Chlorpromazine. Uses. Preparations

Uses and Administration

Chlorpromazine is a phenothiazine antipsychotic. It has a wide range of activity arising from its depressant actions on the CNS and its alpha-adrenergic blocking and antimuscarinic activities. Chlorpromazine is a dopamine inhibitor the turnover of dopamine in the brain is also increased. There is some evidence that the antagonism of central dopaminergic function, especially at the D₂-dopaminergic receptor, is related to therapeutic effect in psychotic conditions.

Chlorpromazine possesses sedative properties but patients usually develop tolerance rapidly to the sedation. It has antiemet-ic, serotonin-blocking, and weak antihistaminic properties and slight ganglion-blocking activity. It inhibits the heat-regulating centre so that the patient tends to acquire the temperature of the surroundings (poikilothermy). Chlorpromazine can relax skeletal muscle. Chlorpromazine is widely used in the management of psychotic conditions as well as in some non-psychotic disorders, such as:

• acute and chronic schizophrenia in adults and children
• to reduce acute mania, as in bipolar disorder
• control of severely disturbed, agitated, or violent behaviour in adults and children and sometimes other psychiatric conditions
• in autistic children
• as an adjunct for the short-term treatment of severe anxiety, and to reduce pre-operative anxiety in adults and children
• as an antiemetic in some forms of nausea and vomiting in adults and children it is ineffective in motion sickness
• in the alleviation of intractable hiccup
• as an adjunct in the treatment of tetanus in adults and children and to control symptoms in acute intermittent porphyria
• for induction of hypothermia Chlorpromazine is given orally as the hydrochloride and the embonate. For both salts, the doses are expressed as the hydrochloride chlorpromazine embonate 144 mg is equivalent to about 100 mg of chlorpromazine hydrochloride. Chlorpromazine is also given by injection as the hydrochloride and doses are expressed in terms of this salt. The base is given rectally as suppositories doses are in terms of the base.

Dosage varies both with the individual and with the purpose for which the drug is being used. In most patients with psychiatric conditions oral treatment may be used from the start, typically commencing with a dosage of 25 mg of the hydrochloride, or its equivalent as the embonate, three times daily and increasing as necessary daily doses of 75 mg may be given as a single dose at night. In some patients doses of 10 mg three times daily may be adequate. Maintenance doses, when required, usually range from 25 to 100 mg three times daily, although psychotic patients may require daily doses of up to 1 g or more.

For parenteral use, deep intramuscular injection is preferable, but diluted solutions have sometimes been given by slow intravenous infusion for indications such as tetanus, severe intractable hiccup, or nausea and vomiting associated with surgery. Subcutaneous injection is contra-indicated. After injection of chlorpromazine, patients should remain in the supine position for at least 30 minutes blood pressure should be monitored. The usual dose by intramuscular injection is 25 to 50 mg repeated every 6 to 8 hours if required, although oral therapy should be substituted as soon as possible.

If the oral and parenteral routes are not suitable chlorpromazine may be given rectally as suppositories containing 100 mg of chlorpromazine base this is stated to have an effect comparable with 40 to 50 mg of the hydrochloride orally or 20 to 25 mg intramuscularly. The usual rectal dose is 100 mg every 6 to 8 hours. Initial oral doses of chlorpromazine of one-third to one-half the usual adult dose have been recommended for elderly or debilitated patients doses should be increased more gradually. Intramuscular doses in the elderly may need to be reduced to up to one-quarter of the usual dose.

Chlorpromazine hydrochloride may be given to childrenaged lto 12 years in a dose of 500 micrograms/kg every 4 to 6 hours orally or every 6 to 8 hours by intramuscular injection. However, for psychiatric indications the oral dose for children aged over 5 years is usually one-third to one-half the adult dose alternatively, the BNFC suggests a dose of 10 mg 3 times daily. Daily doses should not normally exceed 40 mg of chlorpromazine hydrochloride for children aged 1 to 5 years or 75 mg for children over 5 years of age.

Chlorpromazine may be given to infants under 1 year of age if considered to be life-saving. Suppositories containing 25 mg of chlorpromazine base are available in some countries for use in children. Doses of 10 to 25 mg every 4 to 6 hours orally are recommended for control of nausea and vomiting. If necessary an initial dose of 25 mg may be given by intramuscular injection, followed by 25 to 50 mg every 3 to 4 hours until vomiting stops. If intractable hiccup does not respond to an oral dose of 25 to 50 mg three or four times daily for 2 to 3 days then 25 to 50 mg may be given intramuscularly if this fails 25 to 50 mg in 500 to 1000 niL of 0.9% sodium chloride should be given by slow intravenous infusion, with the patient supine, and careful monitoring of the blood pressure.

Action.

The therapeutic effects of antipsychotics appear to be mediated, at least in part, by interference with dopamine transmission in the brain. Chlorpromazine, thioridazine, and thioxan-thene derivatives have relatively equal affinity for D₁ or D₂ receptors, although their metabolites tend to be more potent as D₂ blockers. Butyrophenones (such as haloperidol) and diphenyl-butylpiperidines (such as pimozide) are relatively selective for D₂ receptors, and the substituted benzamides (such as sulphide) are highly D₂-specific. Clozapine has complex actions: it is a relatively weak inhibitor of D₂ receptors but has a high affinity for a number of other receptors including D₁, D₄, and serotonin₂ (5-HT₂) receptors. Other atypicals mostly share this profile of greater 5-HT₂ than D₂ antagonism.

The traditional hypothesis of the action of antipsychotics has been that blockade of D₂ receptors in the limbic and cortical regions is responsible for the antipsychotic effects, and that adverse extrapyramidal motor effects result from blockade of D₂ receptors in the striatum (a typical motor region of the basal ganglia). Modification of prolactin secretion results from blockade of D₂ receptors in the anterior pituitary. However, this hypothesis cannot satisfactorily account for the pharmacological profiles of atypical antipsychotics and the debate concerning their mechanism of action continues.

It has been suggested that the balance between 5-HT₂ and D₂ antagonism is important in determining ‘atypicality’ (but the atypical antipsychotic amisulpride lacks marked 5-HT₂ antagonism), or that rapid dissociation from the D₂ receptor may be the determining factor (but it is not clear that some atypicals such as risperidone meet this criterion). Other systems, such as glutamate, may play a role in modulating effectiveness against negative versus positive symptoms it has been suggested that the calcium antagonist actions of the diphenyl-butylpiperidines may also be important in this respect. Division of antipsychotics into low- and high-potency drugs is discussed in Administration, below. For reference to the actions of antipsychotics on neuroendocrine function, see Effects on Endocrine Function under Adverse Effects, above.

Administration.

The classical antipsychotics are often divided into:

• low-potency drugs (phenothiazines with an aliphatic or piperidine side-chain or thioxanthenes with an aliphatic side-chain)
• high-potency drugs (butyrophenones, diphenylbutylpiperidines, and phenothiazines or thioxanthenes with a piperazine side-chain)

At doses with equipotent antipsychotic activity, the low-potency drugs are more prone to cause sedation and antimuscarinic or α-adrenergic-blocking effects than the high-potency drugs. However, they are associated with a lower incidence of extrapyramidal effects, with the exception of tardive dyskinesia which is likely to occur to the same extent with all classical antipsychotics.

Equivalent doses of antipsychotics quoted in the literature have varied considerably. In the UK the following daily doses of oral antipsychotics have been suggested to have approximately equipotent antipsychotic activity for doses up to the maximum licensed doses:

• chlorpromazine hydrochloride 100 mg
• clozapine 50 mg
• haloperidol 2 to 3 mg
• pimozide 2 mg
• risperidone 0.5 to 1 mg
• sulpiride 200 mg
• thioridazine 100 mg
• trifluoperazine 5 mg

It should be noted that all patients receiving pimozide require an annual ECG and all those receiving more than 16 mg of pimozide daily require periodic ECGs. Thioridazine also requires specialist supervision.

Suggested equipotent doses of intramuscular depot antipsychotics are:

• flupentixol decanoate 40 mg every 2 weeks
• fluphenazine decanoate 25 mg every 2 weeks
• haloperidol (as the decanoate) 100 mg every 4 weeks
• pipotiazine palmitate 50 mg every 4 weeks
• zuclopenthixol decanoate 200 mg every 2 weeks

It has been noted that high doses of antipsychotics (greater than the equivalent of 600 mg of chlorpromazine daily) are generally not necessary for the treatment (both initial and maintenance) of psychotic disorders, and may be associated with an increased risk of adverse effects as well as with a diminished clinical response. However, if high doses of antipsychotics have to be used, then doses should be increased gradually with caution and under the supervision of a specialist with facilities for emergency resuscitation available. The Royal College of Psychiatrists in the UK (which defines high-dose therapy as that involving a total daily dose greater than the upper limit recommended in the BNF) has issued recommendations concerning the use of high-dose antipsychotic medication. It considers:

• current evidence does not justify the routine use of high-dose therapy with antipsychotics
• if high-dose therapy is used, this should only be after evidence-based strategies have failed, and as a carefully-monitored therapeutic trial
• the decision to use high-dose therapy, and the expected outcome, should be fully documented, after expert assessment of the patient
• the possible contra-indications to therapy, and the risk of drug interactions, should be assessed beforehand
• an ECG should be carried out before starting high-dose therapy and should be repeated after a few days, and then every 1 to 3 months in the early stages of treatment, or as clinically indicated
• doses should be increased in relatively small increments, with time to assess response before a further increase
• the use of’as-required antipsychotic medication, and of drug combinations, should be carefully monitored to avoid the inadvertent increase of total doses above high-dose thresholds

The existence of a therapeutic range (or therapeutic window) has not been demonstrated for most antipsychotics (with the possible exception of haloperidol), and plasma concentrations of these drugs must be interpreted with caution. Many factors make it difficult to establish a meaningful correlation between dose, plasma concentrations, and clinical improvement. These include incomplete absorption, first-pass effect, enzyme induction, the presence of active and inactive metabolites, ethnicity, smoking, and factors occurring at the receptor level.

Administration in children.

For reference to the use of lytic cocktails containing chlorpromazine, promethazine, and pethidine, and the view that alternatives should be considered in children, see Lytic Cocktails, under Sedation.

Bipolar disorder.

Patients with bipolar disorder suffering from acute mania with coexisting psychotic features, agitation, or disruptive behaviour are usually treated with antipsychotics as they produce rapid control of symptoms. Classical antipsychotics such as chlorpromazine or haloperidol have been widely used, although use of atypical antipsychotics, such as clozapine or olanzapine, is growing.

Chorea.

For a discussion of the management of various choreas, including mention of the use of phenothiazines such as chlorpromazine.

Dyspnoea.

It has been shown that in healthy subjects an oral dose of 25 mg of chlorpromazine hydrochloride can reduce exercise-induced breathlessness without affecting ventilation or causing sedation. Although other drugs may be preferred in patients with advanced cancer and dyspnoea, chlorpromazine may relieve air hunger unresponsive to usual measures, and, if required, can be used to sedate dying patients who have unrelieved distress. It is recommended that initial doses should be small: 12.5 mg by slow intravenous injection or 25 mg by suppository may be given.

Dystonia.

Antipsychotics such as phenothiazines, haloperidol, or pimozide are sometimes useful in the treatment of idiopathic dystonia in patients who have failed to respond to other drugs. However, they often act non-specifically, damping down excessive movements by causing a degree of drug-induced parkinsonism and there is the risk of adding drug-induced extrapyramidal disorders to the dystonia being treated (see Extrapyramidal Disorders under Adverse Effects, above).

Eclampsia and pre-eclampsia.

Drug combinations known as lytic cocktails have been used in many countries for the management of pre-eclampsia and imminent eclampsia. The cocktail has usually consisted of a combination of chlorpromazine, pethidine, and/or promethazine. In general, however, phenothiazines are not recommended in late pregnancy, and other treatments are preferred for hypertension (see Hypertension in Pregnancy, under Hypertension) the management of eclampsia, which is the convulsive phase, is discussed.

Headache.

Some phenothiazines such as chlorpromazine, levomepromazine, and prochlorperazine have been used in migraine to control severe nausea and vomiting unresponsive to antiemetics such as metoclopramide and domperidone, and to relieve the pain of severe migraine attacks unresponsive to parenteral dihydroergotamine or sumatriptan. References.

Hiccup.

A hiccup is an involuntary spasmodic contraction of the diaphragm that causes a sudden inspiration of air which is then checked abruptly by closure of the glottis. Hiccups often have a simple cause such as gastric distension and usually resolve spontaneously or respond to simple measures. Intractable hiccups may stem from a serious underlying cause such as brain disorders, metabolic or endocrine disturbances, CNS infections, and oesophageal or other gastrointestinal disorders. Other precipitants include anaesthesia or drug therapy. Treatment of intractable hiccups should initially be aimed at controlling or removing the underlying cause including the relief of gastric distension or oesophageal obstruction.

Measures that raise carbon dioxide pressure such as breath holding, rebreathing, or alteration of normal respiratory rhythm can be effective. Stimulation of the pharynx can also interrupt hiccups and may explain the action of a host of remedies such as sipping iced water, gargling, and swallowing granulated sugar. Many drugs have been tried in the treatment of hiccups but evidence of efficacy is largely from anecdotal reports or uncontrolled studies. An early treatment protocol for intractable hiccups (based on a review of the literature and the authors experience) suggested stepwise management until an effective measure was found, as follows:

• correction of any metabolic abnormality
• swallowing dry granulated sugar
• decompressing the stomach via nasogastric tube, then irritation of the pharynx
• intravenous chlorpromazine 25 to 50 mg, repeated up to 3 times if necessary if parenteral therapy is effective maintain on chlorpromazine by mouth for 10 days (licensed information recommends the use of oral therapy first — see Uses and Administration, above)
• metoclopramide 10 mg intravenously if successful maintain on metoclopramide by mouth for 10 days
• quinidine 200 mg by mouth 4 times daily
• if this fails, consider left phrenic nerve block and crush

In later discussions, chlorpromazine still emerged as the most consistently effective drug treatment metoclopramide appeared to be an acceptable second choice and nifedipine an appropriate third choice, although haloperidol was also considered to be of value. Other phenothiazines that have been used for intractable hiccup include perphenazine and promazine. It was also considered that clonazepam, carbamazepine, phenytoin, and valproic acid might be of value, especially in neuropathic hiccups.

Some beneficial results have been reported with amitriptyline and amantadine other drugs being tried in the treatment of hiccups include baclofen and gabapentin. The BNF recommends that in palliative care patients, a preparation combining an antacid with an antiflatulent be given for hiccups due to gastric distension. If this fails, metoclopramide (orally or by subcutaneous or intramuscular injection) should be added baclofen, nifedipine, or chlorpromazine should be reserved for those patients in whom metoclopramide is also ineffective.

Lesch-Nyhan syndrome.

The Lesch-Nyhan syndrome is an inherited disorder caused by a complete deficiency of hypoxanthine-guanine phosphoribosyl transferase, an enzyme involved in purine metabolism. It is characterised by hyperuricaemia, spasticity, choreoathetosis, self-mutilation, and mental retardation. The hyperuricaemia can be controlled by drugs such as allopurinol but there appears to be no effective treatment for the neurological deficits. It has been suggested that the behavioural problems might be associated with alterations in the brain’s dopamine system. There have been rare reports of improvement in self-mutilation in patients given antipsychotics or anti epileptics such as carbamazepine and gabapentin. References.

Migraine.

See under Headache, above.

Nausea and vomiting.

Many antipsychotics, with the notable exception of thioridazine, have antiemetic properties and have been used in the prevention and treatment of nausea and vomiting arising from a variety of causes such as radiation sickness, malignancy, and emesis caused by drugs, including antineoplastics and opioid analgesics. Reference to the risk to the fetus of therapy with phenothiazines during pregnancy can be found under Precautions.

Schizophrenia.

Classical antipsychotics such as chlorpromazine, haloperidol, and thioridazine have been the traditional drug treatment of choice for patients with schizophrenia however, atypical antipsychotics may now be preferred as first-line therapy. There is little difference in efficacy between the classical antipsychotics, but the use of thioridazine is now restricted in the treatment of schizophrenia because of the risk of cardiotoxicity.

Substance dependence.

ALCOHOL

For advice against the use of antipsychotics for alcohol withdrawal.

OPIOIDS.

In a discussion of neonatal abstinence syndrome, it was observed in 1986 that, although opioids, diazepam, and phenobarbital were widely used in the USA for the management of this condition, chlorpromazine had tended to be the preferred treatment in the UK. This was still true as late as the mid-1990s, although practice varied widely. However, a systematic review found insufficient evidence to support the use of chlorpromazine in the management of neonatal abstinence syndrome.

The following dosage schedule has been suggested: chlorpromazine is begun with a loading dose of 3 mg/kg, followed by a total oral maintenance dose of 3 mg/kg daily, divided into 4 or 6 doses. The authors suggested that this dose might be increased by 3 mg/kg daily if withdrawal symptoms were particularly severe. Once stabilised a reduction in the dose of chlorpromazine by 2 mg/kg every third day is attempted. Complications of phenothiazine usage have been notably absent, although rarely seizures may occur.

Taste disorders.

Disturbances of the sense of taste may be broadly divided into either loss or distortion of taste. Loss of taste may be either complete (ageusia) or partial (hypogeusia). Distortion of taste (dysgeusia) may occur as aliageusia in which stimuli such as food or drink produce an inappropriate taste or as phan-togeusia in which an unpleasant taste is not associated with an external stimuli and is sometimes referred to as a gustatory hallucination. Taste disturbances have many causes including infections, metabolic or nutritional disturbances, radiation, CNS disorders, neoplasms, drug therapy, or may occur as a consequence of normal ageing.

Management primarily consists of treatment of any underlying disorder. Withdrawal of offending drug therapy is commonly associated with resolution but occasionally effects persist and may require treatment. Zinc or vitamin therapy has been used but there is insufficient evidence to indicate efficacy’ for taste disturbances secondary to drug therapy or medical conditions that do not involve low zinc or vitamin concentrations. Phantogeusia might be linked to excessive activity of dopaminergic receptors as it has been reported to respond to short-term treatment with small doses of antipsychotic drugs such as haloperidol or pimozide.

Preparations

British Pharmacopoeia 2008: Chlorpromazine Injection; Chlorpromazine Oral Solution; Chlorpromazine Suppositories; Chlorpromazine Tablets

The United States Pharmacopeia 31, 2008: Chlorpromazine Hydrochloride Injection; Chlorpromazine Hydrochloride Oral Concentrate; Chlorpromazine Hydrochloride Syrup; Chlorpromazine Hydrochloride Tablets; Chlorpromazine Suppositories.

Proprietary Preparations

Argentina: Ampliactil Conrax

Australia: Largactil

Brazil: Amplictil Clorpromaz Longactil

Canada: Chlorpromanyl Largactil

Chile: Largactil

Czech Republic: Plegomazin

Denmark: Largactil

Finland: Klorproman

France: Largactil

Germany: Propaphenin

Greece: Largactil Solidon Zuledin

Hong Kong: Largactil

Hungary: Hibernal

Indonesia: Cepezet Meprosetil Promactil

Ireland: Clonazine Largactil

Israel: Taroctyl

Italy: Largactil Prozin

Malaysia: Matcine

Mexico: Largactil

The Netherlands: Largactil

Norway: Largactil

New Zealand: Largactil

Philippines: Laractyl Psynor Thorazine

Poland: Fenactil

Portugal: Largactil Largatrex

Russia: Aminazin

South Africa: Largactil

Singapore: Largo Matcine

Spain: Largactil

Sweden: Hibernal

Switzerland: Chlorazin

Thailand: Chlormazine Chlorpromasit Chlorpromed Duncan Matcine Pogetol Prozine

Turkey: Largactil

UK: Largactil

USA: Thorazine

Venezuela: Largactil

Multi-ingredient

Argentina: 6 Copin

India: Trinicalm Forte

Spain: Largatrex

Thailand: Ama