1.

NAME
1.1 Substance
Chlorpromazine
(INN, 1992)
1.2 Group
Psycholeptics (N05)/
Antipsychotics (N05A)
(ATC classification index [WHO] 1992])
1.3 Synonyms
Chlorpromazini hydrochloridum
Aminazine
(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
Ampliactil
Cesalgin
Largactil
Promactil
Thorazine
Aminasine
(To be completed by each Centre using local datata)
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
occur.

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

value.

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. PHYSICO-CHEMICAL PROPERTIES

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
embonate
Chlorpromazine C17H19C1N2S,HCl
hydrochloride
Molecular weight
Chlorpromazine 318.9
Chlorpromazine 1026.1
embonate
Chlorpromazine 355.3
hydrochloride
Chemical names

3-(2-Chlorophenothiazin-10-yl)propyldimethylamine

2-Chloro-N,N-dimethyl-10H-phenothiazine-10-propanamine

2-Chloro-10-(3-dimethylaminopropyl)phenothiazine

N-(3-dimethylaminopropyl)-3-chlorophenothiazine

(Martindale, 1993; Merck Index, 1989)

3.3 Physical properties

3.3.1 Properties of the substance

3.3.1.1 Colour

White to creamy-white (Base and hydrochloride)

Both forms darken on prolonged exposure to
light.
 3.3.1.2 State/Form

Powder or waxy solid (Base)

Crystalline powder (Hydrochloride)

3.3.1.3 Description

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

disorders.

For the relief of restlessness and apprehension before

surgery.

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
restlessness.

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)

Parenteral

Intramuscular

25 to 50 mg three to 4 times daily.

Intravenous

25 mg to 50 mg (repeated as required).

Rectal

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

Oral

0.5 mg/kg bodyweight every 4 to 6 hours.

Parenteral

Intramuscular

500 mcg/kg bodyweight every 6 to 8 hours.

Rectal

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
years
 (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. ROUTES OF ENTRY

5.1 Oral

Chlorpromazine is available in tablet or syrup forms for oral

ingestion.

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. KINETICS

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
drug.

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. PHARMACOLOGY AND TOXICOLOGY

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
sedation.

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

7.2.1.1 Adults

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).
7.2.1.2 Children

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

LD50
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

guanethidine.

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

reported.

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
possible.

8. TOXICOLOGICAL AND BIOMEDICAL INVESTIGATIONS

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
erythrocytes.

8.1.1 Sampling and specimen collection

8.1.1.1 Macroscopic and microscopic analysis

8.1.1.2 Toxicological analyses

8.1.1.3 Biological analyses

8.1.1.4 Arterial blood gas analysis

8.1.1.5 Haematological analyses

 8.1.1.6 Other (unspecified) analyses

8.1.2 Storage of laboratory samples and specimens

8.1.2.1 Macroscopic and microscopic analysis

8.1.2.2 Toxicological analyses

8.1.2.3 Biochemical analyses

8.1.2.4 Arterial blood gas analysis

8.1.2.5 Haematological analyses

8.1.2.6 Other (unspecified) analyses

8.1.3 Transport of laboratory samples and specimens

8.1.3.1 Macroscopic and microscopic analysis

8.1.3.2 Toxicological analyses

8.1.3.3 Biochemical analyses

8.1.3.4 Arterial blood gas analysis

8.1.3.5 Haematological analyses

8.1.3.6 Other (unspecified) analyses

8.2 Toxicological analyses and their interpretation

8.2.1 Tests on toxic ingredient(s) of material

8.2.1.1 Simple qualitative test(s)

8.2.1.2 Advanced qualitative confirmation test(s)

8.2.1.3 Simple quantitative method(s)

8.2.1.4 Advanced quantitative method(s)

8.2.2 Tests on biological specimens

8.2.2.1 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.

8.2.2.2 Advanced qualitative confirmation test(s)

8.2.2.3 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

8.2.2.4 Advanced quantitative method(s)

8.2.2.5 Other dedicated method(s)

8.2.3 Interpretation of toxicological analyses

8.3 Biomedical investigations and their interpretation

8.3.1 Blood, plasma or serum

Serum electrolytes, glucose, creatine kinase should be

performed in symptomatic patients.

"Basic analyses"
"Dedicated analyses"
"Optional analyses"

8.3.1.2 Urine
 "Basic analyses"
"Dedicated analyses"
"Optional analyses"

8.3.1.3 Other fluids

 8.3.2 Arterial blood gas analyses

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

interpretation

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

reported.

8.6 References

9. CLINICAL EFFECTS
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,
1968).

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
dyscrasias.

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

9.4.3.1 Central nervous system (CNS)

Neuromuscular (extrapyramidal) reactions

Neuromuscular reactions include dystonias,

motor restlessness, pseudoparkinsonism and
tardive dyskinesia, and appear to be dose
related.

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
described.

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).

9.4.3.2 Peripheral nervous system

Chlorpromazine is a potent local anaesthetic,

but the drug has never been used for this
purpose.

9.4.3.3 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).

9.4.3.4 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
discontinued.

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
pruritus.

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
therapy.
9.4.6 Urinary

9.4.6.1 Renal

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.

9.4.6.2 Other

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
hormones.

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
reinstituted.

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 ý-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

9.4.12.1 Acid-base disturbances

No data available.
 9.4.12.2 Fluid and electrolyte disturbances

No data available.

9.4.12.3 Others

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
discontinued.

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,
1978).

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

Pregnancy

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
delivery.

Breast-feeding

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. MANAGEMENT

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

effects.

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

treatment

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
important.

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
necrosis.

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
carefully.

Seizures

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
lavage.

10.5 Elimination

Because of the high protein binding and large volumes of

distribution, haemodialysis and forced diuresis are
ineffective.

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. ILLUSTRATIVE CASES

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. ADDITIONAL INFORMATION

12.1 Availability of antidotes

There is no specific antidote available.

12.2 Specific preventive measures

No data available.

12.3 Other

Not relevant

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

Author Dr Julia Higa de Landoni

Sección Toxicologia
Hospital de Clinicas
Jose de San Martin
Universidad de Buenos Aires

Tel:
Fax:

Date
http://www.inchem.org/documents/pims/pharm/chlorpro.htm