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DESCRIPCION
La trifluoperazina es un fármaco antipsicótico de la familia de las fenotiazinas
mine turnover by blockade of the D2 somatodendritic autoreceptor. After about 12 weeks of chronic therapy, depolarization blockade of dopamine tracts occurs. The decrease in dopamine neurotransmission has been found to correlate to the antipsychotic effects. This D2 blockade is also responsible for the strong extrapyramidal effects observed with this drug. Dopamine blockade in the chemoreceptor trigger zone accounts for the antiemetic effects. Trifluoperazine possesses weak anticholinergic and alpha-adrenergic receptor blocking effects. Blockade of alpha1-adrenergic receptors produces sedation, muscle relaxation, and cardiovascular effects such as hypotension, reflex tachycardia, and minor changes in ECG patterns.
Pharmacokinetics: Trifluoperazine is rapidly absorbed following oral administration, but there is considerable individual patient variation in peak plasma concentrations because the drug undergoes metabolism in the gastric mucosa and during first pass through the liver. Following IM administration, more unchanged drug reaches the systemic circulation than from the oral route because of first-pass hepatic metabolism. Antipsychotic effects are gradual, with considerable individual patient variation, and peak effects may not occur for 6 weeks to 6 months. Phenothiazines are distributed widely into body tissues and fluids, and cross the blood-brain barrier. Trifluoperazine is highly plasma protein-bound (91—99%), predominantly to alpha1-acid glycoprotein. The drug crosses the placenta and may be excreted into breast milk although insufficient data are available. Metabolism is extensive and some enterohepatic circulation may occur. Most of the metabolites formed are pharmacologically inactive. There is some conjugation with glucuronides, and these, along with unconjugated metabolites, account for most of the drug found in urine; only a small amount is excreted as unchanged drug. Some excretion may occur via the biliary tract and feces. [ Revised 2/20/01 ] Clinical Pharmacology 2000 Copyright © 2001
Indications...Dosage For treatment of psychotic disorders, such as schizophrenia: •for the routine management of psychotic disorders: Oral dosage: Adults: Initially, 2—5 mg PO once daily or twice daily. May increase gradually as needed and tolerated. Optimum response generally occurs with 15—20 mg/day, some may require up to 40 mg/day. Doses of 60—100 mg/day have been used for short periods. Elderly and debilitated patients: See adult dosage; lower initial doses and slower titration are recommended. Children >= 6 years: 1 mg PO once daily or twice daily. Adjust gradually as needed and tolerated. Generally, dose not to exceed 15 mg/day. Children < 6 years: Safe and effective use has not been established. Intramuscular dosage: Adults: Initially, 1—5 mg IM every hour as needed to calm (not sedate) the agitated patient. Dose limit normally 6 mg in a 24 hour period. Use caution in those requiring > 4 doses per 24 hours. Convert to oral therapy as soon as possible. Children >= 6 years: Data are limited; may use 1 mg IM once or twice a day; convert to oral therapy as soon as possible. Children < 6 years: Safe and effective use has not been established. •for the treatment of severe behavioral disturbances (e.g., agitation, aggression, psychosis, etc.) due to organic brain syndromes† or dementia† ( e.g., Alzheimer's disease, late-stage Parkinson's disease, or dementia with Lewy bodies): Oral dosage: Elderly: Initially, 0.5—1 mg PO 1—2 times per day. May gradually increase at weekly intervals, as needed and tolerated. Dose may range from 2—20 mg/day PO. Federal OBRA guidelines for nursing homes recommend dosage not exceed 8 mg/day PO given in 1—2 divided doses, unless higher dosages are needed to maintain the resident's functional status. After the maximum response has been obtained, gradual reduction of the dosage is recommended to the lowest effective dose. For the short-term treatment of non-psychotic anxiety: Oral dosage: Adults and elderly: Initially, 1 or 2 mg PO 1—2 times per day. Do not exceed 6 mg/day PO. Do not administer for > 12 weeks. Maximum Dosage Limits: •Adults: 40 mg/day PO; dosage may be increased to 60—100 mg/day PO for short periods. Debilitated patients require lower dosages. •Elderly: 40 mg/day PO; dosage may be increased to 60—100 mg/day PO for short periods. Debilitated patients require lower dosages. •Adolescents: 40 mg/day PO; dosage may be increased to 60—100 mg/day PO for short periods. Debilitated patients require lower dosages. •Children 6—12 years: 15 mg/day PO. •Children < 6 years: Safe and effective use has not been established. Patients with hepatic impairment: In general, phenothiazines are contraindicated in patients with significant hepatic impairment. Patients with renal impairment: Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
Administration NOTE: Dosage is expressed in terms of trifluoperazine base. Oral administration •All dosage forms: Administer with food, milk, or a full glass of water to minimize gastric irritation. •Tablets: May be crushed and mixed with food or fluids for patients with difficulty swallowing. •Oral concentrate: Administer using a calibrated measuring device. Dilute prior to administration with tomato or fruit juice, milk, carbonated beverages, coffee, tea, or water. Semi-solid foods such as pudding or soups may be used. Avoid spilling the solution on the skin and clothing. Intramuscular Administration •For intramuscular (IM) use only, do not give intravenously or subcutaneously. •Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Slight yellow color does not alter potency. Intramuscular injection: •No dilution necessary. •Inject slowly and deeply into a well developed muscle. Aspirate prior to injection to avoid injection into a blood vessel. Keep patient in a recumbent position for at least 30 minutes following injection to minimize hypotensive effects.
Contraindications Trifluoperazine is contraindicated for use in patients with known phenothiazine hypersensitivity. Cross-sensitivity may occur. This contraindication includes patients who have experienced bone marrow suppression, blood dyscrasias, or jaundice due to phenothiazine therapy. Phenothiazines should be used with caution in patients with preexisting hematological disease. Though rare, agranulocytosis and other hematologic disorders have been reported with the use of phenothiazines. Patients should report the appearance of fever, sore throat, lethargy or other signs of decreased blood cell counts or infection to their health care provider immediately. Serum blood counts with differentials should be monitored periodically; the phenothiazine may need to be discontinued if significant suppression of blood counts occurs. Trifluoperazine oral concentrate may contain sulfites. Sulfites may cause allergic reactions in some people. They should be used with caution in patients with known sulfite hypersensitivity. Patients who have asthma are more likely to experience this sensitivity reaction than non-asthmatic patients. Trifluoperazine injections are not for intravenous administration. The injection is for intramuscular administration only. Phenothiazines are contraindicated for use in patients with significant CNS depression (e.g., coma, acute head trauma). The phenothiazines may have deleterious effects on neuronal recovery following acute brain injuries. In addition, brain-injured patients are more susceptible to adverse CNS effects of the phenothiazines. Because trifluoperazine may impair mental and/or physical abilities, all patients should be cautioned against driving or operating machinery, or performing other tasks requiring mental alertness, until they are aware of how the medication affects them. Ethanol intoxication should be avoided. Phenothiazines may prolong and intensify the sedative actions of CNS depressant medications (e.g., anesthetics, barbiturates, ethanol, hypnotics, and opiates). Where possible, it is recommended that these agents be discontinued prior to initiation of phenothiazine treatment. Trifluoperazine should be used cautiously during dental work, surgery, and other procedures where the use of CNS depressant medications is common. Phenothiazines may lower the seizure threshold. Patients who have a history of seizure disorder, epilepsy, or EEG abnormalities should be carefully monitored during therapy with trifluoperazine. Phenothiazines do not intensify the anticonvulsant effects of the barbiturates or other anticonvulsants; patients with seizures who are on anticonvulsants should not have their anticonvulsant dosages reduced. Patients with a pre-existing intracranial mass may be more susceptible to seizures if phenothiazines are administered. The continuation of adequate anticonvulsant therapy should prevent an increase in seizure frequency during phenothiazine treatment. If trifluoperazine therapy is needed, it should be intiated with a low dosage and titrated upward slowly to desired clinical effect. Abrupt increases in phenothiazine dosage should be avoided. Patients or their guardians should be informed of the risk of phenothiazine-induced neurological disease. Phenothiazines may induce extrapyramidal symptoms, including tardive dyskinesia, dystonias, and other movement disorders. Tardive dyskinesia may be irreversible. A rare but potentially fatal syndrome, neuroleptic malignant syndrome (NMS), may occur and requires immediate drug discontinuation. Patients at an increased risk for developing extrapyramidal reactions include patients with hypocalcemia, young patients, and geriatric populations. Periodic clinical observation for the presence of movement disorders is recommended (e.g., AIMS assessments). Trifluoperazine should be used with caution in patients with prostatic hypertrophy, closed-angle glaucoma, paralytic ileus, or urinary retention because the drug exhibits anticholinergic activity that can exacerbate these conditions. The anticholinergic effects of the phenothiazines may be additive to other anticholinergic medications. Phenothiazines should be used cautiously in patients with significant cardiac disease or pulmonary disease. Phenothiazines may induce angina, tachycardia and/or orthostatic hypotension. Phenothiazines may potentiate hypotension caused by hypovolemia, the presence of antihypertensive drugs, or dehydration. Serious cardiac or respiratory events have been reported with phenothiazine therapy. QT prolongation may occur. Hypotension, syncope, cardiac arrhythmias, and respiratory arrest may be associated with aggressive dose titration. If trifluoperazine is prescribed in patients with cardiac or severe chronic pulmonary disease, a low initial dosage should be used, followed by gradual dosage titration. Sudden, unexpected deaths have been reported in some patients, appearing to result from asphyxia or cardiac arrest. Trifluoperazine should not be used to treat conditions in children for which specific pediatric dosages have not been established. Children with acute illnesses (e.g., varicella-zoster infections, CNS infections, measles, gastroenteritis, or dehydration) may be more susceptible to developing adverse reactions, respiratory depression, and extrapyramidal symptoms from the phenothiazines. Children may also be more susceptible to the cardiac effects of the phenothiazines, particularly if there is a known history of familial QT prolongation. Routine cardiovascular monitoring has been suggested for children receiving phenothiazines due to the potential of these agents to produce adverse cardiac effects.[2348] Phenothiazines should not be administered to children or adolescents whose signs and symptoms are suggestive of Reye's syndrome. Phenothiazines should be used cautiously in patients with hepatic disease. Patients with hepatic disease may have decreased hepatic metabolism of these drugs. Patients with a history of jaundice secondary to phenothiazine use should not, if possible, be reexposed to phenothiazine treatment. Patients with a history of hepatic encephalopathy secondary to cirrhosis have increased CNS sensitivity (e.g., decreased cerebration, EEG-wave slowing) to the phenothiazines. Elderly patients may be more susceptible to the actions and adverse effects of phenothiazines, including tardive dyskinesia, dystonias, orthostatic hypotension, and anticholinergic effects. Intitially, lower trifluoperazine doses should be employed, followed with careful dosage titration. Phenothiazines should be used cautiously in patients with Parkinson's disease. Central blockade of dopamine (D2) receptors by phenothiazines may dramatically worsen the extrapyramidal symptoms of Parkinson's disease. Photosensitivity may occur with the use of phenothiazines; patients should avoid undue sunlight (UV) exposure and the use of tanning beds. Also, phenothiazines disrupt central and peripheral temperature regulation in the hypothalamus. Patients should avoid exposure to extremes of cold or heat to prevent hypothermia or heat stroke. Oral solutions of phenothiazines should not come in contact with the skin. Contact dermatitis has been reported with accidental exposure to phenothiazines. The use of latex gloves has been recommended when administering the oral liquid or injectable forms of this drug. Phenothiazines do not cause physical or psychological dependence. However, abrupt discontinuation of phenothiazines can produce nausea, dizziness, and trembling. These effects are only temporary, and can be reduced by a gradual reduction in dosage, or continuation of concomitant antiparkinsonian agents for several weeks after the phenothiazine is withdrawn. Phenothiazines are not successfully removed by hemodialysis due to their high-protein binding in the serum (>= 90%). Use with caution in patients with renal failure. Phenothiazines may cause various forms of ocular disease (see Adverse Reactions). All patients should be closely monitored for changes in visual acuity and corneal deposits. Routine periodic ophthalmologic exams are recommended. The antiemetic activity of phenothiazines may mask the signs and symptoms (i.e., vomiting) or the diagnosis of certain medical conditions (i.e., GI obstruction, ileus). Likewise, the symptoms of certain medication toxicities (i.e., vomiting due to chemotherapy; ototoxicity of aminoglycosides) may be masked. Phenothiazines should be used cautiously in these patients. There is some evidence to suggest that patients who smoke large amounts of cigarettes (i.e., > 20/day) may have increased metabolism of the phenothiazines. Clinicians should be aware that increased dosage requirements may occur in some tobacco smokers. Conversely, if patients stop tobacco smoking, the dosage of the phenothiazine may need to be reduced. Trifluoperazine is classified as a FDA pregnancy category C drug. Phenothiazines readily crosses the placenta. Reproductive studies in animals have shown an increased incidence of malformations, reduced birth weights, and litter size attributable to maternal toxicity when the drug was administered at doses 600 times the human dose. However, no well-controlled data are available in humans. To be safe, trifluoperazine should be used during pregnancy only when the benefits to the mother outweigh the potential risks to the fetus. The lowest effective dosage should be used. Usage of phenothiazines near term or during labor may result in significant maternal hypotension or other events (e.g., neonatal jaundice, neonatal hypo- or hyperreflexia or EPS) that may be detrimental to the health of the mother or the neonate. Trifluoperazine is not recommended for use in lactating women who are breast-feeding their infants. Phenothiazines are excreted into breast milk. Reported adverse effects to nursing infants have included drowsiness or lethargy; the physiology of the young infant should be considered when evaluating risk of exposure to the phenothiazines. A decision should be made to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. In addition, phenothiazines may induce hyperprolactinemia and galactorrhea, and thus may interfere with proper lactation. Phenothiazine antipsychotics stimulate the release of prolactin and may induce infertility in either men or women, or may induce other endocrine abnormalities (see Adverse Reactions). Some human breast cancers may be prolactin-dependent and therefore phenothiazines should be used extremely cautiously in patients who have a history of breast cancer. Neither clinical or epidemiological evidence to date have supported an association between phenothiazine use and breast cancer. Phenothiazines should not be administered to patients receiving radiographic contrast administration of metrizamide (Amipaque®), due to a potential increased risk of seizures. Phenothiazines should be discontinued 48 hours before the myelography and should not be resumed until 24—48 hours after the procedure. The possibility of a suicide attempt is inherent in patients with symptoms of depression concomitantly with other psychoses. Patients with a history of suicidal ideation and who are at high risk for suicide attempt should be closely supervised during initial drug therapy with the phenothiazines. In addition, the phenothiazines should be prescribed in the smallest quantity consistent with good patient management in order to reduce the risk of overdose.
nteractions Phenothiazines can potentiate the CNS-depressant action of other drugs such as benzodiazepines; dronabinol, THC; entacapone; ethanol; general anesthetics; skeletal muscle relaxants; opiate agonists; butorphanol; nalbuphine; pentazocine; or other anxiolytics, sedatives, and hypnotics. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or hypotension. Antacids, attapulgite, and kaolin may reduce the oral bioavailability of the phenothiazines. To avoid this interaction, administer the antacid or absorbant antidiarrheal medication at least 1 hour before or 2 hours after a phenothiazine dose. Phenothiazines can potentiate the CNS-depressant action of the barbiturates. The pre-anesthesia administration of phenothiazines may increase the hypotensive effects of barbiturate anesthetics. Barbiturates, when used for other purposes, may induce the hepatic metabolism of the phenothiazines, possibly resulting in decreased neuroleptic effect. It should be noted that phenothiazines do not intensify the anticonvulsant effects of the barbiturates. Due to a lowering of seizure threshold by the phenothiazines, adequate barbiturate therapy should be maintained, if administered for anticonvulsant purposes, when a phenothiazine is added. Phenothiazine neuroleptics may produce alpha-adrenergic blockade and appear to have additive hypotensive or CNS effects when administered concurrently with clonidine. Until more clinical information is available, other centrally-acting alpha-antagonists (e.g., guanfacine or guanabenz) should also be considered to potentially interact with the phenothiazine neuroleptics in this manner. Phenothiazines appear to inhibit the hypotensive effect of peripheral adrenergic blocking agents (e.g., guanethidine) by decreasing the uptake of these drugs into the adrenergic neuron. Clinically significant increases in mean blood pressure have occured after the initiation of chlorpromazine in patients stabilized on guanethidine. Similar problems have been reported in isolated hypertensive patients taking a phenothiazine concurrently with methyldopa or guanadrel. Patients should be monitored for maintenance of appropriate clinical response to antihypertensive therapy if a phenothiazine is added; these combinations should be avoided whenever possible. Propranolol appears to inhibit the hepatic metabolism of phenothiazine neuroleptics, and phenothiazines appear to decrease the hepatic metabolism of propranolol. Increased serum concentrations and pharmacologic effects (e.g., CNS, hypotension) of either propranolol or the phenothiazines may occur. It is not known if other hepatically-metabolized beta-blockers interact with the phenothiazines in this manner. beta-blockers with greater renal elimination (e.g., atenolol, nadolol) are less likely to have an interaction with phenothiazines. The phenothiazines, when used concomitantly with various anticonvulsants (e.g., fosphenytoin, phenytoin, valproic acid, etc.) can increase CNS depression and also can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazines is added; patients should be monitored for clinical evidence of loss of seizure control or the need for dosage adjustments of either the phenothiazine or the anticonvulsant. In addition to these pharmacodynamic interactions, individual anticonvulsant agents interact in other ways with phenothiazines. Carbamazepine is a potent inducer of the cytochrome P-450 mixed-function hepatic oxidase system, and can reduce plasma concentrations of the phenothiazines by 47% or more. If a phenothiazine and carbamazepine must be used together, dosage adjustments of the phenothiazine may be required. Because they also block central dopamine receptors, droperidol, haloperidol, metoclopramide, metyrosine, and risperidone should be avoided or used cautiously in patients receiving a phenothiazine to minimize the risk of additive adverse CNS effects. Rifampin is a potent hepatic microsomal enzyme inducer; limited data suggest that rifampin can increase the metabolism or reduce the bioavailability of the phenothiazines. Dosage adjustments of chlorpromazine may be necessary following the addition of rifampin or another rifamycin (e.g., rifabutin, rifapentine). Erythromycin can inhibit the metabolism of fluphenazine. Dosage adjustments of the phenothiazine may be necessary in patients receiving erythromycin. Although a causal relationship has not been established, administration of thioridazine to patients with lithium serum levels in excess of 1.2 mEq/L can lead to an encephalopathic syndrome. This syndrome is characterized by weakness; lethargy; fever; confusion; extrapyramidal symptoms; leukocytosis; elevated serum enzymes, BUN, and fasting blood glucose. Additive extrapyramidal effects also have been noted in patients receiving both agents. Although this reaction has been associated with thioridazine, it is also possible during concomitant therapy with other phenothiazines. In addition, pharmacokinetic interactions have been noted during therapy with lithium and chlorpromazine (e.g., lithium-induced reductions in chlorpromazine plasma concentrations, and chlorpromazine-induced acceleration of lithium renal clearance.) The alpha-adrenergic effects of epinephrine, and possibly of other adrenergic agonists, can be blocked during concurrent administration of phenothiazines. This blockade can cause an apparently paradoxical condition called "epinephrine reversal," which can lead to severe hypotension, tachycardia, and, potentially, myocardial infarction. Patients taking phenothiazines can have reduced pressor response to ephedrine, methoxamine, phenylephrine, metaraminol, or norepinephrine, but these drugs are preferred over epinephrine if a vasopressor agent is required. The vasoconstrictive properties of dopamine infusion can be decreased due to the alpha-adrenergic blocking capability of phenothiazines. Dopamine infusions intended to improve renal perfusion can be ineffective due to phenothiazine-induced dopamine receptor blockade. Phenothiazines may inhibit the clinical antiparkinsonian response to levodopa, pergolide, pramipexole, or ropinirole therapy by blocking dopamine receptors in the brain. In general, phenothiazines should be avoided in patients requiring therapy for Parkinson's disease unless the benefit of the neuroleptic outweighs the risk of decreased therapeutic response to levodopa or other treatments. Amphetamine or dextroamphetamine and chlorpromazine can interfere with the therapeutic actions of each other. Amphetamines appear to aggravate psychotic symptoms; and chlorpromazine blocks dopamine and norepinephrine reuptake and has thus decreased the anorectic and CNS stimulatory effects of the amphetamines. Chlorpromazine has been helpful in treating amphetamine overdoses, however, these combinations should be avoided in other therapeutic situations. Other phenothiazines may produce similar inhibition of psychostimulant activity. Agents that prolong the QT interval could lead to additive orthostatic hypotension and/or prolonged QT syndrome and torsade de pointes when combined with a phenothiazine and are generally contraindicated for combined use. The following agents may produce QT interval prolongation under certain circumstances: amiodarone, arsenic trioxide, astemizole, bepridil, cisapride, dofetilide, flecainide, grepafloxacin, ibutilide, pimozide, procainamide, probucol, quinidine, sotalol, sparfloxacin, terfenadine, some antidepressants, and tocainide. Conflicting data exist about combining MAOIs and neuroleptics. The combination of tranylcypromine and trifluoperazine led to a reduction of side effects from either agent. In other cases, however, extrapyramidal reactions were increased when an MAOI was added. In general, these two classes of drugs can be used together safely, although clinicians should monitor these patients carefully for exaggerated reactions. Depending on the specific agent, additive anticholinergic effects may be seen when phenothiazines are used concomitantly with other drugs with antimuscarinic activity. The following drugs are known to possess anticholinergic properties and should be used together cautiously: atropine and other similar antimuscarinics (e.g., glycopyrrolate, scopolamine); some H1-blockers (except astemizole, cetirizine, loratidine, and terfenadine); other phenothiazines; some tricyclic antidepressants; and other drugs with antimuscarinic properties such as amantadine, benztropine, clozapine, cyclobenzaprine, dicyclomine, diphenoxylate, disopyramide, hyoscyamine, maprotiline, meclizine, molindone, orphenadrine, oxybutinin, propantheline, tolterodine, and trihexyphenidyl. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Phenothiazine absorption is reduced when coadministered with activated charcoal. Concomitant administration of phenothiazines and activated charcoal is not recommended, however, coadministration with activated charcoal may be appropriate in certain overdose situations. Due to antagonistic mechanisms of action, the phenothiazines may limit the ability of bromocriptine to lower serum prolactin concentrations. The combination should be avoided where possible. Bromocriptine does not appear to interfere with the antipsychotic effects of the phenothiazines if it is added to stable neuroleptic regimens. Concomitant administration of tramadol with agents that lower the seizure threshold, like phenothiazines, may increase seizure risk. Post-marketing reports of seizures due to tramadol have been noted primarily in patients receiving either tricyclic antidepressants or selective-serotonin reuptake inhibitors concomitantly. In addition, additive CNS depressant effects may be seen with the combination of phenothiazines and tramadol. Caution is advised in concomitant administration of tramadol with phenothiazines. There have been reports of additive hypotension resulting from the combination of trazodone with phenothiazine neuroleptics. Monitor patients for changes in blood pressure if the two are used concurrently. Fluoxetine impairs metabolism of the CYP2D6 (cytochrome P-450 isozyme 2D6) pathway at therapeutic doses. This may result in increases in concentrations of other drugs metabolized via the same pathway, including the phenothiazines. Other SSRIs that inhibit CYP2D6 metabolism (e.g., paroxetine, sertraline) may also have this effect. In one case report, the initiation of venlafaxine (a drug with SSRI-like activity), in a patient taking trifluoperazine resulted in symptoms consistent with neuroleptic malignant syndrome (NMS). After discontinuation of all psychiatric medications and treatment for NMS, the patient recovered and was able to reinitiate trifluoperazine without further problems. Venlafaxine was not administered a second time. This case report, thought isolated, may signal the need to be cautious in combining venlafaxine with the antipsychotic phenothiazines. Although a causal association has not been established, a case of death after the administration of phenylpropanolamine (PPA) in a young adult female stabilized on a phenothiazine has been reported. It has been proposed that the mechanism of the interaction was cardiac arrhythmia. Until more is known on the safety of these medications in combination use, advise patients on phenothiazines to avoid phenylpropanolamine (PPA) and combinations containing PPA except under the advice of their health-care prescriber. Phenothiazines may increase the effects of photosensitizing agents used during photodynamic therapy. Other medications may also cause additive photosensitization with phenothiazines including oral contraceptives, quinolones, retinoids, sulfonamides, sulfonylureas, tetracyclines, and thiazide diuretics. Patients should avoid ultra-violet (UV) exposure whenever possible. Phenothiazines rarely induce bone marrow suppression and blood dyscrasias, but they should be used cautiously with other agents that may cause significant bone marrow suppression including: antineoplastic agents, immunosuppressives, and antithyroid agents. When used for the treatment of nausea and vomiting, antiemetic phenothiazines may effectively mask vestibular symptoms (e.g. dizziness, tinnitus, or vertigo) that are associated with ototoxicity induced by various medications, including the aminoglycosides. Due to antagonistic mechanisms of action, the phenothiazines may limit the ability of bromocriptine or cabergoline to lower serum prolactin concentrations. The combination should be avoided where possible. The dopamine agonists do not appear to interfere with the antipsychotic effects of the phenothiazines if they are added to stable neuroleptic regimens. In the absence of relevant data and as a precaution, drugs that cause hyperprolactinemia, such as antipsychotics, should not be administered concomitantly with gonadotropin releasing hormone (GnRH) analogs (cetrorelix, ganirelix, goserelin, leuprolide, or triptorelin) since hyperprolactinemia downregulates the number of pituitary GnRH receptors.
The adverse effects of phenothiazines can affect all organ systems and may be attributed either to the drug's effects on the central and autonomic nervous system, or to hypersensitivity reactions to the drug. Extrapyramidal symptoms (EPS) occur frequently during treatment with phenothiazines and appear to be the result of D2-receptor blockade. These symptoms occur with greater severity and frequency during high-dose therapy. Extrapyramidal symptoms are categorized as dystonic reaction, akathisia (subjective and objective motor restlessness), and pseudoparkinsonism. Parkinsonian-like symptoms are more common in the elderly, whereas children most often develop dystonic reactions, which can be worsened by acute infections or severe dehydration. Dystonic reactions are seen during the first week of treatment. Akathisia and parkinsonian-like symptoms usually develop several days to weeks into therapy. Dystonia and pseudoparkinsonism usually are easily treated with concomitant benztropine, diphenhydramine, lorazepam, or amantadine. Akathisia may respond to dosage reduction or concomitant administration of a benzodiazepine (usually lorazepam) or propranolol. In rare patients, an alternate antipsychotic may be necessary. Neuroleptic malignant syndrome (NMS) can occur in patients receiving phenothiazines. NMS is characterized by hyperthermia, severe extrapyramidal dysfunction, alterations in consciousness, altered mental status, and autonomic instability (sinus tachycardia, low blood pressure or hypertension, diaphoresis). Increased serum creatine phosphokinase (CPK), acute renal failure, and leukocytosis also have occurred. NMS does not appear to be dose-related. Severe cases have resulted in death 3—30 days after the onset of the syndrome. Several predisposing factors may contribute to the development of NMS including heat stress, physical exhaustion, dehydration, and organic brain disease. NMS occurs more frequently in young men. The phenothiazine should be immediately discontinued and appropriate supportive therapy initiated as soon as symptoms of NMS are discovered. Hypothermia and hyperthermia have been reported with phenothiazines independent of the neuroleptic malignant syndrome and may be caused by the effect of the phenothiazine on the hypothalamic control of temperature regulation. Hyperpyrexia and heat stroke unrelated to NMS also have occurred. Tardive dyskinesia (TD) is characterized by involuntary movements of the perioral region (tongue, mouth, jaw, eyelids, or face) or choreoathetoid movements in the extremities. It can develop during long-term therapy or following discontinuation of phenothiazine therapy, and it is observed more frequently in elderly women. The incidence of TD may be higher in patients with bipolar disorder than with schizophrenia. Some cases can be irreversible. While contradictory evidence exists, it has been suggested that the likelihood of developing TD increases with prolonged treatment and cumulative doses. Although this complication often occurs following prolonged treatment or with administration of high dosages, it also has been reported to occur after short periods of time and with low dosages. Routine monitoring (at 3- to 6-month intervals) of movement disorders is considered the standard practice when using phenothiazines. If signs or symptoms of TD develop, the neuroleptic should be reevaluated and possibly discontinued. Phenothiazines can cause a variety of CNS effects. Drowsiness occurs occasionally during initial treatment with some phenothiazines. Tolerance usually develops with continued therapy. Dizziness may occur as a result of orthostatic hypotension. Other CNS effects reported less frequently include restlessness, insomnia, depression, headache, and cerebral edema. Seizures can occur and are of special significance in patients with preexisting seizure disorders or EEG abnormalities. Anticholinergic effects of phenothiazines include blurred vision, xerostomia, mydriasis, nausea, adynamic ileus, urinary retention, impotence, and constipation. These effects can be enhanced by the concomitant administration of anticholinergic antiparkinsonian drugs, antidepressants, or other anticholinergic agents. Leukopenia including agranulocytosis is the most common hematologic disturbance that has been reported during phenothiazine administration. Agranulocytosis has occurred rarely and has been associated with combination treatment with other agents. Other hematologic abnormalities that have been associated with phenothiazine therapy include leukocytosis (usually in association with the neuroleptic malignant syndrome), eosinophilia, thrombocytopenia, pancytopenia, aplastic anemia, and anemia. Prolonged therapy with phenothiazines can lead to skin hyperpigmentation. Hyperpigmentation generally is restricted to areas of the body exposed to sunlight. Photosensitivity can result, and patients should be warned either to keep out of the sun or to use effective sunscreens (SPF 15+) on exposed areas of the body. Withdrawal of the drug can reverse the effects. Contact dermatitis is also possible in predisposed individuals if they come in contact with liquid dosage forms of phenothiazines. Phenothiazines can cause ocular changes. Pigmentary retinopathy can occur with or without pigmentary changes in the skin during therapy with phenothiazines. Symptoms of blurred vision, difficulty with nighttime vision, or defective color vision should be investigated promptly. Wearing protective dark glasses can reduce the possibility of this reaction. Phenothiazines have been associated with deposition of fine particles in the lens and cornea, which can lead to corneal opacification and visual impairment. Liver impairment in the form of cholestasis has been reported rarely with administration of phenothiazines. Jaundice is also possible and may even occur in neonates of mothers who received phenothiazines during pregnancy. Cholestatic jaundice from phenothiazines is generally considered a hypersensitivity reaction. Adverse cardiovascular reactions that have occurred during antipsychotic therapy include hypotension, hypertension, ventricular tachycardia, ECG changes such as QT prolongation, and other cardiac arrhythmias such as torsade de pointes. Cardiac arrhythmias such as torsade de pointes secondary to antipsychotic therapy have mainly been associated with thioridazine[334] and haloperidol.[336] Dopamine blockade can lead to hyperprolactinemia. As a result, neuroleptics can cause galactorrhea. Other endocrine changes that can occur during therapy with neuroleptics include amenorrhea or other menstrual irregularity, breast enlargement or mastalgia, libido decrease, impotence, ejaculation dysfunction (no ejaculation), and priapism. Weight gain may also occur during therapy with phenothiazines. Phenothiazines do not cause physical or psychological dependence. However, sudden withdrawal of trifluoperazine can produce nausea/vomiting, dizziness and trembling. These effects are only temporary, and can be reduced by a gradual reduction in dosage, or continuation of concomitant antiparkinsonian agents.
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