The full article

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.

Editor's Pick

Spruce 750mg Lab Grade CBD Oil

Specifically formulated to be more palatable to CBD users
Spruce 750mg Lab Grade CBD Oil Bottle
  • Overall Clinical Score
    99%
    Editor's Pick
  • Clinical Scores
    Value
    Quality
    Strength
    Customer Service
    Lab Testing Transparency
    Effectiveness
    Perfect for...New CBD users
  • Summary

    Each bottle of the 750mg CBD oil tincture contains 25mg of CBD per dropper full. The oil is peppermint flavor to mask any unpleasant tastes related to CBD.

    Pro's
    Cons's
     Mid-strength  No other flavors
     Natural peppermint flavor
     Made from 100% organic and natural ingredients
  • Features
    Discount pricing available? 20% Off Coupon Code: CBDCLINICALS
    Source
    Source of Hemp
    Kentucky, USA & North Carolina, USA
    Form Oil Tincture
    Ingredients Organic Hemp Seed Oil, Full Spectrum CBD Oil
    Type
    Type of CBD
    Full Spectrum
    Extraction
    Extraction Method
    Moonshine extraction method
    How to take it Under tongue
    Potency
    Potency - CBD Per Bottle
    750 mg per bottle
    Carrier Oil Organic Hemp Seed Oil
    Concentration
    CBD Concentration Per Serving
    25mg of CBD per dropper full (1ml)
    Drug Test Contains 0.3% THC but there is a chance you may test positive for marijuana
    Flavours Peppermint
    Price Range $89 ($75.65 for subscriptions, 15% discount from regular price)
    $/mg CBD
    Price ($/mg)
    $0.12/mg ($0.10/mg with subscription)
    Shipping
    Shipping/Time to delivery
    2-4 business days (first class USPS)
    Lab Tests
    Lab Testing Transparency
    Third Party Lab Tested post formulation for safety and potency, available on website
    Contaminants Organic, Non-GMO, no pesticides, no herbicides, no solvents or chemical fertilizers, No preservatives or sweeteners
    Allergens Vegan, Gluten free
    Refund policy Within 30 days
    Recommended for New CBD users
    Countries served USA only (all 50 states)
Check Latest Prices
Best Organic

NuLeaf Naturals 900mg Full Spectrum Hemp CBD Oil

Perfect for anyone who are looking for CBD products that promote a healthy body and mind.
NuLeaf Naturals 900mg Full Spectrum Hemp CBD Oil
  • Overall Clinical Score
    99%
    Best Organic
  • Clinical Scores
    Value
    Quality
    Strength
    Customer Service
    Lab Testing Transparency
    Effectiveness
    Perfect for...Health-conscious persons
  • Summary

    Natural remedy for various illnesses. NuLeaf Naturals’ CBD oil is a whole-plant extract containing a full spectrum of naturally occurring synergistic cannabinoids and terpenes.

    Pro's
    Cons's
     Pure CBD hemp  No other flavors
     All natural
     Approximately 300 drops total
  • Features
    Discount pricing available? 20% Off Coupon Code: CBDCLINICALS20
    Source
    Source of Hemp
    Colorado, USA
    Form Oil Tincture
    Ingredients Full Spectrum Hemp Extract, Organic Virgin Hemp Seed Oil
    Type
    Type of CBD
    Full Spectrum CBD
    Extraction
    Extraction Method
    CO2 Method
    How to take it Under the tongue for approximately 30 seconds before swallowing
    Potency
    Potency - CBD Per Bottle
    900mg per bottle
    Carrier Oil Organic Hemp Oil
    Concentration
    CBD Concentration Per Serving
    60mg per dropper full (1ml)
    Drug Test Contains 0.3% THC but there is a chance you may test positive for marijuana
    Flavours Natural
    Price Range $99 - $434
    $/mg CBD
    Price ($/mg)
    $0.08 - $0.13
    Shipping
    Shipping/Time to delivery
    2-3 Days via USPS
    Lab Tests
    Lab Testing Transparency
    Third Party Lab Tested post formulation for safety and potency, available on website
    Contaminants No additives or preservatives, Non-GMO, NO herbicides, pesticides, or chemical fertilizers
    Allergens Not specified
    Refund policy Within 30 days
    Recommended for Health-conscious persons
    Countries served USA (all 50 states) and over 40 countries including Australia, Azerbaijan, Beliza, Bosnia & Herzegovina, Brazil, Chile, China, Croatia, Czech Republic, Estonia, France, Hong Kong, Hungary, Ireland, Israel, Japan, Latvia, Lebanon, Lithuania, Macao, Malaysia, Malta, Netherlands, New Zealand, Oman, Paraguay, Poland, Portugal, Saudi Arabia, Serbia, Singapore, South Korea, Sweden, Switzerland, United Arab Emirates, United Kingdom, Uruguay, and many more.
Check Latest Prices
Best Customer Service

Sabaidee Super Good Vibes CBD Oil

4x the strength of a regular cbd oil
Sabaidee Super Good Vibes CBD Oil
  • Overall Clinical Score
    99%
    Best Customer Service
  • Clinical Scores
    Value
    Quality
    Strength
    Customer Service
    Lab Testing Transparency
    Effectiveness
    Perfect for...Patients who are looking for serious CBD oil support
  • Summary

    Super Good Vibes CBD Oil provides the purest and highest quality Cannabidiol (CBD) on the market as well as other high quality phytocannabinoids, terpenes, vitamins, omega fatty acids, trace minerals, and other beneficial for your health elements, which all work together to provide benefits.

    Pro's
    Cons's
     Extra strong  No other flavors
     Significant benefits with just a few drops
     100% Natural ingredients
  • Features
    Discount pricing available? 15% Off Coupon Code: CBDCLINICALS15
    Source
    Source of Hemp
    Colorado, USA
    Form Oil Tincture
    Ingredients Cannabidiol (CBD), Coconut Medium-chain triglycerides (MCT) Oil, Peppermint oil
    Type
    Type of CBD
    Broad Spectrum
    Extraction
    Extraction Method
    CO2-extraction
    How to take it Using 1-3 servings per day as needed is a good start to determine how much you need
    Potency
    Potency - CBD Per Bottle
    1000 mg per bottle
    Carrier Oil Coconut MCT Oil
    Concentration
    CBD Concentration Per Serving
    33.5 mg per dropper (1ml)
    Drug Test Contains 0.3% THC but there is a chance you may test positive for marijuana
    Flavours Peppermint
    Price Range Single Bottle - $119.95, 2-Pack - $109.97 each, 3-Pack - $98.31 each, 6-Pack - $79.99 each
    $/mg CBD
    Price ($/mg)
    Single bottle - $0.010, 2-Pack - $0.011, 3-Pack - $0.009, 6-Pack - $0.007
    Shipping
    Shipping/Time to delivery
    3-5 Business days
    Lab Tests
    Lab Testing Transparency
    Third Party Lab Tested post formulation for safety and potency, available on website
    Contaminants Contaminant-free
    Allergens Vegan and Gluten-free
    Refund policy Within 30 days
    Recommended for Patients who are looking for serious CBD oil support
    Countries served USA only (all 50 states)
Check Latest Prices

Natural Alternative

cbdMD CBD Oil Tinctures

Uses USA hemp that is grown on non-GMO farms, and is both vegan and gluten-free
cbdMD CBD Oil Tinctures Products
  • Overall Clinical Score
    99%
    Natural Alternative
  • Clinical Scores
    Value
    Quality
    Strength
    Customer Service
    Lab Testing Transparency
    Effectiveness
    Perfect for...CBD users with different needs
  • Summary

    cbdMD’s CBD oil tinctures are made using only CBD sourced from medical hemp and MCT oil as a carrier oil. Tinctures are offered in orange, mint, natural, and berry flavors. Safe for daily use, the oil tinctures are packaged with a built-in rubber dropper to adjust CBD dosage easily. The packaging is made to be easy to transport and discreet to use.

    Pro's
    Cons's
     Plenty of concentrations to choose from for all people with various kinds of needs  cbdMD uses MCT as its carrier oil so individuals who are allergic with coconuts should consider other brand options
     Has vegan, organic, and gluten-free ingredients
     Affordable pricing
     Affordable pricing
  • Features
    Discount pricing available? 15% Off Coupon Code: cbdMD15
    Source
    Source of Hemp
    Kentucky, USA
    Form Oil Tincture
    Ingredients Cannabidiol (CBD), MCT Oil, and Flavoring
    Type
    Type of CBD
    Broad Spectrum
    Extraction
    Extraction Method
    CO2 extraction method
    How to take it Under tongue
    Potency
    Potency - CBD Per Bottle
    300 mg - 7500 mg / 30 ml bottle, 1000 mg - 1500 mg / 60 ml bottle
    Carrier Oil Organic Coconut MCT Oil
    Concentration
    CBD Concentration Per Serving
    30 ml: 300 mg - 10 mg per dropper (1ml), 750 mg - 25 mg per dropper (1ml), 1500 mg - 50 mg per dropper (1ml), 3000 mg - 100 mg per dropper (1ml), 5000 mg - 166.6 mg per dropper (1ml), 7500 mg - 250 mg per dropper (1ml), 60 ml: 1000 mg - 16.6 mg per dropper (1ml), 1500 mg - 25 mg per dropper (1ml)
    Drug Test Containing less than 0.3% THC, there are still trace amounts
    Flavours Natural, Berry, Orange and Mint
    Price Range 30 ml Bottles: $29.99 for 300 mg, $69.99 for 750 mg, $99.99 for 1500 mg, $149.99 for 3000 mg, $239.99 for 5000 mg, $339.99 for 7500 mg 60 ml Bottles: $74.99 for 1000 mg, $99.99 for 1500 mg
    $/mg CBD
    Price ($/mg)
    30 ml - $0.05 - $0.10, 60 ml - $0.06 - $0.07
    Shipping
    Shipping/Time to delivery
    2-5 Business days (via Fedex)
    Lab Tests
    Lab Testing Transparency
    Third Party Lab Tested post formulation for safety and potency, available on website
    Contaminants 100% organic, non-GMO, and vegan-certified
    Allergens Vegan, Gluten free
    Refund policy Within 30 days
    Recommended for CBD users with different needs
    Countries served USA only (all 50 states)
Check Latest Prices

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.

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.

More Info

Less Info

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

  1. 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

  1. 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

  1. 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

  1. ROUTES OF EXPOSURE

   5.1 Oral

   5.2 Inhalation

   5.3 Dermal

   5.4 Eye

   5.5 Parenteral

   5.6 Other

  1. 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

  1. 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

  1. 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

  1. 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

  1. 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

  1. ILLUSTRATIVE CASES

   11.1 Case reports from literature

  1. Additional information

   12.1 Specific preventive measures

   12.2 Other

  1. REFERENCES
  2. 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

 

  1. 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.

 

  1. 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

 

  1. 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

 

  1. ROUTES OF EXPOSURE

 

        5.1  Oral

        5.2  Inhalation

        5.3  Dermal

        5.4  Eye

        5.5  Parenteral

        5.6  Other

 

  1. 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

 

  1. 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

 

  1. 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

 

  1. 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

 

  1. 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.

 

  1. ILLUSTRATIVE CASES

 

        11.1 Case reports from literature

 

  1. Additional information

 

        12.1 Specific preventive measures

 

        12.2 Other

 

  1. 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

  1. 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.

 

  1. 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:   [email protected]

    

        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.

  1. 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

 

  1. 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

  1. 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

  1. 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

  1. 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

  1. ROUTES OF EXPOSURE

   5.1 Oral

   5.2 Inhalation

   5.3 Dermal

   5.4 Eye

   5.5 Parenteral

   5.6 Other

  1. 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

  1. 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

  1. 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

  1. 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

  1. 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

  1. ILLUSTRATIVE CASES

   11.1 Case reports from literature

  1. Additional information

   12.1 Specific preventive measures

   12.2 Other

  1. REFERENCES
  2. 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

 

  1. 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.

 

  1. 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).

 

  1. 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

 

  1. ROUTES OF EXPOSURE

 

        5.1  Oral

        5.2  Inhalation

        5.3  Dermal

        5.4  Eye

        5.5  Parenteral

        5.6  Other

 

  1. 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

 

  1. 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

 

  1. 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

 

  1. 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

 

  1. 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.

 

  1. ILLUSTRATIVE CASES

 

        11.1 Case reports from literature

 

  1. Additional information

 

        12.1 Specific preventive measures

 

        12.2 Other

 

  1. 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.

    

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        of chlordiazepoxide and its correlation to blood concentration. 

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        after flumazenil administration in a case of combined

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        Med,  12: 1733-1734.

    

        Notarianni LJ. (1990) Plasma protein binding of drugs in pregnancy

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        Pharmaceutical Press, London, 699-744.

    

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  1. Willians & Wilkins, Baltimore.

    

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        470-2.

 

  1. 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:   [email protected]

    

        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

  1. 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

  1. 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

  1. 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

  1. ROUTES OF EXPOSURE

   5.1 Oral

   5.2 Inhalation

   5.3 Dermal

   5.4 Eye

   5.5 Parenteral

   5.6 Other

  1. 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

  1. 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

  1. 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

  1. 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

  1. 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

  1. ILLUSTRATIVE CASES

   11.1 Case reports from literature

  1. Additional information

   12.1 Specific preventive measures

   12.2 Other

  1. REFERENCES
  2. 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

 

  1. 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.

 

  1. 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).

 

  1. 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

 

  1. ROUTES OF EXPOSURE

 

        5.1  Oral

        5.2  Inhalation

        5.3  Dermal

        5.4  Eye

        5.5  Parenteral

        5.6  Other

 

  1. 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

 

  1. 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

 

  1. 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

 

  1. 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

 

  1. 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.

 

  1. ILLUSTRATIVE CASES

 

        11.1 Case reports from literature

 

  1. Additional information

 

        12.1 Specific preventive measures

 

        12.2 Other

 

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        Stark C, Sykes R & Mullin P (1987)  Temazepam abuse (letter).

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        Sullivan RJ Jr (1989) Respiratory depression requiring ventilatory

        support following 0.5 mg of Triazolam. J Am Geriatr,  Soc  37:

        450-452.

    

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        470-2.

 

  1. 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: [email protected]

    

        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.

  1. 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

  1. 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

  1. 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

  1. 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

  1. ROUTES OF ENTRY

   5.1 Oral

   5.2 Inhalation

   5.3 Dermal

   5.4 Eye

   5.5 Parenteral

   5.6 Other

  1. 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

  1. 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

  1. 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

  1. 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

  1. 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

  1. ILLUSTRATIVE CASES

   11.1 Case reports from literature

  1. ADDITIONAL INFORMATION

   12.1 Specific preventive measures

   12.2 Other

  1. REFERENCES
  2. 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

 

  1. 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.

 

  1. 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).

 

  1. 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).

 

  1. 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.

 

  1. 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).

 

  1. 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.

 

  1. 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.

 

  1. 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

 

  1. 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.

 

  1. 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.

 

  1. 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.

 

  1. REFERENCES

 

        Asnes RS & Lamb JM (1969)  Neonatal respiratory depression

        secondary to maternal analgesics;  treated by exchange

        transfusion.  Pediatrics 43: 94.

    

        Banen DM & Resnick O (1973)  Lorazepam v. glutethimide as a

        sleep-inducing agent for the geriatric patient.  J Am Geriat Soc,

        21: 507.

    

        Baum G, Bill CES, Freeling P et al. (1965)  Sedation with a new

        non-barbiturate compound.  Practitioner 195: 366.

    

        Burdon JGW & Cade JF (1979)  Barbiturate burns caused by

        glutethimide. Med J Aust, 1: 101.

    

        Chartier DM (1983)  Glutethimide and codeine overdose.  Emerg

        Nursing 9: 307.

    

        Chazan JA & Garella S (1971) Glutethimide intoxication.  A

        prospective study of 70 patients treated conservatively without

        hemodialysis.   Arch Int Med, 128: 215.

    

        Crawshaw JA (1968)  Hypocalcaemia in glutethimide overdose. 

        Practitioner, 200: 739.

    

        Curry SH, Riddal D, Gordan JS et al. (1971)  Disposition of

        glutethimide in man.  Clin Pharmacol Ther, 12: 849.

    

        Curry SC, Hubbard JM, Gerkin R, Selden B, Ryan PJ, Meinhart R,

        Hagner D (1987)  Lack of correlation between plasma

        4-hydroxyglutethimide and severity of coma in acute glutethimide

        poisoning: A case report and brief review of the literature.  Med

        Toxicol, 2: 309-316.

    

        Dain D, Trainer TD (1970)  Simultaneous spectrophotometric

        determination of glutethimide and barbiturates.  Clin Chem, 16:

        318-321.

    

        Ellenhorn MS & Barceloux DG (1988)  Medical Toxicology.  Elsevier

        Science Publishing Co., New York.

 

    

        Filippini VL (1965)  Methemoglobinaemie bei Doriden-Intoxication. 

        Schweiz Med Wschr, 95: 1618.

    

        Finkle BS (1975)  In: Sunshine I ed.  Methodology for Analytical

        Toxicology. Cleveland Ohio, CRC Press, pp178-180.

    

        Flanagan RJ, Berry DJ (1977)  Routine analysis of barbiturates and

        some other hypnotic drugs in blood plasma as an aid to the

        diagnosis of acute poisoning.  J Chromatogr, 131:  131-146.

    

        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.

 

  1. 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,

  1. 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:  [email protected]

    

 

        Date:       March 1998

    

        Editor:     Mrs J. Duménil

                    International Programme on Chemical Safety

    

        Date:       May 1999

    

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SabaiDee Review

SabaiDee CBD products are tested both in-house and by independent laboratories to verify the quality of every batch. Their products all come with SabaiDee’s Happiness Guarantee. 

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Best CBD Oil for Dogs With Cancer

Why Some People are Using CBD for Dogs with Cancer? An article posted by the American Kennel Club (AKC) says that there is no conclusive scientific data on using cannabidiol (CBD) to treat dogs specifically. However, there is anecdotal evidence from dog owners suggesting that CBD can help with neuropathic...

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CBD Oil for Kids with Anxiety

Why People are Turning to CBD for Children with Anxiety? CBD has become a popular OTC treatment that parents give their children, says Doris Trauner, M.D., professor of neurosciences and pediatrics at the University of California San Diego School of Medicine and a physician at San Diego’s Rady Children’s Hospital....

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CBD Oil for Candida

Why People are Turning to CBD for Candida? Candidiasis or thrush is a medical condition caused by Candida albicans, a yeast-like fungus. This type of fungus spreads over within the mouth and throat, and it usually infects men and women alike. Certain cannabinoids, like CBD, have been shown as a...

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