Tris

Uses

Thioridazine is used for the management of schizophrenic patients who fail to respond adequately to treatment with other antipsychotic drugs. Due to the risk of significant, potentially life-threatening, proarrhythmic effects with thioridazine treatment, thioridazine should be used only in patients who have failed to respond adequately to treatment with appropriate courses of other antipsychotic drugs, either because of insufficient effectiveness or the inability to achieve an effective dose due to intolerable adverse effects from those drugs. Consequently, before initiating treatment with thioridazine, it is strongly recommended that a patient be given at least 2 trials, each with a different antipsychotic drug product, at an adequate dose, and for an adequate duration.

However, the prescriber should be aware that thioridazine has not been systematically evaluated in controlled trials in treatment refractory schizophrenic patients and its efficacy in such patients is unknown.

Anxiety states: It controls excessive anxiety, tension, and agitation seen in neuroses or associated with somatic conditions. The treatment or prevention of nausea and vomiting of various causes. The management of psychotic disorders, such as acute or chronic catatonic, hebephrenic and paranoid schizophrenia; psychosis due to organic brain damage, toxic psychosis, and the manic phase of manic-depressive illness.

Trihexyphenidyl Hydrochloride is used for an adjunct treatment of all forms of parkinsonism (postencephalitic, arteriosclerotic & idiopathic). Additionally, it is used for the control of extrapyramidal disorders caused by central nervous system drugs such as dibenzoxazepines, phenothiazines, thioxanthenes & butyrophenones.

Tris is also used to associated treatment for these conditions: Psychosis, SchizophreniaAgitation, Psychosis, Schizophrenia, Acute non-psychotic AnxietyExtrapyramidal disorder, Extrapyramidal symptoms caused by butyrophenones, Extrapyramidal symptoms caused by dibenzoxazepines, Extrapyramidal symptoms caused by phenothiazines, Extrapyramidal symptoms caused by thioxanthenes, Idiopathic Parkinson's Disease, Parkinsonism post encephalitic, Arteriosclerotic Parkinsonism

How Tris works

Thioridazine blocks postsynaptic mesolimbic dopaminergic D1 and D2 receptors in the brain; blocks alpha-adrenergic effect, depresses the release of hypothalamic and hypophyseal hormones and is believed to depress the reticular activating system thus affecting basal metabolism, body temperature, wakefulness, vasomotor tone, and emesis.

Trifluoperazine blocks postsynaptic mesolimbic dopaminergic D1 and D2 receptors in the brain; depresses the release of hypothalamic and hypophyseal hormones and is believed to depress the reticular activating system thus affecting basal metabolism, body temperature, wakefulness, vasomotor tone, and emesis.

Trihexyphenidyl is a non-selective muscarinic acetylcholine receptor antagonist but binds with higher affinity to the M1 subtype. In vivo studies have shown that trihexyphenidyl demonstrates higher affinity for central muscarinic receptors located in the cerebral cortex and lower affinity for those located peripherally. Other studies suggest that trihexyphenidyl may modify nicotinic acetylcholine receptor neurotransmission, leading indirectly to enhanced dopamine release in the striatum. Although the anticholinergic has proven to be useful in the treatment of symptoms associated with Parkinson’s disease or other movement disorders, its mechanism of action has yet to be fully elucidated.

Dosage

Tris dosage

Since thioridazine is associated with a dose-related prolongation of the QTc interval, which is a potentially life-threatening event, its use should be reserved for schizophrenic patients who fail to respond adequately to treatment with other antipsychotic drugs. Dosage must be individualized and the smallest effective dosage should be determined for each patient

Adults: The usual starting dose for adult schizophrenic patients is 50 to 100 mg three times a day, with a gradual increment to a maximum of 800 mg daily if necessary. Once effective control of symptoms has been achieved, the dosage may be reduced gradually to determine the minimum maintenance dose. The total daily dosage ranges from 200 to 800 mg, divided into two to four doses.

Pediatric: For pediatric patients with schizophrenia who are unresponsive to other agents, the recommended initial dose is 0.5 mg/kg/day given in divided doses. Dosage may be increased gradually until optimumtherapeuticeffect is obtained or the maximum dose of 3 mg/kg/day has been reached.

Schizophrenia and other psychoses:

• Adults and child over 12 years: Recommended starting dose is 2-5 mg b.i.d, increased by 5 mg daily after 1 week then at interval of 3 days, according to response.
• Children (6-12 years): Dosage should be adjusted to the weight of the child and severity of the symptoms. The starting dosage is 1 mg b.i.d. Dosage may be increased gradually until symptoms are controlled or until side effects become troublesome. While it is usually not necessary to exceed dosages of 15 mg daily.
• Elderly: Reduce initial dose by at least half

Short-term management of severe anxiety:

• Adult and child over 12 years: 1-2 mg b.i.d, increased if necessary to 6 mg daily.
• Child (3-5 years): 1 mg daily
• Child (6-12 years): Up to 4 mg daily in divided dose.
• Elderly: Reduce initial dose by at least half

Antiemetic:

• Adult: 2-4 mg daily in divided doses; max. 6 mg daily;
• Child 3-5 years: up to 1 mg daily, 6-12 years up to 4 mg daily.

Dosage should be individualized. The initial dose should be low and then increased gradually, especially in patients over 60 years of age. Whether Trihexyphenidyl may best be given before or after meals should be determined by the way the patient reacts.

Idiopathic Parkinsonism: 1 mg of Trihexyphenidylmay be administered the first day. The dose may then be increased by 2 mg increments at intervals of three to five days.

Drug-Induced Parkinsonism: Commence therapy with a single 1 mg dose increase the total daily dosage to 5-15 mg range if the extrapyramidal manifestations are not controlled.

Concomitant Use with Levodopa: When Trihexyphenidyl is used concomitantly with levodopa, the usual dose is 3-6 mg daily.

Side Effects

Tardive dyskinesia; leucopenia, neutropenia, agranulocytosis; drowsiness, pseudoparkinsonism and other extrapyramidal symptoms; dry mouth, blurred vision, constipation, nausea, vomiting, diarrhoea, nasal stuffiness, pallor; galactorrhoea, breast engorgement, amenorrhoea, inhibition of ejaculation, peripheral oedema; dermatitis, skin eruptions. Rarely, nocturnal confusion, hyperactivity, lethargy, psychotic reactions, restlessness, headache, photosensitivity, parotid swelling.

Common side effects are transient restlessness, dystonias or may resemble parkinsonism. Other CNS Reactions are drowsiness, dizziness, fatigue, blurred vision, seizures. Without these Peripheral oedema, blood dyscrasias, jaundice may occasionally occur. Tachycardia, constipation, urinary hesitancy and retention and hyperpyrexia have been reported very rarely.

Minor side effects such as dryness of the mouth, blurring of vision, dizziness, mild nausea or nervousness. Patients with arteriosclerosis or with a history of idiosyncrasy to other drugs may exhibit reactions of mental confusion, agitation, disturbed behavior, or nausea and vomiting. Potential side effects are constipation, drowsiness, urinary hesitancy or retention, pupil dilation, increased intraocular tension, vomiting and headache.

Toxicity

LD₅₀=956-1034 mg/kg (Orally in rats); Agitation, blurred vision, coma, confusion, constipation, difficulty breathing, dilated or constricted pupils, diminished flow of urine, dry mouth, dry skin, excessively high or low body temperature, extremely low blood pressure, fluid in the lungs, heart abnormalities, inability to urinate, intestinal blockage, nasal congestion, restlessness, sedation, seizures, shock

Symptoms of overdose include agitation, coma, convulsions, difficulty breathing, difficulty swallowing, dry mouth, extreme sleepiness, fever, intestinal blockage, irregular heart rate, low blood pressure, and restlessness.

Symptoms of overdose include mydriasis, dryness of mucous membranes, red face, atonic states of bowels and bladder, and hyperthermia in high doses. Trihexyphenidyl causes agitation, confusion, and hallucinations due to its effects on the central nervous system. Untreated overdose may result in death, especially in children. Respiratory depression and cardiac arrest may be seen as premortal signs.

Patients experiencing an overdose of trihexyphenidyl may experience dry mouth, anhidrosis, mydriasis, nausea, vomiting, tachycardia, hyperpyrexia, reduced gastrointestinal motility, urinary hesitancy or retention, rash, hyperthermia, confusion, restlessness, agitation, poor coordination, paranoia, psychosis, delirium, hallucinations, coma, respiratory failure, circulatory failure, and death. Patients should be treated with symptomatic and supportive care which may include airway maintenance and the use of physostigmine.

Precaution

Patient with severe CV disease, narrow-angle glaucoma, Parkinson's disease, seizure disorder. Avoid abrupt withdrawal. Hepatic and renal impairment. Elderly with dementia-related psychosis. Pregnancy and lactation.

Care should be taken when treating elderly patients, and initial dosage should be reduced. Such patients can be specially sensitive, particularly to extra pyramidal and hypotensive effects. Patients with cardiovascular disease including arrhythmias should also be treated with caution. Care should be taken in patients with angina pectoris.

Patients with cardiac, liver, or kidney disorders, or with hypertensioon, should closely be monitored. Since trihexyphenidyl has parasympatholytic activity, it should be used with caution in patients with glaucoma, obstructive disease of the gastrointestinal or genitourinary tracts, and in elderly males with possible prostatic hypertrophy. Trihexyphenidyl is not recommended for use in patients with tardive dyskinesia unless they have concomitant Parkinson’s disease. Abrupt withdrawal of treatment for parkinsonism may result in acute exacerbation of parkinsonism symptoms; therefore, abrupt withdrawal should be avoided.

Interaction

May potentiate the effects of CNS depressants (e.g. anaesth, barbiturates, narcotics, opiates, other psychoactive drugs).

Trifluoperazine may diminish the effect of oral anticoagulants. Concomitant administration of propranolol with trifluoperazine results in increased plasma levels of both drugs. Antihypertensive effects of guanethidine and related compounds may be counteracted when phenothiazines are used concurrently. Potentiation may occur if antipsychotic drugs are combined with CNS depressants such as alcohol. hypnotics and anticonvulsant.

Cannabinoids, barbiturates, opiates, and alcohol may have additive effects with trihexyphenidyl, and thus, an abuse potential exists. Concurrent use of alcohol or other CNS depressants with trihexyphenidyl may cause increased sedative effects. It may be contraindicated in patients taking monoamine oxidase inhibitors & tricycllic antidepressants.

Elimination Route

60%

Trihexyphenidyl is absorbed from the gastrointestinal tract. Trihexyphenidyl reaches a C_max of 7.2 ng/mL, with a T_max of 1.3 hours, and an AUC of 201 ng*h/mL.

Half Life

21-25 hours

10-20 hours

The mean elimination half life of trihexyphenidyl is 3.2 ± 0.3 hours.

Elimination Route

Data regarding the route of elimination of trihexyphenidyl are not readily available. However, it is likely eliminated predominantly in the urine.

Pregnancy & Breastfeeding use

Pregnancy Category C: Either studies in animals have revealed adverse effects on the foetus (teratogenic or embryocidal or other) and there are no controlled studies in women or studies in women and animals are not available. Drugs should be given only if the potential benefit justifies the potential risk to the foetus.

Pregnancy: Safety for the use of trifluoperazine during pregnancy has not been established. Therefore, it is not recommended that the drug be given to pregnant patients except when, in the judgement of the physician, it is essential. The potential benefits should clearly outweigh possible hazards. There are reported instances of prolonged jaundices, extrapyramidal signs, hyperreflexia or hypoflexia in newborn infants whose mother received phenothiazines.

Lactation: Adequate human data are not available in case of lactation.

Pregnancy Category C. It is not known whether the drug is excreted in human milk and therefore trihexyphenidyl should only be used if the expected benefit to the mother outweighs the potential risk to the infant.

Contraindication

Patients with reduced levels of CYP2D6 isoenzyme, congenital long QT syndrome or history of cardiac arrhythmias; severe CNS depression or comatose states of any cause; hypertensive or hypotensive heart disease of extreme degree. Concomitant use with drugs that prolong QTc interval, CYP2D6 isoenzyme inhibitors and drugs which reduce thioridazine clearance by other mechanisms.

Do not use Trifluoperazine in comatose patients, or in those with existing blood dyscrasias or known liver damage, or in those hypersensitive to the active ingredient or related compounds.

Trihexyphenidyl is contraindicated in patients with hypersensitivity in patients to trihexyphenidyl HCl or to any of the tablet or elixir ingredients. Trihexyphenidyl is also contraindicated in patients with narrow angle glaucoma. Blindness after long-term use due to narrow angle glaucoma has been reported.

Special Warning

Renal Impairment: Lower initial doses and more gradual dosage increase.

Hepatic Impairment: Lower initial doses and more gradual dosage increase.

Acute Overdose

Symptoms: Cardiotoxicity (e.g. prolongation of QT interval and QRS complex).

Management: Symptomatic and supportive treatment with CV (e.g. ECG) monitoring. Establish a patent airway and ensure adequate oxygenation and ventilation. Employ gastric lavage and administer repeated doses of activated charcoal. May include ventricular pacing, defibrillation, admin of IV Mg sulfate, lidocaine, phenytoin or isoproterenol, correction of electrolyte abnormalities and/or acid-base balance to manage arrhythmias. Administer lidocaine with caution as it may increase the risk of developing seizures.

Signs and symptoms will be predominantly extrapyramidal; hypotension may occur. Treatment consists of gastric lavage together with supportive and symptomatic measures. Do not induce vomiting. Extra pyramidal symptoms may be treated with an anticholinergic, antiparkinsonism drug. Treat hypotension with fluid replacement; if severe or persistent. nor adrenaline may be considered. Adrenaline is contraindicated.

Overdosage with trihexyphenidyl produces typical central symptoms of atropine intoxication ( the central anticholinergic syndrome). Signs & symptoms are: dilated and sluggish pupils, warm, dry skin, facial flushing, decreased secretions of mouth, pharynx, nose and bronchi, foul smelling breath, tachycardia etc. Neuropsychiatric signs such as delirium, disorientation, anxiety, hallucinations etc. The condition can progress to stupor, coma, paralysis, cardiac, respiratory arrest and death.

Storage Condition

Store between 15-30° C. Protect from light.

It should be store at room temperature between 15-30° C away from light and moisture.

Innovators Monograph

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