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THIORIDAZINE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Thioridazine is a piperidine phenothiazine antipsychotic now rarely used in the treatment of schizophrenia. Because of its cardiotoxic potential, use is restricted to patients have failed to respond to other antipsychotics.

Specific Substances

    1) thioridazine
    2) thioridazin
    3) thioridazinum
    4) thioridatsiini
    5) tioridazina
    6) tioridazinas
    7) CAS 50-52-2
    8) molecular formula C21H26N2S2
    1.2.1) MOLECULAR FORMULA
    1) C21-H26-N2-S2 -HCl

Available Forms Sources

    A) FORMS
    1) Thioridazine is available as 10 mg, 25 mg, 50 mg and 100 mg tablets (Prod Info thioridazine hcl oral tablets, 2003; Prod Info thioridazine hcl oral tablets, 2002) and as a syrup containing 25 mg thioridazine/5ml.
    B) USES
    1) Thioridazine is a piperidine phenothiazine antipsychotic used in the treatment of schizophrenia. Because of its cardiotoxic potential, use is restricted to patients have failed to respond to other antipsychotics (Prod Info thioridazine hcl oral tablets, 2003).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Thioridazine is classified as a typical, low-potency antipsychotic. Structurally, it is piperidine subtype of the phenothiazine class of compounds. It is used to control the positive symptoms of schizophrenia: hallucinations, delusions, paranoia, and disorganized thought.
    B) PHARMACOLOGY: Thioridazine is a dopamine receptor antagonist (D2 subtype). Therapeutic effect is likely due to decreased dopaminergic neuron firing in the mesolimbic and mesocortical regions of the brain.
    C) TOXICOLOGY: Thioridazine has a tricyclic structure, and can block fast sodium channel blockade resulting in dysrhythmias and cardiovascular collapse. A high degree of alpha-1 adrenergic antagonism leads to hypotension secondary to peripheral vasodilation. Overdose and therapeutic use can result in anticholinergic symptoms; dry mucous membranes and tachycardia are most commonly seen. QT prolongation and torsade de pointes can result from binding to the potassium rectifier (1Kr) channels in the heart.
    D) EPIDEMIOLOGY: Thioridazine is rarely used today because of its adverse effects on the neurologic and cardiovascular systems. Overdose and therapeutic adverse reactions are now rare, but can be severe and fatalities have been reported.
    E) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: Mild anticholinergic symptoms are expected with therapeutic use, especially dry mouth. Extrapyramidal symptoms are strongly associated with thioridazine. These symptoms result from dopaminergic antagonism in the striatal pathways.
    2) EXTRAPYRAMIDAL SYMPTOMS: ACUTE DYSTONIA: Usually of the head and neck. Torticollis, grimacing, and tongue protrusion are common; laryngeal dystonia is rare but can be life-threatening. Onset: within a few hours of treatment initiation. AKATHISIA: Uncontrollable restlessness; typically occurs early in treatment. PARKINSONISM: Due to antagonism of dopaminergic neurons in the nigrostriatal pathways. TARDIVE DYSKINESIA: may be present. Chorea, dystonia, myoclonus, tics, and blepharospasms may also be present. NEUROLEPTIC MALIGNANT SYNDROME: It can develop due to abrupt reductions in striatal and hypothalamic dopamine transmission. More likely to develop with therapeutic use, not overdose. Signs and symptoms develop over a period of several days, usually within 2 weeks of starting treatment. Symptoms can be highly variable (wax and wane) over the course of the patient's illness.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Tachycardia and sedation are the main consequence of overdose. QT prolongation may develop.
    2) SEVERE TOXICITY: QRS widening, AV blocks, ventricular dysrhythmias (including torsades de pointes and recurrent ventricular tachycardia), hypotension, coma, pulmonary edema, and rarely renal failure and seizures may develop with severe poisoning. Refractory dysrhythmias and respiratory complications are the most common causes of death.
    0.2.20) REPRODUCTIVE
    A) Third-trimester antipsychotic drug exposure has been associated with extrapyramidal and/or withdrawal symptoms in neonates. The use of phenothiazines during human pregnancy has not resulted in increased fetal malformations over the incidence observed in the general population.

Laboratory Monitoring

    A) Monitor vital signs, mental status, and respiratory status.
    B) Institute continuous cardiac monitoring and obtain an ECG. Evaluate for QT prolongation and dysrhythmias.
    C) Monitor serum electrolyte, renal function, and creatine phosphokinase levels until all symptoms have resolved.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Acute dystonic reactions and akathisia should initially be treated with cessation of thioridazine. Antihistamines, especially benztropine, can be used to treat symptoms. Benztropine 2 mg IV or diphenhydramine 50 mg IV are generally sufficient. Parkinson symptoms can be treated with anticholinergic therapy or a dopamine agonist like levodopa/carbidopa and drug withdrawal. Mild acute overdoses can be managed with supportive care including telemetry monitoring for QRS prolongation and QT prolongation.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) ACUTE OVERDOSE: Impaired consciousness can lead to loss of airway reflexes requiring intubation. Dramatic anticholinergic toxicity can occur requiring sedation with benzodiazepines. Hypotension secondary to alpha adrenergic blockade usually responds well to IV fluids, add vasopressors, if hypotension persists. QRS prolongation should be treated with boluses of sodium bicarbonate (1 to 2 mEq/kg). QT prolongation should be treated with electrolyte repletion. Treat torsades de pointes with IV magnesium, add overdrive pacing if torsades de pointes persists. Seizures should be treated with standard doses of benzodiazepines, add propofol or barbiturates if seizures persist.
    C) DECONTAMINATION
    1) PREHOSPITAL: Prehospital decontamination is not indicated.
    2) HOSPITAL: Activated charcoal can be considered shortly after overdose in patients who can protect their airway
    D) AIRWAY MANAGEMENT
    1) Patients with mild CNS depression and normal respirations and airway reflexes should not be intubated prophylactically. Patients with more severe CNS depression or hemodynamic instability should be intubated. Patient's with NMS should be intubated as chest wall rigidity and severely altered mental status can occur.
    E) NEUROLEPTIC MALIGNANT SYNDROME
    1) NMS is the most severe manifestation of toxicity and may occur with therapeutic dosing. Supportive care is the most important element of treatment. Airway protection and volume resuscitation are usually necessary. Hyperthermia is multifactorial and will not respond to antipyretics. Submersion in an ice bath is the most rapidly efficient technique. Active cooling blankets, ice packs in the groin and axillae, and evaporative cooling with mist and fans may be more practical. Hypovolemia must be avoided to help prevent rhabdomyolysis-induced renal failure. Benzodiazepines are first-line therapy for NMS. Dantrolene and bromocriptine are of questionable benefit, but should be considered in severe cases where incremental benefit outweighs potential harm.
    F) TORSADES DE POINTES
    1) Correct electrolyte abnormalities (particularly hypokalemia, hypocalcemia, hypomagnesemia). Administer magnesium 1 to 2 g IV, may repeat a second 2 g dose and begin an infusion of 0.5 to 1 g (4 to 8 mEq) per hour for recurrent or persistent dysrhythmias. Institute overdrive pacing if TDP persists.
    G) ANTIDOTE
    1) No specific antidote exists, but benztropine should be used for acute extrapyramidal reactions. Levodopa/carbidopa and bromocriptine may improve parkinsonian symptoms. Hypertonic sodium bicarbonate should be administered for ventricular dysrhythmias.
    H) ENHANCED ELIMINATION
    1) Enhanced elimination is not indicated due to its large volume of distribution and high protein binding.
    I) PATIENT DISPOSITION
    1) HOME CRITERIA: Thioridazine has a narrow therapeutic index and toxicity has been reported at just above therapeutic doses (900 mg). Asymptomatic, otherwise healthy adults who inadvertently ingest a dose of less than 800 mg may be observed at home. Older adults or adults with significant co-morbidities should be referred for evaluation if the ingestion is more than 300 mg. Children who ingest less than 0.5 mg/kg may be observed at home.
    2) OBSERVATION CRITERIA: The following patients should be referred to a healthcare facility for evaluation and treatment: symptomatic patients, those with deliberate ingestions, adults who are elderly or with underlying health problems who ingest more than 300 mg; healthy adults who ingest 800 mg or more, and children who ingest 0.5 mg/kg or more. Patients without significant signs and symptoms can likely be discharged after a 6 hour observation period.
    3) ADMISSION CRITERIA: Patients with severe CNS depression, and/or coingestion of other more toxic symptoms may require admission. Patients with QRS/QT prolongation, neuromuscular symptoms or hyperthermia warrant ICU admission.
    4) CONSULT CRITERIA: Patients with signs and symptoms of severe toxicity warrant admission and toxicologic consult.
    J) PITFALLS
    1) The main pitfall is failure to recognize the progression of NMS as worsening psychosis.
    K) PHARMACOKINETICS
    1) Rapid absorption occurs after oral dosing. Peak concentrations are reached 2 hours after ingestion. Volume of distribution is 18 L/kg. Protein binding is 96%. It has a half-life of 26 to 36 hours. There are active metabolites that are not thought to contribute significantly to toxicity or clinical effect.
    L) TOXICOKINETICS
    1) In overdose, the duration of effects and absorption are prolonged due to antimuscarinic effects.
    M) PREDISPOSING CONDITIONS
    1) Toxicity is more frequent in patients with advanced age, ethanol use, affective disorder, prior electroconvulsive therapy, diabetes mellitus, and a myriad of genetic factors. Patients with an underlying long QT and those with concomitant ingestion of other drugs that prolong the QT are at increased risk for dysrhythmias.
    N) DIFFERENTIAL DIAGNOSIS
    1) Serotonin syndrome, worsening psychosis, lithium toxicity, and tricyclic antidepressant toxicity.

Range Of Toxicity

    A) TOXIC DOSE: ADULT: In adults, 300 mg has been lethal in patients with concomitant predisposing conditions (eg, cardiovascular disease, electrolyte derangements), and 900 mg was the lowest lethal dose in patients without underlying risk factors. Adults have developed severe cardiac toxicity but survived after ingestions of 1 to 16 grams. PEDIATRIC: A 3-year-old developed CNS depression but recovered after ingesting 100 mg.
    B) THERAPEUTIC DOSE: ADULT: 200 to 800 mg daily. PEDIATRIC: Initial Dose: 0.5 mg/kg/day in divided doses. Dosage may be gradually increased up to a maximum of 3 mg/kg/day in divided doses, if needed.

Clinical Effects

Summary Of Exposure

    A) USES: Thioridazine is classified as a typical, low-potency antipsychotic. Structurally, it is piperidine subtype of the phenothiazine class of compounds. It is used to control the positive symptoms of schizophrenia: hallucinations, delusions, paranoia, and disorganized thought.
    B) PHARMACOLOGY: Thioridazine is a dopamine receptor antagonist (D2 subtype). Therapeutic effect is likely due to decreased dopaminergic neuron firing in the mesolimbic and mesocortical regions of the brain.
    C) TOXICOLOGY: Thioridazine has a tricyclic structure, and can block fast sodium channel blockade resulting in dysrhythmias and cardiovascular collapse. A high degree of alpha-1 adrenergic antagonism leads to hypotension secondary to peripheral vasodilation. Overdose and therapeutic use can result in anticholinergic symptoms; dry mucous membranes and tachycardia are most commonly seen. QT prolongation and torsade de pointes can result from binding to the potassium rectifier (1Kr) channels in the heart.
    D) EPIDEMIOLOGY: Thioridazine is rarely used today because of its adverse effects on the neurologic and cardiovascular systems. Overdose and therapeutic adverse reactions are now rare, but can be severe and fatalities have been reported.
    E) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: Mild anticholinergic symptoms are expected with therapeutic use, especially dry mouth. Extrapyramidal symptoms are strongly associated with thioridazine. These symptoms result from dopaminergic antagonism in the striatal pathways.
    2) EXTRAPYRAMIDAL SYMPTOMS: ACUTE DYSTONIA: Usually of the head and neck. Torticollis, grimacing, and tongue protrusion are common; laryngeal dystonia is rare but can be life-threatening. Onset: within a few hours of treatment initiation. AKATHISIA: Uncontrollable restlessness; typically occurs early in treatment. PARKINSONISM: Due to antagonism of dopaminergic neurons in the nigrostriatal pathways. TARDIVE DYSKINESIA: may be present. Chorea, dystonia, myoclonus, tics, and blepharospasms may also be present. NEUROLEPTIC MALIGNANT SYNDROME: It can develop due to abrupt reductions in striatal and hypothalamic dopamine transmission. More likely to develop with therapeutic use, not overdose. Signs and symptoms develop over a period of several days, usually within 2 weeks of starting treatment. Symptoms can be highly variable (wax and wane) over the course of the patient's illness.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Tachycardia and sedation are the main consequence of overdose. QT prolongation may develop.
    2) SEVERE TOXICITY: QRS widening, AV blocks, ventricular dysrhythmias (including torsades de pointes and recurrent ventricular tachycardia), hypotension, coma, pulmonary edema, and rarely renal failure and seizures may develop with severe poisoning. Refractory dysrhythmias and respiratory complications are the most common causes of death.

Vital Signs

    3.3.3) TEMPERATURE
    A) WITH POISONING/EXPOSURE
    1) Hyperthermia is associated with the development of the neuromuscular malignant syndrome (NMS) (Baker et al, 1988). Hypothermia (Annane et al, 1996) has been reported rarely with thioridazine overdose.
    3.3.4) BLOOD PRESSURE
    A) WITH POISONING/EXPOSURE
    1) Reported incidence of hypotension in 159 patients who overdosed on thioridazine was 12% (Blaye et al, 1993). Elderly patients may be particularly predisposed to this effect (McCarthy et al, 1986).
    2) Hypertension may occur with thioridazine overdose (Baker et al, 1988).

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) Thioridazine has produced pigmentary retinopathy with visual impairment. This effect appears to be dose related. Patients develop pigmentary changes within 2 to 8 weeks after initiation of therapy with acute symptoms including blurred vision, night blindness, and partial color blindness. After thioridazine is discontinued, pigmentary changes may still progress, however, visual function usually improves. Thioridazine appears to bind to the melanin granules in the retinal pigment epithelium which alters retinal enzyme kinetics (Shah et al, 1998). The manufacturer cautions not to exceed a maximum daily dose of 800 mg/day to avoid this adverse effect (Prod Info Mellaril(R), 2002).
    2) Thioridazine (TDZ) toxicity to the eye has been described as "progressive chorioretinopathy", but this designation can be misleading. During the first year after TDZ exposure, retinal pigmentation evolves from a granular to a patchy or nummular appearance. However, visual function and the electroretinogram typically improve during this period. Some cases may show chorioretinal atrophy and functional loss many years later, but there is little evidence for drug-related progression. Late atrophy may represent degeneration of cells that were injured subclinically during the time of initial drug exposure. Although TDZ toxicity produces an evolving pigmentary disturbance, functional changes must be monitored independently of fundus appearance (Marmor, 1990).
    3) Measurement of the oscillatory potentials of the electroretinogram (ERG) and the O2 wavelet may be necessary to detect early changes of the retina caused by thioridazine therapy. The investigators feel a daily dosage of 160 mg over the long term or 400 mg for shorter periods are critical levels of drug administration (Miyata et al, 1980).
    4) A 28-year-old woman experienced decreased vision in both eyes for 2 weeks after receiving thioridazine 800 mg 4 times daily for 8 weeks. Her dilated fundus revealed a diffuse pigmentary retinopathy of the entire post-equatorial fundus. With fluorescein angiography, confluent areas of punctate hyperfluorescence consistent with diffuse retinal pigment epithelial alterations were seen (Shah et al, 1998)
    5) Three cases of NUMMULAR RETINOPATHY caused by thioridazine were reported. This retinopathy is a clinical subset of classic thioridazine pigmentation retinopathy. Nummular areas of retinal pigment epithelial atrophy separated by relatively intact pigment epithelium are found in the midretinal periphery with sparing of central vision. This can occur with doses of thioridazine previously considered safe (Kozy et al, 1984). Severe nummular retinopathy and visual dysfunction were reported in a 52-year-old man with paranoid schizophrenia taking thioridazine 200 mg or less, over the past 13 years (Tekell et al, 1996).
    6) A 51-year-old woman developed pigmentation retinopathy after taking 400 to 800 mg thioridazine for 2 months. This is below the 800 mg ceiling dose recommended by the manufacturer and suggests that clinicians should carefully investigate visual complaints of patients taking thioridazine in the upper end of the approved dosage range (Hamilton, 1985).
    B) WITH POISONING/EXPOSURE
    1) Mydriasis has been reported in patients with severe thioridazine overdose (Hollow et al, 1974; Annane et al, 1996).
    2) CASE REPORT: A 29-year-old man intentionally ingested over 1500 mg of thioridazine with alcohol and was admitted unconscious. He awoke the following day and left the hospital against medical advise. Eleven days later he complained to his primary care physician of decreased vision and developed acute vision loss. Testing showed a visual acuity of 3/60 (right eye) and 2/60 (left eye) with a fundoscopic exam consistent with central retinal artery nonperfusion, likely due to an acute episode of hypotension secondary to thioridazine. The patient again failed to return for follow-up care (Anderton & Bishop, 2001).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) TACHYCARDIA
    1) WITH POISONING/EXPOSURE
    a) Tachycardia is common after thioridazine overdose. Tachycardia developed in 48% of 97 patients with thioridazine overdose in one series (Buckley et al, 1995), and in 22 of 223 patients in another series (Blaye et al, 1993).
    B) PROLONGED QT INTERVAL
    1) WITH THERAPEUTIC USE
    a) THIORIDAZINE lengthens the QT-interval in a dose-related manner, and drugs with this potential, including THIORIDAZINE, have been associated with dysrhythmias of the torsades de pointes-type and sudden death. In 9 healthy men, QT-interval increased by 23 milliseconds following a 50-mg dose of thioridazine (Prod Info Mellaril(R), 2000).
    b) Thioridazine use was associated with a significant risk for QT-interval prolongation in patients on psychotropic medications, with an odds ratio of 5.4 linking thioridazine therapy with QT-interval abnormalities (p less than 0.001). This conclusion was based on a study using logistic regression and backwards step-wise regression to determine risk factors for QT-interval lengthening in patients enrolled in psychiatric treatment programs (n=495). Overall, 64 of 495 patients were taking thioridazine. Of the 64 thioridazine-users, 15 (almost 25%) were found to have abnormally lengthened QT-intervals (456 ms or greater). Two of the 4 thioridazine-treated patients taking 600 mg/day or more had abnormally prolonged QTc-intervals (Reilly et al, 2000).
    c) Due to the association between thioridazine therapy and QT interval prolongation, the U.S. Food and Drug Administration requested a labeling change as of July 2000, such that use of thioridazine should be reserved for schizophrenic patients who have failed to respond to other antipsychotic agents. Occasionally, prolongation of the QT interval has led to the development of torsades de pointes (Kiriike et al, 1987).
    2) WITH POISONING/EXPOSURE
    a) In a series of 223 cases of acute thioridazine overdose reported to the manufacturer, Sandoz Pharma Ltd, through January 1992, 17 patients developed prolonged QT interval and many of these went on to develop ventricular tachycardia or fibrillation (Blaye et al, 1993).
    b) In a series of 97 patients with thioridazine overdose, 10% had a prolonged QT interval (> 450 msec) and 60% had a prolonged QT interval (Buckley et al, 1995).
    c) In a study of 36 patients with thioridazine overdose, there was a correlation between the stated dose ingested and both the extent of QT interval prolongation and the heart rate (Strachan et al, 2004).
    C) VENTRICULAR ARRHYTHMIA
    1) WITH THERAPEUTIC USE
    a) In a case control study of psychiatric inpatients who died suddenly, current treatment with thioridazine was associated with unexpected death (adjusted odds ration 5.3, 95% CI 1.7 to 16.2) (Reilly et al, 2002). The mechanism was thought to be thioridazine-induced dysrhythmia.
    2) WITH POISONING/EXPOSURE
    a) In a series of 223 cases of acute thioridazine overdose reported to the manufacturer, Sandoz Pharma Ltd, through January 1992, 23 patients developed ventricular tachycardia (VT) or fibrillation (VF), and one patient developed torsades de pointes (Blaye et al, 1993). Nine of these patients had isolated VT or VF without other associated ECG changes; the mean dose ingested by this group was 12 grams.
    b) In a series of 97 patients with thioridazine overdose, 5 patients developed ventricular dysrhythmias, 2 of whom also had QRS widening and 4 of whom had prolonged QT intervals. Onset of dysrhythmia was late in some patients, with the range being 1 to 18 hours after overdose (Buckley et al, 1995).
    c) CASE REPORT: A 35-year-old woman on flunitrazepam, cyamerazine and thioridazine, presented comatose, hypoxic and hypothermic after ingesting 1 gram thioridazine (Annane et al, 1996). Initial ECG showed sinus tachycardia with QRS widening (120 msec) and prolonged QT (450 msec). She was intubated and ventilated, and received intravenous sodium bicarbonate. Three hours after admission she developed ventricular tachycardia (VT) requiring defibrillation. She received amiodarone and developed torsades de pointes; amiodarone was discontinued and cardiac pacing was commenced. Over the next 36 hour she had repeated episodes of VT and hypotension unresponsive to intravenous lidocaine and sodium bicarbonate, and was cardioverted nearly 100 times. She ultimately recovered.
    d) CASE REPORT: A 52-year-old woman developed multiple dysrhythmias and ECG abnormalities after thioridazine overdose, including nodal rhythm with multifocal premature ventricular contractions, ventricular tachycardia, ventricular fibrillation, prolonged QT interval, bifid T waves, U waves, and wide bizarre QRS complexes (Hollow et al, 1974). She recovered with supportive care.
    e) CASE REPORT: A 68-year-old man who ingested 16 g of sustained release thioridazine developed multiple dysrhythmias and ECG abnormalities including wide QRS complexes, QT prolongation, bigeminy, torsades de pointes, ventricular tachycardia, and junctional rhythm (Schmidt & Lang, 1997). He recovered with intensive supportive care.
    D) ATRIOVENTRICULAR BLOCK
    1) WITH POISONING/EXPOSURE
    a) In a series of 223 cases of acute thioridazine overdose reported to the manufacturer, Sandoz Pharma Ltd, through January 1992, 5 patients developed 3rd degree AV block, 10 developed 1st or 2nd degree AV block, and 10 had bundle branch block. Patients with 3rd degree AV block had a mortality rate of 60%. These conduction disturbances were generally associated with ingestion of more than 2 g thioridazine, and were often associated with the development of ventricular dysrhythmias (Blaye et al, 1993).
    b) CASE REPORT: A 72-year-old woman ingested 3 g of thioridazine and 60 tablets of acetaminophen 325 mg/codeine 30 mg. She presented to the ED the following day comatose, with a pulse of 48 in 3rd degree AV block with a prolonged QT interval of 0.52 seconds (Hulisz et al, 1994). She developed multiple premature ventricular contractions, ventricular bigeminy, and a non-sustained episode of torsades de pointes. She was treated with isoproterenol, magnesium and external pacing; within 40 hours of admission her dysrhythmias resolved and she recovered.
    c) CASE REPORT: A 68-year-old man ingested approximately 16 g of slow-release thioridazine tablets in a suicide attempt. Approximately 17 hours postingestion, the patient developed an atrioventricular junctional escape rhythm that resolved upon implantation of an atrial pacemaker (Schmidt & Lang, 1997).
    E) HYPOTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) In a series of 223 cases of acute thioridazine overdose reported to the manufacturer, Sandoz Pharma Ltd, through January 1992, 19 patients developed hypotension (Blaye et al, 1993).
    b) In a series of 97 patients with thioridazine overdose, 10% developed hypotension (Buckley et al, 1995).
    c) Progressive hypotension occurred in a 68-year-old man approximately 17 hours after intentionally ingesting 16 g of slow-release thioridazine tablets. The hypotension resolved following implantation of an atrial pacemaker (Schmidt & Lang, 1997).
    F) TORSADES DE POINTES
    1) WITH THERAPEUTIC USE
    a) Atypical ventricular tachycardia (torsades de pointes), presumably secondary to thioridazine, was reported in a 53-year-old man and was successfully treated with isoproterenol infusion after unsuccessful use of other agents (Kemper et al, 1983).
    b) A 56-year-old schizophrenic patient receiving thioridazine, trifluoperazine, and benztropine experienced syncope (Raehl et al, 1985). The patient experienced episodes of ventricular tachycardia with multifocal PVCs and torsades de pointes.
    c) A patient had a preexisting prolonged QT interval that led to the development of potentially fatal ventricular arrhythmia (torsades de pointes) during low-dose, short-term therapy with thioridazine. The recurrent ventricular tachyarrhythmia was exacerbated by lidocaine and procainamide therapy but was effectively controlled by cardiac pacing (Kiriike et al, 1987).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 68-year-old man developed widened QRS complexes, a prolonged QT interval, ventricular dysrhythmias, including ventricular tachycardia and torsades de pointes, and ventricular flutter requiring repeated cardioversion approximately 17 hours after intentionally ingesting 16 g of thioridazine slow-release tablets. The dysrhythmias resolved following administration of physostigmine (Schmidt & Lang, 1997).
    G) ELECTROCARDIOGRAM ABNORMAL
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 58-year-old woman presented comatose, with muscular rigidity, opisthotonus, and external rotation of her upper limbs in response to pain. Initial ECG showed a prolonged QT interval. ECG the following day showed Brugada-like abnormalities which resolved over the next 72 hours. Serum thioridazine on the 4th day of admission was 1.48 mcg/mL (therapeutic up to 2 mcg/dL) (Copetti et al, 2005).
    H) HYPERTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 43-year-old man developed hypertension, hyperreflexia, coma, clonus, myoclonus, increased muscle tone, and upgoing plantar reflexes without evidence of seizure activity on EEG after thioridazine overdose (Baker et al, 1988). He became hyperthermic about 10 hours after admission. Serum thioridazine concentration was 8763 ng/mL (therapeutic 250 to 1250 ng/mL) and plasma catecholamine concentrations were elevated (norepinephrine 4,500 pg/mL and epinephrine 103 pg/mL, normal 40 to 400 pg/mL and 30 to 100 pg/mL respectively). He recovered with supportive care, and blood pressure returned to normal.

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) ACUTE LUNG INJURY
    1) WITH POISONING/EXPOSURE
    a) Pulmonary edema has been reported in patients with severe thioridazine overdose. It often develops in conjunction with dysrhythmias and is associated with a higher mortality rate (Blaye et al, 1993).
    B) ASPIRATION PNEUMONIA
    1) WITH POISONING/EXPOSURE
    a) Aspiration pneumonia has developed in patients with severe thioridazine overdose (Annane et al, 1996; Blaye et al, 1993).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) DISTURBANCE OF CONSCIOUSNESS
    1) WITH POISONING/EXPOSURE
    a) CASE SERIES
    1) In a series of 223 cases of acute thioridazine overdose reported to the manufacturer, Sandoz Pharma Ltd, through January 1992, 98 patients developed some disturbance in the level of consciousness (Blaye et al, 1993).
    2) In a series of 97 patients with acute thioridazine overdose, 14% were stuporous, and 4% developed coma (Buckley et al, 1995).
    3) In a retrospective analysis of 141 adult thioridazine single drug ingestions, the most frequent symptoms of toxicity, were drowsiness and sinus tachycardia (Schurch et al, 1996). Drowsiness occurred after ingestion of 1225 mg (median; range 100 to 5000 mg) and sinus tachycardia occurred after ingestion of 1125 mg (median; range 250 to 8000 mg). The most frequent symptom of intoxication in 61 pediatric cases was drowsiness, which occurred after a median thioridazine ingestion of 4 mg/kg (range 2.2 to 27 mg/kg).
    b) CASE REPORTS
    1) ADULT: A 29-year-old man intentionally ingested over 1500 mg of thioridazine with alcohol and was admitted unconscious. The patient left the hospital the following morning without any further medical care. Eleven days later he complained to his primary care physician of decreased vision and developed acute vision loss. Once again he failed to return for follow-up care (Anderton & Bishop, 2001)
    2) PEDIATRIC: A 3-year-old boy with bronchitis was inadvertently given a 100 mg dose of thioridazine (due to a compounding error) and complained of drowsiness and became unconscious. His Glasgow coma score was 12 (E3, V4, M5) on admission. Vital signs included sinus tachycardia (heart rate: 148 beats/min) along with tachypnea (respiratory rate: 40 breaths/min); no dysrhythmias or QT prolongation. Gastric lavage was started. A head CT showed mild diffuse edema that was treated with 10% glycerol (100 mL) and 10 mg of furosemide. He awoke 18 hours later. The patient was neurologically stable but remained hospitalized for several days for antibiotic therapy secondary to bronchitis. A serum thioridazine level of 1124.5 ng/mL was found on admission (Kato et al, 2009).
    B) SEIZURE
    1) WITH POISONING/EXPOSURE
    a) In a series of 223 cases of acute thioridazine overdose (200 of them adults) reported to the manufacturer, Sandoz Pharma Ltd, through January 1992, 5 adults developed seizures, all of whom had ingested more than 2 g thioridazine (Blaye et al, 1993).
    b) In a series of 97 patients with acute thioridazine overdose, 2% developed seizures (Buckley et al, 1995).
    C) INCREASED MUSCLE TONE
    1) WITH POISONING/EXPOSURE
    a) SUMMARY: Patients have developed rigidity and hyperreflexia with myoclonic jerking following thioridazine overdose (Baker et al, 1988).
    b) CASE REPORT: A 43-year-old man developed hypertension, hyperreflexia, coma, clonus, myoclonus, increased muscle tone, and upgoing plantar reflexes without evidence of seizure activity on EEG after thioridazine overdose (Baker et al, 1988). He became hyperthermic about 10 hours after admission. Cranial CT and results of lumbar puncture were normal. Serum thioridazine concentration was 8763 ng/mL (therapeutic 250 to 1250 ng/mL) and plasma catecholamine concentrations were elevated (norepinephrine 4,500 pg/mL and epinephrine 103 pg/mL; normal 40 to 400 pg/mL and 30 to 100 pg/mL respectively). He recovered with supportive care.
    c) CASE REPORT: A 58-year-old woman presented in coma with muscular rigidity, opisthotonus, and external rotation of her upper limbs in response to pain. Cranial CT and results of lumbar puncture were normal. Thioridazine concentration on the fourth day of hospitalization was 148 mcg/mL (therapeutic up to 2 mcg/dL) (Copetti et al, 2005).
    D) DYSTONIA
    1) WITH THERAPEUTIC USE
    a) The most common neurologic adverse drug reaction with thioridazine is akathisia. Restlessness, agitation, and tremor also occur. Tardive dyskinesia has been reported after long-term therapeutic use (Prod Info thioridazine hcl oral tablets, 2003; Kumar, 1976)
    2) WITH POISONING/EXPOSURE
    a) Extrapyramidal symptoms occurred in 16% of 159 patients with acute thioridazine overdose (Blaye et al, 1993). Acute dystonias may involve oculogyric crisis, torticollis, trismus, and/or opisthotonus (Prod Info thioridazine hcl oral tablets, 2003).
    b) CASE REPORT: An 8-year-old boy experienced a dystonic reaction after receiving an unintentional overdose ingestion of 10 mL thioridazine syrup (5 mg/mL) twice daily for 4 doses (prescribed dose was 2 mL twice daily) (Smolinske & Larson, 2000).
    E) NEUROLEPTIC MALIGNANT SYNDROME
    1) WITH THERAPEUTIC USE
    a) A case of neuroleptic malignant syndrome (NMS) was reported in a 70-year-old psychiatric patient who had taken 100 to 300 mg of thioridazine per day for 18 months (Twemlow & Bair, 1983).
    b) Neuroleptic malignant syndrome was described in a 22-year-old woman with psychosis following an increase of her dose of thioridazine to 75 mg daily (Zammit & Sullivan, 1987). The patient responded initially to withdrawal of thioridazine, however haloperidol administration for 1 day was followed by return of symptoms. Withdrawal of haloperidol resulted in stabilization.

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) RENAL FAILURE SYNDROME
    1) WITH POISONING/EXPOSURE
    a) In a series of 223 cases of acute thioridazine overdose reported to the manufacturer, Sandoz Pharma Ltd, through January 1992, 6 patients developed oliguria and/or uremia. Renal failure was associated with a higher mortality rate, and is likely secondary to hypoperfusion and hemodynamic instability (Blaye et al, 1993).
    B) PRIAPISM
    1) WITH THERAPEUTIC USE
    a) Four men, age range 20 to 40 years, treated with oral thioridazine 100 mg 4 times/day developed histories of priapism which persisted for 1 to 2 days. All patients were treated with corporeal aspiration and corpus cavernosum-corpus spongiosum shunts with good results. The authors postulated the mechanism to be due to peripheral adrenergic blockade (Dorman & Schmidt, 1976).
    b) An 11-year-old boy receiving thioridazine for attention deficit disorder presented to the emergency room with priapism 30 hours in duration. He was treated with intracorporeal phenylephrine with good results (Siegel & Reda, 1997).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) AGRANULOCYTOSIS
    1) WITH THERAPEUTIC USE
    a) There is a risk of agranulocytosis with therapeutic use. This risk appears to be greatest among the elderly (Prod Info thioridazine hcl oral tablets, 2003).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) RHABDOMYOLYSIS
    1) WITH POISONING/EXPOSURE
    a) Mild rhabdomyolysis has been reported after thioridazine overdose (Annane et al, 1996), and may develop in patients with prolonged coma, muscle rigidity, hyperthermia, or seizures .
    b) CASE REPORT: A 22-year-old man intentionally ingested 9.4g thioridazine and presented with difficulty walking, speaking and moving his arms. He reported no other drug use. Ataxia and dysarthria were present and attributable to general muscle weakness. He did not develop seizures, coma or features of NMS. Serum creatinine kinase was 32,620 International Units/L and myoglobinuria. Gastric lavage and activated charcoal were given. Treatment included IV fluids, mannitol and sodium bicarbonate. Within one week, laboratory results were normal and muscle tenderness and weakness had resolved (Nankivell et al, 1994).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) SYNDROME OF INAPPROPRIATE VASOPRESSIN SECRETION
    1) WITH THERAPEUTIC USE
    a) SIADH was reported in a 42-year-old man receiving thioridazine 400 mg daily. The patient presented with symptoms of hyponatremia (serum sodium of 113 mEq/L), metabolic alkalosis, and coma. The sodium level returned to normal following discontinuation of thioridazine and supportive therapy, which included a normal saline infusion. The patient had similar hyponatremic episodes with other phenothiazine derivatives (Ananth & Lin, 1986).
    b) A 58-year-old woman with chronic depression became acutely agitated and received 500 mg of thioridazine within an hour. It was noted that her water consumption increased during a 9-hour period. The patient was found unresponsive with intermittent seizure activity. Serum sodium was 114 mEq/L, while plasma and urine osmolality were 235 and 512 mOsm/kg, respectively. Fluid restriction improved the signs and symptoms of SIADH (Vincent & Emery, 1978).
    c) One case of syndrome of inappropriate antidiuretic hormone secretion (SIADH) was reported in a 60-year-old schizophrenic patient who received thioridazine 150 mg/day for several months. The patient was comatose, with a serum sodium of 112 mEq/L, urine sodium of 17 mEq/L, and serum and urine osmolality of 239 and 257 mOsm/kg, respectively. The patient was treated with fluid restriction, regained consciousness, and was subsequently discharged (Matuk & Kalyanaraman, 1977).

Reproductive

    3.20.1) SUMMARY
    A) Third-trimester antipsychotic drug exposure has been associated with extrapyramidal and/or withdrawal symptoms in neonates. The use of phenothiazines during human pregnancy has not resulted in increased fetal malformations over the incidence observed in the general population.
    3.20.3) EFFECTS IN PREGNANCY
    A) LACK OF INFORMATION
    1) Although phenothiazines have been implicated in several cases of congenital malformations (Freeman, 1972; Rafla, 1987), establishing a definite cause-effect relationship is extremely difficult; the incidence of malformations does not appear to be greater than that seen in the general population. Most studies have found phenothiazines to be safe for both mother and fetus if used in low doses during pregnancy (Ayd, 1976; Kris, 1965; Miklovich & van den Berg, 1976).
    B) EXTRAPYRAMIDAL AND/OR WITHDRAWAL SYMPTOMS
    1) Maternal use of antipsychotic drugs during the third trimester of pregnancy has been associated with an increased risk of neonatal extrapyramidal and/or withdrawal symptoms (eg, agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder) following delivery. Severity of these adverse effects have ranged from cases that are self-limiting to cases that required prolonged periods of hospitalization and ICU care (Prod Info thioridazine HCl oral tablet, 2010).
    2) Extrapyramidal symptoms, including hypertonia, tremor, and abnormal hand posturing, which resolved between 10 and 22 months of age, were reported in an infant maternally exposed to thioridazine, trifluoperazine, and chlorpromazine (Hill et al, 1966).
    C) LACK OF EFFECT
    1) In pooled data of 2948 women exposed to phenothiazines during pregnancy, no increased risk for fetal malformations was demonstrated (relative risk, 1.03; 95% confidence interval, 0.88 to 1.22). One study did show a relationship between phenothiazine use and teratogenicity, but the study had many confounders (Magee et al, 2002).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) No reports describing the use of thioridazine during human lactation are available and the effects on the nursing infant from exposure to the drug in milk are unknown.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs, mental status, and respiratory status.
    B) Institute continuous cardiac monitoring and obtain an ECG. Evaluate for QT prolongation and dysrhythmias.
    C) Monitor serum electrolyte, renal function, and creatine phosphokinase levels until all symptoms have resolved.

Methods

    A) FALSE POSITIVE TRICYCLIC ANTIDEPRESSANT ASSAY
    1) Thioridazine, at serum concentrations of 125 ng/mL or greater, has been found to cause false positive results using the DuPont Automatic Clinical Analyzer serum tricyclic antidepressant screen (Ryder & Glick, 1986).
    2) Thioridazine, at a 4000 nanomolar serum concentration, was found to cause a false positive using the Syva EMIT assay for serum tricyclic antidepressants (Benitez et al, 1986).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients with severe CNS depression, and/or coingestion of other more toxic symptoms may require admission. Patients with QRS/QT prolongation, neuromuscular symptoms or hyperthermia warrant ICU admission.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Thioridazine has a narrow therapeutic index and toxicity has been reported at just above therapeutic doses (900 mg). Asymptomatic, otherwise healthy adults who inadvertently ingest a dose of less than 800 mg may be observed at home. Older adults or adults with significant co-morbidities should be referred for evaluation if the ingestion is more than 300 mg. Children who ingest less than 0.5 mg/kg may be observed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Patients with signs and symptoms of severe toxicity warrant admission and toxicologic consult.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) The following patients should be referred to a healthcare facility for evaluation and treatment: symptomatic patients, those with deliberate ingestions, adults who are elderly or with underlying health problems who ingest more than 300 mg; healthy adults who ingest 800 mg or more, and children who ingest 0.5 mg/kg or more. Patients without significant signs and symptoms can likely be discharged after a 6 hour observation period.

Monitoring

    A) Monitor vital signs, mental status, and respiratory status.
    B) Institute continuous cardiac monitoring and obtain an ECG. Evaluate for QT prolongation and dysrhythmias.
    C) Monitor serum electrolyte, renal function, and creatine phosphokinase levels until all symptoms have resolved.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Prehospital decontamination is not indicated because of the potential risk of aspiration.
    6.5.2) PREVENTION OF ABSORPTION
    A) Perform endotracheal intubation for airway protection prior to any attempt at GI decontamination in patients with mental status depression, seizures, or hemodynamic instability.
    B) CHARCOAL ADMINISTRATION
    1) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    C) CHARCOAL DOSE
    1) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    a) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    2) ADVERSE EFFECTS/CONTRAINDICATIONS
    a) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    b) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    D) INDICATIONS: Consider gastric lavage with a large-bore orogastric tube (ADULT: 36 to 40 French or 30 English gauge tube {external diameter 12 to 13.3 mm}; CHILD: 24 to 28 French {diameter 7.8 to 9.3 mm}) after a potentially life threatening ingestion if it can be performed soon after ingestion (generally within 60 minutes).
    1) Consider lavage more than 60 minutes after ingestion of sustained-release formulations and substances known to form bezoars or concretions.
    E) PRECAUTIONS:
    1) SEIZURE CONTROL: Is mandatory prior to gastric lavage.
    2) AIRWAY PROTECTION: Place patients in the head down left lateral decubitus position, with suction available. Patients with depressed mental status should be intubated with a cuffed endotracheal tube prior to lavage.
    F) LAVAGE FLUID:
    1) Use small aliquots of liquid. Lavage with 200 to 300 milliliters warm tap water (preferably 38 degrees Celsius) or saline per wash (in older children or adults) and 10 milliliters/kilogram body weight of normal saline in young children(Vale et al, 2004) and repeat until lavage return is clear.
    2) The volume of lavage return should approximate amount of fluid given to avoid fluid-electrolyte imbalance.
    3) CAUTION: Water should be avoided in young children because of the risk of electrolyte imbalance and water intoxication. Warm fluids avoid the risk of hypothermia in very young children and the elderly.
    G) COMPLICATIONS:
    1) Complications of gastric lavage have included: aspiration pneumonia, hypoxia, hypercapnia, mechanical injury to the throat, esophagus, or stomach, fluid and electrolyte imbalance (Vale, 1997). Combative patients may be at greater risk for complications (Caravati et al, 2001).
    2) Gastric lavage can cause significant morbidity; it should NOT be performed routinely in all poisoned patients (Vale, 1997).
    H) CONTRAINDICATIONS:
    1) Loss of airway protective reflexes or decreased level of consciousness if patient is not intubated, following ingestion of corrosive substances, hydrocarbons (high aspiration potential), patients at risk of hemorrhage or gastrointestinal perforation, or trivial or non-toxic ingestion.
    6.5.3) TREATMENT
    A) AIRWAY MANAGEMENT
    1) Perform endotracheal intubation in any patient with depressed mental status, seizures, or hemodynamic instability.
    B) MONITORING OF PATIENT
    1) Monitor vital signs and mental status. Institute continuous cardiac monitoring and obtain an ECG. Monitor serum electrolytes, renal function and creatine phosphokinase levels should be monitored until all symptoms resolve.
    C) HYPOTENSIVE EPISODE
    1) Administer intravenous 0.9% saline 10 to 20 ml/kg. If pressors are needed pure alpha agonists such as phenylephrine, metaraminol or levarterenol are preferred. Agents with mixed alpha and beta agonist effects may worsen hypotension.
    2) PHENYLEPHRINE
    a) MILD OR MODERATE HYPOTENSION
    1) INTRAVENOUS: ADULT: Usual dose: 0.2 mg; range: 0.1 mg to 0.5 mg. Maximum initial dose is 0.5 mg. A 0.5 mg IV dose can elevate the blood pressure for approximately 15 min (Prod Info phenylephrine HCl subcutaneous injection, intramuscular injection, intravenous injection, 2011). PEDIATRIC: Usual bolus dose: 5 to 20 mcg/kg IV repeated every 10 to 15 min as needed (Taketomo et al, 1997).
    b) CONTINUOUS INFUSION
    1) PREPARATION: Add 10 mg (1 mL of a 1% solution) to 500 mL of normal saline or dextrose 5% in water to produce a final concentration of 0.2 mg/mL.
    2) ADULT DOSE: To raise blood pressure rapidly; start an initial infusion of 100 to 180 mcg/min until blood pressure stabilizes; then reduce infusion to 40 to 60 mcg/min titrated to desired effect. If necessary, additional doses in increments of 10 mg or more may be added to the infusion solution and the rate of flow titrated to the desired effect (Prod Info phenylephrine HCl subcutaneous injection, intramuscular injection, intravenous injection, 2011).
    3) PEDIATRIC DOSE: Intravenous infusion should begin at 0.1 to 0.5 mcg/kg/min; titrate to the desired effect (Taketomo et al, 1997).
    c) ADVERSE EFFECTS
    1) Headache, reflex bradycardia, excitability, restlessness and rarely dysrhythmias may develop (Prod Info phenylephrine HCl subcutaneous injection, intramuscular injection, intravenous injection, 2011).
    D) VENTRICULAR ARRHYTHMIA
    1) Defibrillate unstable rhythms. Correct electrolyte imbalances. Administer sodium bicarbonate. Lidocaine may be used but is often ineffective. Avoid disopyramide, procainamide, and quinidine as they may worsen QT prolongation and subsequent dysrhythmias.
    2) Administer sodium bicarbonate, 1 to 2 mEq/kg as a bolus. Monitor QRS complex duration and repeat as necessary. Monitor arterial blood gases, goal is pH of 7.45 to 7.55.
    3) LIDOCAINE/DOSE
    a) ADULT: 1 to 1.5 milligrams/kilogram via intravenous push. For refractory VT/VF an additional bolus of 0.5 to 0.75 milligram/kilogram can be given at 5 to 10 minute intervals to a maximum dose of 3 milligrams/kilogram (Neumar et al, 2010). Only bolus therapy is recommended during cardiac arrest.
    1) Once circulation has been restored begin a maintenance infusion of 1 to 4 milligrams per minute. If dysrhythmias recur during infusion repeat 0.5 milligram/kilogram bolus and increase the infusion rate incrementally (maximal infusion rate is 4 milligrams/minute) (Neumar et al, 2010).
    b) CHILD: 1 milligram/kilogram initial bolus IV/IO; followed by a continuous infusion of 20 to 50 micrograms/kilogram/minute (de Caen et al, 2015).
    4) LIDOCAINE/MAJOR ADVERSE REACTIONS
    a) Paresthesias; muscle twitching; confusion; slurred speech; seizures; respiratory depression or arrest; bradycardia; coma. May cause significant AV block or worsen pre-existing block. Prophylactic pacemaker may be required in the face of bifascicular, second degree, or third degree heart block (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010).
    5) LIDOCAINE/MONITORING PARAMETERS
    a) Monitor ECG continuously; plasma concentrations as indicated (Prod Info Lidocaine HCl intravenous injection solution, 2006).
    E) TORSADES DE POINTES
    1) SUMMARY
    a) Withdraw the causative agent. Hemodynamically unstable patients with Torsades de pointes (TdP) require electrical cardioversion. Emergent treatment with magnesium (first-line agent) or atrial overdrive pacing is indicated. Detect and correct underlying electrolyte abnormalities (ie, hypomagnesemia, hypokalemia, hypocalcemia). Correct hypoxia, if present (Drew et al, 2010; Neumar et al, 2010; Keren et al, 1981; Smith & Gallagher, 1980).
    b) Polymorphic VT associated with acquired long QT syndrome may be treated with IV magnesium. Overdrive pacing or isoproterenol may be successful in terminating TdP, particularly when accompanied by bradycardia or if TdP appears to be precipitated by pauses in rhythm (Neumar et al, 2010). In patients with polymorphic VT with a normal QT interval, magnesium is unlikely to be effective (Link et al, 2015).
    2) MAGNESIUM SULFATE
    a) Magnesium is recommended (first-line agent) for the prevention and treatment of drug-induced torsades de pointes (TdP) even if the serum magnesium concentration is normal. QTc intervals greater than 500 milliseconds after a potential drug overdose may correlate with the development of TdP (Charlton et al, 2010; Drew et al, 2010). ADULT DOSE: No clearly established guidelines exist; an optimal dosing regimen has not been established. Administer 1 to 2 grams diluted in 10 milliliters D5W IV/IO over 15 minutes (Neumar et al, 2010). Followed if needed by a second 2 gram bolus and an infusion of 0.5 to 1 gram (4 to 8 mEq) per hour in patients not responding to the initial bolus or with recurrence of dysrhythmias (American Heart Association, 2005; Perticone et al, 1997). Rate of infusion may be increased if dysrhythmias recur. For persistent refractory dysrhythmias, a continuous infusion of up to 3 to 10 milligrams/minute in adults may be given (Charlton et al, 2010).
    b) PEDIATRIC DOSE: 25 to 50 milligrams/kilogram diluted to 10 milligrams/milliliter for intravenous infusion over 5 to 15 minutes up to 2 g (Charlton et al, 2010).
    c) PRECAUTIONS: Use with caution in patients with renal insufficiency.
    d) MAJOR ADVERSE EFFECTS: High doses may cause hypotension, respiratory depression, and CNS toxicity (Neumar et al, 2010). Toxicity may be observed at magnesium levels of 3.5 to 4.0 mEq/L or greater (Charlton et al, 2010).
    e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respiratory rate, motor strength, deep tendon reflexes, serum magnesium, phosphorus, and calcium concentrations (Prod Info magnesium sulfate heptahydrate IV, IM injection, solution, 2009).
    3) OVERDRIVE PACING
    a) Institute electrical overdrive pacing at a rate of 130 to 150 beats per minute, and decrease as tolerated. Rates of 100 to 120 beats per minute may terminate torsades (American Heart Association, 2005). Pacing can be used to suppress self-limited runs of TdP that may progress to unstable or refractory TdP, or for override refractory, persistent TdP before the potential development of ventricular fibrillation (Charlton et al, 2010). In a case series overdrive pacing was successful in terminating TdP associated with bradycardia and drug-induced QT prolongation (Neumar et al, 2010).
    4) POTASSIUM REPLETION
    a) Potassium supplementation, even if serum potassium is normal, has been recommended by many experts (Charlton et al, 2010; American Heart Association, 2005). Supplementation to supratherapeutic potassium concentrations of 4.5 to 5 mmol/L has been suggested, although there is little evidence to determine the optimal range in dysrhythmia (Drew et al, 2010; Charlton et al, 2010).
    5) ISOPROTERENOL
    a) Isoproterenol has been successful in aborting torsades de pointes that was resistant to magnesium therapy in a patient in whom transvenous overdrive pacing was not an option (Charlton et al, 2010) and has been successfully used to treat torsades de pointes associated with bradycardia and drug induced QT prolongation (Keren et al, 1981; Neumar et al, 2010). Isoproterenol may have a limited role in pharmacologic overdrive pacing in select patients with drug-induced torsades de pointes and acquired long QT syndrome (Charlton et al, 2010; Neumar et al, 2010). Isoproterenol should be avoided in patients with polymorphic VT associated with familial long QT syndrome (Neumar et al, 2010).
    b) DOSE: ADULT: 2 to 10 micrograms/minute via a continuous monitored intravenous infusion; titrate to heart rate and rhythm response (Neumar et al, 2010).
    c) PRECAUTIONS: Correct hypovolemia before using; contraindicated in patients with acute cardiac ischemia (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    1) Contraindicated in patients with preexisting dysrhythmias; tachycardia or heart block due to digitalis toxicity; ventricular dysrhythmias that require inotropic therapy; and angina. Use with caution in patients with coronary insufficiency (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    d) MAJOR ADVERSE EFFECTS: Tachycardia, cardiac dysrhythmias, palpitations, hypotension or hypertension, nervousness, headache, dizziness, and dyspnea (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respirations and central venous pressure to guide volume replacement (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    6) OTHER DRUGS
    a) Mexiletine, verapamil, propranolol, and labetalol have also been used to treat TdP, but results have been inconsistent (Khan & Gowda, 2004).
    7) AVOID
    a) Avoid class Ia antidysrhythmics (eg, quinidine, disopyramide, procainamide, aprindine), class Ic (eg, flecainide, encainide, propafenone) and most class III antidysrhythmics (eg, N-acetylprocainamide, sotalol) since they may further prolong the QT interval and have been associated with TdP.
    F) SEIZURE
    1) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    2) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    3) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    4) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).
    5) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    6) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).

Enhanced Elimination

    A) SUMMARY
    1) Because of the high protein binding and large volume of distribution of thioridazine, methods such as hemodialysis and hemoperfusion are unlikely to be useful.

Abstracts

Case Reports

    A) ADULT
    1) Burgess et al (1979) reported a case of a 22-year-old patient treated for schizophrenia with thioridazine 50 mg 4 times daily for 18 months who deliberately ingested 5000 mg of the drug. Electrocardiogram showed no abnormalities until 10 hours after ingestion when the patient began to have episodes of ventricular tachycardia (thioridazine blood concentration was 15.1 micromoles/L) that were unresponsive to lidocaine, procainamide, or direct cardioversion but resolved spontaneously. Propranolol and verapamil showed initial utility only. Physostigmine and neostigmine affected only level of consciousness, but not dysrhythmias. Clinical course included first degree AV block, ventricular tachycardia, then fibrillation. Late attempts at pacing were unsuccessful and the patient died (Burgess et al, 1979).
    2) A 43-year-old man developed coma, hypertension, muscle rigidity, hyperreflexia with myoclonic jerking, and hyperthermia following overdose of thioridazine. The blood thioridazine concentration was 8,763 ng/mL. Sinus tachycardia and a widened QRS interval were also present. Hyperthermia and rigidity resolved 2 hours after infusion of dantrolene 70 mg (Baker et al, 1988).

Range Of Toxicity

Summary

    A) TOXIC DOSE: ADULT: In adults, 300 mg has been lethal in patients with concomitant predisposing conditions (eg, cardiovascular disease, electrolyte derangements), and 900 mg was the lowest lethal dose in patients without underlying risk factors. Adults have developed severe cardiac toxicity but survived after ingestions of 1 to 16 grams. PEDIATRIC: A 3-year-old developed CNS depression but recovered after ingesting 100 mg.
    B) THERAPEUTIC DOSE: ADULT: 200 to 800 mg daily. PEDIATRIC: Initial Dose: 0.5 mg/kg/day in divided doses. Dosage may be gradually increased up to a maximum of 3 mg/kg/day in divided doses, if needed.

Therapeutic Dose

    7.2.1) ADULT
    A) INITIAL DOSE: 50 to 100 mg 3 times daily. Dose may be gradually increased to a maximum of 800 mg/day, if needed. Once symptoms are effectively controlled, decrease dose gradually as tolerated. Usual maintenance dose is 200 to 800 mg/day divided in 2 to 4 doses (Prod Info thioridazine HCl oral tablets, 2014).
    7.2.2) PEDIATRIC
    A) INITIAL DOSE: 0.5 mg/kg/day in divided doses. If needed, dosage may be gradually increased up to a maximum of 3 mg/kg/day in divided doses (Prod Info thioridazine HCl oral tablets, 2014).

Minimum Lethal Exposure

    A) SUMMARY
    1) In adults, 300 mg has been lethal in patients with concomitant predisposing conditions (eg., cardiovascular disease, electrolyte derangements), and 900 mg was the lowest lethal dose in patients without underlying risk factors (Blaye et al, 1993).

Maximum Tolerated Exposure

    A) CASE REPORTS
    1) ADULT
    a) A 68-year-old man developed coma, respiratory failure, hypotension, ventricular tachycardia and torsades de pointes after ingesting 16 g thioridazine (Schmidt & Lang, 1997). He recovered with intensive supportive care.
    b) A 35-year-old woman developed coma, hypothermia, respiratory failure, and recurrent ventricular tachycardia after ingesting 1 g of thioridazine (Annane et al, 1996). She recovered with intensive supportive care.
    c) A 72-year-old woman developed coma, respiratory failure, third degree AV block, and torsades de pointes after ingesting 3 g of thioridazine (Hulisz et al, 1994). She recovered with intensive supportive care.
    d) A 22-year-old man intentionally ingested 9.4 g thioridazine and developed rhabdomyolysis Serum creatinine kinase was 32,620 International Units/L along with myoglobinuria. Sinus tachycardia and a prolonged QT interval were also present. All signs and symptoms were normal within one week following decontamination and supportive care for rhabdomyolysis (Nankivell et al, 1994).
    2) PEDIATRIC
    a) CASE REPORT/PEDIATRIC: A 3-year-old boy with bronchitis was inadvertently given a 100 mg dose of thioridazine (due to a compounding error) and complained of drowsiness and became unconscious. His Glasgow coma score was 12 (E3, V4, M5) on admission. Vital signs included sinus tachycardia (heart rate: 148 beats/min) along with tachypnea (respiratory rate: 40 breaths/min); no dysrhythmias or QT prolongation. Gastric lavage was started. A head CT showed mild diffuse edema that was treated with 10% glycerol (100 mL) and 10 mg of furosemide. He awoke 18 hours later. The patient was neurologically stable, but remained hospitalized for several days for antibiotic therapy secondary to bronchitis. A serum thioridazine level of 1124.5 ng/mL was found on admission (Kato et al, 2009).
    B) CASE SERIES
    1) In a retrospective study of 202 patients with thioridazine only overdose (141 adults), severe intoxication with coma and ventricular dysrhythmias was observed after ingesting of 2 g or more (Schurch et al, 1996).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) CASE REPORTS: Serum concentrations ranging from 2.4 to 11.8 mg/L have been recorded during nonfatal intoxications with thioridazine (Baselt, 2000). Blood concentrations of 0.8 to 13 mg/L were reported in 8 cases of fatal overdose (Baselt et al, 1978).
    2) Relationships between adverse effects and serum concentrations of thioridazine and metabolites were studied in 38 patients. A correlation was shown between serum concentrations of thioridazine or metabolites and tremor (increase), pulse rate (decrease), and blood pressure (decrease). However, there was considerable variability in sensitivity to a given blood concentration (Axelsson & Martensson, 1980).
    3) Gottshalk et al (1978) found no relationship between ECG abnormalities (T-wave blunting or inversion, lengthened repolarization) and concentration of thioridazine or metabolites (Gottshalk et al, 1978).
    4) CASE REPORT: Serum concentration peaked at 6480 ng/mL approximately 24 hours after a 68-year-old man ingested 16 grams of slow-release thioridazine tablets in a suicide attempt (Schmidt & Lang, 1997).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Antipsychotic effects are believed to be secondary to blocking post synaptic dopamine (D2) receptors in the brain, particularly the mesolimbic and mesocortical tracts.

Toxicologic Mechanism

    A) Thioridazine possesses calcium antagonist activity, which may be responsible for some of the cardiac adverse effects (Gould et al, 1984).

Physicochemical

Physical Characteristics

    A) White to slightly yellow crystalline or micronized powder.

Molecular Weight

    A) 407.05

References

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