, nose, throat: local effects Mydriasis and papilloedema have been observed (Wright & Roscoe, 1970). 9.4.10 Haematological Significant methaemoglobinemia has been reported rarely (Filippini, 1965); in a further case, megaloblastic anaemia, thrombocytopenia and aplastic anaemia occurred (Pearson, 1965). 9.4.11 Immunological No data available. 9.4.12 Metabolic 9.4.12.1 Acid-base disturbances Acid base disturbances may occur secondary to coma or shock. 9.4.12.2 Fluid and electrolyte disturbances Hypocalcaemia has been described (Crawshaw, 1968). 9.4.12.3 Others Hypothermia has been described (Skoutakis & Acchiardo, 1982; Ozdemir & Tannenberg, 1972). 9.4.13 Allergic reactions No data available. 9.4.14 Other clinical effects No data available. 9.4.15 Special risks Glutethimide readily crosses the placenta and may cause neonatal respiratory depression (Kurtz et al., 1966, Reveri et al., 1977) and neonatal withdrawal symptoms (Asnes & Lamb, 1969). Eight to 12 hours after a maternal does of 500 mg of glutethimide, a peak concentration of 270 nanogram per mL in breast milk has been reported (Curry et al., 1971). 9.5 Other No data available. 9.6 Summary 10. MANAGEMENT 10.1 General principles Patients with mild poisoning who are only sedated need little or no treatment. Emptying the stomach by emesis and/or lavage should be done within the first four hours after ingestion if the clinical condition of the patient allows it. If the patient is obtunded, gastric lavage should be performed after endotracheal intubation. Coma associated with shock is the most important feature of severe poisoning. Treatment is symptomatic. There is no specific antidotes. Procedures to enhance elimination are not recommended: forced diuresis has been shown to be ineffective; haemodialysis (even using oil as dialyzing fluid) and haemoperfusion have not proven to be effective. 10.2 Life supportive procedures and symptomatic/specific treatment Patients with mild signs of overdose do not need special treatment but should be under continuous clinical observation, especially during the early stages of poisoning. Intestinal absorption of additional amounts of glutethimide may unpredictably precipitate deep coma requiring intensive care. Severe poisoning with coma always needs intensive care. It is essential to maintain a clear airway and provide oxygen. Perform endotracheal intubation and support ventilation. Frequent change of the position of the patient and vigorous physiotherapy are indicated to prevent pneumonia and pulmonary infarctions. Pneumonia must be treated with appropriate antibiotics. Maintain one central or peripheral intravenous route. Administer intravenous fluids in amounts adequate to maintain daily diuresis of two to three litres. Urinary catheterization is necessary in the comatose patient to measure hourly urine output and obtain urine samples. In case of significant hypotension, hypovolaemia must be considered as a possible cause and be corrected. If hypotension is severe, infusion of dopamine may be required (2 to 5 µg/kg/minute, not more than 10 µg/kg/minute). Monitoring of central venous pressure, and if possible pulmonary artery pressures is indicated (Swan-Ganz catheter). Papilledema or other signs of cerebral edema (Wright & Roscoe, 1970) may indicate the need for mannitol 20%. Correct acidosis. 10.3 Decontamination Since ingestion is the route of poisoning only decontamination of the gastrointestinal tract should be considered. Induce vomiting and perform gastric lavage within the first four hours following ingestion, but only in the conscious patient. If the patient is drowsy or comatose, gastric lavage should be done after endotracheal intubation. Activated charcoal and cathartics should be given, unless contraindicated (Ellenhorn & Barceloux, 1988). 10.4 Enhanced elimination Forced diuresis does to enhance elimination of glutethimide (Wright & Roscoe, 1970). Haemodialysis (even using oil as the dialyzing fluid), (Chazan & Garella, 1971); and haemoperfusion through charcoal column (Koffler et al., 1978) or resin column (Raja, 1986) have not proved effective. Experience at the Warsaw Poison Centre with oil haemodialysis and charcoal haemoperfusion is not convincing. 10.5 Antidote treatment 10.5.1 Adults No antidote available. 10.5.2 Children No antidote available. 10.6 Management discussion Supportive treatment is essential for the successful management of acute glutethimide poisoning. The prognosis is favourable even in severe cases but the possibility of mixed poisoning must always be considered. 11. ILLUSTRATIVE CASES 11.1 Case reports from literature The most recent publications have reviewed many cases of acute poisoning and their conclusions are included in this monograph (Wright & Roscoe, 1970; Chazan & Garella, 1971). Short descriptions and discussion of particular cases will be presented under 11.2. Only two cases of chronic poisoning are mentioned here. Case 1 (Nover, 1967): A 37 year-old woman was treated with glutethimide, up to 5 g per day, for five years. She developed sensory neuropathy with glove-and-stocking paraesthesias and noted poor recent memory and calculating ability. She felt very weak, was unable to stand or walk unaided and complained of ataxia. Neurological examination found absent position, vibration, light touch, and pin prick sensations distally in all four extremities. Decreased nerve conduction velocity was found. Glutethimide was withdrawn over 20 days despite a grand mal seizure occurring when the patient was changed to phenobarbital. Even two weeks after the complete withdrawal of glutethimide the patient was unable to walk or stand without assistance and complained of paraesthesias. Sensory findings were somewhat improved but some symptoms and signs persisted for several months. Case 2 (Pearson, 1965): A 47-year-old man was treated with 100 to 400 mg of glutethimide for five years and developed megaloblastic anaemia with haemoglobin value as low as 6 g/dL and megaloblastic hyperplasia in the bone marrow. Discontinuation of glutethimide and administration of folic acid resulted in normalization of the peripheral blood and bone marrow. 12. ADDITIONAL INFORMATION 12.1 Specific preventive measures Since there are safer hypnotic drugs currently available, it seems, there is no reason to continue the use of glutethimide. 12.2 Other No data available. 13. REFERENCES Asnes RS & Lamb JM (1969) Neonatal respiratory depression secondary to maternal analgesics; treated by exchange transfusion. Pediatrics 43: 94. 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Gold M, Tassoni E, Etzl E, Mathew G (1974) Concentration of glutethimide and associated compounds in human serum and cerebrospinal fluid after drug overdose. Clin Chem, 20: 195- 199. Greenwood RH, Prunty FT & Silver J (1973) Osteomalacia after prolonged glutethimide administration. B Med J, 1: 643. Hansen AR & Fischer LJ (1974) Gas-chromatographic simultaneous analysis for glutethimide and an active hydroxylated metabolite in tissues, plasma and urine. Clin Chem, 20: 236. Hansen AR, Kennedy KA, Ambre JJ et al. (1975) Glutethimide poisoning; a metabolite contributes to morbidity and mortality. N Engl J Med, 292: 250. Hansten PD & Horn JR (1989) Drug interactions, 6th ed., Lea & Febiger, Philadelphia, PA. Huttenlocher PR (1963) Accidental glutethimide intoxication in children. N Eng J Med, 269: 38. Johnson FA & Van Buren HC (1962) Abstinence syndrome following glutethimide intoxication. JAMA, 180: 1024. Kabra PM, Koo HY, Marton LJ (1978) Simultaneous liquid-chromatographic determination of 12 common sedatives and hypnotics in serum. Clin Chem, 24: 657-662. Kastrup EK (ed) (1987) Facts and comparisons. JB Lippincott Co, St Louis, MO, 87: 269b. Keberle H, Hoffmann K & Bernhard K (1962) The metabolism of glutethimide (Doriden). Experientia, 18: 105. Kennedy KA, Ambre JJ, Fischer LJ (1978) A selected ion monitoring method for glutethimide and six metabolites: Application to blood and urine from humans intoxicated with glutethimide. Biomed Mass Spec, 5: 679-685. Koffler A, Bernstein H, La Sette A et al. (1978) Fixed-bed charcoal hemoperfusion. Treatment of drug overdose. Arch Intern Med, 138: 1691. Kurtz GG, Michael EF, Morosi HJ et al. (1966) Hemodialysis during pregnancy. Arch Intern Med, 118: 30. Leavell VM, Coyer JR & Taylor RJ (1972) Dermographism and erythematous lines in glutethimide overdose. Arch Derm, 106: 724. Maher JF (1970) Determinants of serum half-life of glutethimide in intoxicated patients. J Pharmacol Exp Ther, 174: 450. Moffat AC, Jackson JV, Moss MS, & Widdop B eds. (1986) Clarke's Isolation and Identification of Drugs. London, Pharmaceutical Press. Nover R (1967) Persistent neuropathy following chronic use of glutethimide. Clin Pharm Ther, 8: 283. Ober KP, Hennessy JF & Hellman RM (1981) Severe hypocalcemia associated with chronic glutethimide addiction. Am J Psych, 138: 1239. Ozdemir AI & Tannenberg AM (1972) Peritoneal and hemodialysis for acute glutethimide overdosages. NY State J Med, 72: 2076. Pearson D (1965) Megaloblastic anaemia due to glutethimide. Lancet, 1: 110. Raja RM (1986) Resin hemoperfusion for drug intoxication - an update. Int J Artif Org, 9: 319. Reveri M, Pyatis SP & Pildes RS (1977) Neonatal withdrawal symptoms associated with glutethimide (Doriden) addiction in the mother during pregnancy. Clin Pediatr, 16: 424. Reynolds JEF (ed.) (1989) Martindale: The Extra Pharmacopoeia, 29th Ed. Shamoian CA (1975) Codeine and glutethimide; euphoric, addicting combination. NY State J Med, 75: 97. Skoutakis VA & Acchiardo SR (1982) Glutethimide intoxication. Clin Toxicol Consultant, 4: 18. Sramek JJ & Klajawal A (1981) Loads. N Engl J Med, 305: 231. Sunshine I, Maes R, Faracci R (1969) Determination of glutethimide (Doriden) and its metabolites in biologic specimens. Clin Chem, 14: 595-609. Svinarov DA, Dotchev DC (1989) Simultaneous liquid-chromatographic determination of some bronchodilators, anticonvulsants, chloramphenicol, and hypnotic agents, with Chromosorb P columns used for sample preparation. Clin Chem 1989, 35: 1615-1618. Wesolowski JW et al. (1968) J Pharm Sci, 87: 811. Wright N & Roscoe PR (1970) Acute glutethimide poisoning. Conservative treatment of 31 patients. JAMA, 214: 1704. 14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES) Author: Janusz Szajewski, MD Warsaw Poison Control Centre Szpital Praski III Oddzial Chorob Wewnetrznych Al. Swierczewskiego 67 03-701 Warsaw Poland Date: August 1992 Peer Review: London, United Kingdom, September 1992 (Members of the Group: M. Balali-Mood, J. Szajewski, O. Kasilo, A. Wong, J.F. Deng, J. Higa, S. Shintani) IPCS update: May 1994 Author Section 8: Dr S. Dawling Center for Clinical Toxicology Vanderbilt University Medical Center 501 Oxford House 1161 21st Avenue South Nashville, TN 37232-4632 United States of America Tel: 1-615-9360760 Fax: 1-615-9360756 E-mail: sheila.dawling@mcmail.vanderbilt.edu Date: March 1998 Editor: Mrs J. Duménil International Programme on Chemical Safety Date: May 1999