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The P-I-E-N-O Parkinsn's List Drug Database
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thiothixene / NavaneTM
HIGH RISK
Description: Thiothixene is an antipsychotic drug that is structurally similar to trifluoperazine and shares some of the pharmacological properties of the high-potency antipsychotics. It is used in the treatment of psychotic disorders and schizophrenia. Five milligrams of thiothixene is equivalent to 100 mg of chlorpromazine, the prototype antipsychotic. Thiothixene was approved by the FDA in 1967.
Mechanism of Action: Thiothixene blocks postsynaptic dopamine receptors in the mesolimbic system and increases dopamine turnover by blockade of the DA somatodendritic autoreceptor. After approximately 12 weeks of chronic therapy, depolarization blockade of dopamine tracts occurs. The decrease in dopamine neurotransmission has been found to correlate with the antipsychotic effects. This DA blockade is also responsible for the potent extrapyramidal effects observed with this drug. Dopamine blockade in the chemoreceptor trigger zone accounts for the antiemetic effects. Thiothixene possesses weak anticholinergic and ›-adrenergic receptor blocking effects. Blockade of ›A-adrenergic receptors produces sedation; muscle relaxation; and cardiovascular effects such as hypotension, reflex tachycardia, and minor changes in ECG patterns.
Pharmacokinetics: Following oral administration, thiothixene is rapidly and well absorbed. Peak concentrations occur 1-3 hours following a dose. Distribution is extensive, and the drug can be detected in the body for several weeks after use. Metabolism takes place in the liver, but large amounts of drug are excreted with metabolites in the feces, via the bile. Profound increases in clearance of thiothixene can be observed in the presence of carbamazepine. The elimination is biphasic, with an initial half-life of 3.4 hours and a terminal half-life of 34 hours.
CONTRAINDICATIONS/PRECAUTIONS: Thiothixene should be used with extreme caution in patients with thyroid disease such as thyrotoxicosis or hyperthyroidism. Antipsychotic agents can cause extremely severe extrapyramidal symptoms such as dystonias or rigidity. Laryngospasm can prevent breathing and could be life-threatening.
Patients with hypocalcemia may be at an increased risk for having dystonic reactions, so thiothixene should be used with caution in this patient population.
Rarely, thiothixene can cause hypotension or precipitate angina; therefore, it should be used with extreme caution in patients with cardiac disease.
Thiothixene is classified as a pregnancy category C drug. It is likely that thiothixene crosses the placenta. Studies in humans have not been performed. No birth defects have been reported to be caused by thiothixene, but use of the drug in pregnant rats and rabbits showed an increase in resorption rate. To be safe, thiothixene should be used during pregnancy only when the benefits outweigh the potential risks to the fetus. It is not known if thiothixene is excreted into breast milk. Potential adverse effects to the nursing infant, if any, remain unknown. Therefore, thiothixene should be used during breast-feeding only when a benefit-to-risk assessment shows that it is clearly needed.
Oral solutions of thiothixene should not come in contact with the skin. Contact dermatitis has been reported with similar medications.
Severe adverse CNS reactions induced by thiothixene may appear similar to neurologic symptoms of CNS disorders such as encephalitis, Reye's syndrome, encephalopathy, meningitis, brain tumor, and tetanus. In addition, the drug can suppress the symptoms of these disorders, if they are present. Thiothixene is contraindicated in patients who are in a coma or who exhibit severe toxic CNS depression.
Patients with a history of hepatic encephalopathy secondary to cirrhosis may be at an increased risk for potentiation of the CNS effects of thiothixene. Although preexisting hepatic disease does not appear to increase the probability of jaundice occurring in patients receiving antipsychotic agents, thiothixene should be used with caution in this patient population.
Children with acute illnesses, including varicella-zoster infections, CNS infections, measles, gastroenteritis, or dehydration, can be more susceptible to developing extrapyramidal symptoms, particularly dystonias.
Elderly patients can be more susceptible to the actions and adverse effects of phenothiazines. Lower initial doses should be considered.
Hematologic reactions have been reported following administration of antipsychotic agents. Although these reactions are rare, thiothixene should be used with caution in patients with preexisting hematological disease. If sore throat or other signs or symptoms of infection occur, obtain a complete blood count and consider discontinuing thiothixene treatment.
Patients receiving anticonvulsant agents or who have a history of seizures, epilepsy, or EEG abnormalities should be carefully monitored during therapy with thiothixene due to its potential lowering of seizure threshold. Adequate anticonvulsant therapy should prevent an increase in seizure frequency during treatment with thiothixene. High doses and large changes in dose of thiothixene should be avoided in patients with a known seizure disorder.
The anticholinergic effects of thiothixene or concomitant antiparkinsonian agent can worsen angle closure glaucoma, so they should be used with caution in patients with preexisting angle closure glaucoma.
Thiothixene should be used cautiously in patients with prostatic hypertrophy because the anticholinergic effects of thiothixene or concomitant antiparkinsonian agent can worsen urinary retention.
Thiothixene is contraindicated in patients with Parkinson's disease. Blockade of dopamine receptors centrally by thiothixene will dramatically worsen Parkinson's disease, possibly incapacitating the patient.
Thiothixene can disrupt the hypothalamic mechanism for temperature regulation. Patients therefore should avoid exposure to extreme temperature variations to prevent hyperthermia or hypothermia.
Antipsychotics stimulate the release of prolactin and should be used extremely cautiously in patients who have a history of breast carcinoma.
Cigarette smoking can induce hepatic metabolism and reduce plasma concentrations of thiothixene compared with those of nonsmokers receiving the same dose. Dosage adjustments may be required in patients who start or stop smoking while receiving phenothiazines.
DRUG INTERACTIONS: Thiothixene can potentiate the actions of other CNS depressants such as opiate agonists, barbiturates, ethanol, or general anesthetics. Caution should be exercised with simultaneous use of these agents due to potential excessive CNS effects.
Carbamazepine is a potent inducer of the cytochrome P-450 mixed-function hepatic oxidase system. Carbamazepine can reduce plasma concentrations of thiothixene to undetectable levels. Carbamazepine either should be avoided or an antipsychotic other than a phenothiazine should be used. If thiothixene and carbamazepine must be used together, then dosage adjustments of thiothixene may be required.
Limited data suggest that rifampin can increase the metabolism or reduce the bioavailability of thiothixene. Patient response, adverse effects, and plasma thiothixene concentrations should be monitored following addition or deletion of rifampin during treatment with thiothixene.
Erythromycin can inhibit metabolism of thiothixene. Dosage adjustments of the phenothiazine may be necessary in patients receiving erythromycin.
Propranolol can inhibit the metabolism of phenothiazines. In addition, concomitant administration of propranolol with phenothiazines can lead to additive hypotension. Seizures also have been reported during concomitant use of propranolol with thiothixene. While coadministration is not contraindicated, patients should be monitored carefully for exaggerated responses to the phenothiazine. 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 have also been noted in patients receiving both agents. Although this reaction has been associated with thioridazine, it is also possible during concomitant therapy with thiothixene. 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).
Phenothiazines possess anticholinergic properties to varying degrees. Concomitant use of a phenothiazine with other anticholinergic agents can lead to additive anticholinergic effects. Thiothixene should be used cautiously with any of the following drugs: atropine, benztropine, dicyclomine, HA-blockers, tricyclic antidepressants, or other anticholinergics. Severe constipation, increased intraocular pressure, or paralytic ileus can result from additive anticholinergic effects.
Phenothiazines should be used cautiously in patients receiving certain antihypertensive agents. Concurrent administration of haloperidol and methyldopa has been reported to cause dementia in some cases. The clinical importance of this interaction has not been established, but caution is reasonable during simultaneous use of thiothixene and methyldopa. In addition, phenothiazines can antagonize the pharmacologic actions of guanethidine. Both guanethidine and guanadrel should be avoided in patients receiving a phenothiazine.
Patients taking thiothixene 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 ›-adrenergic effects of epinephrine can be blocked during concurrent administration of phenothiazines, possibly causing an apparently paradoxical condition called "epinephrine reversal." Epinephrine reversal can lead to severe hypotension, tachycardia, and, potentially, myocardial infarction. The vasoconstrictive properties of dopamine infusion can be decreased due to the ›-adrenergic blocking capability of thiothixene. Dopamine infusions intended to improve renal perfusion can be ineffective due to thiothixene's dopamine receptor blockade.
Thiothixene is a direct antagonist of levodopa, bromocriptine, or pergolide at the DA-receptor. In theory, thiothixene should inhibit the clinical response to these agents, but there is a paucity of clinical data to support this. Limited research data suggest that there could be therapeutic benefits from the addition of levodopa in a small number of refractory schizophrenic patients. Nevertheless, in general, phenothiazines should not be used in patients requiring therapy with levodopa, bromocriptine, or pergolide.
The combination of quinidine with a phenothiazine could lead to additive orthostatic hypotension or, if either agent is used in high doses, prolonged QT syndrome. While concomitant use is not contraindicated, patients receiving both agents should be monitored for ECG changes.
Antacids can significantly reduce the oral bioavailability of chlorpromazine. Until additional data are available, other neuroleptics should not be administered within 2 hours of antacid doses.
Conflicting data exist for the combination of MAOIs and neuroleptics. The combination of tranylcypromine and trifluoperazine leads 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.
Dextroamphetamine and neuroleptics can interfere with the therapeutic actions of the other. One should avoid this drug combination whenever possible.
ADVERSE REACTIONS: 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 DA-receptor blockade. These symptoms occur with greater severity and frequency during high-dose therapy. Extrapyramidal symptoms are categorized as dystonia, akathisia (subjective and objective motor restlessness), and parkinsonism. Parkinsonian 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 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 thioridazineI and haloperidol.
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.
PATIENT INFORMATION:
What do thiothixene capsules do?
Thiothixene (NavaneTM ) helps to treat schizophrenia. Thiothixene can help you to keep in touch with reality and reduce your mental problems. Generic thiothixene capsules are available.
What should my doctor, dentist, or pharmacist know before I take thiothixene?
They need to know if you have any of these conditions:
How should I take this medicine?
Take thiothixene capsules by mouth. Follow the directions on the prescription label. Swallow the capsules with a drink of water. If thiothixene upsets your stomach you can take it with food. Take your doses at regular intervals. Do not take your medicine more often than directed. Do not stop taking except on your doctor's advice.
Special precautions for use in children:
This medicine is not for children under 12 years old.
What if I miss a dose?
If you miss a dose, take it as soon as you can. If it is almost time for your next dose, take only that dose. If you take only one dose a day at bedtime and forget, do not take it in the morning without calling your doctor for advice. Do not take double or extra doses.
What other medicines can interact with thiothixene?
Tell your doctor or pharmacist: about all other medicines you are taking, including non-prescription medicines; if you are a frequent user of drinks with caffeine or alcohol; if you smoke; or if you use illegal drugs. These may affect the way your medicine works. Check before stopping or starting any of your medicines.
What side effects may I notice from taking thiothixene?
Serious side effects with thiothixene include:
Call your doctor as soon as you can if you get any of these side effects.
Minor side effects with thiothixene include:
Let your doctor know about these side effects if they do not go away or if they annoy you.
What do I need to watch for while I take thiothixene?
Visit your doctor for regular checks on your progress. It may be several weeks before you see the full effects of thiothixene. Do not suddenly stop taking thiothixene. You may need to gradually reduce the dose. Only stop taking thiothixene on your doctor's advice.
You may get dizzy or drowsy. Do not drive, use machinery, or do anything that needs mental alertness until you know how thiothixene affects you. Do not stand or sit up quickly, especially if you are an older patient. This reduces the risk of dizzy or fainting spells. Alcohol can increase dizziness and drowsiness. Avoid alcoholic drinks. You can get a hangover effect the morning after a bedtime dose.
Do not treat yourself for colds, diarrhea or allergies. Ask your doctor or pharmacist for advice, some nonprescription medicines may increase possible side effects.
If you are going to have surgery tell your doctor or dentist that you are taking thiothixene.
Thiothixene may make you more sensitive to sun or ultraviolet light. Keep out of the sun, or wear protective clothing outdoors and use a sunscreen (at least SPF 15). Do not use sun lamps, or sun tanning beds or booths. To protect your eyes wear sunglasses even on cloudy days.
Avoid extreme heat or cold. Thiothixene can stop you sweating and increase your body temperature. It can also make your body unable to stand extreme cold. Avoid hot baths and saunas. Be careful about exercising especially in hot weather. Dress warmly in cold weather and do not stay out long in the cold.
Thiothixene may make your mouth dry. Chewing sugarless gum or sucking hard candy, and drinking plenty of water will help. Be careful when brushing and flossing your teeth to avoid mouth infections or damage to your gums. See your dentist regularly.
Do not take antacids or medicine for diarrhea within 2 hours of taking loxapine.
Where can I keep my medicine?
Keep out of the reach of children in a container that small children cannot open.
Store at room temperature between 15 and 30C (59 and 86F). Protect from light. Throw away any unused medicine after the expiration date.
The P-I-E-N-O Parkinsn's List Drug Database Index
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