Antipsychotic drugs in the general hospital: Uses and cautions

JERROLD G. BERNSTEIN, M.D.

Antipsychotic drugs in the general hospital: Uses and cautions A variety of clinical problems may arise when a patient being treated with antipsychotic drugs is admitted to a general hospital for a medical or surgical problem. Other difficulties arise when a patient becomes acutely psychotic while hospitalized for a nonpsychiatric illness. This report focuses on the use of antipsychotic drugs in medically ill hospitalized patients, including a description of the major drug interactions that may occur and the physical effects of antipsychotic drugs that may be of importance in medically ill patients.

ABSTRACT:

The therapeutic value of antipsychotic drugs in the management of acute schizophrenia and manic illness, and for maintenance therapy to prevent recurrence of psychotic symptoms in schizophrenic patients, is well known. In patients admitted to the general hospital for medical or surgical problems, these drugs have three major indications: (I) treatment ofacute psychosis; (2) maintenance of schizophrenic patients; (3) treatment of agitation, anxiety, and confusion.

A favorable response to antipsychotic chemotherapy depends on the choice of an appropriate drug and must take into account potential interactions between antipsychotics and other medications the patient may be receiving. An awareness of drug-illness interactions, in which a particular side-effect of a drug may exacerbate a patient's physical illness, is also essential. This presentation will focus on medical and psychiatric aspects of

Dr. Bernstein is assistant clinical professor ofpsychiatry at Harvard Medical School, assistant psychiatrist at Massachusetts General Hospital, and associate medical director at the Human Resource Institute ofBoston. Reprint requests to Dr. Bernstein at 227 Babcock Street, Brookline, MA 02146. MAY 1979· VOL 20· NO 5

the safe use of antipsychotic drugs in patients suffering from concurrent medical or surgical illness. Since some understanding of the pharmacology and potential adverse effects of antipsychotic drugs is of particular importance in the treatment of patients whose general health is impaired, I shall begin by briefly discussing these aspects of antipsychotic drugs. I will then discuss various clinical problems that may arise in hospitalized patients receiving antipsychotic drugs and give guidelines for the use of these drugs in specific situations. These guidelines are presented in outline form in the Box.

PHARMACOLOGY Many chemical substances have the ability to alleviate psychotic symptoms such as hallucinations, delusions, disordered thinking, and agitation. These substances may be divided into five chemically distinct groups: (I) phenothiazines, such as chlorpromazine, thioridazine, and trifluoperazine; (2) thioxanthenes, such as thiothixene; (3) butyrophenones, such as haloperidol; (4) 335

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dihydroindolones, such as molindone; and (5) dibenzoxazepines, such as loxapine. In addition to the structural differences among the various antipsychotic drugs, they also differ in their potency, efficacy, and side-effects. The one thing that all drugs with proven antipsychotic effect have in common is their ability to block dopamine. It is generally believed that their dopamineblocking ability determines their ability to inhibit psychotic symptoms. Furthermore, the affinity of the various antipsychotic drugs for dopamine receptors parallels their clinical potency and efficacy. Those drugs with lower dopamine-receptor-blocking activity, such as chlorpromazine, exhibit less antipsychotic action clinically. The antipsychotic drug with the greatest affinity for dopamine receptors is haloperidol, which shows the greatest clinical potency among antipsychotic drugs. I Antipsychotic drugs also antagonize alpha-adrenergic and cholinergic receptors. This action is of considerable importance when these drugs are used clinically, particularly in patients with cardiovascular disease or other medical problems. 1.2 CLINICAL ASPECTS Hypotension Peripheral alpha-adrenergic blockade gives rise to vasodilation and hypotension. Hypotension is particularly prominent in association with postural change, but blood pressure may also diminish in some patients without postural change. Among the antipsychotic drugs, chlorpromazine has the greatest alpha-adrenergic blocking activity and the greatest likelihood of producing hypotension, while thioridazine also has considerable ability MAY 1979· VOL 20· NO 5

to lower blood pressure. The piperazine phenothiazines such as trifluoperazine and fluphenazine have much less hypotensive activity, while the butyrophenone haloperidol has the least ability to block alpha receptors and, therefore, the least hypotensive potential of the currently available antipsychotic drugs. Patients with low blood pressure, those with a history of postural hypotension, and those whose circulatory homeostasis is impaired present particular risks when treated with the more hypotensive antipsychotic drugs such as chlorpromazine and thioridazine. In such patients, haloperidol is the

Another significant medical effect ofantipsychotic drugs is their ability to modify the electrocardiogram. drug of choice because of its lesser effect on circulation. However, if chlorpromazine and haloperidol are given intramuscularly within a short time interval of each other, the risk of hypotension increases. In general, patients who complain of fainting episodes or weakness should not be treated with the more hypotensive antipsychotic drugs. Furthermore, individuals who are receiving peripheral, coronary, or cerebral vasodilators may be particularly susceptible to the hypotensive action of drugs such as chlorpromazine and thioridazine. Also, patients receiving other alpha-adrenergic blocking drugs or beta-adrenergic antagonists such as propranolol may be more susceptible to the hypotensive action of the antipsychotic agents. This may have particular clinical importance, since the production of systemic

vasodilation and hypotension may impair both coronary and cerebral perfusion. 1.2 Anticholinergic action The ability of antipsychotic drugs to block cholinergic receptors is well known to all clinicians. The most common signs of anticholinergic action are blurred vision, dry mouth, decreased sweating, constipation, urinary retention, and tachycardia. The commonly used antiparkinsonian drugs and all of the tricyclic antidepressants have anticholinergic effects that are additive with those produced by the antipsychotic agents. Furthermore, patients in a general hospital setting may also be receiving atropine or other anticholinergic agents for medical indications. These patients may also be receiving antihistamines, which often possess prominent anticholinergic activity. All these drugs produce additive drug interactions with the anticholinergic effect of neuroleptics. In addition to the commonly seen physiologic manifestations of cholinergic blockade, it is not uncommon to see behavioral consequences of this pharmacologic action, as manifested by agitation, bizarre behavior, confusion, and disorientation. These unwanted effects are particularly likely to occur in patients treated in the general hospital setting, especially the elderly, the seriously ill, and those with underlying organic brain syndromes. Among the commonly used antipsychotic drugs, thioridazine has the greatest anticholinergic effect, while chlorpromazine also exerts prominent cholinergic blockade. Trifluoperazine and fluphenazine have less anticholinergic action, and haloperidol appears to have the least anticholinergic potency. In 339

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order to minimize the risk of physical and behavioral complications of cholinergic blockade, it is generally preferable to utilize the more potent antipsychotic drugs that have limited anticholinergic activity. Also, it is important to minimize the unnecessary use of antiparkinsonian drugs and other agents with anticholinergic activity when using antipsychotic agents in the treatment of medical patients. Patients at risk Elderly persons are particularly susceptible to constipation and may be especially sensitive to the development of this effect of antipsychotic agents. Patients with urinary tract anomalies, prostatic hypertrophy, and carcinoma of the prostate are likely to suffer urinary retention if they are subjected to excessive cholinergic blockade. Patients with narrow-angle glaucoma are at high risk for visual impairment and further optic damage when treated with anticholinergic drugs, although such agents generally can be used safely in the presence of open-angle glaucoma. Excessive cholinergic blockade can produce sinus tachycardia, which may be quite benign though perhaps unpleasant in a young, healthy individual; in an elderly person or one with serious cardiac disease, however, a dramatic increase in heart rate will decrease ventricular filling time and may lead to decreased cardiac output or perhaps even the development or worsening of congestive heart failure. 3,4 Use of physostigmine

A patient who becomes more confused, agitated, or disoriented during treatment with antipsychotic drugs or other compounds with an342

ticholinergic actIvIty may benefit by the administration of physostigmine, a cholinesterase inhibitor that increases availability of acetylcholine by blocking its metabolism. The administration of I mg of physostigmine intramuscularly or by slow intravenous injection will produce signs of cholinergic stimulation, including increased salivation, sweating, abdominal cramping, the desire to urinate or defecate, and often a reduction in heart rate. Development of these physiologic effects following physostigmine administration, along with a clearing of the confusional state or behavioral abnormality, suggests that the

Antipyschotic drugs are not recommended in the treatment ofbarbiturate or sedative drug withdrawal behavioral symptoms occurred as a result of excessive cholinergic blockade. Such a positive physostigmine test should lead the clinician to discontinue temporarily the administration of drugs with anticholinergic activity, and to sedate the patient; subsequently, if appropriate, an antipsychotic agent with lower anticholinergic potential, such as haloperidol or one of the piperazine phenothiazines, should be given. s ECG changes Another significant medical effect of antipsychotic drugs is their ability to modify the electrocardiogram. The most prominent electrocardiographic changes seen in association with phenothiazine therapy consist of ST -segment depression, T-wave flattening or inversion, and prolongation of the

Q-T interval. These changes are most likely to occur with thioridazine; in fact, they have been recorded in up to 50% of patients receiving this drug in a dose of 100 to 300 mg daily. Similar electrocardiographic changes have also occurred in association with chlorpromazine. l ,2 The piperazine phenothiazines and thiothixene are less likely to affect the electrocardiogram, while haloperidol has not been reported to produce electrocardiographic changes. The changes produced by phenothiazines in the electrocardiogram often resemble the ECG pattern of coronary ischemia. Though these agents do not produce myocardial ischemia, the ECG abnormalities seen may be particularly confusing to the clinician and may lead to overly aggressive treatment of the patient whose electrocardiogram has become abnormal. Phenothiazine-induced ST-segment and Twave abnormalities generally disappear after the antipsychotic drug is discontinued. On the other hand, the development of these ECG abnormalities does not imply myocardial pathology and does not necessarily call for discontinuation of medication. Prolongation of the Q-T interval, which can result during phenothiazine therapy, may be of more significant importance: conduction disturbances and arrhythmias have been noted to occur with phenothiazines, and occasional sudden deaths, presumably arrhythmic, have resulted during phenothiazine therapy. It is also conceivable that in susceptible individuals who develop conduction disturbances during phenothiazine therapy, this effect may be further complicated by the co-administration of various antiarrhythmic drugs such as PSYCHOSOMATICS

quinidine and procainamide. 4 Recent studies indicate that tricyclic antidepressants such as imipramine have quinidine-like activity and could conceivably produce an additive drug interaction when used along with conventional antiarrhythmic drugs. 4 In fact, tricyclic antidepressants may depress myocardial contractility and perhaps lead to congestive heart failure; the possibility of a similar effect being produced by phenothiazines must also be kept in mind, in light of their structural similarity to the tricyclic antidepressants. 4•6 Seizure threshold Antipsychotic medications have an ability to lower the seizure threshold experimentally and clinically. This is of primary importance in a patient who has a seizure disorder and who requires treatment for psychosis. Chlorpromazine has the greatest ability to lower seizure threshold; the piperazine phenothiazines are less likely to do so; haloperidol has even less effect; and thioridazine has the least effect. Therefore, in a patient whose seizures have been difficult to control and who requires antipsychotic medicine, haloperidol or thioridazine would be the preferable agent, and chlorpromazine would be the least desirable. Patients on antipsychotic drug maintenance whose seizure disorders become difficult to manage should be reassessed and possibly have their antipsychotic regimen changed. 1.7.8 Liver disease Patients with hepatic disease may, from time to time, require antipsychotic drug therapy. If so, two things should be kept in mind: first, drug metabolism is slowed in an individual with impaired liver MAY 1979· VOL 20' NO 5

function; and second, some drugs produce their own adverse effects on liver function. 8 Among the antipsychotic drugs, chlorpromazine is most likely to affect liver function adversely by producing cholestasis, presumably as an allergic response. This effect of chlorpromazine is relatively uncommon, occurring in perhaps less than 1% of patients taking the drug. Piperazine phenothiazines are even less likely to induce this effect, and haloperidol has not been associated with cholestatic jaundice. In any patient with impaired liver function, it is important to use the lowest possible dose of antipsychotic drug and titrate the dosage upward slowly, preferably using a piperazine phenothiazine or haloperidol. Agranulocytosis Although agranulocytosis is rarely seen in association with antipsy-

chotic drugs, the possibility of this adverse effect should be kept in mind. 8 If it does occur, it generally appears in the first few weeks of treatment and rarely after the first two months. The awareness of this possibility is primarily important when patients with known hematologic disease are treated with antipsychotic agents. Prolactin levels The antipsychotic drugs tend to elevate circulation levels of prolactin, and this mechanism appears to account for the rare occurrence of gynecomastia in men and the occasional occurrence of galactorrhea and breast enlargement in women. All antipsychotic drugs are capable of inducing these effects and, thus far, there is no evidence to suggest that one drug is less likely to be problematic in this area than another. Amenorrhea and other men-

Guidelines tor U 01 Antipsychotic Drugs In the General HospItal 1. Hospitalized patients are likely to be receiving multiple drugs, which may interact with antipsychotic agents. 2. Use of more potent antipsychotic agents such as haloperldol is generally preferable because of lesser likelihood of cardiovascular and anticholinergic effects. 3. Chlorpromazine and thioridazine may produce ECG changes resembling those of coronary ischemia. 4. Avoid prophylactic antiparkinsonian drugs. if possible. If needed, administer them in the lowest possible dosage, and remember that the patient may be getting other drugs with anticholinergic effects. 5. Do not give chlorpromazine to patients with seizure disorders. especially if poorly controlled. Instead, use thloridazine or haloperldol. 6. Administer antipsychotic drugs in divided doses, titrating dosage upward as needed to provide the desired effect. 7. Be cautious about drug dosage in patients with impaired metabolic ability, such as those with hepatic. renal, and pulmonary disease. 8. Avoid antipsychotic drugs In patients who may be withdrawing from barbiturates or sedative/hypnotic drugs until their clinical status is clarified by a pentobarbital-tolerance test.

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strual irregularities occasionally occur in psychiatric patients with or without drug treatment 8; the ability of neuroleptic agents to increase serum prolactin levels, however, may explain their ability to induce menstrual disturbances. Awareness of the possible development of these endocrinologic effects of antipsychotic drugs is particularly important in patients who may have coexisting gynecologic or endocrine disorders.

Drug withdrawal A final word of caution regarding the use of antipsychotic drugs in general hospital patients is that patients withdrawing from sedative/ hypnotic drugs such as the barbiturates and benzodiazepines may have their clinical picture blurred or worsened by the administration of antipsychotic drugs. Patients

who are addicted to sedative/hypnotic drugs are often seen in the general hospital; they need to be evaluated by a pentobarbital-tolerance test and subsequently withdrawn, using gradually reduced dosages of a barbiturate such as phenobarbital. If an antipsychotic drug is given instead of the proper course of withdrawal, such a patient may have a greater potential to develop seizures or hypotension. The agent of greatest concern in patients withdrawing from sedatives is chlorpromazine, since it has the greatest ability to lower seizure threshold and produce hypotension. If haloperidol is inadvertently given to such a patient, or must be given during the course of barbiturate detoxification, serious adverse reactions are not likely to occur since this drug has a limited ability to lower seizure threshold and min-

imallikelihood of producing hypotension. Nevertheless, antipsychotic drugs are not recommended in the treatment of barbiturate or sed0 ative drug withdrawal. I REFERENCES 1. Bernstein JG (ad): Clinical Psychopharmacology. Littleton, Mass, PSG Publishing Co. 1978. 2. Bernstein JG: Medical psychiatric-drug interactiOns. in Hackett TP. Cassem NH (ads): MGH Handbook of General Hospital Psychiatry. SI. Louis, CV Mosby Co. 1978. pp

483-507. 3. Bigger JT. Giardina EGV, Perel JM. et al: Cardiac antiarrhythmic effect ot imipramine hydrochloride. N EnglJ Med2H:206-208. 1977. 4. Fowler NO, McCall D. Chou TC. et al: ElectrocardiOgraphic change and cardiac arrhythmias in patients receiving psychotropic drugs. Am J Cardio/37:223-230. 1976. 5. Granacher AP, Baldessarini AJ: Physostigmine. Arch Gen Psychiatry 32:375-380.1975. 6. Jefferson JW: A review of the cardiOvascular effects and toxicity of tricyclic antidepressants. Psychosom Med 37:160-179,1975. 7. Shader AI: Psychiatric Complications of Medical Drugs. New York. Aaven Press. 1972. 8. Shader AI. DiMasciO A: Psychotropic Drug Side Effects. Bahimore. W~liams & Wilkins Co, 1970.

Case Reports PSYCHOSOMATICS has recently introduced a new department for the presentation of Case Reports. Submissions are invited of reports of provocative or interesting clinical experiences in psychosomatic medicine-particularly those that suggest improved therapies or raise pertinent questions about currently used therapies. Contributions should include a brief introduction, followed by a description of one or two cases, a short statement of their significance, and suggestions for further study, They should not exceed 1,200 words. Attach a short list of references, cited by number in the text of the report. Submit two copies to: Wilfred Dorfman, M.D. Editor in Chief Psychosomatics 1921 Newkirk Avenue Brooklyn, NY 11226

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