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Toxicity, Tricyclic Antidepressant: Treatment & Medication
Updated: Oct 22, 2009
- Overview
- Differential Diagnoses & Workup
- Treatment & Medication
- Follow-up
- Multimedia
Treatment
Medical Care
As always, the first priority in patients with cyclic antidepressant (CA) poisoning is to assess and treat ABCs as appropriate. Good supportive care is the mainstay of treatment in any overdose.
- Early intubation for patients with significant signs of toxicity, including seizures and CNS depression, is prudent. Patients who are obtunded and those with impending respiratory failure should clearly be intubated for airway protection and ventilatory support.
- Intravenous fluids should be started for patients who are hypotensive.
- Cardiac monitoring should be instituted as soon as possible because of the risk of arrhythmias in patients with cardiovascular toxicity.
- Seizures should be treated with benzodiazepines.
- If the patient is symptomatic, a Foley catheter should be placed to relieve urinary obstruction due to anticholinergic effects and to monitor the adequacy of fluid resuscitation.
- The patient should be examined for signs and symptoms of cyclic antidepressant toxicity, and ECG should be performed early to look for a terminal R wave in lead aVR and for prolongation of the QRS and QT intervals.
- Symptoms of cyclic antidepressant toxicity generally present within 2 hours of ingestion. Seizures and arrhythmias are most likely to occur in the first 6 hours after ingestion. All patients with suspected cyclic antidepressant ingestion should undergo cardiac monitoring for a minimum of 6-8 hours. Monitoring should continue in symptomatic patients until the ECG findings have been normal for 24 hours.
- Asymptomatic patients should be screened for suicidal intent and admitted to a psychiatric facility as appropriate after an observation period of at least 8 hours.
- Decontamination measures include the following:
- Syrup of ipecac is contraindicated because of the high risk of aspiration if patients become symptomatic during emesis. Patients with exposures large enough to cause symptoms may have acute alterations in mental status due to either direct CNS effects (drowsiness, delirium, seizure) or hemodynamic instability.
- Consider gastric lavage if the patient has a known or suspected significant ingestion that occurred within 1 hour of presentation. If a lavage is to be performed, the patient should be intubated first, and a dose of charcoal should be administered via the orogastric tube prior to lavage. The same amount, or more, of the ingested dose is propelled into the small intestine as is recovered during lavage, and this bolus is preferably mixed with an adsorbing substance.
- Regardless of the decision to lavage, 1 g/kg of activated charcoal should be administered as soon as possible. Multidose charcoal may enhance elimination and should be considered.
- Because of the large volume of distribution and high protein binding of cyclic antidepressants, hemodialysis and hemoperfusion are not effective in enhancing drug removal.
- Tricyclic-specific fragment antigen–binding (FAB) fragments have been developed and may eventually play a role in the decontamination of patients with cyclic antidepressant poisoning. The FAB fragments have been shown to reverse cardiotoxicity in some animal studies, and a small preliminary study in humans demonstrated no significant side effects and some clinical improvement in patients with severe cyclic antidepressant poisoning.11
- Hypotension should be initially treated with intravenous fluid boluses. Refractory hypotension should be treated with pressors. Agents with alpha-adrenergic effects should be chosen. Dopamine is not usually effective in these patients because it partially depends on the release of endogenous norepinephrine for its action. Cyclic antidepressants block reuptake of norepinephrine, and stores may be depleted in overdose. Animal studies have suggested that epinephrine may cause fewer arrhythmias than norepinephrine in this setting.
- Treatment of cardiac arrhythmias is as follows:
- Cardiac arrhythmias should be treated according to the hemodynamic stability of the patient. Correction of hypoxia, hypotension and acidosis should be the first-line approach to conduction abnormalities
- If antiarrhythmics are needed, class IA, class IC, class II, and class III drugs should be avoided. Like cyclic antidepressants, class IA and IC drugs block sodium channels and prolong depolarization and, therefore, may exacerbate their effects on the myocardium. Beta-blockers are likely to further depress myocardial contractility and cause worsening hypotension. Class III drugs prolong the QT interval and may increase the risk of a malignant ventricular arrhythmia.
- However, class IB antiarrhythmics can increase the rate of phase zero depolarization, and phenytoin has been reported to correct conduction defects in at least one small series of patients. Several case reports of the use of magnesium and glucagons have suggested that these agents may correct ventricular arrhythmias in patients with severe cyclic antidepressant toxicity.
- Sodium bicarbonate therapy
- Serum alkalinization with sodium bicarbonate is the mainstay of therapy in cyclic antidepressant overdose. Alkalinization of the serum to a pH level of 7.45-7.55 increases protein binding and has been shown to decrease the QRS interval, stabilize arrhythmias, and increase blood pressure in patients with tricyclic antidepressant (TCA) poisoning.
- Sodium bicarbonate may also be beneficial in treating cyclic antidepressant overdose because of the high sodium load. Animal studies and some human case reports of treatment with hypertonic saline (without serum alkalinization) have shown similar effects on myocardial conduction parameters.12 Therapy with hypertonic saline should be strongly considered in patients who are already alkalemic and in those who cannot tolerate the large volume load associated with intravenous bicarbonate administration.
- Blood gases should be monitored for the development of acidosis. Sodium bicarbonate should be administered if the patient has a pH level of less than 7.1, QRS interval of more than 100 milliseconds, arrhythmias, or hypotension.
- Bicarbonate should be administered as an initial bolus of 1-2 mEq/kg, followed by an infusion titrated to a QRS width of 100 milliseconds.
- The serum pH should be closely monitored and should not be allowed to exceed 7.55. Serum potassium should also be closely monitored for the development of hypokalemia.
- ECG should be monitored for the desired effect of QRS narrowing during and immediately after bolus therapy. The QTc interval should also be monitored because bicarbonate therapy may prolong the QTc. Case reports and an animal model suggest that the use of extracorporeal life support may be lifesaving in TCA overdoses that are refractory to advanced life-support measures and traditional therapies.
- All patients should be monitored for arrhythmias for at least 12 hours, and symptomatic patients should be admitted to an ICU setting.
Consultations
- The local poison control center or a clinical toxicologist should be consulted in all cases of suspected poisoning.
- A pediatric psychiatrist should be consulted if intentional ingestion is suspected.
- Child protective services should be notified if inadequate supervision or Münchhausen syndrome by proxy is suspected.
Medication
Cardiotoxicity
As discussed above, sodium bicarbonate therapy is the cornerstone of treatment for cyclic antidepressant (CA)-induced conduction disturbances, ventricular arrhythmias, and hypotension. Serum alkalinization to a pH of 7.45-7.55 appears to uncouple tricyclic antidepressant (TCA) from myocardial sodium channels, and the sodium load increases extracellular sodium concentration, improving the gradient across the channel.
Controlled studies have demonstrated that bicarbonate loading with an initial bolus of 1-2 mEq/kg of sodium bicarbonate is beneficial. Continuing a bicarbonate drip after the initial bolus, which is titrated to achieve a QRS width of 100 milliseconds, is accepted practice.
Ventricular arrhythmias that are refractory to sodium bicarbonate may require treatment with lidocaine, magnesium sulfate, or both. Class IA (eg, quinidine, procainamide, disopyramide) and class IC (eg, flecainide, propafenone) drugs are contraindicated because they may worsen sodium channel inhibition. Class III drugs (eg, amiodarone, bretylium, sotalol) are contraindicated because they can further prolong the QT interval, leading to ventricular arrhythmia. Class II beta-blockers (eg, propranolol, esmolol, metoprolol) and class IV calcium channel blockers (eg, verapamil, diltiazem, nifedipine, nicardipine) are contraindicated because they may potentiate or worsen hypotension.
Patients with hypotension refractory to fluid resuscitation and sodium bicarbonate require vasopressor support. Direct-acting alpha-agonists (eg, norepinephrine, phenylephrine) are most effective because severe hypotension is generally due to direct alpha1-blocking effects in these cases. Dopamine may not be as effective because its action is partially mediated by the release of endogenous catecholamines, and these may be depleted.
CNS toxicity
Seizures secondary to cyclic antidepressant toxicity are generally self-limiting but should be treated because the acidosis produced by vigorous muscle contraction and impaired ventilation during seizure activity may increase the concentration of free drug and increase toxicity.
Benzodiazepines are the agents of choice. Phenobarbital may also be used as a long-acting anticonvulsant.
Phenytoin is not recommended because it also blocks sodium channels and may exacerbate or cause dysrhythmias in a patient with cyclic antidepressant poisoning. Despite the fact that phenytoin has been reported to correct cardiac conduction defects in at least one small series of patients, it is still not recommended for seizure control.
Physostigmine is an acetylcholinesterase inhibitor that is contraindicated in patients with cyclic antidepressant overdoses. Although physostigmine was previously advocated for relief of anticholinergic effects, it may cause bradycardia and asystole in cyclic antidepressant cardiotoxicity.
Flumazenil, a benzodiazepine antagonist, is also contraindicated, even in the presence of benzodiazepine co-ingestion. Several case reports describe patients with concomitant cyclic antidepressant overdoses who had seizures after the administration of flumazenil.
Decontaminants
Activated charcoal is used to prevent drug absorption. Activated charcoal is not absorbed and is excreted entirely through the GI tract. It decreases the extent of cyclic antidepressant absorption from the GI tract, thereby reducing systemic toxicity.
Activated charcoal (Actidose-Aqua, Liqui-Char)
Network of pores present in activated charcoal absorbs 100-1000 mg of drug per gram of charcoal. Binds TCAs present in GI tract, thereby limiting systemic absorption and hastening elimination.
Adult
60-100 g PO/NG
Pediatric
1 g/kg PO/NG
May inactivate ipecac syrup if used concomitantly; effectiveness of other medications decreases with coadministration; do not mix charcoal with sherbet, milk, or ice cream (decreases absorptive properties)
Documented hypersensitivity; poisoning with or overdose of mineral acids and alkalies
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Not effective in poisonings with ethanol, methanol, and iron salts; induce emesis before administering activated charcoal; after emesis with ipecac syrup, patient may not tolerate activated charcoal for 1-2 h; can administer in early stages of gastric lavage; gastric lavage return is black without sorbitol
Alkalinizing agents
Sodium bicarbonate remains the first-line therapy for cyclic antidepressant-induced cardiotoxicity. Sodium bicarbonate may have beneficial effects in the treatment of cyclic antidepressant-induced seizures, although data have been far less compelling. Prophylactic use is not indicated in a patient who displays no signs of cardiotoxicity. Sodium bicarbonate provides a source of sodium and alkali, both of which are useful in cyclic antidepressant overdose.
Sodium bicarbonate
DOC in limiting cardiovascular morbidity in TCA overdoses.
Adult
Initial bolus: 1-2 mEq/kg IV push over 1-2 min; not to exceed 100 mEq/dose
Follow-up infusion: 100-150 mEq in 1 L D5/0.45% NaCl infused 100-200 mL/h IV; titrate infusion to achieve blood pH of 7.45-7.55
Pediatric
Prepare infusion as in adults; infuse at 1.5- to 2-times maintenance fluid requirements
Urinary alkalinization, induced by increased sodium bicarbonate concentrations, may cause decreased levels of lithium, tetracyclines, chlorpropamide, methotrexate, and salicylates; increases levels of amphetamines pseudoephedrine, flecainide, anorexiants, mecamylamine, ephedrine, quinidine, and quinine
Documented hypersensitivity; alkalosis, hypernatremia, hypocalcemia, severe pulmonary edema, and abdominal pain of unknown origin
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Monitor closely for development of severe metabolic alkalosis, hypernatremia, hypokalemia, or hypocalcemia; leftward shift of oxyhemoglobin dissociation curve; tissue necrosis with extravasation
Vasopressors
These agents are indicated for persistent hypotension that is unresponsive to fluid resuscitation and sodium bicarbonate.
Norepinephrine (Levophed)
DOC for calcium-induced hypotension refractory to fluid or sodium bicarbonate. Stimulates beta1-adrenergic and alpha-adrenergic receptors, which, in turn, increases cardiac muscle contractility, heart rate, and vasoconstriction. As a result, systemic blood pressure and coronary blood-flow increases.
Adult
Refractory hypotension: 0.5-30 mcg/min continuous IV infusion; titrate to effect
Pediatric
0.05-1 mcg/kg/min continuous IV infusion; titrate to effect
Calcium antagonists, MAOIs, antihistamines, guanethidine, ergot alkaloids, and methyldopa may potentiate norepinephrine effects
Documented hypersensitivity; peripheral or mesenteric vascular thrombosis because ischemia and area of infarction may be increased
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Correct blood-volume depletion, if possible, before administering norepinephrine therapy; extravasation may cause severe tissue necrosis and, thus, should be administered into large veins; caution in occlusive vascular disease
Phenylephrine (Neo-Synephrine)
Strong postsynaptic alpha-receptor stimulant with little beta-adrenergic activity that produces vasoconstriction of arterioles in the body. Increases peripheral venous return.
Adult
1-4 mcg/kg/min (range 20-200 mcg/min) continuous IV infusion
Pediatric
0.1-0.5 mcg/kg/min continuous IV infusion; titrate to effect
Bretylium may potentiate action of vasopressors on adrenergic receptors, possibly resulting in arrhythmias; MAOIs may significantly enhance adrenergic effects of phenylephrine, and pressor response may be increased 2-3 fold; guanethidine may increase pressor response of direct-acting vasopressors, possibly resulting in severe hypertension
Documented hypersensitivity; severe hypertension; ventricular tachycardia
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Central venous infusion strongly recommended because of significant risk of ischemic or extravasation injury when infused peripherally; caution in hyperthyroidism, myocardial disease, bradycardia, partial heart block, or severe arteriosclerosis; in hypovolemia, is not substitute for replacement of blood, fluids, electrolytes, and plasma (these should be restored promptly when loss has occurred)
Inotropic agents
Positive inotropic agents increase the force of contraction of the myocardium and are used to treat acute and chronic congestive heart failure. Some may also increase or decrease the heart rate (ie, positive or negative chronotropic agents), provide vasodilatation, or improve myocardial relaxation.
These agents are indicated for hypotension that is unresponsive to fluid, sodium bicarbonate, and norepinephrine therapy and is believed to be caused by myocardial depression.
Dopamine
Stimulates both adrenergic and dopaminergic receptors. Hemodynamic effect is dependent on the dose. Lower doses predominantly stimulate dopaminergic receptors, which, in turn, produce renal and mesenteric vasodilation. Cardiac stimulation and renal vasodilation are produced by higher doses.
After initiating therapy, increase dose by 1-4 mcg/kg/min q10-30min until optimal response is obtained. Satisfactory maintenance is obtained using doses of <20 mcg/kg/min in more than 50% of patients.
In TCA cardiotoxicity, higher starting doses should be initiated to avoid unopposed beta effects.
Not usually effective in these patients because it partially depends on the release of endogenous norepinephrine for its action.
Adult
10-20 mcg/kg/min continuous IV infusion
Pediatric
Administer as in adults
Phenytoin, alpha-adrenergic and beta-adrenergic blockers, general anesthesia, and MAOIs increase and prolong effects of dopamine
Documented hypersensitivity; pheochromocytoma or ventricular fibrillation
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Central venous infusion is strongly recommended because of significant risk of ischemic or extravasation injury when infused peripherally; closely monitor urine flow, cardiac output, and blood pressure during infusion; correct hypovolemia before infusion; monitoring central venous pressure or left ventricular filling pressure may be helpful in detecting and treating hypovolemia
Dobutamine (Dobutrex)
Strong beta1-agonist producing excellent inotropy. Weak beta2-agonist that produces mild-to-moderate peripheral vasodilation.
Adult
2-20 mcg/kg/min continuous IV infusion; titrate to effect
Pediatric
Administer as in adults
Beta-adrenergic blockers antagonize effects of dobutamine; general anesthetics may increase toxicity
Documented hypersensitivity; idiopathic hypertrophic subaortic stenosis and atrial fibrillation or flutter
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Use with extreme caution and only with appropriate pharmacologic alpha-stimulation (norepinephrine or phenylephrine); central venous infusion strongly recommended; hypovolemic state should be corrected before therapy
Antiarrhythmic agents
Sodium bicarbonate is the initial and most effective drug for the treatment of cyclic antidepressant-induced conduction disturbances and arrhythmias. Lidocaine and magnesium sulfate should be reserved for arrhythmias that are unresponsive to alkalization and sodium loading.
Lidocaine (Xylocaine)
Class IB antiarrhythmic that increases electrical stimulation threshold of the ventricle, suppressing automaticity of conduction through the tissue.
Second-line treatment for CA-induced arrhythmias. Alkalinization and sodium loading must be attempted before the use of any antiarrhythmic for CA-induced cardiotoxicity.
Adult
1-1.5 mg/kg IV push initially; followed by 1-4 mg/min continuous IV infusion; titrate to effect
Pediatric
1-1.5 mg/kg IV push initially; followed by 20-50 mcg/kg/min continuous IV infusion; titrate to effect
Coadministration with cimetidine or beta-blockers increases toxicity of lidocaine; coadministration with procainamide and tocainide may result in additive cardiodepressant action; may increase effects of succinylcholine
Documented hypersensitivity; avoid in Adams-Stokes syndrome and Wolf-Parkinson-White syndrome; avoid in severe sinoatrial, AV, or intraventricular block if artificial pacemaker is not in place
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Use solution without preservatives; caution in heart failure, hepatic disease, hypoxia, hypovolemia or shock, respiratory depression, and bradycardia; may increase risk of adverse CNS and cardiac effects in elderly persons; high plasma concentrations can cause seizures, heart block, and AV conduction abnormalities
Magnesium sulfate
Prevents calcium influx. Also activates sodium-potassium ATPase, thus affecting sodium and potassium transport across cell membranes, which can facilitate the maintenance of the resting potential. May be of particular use in patients with torsade de pointes type of ventricular tachycardia.
Adult
1-2 g IV diluted in 10 mL of D5W administered over 1-2 min
Pediatric
25-50 mg/kg/dose IV diluted in 10 mL of D5W administered over 1-2 min; not to exceed 2 g/dose
Concurrent use with nifedipine may cause hypotension and neuromuscular blockade; may increase neuromuscular blockade observed with aminoglycosides and potentiate neuromuscular blockade produced by tubocurarine, vecuronium, and succinylcholine; may increase CNS effects and toxicity of CNS depressants and betamethasone and cardiotoxicity of ritodrine
Documented hypersensitivity; heart block; Addison disease; myocardial damage; severe hepatitis
Pregnancy
A - Fetal risk not revealed in controlled studies in humans
Precautions
Magnesium may alter cardiac conduction, leading to heart block in patients taking digitalis; respiratory rate, deep tendon reflex, and renal function should be monitored when electrolyte is administered parenterally; caution when administering magnesium dose because may produce significant hypertension or asystole; in overdose, calcium gluconate, 10-20 mL IV of 10% solution, can be administered as antidote for clinically significant hypermagnesemia
Anticonvulsant agents
These agents are used to prevent seizures and terminate clinical and electrical seizure activity.
Lorazepam (Ativan)
Sedative and anticonvulsant that may be effective in controlling CA-induced agitation or seizures. By increasing the action of GABA, which is a major inhibitory neurotransmitter in the brain, may depress all levels of the CNS, including limbic and reticular formation.
Adult
2-4 mg/dose IV slowly over 2-5 min, may repeat in 10-15 min prn; not to exceed cumulative dose of 8 mg
Pediatric
0.1 mg/kg IV slowly over 2-5 min, may repeat prn in 10-15 min at 0.05 mg/kg; not to exceed cumulative dose of 4 mg
Toxicity of benzodiazepines in CNS increases when used concurrently with alcohol, phenothiazines, barbiturates, and MAOIs
Documented hypersensitivity; preexisting CNS depression; hypotension; narrow-angle glaucoma
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Use with caution in patients with hypotension or respiratory depression; health care providers must be prepared to manage airway and breathing
Diazepam (Valium, Diastat)
Depresses all levels of the CNS (eg, limbic and reticular formation), possibly by increasing activity of GABA. Sedative and anticonvulsant that may be effective in controlling CA-induced agitation or seizures.
Adult
5-15 mg IV q5min, repeat prn; not to exceed 30 mg/8 h
Pediatric
0.05-0.3 mg/kg/dose IV over 2-3 min q15-30min; not to exceed cumulative dose of 10 mg/2-4 h; may repeat q2-4h prn
Diastat rectal gel:
<2 years: Not established
2-5 years: 0.5 mg/kg PR
6-11 years: 0.3 mg/kg PR
>12 years: 0.2 mg/kg PR
Increases toxicity of benzodiazepines in CNS with coadministration of phenothiazines, barbiturates, alcohols, and MAOIs
Documented hypersensitivity; narrow-angle glaucoma
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Caution with other CNS depressants, low albumin levels, or hepatic disease (may increase toxicity)
Phenobarbital (Luminal)
In status epilepticus, achieving therapeutic levels as quickly as possible is important. IV dose may require approximately 15 min to attain peak levels in the brain. If injected continuously until convulsions stop, brain concentrations may continue to rise and can exceed that required to control seizures. Important to use minimal amount required and to wait for anticonvulsant effect to develop before administering a second dose.
Adult
300-800 mg IV followed by 120-240 mg/dose at 20-min intervals until seizures are controlled or cumulative dose of 1-2 g is administered
Pediatric
15-20 mg/kg over 10-15 min IV in single or divided dose
Some patients may require 5 mg/kg/dose IV q15-30min until seizure is controlled or cumulative dose of 40 mg/kg is administered
May decrease effects of chloramphenicol, digitoxin, corticosteroids, carbamazepine, theophylline, verapamil, metronidazole, and anticoagulants (patients stabilized on anticoagulants may require dosage adjustments if regimen is added to or withdrawn); coadministration with alcohol may produce additive CNS effects and death; chloramphenicol, valproic acid, and MAOIs may increase phenobarbital toxicity; rifampin may decrease phenobarbital effects; induction of microsomal enzymes may result in decreased effects of PO contraceptives in women (must use additional contraceptive methods to prevent unwanted pregnancy; menstrual irregularities may occur)
Documented hypersensitivity; severe respiratory disease; marked impairment of liver function; nephritis
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
In prolonged therapy, evaluate hematopoietic, renal, hepatic, and other organ systems; caution in fever, hyperthyroidism, diabetes mellitus, and severe anemia because adverse reactions can occur; caution in myasthenia gravis and myxedema
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| Overview: Toxicity, Tricyclic Antidepressant |
| Differential Diagnoses & Workup: Toxicity, Tricyclic Antidepressant |
 Treatment & Medication: Toxicity, Tricyclic Antidepressant |
| Follow-up: Toxicity, Tricyclic Antidepressant |
| Multimedia: Toxicity, Tricyclic Antidepressant |
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Further Reading
Keywords
cyclic antidepressant, cyclic antidepressant toxicity, CA toxicity, CA overdose, CA poisoning, CA, tricyclic antidepressant toxicity, TCA, TCA overdose, TCA toxicity, TCA poisoning, antidepressant overdose, antidepressant toxicity, antidepressant poisoning
