71: Cyclic Antidepressants

Erica L. Liebelt

HISTORY AND EPIDEMIOLOGY

The term cyclic antidepressant (CA) refers to a group of pharmacologically related xenobiotics used

for treatment of depression, neuralgic pain, migraines, enuresis, and attention deficit hyperactivity

disorder. Most CAs have at least three rings in their chemical structure. They include the traditional

tricyclic antidepressants (TCAs) imipramine, desipramine, amitriptyline, nortriptyline, doxepin,

trimipramine, protriptyline, and clomipramine, as well as other cyclic compounds such as maprotiline

and amoxapine.

Imipramine was the first TCA used for treatment of depression in the late 1950s. However, the

synthesis of iminodibenzyl, the “tricyclic” core of imipramine, and the description of its chemical

characteristics date back to 1889. Structurally related to the phenothiazines, imipramine was

originally developed as a hypnotic for agitated or psychotic patients and was serendipitously found to

alleviate depression. From the 1960s until the late 1980s, the TCAs were the major pharmacologic

treatment for depression in the United States. However, by the early 1960s, cardiovascular and

central nervous system (CNS) toxicities were recognized as major complications of TCA overdoses.

The newer CAs developed in the 1980s and 1990s were designed to decrease some of the adverse

effects of older TCAs, improve the therapeutic index, and reduce the incidence of serious toxicity.

Other CAs include the tetracyclic drug maprotiline and the dibenzoxapine drug amoxapine.

The epidemiology of CA poisoning has evolved significantly in the past 30 years, resulting in great

part from the introduction of the selective serotonin reuptake inhibitors (SSRIs) and other newer

antidepressants for the treatment of depression. Although the use of CAs for depression has

decreased over the past 20 years, other medical indications, including chronic pain, obsessive-

compulsive disorder, and, particularly in children, enuresis and attention deficit hyperactivity disorder

have emerged, resulting in their continued use. The antidepressants are a leading cause of drug-

related self-poisonings in the developed world, primarily because of their ready availability to people

with depression or chronic pain who by virtue of their diseases are at high risk for overdose.

However, despite the increase in SSRI use and overdose, patients with TCA overdoses continue to

have higher rates of hospitalization and fatality than do those with SSRI overdose.

Children younger than 6 years have consistently accounted for approximately 12% to 13% of all CA

exposures reported to poison centers during each of the last 15 years (Chap. 136). Despite the

emergence of the SSRIs in the early 1990s, TCAs are still frequently prescribed by pediatric office

based practices for many of the conditions noted above. Following the October 2004 US Food and

Drug Administration Black Box Warning about the increased risk of suicidal behavior associated with

antidepressant use, several reports have described significant declines in antidepressant dispensing

in children compared to historical trends.25 Nevertheless, CA poisoning likely will continue to be

among the most lethal unintentional drug ingestions in younger children because only one or two

adult-strength pills can produce serious clinical effects in young children.

PHARMACOLOGY

In general, the TCAs can be classified into tertiary and secondary amines based on the presence of

a methyl group on the propylamine side chain (Table 71–1). The tertiary amines amitriptyline and

imipramine are metabolized to the secondary amines nortriptyline and desipramine, respectively,

which themselves are marketed as antidepressants. In therapeutic doses, the CAs produce similar

pharmacologic effects on the autonomic system, CNS, and cardiovascular system. However, they

can be distinguished from each other by their relative potencies.112

TABLE 71–1. Cyclic Antidepressants—Classification by Chemical Structure

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At therapeutic doses, CAs inhibit presynaptic reuptake of norepinephrine and/or serotonin, thus

functionally increasing the amount of these neurotransmitters at CNS receptors. The tertiary amines,

especially clomipramine, are more potent inhibitors of serotonin reuptake, whereas the secondary

amines are more potent inhibitors of norepinephrine reuptake. Although these pharmacologic actions

formed the basis of the monoamine hypothesis of depression in the 1960s, antidepressant actions of

these drugs appear to be much more complex.

Extensive research has led to the “receptor sensitivity hypothesis of antidepressant drug action,”

which postulates that following chronic CA administration, alterations in the sensitivity of various

receptors are responsible for antidepressant effects. Chronic TCA administration alters the number

and/or function of central β-adrenergic and serotonin receptors. In addition, TCAs modulate

glucocorticoid receptor gene expression and cause alterations at the genomic level of other

receptors.8 All of these actions likely play a role in the antidepressant effects of TCAs.

Additional pharmacologic mechanisms of CAs are responsible for their side effects with therapeutic

dosing and clinical effects following overdose. All of the CAs are competitive antagonists of the

muscarinic acetylcholine receptors, although they have different affinities. The CAs also antagonize

peripheral α1-adrenergic receptors. The most prominent effects of CA overdose result from binding to

the cardiac sodium channels, which is also described as a membrane-stabilizing effect (Fig. 71–1)

(Chap. 16). The tricyclic antidepressants are potent inhibitors of both peripheral and central

postsynaptic histamine receptors. Finally, animal research demonstrates that the CAs interfere with

chloride conductance by binding to the picrotoxin site on the γ-aminobutyric acid (GABA)–chloride

complex.102

FIGURE 71–1.

Effects of cyclic antidepressants (CAs) on the fast sodium channel. (A) Sodium depolarizes the cell, which both

propagates conduction; allowing complete cardiac depolarization; and opens voltage-dependent Ca2+channels,

producing contraction. (B) CAs and other sodium channel blockers alter the conformation of the sodium channel,

slowing the rate of rise of the action potential, which produces both negative dromotropic and inotropic effects. (C)

Raising the Na+ gradient across the affected sodium channel speeds the rate of rise of the action potential,

counteracting the drug-induced effects. Raising the pH removes the CA from the binding site on the Na+ channel.

See Fig. 71–3 for the effects noted on the electrocardiograph.

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Amoxapine is a dibenzoxapine CA derived from the active antipsychotic loxapine. Although it has a

three-ringed structure, this drug has little similarity to the other tricyclics. It is a potent norepinephrine

reuptake inhibitor, has no effect on serotonin reuptake, and blocks dopamine receptors. Maprotiline

is a tetracyclic antidepressant that predominantly blocks norepinephrine reuptake. Both of these CAs

have a slightly different toxic profile than the traditional TCAs.55,56,112

PHARMACOKINETICS AND TOXICOKINETICS

The CAs are rapidly and almost completely absorbed from the gastrointestinal (GI) tract, with peak

concentrations 2 to 8 hours after administration of a therapeutic dose. They are weak bases (high

pKa). In overdose, the decreased GI motility caused by anticholinergic effects and ionization in

gastric acid delay CA absorption. Because of extensive first-pass metabolism by the liver, the oral

bioavailability of CAs is low and variable, although metabolism may become saturated in overdose,

increasing bioavailability.

The CAs are highly lipophilic and possess large and variable volumes of distribution (15–40 L/kg).

They are rapidly distributed to the heart, brain, liver, and kidney, where the tissue to plasma ratio

generally exceeds 10:1. The octanol/water partition coefficient (Log P) is an often cited measure of

lipid-solubility with the Log D representing Log P at physiological pH—a more representative

measure. The latter pharmacologic property becomes important when evaluating the potential

effectiveness of lipid emulsion therapy for CA toxicity. Some examples of Log D values for CAs

are amitriptyline, 3.96; nortriptyline, 2.86; imipramine, 2.06; desipramine, 1.05; and doxepin, 2.93.

Less than 2% of the ingested dose is present in blood several hours after overdose, and serum CA

concentrations decline biexponentially. The CAs are extensively bound to α1-acid glycoprotein (AAG)

in the plasma, although differential binding among the specific CAs is observed.2 Changes in AAG

concentration or pH can alter binding and the percentage of free or unbound drug.87,95 Specifically, a

low blood pH (which often occurs in a severely poisoned patient) may increase the amount of free

drug, making it more available to exert its effects. This property serves as one basis for alkalinization

therapy (see below).

The CAs undergo demethylation, aromatic hydroxylation, and glucuronide conjugation of the hydroxy

metabolites. The tertiary amines imipramine and amitriptyline are demethylated to desipramine

andnortriptyline, respectively. The hydroxy metabolites of both tertiary and secondary amines are

pharmacologically active and may contribute to toxicity. The glucuronide metabolites are inactive.

Genetically based differences in the activity of the CYP2D6 enzymes, which are responsible for

hydroxylation of imipramine and desipramine, account for wide interindividual variability in

metabolism and steady-state serum concentrations.19“Poor metabolizers” may recover more slowly

from an overdose or demonstrate toxicity with therapeutic dosing.106The metabolism of CAs also may

be influenced by concomitant ingestion of ethanol and other medications that induce or inhibit the

CYP2D6 isoenzyme (Chap. 13, Appendix). Patient variables such as age and ethnicity also affect

CA metabolism.

Elimination half-lives for therapeutic doses of CAs vary from 7 to 58 hours (54–92 hours for

protriptyline), with even longer half-lives in the elderly. The half-lives may also be prolonged following

overdose as a result of saturable metabolism. A small fraction (15%–30%) of CA elimination occurs

through biliary and gastric secretion. The metabolites are then reabsorbed in the systemic

circulation, resulting in enterohepatic and enterogastric recirculation and reducing their fecal

excretion. Finally, less than 5% of CAs are excreted unchanged by the kidney.

PATHOPHYSIOLOGY

The CAs slow the recovery from inactivation of the fast sodium channel, slowing phase 0

depolarization of the action potential in the distal His-Purkinje system and the ventricular

myocardium (Fig. 71–1 and Fig. 22–2; Chap. 16). Impaired depolarization within the ventricular

conduction system slows the propagation of ventricular depolarization, which manifests as

prolongation of the QRS interval on the electrocardiogram (ECG) (Fig. 71–1). The right bundle

branch has a relatively longer refractory period, and it is affected disproportionately by xenobiotics

that slow intraventricular conduction. This slowing of depolarization results in a rightward shift of the

terminal 40 millisecond (T40-msec) of the QRS axis and the right bundle branch block pattern that is

noted on the ECG of patients who are exposed to, or overdose with, a CA.114

Because CAs are weakly basic, they are increasingly ionized as the ambient pH falls, and less

ionized as the pH rises. Changing the ambient pH therefore likely alters their binding to the sodium

channel. That is, since it is probable that 90% of the binding of CA to the sodium channel occurs in

the ionized state, alkalinizing the blood facilitates the movement of the CA away from the hydrophilic

sodium channel and into the lipid membrane.

Sinus tachycardia is due to the antimuscarinic, vasodilatory (reflex tachycardia), and

sympathomimetic effects of the CAs. Wide-complex tachycardia most commonly represents

aberrantly conducted sinus tachycardia rather than ventricular tachycardia. However, by prolonging

anterograde conduction, nonuniform ventricular conduction may result, leading to reentrant

ventricular dysrhythmias.

Electrophysiologic studies in a canine model demonstrate that QRS prolongation is rate dependent,

a characteristic effect of the class I antidysrhythmics (Chap. 64). In these studies, when the heart

rate could not accelerate because of a crushed sinus node, the dogs never developed QRS

prolongation. Furthermore, pharmacologic induction of bradycardia prevents or narrows wide-

complex tachycardia by allowing time for recovery of the sodium channel from

inactivation.4,94 However, since bradycardia adversely affects cardiac output, induction of bradycardia

is not recommended.

A Brugada ECG pattern, specifically type 1 or “coved” pattern, is rarely associated with CA

overdose. The Brugada syndrome originates from a structural change in the myocardial sodium

channel that results in functional sodium channel alterations similar to those caused by the CAs.11,77 It

is possible that this small cohort of patients may have had subclinical Brugada syndrome that was

uncovered by the CA (Chap. 16).

QT interval prolongation can occur in the setting of both therapeutic use and overdose of CAs. This

apparent prolongation of repolarization results primarily from slowed depolarization (ie, QRS

prolongation) rather than altered repolarization.90 Although QT prolongation predisposes to the

development of torsade de pointes, this dysrhythmia is uncommon in patients with CA poisoning due

to the prominent tachycardia.

Hypotension is caused by direct myocardial depression secondary to altered sodium channel

function, which disrupts the subsequent excitation-contraction coupling of myocytes and impairs

cardiac contractility. Peripheral vasodilation from α-adrenergic blockade by CAs also contributes

prominently to postural hypotension. In addition, downregulation of adrenergic receptors may cause

a blunted physiologic response to catecholamines.76

Agitation, delirium, and depressed sensorium are primarily caused by the central anticholinergic and

antihistaminic effects. Hemodynamic effects are likely to contribute in only the most severely

poisoned patients. Details regarding the exact mechanism of CA-induced seizures remain elusive.

CA-induced seizures may result from a combination of an increased concentration of monoamines

(particularly norepinephrine), muscarinic antagonism, neuronal sodium channel alteration, and

GABA inhibition.78

Acute respiratory distress syndrome (ARDS) may occur in the setting of CA overdose. In one

study, amitriptyline exposure caused dose-related vasoconstriction and bronchoconstriction in

isolated rat lungs.105 Many substances implicated in ARDS, such as platelet-activating factor and

protein kinase activation, were important in mediating amitriptyline-induced impairment of lung

function in this experimental model. Another animal model demonstrated that

acute amitriptyline poisoning causes dose-dependent rises in pulmonary artery pressure, pulmonary

edema, and sustained vasoconstriction that could be attenuated by either calcium channel inhibition

or a nitric oxide donor.66

CLINICAL MANIFESTATIONS

The toxic profile is qualitatively the same for all of the first-generation TCAs but is slightly different for

some of the other CAs.112 The progression of clinical toxicity is unpredictable and may be rapid.

Patients commonly present to the emergency department (ED) with minimal apparent clinical

abnormalities, only to develop life-threatening cardiovascular and CNS toxicity within hours.

The CAs have a low therapeutic index, meaning that a small increase in serum concentration over

the therapeutic range may result in toxicity. Acute ingestion of 10 to 20 mg/kg of most CAs causes

significant cardiovascular and CNS manifestations (therapeutic dose, 2–4 mg/kg/d). Thus, in adults,

ingestions of more than 1 g of a CA is usually associated with life-threatening effects. As few as two

50 mg imipramine tablets may cause significant toxicity in a 10 kg toddler (ie, 10 mg/kg). In a series

of children with unintentional TCA exposure, all patients with reported ingestions of more than 5

mg/kg manifested clinical toxicity.72

Acute Toxicity

Most of the reported toxicity from CAs derives from patients with acute ingestions, especially in

patients who are chronically taking the medication. Clinical manifestations of these two cohorts do

not appear to be different, and most studies do not distinguish between them.

Acute Cardiovascular Toxicity.

Cardiovascular toxicity is primarily responsible for the morbidity and mortality attributed to CAs.

Refractory hypotension due to myocardial depression probably is the most common cause of death

from CA overdose.20,104 Hypoxia, acidosis, volume depletion, seizures, or concomitant ingestion of

other cardiodepressant or vasodilating drugs can exacerbate hypotension.

The most common dysrhythmia observed following CA overdose is sinus tachycardia (rate, 120–160

beats/min in an adult), and this finding is present in most patients with clinically significant TCA

poisoning. The ECG typically demonstrates intraventricular conduction delay that manifests as a

rightward shift of the T40-msec QRS axis and a prolongation of the QRS complex duration. These

findings can be used to identify and risk stratify, respectively, patients with CA poisoning

(seeDiagnostic Testing). PR, QRS, and QT interval prolongation can occur in the setting of both

therapeutic and toxic amounts of TCAs.68

Wide-complex tachycardia is the characteristic potentially life-threatening dysrhythmia observed in

patients with severe toxicity (Fig. 71–2A-C). Ventricular tachycardia may be difficult to distinguish

from aberrantly conducted sinus tachycardia which occurs more commonly. In the former cases, the

preceding P wave may not be apparent because of prolonged atrioventricular conduction, widened

QRS interval, or both. Ventricular tachycardia occurs most often in patients with prolonged QRS

complex duration and/or hypotension.63,108 Hypoxia, acidosis, hyperthermia, seizures, and β-

adrenergic agonists may also predispose to ventricular tachycardia.63,108 Fatal dysrhythmias are rare,

as ventricular tachycardia and fibrillation occur in only approximately 4% of all cases.41,85 Both the

Brugada type I ECG pattern and torsade de pointes are uncommon with acute TCA overdose.

FIGURE 71–2.

(A) Electrocardiograph (ECG) shows a wide-complex tachycardia with a variable QRS duration (minimum, 220

msec). (B) ECG 30 minutes after presentation following sodium bicarbonate shows narrowing of the QRS interval to a

duration of 140 msec and an amplitude of RaVR of 6.0 mm. (C) ECG 9 hours after presentation shows further

narrowing of the QRS interval to 80 msec and decrease in the amplitude of RaVR to 4.5 mm.(Reproduced with

permission from Liebelt EL: Targeted management strategies for cardiovascular toxicity from tricyclic antidepressant

overdose: the pivotal role for alkalinization and sodium loading. Pediatr Emerg Care. 1998;14:293–298.)

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Acute Central Nervous System Toxicity.

Altered mental status and seizures are the primary manifestations of CNS toxicity. Delirium,

agitation, and/or psychotic behavior with hallucinations may be present and most likely result from

antagonism of muscarinic and histaminergic receptors. These alterations in consciousness usually

are followed by lethargy, which is followed by rapid progression to coma. The duration of coma is

variable and does not necessarily correlate or occur concomitantly with ECG abnormalities.56

Seizures usually are generalized and brief, most often occurring within 1 to 2 hours of

ingestion.28 The incidence of seizures is similar to ventricular tachycardia and occurs in an estimated

4% of patients presenting with overdose and 13% of fatal cases.115 Status epilepticus is uncommon.

Abrupt deterioration in hemodynamic status, namely hypotension and ventricular dysrhythmias, may

develop during or within minutes after a seizure.28,63,108 This rapid cardiovascular deterioration likely

results from seizure-induced acidosis that exacerbates cardiovascular toxicity. The risk of seizures

with CA overdoses may be increased in patients undergoing long-term therapy or who have other

risk factors such as history of seizures, head trauma, or concomitant drug withdrawal.100 Myoclonus

and extrapyramidal symptoms may also occur in CA-poisoned patients.

Cessation of CAs may produce a drug discontinuation syndrome in some patients, which is typified

by GI and somatic distress, sleep disturbances, movement disorders, and mania.37

Other Clinical Effects.

Anticholinergic effects can occur early or late in the course of CA toxicity. Pupils may be dilated and

poorly reactive to light. Other anticholinergic effects include dry mouth, dry flushed skin, urinary

retention, and ileus. Although prominent, these findings are typically clinically inconsequential.

Reported pulmonary complications include ARDS, aspiration pneumonitis, and multisystem organ

failure. ARDS may be the result of aspiration, hypotension, pulmonary infection, and excessive fluid

administration, along with the primary toxic effects of CAs.96,97 Bowel ischemia, pseudoobstruction,

and pancreatitis are reported in patients with CA overdose.74

Death directly caused by CA toxicity usually occurs in the first several hours after presentation and is

secondary to refractory hypotension in patients who reach health care facilities. Late deaths (>1–2

days after presentation) usually are secondary to other factors such as aspiration pneumonitis, adult

respiratory distress syndrome from refractory hypotension, and/or infection.21

Chronic Toxicity

Chronic CA toxicity usually manifests as exaggerated side effects, such as sedation and sinus

tachycardia, or is identified by supratherapeutic drug concentrations in the blood in the absence of

an acute overdose.39Unlike chronic theophylline and aspirin poisoning, chronic CA toxicity does not

appear to cause life-threatening toxicity.

A sparse literature describes the clinical course of this cohort. However, a recent case report

described chronic amitriptyline overdose in a child (15 mg/kg a day for a month), which resulted in

status epilepticus and significant cardiac conduction abnormalities but normal neurological

outcome.26 Genetic analysis of this patient’s CYP450 system showed two copies of wild-type alleles

for the genes responsible for CYP2D6 activity; thus, concluding the patient was not a “rapid

metabolizer.” Several possible protective mechanisms are presented and further illustrate the

complexity of this drug, its metabolism, and toxicity. These include a unique pharmacogenomics

profile that yields an abnormal receptor profile or metabolic pathway (eg, polymorphism in the gene

for myocardial fast sodium channels), another medication causing a beneficial drug-drug interaction,

a cardioprotective role for caffeine if the patient’s intake was high causing adenosine receptor anta-

gonism and the protective effect from other drugs the patient was taking—guanfacine and

clonidine—adrenergic medications that may have offered some protective effect from the α-

adrenergic blockade caused by amitriptyline.

Several reports describe sudden death in children taking therapeutic doses of CAs.88,89,107 QT

prolongation with resultant torsade de pointes, advanced atrioventricular conduction delays, blood

pressure fluctuations, and ventricular tachycardia are postulated mechanisms, although whether any

of these effects contributed to the deaths is unknown. Prospective studies using 12-lead ECG, 24-

hour ECG recording, and Doppler echocardiography in children receiving therapeutic doses of CAs

have failed to find any significant cardiac abnormalities when compared to children not taking

CAs.14,31 However, authors recommend that CAs not be initiated or continued in any child with a

resting QT interval greater than 450 msec or with bundle branch block.34 This is an ongoing area of

research as it becomes problematic in making decisions about pharmacotherapy interventions.

Unique Toxicity from “Atypical” Cyclic Antidepressants

Although the incidence of serious cardiovascular toxicity is lower in patients with amoxapine

overdoses, the incidence of seizures is significantly greater than with the traditional

CAs.56,65 Moreover, seizures may be more frequent, or status epilepticus may develop.77Similarly, the

incidences of seizures, cardiac dysrhythmias, and duration of coma are greater with maprotiline

toxicity compared to the CAs.55

DIAGNOSTIC TESTING

Diagnostic testing for patients with CA poisoning primarily relies on indirect bedside tests (ECG) and

other qualitative laboratory analyses. Quantification of CA concentration provides little help in the

acute management of patients with CA overdose but provides adjunctive information to support the

diagnosis.

Electrocardiography

The ECG can provide important diagnostic information and may predict clinical toxicity after a CA

overdose. CA toxicity results in distinctive and diagnostic ECG changes that may allow early

diagnosis and targeted therapy when the clinical history and physical examination are unreliable.

A T40-msec axis between 120° and 270° is associated with CA toxicity and was a sensitive indicator

of drug presence in one study.22,79,114 A terminal QRS vector between 130° and 270° discriminated

between 11 patients with positive toxicology screens for CAs and 14 patients with negative

toxicology screens.79 With further analyses, this report concluded that the positive and negative

predictive values of this ECG parameter for CA ingestions were 66% and 100%, respectively, in a

population of 299 general overdose patients. A retrospective study reported that a CA-poisoned

patient was 8.6 times more likely to have a T40-msec axis greater than 120° than was a non–CA-

poisoned patient.114 This parameter was a more sensitive indicator of CA-induced altered mental

status but not necessarily of seizure or dysrhythmia. However, the T40-msec axis is not easily

measured in the absence of specialized computer-assisted analysis, which limits its practical utility.

An abnormal terminal rightward axis can be estimated by observing a negative deflection (terminal S

wave) in leads I and aVL and a positive deflection (terminal R wave) in lead aVR (Fig. 71–3).

FIGURE 71–3.

(A) Normal QRS complex in lead aVR. (B) Abnormal QRS complex in a patient with cyclic antidepressant (CA)

poisoning. The R wave in lead aVRis measured as the maximal height in millimeters of the terminal upward deflection

in the QRS complex. In this example, the QRS complex duration is prolonged, indicating significant CA poisoning.

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The maximal limb lead QRS complex duration is an easily measured ECG parameter that is a

sensitive indicator of toxicity. One investigation reported that 33% of patients with a limb lead QRS

interval greater than or equal to 100 msec developed seizures and 14% developed ventricular

dysrhythmias.17 No seizures or dysrhythmias occurred in those patients whose QRS interval

remained less than 100 msec. There was a 50% incidence of ventricular dysrhythmias among

patients with a QRS duration greater than or equal to 160 msec. No ventricular dysrhythmias

occurred in patients with a QRS duration less than 160 msec. Subsequent studies confirmed that a

QRS duration greater than 100 msec is associated with an increased incidence of serious toxicity,

including coma, need for intubation, hypotension, seizures, and dysrhythmias, making this ECG

parameter a useful indicator of toxicity.22,61

Evaluation of lead aVR on a routine ECG may also predict toxicity (Figs. 71–2 and 71–3). When

prospectively studied, 79 patients with acute CA overdoses demonstrated that the amplitude of the

terminal R wave and R/S wave ratio in lead aVR (RaVR, R/SaVR) were significantly greater in patients

who developed seizures and ventricular dysrhythmias.61 The sensitivity of RaVR= 3 mm and R/SaVR=

0.7 in predicting seizures and dysrhythmias was comparable to the sensitivity of QRS = 100 msec.

The type 1 Brugada pattern is similar to a right bundle branch block (rSR′), with downsloping ST

elevations (“coved”) in the right precordial leads (V1–V3).11,77 This pattern is neither highly sensitive

nor specific for CA toxicity, and it is reported in patients with cocaine and phenothiazine toxicity as

well as those on class IA antidysrhythmic therapy. In one series of more than 400 patients with CA

overdose, a significant increase in adverse outcomes (ie, seizures, widened QRS interval, and

hypotension) was identified in those patients with a Brugada ECG pattern compared to those who

did not have the pattern.11 However, there were no deaths or dysrhythmias in the nine patients with

this pattern.

Serial ECGs should be obtained because the ECG changes can be dynamic. ECG parameters

should always be interpreted in conjunction with the clinical presentation, history, and course during

the first several hours to assist in decision making regarding interventions and disposition.62

Laboratory Tests

Determination of serum CA concentrations has limited utility in the immediate evaluation and

management of patients with acute overdoses. In one study, serum drug concentrations failed to

accurately predict the development of seizures or ventricular dysrhythmias.17 The pharmacologic

properties of CAs—namely, large volumes of distributions, prolonged absorption phase, long

distribution half-lives, pH-dependent protein binding, and the wide interpatient variability of terminal

elimination half-lives—explain the limited value of serum concentrations in this situation. Any

concentration above the therapeutic range (50–300 ng/mL, including active metabolites) may be

associated with adverse effects, and is an indication to decrease or discontinue the medication.

Although CA concentrations greater than 1000 ng/mL usually are associated with significant clinical

toxicity such as coma, seizures, and dysrhythmias, life-threatening toxicity may be observed in

patients with serum concentrations less than 1000 ng/mL.17,57 Serious toxicity at lower concentrations

probably results from a number of factors, including the timing of the specimen in relation to the

ingestion and the limitations of measuring the concentration in blood and not the affected tissue.

Quantitative concentrations usually cannot be readily obtained in most hospital laboratories.

However, qualitative screens for CAs using an enzyme-multiplied immunoassay test are available at

many hospitals. Unfortunately, false-positive results can occur with many drugs such

ascarbamazepine, cyclobenzaprine, thioridazine, diphenhydramine, quetiapine, and cyproheptadine

(Chap. 6). Thus, the presence of a CA on a qualitative assay should not be relied upon to confirm

the diagnosis of CA poisoning in the absence of corroborating historical or clinical evidence.

Quantitative concentrations may be helpful in determining the cause of death in suspected overdose

patients. CA concentrations reported in lethal overdoses typically range from 1100–21,800 ng/mL.

CA concentrations may increase more than fivefold because of postmortem redistribution (Chap.

34).5 Measurement of liver CA concentration or the parent-to-metabolite drug ratio may be useful in

the postmortem setting.

MANAGEMENT

Any person with a suspected or known ingestion of a CA requires immediate evaluation and

treatment (Table 71–2). The patient should be attached to a cardiac monitor, and intravenous

access should be secured. Early intubation is advised for patients with CNS depression and or

hemodynamic instability because of the potential for rapid clinical deterioration. A 12-lead ECG

should be obtained for all patients. Laboratory tests, including concentrations of glucose and

electrolytes, should be performed for all patients with altered mental status, as well as blood gas

analysis to both assess the degree of acidemia and guide alkalinization therapy. Aggressive

interventions for maintenance of blood pressure and peripheral perfusion must be performed early to

avoid irreversible damage. Both children and adults receiving cardiopulmonary resuscitation have

recovered successfully despite periods of asystole exceeding 90 minutes.24,27,79,101 The options for GI

decontamination discussed in the following section should then be considered.

TABLE 71–2. Treatment of Cyclic Antidepressant (CA) Toxicity

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Gastrointestinal Decontamination

Induction of emesis is contraindicated, given the potential for precipitous neurologic and

hemodynamic deterioration. Because of the potential lethality of large quantities of CAs, orogastric

lavage should be considered in the symptomatic patient with an overdose. Although the benefits of

orogastric lavage for CA toxicity are not substantiated by controlled trials, the potential benefits of

removing significant quantities of a highly toxic drug must be weighed against the risks of the

procedure (Chap. 8).18 Because the anticholinergic actions of some CAs may decrease spontaneous

gastric emptying, attempts at orogastric lavage up to 12 hours after ingestion may yield unabsorbed

drug. Because of the potential for rapid deterioration of mental status and seizures, orogastric lavage

should be performed only after endotracheal intubation has ensured airway protection. Orogastric

lavage in young children with unintentional ingestions of CAs may be associated with more risk and

impracticalities, such as the inadequate hole size of pediatric tubes, and less benefit given the

amount of drug usually ingested. Activated charcoal should be administered in nearly all cases.

Irrespective of age, an additional dose of activated charcoal several hours later is reasonable in a

seriously poisoned patient in whom unabsorbed drug may still be present in the GI tract or in the

case of desorption of CAs from activated charcoal. It is important to monitor for the development of

an ileus to prevent abdominal complications from additional doses of activated charcoal.74

Wide-Complex Dysrhythmias, Conduction Delays, and Hypotension

The mainstay therapy for treating wide-complex dysrhythmias and for reversing conduction delays

and hypotension is the combination of serum alkalinization and sodium loading. Increasing the

extracellular concentration of sodium, or sodium loading, may overwhelm the effective blockade of

sodium channels, presumably through gradient effects (Fig. 71–1). Controlled in vitro and in vivo

studies in various animal models demonstrate that hypertonic sodium bicarbonateeffectively reduces

QRS complex prolongation, increases blood pressure, and reverses or suppresses ventricular

dysrhythmias caused by CAs.82,92, 93, and 94 These studies showed a clear benefit of hypertonicsodium

bicarbonate when compared to hyperventilation, hypertonicsodium chloride, or nonsodium buffer

solutions. A systematic review of all animal and human studies published before 2001 revealed that

alkalinization therapy was the most beneficial therapy for consequential dysrhythmias and

shock16 (Antidotes in Depth: A5).

The optimal dosing and mode of administration of hypertonic sodium bicarbonate and the indications

for initiating and terminating this treatment are unsupported by controlled clinical studies. Instead,

the information is extrapolated from animal studies, clinical experience, and an understanding of the

pathophysiologic mechanisms of CA toxicity. A bolus, or rapid infusion over several minutes, of

hypertonic sodium bicarbonate (1–2 mEq/kg) should be administered initially.70,98 Additional boluses

every 3 to 5 minutes can be administered until the QRS interval narrows and the hypotension

improves (Fig. 71–2). Blood pH should be carefully monitored after several bicarbonate boluses,

aiming for a target pH of no greater than 7.50 or 7.55. Because CAs may redistribute from the

tissues into the blood over several hours, it may be reasonable to begin a continuous sodium

bicarbonate infusion to maintain the pH in this range. Differences in outcomes between repetitive

boluses versus bicarbonate infusions are not well studied. Although diluting sodium bicarbonate in

5% dextrose in water and infusing it slowly renders it less able to increase the sodium gradient

across the cell, the beneficial effects of pH elevation still warrant its use once the patient is

stabilized. No evidence supports prophylactic alkalinization in the absence of cardiovascular toxicity

(eg, QRS < 100 msec). In addition, alkalization would inevitably cause a decrease in potassium,

which may cause QT prolongation and potentially contribute to other dysrhythmias.

Hypertonicsodium chloride (3% NaCl) reverses cardiotoxicity in several animal studies,47,71,82 and

numerous reports and extensive clinical experience support its efficacy in humans.16,48,49,73 However,

the dose of hypertonic saline for CA poisoning has never been evaluated in humans for safety or

efficacy, and the dose suggested by animal studies (up to 15 mEq/kg) exceeds the amount that most

clinicians would consider safe (1–2 mEq/kg). Hypertonic sodium chloride is associated with a

hyperchloremic metabolic acidosis, an undesired effect that highlights one benefit of

hypertonic sodium bicarbonate. However, hypertonic saline could be considered in situations in

which alkalinization withsodium bicarbonate is not possible.

Hyperventilation of an intubated patient is a more rapid and easily titratable method of serum

alkalinization but is not as effective as sodium bicarbonate in reversing

cardiotoxicity.51,70 Simultaneous hyperventilation and sodium bicarbonate administration may result in

profound alkalemia and should be performed only with extreme caution and careful monitoring of pH.

Hyperventilation without bicarbonate administration may be indicated in patients with ARDS or

congestive heart failure in whom administration of large quantities of sodium is contraindicated.

Alkalinization and sodium loading with hypertonic sodium bicarbonateand or hypertonic saline along

with controlled ventilation (if clinically indicated) should be administered to all CA overdose patients

presenting with major cardiovascular toxicity and altered mental status. Indications include

conduction delays (QRS > 100 msec) and hypotension. It is imperative to initiate treatment until CA

toxicity can be excluded because of the risk of rapid and precipitous deterioration. Although

commonly assumed, it is unclear whether the failure of the QRS complex to narrow with sodium

bicarbonate treatment excludes CA toxicity.

It is unclear whether alkalinization and sodium loading is effective for reversing the Brugada pattern.

The sparse available literature is equivocal.12,77 It would seem prudent to administer sodium

bicarbonatein the presence of a presumed CA-induced Brugada pattern, especially with concomitant

signs of other CA toxicity.

Alkalinization may be continued for at least 12 to 24 hours after the ECG has normalized because of

the redistribution of the drug from the tissue. However, the time observed for resolution or

normalization of conduction abnormalities is extremely variable, ranging from several hours to

several days, despite continuous bicarbonate infusion.62 We recommend stopping alkalinization

when the patient’s mental status improves and there is improvement, but not necessarily

normalization, of abnormal ECG findings.

Antidysrhythmic Therapy

Lidocaine is the antidysrhythmic most commonly advocated for treatment of CA-induced

dysrhythmias, although no controlled human studies demonstrate its

efficacy.86 Because lidocaine has sodium channel blocking properties, some investigators argue

against its use in CA poisoning.1 These theoretical concerns are not well supported in the literature,

and the class IB antidysrhythmic channel binding kinetics may prove favorable. Although limited data

also suggest that the IB antidysrhythmic phenytoin prevents or reverses conduction

abnormalities,43,69 these data were poorly controlled for other confounding factors, such as blood pH

and sodium bicarbonateadministration; they had very small numbers; and, in some, the cardiotoxicity

was not severe. Since phenytoin exacerbates ventricular dysrhythmias in animals21 and fails to

protect against seizures,10 its use is no longer recommended.

The use of class IA (quinidine, procainamide, disopyramide, and moricizine) and class IC (flecainide,

propafenone) antidysrhythmics is absolutely contraindicated because they have similar

pharmacologic actions to CAs and thus may worsen the sodium channel inhibition and exacerbate

cardiotoxicity. Class III antidysrhythmics (amiodarone, bretylium, and sotalol) prolong the QT interval

and, although unstudied, may be contraindicated as well (Chap. 64).

Because magnesium sulfate has antidysrhythmic properties, it may be beneficial in the treatment of

ventricular dysrhythmias. Animal studies of the effects of magnesium on CA-induced dysrhythmias

yield conflicting results.52,53 However, successful use of magnesium sulfate in the treatment of

refractory ventricular fibrillation after TCA overdose is reported.24,27,54,91 A case control study suggested

that magnesium sulfate and sodium bicarbonate resulted in lower fatality incidence and shorter

intensive care unit stay compared to sodium bicarbonatealone.29 When dysrhythmias fail to reverse

after alkalinization, sodium loading, and a trial of lidocaine, or magnesium sulfate may be warranted.

Slowing the heart rate in the presence of CAs may allow more time during diastole for CA unbinding

from sodium channels and result in an improvement in ventricular conduction.3,92 This may abolish

the reentry mechanism for dysrhythmias and was one rationale for the past use ofphysostigmine and

propranolol. Thus, decreasing the sinus rate may itself be effective in abolishing ventricular

dysrhythmias by eliminating rate-dependent conduction slowing. Propranolol terminated ventricular

tachycardia in an animal model but also caused significant hypotension and death.94 In one case

series, patients developed severe hypotension or had a cardiac arrest shortly after receiving a β-

adrenergic antagonist.36 Other animal studies suggest that preventing or abolishing tachycardia by

sinus node destruction, or by using bradycardic agents that impede sinus node automaticity without

affecting myocardial repolarization or contractility, may successfully prevent CA-induced ventricular

dysrhythmias.3,4 The combined negative inotropic effects of β-adrenergic antagonists and CAs, along

with the significant cardiac and CNS effects reported with physostigmine use, do not support their

routine use in the management of CA-induced tachydysrhythmias.

Hypotension

Standard initial treatment for hypotension should include volume expansion with isotonic saline

or sodium bicarbonate. Hypotension unresponsive to these therapeutic interventions necessitates

the use of inotropic or vasopressor support and possibly extracorporeal cardiovascular support.

No controlled human trials are available to guide the use of vasopressor therapy. The pharmacologic

properties of CAs complicate the choice of a specific agent. Specifically, CA blockade of

neurotransmitter reuptake theoretically could result in depletion of intracellular catecholamines. This

could blunt the effect of dopamine, which is dependent on the release of endogenous

norepinephrine for its inotropic activity. This suggests that a direct-acting vasopressor such as

norepinephrine is more efficacious than an indirect-acting catecholamine such as dopamine.

In fact, limited clinical data suggest that norepinephrine is more efficacious than dopamine.109 In a

retrospective study of 26 adult hypotensive patients receiving nonstandardized therapy, response

rates to norepinephrine (5–53 μg/min) were significantly better than response rates to dopamine (5–

10 μg/kg/min).110 Patients who did not respond to dopamine at vasopressor doses (10–50 μg/kg/min)

responded to norepinephrine (5–74 μg/min). Animal data comparing various treatments are

conflicting, and their direct applicability to clinical human poisoning is limited.32,111 Both norepinephrine

and epinephrineincreased the survival rate in CA-poisoned rats. In addition, epinephrinewas superior

to norepinephrine when used both with and without sodium bicarbonate, and the most effective

treatment regimen in this study wasepinephrine plus sodium bicarbonate; neither precipitated

dysrhythmias. The authors propose that epinephrine is more efficacious because it augments

myocardial perfusion more than norepinephrine and improves the recovery of CA sodium channel

blockade by hyperpolarization of the membrane potential through its stimulation of increased

potassium intracellular transport.

Based on the available data, pharmacologic effects, theoretical concerns, and experience,

norepinephrine (0.1–0.2 μg/kg/min) is recommended for hypotension that is unresponsive to volume

expansion and hypertonic sodium bicarbonate therapy. Central venous pressure and or pulmonary

artery catheterization may be necessary to guide the choice of additional vasopressor or inotropic

agents, especially in the presence of other cardiodepressant drugs.

If these measures fail to correct hypotension, extracorporeal life support measures should be

considered. Extracorporeal membrane oxygenation, extracorporeal circulation, and cardiopulmonary

bypass are successful adjuncts for refractory hypotension and life support when maximum

therapeutic interventions fail.42,101,113 These modalities can provide critical perfusion to the heart and

brain and maintain metabolic function while giving the body time to metabolize and eliminate the CA

by maintaining hepatorenal blood flow.

Emerging Therapies

Vasopressin is increasingly being used in the setting of vasodilatory shock with successful increases

in arterial blood pressure based on its vasoconstrictive actions from several mechanisms. Its

successful use for intractable hypotension due to CA toxicity, unresponsive to α-receptor agonists

and pH manipulation, has been described and warrants further investigation.9

Intravenous fat emulsion is reported to be effective in reversing cardiovascular toxicity due to several

lipophilic drugs includingamitriptyline and clomipramine. Its utilization and effectiveness appears

logical given their pharmacological properties—Log D and Log P—octanol/water partition coefficient

discussed previously.

Several controlled animal studies have demonstrated improved survival in clomipramine-induced

cardiovascular collapse when intravenous lipid emulsion is given either as pretreatment or

resuscitation in comparison with saline controls and sodium bicarbonate infusion.44 Other animal

studies failed to demonstrate any benefit.7,64 Specifically, one failed to demonstrate a statistically

significant benefit in amitriptyline-poisoned rats pretreated with intravenous fat emulsion.7 Case

series and case reports demonstrate clinical improvement when lipids have been administered for

cardiovascular collapse or instability refractory to other therapies.38,44,50,58,99 The dosing and timing of

administration are variable as well as other concomitant therapies, making it difficult to reach any

definitive conclusions regarding its effectiveness. In addition, significant adverse reactions and

complications have been noted including ARDS and pancreatitis. More data is emerging allowing

more evidence-based criteria for its use and dosing. Certainly for patients with refractory

hypotension and or ventricular dysrhythmias, fat emulsiontherapy should be strongly considered,

given the high mortality rate with these medications (Antidotes in Depth: A20).

Central Nervous System Toxicity

Seizures caused by CAs usually are brief and may stop before treatment can be initiated. Recurrent

seizures, prolonged seizures (>2 minutes), and status epilepticus require prompt treatment to

prevent worsening acidosis, hypoxia, and development of hyperthermia and rhabdomyolysis.

Benzodiazepines are effective as first-line therapy for seizures. If this therapy fails, barbiturates or

propofol should be administered. Propofol controlled refractory seizures resulting from amoxapine

toxicity.75 Failure to respond to barbiturates or propofol should lead to consideration of

neuromuscular paralysis and general anesthesia with continuous electroencephalographic

monitoring. Phenytoin is not recommended for seizures because data not only demonstrate a failure

to terminate seizures but also suggest enhanced cardiovascular toxicity.9,21

Use of flumazenil in a patient with known or suspected CA ingestion is contraindicated. Several case

reports of patients with CA overdoses describe seizures following administration of

flumazenil59 (Antidotes in Depth: A27). Physostigmine was used in the past to reverse the acute CNS

toxicity of CAs (Antidotes in Depth: A9). However, physostigmine is not recommended because it

may increase the risk of cardiac toxicity, cause bradycardia and asystole, and precipitate seizures in

acutely CA-poisoned patients.84

Enhanced Elimination

No specific treatment modalities have demonstrated clinical significant efficacy in enhancing the

elimination of CAs. Some investigators propose multiple doses of activated charcoal to enhance CA

elimination because of their small enterohepatic and enterogastric circulation.67 Human volunteer

studies and case series of patients with CA overdoses suggest that the half-life of CAs may be

decreased by multiple-dose activated charcoal (MDAC).107 Activated charcoal reduced the apparent

half-life ofamitriptyline to 4 to 40 hours in overdose patients, compared to previously published

values of 30 to more than 60 hours.107 Changes in the severity or duration of clinical toxicity,

however, were not reported. Other investigators showed that in human volunteers MDAC reduced

the half-life of therapeutic doses of amitriptyline approximately 20% compared with no activated

charcoal administration. However, the methodologic flaws and equivocal findings of these studies

and the lack of any positive outcome data for this intervention from additional studies do not provide

evidence supporting its use in this setting.23,40Pharmacokinetic properties of CAs (large volumes of

distribution, high plasma protein binding) weighed against the small increases in clearance and the

potential complications of MDAC, such as impaction, intestinal infarction, and perforation, do not

warrant its routine use.23,74One additional dose of activated charcoal may be given to decrease GI

absorption in patients with evidence of significant CNS and cardiovascular toxicity if bowel sounds

are present.

Measures to enhance urinary CA excretion have a minimal effect on total clearance. Urinary

alkalinization does not enhance, and may reduce, urinary clearance due to passive reabsorption of

the unionized CA from an alkaline urine. Hemodialysis is ineffective in enhancing the elimination of

CAs because of their large volumes of distribution, high lipid solubility, and extensive protein

binding.45 Hemoperfusion overcomes some of the limitations of hemodialysis but may not be effective

because of the large volumes of distributions of CAs. Although several uncontrolled case reports and

a case series described improvement in cardiotoxicity during hemoperfusion, this finding may be

coincidental.13,24,35

Hospital Admission Criteria

All patients who present with known or suspected CA ingestion should undergo continuous cardiac

monitoring and serial ECG for a minimum of 6 hours. Recommendations in the older literature for 48

to 72 hours of intensive care unit monitoring even for patients with minor CA ingestions stem from

isolated case reports of late-onset dysrhythmias, CNS effects, and sudden deaths.83 However,

review of these cases shows inadequate GI decontamination, inadequate therapeutic interventions,

and significant ongoing complications of overdose. Several retrospective studies demonstrate that

late, unexpected complications in CA overdoses such as seizures, dysrhythmias, and death did not

occur in patients who had few or no major signs of toxicity at presentation or a normal level of

consciousness and a normal ECG for 24 hours.20,27,30,85A disposition algorithm has been proposed

based on clinical signs and symptoms.6,108 If the patient is asymptomatic at presentation, undergoes

GI decontamination, has normal ECGs, or has sinus tachycardia (with normal QRS complexes) that

resolves, and the patient remains asymptomatic in the health care facility for a minimum of 6 hours

without any treatment interventions, the patient may be medically cleared for psychiatric evaluation

(if appropriate) or discharged home as appropriate.

A prospective study of 67 patients used the Antidepressant Overdose Risk Assessment (ADORA)

criteria to identify patients who were at high risk for developing serious toxicity and proposed criteria

for hospitalization.33 In this study, the presence of QRS interval greater than 100 msec, cardiac

dysrhythmias, altered mental status, seizures, respiratory depression, or hypotension on

presentation to the ED (or within 6 hours of ingestion, if the time was known) was 100% sensitive in

identifying patients with significant toxicity and subsequent complications. Criteria specific for

intensive care unit admission (other than patients requiring ventilatory and or blood pressure

support), versus an inpatient bed with continuous cardiac monitoring, are less clear and probably are

institution dependent.103

The disposition of patients with persistent isolated sinus tachycardia, prolonged QT interval with no

concomitant altered mental status, or blood pressure changes, is not clearly defined. Previous

studies demonstrate that these two parameters alone are not predictive of subsequent clinical

toxicity or complications.33,34 In addition, the sinus tachycardia may persist for up to one week

following ingestion. However, a study of isolated CA overdose patients reported that a heart rate

greater than 120 beats/min and QT interval greater than 480 msec were associated with an

increased likelihood of major toxicity.22 These patients are candidates for observation units with

continuous ECG monitoring and serial ECGs for 24 hours.

Inpatient Cardiac Monitoring

The duration of cardiac monitoring in any patient initially exhibiting signs of major clinical toxicity

depends on many factors. Certainly the duration of CA cardiotoxicity and neurotoxicity may be

prolonged, and using normalization of ECG abnormalities as an end point for therapy and discharge

is problematic. Some studies document the variable resolution and normalization of QRS

prolongation and T40-msec axis rotation.81,97Based on the available literature, it is reasonable to

recommend that after the mental status and blood pressure normalize, and the ECG improves,

patients who exhibited significant poisoning should be monitored for another 24 hours off of all of

therapy, including alkalinization, antidysrhythmics, and inotropics/vasopressors.

SUMMARY

CA poisoning continues to be a cause of serious morbidity and mortality worldwide.

The distinctive characteristics of these drugs can cause significant CNS and cardiovascular

toxicity, the latter being responsible for mortality as a result of overdose of these drugs.

Cardiovascular toxicity ranges from mild conduction abnormalities and sinus tachycardia to

wide-complex tachycardia, hypotension, and asystole. CNS toxicity includes delirium,

lethargy, seizures, and coma.

The ECG is a simple, readily available diagnostic test that can predict the development of

significant toxicity, particularly seizures and/or dysrhythmias.

Management strategies are based primarily on the pathophysiology of these drugs, namely,

sodium channel blockade in the myocardium. Alkalinization and sodium loading with

hypertonic sodium bicarbonate is the principal therapy for cardiovascular toxicity.

Guidelines for observing or admitting patients to the hospital may be based on initial clinical

presentation or development of clinical effects and ECG changes.

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