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The widespread use of psychotropic medications has caused many patients to seek help because of drug toxicity. In such cases, the emergency clinician's goals include rapidly reversing the toxicity, counseling and educating the patient on how to prevent further problems, and encouraging him to pursue follow-up care with the prescribing physician or clinic.
Because patients seen in the emergency service for drug reactions are being treated elsewhere, the clinician has a dual role; to treat the patient and to preserve the continuity of the therapy. Perhaps the most important clinical responsibility in this area is alertness to psychotropic drug side effects, especially in vulnerable populations such as elderly patients.
In general, the clinician should take the following approach to patients with psychotropic drug toxicity:
Chronically psychotic persons living in community residences are commonly treated with high doses of a high-potency oral or long-acting intramuscular (depot) neuroleptic (antipsychotic) agent. Because the patient's clinic appointments may be 2 to 4 weeks apart, the clinician in the psychiatric emergency service or hospital may be the one to discover and treat drug side effects. The side effects of antipsychotic agents are so numerous that the interested reader should consult a textbook of psychopharmacology (Baldessarini, 1985; Mason and Granacher, 1980). Fortunately, most drug reactions are not emergencies, and many patients can be referred to their treating physicians.
Antipsychotic drugs have specific effects on dopamine systems and general effects on alertness. Common central nervous system (CNS) effects caused by these agents are sedation (drowsiness or "drugged" feeling), ataxia (unsteady gait or incoordination), slurred speech, dysphoria (generalized emotional discomfort), and loss of energy or initiative.
Differential diagnosis. For psychotic patients receiving antipsychotic drugs, the differential diagnosis for drug side effects includes primary symptoms of schizophrenia (apathy, dysphoria), interaction with alcohol or another sedative or hypnotic agent, depression, and metabolic or traumatic brain dysfunction.
Interpersonal intervention. After the differential diagnoses are ruled out, the clinician should advise the patient to discontinue the medication for the rest of the day and to contact the prescribing physician as soon as possible. The patient should be told not to engage in activities in which sedation would be hazardous - for example, driving a car.
Educational intervention. Before the patient leaves the emergency service, the clinician should explain that the side effects indicate that the drug is working, but that adjustments in dosage may be needed. For a patient recently placed on an antipsychotic agent, the clinician can point out that the sedation should be temporary. For other patients, such as those recently discharged from an acute care hospital on high doses of medication, the clinician can begin to educate them about the difference between acute and maintenance doses and suggest that they continue this discussion with the prescribing physician.
Neuroleptic drugs act diffusely on dopamine receptors in the brain. producing both antipsychotic effects and unwanted motor effects. or extrapyramidal symptoms (EPS). As a rule, the more potent the neuroleptic drug, the higher the risk for EPS, although any neu-roleptic agent can cause EPS.
The clinician should be familiar with the emergency treatment of EPS.
Akinesia. This syndrome, marked by a loss of spontaneous movement, is related to parkinsonism and may occur in conjunction with it. The patient is drowsy and looks and acts "washed out." Muscle rigidity cogwheeling (a ratchet like feeling when limbs are passively moved), and tremor are typically present (Mason and Granacher. 1980). Akinesia can progress to a catatonic like state, which must be differentiated from catatonia itself and from neuroleptic malignant syndrome.
Because akinesia results from dopamine blockade, the drug of choice is an antiparkinsonian agent, such as diphenhydramine (Benadryl) 50 mg or benztropine (Cogentin) 2 mg, I.M. or I.V. The akinetic patient usually responds in several minutes to 1 hour. If no response occurs, the clinician can repeat the dose once. If successful, the drug should be continued orally (25 mg of diphenhy-dramine two to four times daily or 1 mg of benztropine twice daily).
Bear in mind that antiparkinsonian drugs are not benign and have serious toxic effects of their own, including delirium (central anticholinergic syndrome), euphoria or dysphoria, urine retention. glaucoma exacerbation, constipation, dry mouth, blurred vision. diminished sweating (possibly hyperthermia), and tachycardia. These effects are more severe in elderly patients and in those taking low-potency neuroleptic drugs.
An alternative initial intervention is to switch the akinetic patient from a high-potency to a low-potency antipsychotic agent, such as chlorpromazine (Thorazine) or thioridazine (Mellaril).
Parkinsonism. Sometimes called pseudoparkinsonism because it mimics Parkinson's disease, this syndrome is the most common EPS (Mason and Granacher, 1980). Key physical findings in patients with parkinsonism are shuffling or unsteady gait; resting tremor, usually of the "pillrolling" type; loss of expressive movements or masklike face; muscle rigidity; and drooling.
Elderly patients are especially susceptible to drug induced parkinsonism. The clinician can distinguish parkinsonism from Parkinson's disease because the drug effect occurs after the introduction of the drug, whereas the disease has an insidious onset.
Like akinesia, this syndrome is readily reversed by antiparkinsonian drugs of the anticholinergic or antihistaminic type, such as diphenhydramine, benztropine, and trihexyphenidyl (Artane). The dopamine agonist drugs, such as levodopa-carbidopa (Sinemet). that are used to treat Parkinson's disease should not be used for drug-induced parkinsonism. The clinician can administer the antiparkinsonian drugs orally, and relief should be apparent within hours or days. Recommended dosages are diphenhydramine 25 mg two to four times daily, benztropine 1 to 2 mg twice daily, or trihexyphenidyl 2 to 5 mg twice daily.
Rabbit syndrome, a variant of parkinsonism, causes a perioral tremor (rapid chewing movements). This EPS responds to the an-tiparkinsonian regimen described for parkinsonism.
Dystonia. Also called acute dystonic reaction, dystonia is one of the most serious and subjectively distressing EPS. The clinical presentation and treatment of dystonia during rapid tranquilization are discussed in Chapter 3, Delirium.
Dystonia is characterized by slurred or dysarthric speech from tongue dystonia, eyes painfully diverted upward (oculogyric crisis). head turned to the side (torticollis) or backward (retrocollis). severe extension (arching) of the back (opisthoionos), and, rarely, laryn-gospasm from contraction of the muscles of the larynx.
The dystonic patient should immediately be given I.V. antipar-kinsonian drugs (such as diphenhydramine 50 mg or benztropine 2 mg). If symptoms persist, the clinician should repeat the dose after 5 minutes. On discharge, the patient should be given a 3-day supply of an oral antiparkinsonian drug (such as diphenhydramine 25 to 50 mg three times daily or benztropine 1 to 2 mg twice daily) and referred to the prescribing physician.
Although dystonia is rarely life-threatening, this syndrome is frightening to the patient and may contribute to subsequent non-compliance with the medication regimen. For patients started on neuroleptic agents in the emergency setting, the clinician must consider prescribing antiparkinsonian drugs to prevent dystonia in those patients being discharged or held for a few days in the crisis area. Although increasing evidence supports this strategy, it may not be needed in every case.
Preventive use of antiparkinsonian drugs concurrently with neuroleptic agents is indicated when the patient:
Caution the patient about the potential toxicity of (lie antiparkinsonian agent and provide instructions about how to deal with future reactions. (The usual response is to return to the emergency service.)
Be alert to the drug abuser who fakes acute dystonia to obtain antiparkinsonian agents for their euphoric properties. Suspect prescription drug abuse in a patient who appears to have dystonia but has not recently been started on a neuroleptic agent or received a depot injection within the past week.
Akathisia. Motor restlessness can occur after the start of aniipsy-chotic drug therapy, after an increase in dosage, or after a depot injection of fluphenazine (Prolixin) or haloperidol decanoate (Hal-dol). The akathisic patient cannot sit still, which is sometimes described as a "racing motor" inside the patient. This EPS is more common than suspected and is extremely distressing to the patient. Severe akathisia has been associated with self-destructive and homicidal behavior.
The most critical initial intervention is to provide immediate relief, if possible. The medications for EPS, diphenhydramine 50 mg I.M. or benztropine 2 mg IX, are widely used but sometimes ineffective. Sedatives, such as lorazepam (Ativan) 2 mg orally or 1 mg I.M., may reduce the dysphoria of akathisia for a few hours. The novel approach of using propranolol (Inderal) 20 to 60 mg/day is worth considering for refractory cases of akathisia. However, propranolol is contraindicaied in patients with asthma, congestive heart failure, cardiac conduction defects, and diabetes (Neppe, 1989).
The patient with akathisia may feel a loss of control. Reassure the patient that akathisia is a drug side effect, not a worsening of the illness. Brief hospitalization may be beneficial in severe or unresponsive cases.
Tardive dyskinesia. Unique in both its physiology and frequent lack of reversibility, tardive dyskinesia (TD) usually appears after years of neuroleptic treatment as involuntary movements of the mouth or extremities. Because the syndrome can also occur within months of starting neuroleptic therapy, warn all patients receiving such treatment about the possibility of TD. Although not an emergency, TD can lead to physical and social disability because of the uncontrollable abnormal movements.
No immediate treatment is necessary; the long-term approach to the problem must be worked out between the patient and his prescribing physician. However, the emergency clinician can alert the physician and tell the patient (without alarming him) to discuss the abnormal movements with the psychiatrist.
The physiology of TD renders antiparkinsonian drugs useless; these drugs may even intensify TD symptoms (Mason and Gran-acher, 1980). If a TD patient is taking antiparkinsonian agents, consider discontinuing this medication.
In every case, document all abnormal movements, both for continuity of care and medicolegal reasons.
Antipsychotic drugs have diverse effects, including blockade of cholinergic (muscarinic) and alpha-adrenergic neuroreceptors, both in the CNS and peripherally. As a rule, these effects are more likely to occur with low potency than high-potency drugs.
Anticholinergic effects. These autonomic side effects include dry mouth, constipation, blurred vision, urinary hesitancy, palpitation. and light-headedness. Many patients respond to a cholinergic agent, such as bethanechol (Urecholine) 25 mg three times daily. Reducing the dosage of the antipsychotic drug or eliminating an antiparkinsonian agent is commonly necessary to relieve these peripheral symptoms.
Central anticholinergic syndrome. Low-potency neuroleptic drugs can also cause CNS toxicity in the form of delirium or central anticholinergic syndrome. Other causes of this syndrome are atropine-like or antiparkinsonian drugs, antidepressants, and over-the-counter medications. In addition to the mental status features of delirium, the clinician should look for the symptoms of central anticholinergic syndrome, which include dry skin, flushed face, dilated and unreactive pupils, tachycardia, diminished or absent bowel sounds, and urine retention.
Begin treatment with physostigmine (Antilirium) 1 to 2 mg I.V. (slow push) or I.M. (Dubin et al., 1986). Because physostigmine's duration of action is only 2 hours, the dose can be repeated in 2-hour intervals, or more frequently if needed. Overly aggressive treatment may precipitate a cholinergic crisis, which can be reversed with atropine 0.5 mg for each 1 mg of physostigmine (Hall et al.. 1981). Further complications of physostigmine treatment are vomiting, hypotension, and seizures.
Hypotension. Through alpha-adrenergic blockade, neuroleptic agents-especially chlorpromazine and thioridazine - can lower blood pressure. This effect is most evident when the patient stands or rises after bed rest (orthostatic hypotension). Severe hypotension (systolic blood pressure less than 60 mm Hg) is a medical emergency.
The hypotensive patient who comes to the emergency service should be kept supine in the reverse Trendelenberg position. I.V. fluids should be administered for volume expansion. Begin a pharmacologic intervention with alpha-adrenergic drugs, such as meta-raminol (Aramine). Beta-adrenergic agonist drugs, such as isoproterenol (Isuprel), and mixed alpha and beta-adrenergic drugs should not be used because they can exacerbate the hypotension (Dubin and Feld, 1989).
Neuroleptic malignant syndrome (NMS) has been recognized since neuroleptic agents were first used but has only recently received widespread attention (Lazarus et al., 1989). NMS is a serious, potentially fatal syndrome of muscular rigidity, hyperpyrexia, auto-nomic instability, and diminished arousal. The pathophysiology of NMS is being studied, with the focus on dopamine neurotransmis-sion (Lazarus et al., 1989).
To be diagnosed with NMS, a patient must concurrently exhibit all five of the diagnostic criteria proposed by Lazarus et al. (1989):
Once NMS is recognized or suspected, the clinician must stop all psychotropic medications, including anticholinergic antiparkin-sonian drugs. Initiate life support measures to reduce the patient's temperature, increase oxygenation, and stabilize the blood pressure and heart rate. Carry out NMS treatment in collaboration with medical specialists.
Pharmacologic intervention to treat the somatic symptoms include (Lazarus et al, 1989):
Patients may report the following problems but are not usually aware that these are drug side effects.
Sexual dysfunction. Thioridazine can produce retrograde ("dry") ejaculation. Patients with this complaint can be switched to another neuroleptic agent, such as chlorpromazine. Neuroleptic drugs also can cause lowered libido, amenorrhea, hyperprolactinemia, and galactorrhea (also seen in men).
Sunburn. Patients may show signs of photosensitivity, including severe sunburn and deep pigmentation of the skin after prolonged exposure to the sun. Advise patients receiving neuroleptic medication to avoid the sun as much as possible, to wear protective clothing and hats, and to use a sunblocking lotion.
Heatstroke. Patients on neuroleptic medication may have an impaired ability to dissipate heat. The clinician must differentiate this drug effect on thermoregulation from NMS.
Rash. A rash, especially on the torso, may be caused by neuroleptic agents. Patients with a rash can be given an antihistamine or switched to an antipsychotic agent of a different chemical class.
Blood dyscrasias. Neuroleptic drugs can lower the white blood cell count, which is benign, and cause agranulocytosis (a decrease in neutrophils), which is rare and serious. Early signs of agranulocytosis — persistent sore throat, mouth ulceration, chills, and fever-can be identified in the emergency setting. If a patient has agranulocytosis, immediately discontinue the neuroleptic medication and refer the patient to an internist or hematologist. Blood should be drawn for a "stat" complete blood count and differential.
Neuroleptic agents used in combination with antidepressant5, antianxiety drugs, or anticonvulsants can increase sedation. Antide-pressants can also increase anticholinergic and hypotensive effects, while antiparkinsonian agents can increase anticholinergic symptoms and predispose the patient to delirium. Concomitant use of lithium carbonate (Eskalith) may increase the patient's risk for NMS. Other drug interactions include antihypertensive drugs with low potency neuroleptics, such as chlorpromazine, which can interfere with or potentiate blood pressure effects. Beta blockers can inhibit chlorpromazine metabolism and raise the blood levels of this drug. Levodopa (Dopar) combined with a neuroleptic agent blocks its effect in Parkinson's disease. Phenytoin (Dilantin) metabolism may be reduced, leading to increased phenytoin blood levels and toxicity.
An overdose with neuroleptic drugs alone is rarely fatal. However. when tricyclic antidepressants, antiparkinsonian agents, sedatives, or alcohol are combined with a neuroleptic agent, the mortality risk increases. The clinician's immediate concern is to treat the coma. hypothermia, hypotension, and EPS that can result from an overdose. After the patient is medically cleared, the psychiatric condition that caused the patient to take the overdose should be treated in the hospital.
Medications used to treat depression are of concern for several reasons. Depressed patients may intentionally overdose themselves. Elderly patients, among whom depression is prevalent, are susceptible to autonomic side effects. Adverse drug reactions that lead to noncompliance expose the patient to increased morbidity from depression, and the drug treatment of depression is typically lengthy. which increases the likelihood that a toxic reaction will develop. The clinician in the psychiatric emergency service is called on to examine patients with various toxic conditions caused by antidepressant drugs.
Because antidepressant drugs can cause both sedation and arousal, a patient may complain of either somnolence or restlessness. As a rule, tricyclic drugs (amitriptyline [Elavilj, nortriptyline, [Aventyl], imipramine [Tofranilj, desipramine [Norpraminj, trimipramine [Surmontil], and doxepin [Sinequan]) exert their sedative effects in the first few weeks of treatment. Amoxapine [Asendin] and mapro-tiline [Ludiomil] can also cause sedation within a few weeks of the start of therapy. Trazodone (Desyrel), a sedating nomricyclic anti-depressant, can be used to relieve insomnia in a depressed patient.
Antidepressants can cause agitation, restlessness, nervousness, or insomnia. The monoamine oxidase (MAO) inhibitors (phenelzine [Nardil] and tranylcypromine [Parnate]) may trigger an early amphetamine-like effect, including jitteriness and insomnia. Fluoxetine [Prozacj tends to exert its activating effect at about 2 weeks, when its serum level is established. This activating effect can progress to anxiety and agitation. The effect may also be seen with clomipramine (Anafranil) and bupropion (Wellbutrin), drugs that may also reduce seizure threshold.
The clinician can treat general side effects of antidepressant medication by reducing the dosage, prescribing sedating antidepressants to improve the sleep wake cycle, or switching drugs. Always consult the prescribing physician before beginning any intervention. Giving the patient a new prescription for a benzodiazepine to counteract the effect of an antidepressant is not recommended.
The effects of tricyclic drugs on the autonomic nervous system are similar to those produced by low-potency antipsychotic agents and include hypotension (light-headedness upon standing up), blurred vision, sweating, dry mouth, constipation, and urine retention. Of the tricyclic agents, nortriptyline causes the least hypotension. In contrast, MAO inhibitors can significantly lower blood pressure, which is sometimes forgotten because of their more notorious "cheese reaction" (hypertension precipitated by tyramine - containing foods and beverages).
MAO inhibitors and hypertensive crisis. Patients taking the antidepressants phenelzine or tranylcypromine must adhere to food and drug restrictions to prevent a hypertensive crisis. Foods to be avoided are wine and beer, aged cheeses, cured meats, pickled herring, chopped liver, and yeast extracts. Forbidden drugs include stimulants, diet pills, decongestants, local anesthetics containing epi-nephrine, meperidine (Demerol), opiates, levodopa, and other antidepressants. Patients on MAO inhibitors who report severe headache must be examined for a hypertensive crisis. Any patient who is unfamiliar with the food and drug restrictions should be given a list.
The clinician can treat the hypotensive effect of an antidepressant drug by decreasing the dosage, instituting bedtime dosing, or switching to another agent. Consider adding ephedrine (Ephed II) for hypotension (but not if the patient is taking an MAO inhibitor) or bethanechol for anticholinergic effects. For an MAO inhibitor-induced hypertensive crisis, emergency intervention includes administration of phentolamine (Regitine) 5 mg I.M. or I.V. or other potent antihypertensive agents. Staff members should follow the hospital's code protocols. Outpatients treated with MAO inhibitors are sometimes given a 20-mg capsule of nifedipine (Procardia) to use in case of severe headache, sometimes the first sign of a hypertensive crisis. However, such patients must be cautioned that this self-treatment can lead to hypotension.
Because antidepressant drugs have diverse effects, the emergency clinician may encounter patients with some of the following complaints.
Sexual dysfunction. Erectile dysfunction, priapism (with trazodonc only), and anorgasmia (especially in women taking MAO inhibitors) can be caused by antidepressant drugs.
Drenching sweat. This effect commonly occurs during sleep or as an excessive reaction to heat.
Tinnitus. Patients may report an uncomfortable ringing or rushing sound in their ears.
Delirium. This side effect is predominantly seen in elderly persons. Amitriptyline and other sedating tricyclic antidepressants can cause central anticholinergic syndrome (see Chapter 14, Geriatric Emergencies).
Seizures. High blood levels of tricyclic antidepressants can lower a patient's seizure threshold. Patients taking maprotiline at doses greater than 200 mg/day are at especially high risk. A combination of a tricyclic antidepressant and nuoxetine, which is not recommended, can elevate the tricyclic antidepressam's serum levels and induce seizures.
Sedation can be increased when an antidepressant drug is given in combination with neuroleptics, antianxiety agents, or anticonvul-sants. The concomitant use of neuroleptics (especially low potency) increases anticholinergic and hypotensive effects and may increase tricyclic antidepressant blood levels. Fluoxetine can raise the blood levels of other drugs, such as tricyclic antidepressants or haloperidol (Haldol), which may lead to toxicity.
Because of uncertain effects on blood pressure, MAO inhibitors should not be used with other antidepressants, stimulants, diet pills, decongestants, disulfiram (Antabuse), alcohol, opiates, or sedatives.
Tricyclic antidepressants, such as amitriptyline, can interfere with the action of antihypertensive agents, and smoking may reduce tricyclic antidepressant blood levels.
Depressed patients are treated with some of the. most toxic psy-chotropic drugs. A 1- or 2-week supply (2 g or less) of a tricyclic antidepressant can constitute a lethal overdose. Patients who have overdosed are delirious and hypotensive and have depressed consciousness and severe anticholinergic toxicity. The resulting cardiac arrhythmias and respiratory depression can be fatal and therefore constitute a medical emergency.
Overdose of a tricyclic antidepressant is both common and dangerous (Callaham and Kassel, 1985; Frommer et al., 1987: Stewart 1979). Although the patient may look deceptively well, the overdose is rapidly fatal (Frommer et al., 1987; Callaham and Kassel, 1985). Be alert for overdose patients who are medically cleared too quickly (Fouike and Albertson, 1987); such patients can die on a psychiatric unit.
An MAO inhibitor overdose is occasionally fatal but more likely to cause delirium, seizures, and hyperthermia (Lazarus et al.. 1989 Overdoses of trazodone and Huoxetine usually do not produce fatal outcomes. Although stimulants (amphetamine and methylpheni-date) are rarely used to treat depression, their overdose effects include autonomic overactivity, delirium, seizures, and. occasionally, death.
To treat a tricylic antidepressant overdose, start an I.V. line. monitor the patient's heart, and observe the patient closely (Callaham and Kassel, 1985). Additionally, the patient's stomach contents must be evacuated and activated charcoal administered. Initiate advanced interventions, as needed, for depressed consciousness and respiration, hypotension, arrhythmias, cardiac conduction blocks, and seizures. Once the patient is medically stabilized, usually within 24 hours (Frommer et al., 1987), consider transferring him to a psychiatric setting.
Lithium carbonate is a remarkably effective medication for preventing episodes of bipolar disorder. However, clinicians and patients alike must know the early signs of toxicity and the/importance of regular blood monitoring to maintain safe serum lithium levels.
Even at ordinary serum levels (0.5 to 1.2 mEq/liter), lithium can cause side effects severe enough to warrant emergency intervention. These include fine tremor; excessive thirst (polydipsia); excessive urination (polyuria); nausea, vomiting, and diarrhea; and mild ataxia. Less serious lithium side effects are acne, dermatitis, nontoxic goiter, and a benign elevation of the white blood cell count. The intervention consists of obtaining a serum lithium level, keeping the patient hydrated, stopping further doses, and informing the prescribing physician.
Neuroleptic agents, in combination with lithium, may increase the risk of NMS. Thiazide diuretics, such as hydrochlorothiazide (Esidrix), and nonsteroidal anti inflammatory drugs can decrease lithium excretion and lead to toxicity.
At serum lithium levels exceeding 1.5 to 2.0 mEq/liter, toxic symptoms become more dramatic-coarse tremor, ataxia and slurred speech, nystagmus, and severe vomiting. Serum levels of 4.0 mEq/ liter or more are potentially fatal.
Lithium overdose is treated by supportive measures, based on the patient's symptoms and serum level. According to Schoonover and Gelenberg (1984), in managing a patient with lithium toxicity. the clinician should:
Treating severe lithium intoxication (serum lithium level greater than 4 mEq/liter) is a complex medical intervention, and such issues as forced diuresis and peritoneal dialysis remain controversial (Jefferson et al., 1987). Thus, treatment of a patient with severe lithium intoxication should be left to experienced internists and emergency department physicians.
All patients should understand the need for regulating the serum level of lithium within a narrow range. In addition, instruct patients to use table salt regularly. However, patients on lithium do not need salt tablets in the summer, since sweating, unlike gross dehydration. does not increase lithium levels.
Patients should know that they can take their total daily dose of lithium at bedtime and that blood for lithium levels must be drawn at the same time relative to the last dose (usually 8 to 12 hours afterward). Patients should have blood tests for kidney and thyroid function twice a year so that any serious change in lithium clearance can be detected early.
Benzodiazepines, the principal drugs used in the emergency treatment of anxiety, are usually safe when used alone (see Chapter 10. Anxiety). However, when taken in combination with alcohol or other drugs, benzodiazepines can cause unwanted effects that lead to emergency visits.
Because benzodiazepines are sedatives, the most prevalent sign of toxicity is drowsiness. Sedation, in turn, can lead to impaired coordination and cognitive function. In elderly persons, sedation can contribute to hip fracture from falls (Ray, 1987).
To treat simple benzodiazepine intoxication, reduce the patients dosage and advise him not to drive or engage in any activity requiring alertness. For intoxication complicated by alcohol use, try to detoxify the patient from both substances. Sometimes a patient experiences wild excitement after taking a benzodiazepine in regular doses, usually after having just started the drug. This paradoxical reaction can produce destructive results, including criminal behavior. Benzodiazepines must be discontinued in such patients.
The short elimination half-lives of some benzodiazepines, such as alprazolam (Xanax), oxazepam (Serax), lorazepam, and triazolam (Halcion), can cause significant decreases in serum levels between doses, especially if the medication is used only at bedtime or once or twice a day. In a patient who rapidly metabolizes alprazolam, the functional elimination half-life may be as short as 6 hours. If the patient takes alprazolam at 8 a.m., 3 p.m., and 10 p.m., significant gaps in anxiety coverage can ensue.
Patients with imerdose breakthrough anxiety are on an emotional roller coaster. The patient may describe a sudden and intense increase in anxiety, accompanied by a craving for the drug. He may interpret these symptoms as a worsening of the condition, leading to requests for increased doses and, occasionally, to uncontrolled self medication.
Treatment of breakthrough anxiety is best accomplished by the prescribing physician. The emergency clinician who chooses to initiate treatment should consult with the prescribing physician. One intervention is to change the dosing pattern to every 4 hours, if possible, without altering the total dosage. Another intervention is to switch the patient from the benzodiazepine with the short elimination half-life to one with a long elimination half life, such as diazepam (Valium), chlordiazepoxide (Librium), or clorazepate (Tranxene).
If the treatment is for chronic anxiety, switching to buspirone may eliminate the breakthrough effect. However, patients must not be switched directly from a benzodiazepine to buspirone, because acute benzodiazepine withdrawal can result.
An abstinence syndrome occurs in approximately 4?% of patients who withdraw from benzodiazepines after at least 8 months of continuous use (Rickels, 1983). Patients in withdrawal may have a panic attack, insomnia, anxiety, and phobias, or they may become irritable, paranoid, and restless. Somatic symptoms of withdrawal include malaise, tremor, nausea, hyperreflexia, seizures, increased heart rate, and elevated blood pressure. For drugs with short elimination half-life metabolites (alprazolam, lorazepam, oxazepam). the peak risk period for withdrawal occurs 2 to 3 days after the drug is discontinued. Withdrawal symptoms from drugs with long elimination half-life metabolites, such as diazepam, chlordiazepox-ide, clorazepate, and flurazepam (Dalmane), are seen within 5 to 7 days. The key clinical discriminator between withdrawal and relapse (a return of symptoms) is that withdrawal symptoms are different from and more intense than the original symptoms.
To treat benzodiazepine withdrawal, the clinician should administer a challenge dose of the drug. If the challenge dose relieves the symptoms within an hour or two, give the patient a prescription for no more than 3 days' worth of the usual dosage. Instruct the patient to visit his prescribing physician as soon as possible.
If the patient is a recognized drug abuser, referral to a detoxification program may be indicated. Do not feel obligated to perpetuate the drug dependency, but treat acute withdrawal symptoms.
A nonsedating antianxiety drug, buspirone (BuSpar) is a partial serotonin agonist that occasionally exacerbates anxiety or insomnia. Many patients overcome this side effect and benefit greatly from buspirone treatment. The usual dosage ranges from 5 mg four time^ daily to 10 mg three times daily. Buspirone can cause a dysphoric reaction if a large dose (about 40 mg) is given all at once, but the drug does not cause significant overdose toxicity.
Benzodiazepines increase sedation caused by neuroleptics, anti-depressants, anticonvulsants, and alcohol. Buspirone should not be used in patients taking MAO inhibitors because it can induce hypertension. In addition, buspirone may displace digoxin (Lanoxin) from blood proteins, which can cause digoxin toxicity. Antacids can interfere with benzodiazepine absorption and decrease the drug's effect. Smoking can reduce benzodiazepine blood levels.
Carbamazepine (Tegretol) is commonly used to treat complex partial seizures (temporal lobe epilepsy) that have a behavioral component, such as aggression, perceptual disturbances, and paranoia. Carbamazepine has also been used in combination with lithium to prevent the mood swings of bipolar disorder.
Toxic doses of Carbamazepine can produce slurred speech, ataxia, sedation, and a worsening of seizures. The clinician who suspects toxicity should draw blood for serum level tests. Hematologic disturbances associated with Carbamazepine overdose include aplastic anemia (low red blood cell count), agranulocytosis (low white blood cell count), and thrombocytopenia (low platelet count). Patients who complain of fever, sore throat, and malaise may be suffering from carbamazepine-induced agranulocytosis. In such cases, the clinician should draw blood for a "stat" complete blood cell count and differential and consult a medical specialist.
Using Carbamazepine with MAO inhibitors can precipitate a hy-pertensive crisis. Verapamil (Calan), cimetidine (Tagamet), and pro-poxyphene (Darvon) increase Carbamazepine levels, whereas phenobarbital (Barbita), phenytoin (Dilantin), and primidone (Mysoline) lower them. Carbamazepine itself can lower blood levels of warfarin (Coumadin), phenytoin, haloperidol, and theophylline (TheoDur).
Antihistaminic agents, such as diphenhydramine (Benadryl) and hydroxyzine (Atarax), are an alternative to benzodiazepines and can be used as bedtime or as-needed sedatives. Despite their reputation as benign drugs, antihistamines can cause significant toxic effects, including delirium, seizures, respiratory arrest, and death. Drug abusers may attempt to snort or inject powdered forms of antihistamines.
Patients treated with propranolol (Inderal) or atenolol (Tenormin) for situational anxiety (test taking, stage fright) or as an adjunct in panic disorder may complain of depression, lethargy, insomnia, nightmares, and sexual dysfunction. Serious toxicity causes hypo-tension or bradycardia.
Disulfiram (Antabuse) is an adjunctive therapy for maintaining abstinence in alcoholic patients. By blocking the liver enzyme aldehyde dehydrogenase, disulfiram causes faulty alcohol metabolism, which leads to an accumulation of acetaldehyde. This, in turn, produces various noxious symptoms, such as severe, throbbing headache; nausea; vomiting; chest pain and palpitations; hypotension; fainting; anxiety; hyper-ventilation; weakness; sweating; and thirst (Spring-house Drug Reference, 1988). Severe reactions include cardiovascular collapse, seizures, and death. In addition to the reaction with alcohol, disulfiram has a side effect profile that includes sedation, fatigue, delirium, depression, psychosis, and headache. Brief treatment with a neuroleptic agent may be indicated in disulfiram induced psychosis or delirium. Otherwise, discontinuation of the drug and outpatient follow-up are sufficient. The clinician must warn patients who discontinue disulfiram that the reaction with alcohol can persist for several days or more.