Mesoridazine Disease Interactions

Older patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death; although the causes were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. A causal relationship with antipsychotic use has not been established. In controlled trials in older patients with dementia-related psychosis, patients randomized to risperidone, aripiprazole, and olanzapine had higher incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities, compared to patients treated with placebo. These agents are not approved for the treatment of patients with dementia-related psychosis.

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The use of phenothiazines is contraindicated in patients with acute alcohol intoxication exhibiting depressed vital signs. The central nervous system depressant effects of phenothiazines may be additive with those of alcohol. Severe respiratory depression and respiratory arrest may occur. Therapy with phenothiazines should be administered cautiously in patients who might be prone to acute alcohol intake.

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Phenothiazines may cause hypotension (including orthostatic hypotension), reflex tachycardia, increased pulse rate, syncope, and dizziness, particularly after the first parenteral dose but rarely after the first oral dose. Low-potency agents such as chlorpromazine and thioridazine are more likely to induce these effects, which usually subside within the first couple of hours following administration. Tolerance to the hypotensive effects often develops after a few doses. Rarely, fatal cardiac arrest has occurred secondary to severe hypotension. Other reported adverse cardiovascular effects include edema, thrombosis, and ECG abnormalities such as PR and QT interval prolongation, diffuse T-wave flattening, and ST segment depression. Therapy with phenothiazines should be avoided or otherwise administered cautiously in patients with severe cardiovascular disease, pheochromocytoma, a predisposition to hypotension, or conditions that could be exacerbated by hypotension such as a history of myocardial infarction, angina, or ischemic stroke. Close monitoring of cardiovascular status, including ECG changes, is recommended at all dosages. If parenteral therapy is given, patients should be in a supine position during administration and for at least 30 to 60 minutes afterwards. Patients who experience orthostatic hypotension should be cautioned not to rise too abruptly. Occasionally, when severe, hypotension may require treatment with vasoconstrictive agents such as norepinephrine or phenylephrine. Epinephrine should not be used, however, since phenothiazines can reverse its vasopressor effects and cause a further lowering of blood pressure.

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The use of phenothiazines is contraindicated in comatose patients and patients with severe central nervous system depression. Phenothiazines may potentiate the CNS and respiratory depression in these patients.

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The use of phenothiazines is contraindicated in patients with suspected or established subcortical brain damage, with or without hypothalamic involvement. Phenothiazines can interfere with thermoregulatory mechanisms, and a hyperthermic reaction with temperatures in excess of 104 F may occur in such patients, sometimes not until 14 to 16 hours after drug administration.

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Phenothiazines have anticholinergic activity, to which elderly patients are particularly sensitive. Low-potency agents such as chlorpromazine and thioridazine tend to exhibit greater anticholinergic effects than other agents in the class. Therapy with phenothiazines should be administered cautiously in patients with preexisting conditions that are likely to be exacerbated by anticholinergic activity, such as urinary retention or obstruction; angle-closure glaucoma, untreated intraocular hypertension, or uncontrolled primary open-angle glaucoma; and gastrointestinal obstructive disorders.

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The chronic use of phenothiazines is associated with persistent elevations in prolactin levels. Based on in vitro data, approximately one-third of human breast cancers are thought to be prolactin-dependent. The clinical significance of this observation is unknown. Chronic administration of neuroleptic drugs has been associated with mammary tumorigenesis in rodent studies but not in human clinical or epidemiologic studies. Therapy with phenothiazines should be administered cautiously in patients with existing or suspected malignancy of the breast.

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Phenothiazines may cause acute, dose-related dystonic reactions secondary to central dopaminergic blockade. These reactions are characterized by spastic contraction of discrete muscle groups and may include torticollis, opisthotonos, carpopedal spasm, trismus, difficulty swallowing, perioral spasms with protrusion of the tongue, and oculogyric crisis. Onset is usually within 24 to 96 hours following initiation of therapy or an increase in dosage. Risk factors include young age, male gender, use of high-potency agents (e.g., fluphenazine, perphenazine, trifluoperazine), high dosages, and IM administration. Therapy with phenothiazines should be administered cautiously in patients, particularly children, with hypocalcemia or severe dehydration, since these patients may be more susceptible to dystonic reactions. Most symptoms subside within a few hours and are almost always reversible within 24 to 48 hours following withdrawal of therapy. However, severe reactions such as laryngospasm may be life-threatening and require appropriate supportive therapy. Parenteral administration of an anticholinergic antiparkinsonian agent (e.g., benztropine, trihexyphenidyl) or diphenhydramine usually produces a prompt response and may be given orally for short-term maintenance to prevent recurrence of symptoms if phenothiazine therapy must be continued.

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Phenothiazines may infrequently cause hematologic toxicity, including agranulocytosis, thrombocytopenia, eosinophilia, aplastic anemia, purpura, granulocytopenia, and hemolytic anemia. Mild leukopenia may occur frequently with large doses over prolonged periods but is generally reversible despite continued treatment. Therapy with phenothiazines should be administered cautiously, if at all, in patients with preexisting blood dyscrasias or bone marrow suppression. Complete blood counts should be obtained regularly, and patients should be instructed to immediately report any signs or symptoms suggestive of blood dyscrasia such as fever, sore throat, local infection, bleeding, pallor, dizziness, or jaundice. Most cases of agranulocytosis have occurred between the fourth and tenth weeks of therapy.

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Phenothiazines are extensively metabolized by the liver and may accumulate in patients with hepatic impairment. In addition, the use of some phenothiazines has been associated with adverse hepatic effects including cholestatic jaundice and elevated liver enzymes, generally within the first few months of therapy. Cholestatic jaundice usually occurs between the second and fourth weeks of therapy in approximately 0.1% to 4% of all patients. Therapy with phenothiazines should be administered cautiously in patients with preexisting liver disease, liver enzyme abnormalities, or hepatitis. Liver function and urine bilirubin tests should be performed periodically during prolonged therapy, and patients should be instructed to immediately report any signs or symptoms suggestive of cholestatic jaundice such as upper abdominal pain, nausea, yellow skin, influenza-like symptoms, rash, and fever. Phenothiazine therapy should be discontinued, preferably permanently, if jaundice occurs and is attributable to the drug. Clinical recovery is usually observed within a few weeks following withdrawal of therapy, although histopathologic changes may persist for longer periods.

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The central dopaminergic blocking effects of phenothiazines may precipitate or aggravate a potentially fatal symptom complex known as Neuroleptic Malignant Syndrome (NMS). NMS is observed most frequently when high-potency neuroleptic agents like haloperidol or fluphenazine are administered intramuscularly but may occur with any agent possessing neuroleptic activity given for any length of time. Clinical manifestations of NMS include hyperpyrexia, muscle rigidity, altered mental status and autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac arrhythmias). Phenothiazine therapy should not be initiated in patients with active NMS and should be immediately discontinued if currently being administered in such patients. In patients with a history of NMS, introduction or reintroduction of phenothiazines should be carefully considered, since NMS may recur.

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The use of phenothiazines is associated with pseudo-parkinsonian symptoms such as akinesia, bradykinesia, tremors, pill-rolling motion, cogwheel rigidity, and postural abnormalities including stooped posture and shuffling gait. The onset is usually 1 to 2 weeks following initiation of therapy or an increase in dosage. Propylamino derivatives such as chlorpromazine, promazine, and triflupromazine may be more likely to induce these effects. Therapy with phenothiazines should be administered cautiously in patients with Parkinson's disease or parkinsonian symptoms.

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Phenothiazines and their metabolites are excreted by the kidney. There are very limited data concerning the use of phenothiazines in patients with renal disease. Therapy with phenothiazines should be administered cautiously in patients with significantly impaired renal function. The manufacturers recommend periodic renal function tests for all patients during prolonged therapy.

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Phenothiazines may suppress the cough reflex. Therapy with phenothiazines should be administered cautiously in patients with chronic respiratory disorders, including severe asthma, emphysema, or acute respiratory tract infections.

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Phenothiazines can lower the seizure threshold and induce seizures, particularly when dosages are high or increased rapidly and during the initiation of therapy. Of the phenothiazines used in the treatment of psychosis, chlorpromazine appears to have the greatest epileptogenic potential, while fluphenazine and thioridazine have the least. Therapy with phenothiazines should be administered cautiously in patients with a history of seizures or other factors predisposing to seizures such as abnormal EEG, preexisting CNS pathology, or head trauma. Adequate anticonvulsant therapy should be maintained during administration of phenothiazines.

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Phenothiazines may commonly precipitate symptoms of tardive dyskinesia (TD), a syndrome consisting of rhythmic involuntary movements variously involving the tongue, face, mouth, lips, jaw, and/or trunk and extremities, following chronic use of at least several months but often years. Elderly patients, particularly women, are most susceptible. Also, propylpiperazine derivatives like fluphenazine, perphenazine, prochlorperazine, and trifluoperazine may be more likely to induce this syndrome. Both the risk of developing TD and the likelihood that it will become irreversible increase with the duration and total cumulative dose of phenothiazine therapy administered. However, patients may infrequently develop symptoms after relatively brief treatment periods at low dosages. If TD occurs during phenothiazine therapy, prompt withdrawal of the offending agent or at least a lowering of the dosage should be considered. TD symptoms usually become more severe after drug discontinuation or a dosage reduction, but may gradually improve over months to years. In patients with preexisting drug-induced TD, initiating or increasing the dosage of phenothiazine therapy may temporarily mask the symptoms of TD but may eventually worsen the condition. The newer, atypical neuroleptic agents (e.g., risperidone, quetiapine, olanzapine) tend to be associated with a substantially reduced risk of inducing TD and are considered the drugs of choice in patients being treated for psychosis.

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