Amitriptyline/perphenazine 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.

The manufacturer considers the use of perphenazine to be contraindicated in patients with preexisting liver damage. Phenothiazines are extensively metabolized by the liver and may accumulate in patients with hepatic impairment.

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.

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.

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.

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.

Tricyclic and tetracyclic antidepressants (TCAs) have anticholinergic activity, to which elderly patients are particularly sensitive. Tertiary amines such as amitriptyline and trimipramine tend to exhibit greater anticholinergic effects than other agents in the class. Therapy with TCAs 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. In patients with angle-closure glaucoma, even average doses can precipitate an attack. Glaucoma should be treated and under control prior to initiation of therapy with TCAs, and intraocular pressure monitored during therapy.

Tricyclic and tetracyclic antidepressants (TCAs) may cause orthostatic hypotension, reflex tachycardia, syncope, and dizziness, particularly during initiation of therapy or rapid escalation of dosage. Imipramine appears to have the greatest propensity to induce these effects, while secondary amines such as nortriptyline may do so less frequently. Tolerance to the hypotensive effects often develops after a few doses to a few weeks. Rarely, collapse and sudden death have occurred secondary to severe hypotension. Other reported adverse cardiovascular effects include tachycardia, arrhythmias, heart block, hypertension, thrombosis, thrombophlebitis, myocardial infarction, strokes, congestive heart failure, and ECG abnormalities such as PR and QT interval prolongation. Therapy with TCAs should be avoided during the acute recovery phase following myocardial infarction, and should be administered only with extreme caution in patients with hyperthyroidism, a history of cardiovascular or cerebrovascular disease, or a predisposition to hypotension. Close monitoring of cardiovascular status, including ECG changes, is recommended at all dosages. Many of the newer antidepressants, including bupropion and the selective serotonin reuptake inhibitors (SSRIs), are considerably less or minimally cardiotoxic and may be appropriate alternatives.

Tricyclic and tetracyclic antidepressants (TCAs) may potentiate the effects of circulating catecholamines. Enhanced sympathetic activity can provoke hypertensive crises in patients with pheochromocytoma or other tumors of the adrenal medulla, such as some neuroblastomas. Therapy with TCAs should be administered cautiously in patients with these tumors.

The use of most tricyclic antidepressants is contraindicated in patients that are going through the acute recovery period after a myocardial infarction.

Tricyclic antidepressants should be used with extreme caution in patients with evidence of cardiovascular disease because of the possibility of fluctuations in the blood pressure, arrhythmias, conduction defects, tachycardia, myocardial infarction and stroke. This also applies to patients who have family history of sudden death, cardiac dysrhythmias, or conduction disturbances. In some cases a gradual dose titration is recommended.

Tricyclic antidepressants (TCAs), can lower the seizure threshold and trigger seizures. These drugs should be used with extreme caution in patients with a history of seizures, or other predisposing factors, such as head trauma, CNS abnormalities, and alcoholism. Daily dose restrictions might apply for specific antidepressants. Physicians are encouraged to get additional dosing recommendations on the manufacturer's prescribing information.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

The use of tricyclic and tetracyclic antidepressants (TCAs) has rarely been associated with bone marrow suppression. Leukopenia, agranulocytosis, thrombocytopenia, anemia, eosinophilia, purpura, and pancytopenia have been reported with some TCAs. Patients with preexisting bone marrow suppression or blood dyscrasias receiving TCAs should be monitored closely during therapy for further decreases in blood counts.

Both elevation and lowering of blood sugar levels have been reported with the use of some tricyclic antidepressants (TCAs). Rarely, these effects have also occurred with maprotiline, a tetracyclic antidepressant. Patients with diabetes should be monitored for worsening control of blood glucose when treated with these agents, particularly during dosage escalation or whenever dosage has been altered.

Tricyclic and tetracyclic antidepressants (TCAs) are known to undergo metabolism in the liver. Some of the metabolites, such as those of imipramine, clomipramine and desipramine, may be pharmacologically active. Many of the metabolites are also excreted by the kidney. There are very limited data concerning the use of TCAs in patients with renal and/or liver disease. Therapy with TCAs should be administered cautiously in patients with significantly impaired renal or hepatic function. Dosage adjustments may be necessary.

Tricyclic antidepressants (TCAs) may aggravate symptoms of psychosis in schizophrenic patients, particularly those with paranoid symptomatology. Depressed patients, usually those with bipolar disorder, may experience a switch from depression to mania or hypomania. These occurrences have also been reported rarely with the tetracyclic antidepressant, maprotiline. Therapy with these agents should be administered cautiously in patients with schizophrenia, bipolar disorder, or a history of mania.

Tricyclic and tetracyclic antidepressants (TCAs) have anticholinergic activity, to which elderly patients are particularly sensitive. Tertiary amines such as amitriptyline and trimipramine tend to exhibit greater anticholinergic effects than other agents in the class. As with other drugs that possess anticholinergic activity, TCAs may aggravate tardive dyskinesia or induce previously suppressed symptoms. Patients with tardive dyskinesia requiring therapy with TCAs should be monitored for exacerbation of the condition.

Tricyclic antidepressants can enhance the response to alcohol. In patients who may use alcohol excessively, it should be borne in mind that the potentiation may increase the danger inherent in any suicide attempt or overdosage.

A major depressive episode can be the initial presentation of bipolar disorder. Patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder prior to initiating treatment with a tricyclic antidepressant. This screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that tricyclic antidepressants are not approved for use in treating bipolar depression.

Tricyclic antidepressants as other type of antidepressants have an effect on pupil size causing dilation. This effect can potentially narrow the eye angle resulting in increased intraocular pressure and angle closure glaucoma, especially in predisposed patients. These drugs should be used with caution in patients with anatomically narrow angle or history of glaucoma. Doxepin hydrochloride capsules are contraindicated in patients with glaucoma.

There have been reports of both elevation and lowering of blood sugar levels in patients receiving tricyclic antidepressants. These drugs should be used with caution in patients with hypoglycemia, hyperglycemia or diabetes. Monitoring sugar levels is recommended.

In general, tricyclic antidepressants should be used with caution in patients with liver or renal disease, as these drugs are metabolized and excreted through the liver and kidneys. Dose selection, especially in the elderly patients that might have liver or renal dysfunction, should usually be limited to the smallest effective total daily dose. Some tricyclic antidepressants such as clomipramine and nortriptyline have occasionally been associated with elevations in SGOT (AST) and SGPT (ALT), and other hepatic adverse events such as jaundice. Although serious liver injury has only been reported rarely, therapy with these drugs should be administered cautiously in patients with preexisting liver disease and periodic monitoring of liver enzyme levels is recommended.

The use of some tricyclic antidepressants has been associated with neutropenia (ANC < 500/mm3) and agranulocytosis (ANC < 500/mm3). Leukocyte and differential blood counts should be performed in patients that develop fever and sore throat during treatment. Therapy should be discontinued if there is evidence of pathologic neutrophil depression.

Some tricyclic antidepressants have shown to cause activation or exacerbation of psychosis in schizophrenic patients. A dosage reduction might be required.

Most tricyclic antidepressants should be administered with caution in hyperthyroid patients or those receiving thyroid medication as they may develop arrhythmias when these drugs are given.

Due to their anticholinergic properties, tricyclic antidepressants should be administered with caution in patients with history of urinary retention. Particularly doxepin hydrochloride capsules are contraindicated in patients with tendency to urinary retention.