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Phenothiazine and Butyrophenone Intoxication in Children
Pediatric Toxicology
Phenothiazine and Butyrophenone Intoxication in Children
M. E. Knight, M.D.,* and R.]. Roberts, M.D., Ph.D.t
Phenothiazine- and butyrophenone-type drugs are used for a variety of clinical problems, including chronic treatment of psychotic disorders in adults and children, acute symptoms of nausea and vomiting, cold symptoms, as antitussive agents, and for sedation for diagnostic procedures (bone marrow biopsy, cardiac catheterization, and so on). These drugs are associated with a wide variety of adverse effects. It is therefore important for the clinician to be aware of the clinical presentation and treatment of a child who experiences an adverse effect to one of these agents. This review will deal with the pharmacologic characteristics and features of toxicity of these agents and the evaluation and treatment of a child intoxicated with one of these drugs.
PHARMACOLOGY Chemical Classification of Agents and Actions The phenothiazine agents can be divided into three groups based on their chemical structure (Table 1).19 The dimethylamine group usually causes autonomic nervous system effects, including orthostatic hypotension and anticholinergic manifestations (e.g., dry mucous membranes, tachycar" dia). The piperazine group primarily elicits extrapyramidal symptoms. Agents in the third group, the piperidine class, are the most potent pharmacologically of all three groups, but they do not usually cause extrapyramidal symptoms. However, a drug from any of the three groups can elicit manifestations of the other groups. 19 The most common drug of the butyrophenone class (Table 1), haloperidol, is used as an antipsychotic agent.2 The other major drug of the *Division of Pediatric Clinical Pharmacology, Department of Pediatrics, College of Medicine, University of Florida, Gainesville, Florida tDivision of Pediatric Clinical Pharmacology, Department of Pediatrics, College of Medicine, University of Iowa, Iowa City, Iowa
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Table 1. Drug Classification and Associated Toxic Effects CLASS
Phenothiazines Dimethylamine Promazine Chlorpromazine Triflupromazine Methoxypromazine Piperazine Prochlorperazine Trifluoperazine Thiopropazate Perphenazine Fluphenazine Piperidine Thioridazine Pipamazine Mepazine Butyrophenones Haloperidol Droperidol Thioxanthines Thiothixine Chlorprothixene
TOXICITY MANIFESTATIONS
Anticholinergic effects (orthostatic hypotension. tachycardia, dry mucous membranes), disturbance of body temperature, dysrhythmias, neuroleptic malignant syndrome Sedation, extrapyramidal signs (dystonia, oculogyric crises, chorea), disturbance of body temperature, dysrhythmias, neuroleptic malignant syndrome
Most potent of three groups (above manifestations), but less likely to have extrapyramidal signs
Extrapyramidal signs, less anticholinergic signs and less sedation than phenothiazines, neuroleptic malignant syndrome Similar to phenothiazine class
Loxapine Similar to phenothiazine class
butyrophenone class is droperidol, which is used as an adjunct to narcotic analgesia. Another major chemical class, the thioxanthines, have side effects and toxic reactions very similar to the phenothiazines. 19 Loxapine, another chemically distinct agent, will also show clinical manifestations similar to phenothiazines. 19 The phenothiazine and butyrophenone drugs are reported to reduce psychotic symptoms, including hallucinations, paranoia, and delusions. 2 They also have sedative and anxiolytic properties. 2 Their mechanism of action is by antagonism of dopamine action in the central nervous system (eNS). The eNS synthesis of catecholamines is also reduced, especially in the hypothalamus, sensory areas, and the emetic center. Additional actions resulting from eNS effects include muscle relaxation, lowering of seizure threshold, and depression of vasomotor reflexes in the brain stem. The phenothiazines also have a number of other pharmacologic actions in the peripheral nervous system, including blockade of alpha-receptors, antihistaminic and anticholinergic properties, and blockade of re-uptake of adrenergic catecholamines in peripheral synapses. The alpha-blockade is believed to account for the increased levels of circulating norepinephrine and epinephrine observed after these agents have been taken. 2 Pharmacokinetics
About 40 to 80 per cent of the dose of phenothiazines and butyrophenones are absorbed from the gastrointestinal tract. 19 They are lipophilic
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drugs and are highly plasma protein bound (> 90 per cent).2 The volume of distribution is very large, 20 Llkg, accounting for the large amount of these agents within tissues. 2 The serum pharmacokinetics are multiphasic, with the alpha-T1I2 phase averaging 2 hours and the beta-T1I2 phase averaging 10 to 20 hours. 2 Due to the large volume of distribution and the lipophilic nature of these substances, the plasma elimination is more rapid than tissue elimination. The therapeutic dose range for these agents is wide, suggesting a large therapeutic index. 2, 19 In adults, 25 to 5000 mg/day for chlorpromazine and 0.5 to 30 mg/day for haloperidol are used for the treatment of chronic psychotic disorders. 2, 19 The recommended pediatric doses of chlorpromazine are from 0.5 mg/kg to a total of 40 mg for children younger than 5 years of age or a total of 75 mg for children 5 to 12 yrs of age. 3 The pediatric dose of haloperidol is reported to be 0.01 to 0.03 mglkg. 3 The reported fatal dose of these agents is from 30 to 300 times higher than the therapeutic dose (15 to 150 mg/kg), depending upon the particular agent used. 2, 3, 19 Much of the information regarding the toxicity of these agents comes from adverse effects seen during therapeutic uses of these drugs. Because of the wide range of therapeutic doses, the high therapeutic index, and the wide variety of complex pharmacologic actions, intoxication from antipsychotic agents may be difficult to anticipate or appreciate. Both phenothiazines and butyrophenones are metabolized extensively in the liver by glucuronidation and sulfoxidation. 2 There are many metabolites formed, some of which are pharmacologically active. The pharmacologic activity of the phenothiazines and butyrophenones may be of longer duration than their pharmacokinetics would predict due to the persistence of these agents in tissues and the presence of active metabolites. 2 The phenothiazines and butyrophenones can significantly potentiate the actions of sedative-hypnotic agents, analgesics, and antihistamines. 2
CLINICAL TOXICOLOGY The phenothiazines and butyrophenones have a large number of diverse toxic actions. The onset of toxic manifestations following phenothiazine or butyrophenone ingestion may be delayed 6 to 24 hours after the ingestion, and they may be intermittent in nature. 18, 19, 33 The systems involved with clinical intoxication are reviewed below. Central Nervous System. The signs of CNS intoxication include akathisia, akinesia, trismus, opisthotonos, torticollis, chorea, dystonia, and oculogyric crises. 12, 14, 18, 19, 30, 33 Diffuse eNS motor signs, including hyperreflexia, spasticity, and extensor plantar responses, may also be present. In adults, the signs tend to involve mainly the face and trunk, whereas children tend to have more generalized manifestations. Generalized dystonic reactions and oculogyric crises in particular are more frequent in children younger than 15 years of age. 19 Difficulty swallowing and dysarthria are also reported. Disturbances of temperature control with hypothermia or hyperthermia have also been observed. 19 The extrapyramidal signs may
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develop acutely after a single therapeutic dose or nontherapeutic ingestion or may develop after chronic therapy with these agents. 1. 10. 12. 14, 18, 30. 33, 36 The phenothiazines and butyrophenones are not actually physically addicting, but there may be a mild withdrawal syndrome manifested by difficulty sleeping, restlessness, and muscle aches. 2 Although the patient may become tolerant to the sedative properties of these agents, abrupt discontinuation may also lead to the emergence of dyskinesias and extrapyramidal signs. 2, 30 At therapeutic doses, irritability may also be a sign of a phenothiazine adverse effect and may be mistakenly interpreted as a sign of inadequate sedation. Administration of additional medication in these situations will further increase the intoxication. 10 Cardiovascular. The cardiovascular manifestations of phenothiazine intoxication include the following EKG changes: prolonged PR and QT interval; flattened, biphasic, or inverted T waves; and dysrhythmias, including supraventricular tachycardia, ventricular tachycardia, ventricular fibrillation, and atrioventricular dissociation. 2, 6, 19, 27 These EKG changes are due to the quinidine-like properties of phenothiazines. 2,19 The phenothiazines also have a negative inotropic influence on the myocardium. 2 Thioridazine, in particular, has been associated with more severe EKG and cardiac adverse effects. 6, 7 Orthostatic hypotension has been frequently seen in cases of phenothiazine ingestions. 2, 19 Up to 15 per cent of patients on therapeutic doses of chlorpromazine may experience orthostatic hypotension, although tolerance to this effect can emerge with continued therapy.19 The effects on blood pressure are complex due to the multiple pharmacologic actions (central, autonomic, direct).2, 19 Transient elevated blood pressure has been reported in one patient 34 hours after ingestion of haloperidol. 13 Otherwise, there have been no other consistent cardiovascular effects of haloperidol on the cardiovascular system. Cutaneous. Phenothiazine and haloperidol have been reported to cause several photosensitivity-type reactions. 19 In general, these reactions are less severe and less common with haloperidol than with the phenothiazines. Reactions have varied from an exaggerated sunburn reaction to a dermatitis on light-exposed areas, urticaria, and a purple-gray discoloration of the skin. 19 Hepatic. A type of presumed hypersensitivity reaction has been reported in 1 to 3 per cent of individuals on phenothiazines as well as in patients on haloperidol. 15, 19 The manifestations include jaundice and other features of liver injury, including fever, abdominal discomfort, malaise, anorexia, nausea, itching, eosinophilia, rash, and elevated transaminases and alkaline phosphatase. Serial liver biopsies of one patient have shown a picture of mainly cholestasis, with progression to spotty necrosis and fibrosis and bile duct damage. 15 Rarely do patients progress to cirrhosis, and recovery within 2 to 12 months is to be expected. 15 Ocular. The eye may also be a target of phenothiazine toxicity. The damage seen is due to alteration of several enzyme systems in melanincontaining cells (rods and cones). Phenothiazines bind to melanin and concentrate in these tissues. 31 This binding may cause alterations in normal
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activity of many enzyme systems in the rods and cones associated with metabolic processes involved with the biochemistry of vision perception. Clinically, visual acuity, visual fields, and color vision perception may be altered. 31 Hematologic. Severe reversible neutropenia has been reported in one 5-year-old child 45 hours after an acute ingestion of 100 to 200 mg of chlorpromazine. 5 The platelets, hemoglobin, and hematocrit were all normal. The mechanism is unknown, although a direct toxic action or immunologic mechanisms have been proposed. Miscellaneous. Transient ketoacidosis with hyperglycemia has been reported in a 17-year-old girl on 1200 mg/day of chlorpromazine and 100 mg/week of fluphenazine. 23 This disturbance was temporary and resolved with temporary insulin therapy. Deaths from Phenothiazine Overdose. Death associated with phenothiazine ingestion is uncommon but has been reported. 6, 21, 37 Theories on the cause of death in phenothiazine ingestion include sudden dysrhythmia or respiratory depression. Although therapeutic doses of phenothiazines decrease tidal volume and change the rhythm of respiration, these effects are generally not clinically significant. It has been argued that some individuals may have an exaggerated response to phenothiazines, which leads to death from respiratory depression. Thioridazine has been reported to have caused deaths. 6, 21 One individual experienced ventricular tachycardia and then a ventricular dysrhythmia with poor cardiac output after ingestion of 5000 mg of thioridazine. Another fatality occurred after ingestion of 3000 mg of thioridazine. At autopsy, extensive pulmona.ry damage was seen with pulmonary congestion, edema, and hyaline membrane formation. 6, 21 Nonspecific acute renal tubular necrosis was also seen, In a review of 56 children with sudden infant de~th syndrome (SIDS) and 36 children with near-miss SIDS episodes, there was greater use of phenothiazines in these children than in controls,22 This has suggested a role for phenothiazines in SIDS, but further documentation is needed,
CLINICAL EVALUATION AND TREATMENT There are three major presentations in patients affected with antipsychotic toxicity: (1) depressed neurologic status, meiosis, hypotension, and dysrhythmias;19 (2) extrapyramidal manifestations/ 9 and (3) neuroleptic malignant syndrome (Table 2). Acute Overdose. With a large acute ingestion of antipsychotic agents, the patient may present with coma, meiosis, hypotension, and dysrhythmias, Disturbance of body temperature homeostasis is also common, with hypothermia (more often seen with haloperidol) or hyperthermia (more often seen with a phenothiazine), 1, 2 Respiratory depression of clinical significance is usually not a major problem unless the patient has taken another respiratory depressing agent; for example, a narcotic in which the effect will be potentiated by the antipsychotic agent. 4 Extrapyramidal Symptoms. Extrapyramidal signs are associated with
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Table 2. Presentations of Phenothiazine or Butyrophenone Intoxications ACUTE OVERDOSE
Altered mental status (including coma) Orthostatic hypotension Dysrhythmia and EKG changes Pinpoint pupils Depressed respirations Usually occurs after a single large ingestion EXTRAPYRAMIDAL SYMPTOMS
Awake and alert patient Torsion of head and neck, dystonia, chorea-like movements, oculogyric crises, trismus May be intermittent and delayed up to 24 hours from ingestion May occur with acute or chronic therapeutic dosing NEUROLEPTIC MALIGNANT SYNDROME
Fever, diaphoresis, rigidity, tachycardia, coma Develops gradually over 24 to 72 hours Occurs in psychiatric and non psychiatric patients No relationship to duration of treatment with phenothiazines or haloperidol; may occur after a single dose
either an acute ingestion or are side effects of chronic treatment. They have also been associated with a single therapeutic dose, as in sedation for procedures (cardiac catheterization, biopsy, and so on). They may be delayed in onset up to 24 hours or more, and they may be intermittent in nature. Younger children tend to be prone to extrapyramidal signs and to have generalized manifestations, whereas adolescents and adults tend to have signs localized to the face and trunk. 18. 19. 33 Neuroleptic Malignant Syndrome. An uncommon but potentially lifethreatening adverse effect of phenothiazines or butyrophenones has been recently recognized. 8. 16. 20, 34 The characteristics of the neuroleptic malignant syndrome include fluctuating mental status progressing to coma and extrapyramidal symptoms, especially rigidity, fever, diaphoresis, tachycardia, and hypotension or hypertension. Laboratory findings include elevated white blood count, elevated CPK, and liver transaminases,8, 16, 20, 26, 34 This syndrome occurs in 1/2 to 1 per cent of patients on antipsychotic therapy, especially those on haloperidol or fluphenazine. It may be more common in people who have relatives with idiopathic Parkinson's disease. The mortality rate is 20 per cent and is due to cardiovascular and respiratory failure. The clinical features of the syndrome evolve gradually over 24 to 72 hours. There is no known relationship between dose or duration of dose or dosage and the development of neuroleptic malignant syndrome. It has occurred both in psychiatric patients on chronic treatment with antipsychotic agents and in nonpsychiatric patients after a single dose for sedative purposes. The pathophysiology of the disorder is thought to be due, at least in part, to altered regulation of dopamine metabolism in the CNS induced by phenothiazines or haloperidol. 20 The differential diagnosis includes acute lethal catatonia; malignant hyperthermia, CNS infection, post-infectious encephalopathy, CNS manifestation of connective tissue disease, an acute cerebrovascular catastrophe, including hemorrhage or stroke, heat stroke,
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Table 3. Drugs and Toxins to Consider in Differential Diagnosis of Coma Sedatives Barbiturates Non-barbiturates Narcotics Alcohol Salicylates Organophosphate insecticides Lead Tricyclic antidepressants Carbon monoxide
tetanus, and strychnine poisoning. Because of its high mortality and the inability to anticipate its occurrence, it is important that the clinician be aware of the neuroleptic malignant syndrome. Recognition is the key to successfully treating this entity. Treatment includes stopping the antipsychotic agent and immediately initiating measures to reduce the patient's fever (e. g., ice water lavage, reducing environmental heat), hydration, and vigorous monitoring of respiratory and cardiovascular function, neurologic status, fluid status, and renal function. 8, 16, 20, 34 Therapy with the muscle relaxant dantrolene has been reported to be successful in a few cases. II. 17 One theory supporting its use is that the altered central dopamine metabolism leads to muscle rigidity. Dantrolene may act to reduce muscle rigidity peripherally and reduce heat generation and oxygen consumption. The dose of dantrolene used in adults has varied from 50 to 200 mg every 12 hours orally. Evaluation The diagnosis of phenothiazine or butyrophenone intoxication may be difficult due to the wide variety of presenting signs and symptoms. In an acute ingestion, the patient may only present with depressed state of consciousness. The differential diagnosis should include all other causes of acute coma, including infection, trauma, eNS hemorrhage, post-ictal state, metabolic disturbances, embolic problems following a dysrhythmia, electrolyte disturbance, and intoxication. A partial listing of agents presenting with coma is given in Table 3. If the patient presents with coma that is otherwise unexplained, a dysrhythmia, and pinpoint pupils, a phenothiazine ingestion should be suspected. The EKG abnormalities and orthostatic hypotension mentioned above, although not specific for antipsychotic intoxication, will be useful in the assessment of the patient. Acute onset of extrapyramidal signs should strongly suggest the diagnosis of either phenothiazine or butyrophenone ingestion. Other disorders that present with extrapyramidal signs such as Sydenham's chorea, dystonic cerebral palsy, dystonia musculorum deformans, Wilson's disease, and benign familial chorea present more gradually and usually with other associated findings. The urine ferric chloride test for phenothiazines is useful only if positive.I8 It is performed by adding a few drops of ferric chloride to a
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Table 4. Treatment of Phenothiazine or Butyrophenone Intoxications Support and monitoring of respiratory and cardiovascular status Ipecac if patient is awake and cooperative Gastric lavage if patient is unresponsive Activated charcoal to bind unabsorbed drug Extrapyramidal signs: IV benztropine mesylate 0.5 mg/kg, or IV diphenhydramine 2 mg/kg given slowly over 2-5 minutes. Dysrhythmias Ventricular-Phenytoin 10-15 mg/kg IV given slowly Lidocaine 1 mg/kg IV push Supraventricular-Supportive if not hemodynamically significant, cardioversion if unstable AV dissociation-Pacemaker Physostigmine-not a routine treatment-use for: Hemodynamically unstable supraventricular tachycardia unresponsive to cardioversion Actively convulsing patient who has not responded to adequate anticonvulsant treatment Ventricular dysrhythmias unresponsive to phenytoin, lidocaine, or cardioversion Neuroleptic malignant syndrome Reducing temperature-ice water, lavage, bathe in cool water Support of respiratory and cardiovascular symptoms Monitor respiratory, cardiovascular, eNS, and hydration status Dantrolene-O.5 mg/kg orally every 12 hr (experimental)
sample of acidified urine. A positive test gives a purple color. A negative test, however, does not rule out a phenothiazine ingestion. 18 Serum drug concentrations do not correlate well with clinical or pharmacologic activity of these agents. 28,35 Drug concentrations are typically quite different in children given the same dose. Serum haldoperidol concentrations ranged from 0.7 to 19 ng/ml, with doses ranging from 15 to 285 f,Lg/kg/day. There was no correlation between dose and plasma drug level, and a 15-fold variability was seen at the same daily dose (dose: 175 f,Lg/kg/day; plasma drug level ranged from 1.2 to 18 ng/ml).28, 35 Treatment
A summary of the treatment for intoxication by phenothiazines and butyrophenones is presented in Table 4. The treatment for antipsychotic agent ingestion is first and foremost supportive. Monitoring and support of respiratory and cardiovascular function is of primary importance. 2 Although they are not serious respiratory depressants, antipsychotic agents will potentiate respiratory depression from other agents such as narcotics. 4 If not contraindicated, administration of ipecac will aid in emptying the stomach of unabsorbed drug. If the patient is not alert enough for ipecac, gastric lavage may be useful. Due to the large volume of distribution and extensive tissue binding of these agents, hemodialysis, hemoperfusion, and forced diuresis are ineffective in enhancing drug removal from the patient and have no role in the treatment of antipsychotic intoxication. Phenytoin or lidocaine should be used for treatment of ventricular
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dysrhythmias. Drugs such as quinidine and procainamide should not be given, because they will add to the quinidine effect of phenothiazines. 19 If the child is hemodynamically unstable due to a supraventricular dysrhythmia, cardioversion is indicated. A pacemaker may be needed if the patient has atrioventricular (AV) dissociation. The extrapyramidal symptoms will, in most cases, respond to IV benztropine mesylate, 0.5 mg/kg, or IV diphenhydramine, 2 mg/kg.19, 25, 29 These agents are especially useful for acute dystonic reactions and will generally be successful in 2 to 5 minutes. There is a report that benztropine mesylate is preferred over diphenhydramine because of its less sedative properties. 25 There is also a report of the successful use of diazepam to treat 'a series of 20 patients who experienced dystonic reactions following phenothiazine administration. 32 Physostigmine is a reversible cholinesterase inhibitor, which has been used to treat patients with anticholinergic poisoning. It readily penetrates the blood-brain barrier and will act centrally to reverse eNS anticholinergic manifestations such as hallucinations, slurred speech, ataxia, and disorientation. Although physostigmine has been recommended by some investigators for the routine treatment of anticholinergic intoxications,9 there are major side effects, including bradycardia, mydriasis, ileus, urinary retention, seizures, severe bradycardia, asystole, hypotension, ventricular tachycardia, and atrial fibrillation. 24 Physostigmine is contraindicated in patients with asthma, cardiovascular disease, gastrointestinal obstruction, or urinary obstruction. Physostigmine is indicated for treatment (1) if the patient is experiencing severe hallucinations and agitation that may lead to severe self-induced injury, (2) if supraventricular dysrhythmias are present and the patient is hemodynamically unstable, (3) if the patient is seizing and has not responded to adequate treatment with standard anticonvulsants, and (4) if the patient has a ventricular dysrhythmia unresponsive to phenytoin or lidocaine. 24 According to the guidelines set forth by Kulig and Rumack,24 (1) Physostigmine should not be used just to "wake" the patient. (2) It should be used only when advanced life support is immediately available. (3) It should be used only with and after good supportive care has been instituted. (4) Atropine should be immediately available to be given if cholinergic toxicity develops. If cholinergic signs are present, atropine should be given at one half the dose of the physostigmine initially given. The treatment of neuroleptic malignant syndrome as mentioned above is supportive; recognition of the clinical entity and discontinuing the neuroleptic is of primary importance. The mainstays of therapy of this syndrome are to reduce the hyperthermia with lavage, cooling blankets, or chilled water baths; to support the respiratory and cardiovascular status; and to monitor neurologic and fluid status. Also, as noted above, dantrolene has been used to reduce muscle rigidity and oxygen consumption in a few cases. At the present time, there is not substantial evidence for the routine use of dantrolene in this disorder.
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SUMMARY Antipsychotic agents are widely used for the treatment of psychotic disorders as well as for the acute treatment of nausea and vomiting, cough and cold treatments, and as supplementary agents for sedation for minor surgical or diagnostic procedures. There are many different circumstances in which the clinican may encounter a child who has experienced antipsychotic drug toxicity, such as from an acute accidental ingestion or as a side effect from therapeutic use. The phenothiazines and butyrophenone drugs have many pharmacologic actions. Thus, a wide range of clinical symptoms and signs may be encountered with their use. Treatment of antipsychotic drug toxicity includes general supportive care and monitoring, along with specific treatment of certain situations such as acute extrapyramidal syndromes and neuroleptic malignant syndrome. An awareness of the diverse and complex manifestations that may be associated with these agents will greatly aid in the evaluation of a child who presents with unusual behavioral or neurologic problems. Due to the unpredictable toxicity of these drugs, routine therapeutic use for such conditions as nausea and vomiting and as cough or cold aids is not recommended.
REFERENCES 1. Ayd, F. J.: A survey of drug-induced extrapyramidal reactions. J.A.M.A., 175:1054-1060, 1961. 2. Baldersarian, R. J.: Drugs and the treatment of psychiatric disorders. In Gilman, A. C., Goodman, L. S., and Gilman, A. (eds.): The Pharmacological Basis of Therapeutics, Edition 6. New York, MacMillan, 1980, pp. 395--414. 3. Benitz, W. E., and Tatro, D. S.: The Pediatric Drug Handbook. Chicago, Year Book Medical Publishers, 1981, pp. 401-407. 4. Benusis, K. P., Kapaun, D., and Furnam, L. J.: Respiratory depression in a child following meperidine, promethazine, and chlorpromazine: Report of a case. J. Dent. Child., 46:50-53, 1979. 5. Burckart, G. J., Snidow, J., and Bruce, W.: Neutropenia following acute chlorpromazine ingestion. Clin. Toxico!., 18:797-801, 1981. 6. Burda, C. D.: Electrocardiographic abnormalities induced by thioridazine (Mellaril). Am. Heart J., 76:153-156, 1968. 7. Burgess, K. R., Jeffries, R. W., and Stevenson, 1. F.: Fatal thioridazine cardiotoxicity. Med. J. Aust., 2:177-178,1979. 8. Caroff, S. N.: The neuroleptic malignant syndrome. J. Clin. Psychiatry, 41:79--83, 1980. 9. Cleghorn, G. C., and Bourke, G.: Physostigmine for promethazine poisoning. Lancet, 2(8190):368-369, 1980. 10. Cohen, G. H., Cartas, A., Sapine, D. W., et al.: Decorticate posturing following "cardiac cocktail"; a transient complication of sedation for catheterization. Pediatr. Cardio!., 2:251-253, 1982. 11. Coons, D. J., Hillman, F. J., and Marshall, R. W.: Treatment of neuroleptic malignant syndrome with dantrolene sodium: A case report. Am. J. Psychiatry, 139:944-945, 1982. 12. Corless, J. D., and Buchanan, D. S.: Phenothiazine intoxication in children: A report of three cases. J.A.M.A., 194:565--567, 1965. 13. Cunningham, D. G., and Challopalli, M.: Hypertension in acute haloperidol poisoning. J. Pediatr., 95:489, 1979. 14. Darwish, H., Grant, R., Harlam, R., et al.: Promethazine-induced acute dystonic reactions. Am. J. Dis. Child., 134:990-991, 1980.
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15. Dincsoy, H. P., and Saelinger, D. A.: Haloperidol-induced chronic cholestatic liver disease. Gastroenterology, 83:694-700, 1982. 16. Geller, B., and Greydanus, D. E.: Haloperidol-induced comatose state with hyperthermia and rigidity in adolescence: Two case reports and a literature review. J. Clin. Psychiatry, 40:102-103, 1979. 17. Goulon, M., Chabot, P., Elkagarrat, D., et al.: Beneficial effects of dantrolene in the treatment of neuroleptic malignant syndrome: A report of 2 cases. Neurology, 33:516-518, 1983. 18. Gupta, J. M., and Lovejoy, F. H.: Acute phenothiazine toxicity in childhood: A five-year survey. Pediatrics, 39:771-774, 1967. 19. Guzzardi, L.: Phenothiazines and the antipsychotic agents. In Haddad, L. M., and Winchester, J. F. (eds.): Clinical Management of Poisoning and Drug Overdose. Philadelphia, W. B. Saunders Co., 1983, pp. 487-496. 20. Henderson, V. W., and Wooten, G. F.: Neuroleptic malignant syndrome: A pathogenic role for dopamine receptor blockade? Neurology, 31:132-137, 1981. 21. Joubert, P. A., and Olivia, J. A.: Fatal suicidal ingestion ofthioridazine. Clin. Toxicol., 7:133-138, 1974. 22. Kahn, A., and Blum, D.: Phenothiazine and sudden infant death syndrome. Pediatrics, 70:75-78, 1982. 23. Kaplan, A., Crawford, J., and Hamre, R: Phenothiazine-induced ketoacidosis. J. Iowa Med. Soc., 71:19-22, 1981. 24. Kulig, K., and Rumack, B. H.: Anticholinergic poisoning. In Haddad, L. M., and Winchester, J. F. (eds.): Clinical Management of Poisoning and Drug Overdose. Philadelphia, W. B. Saunders Co., 1983, pp. 485-486. 25. Lee, A. S.: Treatment of drug-induced dystonic reactions. J.A.C.E.P., 8:453-457, 1979. 26. Lui, W. Y.: Phenothiazine-induced dystonia associated with an increase in serum creatine phosphokinase. Arch. Dis. Child., 54:150-151, 1979. 27. Lumpkin, J., Watanabe, A., Rumack, B., et al.: Phenothiazine-induced ventricular tachycardia following acute overdose. J.A.C.E.P., 8:476-478, 1979. 28. Morselli, P. L., Bianchetti, G., Durand, G., et al.: Haloperidol plasma level monitoring in pediatric patients. Ther. Drug Monit., 1:35-46, 1979. 29. Ott, D. A., and Golden, S. R: Treatment of acute phenothiazine reaction. J.A.C.E.P., 8:471-472, 1979. 30. Petty, L. K., and Spar, C. J.: Haloperidol-induced tardive dyskinesia in a lO-year-old girl. Am. J. Psychiatry, 137:745-746, 1980. 31. Potts, A. M., and Gonaren, L. M.: Toxic responses of the eye. In Doull, J., Klassen, C. D., and Amdur, M. O. (eds.): Carsarett and Doull's Toxicology. New York, MacMillan, 1980, pp. 293-295. 32. Rainier-Pope, C. R: Treatment with diazepam of children with drug-induced extrapyramidal symptoms. S. Afr. Med. J., 55:328-330, 1979. 33. Sinaniotis, C. A., Spyrides, P., Vlachos, P., et al.: Acute haloperidol poisoning in children. J. Pediatr., 93:1038-1039, 1978. 34. Smego, R. A., and Durack, D. T.: The neuroleptic malignant syndrome. Arch. Intern. Med., 142:1183-1185, 1982. 35. Tsujimoto, A., Tsujimoto, G., Ishukazi, T., et al.: Toxic reactions with observation of serum haloperidol concentrations in two children. Dev. Pharmacol. Ther., 4:12-17, 1982. 36. Valachos, P.: Dystonic reactions following triethylperazine in children. Toxicol. Lett., 13:183-184, 1982. 37. Whyman, A.: Phenothiazine death: An unusual case report. J. Nerv. Ment. Dis., 163:214-217, 1976.
Department of Pharmacology University of Florida Gainesville FL 32610
Phenothiazine and Butyrophenone Intoxication in Children
M. E. Knight, M.D.,* and R.]. Roberts, M.D., Ph.D.t
Phenothiazine- and butyrophenone-type drugs are used for a variety of clinical problems, including chronic treatment of psychotic disorders in adults and children, acute symptoms of nausea and vomiting, cold symptoms, as antitussive agents, and for sedation for diagnostic procedures (bone marrow biopsy, cardiac catheterization, and so on). These drugs are associated with a wide variety of adverse effects. It is therefore important for the clinician to be aware of the clinical presentation and treatment of a child who experiences an adverse effect to one of these agents. This review will deal with the pharmacologic characteristics and features of toxicity of these agents and the evaluation and treatment of a child intoxicated with one of these drugs.
PHARMACOLOGY Chemical Classification of Agents and Actions The phenothiazine agents can be divided into three groups based on their chemical structure (Table 1).19 The dimethylamine group usually causes autonomic nervous system effects, including orthostatic hypotension and anticholinergic manifestations (e.g., dry mucous membranes, tachycar" dia). The piperazine group primarily elicits extrapyramidal symptoms. Agents in the third group, the piperidine class, are the most potent pharmacologically of all three groups, but they do not usually cause extrapyramidal symptoms. However, a drug from any of the three groups can elicit manifestations of the other groups. 19 The most common drug of the butyrophenone class (Table 1), haloperidol, is used as an antipsychotic agent.2 The other major drug of the *Division of Pediatric Clinical Pharmacology, Department of Pediatrics, College of Medicine, University of Florida, Gainesville, Florida tDivision of Pediatric Clinical Pharmacology, Department of Pediatrics, College of Medicine, University of Iowa, Iowa City, Iowa
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Table 1. Drug Classification and Associated Toxic Effects CLASS
Phenothiazines Dimethylamine Promazine Chlorpromazine Triflupromazine Methoxypromazine Piperazine Prochlorperazine Trifluoperazine Thiopropazate Perphenazine Fluphenazine Piperidine Thioridazine Pipamazine Mepazine Butyrophenones Haloperidol Droperidol Thioxanthines Thiothixine Chlorprothixene
TOXICITY MANIFESTATIONS
Anticholinergic effects (orthostatic hypotension. tachycardia, dry mucous membranes), disturbance of body temperature, dysrhythmias, neuroleptic malignant syndrome Sedation, extrapyramidal signs (dystonia, oculogyric crises, chorea), disturbance of body temperature, dysrhythmias, neuroleptic malignant syndrome
Most potent of three groups (above manifestations), but less likely to have extrapyramidal signs
Extrapyramidal signs, less anticholinergic signs and less sedation than phenothiazines, neuroleptic malignant syndrome Similar to phenothiazine class
Loxapine Similar to phenothiazine class
butyrophenone class is droperidol, which is used as an adjunct to narcotic analgesia. Another major chemical class, the thioxanthines, have side effects and toxic reactions very similar to the phenothiazines. 19 Loxapine, another chemically distinct agent, will also show clinical manifestations similar to phenothiazines. 19 The phenothiazine and butyrophenone drugs are reported to reduce psychotic symptoms, including hallucinations, paranoia, and delusions. 2 They also have sedative and anxiolytic properties. 2 Their mechanism of action is by antagonism of dopamine action in the central nervous system (eNS). The eNS synthesis of catecholamines is also reduced, especially in the hypothalamus, sensory areas, and the emetic center. Additional actions resulting from eNS effects include muscle relaxation, lowering of seizure threshold, and depression of vasomotor reflexes in the brain stem. The phenothiazines also have a number of other pharmacologic actions in the peripheral nervous system, including blockade of alpha-receptors, antihistaminic and anticholinergic properties, and blockade of re-uptake of adrenergic catecholamines in peripheral synapses. The alpha-blockade is believed to account for the increased levels of circulating norepinephrine and epinephrine observed after these agents have been taken. 2 Pharmacokinetics
About 40 to 80 per cent of the dose of phenothiazines and butyrophenones are absorbed from the gastrointestinal tract. 19 They are lipophilic
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drugs and are highly plasma protein bound (> 90 per cent).2 The volume of distribution is very large, 20 Llkg, accounting for the large amount of these agents within tissues. 2 The serum pharmacokinetics are multiphasic, with the alpha-T1I2 phase averaging 2 hours and the beta-T1I2 phase averaging 10 to 20 hours. 2 Due to the large volume of distribution and the lipophilic nature of these substances, the plasma elimination is more rapid than tissue elimination. The therapeutic dose range for these agents is wide, suggesting a large therapeutic index. 2, 19 In adults, 25 to 5000 mg/day for chlorpromazine and 0.5 to 30 mg/day for haloperidol are used for the treatment of chronic psychotic disorders. 2, 19 The recommended pediatric doses of chlorpromazine are from 0.5 mg/kg to a total of 40 mg for children younger than 5 years of age or a total of 75 mg for children 5 to 12 yrs of age. 3 The pediatric dose of haloperidol is reported to be 0.01 to 0.03 mglkg. 3 The reported fatal dose of these agents is from 30 to 300 times higher than the therapeutic dose (15 to 150 mg/kg), depending upon the particular agent used. 2, 3, 19 Much of the information regarding the toxicity of these agents comes from adverse effects seen during therapeutic uses of these drugs. Because of the wide range of therapeutic doses, the high therapeutic index, and the wide variety of complex pharmacologic actions, intoxication from antipsychotic agents may be difficult to anticipate or appreciate. Both phenothiazines and butyrophenones are metabolized extensively in the liver by glucuronidation and sulfoxidation. 2 There are many metabolites formed, some of which are pharmacologically active. The pharmacologic activity of the phenothiazines and butyrophenones may be of longer duration than their pharmacokinetics would predict due to the persistence of these agents in tissues and the presence of active metabolites. 2 The phenothiazines and butyrophenones can significantly potentiate the actions of sedative-hypnotic agents, analgesics, and antihistamines. 2
CLINICAL TOXICOLOGY The phenothiazines and butyrophenones have a large number of diverse toxic actions. The onset of toxic manifestations following phenothiazine or butyrophenone ingestion may be delayed 6 to 24 hours after the ingestion, and they may be intermittent in nature. 18, 19, 33 The systems involved with clinical intoxication are reviewed below. Central Nervous System. The signs of CNS intoxication include akathisia, akinesia, trismus, opisthotonos, torticollis, chorea, dystonia, and oculogyric crises. 12, 14, 18, 19, 30, 33 Diffuse eNS motor signs, including hyperreflexia, spasticity, and extensor plantar responses, may also be present. In adults, the signs tend to involve mainly the face and trunk, whereas children tend to have more generalized manifestations. Generalized dystonic reactions and oculogyric crises in particular are more frequent in children younger than 15 years of age. 19 Difficulty swallowing and dysarthria are also reported. Disturbances of temperature control with hypothermia or hyperthermia have also been observed. 19 The extrapyramidal signs may
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develop acutely after a single therapeutic dose or nontherapeutic ingestion or may develop after chronic therapy with these agents. 1. 10. 12. 14, 18, 30. 33, 36 The phenothiazines and butyrophenones are not actually physically addicting, but there may be a mild withdrawal syndrome manifested by difficulty sleeping, restlessness, and muscle aches. 2 Although the patient may become tolerant to the sedative properties of these agents, abrupt discontinuation may also lead to the emergence of dyskinesias and extrapyramidal signs. 2, 30 At therapeutic doses, irritability may also be a sign of a phenothiazine adverse effect and may be mistakenly interpreted as a sign of inadequate sedation. Administration of additional medication in these situations will further increase the intoxication. 10 Cardiovascular. The cardiovascular manifestations of phenothiazine intoxication include the following EKG changes: prolonged PR and QT interval; flattened, biphasic, or inverted T waves; and dysrhythmias, including supraventricular tachycardia, ventricular tachycardia, ventricular fibrillation, and atrioventricular dissociation. 2, 6, 19, 27 These EKG changes are due to the quinidine-like properties of phenothiazines. 2,19 The phenothiazines also have a negative inotropic influence on the myocardium. 2 Thioridazine, in particular, has been associated with more severe EKG and cardiac adverse effects. 6, 7 Orthostatic hypotension has been frequently seen in cases of phenothiazine ingestions. 2, 19 Up to 15 per cent of patients on therapeutic doses of chlorpromazine may experience orthostatic hypotension, although tolerance to this effect can emerge with continued therapy.19 The effects on blood pressure are complex due to the multiple pharmacologic actions (central, autonomic, direct).2, 19 Transient elevated blood pressure has been reported in one patient 34 hours after ingestion of haloperidol. 13 Otherwise, there have been no other consistent cardiovascular effects of haloperidol on the cardiovascular system. Cutaneous. Phenothiazine and haloperidol have been reported to cause several photosensitivity-type reactions. 19 In general, these reactions are less severe and less common with haloperidol than with the phenothiazines. Reactions have varied from an exaggerated sunburn reaction to a dermatitis on light-exposed areas, urticaria, and a purple-gray discoloration of the skin. 19 Hepatic. A type of presumed hypersensitivity reaction has been reported in 1 to 3 per cent of individuals on phenothiazines as well as in patients on haloperidol. 15, 19 The manifestations include jaundice and other features of liver injury, including fever, abdominal discomfort, malaise, anorexia, nausea, itching, eosinophilia, rash, and elevated transaminases and alkaline phosphatase. Serial liver biopsies of one patient have shown a picture of mainly cholestasis, with progression to spotty necrosis and fibrosis and bile duct damage. 15 Rarely do patients progress to cirrhosis, and recovery within 2 to 12 months is to be expected. 15 Ocular. The eye may also be a target of phenothiazine toxicity. The damage seen is due to alteration of several enzyme systems in melanincontaining cells (rods and cones). Phenothiazines bind to melanin and concentrate in these tissues. 31 This binding may cause alterations in normal
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activity of many enzyme systems in the rods and cones associated with metabolic processes involved with the biochemistry of vision perception. Clinically, visual acuity, visual fields, and color vision perception may be altered. 31 Hematologic. Severe reversible neutropenia has been reported in one 5-year-old child 45 hours after an acute ingestion of 100 to 200 mg of chlorpromazine. 5 The platelets, hemoglobin, and hematocrit were all normal. The mechanism is unknown, although a direct toxic action or immunologic mechanisms have been proposed. Miscellaneous. Transient ketoacidosis with hyperglycemia has been reported in a 17-year-old girl on 1200 mg/day of chlorpromazine and 100 mg/week of fluphenazine. 23 This disturbance was temporary and resolved with temporary insulin therapy. Deaths from Phenothiazine Overdose. Death associated with phenothiazine ingestion is uncommon but has been reported. 6, 21, 37 Theories on the cause of death in phenothiazine ingestion include sudden dysrhythmia or respiratory depression. Although therapeutic doses of phenothiazines decrease tidal volume and change the rhythm of respiration, these effects are generally not clinically significant. It has been argued that some individuals may have an exaggerated response to phenothiazines, which leads to death from respiratory depression. Thioridazine has been reported to have caused deaths. 6, 21 One individual experienced ventricular tachycardia and then a ventricular dysrhythmia with poor cardiac output after ingestion of 5000 mg of thioridazine. Another fatality occurred after ingestion of 3000 mg of thioridazine. At autopsy, extensive pulmona.ry damage was seen with pulmonary congestion, edema, and hyaline membrane formation. 6, 21 Nonspecific acute renal tubular necrosis was also seen, In a review of 56 children with sudden infant de~th syndrome (SIDS) and 36 children with near-miss SIDS episodes, there was greater use of phenothiazines in these children than in controls,22 This has suggested a role for phenothiazines in SIDS, but further documentation is needed,
CLINICAL EVALUATION AND TREATMENT There are three major presentations in patients affected with antipsychotic toxicity: (1) depressed neurologic status, meiosis, hypotension, and dysrhythmias;19 (2) extrapyramidal manifestations/ 9 and (3) neuroleptic malignant syndrome (Table 2). Acute Overdose. With a large acute ingestion of antipsychotic agents, the patient may present with coma, meiosis, hypotension, and dysrhythmias, Disturbance of body temperature homeostasis is also common, with hypothermia (more often seen with haloperidol) or hyperthermia (more often seen with a phenothiazine), 1, 2 Respiratory depression of clinical significance is usually not a major problem unless the patient has taken another respiratory depressing agent; for example, a narcotic in which the effect will be potentiated by the antipsychotic agent. 4 Extrapyramidal Symptoms. Extrapyramidal signs are associated with
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Table 2. Presentations of Phenothiazine or Butyrophenone Intoxications ACUTE OVERDOSE
Altered mental status (including coma) Orthostatic hypotension Dysrhythmia and EKG changes Pinpoint pupils Depressed respirations Usually occurs after a single large ingestion EXTRAPYRAMIDAL SYMPTOMS
Awake and alert patient Torsion of head and neck, dystonia, chorea-like movements, oculogyric crises, trismus May be intermittent and delayed up to 24 hours from ingestion May occur with acute or chronic therapeutic dosing NEUROLEPTIC MALIGNANT SYNDROME
Fever, diaphoresis, rigidity, tachycardia, coma Develops gradually over 24 to 72 hours Occurs in psychiatric and non psychiatric patients No relationship to duration of treatment with phenothiazines or haloperidol; may occur after a single dose
either an acute ingestion or are side effects of chronic treatment. They have also been associated with a single therapeutic dose, as in sedation for procedures (cardiac catheterization, biopsy, and so on). They may be delayed in onset up to 24 hours or more, and they may be intermittent in nature. Younger children tend to be prone to extrapyramidal signs and to have generalized manifestations, whereas adolescents and adults tend to have signs localized to the face and trunk. 18. 19. 33 Neuroleptic Malignant Syndrome. An uncommon but potentially lifethreatening adverse effect of phenothiazines or butyrophenones has been recently recognized. 8. 16. 20, 34 The characteristics of the neuroleptic malignant syndrome include fluctuating mental status progressing to coma and extrapyramidal symptoms, especially rigidity, fever, diaphoresis, tachycardia, and hypotension or hypertension. Laboratory findings include elevated white blood count, elevated CPK, and liver transaminases,8, 16, 20, 26, 34 This syndrome occurs in 1/2 to 1 per cent of patients on antipsychotic therapy, especially those on haloperidol or fluphenazine. It may be more common in people who have relatives with idiopathic Parkinson's disease. The mortality rate is 20 per cent and is due to cardiovascular and respiratory failure. The clinical features of the syndrome evolve gradually over 24 to 72 hours. There is no known relationship between dose or duration of dose or dosage and the development of neuroleptic malignant syndrome. It has occurred both in psychiatric patients on chronic treatment with antipsychotic agents and in nonpsychiatric patients after a single dose for sedative purposes. The pathophysiology of the disorder is thought to be due, at least in part, to altered regulation of dopamine metabolism in the CNS induced by phenothiazines or haloperidol. 20 The differential diagnosis includes acute lethal catatonia; malignant hyperthermia, CNS infection, post-infectious encephalopathy, CNS manifestation of connective tissue disease, an acute cerebrovascular catastrophe, including hemorrhage or stroke, heat stroke,
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Table 3. Drugs and Toxins to Consider in Differential Diagnosis of Coma Sedatives Barbiturates Non-barbiturates Narcotics Alcohol Salicylates Organophosphate insecticides Lead Tricyclic antidepressants Carbon monoxide
tetanus, and strychnine poisoning. Because of its high mortality and the inability to anticipate its occurrence, it is important that the clinician be aware of the neuroleptic malignant syndrome. Recognition is the key to successfully treating this entity. Treatment includes stopping the antipsychotic agent and immediately initiating measures to reduce the patient's fever (e. g., ice water lavage, reducing environmental heat), hydration, and vigorous monitoring of respiratory and cardiovascular function, neurologic status, fluid status, and renal function. 8, 16, 20, 34 Therapy with the muscle relaxant dantrolene has been reported to be successful in a few cases. II. 17 One theory supporting its use is that the altered central dopamine metabolism leads to muscle rigidity. Dantrolene may act to reduce muscle rigidity peripherally and reduce heat generation and oxygen consumption. The dose of dantrolene used in adults has varied from 50 to 200 mg every 12 hours orally. Evaluation The diagnosis of phenothiazine or butyrophenone intoxication may be difficult due to the wide variety of presenting signs and symptoms. In an acute ingestion, the patient may only present with depressed state of consciousness. The differential diagnosis should include all other causes of acute coma, including infection, trauma, eNS hemorrhage, post-ictal state, metabolic disturbances, embolic problems following a dysrhythmia, electrolyte disturbance, and intoxication. A partial listing of agents presenting with coma is given in Table 3. If the patient presents with coma that is otherwise unexplained, a dysrhythmia, and pinpoint pupils, a phenothiazine ingestion should be suspected. The EKG abnormalities and orthostatic hypotension mentioned above, although not specific for antipsychotic intoxication, will be useful in the assessment of the patient. Acute onset of extrapyramidal signs should strongly suggest the diagnosis of either phenothiazine or butyrophenone ingestion. Other disorders that present with extrapyramidal signs such as Sydenham's chorea, dystonic cerebral palsy, dystonia musculorum deformans, Wilson's disease, and benign familial chorea present more gradually and usually with other associated findings. The urine ferric chloride test for phenothiazines is useful only if positive.I8 It is performed by adding a few drops of ferric chloride to a
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Table 4. Treatment of Phenothiazine or Butyrophenone Intoxications Support and monitoring of respiratory and cardiovascular status Ipecac if patient is awake and cooperative Gastric lavage if patient is unresponsive Activated charcoal to bind unabsorbed drug Extrapyramidal signs: IV benztropine mesylate 0.5 mg/kg, or IV diphenhydramine 2 mg/kg given slowly over 2-5 minutes. Dysrhythmias Ventricular-Phenytoin 10-15 mg/kg IV given slowly Lidocaine 1 mg/kg IV push Supraventricular-Supportive if not hemodynamically significant, cardioversion if unstable AV dissociation-Pacemaker Physostigmine-not a routine treatment-use for: Hemodynamically unstable supraventricular tachycardia unresponsive to cardioversion Actively convulsing patient who has not responded to adequate anticonvulsant treatment Ventricular dysrhythmias unresponsive to phenytoin, lidocaine, or cardioversion Neuroleptic malignant syndrome Reducing temperature-ice water, lavage, bathe in cool water Support of respiratory and cardiovascular symptoms Monitor respiratory, cardiovascular, eNS, and hydration status Dantrolene-O.5 mg/kg orally every 12 hr (experimental)
sample of acidified urine. A positive test gives a purple color. A negative test, however, does not rule out a phenothiazine ingestion. 18 Serum drug concentrations do not correlate well with clinical or pharmacologic activity of these agents. 28,35 Drug concentrations are typically quite different in children given the same dose. Serum haldoperidol concentrations ranged from 0.7 to 19 ng/ml, with doses ranging from 15 to 285 f,Lg/kg/day. There was no correlation between dose and plasma drug level, and a 15-fold variability was seen at the same daily dose (dose: 175 f,Lg/kg/day; plasma drug level ranged from 1.2 to 18 ng/ml).28, 35 Treatment
A summary of the treatment for intoxication by phenothiazines and butyrophenones is presented in Table 4. The treatment for antipsychotic agent ingestion is first and foremost supportive. Monitoring and support of respiratory and cardiovascular function is of primary importance. 2 Although they are not serious respiratory depressants, antipsychotic agents will potentiate respiratory depression from other agents such as narcotics. 4 If not contraindicated, administration of ipecac will aid in emptying the stomach of unabsorbed drug. If the patient is not alert enough for ipecac, gastric lavage may be useful. Due to the large volume of distribution and extensive tissue binding of these agents, hemodialysis, hemoperfusion, and forced diuresis are ineffective in enhancing drug removal from the patient and have no role in the treatment of antipsychotic intoxication. Phenytoin or lidocaine should be used for treatment of ventricular
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dysrhythmias. Drugs such as quinidine and procainamide should not be given, because they will add to the quinidine effect of phenothiazines. 19 If the child is hemodynamically unstable due to a supraventricular dysrhythmia, cardioversion is indicated. A pacemaker may be needed if the patient has atrioventricular (AV) dissociation. The extrapyramidal symptoms will, in most cases, respond to IV benztropine mesylate, 0.5 mg/kg, or IV diphenhydramine, 2 mg/kg.19, 25, 29 These agents are especially useful for acute dystonic reactions and will generally be successful in 2 to 5 minutes. There is a report that benztropine mesylate is preferred over diphenhydramine because of its less sedative properties. 25 There is also a report of the successful use of diazepam to treat 'a series of 20 patients who experienced dystonic reactions following phenothiazine administration. 32 Physostigmine is a reversible cholinesterase inhibitor, which has been used to treat patients with anticholinergic poisoning. It readily penetrates the blood-brain barrier and will act centrally to reverse eNS anticholinergic manifestations such as hallucinations, slurred speech, ataxia, and disorientation. Although physostigmine has been recommended by some investigators for the routine treatment of anticholinergic intoxications,9 there are major side effects, including bradycardia, mydriasis, ileus, urinary retention, seizures, severe bradycardia, asystole, hypotension, ventricular tachycardia, and atrial fibrillation. 24 Physostigmine is contraindicated in patients with asthma, cardiovascular disease, gastrointestinal obstruction, or urinary obstruction. Physostigmine is indicated for treatment (1) if the patient is experiencing severe hallucinations and agitation that may lead to severe self-induced injury, (2) if supraventricular dysrhythmias are present and the patient is hemodynamically unstable, (3) if the patient is seizing and has not responded to adequate treatment with standard anticonvulsants, and (4) if the patient has a ventricular dysrhythmia unresponsive to phenytoin or lidocaine. 24 According to the guidelines set forth by Kulig and Rumack,24 (1) Physostigmine should not be used just to "wake" the patient. (2) It should be used only when advanced life support is immediately available. (3) It should be used only with and after good supportive care has been instituted. (4) Atropine should be immediately available to be given if cholinergic toxicity develops. If cholinergic signs are present, atropine should be given at one half the dose of the physostigmine initially given. The treatment of neuroleptic malignant syndrome as mentioned above is supportive; recognition of the clinical entity and discontinuing the neuroleptic is of primary importance. The mainstays of therapy of this syndrome are to reduce the hyperthermia with lavage, cooling blankets, or chilled water baths; to support the respiratory and cardiovascular status; and to monitor neurologic and fluid status. Also, as noted above, dantrolene has been used to reduce muscle rigidity and oxygen consumption in a few cases. At the present time, there is not substantial evidence for the routine use of dantrolene in this disorder.
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SUMMARY Antipsychotic agents are widely used for the treatment of psychotic disorders as well as for the acute treatment of nausea and vomiting, cough and cold treatments, and as supplementary agents for sedation for minor surgical or diagnostic procedures. There are many different circumstances in which the clinican may encounter a child who has experienced antipsychotic drug toxicity, such as from an acute accidental ingestion or as a side effect from therapeutic use. The phenothiazines and butyrophenone drugs have many pharmacologic actions. Thus, a wide range of clinical symptoms and signs may be encountered with their use. Treatment of antipsychotic drug toxicity includes general supportive care and monitoring, along with specific treatment of certain situations such as acute extrapyramidal syndromes and neuroleptic malignant syndrome. An awareness of the diverse and complex manifestations that may be associated with these agents will greatly aid in the evaluation of a child who presents with unusual behavioral or neurologic problems. Due to the unpredictable toxicity of these drugs, routine therapeutic use for such conditions as nausea and vomiting and as cough or cold aids is not recommended.
REFERENCES 1. Ayd, F. J.: A survey of drug-induced extrapyramidal reactions. J.A.M.A., 175:1054-1060, 1961. 2. Baldersarian, R. J.: Drugs and the treatment of psychiatric disorders. In Gilman, A. C., Goodman, L. S., and Gilman, A. (eds.): The Pharmacological Basis of Therapeutics, Edition 6. New York, MacMillan, 1980, pp. 395--414. 3. Benitz, W. E., and Tatro, D. S.: The Pediatric Drug Handbook. Chicago, Year Book Medical Publishers, 1981, pp. 401-407. 4. Benusis, K. P., Kapaun, D., and Furnam, L. J.: Respiratory depression in a child following meperidine, promethazine, and chlorpromazine: Report of a case. J. Dent. Child., 46:50-53, 1979. 5. Burckart, G. J., Snidow, J., and Bruce, W.: Neutropenia following acute chlorpromazine ingestion. Clin. Toxico!., 18:797-801, 1981. 6. Burda, C. D.: Electrocardiographic abnormalities induced by thioridazine (Mellaril). Am. Heart J., 76:153-156, 1968. 7. Burgess, K. R., Jeffries, R. W., and Stevenson, 1. F.: Fatal thioridazine cardiotoxicity. Med. J. Aust., 2:177-178,1979. 8. Caroff, S. N.: The neuroleptic malignant syndrome. J. Clin. Psychiatry, 41:79--83, 1980. 9. Cleghorn, G. C., and Bourke, G.: Physostigmine for promethazine poisoning. Lancet, 2(8190):368-369, 1980. 10. Cohen, G. H., Cartas, A., Sapine, D. W., et al.: Decorticate posturing following "cardiac cocktail"; a transient complication of sedation for catheterization. Pediatr. Cardio!., 2:251-253, 1982. 11. Coons, D. J., Hillman, F. J., and Marshall, R. W.: Treatment of neuroleptic malignant syndrome with dantrolene sodium: A case report. Am. J. Psychiatry, 139:944-945, 1982. 12. Corless, J. D., and Buchanan, D. S.: Phenothiazine intoxication in children: A report of three cases. J.A.M.A., 194:565--567, 1965. 13. Cunningham, D. G., and Challopalli, M.: Hypertension in acute haloperidol poisoning. J. Pediatr., 95:489, 1979. 14. Darwish, H., Grant, R., Harlam, R., et al.: Promethazine-induced acute dystonic reactions. Am. J. Dis. Child., 134:990-991, 1980.
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15. Dincsoy, H. P., and Saelinger, D. A.: Haloperidol-induced chronic cholestatic liver disease. Gastroenterology, 83:694-700, 1982. 16. Geller, B., and Greydanus, D. E.: Haloperidol-induced comatose state with hyperthermia and rigidity in adolescence: Two case reports and a literature review. J. Clin. Psychiatry, 40:102-103, 1979. 17. Goulon, M., Chabot, P., Elkagarrat, D., et al.: Beneficial effects of dantrolene in the treatment of neuroleptic malignant syndrome: A report of 2 cases. Neurology, 33:516-518, 1983. 18. Gupta, J. M., and Lovejoy, F. H.: Acute phenothiazine toxicity in childhood: A five-year survey. Pediatrics, 39:771-774, 1967. 19. Guzzardi, L.: Phenothiazines and the antipsychotic agents. In Haddad, L. M., and Winchester, J. F. (eds.): Clinical Management of Poisoning and Drug Overdose. Philadelphia, W. B. Saunders Co., 1983, pp. 487-496. 20. Henderson, V. W., and Wooten, G. F.: Neuroleptic malignant syndrome: A pathogenic role for dopamine receptor blockade? Neurology, 31:132-137, 1981. 21. Joubert, P. A., and Olivia, J. A.: Fatal suicidal ingestion ofthioridazine. Clin. Toxicol., 7:133-138, 1974. 22. Kahn, A., and Blum, D.: Phenothiazine and sudden infant death syndrome. Pediatrics, 70:75-78, 1982. 23. Kaplan, A., Crawford, J., and Hamre, R: Phenothiazine-induced ketoacidosis. J. Iowa Med. Soc., 71:19-22, 1981. 24. Kulig, K., and Rumack, B. H.: Anticholinergic poisoning. In Haddad, L. M., and Winchester, J. F. (eds.): Clinical Management of Poisoning and Drug Overdose. Philadelphia, W. B. Saunders Co., 1983, pp. 485-486. 25. Lee, A. S.: Treatment of drug-induced dystonic reactions. J.A.C.E.P., 8:453-457, 1979. 26. Lui, W. Y.: Phenothiazine-induced dystonia associated with an increase in serum creatine phosphokinase. Arch. Dis. Child., 54:150-151, 1979. 27. Lumpkin, J., Watanabe, A., Rumack, B., et al.: Phenothiazine-induced ventricular tachycardia following acute overdose. J.A.C.E.P., 8:476-478, 1979. 28. Morselli, P. L., Bianchetti, G., Durand, G., et al.: Haloperidol plasma level monitoring in pediatric patients. Ther. Drug Monit., 1:35-46, 1979. 29. Ott, D. A., and Golden, S. R: Treatment of acute phenothiazine reaction. J.A.C.E.P., 8:471-472, 1979. 30. Petty, L. K., and Spar, C. J.: Haloperidol-induced tardive dyskinesia in a lO-year-old girl. Am. J. Psychiatry, 137:745-746, 1980. 31. Potts, A. M., and Gonaren, L. M.: Toxic responses of the eye. In Doull, J., Klassen, C. D., and Amdur, M. O. (eds.): Carsarett and Doull's Toxicology. New York, MacMillan, 1980, pp. 293-295. 32. Rainier-Pope, C. R: Treatment with diazepam of children with drug-induced extrapyramidal symptoms. S. Afr. Med. J., 55:328-330, 1979. 33. Sinaniotis, C. A., Spyrides, P., Vlachos, P., et al.: Acute haloperidol poisoning in children. J. Pediatr., 93:1038-1039, 1978. 34. Smego, R. A., and Durack, D. T.: The neuroleptic malignant syndrome. Arch. Intern. Med., 142:1183-1185, 1982. 35. Tsujimoto, A., Tsujimoto, G., Ishukazi, T., et al.: Toxic reactions with observation of serum haloperidol concentrations in two children. Dev. Pharmacol. Ther., 4:12-17, 1982. 36. Valachos, P.: Dystonic reactions following triethylperazine in children. Toxicol. Lett., 13:183-184, 1982. 37. Whyman, A.: Phenothiazine death: An unusual case report. J. Nerv. Ment. Dis., 163:214-217, 1976.
Department of Pharmacology University of Florida Gainesville FL 32610