71: Cyclic Antidepressants

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.

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

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

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

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 pK_a). 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 and nortriptyline, 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.¹⁰⁶ The 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.

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

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 (see Diagnostic 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.

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.³⁹ Unlike 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 anta­gonism 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.⁷⁷ Similarly, the incidences of seizures, cardiac dysrhythmias, and duration of coma are greater with maprotiline toxicity compared to the CAs.⁵⁵

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 aV_L and a positive deflection (terminal R wave) in lead aV_R (Fig. 71–3).

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 aV_R 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 aV_R (RaV_R, R/SaV_R) were significantly greater in patients who developed seizures and ventricular dysrhythmias.⁶¹ The sensitivity of RaV_R= 3 mm and R/SaV_R= 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 as carbamazepine, 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.

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.

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 bicarbonate effectively 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 hypertonic sodium bicarbonate when compared to hyperventilation, hypertonic sodium 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. Hypertonic sodium 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 with sodium 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 bicarbonate and 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 bicarbonate in 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 bicarbonate administration; 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 bicarbonate alone.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 of physostigmine 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 epinephrine increased the survival rate in CA-poisoned rats. In addition, epinephrine was superior to norepinephrine when used both with and without sodium bicarbonate, and the most effective treatment regimen in this study was epinephrine 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 including amitriptyline 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 emulsion therapy 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 of amitriptyline 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.^23,40 Pharmacokinetic 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.^23,74 One 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.^20,27,30,85 A 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.^81,97 Based 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.

• 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.

References