The P-I-E-N-O Parkinsn's List Drug Database
thioridazine / MellarilTM , AldazineTM
MODERATE RISK
Description: Thioridazine is a piperidine phenothiazine that is structurally similar to mesoridazine (SerentilTM ), which is one of its metabolites. It is used to treat psychotic disorders and schizophrenia. Thioridazine also has been used to treat anxiety associated with major depression, dementia in the elderly, and severe behavioral problems in children. Dosing is limited by retinal pigmentation. It has the fewest extrapyramidal symptoms (EPS) of any typical antipsychotic. It is equipotent to chlorpromazine, the prototype antipsychotic. Thioridazine was approved by the FDA in 1959.
Mechanism of Action: Thioridazine blocks postsynaptic dopamine receptors in the mesolimbic system and increases dopamine turnover by blockade of the DA somatodendritic autoreceptor. After ~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 DA 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. Thioridazine possesses strong 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: Thioridazine 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. 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. Thioridazine is highly plasma protein-bound (91-99%), predominantly to ›A-acid glycoprotein. The drug crosses the placenta and may be excreted into breast milk although insufficient data are available. Metabolism is extensive, and about 12 metabolites have been identified. There may be some enterohepatic circulation, and two of the metabolites, mesoridazine and sulphoridazine, are pharmacologically active. 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.
CONTRAINDICATIONS/PRECAUTIONS: Thioridazine 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.
The use of phenothiazines in patients with GI obstruction can mask the symptoms of their condition (i.e., vomiting). Phenothiazines should be used cautiously in these patients.
Patients with hypocalcemia may be at an increased risk for developing dystonic reactions. Therefore, thioridazine should be used with caution in this patient population.
Thioridazine rarely can cause hypotension or precipitate angina, so it should be used with extreme caution in patients with cardiac disease.
Thioridazine is classified as a pregnancy category C drug. It is likely that thioridazine crosses the placenta. Studies in humans have not been performed, but no birth defects were reported to have been caused by thioridazine. In pregnant rats and rabbits, however, thiothixene showed an increase in the resorption rate. To be safe, thioridazine should be used during pregnancy only when the benefits to the mother outweigh the potential risks to the fetus. It is not known if thioridazine is excreted into breast milk. Potential adverse effects to the nursing infant remain unknown. Therefore, thioridazine should be used during breast-feeding only when a benefit-to-risk assessment shows that it is clearly needed.
Oral solutions of thioridazine should not come in contact with the skin. Contact dermatitis has been reported with similar medications.
Severe adverse CNS reactions induced by thioridazine may appear similar to neurologic symptoms of CNS disorders including encephalitis, Reye's syndrome, encephalopathy, meningitis, and tetanus. In addition, the drug may suppress the symptoms of these disorders if they are present. Thioridazine 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 thioridazine. Although preexisting hepatic disease does not appear to increase the probability of jaundice occurring in patients receiving antipsychotic agents, thioridazine should be used with caution in this patient population. Alcoholism is a relative contraindication to phenothiazine therapy.
All phenothiazines, including thioridazine can cause neuromuscular reactions, particularly dystonias. Children with acute illnesses, including varicella-zoster infections, CNS infections, measles, gastroenteritis, or dehydration, may be more susceptible to developing extrapyramidal symptoms, particularly dystonias.
Elderly patients may 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 quite rare, thioridazine 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 treatment with thioridazine.
Patients receiving anticonvulsant agents or having a history of seizures, epilepsy, or EEG abnormalities should be carefully monitored during therapy with thioridazine because it could lower seizure threshold. Adequate anticonvulsant therapy should prevent an increase in seizure frequency during treatment with thioridazine. High doses and large changes in dose of thioridazine should be avoided in patients with a known seizure disorder. Patients with a pre-existing intracranial mass may be more susceptible to seizures if phenothiazines are administered.
Angle-closure glaucoma can be worsened due to the anticholinergic effects of thioridazine or concomitant antiparkinsonian agent; therefore, it should be used with caution in patients with preexisting angle-closure glaucoma.
Thioridazine should be used cautiously in patients with prostatic hypertrophy. Urinary retention can worsen from the anticholinergic effects of thioridazine.
Thioridazine is contraindicated in patients with Parkinson's disease. Central blockade of dopamine receptors by thioridazine will dramatically worsen Parkinson's disease, possibly incapacitating the patient.
Thioridazine may disrupt the hypothalamic mechanism for temperature regulation. Therefore, patients 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.
Tobacco smoking can induce the hepatic metabolism and has been shown to reduce plasma concentrations of thiothixene, a related agent, compared with those of nonsmokers receiving the same dose. Dosage adjustments may be required in patients that start or stop smoking while receiving phenothiazines.
DRUG INTERACTIONS Thioridazine can potentiate the CNS-depressant action of other drugs such as opiate agonists, barbiturates, benzodiazepines, ethanol, or general anesthetics. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects.
Carbamazepine is a potent inducer of the cytochrome P-450 mixedfunction hepatic oxidase system. Carbamazepine can reduce plasma concentrations of thioridazine to undetectable levels. Carbamazepine should be avoided in patients receiving a phenothiazine, or an antipsychotic other than a phenothiazine should be used if carbamazepine is administered. If thioridazine and carbamazepine must be used together, then dosage adjustments of thioridazine may be required. It has been demonstrated that thioridazine does not affect the pharmacokinetics of carbamazepine, although no data are available regarding other phenothiazines.
Because they also block central dopamine receptors, droperidol, haloperidol, and metoclopramide should be avoided or used cautiously in patients receiving a phenothiazine to minimize the risk of additive toxicity.
Limited data suggest that rifampin can increase the metabolism or reduce the bioavailability of thioridazine. Larger doses of thioridazine may be necessary following the addition of rifampin.
Erythromycin can inhibit the metabolism of thioridazine. 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 have also been reported during concomitant use of high-dose propranolol with thiothixine, a related agent. Concomitant administration is not contraindicated, but patients should be monitored carefully for exaggerated responses to the phenothiazine if œ-blockers are added.
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; and 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.)
Phenothiazines possess anticholinergic properties. The combination of a phenothiazine with other anticholinergics can lead to additive anticholinergic effects. Thioridazine should be used cautiously with any of the following: amantadine, 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. Phenothiazines can antagonize the pharmacologic actions of guanethidine. Both guanethidine and guanadrel should be avoided in patients receiving a phenothiazine. In addition, 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 phenothiazines and methyldopa.
Patients taking thioridazine 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, and possibly 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. The vasoconstrictive properties of dopamine infusion can be decreased due to the ›-adrenergic blocking capability of phenothiazines. Dopamine infusions intended to improve renal perfusion may be ineffective due to phenothiazine-induced dopamine receptor blockade.
Phenothiazines are pharmacologic antagonists of levodopa, bromocriptine, and pergolide at the DA-receptor. In theory, phenothiazines 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 Q-T syndrome. While concomitant use is not contraindicated, patients receiving both agents should be monitored for ECG changes. Probucol could have a similar interaction with phenothiazines.
Antacids or cimetidine 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 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.
Dextroamphetamine and neuroleptics can interfere with the therapeutic actions of each other. It is recommended that one avoid this drug combination whenever possible.
Both phenothiazines and antithyroid agents have been associated with serious bone marrow toxicity. Whenever possible, this drug combination should be avoided.
Aminoglycosides are well known to cause ototoxicity. Some phenothiazines are used to treat nausea. It is possible that phenothiazines could mask aminoglycoside-induced ototoxicity.
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 330 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 3to 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.
Phenothiazines do not cause physical or psychological dependence. However, sudden withdrawal of thioridazine 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.
PATIENT INFORMATION:
What do thioridazine tablets do?
Thioridazine (MellarilTM ) helps to treat disordered thoughts and some other emotional, nervous, and mental problems. It also treats behavioral problems in children. Generic thioridazine tablets are available.
What should my doctor, dentist, or pharmacist know before I take thioridazine?
They need to know if you have any of these conditions:
How should I take this medicine?
Take thioridazine tablets by mouth. Follow the directions on the prescription label. Swallow the tablets with a drink of water. Take thioridazine with food or milk if it upsets your stomach. Take your doses at regular intervals. Do not take your medicine more often than directed.
Special precautions for use in children:
This medicine is not for children under 2 years old.
Elderly patients over age 65 years may have a stronger reaction to this medicine and need smaller doses.
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. Try to take your doses at the same time each day. Do not take double or extra doses.
What other medicines can interact with thioridazine?
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 thioridazine?
Serious side effects with thioridazine include:
Call your doctor as soon as you can if you get any of these side effects.
Minor side effects with thioridazine 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 thioridazine? Visit your doctor for regular checks on your progress. Do not stop taking thioridazine suddenly; this can cause nausea, vomiting, and dizziness. Ask your doctor for advice if you are to stop taking this medicine.
You may get drowsy, dizzy, or have blurred vision. Do not drive, use machinery, or do anything that needs mental alertness until you know how thioridazine 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 possible dizziness or drowsiness. Avoid alcoholic drinks.
Thioridazine can reduce the response of your body to heat or cold. Try not to get overheated. Avoid temperature extremes, such as saunas, hot tubs, or very hot or cold baths or showers. Dress warmly in cold weather.
Thioridazine can make your skin 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. Wear sunglasses to protect your eyes.
Thioridazine may make your mouth dry, chewing sugarless gum or sucking hard candy and drinking plenty of water will help.
Do not treat yourself for coughs, colds, sore throat, indigestion, diarrhea, or allergies. Ask your doctor or pharmacist for advice.
If you are going to have surgery, tell your doctor or dentist that you are taking thioridazine.
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 below 30C (86F). Keep container tightly closed. Throw away any unused medicine after the expiration date.
Parkinsn's Archive Treasures Page
John Cottingham is the webmaster of this site.
