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    Anxiety disorders plague about 40 million people over 18 years old living in the U.S. on an annual basis. Unfortunately, only about 40 percent of those who have these disorders get any treatment to help manage their symptoms. Anxiety is one of the most manageable diseases to treat. But, the medications that are used, classified as anxiolytic, have side effects that can alter someone’s life. For anyone trying to figure out how to manage anxiety through a more natural approach, some options do not involve medication. One of the most promising choices that are currently on the market is CBD oil. It is showing promise in treating issues people struggle with and preventing future problems from forming.

What Is CBD Oil?

CBD, which stands for cannabidiol, is pressed out of a hemp plant. Hemp is just one of the most well-known species of the cannabis plant. Marijuana is the other famous species. The difference between hemp and marijuana is that the marijuana plant contains tetrahydrocannabinol or THC. This is the chemical responsible for the psychoactive effects or “high” that cannabis users typically report. The other substance is the cannabidiol, which is responsible for the relaxing effects that come with CBD. This has no effect that gives a feeling of dissociation because there is no psychoactive component. 

When hemp is pressed, the oil that comes out is then purified and bottled, creating CBD oil. This can be used to help manage pain and anxiety, among other medical conditions. People using these products do not have to worry about the same effects that come from marijuana since there is no THC in them. The “high” will not happen, and the relief they can experience is natural. Plus, the side effects of many of the anti-anxiety medications on the market are nothing to worry about, either. 

Is CBD Different Than Medical Marijuana?

There are many uses for medical marijuana, and it is a substance that is becoming legal in a growing number of states. However, the substances are different. Medical cannabis needs a prescription to get, and still contains some of the THC that causes the “high.” The amounts are just much lower than traditional cannabis has. CBD from hemp has less than 0.3 percent of THC in it, making it incapable of providing any psychoactive effect. While CBD can help with many medical issues, it is not used for the same things that cannabis is used since the cannabis offers the “high” and CBD does not.

What Effects Do People Taking CBD Feel Most?

When people start to take CBD, overall, they feel better. It is not one specific area of the body that begins to feel better, but the body as a whole. That is due to the effects of CBD on how the body functions. Medications are usually used for a specific ailment, and only work to fix that ailment. CBD, on the other hand, is put into the body to help improve how the body functions. It helps the body recognize areas that were not working as well as they should have been and gets those body parts to become more responsive and alert.

For people with anxiety, the CBD helps the body realize that it was not functioning as it should. As CBD goes into the body, it moves along the endocannabinoid system. This system is set up to hold the different CB receptors in the body and to receive messages that the body sends. Unfortunately, in many instances, when someone faces anxiety issues, those receptors are not working correctly. The receptors forget to open or do not open in time to receive a message. CBD helps to naturally remind those receptors to open and take in the messages being sent around. From there, the receptor can decipher what was the message and reply in a way that makes sense. Medication forces the body to act in some specific way, but CBD allows the body to respond naturally. This helps the body relearn how to move in ways it once forgot, or learn how to act in ways it never knew. 

When someone has anxiety, those messages only sometimes get opened. Many times, when the signals of worry or concern are opened, sometimes the receptors send back inadequate responses, such as not being able to breathe correctly or tensing up the muscles. CBD allows the body and the central nervous system a chance to synchronize backup and work together as they should. This is not an instant fix, nor does it work for everyone, but in many cases, CBD may help alleviate anxiety symptoms and put the person back in control. 

There are other effects that those taking CBD also feel, including: 
    

Causes of Anxiety Disorders

Many different things can lead to an anxiety issue. Some things are controllable, such as situations in life, while others are not. The most common causes of anxiety include: 
    
    

Which Forms of Anxiety Are Most Present in the Population?

People all around the United States struggle with anxiety, but the specific type of stress varies. Here are some of the most common forms of anxiety that people are trying to manage.


Most Common Treatments for Anxiety

By far, the most common way of treating anxiety is medication, at least out of the people who seek treatment. However, most people do not try to receive treatment. The classifications of medication often used to treat anxiety include: 

Another treatment option that is coming to light is CBD oil. The properties of CBD allow it to be an excellent way for many people to relax. Plus, cannabinoids are natural, therefore causing fewer adverse effects to the people taking them. Instead of racing heart rates, the inability to focus, or being so sedated that it can be challenging to function, many people want to get similar results without those negative feelings that come with it. 

People have been noticing the benefits of CBD a lot, and people are not the only ones taking notice. The FDA has been running clinical trials and approved at least one medication that contains CBD for use in the U.S. so far, and more are on the horizon. Plus, several animal studies are going on testing several cannabis products, since the bodies of animals are so similar to human bodies in how they react to many substances. 

Can CBD Products Be Used as Any Other Potential Treatment Option?

Using CBD for medical ailments aside from anxiety is also possible. It is already used medicinally to treat seizures and some forms of epilepsy, but there are other ailments that it could help with, too. Some of those ailments include: 
    
 
    
 
Health Benefits and Risks That Come From Cannabinoids

Aside from a reduction of anxiety, there are other benefits that products containing CBD can provide. Here are some of the most common: 



There is constant testing happening on all types of products that contain CBD because of the promising effects of cannabidiol. There are very few risks that come with using CBD in any form. They include: 

    Feeling tired some of the time after taking the CBD. This usually passes after a short time and stops once the body adjusts to the new chemical. 
    Diarrhea sometimes happens when the doses of CBD are too high. To remove this effect, all people have to do is decrease the dose they are taking. 
    The use of CBD is often associated with dry mouth. This can be easily combated by adding more water into the diet daily. 
    Occasionally people taking CBD feel dizzy. This is due to lower blood pressure and will pass as the body gets used to the change in nearly all instances. 

How Can CBD Products Be Taken?

There are many ways to use CBD. It all depends on what the results are that the person wants and how quickly he or she wants those results. Various methods provide different results in how immediately the effects are felt and in terms of how long the effects last. Here are the most common methods of ingestion for products containing CBD: 



Items taken under the tongue or through inhalation hit the system much more quickly than those that have to be absorbed or ingested. However, they also tend to wear off more quickly. Those that are eaten or absorbed take a little longer to start working, but they also last longer. Some products need to be taken every few hours, others need to be taken when symptoms arise, and others need to be taken on a schedule, such as twice per day. It all depends on what method of ingestion is used and what the goal results are. 

Conclusion

Anxiety is more common than most people realize. Unfortunately, it is treated far less often than it should be. There are ways of being able to combat anxiety naturally, and CBD is one of the most promising methods around. Testing is being done on many products that contain CBD to see not only how effectively it can treat issues like depression and anxiety, but also what other benefits come with it. People can face situations they never could before while on CBD, including simulated public speaking and talking with people who once made the users afraid. If CBD can provide these effects currently, imagine what it could do in the near future for extensive medical and mental health issues.

Having anxiety during pregnancy is a real mental health condition. It is not a sign of weakness, but rather a sign that a woman’s body needs help. A pregnant woman who suspects she has anxiety or experiences panic attacks should get help right away for the health of her baby.

What Is Normal?

Pregnancy can be a stressful time. If a woman is experiencing normal anxiety, she will find that it comes and goes. Often it is triggered by a stressful experience, such as a fight with a loved one or problems with other children. While some stress during pregnancy is normal, if it is beginning to bother the mother or impact her daily life, she should consult her doctor.

Antenatal Anxiety

A pregnant woman experiencing antenatal anxiety, or anxiety during pregnancy, may feel intense and excessive anxiety. Often, she cannot be able to pinpoint the reason for her anxiety. Even small tasks like paying the bills may make her feel anxious.
An expectant mother also experiences other symptoms in antenatal anxiety. Anxiety is one of the most common mental disorders, affecting one in four people, and the risk of anxiety is thought to increase during pregnancy.

Symptoms

Each case of antenatal anxiety is different for each patient. However, there are some common symptoms pregnant women can look out for. While having one or two of these symptoms does not necessarily indicate anxiety, having several of these symptoms may mean an expectant mother should see her doctor.



Because anxiety and depression go together during pregnancy, having anxiety may be a symptom of depression.

Causes

Women are more at risk for anxiety and depression during pregnancy because hormone changes can affect hormones in the brain that are related to depression and anxiety. Difficult life situations can also lead to feelings of depression and anxiety.

Depression

Depression and anxiety during pregnancy often go hand in hand. Moreover, in some cases, it can be a vicious cycle. Feeling depressed can lead to anxiety about why one is feeling depressed. The American College of Obstetricians and Gynecologists estimates that between 14 percent and 23 percent of women experience depression during pregnancy.
Like clinical depression, depression during pregnancy is a mental disorder.

Panic Attacks

Anxiety can lead to panic attacks. These attacks can come quickly, seemingly without a cause. There are many symptoms of a panic attack, some of which a woman might experience all at once. Women experiencing panic attacks can have a racing heartbeat, dizziness, sweating, shaky limbs, tingling, shortness of breath, and a severe feeling of dread.
These attacks can last anywhere from five minutes to 20 minutes. While they can be terrifying, they are generally not dangerous for the mother or baby.

Effect on the Baby

Left untreated, anxiety during pregnancy can harm the baby. One study found that when a woman experiences anxiety during her pregnancy, the child’s neurodevelopment is at risk, and the baby is more likely to be born preterm.
After birth, any anxiety or depression a mother still has makes it harder for her to bond with her baby. Bonding with the baby right away is important for the baby’s development.
If a woman has lingering depression after her baby’s birth, she may not have the desire or strength to care for her baby. These babies may be less active and show higher levels of agitation.

Risk Factors

Anyone can experience anxiety during pregnancy. However, there are a few risk factors which can make a woman more likely to develop anxiety in pregnancy.



While researchers do not know every risk factor that can result in anxiety, they believe that factors such as environment, physical well-being, and emotional well-being all play into a woman’s risk of having anxiety during pregnancy.

Treatment

The good news is, there are many treatments for anxiety that can help an expectant mother feel better and calmer about her pregnancy. A pregnant woman’s doctor may suggest she use coping mechanisms. These include cognitive behavioral therapy, self-help resources, activity for emotional release, or medication.

Cognitive Behavioral Therapy

Cognitive behavioral therapy teaches skills to cope with different problems such as anxiety. The idea behind cognitive behavioral therapy is that people’s feelings and behavior tend to reflect how they think about different situations. If they think about situations negatively, their feelings imitate that. In cognitive behavioral therapy, an individual suffering from anxiety works with a therapist to identify negative thinking patterns that may be causing anxiety.

Self-help Resources

Self-help resources can also help anxiety. A woman with anxiety may work through these resources by herself or with another individual who has suffered from similar problems.

Finding Release

It can help pregnant women with anxiety to find a release for their emotions. It can help them take their minds off their problems. Engaging in physical activity, such as walking, swimming, or yoga, can help the brain release endorphins. Endorphins kill pain, boost happiness, and relieve stress. Physical activity for as little as five minutes can help release endorphins from the brain.
For pregnant women where physical activity is not an option, mind-body wellness strategies can work. An expectant mother might try meditation, deep breathing exercises, journaling, or even acupuncture.

Medication

If these anxiety treatments are not working, or a pregnant woman’s anxiety is severe, her doctor may prescribe medication to ease her anxiety. A woman’s doctor may recommend antidepressants, such as selective serotonin reuptake inhibitors, which are fairly safe to take during pregnancy.

Conclusion

Anxiety in pregnancy is a very common thing. Having it does not mean a woman will be a bad mother. There are several ways to treat it, and expectant mothers should remember there is no “one size fits all” approach. What works for one woman may not work for another. Trying different techniques, such as stress management, self-help, and cognitive behavioral therapy, helps a woman get the peace of mind which is essential for her health and her baby.



    ACUTE ANTICHOLINERGIC SYNDROME



    DEFINITION



    Clinical syndrome resulting from antagonization of acetylcholine at

    the muscarinic receptor.



    TOXIC CAUSES



    Antihistamines (especially Promethazine, Trimeprazine,

    Dimenhydrinate)

    Antiparkinsonian drugs (e.g., Benztropine, Biperiden, Orphenadrine,

    Procyclidine)

    Antispasmodic agents (e.g., Clidinium, Glycopyrrolate,

    Propantheline)

    Belladonna alkaloids (e.g., Belladonna extract, Atropine, Hyoscine,

    L-Hyoscyamine sulphate, Scopolamine hydrobromide)

    Cyclic Antidepressants

    Ophthalmic cycloplegics (e.g., Cyclopentolate, Homatropine,

    Tropicamide)

    Phenothiazines

    Plants containing anticholinergic alkaloids (e.g., Atropa

    belladonna, Brugmansia spp, Cestrum spp, Datura spp, Hyoscyamus

    niger, Solanum spp).  The tropane derivatives (alkaloids of

    solanaceous plants and related drugs) are of greatest practical

    importance.



    CLINICAL FEATURES



    The clinical diagnosis is based on the appearance of the

    anticholinergic toxidrome.  This toxidrome has central and

    peripheral components:



    The central anticholinergic signs and symptoms include altered

    mental status, disorientation, incoherent speech, delirium,

    hallucinations, agitation, violent behaviour, somnolence, coma,

    central respiratory failure, and, rarely, seizures.



    The peripheral anticholinergic syndrome includes hyperthermia,

    mydriasis, dry mucosa membranes, dry, hot and red skin, peripheral

    vasodilatation, tachycardia, diminished bowel motility (even

    paralytic ileus), and urinary retention.



    Rhabdomyolysis, cardiogenic shock or cardiorespiratory arrest may

    occur exceptionally.  Patients with closed-angle glaucoma may

    suffer an acute precipitation of the condition.  Patients with

    benign prostatic hyperplasia are particularly prone to develop

    urinary retention.



    DIFFERENTIAL DIAGNOSIS



    Alcohol withdrawal

    Organic delirium (usually secondary to sepsis)

    Psychiatric illness

    Psychedelic drugs

    Sympathomimetic drugs



    RELEVANT INVESTIGATIONS



    Measurement of blood and urine levels of the anticholinergic agents

    are of little or no practical value.

    Other laboratory examinations may be needed as dictated by the

    general condition of the patient. 



    TREATMENT



    Treatment is primarily supportive.  The patient must be protected

    from self-inflicted injury.  This may require physical and/or

    pharmacological restraint.  Respiratory failure may require

    intubation and controlled respiration.  In cases of ingestion,

    decontamination may be considered.



     Diazepam: Administer 5 to 10 mg intravenously over 1 to 3

    minutes.  Repeat this dose as necessary to a maximal total dose of

    30 mg.



    The paediatric dose of  diazepam is 0.25 to 0.4 mg/kg up to

    maximal total dose of 5 mg in children up to 5-years-old and 10mg

    in children over 5-years-old.



     Physostigmine is a specific antidote for anticholinergic

    poisoning and may be used under the following conditions :



         1.   Severe agitation or psychotic behaviour unresponsive to

              other treatments.

         2.   Clinical evidence of both peripheral and central

              anticholinergic syndrome.

         3.   No history of seizures.

         4.   Normal ECG, especially QRS width.

         5.   No history of ingestion or co-ingestion of tricylic

              antidepressants or other drugs that delay

              intraventricular conduction.

         6.   Cardio-respiratory monitoring in place and resuscitation

              facilities available.



    The dose of  physostigmine is 1 to 2 mg (0.5 mg in children) by

    intravenous injection over 2 to 5 minutes.  If necessary, this dose

    can be repeated after 40 minutes.



    CLINICAL COURSE AND MONITORING



    Complete recovery is expected over a period of hours to days.



    In more severe cases of anticholinergic syndrome, cardiac rhythm

    should be monitored and blood pressure frequently measured.  Urine

    output should be monitored so as not to overlook urinary retention.



    LONG TERM COMPLICATIONS



    Nil specific.



    AUTHOR(S)/PEER REVIEW



    Author:        Dr J. Szajewski, Director, Warsaw Poison Control

                   Centre, Warsaw, Poland.



    Peer Review:   Berlin, October 1995: R. Dowsett, J. Pronczuk.

    

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

5. 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)



------------------------------
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    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
    Address        Lambert Court, Chestnut Avenue, Eastleigh, Hampshire
                   SO53 3ZQ
    Telephone      01703 620500
    Fax            01703 629812

    of Tryptizol(R)
    Name           Thomas Morson Pharmaceuticals (a subsidiary of Merck
                   Sharp & Dohme Ltd)
    Address        Hertford Road, Hoddesdon, Hertfordshire EN11 9BU
    Telephone      01992 467272
    Fax            01992 451006

    of Domical(R)
    Name           Berk Pharmaceuticals (a subsidiary of Approved
                   Prescription Services Ltd)
    Address        Brampton Road, Hampden Park, Eastbourne, East Sussex
                   BN22 9AG
    Telephone      01323 501111
    Fax            01232 520306

    of Elavil(R)
    Name           DDSA Pharmaceuticals Ltd
    Address        310 Old Brompton Road, London SW5 9JQ
    Telephone      0171 373 7884
    Fax            0171 370 4321

    Supplier/importer

    In addition to the branded products listed above, non-proprietary
    products are available from Antigen, APS and Cox.

    Name           Antigen Pharmaceuticals Ltd
    Address        Antigen House, 82 Waterloo Rd, Hillside, Southport,
                   Merseyside, PR8 4QW
    Telephone      01704 562777
    Fax            01704 562888

    Name           APS (Approved Prescription Services Ltd)
    Address        Brampton Road, Hampden Park, Eastbourne, East Sussex
                   BN22 9AG
    Telephone      01323 501111
    Fax            01323 520306

    Name           AH Cox & Co Ltd
    Address        Whiddon Valley, Barnstaple, Devon EX32 8NS
    Telephone      01271 311257
    Fax            01271 321326

    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
    al. 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
    al. 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
    al. 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

    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).

    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.

    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

    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).

    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.

    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.

    2.   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.

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

    4.   Monitor the cardiac rhythm and blood pressure.

    5.   Single, brief convulsions do not require treatment but if they
         are prolonged or recurrent, they should be controlled with
         intravenous diazepam.

    6.   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
    al. 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.

    2.   Maintain adequate ventilation to prevent hypoxia with
    supplemental oxygen or artificial ventilation as appropriate.

    3.   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:
    i) more than 1 mg/kg has been ingested by a child,
    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:

    i) a chest X-ray will be needed to exclude pulmonary complications,
    ii) measure serum creatine kinase and other skeletal muscle enzyme
    activity (e.g. AST, ALT, and lactic dehydrogenase),
    iii) assess renal function,
    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),
    2.   a maximal limb-lead QRS duration of 0.16 second or longer as a
    predictor of the risk of ventricular arrhythmias (Boehnert & Lovejoy
    1985),
    3.   plasma tricyclic levels greater than 0.8 mg/L (Caravati & Bossart
    1991),
    4.   the ECG terminal 40-ms frontal plane QRS axis of more than 120°
    (Wolfe et al. 1989).
    5.   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
    mg. 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

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    Mordel A, Winkler E, Almog S, Tirosh M, Ezra D.
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    1992; 20: 1733-1734.

    Newton RW.
    Physostigmine salicylate in the treatment of tricyclic antidepressant
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    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
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    Pentel P, Peterson CD.
    Asystole complicating physostigmine treatment of tricyclic
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    Pimentel L, Trommer L.
    Cyclic antidepressant overdoses: a review. Emerg Med Clin N Am 1994;
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    Preskon SH, Mac DS.
    Plasma levels of amitriptyline: effect of age and sex. J Clin
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    Richelson E.
    The pharmacology of antidepressants at the synapse: focus on newer
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    Amitriptyline metabolism in elderly depressed patients and normal
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--------------

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
2. SUMMARY
   2.1 Main risks and target organs
   2.2 Summary of clinical effects
   2.3 Diagnosis
   2.4 First aid measures and management principles
3. PHYSICO-CHEMICAL PROPERTIES
   3.1 Origin of the substance
   3.2 Chemical structure
   3.3 Physical properties
      3.3.1 Colour
      3.3.2 State/Form
      3.3.3 Description
   3.4 Other characteristics
      3.4.1 Shelf-life of the substance
      3.4.2 Storage conditions
4. USES
   4.1 Indications
      4.1.1 Indications
      4.1.2 Description
   4.2 Therapeutic dosage
      4.2.1 Adults
      4.2.2 Children
   4.3 Contraindications
5. ROUTES OF EXPOSURE
   5.1 Oral
   5.2 Inhalation
   5.3 Dermal
   5.4 Eye
   5.5 Parenteral
   5.6 Other
6. KINETICS
   6.1 Absorption by route of exposure
   6.2 Distribution by route of exposure
   6.3 Biological half-life by route of exposure
   6.4 Metabolism
   6.5 Elimination and excretion
7. PHARMACOLOGY AND TOXICOLOGY
   7.1 Mode of action
      7.1.1 Toxicodynamics
      7.1.2 Pharmacodynamics
   7.2 Toxicity
      7.2.1 Human data
         7.2.1.1 Adults
         7.2.1.2 Children
      7.2.2 Relevant animal data
      7.2.3 Relevant in vitro data
   7.3 Carcinogenicity
   7.4 Teratogenicity
   7.5 Mutagenicity
   7.6 Interactions
   7.7 Main adverse effects
8. TOXICOLOGICAL 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
9. CLINICAL EFFECTS
   9.1 Acute poisoning
      9.1.1 Ingestion
      9.1.2 Inhalation
      9.1.3 Skin exposure
      9.1.4 Eye contact
      9.1.5 Parenteral exposure
      9.1.6 Other
   9.2 Chronic poisoning
      9.2.1 Ingestion
      9.2.2 Inhalation
      9.2.3 Skin exposure
      9.2.4 Eye contact
      9.2.5 Parenteral exposure
      9.2.6 Other
   9.3 Course, prognosis, cause of death
   9.4 Systematic description of clinical effects
      9.4.1 Cardiovascular
      9.4.2 Respiratory
      9.4.3 Neurological
         9.4.3.1 Central nervous system
         9.4.3.2 Peripheral nervous system
         9.4.3.3 Autonomic nervous system
         9.4.3.4 Skeletal and smooth muscle
      9.4.4 Gastrointestinal
      9.4.5 Hepatic
      9.4.6 Urinary
         9.4.6.1 Renal
         9.4.6.2 Other
      9.4.7 Endocrine and reproductive systems
      9.4.8 Dermatological
      9.4.9 Eye, ear, nose, throat: local effects
      9.4.10 Haematological
      9.4.11 Immunological
      9.4.12 Metabolic
         9.4.12.1 Acid-base disturbances
         9.4.12.2 Fluid and electrolyte disturbances
         9.4.12.3 Others
      9.4.13 Allergic reactions
      9.4.14 Other clinical effects
      9.4.15 Special risks
   9.5 Other
   9.6 Summary
10. MANAGEMENT
   10.1 General principles
   10.2 Life supportive procedures and symptomatic/specific treatment
   10.3 Decontamination
   10.4 Enhanced elimination
   10.5 Antidote treatment
      10.5.1 Adults
      10.5.2 Children
   10.6 Management discussion
11. ILLUSTRATIVE CASES
   11.1 Case reports from literature
12. ADDITIONAL INFORMATION
   12.1 Specific preventive measures
   12.2 Other
13. REFERENCES
14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE



    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

    2.  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.

    3.  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.

    4.  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).

    5.  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.

    6.  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).

    7.  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).

    8.  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

    9.  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

    10. 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.

    11. 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.

    12. ADDITIONAL INFORMATION

        12.1 Specific preventive measures

             No data

        12.2 Other

             No data

    13. 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
        ed. 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

    14. 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
    
        Telephone 33 326 862 686
        Fax 33 326 865 548
        E-mail: marie-odile.rambourg@wanadoo.fr
    
        Reviewer: WA Watson 
        Emergency Medicine. Truman Medical Center.
        2301 Holmes Street. Kansas City, MO, USA
    
        E-mail: wawatson@CCTR.UMKC.EDU
    
        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, 9 Castle Quay, Castle Boulevard, Nottingham,
    Nottinghamshire NG7 1FW
    Tel no. 0115 912 5000

    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:

    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).

    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.

    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:

    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).

    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.

    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.

    2.   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.

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

    4.   Monitor the cardiac rhythm and blood pressure.

    5.   Single, brief convulsions do not require treatment but if they
         are prolonged or recurrent, they should be controlled with
         intravenous diazepam.

    6.   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.

    7.   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.

    2.   Maintain adequate ventilation to prevent hypoxia with
         supplemental oxygen or artificial ventilation as appropriate.

    3.   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).

    2. COMA
    Good supportive care is essential.

    3. 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).

    4. 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.

    5. 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:

         i) more than 1mg/kg has been ingested by a child,
         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:
         i) a chest X-ray will be needed to exclude pulmonary
         complications,
         ii) measure serum creatine kinase and other skeletal muscle
         enzyme activity (e.g. AST, ALT, and lactic dehydrogenase),
         iii) assess renal function,
         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),
    2.   a maximal limb-lead QRS duration of 0.16 second or longer as a
         predictor of the risk of ventricular arrhythmias (Boehnert &
         Lovejoy 1985),
    3.   plasma tricyclic levels greater than 0.8 mg/L (Caravati & Bossart
         1991),
    4.   the ECG terminal 40-ms frontal plane QRS axis of more than 120°
         (Wolfe et al. 1989),
    5.   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

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    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, PO Box 79, Saunderton, High Wycombe, Bucks HP14
    4HJ
    Tel no. 01494 567567

    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.

    2.  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).

    2.  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.

    2.  Acute dystonic reactions can be managed with IV procyclidine or
        benztropine, followed by oral doses to prevent recurrence.

    3.  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).

    2. 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.

    3. 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).

    4. 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.

    5. 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.
    
    
---------------
INTOX Home Page

    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, RPR House, 50 Kings Hill Ave., Kings Hill,
    West Malling, Kent, ME19 4AH.
    Tel. no. 01732 584000
    Fax. no. 01732 584086

    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.

    2.   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).
    3.   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.

    4.   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.

    2.   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.

    3.   Monitor the cardiac rhythm.

    4.   Manage hypotension with IV fluids.

    5.   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.

    2.  COMA
    Good supportive care is essential.

    3.  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.

    4.  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).

    5.  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.

    6.  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.

    7.  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).

    8.  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:
         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),
         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

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See Also:
        Chlorpromazine (PIM 125)


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