1.1 Substance
   1.2 Group
   1.3 Synonyms
   1.4 Identification numbers
      1.4.1 CAS
      1.4.2 Other numbers
   1.5 Brand names, Trade names
   1.6 Manufacturers, Importers
   1.7 Presentation, Formulation
   2.1 Main risks and target organs
   2.2 Summary of clinical effects
   2.3 Diagnosis
   2.4 First aid measures and management principles
   3.1 Origin of the substance
   3.2 Chemical structure
   3.3 Physical properties
      3.3.1 Properties of the substance Colour State/Form Description
      3.3.2 Properties of the locally available formulation
   3.4 Other characteristics
      3.4.1 Shelf-life of the substance
      3.4.2 Shelf-life of the locally available formulation
      3.4.3 Storage conditions
      3.4.4 Bioavailability
      3.4.5 Specific properties and composition
   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
   5.1 Oral
   5.2 Inhalation
   5.3 Dermal
   5.4 Eye
   5.5 Parenteral
   5.6 Other
   6.1 Absorption by route of exposure
   6.2 Distribution by route of exposure
   6.3 Biological half-life by route of exposure
   6.4 Metabolism
   6.5 Elimination by route of exposure
   7.1 Mode of action
      7.1.1 Toxicodynamics
      7.1.2 Pharmacodynamics
   7.2 Toxicity
      7.2.1 Human data Adults 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
   8.1 Material sampling plan
      8.1.1 Sampling and specimen collection Macroscopic and microscopic analysis Toxicological analyses Biological analyses Arterial blood gas analysis Haematological analyses Other (unspecified) analyses
      8.1.2 Storage of laboratory samples and specimens Macroscopic and microscopic analysis Toxicological analyses Biochemical analyses Arterial blood gas analysis Haematological analyses Other (unspecified) analyses
      8.1.3 Transport of laboratory samples and specimens Macroscopic and microscopic analysis Toxicological analyses Biochemical analyses Arterial blood gas analysis Haematological analyses Other (unspecified) analyses
   8.2 Toxicological analyses and their interpretation
      8.2.1 Tests on toxic ingredient(s) of material Simple qualitative test(s) Advanced qualitative confirmation test(s) Simple quantitative method(s) Advanced quantitative method(s)
      8.2.2 Tests on biological specimens Simple qualitative test(s) Advanced qualitative confirmation test(s) Simple quantitative method(s) Advanced quantitative method(s) Other dedicated method(s)
      8.2.3 Interpretation of toxicological analyses
   8.3 Biomedical investigations and their interpretation
      8.3.1 Blood, plasma or serum Urine Other fluids
      8.3.2 Arterial blood gas analyses
      8.3.3 Haematological analyses
      8.3.4 Interpretation of biomedical investigations
   8.4 Other biomedical (diagnostic) investigations and their interpretation
   8.5 Overall interpretation of all toxicological analyses and toxicological investigations
   8.6 References
   9.1 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 Central nervous system (CNS) Peripheral nervous system Autonomic nervous system Skeletal and smooth muscle
      9.4.4 Gastrointestinal
      9.4.5 Hepatic
      9.4.6 Urinary Renal 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 Acid-base disturbances Fluid and electrolyte disturbances Others
      9.4.13 Allergic reactions
      9.4.14 Other clinical effects
      9.4.15 Special risks
   9.5 Other
   10.1 General principles
   10.2 Relevant laboratory analyses
      10.2.1 Sample collection
      10.2.2 Biomedical analysis
      10.2.3 Toxicological analysis
      10.2.4 Other investigations
   10.3 Life supportive procedures and symptomatic/specific treatment
   10.4 Decontamination
   10.5 Elimination
   10.6 Antidote treatment
      10.6.1 Adults
      10.6.2 Children
   10.7 Management discussion
   11.1 Case reports from literature
   11.2 Internally extracted data on cases
   11.3 Internal cases
   12.1 Availability of antidotes
   12.2 Specific preventive measures
   12.3 Other
    1. NAME
       1.1 Substance 
           (INN, 1992) 
       1.2 Group
           Psycholeptics (N05)/ 
           Antipsychotics (N05A) 
           (ATC classification index [WHO] 1992]) 
       1.3 Synonyms
           Chlorpromazini hydrochloridum
           (Martindale, 1993) 
       1.4 Identification numbers
           1.4.1 CAS
                 Chlorpromazine 50-53-3
           1.4.2 Other numbers
                 Chlorpromazine hydrochloride   69-09-0
                 RTECS                          SN8925000
       1.5 Brand names, Trade names
           (To be completed by each Centre using local data)
       1.6 Manufacturers, Importers
           Rhone-Poulenc, Rhodia Argentina SA, Cetus
           (To be completed by each Centre using local data)
       1.7 Presentation, Formulation
           Injection (Hydrochloride)
           Solution of 0.5% (25 mg) and 2.5% (50 mg)
           Tablets (Hydrochloride)
           25 mg,  100 mg
           Oral suspension (Embonate)
           Suppository (Base)
           100 mg
           (To be completed by each Centre using local data)
    2. SUMMARY
       2.1 Main risks and target organs
           The principal pharmacological actions are psychotropic.  It 
           also exerts sedative and antiemetic activity.  Chlorpromazine 
           has actions at all levels of the central nervous system - 
           primarily at subcortical levels - as well as on multiple 
           organ systems.  Chlorpromazine has strong antiadrenergic and 
           weak peripheral anticholinergic activity; ganglionic blocking 
           action is relatively slight.  It also possesses slight 
           antihistaminic and antiserotonin activity.
       2.2 Summary of clinical effects
           Central nervous depression may progress from drowsiness to 
           coma, ultimately with areflexia.  In early or mild 
           intoxications, some patients suffer from restlessness, 
           confusion and excitement.
           Tremor or muscular twitching, spasm, rigidity, convulsions, 
           muscular hypotonia, difficulty in swallowing may be present.
           Extrapyramidal signs of overdose include dystonia,
           torticollis, oculogyric crises and opisthotonos.
           Either hypothermia or hyperthermia may be encountered.
           Difficulty in breathing, cyanosis, respiratory and/or 
           vasomotor collapse, respiratory depression and distress, 
           sudden apnoea and even cyanosis may occur.
           Hypotension, tachycardia, cardiac arrhythmias, conduction 
           defects, ventricular fibrillation or cardiac arrest may be 
       2.3 Diagnosis
           Diagnosis of phenothiazine poisoning should be considered 
           when extrapyramidal syndrome or cardiac arrhythmias occur in 
           a neurologically depressed patient.  Qualitative 
           toxicological analyses including urine spot test for 
           phenothiazine may confirm the diagnosis.
       2.4 First aid measures and management principles
           Consider inducing vomiting with Ipecac syrup even though 
           chlorpromazine is antiemetic. Emesis should be not induced if 
           the patient is already drowsy or if more than 1 hour has 
           elapsed since ingestion.
           Gastric lavage may be considered up to 2 hours after 
           ingestion because gastric motility is reduced.  Use 
           precautions against aspiration. A slurry at 50 to 100 mg 
           activated charcoal, repeated every 4 hours, may be given.
           Avoid epinephrine and other cathecolamines because they may 
           induce cardiac arrhythmias.  Hypotension should be managed 
           with intravenous fluids and plasma expander.  The use of a 
           vasoactive drug such as dopamine should be considered in 
           severe hypotension.  Oxygen and artificial respiration may be 
           necessary.  Hypothermia is common and sometimes difficult to 
           control.  Both blankets and heat lamps may be required. 
           Caution is indicated, however, because fever may also occur.
           In hot weather, even the comatose patient may present with 
           dangerous hyperpyrexia requiring prompt intervention.
           Forced diuresis, haemodialysis and haemoperfusion are of no 
           Continuously monitor the ECG, in the event of irregularities 
           in rhythm or conduction.
           Although parenteral physostigmine may have some analeptic 
           value, it is potentially dangerous and is not recommended.
           Biperiden and benztropine mesylate intravenously have been 
           shown to be effective against extrapyramidal features.
       3.1 Origin of the substance
           It is a synthetic dimethylamine derivative of phenothiazine.
       3.2 Chemical structure 
           Structural formula
           Molecular formula
           Chlorpromazine         C17H19C1N2S
           Chlorpromazine         (C17H19ClN2S)2,C23H16O6
           Chlorpromazine         C17H19C1N2S,HCl
           Molecular weight
           Chlorpromazine         318.9
           Chlorpromazine         1026.1
           Chlorpromazine         355.3
           Chemical names
           (Martindale, 1993; Merck Index, 1989)
       3.3 Physical properties
           3.3.1 Properties of the substance
                         White to creamy-white (Base and hydrochloride) 
                         Both forms darken on prolonged exposure to 
                         Powder or waxy solid (Base)
                         Crystalline powder (Hydrochloride)
                  Chlorpromazine base
                 Odourless or with an amine-like odour
                 Melting point     56°C to 58°C.
                 Chlorpromazine is practically insoluble in water, 
                 soluble 1 in 2 of alcohol, 1 in less than 1 of 
                 chloroform, and 1 in 1 of ether.  USP solubilities are 
                 1 in 3 of alcohol, 1 in 2 of chloroform, and 1 in 3 
                 ether;  freely soluble in dilute mineral acids; 
                 practically insoluble in dilute alkali hydroxides.
                  Chlorpromazine hydrochloride
                 Soluble 1 in 0.4 of water, 1 in 13 of alcohol and of 
                 chloroform, and practically insoluble in ether.
                 A 10% aqueous solution has a pH of 3.5 to 4.5.
                 (Martindale, 1993)
           3.3.2 Properties of the locally available formulation
                 To be completed by each Centre using local data.
       3.4 Other characteristics
           3.4.1 Shelf-life of the substance
                 No data available
           3.4.2 Shelf-life of the locally available formulation
                 To be completed by each Centre, using local data.
           3.4.3 Storage conditions
                 Store in airtight containers.  Protect from light.
           3.4.4 Bioavailability
                 To be completed by each Centre using local data.
           3.4.5 Specific properties and composition
                 Chlorpromazine 100 mg is approximately equivalent to 
                 111 mg of chlorpromazine hydrochloride.
                 Chlorpromazine hydrochloride 100 mg is approximately 
                 equivalent to 144 mg of chlorpromazine embonate.
                 (Martindale, 1993)
                 (To be completed by each Centre using local data).
    4. USES
       4.1 Indications
           4.1.1 Indications
           4.1.2 Description
                 For the management of manifestations of psychotic 
                 For the relief of restlessness and apprehension before 
                 To control the manifestations of the manic type of 
                 manic-depressive illness.
                 For the treatment of severe behavioural problems in 
                 children marked by combativeness and/or explosive 
                 hyperexcitable behaviour (out of proportion to 
                 immediate provocations).
                 For short term treatment of hyperactive children who 
                 show excessive motor activity with accompanying conduct 
                 disorders consisting of some or all of the following 
                 symptoms:  impulsivity, difficulty sustaining 
                 attention, aggressiveness, mood lability and poor 
                 frustration tolerance.
                 For controlling nausea, vomiting and intractable 
                 hiccup, as well as pre-surgical apprehension and 
                 It is useful as an adjunct in the treatment of tetanus.
       4.2 Therapeutic dosage
           4.2.1 Adults
                 Oral (Hydrochloride)
                 25 mg to 50 mg three times a day (initial dose).
                 75 mg at night as a single dose.
                 25 to 100 mg three times daily (maintenance dose).
                 1 g or more per day (certain psychotic patients)
                 25 to 50 mg three to 4 times daily.
                 25 mg to 50 mg (repeated as required).
                 Up to 4 x 100 mg suppositories may be given in 24 hours
                 Note: Dosage of above forms varies according to the 
                 individual patient and to the indication.
                 (Martindale, 1993).
           4.2.2 Children
                 0.5 mg/kg bodyweight every 4 to 6 hours.
                 500 mcg/kg bodyweight every 6 to 8 hours.
                 25 mg suppositories available.
                 Note: For psychiatric indications in children over 5 
                 years of age, one-third to one-half the adult dose of 
                 the above dose forms may be given.
                  Maximum daily doses for children (all dose forms)
                 1 to 5 years      40 mg
                 More than 5       75 mg
                 (Martindale, 1993)
       4.3 Contraindications
           Do not use in comatose states or in the presence of large 
           amounts of central nervous system depressants (alcohol, 
           barbiturates, anaesthetics narcotics, etc.), because 
           chlorpromazine prolongs and intensifies the action of such 
           CNS depressants.
           Chlorpromazine should be administered cautiously to persons 
           with cardiovascular or liver disease.
           There is evidence that patients with a history of hepatic 
           encephalopathy due to cirrhosis have increased sensitivity to 
           the CNS effect of chlorpromazine (e.g. impaired cerebration 
           and abnormal slowing of the EEG).
           Because of this CNS depressant effect, it should be used with 
           caution in patients with chronic respiratory disorders such 
           as severe asthma, emphysema and acute respiratory infections, 
           particularly in children.
           Because it can suppress the cough reflex, aspiration of 
           vomitus is possible.
           Subcutaneous injection is contraindicated.
       5.1 Oral
           Chlorpromazine is available in tablet or syrup forms for oral 
       5.2 Inhalation
           Not relevant.
       5.3 Dermal
           Not relevant.
       5.4 Eye
           Not relevant.
       5.5 Parenteral
           It is present in injectable forms for use through the 
           intramuscular or intravenous routes.
       5.6 Other
           Rectal route with suppositories.
       6.1 Absorption by route of exposure
           The absorption of orally administered chlorpromazine is 
           dependent on the dosage form, the elixir giving the highest 
           plasma concentration of drug.  Peak plasma levels are reached 
           at 2 to 3 hours.  There is a wide inter-subject variability 
           (ten times or more) in the plasma concentrations achieved. 
           Plasma concentrations may be decreased significantly by food 
           in the stomach and by the concomitant administration of 
           anticholinergic antiparkinsonism drugs.
           Owing to the first-pass effect, plasma concentrations 
           following oral administrations are much lower than those 
           following intramuscular administrations.
       6.2 Distribution by route of exposure
           Chlorpromazine is widely distributed in the body and crosses 
           the blood-brain barrier to achieve higher concentrations in 
           the brain than in the plasma.
           Chlorpromazine and its metabolites also cross the placental 
           barrier and are excreted in milk (Martindale, 1989).
           Chlorpromazine is highly bound to plasma proteins, varying 
           from 91.8% to 97% over the range of clinical blood 
           concentrations (0.01 to 1 mcg/mL). Binding is easily reversed 
           (Curry, 1970).
           The volume of distribution is 21 (+/- 9) L/kg (Goodman & 
           Gilman, 1990).
       6.3 Biological half-life by route of exposure
           Although the plasma half-life of chlorpromazine itself has 
           been reported to be only a few hours, elimination of the 
           metabolites may be very prolonged.
           Blood studies show a range of 2 to 3 days and for the urinary 
           studies up to about 18 days.  However, chlorpromazine brings 
           about changes that can persist much longer than these times 
           after discontinuation of the drug. The exact relationship of 
           persisting therapeutic effects to administered chlorpromazine 
           is uncertain.  There is the possibility that minute amounts 
           of chlorpromazine and/or metabolites persist at active sites 
           in slowly reversible or relatively irreversible ways.  It 
           also seems that some chlorpromazine is stored in adipose 
           tissue and slowly mobilized after stopping chlorpromazine 
           administration (Lacoursiere, 1976).
       6.4 Metabolism
           Paths of metabolism of chlorpromazine include hydroxylation, 
           and conjugation with glucuronic acid, N-oxidation, oxidation 
           of a sulphur atom, and dealkylation.
           In man, after chronic use, the highest concentration of 
           unconjugated chlorpromazine metabolites is found in the lung 
           and liver.
           The 7-hydroxy chlorpromazine that is found in body tissues 
           appears to be an active metabolite.  This may account for 
           reports that plasma concentrations of free chlorpromazine do 
           not correlate with the therapeutic responses. However, plasma 
           concentrations of the drug concurrently measured free, 
           protein bound, and as 7-hydroxy chlorpromazine may provide in 
           the future a guide for dosage.
           Since there is some evidence that chlorpromazine can cause 
           hepatic microsomal enzyme induction, it may accelerate its 
           own metabolism; this may account for progressively decreasing 
           plasma concentrations of free drug during maintenance of a 
           fixed dosage schedule.
           One hundred and sixty-eight possible metabolites of 
           chlorpromazine have been postulated and many of them actually 
           isolated from human urine (Williams and Parke, 1964).
           Hydroxylation in the 3 and 7 positions and subsequent 
           conjugation with glucuronic acid represent the principal 
           metabolic pathway.
           The formation of the sulfoxides is a common effect. Metabolic 
           alterations in the side chain also occur. Approximately half 
           of the metabolites of chlorpromazine are found in the urine 
           and the rest in the faeces. Various metabolites are 
           detectable in the urine long after discontinuation of the 
           In man, urinary excretion of chlorpromazine plus its 
           sulfoxides varies from 1 to 20% of the daily dose 
           administered (Huang and Kurland, 1961).  The average ratio of 
           free chlorpromazine to the sulfoxide in the urine is about 
           1:16.  There is much evidence that the sulfoxide undergoes 
           additional metabolism, probably to sulfones.  The various 
           phenothiazine congeners of chlorpromazine undergo similar 
           metabolic degradation.
           Demethylation is another method of detoxication by the liver 
           (Meyers, 1978).
       6.5 Elimination by route of exposure
           Chlorpromazine is excreted in both urine and faeces.  A 
           reciprocal relationship exists between the amounts excreted 
           by each route.
       7.1 Mode of action
           7.1.1 Toxicodynamics
                 Chlorpromazine has a wide range of activity arising 
                 from its depressant actions on the central nervous 
                 system and its alpha-adrenergic blocking and weak 
                 antimuscarinic activities.
                 Chlorpromazine possesses sedative properties but 
                 patients usually develop tolerance rapidly to the 
                 Its action on the autonomic system produces 
                 vasodilation, hypotension, and tachycardia.  Salivary 
                 and gastric secretions are reduced (Martindale, 1989).
                 The sulfoxides of the phenothiazines have been 
                 intensively studied and found to be significantly less 
                 potent than the parent compound.
           7.1.2 Pharmacodynamics
                 It is a dopamine inhibitor.  In inhibits prolactin 
                 release inhibitory factor, thus stimulating the release 
                 of prolactin.  The turnover of dopamine in the brain is 
                 also increased.  There is some evidence that the 
                 antagonism of central dopaminergic function, especially 
                 at the postulated D2-dopaminergic receptor, is related 
                 to therapeutic effect in psychotic conditions.
                 Chlorpromazine has anti-emetic, antipruritic, 
                 serotonin-blocking, and weak antihistaminic properties, 
                 but slight ganglion-blocking activity.  It inhibits the 
                 heat regulating centre so that the patient tends to 
                 acquire the temperature of his surroundings 
                 (poikilothermism).  Chlorpromazine can relax skeletal 
                 muscle.  It has membrane-stabilizing and hence local 
                 anaesthetic properties.
       7.2 Toxicity
           7.2.1 Human data
                         A 40-year-old woman was found dead after an 
                         estimated total dose of 2 g (Algeria et al., 
                         1959).  Given medical care, adults have 
                         recovered from 10 to 30 g (Brophy, 1967; 
                         Douglas and Bates, 1957;  Samuels, 1957).  In 
                         an unpublished case seen by the author, a 19 
                         year-old male recovered after a single dose of 
                         17.5 g (Gosselin, 1984).
                         A 13-month-old girl died following the 
                         ingestion of 750 mg or about 75 mg/kg 
                         (Haggerty, 1957);  a 4-year-old girl died after 
                         350 mg (Wallman, 1957);  and a 3-year-old boy 
                         died after 800 mg (Dilworth et al., 1963).
           7.2.2 Relevant animal data
    Species     Oral mg/kg     intraperit.      intravenous
                               mg/kg            mg/kg
    Mouse          376                 115                   31
    Rat            -                   58                    -
    Dog            -                   -                     37
           7.2.3 Relevant in vitro data 
                 No data available.
       7.3 Carcinogenicity
           No data available.
       7.4 Teratogenicity
           If given in high doses over a long period during pregnancy, 
           chlorpromazine may cause damage to the retina of the foetus 
           (Stirrat, 1973).
       7.5 Mutagenicity
           No data available.
       7.6 Interactions
           Chlorpromazine may block the antihypertensive effects of 
           Patients being treated with phenothiazines should be advised 
           that their susceptibility to alcohol may be increased. 
           Chlorpromazine has been shown to increase the miotic and 
           sedative effects of morphine.
           Chlorpromazine may enhance the respiratory depression 
           produced particularly by CNS depressants. Mutual inhibition 
           of liver enzymes concerned with the metabolism of both 
           chlorpromazine and the other drug (e.g. a tricyclic 
           antidepressant) might result in increased plasma- 
           concentrations of either drug.
           Chlorpromazine is reported to interfere with a number of 
           laboratory tests, such as pregnancy tests, thyroid function 
           tests, the Coombs' test where a false positive result can be 
           achieved, and adrenal medullary tests. It is also reported to 
           interfere with estimations for serum 5-hydroxyindole-acetic 
           acid, blood, urea, urinary ketones and steroids, urinary 
           porphobilinogen, and vitamin B12.
       7.7 Main adverse effects
           Therapeutic doses of chlorpromazine, may cause palpitation, 
           nasal stuffiness, dry mouth, and slight constipation. The 
           patient may complain of being cold, drowsy, or weak.
           Orthostatic hypotension, which may result in syncope.
           A mild elevation of temperature may be seen during the first 
           few days, particularly if the drug is given parenterally.  On 
           the other hand, hypothermia can occur and may be due both to 
           the action on the heat regulating centre and to direct 
           peripheral vasodilation.  Sensitivity and adaptation to 
           environmental temperature change are impaired so that fatal 
           hyperthermia and heat stroke are possible complications.
           Chlorpromazine has produced haematological disorders, 
           including agranulocytosis, eosinophilia, leucopenia, 
           haemolytic anaemia, aplastic anaemia, thrombocytopenic 
           purpura and pancytopenia.
           Hyperglycaemia, hypoglycaemia and glycosuria have also been 
           Note: In those situations in which a few small doses of 
           chlorpromazine are used, it might be possible to 
           differentiate side-effects and overdosage toxicity. However, 
           because chlorpromazine is often used in large doses for 
           prolonged periods, this differentiation is not always 
       8.1 Material sampling plan
           Blood levels do not correlate well with clinical effects in 
           part because of the large number of active metabolites. 
           Chlorpromazine appears unstable in plasma but more stable in 
           8.1.1 Sampling and specimen collection
        Macroscopic and microscopic analysis
        Toxicological analyses
        Biological analyses
        Arterial blood gas analysis
        Haematological analyses
        Other (unspecified) analyses
           8.1.2 Storage of laboratory samples and specimens
        Macroscopic and microscopic analysis
        Toxicological analyses
        Biochemical analyses
        Arterial blood gas analysis
        Haematological analyses
        Other (unspecified) analyses
           8.1.3 Transport of laboratory samples and specimens
        Macroscopic and microscopic analysis
        Toxicological analyses
        Biochemical analyses
        Arterial blood gas analysis
        Haematological analyses
        Other (unspecified) analyses
       8.2 Toxicological analyses and their interpretation
           8.2.1 Tests on toxic ingredient(s) of material
        Simple qualitative test(s)
        Advanced qualitative confirmation test(s)
        Simple quantitative method(s)
        Advanced quantitative method(s)
           8.2.2 Tests on biological specimens
        Simple qualitative test(s)
                         Phenistix testing of the urine also may suggest 
                         the presence of phenothiazines.  The 
                         persistence of the positive violet colour upon 
                         addition of 50% H2SO4 to the strip confirms the 
                         presence of phenothiazines.
                         The ferric chloride urine test also is a quick 
                         qualitative screen for phenothiazines (25 mg of 
                         phenothiazine per 100 ml of urine is necessary 
                         for a positive reaction).  The 10% ferric 
                         chloride solution should be kept in a dark 
                         bottle in a dark cabinet.
                         One millilitre of urine added to 10 to 15 drops 
                         of 10% ferric chloride solution will yield a 
                         deep burgundy, port wine colour if sufficient 
                         phenothiazines are present.
        Advanced qualitative confirmation test(s)
        Simple quantitative method(s)
                         The Forrest colorimetric test provides a 
                         relative quick semi-quantitative urine 
                         screening test for phenothiazines (test 
                         solution: 20 parts 5% ferric chloride; 80 parts 
                         10% sulphuric acid).
                         Performance of test:  mix 1 ml urine with 1 ml 
                         test solution: read within 20 seconds.
                         Resulting test colours and daily dosage (mg)
                         Pink    Purple   Dark blue   Dark grey
                         +         ++          +++             ++++
                         100-300   300-600     600-900         > 900
        Advanced quantitative method(s)
        Other dedicated method(s)
           8.2.3 Interpretation of toxicological analyses
       8.3 Biomedical investigations and their interpretation
           8.3.1 Blood, plasma or serum
                 Serum electrolytes, glucose, creatine kinase should be 
                 performed in symptomatic patients.
                 "Basic analyses"
                 "Dedicated analyses"
                 "Optional analyses"
                         "Basic analyses"
                         "Dedicated analyses"
                         "Optional analyses"
        Other fluids
           8.3.2 Arterial blood gas analyses
                 Monitor arterial blood gases in particular with 
                 respiratory symptoms with malignant hyperthermia.
           8.3.3 Haematological analyses
                 Serial blood counts should be performed, especially in 
                 patients who have history of prolonged use.
                 "Basic analyses"
                 "Dedicated analyses"
                 "Optional analyses"
           8.3.4 Interpretation of biomedical investigations
       8.4 Other biomedical (diagnostic) investigations and their 
           Continuous ECG monitoring should be performed for patients 
           with suspected or overt cardiac arrhythmia.
       8.5 Overall interpretation of all toxicological analyses and 
           toxicological investigations 
           Chlorpromazine has produced haematological disorders, 
           including agranulocytosis, eosinophilia, leucopenia, 
           haemolytic anaemia, aplastic anaemia, thrombocytopenic 
           purpura and pancytopenia.
           Hyperglycaemia, hypoglycaemia and glycosuria have also been 
       8.6 References
       9.1 Acute Poisoning
           9.1.1 Ingestion
                 The prominent manifestations of acute intoxication 
                 reflect varying degrees of central nervous depression 
                 as evidenced by coma, hypotension, hypothermia, 
                 suppression of tendon reflexes and miosis (Algeria et 
                 al., 1959); Cann and Verhulst, 1960).
                 Respiratory difficulties have been ascribed to partial 
                 obstruction from a relaxed pharyngeal wall and weak 
                 respiratory movement (Ferguson, 1957).  Pulmonary 
                 oedema has been observed in at least three fatal cases 
                 of chlorpromazine ingestion.  Aspiration of vomitus 
                 seems the most likely cause for this complication, but 
                 an interference with pulmonary surfactant production 
                 could not be ruled out (Joubert and Oliver, 1974).
                 In contrast to the flaccidity seen in severe 
                 barbiturate poisoning, coma due to chlorpromazine is 
                 often punctuated by periods of motor restlessness, 
                 tremors, spasms, and other signs ascribed to 
                 extrapyramidal tract activity.  In one child, thought 
                 not to be a latent diabetic, a prolonged quiet sleep 
                 occurred with hyperglycaemia and acetonemia (Strauss, 
                 Tonic and clonic convulsions were described in a 18- 
                 year-old girl after ingestion of huge amounts (Samuels, 
                 1957);  EEG patterns in patients receiving therapeutic 
                 doses of chlorpromazine resemble those seen after many 
                 other sedatives (e.g. accentuation of the alpha- 
                 rhythm), but some epileptics do not tolerate 
                 chlorpromazine because of an increased incidence of 
                 focal spikes and of overt convulsions.  In at least one 
                 poison victim (Maucer and Strauss, 1956), diffuse 
                 spikes resembling those seen after pentylenetetrazol 
                 (Metrazol) were prominent in the EEG in the absence of 
                 clinical convulsions or a history of convulsions.  A 
                 necrosing encephalopathy with neuronal, glial, myelinic 
                 and vascular lesions developed in one infant weeks 
                 after apparent recovery from an accidental overdose 
                 (Arseni et al., 1976).
           9.1.2 Inhalation
                 Not relevant.
           9.1.3 Skin exposure
                 Not relevant.
           9.1.4 Eye contact
                 Not relevant.
           9.1.5 Parenteral exposure
                 See 9.1.1.
           9.1.6 Other 
       9.2 Chronic poisoning
           9.2.1 Ingestion
                 The phenothiazines have a high therapeutic index and 
                 are remarkably safe agents.  Furthermore, most 
                 phenothiazines have a relatively flat dose-response 
                 curve, so that they can be used over a wide range of 
                 dosage.  Side effects are extensions of the many 
                 pharmacological actions of the drugs.  The most 
                 important are those on the CNS, cardiovascular system, 
                 and endocrine functions.  The extrapyramidal effects 
                 are of great importance.  The most dangerous effects of 
                 the phenothiazines are those resulting from 
                 hypersensitivity reactions, particularly blood 
           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
           Although successful suicides due to congeners of 
           chlorpromazine are occasionally encountered (Donlon and 
           Tupin, 1977; Joubert and Oliver, 1974) published reports of 
           human fatalities from chlorpromazine are remarkably rare 
           (Brophy, 1967;  Davis et al., 1968).  Sudden death, 
           apparently due to cardiac arrest, has been reported.
       9.4 Systematic description of clinical effects
           9.4.1 Cardiovascular
                 The phenothiazines are chemically related to the so- 
                 called tricyclic antidepressants and have some 
                 pharmacological properties in common with them. 
                 Poisoning by imipramine, however, is a more serious 
                 threat to life than a comparable overdose of 
                 chlorpromazine because of the cardiac arrhythmias and 
                 conduction defects associated with the former. Except 
                 in patients with preexisting heart disease, 
                 cardiotoxicity is infrequently described in 
                 phenothiazine intoxications, but ECG changes, 
                 arrhythmias (especially the "torsades de pointes" 
                 type), conduction disturbances, myocardial failure and 
                 coronary complications are occasionally recognized and 
                 resemble their counterparts produced by tricyclic 
                 antidepressants (Alexander and Nino, 1969).  As adverse 
                 drug reactions with therapeutic doses, disorders of the 
                 cardiac mechanism are more commonly encountered with 
                 piperazine and piperidine type phenothiazine 
                 tranquillizers than with chlorpromazine (Weiss, 1981).
                 In a patient who consumed 6 g chlorpromazine and 6 g 
                 thioridazine, the ventricular tachycardia did not 
                 respond to conventional drug therapy, and a transvenous 
                 pacemaker had to be inserted (Lumpkin et al., 1979).  A 
                 glucose load seemed to increase repolarization 
                 abnormalities in patients chronically treated with 
                 perphenazine (Chouinard and Annable, 1977).
                 Perhaps cardiotoxicity is involved in sudden, 
                 unexplained deaths among patients being treated with 
                 phenothiazines (Hollister and Kosek, 1965). In one of 
                 the cases, irreversible ventricular fibrillation was 
                 demonstrated. Central respiratory failure, however, has 
                 also been suspected in sudden, autopsy negative deaths 
                 (Whyman, 1976).
                 The intensification of the beta agonist effects 
                 (vasodilation) of the sympathomimetic amines was 
                 described above as the basis for the fall in blood 
                 pressure.  This side effect is especially troublesome 
                 after injection of the tranquillizer and early in 
                 treatment.  It may be intense enough to cause dizziness 
                 or fainting.
           9.4.2 Respiratory
                 Respiratory failure may occur.  Muscular paralysis may 
                 result in prolonged apnoea.  Asthma may be an allergic 
                 reaction in some cases.
           9.4.3 Neurological 
        Central nervous system (CNS)
                         Neuromuscular (extrapyramidal) reactions
                         Neuromuscular reactions include dystonias, 
                         motor restlessness, pseudoparkinsonism and 
                         tardive dyskinesia, and appear to be dose 
                          Tardive dyskinesia
                         As with all antipsychotic agents, tardive 
                         dyskinesia may appear in some patients on long 
                         term therapy or may appear after drug therapy 
                         has been discontinued.
                         This syndrome can also develop, although much 
                         less frequently, after relatively brief 
                         treatment periods at low doses.
                         This syndrome appears in all age groups. 
                         Although its prevalence appears to be highest 
                         among elderly women, it is impossible to rely 
                         upon prevalence estimates to predict at the 
                         inception of neuroleptic symptoms which 
                         patients are likely to develop the syndrome. 
                         The symptoms are persistent and in some 
                         patients appear to be irreversible.  The 
                         syndrome is characterized by rhythmical 
                         involuntary movements of the tongue, face, 
                         mouth or jaw (puffing of cheek, puckering of 
                         mouth, chewing movements).  Sometimes these may 
                         be accompanied by involuntary movements of the 
                         extremities as the only manifestations of 
                         tardive dyskinesia.  A variant of tardive 
                         dyskinesia, tardive dystonia, has also been 
                          Adverse behavioral effects
                         Psychotic symptoms and catatonic-like states 
                         have been reported rarely.
                          Other CNS effects
                         Cerebral oedema has been reported.  Convulsive 
                         seizures (petit mal and grand mal)  have been 
                         reported, particularly in patients with EEG 
                         abnormalities or history of such disorders. 
                         Abnormalities of the cerebrospinal fluid 
                         proteins has also been reported (PDR, 1987).
        Peripheral nervous system
                         Chlorpromazine is a potent local anaesthetic, 
                         but the drug has never been used for this 
        Autonomic nervous system
                         As one might expect, a drug with peripheral 
                         cholinergic blocking activity, alpha-adrenergic 
                         blocking actions and adrenergic activity 
                         (secondary to the block of re-uptake of amines) 
                         has complex effects on the autonomic nervous 
                         system. The antihistaminic and 
                         antitryptaminergic effects further complicate 
                         the picture. Chlorpromazine either blocks or 
                         reverses the pressor effects of epinephrine. 
                         The arrhythmogenic effects of epinephrine in 
                         rabbit and dogs are also blocked by 
                         chlorpromazine (Meyers, 1978).
                         Parasympatholytic side effects may be quite 
                         prominent. They include dry mouth, blurred 
                         vision and constipation or rarely paralytic 
                         ileus. Tachycardia and pupillary dilatation may 
                         appear, especially with large doses, or 
                         bradycardia and pupillary constriction may be 
                         observed. This variability in the response of 
                         the heart rate and pupillary size suggests that 
                         a central sympatholytic effect is also present 
                         (Meyers, 1978).  Other observed symptoms are 
                         urinary retention, priapism, atonic colon, 
                         ejaculatory disorders/impotence (PDR, 1978).
        Skeletal and smooth muscle
                         Symptoms may include spasms of the neck 
                         muscles, sometimes progressing to acute, 
                         reversible torticollis, extensor rigidity of 
                         back muscles, sometimes progressing to 
                         opisthotonos, carpopedal spasms, trismus, 
                         swallowing difficulty, oculogyric crisis and 
                         protrusion of the tongue.  These usually 
                         subside within a few hours, and almost always 
                         within 24 to 48 hours after the drug has been 
           9.4.4 Gastrointestinal
                 Constipation and decreased gastric secretion and 
                 motility are observed in patients given chlorpromazine. 
                 Doses of 1 to 3 mg/kg can block the effects of 
                 physostigmine on intestinal tone and peristalsis, 
                 presumably as a result of cholinergic blockade. 
                 Decreased sweating and salivation are other 
                 manifestations of the anticholinergic effects of the 
                 phenothiazines (Meyers, 1978).
           9.4.5 Hepatic 
                 Jaundice was observed in patients shortly after the 
                 introduction of chlorpromazine into psychiatric therapy 
                 and was a cause for alarm.  The incidence of this 
                 complication is relatively low, not more than 2 to 4%. 
                 Commonly occurring during the second to fourth week of 
                 therapy, it is characterized by bile in the urine and 
                 abnormally high levels of alkaline phosphatase 
                 associated with high plasma bilirubin concentrations. 
                 There is usually a normal cephalin flocculation.  The 
                 jaundice is generally mild, with the plasma bilirubin 
                 rarely rising higher than 15 mg/dL; the direct 
                 bilirubin is higher than indirect.  Fever, anorexia and 
                 hepatic tenderness are usually not present but may be 
                 prodromal symptoms of impending jaundice.  Despite the 
                 presence of jaundice, patients rarely complain of 
                 The jaundice is of the obstructive type; this has been 
                 confirmed by liver biopsy and at autopsy. The biopsy 
                 specimens show centrilobular cholestasis, with little 
                 or no parenchymatous damage and with mild inflammatory 
                 response.  It is thought that the presence of 
                 inspissated bile in the hepatic canaliculi is caused by 
                 an increase in viscosity of the bile or by periductal 
                 oedema.  In one comparative study, forcing of fluids 
                 decreased the incidence of jaundice dramatically.  This 
                 was attributed to dilution of the bile.
                 There is a general agreement that the jaundice 
                 following chlorpromazine administration is a 
                 hypersensitivity manifestation.  Eosinophilic 
                 infiltration of the liver, as well as eosinophilia, are 
                 frequently present.  There is prompt recurrence of 
                 jaundice when the patient is given the same drug, and 
                 there is no correlation between the dose administered 
                 and the appearance of jaundice.  Ayd (1962) has 
                 indicated that desensitization to chlorpromazine may 
                 occur with repeated administration in individuals 
                 exhibiting jaundice.  If jaundice is not observed 
                 within the first month of treatment with a 
                 phenothiazine, the chance of its later occurrence 
                 decreases with time. Since there is always the 
                 possibility of shifting a patient from one drug to 
                 another without the recurrence of a hypersensitivity 
                 reaction, it is felt by some investigators that therapy 
                 should be carefully continued in case of jaundice when 
                 the psychiatric disorder calls for uninterrupted drug 
           9.4.6 Urinary
                         Chlorpromazine may have diuretic effects in 
                         animals and man, due either to a depressant 
                         action upon the secretion of antidiuretic 
                         hormone (ADH) or to inhibition of reabsorption 
                         of water and electrolytes by a direct action on 
                         the renal tubule, or both.
                         It may prevent the fall in renal blood flow 
                         occurring in shock. The slight fall in blood 
                         pressure that occurs with chlorpromazine is not 
                         found to be associated with any significant 
                         change in glomerular filtration rate, and there 
                         is tendency toward an increase in renal flow.
                         No data available.
           9.4.7 Endocrine and reproductive systems
                 The effect of chlorpromazine on hypothalamic regulatory 
                 hormones results in profound changes in the endocrine 
                 system. The release and/or action of the prolactin 
                 release-inhibiting hormone is impaired;  the drug has 
                 also been shown to reduce urinary concentrations of 
                 gonadotrophins, as well as oestrogens and progestins. 
                 As a result of these derangements, galactorrhoea and 
                 gynaecomastia can occur. Amenorrhoea is also seen with 
                 chlorpromazine, but this is relatively infrequent.  In 
                 animals the drug can block ovulation, suppress the 
                 oestrus cycle, cause infertility and pseudopregnancy, 
                 and maintain endometrial decidual reaction.  Inhibition 
                 of gonadotropin secretion also can result in decreased 
                 testicular weight.
                 Non-reproductive functions are also affected. 
                 Chlorpromazine may cause a decrease in the secretion of 
                 adrenocorticosteroid as a result of diminished release 
                 of corticotrophin.  It interferes with growth by 
                 inhibiting the secretion of pituitary growth hormone, 
                 an effect utilized in the treatment of acromegaly 
                 (Kolodny et al., 1971).  In addition, chlorpromazine 
                 can decrease the secretion of neurohypophysial 
                 Weight gain and increase in appetite may occur. 
                 Peripheral oedema occurs in 1 to 3% of patients and may 
                 be of endocrine origin.
           9.4.8 Dermatological
                 Urticaria or dermatitis occurs in about 5% of patients 
                 receiving chlorpromazine.  Three types of skin 
                 disorders are associated with the use of 
                 phenothiazines, including chlorpromazine.
                 The first is hypersensitivity reaction that may be 
                 urticarial, maculopapular, petechial or oedematous.  It 
                 usually occurs between the first and fifth week of 
                 treatment.The skin clears following discontinuation of 
                 the drug and may remain so even if drug therapy is 
                 Secondly, contact dermatitis may occur in personnel who 
                 handle chlorpromazine and there may be a certain degree 
                 of cross sensitivity to the other phenothiazines.
                 Thirdly, photosensitivity occurs, the reaction 
                 resembling that seen with severe sunburn.  This 
                 complication may be prevented simply by keeping the 
                 patient well covered.  An effective sunscreen 
                 preparation containing para-aminobenzoic acid should be 
                 prescribed for outpatients during the summer.
                 Abnormal pigmentation induced by long-term 
                 administration of phenothiazines in high doses to 
                 chronic schizophrenics has been reported.  Patients 
                 showing this effect have generally received any of a 
                 number of phenothiazines, but chlorpromazine is the 
                 drug most commonly implicated.  The reaction manifests 
                 itself as a grey-blue pigmentation in regions exposed 
                 to the sun.  The dermis contains deposits of melanin 
                 located throughout the depth of the corium. Ultraviolet 
                 light with wavelengths above 3200A seems to be 
                 primarily responsible for the effects.
           9.4.9 Eye, ear, nose, throat:  local effects
                 The cholinergic blocking effects of the drug are weak, 
                 but the blurring of vision commonly experienced with 
                 chlorpromazine may be due to anticholinergic action on 
                 the ciliary muscle.
                 Chlorpromazine regularly produces miosis in man, which 
                 can be due to ŭ-adrenergic blockade.
                 Epithelial keratopathy is often observed in patients on 
                 long-term therapy with chlorpromazine, and 
                 opacification in the cornea and in the lens of the eye 
                 have also been noted.  In very extreme cases the 
                 deposits in the lens may result in impairment of 
                 vision.  Pigmentary retinopathy which has been reported 
                 particularly following the use of thioridazine, may be 
                 a closely related toxic effect of the phenothiazines 
                 (Zelickson and Zeller, 1964);  thus far, it has been 
                 reported only with doses of thioridazine in excess of 
                 1000 mg per day.
           9.4.10 Haematological
                  Leucocytosis, leucopenia and eosinophilia may occur 
                  with chlorpromazine medication.
                  Leucopenia may appear in patients whose white-blood- 
                  cell counts were low before the institution of drug 
                  therapy.  It is difficult to determine whether a 
                  leucopenia occurring during the administration of 
                  chlorpromazine is a forewarning of impending 
                  agranulocytosis.  This serious complication occurs in 
                  approximately 1 in 10,000 patients receiving 
                  chlorpromazine, usually during the first 6 weeks of 
                  treatment and more often in older women than in men. 
                  Since the onset of the blood dyscrasia may be sudden, 
                  the appearance of an apparent upper respiratory 
                  infection in a patient being started on antipsychotic 
                  drugs should be followed immediately by a complete 
                  blood count.
           9.4.11 Immunological
                  No data available.
           9.4.12 Metabolic 
         Acid-base disturbances
                           No data available.
         Fluid and electrolyte disturbances
                           No data available.
                           It has been observed that chlorpromazine 
                           raises plasma cholesterol levels consistently 
                           and significantly (Clark et al., 1967).
                           Weight gain is a common side effect of 
                           prolonged administration of chlorpromazine. 
                           The increase in caloric intake cannot be 
                           explained by changes in the behavioural 
                           state, that is, it does not merely reflect an 
                           elevation of mood, as is true for the similar 
                           effect of antidepressant drugs.
           9.4.13 Allergic reactions
                  Allergic reaction of a mild urticarial type of 
                  photosensitivity are seen.  Avoid undue exposure to 
                  sun.  More severe reactions, including exfoliative 
                  dermatitis, have been reported occasionally.
                  In addition, asthma, laryngeal oedema, angioneurotic 
                  oedema and anaphylactoid reactions have been reported.
           9.4.14 Other clinical effects
                  The phenothiazines do not appear to be addicting. 
                  However, some degree of physical dependence may occur. 
                  There are reports of muscular discomfort and 
                  difficulty in sleeping that develop several days after 
                  abrupt discontinuation. EEG changes upon sudden 
                  withdrawal have not been detected. Monkeys given 2 
                  mg/kg four times a day for over a month showed no 
                  obvious withdrawal symptoms when the drug was 
                  Tolerance develops to the sedative effects of 
                  chlorpromazine and other phenothiazines. This takes 
                  place over a period of days or weeks, and has been 
                  demonstrated by a variety of objective tests (Meyer, 
                  Chlorpromazine and the other phenothiazine 
                  tranquillizers may cause a failure of thermoregulation 
                  and lead to serious deviations in the deep body 
                  temperature.  Among comatose patients in a cool or 
                  temperate environment, impaired body heat conservation 
                  and the absence of shivering often result in at least 
                  a small drop in deep body temperature; in some cases 
                  the hypothermia is intense.  In a warm or hot 
                  environment, overdoses or even conventional doses 
                  sometimes lead to severe hyperpyrexia (heat stroke) 
                  and several deaths have been ascribed to this 
                  complication (Ayd, 1956; Zelman and Guillan, 1970).
                  Phenothiazine hyperthermia is not always associated 
                  with hot weather.  An unusual syndrome encountered in 
                  France has been named the "malignant neuroleptic 
                  syndrome".  It occurs with conventional doses of 
                  tranquillisers of both the phenothiazine and 
                  butyrophenone types and consists of the gradual onset 
                  of hyperpyrexia, hypertonia rhabdomyolysis, metabolic 
                  acidosis, hyperkalaemia and respiratory distress.  The 
                  incidence is said to be about 40 cases annually in 
                  France, and the mortality rate in untreated cases is 
                  30 to 50%.  There is no known genetic predisposition 
                  as in malignant hyperpyrexia, but like the latter 
                  disease the malignant neuroleptic syndrome may be 
                  responsive to treatment by intravenous sodium 
                  dantrolene (Bismuth et al., 1982).
                  Peripheral oedema and a systemic lupus erythematosus- 
                  like syndrome have been reported (PDR; 1987).
           9.4.15 Special risks   
                  Chlorpromazine and its metabolites were found in the 
                  maternal plasma and urine, in the foetal plasma and 
                  amniotic fluid, and in neonatal urine after doses of 
                  50 to 100 mg of chlorpromazine were given 
                  intramuscularly to pregnant women shortly before 
                  Preliminary data suggests that in mothers taking 
                  chlorpromazine concentrations can be higher in milk 
                  than in maternal plasma and might be associated with 
                  drowsiness and lethargy in the infant.
       9.5 Other
           No data available.
        10.1 General principles
             The mainstay of treatment is supportive care. In patients 
             with a history of significant neuroleptic ingestion, gut 
             decontamination should be considered within the first two 
             hours after ingestion. An electrocardiogram and cardiac 
             monitoring are important in the comatose patient. 
             Symptomatic patients (e.g. hypotension, conduction delay, 
             dysrhythmia) should be admitted until the ECG is normal for 
             24 hours.  Asymptomatic patients can be released after a 
             four hour observation period.
        10.2 Relevant laboratory analyses
             10.2.1 Sample collection
                    Collect urine and blood samples for toxicology and 
                    biomedical analysis.
             10.2.2 Biomedical analysis
                    Not relevant
             10.2.3 Toxicological analysis
                    Blood levels do not correlate well with clinical 
             10.2.4 Other investigations
                    Haemodynamic and ECG monitoring should be performed 
                    in unstable patients.  Serial blood tests should be 
                    obtained in chronic users.
        10.3 Life supportive procedures and symptomatic/specific 
             Haemodynamic and ECG monitoring should be performed in 
             unstable patients. Serial blood tests should be obtained in 
             chronic users.
             Patients with vital signs or cardiac abnormalities should 
             receive cardiac monitoring.  Hypotension is the most common 
             sign.  Direct acting alpha-adrenergic agonists (e.g. 
             norepinephrine, methoxamine) are the theoretical 
             vasopressors of choice.  Vasopressors with mixed alpha and 
             beta adrenergic function (e.g. epinephrine, dopamine) may 
             cause worsened hypotension because of the unopposed beta- 
             adrenergic stimulation from phenothiazine-induced alpha 
             blockade.  Care with serious arrhythmias arising from 
             sensitised myocardium should be considered.
             Although lidocaine and phenytoin have been proposed as the 
             antiarrhythmic drugs of choice for ventricular 
             dysrhythmias, these and other antiarrhythmics are best 
             avoided in drug-induced arrhythmias, especially in 
             "torsades de pointes" type of dysrhythmias. In these 
             situations the treatment of underlying conditions (e.g. 
             hypoxia, hypokalaemia) or overdrive pacing is more 
             Sodium bicarbonate may be used in a manner similar to its 
             use in treating tricyclic antidepressant-induced 
             dysrhythmias.  However, its efficacy is not established in 
             phenothiazine overdoses.
             Quinidine, procainamide and disopyramide are 
             contraindicated.  With the exception of the "torsades de 
             pointes" dysrhythmias, isoproterenol (isoprenaline) is 
             usually contraindicated because of the exacerbations of 
             hypotension by its beta-adrenergic agonist effects.
              Tardive dyskinesia
             Once this syndrome has developed, treatment is difficult. 
             Anticholinergic drugs used in acute dystonic reactions do 
             not improve this condition and in fact may worsen it.  The 
             use of diltiazem in doses up to 360 mg daily has been 
             associated with immediate clinical improvement lasting for 
             weeks in an initial study (Ross, 1987).
              Thermal dysregulation
             Hypothermia invariably is mild unless the patient has been 
             exposed to a low ambient temperature. It is usually 
             responsive to measures used to correct other vital signs 
             and to passive rewarming.  True hyperthermia represents a 
             greater risk and the development of the neuroleptic 
             malignant syndrome requires prompt treatment.  Careful 
             attention should be directed towards maintaining fluid and 
             electrolyte balance and controlling seizures.  Cooling 
             blankets or ice packs are helpful and antipyretics probably 
             are not. Haloperidol and other anticholinergic drugs should 
             be stopped.  The development of myoglobinuria indicates the 
             need for alkaline diuresis to prevent acute tubular 
             For malignant hyperthermia, dantrolene may be administered 
             at an initial intravenous dose of 2.5 mg/kg up to a maximum 
             of 10 mg/kg.  The maintenance dantrolene dose is 2.5 mg/kg 
             every 6 hours until the crisis resolves. (See IPCS antidote 
             monograph on dantrolene). Monitor arterial blood gases 
             (O2, pH) serum electrolytes, glucose and creatinine-kinase 
             Diazepam and phenytoin are the anticonvulsant drugs of 
             choice.  Persistence of seizures for an hour is an 
             indication for intubation, curarization, and thiopental 
             general anaesthesia.
             Urine myoglobin concentration and serum muscle activity 
             should be considered in all patients with prolonged muscle 
             rigidity or seizures.
              Acute dystonic reactions
             Intravenous benztropine mesylate (2 mg in adults) and 
             biperiden (0.15 mg/kg up to 5 mg intramuscularly or 
             intravenously) are the drugs of choice and should relieve 
             symptoms in 5 to 15 to 20 minutes.  Mild sedation is the 
             main side effects.  Follow up treatment with an 
             anticholinergic agent (e.g. trihexylphenidyl 2 mg oral 
             twice daily) may be given over 2 to 3 days because of the 
             long half-life of major tranquillisers. Phenothiazines 
             should be discontinued.
             Akathisias and Parkinson-like syndrome may be relieved by 
             reduction of the dose of use of antiparkinsonian drugs 
             (e.g. biperiden or benztropine).  Often, akathisias appear 
             resistant to anticholinergic drugs and benzodiazepines. A 
             recent trial of low dose propranolol suggests that beta- 
             adrenergic blockers may be efficacious (Alder, 1986).
        10.4 Decontamination
             Phenothiazines are water soluble and delay gastric 
             emptying. Although gastric emptying may be delayed, there 
             is no indication of efficacy of emesis induced later than 
             one hour following ingestion.
             Similarly, obtunded patients may benefit from lavage up to 
             2 hours post-ingestion.
             Several repeated doses of charcoal (0.5 g/kg every 2 to 3 
             hours) may be useful to bind the remaining drug in the gut, 
             similar to tricyclic antidepressants.
             The decision between ipecac and lavage may have to be made 
             if seizures and rapid obtundation occur.  In these 
             situations it is preferable to use activated charcoal and 
        10.5 Elimination
             Because of the high protein binding and large volumes of 
             distribution, haemodialysis and forced diuresis are 
             Haemoperfusion has not been well studied, but it is 
             unlikely to be efficacious.
             Plasmapheresis has not being sufficiently used as yet, and 
             further experience is required.
        10.6 Antidote treatment 
             10.6.1 Adults
                    There is no antidote.
             10.6.2 Children
                    There is no antidote.
        10.7 Management discussion
             Physostigmine has been used for conduction delays, coma and 
             seizures in mixed phenothiazine and tricyclic 
             antidepressant overdose with anecdotal success (Weisdorf, 
             1978).  However, serious adverse reactions such as asystole 
             have occurred, thereby relegating its use in the treatment 
             of dysrhythmias or seizures to a last-line drug.
        11.1 Case reports from literature
             Case 1
             Report of death in a 44-year-old-man being given 
             chlorpromazine in hospital for continued treatment of 
             schizophrenic symptoms. The initial dose was 400 mg daily 
             and was increased to 1600 mg daily. After several days 400 
             mg daily of thioridazine was added to the existing 
             treatment regimen. Four days later he became violently 
             assaultive and died as he was being restrained. The post- 
             mortem was unremarkable (Hollister & Kosseck, 1965).
             Case 2
             A 31-year-old man was treated with 1600 mg daily of 
             chlorpromazine for a schizophrenic reaction. This was 
             reduced to 1050 mg of chlorpromazine daily when it was 
             combined with 1200 mg daily of thioridazine. At the time of 
             his death the regimen had been reduced to 400 mg 
             chlorpromazine daily with 2 mg of biperiden hydrochloride. 
             The post-mortem was unremarkable. Blood chlorpromazine was 
             3 mcg/mL and a strongly positive test for chlorpromazine 
             was obtained in urine(Hollister & Kosseck, 1965).
             Case 3
             Report of a 54-year-old woman on chlorpromazine who had a 
             15-year old history of pruritic eruptions in light exposed 
             areas. Recurrences had occurred once or twice a year. An 
             eruption on the hands occurred more frequently. Subsequent 
             skin tests indicated that she had a combination of 3 types 
             of hypersensitivity to chlorpromazine, i.e. allergic 
             contact dermatitis, photocontact dermatitis and immediate 
             allergic photosensitivity (Horio, 1975).
             Other Case reports
             Hollander et al. (1985) reported mild to severe dystonia in 
             4 out of 11 patients with AIDS-related Pneumocystis carinii 
             pneumonia, following treatment with an intramuscular or 
             oral daily dose of no more than 40 mg of chlorpromazine. 
             All reactions occurred within 48 hours of the first dose.
             Solomon (1977) reviewed cases of sudden deaths from, inter 
             alia, chlorpromazine. Out of the 10 cases in which 
             chlorpromazine was implicated, chlorpromazine was the only 
             drug being used in 4 cases. The doses being taken at time 
             of death were as follows:
             30-year-old female     200 mg orally 4 times a day.
             50-year-old male       Dose not stated. Drug taken for
                                    10 months
             72-year-old female     10 mg orally twice a day.
             19-year-old male       600 mg orally per day for 12 days.
             The author noted that these deaths might be attributed to 
             aspiration of food or stomach contents consequent to the 
             development of severe extrapyramidal effects.
        11.2 Internally extracted data on cases
             To be completed by each Centre, using local data
        11.3 Internal cases
             To be completed by each Centre, using local data
        12.1 Availability of antidotes
             There is no specific antidote available.
        12.2 Specific preventive measures
             No data available.
        12.3 Other
             Not relevant
        Alder L et al. (1986)  A controlled study of propranolol in the 
        treatment of neuroleptic induced akathisia.  Br J  Psychiatry, 
        Alexander CS, Nino A (1969) Cardiovascular complication in young 
        patients taking psychotropic drugs.  A  Heart  J,  78:757-769.
        Algeri E et al. (1976)  Toxicology of some new drugs. 
        Glutethimide, meprobamate and chlorpromazine.  J  Forensic  Sci, 
        Arsenic C et al.  (1976)  Encephalopathy subsequent to 
        accidental poisoning with chlorpromazine.  Europ Neurol, 
        Ayd FJ (1956)  Fatal hyperpyrexia during chlorpromazine therapy. 
        J  Cli Exp Psychopath,  17:189-192.
        Ayd FJ (1962): in Meyers FH, Jawetz E, Goldfien A (1978)  Review 
        of medical pharmacology 6th Ed.  Lange Medical Publications. 
        California.  158-165.
        Bismuth C et al. (1982)  Theoretical indication of dantrolene in 
        malignant neuroleptic syndrome.  Efficacy in 3 cases.  Vet 
        Human  Toxicol,  24:280.
        Brophy JJ (19679  Suicide attempts with psychotherapeutic drugs. 
        Arch Gen Psychiatric  17:652-657.
        Burckart GJ, Snidow J, Bruce W (1981)  Neutropenia following 
        acute chlorpromazine ingestion.  Clin Toxicol, 18:797-801.
        Cann HM, Verhust HL (1960)  Accidental ingestion and overdosage 
        involving psychopharmacologic drugs.  N  Engl  J  Med, 263:719- 
        Chouinard G,  Annable L (1977) Phenothiazine induced ECG 
        abnormalities:  effect of a glucose load.  Arch Gen  Psychiatry, 
        Clark et al. (1967)  in Meyers FH, Jawetz E, Goldfien A (1978) 
        Review of medical pharmacology 6th Ed.  Lange Medical 
        Publications.  California  158-165.
        Curry SH (1970) in Martindale (1989), Reynolds J ed. The Extra 
        Pharmacopoeia, Twenty-ninth Ed., London, The Pharmaceutical 
        Davis JM, Bartelett E, Termini BA (1968)  Overdosage of 
        psychotropic drugs.  A review.  Dis Nerv System, 29:157-164 
        and 246-256.
        Donlon PT, Tupin JP (197)  Successful suicides with thioridazine 
        and mesoridazine.  Arch Gen Psychiatry, 34:955-957.
        Douglas ADM, Bates TJN (1957)  Chlorpromazine as a suicidal 
        agent.  Br Med J, 1:1514.
        Ferguson JT (1957)  Neuropharmacological agents in 
        rehabilitation of patients of chronical mental illness, JAM 
        Goodman-Gillman (1975)  The Pharmacological Basis of 
        Therapeutics.  5th ed. Mac Millan Publishing,  251-163;
        Goodman-Gillman (1990)  The Pharmacological Basis of 
        Therapeutics.  5th ed. Mac Millan Publishing, p 1668.
        Gossellin RE, Smith RP and Hodge H (1984)  Clinical Toxicology 
        of Commercial Products, 5th ed.  Williams and Williams. 
        Baltimore  109-114.
        Hollander H, Golden J, Mendelson T, Cortland D : Extrapyramidal 
        symptoms in aids patients given low-dose metoclopramide of 
        chlorpromazine. Lancet 1985 II: 1186
        Hollister LE, Kosek JC (1965)  Sudden death during treatment 
        with phenothiazine derivatives.  JAMA  192:1035-1038.
        Horio T. Chlorpromazine photo allergy. Co-existence of immediate 
        and delayed type. Arch Dermatol 1975 111: 1469-1471
        Huang and Kurland (1961):  in Meyers FH, Jawetz E, Goldfien A 
        81978):  Review of medical pharmacology 6th ed.  Lange Medical 
        Publications.  California, 158-165.
        Joubert PH, Olivier JA (1974)  Fatal suicidal ingestion of 
        thioridazine.  Clin Toxicol, 7:133-138.
        Kolodny HO et al. (1971)  Acromegaly treated with 
        chlorpromazine.  N  Engl  J Med,  284-819.
        Lacoursiere RB, Spohn HE (1976):  in Martindale (1989), Reynolds 
        J ed. The Extra Pharmacopoeia, Twenty-Ninth Ed., The 
        Pharmaceutical Press, 722-725.
        Lumkin J et al. (1979)  Phenothiazine induced ventricular 
        tachycardia following acute overdose.  J Am Coll Emerg  Phys, 
        Martindale (1989), Reynolds J ed. The Extra Pharmacopoeia, 
        Twenty-ninth Ed., London, The Pharmaceutical Press.
        Mauceri J, Strauss H (1959)  Effects of chlorpromazine on 
        electroencephalogram with reports of case of chlorpromazine 
        intoxication.  Electroencephalogr  Clin Neurophysiol  8:671-675.
        Meyers FH, Jawetz E, Goldfien A (1978)  Review of Medical 
        Pharmacology 6th ed. Lange Medical Publication.  California, 
        Moccetti T et al. (1971)  Kardiotoxizital der trizyklischen 
        Antidepressiva Schweiz Med Wochenschr, 101:1-10.
        O'Donoghue SEF (1971):  in Martindale (1989), Reynolds J ed. The 
        Extra Pharmacopoeia, Twenty-Ninth Ed., London, The 
        Pharmaceutical Press, 722-725.
        PDR (1987)  Physicians Desk Reference. Medical Economics Co. 
        Prien et al. (1970):  in Meyers FH, Jawetz E, Goldfien A, 1978. 
        Review of medical pharmacology 6th ed.  Lange Medical 
        Publications.  California, 158-165.
        Ross JL et al. (1987)  Diltiazem for tardive dyskinesia.  Lancet 
        RTECS:  Registry of Toxic and Chemical Substances (1985-1986) 
        US Department of Health and Human Services, National Institute 
        for Occupational Safety and Health, Vol. 1-611.
        Samuels AS (1957)  Acute chlorpromazine poisoning.  Am  J 
        Psychiatry, 113:746-748.
        Solomon K Phenothiazine induced bulbar palsy like syndrome and 
        sudden death. Am J Psychiatry 1977. 134:308-311
        Stirrat GM (1973):  in Martindale (1989), Reynolds J ed. The 
        Extra Pharmacopoeia, Twenty-Ninth Ed., London, The 
        Pharmaceutical Press, 722-725.
        Strauss AJ (1968)  Coma for accidental phenothiazine ingestion, 
        an unusual metabolic effect.  Clin Pediatr,  7:59-60.
        Weisford et al. (1978)  Physostigmine for cardiac and 
        neurological manifestations of phenothiazine poisoning.  Clin 
        Pharmacol Ther,  24:663-667.
        Weiss LR (1981)  The cardiotoxicity of neuroleptic and tricyclic 
        antidepressant drugs.  In Cardiac Toxicology, Vol. II, Tibor- 
        Balazs ed. CRC Press Inc.  Boca Raton, Florida, 125-143.
        Whyman A (1976)  Phenothiazine deaths:  an unusual case report. 
        J Nerv Ment Dis,  34:951-954.
        Wiles DH et la. (1978): in Martindale (1989), Reynolds J ed. The 
        Extra Pharmacopoeia, Twenty-Ninth Ed., London, The 
        Pharmaceutical Press, 722-725.
        Zelman S, Guillan R (1970)  Heat stroke in phenothiazine treated 
        patients.  A report of three fatalities.  Am J Psychiatry, 
        Zelickson and Zeller (1970):  in Meyers Fh, Jawetz E, Goldfien 
        A, 1978.  Review of Medical Pharmacology 6th ed. Lange Medical 
        Publications, California, 158-165.
        Author  Dr Julia Higa de Landoni
                 Sección Toxicologia
                 Hospital de Clinicas
                 Jose de San Martin
                 Universidad de Buenos Aires

    See Also:
       Toxicological Abbreviations
       Chlorpromazine (WHO Food Additives Series 29)
       CHLORPROMAZINE (JECFA Evaluation)