Can CBD oil help with anxiety?

  • A 2015 review published in the journal Neurotherapeutics demonstrated CBD’s efficacy in reducing anxiety behaviors linked to multiple disorders, including generalized anxiety disorder (GAD), social anxiety disorder (SAD), obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), and panic disorder (PD)(1).
  • Researchers of a 2019 study published in the Brazilian Journal of Psychiatry found that CBD’s anti-anxiety effect might help reduce the response to stressful environmental factors(2).
  • Published in CNS and Neurological Disorders – Drug Targets, a study showed that CBD, a cannabis Sativa constituent with great psychiatric potential, had therapeutic uses as an anxiolytic-like and an antidepressant-like compound(3).
  • Researchers of a study published in The Permanente Journal in 2019 measured sleep and anxiety scores in human subjects and found that CBD could hold benefits for anxiety-related disorders(4).
  • Results of a study published in the Neuropharmacology Journal suggested that CBD might block anxiety-induced sleep disturbances through its anti-anxiety effect on the brain(5).

Best CBD Oils for Anxiety

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
  • Score breakdown
    Value
    Quality
    Strength
    Customer Service
    Lab Testing Transparency
    Effectiveness
  • 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
    •  Natural peppermint flavor
    •  Made from 100% organic and natural ingredients
    •  No other flavors
  • 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)
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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
  • Score breakdown
    Value
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    Lab Testing Transparency
    Effectiveness
  • 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
    •  All natural
    •  Approximately 300 drops total
    •  No other flavors
  • 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.
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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
  • Score breakdown
    Value
    Quality
    Strength
    Customer Service
    Lab Testing Transparency
    Effectiveness
  • 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
    •  Significant benefits with just a few drops
    •  100% Natural ingredients
    •  No other flavors
  • 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)
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Why People Are Turning to CBD for Anxiety

CBD has been known for its numerous health benefits, from helping to reduce chronic pain to alleviating cancer symptoms(6). 

There have also been other studies conducted to understand better the anxiolytic (anti-anxiety) characteristics of CBD.

CBD’s potential for anxiety relief is also linked to its ability to help with sleep problems, reduce stress, and manage depression

Esther Blessing, Ph.D. of New York University, led a group of researchers in 2015 and investigated the benefits of CBD in helping with anxiety. Their review of 49 studies yielded promising results(7). 

Blessing noted that animal studies conclusively demonstrated CBD’s efficacy in reducing anxiety behaviors linked to multiple disorders. 

These disorders include panic disorder (PD), generalized anxiety disorder (GAD), social anxiety disorder (SAD), obsessive-compulsive disorder (OCD), and post-traumatic stress disorder (PTSD).

Blessing added that the results were supported by human experimental findings, which also suggested CBD’s minimal sedative effects and excellent safety profile.

Unlike THC (tetrahydrocannabinol), another well-known compound of the cannabis plant, CBD (cannabidiol), is non-addictive and does not get users high, making it an appealing option for most people dealing with anxiety.

However, the results could not confirm that treatment with CBD would have comparable effects for those with chronic anxiety. Further tests are needed to determine the impact of prolonged CBD use on individuals. 

Meanwhile, researchers of a 2019 study, published in the Brazilian Journal of Psychiatry, looked at CBD’s effects on anxiety and stress. 

The study demonstrated that CBD might help reduce the response to stressful environmental factors when given in the optimal dosage(8).

Orrin Devinsky, M.D., director of NYU Langone’s Comprehensive Epilepsy Center in New York City and a principal investigator in the Epidiolex trials, says there is growing evidence that CBD can ease anxiety. 

This disorder sometimes accompanies attention-deficit/hyperactivity disorder (ADHD)(9).

A study published in the Neuropsychopharmacology journal simulated public speaking and demonstrated that a single dose of CBD could decrease the discomfort in people with a social anxiety disorder(10). 

A review published in the Brazilian Journal of Psychiatry in 2019 yielded similar effects on healthy people in anxiety-inducing situations(11).  

Researchers are also exploring CBD as a means of soothing anxiety in people with an autism spectrum disorder (ASD). 

In a study published in Frontiers in Pharmacology in 2019, the authors found an increase in the use of cannabidiol in children with ASD(12). 

Based on the parents’ reports, the findings suggest that CBD may be useful in improving ASD symptoms, such as anxiety, aggression, and hyperactivity. 

However, the authors also note that CBD’s efficacy and safety need large-scale clinical trials and further evaluation in children with ASD.

Orrin Devinsky is also involved in two clinical trials that aim to test whether CBD can meaningfully reduce the irritability and anxiety of those with autism(13). 

In another study, published in the Brazilian Journal of Psychiatry, researchers suggested that the therapeutic benefits from the use of CBD oil may be attributed to its anti-anxiety and sleep-inducing effects(14). 

Results of an animal study published in the Neuropharmacology Journal in 2012 also had comparable results that supported the use of CBD treatment. 

The findings suggested that CBD might block anxiety-induced sleep disturbances through its anxiolytic effect on the brain(15). 

A case report in The Permanente Journal, meanwhile, noted the effectiveness of CBD oil for anxiety and insomnia related to post-traumatic stress disorder (PTSD)(16). 

The authors of the 2016 study found that CBD oil reduced the feelings of anxiety and reduced the insomnia of one 10-year old girl.

The strength of this particular case is that the child was receiving no prescription medications other than the nonprescription diphenhydramine. 

With only nutritional supplements and the CBD oil to control her symptoms, her scores on the sleep and anxiety scales consistently and steadily decreased over 5 months. 

Ultimately, she was able to sleep on most nights in her room, behave appropriately, and become less anxious at school and home. 

For people who deal with the misery of insomnia, studies suggest that CBD may help with both falling asleep and staying asleep(17).

A study published in Pharmaceuticals (Basel) in 2012 even compared CBD with a sleep aid called nitrazepam(18). 

The authors found that a high dose of 160 milligrams of CBD (equivalent to 0.16 milliliter of CBD) increased the subject’s duration of sleep.

Similarly, a 2017 study published in the Current Psychiatry Reports noted that at moderate to high doses of CBD, the compound might have therapeutic potential for the treatment of insomnia(19).

Researchers of a study published in The Permanente Journal in 2019 measured sleep and anxiety scores in human subjects and found that CBD could hold benefits for anxiety-related disorders(20). 

A 2018 study published in the Frontiers in Immunology Journal demonstrated CBD as a potential remedy to depression(21). 

In the study, researchers examined the experimental and clinical use of CBD. They found that CBD showed anti-anxiety, anti-epileptic, and antipsychotic properties that might potentially help reduce depression linked to stress.

CBD is a cannabis Sativa constituent with great psychiatric potential, including uses as an anxiolytic-like and an antidepressant-like compound, as a 2014 study published in CNS and Neurological Disorders – Drug Targets suggested(22).

In one study, results showed that CBD could induce rapid-acting antidepressant-like effects and enhance neurotransmission(23). Neurotransmission is the process of communication between nerve cells.

How CBD Works to Help With Anxiety

To fully understand how CBD works to help with anxiety, one must understand how the endocannabinoid system (ECS) works. 

The therapeutic effects of cannabinoids, such as CBD, are realized by their interaction with the body’s ECS and its specialized cannabinoid receptors. 

The ECS, integral to the body’s physiologies, is responsible for regulating a wide range of body functions, including pain sensation, immune response, anxiety, sleep, mood, appetite, metabolism, and memory.

CB1 and CB2 are the two main types of receptors found in specific parts of the human body. These receptors each have particular roles in the ECS.

CB1 receptors are mostly located in the brain and central nervous system. However, they are also found in the reproductive organs, gastrointestinal and urinary tracts, liver, lungs, and retina(24). 

 CB1 receptors play a role in motor regulation, memory processing, appetite, pain sensation, mood, and sleep(25). 

The activation of CB1 receptors has also been related to neuroprotective responses. 

This activity suggests the cannabinoids with a higher affinity for CB1 receptors could help in the treatment and prevention of neurodegenerative conditions, such as Parkinson’s disease, Alzheimer’s disease, and multiple sclerosis.

Meanwhile, CB2 receptors are primarily situated on cells in the immune system and its associated structures.

When CB2 receptors are triggered, they stimulate a response that fights inflammation, reducing pain, and minimizing damage to tissues.

These anti-inflammatory responses are useful for treating inflammation-related conditions, such as chronic inflammatory demyelinating polyneuropathy (CIDP), Crohn’s disease, arthritis, and inflammatory bowel syndrome(26).  

CBD acts indirectly against cannabinoid agonists. Agonists are substances that attach to a receptor and cause the same action as the substances that typically bind to the receptor.

CBD also interacts with several other receptors in the body, such as the 5-HT1A receptor, which is linked to serotonin, a neurotransmitter found to be a contributor to feelings of well-being. It is through this interaction that these cannabinoids promote healing and balance(27).

A 2005 research published in the Neurochemical Research Journal indicated that cannabidiol could inhibit the reuptake of serotonin in the brain, making serotonin more available for the body(28). 

Serotonin occurs throughout the body, and it impacts a variety of body and psychological functions. In the brain, serotonin influences levels of anxiety, mood, and happiness. 

The researchers believe that with better regulation of serotonin, CBD could help stabilize mood and reduce anxiety. In fact, many pharmaceutical antidepressants work directly on serotonin pathways.

In the Translational PsychiatryJournal, a 2012 study demonstrated CBD’s ability to trigger the endocannabinoid system (ECS) in the body to produce more of its natural cannabinoids, including anandamide, which regulates emotions(29). 

Results showed that anandamide levels were higher in subjects exposed to CBD.

The ECS plays a vital role in the human body due to its ability to maintain homeostasis or state of balance, as explained in a 2018 research published in the Journal of Young Investigators(30). 

Increased anandamide production in the brain is believed to guard against the effects of stress while reducing behavioral signs of anxiety and fear, according to a 2019 study published in the Journal of Neuroscience(31). 

In another 2019 study published in the journal Current Psychiatry Reports, results indicated that CBD might have the potential to help elevate anandamide levels for the treatment of anxiety-related disorders in the future (32). 

Studies in the journal Cannabis and Cannabinoid Research showed that CBD might stimulate the hippocampus, a part of the brain important for memory, to regenerate neurons (nerve cells)(33). 

Preclinical studies have shown some evidence suggesting that the pro-neurogenic action of CBD through the hippocampus might trigger its anxiolytic (anti-anxiety) effects(34). 

The Pros and Cons of CBD Oil for Anxiety

The Pros

  • Studies have shown that CBD might be beneficial in alleviating anxiety, stress, and depression.
  • Unlike the commonly prescribed medications for anxiety, such as selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and benzodiazepines, CBD oil may be purchased without a prescription in locations where it is legally available.
  • CBD is non-addictive, says Nora Volkow, director of the National Institute on Drug Abuse (NIDA) in a 2015 article(35). This characteristic makes CBD an appealing option for people with anxiety. 
  • CBD “is generally well tolerated with a good safety profile,” as the World Health Organization (WHO) states in a critical review(36). 
  • In a 2017 review published in the Cannabis and Cannabinoid Research Journal, the authors found CBD to be well-tolerated at doses of up to 1,500 mg per day(37). 

The Cons

  • Studies are too limited to determine whether or not CBD is an effective treatment for conditions other than the ones approved by the U.S. Food and Drug Administration (FDA). The FDA has only approved Epidiolex, a drug for seizures that has CBD as its main ingredient(38). 
  • As with the use of any natural chemical compound, there are risks involved in using CBD. Possible side effects of CBD use include diarrhea, fatigue, and changes in appetite and weight. CBD can also alter how the body breaks down certain medications(39).  
  • Research published in Medicines Journal in 2019 indicates that the CYP450 family of enzymes is responsible for breaking down several phytocannabinoids (cannabinoids that exist naturally in the cannabis plant), including CBD(40). Thus, taking CBD in combination with medications that have a “grapefruit warning” is not recommended(41). 
  • CBD products marketed online and in dispensaries are mostly unregulated, making it difficult to determine whether the CBD oil tinctures, CBD gummies, CBD balms, and CBD softgels contain the amount of CBD the product labels claim(42). 

A 2107 review published in the Journal of the American Medical Association revealed labeling inaccuracies among CBD products(43). Some products had less CBD than stated, while others had more.

How CBD Oil Compares to Alternative Treatments for Anxiety

Yoga and massage are alternative treatments for anxiety.

According to an article posted by Harvard Health Publishing of the Harvard Medical School of Harvard University, yoga functions like other self-soothing techniques, such as relaxation, exercise, meditation, or even socializing with friends(44).  

By decreasing levels of perceived stress and anxiety, yoga modulates stress response systems, which consequently leads to a decreased heart rate, reduced blood pressure, and natural respiration.

Self-soothing methods also include massages or other types of tactile treatments which represent different kinds of relationships with other living beings, like pets. 

Oxytocin, a hormone produced in the brain, is released in response to several kinds of massage(45). 

Oxytocin is linked to increased levels of social interaction, well-being, and anti-stress effects, according to a 2015 study published in the journal Frontiers in Psychology (46). 

Although using oxytocin to treat mental health conditions has not yet been studied sufficiently, low oxytocin levels have been linked to depression, says the Endocrine Society(47).

The benefits of aromatherapy and essential oils include reducing anxiety and depression symptoms and improving sleep, according to a 2012 study(48). 

CBD used in aromatherapy and massage takes advantage of the cannabis plant’s terpenes that are used to create an essential oil. 

Terpenes are responsible for the flavors and aroma of cannabis and influence its effects by interacting with cannabinoids.

When combined with other essential oils, CBD stimulates one’s sense of smell and heightens the soothing benefits of a massage. 

When applied topically, CBD oil gets absorbed into the skin and targets cannabinoid receptors found in the skin’s mast cells and nerve fibers. 

The reaction gives a calming, anti-inflammatory effect with localized benefits all over the skin and muscles. 

Massages are used as a wellness and healing practice, and with an infusion of pure CBD hemp extract, the therapeutic benefits increase.

Studies have found that massage can also help relieve pain in people with cancer, as it helps relieve anxiety, fatigue, and stress(49). 

Meanwhile, according to an article published by the American Massage Therapy Association (AMTA), the potential value of massage therapy for individuals with depression comes from interrupting the pattern of symptoms regularly. 

Each time one interrupts the pattern and experiences calm, it is easy to remember what it is like to live in a healthy state, providing hope that it is possible(50). 

How to Choose the Right CBD for Anxiety

Full-spectrum CBD oil contains all phytonutrients from hemp, including trace amounts of THC, terpenes, flavonoids, fatty acids, and essential oils. 

Broad-spectrum CBD oils are like full-spectrum oils without THC.

Meanwhile, CBD isolates carry only pure, isolated cannabidiol.

For individuals allergic to specific components of the hemp plant, or do not want any amount of THC in their system, CBD isolates are an option.

Regardless of the form of CBD products that one chooses, careful consideration must be employed in selecting the best CBD oil for anxiety that is suitable for his or her lifestyle and preferences.

The following factors are essential to ensure the safety and reliability of the CBD products purchased:

  1. Research on the exact legal stipulations applicable to CBD in the area where it would be purchased and used.
  2. Purchase only high-quality, non-GMO, organic hemp-derived CBD products from legitimate and reliable CBD brands. The majority of companies that manufacture the best CBD oil products grow their hemp from their own farms, or they purchase from licensed and reputable hemp producers. Popular CBD brands, like NuLeaf Naturals, CBDistillery, and CBDPure, source their hemp from Colorado. Colorado in the United States has been at the forefront of hemp production as producers have benefited from the State’s favorable regulations. 
  3. When buying from an online store, research product reviews. When buying from a physical store or dispensary, check whether the store is authorized by the government to sell CBD.
  4. Knowing the extraction methods used in making the CBD oil is also essential. Researchers of a study indicate that the Supercritical-CO2 extraction process is recognized as safe by the U.S. Food and Drug Administration (FDA) in pharmaceutical manufacturing(51). 
  5. One important thing to look for in CBD products is certification codes. Several certification authorities approve certain products only after some thorough screening tests. 
  6. Compare company claims about their products’ potency with that of the third-party lab testing reports. 
  7. Consulting with a trusted medical professional who is experienced in CBD use is ideal before trying any CBD brands or cannabis products. 

CBD Dosage for Anxiety

Several factors determine the correct dose for an individual, including body weight, the amount of CBD is in each product, and the desired results.

Still, the guidelines for the correct dosage of CBD for specific medical conditions are unclear.

The U.S. Food and Drug Administration (FDA) has not approved cannabidiol as a supplement. 

Researchers of the 2016 study that was published in The Permanente Journal say they have no foundation to suggest doses of CBD based on the data from their studies(52). 

However, in their experience, the CBD supplement given in different dosages of 12 mg to 25 mg of CBD once daily appears to offer relief of key symptoms, such as anxiety and sleep problems, with nominal side effects

Notably, the subject of their study did report any complaints or discomfort from the use of CBD. Clearly further large scale prospective studies are necessary in order to generalize CBD dosing to the general population.

While CBD is considered generally safe, as the 2011 review in the Current Drug Safety Journal suggests, the long-term effects are yet to be examined further(53). 

How to Take CBD Oil for Anxiety

CBD oil capsules and edibles, such as brownies, gummies, and lozenges, are a convenient and straightforward way to take CBD oil, especially for beginners.

Meanwhile, CBD oil tinctures or drops may be a practical option for those who seek fast results and maximum dosage control. 

CBD oil tinctures may be directly discharged under the tongue by using a dropper, allowing the oil to be absorbed into the bloodstream.

Sublingual (under the tongue) absorption is an efficient way of consuming CBD tinctures. According to studies, CBD oil has a sublingual bioavailability of 13% to 19%, with some studies putting it as high as 35%(54).

Bioavailability is the extent and rate to which a compound or an active drug ingredient is absorbed and becomes readily available for the body to use(55). 

In a 2010 review, published in the International Journal of Pharmacy and Pharmaceutical Sciences, researchers found that peak blood levels of most substances given sublingually are achieved in 10 to 15 minutes, which is faster than when those same drugs are ingested orally(56). 

For those who find the taste of pure CBD hemp extract unappealing, there are CBD gummies that come in many delicious flavors. 

Each gummy also comes in a fixed dose, making it an excellent way to give CBD, even to kids with anxiety.

CBD oil can also be mixed with other foods and beverages. However, keep in mind that oil and water do not mix.

Given that CBD is a highly lipophilic (soluble in lipids or oils) molecule, it may dissolve in the fat content of food, increasing its solubility and absorption, according to a 2018 study published in the journal Frontiers in Pharmacology(57). 

An additional fat, like milk, may be necessary for the oil to bind and completely dissolve while maintaining the smooth consistency of the drink. 

CBD may also be used in massage therapies or applied as a lotion, cream, balm, or salve. There is, however, limited absorption through the skin with topical CBD oil.

For topical products, look for keywords on the product labels that indicate that the product uses nano technology, encapsulation, or micellization of CBD. 

These words indicate that their solution can carry CBD through the dermal layers, rather than staying on the skin.

CBD vapes, meanwhile, are one of the quickest ways to get CBD into the body since it enters the bloodstream through the lungs without going through the digestive system. 

However, vaping is not for everyone. Experts are not sure if vaping indeed caused lung problems but believe the most likely culprit is a contaminant, not an infectious agent. 

Possibilities include chemical irritation or allergic or immune reactions to various chemicals or other substances in the inhaled vapors(58). 

Thus, individuals contemplating vaping CBD for the first time must proceed with caution and first consult with a doctor experienced in cannabis use.

A Close Look at Anxiety Disorders

The U.S. Department of Health & Human Services lists five significant types of anxiety disorders(59):

Generalized Anxiety Disorder (GAD)

GAD is characterized by exaggerated worry, chronic anxiety, and tension, even when there is little or nothing to provoke it.

Generalized anxiety disorder symptoms include:(60)

  • Restlessness and irritability
  • Fatigue
  • Difficulty concentrating
  • Muscle tension
  • Sleep problems

Obsessive-Compulsive Disorder (OCD)

OCD is characterized by recurrent, unwanted thoughts or obsessions and repetitive behaviors or compulsions. 

Repetitive behaviors, like hand washing and counting, are often done in the hope of making them go away. 

Doing these so-called rituals, however, provides only temporary relief, while not performing them increases anxiety.

People with OCD may also have other mental disorders, such as depression, anxiety, and body dysmorphic disorder, in which someone believes a part of his or her body is abnormal(61). 

Panic Disorder

Panic disorder is described by unexpected and repeated episodes of intense fear.

People with panic disorder sometimes worry about when the next attack can happen and try to prevent future attacks by avoiding certain places, situations, or behaviors they link to the panic attacks.

Worrying about panic attacks and exerting too much effort trying to avoid attacks cause significant problems in various aspects of life.

During a panic attack, people may experience:(62)

  • Heart palpitations or an accelerated heart rate
  • Trembling or shaking
  • Sweating
  • Sensations of shortness of breath or choking
  • Feelings of impending doom and being out of control

Post-Traumatic Stress Disorder (PTSD)

PTSD may develop after exposure to a terrifying ordeal or event in which severe physical harm occurred.

Traumatic events that can trigger PTSD also include violent personal assaults, natural or human-caused disasters, accidents, or military combat(63). 

Anyone can develop PTSD at any age. Those at risk include war veterans, children, and people who have been through a physical or sexual assault, abuse, accident, and disaster. 

According to the National Center for PTSD, 7 or 8 out of every 100 people experience PTSD at some point in their lives(64). 

Women are more likely to have PTSD than men. Also, some genes can make some people more likely to develop PTSD than others.

Not everyone with PTSD has experienced a dangerous event, however. Some people may develop PTSD after a friend or family member experiences danger or harm. The unexpected or sudden passing of a loved one can also lead to PTSD.

Social Phobia or Social Anxiety Disorder (SAD)

SAD is characterized by overwhelming anxiety and excessive self-consciousness in everyday social situations(65). 

Social phobia may be limited to one type of situation, such as a fear of speaking during formal situations or eating in front of others.

In its most severe form, a person with SAD may experience symptoms almost anytime they are around other people.

FAQs on CBD

How is CBD different from THC?

CBD comes from cannabis and is naturally found in hemp plants. CBD is one of more than 100 cannabinoids that occur naturally within the plant. This compound is also commonly used to produce CBD hemp oil supplements. 

Cannabis oil is a term used to refer to any extract of the cannabis plant, including marijuana plant and hemp plant, that removes the plant’s naturally thick, viscous oil from dried or fresh cannabis.

Medical marijuana, also called medical cannabis, is made of dried parts of the Cannabis sativa plant.

Hemp seed oil is produced by extracting the oil from the seeds of the hemp plant itself. This oil is abundant in nutrients, such as omega-3 and omega-6 fatty acids, making it ideal for digestion. 

Although some people refer to “hemp extract” as hemp oil, the term “hemp oil” is synonymous with the term “hemp seed oil.”

Chemical compounds in cannabis, called cannabinoids, have shown various potential benefits by activating the body’s endocannabinoid system (ECS)

The ECS is involved in regulating a variety of body processes and functions, including sleep, appetite, pain, and immune system response(66). 

The body produces endocannabinoids, which are neurotransmitters that bind to cannabinoid receptors in the nervous system.

The medicinal efficacy of cannabis can be optimized by incorporating the various cannabinoids, flavonoids, and terpenes that are intrinsic components of cannabis plants.

CBD is non-psychoactive, contrasting with THC (delta-9-tetrahydrocannabinol), another primary cannabinoid

THC is the most significant factor contributing to the high associated with using cannabis. 

Consuming CBD without any THC does not produce those effects, which means that nearly everyone should be able to function as they usually do when taking CBD. 

The lack of high lets one continue with work, school, and other commitments without a decrease in performance. 

The absence of psychoactive effects also makes CBD oil safe to take, even for those who must pass regular or random drug tests.

CBD oil must not contain any THC for CBD not to induce psychoactive effects. 

Products containing CBD isolates do not have THC, while full-spectrum CBD oil products do. 

The full spectrum of cannabinoids, terpenes, fatty acids, and essential oils extracted from the plant all work together in synergy. 

This synergy magnifies the therapeutic benefits of individual cannabinoids and produces a phenomenon known as the “entourage effect.”

Any product that one buys should also state the percentage of THC, information which one can also get from its certificate of analysis.

What are the FDA-approved drugs that contain CBD and synthetic cannabinoids?

CBD is used in the treatment of some types of epilepsy, such as Dravet’s Syndrome, a complex disorder in children that is associated with a high rate of mortality and drug-resistant seizures.

Epidiolex (cannabidiol) oral solution is the first drug approved by the FDA for the treatment of seizures in individuals two years of age and older(67). 

The scientific study of cannabinoids has led to two FDA-approved drugs, dronabinol and nabilone. These medications contain THC in pill form(68).   

Is CBD safe?

Side effects of CBD include fatigue, nausea, and irritability. CBD can intensify the level of the blood thinner coumadin in the bloodstream, and it can raise levels of certain other medications in the system.

Another significant safety concern with CBD is that it is primarily marketed and sold as a supplement, not a medication(69). 

Currently, the FDA does not regulate the purity and safety of dietary supplements. Thus, consumers cannot know for sure that the product they are buying has active ingredients at the dose printed on the label. The product may also contain other unknown elements. 

Although the World Health Organization says that CBD is safe and well-tolerated, it is not clear how much to take or how often a person should use it for any particular problem. 

High doses of CBD may interact with other medications, such as blood thinners, antidepressants, and immune suppressors(70).

CBD is readily obtainable in many parts of the United States, although its exact legal status continually changes. 

In December 2015, the FDA eased the regulatory stipulations to allow researchers to conduct CBD investigations and trials. Currently, many people are able to get CBD online without a medical cannabis license(71). 

The government’s position on CBD is confusing, and it depends in part on whether the CBD comes from hemp or marijuana(72).

The legality of CBD is expected to change. Currently, there is a bipartisan consensus in Congress to make the hemp crop legal, which would make CBD difficult to prohibit, says Dr. Peter Grinspoon, the author of Free Refills: A Doctor Confronts His Addiction, in a 2019 article published by Harvard Health(73). 

Many states and Washington, D.C., have passed cannabis-related laws, making medical marijuana with high levels of THC legal. Still, marijuana may require a prescription from a licensed physician(74).

Also, several states have made recreational use of marijuana and THC legal. One should be able to buy CBD in states where marijuana is legal for recreational or medical purposes.

To get more information on state laws and penalties, click here(75).

Individuals who possess cannabis-related products in a state where they are illegal or do not have a medical prescription in states where the products are legal for medical treatment could face legal penalties.

For a complete list of legal medical marijuana states and D.C., including the corresponding laws, fees, and possession limits, click here(76).

What does a Farm Bill have to do with CBD?

The 2018 Farm Bill legalized industrial hemp and hemp-derived products at the federal level, removing them from the jurisdiction of the Drug Enforcement Administration (DEA). 

Since hemp is no longer categorized under controlled substances, it is now the job of the United States Department of Agriculture (USDA) to regulate the crop as it does other agricultural commodities. 

The law defined “agricultural hemp” as cannabis strains that contain less than 0.3% THC. Additionally, the Farm Bill explicitly legalized the “extracts, cannabinoids, and derivatives” of hemp. 

Does CBD show up on a drug test? 

CBD products from hemp sold online and in retail stores are not supposed to contain over 0.3 percent THC, the compound in marijuana that can get the user high.

However, sometimes, CBD products contain more THC than the amount printed on the label, says Barry Sample, senior director of science and technology at Quest Diagnostics, the largest administrator of drug tests in the U.S.(77).

It is also possible that, eventually, the trace amounts of THC allowed in CBD products could accumulate in the body to detectable levels, Sample explains.

THC is fat-soluble, adds Norbert Kaminski, Ph.D., professor of pharmacology and toxicology at Michigan State University in East Lansing. Thus, THC that is not immediately broken down by the body is stored in fat tissues(78). 

Over time, THC and THC metabolites (substances made when the body breaks down chemicals) are slowly released,” Kaminski says. As a result, it is possible to test positive for THC and not pass a drug test, even after one has stopped taking the product.

Conclusion

CBD has shown potential therapeutic efficacy in reducing both physiological and behavioral measures of stress and anxiety(79). 

In addition, in small clinical trials, CBD has shown benefits in helping to reduce symptoms of anxiety with few or no adverse effects

Research on cannabidiol oil (CBD oil) is still in its infancy. However, there has been mounting scientific evidence to suggest that it can help provide anxiety relief or reduce anxiety symptoms.

Still, the long-term side effects of CBD are unknown, and longitudinal scientific research is still significantly lacking.

Thus, consult with a doctor experienced in the use of cannabis products before using CBD as an adjunct anxiety therapy or as a remedy for anxiety and other medical conditions.


  1. Blessing EM, Steenkamp MM, Manzanares J, Marmar CR. Cannabidiol as a Potential Treatment for Anxiety Disorders. Neurotherapeutics. 2015;12(4):825–836. DOI:10.1007/s13311-015-0387-1.
  2. Linares IM, Zuardi AW, Pereira LC, et al. Cannabidiol presents an inverted U-shaped dose-response curve in a simulated public speaking test. Braz J Psychiatry. 2019;41(1):9–14. DOI:10.1590/1516-4446-2017-0015.
  3. de Mello A et al. “Antidepressant-Like and Anxiolytic-Like Effects of Cannabidiol: A Chemical Compound of Cannabis sativa”, CNS & Neurological Disorders – Drug Targets (2014) 13: 953. https://doi.org/10.2174/1871527313666140612114838.
  4. Shannon S, Lewis N, Lee H, Hughes S. Cannabidiol in Anxiety and Sleep: A Large Case Series. Perm J. 2019;23:18–041. DOI:10.7812/TPP/18-041.
  5. Hsiao YT, Yi PL, Li CL, Chang FC. Effect of cannabidiol on sleep disruption induced by the repeated combination tests consisting of open field and elevated plus-maze in rats. Neuropharmacology. 2012 Jan;62(1):373-84. DOI: 10.1016/j.neuropharm.2011.08.013. Epub 2011 Aug 16.
  6. Grinspoon, P. (2019, Aug 27). Cannabidiol (CBD) — what we know and what we don’t. Retrieved from https://www.health.harvard.edu/blog/cannabidiol-cbd-what-we-know-and-what-we-dont-2018082414476; Velasco G, Hernández-Tiedra S, Dávila D, Lorente M. The use of cannabinoids as anticancer agents. Prog Neuropsychopharmacol Biol Psychiatry. 2016;64:259–266. DOI:10.1016/j.pnpbp.2015.05.010.
  7. Blessing EM et al. op. cit.
  8. Linares IM et al. op.cit.
  9. Peachman, RB. (2019, Feb 26). Can CBD Help Your Child? Retrieved from https://www.consumerreports.org/cbd/can-cbd-help-your-child/.
  10. Bergamaschi MM, Queiroz RH, Chagas MH, et al. Cannabidiol reduces the anxiety induced by simulated public speaking in treatment-naïve social phobia patients. Neuropsychopharmacology. 2Linares IM, Zuardi AW, Pereira LC, et al. Cannabidiol presents an inverted U-shaped dose-response curve in a simulated public speaking test. Braz J Psychiatry. 2019;41(1):9–14. DOI:10.1590/1516-4446-2017-0015.011;36(6):1219–1226. DOI:10.1038/npp.2011.6.
  11. Linares IM et al. op. cit.
  12. Barchel D, Stolar O, De-Haan T, et al. Oral Cannabidiol Use in Children With Autism Spectrum Disorder to Treat Related Symptoms and Comorbidities. Front Pharmacol. 2019;9:1521. Published 2019 Jan 9. DOI:10.3389/fphar.2018.01521.
  13. Devinsky, O. et al. Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome. N Engl J Med 2017; 376:2011-2020. DOI: 10.1056/NEJMoa1611618; Devinsky, O. et al. Effect of Cannabidiol on Drop Seizures in the Lennox–Gastaut Syndrome. N Engl J Med 2018; 378:1888-1897. DOI: 10.1056/NEJMoa1714631.
  14. Zuardi, A. W. (2008). Cannabidiol: From an inactive cannabinoid to a drug with wide spectrum of action. Revista Brasileira de Psiquiatria, 30(3), 271–280. https://doi.org/10.1590/S1516-44462008000300015.
  15. Hsiao YT, Yi PL, Li CL, Chang FC. Effect of cannabidiol on sleep disruption induced by the repeated combination tests consisting of open field and elevated plus-maze in rats. Neuropharmacology. 2012 Jan;62(1):373-84. DOI: 10.1016/j.neuropharm.2011.08.013. Epub 2011 Aug 16.
  16. Shannon S, Opila-Lehman J. Effectiveness of Cannabidiol Oil for Pediatric Anxiety and Insomnia as Part of Posttraumatic Stress Disorder: A Case Report. Perm J. 2016;20(4):16-005. DOI:10.7812/TPP/16-005.
  17. Grinspoon P. (2019, Aug 27). Cannabidiol (CBD) — what we know and what we don’t. Retrieved from https://www.health.harvard.edu/blog/cannabidiol-cbd-what-we-know-and-what-we-dont-2018082414476.
  18. Zhornitsky S, Potvin S. Cannabidiol in humans-the quest for therapeutic targets. Pharmaceuticals (Basel). 2012;5(5):529–552. Published 2012 May 21. DOI:10.3390/ph5050529.
  19. Babson KA, Sottile J, Morabito D. Cannabis, Cannabinoids, and Sleep: a Review of the Literature. Curr Psychiatry Rep. 2017;19(4):23. DOI:10.1007/s11920-017-0775-9.
  20. Shannon S, Lewis N, Lee H, Hughes S. Cannabidiol in Anxiety and Sleep: A Large Case Series. Perm J. 2019;23:18–041. DOI:10.7812/TPP/18-041.
  21. Crippa JA, Guimarães FS, Campos AC, Zuardi AW. Translational Investigation of the Therapeutic Potential of Cannabidiol (CBD): Toward a New Age. Front Immunol. 2018;9:2009. Published 2018 Sep 21. DOI:10.3389/fimmu.2018.02009.
  22. de Mello A et al. “Antidepressant-Like and Anxiolytic-Like Effects of Cannabidiol: A Chemical Compound of Cannabis sativa”, CNS & Neurological Disorders – Drug Targets (2014) 13: 953. https://doi.org/10.2174/1871527313666140612114838.
  23. Linge R et al. Cannabidiol induces rapid-acting antidepressant-like effects and enhances cortical 5-HT/glutamate neurotransmission: role of 5-HT1A receptors. Neuropharmacology. 2016 Apr;103:16-26. doi: 10.1016/j.neuropharm.2015.12.017. Epub 2015 Dec 19.DOI: 10.1016/j.neuropharm.2015.12.017.
  24. Reggio PH. Endocannabinoid binding to the cannabinoid receptors: what is known and what remains unknown. Curr Med Chem. 2010;17(14):1468–1486. DOI:10.2174/092986710790980005.
  25. ECHO. (2017, April 18). Retrieved from  https://echoconnection.org/look-endocannabinoid-systems-cb1-cb2-receptors/.   
  26. Turcotte C, Blanchet MR, Laviolette M, Flamand N. The CB2 receptor and its role as a regulator of inflammation. Cell Mol Life Sci. 2016;73(23):4449–4470. DOI:10.1007/s00018-016-2300-4.
  27. ECHO. (2017, March 29). Retrieved from https://echoconnection.org/differences-cbd-thc/
  28. Russo, E.B., Burnett, A., Hall, B. et al. Agonistic Properties of Cannabidiol at 5-HT1a Receptors. Neurochem Res 30, 1037–1043 (2005). https://doi.org/10.1007/s11064-005-6978-1.
  29. Leweke FM, Piomelli D, Pahlisch F, et al. Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. Transl Psychiatry. 2012;2(3):e94. Published 2012 Mar 20. DOI:10.1038/tp.2012.15.
  30. Sallaberry, C. and Astern, L. The Endocannabinoid System, Our Universal Regulator. Retrieved from https://www.jyi.org/2018-june/2018/6/1/the-endocannabinoid-system-our-universal-regulator
  31. Morena M., Aukema, R., […], and Hill M. Upregulation of Anandamide Hydrolysis in the Basolateral Complex of Amygdala Reduces Fear Memory Expression and Indices of Stress and Anxiety. Journal of Neuroscience 13 February 2019, 39 (7) 1275-1292; DOI: https://doi.org/10.1523/JNEUROSCI.2251-18.2018.
  32. Papagianni EP, Stevenson CW. Cannabinoid Regulation of Fear and Anxiety: an Update. Curr Psychiatry Rep. 2019;21(6):38. Published 2019 Apr 27. DOI:10.1007/s11920-019-1026-z.
  33. Beale C, Broyd SJ, Chye Y, et al. Prolonged Cannabidiol Treatment Effects on Hippocampal Subfield Volumes in Current Cannabis Users. Cannabis Cannabinoid Res. 2018;3(1):94–107. Published 2018 Apr 1. DOI:10.1089/can.2017.0047.
  34. Campos AC, Ortega Z, […], and Guimarães FS. The anxiolytic effect of cannabidiol on chronically stressed mice depends on hippocampal neurogenesis: involvement of the endocannabinoid system. Int J Neuropsychopharmacol. 2013 Jul; 16(6):1407-19. 
  35. NIDA. Researching Marijuana for Therapeutic Purposes: The Potential Promise of Cannabidiol (CBD). National Institute on Drug Abuse website. https://www.drugabuse.gov/about-nida/noras-blog/2015/07/researching-marijuana-therapeutic-purposes-potential-promise-cannabidiol-cbd. July 20, 2015. Accessed January 31, 2020.
  36. Expert Committee on Drug Dependence Fortieth Meeting. Cannabidiol (CBD) Critical Review Report. June 2018. https://www.who.int/medicines/access/controlled-substances/WHOCBDReportMay2018-2.pdf.
  37. Iffland K, Grotenhermen F. An Update on Safety and Side Effects of Cannabidiol: A Review of Clinical Data and Relevant Animal Studies. Cannabis Cannabinoid Res. 2017;2(1):139–154. Published 2017 Jun 1. DOI:10.1089/can.2016.0034.
  38. U.S. Food and Drug Administration. (2020, Jan 15). FDA Regulation of Cannabis and Cannabis-Derived Products, Including Cannabidiol (CBD). Retrieved from https://www.fda.gov/news-events/public-health-focus/fda-regulation-cannabis-and-cannabis-derived-products-including-cannabidiol-cbd.
  39. Iffland et al. op cit.
  40. Alsherbiny MA, Li CG. Medicinal Cannabis-Potential Drug Interactions. Medicines (Basel). 2018;6(1):3. Published 2018 Dec 23. DOI:10.3390/medicines6010003.
  41. U.S. Food and Drug Administration. (2017, July 18). Grapefruit Juice and Some Drugs Don’t Mix. Retrieved from https://www.fda.gov/consumers/consumer-updates/grapefruit-juice-and-some-drugs-dont-mix.
  42. Peachman, RB. (2019, Feb 26). Can CBD Help Your Child? Retrieved from https://www.consumerreports.org/cbd/can-cbd-help-your-child/.
  43. Bonn-Miller MO, Loflin MJE, Thomas BF, Marcu JP, Hyke T, Vandrey R. Labeling Accuracy of Cannabidiol Extracts Sold Online. JAMA. 2017;318(17):1708–1709. DOI:10.1001/jama.2017.11909.
  44. Harvard Health Publishing. Yoga for anxiety and depression. Retrieved from https://www.health.harvard.edu/mind-and-mood/yoga-for-anxiety-and-depression.
  45. Uvnäs-Moberg K. (2004). “Massage, relaxation and well-being: a possible role for oxytocin as an integrative principle?,” in Touch and Massage in Early Child Development, ed. Field T. (Calverton, NY: Johnson & Johnson Pediatric Institute.
  46. Uvnäs-Moberg K, Handlin L, Petersson M. Self-soothing behaviors with particular reference to oxytocin release induced by non-noxious sensory stimulation. Front Psychol. 2015;5:1529. Published 2015 Jan 12. DOI:10.3389/fpsyg.2014.01529.
  47. Hormone Health Network. (2018, Nov). What is Oxytocin? Retrieved from https://www.hormone.org/your-health-and-hormones/glands-and-hormones-a-to-z/hormones/oxytocin.
  48. Boehm K, Büssing A, Ostermann T. Aromatherapy as an adjuvant treatment in cancer care–a descriptive systematic review. Afr J Tradit Complement Altern Med. 2012;9(4):503–518. Published 2012 Jul 1. DOI:10.4314/ajtcam.v9i4.7.
  49. Mayo Clinic. (2020, Jan 17). Alternative cancer treatments: 10 options to consider. Retrieved from https://www.mayoclinic.org/diseases-conditions/cancer/in-depth/cancer-treatment/art-20047246.
  50. Vallet, M. (2014, May 28). Massage + Depression. Retrieved from https://www.amtamassage.org/articles/3/MTJ/detail/2942/massage-depression.
  51. Kankala RK, Chen BQ, Liu CG, Tang HX, Wang SB, Chen AZ. Solution-enhanced dispersion by supercritical fluids: an ecofriendly nanonization approach for processing biomaterials and pharmaceutical compounds. Int J Nanomedicine. 2018;13:4227–4245. Published 2018 Jul 23. doi:10.2147/IJN.S166124; Djerafi R, Masmoudi Y, Crampon C, Meniai A, Badens E. Supercritical anti-solvent precipitation of ethyl cellulose. J Supercrit Fluids. 2015;105:92–98.
  52. Shannon S, Opila-Lehman J. Effectiveness of Cannabidiol Oil for Pediatric Anxiety and Insomnia as Part of Posttraumatic Stress Disorder: A Case Report. Perm J. 2016;20(4):16-005. DOI:10.7812/TPP/16-005.
  53. Bergamaschi MM, Queiroz RH, Chagas MH, et al. Cannabidiol reduces the anxiety induced by simulated public speaking in treatment-naïve social phobia patients. Neuropsychopharmacology. 2011;36(6):1219–1226. DOI:10.1038/npp.2011.6.
  54. Mechoulam R, Parker LA, Gallily R. Cannabidiol: an overview of some pharmacological aspects. J Clin Pharmacol. 2002 Nov;42(S1):11S-19S. DOI: 10.1002/j.1552-4604.2002.tb05998.x; Russo EB. Cannabinoids in the management of difficult to treat pain. Ther Clin Risk Manag. 2008;4(1):245–259. DOI:10.2147/tcrm.s1928.
  55. Chow SC. Bioavailability and Bioequivalence in Drug Development. Wiley Interdiscip Rev Comput Stat. 2014;6(4):304–312. DOI:10.1002/wics.1310.
  56. Narang, N. and Sharma, J. (2010, Dec 08). Sublingual Mucosa as A Route for Systemic Drug Delivery. https://innovareacademics.in/journal/ijpps/Vol3Suppl2/1092.pdf.
  57. Millar SA, Stone NL, Yates AS, O’Sullivan SE. A Systematic Review on the Pharmacokinetics of Cannabidiol in Humans. Front Pharmacol. 2018;9:1365. Published 2018 Nov 26. DOI:10.3389/fphar.2018.01365.
  58. Shmerling, R. (2019, Dec 10). Can vaping damage your lungs? What we do (and don’t) know. https://www.health.harvard.edu/blog/can-vaping-damage-your-lungs-what-we-do-and-dont-know-2019090417734.
  59. HHS. (2014, Feb 12). What are the five major types of anxiety disorders? Retrieved from https://www.hhs.gov/answers/mental-health-and-substance-abuse/what-are-the-five-major-types-of-anxiety-disorders/index.html.
  60. NIMH. (2018, Juy). Anxiety Disorders. Retrieved from https://www.nimh.nih.gov/health/topics/anxiety-disorders/index.shtml.
  61. NIMH. (2019, Oct). Obsessive-Compulsive Disorder. Retrieved from https://www.nimh.nih.gov/health/topics/obsessive-compulsive-disorder-ocd/index.shtml.
  62. NIMH. op. cit.
  63. NIMH. (2019, May). Post-Traumatic Stress Disorder. Retreived from https://www.nimh.nih.gov/health/topics/post-traumatic-stress-disorder-ptsd/index.shtml.
  64. National Center for PTSD. (2019, Oct 17). How Common is PTSD in Adults? Retreived from https://www.ptsd.va.gov/understand/common/common_adults.asp.
  65. NIMH. op. cit.
  66. Mouslech Z, Valla V. Endocannabinoid system: An overview of its potential in current medical practice. Neuro Endocrinol Lett. 2009;30(2):153–179.
  67. USFDA. (2018, June 25). FDA approves first drug comprised of an active ingredient derived from marijuana to treat rare, severe forms of epilepsy. Retrieved from https://www.fda.gov/news-events/press-announcements/fda-approves-first-drug-comprised-active-ingredient-derived-marijuana-treat-rare-severe-forms.
  68. NIH Drug Facts. (2019, July). Marijuana as Medicine. Retrieved from https://www.drugabuse.gov/publications/drugfacts/marijuana-medicine.
  69. Grinspoon, P. op. cit.
  70. Harvard Health Publishing. (2019, Oct). Know the facts about CBD products. Retrieved from https://www.health.harvard.edu/staying-healthy/know-the-facts-about-cbd-products
  71. Grinspoon, P. op. cit.
  72. Rosenberg, C. (2016, Dec 7). Federal Register. Establishment of a New Drug Code for Marihuana Extract. Retrieved from https://www.federalregister.gov/documents/2016/12/14/2016-29941/establishment-of-a-new-drug-code-for-marihuana-extract
  73. Grinspoon, P. op. cit.
  74. ProCon.org. (2019, July 24). Legal Medical Marijuana States and DC Laws, Fees, and Possession Limits. Retrieved from https://medicalmarijuana.procon.org/legal-medical-marijuana-states-and-dc/
  75. State Laws. Retrieved from https://norml.org/laws
  76. ProCon.org. op.cit. 
  77. Gill, L. (2019, May 15). Can You Take CBD and Pass a Drug Test? Retrieved from https://www.consumerreports.org/cbd/can-you-take-cbd-and-pass-a-drug-test/
  78. ibid.
  79. Guimaraes et al. Antianxiety effect of cannabidiol in the elevated plus-maze. Psychopharmacology (Berl) 100:558–559 (1990); Lemos et al. Involvement of the prelimbic prefrontal cortex on cannabidiol-induced attenuation of contextual conditioned fear in rats. Behav Brain Res 207:105–111(2010).

More Info

Less Info

 

DOXEFAZEPAM

(Group 3)

For definition of Groups, see Preamble Evaluation.

 

VOL.: 66 (1996) (p. 97)

 

CAS No.: 40762-15-0

Chem. Abstr. Name: 7-Chloro-5-(2-fluorophenyl)-1,3-dihydro-3-hydroxy-1-(2-hydroxyethyl)-2H-1,4-benzodiazepin-

2-one

 

  1. Summary of Data Reported and Evaluation

5.1 Exposure data

Doxefazepam is a benzodiazepine hypnotic that was used in the past to a limited extent in the short-term management of insomnia.

 

5.2 Human carcinogenicity data

 

No data were available to the Working Group.

 

5.3 Animal carcinogenicity data

 

Doxefazepam was tested for carcinogenicity in one experiment in rats by oral administration in the diet. A slight dose-related increase in the incidence of hepatocellular adenomas was observed.

 

5.4 Other relevant data

 

Doxefazepam disposition has received little study. In humans, the drug was eliminated in urine mainly as a conjugate, and two oxidative metabolites were identified. The elimination half-life was 3-4 h. No satisfactory metabolism studies in animals were available. Data on human toxicity were not available. In rats treated with 60 mg/kg bw per day for 26 weeks, increased liver weights were reported without other clinical, haematological or histopathological signs of toxicity. In a single study, doxefazepam was not teratogenic in rats or rabbits. The few data available on genetic effects were negative.

 

5.5 Evaluation

 

There is inadequate evidence in humans for the carcinogenicity of doxefazepam.

 

There is limited evidence in experimental animals for the carcinogenicity of doxefazepam.

 

Overall evaluation

 

Doxefazepam is not classifiable as to its carcinogenicity to humans (Group 3).

 

For definition of the italicized terms, see Preamble Evaluation.

 

Synonyms

 

N-1-Hydroxyethyl-3-hydroxyflurazepam

Doxans

SAS 643

Last updated 05/22/97

 

See Also:

Doxefazepam (PIM 924)

 

See Also:

Doxefazepam (PIM 924)

——————————

INTOX Home Page

 

MONOGRAPH FOR UKPID

AMITRIPTYLINE HYDROCHLORIDE

HY Allen

ZM Everitt

AT Judd

 

National Poisons Information Service (Leeds Centre)

Leeds Poisons Information Centre

Leeds General Infirmary

Leeds

LS1 3EX

UK

 

This monograph has been produced by staff of a National Poisons

Information Service Centre in the United Kingdom.  The work was

commissioned and funded by the UK Departments of Health, and was

designed as a source of detailed information for use by poisons

information centres.

 

Peer review group: Directors of the UK National Poisons Information

Service.

 

MONOGRAPH FOR UKPID

 

Drug name

 

Amitriptyline hydrochloride.

 

Chemical group

 

Tricyclic antidepressant.

 

Origin of substance

 

Synthetic.

 

Name

 

UK Brand name(s)

 

e.g. Lentizol(R), Tryptizol(R), Domical(R), Elavil(R).

Also available in compound preparations with perphenazine as

Triptafen(R) and Triptafen-M(R).

 

Synonyms

 

Common names/street names

 

Pharmacotherapeutic group

 

Drug acting upon CNS; antidepressant; tricyclic.

 

Reference number

 

Product licence

 

Lentizol(R) 25 mg capsules: 0018/0173R

Lentizol(R) 50 mg capsules: 0018/0174R

Tryptizol(R) 10 mg tablets: 0025/0093

Tryptizol(R) 25 mg tablets: 0025/0094

Tryptizol(R) 50 mg tablets: 0025/0095

Tryptizol(R) injection: 0025/5036

Tryptizol(R) syrup: 0025/5037

 

Other

 

CAS 549-18-8

 

Manufacturer

 

of Lentizol(R)

Name           Parke-Davis Medical

 

of Tryptizol(R)

Name           Thomas Morson Pharmaceuticals (a subsidiary of Merck

Sharp & Dohme Ltd)

 

of Domical(R)

Name           Berk Pharmaceuticals (a subsidiary of Approved

Prescription Services Ltd)

 

of Elavil(R)

Name           DDSA Pharmaceuticals Ltd

 

Supplier/importer

 

In addition to the branded products listed above, non-proprietary

products are available from Antigen, APS and Cox.

 

Name           Antigen Pharmaceuticals Ltd

 

Name           APS (Approved Prescription Services Ltd)

 

Name           AH Cox & Co Ltd

 

Presentation

 

Form

 

Oral tablets, modified release capsules, and mixture. Injection for

intramuscular or intravenous administration.

 

Formulation details

 

Tablets of 10 mg, 25 mg, and 50 mg.

Modified release capsules of 25 mg and 50 mg.

Mixture (as amitriptyline embonate) equivalent to 10mg/5ml.

Injection of 10mg/ml.

 

Pack size(s)

 

Lentizol(R)

25 mg and 50 mg modified release capsules: blister packs of 56 or

100.

Tryptizol(R)

10 mg tablets: blister packs of 30,

25 mg tablets: blister packs of 30,

50 mg tablets: blister packs of 30,

mixture: bottle of 200 ml,

injection: vials of 10 ml.

 

Packaging

 

Lentizol(R) 25 mg: pink capsules of 25 mg amitriptyline hydrochloride

in a modified release form, marked ‘LENTIZOL 25’,

Lentizol(R) 50 mg: pink/red capsules of 50 mg amitriptyline

hydrochloride in a modified release form, marked ‘LENTIZOL 50’.

 

Tryptizol(R) 10 mg: blue tablets of 10 mg amitriptyline hydrochloride

marked ‘MSD23′,

Tryptizol(R) 25 mg: yellow tablets of 25 mg amitriptyline

hydrochloride marked’ MSD 45′,

Tryptizol(R) 50 mg: brown tablets of 50 mg amitriptyline hydrochloride

marked ‘MSD 102’,

Tryptizol(R) syrup: pink suspension of amitriptyline embonate

equivalent to 10 mg/5 ml amitriptyline,

Tryptizol(R) injection: colourless solution for injection containing

10mg/ml amitriptyline hydrochloride.

 

Compound preparations

 

Triptafen(R): pink tablets of 25 mg amitriptyline hydrochloride and 2

mg perphenazine.

Triptafen-M(R): pink tablets of 10 mg amitriptyline hydrochloride and

2 mg perphenazine.

 

Amitriptyline is also available in generic and branded-generic

formulations, the appearance of which will differ from the branded

products listed.

 

Physico-chemical properties

 

Solubility in water

 

Freely soluble (Martindale 1996).

 

Solubility in ether

 

Practically insoluble (Martindale 1996).

 

Solubility in other solvents

 

Freely soluble in alcohol, chloroform, methyl alcohol and

methylene chloride (Martindale 1996).

 

Chemical structure

 

3-(10,11-Dihydro- 5H-dibenz-[ a,d]cyclohepten-5-

ylidene)propyldimethylamine hydrochoride

 

C20H23N,HCl = 313.9

 

Uses

 

Indication

 

Symptomatic treatment of depressive illness especially where sedation

is required. Nocturnal enuresis in children.

 

Therapeutic dosage

 

in adults

In depression

by mouth: 75-150 mg daily in single or divided doses (lower doses in

elderly and adolescents).

by IM or IV injection: 10-20 mg four times daily.

 

in children

For nocturnal enuresis:

6-10 years: 10-20 mg daily by mouth.

11-16 years: 25-50 mg daily by mouth.

Modified release preparations are not licensed for use in children.

 

Contra-indications

 

Recent myocardial infarction or coronary artery insufficiency. Heart

block or other cardiac arrhythmia. Mania. Severe liver disease.

Co-administration with monoamine oxidase inhibitors. Hypersensitivity

to amitriptyline. Lactation. Children under 6 years of age.

 

Abuses

 

Pharmacokinetics

 

Absorption

 

Amitriptyline is well absorbed orally with maximum plasma

concentrations being reached after approximately 3 hours (Schulz et

  1. 1985). It undergoes extensive first-pass metabolism, the systemic

 

bioavailability being in the region of 45%(Schulz et al. 1985).

Little information is available on the disposition of amitriptyline

following parenteral administration.

 

Distribution

 

Amitriptyline is widely distributed throughout the body with an

apparent volume of distribution of about 19 L/kg (Schulz et al. 1985).

Approximately 95% of amitriptyline in the plasma is bound to proteins

(Schulz et al. 1985). The plasma protein binding of tricyclic

antidepressants is pH sensitive, with a small reduction in plasma pH

being associated with large increases in unbound (pharmacologically

active) drug (Nyberg & Martensson 1984).

 

Metabolism

 

There is wide individual variation in the pharmacokinetic profile of

amitriptyline. Amitriptyline is metabolised in the liver, the primary

routes of metabolism being demethylation, hydroxylation and

conjugation. It is considered that the metabolic pathways are mediated

by the enzymes CYP2D6 and CYP2C19, although other enzymes are probably

also involved (Schmider et al. 1995). The major active metabolites

formed are nortriptyline, 10-hydroxyamitriptyline, and

10-hydroxynortriptyline. Both nortriptyline and

10-hydroxynortriptyline contribute significantly to the antidepressant

effect (Bertilsson et al. 1979).

 

Elimination

 

Amitriptyline is excreted mainly in the urine as conjugated and

unconjugated metabolites. Less than 5% is excreted as unchanged drug

(Dollery 1991).

Significant gastric and biliary secretion of amitriptyline and its

metabolites occurs, resulting in enteroenteric and enterohepatic

circulations (Gard et al. 1973).

Dialysis as a means of promoting drug and metabolite elimination is

ineffective (Dawling et al. 1982).

 

Half-life

 

substance

 

Amitriptyline: 21 hours (range 13-36 hours)(Schulz et al. 1985).

 

metabolite(s)

 

Nortriptyline: 25 hours (Dawling et al. 1982).

10-hydroxynortriptyline: 26 hours (Dawling et al. 1982).

 

Special populations

 

Elderly: metabolic changes in the elderly result in higher plasma

amitriptyline concentrations than in younger populations (Schmider et

  1. 1995).

 

Renal impairment: reduced metabolite clearance in renal impairment

results in accumulation, particularly of the hydroxymetabolites

(Dawling et al. 1982).

Hepatic impairment: reduced metabolic capacity in liver impairment

results in accumulation of amitriptyline (Hrdina et al. 1985).

Gender: there is some evidence to suggest that higher plasma

concentrations of amitriptyline occur in females over the age of 50

than in males of a similar age, but factors other than gender

complicate the picture (Preskorn & Mac 1985, Schmider et al. 1995).

 

Breast milk

 

Amitriptyline and its metabolites are secreted into breast milk. In

one patient the amounts of amitriptyline and nortriptyline in the

breast milk and serum were approximately equal (Bader & Newman 1980).

In a second patient the concentrations of amitriptyline, nortriptyline

and 10-hydroxynortriptyline in breast milk were about 50%, 75%, and

70% of the maternal serum concentrations respectively (Breyer-Pfaff et

  1. 1995). The doses to the infants in these two cases are

approximately 3% and 1% of the maternal doses respectively.

 

Toxicokinetics

 

Absorption

 

In a study of 27 tricyclic overdose patients, peak plasma

concentrations occurred within 3 hours of the overdose (Bramble et al.

1985).

There was no evidence of prolonged absorption from the gut following

amitriptyline overdose in 9 patients (Hulten et al. 1992).

 

Distribution

 

Amitriptyline is rapidly distributed into body tissues with plasma

drug concentrations beginning to fall within 3 hours of overdose

(Bramble et al. 1985).

The value for protein binding remains within the range observed with

therapeutic doses and is likewise pH sensitive (Hulten et al. 1992).

 

Metabolism

 

A comparison of half-life values for amitriptyline following overdose

with values after therapeutic dosing suggests that saturation of

metabolic process may occur. Insufficient data are available to draw

firm conclusions.

 

Elimination

 

There is evidence to show that enterohepatic or enteroenteral

circulation of the metabolite nortriptyline occurs (Hulten et al.

1992).

Less than 5% of a dose is excreted in urine during the first 24 hours

after overdose (Gard et al. 1973).

 

Half-life

 

substance

 

Following overdose, half-life values between 15 hours and 81 hours

have been reported (Hulten et al. 1992, Spiker & Biggs 1976).

 

metabolite(s)

 

Special populations

 

Breast milk

 

Adverse effects

 

Antimuscarinic effects, sedation, ECG changes, arrhythmias, postural

hypotension, tachycardia, syncope, sweating, tremor, rashes,

hypersensitivity reactions, behavioral disturbances, hypomania or

mania, confusion, interference with sexual function, blood sugar

changes, weight gain, convulsions, movement disorders and dyskinesias,

fever, hepatic and haematological reactions.

 

Interactions

 

Pharmacodynamic

 

  1. a) A potentially hazardous interaction may occur between a tricyclic

antidepressant and a monoamine oxidase inhibitor (including

moclobemide and selegiline) resulting in increased amounts of

noradrenaline and serotonin at the synapse. Coma, hyperthermia,

convulsions, delirium, or death may result (White & Simpson 1984).

 

  1. b) There is an increased risk of cardiotoxicity when administered with

other drugs which prolong the QT interval e.g. anti-arrhythmics,

astemizole, halofantrine, terfenadine.

 

  1. c) The pharmacology of amitriptyline suggests that concomitant

ingestions of selective serotonin reuptake inhibitors, phenothiazines,

sympathomimetics, or other tricyclic antidepressants will enhance its

toxicity.

 

Pharmacokinetic

 

  1. a)  The metabolism of tricyclic antidepressants is inhibited by most

selective serotonin reuptake inhibitors resulting in elevated

tricyclic plasma concentrations. Fluoxetine, fluvoxamine, and

paroxetine appear to exert a greater effect than sertraline. Limited

data suggest that citalopram does not inhibit tricyclic metabolism

(Baettig et al. 1993, Taylor 1995).

 

  1. b) As the metabolism of amitriptyline is mediated by cytochrome P450

microsomal enzymes, particularly CYP2D6 and CYP2C19, the potential

exists for interactions with drugs which are substrates of these

pathways.

 

  1. c) Cimetidine reduces the metabolic clearance of amitriptyline by

inhibition of liver enzymes, resulting in higher plasma amitriptyline

concentrations (Stockley 1996).

 

Ethanol

 

Plasma concentrations of amitriptyline are higher when ingested with

ethanol, probably as a result of reduced first-pass metabolism (Shoaf

& Linnoila 1991).

 

Summary

 

Type of product

 

A tricyclic antidepressant.

 

Ingredients

 

Amitriptyline tablets: 10 mg, 25 mg, 50 mg.

Amitriptyline in a modified release capsule: 25 mg, 50 mg.

Amitriptyline mixture: equivalent to 10mg/5ml.

Amitriptyline injection: 10mg/ml.

 

Summary of toxicity

 

Patients with only mild signs of toxicity may rapidly develop life-

threatening complications. Where major toxic events occur these

usually develop within 6 hours of overdose, the risk of toxicity being

greatest 2-4 hours after ingestion.

 

Amitriptyline overdose must be managed on a clinical basis rather than

on the amount ingested, but as a guide, doses of 750 mg in adults have

been associated with severe toxicity. Ingestions of tricyclic

antidepressants in children indicate that doses of 15 mg/kg may prove

fatal to a child, although recovery has followed reported ingestions

of over 100 mg/kg.

 

Sinus tachycardia, hypotension, and anticholinergic symptoms are

common features. Cardiotoxicity, impaired consciousness, seizures,

acidosis, and respiratory insufficiency are associated with severe

toxicity. The occurrence of seizures may precipitate the onset of

cardiac arrhythmias and hypotension. Delirium may be a complication on

recovery.

 

Common features

 

Dry mouth, blurred vision, dilated pupils, urinary retention, sinus

tachycardia, drowsiness, hypothermia, and confusion. Hypoxia,

acidosis, hypotension, convulsions, cardiac arrhythmias, and coma.

 

Uncommon features

 

Skin blisters, rhabdomyolysis, disseminated intravascular coagulation,

adult respiratory distress syndrome, and absent brain stem reflexes.

 

Summary of management

 

SUPPORTIVE

 

  1.   Maintain a clear airway and adequate ventilation if consciousness

is impaired.

 

  1.   If within 1 hour of the ingestion and more than 300 mg has been

taken by an adult or more than 1mg/kg by a child, give activated

charcoal.

 

  1.   Carry out arterial blood gas analysis, and correct any acidosis

and hypoxia.

 

  1.   Monitor the cardiac rhythm and blood pressure.

 

  1.   Single, brief convulsions do not require treatment but if they

are prolonged or recurrent, they should be controlled with

intravenous diazepam.

 

  1.   Other measures as indicated by the patient’s clinical condition.

 

Epidemiology

 

Over an 11 year period between 1975 and 1985, more than 1,200 deaths

were attributable to amitriptyline poisoning in the UK, or 47 deaths

per million prescriptions dispensed (Montgomery et al. 1989).

Fatalities tend to occur in older rather than younger patients. In

both fatal and non-fatal overdose, there are a greater number of

ingestions in females than in males (Crome 1986).

The overall incidence of serious cardiac complications in patients who

are admitted to hospital following tricyclic overdose is reported to

be less than 10%. Some degree of coma occurs in about 50% of cases,

but is only unresponsive to painful stimuli in about 10-15% of cases

(Crome 1986). Convulsions occur in approximately 6% of patients

(Taboulet 1995). The death rate in patients admitted to hospital is

estimated to be 2%-3% (Dziukas & Vohra 1991).

 

Mechanism of action/toxicity

 

Mechanism of action

 

The precise mechanism of antidepressant action is unclear, but results

from the potent inhibition of noradrenaline and serotonin reuptake

into presynaptic neurones, and adaptive changes in receptor

sensitivity (Richelson 1994).

 

Amitriptyline inhibits the reuptake of noradrenaline and serotonin

with similar potency, whilst the metabolite nortriptyline inhibits the

reuptake of noradrenaline to a greater degree than serotonin. The

hydroxy metabolites of amitriptyline and nortriptyline inhibit

noradrenaline reuptake, but to a lesser degree than the parent drugs.

They do not have any significant effect on serotonin reuptake

(Bertilsson et al. 1979).

 

Amitriptyline is a potent antagonist of both peripheral and central

muscarinic cholinergic receptors. It has also relatively potent

antagonist activity at H1 histamine and a1 adrenergic receptors.

These antagonist actions account for its anticholinergic, sedative,

and hypotensive properties (Richelson 1994).

 

Mechanism of toxicity

 

Toxicity is due to depression of myocardial function (a quinidine-like

effect), central and peripheral muscarininic receptor blockade, a1

adrenergic receptor blockade, and respiratory insufficiency.

The risk of toxicity is greatest 2-4 hours after ingestion when plasma

levels are maximal.

 

Features of poisoning

 

Acute

 

Ingestion

 

Mild to moderate toxicity: dilated pupils, sinus tachycardia,

drowsiness, dry mouth, blurred vision, urinary retention, absent bowel

sounds, confusion, agitation, body temperature disturbances,

twitching, delirium, hallucinations, nystagmus, and ataxia.

Increased tone and hyperreflexia may be present with extensor plantar

responses (Callaham 1979, Crome 1986, Dziukias & Vohra 1991).

 

Severe toxicity: coma, hypotension, convulsions, supraventricular

and ventricular arrhythmias, hypoxia, metabolic/respiratory acidosis,

and cardiac arrest (Crome 1986, Dziukias & Vohra 1991).

 

ECG changes (in the usual order of appearance) include non-specific ST

or T wave changes, prolongation of the QT, PR, and QRS intervals,

right bundle branch block, and atrioventricular block. The terminal

0.04 second frontal plane QRS axis often shows a right axis deviation

(Dziukas & Vohra 1991).

 

Delayed features: adult respiratory distress syndrome (Varnell et

  1. 1989).

 

Uncommon features: skin blisters, rhabdomyolysis, disseminated

intravascular coagulation, gaze paralysis, and absent brain reflexes

(Dziukias & Vohra 1991, White 1988, Yang & Dantzker 1991). See case

report 1.

 

Inhalation

 

Dermal

 

Ocular

 

Other routes

 

Chronic

 

Ingestion

 

Inhalation

 

Dermal

 

Ocular

 

Other routes

 

At risk groups

 

Elderly

 

There is an increased risk of toxicity resulting from impaired drug

metabolism (Schmider et al. 1995).

 

Pregnancy

 

There is relatively wide experience with the therapeutic use of

amitriptyline during pregnancy. Although a few birth defects have been

reported, the number is insufficient to support an association with

amitriptyline administration (Briggs 1994).

 

Children

 

Ingestions in children result in features similar to those following

adult ingestion (Crome & Braithwaite 1978, Goel & Shanks 1974, James &

Kearns 1995). See case report 2.

 

Enzyme deficiencies

 

The metabolism of amitriptyline is in part mediated by the microsomal

enzymes CYP2D6 and CYP2C19 which are subject to genetic polymorphism

(Schmider et al. 1995). Metabolic processes will differ in individuals

deficient in these enzymes and there is a risk of amitriptyline

accumulation.

 

Enzyme induced

 

The metabolism of amitriptyline is increased in the presence of enzyme

inducing drugs, but is of doubtful clinical relevance as the

metabolites formed also have pharmacological activity.

 

Others

 

Renal impairment: increased risk of toxicity due to accumulation of

metabolites.

Hepatic impairment: increased risk of toxicity due to impaired

amitriptyline metabolism.

Cardiac disease: increased risk of cardiotoxicity due to underlying

disease.

Epilepsy: increased risk of seizures.

 

Management

 

Decontamination

 

In cases where more than 300 mg has been taken by an adult or more

than 1mg/kg by a child, activated charcoal should be given to reduce

the absorption if administered within one hour of the drug ingestion.

Adult dose; 50 g, child dose; 1 g/kg. If the patient is drowsy this

should be administered via a nasogastric tube, and if there is no gag

reflex present, using a cuffed endotracheal tube to protect the

airway.

 

Supportive care

 

General

 

Clear and maintain the airway, and give cardiopulmonary resuscitation

where necessary. Evaluate the patient’s condition and provide support

for vital functions.

 

Management of the symptomatic patient

 

  1.   Administer intravenous sodium bicarbonate to correct any

acidosis.

 

Adult dose: 50 ml of 8.4%sodium bicarbonate by slow intravenous

injection; child dose: 1 ml/kg of 8.4% sodium bicarbonate by slow

intravenous injection.

 

Subsequent bicarbonate therapy should be guided by arterial blood pH

which should be monitored frequently.

 

  1.   Maintain adequate ventilation to prevent hypoxia with

supplemental oxygen or artificial ventilation as appropriate.

 

  1.   Carefully maintain plasma potassium levels to prevent

hypokalaemia.

 

In mixed overdoses where a benzodiazepine has also been ingested,

the use of the competitive benzodiazepine antagonist flumazenil is

contraindicated (Mordel et al. 1992).

 

Where symptoms develop following mild to moderate overdose, they may

persist for 24 hours. Prolonged or delayed complications following

severe toxicity may require the patient to be hospitalised for several

days.

 

Specific

 

Management of cardiotoxicity.

 

GENERAL NOTE: in practice it is seldom necessary or advisable to use

specific drug treatment for arrhythmias. If hypoxia and acidosis are

reversed and adequate serum potassium levels maintained, then the

majority of patients show improvement with supportive measures.

 

SINUS and SUPRAVENTRICULAR TACHYCARDIAS: no specific treatment

required (Pimentel & Trommer 1994).

 

VENTRICULAR ARRHYTHMIAS: give sodium bicarbonate (even in the absence

of acidosis) before considering antiarrhythmic drug therapy. Where an

antiarrhythmic is considered necessary, lignocaine is the preferred

drug (Pimentel & Trommer 1994).

 

ADULT DOSE: 50-100 mg given by IV bolus over a few minutes,

followed by an intravenous infusion of 4 mg/minute for 30 minutes, 2

mg/minute for 2 hours, then 1 mg/minute (BNF 1998).

The use of quinidine, disopyramide, procainamide, and flecainide are

all contra-indicated as they depress cardiac conduction and

contractility. The use of beta-blockers should also be avoided as they

decrease cardiac output and exacerbate hypotension. The efficacy of

other antiarrhythmic agents (e.g bretylium, amiodarone, calcium

channel blockers) has not been studied in tricyclic antidepressant

poisoning (Pimentel & Trommer 1994).

 

BRADYARRHYTHMIAS and HEART BLOCK: cardiac pacing may have only limited

success as the cardiotoxicity of amitriptyline results from depression

of contractility rather than failure of cardiac pacemakers.

 

CARDIAC ARREST: manage in the standard manner but with continuing

resuscitative measures as some patients have recovered after receiving

several hours of external cardiac massage (Orr & Bramble 1981).

 

Management of coma

 

Good supportive care is essential.

 

Management of hypotension

 

Hypotension should be managed by the administration of intravenous

fluids and by physical means. The majority of patients ingesting

amitriptyline have otherwise healthy cardiovascular systems and

providing cardiac output is good it is unnecessary to use specific

drug therapy.

 

If there is evidence of poor cardiac output (after correction of

acidosis, hypovolaemia, and hypoxia) then the use of a vasoactive

agent may need to be considered. Noradrenaline has been shown to be

helpful in a number of studies (including cases where dopamine therapy

has failed) (Pimentel & Trommer 1994, Teba et al. 1988, Yang &

Dantzker 1991).

 

ADULT DOSE: IV infusion of noradrenaline acid tartrate 80

micrograms/ml (equivalent to noradrenaline base 40 micrograms/ml) via

a central venous catheter at an initial rate of 0.16 to 0.33 ml/minute

adjusted according to response (BNF 1998).

 

CHILD DOSE (unlicensed indication): IV infusion of noradrenaline

acid tartrate 0.04-0.2 microgram/kg/minute (equivalent to 0.02-0.1

microgram/kg/minute of noradrenaline base) in glucose 5% or

glucose/saline via a central venous catheter (Guy’s, Lewisham & St

Thomas Paediatric Formulary, 1997).

 

Management of seizures

 

Administer intravenous diazepam to control frequent or prolonged

convulsions.

 

ADULT DOSE: 10 mg,

CHILD DOSE: 0.25-0.4 mg/kg,

Both by slow IV injection preferably in emulsion form.

 

Where seizure activity proves difficult to manage, paralyse and

ventilate the patient. Continue to monitor the cerebral function to

ensure the cessation of seizure activity.

 

Other management

 

Catheterisation may be required to relieve distressing urinary

retention and to allow continuous monitoring of urine output as a

means of assessing cardiac output (Crome 1986).

Respiratory complications should be managed conventionally with early

respiratory support.

Control delirium with oral diazepam. Large doses may be required (20-

30 mg two-hourly in adults).

 

Monitoring

 

Monitor the cardiac rhythm, arterial blood gases, serum electrolytes,

blood pressure, respiratory rate and depth, and urinary output.

 

Observe for a minimum of 6 hours post-ingestion where:

  1. i) more than 1 mg/kg has been ingested by a child,
  2. ii) more than 300 mg has been ingested by an adult,

iii) the patient is symptomatic.

 

Antidotes

 

None available.

 

Elimination techniques

 

Due to the large volume of distribution and high lipid solubility of

amitriptyline, haemodialysis and haemoperfusion do not significantly

increase drug elimination (Lieberman et al. 1985).

 

Investigations

 

Following severe toxicity:

 

  1. i) a chest X-ray will be needed to exclude pulmonary complications,
  2. ii) measure serum creatine kinase and other skeletal muscle enzyme

activity (e.g. AST, ALT, and lactic dehydrogenase),

iii) assess renal function,

  1. iv) assess haematological status.

 

Management controversies

 

Gastric lavage is not recommended as the procedure may be associated

with significant morbidity, and there is no evidence that it is of any

greater benefit than activated charcoal used alone (Bosse et al.

1995).

If the procedure is used (i.e. in cases where activated charcoal

cannot be administered), a cuffed endotracheal tube should be used to

protect the airway if the patient is drowsy, and activated charcoal

left in the stomach following the lavage.

 

Repeat doses of oral activated charcoal may prevent the reabsorption

of tricyclic antidepressants and their metabolites secreted in gastric

juices and bile (Swartz & Sherman 1984). However, it would not be

expected from the large volume of distribution of amitriptyline that

clinically significant increases in body clearance would result.

 

Physostigmine salicylate is a short acting reversible cholinesterase

inhibitor which has been used historically in the management of

tricyclic overdoses to reverse coma and antimuscarinic effects.

Reports of serious complications from its use include severe

cholinergic activity, convulsions, bradycardia, and asystole (Newton

1975, Pentel & Peterson 1980). The use of physostigmine is no longer

recommended.

 

The use of dopamine in the management of hypotension has been

advocated, but the pressor effect of this indirect acting inotrope may

be diminished in tricyclic overdosed patients due to depleted levels

of noradrenaline (Buchman et al. 1990, Pimentel & Trommer 1994, Teba

et al. 1988).

 

The use of intravenous glucagon has been proposed in cases where

hypotension is unresponsive to volume expansion and sodium bicarbonate

administration, because of its positive inotropic effect and possible

antiarrhythmic property. Its place in therapy has not been established

(Senner et al. 1995).

 

Adult dose: 10 mg by IV bolus followed by an infusion of 10 mg

over 6 hours (unlicensed indication and dose).

 

There are a number of reports of severe arrhythmias or sudden death

occurring up to 1 week after tricyclic overdose, but a review of the

cases show that the patients had continuing toxicity, underlying

disease, or abnormalities (Stern et al. 1985). See case report 3.

 

Several predictors of clinical severity in tricyclic overdoses have

been suggested, including:

 

  1.   a maximal limb-lead QRS duration of 0.1 second or longer as a

predictor of the risk of seizure (Boehnert & Lovejoy 1985),

  1.   a maximal limb-lead QRS duration of 0.16 second or longer as a

predictor of the risk of ventricular arrhythmias (Boehnert & Lovejoy

1985),

  1.   plasma tricyclic levels greater than 0.8 mg/L (Caravati & Bossart

1991),

  1.   the ECG terminal 40-ms frontal plane QRS axis of more than 120°

(Wolfe et al. 1989).

  1.   plasma drug concentrations in excess of 2 mg/L as a predictor of

the development of lung injury (Roy et al. 1989).

 

Whilst none of these features in isolation are predictive of

life-threatening toxicity, they may be helpful in assessing patient

risk.

 

Case data

 

Case report 1

 

Massive ingestion of amitriptyline in an adult.

 

A 46 year old woman took an estimated 9 g of amitriptyline. One hour

later she suffered a grand mal seizure. Diazepam, phenobarbitone and

physostigmine were administered. Her blood pressure was 98/66 mm Hg,

and the pulse was 94 beats per minute. Arterial blood gas values

showed a pH of 7.16, PaCO2 of 31 mm Hg, and PaO2 of 373 mm Hg on 100

percent oxygen. The ECG revealed a widened QRS complex of 160 ms. She

had metabolic acidosis and an anion gap of 24. Dopamine and adrenaline

were given to maintain blood pressure. At this time the woman was

transferred to intensive care facilities as she failed to respond to

pressor therapy. She was comatose with no response to painful stimuli,

without spontaneous respiration, and corneal and oculocephalic

reflexes were absent. The serum amitriptyline level was 2.35 mg/L. Her

blood pressure remained low (75/50) despite an infusion of 30

 

micrograms/kg/min of dopamine, but rose to 130/70 when noradrenaline

was substituted for dopamine. Spontaneous respiration returned after

24 hours, and during the next 3 days corneal, pupillary, and

oculocephalic reflexes also returned. The patient regained full

consciousness five days after the ingestion (Yang & Dantzker 1991).

 

Case report 2

 

Ingestion of 1.15 g amitriptyline in a young child.

 

A 20-month-old girl reportedly ingested 23 tablets of amitriptyline 50

  1. She was cyanotic, comatose, and had continuous clonic-tonic

seizures. Her rectal temperature was 34.7°C, the heart rate was 115

beats/min, and her blood pressure was 59/27 mm Hg. The ECG tracing was

consistent with ventricular tachycardia. After extensive resuscitative

measures, including mechanical ventilation, the girl recovered and was

discharged home one week later (Beal & May 1989).

 

Case Report 3

 

Unexpected death 7 days after overdose in adult.

 

A 34 year old woman was admitted to hospital following an intentional

overdose of amitriptyline and diazepam. She was comatose, had a sinus

tachycardia, nonspecific ST and T wave changes, and was normotensive.

Her electrolyte levels were normal except for a potassium value of 3.3

mmmol/L. During 44 hours of monitoring no arrhythmias occurred and her

mental status returned to normal. On the second day her usual

hydrochlorothiazide diuretic therapy was restarted, the potassium

level being 4 mmmol/L at this time. Five days after admission her

potassium level was 3.2 mmmol/L. Seven days after recovery from

overdose the patient was found unresponsive and in refractory

ventricular fibrillation. Venous blood samples during unsuccessful

resuscitative efforts showed a potassium level of 2.6 mmmol/L.

Post-mortem plasma amitriptyline and nortriptyline levels were both

0.2 mg/L. An autopsy did not reveal an anatomic cause of death (Babb &

Dunlop 1985).

 

Analysis

 

Agent/toxin/metabolite

 

There is no clear relationship between plasma amitriptyline

concentration and clinical response or toxicity. Consequently the

measurement of plasma drug concentration following overdose is not

routinely advised, although it may have diagnostic value.

 

Sample container

 

Storage conditions

 

Transport

 

Interpretation of data

 

There is considerable variation in plasma concentrations of

amitriptyline and its metabolites between individuals.

As a guide, a therapeutic range for amitriptyline of 0.15-0.25 mg/L

has been proposed, whilst moderate to severe toxicity is associated

with combined amitriptyline and nortriptyline concentrations of 1 mg/L

or greater (Bramble et al. 1985, Preskorn & Mac 1985).

 

Conversion factors

 

1 mg/L = 3.186 micromoles/L

1 micromole/L = 0.314 mg/L

 

Other

 

The molecular weight of amitriptyline hydrochloride is 313.9

 

Other toxicological data

 

Carcinogenicity

 

Tumour-inducing effects have not been reported (Dollery 1991).

 

Reprotoxicity

 

Teratogenicity

 

There are occasional reports suggesting an association between

amitriptyline and congenital abnormalities (particularly limb

reductions), but analysis of over 500,000 births failed to confirm

such an association.

A surveillance study between 1985 and 1992 involving over 200,000

completed pregnancies exposed to amitriptyline (of which 467 were

during the first trimester) observed 25 major birth defects (20

expected in a control population). These data do not support an

association between amitriptyline and congenital defects (Briggs

1994).

 

Relevant animal data

 

There is evidence of amitriptyline-induced teratogenicity in some

animals. Encephaloceles and bent tails in hamsters, and skeletal

malformations in rats have been reported (Briggs 1994).

 

Relevant  in vitro data

 

Authors

 

HY Allen

ZM Everitt

AT Judd

 

National Poisons Information Service (Leeds Centre)

Leeds Poisons Information Centre

Leeds General Infirmary

Leeds

LS1 3EX

UK

 

This monograph was produced by the staff of the Leeds Centre of the

National Poisons Information Service in the United Kingdom. The work

was commissioned and funded by the UK Departments of Health, and was

designed as a source of detailed information for use by poisons

information centres.

 

Peer review was undertaken by the Directors of the UK National Poisons

Information Service.

 

Prepared September 1996

Updated May 1998

 

References

 

Babb SV, Dunlop SR.

Case report of sudden and unexpected death after tricyclic overdose

(letter). Am J Psychiatry 1985; 142: 275-276.

 

Bader TF, Newman K.

Amitriptyline in human breast milk and the nursing infant’s serum. Am

J Psychiatry 1980; 137: 855-856.

 

Baettig D, Bondolfi G, Montaldi S, Amey M, Baumann P.

Tricyclic antidepressant plasma levels after augmentation with

citalopram: a case study. Eur J Clin Pharmacol 1993; 44: 403-405.

 

Beal DW, May RB.

Accidental amitriptyline poisoning in a toddler (letter). S Med J

1989: 82: 1588-1589.

 

Bertilsson L, Mellstrom B, Sjoqvist F.

Pronounced inhibition of noradrenaline uptake by 10-hydroxy-

metabolites of nortriptyline. Life Sciences 1979; 25: 1285-1292.

 

BNF Joint Formulary Committee.

British National Formulary, Number 35.

London: British Medical Association & Royal Pharmaceutical Society of

Great Britain, 1998.

 

Boehnert MT, Lovejoy FH.

Value of the QRS duration versus the serum drug level in predicting

seizures and ventricular aahythmias after an acute overdose of

tricyclic antidepressants. N Eng J Med 1985; 313: 474-479.

 

Bosse GM, Barefoot JA, Pfeifer MP, Rodgers GC.

Comparison of three methods of gut decontamination in tricyclic

antidepressant overdose. J Emerg Med 1995; 13: 203-209.

 

Bramble MG, Lishman AH, Purdon J, Diffey BL, Hall RJC.

An analysis of plasma levels and 24-hour ECG recordings in tricyclic

antidepressant poisoning: implications for management. Quat J Med

1985; 56: 357-366.

 

Breyer-Pfaff U, Nill K, Entenmann A, Gaertner HJ.

Secretion of amitriptyline and metabolites into breast milk (letter).

Am J Psychiatry 1995; 152: 812-813.

 

Briggs GG, Freeman RK, Yaffe SJ.

Drugs in Pregnancy and Lactation. 4th ed.

Baltimore: Williams & Wilkins, 1994.

 

Buchman AL, Dauer J, Geiderman J.

The use of vasoactive agents in the treatment of refractory

hypotension seen in tricyclic antidepressant overdose. J Clin

Psychopharmacol 1990; 10: 409-413.

 

Callaham M.

Tricyclic antidepressant overdose. J Am Coll Emerg Phys 1979; 8:

413-425.

 

Caravati EM, Bossart PJ.

Demographic and electrocardiographic factors associated with severe

tricyclic antidepressant toxicity. Clin Toxicol 1991; 29: 31-43.

 

Crome P.

Poisoning due to tricyclic antidepressant overdosage: clinical

presentation and treatment. Med Toxicol 1986; 1: 261-285.

 

Crome P, Braithwaite RA.

Relationship between clinical features of tricyclic antidepressant

poisoning and plasma concentrations in children. Arch Dis Child 1978;

53: 902-905.

 

Dawling S, Lynn K, Rosser R, Braithwaite R.

Nortriptyline metabolism in chronic renal failure: metabolite

elimination. Clin Pharmacol Ther 1982; 32: 322-329.

 

Dollery C (Ed).

Therapeutic Drugs Volume 1.

Edinburgh: Churchill Livingstone, 1991.

 

Dziukas LJ, Vohra J.

Tricyclic antidepressant poisoning. Med J Aust 1991; 154: 344-350.

 

Gard H, Knapp D, Hanenson I, Walle T, Gaffney T.

Studies on the disposition of amitriptyline and other tricyclic

antidepressant drugs in man as it relates to the management of the

overdosed patient. Adv Biochem Psychopharmacol 1973; 7: 95-105.

 

Goel KM, Shanks RA.

Amitriptyline and imipramine poisoning in children. Br Med J 1974; 1:

261-263.

 

Guy’s, Lewisham & St. Thomas’ Hospitals Paediatric Formulary, 4th

Edition. London: Guy’s & St. Thomas’ Hospital Trust, 1997.

 

Hrdina PD, Lapierre YD, Koranyi EK.

Altered amitriptyline kinetics in a depressed patient with porto-caval

anastomosis. Can J Psychiatry 1985; 30: 111-113.

 

Hulten BA, Heath A, Knudsen K, Nyberg G, Svensson C, Martensson E.

Amitriptyline and amitriptyline metabolites in blood and cerebrospinal

fluid following human overdose. Clin Toxicol 1992; 30: 181-201.

 

James LP, Kearns GL.

Cyclic antidepressant toxicity in children and adolescents. J Clin

Pharmacol 1995; 35: 343-350.

 

Lieberman JA, Cooper TB, Suckow RF, Steinberg H, Borenstein M, Brenner

R, Kane JM.

Tricyclic antidepressant and metabolite levels in chronic renal

failure. Clin Pharmacol Ther 1985; 37: 301-307.

 

Martindale, The Extra Pharmacopeia. 31st ed.

Ed Reynolds, JEF. London: The Royal Pharmaceutical Society, 1996.

 

Montgomery SA, Baldwin D, Green M.

Why do amitriptyline and dothiepin appear to be so dangerous in

overdose? Acta Psychiatr Scand 1989; 80 (354, suppl): 47-54.

 

Mordel A, Winkler E, Almog S, Tirosh M, Ezra D.

Seizures after flumazenil administration in a case of combined

benzodiazepine and tricyclic antidepressant overdose. Crit Care Med

1992; 20: 1733-1734.

 

Newton RW.

Physostigmine salicylate in the treatment of tricyclic antidepressant

overdosage. J Am Med Assoc 1975; 231: 941-943.

 

Nyberg G, Martensson E.

Determination of free fractions of tricyclic antidepressants. Arch

Pharmacol 1984; 327: 260-265.

 

Orr DA, Bramble MG.

Tricyclic antidepressant poisoning and prolonged external cardiac

massage during asystole. Br Med J 1981; 283: 1107-1108.

 

Pentel P, Peterson CD.

Asystole complicating physostigmine treatment of tricyclic

anitdepressant overdose. Ann Emerg Med 1980; 9: 588-590.

 

Pimentel L, Trommer L.

Cyclic antidepressant overdoses: a review. Emerg Med Clin N Am 1994;

12: 533-547.

 

Preskon SH, Mac DS.

Plasma levels of amitriptyline: effect of age and sex. J Clin

Psychiatry 1985; 46: 276-277.

 

Richelson E.

The pharmacology of antidepressants at the synapse: focus on newer

compounds. J Clin Psychiatry 1994; 55(9, suppl A): 34-39.

 

Roy TM, Ossorio MA, Cipolla LM, Fields CL, Snider HL, Anderson WH.

Pulmonary complications after tricyclic antidepressant overdose. Chest

1989; 96: 852-856.

 

Schmider J, Deuschle M, Schweiger U, Korner A, Gotthardt U, Heuser IJ.

Amitriptyline metabolism in elderly depressed patients and normal

controls in relation to hypothalamic-pituitary-adrenal system

function. J Clin Psychopharmacol 1995; 15: 250-258.

 

Schulz P, Dick P, Blaschke TF, Hollister L.

Discrepancies between pharmacokinetic studies of amitriptyline. Clin

Pharmacokinet 1985; 10: 257-268.

 

Sener EK, Gabe S. Henry JA.

Response to glucagon in imipramine overdose. Clin Toxicol 1995; 33:

51-53.

 

Shoaf SE, Linnoila M.

Interaction of ethanol and smoking on the pharmacokinetics and

pharmacodynamics of psyhotropic medications. Psychopharmacol Bull

1991; 27: 577-594.

 

Spiker DG, Biggs JT.

Tricyclic antidepressants: prolonged plasma levels after overdose. J

Am Med Assoc 1976; 236: 1711-1712.

 

Stern TA, O’Gara PT, Mulley AG, Singer DE, Thibault GE.

Complications after overdose with tricyclic antidepressants. Crit Care

Med 1985; 13: 672-674.

 

Stockley IH.

Drug Interactions. 4th ed.

London: The Pharmaceutical Press, 1996.

 

Swartz CM, Sherman A.

The treatment of tricyclic antidepressant overdose with repeated

charcoal. J Clin Psychopharmacol 1984; 4: 336-340.

 

Taboulet P, Michard F, Muszynski J, Galliot-Guilley M, Bismuth C.

Cardiovascular repercussions of seizures during cyclic antidepressant

poisoning. Clin Toxicol 1995; 33: 205-211.

 

Taylor D.

Selective serotonin reuptake inhibitors and tricyclic antidepressants

in combination: interactions and therapeutic uses. Br J Psychiatry

1995; 167: 575-580.

 

Teba L, Schiebel F, Dedhia HV, Lazzell VA.

Beneficial effect of norepinephrine in the treatment of circulatory

shock caused by tricyclic antidepressant overdose. Am J Emerg Med

1988: 6: 566-568.

 

Varnell RM, Godwin JD, Richardson ML, Vincent JM.

Adult respiratory distress syndrome from overdose of tricyclic

antidepressants. Radiology 1989; 170: 667-670.

 

White A.

Overdose of tricyclic antidepressants associated with absent

brain-stem reflexes. Can Med Assoc J 1988; 139: 133-134.

 

White K, Simpson G.

The combined use of MAOI’s and tricyclics. J Clin Psychiatry 1984; 45:

67-69.

 

Wolfe TR, Caravati EM, Rollins DE.

Terminal 40-ms frontal plane QRS axis as a marker for tricyclic

antidepressant overdose. Ann Emerg Med 1989; 18: 348-351.

 

Yang KL, Dantzker DR.

Reversible brain death: a manifestation of amitriptyline overdose.

Chest 1991; 99: 1037-1038.

 

 

————–

 

INTOX Home Page

Moclobemide

  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 ANALYSIS AND BIOMEDICAL INVESTIGATIONS

8.1 Material sampling plan

8.1.1 Sampling and specimen collection

8.1.1.1 Toxicological analysis

8.1.1.2 Biomedical analysis

8.1.1.3 Arterial blood gas analysis

8.1.1.4 Haematological analysis

8.1.1.5 Other (unspecified) analysis

8.1.2 Storage of laboratory samples and specimens

8.1.2.1 Toxicological analysis

8.1.2.2 Biomedical analysis

8.1.2.3 Arterial blood gas analysis

8.1.2.4 Haematological analysis

8.1.2.5 Other (unspecified) analysis

8.1.3 Transport of laboratory samples and specimens

8.1.3.1 Toxicological analysis

8.1.3.2 Biomedical analysis

8.1.3.3 Arterial blood gas analysis

8.1.3.4 Haematological analysis

8.1.3.5 Other (unspecified) analysis

8.2 Toxicological analysis 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 Test 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

8.2.2.4 Advanced quantitative method(s)

8.2.2.5 Other dedicated method(s)

8.2.3 Interpretation of toxicological analysis

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 analysis

8.3.3 Haematological analysis

8.3.4 Interpretation of biomedical investigations

8.4 Other biomedical (diagnostic) investigations and their interpretation

8.5 Overall interpretation of all toxicological analysis 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

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

 

MOCLOBEMIDE

 

International Programme on Chemical Safety

Poisons Information Monograph 151

Pharmaceutical

 

  1. NAME

 

1.1  Substance

 

Moclobemide

 

1.2  Group

 

Psycholeptics (N06)/ Antidepressants (N06A)/

Non-hydrazide MAO inhibitors (N06A G02)

 

1.3  Synonyms

 

RO 11-1163

 

1.4  Identification numbers

 

1.4.1  CAS number

 

71320-77-9

 

1.4.2  Other numbers

 

No data available.

 

1.5  Main brand names, main trade names

 

Aurorix (Australia, Austria, Belgium, Germany,

Netherlands, Norway, South Africa, Sweden, Switzerland);

Manerix (Canada, Spain, UK);

Moclamine (France);

 

1.6  Main manufacturers, main importers

 

Roche

 

  1. SUMMARY

 

2.1  Main risks and target organs

 

Moclobemide is a short-acting, selective and reversible

monoamine oxidase type A inhibitor (RIMA).

It is generally well tolerated in overdose when taken

alone.

 

The serotonergic effects of moclobemide may be enhanced by

combination with tricyclic antidepressants, other monoamine

oxidase inhibitors, selective serotonin reuptake inhibitors

(SSRIs), lithium or serotonergic substances. A life-

threatening serotonin syndrome consisting of hyperthermia,

tremor and convulsions can develop when moclobemide is

ingested with these drugs.

The concomitant consumption of large amounts of tyramine-rich

foodstuff may result in a moderate increase of systolic blood

pressure (cheese reaction).

 

2.2  Summary of clinical effects

 

Agitation, drowsiness, disorientation, slow-reacting

pupils, myoclonic jerks in upper extremities; hypo or

hypertension, tachycardia; nausea, vomiting, abdominal

pain.

 

2.3  Diagnosis

 

Diagnosis of moclobemide poisoning is clinical and based

on history of overdose and/or access to moclobemide and the

presence of gastroenterological symptoms and minor

neurological symptoms.

Co-ingestion of tricyclic antidepressants and/or selective

serotonin reuptake inhibitors should be suspected and the

diagnosis of the serotonin syndrome should be considered in

the presence of three or more of the following symptoms:

behavioural change (confusion or hypomania), agitation,

myoclonus, ocular clonus, hyperreflexia, sweating, shivering,

tremor, diarrhoea, motor incoordination, muscle rigidity,

fever. The differential diagnoses include neuroleptic

malignant syndrome, acute poisoning with strychnine, acute

sepsis, or severe metabolic disturbances.

 

2.4  First aid measures and management principles

 

Due to the potential for delayed toxicity, any patient

with a history of acute moclobemide overdose, should be

admitted for observation and remain for 24 hours, even in the

absence of initial symptoms.

Management of moclobemide overdose as a single agent consists

primarily of observation and basic supportive care until

symptoms resolve.

Treatment of the serotonin syndrome may require aggressive

supportive care including diazepam, mechanical ventilation,

external cooling and if necessary, curarization. Although

several deaths have been reported, the symptoms of the

serotonin syndrome usually resolve over 1 to 2 days with

supportive care.

 

  1. PHYSICO-CHEMICAL PROPERTIES

 

3.1  Origin of the substance

 

Obtained by synthesis.

 

3.2  Chemical structure

 

Structural name: 4-Chloro-N (2-morpholinoéthyl)benzamide

 

Molecular formula: C13H17O2N2Cl

 

Molecular weight: 268.7

 

3.3  Physical properties

 

3.3.1  Colour

 

Whiteredish

 

3.3.2  State/Form

 

Solid-crystals

 

3.3.3  Description

 

Weak odour

Solubility (g/100 mL) at 25 °C:

Chloroform: 33.6

Methanol: 11.8

Water: 0.4

Artificial gastric fluid (pH 1.2): 2.6 at 37 °C

Artificial intestinal fluid (pH 6.8): 0.3 at 37 °C

pKa 6.2

Melting point: 138 °C

(Roche lab., 1996)

 

3.4  Other characteristics

 

3.4.1  Shelf-life of the substance

 

3 years at 20 °C

 

3.4.2  Storage conditions

 

Keep at 20 °C in polyethylene bottles or foil

packs.

 

  1. USES

 

4.1  Indications

 

4.1.1  Indications

 

Psychoanaleptic Antidepressant Monoamine oxidase inhibitor;

non-selective;

antidepressant

 

4.1.2  Description

 

Accepted:

Major mental depression

Dysthymia.

Investigational:

Menopausal flushing (Menkes et al., 1994)

Prophylactic treatment of migraine (Meienberg &

Amsler, 1996)

Smoking cessation and abstinence in heavy dependent

smokers (Berlin et al., 1995).

 

4.2  Therapeutic dosage

 

4.2.1  Adults

 

Usual initial dosage is a total daily dose of

300 mg by mouth after food in 2 or 3 doses. This may

be increased to up to 600 mg daily according to

response (Reynolds, 1996).

Dosage should be reduced by one third or half the

normal dosage in patients with significant hepatic

impairment (Roche lab., 1996).

 

4.2.2  Children

 

No data available

 

4.3  Contraindications

 

Absolute:

Hypersensitivity to moclobemide.

Children less than 15 years old.

Breast feeding (in the absence of available data on potential

toxic effects to suckling infants): less than 3 % of the

administered dose of moclobemide is excreted in breast

milk.

Co-administration of sumatriptan: hypertensive crises, severe

coronary vasoconstriction may occur.

Co-administration of pethidine (meperidine),

dextromethorphan: the serotonin syndrome may occur.

(Roche lab., 1996)

 

 

Moclobemide is contra-indicated in patients with acute

confusional states and in those with phaeochromocytoma.

It should be avoided in excited or agitated patients and in

those with severe hepatic impairment.

(Reynolds, 1996)

Relative:

Co-administration of drugs which increase the levels of

monoamines such as serotonin and noradrenaline: tricyclic

antidepressants, selective serotonin re-uptake inhibitor

antidepressants: a serotonin syndrome may occur.

Alcohol (as for other psychoactive drugs).

Pregnancy (no data available)

(Roche lab., 1996).

 

  1. ROUTES OF EXPOSURE

 

5.1  Oral

 

Moclobemide is available as tablets, thus ingestion is

the most common route of exposure.

 

5.2  Inhalation

 

Not relevant

 

5.3  Dermal

 

Not relevant

 

5.4  Eye

 

Not relevant

 

5.5  Parenteral

 

No data available

 

5.6  Other

 

No data available.

 

  1. KINETICS

 

6.1  Absorption by route of exposure

 

Readily absorbed from the gastro-intestinal tract.

Food delays absorption (Fulton and Benfield, 1996).

Peak plasma concentration: 1 to 2 hours after ingestion.

Oral bioavailability was reported as 60 % after a single dose

and 80 % after repeated doses, due to an important and

saturable hepatic first-pass effect (Roche lab., 1996).

 

6.2  Distribution by route of exposure

 

Widely distributed throughout the body. Plasma protein

binding is 50 %.

After oral administration of 50 mg to 6 healthy subjects, the

mean volume of distribution was about 1 L/kg (Raaflaub et

al., 1984).

The therapeutic levels range from 0.5 to 1.5 mg/L (Iwersen &

Schmoldt, 1996).

Less than 3 % of the administered dose is excreted in breast

milk (Mayersohn & Guentert, 1995).

 

6.3  Biological half-life by route of exposure

 

After single oral doses, plasma half-life is 1 to 2

hours; with long term treatment, the half-life is reported to

increase to 2 to 4 hours (Iwersen & Schmoldt, 1996; Roche

lab., 1996).

 

6.4  Metabolism

 

Moclobemide undergoes extensive metabolism, mainly

carbon and nitrogen oxidation in the liver, deamination and

aromatic hydroxylation. Metabolites are inactive (Mayersohn &

Guentert, 1995).

 

6.5  Elimination and excretion

 

Systemic plasma clearance: 310 to 750 mL/min.

Renal clearance: 1 to 5 mL/min

Metabolites of moclobemide and a small amount of unchanged

drug (less than 1 %) are excreted in the urine; after an oral

dose of 50 mg radio-labelled moclobemide, 92 % of the dose

was excreted in the urine within 12 hours (Roche lab.,

1996).

 

  1. PHARMACOLOGY AND TOXICOLOGY

 

7.1  Mode of action

 

7.1.1  Toxicodynamics

 

Moclobemide selectively and reversibly inhibits

the activity of the intracellular enzyme monoamine

oxidase A (MAO-A), thus preventing the normal

metabolism of biogenic amines (noradrenaline,

adrenaline, serotonin, dopamine).

Mono amine oxidase inhibitors (MAOIs) exert their

toxic effects by inhibiting the metabolism of

sympathomimetic amines and serotonin, and by

decreasing noradrenaline stores in post-ganglionic

sympathetic neurons. They do not inhibit MAO

synthesis. MAOIs also inhibit enzymes other than MAO,

 

including dopamine-beta-oxidase, diamine-oxidase,

amino-acid decarboxylase and choline dehydrogenase.

Inhibition of these enzymes occurs only with very high

doses of MAOIs and may be responsible for some of the

toxic effects of MAOIs.

Drugs that enhance serotonin release or reuptake

(tricyclic antidepressants, selective serotonin

reuptake inhibitors) may cause the serotonin syndrome

when they are administered concurrently with the

MAOIs, even at therapeutic doses (Sternbach, 1991;

Livingston & Livingston, 1996).

A toxic reaction to MAOIs may be caused by pressor

amines such as tyramine, resulting in hypertensive

crisis. When the protective role of intestinal and

hepatic MAO is eliminated, increased absorption of

tyramine from certain foods occurs and can cause a

significant increase in blood pressure (“cheese

reaction”) through the release of noradrenaline from

pre-synaptic vesicles (Mayersohn & Guentert,

1995).

Two isoforms of the MAO enzyme have been discovered:

MAO-A and MAO-B. These isoforms differ in anatomical

distribution and preferred substrates. The new MAOIs

such as moclobemide are isoform-selective and

reversibly inhibit MAO-A. Thus having a lower

potential for interactions than non selective MAOIs at

therapeutic doses. Selectivity is lost in overdoses

and in extreme situations such as high-dose

combination therapies and mixed drug overdoses, and

severe toxic reactions may occur (Mayersohn &

Guentert, 1995).

 

7.1.2  Pharmacodynamics

 

The MAOs are a group of enzymes that

metabolise, and therefore inactivate endogenous

pressor amines (such as noradrenaline, adrenaline,

dopamine, serotonin) as well as ingested indogenous

amines (such as tyramine). MAOIs inhibit the

degradation of these amines by MAO. The increased

availability of biogenic amines (such as noradrenaline

and serotonin) is thought to be linked with the

improvement in depression accounted for by MAIO

treatment (Livingston & Livingston, 1996).

Two isoforms of the MAO enzyme have been discovered:

MAO-A and MAO-B, which differ in anatomical

distribution and preferred substrates. The MAO type A

enzymes preferentially metabolize serotonin and

noradrenaline and are located primarily in the

placenta, gut and liver. The MAO type B enzymes are

predominant in brain, liver and platelets, and

phenylethylamine, methylhistamine and tryptamine are

their primary substrates. Both MAO-A and MAO-B

 

metabolize tyramine (Mayersohn & Guentert, 1995).

New MAOIs such as moclobemide, which are isoform-

selective and have reversible inhibition of the enzyme

are called Reversible Inhibitors of MAO-A (RIMA). The

duration of MAO-A inhibition by moclobemide is shorter

(16 to 24 hours) than the inhibition induced by

conventional MAOIs (> 10 days) (Roche lab.,

1996).

The interaction of the newer RIMAs with hepatic

cytochrome P450 appears to be much weaker than with

the irreversible and nonspecific MAOIs. However,

several studies in humans have suggested there is some

involvement of cytochtome P450 in the metabolism of

moclobemide, and also a weak inhibitory effect of

moclobemide for its isoenzyme CYP2D6. The clinical

relevance of this weak interaction is not clear and is

probably of little consequence (Mayersohn & Guentert,

1995).

Like tricyclic antidepressants, SSRIs and other MAOIs,

moclobemide significantly reduces REM (rapid eye

movement) sleep density, REM time and the REM

percentage of total sleep time in patients with major

depression (Roche lab., 1996).

 

7.2  Toxicity

 

7.2.1  Human data

 

7.2.1.1  Adults

 

Myrenfors et al. (1993) reported a

case series of 8 pure moclobemide overdoses.

Patients ingesting up to 2 grams showed no

symptoms or mild gastro-intestinal

disturbances.

Ingestions of 3 to 4 grams were associated

with a slight increase in blood pressure, and

decrease in consciousness.

Fatigue, agitation, tachycardia, increased

blood pressure, and minimally reactive

mydriasis occurred with the ingestion of

moclobemide doses of 7 to 8 grams.

The ingestion of moclobemide with other drugs

produced a more varied and severe clinical

picture, even with moderate doses of

moclobemide.

 

7.2.1.2  Children

 

No data available

 

7.2.2  Relevant animal data

 

In mice: LD 50 (oral): 1141 mg/kg

LD 50 (intraperitoneal): 527 mg/kg

Symptomatology: sedation, muscle twitching,

respiratory depression, death.

 

In rats: LD 50 (oral): 4138 mg/kg

LD 50 (intraperitoneal): 678 mg/kg

Symptomatology: sedation, respiratory depression,

death.

 

In rabbits: LD 50 (oral): 800 mg/kg

Symptomatology: ataxia, decrease in motor activity,

respiratory depression, tremor, seizures, salivation,

death.

(Roche lab., 1996).

 

7.2.3  Relevant in vitro data

 

No data available.

 

7.3  Carcinogenicity

 

Animal studies: moclobemide was not carcinogenic in

rats at doses ranging from 9 to 225 mg/kg/day orally for 2

years. In mice given 10, 50 or 100 mg/kg/day orally over 80

weeks, no carcinogenic effect was observed (Roche lab.,

1996).

 

7.4  Teratogenicity

 

Animal studies:

– doses up to 100 mg/kg/day did not affect fertility in

rats.

– in rabbits and rats oral doses of up to 100 and 200

mg/kg/day respectively did not have embryotoxic or

teratogenic effects

(Roche lab., 1996).

 

7.5  Mutagenicity

 

In vitro and in vivo: moclobemide did not show

mutagenicity (Roche lab., 1996).

 

7.6  Interactions

 

Drug-food interactions:

the dietary restrictions that need to be followed with

irreversible MAOIs are less stringent with selective

reversible inhibitors of monoamine oxidase type A such as

moclobemide. However, the manufacturer of moclobemide

recommends that since some patients may be more sensitive to

tyramine, the consumption of large amounts of tyramine-rich

 

foodstuffs should still be avoided; these foods include

chocolate, aged cheeses, beer, chianti, vermouth, pickled

fish and concentrated yeast extracts (Reynolds, 1996; Roche

lab., 1996).

 

Drug-drug interactions:

Sympathomimetics and anorectic drugs should not be taken with

moclobemide.

Opioid analgesics: Central Nervous System (CNS) excitation or

depression may occur.

Drugs used in anaesthesia: anaesthesia may be performed 24

hours after discontinuation of moclobemide with little

potential for significant interaction (Blom-Peters & Lamy,

1993; Mac Farlane, 1994); when the washout period is not

feasible, the use of pethidine and parenteral

sympathomimetics should be avoided (Roche lab., 1996).

Levodopa: a hypertensive crisis may be precipitated.

Sumatriptan: the manufacturer recommends to not prescribe

moclobemide concominantiantly with sumatriptan which is a

selective agonist at serotonin type 1D receptors, because of

possible hypertensive crises and severe coronary

vasoconstriction, and advises a washout period of 24 hours

after discontinuation of moclobemide; however a clinical

study performed by Blier & Bergeron (1995) involving 103

episodes of migraine, did not show evidence of significant

adverse effects.

The metabolism of moclobemide is inhibited by cimetidine,

leading to a prolonged half-life and increased plasma

concentrations (Livingston & Livingston, 1996); the

manufacturer recommends that the dose of moclobemide be

reduced to half strength in patients who are also given

cimetidine.

The co-administration of drugs that increase the levels of

monoamines such as serotonin and noradrenaline, including

tricyclic antidepressants (mainly clomipramine), selective

serotonin re-uptake inhibitor antidepressants, and

potentially other antidepressants may cause a serotonin

syndrome (Spigset et al., 1993; Kuisma, 1995; Liebenberg et

al., 1996).

Lithium: according to Livingston & Livingston (1996), care

should be taken when co-prescribing RIMAs with lithium, since

it increases serotonin levels, although no interactions have

been reported to date.

Therapy with moclobemide should not be started until at least

7 days following the discontinuation of tricyclic or

serotonin reuptake inhibitor antidepressant treatment (2

weeks in the case of paroxetine; 5 weeks in the case of

fluoxetine) or for at least a week after stopping treatment

with other monoamine oxidase inhibitors (Reynolds, 1996).

Conversely, a washout period of 24 hours is advised when

switching from moclobemide to other antidepressants (Lane &

Fischler, 1995).

 

 

Antipsychotics, benzodiazepines, nifedipine and

hydrochlorothiazide may be coprescribed without major

interaction (Livingston & Livingston, 1996).

 

7.7  Main adverse effects

 

They include sleep disturbances, dizziness, nausea, and

headache.

Confusional states, restlessness or agitation may occur.

Mild elevations in liver enzyme values have been

reported.

Care is required in patients with thyrotoxicosis as

moclobemide may theoretically precipitate a hypertensive

reaction.

Mental alertness may be impaired, patients under treatment

should not drive or operate machinery (Reynolds, 1996).

Manic episodes may be provoked in patients with bipolar

disorders, moclobemide should be discontinued and

antipsychotic therapy should be initiated (Reynolds, 1996;

Roche lab., 1996).

Less common adverse effects include:

– hypertension, although the role of concomitant

administration of clomipramine, buspirone, thyroxine in the

case series reported by Coulter & Pillans (1995) may have

contributed and cannot be disregarded,

– alopecia (Sullivan & Mahmood, 1997),

– a case of fatal intrahepatic cholestasis was described

(Timmings & Lamont, 1996) in a 85 year-old woman after she

was switched from fluoxetine to moclobemide without a washout

period. The role of moclobemide in causing this adverse

reaction is questionable and it is more likely that the

hepatotoxic effect was associated with co-administration of

both drugs,

– a case of sexual hyperarousal in a female patient was

reported by Lauerma (1995),

– a toxic shock like-syndrome was described by O’Kane &

Gottlieb (1996).

 

  1. TOXICOLOGICAL ANALYSIS AND BIOMEDICAL INVESTIGATIONS

 

8.1  Material sampling plan

 

8.1.1  Sampling and specimen collection

 

8.1.1.1  Toxicological analysis

 

8.1.1.2  Biomedical analysis

 

8.1.1.3  Arterial blood gas analysis

 

8.1.1.4  Haematological analysis

 

8.1.1.5  Other (unspecified) analysis

 

8.1.2  Storage of laboratory samples and specimens

 

8.1.2.1  Toxicological analysis

 

8.1.2.2  Biomedical analysis

 

8.1.2.3  Arterial blood gas analysis

 

8.1.2.4  Haematological analysis

 

8.1.2.5  Other (unspecified) analysis

 

8.1.3  Transport of laboratory samples and specimens

 

8.1.3.1  Toxicological analysis

 

8.1.3.2  Biomedical analysis

 

8.1.3.3  Arterial blood gas analysis

 

8.1.3.4  Haematological analysis

 

8.1.3.5  Other (unspecified) analysis

 

8.2  Toxicological analysis 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  Test 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

 

8.2.2.4  Advanced quantitative method(s)

 

8.2.2.5  Other dedicated method(s)

 

8.2.3  Interpretation of toxicological analysis

 

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 analysis

 

8.3.3  Haematological analysis

 

8.3.4  Interpretation of biomedical investigations

 

8.4  Other biomedical (diagnostic) investigations and their

interpretation

 

8.5  Overall interpretation of all toxicological analysis and

toxicological investigations

 

8.6  References

 

  1. CLINICAL EFFECTS

 

9.1  Acute poisoning

 

9.1.1  Ingestion

 

Patients may display minimal or no symptoms

following pure moclobemide overdose. However, the

ingestion of moclobemide may cause nausea, vomiting,

gastric pain; agitation, disorientation, drowsiness,

impaired reflexes, myoclonic jerks in upper

extremities, slow-reacting pupils; slight rise in

blood pressure or moderate hypotension and tachycardia

(Myrenfors et al., 1993; Iwersen & Schmoldt,

1996).

Co-ingestion of tricyclic antidepressants (primarily

clomipramine), opioids, or SSRIs can result in more

varied and severe symptoms appearing within 2 to 3

hours after ingestion, even with lower doses of

moclobemide. Symptoms include: both CNS depression

(confusion, drowsiness) and excitation (seizure),

tremor, mydriasis, hyperthermia with muscle rigidity,

hypertension and metabolic acidosis (Myrenfors et al.,

1993). Several fatal cases have been reported after a

combination of moclobemide with citalopram,

clomipramine and fluoxetine (Power et al., 1995;

Hernandez et al., 1995) and moclobemide with

citalopram and fluoxetine (Neuvonen et al.,

1993).

 

9.1.2  Inhalation

 

Not relevant

 

9.1.3  Skin exposure

 

No data available

 

9.1.4  Eye contact

 

Not relevant

 

9.1.5  Parenteral exposure

 

No data available

 

9.1.6  Other

 

No data available

 

9.2  Chronic poisoning

 

9.2.1  Ingestion

 

No data available

 

9.2.2  Inhalation

 

Not relevant

 

9.2.3  Skin exposure

 

No data available

 

9.2.4  Eye contact

 

Not relevant

 

9.2.5  Parenteral exposure

 

No data available

 

9.2.6  Other

 

No data available

 

9.3  Course, prognosis, cause of death

 

Pure moclobemide overdoses usually have a fairly benign

course.

Several fatalities are reported in the literature, all

involving a co-ingestion (Neuvonen et al., 1993; Power et

al., 1995; Hernandez et al., 1995). The clinical course

consisted of euphoria, agitation, then extreme tremor,

 

followed by convulsions and hyperthermia. Death occured

within 3 to 16 hours after ingestion, after intractable

seizure and/or hyperthermia and its subsequent complications:

disseminated intravascular coagulation and multiple organ

failure.

 

9.4  Systematic description of clinical effects

 

9.4.1  Cardiovascular

 

Mild to moderate hypertension (Myrenfors et

al., 1993)

Moderate hypotension (Heinze & Sanchez, 1986)

Sinus tachycardia (Myrenfors et al., 1993)

 

9.4.2  Respiratory

 

No data available.

 

9.4.3  Neurological

 

9.4.3.1  Central nervous system

 

Mild disorientation, agitation,

slurred speech, anxiety, dizziness; headache;

drowsiness, coma.

 

9.4.3.2  Peripheral nervous system

 

No data available.

 

9.4.3.3  Autonomic nervous system

 

Slow-reacting pupils, mydriasis

(Myrenfors et al., 1993).

 

9.4.3.4  Skeletal and smooth muscle

 

Myoclonic jerks in upper

extremities; muscle rigidity;

rhabdomyolysis.

 

9.4.4  Gastrointestinal

 

Dry mouth; nausea, vomiting, gastric pain; diarrhoea.

 

9.4.5  Hepatic

 

Mild increases in liver enzymes values.

 

9.4.6  Urinary

 

9.4.6.1  Renal

 

No data available.

 

9.4.6.2  Other

 

No data available.

 

9.4.7  Endocrine and reproductive systems

 

No data available.

 

9.4.8  Dermatological

 

Sweating

 

9.4.9  Eye, ear, nose, throat: local effects

 

9.4.10 Haematological

 

DIC has occurred in a fatal case.

 

9.4.11 Immunological

 

No data available.

 

9.4.12 Metabolic

 

9.4.12.1 Acid-base disturbances

 

Acidosis is expected in association

with coma and/or convulsions.

 

9.4.12.2 Fluid and electrolyte disturbances

 

Hyperkalemia

 

9.4.12.3 Others

 

Creatine phosphokinase may be

elevated in patients with muscular

hyperactivity or rigidity.

 

9.4.13 Allergic reactions

 

No data available.

 

9.4.14 Other clinical effects

 

No data available.

 

9.4.15 Special risks

 

No data available.

 

9.5  Other

 

Abuse potential does exist with MAOIs. Although there

are currently no reported cases of dependence on the RIMAs,

it is wise to be cautious when prescribing these drugs for

individuals who have a substance misuse problem, including

alcohol dependence, or for personality-disordered patients

with poor impulse control (Livingston & Livingston,

1996).

 

9.6  Summary

 

  1. MANAGEMENT

 

10.1  General principles

 

The primary management of isolated moclobemide overdose

consists of the institution of careful observation of vital

signs and neurological status and supportive care until signs

and symptoms resolve. Intravenous access should be

established as soon as practical.

In more severe intoxications or where there are other

substances ingested, more aggressive measures such as

establishment of an airway, ventilation, administration of

intravenous fluids, control of seizures, and control of

hyperthermia may be necessary.

 

10.2 Life supportive procedures and symptomatic/specific treatment

 

In pure moclobemide overdose, intensive supportive care

is rarely required. In severe cases or when a serotonin

syndrome occurs, measures that may be required include:

endotracheal intubation and assisted ventilation if coma is

present, intravenous fluid resuscitation if hypotension is

present, pharmacological control of seizures, and cooling if

hyperthermia is present.

 

10.3 Decontamination

 

For doses of up to 2000 mg, gastrointestinal

decontamination by administration of a single oral dose of

activated charcoal should be considered. Gastric lavage

followed by activated charcoal should be advocated in

patients who have ingested higher doses and/or when there has

been a co-ingestion.

 

10.4 Enhanced elimination

 

There are no effective methods known to enhance the

elimination of moclobemide.

 

10.5 Antidote treatment

 

10.5.1 Adults

 

No data

 

10.5.2 Children

 

No data

 

10.6 Management discussion

 

Although dantrolene has been used successfully by

Myrenfors et al. (1993), its role in the management of the

serotonin syndrome has yet to be defined.

 

  1. ILLUSTRATIVE CASES

 

11.1 Case reports from literature

 

Iwersen & Schmoldt (1996) described a 46-year-old

female who ingested 3000 mg of moclobemide. Gastric lavage

was performed and activated charcoal was administered two

hours after ingestion. The patient was fully orientated. Her

temperature was 37 °C, blood pressure remained within a range

of 110/70 to 143/81 mmHg during 24 hours following admission,

and heart rate remained stable between 58 and 74 bpm. No

abnormalities were observed during the period of continuous

ECG monitoring. After 24 hours the patient was discharged. On

admission, the plasma moclobemide was 60.9 mg/L, 12 hours

later the concentration was 4.6 mg/L.

 

Myrenfors et al. (1993) described a 24-year-old woman who

ingested a combination of moclobemide (5000 mg) with

clomipramine (625 mg), nitrazepam (20 mg) and one bottle of

wine. Two hours later she was admitted to the emergency

department with mild disorientation, nausea and drowsiness.

Blood pressure was 90/60 mmHg, heart rate 145 bpm, and

respiratory rate 21/minute. ECG showed sinus tachycardia. The

stomach was emptied and activated charcoal was administered.

15 minutes later she developed convulsions. She was intubated

and mechanically ventilated and a continuous infusion of

thiopentone (2 mg/kg) was given. The temperature was 38.7 °C

and mild metabolic acidosis was present. Three hours later

the patient’s temperature rose to 41.9 °C and dantrolene

sodium was given at a dose of 1 mg/kg body weight. Because of

persisting fever and muscle rigidity, another dose was given

2.5 hours later. Within 4.5 hours the temperature had

declined to 37.9 °C and the muscle rigidity was less

pronounced. The patient was extubated 48 hours after

admission, fully alert but complaining of muscular stiffness

and pain, mainly in her legs. A third dose of dantrolene

sodium was given. After developing pneumonia, the patient

 

recovered uneventfully and was discharged on the 10th day.

The muscle pain and stiffness were still present 1 month

after the intoxication. Biological disturbances included:

increased serum CPK, transient myoglobinuria and increased

liver enzymes.

 

Neuvonen et al. (1993) reported several fatalities after

moclobemide-clomipramine overdoses. Two patients (male 23-

year-old, female 19-year-old) ingested 1000 to 1500 mg of

moclobemide and 225 to 500 mg of clomipramine in order to get

“high”. 2 to 3 hours later they were euphoric, but within the

next 2 hours both had severe tremors, followed by convulsions

and loss of consciousness. One patient also exhibited

hyperthermia.  Both died 9 to 10 hours after taking the

drugs. Blood concentrations of moclobemide and clomipramine

at admission and at necropsy showed only moderate

overdosage.

 

  1. ADDITIONAL INFORMATION

 

12.1 Specific preventive measures

 

No data

 

12.2 Other

 

No data

 

  1. REFERENCES

 

Berlin I, Said S, Spreux-Varoquaux O, Launay JM, Olivares R,

Millet V, Lecrubier Y & Puech AJ (1995) A reversible monoamine

oxidase A inhibitor (moclobemide) facilitates smoking cessation

and abstinence in heavy, dependent smokers. Clin Pharmacol Ther,

58: 444-452

 

Blier P & Bergeron R (1995) The safety of concomitant use of

sumatriptan and antidepressant treatments. J Clin Psychopharmacol,

15: 106-109

 

Blom-Peters L & Lamy M (1993) Monoamine oxidase inhibitors and

anaesthesia., 44, 2: 57-60

 

Coulter DM & Pillans PI (1995) Hypertension with moclobemide.

Lancet, 346: 1032

 

Fulton B & Benfield P (1996) Moclobemide An update of its

Pharmacological Properties and Therapeutic Use. Drug 53(3): 450-

474

 

Heinze G & Sanchez A (1986) Overdose with moclobemide. J Clin

Psychiatry, 47: 438

 

 

Hernandez AF, Montero MN, Pla A, & Enrique V (1995) Fatal

Moclobemide overdose or death caused by serotonin syndrome?

Journal of Forensic Sciences 40(1): 128-130.

 

Iwersen S & Schmoldt A (1996) Three suicide attempts with

moclobemide. Clin Toxicol, 34: 223-225

 

Kuisma MJ (1995) Fatal serotonin syndrome with trismus. Ann Emerg

Med, 26, 1: 108

 

Lane R & Fischler B (1995) The serotonin syndrome: co-

administration, discontinuation and washout periods for the

selective serotonin reuptake inhibitors (SSRIs). J Serotonin

Research, 3: 171-180

 

Lauerma H (1995) A case of moclobemide-induced hyperorgasmia. Int

Clin Psychopharmacol, 10, 2: 123-124

 

Liebenberg R, Berk M & Winkler G (1996) Serotonergic syndrome

after concomitant use of moclobemide and fluoxetine. Human

Psychopharmacol: Clin and Experiment, 11: 146-147

 

Livingston M & Livingston H (1996) Monoamine oxidase inhibitors.

An update on drug interactions. Drug Safety, 14, 4: 219-227

 

Mac Farlane (1994) Anaesthesia and the new generation monoamine

oxidase inhibitors. Anaesthesia, 49, 7: 597-599

 

Mayersohn M & Guentert TW (1995) Clinical pharmacokinetics of the

monoamine oxidase-A inhibitor moclobemide. Clin Pharmacokinet, 29,

5: 292-332

 

Meienberg O & Amsler F (1996) Moclobemide in the prophylactic

treatment of migraine. A retrospective analysis of 44 case. Eur

Neurol, 36: 109-110

 

Menkes DB, Thomas MC & Phipps RF (1994) Moclobemide for menopausal

flushing. Lancet, 344, 8923: 691-692

 

Myrenfors PG, Eriksson T, Sansdtedt CS & Sjoberg G (1993)

Moclobemide overdose. J Intern Med, 233: 113-115

 

Neuvonen P, Pohjola-Sintonen S, Tacke U & Vuori E (1993) Five

fatal cases of serotonin syndrome after moclobemide-citalopram or

moclobemide-clomipramine overdoses. Lancet, 342: 1419

 

O’Kane GM & Gottlieb T (1996) Severe adverse reaction to

moclobemide. Lancet, 347: 1329-1330

 

Power BM, Pinder M, Hackett LP & Ilett KF (1995) Fatal serotonin

syndrome following a combined overdose of moclobemide,

clomipramine and fluoxetine. Anaesth Intens Care, 23: 499-502

 

 

Raaflaub J, Haefelfinger P & Trautman KH (1984) Single-dose

pharmacokinetics of the MAO-inhibitor moclobemide in man. Arzneim

Forsch, 34: 80-82

 

Reynolds JEF ed (1996) Martindale: the extra pharmacopoeia, 31st

  1. London, The Pharmaceutical Press

 

Roche laboratoires: Moclamine. Manufacturer information. 92521

Neuilly sur Seine France, 1996

 

Spigset O, Mjorndal T & Lovheim O (1993) Serotonin syndrome caused

by a moclobemide-clomipramine interaction. Br Med J, 306, 6872:

248

 

Sternbach H (1991) The serotonin syndrome. Am J Psychiatry, 148:

705-713

 

Sullivan G & Mahmood A (1997) Hair loss associated with

moclobemide use. Human Psychopharmacol: Clin and Experiment, 12:

81-82

 

Timmings P & Lamont D (1996) Intrahepatic cholestasis associated

with moclobemide leading to death. Lancet, 347: 762-763

 

  1. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE

ADDRESS(ES)

 

Author: MO Rambourg Schepens

Centre Anti-Poisons de Champagne Ardenne

Centre Hospitalier Universitaire

F- 51092 Reims cedex France

 

 

Reviewer: WA Watson

Emergency Medicine. Truman Medical Center.

 

Date: June 1997

 

Peer review: Oslo (2 July, 1997) Members of group: Marie-Odile

Rambourg, Bill Watson, Rob Dowsett, Barbara Groszek, Michael

Ruse

 

Editor: Dr. M. Ruse (August, 1997)

 

———————

MONOGRAPH FOR UKPID

DOTHIEPIN HYDROCHLORIDE

 

HY Allen

ZM Everitt

AT Judd

 

National Poisons Information Service (Leeds Centre)

Leeds Poisons Information Centre

Leeds General Infirmary

Leeds

LS1 3EX

UK

 

This monograph has been produced by staff of a National Poisons

Information Service Centre in the United Kingdom.  The work was

commissioned and funded by the UK Departments of Health, and was

designed as a source of detailed information for use by poisons

information centres.

 

Peer review group: Directors of the UK National Poisons Information

Service.

 

MONOGRAPH FOR UKPID

 

Drug Name

 

Dothiepin hydrochloride

 

Chemical group

 

Tricyclic antidepressant

 

Origin

 

Synthetic

 

Name

 

UKBrand name(s)

 

Prothiaden(R), Dothapax(R), Prepadine(R).

 

Synonyms

 

Dosulepin hydrochloride (INN).

 

Common names

 

Product licence number(s)

 

Prothiaden(R) 25 mg: 00169/0086

Prothiaden(R) 75 mg: 00169/0087

 

CAS number

 

7081-53-0

 

Manufacturer

 

Prothiaden(R), Knoll Ltd

 

APS, Ashbourne (Dothapax(R)), Berk (Prepadine(R)), Cox, Generics,

Hillcross, Kent, Pharm and Norton.

 

Presentation

 

Form

 

Capsules, tablets.

 

Formulation details

 

Capsules of 25mg.

Tablets of 75mg.

 

Pack size(s)

 

25mg capsules – packs of 100 and 600.

75mg tablets – packs of 28 and 500.

Generics or branded generics may have different pack sizes.

 

Packaging

 

Prothiaden(R) 25mg – red/brown capsules marked P25

Prothiaden(R) 75 mg – red sugar-coated tablets marked P75

Generic formulations or branded generics will differ in presentation.

 

Properties

 

Chemical structure C19H21NS.HCl = 331.9

Chemical name 11-(3-Dimethylaminopropylidene)-6,-11-

dihydrodibenz [b,e]thiepin hydrochloride

 

Indications

 

Depressive illness especially where an anti-anxiety effect is

required.

 

Therapeutic Dosage

 

ADULTS: 50 mg – 150 mg daily in either divided doses or as a single

dose at night.

In severely depressed patients, doses of up to 225 mg daily have been

used.

CHILD: Not recommended.

 

Contra-indications

 

Recent myocardial infarction, heart block or other cardiac arrhythmia,

mania, severe liver disease.

 

Abuses

 

Epidemiology

 

Over a four year period between 1989 and 1992 there were over 600

deaths from dothiepin overdose (ONS 1996). Tricyclic fatalities tend

to occur in older rather than in younger patients. In both fatal and

non-fatal overdose, there are a greater number of tricyclic ingestions

in females than in males (Crome 1986).

The overall incidence of serious cardiac complications in patients who

are admitted to hospital following tricyclic overdose is reported to

be less than 10%. Some degree of coma occurs in about 50% of cases,

but is only unresponsive to painful stimuli in about 10-15% of cases

(Crome 1986). Convulsions occur in approximately 6% of patients

(Taboulet 1995). The death rate in patients admitted to hospital is

estimated to be 2%-3% (Dziukas & Vohra 1991).

 

Adverse effects

 

Antimuscarinic effects, sedation, arrhythmias, postural hypotension,

tachycardia, sweating, tremor, rashes, hypomania or mania, confusion,

interference with sexual function, weight gain, convulsions, hepatic

and haematological reactions.

 

Interactions

 

Pharmacodynamic:

 

  1. a)   A potentially hazardous interaction may occur between a tricyclic

antidepressant and a MONOAMINE OXIDASE INHIBITOR (including

moclobemide and selegiline) resulting in increased amounts of

noradrenaline and serotonin at the synapse. Coma, hyperthermia,

hypertension, convulsions, delirium, or death may result (Lipman 1981,

White & Simpson 1984).

 

  1. b)   There is an increased risk of cardiotoxicity when administered

with other DRUGS WHICH PROLONG THE QT INTERVAL e.g. anti-arrhythmics,

astemizole, halofantrine, or terfenadine.

 

  1. c)   The pharmacology of dothiepin suggests that concomitant

ingestions of SELECTIVE SEROTONIN REUPTAKE INHIBITORS, PHENOTHIAZINES,

SYMPATHOMIMETICS, or OTHER TRICYCLIC ANTIDEPRESSANTS will enhance its

toxicity.

 

Pharmacokinetic:

 

  1. a)   The metabolism of tricyclic antidepressants is inhibited by most

SELECTIVE SEROTONIN REUPTAKE INHIBITORS, resulting in elevated

tricyclic plasma concentrations. Fluoxetine, fluvoxamine, and

paroxetine appear to exert a greater effect than sertraline. Limited

data suggest that citalopram does not inhibit tricyclic metabolism

(Baettig et al. 1993, Taylor 1995).

 

  1. b)   As the metabolism of dothiepin is mediated by cytochrome P450

microsomal enzymes, the potential exists for interactions with other

drugs which are substrates of this system.

 

  1. c)   CIMETIDINE reduces the metabolic clearance of tricyclic

antidepressants by inhibition of liver enzymes, resulting in higher

plasma tricyclic concentrations (Stockley 1996).

 

Ethanol

 

Information about any interaction between dothiepin and ethanol is

lacking. Two other tricyclic antidepressants (amitriptyline, doxepin)

are known to interact with ethanol resulting in an increased

impairment of psychomotor skills, whilst a number of other tricyclics

appear to interact with ethanol only minimally (Stockley 1996).

 

Mechanism of action

 

The precise mechanism of antidepressant action is unclear, but results

from the inhibition of noradrenaline and serotonin reuptake into

presynaptic neurones, and adaptive changes in receptor sensitivity.

In addition to inhibiting the reuptake of noradrenaline and serotonin,

dothiepin is also an antagonist of muscarinic cholinergic receptors,

histamine receptors, and to a lesser extent alpha1 adrenergic

receptors (Rudorfer et al. 1994). These antagonist actions account for

its anticholinergic, sedative, and hypotensive properties.

The contributions of the metabolites nordothiepin and the combined

sulphoxides to the total antidepressant activity are similar to that

of dothiepin itself (Rees 1981).

 

Mechanism of toxicity

 

The toxicity of dothiepin in overdose results from depression of the

myocardial function (a quinidine-like effect), anticholinergic

activity, alpha adrenergic receptor blockade, and respiratory

insufficiency. The risk of toxicity is greatest 2-4 hours after

ingestion when plasma levels are at the highest.

 

Pharmacokinetics

 

ABSORPTION

 

Dothiepin is rapidly absorbed after oral administration with maximum

plasma concentrations being reached after approximately 3 hours

(Maguire et al. 1983).

Extensive first-pass metabolism occurs (Rees 1981), the estimated oral

bioavailability of dothiepin being approximately 30% (Yu et al. 1986).

 

DISTRIBUTION

 

Dothiepin is widely distributed throughout the body with an apparent

volume of distribution of over 10 L/kg (Rees 1981).

Dothiepin is 80-90% bound to plasma proteins at therapeutic

concentrations (Dollery 1991). The plasma protein binding of tricyclic

antidepressants is pH sensitive with a small reduction in plasma pH

being associated with large increases in unbound (pharmacolgically

active) drug (Nyberg & Martensson 1984).

 

METABOLISM

 

The metabolic profile of dothiepin varies widely between individuals.

Dothiepin is metabolised by demethylation and S-oxidation in the

liver, resulting in the active metabolites, nordothiepin (also known

as northiaden or desmethyldothiepin), dothiepin sulphoxide and

nordothiepin sulphoxide, all of which contribute to the antidepressant

effect (Rees 1981).

Inactive conjugated glucuronide metabolites have also been isolated

(Rees 1981).

 

ELIMINATION

 

The major route of excretion is in urine, although significant faecal

elimination also occurs. Less than 0.5% of a dose is excreted as

unchanged dothiepin in urine (Rees 1981).

Enteroenteric and enterohepatic recycling of dothiepin and its

metabolites is considered to occur (Pimentel & Trommer 1994, Rees

1981).

 

HALF LIFE

 

Dothiepin: 20 hours (Yu et al. 1996).

Active metabolites: 24-40 hours (Yu et al. 1996).

 

SPECIAL POPULATIONS

 

ELDERLY:

 

Metabolic changes in the elderly result in higher plasma

concentrations, longer half-lives, and reduced clearance than in

younger populations (Ogura et al. 1983).

 

LIVER IMPAIRMENT:

 

Reduced metabolic capacity in liver disease suggests that accumulation

of dothiepin will occur, but the clinical implications are unclear due

to a corresponding reduction in active metabolite production.

 

RENAL IMPAIRMENT:

 

Reduced clearance in renal impairment suggests that accumulation of

active metabolites will occur.

 

GENDER:

 

Elimination half-lives for dothiepin and nordothiepin are reported to

be several hours longer in females than in males (Maguire et al.

1983).

 

BREAST MILK

 

Dothiepin and its active metabolites are excreted into human breast

milk.

In an early study, a patient treated with dothiepin 25 mg three times

daily for 3 months had milk and serum dothiepin concentrations of

0.011 and 0.033 mg/L respectively (Rees et al. 1976). These data

suggest that a baby would ingest less than 0.2% of the maternal

dothiepin dose based on a daily milk intake of 150 ml/kg, but in this

study no account was taken of active metabolites.

A later study considered both the excretion of dothiepin and its

active metabolites into breast milk. Concentrations of dothiepin,

nordothiepin, dothiepin-S-oxide and nordothiepin-S-oxide were measured

 

in blood and milk samples from five breast feeding women, and in

plasma samples from their infants. The data show that the mean total

infant daily dose is 4.5% of the maternal dothiepin dosage in

dothiepin equivalents (Ilett et al. 1992).

 

Toxicokinetics

 

Absorption

 

Distribution

 

Metabolism

 

Elimination

 

Half life

 

Dothiepin: 11-29 hours (Ilett et al. 1991)

 

Special populations

 

Breast milk

 

Summary

 

TYPE OF PRODUCT

 

A tricyclic antidepressant.

 

INGREDIENTS

 

Dothiepin capsules: 25 mg

Dothiepin tablets: 75mg

 

SUMMARY OF TOXICITY

 

Patients presenting with only mild signs of toxicity may rapidly

develop life-threatening complications. Where major toxic events occur

these usually develop within 6 hours of overdose, the risk of toxicity

being greatest 2-4 hours after ingestion.

 

Dothiepin overdose should be managed on a clinical basis rather than

on the amount ingested, but as a guide, doses of 1 g in adults have

been associated with severe toxicity. Ingestions of tricyclic

antidepressants in children indicate that doses of 15 mg/kg may prove

fatal to a child, although recovery has followed reported ingestions

of over 100 mg/kg.

 

Sinus tachycardia, hypotension, and anticholinergic symptoms are

common features. Cardiotoxicity, impaired consciousness, seizures,

acidosis, and respiratory insufficiency are associated with severe

toxicity. The occurrence of seizures may precipitate the onset of

cardiac arrhythmias and hypotension. Delirium may be a complication on

recovery.

 

FEATURES

 

Dry mouth, blurred vision, dilated pupils, urinary retention, sinus

tachycardia, drowsiness, hypothermia, and confusion. Hypoxia,

acidosis, hypotension, convulsions, cardiac arrhythmias, and coma.

 

UNCOMMON FEATURES

 

Skin blisters, rhabdomyolysis, disseminated intravascular coagulation,

adult respiratory distress syndrome, and absent brain stem reflexes.

 

SUMMARY OF MANAGEMENT: SUPPORTIVE

 

  1.   Maintain a clear airway and adequate ventilation if consciousness

is impaired.

 

  1.   If within 1 hour of the ingestion and more than 300 mg has been

taken by an   adult, or more than 1mg/kg by a child, give

activated charcoal.

 

  1.   Carry out arterial blood gas analysis, and correct any acidosis

and hypoxia.

 

  1.   Monitor the cardiac rhythm and blood pressure.

 

  1.   Single, brief convulsions do not require treatment but if they

are prolonged or recurrent, they should be controlled with

intravenous diazepam.

 

  1.   Ventricular arrhythmias should be managed with intravenous sodium

bicarbonate and supportive measures. Where these measures fail

and an anti-arrhythmic is considered essential, lignocaine is the

preferred drug.

 

  1.   Other measures as indicated by the patient’s clinical condition.

 

Clinical Features

 

ACUTE INGESTION

 

Mild to moderate toxicity: dilated pupils, sinus tachycardia,

drowsiness, dry mouth, blurred vision, urinary retention, absent bowel

sounds, confusion, agitation, body temperature disturbances,

twitching, delirium, hallucinations, nystagmus, and ataxia.

Increased tone and hyperreflexia may be present with extensor plantar

responses.

(Callaham 1979, Crome 1986, Dziukas & Vohra 1991, Noble & Matthews

1969).

 

Severe toxicity: coma, hypotension, convulsions, supraventricular and

ventricular arrhythmias, hypoxia, metabolic and/or respiratory

acidosis, and cardiac arrest (Crome 1986, Dziukas & Vohra 1991).

 

ECG changes (in the usual order of appearance) include non-specific ST

or T wave changes, prolongation of the QT, PR, and QRS intervals,

right bundle branch block, and atrioventricular block. The terminal

0.04 second frontal plane QRS axis often shows a right axis deviation

(Dziukas & Vohra 1991).

 

Delayed features: adult respiratory distress syndrome (Varnell et al.

1989).

 

Uncommon features: skin blisters, rhabdomyolysis, disseminated

intravascular coagulation, gaze paralysis, and absent brain reflexes

(Dziukas & Vohra 1991, White 1988).

 

INHALATION

 

DERMAL

 

OCULAR

 

OTHER

 

CHRONIC

 

INGESTION

 

INHALATION

 

DERMAL

 

OCULAR

 

OTHER

 

At risk groups

 

ELDERLY

 

There is an increased risk of toxicity resulting from impaired drug

metabolism and elimination. The elderly are also particularly

susceptible to the central anticholinergic effects such as confusion,

disorientation, acute psychosis and hallucinations (Nolan & O’Malley

1992).

 

PREGNANCY

 

The safety of dothiepin (or tricyclic antidepressants in general)

during pregnancy has not been established.

A handful of cases were reported in the early 1970’s linking tricyclic

antidepressant administration during pregnancy to birth defects,

particularly limb deformities. Retrospective studies, subsequently

reported, showed no correlation between tricyclic antidepressant use

and increased malformations. However, a more recent report of a large

 

case-controlled study found a greater occurrence (not quantified) of

congenital malformation with tricyclic antidepressants than in control

groups (Schardein 1993).

Fetal tachyarrhythmia has been reported where dothiepin has been given

in pregnancy – see case report 1.

 

CHILDREN

 

Comparison with other tricyclic antidepressants would suggest that

ingestions in children result in symptoms typical of tricyclic

antidepressant overdose in adults (Crome & Braithwaite 1978, Goel &

Shanks 1974).

See case report 2 for clinical details of dothiepin ingestion in a

young child.

 

ENZYME DEFICIENCIES

 

Dothiepin is metabolised by microsomal enzymes in the liver which may

be subject to genetic polymorphism.

 

ENZYME INDUCED

 

The metabolism of dothiepin is likely to be increased in the presence

of enzyme inducing drugs, but is of doubtful clinical relevance as the

metabolites formed also have antidepressant activity.

 

OCCUPATIONS

 

OTHERS

 

RENAL IMPAIRMENT: increased risk of toxicity due to accumulation of

metabolites.

HEPATIC IMPAIRMENT: increased risk of toxicity due to impaired

metabolism.

CARDIAC DISEASE: increased risk of toxicity due to underlying disease.

EPILEPSY: increased risk of seizures.

 

Management

 

Decontamination

 

If within one hour of ingestion, and more than 300mg has been taken by

an adult or more than 1mg/kg by a child, activated charcoal should be

given to reduce the absorption.

 

ADULT DOSE; 50 g,

CHILD DOSE; 1 g/kg.

 

If the patient is drowsy this should be administered via a nasogastric

tube, and if there is no gag reflex present, using a cuffed

endotracheal tube to protect the airway.

 

Supportive care

 

GENERAL MANAGEMENT OF THE SYMPTOMATIC PATIENT

 

Clear and maintain the airway, and give cardiopulmonary resuscitation

if necessary.

Evaluate the patient’s condition and provide support for vital

functions.

 

  1.   Administer intravenous sodium bicarbonate to correct any

acidosis.

 

ADULT DOSE: 50 ml of 8.4% sodium bicarbonate by slow intravenous

injection; CHILD DOSE: 1 ml/kg of 8.4% sodium bicarbonate by slow

intravenous injection.

 

Subsequent bicarbonate therapy should be guided by arterial blood pH

which should be monitored frequently.

 

  1.   Maintain adequate ventilation to prevent hypoxia with

supplemental oxygen or artificial ventilation as appropriate.

 

  1.   Carefully maintain plasma potassium levels to prevent

hypokalaemia.

 

IN MIXED OVERDOSES WHERE A BENZODIAZEPINE HAS ALSO BEEN INGESTED, THE

USE OF THE COMPETITIVE BENZODIAZEPINE ANTAGONIST FLUMAZENIL IS

CONTRA-INDICATED (Mordel et al. 1992).

 

Where symptoms develop following mild to moderate overdose, they may

persist for 24 hours. Prolonged or delayed complications following

severe toxicity may require the patient to be hospitalised for several

days.

 

SPECIFIC MANAGEMENT OF THE SYMPTOMATIC PATIENT

 

  1. CARDIOTOXICITY

GENERAL NOTE: in practice it is seldom necessary or advisable to use

specific drug treatment for arrhythmias. If hypoxia and acidosis are

reversed and adequate serum potassium levels maintained, then the

majority of patients show improvement with supportive measures.

 

SINUS and SUPRAVENTRICULAR TACHYCARDIAS: no specific treatment

required (Pimentel & Trommer 1994).

 

VENTRICULAR ARRHYTHMIAS: give intravenous sodium bicarbonate (even in

the absence of acidosis) before considering antiarrhythmic drug

therapy. Where an antiarrhythmic is considered necessary, lignocaine

is the preferred drug (Pimentel & Trommer 1994).

 

ADULT DOSE: 50-100 mg lignocaine by IV bolus over a few minutes,

followed by an intravenous infusion of 4 mg/minute for 30 minutes, 2

mg/minute for 2 hours, then 1 mg/minute (BNF 1998).

 

The use of quinidine, disopyramide, procainamide, and flecainide are

all contra-indicated as they depress cardiac conduction and

contractility. The use of beta-blockers should also be avoided as they

decrease cardiac output and exacerbate hypotension. The efficacy of

other antiarrhythmic agents (e.g bretylium, amiodarone, calcium

channel blockers) has not been studied in tricyclic antidepressant

poisoning (Pimentel & Trommer 1994).

 

BRADYARRHYTHMIAS and HEART BLOCK: cardiac pacing may have only limited

success as the cardiotoxicity of dothiepin results from depression of

contractility rather than failure of cardiac pacemakers.

 

CARDIAC ARREST: manage in the standard manner but with continuing

resuscitative measures as some patients have recovered after receiving

several hours of external cardiac massage (Orr & Bramble 1981).

 

  1. COMA

Good supportive care is essential.

 

  1. HYPOTENSION

Hypotension should be managed by the administration of intravenous

fluids and by physical means. The majority of patients ingesting

dothiepin have otherwise healthy cardiovascular systems and providing

cardiac output is good it is unnecessary to use specific drug therapy.

If there is evidence of poor cardiac output (after correction of

acidosis, hypovolaemia, and hypoxia) then the use of a vasoactive

agent may need to be considered. Noradrenaline has been shown to be

helpful in a number of studies (including cases where dopamine therapy

has failed) (Teba et al. 1988, Yang & Dantzker 1991).

 

ADULT DOSE: IV infusion of noradrenaline acid tartrate 80

micrograms/ml (equivalent to noradrenaline base 40 micrograms/ml) via

a central venous catheter at an initial rate of 0.16 to 0.33 ml/minute

adjusted according to response (BNF 1998).

CHILD DOSE (unlicensed indication): IV infusion of noradrenaline

acid tartrate 0.04-0.2 microgram/kg/minute (equivalent to 0.02-0.1

microgram/kg/minute of noradrenaline base) in glucose 5% or

glucose/saline via a central venous catheter (Guy’s, Lewisham & St

Thomas Paediatric Formulary, 1997).

 

  1. SEIZURES

Administer intravenous diazepam to control frequent or prolonged

convulsions.

 

ADULT DOSE: 10 mg

CHILD DOSE: 0.25-0.4 mg/kg

Both by slow IV injection preferably in emulsion form.

 

Where seizure activity proves difficult to manage, paralyse and

ventilate the patient. Continue to monitor the cerebral function to

ensure the cessation of seizure activity.

 

  1. OTHER

Catheterisation may be required to relieve distressing urinary

retention and to allow continuous monitoring of urine output as a

means of assessing cardiac output (Crome 1986).

Respiratory complications should be managed conventionally with early

respiratory support.

Control delirium with oral diazepam. Large doses may be required (20-

30mg two-hourly in adults).

 

Monitoring

 

Monitor the heart rate and rhythm, arterial blood gases, blood

pressure, serum electrolytes, body temperature, respiratory rate and

depth, and urinary output.

 

Observe for a minimum of 6 hours post-ingestion where:

 

  1. i) more than 1mg/kg has been ingested by a child,
  2. ii) more than 300 mg is known to have been ingested by an adult,

iii) the patient is symptomatic.

 

Antidotes

 

None available

 

Elimination techniques

 

Dialysis and haemoperfusion are ineffective as means of promoting drug

or metabolite elimination.

 

Investigations

 

Following severe toxicity:

  1. i) a chest X-ray will be needed to exclude pulmonary

complications,

  1. ii) measure serum creatine kinase and other skeletal muscle

enzyme activity (e.g. AST, ALT, and lactic dehydrogenase),

iii) assess renal function,

  1. iv) assess haematological status.

 

Management controversies

 

Gastric lavage is not recommended as the procedure may be associated

with significant morbidity, and there is no evidence that it is of any

greater benefit than activated charcoal used alone (Bosse et al.

1995).

If the procedure is used (i.e. in cases where activated charcoal

cannot be administered), a cuffed endotracheal tube should be used to

protect the airway if the patient is drowsy, and activated charcoal

left in the stomach following the lavage.

 

Repeat doses of oral activated charcoal may prevent the reabsorption

of tricyclic antidepressants and their metabolites secreted in gastric

juices and bile (Swartz & Sherman 1984). However, it would not be

expected from the large volume of distribution of the tricyclics that

clinically significant increases in body clearance would result.

 

Physostigmine salicylate is a short acting reversible cholinesterase

inhibitor which has been used historically in the management of

tricyclic overdoses to reverse coma and antimuscarinic effects.

Reports of serious complications from its use include severe

cholinergic activity, convulsions, bradycardia, and asystole (Newton

1975, Pentel & Peterson 1980). The use of physostigmine is no longer

recommended.

 

The use of dopamine in the management of hypotension has been

suggested, but the pressor effect of this indirect acting inotrope may

be diminished in tricyclic overdosed patients due to depleted levels

of noradrenaline (Buchman et al. 1990, Teba et al. 1988).

 

The use of intravenous glucagon has been proposed in cases where

hypotension is unresponsive to volume expansion and sodium bicarbonate

administration, because of its positive inotropic effect and possible

antiarrhythmic property. Its place in therapy has not been established

(Sener et al. 1995).

ADULT DOSE: 10 mg by IV bolus followed by an infusion of 10 mg

over 6 hours (unlicensed indication and dose).

 

There are a number of reports of severe arrhythmias or sudden death

occurring up to 1 week after tricyclic overdose, but a review of the

cases show that the patients had continuing toxicity, underlying

disease or abnormalities (Stern et al. 1985).

 

Several predictors of clinical severity in tricyclic overdoses have

been suggested, including:

 

  1.   a maximal limb-lead QRS duration of 0.1 second or longer as a

predictor of the risk of seizure (Boehnert & Lovejoy 1985),

  1.   a maximal limb-lead QRS duration of 0.16 second or longer as a

predictor of the risk of ventricular arrhythmias (Boehnert &

Lovejoy 1985),

  1.   plasma tricyclic levels greater than 0.8 mg/L (Caravati & Bossart

1991),

  1.   the ECG terminal 40-ms frontal plane QRS axis of more than 120°

(Wolfe et al. 1989),

  1.   plasma drug concentrations in excess of 2 mg/L as a predictor of

the development of lung injury (Roy et al. 1989).

 

Whilst none of these features in isolation are predictive of

life-threatening toxicity, they may be helpful in assessing patient

risk.

 

Case data

 

CASE REPORT 1 – Fetal tachyarrhythmia attributed to maternal drug

treatment with dothiepin.

A 26 year old woman was started on dothiepin 50 mg daily during the

first trimester of pregnancy. This was increased to 75 mg daily at

about 16 weeks of gestation and subsequently reduced to 50 and 25 mg

daily at 30 and 34 weeks respectively. At 37 weeks there had been

little growth over the previous three weeks, the patients weight

remaining the same. The fetal heart rate was irregular with over 180

beats per minute. An ultrasound scan showed a normally grown fetus

with no evidence of cardiac failure. The dothiepin was stopped after a

few days. The frequency and the duration of the tachyarrhythmias

decreased and within four days no abnormalities of the fetal heart

rate were detected. At subsequent review in antenatal clinics no

abnormalities were noted, and the patient delivered a healthy infant

at term (Prentice & Brown 1989).

 

CASE REPORT 2 – Dothiepin ingestion in an infant.

An 11-month-old child weighing 9.7 kg ingested about 13 dothiepin 75

mg tablets (100 mg/kg). She was drowsy, had muscle twitching and a

generalised convulsion. On admission to hospital one and a half hours

later she was comatose and convulsing. Her pulse was 160 beats/minute,

blood pressure 80/50 mm Hg, respirations regular, and pupils fixed and

dilated. Electrocardiography showed sinus tachycardia. Her convulsions

were controlled with 10 mg IV diazepam and 4 ml IM paraldehyde. She

was intubated and her stomach emptied. She suddenly became bradycardic

(pulse 50 beats/minute, blood pressure unrecordable), with wide QRS

complexes showing on the ECG. Cardiac massage and assisted ventilation

were started. She was unresponsive to IV atropine, and was given

5 mmol sodium bicarbonate and 50 ml plasma protein fraction. Blood gas

analysis showed hypoxia with metabolic and respiratory acidosis.

Further sodium bicarbonate was given (30 mmol) and hyperventilation

started. One hour later blood gas analysis showed correction of her

acidosis, her pulse returned to 104 beats/minute, and her blood

pressure was 75 mm Hg systolic. Over the next few hours there was

narrowing of the QRS complexes, some ST depression, and ventricular

ectopic beats. She was responsive to pain ten hours after ingestion,

and made an uneventful recovery (Hodes 1984).

 

Analysis

 

Agent/toxin/metabolite

 

There is no clear relationship between plasma dothiepin concentration

and clinical response or toxicity. Consequently the measurement of

plasma drug concentration following overdose is not routinely advised,

although it may have diagnostic value.

 

Sample container

 

Optimum storage

 

Transport of samples

 

Interpretation of data

 

There is considerable variation in plasma concentration of dothiepin

between individuals.

As a guide, it has been suggested that therapeutic effect is

associated with plasma dothiepin concentrations in excess of 0.1 mg/L

(Rees 1981).

Forensic studies have found lethal tricyclic antidepressant levels

ranging from 1.1 mg/L to 21.8 mg/L (Frommer et al. 1987).

 

Conversion factors

 

1 mg/L = 3.013 micromoles/L

1 micromole/L = 0.332 mg/L

 

The molecular weight of dothiepin hydrochloride is 331.9

 

Other recommendations

 

Prevention of poisoning

 

Other toxicological data

 

Carcinogenicity

 

Genotoxicity

 

Mutagenicity

 

Reprotoxicity

 

Teratogenicity

 

Relevant animal data

 

Animal tests show no evidence of carcinogenicity, teratogenicity,

genotoxicity, or reprotoxicity (Dollery 1991, Goldstein & Claghorn

1980).

 

Relevant in vitro data

 

Laboratory tests involving mammalian cells, human lymphocytes, and

bacteria show no evidence of genotoxicity (Dollery 1991).

 

Other regulatory standards

 

NA

 

Environment

 

NA

 

Hazard

 

NA

 

Authors

 

HY Allen

ZM Everitt

AT Judd

 

National Poisons Information Service (Leeds Centre)

Leeds Poisons Information Centre

Leeds General Infirmary

Leeds

LS1 3EX

UK

 

This monograph was produced by the staff of the Leeds Centre of the

National Poisons Information Service in the United Kingdom. The work

was commissioned and funded by the UK Departments of Health, and was

designed as a source of detailed information for use by poisons

information centres.

 

Peer review was undertaken by the Directors of the UK National Poisons

Information Service.

 

Prepared October 1996

Updated May 1998

 

References

 

Baettig D, Bondolfi G, Montaldi S, Amey M, Baumann P.

Tricyclic antidepressant plasma levels after augmentation with

citalopram: a case study. Eur J Clin Pharmacol 1993; 44: 403-405.

 

BNF Joint Formulary Committee.

British National Formulary, Number 35. London: British Medical

Association & Royal Pharmaceutical Society of Great Britain, 1998.

 

Boehnert MT, Lovejoy FH.

Value of the QRS duration versus the serum drug level in predicting

seizures and ventricular arrhythmias after an acute overdose of

tricyclic antidepressants. N Eng J Med 1985; 313: 474-479.

 

Bosse GM, Barefoot JA, Pfeifer MP, Rodgers GC.

Comparison of three methods of gut decontamination in tricyclic

antidepressant overdose. J Emerg Med 1995; 13: 203-209.

 

Buchman AL, Dauer J, Geiderman J.

The use of vasoactive agents in the treatment of refractory

hypotension seen in tricyclic antidepressant overdose. J Clin

Psychopharmacol 1990; 10: 409-413.

 

Callaham M.

Tricyclic antidepressant overdose. J Am Coll Emerg Phys 1979; 8:

413-425.

 

Caravati EM, Bossart PJ.

Demographic and electrocardiographic factors associated with severe

tricyclic antidepressant toxicity. J Toxicol Clin Toxicol 1991; 29:

31-43.

 

Crome P.

Poisoning due to tricyclic antidepressant overdosage: clinical

presentation and treatment. Med Toxicol 1986; 1: 261-285.

 

Crome P, Braithwaite RA.

Relationship between clinical features of tricyclic antidepressant

poisoning and plasma concentrations in children. Arch Dis Childhood

1978; 53: 902-905.

 

Dollery C(Ed).

Therapeutic Drugs Volume 1. Edinburgh: Churchill Livingstone, 1991:

208-211.

 

Dziukas LJ, Vohra J.

Tricyclic antidepressant poisoning. Med J Aust 1991; 154: 344-350.

 

Frommer DA, Kulig KW, Marx JA, Rumack B.

Tricyclic antidepressant overdose. J Am Med Assoc 1987; 257: 521-526.

 

Goel KM, Shanks RA.

Amitriptyline and imipramine poisoning in children. Br Med J 1974; 1:

261-263.

 

Goldstein BJ, Claghorn JL.

An overview of seventeen years of experience with dothiepin in the

treatment of depression in Europe. J Clin Psychiatry 1980; 41: 64-70.

 

Guy’s, Lewisham & St. Thomas’ Hospitals Paediatric Formulary, 4th

Edition. London: Guy’s & St. Thomas’ Hospital Trust, 1997.

 

Hodes D.

Sodium bicarbonate and hyperventilation in treating an infant with

severe overdose of tricyclic antidepressant. Br Med J 1984; 288:

1800-1801.

 

Ilett KF, Hackett LP, Dusci LJ, Paterson JW.

Disposition of dothiepin after overdose: effects of repeated-dose

activated charcoal. Ther Drug Monit 1991; 13: 485-489.

 

Ilett KF, Lebedevs TH, Wojnar-Horton RE, Yapp P, Roberts MJ, Dusci LJ,

Hackett LP.

The excretion of dothiepin and its primary metabolites in breast milk.

Br J Clin Pharmacol 1992; 33: 635-639.

 

Lipman AG.

Tricyclic antidepressant interactions. Mod Med 1981; 49: 151-152.

 

Maguire KP, Norman TR, McIntyre I, Burrows GD.

Clinical pharmacokinetics of dothiepin. Clin Pharmacokinetic 1983; 8:

179-185.

 

Mordel A, Winkler E, Almog S, Tirosh M, Ezra D.

Seizures after flumazenil administration in a case of combined

benzodiazepine and tricyclic antidepressant overdose. Crit Care Med

1992; 20: 1733-1734.

 

Newton RW.

Physostigmine salicylate in the treatment of tricyclic antidepressant

overdosage. J Am Med Assoc 1975; 231: 941-943.

 

Noble J, Matthew H.

Acute poisoning by tricyclic antidepressants: clinical features and

management of 100 patients. Clin Toxicol 1969; 2: 403-421.

 

Nolan L, O’Malley K.

Adverse effects of antidepressants in the elderly. Drugs & Aging 1992;

2: 450-458.

 

Nyberg G, Martensson E.

Determination of free fractions of tricyclic antidepressants. Arch

Pharmacol 1984; 327: 260-265.

 

Ogura C, Kishimoto A, Mizukawa R, Hazama H, Honma H, Kawahara K.

Age differences in effects on blood pressure, flicker fusion

frequency, salivation and pharmacokinetics of single oral doses of

dothiepin and amitriptyline. Eur J Clin Pharmacol 1983; 25: 811-814.

 

Orr DA, Bramble MG.

Tricyclic antidepressant poisoning and prolonged external cardiac

massage during asystole. Br Med J 1981; 283: 1107-1108.

 

ONS.

Office for National Statistics. St Catherine’s House, 10 Kingsway,

London. Personal communication – 1996.

 

Pentel P, Peterson CD.

Asystole complicating physostigmine treatment of tricyclic

antidepressant overdose. Ann Emerg Med 1980; 9: 588-590.

 

Pimentel L, Trommer L.

Cyclic antidepressant overdoses. Emerg Med Clin N Am 1994; 12:

533-547.

 

Prentice A, Brown R.

Fetal tachyarrhythmia and maternal antidepressant treatment. Br Med J

1989; 298: 190.

 

Rees JA, Glass RC, Sporne GA.

Serum and breast milk concentrations of dothiepin. Practitioner 1976;

217: 686.

 

Rees JA.

Clinical interpretation of pharmacokinetic data on dothiepin

hydrochloride (dosulepin, Prothiaden). J Int Med Res 1981; 9: 98-102.

 

Roy TM , Ossorio MA, Cipolla LM, Fields CL, Snider HL, Anderson WH.

Pulmonary complications after tricyclic antidepressant overdose. Chest

1989; 96: 852-856.

Rudorfer MV, Manji HK, Potter WZ.

Comparative tolerability profiles of the newer versus older

antidepressants. Drug Saf 1994; 10: 18-46.

 

Schardein JL.

Chemically induced birth defects. 2nd ed. New York:Marcel Dekker,

1993.

 

Swartz CM, Sherman A.

The treatment of tricyclic antidepressant overdose with repeated

charcoal. J Clin Psychopharmacol 1984; 4: 336-340.

 

Sener EK, Gabe S, Henry JA.

Response to glucagon in imipramine overdose. J Toxicol Clin Toxicol

1995; 33: 51-53.

 

Stern TA, O’Gara PT, Mulley AG, Singer DE, Thibault GE.

Complications after overdose with tricyclic antidepressants. Crit Care

Med 1985; 13: 672-674.

Stockley IH.

Drug interactions 4th ed. London: The Pharmaceutical Press, 1996.

 

Taboulet P, Michard F, Muszynski J, Galliot-Guilley M, Bismuth C.

Cardiovascular repercussions of seizures during cyclic antidepressant

poisoning. Clin Toxicol 1995; 33: 205-211.

 

Taylor D.

Selective serotonin reuptake inhibitors and tricyclic antidepressants

in combination: interactions and therapeutic uses. Br J Psychiatry

1995; 167: 575-580.

 

Teba L, Schiebel F, Dedhia HV, Lazzell VA.

Beneficial effect of norepinephrine in the treatment of circulatory

shock caused by tricyclic antidepressant overdose. Am J Emerg Med

1988: 6: 566-568.

 

Varnell RM, Godwin JD, Richardson ML, Vincent JM.

Adult respiratory distress syndrome from overdose of tricyclic

antidepressants. Radiology 1989; 170: 667-670.

 

White A.

Overdose of tricyclic antidepressants associated with absent

brain-stem reflexes.Can Med Assoc J 1988; 139: 133-134.

 

White K, Simpson G.

The combined use of MAOI’s and tricyclics. J Clin Psychiatry 1984; 45:

67-69.

 

Wolfe TR, Caravati EM, Rollins DE.

Terminal 40-ms frontal plane QRS axis as a marker for tricyclic

antidepressant overdose. Ann Emerg Med 1989; 18: 348-351.

 

Yang KL, Dantzker DR.

Reversible brain death: a manifestation of amitriptyline overdose.

Chest 1991; 99: 1037-1038.

 

Yu DK , Dimmitt DC, Lanman C, Giesing DH.

Pharmacokinetics of dothiepin in humans: a single dose

dose-proportionality study. J Pharm Sci 1986; 75: 582-585.

 

 

—————

 

INTOX Home Page

 

MONOGRAPH FOR UKPID

HALOPERIDOL DECANOATE

HY Allen

ZM Everitt

AT Judd

 

National Poisons Information Service (Leeds Centre)

Leeds Poisons Information Centre

Leeds General Infirmary

Leeds

LS1 3EX

UK

 

This monograph has been produced by staff of a National Poisons

Information Service Centre in the United Kingdom.  The work was

commissioned and funded by the UK Departments of Health, and was

designed as a source of detailed information for use by poisons

information centres.

 

Peer review group: Directors of the UK National Poisons Information

Service.

 

MONOGRAPH FOR UKPID

 

Drug name

 

Haloperidol decanoate

 

Chemical group

 

Butyrophenone

 

Origin

 

Synthetic

 

Name

 

Brand name

 

Haldol(R) Decanoate

 

Synonyms

 

Common names

 

Product licence number

 

Haldol(R) Decanoate 50mg/ml     0242/0094

Haldol(R) Decanoate 100mg/ml    0242/0095

 

CAS number

 

74050-97-8

 

Manufacturer

 

Janssen-Cilag Limited

 

 

Form

 

Intramuscular depot injection.

NOTE: a separate entry exists for other haloperidol formulations – see

under ‘Haloperidol’.

 

Formulation details

 

Injection of haloperidol decanoate equivalent to 50mg/ml or 100mg/ml

of haloperidol for intramuscular administration. Solutions contain

sesame oil and benzyl alcohol as inactive ingredients.

 

Pack size

 

50 mg/ml: 5x1ml ampoules

100mg/ml: 5x1ml ampoules

 

Packaging

 

Chemical structure

 

C31H41ClFNO3

 

Molecular weight = 530.1

 

Chemical name

 

4-[4-(4-Chlorophenyl)-4-hydroxypiperidino]-4-fluorobutyrophenone

decanoate

 

Indication

 

Long term maintenance in schizophrenia, psychoses especially paranoid,

and other mental and behavioural problems.

 

Therapeutic dosage – adults

 

By deep IM injection:

50-300 mg every 4 weeks (reduced doses in elderly)

 

Therapeutic dosage – children

 

Not recommended

 

Contra-indications

 

Use in children, confusional states, coma caused by CNS depressants,

parkinsonism, hypersensitivity to haloperidol, lesions of the basal

ganglia, and during lactation.

 

Abuses

 

Epidemiology

 

Overdose with haloperidol decanoate tends to be limited to accidental

administration and dosage errors.

 

Adverse effects

 

Extrapyramidal effects such as acute dystonia, Parkinsonian rigidity,

tremor, and akathisia. Also sedation, agitation, drowsiness, insomnia,

headache, nausea, blurring of vision, urinary retention, hypotension,

depression, confusional states, impairment of sexual function, skin

reactions, epileptic fits, hyperprolactinaemia, ventricular

arrhythmias, and abnormalities of liver function tests.

 

Tardive dyskinesia, and neuroleptic malignant syndrome have both been

associated with haloperidol therapy.

 

Interactions

 

PHARMACODYNAMIC

 

  1. Enhancement of central nervous system depression produced by

other CNS DEPRESSANT drugs.

 

  1. Combination with other antidopaminergic agents, such as

METOCLOPRAMIDE or PROCHLORPERAZINE increases the risk of

extrapyramidal effects (Dollery 1991).

 

PHARMACOKINETIC

 

  1. The metabolism of TRICYCLIC ANTIDEPRESSANTS is impaired by

haloperidol resulting in higher serum tricyclic levels (Stockley

1996).

 

OTHER

 

  1. There is limited evidence to suggest that profound drowsiness and

confusion may be associated with combined use of haloperidol and

INDOMETHACIN (Stockley 1996).

 

  1. Combination with high doses of LITHIUM have produced

encephalopathic syndromes and severe extrapyramidal reactions

(Cohen & Cohen 1974, Stockley 1996).

 

ETHANOL

 

Possible enhancement of central nervous system depression, and

precipitation of extrapyramidal side effects by ALCOHOL (Stockley

1996).

 

Mechanism of action

 

Haloperidol decanoate has no intrinsic activity. The pharmacological

effects are those of haloperidol which is released by bioconversion.

The precise mechanism of antipsychotic action is unclear, but is

considered to be associated with the potent dopamine D2 receptor

blocking activity of haloperidol and the resulting adaptive changes in

the brain.

Haloperidol is also a potent antagonist of opiate receptors, and has

weak antagonist activity at muscarinic, histamine H1,

alpha-adrenergic, and serotonin receptors (Dollery 1991).

 

Mechanism of toxicity

 

Toxicity is due to an extension of the pharmacological actions. The

various receptor antagonist actions of haloperidol result in

extrapyramidal reactions, orthostatic hypotension, a reduction of

 

seizure threshold, hypothermia, QT and PR prolongation on the ECG,

sedation, and antimuscarinic effects.

 

Pharmacokinetics

 

ABSORPTION

 

Haloperidol decanoate is slowly released into the circulation where it

is hydrolysed releasing active haloperidol. Peak plasma concentrations

occur within 3-9 days, then decrease slowly (Beresford & Ward 1987).

 

DISTRIBUTION

 

Haloperidol is about 92% bound to plasma proteins (Forsman & Ohman

1977b). It is widely distributed in the body, with an apparent volume

of distribution of 18 L/kg (Holley et al. 1983).

 

METABOLISM

 

Haloperidol decanoate undergoes hydrolysis by plasma and/or tissue

esterases to form haloperidol and decanoic acid (Beresford & Ward

1987).

 

Subsequently, haloperidol is metabolised in the liver, the main routes

of metabolism being oxidative N-dealkylation, and reduction of the

ketone group to form reduced haloperidol (Forsman & Larsson 1978).

Reduced haloperidol is much less active than haloperidol but undergoes

re-oxidation to haloperidol (Chakraborty et al. 1989, Cheng & Jusko

1993). The cytochrome P4502D6 has been shown to be involved in the

oxidative metabolic pathway (Llerena et al. 1992).

 

ELIMINATION

 

Haloperidol is excreted slowly in the urine and faeces. About 30% of a

dose is excreted in urine and about 20% of a dose in faeces via

biliary elimination (Beresford & Ward 1987). Only 1% of a dose is

excreted as unchanged drug in the urine (Forsman et al. 1977). There

is evidence of enterohepatic recycling (Chakraborty et al. 1989).

 

Half-life – substance

 

Haloperidol decanoate: 3 weeks

 

Half-life – metabolites

 

NA

 

Special populations

 

ELDERLY

 

Haloperidol plasma concentrations in the elderly tend to be higher

than in younger patients on equivalent doses but the difference is not

significant (Forsman & Ohman 1977a).

 

RENAL IMPAIRMENT

 

It is not anticipated that renal impairment would alter the

pharmacokinetic profile of haloperidol.

 

HEPATIC IMPAIRMENT

 

The clearance of haloperidol may be reduced in severe liver

impairment.

 

GENDER

 

Gender has been found not to influence haloperidol plasma

concentrations (Forsman & Ohman 1977a).

 

BREAST MILK

 

Haloperidol is excreted in breast milk.

 

Toxicokinetics

 

Absorption

 

Distribution

 

Metabolism

 

Elimination

 

Half-life – substance

 

Half-life – metabolites

 

Special populations

 

Breast milk

 

Summary

 

TYPE OF PRODUCT

 

Intramuscular antipsychotic depot injection.

 

INGREDIENTS

 

Haloperidol decanoate equivalent to 50mg/ml, or 100mg/ml of

haloperidol.

Formulated in benzyl alcohol and sesame oil.

 

NOTE: a separate entry exists for other haloperidol formulations – see

under ‘Haloperidol’.

 

SUMMARY OF TOXICITY

 

Plasma concentrations of haloperidol will be greatest during the first

week after injection. It will be during this period that there is the

greatest risk of acute toxicity. Any symptoms occurring may take

several weeks to resolve. Accidental injection or dose errors tend to

be in patients on long term therapy which carries a risk of

neuroleptic malignant syndrome and tardive dyskinesia in addition to

acute symptoms.

 

FEATURES

 

Rigidity, dystonic reactions, drowsiness, and tremor.

 

UNCOMMON FEATURES

 

Cardiac arrhythmias, neuroleptic malignant syndrome, tardive

dyskinesia.

 

SUMMARY OF MANAGEMENT: SUPPORTIVE

 

  1. Check heart rhythm and blood pressure.

 

  1. Acute dystonic reactions can be managed with IV procyclidine or

benztropine, followed by oral doses to prevent recurrence.

 

  1. Other measures as required by the patients clinical condition.

Peak plasma concentrations occur within 3-9 days of

administration and it is during this time that symptoms are most

likely to occur.

 

Features – acute

 

Ingestion

 

Inhalation

 

Dermal

 

Ocular

 

Other routes

 

BY INJECTION:

 

Erythema, swelling, or tender lumps at the site of injection. Acute

dystonic reactions and other extrapyramidal signs (such as rigidity,

and tremor), drowsiness, hypotension (or rarely hypertension),

hypothermia, hypokalaemia, and cardiac arrhythmias particularly

 

prolongation of the QT interval and torsade de pointes (Aunsholt 1989,

Cummingham & Challapalli 1979, Henderson et al. 1991, Scialli &

Thornton 1978, Sinaniotis et al. 1978, Yoshida et al. 1993, Zee-Cheng

et al. 1985).

 

Features – chronic

 

Ingestion

 

Inhalation

 

Dermal

 

Ocular

 

Other routes

 

BY INJECTION: as for acute injection.

 

At risk groups

 

ELDERLY

 

Increased risk of toxic events.

 

PREGNANCY

 

The safety of haloperidol in human pregnancy has not been established.

There are two reports of limb defects in infants after first trimester

use of oral haloperidol given with other potentially teratogenic drugs

(AHFS 1998, Briggs 1994, Kopelman et al. 1975). Other investigators

have not found an association between haloperidol and birth defects.

 

CHILDREN

 

ENZYME DEFICIENCIES

 

The metabolism of haloperidol is subject to genetic polymorphism.

Subjects deficient in the isoenzyme P4502D6 are poor metabolisers of

haloperidol and will be at risk from high haloperidol plasma

concentrations due to a reduced metabolic capacity (Llerena et al.

1992). Approximately 7% of the caucasian population is deficient in

this enzyme.

 

ENZYME INDUCED

 

Reduced risk of toxicity from haloperidol.

 

Therapeutic administration with enzyme inducing drugs for a period of

1-3 weeks results in lower haloperidol plasma concentrations (Forsman

& Ohman 1977a, Jann et al. 1985).

 

Occupations

 

Others

 

RENAL IMPAIRMENT: renal impairment is unlikely to increase the risk of

toxicity.

HEPATIC IMPAIRMENT: increased risk of toxicity due to impaired

metabolism.

CARDIAC DISEASE: increased risk of cardiotoxicity due to underlying

disease.

EPILEPSY: increased risk of seizures due to lowered seizure threshold.

 

Management

 

Decontamination

 

NA

 

Supportive care

 

MANAGEMENT OF THE SYMPTOMATIC PATIENT: SUPPORTIVE

 

  1. ACUTE DYSTONIC AND OTHER EXTRAPYRAMIDAL REACTIONS

 

Severe dystonic reactions can be controlled within a few minutes by

giving procyclidine or benztropine by the intravenous (or

intramuscular) route. Subsequent oral doses may be required for 2-3

days to prevent recurrence. Less severe extrapyramidal symptoms can be

controlled by oral doses of procyclidine, benztropine, or other

similar anticholinergic drug (Corre et al. 1984, Guy’s, Lewisham & St.

Thomas Paediatric Formulary 1997, BNF 1996).

 

Procyclidine IV, IM:

Adult dose:                 5-10 mg (use lower end of dose

range in elderly),

Child dose under 2 years:   500 micrograms-2 mg (unlicensed

indication)

Child dose 2-10 years:      2-5 mg (unlicensed indication).

 

Procyclidine oral:

Adult dose:                 2.5-10mg three times a day

Child 7-14 years            1.25mg three times a day

(unlicensed indication)

Child over 14 years         2.5mg three times a day (unlicensed

indication)

 

Benztropine dose IV, IM, and oral:

 

Adult dose:   1-2 mg (use lower end of dose range in elderly),

Child dose:   20 micrograms/kg (unlicensed indication).

 

  1. HYPOTENSION

 

Hypotension should be managed by the administration of intravenous

fluids and by physical means. Where these measures fail, consideration

may be given to the use of a direct acting sympathomimetic such as

noradrenaline with appropriate haemodynamic monitoring (e.g. insertion

of Swan-Ganz catheter).

 

ADULT DOSE: IV infusion of noradrenaline acid tartrate 80

micrograms/ml (equivalent to noradrenaline base 40 micrograms/ml) in

dextrose 5% via a central venous catheter at an initial rate of 0.16

to 0.33 ml/minute adjusted according to response (BNF 1998).

CHILD DOSE (unlicensed indication): IV infusion of noradrenaline

acid tartrate 0.04-0.2 microgram/kg/minute (equivalent to 0.02-0.1

microgram/kg/minute of noradrenaline base) in glucose 5% or

glucose/saline via a central venous catheter (Guy’s, Lewisham & St

Thomas Paediatric Formulary 1997).

 

NOTE: sympathomimetics with mixed alpha and beta adrenergic effects

(e.g. adrenaline or dopamine) should not be used as they may aggravate

hypotension.

 

  1. CARDIAC ARRHYTHMIAS

 

The ventricular arrhythmia, torsade de pointes, may prove difficult to

manage. Treatment is aimed at shortening the QT interval by

accelerating the heart rate. The preferred method is by CARDIAC

OVERDRIVE PACING (Henderson et al. 1991).

 

Alternatively isoprenaline may be used to increase the heart rate, but

with caution, as the unopposed beta 2-adrenergic agonist effects will

exacerbate hypotension.

ADULT DOSE: intravenous isoprenaline infused at a starting dose

of 0.2 micrograms/minute and titrated to maintain a heart rate of 100

beats per minute (Kemper et al. 1983).

 

Intravenous magnesium sulphate has also been shown to be effective in

the management of torsade de pointes (Tzivoni et al. 1988).

 

ADULT DOSE; 8 mmol of magnesium sulphate (4 ml of 50% solution)

by intravenous injection over 10-15 minutes, repeated once if

necessary (BNF 1998). CHILD DOSE: clinical experience in children is

lacking, but based on the above recommendations for management in

adults, doses of 0.08-0.2 mmol/kg (0.04-0.1 ml/kg of 50% solution) may

be considered appropriate (based on Guy’s, Lewisham & St Thomas

Paediatric Formulary 1997).

 

  1. TEMPERATURE DISTURBANCES

 

Where the patient is hypothermic the body temperature should be

allowed to recover naturally by wrapping the patient in blankets to

conserve body heat.

 

Conventional external cooling procedures should be used in patients

who are hyperthermic.

 

  1. NEUROLEPTIC MALIGNANT SYNDROME

 

The development of NMS with a high central temperature (over 39°C) is

best treated by paralysing and mechanically ventilating the patient.

This usually controls the muscle spasm and allows the temperature to

fall. If the body temperature is 40°C or over, administer intravenous

dantrolene.

 

ADULT DOSE: dantrolene 1 mg/kg body weight by rapid IV injection

repeated as required to a cumulative maximum of 10 mg/kg (BNF 1998).

 

Monitoring

 

Check the heart rate and rhythm, blood pressure, and body temperature

during the first 7-10 days after administration. Correct any

electrolyte abnormalities.

 

Antidotes

 

None available.

 

Elimination techniques

 

None.

 

Investigations

 

Management controversies

 

Case data

 

Analysis

 

Agent/toxin/metabolite

 

The measurement of plasma haloperidol is of little benefit as no

correlation has been established between plasma haloperidol

concentration and therapeutic or toxic effect.

 

Sample container

 

NA

 

Storage conditions

 

NA

 

Transport

 

NA

 

Interpretation of data

 

It has been suggested that a plasma haloperidol concentration of

0.005-0.012 mg/L may be associated with a clinical response, but this

range should only be viewed as a rough guide (Van Putten et al. 1992).

Peak concentrations following depot injection have been in the range

0.001-0.050 mg/L with steady-state concentrations around 0.008 mg/L

(Nayak et al. 1987).

 

Conversion factors

 

Others

 

NA

 

Toxicological data

 

Carcinogenicity

 

An increase in mammary neoplasms has been observed in rodents

following long term administration of prolactin-stimulating

antipsychotic agents. Although no association between human breast

cancer and long term administration of these drugs has been shown,

current evidence is too limited to be conclusive (AHFS 1998).

 

Genotoxicity

 

Mutagenicity

 

Reprotoxicity

 

Hyperprolactinaemia resulting from haloperidol therapy may lead to

infertility in women and impotence in men.

 

Teratogenicity

 

Haloperidol has been shown to be teratogenic and fetotoxic in animals

at dosages 2-20 times the usual maximum human dosage (AHFS 1998).

In human pregnancy, haloperidol has not been associated with

teratogenic effects when used alone, but there are two reports of limb

defects following the first trimester administration of haloperidol

with other drugs (Briggs 1994, Kopelman et al. 1975).

 

Relevant animal data

 

Relevant in vitro data

 

Authors

 

HY Allen

ZM Everitt

AT Judd

 

National Poisons Information Service (Leeds Centre)

Leeds Poisons Information Centre

Leeds General Infirmary

Leeds

LS1 3EX

UK

 

This monograph was produced by the staff of the Leeds Centre of the

National Poisons Information Service in the United Kingdom. The work

was commissioned and funded by the UK Departments of Health, and was

designed as a source of detailed information for use by poisons

information centres.

 

Peer review was undertaken by the Directors of the UK National Poisons

Information Service.

 

Prepared October 1996

Updated May 1998

 

References

 

AHFS.

AHFS, (American Hospital Formulary Service), Drug Information.

Bethesda MD: American Society of Health-System Pharmacists, 1996.

 

Aunsholt NA.

Prolonged Q-T interval and hypokalemia caused by haloperidol. Acta

Psychiatr Scand 1989; 79: 411-412.

 

Beresford R, Ward A.

Haloperidol decanoate: a preliminary review of its pharmacodynamic and

pharmacokinetic properties and therapeutic use in psychosis. Drugs

1987; 33: 31-49.

 

BNF.

Joint Formulary Committee. British National Formulary, Number 35.

London: British Medical Association & Royal Pharmaceutical Society of

Great Britain, 1998.

 

Briggs GG, Freeman RK, Yaffe SJ.

Drugs in Pregnancy and Lactation. 4th ed. Baltimore: Williams &

Wilkins, 1994: 409/h-410/h.

 

Chakraborty BS, Hubbard JW, Hawes EM, McKay G, Cooper JK, Gurnsey T,

Korchinski ED, Midha KK.

Interconversion between haloperidol and reduced haloperidol in healthy

volunteers. Eur J Clin Pharmacol 1989; 37: 45-48.

 

Cheng H, Jusko WJ.

Pharmacokinetics of reversible metabolic systems. Biopharm Drug Dispos

1993; 14: 721-766.

 

Cohen WJ, Cohen NH.

Lithium carbonate, haloperidol, and irreversible brain damage. J Am

Med Assoc 1974; 230: 1283-1287.

 

Corre KA, Niemann JT, Bessen HA.

Extended therapy for acute dystonic reactions. Ann Emerg Med 1984; 13:

194-197.

 

Cummingham DG, Challapalli M.

Hypertension in acute haloperidol poisoning. J Pediatr 1979; 95:

489-490.

 

Dollery C (Ed).

Therapeutic Drugs Volume 2. Edinburgh: Churchill Livingstone,

1991:H1-H4.

 

Forsman A, Folsch G, Larsson M, Ohman R.

On the metabolism of haloperidol in man. Curr Ther Res 1977; 21:

606-617.

 

Forsman A , Larsson M.

Metabolism of haloperidol. Curr Ther Res 1978; 24: 567-568.

 

Forsman A, Ohman R.

Applied pharmacokinetics of haloperidol in man. Curr Ther Res 1977a;

21: 396-411.

 

Forsman A, Ohman R.

Studies on serum protein binding of haloperidol. Curr Ther Res 1977b;

21: 245-255.

 

Guy’s, Lewisham and St. Thomas’ Paediatric Formulary.

4th edition. London: Guy’s and St. Thomas’ Hospitals Trust, 1997.

 

Henderson RA, Lane S, Henry JA.

Life-threatening ventricular arrhythmia (Torsade de Pointes) after

haloperidol overdose. Human Exper Toxicol 1991; 10: 59-62.

 

Holley FO, Magliozzi JR, Stanski DR, Lombrozo L, Hollister LE.

Haloperidol kinetics after oral and intravenous doses. Clin Pharmacol

Ther 1983; 33: 477-484.

 

Jann MW, Ereshefsky L, Saklad SR, Seidel DR, Davis CM, Burch NR,

Bowden CL.

Effects of carbamazepine on plasma haloperidol levels. J Clin

Psychopharmacol 1985; 5: 106-109.

 

Kemper AJ , Dunlap R, Pietro DA.

Thioridazine-induced torsade de pointes: successful therapy with

isoproterenol. J Am Med Assoc 1983; 249: 2931-2934.

 

Kopelman AE, McCullar FW, Heggeness L.

Limb malformations following maternal use of haloperidol. J Am Med

Assoc 1975; 231: 62-64.

 

Llerena A, Alm C, Dahl M-L, Ekqvist B, Bertilsson L.

Haloperidol disposition is dependent on debrisoquine hydoxylation

phenotype. Ther Drug Monit 1992; 14: 92-97.

 

Nayak RK, Doose DR, Nair NPV.

The bioavailability and pharmacokinetics of oral and depot

intramuscular haloperidol in schizophrenic patients. J Clin Pharmacol

1987; 27: 144-150.

 

Scialli JVK, Thornton WE.

Toxic reactions from a haloperidol overdose in two children: thermal

and cardiac manifestations. J Am Med Assoc 1978; 239: 48-49.

 

Sinaniotis CA, Spyrides P, Vlachos P, Papadatos C.

Acute haloperidol poisoning in children. J Pediatr 1978; 93:

1038-1039.

 

Stockley IH. Drug Interactions. 4th ed. London: The Pharmaceutical

Press, 1994

 

Tzivoni D, Banai S, Schuger C, Benhorin J, Keren A, Gottlieb S, Stern

S.

Treatment of torsade de pointes with magnesium sulfate. Circulation

1988; 77: 392-397.

 

Van Putten T, Marder SR, Mintz J, Poland RE.

Haloperidol plasma levels and clinical response: a therapeutic window

relationship. Am J Psychiatry 1992; 149: 500-505.

 

Yoshida I, Sakaguchi Y, Matsuishi T, Yano E, Yamashito Y, Hayata S,

Hitoshi T,

Yamashita F.

Acute accidental overdosage of haloperidol in children. Acta Paediatr

1993; 82 :877-880.

 

Zee-Cheng C-S, Mueller CE, Seifert CF, Gibbs HR.

Haloperidol and torsade de pointes. Ann Int Med 1985; 102: 418.

 

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MONOGRAPH FOR UKPID

CHLORPROMAZINE HYDROCHLORIDE

HY Allen

ZM Everitt

AT Judd

 

National Poisons Information Service (Leeds Centre)

Leeds Poisons Information Centre

Leeds General Infirmary

Leeds

LS1 3EX

UK

 

This monograph has been produced by staff of a National Poisons

Information Service Centre in the United Kingdom.  The work was

commissioned and funded by the UK Departments of Health, and was

designed as a source of detailed information for use by poisons

information centres.

 

Peer review group: Directors of the UK National Poisons Information

Service.

 

MONOGRAPH FOR UKPID

 

Drug name

 

Chlorpromazine hydrochloride

 

Chemical group

 

Phenothiazine

 

Origin

 

Synthetic

 

Name

 

UK Brand name(s)

Largactil(R), Chloractil(R)

 

Synonyms

 

Common names

 

Product licence number

 

Largactil(R) 10mg: 0012/5108R

Largactil(R) 25mg: 0012/5109R

Largactil(R) 50mg: 0012/5110R

Largactil(R) 100mg: 0012/5111R

Largactil(R) injection solution 2.5%: 0012/5308R

Largactil(R) syrup: 0012/5083R

Largactil(R) Forte Suspension: 0012/5001R

 

CAS number

 

69-09-0

 

Manufacturer

 

Rhône-Poulenc Rorer Ltd

 

Available as Largactil(R) from Rhône-Poulenc Rorer, and as generics or

branded generics from Antigen, APS, DDSA (Chloractil(R)), Hillcross,

Rosemont and Norton.

 

Form

 

Tablets

Oral liquids

Injection

Suppositories

 

Formulation details

 

Tablets of 10 mg, 25 mg, 50 mg, and 100 mg

Syrup containing 25 mg / 5 ml

Forte suspension equivalent to 100 mg/5 ml (as chlorpromazine

embonate)

Injection of 25 mg / ml.

Suppositories of 100 mg (unlicensed product)

 

Pack size

 

Largactil tabs 10 mg, 25 mg, 50 mg, and 100 mg – blister packs of 56

Largactil syrup – 100ml pack

Largactil forte suspension – 100ml pack

Largactil injection – ampoules of 1 ml and 2 ml

 

Pack sizes may differ for generics and branded generics.

 

Packaging

 

Largactil(R) tabs 10mg – white tablets marked LG10

Largactil(R) tabs 25mg – white tablets marked LG25

Largactil(R) tabs 50mg – white tablets marked LG50

Largactil(R) tabs 100mg – white tablets marked LG100

 

Chemical structure

 

C17H19ClN2S.HCl

 

Chemical name

 

3-(2-Chlorophenothiazin-10-yl)propyldimethylamine hydrochloride

 

Indication

 

Schizophrenia and other psychoses, (especially paranoid and

hypomania); short-term adjunctive management of anxiety, psychomotor

agitation, excitement, and violent or dangerously impulsive behaviour;

intractable hiccup; nausea and vomiting of terminal illness (where

other drugs have failed or are not available); induction of

hypothermia; childhood schizophrenia and autism.

 

Therapeutic dosage – adults

 

BY MOUTH: 75-300 mg daily in divided doses (doses up to 1 g used in

psychoses).

BY DEEP IM INJECTION: 25-50 mg every 6-8 hours.

BY RECTUM (unlicensed route): 100 mg every 6-8 hours.

 

For equivalent therapeutic effect:

 

100 mg by rectum ° 20-25 mg by IM injection ° 40-50 mg by mouth

 

Therapeutic dosage – children

 

BY MOUTH: 1-5 years:     500 micrograms/kg 4-6 hourly (maximum 40 mg

daily).

6-12 years:    _ to ´ adult dose (maximum 75 mg daily).

 

BY DEEP IM INJECTION:

500 micrograms/kg 6-8 hourly with maximum daily dose as for

oral dose.

 

BY RECTUM (unlicensed route):

1-4 years:          12.5 mg 3-4 hourly.

5-12 years:         25 mg 3-4 hourly.

over 12 years:      50-100 mg 3-4 hourly.

 

Contra-indications

 

Coma caused by CNS depressants, bone marrow depression,

phaeochromocytoma.

 

Abuses

 

Epidemiology

 

Although the phenothiazines show similar toxic properties to the

tricyclic antidepressants, overdoses tend to be less serious, with

severe hypotension and cardiotoxicity being less common. (Ellenhorn

1997).

 

ADVERSE EFFECTS

 

There are a large number of adverse effects associated with

therapeutic use including changes in hepatic, cardiovascular,

respiratory, haematologic, ocular and endocrine functions, besides

extrapyramidal reactions and the risk of neuroleptic malignant

syndrome.

Postural hypotension commonly occurs, especially after intramuscular

administration.

 

INTERACTIONS

 

PHARMACODYNAMIC

 

  1.   Chlorpromazine enhances the central nervous system depression

produced by other CNS DEPRESSANT drugs.

 

  1.   The hypotensive effect of ANTIHYPERTENSIVE AGENTS is likely to be

enhanced, the exception being GUANETHIDINE where chlorpromazine

may antagonise its hypotensive effect (Fruncillo 1985, Janowsky

1973).

  1.   There is an increased risk of ventricular arrhythmias when

chlorpromazine is taken with drugs that increase the QT interval

e.g. ASTEMIZOLE, TERFENADINE, or ANTI-ARRHYTHMIC AGENTS.

 

  1.   Combination with other antidopaminergic agents such as

METOCLOPRAMIDE or PROCHLORPERAZINE increases the risk of

extrapyramidal effects.

 

PHARMACOKINETIC

 

  1.   The metabolism of TRICYCLIC ANTIDEPRESSANTS is impaired by

chlorpromazine, increasing the risk of toxicity (Balant-Gorgia &

Balant 1987).

 

OTHER

 

An interaction between phenothiazine drugs and ‘caffeinated’ beverages

has been reported. A precipitation occurs when these drugs are diluted

in tea or coffee (including decaffeinated varieties) which is

considered to be a nonspecific reaction between the

nitrogen-containing organic bases and tannic acid. The reaction is

reversible in the acid environment of the stomach (Curry et al. 1991).

 

ETHANOL

 

The administration of ethanol with chlorpromazine results in

potentiated sedative effects and impaired co-ordination (Lieber 1994,

Milner & Landauer 1971, Zirkle 1959).

 

MECHANISM OF ACTION

 

Chlorpromazine blocks post-synaptic D2 dopamine receptors. It is

considered that dopamine receptor blockade in the mesolimbic area

accounts for the antipsychotic effect, whilst blockade in the

nigrostriatal system produces the extrapyramidal effects associated

with chlorpromazine use. The anti-emetic effect results from dopamine

antagonism in the chemoreceptor trigger zone. Chlorpromazine also

possesses antimuscarinic properties. It is an antagonist at histamine

(H1), serotonin and alpha-1-adrenergic receptors (Dollery 1991).

 

MECHANISM OF TOXICITY

 

The extrapyramidal, anticholinergic, sedative, and hypotensive

features of toxicity result from the blockade of dopaminergic,

muscarinic, histaminic, and alpha adrenergic receptors respectively.

The cardiotoxic effects of phenothiazines in overdose are similar to

that of the tricyclic antidepressants. (Ellenhorn 1997). Cardiac

arrhythmia and apparent ‘sudden death’ have been associated with

therapeutic doses of chlorpromazine, the sudden cardiovascular

collapse being attributed to ventricular dysrhythmia (Fowler et al.

1976, Hollister & Kosec 1965).

 

Pharmacokinetics

 

ABSORPTION

 

Peak plasma concentrations occur on average 2-3 hours (range 1.5-8

hours) after an oral dose (Midha et al. 1989, Yeung et al. 1993).

After intramuscular injection chlorpromazine is slowly absorbed from

the injection site, with the peak plasma concentration occurring 6-24

hours after administration (Dahl & Strandjord 1977).

The oral bioavailability of chlorpromazine is about 30% that of

intramuscular doses (Dahl & Strandjord 1977) and about 10% that of

intravenous doses (Yeung et al. 1993) as a result of pre-systemic

metabolism.

 

DISTRIBUTION

 

Chlorpromazine is highly lipid soluble and is 98% bound to plasma

proteins (Dollery 1991). It is extensively distributed throughout the

body and has a mean volume of distribution of 17 L/kg (Yeung et al.

1993).

 

METABOLISM

 

Chlorpromazine is subject to significant pre-systemic metabolism

attributed to first passage through the gut wall, liver and lung

(Yeung et al. 1993).

It is extensively metabolised involving cytochrome P450 microsomal

pathways (Lieber 1994) with more than 100 metabolites being

theoretically possible (Javaid 1994). The major routes of metabolism

include hydroxylation, N-oxidation, sulphoxidation, demethylation,

deamination and conjugation (Dollery 1991). A number of the

metabolites may contribute to the pharmacological effects of

chlorpromazine including 7-hydroxychlorpromazine,

chlorpromazine-N-oxide, 3-hydroxychlorpromazine and

desmethylchlorpromazine (Chetty et al. 1994). Although the metabolite

chlorpromazine-N-oxide does not possess activity in vitro, it exerts

an indirect pharmacological effect in vivo by reverting to

chlorpromazine (Cheng & Jusko 1993). It is considered that one of the

metabolites produced (chlorpromazine-sulphoxide) may oppose the

alpha-adrenergic blocking action of chlorpromazine (Chetty et al.

1994).

There is limited evidence to suggest that following multiple doses,

the metabolism of chlorpromazine may be increased due to induction of

microsomal liver enzymes (Dahl & Strandjord 1977).

 

ELIMINATION

 

Excretion is primarily via the kidneys with less than 1% of a dose

excreted as unchanged drug in the urine, and 20-70% as conjugated or

unconjugated metabolites (Dollery 1991). 5-6% of a dose is excreted in

faeces via biliary elimination (Dollery 1991).

Some metabolites can still be detected up to 18 months after

discontinuation of long-term therapy (Dollery 1991).

 

HALF-LIFE

 

The half-life of chlorpromazine is usually within the range 8-35 hours

(Dollery 1991), although it is as short as 2 hours or as long as 60

hours in some individuals (Midha et al. 1989). The half-lives of the

primary metabolites are generally within the same range (Yeung et al.

1993).

 

Special populations

 

ELDERLY: it has been suggested that the elderly metabolise

antipsychotic drugs more slowly than do the non-elderly adult

population (Balant-Gorgia & Balant 1987).

 

RENAL IMPAIRMENT: the effects of renal disease on chlorpromazine

pharmacokinetics are not known, but since it is extensively

metabolised in the liver, they are not anticipated to be great.

 

HEPATIC IMPAIRMENT: it is considered that hepatic dysfunction will

increase the bioavailability of chlorpromazine and delay its

elimination (Dollery 1991).

 

GENDER:

 

Breast milk

 

Chlorpromazine has been identified in the milk of nursing mothers

receiving the drug.

In one study (Blacker et al. 1962) the peak milk concentration of

chlorpromazine (0.29 mg/L) occurred 2 hours after a single oral dose

of 1200 mg, although in this report the assay design was relatively

nonspecific and no account was taken of active metabolites.

In a later study chlorpromazine and several metabolites were

identified in the breast milk of four nursing mothers receiving the

drug (doses not specified). The milk concentrations ranged from

0.007-0.098 mg/L, with maternal serum levels ranging from 0.016-0.052

mg/L. In two of the four patients the milk concentrations of

chlorpromazine were higher than the maternal plasma concentrations.

One of the babies was reported to be drowsy and lethargic (the milk

chlorpromazine level in this case was 0.092 mg/L) (Wiles et al. 1978).

 

Toxicokinetics

 

Absorption

 

Distribution

 

Metabolism

 

Elimination

 

HALF-LIFE

 

HALF-LIFE – METABOLITES

 

Special populations

 

ELDERLY:

 

RENAL IMPAIRMENT:

 

HEPATIC IMPAIRMENT:

 

GENDER:

 

Breast milk

 

Summary

 

TYPE OF PRODUCT

 

A phenothiazine antipsychotic.

 

INGREDIENTS

 

Tablets of 10 mg, 25 mg, 50 mg, and 100 mg.

Oral liquids containing 25 mg / 5 ml, and 100 mg / 5 ml.

Injection of 25 mg / ml.

Suppositories of 100 mg (unlicensed product).

 

SUMMARY OF TOXICITY

 

Central nervous system depression is the most common feature of

toxicity and usually begins 1-2 hours after ingestion. Hypotension and

anticholinergic symptoms are also common. Acute dystonic reactions and

cardiac arrhythmias may occur. Chlorpromazine lowers the seizure

threshold (a dose-related effect) so convulsions may occur in patients

not previously known to be epileptic.

 

Individual response to chlorpromazine overdose is variable – an

ingestion of 20 g has been survived, whilst 2 g has proved fatal.

 

In children, hypotension and drowsiness can follow doses ranging from

100-375 mg, with severe central nervous system depression resulting

from higher doses. Fatalities have been reported in children, the

doses ingested ranging from 20-74 mg/kg.

 

In mixed drug ingestions chlorpromazine enhances the sedation produced

by other central nervous system depressants including ethanol.

 

FEATURES

 

Drowsiness, hypotension, anticholinergic symptoms (e.g. dry mouth,

dilated pupils, urinary retention, visual disturbances), acute

dystonic reactions, and cardiac arrhythmias.

 

UNCOMMON FEATURES

 

Acute pulmonary oedema, and neuroleptic malignant syndrome.

 

SUMMARY OF MANAGEMENT

 

  1.   Maintain a clear airway and adequate ventilation if consciousness

is impaired.

 

  1.   If within 1 hour of the ingestion and more than 500mg has been

ingested by an adult, or more than 4mg/kg by a child, give oral

activated charcoal.

 

  1.   Monitor the cardiac rhythm.

 

  1.   Manage hypotension with IV fluids.

 

  1.   Treat acute dystonic reactions with IV procyclidine or

benztropine.

 

Clinical Features

 

Features – acute

 

Ingestion

 

Hypotension, sinus tachycardia, varying degrees of CNS depression,

blurred vision, dry mouth, urinary retention, acute dystonic

reactions, akathisia, parkinsonism, ECG changes including prolonged PR

and QT intervals, ventricular tachyarrhythmias, convulsions,

hypothermia (or occasionally hyperthermia), pulmonary oedema, and

respiratory depression (Allen et al. 1980, Barry et al. 1973,

Ellenhorn 1997, Li & Gefter 1992, Reid & Harrower 1984).

 

Inhalation

 

Dermal

 

Contact dermatitis.

 

Ocular

 

Other routes

 

BY INJECTION: as for acute ingestion.

 

Features – chronic

 

Ingestion

 

As for acute ingestion, but with the additional risks of the

development of neuroleptic malignant syndrome (characterised by muscle

rigidity, hyperthermia, altered consciousness, and autonomic

instability), and tardive dyskinesia (involuntary movements of the

tongue, face, jaw, or mouth) (Rosenberg & Green 1989).

 

Inhalation

 

Dermal

 

Contact dermatitis.

 

Ocular

 

Other routes

 

BY INJECTION: as for chronic ingestion.

 

At risk groups

 

ELDERLY

 

Elderly and volume depleted subjects are particularly susceptible to

postural hypotension.

 

PREGNANCY

 

The administration of chlorpromazine near term has been associated

with unpredictable falls in maternal blood pressure which could be

dangerous to the mother and the foetus. Administration near term has

also resulted in an extrapyramidal syndrome in some infants,

characterised by tremors, increased muscle tone, and hyperactive deep

tendon reflexes persisting some months (Briggs 1994).

 

One psychiatric patient who ingested 8 g of chlorpromazine in the last

ten days of pregnancy, delivered a hypotonic, lethargic infant with

depressed reflexes and jaundice (Hammond & Toseland 1970).

 

CHILDREN

 

ENZYME DEFICIENCIES

 

ENZYME INDUCED

 

Occupations

 

Pharmacists, nurses, and other health workers should avoid direct

contact with chlorpromazine due to a risk of contact sensitisation.

Tablets should not be crushed and solutions handled with care (BNF

1998).

 

Others

 

RENAL IMPAIRMENT: renal impairment is unlikely to increase the risk of

toxicity.

HEPATIC IMPAIRMENT: increased risk of toxicity due to impaired

metabolism and hepatotoxic potential.

CARDIAC DISEASE: increased risk of cardiotoxicity due to underlying

disease.

EPILEPSY: increased risk of seizures due to lowered seizure threshold.

 

Management

 

Decontamination

 

If within one hour of the ingestion, and more than 500mg has been

ingested by an adult, or 100mg by a child, oral activated charcoal may

be given to reduce drug absorption.

ADULT DOSE: 50g; CHILD DOSE; 1g/kg.

If the patient is drowsy this should be administered via a nasogastric

tube, and if there is no gag reflex present, using an endotracheal

tube to protect the airway.

 

Supportive care

 

GENERAL MANAGEMENT OF THE SYMPTOMATIC PATIENT

 

Clear and maintain airway, and give cardiopulmonary resuscitation if

necessary.

Evaluate the patient’s condition and provide support for vital

functions. The aim is to maintain vital bodily functions with minimal

intervention whilst the elimination of chlorpromazine takes place.

Particular care should be given to the prevention of hypoxia and

acidosis, and the correction of any electrolyte imbalance.

 

SPECIFIC MANAGEMENT OF THE SYMPTOMATIC PATIENT

 

  1. HYPOTENSION

 

Hypotension should be managed by the administration of intravenous

fluids and by physical means. Where these measures fail, consideration

may be given to the use of a direct acting sympathomimetic such as

noradrenaline with appropriate haemodynamic monitoring (e.g. insertion

of Swan-Ganz catheter).

 

ADULT DOSE: IV infusion of noradrenaline acid tartrate 80

micrograms/ml (equivalent to noradrenaline base 40 micrograms/ml) via

a central venous catheter at an initial rate of 0.16 to 0.33 ml/minute

adjusted according to response (BNF 1998).

CHILD DOSE (unlicensed indication): IV infusion of noradrenaline

acid tartrate 0.04-0.2 microgram/kg/minute (equivalent to 0.02-0.1

microgram/kg/minute of noradrenaline base) in glucose 5% or

glucose/saline via a central venous catheter (Guy’s, Lewisham & St

Thomas Paediatric Formulary, 1997).

 

NOTE: vasopressors with mixed alpha and beta adrenergic effects (e.g.

adrenaline, dopamine) should not be used as hypotension may be

exacerbated.

 

  1. COMA

Good supportive care is essential.

 

  1. CARDIOTOXICITY

 

In practice it is seldom necessary or advisable to use specific drug

treatment for arrhythmias. If hypoxia and acidosis are reversed, and

adequate serum potassium levels maintained, then the majority of

patients will show improvement with supportive measures. Where these

measures fail and life-threatening arrhythmias persist, intravenous

sodium bicarbonate should be given (even in the absence of acidosis)

before considering antiarrhythmic drug therapy.

Where an antiarrhythmic is considered necessary, lignocaine is the

preferred drug.

ADULT DOSE: 50-100 mg lignocaine by IV bolus given over a few

minutes, followed by an infusion of 4 mg/minute for 30 minutes, 2

mg/minute for 2 hours, then 1 mg/minute (BNF 1998).

NOTE: the use of quinidine, procainamide, flecainide, or disopyramide,

is contraindicated as these agents further depress cardiac conduction

and contractility. The use of beta-blockers and calcium channel

blockers should also be avoided as they decrease cardiac output and

exacerbate hypotension.

 

The ventricular arrhythmia, TORSADE DE POINTES, may prove difficult to

manage. The preferred treatment is cardiac overdrive pacing, but in

cases where cardiac pacemaker insertion is not readily available,

intravenous magnesium sulphate has been shown to be effective (Tzivoni

et al. 1988).

ADULT DOSE: 8 mmol of magnesium sulphate (4 ml of 50% solution)

by intravenous injection over 10-15 minutes, repeated once if

necessary (BNF 1998).

CHILD DOSE: clinical experience in children is lacking, but based

on the above recommendations for management in adults, doses of 0.08-

0.2 mmol/kg (0.04-0.1 ml/kg of 50% solution) may be considered

appropriate (based on Guy’s, Lewisham & St Thomas Paediatric

Formulary, 1997).

Torsade de pointes has also been successfully managed in adults by the

intravenous administration of isoprenaline (infused at a starting dose

of 0.2 micrograms/minute and titrated to maintain a heart rate of 100

beats per minute) (Kemper et al. 1983). However it should be used with

caution as its beta-2-adrenergic agonist effects exacerbate

hypotension.

 

  1. ACUTE DYSTONIC AND OTHER EXTRAPYRAMIDAL REACTIONS

 

Severe dystonic reactions can be controlled within a few minutes by

giving procyclidine or benztropine by the intravenous (or

intramuscular) route. Subsequent oral doses may be required for 2-3

 

days to prevent recurrence. Less severe extrapyramidal symptoms can be

controlled by oral doses of procyclidine, benztropine, or other

similar anticholinergic drug (Corre et al. 1984, Guy’s, Lewisham & St.

Thomas Paediatric Formulary, 1997, BNF 1998).

Procyclidine IV, IM, and oral:

ADULT DOSE:    5-10 mg (use lower end of dose range in elderly),

CHILD DOSE under 2 years: 500 micrograms-2 mg (unlicensed

indication)

2-10 years:    2-5 mg (unlicensed indication).

Benztropine dose IV, IM, and oral:

ADULT DOSE:    1-2 mg (use lower end of dose range in elderly),

CHILD DOSE:    20 micrograms/kg (unlicensed indication).

 

  1. SEIZURES/MUSCLE SPASMS

 

Diazepam by slow intravenous injection preferably in emulsion form,

may be given to control muscle spasms and convulsions not remitting

spontaneously.

ADULT DOSE: 10 mg repeated as required depending upon clinical

condition;

CHILD DOSE: 200 – 300 micrograms/kg.

 

  1. TEMPERATURE DISTURBANCES

 

Where the patient is hypothermic the body temperature should be

allowed to recover naturally by wrapping the patient in blankets to

conserve body heat.

Conventional external cooling procedures should be used in patients

who are hyperthermic.

 

  1. NEUROLEPTIC MALIGNANT SYNDROME

 

The development of neuroleptic malignant syndrome with a high central

temperature (over 39°C) is best treated by paralysing and mechanically

ventilating the patient. This usually controls the muscle spasm and

allows the temperature to fall. If the body temperature is 40°C or

over, administer intravenous dantrolene.

ADULT DOSE: 1 mg/kg body weight by rapid IV injection repeated as

required to a cumulative maximum of 10 mg/kg (BNF 1998).

 

  1. OTHER MEASURES

 

Pulmonary oedema typically resolves with conventional supportive

management within 18-40 hours of ingestion (Li & Gefter 1992).

 

Monitoring

 

Monitor the heart rate and rhythm, blood pressure, arterial blood

gases, serum electrolytes, body temperature, respiratory rate and

depth, and urinary output.

 

Observe for a minimum of 4 hours post-ingestion where:

  1. i) more than 4 mg/kg has been ingested by a child (or more than

the child’s normal therapeutic dose, if this is greater),

  1. ii) more than 500 mg is known to have been ingested by an adult

(or more than the patients’s normal therapeutic dose, if this is

greater),

iii) the patient is symptomatic.

Where symptoms develop following overdose, they may persist for 24

hours. Complications following severe toxicity may require the patient

to be hospitalised for several days.

 

Antidotes

 

None available.

 

Elimination techniques

 

Haemodialysis and diuresis are ineffective as ways of increasing drug

elimination due to the large volume of distribution and high lipid

solubility of chlorpromazine. It is not considered that haemoperfusion

will be of benefit (Ellenhorn 1997).

 

Investigations

 

Where there is evidence of severe toxicity a chest radiograph should

be performed within 24 hours of the ingestion to exclude pulmonary

complications.

 

Management controversies

 

GASTRIC LAVAGE is not recommended as the procedure may be associated

with significant morbidity, and there is no evidence that it is of any

greater benefit than activated charcoal used alone.

If the procedure is used (i.e. in cases where activated charcoal

cannot be administered), a cuffed endotracheal tube should be used to

protect the airway if the patient is drowsy, and activated charcoal

left in the stomach following the lavage.

 

Case data

 

CASE REPORT 1

 

A 27 year old woman was admitted 12 hours after ingesting 8 g

chlorpromazine and 150 mg flurazepam. After 18 hours she was fully

alert and normotensive. Six hours later she sustained a cardiac arrest

and was successfully resuscitated. Subsequent ventricular tachycardia

responded to intravenous lignocaine, and a prolonged QT interval

shortened progressively to normal over the next three days (Reid &

Harrower 1984).

 

Analysis

 

Agent/toxin/metabolite

 

Several studies to determine the relationship between plasma

concentration and therapeutic response have been performed. The

majority of studies showed large individual variations in

chlorpromazine concentration relative to dose, and no clear

association between plasma concentration and therapeutic response has

been made (Dahl & Strandjord 1977).

As a consequence the measurement of plasma chlorpromazine

concentrations following overdose is not routinely advised.

 

Sample container

 

Storage conditions

 

Transport

 

Interpretation of data

 

Although no clear relationship exists between plasma concentration and

therapeutic effect,

it has been suggested that therapeutic response may be associated with

the plasma concentration range 0.05-0.30 mg/L (Rivera-Calimlim et al.

1976).

In a study of unexplained deaths in patients receiving multiple

antipsychotic therapy, five cases had concentrations of antipsychotic

drugs which were considered ‘probably’ toxic and were implicated in

the development of ventricular fibrillation. The plasma chlorpromazine

concentrations in these cases were in the range 0.5-7.0 mg/L (Jusic &

Lader 1994).

 

Conversion factors

 

1 mg/L = 2.817 micromoles/L

1 micromole/L = 0.355 mg/L

 

The molecular weight of chlorpromazine hydrochloride is 355.3

 

Others

 

Toxicological data

 

Carcinogenicity

 

Genotoxicity

 

Mutagenicity

 

Reprotoxicity

 

Teratogenicity

 

Chlorpromazine readily crosses the placenta. Although one study found

an increased incidence of malformations in first trimester

phenothiazine-exposed infants compared to non-exposed controls

(3.5%compared to 1.6%), most reports describing the use of

phenothiazines in pregnancy (during all stages of gestation) conclude

that they do not adversely affect the foetus or newborn (Briggs 1994).

 

Relevant animal data

 

Relevant in vitro data

 

Authors

 

HY Allen

ZM Everitt

AT Judd

 

National Poisons Information Service (Leeds Centre)

Leeds Poisons Information Centre

Leeds General Infirmary

Leeds

LS1 3EX

UK

 

This monograph was produced by the staff of the Leeds Centre of the

National Poisons Information Service in the United Kingdom. The work

was commissioned and funded by the UK Departments of Health, and was

designed as a source of detailed information for use by poisons

information centres.

 

Peer review was undertaken by the Directors of the UK National Poisons

Information Service.

 

Prepared November 1996

Updated May 1998

 

References

 

Allen MD, Greenblatt DJ, Noel BJ.

Overdosage with antipsychotic agents. Am J Psychiatry 1980; 137:

234-236.

 

Balant-Gorgia AE, Balant L.

Antipsychotic drugs – clinical pharmacokinetics of potential

candidates for plasma concentration monitoring. Clin Pharmacokinet

1987; 13: 65-90.

 

Barry D, Meyskens FL, Becker CE.

Phenothiazine poisoning – a review of 48 cases. Calif Med 1973; 118:

1-5.

 

Blacker KH, Weinstein BJ, Ellman GL.

Mother’s milk and chlorpromazine. Am J Psychiatry 1962; 119: 178-179.

 

BNF 1998.

Joint Formulary Committee. British National Formulary, Number 35.

London: British Medical Association & Royal Pharmaceutical Society of

Great Britain, 1998.

 

Briggs GG, Freeman RK, Yaffe SJ.

Drugs in Pregnancy and Lactation. 4th ed. Baltimore: Williams &

Wilkins, 1994: 166c-168c.

 

Cheng H, Jusko WJ.

Pharmacokinetics of reversible metabolic systems. Biopharm Drug Dispos

1993; 14: 721-766.

 

Chetty M, Moodley SV, Miller R.

Important metabolites to measure in pharmacodynamic studies of

chlorpromazine. The Drug Monit 1994; 16: 30-36.

 

Corre KA, Niemann JT, Bessen HA.

Extended therapy for acute dystonic reactions. Ann Emerg Med 1984; 13:

194-197.

 

Curry ML, Curry SH, Marroum PJ.

Interaction of phenothiazine and related drugs and caffeinated

beverages (letter). Ann Pharmacother 1991; 25: 437.

 

Dahl SG, Strandjord RE.

Pharmacokinetics of chlorpromazine after single and chronic dosage.

Clin Pharmacol The 1977; 21: 437-448.

 

Dollery C (Ed).

Therapeutic Drugs Volume 1. Edinburgh: Churchill Livingstone, 1991:

C201-C206.

 

Donlon PT, Tupin JP.

Successful suicides with thioridazine and mesoridazine. Arch Gen

Psychiatry 1977; 34: 955-957.

 

Ellenhorn MJ

Ellenhorn,s Medical Toxicology: diagnosis and treatment of human

poisoning. 2nd ed. Baltimore: Williams and Wilkins, 1997.

 

Fowler NO, McCall D, Chou T-C, Holmes JC, Hanenson IB.

Electrocardiographic changes and cardiac arrhythmias in patients

receiving psychotropic drugs. Am J Cardiol 1976; 37: 223-230.

 

Fruncillo RJ, Gibbons WJ, Vlasses PH, Ferguson RK.

Severe hypotension associated with concurrent clonidine and

antipsychotic medication (letter). Am J Psychiatry 1985; 142: 274.

 

Guy’s, Lewisham & St. Thomas’ Hospitals Paediatric Formulary, 4th

Edition. London: Guy’s & St. Thomas’ Hospital Trust, 1997.

 

Hammond JE, Toseland PA.

Placental transfer of chlorpromazine. Arch Dis Child 1970; 45:

139-140.

 

Hollister LE, Kosek JC.

Sudden death during treatment with phenothiazine derivatives. J Am Med

Assoc 1965; 192: 1035-1038.

 

Janowsky DS, El-Yousef MK, Davis JM, Fann WE.

Antagonism of guanethidine by chlorpromazine. Am J Psychiatry 1973;

130: 808-812.

 

Javaid JI.

Clinical pharmacokinetics of antipsychotics. J Clin Pharmacol 1994;

34: 286-295.

 

Jusic N, Lader M.

Post-mortem antipsychotic drug concentrations and unexplained deaths.

Br J Psychiatry 1994; 165: 787-791.

 

Kemper AJ , Dunlap R, Pietro DA.

Thioridazine-induced torsade de pointes: successful therapy with

isoproterenol. J Am Med Assoc 1983; 249: 2931-2934.

 

Li C, Gefter WB.

Acute pulmonary edema induced by overdosage of phenothiazines. Chest

1992; 101: 102-104.

 

Lieber CS.

Mechanisms of ethanol-drug-nutrition interactions. J Toxicol Clin

Toxicol 1994; 32: 631-681.

 

McKown CH, Verhulst HL, Crotty JJ.

Overdosage effects and danger from tranquillizing drugs. J Am Med

Assoc 1963; 185: 425-430.

 

Midha KK, Hawes EM, Hubbard JW, Korchinski ED, McKay G.

Intersubject variation in the pharmacokinetics of chlorpromazine in

healthy men. J Clin Psychopharmacol 1989; 1: 4-8.

 

Milner G, Landauer AA.

Alcohol, thioridazine and chlorpromazine effects on skills related to

driving behaviour. Br J Psychiatry 1971; 118: 351-352.

 

Reid W, Harrower ADB.

Cardiac arrest after apparent recovery from an overdose of

chlorpromazine (letter). Br Med J 1984; 288: 1880.

 

Rivera-Calimlim L, Nasrallah H, Strauss J, Lasagna L.

Clinical response and plasma levels: effect of dose, dosage schedules,

and drug interactions on plasma chlorpromazine levels. Am J Psychiatry

1976; 133: 646-652.

 

Rosenberg MR, Green M.

Neuroleptic malignant syndrome. Arch Intern Med 1989; 149: 1927-1931.

 

Tzivoni D, Banai S, Schuger C, Benhorin J, Keren A, Gottlieb S, Stern

S.

Treatment of torsade de pointes with magnesium sulfate. Circulation

1988; 77: 392-397.

 

Wiles DH, Orr MW, Kolakowska T.

Chlorpromazine levels in plasma and milk of nursing mothers. Br J Clin

Pharmacol 1978; 5: 272-273.

 

Yeung PK-F, Hubbard JW, Korchinski ED, Midha KK.

Pharmacokinetics of chlorpromazine and key metabolites. Eur J Clin

Pharmacol 1993; 45: 563-569.

 

Zirkle GA, King PD, McAtee OB, Van Dyke R. Effects of chlorpromazine

and alcohol on coordination and judgment. J Am Med Assoc 1959; 171:

1496-1499.

 

See Also:

Chlorpromazine (PIM 125)

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