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Phenothiazines
Phenothiazines MM Dougherty and JM Marraffa, Upstate Medical University, Syracuse, NY, USA Ó 2014 Elsevier Inc. All rights reserved. This article is a revision of the previous edition article by Julie Weber, volume 3, pp 399–401, Ó 2005, Elsevier Inc. l l l
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Name: Phenothiazine antipsychotics Example Compound: Chlorpromazine Chemical Abstracts Service Registry Number: 92-84-2 (Phenothiazine), 69-09-0 (Chlorpromazine hydrochloride), 50-53-3 (Chlorpromazine base) Synonyms: Thorazine, Clozapine, Thioridazine, Neuroleptic, Antipsychotic, Chlorpromazine, Largactil, Megaphen Molecular Formula: S(C6H4)2NH Chemical Structures:
Uses
S
Phenothiazines are neuroleptic agents that affect a variety of receptors including dopaminergic receptor sites. Phenothiazines are used to treat psychosis including schizophrenia; violent, agitated, disturbed behavior; and mania secondary to bipolar disorder. Other uses include treatment of pain, headache, hiccups, acute severe anxiety, idiopathic dystonia, withdrawal, taste disorders, leishmaniasis, acute intermittent porphyria, and alleviation of nausea and vomiting. Phenothiazines allow smoother induction of anesthesia, potentiate anesthetic agents, and treat behavioral symptoms secondary to Alzheimer disease and senile dementia. Some phenothiazines exert an antipruritic effect and are useful for the treatment of neurodermatitis and pruriginous eczema, and relieve psychogenic itching.
N H Phenothiazine
S
N
Cl
useful clinically. Chlorpromazine, known colloquially as ‘Laborit’s drug’ was released into the market in 1953 after a trial published in 1952 showed efficacy in treatment of psychosis in 38 individuals who received daily injections of chlorpromazine. Chlorpromazine is the prototypical drug for the phenothiazine class of antipsychotics. The phenothiazines are classified as low-potency antipsychotics and have more side effects at standard doses than the newer agents used as neuroleptics. For example, they are more anticholinergic and have more extrapyramidal effect than newer agents.
CH3
Environmental Fate and Behavior
N
Physicochemical Properties
CH3
Phenothiazine has the standard formula S(C6H4)2NH and includes a tricyclic structure that is related to the thiazines. Thiazines are used in the manufacture of synthetic dies.
Chlorpromazine
Chlorpromazine
Background Phenothiazine was initially synthesized in 1883 by Bernthsen. It was the basis for the development of other drugs including the phenothiazine class of antipsychotics or neuroleptics. Phenothiazines are the largest class of neuroleptics and include agents such as chlorpromazine, thioridazine, and prochlorperazine. In 1933, a derivative of phenothiazine, promethazine, was synthesized. It was found to have much more significant sedative and antihistaminic effects than previous derivatives of phenothiazine and it was used to induce sedation for surgical patients. After promethazine was developed, a series of agents, including chlorpromazine, was synthesized and tested in France at a military hospital by the French physician Laborit. Laborit found that chlorpromazine induced calm in patients and had other effects that might be
Encyclopedia of Toxicology, Volume 3
Chlorpromazine is a white to off-white substance (both the base and the hydrochloride salt) that is a powder or waxy solid as a base and a crystalline powder as the hydrochloride. Chlorpromazine is odorless or has a slightly amine-like odor. It has a melting point of 56–58 C and in the basic form is practically insoluble in water, soluble in alcohol, and less soluble in chloroform and ether. It is freely soluble in dilute mineral acids. As the hydrochloride salt, chlorpromazine is soluble in water, less soluble in alcohol and chloroform, and insoluble in ether. A 10% aqueous solution has a pH of 3.5–4.5.
Exposure Routes Phenothiazines are available in oral, parenteral, and rectal dosage forms. The principal exposure route is intentional ingestion in
http://dx.doi.org/10.1016/B978-0-12-386454-3.00769-7
881
882
Phenothiazines
adults or accidental ingestion in small children. Rectal absorption is rapid. The bioavailability of intramuscular promethazine has been reported to be higher than oral or rectal administration. Phenothiazines pass into breast milk, which may cause drowsiness or unusual muscle movements in the nursing baby. Environmental exposure may occur during the industrial production of phenothiazines through wastewater and sewage from processing.
Toxicokinetics Phenothiazines are readily but incompletely absorbed due to firstpass metabolism. Oral bioavailability ranges from 7 to 52%. Peak serum levels are reached at 2–4 h after oral dosing and 0.5–1 h after immediate-release intramuscular injections. Phenothiazines are extensively metabolized in the liver via oxidative processes. Phenothiazines are widely distributed throughout the body, including the central nervous system (CNS). CNS levels may be up to 10 times greater than plasma levels. Phenothiazines are highly protein bound: 75–99% with a volume of distribution from 10 to 40 l kg 1, with a mean of 20 l kg 1. The main metabolites are excreted both in the urine and feces. Less than 1% is excreted in the urine unchanged. The elimination half-life ranges from 2 to 119 h, with an average of 8–30 h.
may interfere with the temperature-regulating function of the hypothalamus; hyperthermia is seen more often in overdose, but hypothermia has been reported with haloperidol and thioridazine. Neuroleptic malignant syndrome (NMS) has been reported after therapeutic use and acute intoxication. (NMS is a lifethreatening adverse response to neuroleptic or antipsychotic drugs. Symptoms include high fever, sweating, unstable blood pressure, stupor, muscular rigidity, and autonomic dysfunction. In most cases, the disorder develops within the first 2 weeks of treatment with the drug; however, it may develop any time during the therapy period.)
Chronic Toxicity Animal Phenothiazine is used as an antihelminthic in some animal species. Larger doses administered to sick animals have resulted in the development of neurologic effects. Horses seem more sensitive to phenothiazines than other animals and have been noted to develop hemolysis.
Human
Phenothiazines primarily block postsynaptic neurotransmission by binding to dopamine (D1 and D2), muscarinic, histamine H1, and serotonergic 5-HT2 receptors. Phenothiazines also possess peripheral adrenergic receptor blockade and quinidine-like cardiac effects. Phenothiazines may lower the seizure threshold.
Chronic dose-related exposure might cause tardive dyskinesia (lip smacking, tongue protrusion, grimacing, and chewing). Seizures are rarely seen, but are more common with loxapine and clozapine. The most commonly reported adverse reactions following therapeutic use include dry mouth, sedation, orthostatic hypotension, blurred vision, photosensitivity, anorexia, nausea, vomiting, constipation, diarrhea, and dyspepsia. Various hematologic changes have been reported. Clozapine has been linked to fatal agranulocytosis. Women may note changes in menstrual pattern.
Acute Toxicity
Immunotoxicity
Mechanism of Toxicity
Animal General signs associated with overdose include mydriasis, constipation, rigidity, weakness, tremor, ataxia, acute hypotension, respiratory depression, jaundice, eosinophilia and granulocytosis, and circulatory collapse. Other signs include dullness, weakness, anorexia, oliguria, colic, fever, icterus, anemia, and hemoglobinuria. In calves, photosensitivity occurs; photochemical reactions can cause acute keratitis and corneal ulceration. Hypertension, tachycardia, and depression occur in horses.
Chlorpromazine is not known to have specific immunotoxicity other than indirect effects through inhibition or interference with the hypothalamic–pituitary axis.
Genotoxicity Chlorpromazine was positive in the chromosomal aberration assay using human lymphocytes at 0.24–2.0 mg ml 1. Chlorpromazine was positive in the Ames test using Salmonella typhimurium at 5–10 mg ml 1.
Human Clinical signs of toxicity most frequently include sedation, coma, hypotension, extrapyramidal effects, and cardiac arrhythmias. Anticholinergic effects including blurred vision, decreased gastrointestinal motility, delirium, agitation, hallucination, hyperthermia, tachycardia, and seizures have been seen. Cardiac effects include mild hypotension, prolonged QT interval, QRS prolongation, and ventricular dysrhythmias; particularly, ventricular tachycardia may occur, which may progress to torsades de pointes or ventricular fibrillation. Phenothiazines
Reproductive Toxicity Chlorpromazine can interfere with the hypothalamic–pituitary axis and as such can have significant endocrine effects and effects on growth and development. Chlorpromazine and metabolites were found in fetal plasma and amniotic fluid as well as in neonatal urine of babies born to women who took chlorpromazine during pregnancy. In lactating women, chlorpromazine is distributed into breast milk at higher concentrations than in
Phenothiazines
maternal plasma and may be associated with sedation in the infant. In high doses throughout pregnancy, chlorpromazine has been shown to cause damage to the retina of the fetus.
Carcinogenicity Chlorpromazine is not thought to be carcinogenic; however, there is limited information regarding short-term and longterm exposure studies in animals or humans related to carcinogenicity of chlorpromazine. In one study involving a p53 heterozygous mouse model, chlorpromazine was not found to be carcinogenic. Phenothiazines are not listed as carcinogenic agents on the International Agency for Research on Cancer (IARC) list of carcinogens or the California Proposition 65 list of known carcinogens.
883
elevations that may produce acute renal insufficiency secondary to rhabdomyolysis. Asymptomatic patients with normal vital signs may be medically cleared after 4–6 h of observation.
Miscellaneous Phenothiazines and metabolites have resulted in false-positive results for tricyclic antidepressants using various screening methods. Unabsorbed phenothiazine may be radiopaque on abdominal X-ray. Use caution, as the absence of radiographic findings does not rule out ingestion.
See also: Benzodiazepines; Loxapine; Neurotoxicity; Quinidine; Poisoning Emergencies in Humans.
Clinical Management Aggressive supportive care including airway protection should be instituted when necessary. An electrocardiogram should be performed along with continuous cardiac monitoring. Intravenous fluid administration is usually effective in correcting hypotension. If vasopressors are necessary, dopamine or norepinephrine can be considered. Unstable cardiac rhythms require the Advanced cardiac life support protocol and potentially cardioversion. Lidocaine should be considered for ventricular tachycardia, ventricular fibrillation, or if the patient has >5 polyvinyl chlorides min 1. Quinidine, procainamide, and disopyramide are contraindicated. Sodium bicarbonate may be effective in treating dysrhythmias secondary to QRS prolongation. Magnesium is the first line of treatment in the prevention of drug-induced torsades de pointes and should be given for QTc >500 ms regardless of the magnesium level. Initial control of seizures should be attempted with use of benzodiazepines; for persistent or recurrent seizures use phenobarbital, or propofol is recommended. Drug-induced dystonia should be treated with benztropine or diphenhydramine and should be administered for 48–72 h to prevent recurrence. Induced emesis is contraindicated due to possible rapid onset of dystonic reaction and CNS depression followed by subsequent risk of aspiration. Lavage is not routinely recommended but may be considered in massive, potentially life-threatening, recent exposures. Activated charcoal may be beneficial if given within 1 h of ingestion. Whole bowel irrigation may reduce absorption of sustained-release preparations of phenothiazines. Hemodialysis and hemoperfusion have not been shown to be effective due to the high protein binding and large volumes of distribution. Monitor fluid and electrolyte balance closely. Baseline complete blood count, arterial blood gas, and glucose should be obtained. Creatine kinase should be monitored to detect
Further Reading Arana, G.W., 2000. An overview of side effects caused by typical antipsychotics. J. Clin. Psychiatry 61 (Suppl. 8), 5–11. Lang, E., Modicano, P., Arnold, M., Bissinger, R., Faggio, C., Abed, M., Lang, F., 2013. Effect of thioridazine on erythrocytes. Toxins (Basel) 5 (10), 1918–1931. Love, J.N., Smith, J.A., Simmons, R., 2006. Are one or two dangerous? Phenothiazine exposure in toddlers. J. Emerg. Med. 31 (1), 53–59. Mazzola, C.D., Miron, S., Jenkins, A.J., 2000. Loxapine intoxication: case report and literature review. J. Anal. Toxicol. 24 (7), 638–641. Morris, E., Green, D., Graudiins, A., 2009. Neuroleptic malignant syndrome developing after acute overdose with olanzapine and chlorpromazine. J. Med. Toxicol. 5 (1), 27–31. Musselman, M.E., Browning, L.A., Parker Jr., D., Saely, S., 2011. Neuroleptic malignant syndrome associated with the use of prochlorperazine in a patient with a recent history of antipsychotic-induced neuroleptic malignant syndrome. Ann. Pharmacother. 45 (11), e61. Strachan, E.M., Kelly, C.A., Bateman, D.N., 2004. Electrocardiogram and cardiovascular changes in thioridazine and chlorpromazine poisoning. Eur. J. Clin. Pharmacol. 60 (8), 541–545. West, S., Jeffery-Smith, A., Brownlee, W., Kenedi, C., 1 July 2013. Cover clozapine overdose: clozapine toxicity in a naïve patient. Aust. N. Z. J. Psychiatry (Epub ahead of print).
Relevant Websites http://www.inchem.org/documents/pims/pharm/chlorpro.htm – International Programme on Chemical Safety: INCHEM: Chlorpromazine. http://www.inchem.org/documents/jecfa/jecmono/v29je10.htm – Information on teratogenicity, genotoxicity, and carcinogenicity studies relating to chlorpromazine from Inchem. http://emedicine.medscape.com/article/815881-overview – Neuroleptic Agent Toxicity from eMedicine an online clinical resource (Medscape). http://emedicine.medscape.com/article/1950863-overview – Torsade de Pointes – Medscape Reference at eMedicine.com.
l l l
Name: Phenothiazine antipsychotics Example Compound: Chlorpromazine Chemical Abstracts Service Registry Number: 92-84-2 (Phenothiazine), 69-09-0 (Chlorpromazine hydrochloride), 50-53-3 (Chlorpromazine base) Synonyms: Thorazine, Clozapine, Thioridazine, Neuroleptic, Antipsychotic, Chlorpromazine, Largactil, Megaphen Molecular Formula: S(C6H4)2NH Chemical Structures:
Uses
S
Phenothiazines are neuroleptic agents that affect a variety of receptors including dopaminergic receptor sites. Phenothiazines are used to treat psychosis including schizophrenia; violent, agitated, disturbed behavior; and mania secondary to bipolar disorder. Other uses include treatment of pain, headache, hiccups, acute severe anxiety, idiopathic dystonia, withdrawal, taste disorders, leishmaniasis, acute intermittent porphyria, and alleviation of nausea and vomiting. Phenothiazines allow smoother induction of anesthesia, potentiate anesthetic agents, and treat behavioral symptoms secondary to Alzheimer disease and senile dementia. Some phenothiazines exert an antipruritic effect and are useful for the treatment of neurodermatitis and pruriginous eczema, and relieve psychogenic itching.
N H Phenothiazine
S
N
Cl
useful clinically. Chlorpromazine, known colloquially as ‘Laborit’s drug’ was released into the market in 1953 after a trial published in 1952 showed efficacy in treatment of psychosis in 38 individuals who received daily injections of chlorpromazine. Chlorpromazine is the prototypical drug for the phenothiazine class of antipsychotics. The phenothiazines are classified as low-potency antipsychotics and have more side effects at standard doses than the newer agents used as neuroleptics. For example, they are more anticholinergic and have more extrapyramidal effect than newer agents.
CH3
Environmental Fate and Behavior
N
Physicochemical Properties
CH3
Phenothiazine has the standard formula S(C6H4)2NH and includes a tricyclic structure that is related to the thiazines. Thiazines are used in the manufacture of synthetic dies.
Chlorpromazine
Chlorpromazine
Background Phenothiazine was initially synthesized in 1883 by Bernthsen. It was the basis for the development of other drugs including the phenothiazine class of antipsychotics or neuroleptics. Phenothiazines are the largest class of neuroleptics and include agents such as chlorpromazine, thioridazine, and prochlorperazine. In 1933, a derivative of phenothiazine, promethazine, was synthesized. It was found to have much more significant sedative and antihistaminic effects than previous derivatives of phenothiazine and it was used to induce sedation for surgical patients. After promethazine was developed, a series of agents, including chlorpromazine, was synthesized and tested in France at a military hospital by the French physician Laborit. Laborit found that chlorpromazine induced calm in patients and had other effects that might be
Encyclopedia of Toxicology, Volume 3
Chlorpromazine is a white to off-white substance (both the base and the hydrochloride salt) that is a powder or waxy solid as a base and a crystalline powder as the hydrochloride. Chlorpromazine is odorless or has a slightly amine-like odor. It has a melting point of 56–58 C and in the basic form is practically insoluble in water, soluble in alcohol, and less soluble in chloroform and ether. It is freely soluble in dilute mineral acids. As the hydrochloride salt, chlorpromazine is soluble in water, less soluble in alcohol and chloroform, and insoluble in ether. A 10% aqueous solution has a pH of 3.5–4.5.
Exposure Routes Phenothiazines are available in oral, parenteral, and rectal dosage forms. The principal exposure route is intentional ingestion in
http://dx.doi.org/10.1016/B978-0-12-386454-3.00769-7
881
882
Phenothiazines
adults or accidental ingestion in small children. Rectal absorption is rapid. The bioavailability of intramuscular promethazine has been reported to be higher than oral or rectal administration. Phenothiazines pass into breast milk, which may cause drowsiness or unusual muscle movements in the nursing baby. Environmental exposure may occur during the industrial production of phenothiazines through wastewater and sewage from processing.
Toxicokinetics Phenothiazines are readily but incompletely absorbed due to firstpass metabolism. Oral bioavailability ranges from 7 to 52%. Peak serum levels are reached at 2–4 h after oral dosing and 0.5–1 h after immediate-release intramuscular injections. Phenothiazines are extensively metabolized in the liver via oxidative processes. Phenothiazines are widely distributed throughout the body, including the central nervous system (CNS). CNS levels may be up to 10 times greater than plasma levels. Phenothiazines are highly protein bound: 75–99% with a volume of distribution from 10 to 40 l kg 1, with a mean of 20 l kg 1. The main metabolites are excreted both in the urine and feces. Less than 1% is excreted in the urine unchanged. The elimination half-life ranges from 2 to 119 h, with an average of 8–30 h.
may interfere with the temperature-regulating function of the hypothalamus; hyperthermia is seen more often in overdose, but hypothermia has been reported with haloperidol and thioridazine. Neuroleptic malignant syndrome (NMS) has been reported after therapeutic use and acute intoxication. (NMS is a lifethreatening adverse response to neuroleptic or antipsychotic drugs. Symptoms include high fever, sweating, unstable blood pressure, stupor, muscular rigidity, and autonomic dysfunction. In most cases, the disorder develops within the first 2 weeks of treatment with the drug; however, it may develop any time during the therapy period.)
Chronic Toxicity Animal Phenothiazine is used as an antihelminthic in some animal species. Larger doses administered to sick animals have resulted in the development of neurologic effects. Horses seem more sensitive to phenothiazines than other animals and have been noted to develop hemolysis.
Human
Phenothiazines primarily block postsynaptic neurotransmission by binding to dopamine (D1 and D2), muscarinic, histamine H1, and serotonergic 5-HT2 receptors. Phenothiazines also possess peripheral adrenergic receptor blockade and quinidine-like cardiac effects. Phenothiazines may lower the seizure threshold.
Chronic dose-related exposure might cause tardive dyskinesia (lip smacking, tongue protrusion, grimacing, and chewing). Seizures are rarely seen, but are more common with loxapine and clozapine. The most commonly reported adverse reactions following therapeutic use include dry mouth, sedation, orthostatic hypotension, blurred vision, photosensitivity, anorexia, nausea, vomiting, constipation, diarrhea, and dyspepsia. Various hematologic changes have been reported. Clozapine has been linked to fatal agranulocytosis. Women may note changes in menstrual pattern.
Acute Toxicity
Immunotoxicity
Mechanism of Toxicity
Animal General signs associated with overdose include mydriasis, constipation, rigidity, weakness, tremor, ataxia, acute hypotension, respiratory depression, jaundice, eosinophilia and granulocytosis, and circulatory collapse. Other signs include dullness, weakness, anorexia, oliguria, colic, fever, icterus, anemia, and hemoglobinuria. In calves, photosensitivity occurs; photochemical reactions can cause acute keratitis and corneal ulceration. Hypertension, tachycardia, and depression occur in horses.
Chlorpromazine is not known to have specific immunotoxicity other than indirect effects through inhibition or interference with the hypothalamic–pituitary axis.
Genotoxicity Chlorpromazine was positive in the chromosomal aberration assay using human lymphocytes at 0.24–2.0 mg ml 1. Chlorpromazine was positive in the Ames test using Salmonella typhimurium at 5–10 mg ml 1.
Human Clinical signs of toxicity most frequently include sedation, coma, hypotension, extrapyramidal effects, and cardiac arrhythmias. Anticholinergic effects including blurred vision, decreased gastrointestinal motility, delirium, agitation, hallucination, hyperthermia, tachycardia, and seizures have been seen. Cardiac effects include mild hypotension, prolonged QT interval, QRS prolongation, and ventricular dysrhythmias; particularly, ventricular tachycardia may occur, which may progress to torsades de pointes or ventricular fibrillation. Phenothiazines
Reproductive Toxicity Chlorpromazine can interfere with the hypothalamic–pituitary axis and as such can have significant endocrine effects and effects on growth and development. Chlorpromazine and metabolites were found in fetal plasma and amniotic fluid as well as in neonatal urine of babies born to women who took chlorpromazine during pregnancy. In lactating women, chlorpromazine is distributed into breast milk at higher concentrations than in
Phenothiazines
maternal plasma and may be associated with sedation in the infant. In high doses throughout pregnancy, chlorpromazine has been shown to cause damage to the retina of the fetus.
Carcinogenicity Chlorpromazine is not thought to be carcinogenic; however, there is limited information regarding short-term and longterm exposure studies in animals or humans related to carcinogenicity of chlorpromazine. In one study involving a p53 heterozygous mouse model, chlorpromazine was not found to be carcinogenic. Phenothiazines are not listed as carcinogenic agents on the International Agency for Research on Cancer (IARC) list of carcinogens or the California Proposition 65 list of known carcinogens.
883
elevations that may produce acute renal insufficiency secondary to rhabdomyolysis. Asymptomatic patients with normal vital signs may be medically cleared after 4–6 h of observation.
Miscellaneous Phenothiazines and metabolites have resulted in false-positive results for tricyclic antidepressants using various screening methods. Unabsorbed phenothiazine may be radiopaque on abdominal X-ray. Use caution, as the absence of radiographic findings does not rule out ingestion.
See also: Benzodiazepines; Loxapine; Neurotoxicity; Quinidine; Poisoning Emergencies in Humans.
Clinical Management Aggressive supportive care including airway protection should be instituted when necessary. An electrocardiogram should be performed along with continuous cardiac monitoring. Intravenous fluid administration is usually effective in correcting hypotension. If vasopressors are necessary, dopamine or norepinephrine can be considered. Unstable cardiac rhythms require the Advanced cardiac life support protocol and potentially cardioversion. Lidocaine should be considered for ventricular tachycardia, ventricular fibrillation, or if the patient has >5 polyvinyl chlorides min 1. Quinidine, procainamide, and disopyramide are contraindicated. Sodium bicarbonate may be effective in treating dysrhythmias secondary to QRS prolongation. Magnesium is the first line of treatment in the prevention of drug-induced torsades de pointes and should be given for QTc >500 ms regardless of the magnesium level. Initial control of seizures should be attempted with use of benzodiazepines; for persistent or recurrent seizures use phenobarbital, or propofol is recommended. Drug-induced dystonia should be treated with benztropine or diphenhydramine and should be administered for 48–72 h to prevent recurrence. Induced emesis is contraindicated due to possible rapid onset of dystonic reaction and CNS depression followed by subsequent risk of aspiration. Lavage is not routinely recommended but may be considered in massive, potentially life-threatening, recent exposures. Activated charcoal may be beneficial if given within 1 h of ingestion. Whole bowel irrigation may reduce absorption of sustained-release preparations of phenothiazines. Hemodialysis and hemoperfusion have not been shown to be effective due to the high protein binding and large volumes of distribution. Monitor fluid and electrolyte balance closely. Baseline complete blood count, arterial blood gas, and glucose should be obtained. Creatine kinase should be monitored to detect
Further Reading Arana, G.W., 2000. An overview of side effects caused by typical antipsychotics. J. Clin. Psychiatry 61 (Suppl. 8), 5–11. Lang, E., Modicano, P., Arnold, M., Bissinger, R., Faggio, C., Abed, M., Lang, F., 2013. Effect of thioridazine on erythrocytes. Toxins (Basel) 5 (10), 1918–1931. Love, J.N., Smith, J.A., Simmons, R., 2006. Are one or two dangerous? Phenothiazine exposure in toddlers. J. Emerg. Med. 31 (1), 53–59. Mazzola, C.D., Miron, S., Jenkins, A.J., 2000. Loxapine intoxication: case report and literature review. J. Anal. Toxicol. 24 (7), 638–641. Morris, E., Green, D., Graudiins, A., 2009. Neuroleptic malignant syndrome developing after acute overdose with olanzapine and chlorpromazine. J. Med. Toxicol. 5 (1), 27–31. Musselman, M.E., Browning, L.A., Parker Jr., D., Saely, S., 2011. Neuroleptic malignant syndrome associated with the use of prochlorperazine in a patient with a recent history of antipsychotic-induced neuroleptic malignant syndrome. Ann. Pharmacother. 45 (11), e61. Strachan, E.M., Kelly, C.A., Bateman, D.N., 2004. Electrocardiogram and cardiovascular changes in thioridazine and chlorpromazine poisoning. Eur. J. Clin. Pharmacol. 60 (8), 541–545. West, S., Jeffery-Smith, A., Brownlee, W., Kenedi, C., 1 July 2013. Cover clozapine overdose: clozapine toxicity in a naïve patient. Aust. N. Z. J. Psychiatry (Epub ahead of print).
Relevant Websites http://www.inchem.org/documents/pims/pharm/chlorpro.htm – International Programme on Chemical Safety: INCHEM: Chlorpromazine. http://www.inchem.org/documents/jecfa/jecmono/v29je10.htm – Information on teratogenicity, genotoxicity, and carcinogenicity studies relating to chlorpromazine from Inchem. http://emedicine.medscape.com/article/815881-overview – Neuroleptic Agent Toxicity from eMedicine an online clinical resource (Medscape). http://emedicine.medscape.com/article/1950863-overview – Torsade de Pointes – Medscape Reference at eMedicine.com.