Tranquilizer – Antipsychotic
Action And Clinical Pharmacology: The basic pharmacological profile of thioridazine is similar to that of other phenothiazines, but there are significant differences in the clinical spectrum when compared with other agents of this class. The distinctive features of thioridazine are its low propensity to cause extrapyramidal side effects and its low antiemetic activity.
Thioridazine has a wide therapeutic margin. At low and medium doses it relieves tension and anxiety, and acts against multiple symptoms (e.g., agitation, depression, sleep disturbances) of nonpsychotic mental disorders. At higher doses, thioridazine is effective in controlling the symptoms of psychotic disorders.
Pharmacokinetics: Thioridazine is rapidly and completely absorbed from the gastrointestinal tract. Maximum plasma concentrations are reached 2 to 4 hours after ingestion. The average systemic bioavailability is approximately 60%. The relative distribution volume is about 10 L/kg and protein binding is high (more than 95%). Thioridazine is metabolized in the liver with some of the resulting metabolites (e.g., mesoridazine, sulforidazine) possessing pharmacodynamic properties similar to those of the parent compound. Excretion is mainly via the feces (50%), but also via the kidney (less than 4% as unchanged drug, about 30% as metabolites). Plasma elimination half-life is approximately 10 hours. Thioridazine crosses the placenta, and passes into breast milk.
Indications And Clinical Uses: General Medicine: anxiety, tension, mixed states of anxiety and depression, agitation, emotional disturbances accompanied by anxiety and tension, psychosomatic disorders, sleep disturbances.
Geriatrics: senile agitation and confusional states, anxiety and mixed states of anxiety and depression, insomnia.
Pediatrics: anxiety, tension, difficulties with concentration, sleep disturbances, behavioral disorders such as agitation, hyperactivity or aggressiveness.
Psychiatry: multiple symptoms of psychotic and nonpsychotic mental disorders, the latter including anxiety, tension, agitation, depressed mood, sleep disturbances; intractable pain.
Thioridazine is particularly useful: in chronic hospitalized psychotic patients; in psychotic outpatients; in geriatric patients suffering from severe agitation, anxiety or mixed states of anxiety and depression, often associated with various degrees of an organic brain syndrome; during alcohol withdrawal for the relief of symptoms such as anxiety, agitation, hostility, or hallucinations; as an adjuvant treatment in agitated depression; in children with severe behavioral disorders such as emotional instability, hyperexcitability, excessive motor activity, and aggressiveness.
Contra-Indications: In patients with a history of hypersensitivity to other phenothiazines. Also in patients with severe CNS depression or comatose states from any cause, severe cardiovascular disease, bone marrow depression, or a history of blood dyscrasia.
Thioridazine should not be given to children under 1 year of age.
Precautions: Caution is required in patients with narrow-angle glaucoma, prostatic hypertrophy, or cardiovascular disease (severe cardiovascular disease is a contraindication).
Hypotension (which is usually orthostatic) may occur, especially in females, the elderly, and in alcoholic patients. The administration of epinephrine should be avoided in the treatment of drug-induced hypotension in view of the fact that phenothiazines may induce a reverse-epinephrine effect.
As with other phenothiazines, benign repolarization changes such as prolongation of the Q-T interval, flattening of the T wave and the appearance of a U wave have been reported. These changes are usually confined to high doses and are more likely to occur when potassium blood levels are low. Like all phenothiazines, thioridazine may induce arrhythmias.
Sudden and unexplained death, apparently due to arrhythmias or cardiac arrest, has been reported. Previous brain damage or seizures may also be predisposing factors. High doses should be avoided in patients with a history of seizures.
Convulsive seizures have been reported but are infrequent. However, thioridazine has been shown to be helpful in the treatment of behavioral disorders in epileptic patients. In such cases, anticonvulsant medication should be continued and dosage adjustment considered (see Drug Interactions).
Leukopenia and agranulocytosis have been reported but are infrequent. A complete blood count is recommended before the initiation of therapy, especially if long-term treatment is anticipated. Blood counts should be carried out regularly during the first few months of therapy and should be done immediately whenever clinical signs suggestive of blood dyscrasia occur.
Pigmentary retinopathy has been observed after long-term treatment, mostly in patients receiving doses exceeding the recommended maximum of 800 mg/day. Patients receiving higher doses of phenothiazines for prolonged periods should have complete eye examinations at regular intervals.
In patients with liver disease, regular monitoring of liver function is necessary.
Occupational Hazards: Where patients are participating in activities requiring complete mental alertness (e.g., driving vehicles, operating machinery), administer the phenothiazine cautiously since impairment of reactions may occur with large doses and during early treatment.
Pregnancy and Lactation: Safe use of thioridazine in human pregnancy has not been established. Therefore, thioridazine should not be administered to pregnant women (particularly during the first trimester of pregnancy) unless the expected benefit to the patient clearly outweighs the potential risk to the fetus. Thioridazine may appear in human breast milk and therefore mothers receiving thioridazine should not breast-feed.
Children: Thioridazine should be kept out of the reach of children.
Drug Interactions: Phenothiazines may enhance the CNS-depressant effects of alcohol, antihistamines and other CNS depressants as well as atropine and phosphorus insecticides; the antimuscarinic effects of anticholinergic agents; and the inhibitory cardiac effects of quinidine.
Use of epinephrine in the treatment of phenothiazine-induced hypotension may induce a reverse-epinephrine effect.
Phenothiazines may reduce the antiparkinsonian effects of levodopa.
Phenothiazines may lower the seizure threshold in epileptic patients. Dosage adjustment of anticonvulsant medication may be necessary.
Owing to their adrenolytic action, phenothiazines may reduce the pressor effect of adrenergic vasoconstrictors.
Concurrent use with MAO inhibitors may prolong and intensify the sedative and antimuscarinic effects of phenothiazines.
Concomitant use of lithium may aggravate extrapyramidal symptoms and neurotoxicity caused by neuroleptic agents. Early signs of lithium toxicity may be masked by the antiemetic effect of phenothiazines.
Concurrent use with b-adrenergic blocking agents may result in an increased plasma concentration of phenothiazines.
Antacids and antidiarrheal drugs may inhibit the absorption of phenothiazines.
Adverse Reactions: Not all of the following adverse reactions have been observed with every phenothiazine derivative, but they have been reported with one or more and should be considered when drugs of this class are administered.
CNS: drowsiness, sedation, nocturnal confusion, hyperactivity, lethargy, psychotic reactions, restlessness, disturbances of accommodation, vertigo and headache.
Extrapyramidal reactions (including Parkinsonism with motor retardation, rigidity, mask-like facies, tremor, salivation), dystonic reactions (including facial grimacing, tics, trismus, torticollis, opisthotonos, oculogyric crises), tremor, muscular rigidity, akinesia, akathisia.
As with all antipsychotic agents, tardive dyskinesia may appear in some patients on long-term therapy or may occur after drug therapy has been discontinued. This risk seems to be greater in elderly patients on high-dose therapy, especially females. The symptoms are persistent and in some patients appear to be irreversible.
All antipsychotic agents should be discontinued if tardive dyskinesia develops. Should it be necessary to reinstitute treatment, increase the dosage of the agent, or switch to a different antipsychotic agent, the syndrome may be masked. It has been reported that fine vermicular movements of the tongue may be an early sign of the syndrome and if the medication is stopped at that time, the syndrome may not develop.
Slowing of the EEG has been reported.
Behavioral Reactions: oversedation, impaired psychomotor function, paradoxical effects (such as agitation, excitement, insomnia, bizarre dreams, aggravation of psychotic symptoms), toxic confusional states.
Cardiovascular Effects: orthostatic hypotension, tachycardia, ECG changes (see Precautions).
Autonomic Nervous System: dry mouth, fainting, nasal stuffiness, photophobia, miosis, blurred vision.
Blood Dyscrasias: agranulocytosis, leukopenia, granulocytopenia, eosinophilia, thrombocytopenia, anemia, aplastic anemia, pancytopenia.
Gastrointestinal: anorexia, gastric irritation, nausea, vomiting, constipation, diarrhea, obstipation, paralytic ileus, pallor.
Hepatotoxicity: jaundice, biliary stasis.
Endocrine System: menstrual irregularities, altered libido, gynecomastia, galactorrhea, breast engorgement, weight change, edema, false positive pregnancy tests, disturbances of erection and of ejaculation (failure or priapism).
Urinary Disturbances: retention, incontinence.
Skin Reactions: itching, rash, hypertrophic papillae of the tongue, erythema, exfoliative dermatitis, contact dermatitis, photosensitivity.
Allergic Reactions: fever, laryngeal edema, angioneurotic edema, asthma.
Retinal Pigmentation: retinal pigmentation has been observed in psychiatric patients taking doses in excess of the maximum recommended daily dose of 800 mg over long periods of time (see Precautions).
Others: hyperpyrexia. Rare cases described as parotid swelling have been reported.
Neuroleptic Malignant Syndrome: As with other neuroleptic drugs, a symptom complex sometimes referred to as neuroleptic malignant syndrome (NMS) has been reported. Cardinal features of NMS are hyperpyrexia, muscle rigidity, altered mental status (including catatonic signs), and evidence of autonomic instability (irregular pulse or blood pressure). Additional signs may include elevated CPK, myoglobinuria (rhabdomyolysis), and acute renal failure. NMS is potentially fatal and requires symptomatic treatment and immediate discontinuation of neuroleptic treatment.
Symptoms And Treatment Of Overdose: Symptoms: 1) Drowsiness, confusion, disorientation, followed in more severe cases by coma and areflexia. 2) Dry mouth, nasal congestion, blurred vision. 3) Postural hypotension which may be early in onset, severe, and persistent. 4) Respiratory depression may be a late manifestation of severe phenothiazine intoxication. 5) Motor restlessness, hyperreflexia, and convulsions. 6) Hypothermia. 7) Cardiac abnormalities, including arrhythmia, tachycardia.
Note: Acute extrapyramidal symptoms, such as dystonia and oculogyric crisis, have not been reported with acute thioridazine overdosage, but are possible.
Treatment: There is no specific antidote for acute phenothiazine poisoning. Therefore, treatment is directed at minimizing the amount of drug absorbed, eliminating the absorbed drug from the body, and combating the toxic effects of the overdose. Elimination of the offending drug: 1) Emesis: If the patient is conscious, induce vomiting with syrup of ipecac (15 to 30 mL). Unlike other phenothiazines, thioridazine’s antiemetic effect is very low. 2) Perform gastric lavage followed by the administration of activated charcoal if the pharyngeal and laryngeal reflexes are present, and if less than 4 hours have elapsed since ingestion. Do not attempt gastric lavage on an unconscious patient unless cuffed endotracheal intubation has been performed to prevent aspiration and pulmonary complications. 3) Catharsis: Following gastric lavage, a saline cathartic (sodium or magnesium sulfate 30 g in 250 mL of water) may be introduced and left in the stomach. 4) Encourage diuresis with the administration of i.v. fluids assisted, if necessary, by 100 to 150 mL 25% mannitol solution given slowly i.v. Mannitol should not be mixed with blood in a transfusion set, as red cell crenation and agglutination may occur. 5) Exchange transfusion: In children, exchange transfusion may be indicated to remove most of the circulating drug which is strongly bound to plasma proteins.
Note: Peritoneal dialysis and hemodialysis have been found ineffective in the treatment of acute phenothiazine poisoning.
Maintenance of Adequate Pulmonary Ventilation: Perform pharyngeal and tracheal suction diligently to remove excess mucous secretions. Judicious administration of oxygen is also indicated. However, oxygen without assisted respiration must be used with caution, as its use in hypoventilation hypoxia may result in further respiratory depression and hypercapnia. In more critical cases, endotracheal intubation or tracheotomy, with or without assisted respiration, may be necessary.
Correction of Hypotension: 1) Mild cases: The usual head down position and other supportive measures may be adequate. 2) Severe cases: Vasopressors (dopamine, norepinephrine) may be given i.v. with the usual precautions and serial blood pressure monitoring.
Caution: Epinephrine should not be administered in phenothiazine overdosage. Phenothiazine derivatives may reverse the usual blood pressure elevating action and cause a further lowering of pressure.
General Supportive Measures: 1) Good nursing care is of prime importance, particularly in the comatose patient, and should include regular observation and accurate recording of the vital signs and depth of coma, maintenance of a free airway, frequent turning and other routine measures usually adopted with unconscious patients. 2) Careful supervision and recording of fluid intake and output is essential. 3) Because hypothermia may occur in phenothiazine intoxication, maintain normal body temperature and avoid overheating.
Dosage And Administration: All dosages must be adjusted to meet the individual requirements of the patients.
It is recommended that the initial dose be at the lower end of the ranges mentioned below and be gradually increased until the fully effective level is reached. In underweight patients, in patients with liver or kidney disease, and in the elderly a particularly low initial dose followed by small increments are recommended. The daily amounts of thioridazine are usually given in 2 to 4 divided doses.
The maximum daily dose is 800 mg.
Psychiatry: Mild mental and emotional disturbances: 30 to 75 mg daily; moderate disturbances: 50 to 200 mg daily; severe disturbances (e.g., schizophrenic, manic or toxic psychoses and agitated depressions), ambulatory outpatients: 150 to 400 mg daily; severe disturbances, hospitalized patients: 200 to 800 mg daily.
General Medicine: Mild conditions: 10 mg 3 times daily; moderate disturbances: 50 to 200 mg daily.
Geriatrics: Most geriatric patients will require 25 mg 3 times daily.
Children: Thioridazine is not intended for children under 2 years of age and is contraindicated in children under 1 year of age. For children aged 2 to 12, the dosage of thioridazine ranges from 0.5 mg/kg to a maximum of 3.0 mg/kg per day. For children with moderate disorders, 10 mg 2 or 3 times a day is the usual starting dose. For hospitalized, severely disturbed, or psychotic children, 25 mg 2 or 3 times daily is the usual starting dose. Dosage may be increased gradually until optimum therapeutic effect is obtained or the maximum has been reached.
Availability And Storage: Solution: Each mL of solution contains: thioridazine HCl USP 30 mg. Nonmedicinal ingredients: ethanol, flavor cherry (artificial), methylparaben, propylparaben, purified water and sorbitol. Alcohol: 24.5 mg. Bottles of 115 mL with calibrated droppers.
Suspension: Each 5 mL of fruit-flavored suspension contains: thioridazine (base) 10 mg. Nonmedicinal ingredients: carboxymethylcellulose, castor oil, flavor apricot (artificial), microcrystalline cellulose, microcrystalline sodium, purified water and sorbitol. Bottles of 230 mL.
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MELLARIL® Novartis Pharmaceuticals Thioridazine HCl Tranquilizer – Antipsychotic