Chlorpromazine and other phenothiazines are contra-indicated in patients with pre-existing CNS depression or coma, bone-marrow suppression, phaeochromocytoma, or prolactin-dependent tumours. They should be used with caution or not at all in patients with impaired liver, kidney, cardiovascular, cerebrovascular, and respiratory function and in those with angle-closure glaucoma, a history of jaundice, parkinsonism, diabetes mellitus, hypothyroidism, myasthenia gravis, paralytic ileus, prostatic hyperplasia, or urinary retention.
Care is required in patients with epilepsy or a history of seizures as phenothiazines may lower the seizure threshold. Debilitated patients may be more prone to the adverse effects of phenothiazines as may the elderly, especially those with dementia. For precautions of phenothiazines in pregnancy, see below. The sedative effects of phenothiazines are most marked in the first few days of treatment affected patients should not drive or operate machinery.
The effects of phenothiazines on the vomiting centre may mask the symptoms of overdosage of other drugs, or of disorders such as gastrointestinal obstruction. Use at extremes of temperature may be hazardous since body temperature regulation is impaired by phenothiazines.
Regular eye examinations are advisable for patients receiving long-term phenothiazine therapy and avoidance of undue exposure to direct sunlight is recommended. Phenothiazines should be used with caution in the presence of acute infection or leucopenia. Blood counts are advised if the patient develops an unexplained infection or fever.
Patients should remain supine for at least 30 minutes after parenteral doses of chlorpromazine blood pressure should be monitored.
Abrupt withdrawal of phenothiazine therapy is best avoided.
Isolated reports’ have suggested that patients with AIDS may be particularly susceptible to antipsychotic-induced extrapyramidal effects.
Findings of a retrospective case-control study appeared to indicate that asthmatic patients given antipsychotics were at an increased risk of death or near death from asthma.
The American Academy of Pediatrics considers that the use of chlorpromazine by mothers during breast feeding may be of concern, since there have been reports of galactorrhoea in the mother and of drowsiness, lethargy, and declines in developmental scores in the infant. The BNF considers that the use of antipsychotics such as chlorpromazine should be avoided by breast-feeding mothers unless absolutely necessary. Chlorpromazine was detected in all milk samples from 4 women at concentrations ranging from 7 to 98 nanograms/mL. Two of the women breast-fed their infants, but one infant showed no effects while the other was noted to be drowsy and lethargic milk-chlorpromazine concentrations were 7 and 92 nanograms/mL, respectively.
Few phenothiazines are recommended for use in children in particular there have been concerns about the use of phenothiazine derivatives in infants (see Sudden Infant Death Syndrome). For reference to the use of chlorpromazine in infants suffering neonatal abstinence syndrome see Substance Dependence, Opioids, under Uses and Administration, below. References.
The BNF warns that because of the risk of contact sensitisation, health workers should avoid direct contact with chlorpromazine tablets should not be crushed and solutions should be handled with care.
The risk of hip fracture has been reported to be increased in elderly patients given antipsychotics. A large case-control study in patients over 65 found that current users of antipsychotics had a twofold increase in the risk of hip fractures. The effect was dose-related and the increased risk was similar for chlorpromazine, haloperidol, and thioridazine. It was suggested that antipsychotic-induced sedation or orthostatic hypotension could increase the risk of falls in elderly persons.
A study in 12 schizophrenic patients receiving antipsychotics plus other drugs such as antimuscarinics or benzodiazepines has suggested that long-term treatment with antipsychotics may decrease bone mineralisation. A later study suggested that any increased risk of falls might be due to an effect of antipsychotics on balance as thioridazine was found to increase sway in elderly but not young subjects. A meta-analysis of 40 studies concluded that there was a small, but consistent, association between the use of most classes of psychotropic drugs, including antipsychotics, and falls. However, the evidence from these studies was based solely on observational data, with minimal adjustment for confounders, dosage, or duration of therapy.
There is some evidence to suggest that the use of antipsychotics to manage behavioural complications of dementia may increase the rate of cognitive decline. Elderly patients with dementia, especially Lewy-body dementia, are reported to be highly susceptible to the extrapyramidal adverse effects of antipsychotic drugs, and the reaction can be extremely serious, even fatal. If these drugs are to be used in elderly patients with dementia, then very low doses should be used, and special care should be taken if the dementia is suspected to be of the Lewy-body type since sudden life-threatening deterioration may occur.
Depot preparations should not be used and, since dopamine D2 receptors may be involved, it has been suggested that consideration could be given to using an antipsychotic such as clozapine that does not principally antagonise those receptors however, the FDA now recommends that atypical antipsychotics should not be used in such patients because of evidence of an increased death rate (see Dementia).
An increased risk of death has also been noted in elderly patients given classical antipsychotics. A retrospective cohort study, involving nearly 23 000 patients given atypical or classical antipsychotics, found that classical antipsychotics were at least as likely as the atypicals to increase the risk of death in the elderly. The authors also suggested that the greatest increase in risk occurred soon after starting therapy and with higher doses of classical antipsychotics. A similar increase in risk with use of classical antipsychotics was also seen in a large retrospective population-based study in elderly patients with dementia when compared with that seen with use of atypicals in this patient group.
For further discussion of the problems associated with the use of antipsychotics in disturbed behaviour in the elderly.
See Convulsions under Adverse Effects, above.
Folic acid deficiency.
Concentrations of folate in serum and erythrocytes were reduced in 15 patients receiving long-term treatment with chlorpromazine or thioridazine. All the patients had significant induction of hepatic microsomal enzymes. It was suggested that folate deficiency due to the induction of microsomal enzymes might subsequently limit enzyme induction and hence reduce drug metabolism, which could lead to symptoms of toxicity in patients apparently stabilised for a number of years. The dietary intake of patients on long-term treatment with enzyme-inducing drugs might be inadequate.
There have been rare reports’ of acute dystonic reactions associated with the use of phenothiazines in patients with untreated hypoparathyroidism. Caution was recommended in giving phenothiazine derivatives to patients with hypoparathyroidism and it was suggested that any acute reaction to such a drug should prompt investigation for some form of latent tetany.
Licensed product information generally does not recommend the use of phenothiazines in late pregnancy such use may be associated with intoxication of the neonate. Chlorpromazine may prolong labour and should be withheld until the cervix is dilated 3 to 4 cm. Overall, however, it has been suggested that the criteria for the selection of an antipsychotic for use in pregnant women do not differ from those used in non-pregnant women. It was also concluded that the benefits of continuing antipsychotic treatment at the minimum effective dose would usually outweigh any risks to the fetus.
A review of the use of phenothiazines in pregnancy concluded that there was no clear evidence that these drugs caused a significant increase in fetal malformations. Nevertheless it was considered advisable that if pregnant patients required such treatment, then a single phenothiazine should be used and that it should be one of the established drugs.
A subsequent review of the literature reported that women with schizophrenia are generally at increased risk for poor obstetric outcomes including preterm delivery, low birth-weight, and ne-onates who are small for their gestational age. It was also considered that there was an increased risk of congenital malformation when the fetus was exposed to phenothiazines during weeks 4 to 10 of gestation but this conclusion and the methods used to select the data to review have been criticised
See also for the use of phenothiazines as antiemetics during pregnancy.
Although there do not seem to be specific indications for dosage adjustment of phenothiazines in renal impairment, the BNF considers that cerebral sensitivity to antipsychotics may be increased in severe renal impairment. Phenothiazine-induced toxic psychosis occurred in 4 patients with chronic renal failure who had been given chlorpromazine.
The most common interactions encountered with phenothiazines such as chlorpromazine result from use with drugs that have similar pharmacological actions. Symptoms of CNS depression may be enhanced by other drugs with CNS-depressant properties including alcohol, general anaesthetics, hypnotics, anxiolytics, and opioids. When given with other drugs that produce orthostatic hypotension, dosage adjustments may be necessary. However, it should be noted that phenothiazines have been reported to reduce the antihypertensive action of guanethidine and other adrenergic neurone blockers.
As many phenothiazines possess antimuscarinic actions they can potentiate the adverse effects of other drugs with antimuscarinic actions, including tricyclic antidepressants and the antimuscarinic antiparkinsonian drugs that may be given to treat phenothiazine-induced extrapyramidal effects. In theory, antipsychotics with dopamine-blocking activity and dopaminergic drugs such as those used to treat parkinsonism may be mutually antagonistic. Use with metoclopramide may increase the risk of antipsychotic-induced extrapyramidal effects.
There is an increased risk of arrhythmias when antipsychotics are used with drugs that prolong the QT interval, including certain antiarrhythmics, other antipsychotics, some non-sedating antihistamines, antimalarials, and cisapride use with diuretics that cause electrolyte imbalance (particularly hypokalaemia) may also have the same effect. There is also an increased risk of arrhythmias when tricyclic antidepressants are used with antipsychotics that prolong the QT interval. Because of an increased risk of seizures US licensed product information for chlorpromazine recommends withdrawal before the use of metrizamide for radio-graphic procedures.
Most interactions with antipsychotics are as a result of additive pharmacological effects. Since tolerance develops to many of these adverse effects, interactions are likely to be most important in the early stages of combination therapy.
Phenothiazines may increase the CNS depressant effects of alcohol. There has been a report of akathisia and dy stonia after consumption of alcohol by patients taking antipsychotics alcohol might lower the threshold of resistance to neurotoxic adverse effects.
Studies in 6 patients showed that chlorpromazine plasma concentrations were significantly lower after giving chlorpromazine with an aluminium hydroxide and magnesium trisilicate antacid gel (Gelusil) than after chlorpromazine alone. In-vitro studies indicated that chlorpromazine was highly bound to the gel.
There is an increased risk of arrhythmias when antipsychotics are given with other drugs that prolong the QT interval. It has been recommended that the use of pimozide or thioridazine with antiarrhythmics (especially amiodarone, disopyramide, procainamide, and quinidine) should be avoided. Use of haloperidol with amiodarone is also not recommended. A study in healthy subjects has suggested that quinidine might increase plasma concentrations of haloperidol.
Seven schizophrenic patients whose antituber-cular therapy included rifampicin (in addition to isoniazid, and in some cases also ethambutol) had lower serum concentrations of haloperidol compared with tuberculotic schizophrenic patients receiving no antimycobacterials and with non-tuberculotic schizophrenics. Pharmacokinetic studies involving some of these patients indicated accelerated haloperidol clearance in the presence of rifampicin. Abnormally high serum-haloperidol concentrations were observed in 3 of 18 patients treated with isoniazid alone.
Black galactorrhoea occurred in a patient receiving minocycline, perphenazine, amitriptyline hydro chloride, and diphenhydramine hydrochloride. Simultaneous occurrence of phenothiazine-induced galactorrhoea and tetracycline-induced pigmentation was considered responsible.
Sudden cardiac deaths have been reported in patients given clarithromycin and pimozide. Elevated pimozide plasma concentrations were recorded after pretreatment with clarithromycin. The manufacturer of pimozide has recommended that pimozide should not be used with macrolide antibacterials.
For reference to the effects of some antipsychotics on the activity of anticoagulants, see under Warfarin.
Interactions between antipsychotics and tricyclic antidepressants are generally of two forms: additive pharmacological effects such as antimuscarinic effects or hypotension or pharmacokinetic interactions. Although not commonly reported in the literature, additive antimuscarinic activity may be a significant risk especially in the elderly. Careful drug selection might help to prevent the development of serious adverse effects. Mutual inhibition of liver enzymes involved in the metabolism of both the antipsychotic and the tricyclic antidepressant might result in increased plasma concentrations of either drug. In one study, addition of nortriptyline to chlorpromazine therapy produced an increase in plasma concentrations of chlorpromazine but this resulted in a paradoxical increase in agitation and tension.
There is an increased risk of arrhythmias when tricyclic antidepressants are given with other drugs that prolong the QT interval. It has been recommended that the use of pimozide or thioridazine with tricyclic antidepressants should be avoided. Increased serum concentrations of haloperidol have occurred when patients were also given fluoxetine, fluvoxamine or nefazodone. Isolated reports of extrapyramidal symptoms, psychoneuromotor syndrome, stupor, bradycardia, and urinary retention associated with use of fluoxetine with antipsychotics suggest that fluoxetine might exacerbate the adverse effects of antipsychotics or produce additive toxicity.
Similar CNS effects have been noted in subjects given perphenazine and paroxetine® There has also been an isolated report of a patient who complained of amenorrhoea and galactorrhoea after fluvoxamine was added to loxapine therapy. Significant increases in the plasma concentrations of thioridazine have occurred after use with fluvoxamine. Paroxetine may also inhibit the metabolism of thioridazine, resulting in increased thioridazine plasma concentrations UK licensed product information for paroxetine contra-indicates their concomitant use. The US licensed product information for paroxetine states that giving paroxetine with pimozide was associated with a mean increase of 151 % in the area under the concentration-time curve of pimozide and 62% in its mean maximum plasma concentration. Due to the narrow therapeutic index of pimozide concomitant use of these 2 drugs is contra-indicated.
Combinations of antipsychotics and lithium should be used with care. Lithium can reduce plasma-chlorpromazine concentrations and there is a report of ventricular fibrillation on withdrawal of lithium from a patient also taking chlorpromazine. Chlorpromazine has also been reported to enhance the excretion of lithium. Neurotoxic or extrapyramidal symptoms have been reported rarely in patients taking antipsychotics and lithium these may be atypical cases of lithium toxicity or neuroleptic malignant syndrome. The above issues are discussed in detail, and references given.
A patient on long-term trifluoperazine treatment developed neuroleptic malignant syndrome after a single dose ofvenlafaxine The authors noted that the manufacturers of venlafaxine have received a small number of similar reports after introduction of venlafaxine in patients receiving antipsychotics including molindone.
There have been occasional reports of sexual disinhibition in patients taking tryptophan with phenothiazines.
Since chlorpromazine may cause hyperglycaemia or impair glucose tolerance the dose of oral hypoglycaemics or of insulin may need to be increased in diabetics.
Carbamazepine, phenobarbital, and phenyioin are potent enzyme inducers and use may decrease plasma concentrations of antipsychotics or their active metabolites. The clinical effect of any interaction has not been consistent worsening, improvement, or no change in psychotic symptoms have all been noted. Delirium has been reported in a patient given haloperidol and carbamazepine. Phenytoin might also exacerbate antipsychotic-induced dyskinesia. Care should be taken when withdrawing enzyme-inducing antiepileptics as this may result in a rise in antipsychotic serum concentrations. The effect of antipsychotics on antiepileptic concentrations is discussed on carbamazepine and phenytoin. It should also be remembered that antipsychotics may lower the seizure threshold.
For the effect of a preparation containing chlorphenamine maleate and phenylpropanolamine hydrochloride on thioridazine, see Sympathomimetics (below). There is an increased risk of arrhythmias when antipsychotics are given with other drugs that prolong the QT interval. It has been recommended that the use of pimozide or thioridazine with antihistamines such as astemizole or terfenadine should be avoided.
For discussion of the interaction between phenothiazines and drugs with hypotensive properties, see Interactions, above. For a report of chlorpromazine enhancing the hyperglycaemic effect of diazoxide. For reports of hypertension or dementia in patients given meihyldopa and antipsychotics.
Pretreatment with single doses of chloroquine sulfate, amodiaquine hydrochloride, or sulfadoxine with pyrimeihamine increased the plasma concentrations of chlorpromazine and 7-hydroxychlorpromazine, but not of chlorpromazine sulfoxide, in schizophrenic patients maintained on chlorpromazine. The raised plasma concentrations appeared to be associated with a greater level of sedation. There is an increased risk of arrhythmias when antipsychotics are given with other drugs that prolong the QT interval. It has been recommended that the use of antipsychotics, and pimozide in particular, with antimalarials such as halofantrine, mefloquine, or quinine should be avoided. For the possible effects of the use of quinidine with antipsychotics see Antiarrhythmics, above.
A report of a patient receiving loxapine who had a dystonic reaction within 15 minutes of subcutaneous sumatriptan suggests that these two drugs might interact or potentiate each other’s adverse effects. However, the patient had a previous history of dystonic reactions associated with haloperidol and was receiving benzatropine prophylactic ally. Furthermore, the dose of loxapine had been increased 2 days before the event and this may have predisposed the patient to dystonia.
Antiparkinsonian drugs are sometimes given with antipsychotics for the management of antipsychotic-induced adverse effects including extrapyramidal disorders (see under Adverse Effects, above). Theoretically, dopaminergics such as levodopa and bromocriptine might induce or exacerbate psychotic symptoms. A study in 18 subjects and review of the literature suggested that bromocriptine can be used safely in patients at risk of psychotic illness provided they are clinically stable and maintained on antipsychotics. Conversely, antipsychotics might antagonise the effects of dopaminergics diminished therapeutic effects of levodopa have been noted with several antipsychotics and thioridazine has been reported to oppose the prolactin-lowering action of bromocriptine.
Additive antimuscarinic adverse effects are obviously a risk when antimuscarinic antiparkinsonian drugs are given with antipsychotics. Although these are generally mild, serious reactions have occurred. Trihexyphenidyl and orphenadrine have both been reported to decrease plasma concentrations of chlorpromazine, possibly by interfering with absorption from the gastrointestinal tract. Reports suggesting that antimuscarinics may antagonise the antipsychotic effects of antipsychotics at the neurotransmitter level require substantiating.
Elevated plasma levels of haloperidol were reported in a patient being treated for schizophrenia when chlorpromazine or clozapine were also given.
Ritonavir may increase the plasma concentration of some antipsychotics. The increases expected for pimozide were considered in licensed product information for ritonavir to be large enough to recommend that these drugs should not be used together. Other classical antipsychotics predicted to have increases include haloperidol, perphenazine, and thioridazine it was recommended that monitoring of drug concentrations and/or adverse effects were required when used with ritonavir.
Chlorpromazine andpropranololmay mutually inhibit each other’s hepatic metabolism. Propranolol has been reported to increase plasma concentrations of chlorpromazine and thioridazine, andpindolol to increase plasma-thioridazine concentrations. Neither beta blocker tested had a significant effect on haloperidol concentrations, although there is a report of severe hypotension or cardiopulmonary arrest occurring on 3 occasions in a schizophrenic patient given haloperidol with propranolol. The clinical significance of antipsychotic-beta blocker interactions is unclear.
For the effect of chlorpromazine on propranolol, see Anxiolytics and Antipsychotics, under Interactions of Beta Blockers. There is an increased risk of arrhythmias when antipsychotics are given with other drugs that prolong the QT interval. The use of antipsychotics, and pimozide in particular, with sotalol should be avoided.
The use of haloperidol with buspirone has resulted in increased serum haloperidol concentrations. However, while some found the mean rise in serum-haloperidol concentrations to be 26%, that observed by others was not statistically significant.
Despite expectations that cimetidine might reduce the metabolism of chlorpromazine, mean steady-state plasma concentrations of chlorpromazine fell rather than rose in 8 patients given cimetidine for 7 days in addition to regular chlorpromazine therapy. The explanation was probably that cimetidine interfered with chlorpromazine absorption. Excessive sedation, necessitating a reduction in chlorpromazine dosage, has been reported after addition of cimetidine to the drug therapy of 2 chronic schizophrenics.
The risk of antipsychotic-induced dystonic reactions may be increased in cocaine abusers. Dystonia occurred in 6 of 7 cocaine abusers treated with haloperidol.
Loss of consciousness lasting 48 to 72 hours occurred in 2 patients given prochlorperazine during desferrioxamine therapy. Prochlorperazine may enhance the removal of transition metals from brain cells by desferrioxamine.
A psychotic patient, previously maintained with plasma-perphenazine concentrations of 2 to 3 nanomol/mL on a dose of 8 mg twice daily by mouth, was readmitted with subtherapeutic plasma-perphenazine concentrations of less than 1 nanomol/mL, despite unchanged dosage, after disulfiram therapy. The concentration of the sulfoxide metabolite of perphenazine was much increased. After a change from oral to intramuscular perphenazine therapy there was a substantial clinical improvement associated with a return to therapeutic plasma concentrations of perphenazine and a fall in concentration of the metabolite. Disulfiram appears to greatly enhance biotransforma-tion of oral perphenazine to inactive metabolites, but parenteral administration avoids the ‘first-pass’ effect in the liver.
A schizophrenic patient without a history of epilepsy who was receiving oral chlorpromazine and fiupentixol depot injection had a convulsive seizure when given enflurane anaesthesia.
Two patients maintained on thioridazine experienced intense sleepiness and lethargy after receiving 2 doses of naltrexone.
A report of severe drowsiness and confusion in patients given haloperidol with indometacin.
For reference to the effects of phenothiazines onpethidine.
There has been an isolated report of convulsions associated with the use of chlorpromazine in a child who had received piperazine several days earlier. Subsequent animal studies produced conflicting evidence for an interaction and it was suggested that an interaction would only be clinically significant when high concentrations of piperazine were reached in the body.
For reference to the possible interaction between phenothiazines and adrenaline, see Treatment of Adverse Effects, above.
A 27-year-old woman with schizophrenia and T-wave abnormality of the heart, receiving thioridazine 100 mg daily withprocyclidine 2.5 mg twice daily, died from ventricular fibrillation within 2 hours of also taking a single dose of a preparation reported to contain chlorphenamine maleate 4 mg with phenylpropanolamine hydrochloride 50 mg (Contac C).
Smoking has been shown to decrease the incidence of chlorpromazine-induced sedation and orthostatic hypotension. Studies indicate that the clearance of chlorpromazine, fluphenazine, tiotixene, haloperidol, and thioridazine may be increased in patients who smoke. It has been suggested that some of the components of smoke may act as liver-enzyme inducers. The clinical significance of this effect is unclear but the possible need to use increased doses in smokers should be borne in mind.
Giving ascorbic acid, for vitamin C deficiency, to a patient receiving fluphenazine for bipolar disorder was associated with a fall in serum concentrations of fluphenazine and a deterioration of behaviour.
Studies in vitro have shown precipitation of some antipsychotics from solution by addition of coffee and tea. However, in a study of 16 patients taking antipsychotics no correlation could be found between plasma-antipsychotic concentrations or behaviour and tea or coffee consumption.
Chlorpromazine is readily, although sometimes erratically, absorbed from the gastrointestinal tract peak plasma concentrations are attained 2 to 4 hours after ingestion. It is subject to considerable first-pass metabolism in the gut wall and is also extensively metabolised in the liver and is excreted in the urine and bile in the form of numerous active and inactive metabolites there is some evidence of enterohepatic recycling. Owing to the first-pass effect, plasma concentrations after oral doses are much lower than those after intramuscular doses.
Moreover, there is very wide intersubject variation in plasma concentrations of chlorpromazine no simple correlation has been found between plasma concentrations of chlorpromazine and its metabolites, and their therapeutic effect (see Administration under Uses and Administration, below). Paths of metabolism of chlorpromazine include hydroxylation and conjugation with glucuronic acid, N-oxidation, oxidation of a sulfur atom, and dealkylation.
Although the plasma half-life of chlorpromazine itself has been reported to be about 30 hours, elimination of the metabolites may be very prolonged. There is limited evidence that chlorpromazine induces its own metabolism. Chlorpromazine is about 95 to 98% bound to plasma proteins. Itis 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 placenta and are distributed into breast milk.
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