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Toxicity, Antidepressant Last Updated: January 5, 2006 |
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| Synonyms and related keywords: tricyclic antidepressants, TCAs, cyclic antidepressants, antidepressant toxicity, antidepressant overdose, antidepressant poisoning, TCA toxicity, TCA overdose, TCA exposure, treatment of depression
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AUTHOR INFORMATION
| Section 1 of 11   |
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| Author: Eric Legome, MD, Residency Director, Assistant Professor of Emergency Medicine, Department of Emergency Medicine New York University, New York University Hospital, Bellevue Hospital Center, Manhattan VA Coauthor(s): Craig Smollin, MD, Fellow, University of California at San Francisco |
| Eric Legome, MD, is a member of the following medical societies:
Alpha Omega Alpha,
American College of Emergency Physicians,
Council of Emergency Medicine Residency Directors, and
Society for Academic Emergency Medicine |
| Editor(s): David C Lee, MD, Research Director, Assistant Professor, Department of Emergency Medicine, North Shore University Hospital and New York University Medical School; John T VanDeVoort, PharmD, Clinical Assistant Professor, College of Pharmacy, University of Minnesota;
Michael J Burns, MD, Instructor, Department of Emergency Medicine, Harvard University Medical School, Beth Israel Deaconess Medical Center;
John Halamka, MD, Chief Information Officer, CareGroup Healthcare System, Assistant Professor of Medicine, Department of Emergency Medicine, Beth Israel Deaconess Medical Center; Assistant Professor of Medicine, Harvard Medical School;
and Raymond J Roberge, MD, MPH, FAAEM, FACMT, Clinical Associate Professor of Emergency Medicine, University of Pittsburgh School of Medicine; Consulting Staff, Department of Emergency Medicine, Magee-Women's Hospital of the University of Pittsburgh Medical Center |
Disclosure
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INTRODUCTION
| Section 2 of 11   |
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Background: Tricyclic antidepressants (TCAs) cause the overwhelming majority of antidepressant poisoning resulting in morbidity and mortality. Of the newer generation cyclic antidepressants, only amoxapine and maprotiline have strong potential to cause serious morbidity.
Pathophysiology: Although the mechanism by which TCAs exert their therapeutic effects is unclear, they are thought to function by inhibiting the presynaptic reuptake of biogenic amines (serotonin and norepinephrine). TCAs can be divided into first- and second-generation antidepressants, with second-generation antidepressants exerting more selective effects on serotonin and dopamine reuptake.
TCAs produce a wide variety of toxic effects; the most severe toxicity occurs in the cardiovascular system, the peripheral nervous system (PNS), and the central nervous system (CNS).
Cardiovascular toxicity results from direct myocardial depression, cardiac conduction disturbances, effects on peripheral vasomotor tone, and changes in the autonomic nervous system.
TCAs bind to and inhibit the fast sodium channel, thereby slowing phase O depolarization in His-Purkinje and ventricular myocytes (quinidinelike effect). This results in slowed cardiac conduction (eg, prolonged QRS on the ECG), impaired cardiac contractility (via impaired cellular calcium entry), and possible ventricular dysrhythmias (caused by nonuniform sodium channel blockade). The sodium channel blockade present in TCAs is mitigated by larger concentrations of extracellular sodium (overcome competitive blockade) and alkalemia (eg, sodium bicarbonate administration).
TCAs block phase 3 repolarization in His-Purkinje myocytes, resulting in prolonged QTc on the ECG. Specifically, TCAs inhibit outward potassium current by blocking potassium channels in phase 3, which ultimately results in prolongation of the QT interval. Torsade de pointes is uncommon because the anticholinergic effects of these drugs produce offsetting tachycardia.
TCAs block L-type voltage-sensitive calcium channels; negative inotropic effects and conduction disturbances may, in part, be mediated by these effects.
TCAs inhibit alpha1-adrenergic receptors, resulting in peripheral vasodilation and orthostatic hypotension. These effects mediate, in part, refractory hypotension observed with severe TCA poisoning.
TCAs produce tachycardia from competitive blockade at muscarinic acetylcholine receptors.
TCAs block norepinephrine reuptake in the CNS and PNS (autonomic ganglia). Initially, this may result in hypertension and tachycardia. However, with prolonged blockade of reuptake, norepinephrine is depleted from the presynaptic nerve terminal (most norepinephrine released is from a recycled neurotransmitter), which results in refractory hypotension and bradycardia.
Neurologic toxicity results from CNS blockade of muscarinic acetylcholine, H1-histamine, and gamma-aminobutyric acid (GABA) receptors; inhibition of norepinephrine, serotonin, and dopamine reuptake; and blockade of neuronal fast sodium channels. Specifically, seizures likely are mediated by inhibition of norepinephrine reuptake, neuronal fast sodium channel blockade, and GABA and N-methyl-D-aspartate (NMDA)-glutamate receptor blockade.
TCAs are potent, competitive antagonists at central and peripheral muscarinic acetylcholine receptors; they readily produce anticholinergic stigmata, particularly central anticholinergic delirium. Frequency:
- In the US: According to the Toxic Exposure Surveillance System (TESS) data from the American Association of Poison Control Centers (AAPC), 12,710 cyclic antidepressant exposures were reported in 2003. Amitriptyline accounted for most exposures with 7,309 (58%). Of all TCA exposures, 7,835 (62%) were intentional overdoses, 9,622 (76%) were treated at a health care facility, 1,373 (11%) resulted in major toxicity, and 93 (0.007%) resulted in death. In 1998, 15,710 cyclic antidepressant exposures were reported in the United States; of these exposures, 1694 (11%) resulted in major toxicity and 88 (0.6%) resulted in fatality. Most exposures were intentional and required treatment in a health care facility.
TCA use has declined in relation to the newer, less toxic, selective serotonin reuptake inhibitor (SSRI) antidepressants, but TCAs remain widely prescribed and are among the most commonly reported drugs associated with overdose. TCAs are used for depression but also are prescribed for nontraditional uses (eg, chronic pain syndromes, migraine prophylaxis, peripheral neuropathies).
Mortality/Morbidity: Antidepressants are reportedly responsible for about 1% of in-hospital fatalities. One review reported a much higher percentage of out-of-hospital deaths from intentional suicides caused by antidepressants.
Refractory hypotension most often causes in-hospital fatality.
History: Symptoms typically progress rapidly. Onset of signs and symptoms often occurs within 2 hours following ingestion, and life-threatening effects almost always are evident 6 hours postingestion. Not uncommonly, patients present asymptomatically or minimally symptomatic and progress to life-threatening cardiovascular and neurologic toxicity within 1 hour. - Agitation, which can proceed rapidly to lethargy, stupor, and coma
- Coma, usually resolves by 24 hours
- Seizures in 10-25% of patients; can occur without preceding mental status changes; risk of status epilepticus with amoxapine and maprotiline
- Myoclonus and/or choreoathetosis in 40% of patients; should not be confused with or treated as seizures
- Hypertension (early); caused by inhibition of norepinephrine reuptake
- Adult respiratory distress syndrome (ARDS)
- Dry skin and/or mucous membranes
- Decreased gastric motility and/or urinary retention
Physical: Mostly caused by anticholinergic effects - Decreased or absent bowel sounds
Causes: - Quinidinelike effects from blockade of fast sodium channels
- Tachycardia caused by muscarinic anticholinergic effects
- Hypotension as a result of dysrhythmias, alpha-adrenergic blockade, cardiac conduction abnormalities and direct myocardial depression, autonomic neuron neurotransmitter depletion (caused by reuptake blockade), and capillary leakage
- Pulmonary - Hypoxia caused by hypoventilation, aspiration, and capillary leakage
- CNS - Signs and symptoms result from blockade of H1-histamine, muscarinic cholinergic, GABA, and NMDA-glutamate receptors, neuronal fast sodium channel blockade, and reuptake blockade of monoaminergic neurotransmitters
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DIFFERENTIALS
| Section 4 of 11 |
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Alcoholic Ketoacidosis
Anaphylaxis
Anxiety
Delirium Tremens
Heart Block, First Degree
Heart Block, Second Degree
Heart Block, Third Degree
Hyperkalemia
Hyperosmolar Hyperglycemic Nonketotic Coma
Neuroleptic Malignant Syndrome
Pediatrics, Reye Syndrome
Shock, Cardiogenic
Shock, Septic
Subarachnoid Hemorrhage
Subdural Hematoma
Toxicity, Anticholinergic
Toxicity, Antidysrhythmic
Toxicity, Antihistamine
Toxicity, Beta-blocker
Toxicity, Calcium Channel Blocker
Toxicity, Clonidine
Toxicity, Cocaine
Toxicity, Digitalis
Toxicity, Isoniazid
Toxicity, Monoamine Oxidase Inhibitor
Toxicity, Neuroleptic Agents
Toxicity, Phencyclidine
Other Problems to be Considered:
Antimalarial toxicity (eg, chloroquine, primaquine)
Chloral hydrate toxicity
Intrinsic cardiac disease (cardiomyopathy with conduction disturbances)
Intrinsic neurologic disease (seizure disorder) |
| Related Articles | Alcoholic Ketoacidosis
Anaphylaxis
Anxiety
Delirium Tremens
Heart Block, First Degree
Heart Block, Second Degree
Heart Block, Third Degree
Hyperkalemia
Hyperosmolar Hyperglycemic Nonketotic Coma
Neuroleptic Malignant Syndrome
Pediatrics, Reye Syndrome
Shock, Cardiogenic
Shock, Septic
Subarachnoid Hemorrhage
Subdural Hematoma
Toxicity, Anticholinergic
Toxicity, Antidysrhythmic
Toxicity, Antihistamine
Toxicity, Beta-blocker
Toxicity, Calcium Channel Blocker
Toxicity, Clonidine
Toxicity, Cocaine
Toxicity, Digitalis
Toxicity,
Isoniazid
Toxicity, Monoamine Oxidase Inhibitor
Toxicity, Neuroleptic Agents
Toxicity, Phencyclidine
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Lab Studies:
- A toxicology screen may be helpful if concurrent ingestion is possible or symptoms are not fully explained by TCAs. An abbreviated screen for acetaminophen and aspirin usually is sufficient.
- Quantitative screening or tricyclic serum concentrations rarely are worthwhile in the acute setting; they do not always correlate with the severity of ingestion and are not available in a timely manner. Severity of toxicity correlates more closely with the ECG. ECG can be used to predict the likelihood of subsequent serious cardiac (eg, ventricular arrhythmia) and neurologic (eg, seizure) toxicity and can be used in conjunction with physical findings to guide therapy. On the ECG, a QRS duration greater than 100 milliseconds is associated with a significant incidence of seizures, and a QRS duration greater than 160 milliseconds is associated with high incidence of ventricular arrhythmias. On the ECG, an R-wave greater than 3 mm on an aVR is one of the earliest signs of cardiac conduction disturbances from a TCA. Prospective data suggest that the typical period of QRS prolongation after severe tricyclic antidepressant ingestion is 12-18 hours but may be as long 3 days.
- Electrolytes should be used to screen for anion gap acidosis that exists with other ingestions and to look for metabolic disturbances that can alter mental status, cause seizures, or change the ECG.
- Attempt to maintain an alkaline environment (pH = 7.45-7.55).
- Acidemia allows a greater degree of fast sodium channel binding by the TCA and produces a wider QRS on the ECG.
Imaging Studies:
- Obtain a chest radiograph after intubation or if evidence of hypoxia, aspiration, or ARDS is present.
Other Tests:
- ECG is the single most important test for diagnosis and prognostication.
- In one study, a QRS greater than 100 milliseconds predicted seizures in 34% of patients, and a QRS greater than 160 milliseconds predicted ventricular arrhythmias in 50% of patients.
- A terminal R wave in aVR greater than 3 mm showed an 81% sensitivity and 73% specificity for seizures or arrhythmias.
- An R/S ratio of greater than 0.7 in aVR also is associated with major complications.
- Rightward deviation of QRS vector (a negative deflection in lead 1 and a positive final deflection in lead aVR) is associated with TCA toxicity.
- Case reports have described ECGs in TCA toxicity mimicking acute myocardial infarction and the Brugada syndrome.
Procedures:
- No clear consensus on the usefulness of gastric lavage exists; however, it generally is recommended for more than a trivial TCA ingestion or minimal symptomatology within 1.5-2 hours postingestion.
- If patient exhibits declining mental status, perform intubation first. Administer activated charcoal to all patients. Orogastric lavage may be helpful if initiated within 60 minutes of ingestion in a patient who is obtunded or deteriorating rapidly while in the emergency department. Always follow orogastric lavage with activated charcoal. Orogastric lavage is acceptable therapy but not absolutely required for obtunded patients.
- Aggressively manage airway for patients who present agitated or with a decreased level of consciousness. For these patients, endotracheal intubation may be required before gastric lavage or activated charcoal to prevent aspiration.
- The patient should be hyperventilated after intubation. Check proper placement with a chest x-ray. The target PaCO2 is 30 mm Hg by ABG following intubation.
- A central venous line may be helpful in administering medication and monitoring fluid status.
- Hemodialysis and hemoperfusion are not effective and not recommended for TCA poisoning.
- The poor efficacy of hemodialysis probably is because only a small amount of free TCA is present in the serum. TCA is highly bound to serum proteins and tissues, with a large volume of distribution.
- Only anecdotal evidence supports the efficacy of an intraaortic balloon pump (IABP) for intractable hypotension.
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TREATMENT
| Section 6 of 11 |
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Prehospital Care: Rapidly transport all patients with suggested TCA ingestion to the hospital because rapid, cataclysmic, clinical deterioration may occur shortly after overdose. - Sodium bicarbonate is the first-line therapy if TCA ingestion is known or strongly suspected.
- Procainamide, quinidine, beta-blockers, and calcium channel blockers are contraindicated.
- Hypotension
- Hypotension is treated with sodium bicarbonate and intravenous fluids.
- A less well studied alternative is hypertonic saline. Hypertonic saline has been shown to reverse cyclic antidepressant cardiotoxicity and may be especially useful as an alternative to sodium bicarbonate in the hypotensive patient.
- Vasopressors are recommended for refractory hypotension.
- A few case reports have described efficacy with glucagon for hypotension not responsive to usual measures.
Consultations: - Consider consulting a regional poison control center or medical toxicologist.
- Patients with abnormal vital signs or mental status changes will need intensive care unit (ICU) care, which may require the consultation of an intensivist.
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MEDICATION
| Section 7 of 11 |
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The major clinical signs and symptoms requiring therapy are CNS and cardiac dysfunction. Seizure is the major CNS indication for treatment, while QRS widening or any associated dysrhythmia requires emergent medical therapy. Hypotension with evidence of shock not responsive to judicious fluid therapy and sodium bicarbonate are indications for pressors. Narcan or thiamine and immediate measurement of serum glucose concentration are indicated for all patients with altered mental status.
Drug Category: GI decontaminant -- Activated charcoal is indicated for all TCA ingestions, even when a patient presents late following ingestion. The anticholinergic effects of TCAs delay gastric emptying, slow GI motility, and may allow efficacy for charcoal when administered late postingestion. Drug Name
| Activated charcoal (Liqui-Char) -- Binds TCAs, limiting absorption and speeding elimination. Clinical benefit of multiple doses has not been demonstrated clearly and is not recommended. | | Adult Dose | 1 g/kg PO/NGT initial (may be administered with sorbitol or comparable cathartic or in aqueous solution) |
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| Pediatric Dose | 1 g/kg PO (typical 12.5-25 g)
<2 years: Use aqueous charcoal without cathartic| Contraindications | Documented hypersensitivity; poisoning or overdosage of mineral acids and alkalies; unprotected airway and absent gag reflex |
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| Interactions | 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 adsorptive properties) |
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| Pregnancy |
C - Safety for use during pregnancy has not been established.
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| Precautions | Not very effective in poisonings of ethanol, methanol, and iron salts; induce emesis before administering; after emesis with ipecac, patient may not tolerate activated charcoal for 1-2 h; can administer in early stages of gastric lavage; without sorbitol, gastric lavage returns are black; intubate before administration in altered mental status |
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Drug Category: Cardiovascular agents -- Serum alkalinization is the first-line and most effective therapy for arrhythmias. Vasopressors can be useful in correcting hypotension. Lidocaine and bretylium are second-line and third-line agents behind alkalinization for arrhythmias. Class 1-A and 1-C agents (eg, procainamide, disopyramide, quinidine, flecainide, encainide) are contraindicated, as are beta-blockers and calcium channel blockers.Drug Name
| Sodium bicarbonate (Neut) -- First-line drug for cardiovascular morbidity in TCA poisoning. Provides exogenous sodium to overcome the competitive fast sodium channel blockade produced by TCA, and it produces an alkalemia (or reverses acidemia) that mitigates the fast sodium channel blockade by TCA.
Prepare with 3 ampules of bicarbonate in 1 L of D5W, run at 150-250 mL/h (monitor pH = 7.45-7.55). Maintain serum potassium levels (see Precautions below).
Alternatively, patient can be monitored and given boluses of bicarbonate prn if QRS widening and block resolves with initial treatment.| Adult Dose | 1-2 mEq/kg IV bolus, followed by an IV drip of 1000 cc of D5W to which 100-150 mEq of sodium bicarbonate has been added; initiate drip rate at 3 times maintenance IVF rate and titrate drip rate to urinary pH (target >8). |
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| Pediatric Dose | Administer as in adults |
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| Contraindications | Documented hypersensitivity; alkalosis (pH >7.5); volume overload; severe hypernatremia; hypocalcemia; severe pulmonary edema; unknown abdominal pain |
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| Interactions | 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; may inactivate sympathomimetic agents (eg, epinephrine, norepinephrine) |
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| Pregnancy |
C - Safety for use during pregnancy has not been established.
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| Precautions | Serum potassium level must be >4 mEq/L because urinary alkalinization cannot occur in the presence of hypokalemia; can cause alkalosis, decreased plasma potassium, hypocalcemia, and hypernatremia; caution in electrolyte imbalances such as in patients with CHF, cirrhosis, edema, corticosteroid use, or renal failure; when administering, avoid extravasation, which can cause tissue necrosis |
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Drug Name
| Norepinephrine (Levophed) -- DOC. Vasopressors are indicated for persistent hypotension not responsive to judicious fluid loading and sodium bicarbonate. |
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| Adult Dose | 0.05-0.15 mcg/kg/min IV infusion; titrate to effect |
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| Pediatric Dose | 0.1-1 mcg/kg/min IV infusion; titrate to effect |
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| Contraindications | Documented hypersensitivity; peripheral or mesenteric vascular thrombosis because ischemia may be increased and the area of the infarct extended; uncorrected hypovolemia |
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| Interactions | Chlorpromazine enhances the pressor response of norepinephrine by blocking the reflex bradycardia caused by norepinephrine |
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| Pregnancy |
D - Unsafe in pregnancy
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| Precautions | Correct blood volume depletion, if possible, before administering; extravasation may cause severe tissue necrosis and, thus, should be administered into a large vein; caution in occlusive vascular disease; consider risk vs benefit if hypercapnia is present |
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Drug Name
| Epinephrine (Adrenaline) -- Has alpha-agonist effects that include increased peripheral vascular resistance, reversed peripheral vasodilatation, systemic hypotension, and vascular permeability. Beta-agonist effects of epinephrine include bronchodilatation, chronotropic cardiac activity, and positive inotropic effects. |
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| Adult Dose | 1-10 mcg/min IV; titrate dose to desired effect; severe cardiac dysfunction may require doses >10 mcg/min (up to 0.1 mcg/kg/min) |
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| Pediatric Dose | 0.1-1 mcg/kg/min IV; titrate dose to desired effect |
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| Contraindications | Documented hypersensitivity; cardiac arrhythmias; angle-closure glaucoma; local anesthesia in areas such as fingers or toes because vasoconstriction may produce sloughing of tissue; do not use during labor (may delay second stage of labor) |
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| Interactions | Increases toxicity of beta-blocking and alpha-blocking agents and halogenated inhalational anesthetics |
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| Pregnancy |
C - Safety for use during pregnancy has not been established.
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| Precautions | Caution in elderly patients, prostatic hypertrophy, hypertension, cardiovascular disease, diabetes mellitus, hyperthyroidism, and cerebrovascular insufficiency; rapid IV infusions may cause death from cerebrovascular hemorrhage or cardiac arrhythmias; correct blood volume depletion, if possible, before administering |
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Drug Name
| 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. Generally not used as a first-line agent. Correct volume deficits before administration |
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| Adult Dose | 100-180 mcg/min IV; decrease to 40-60 mcg/min when pressure stabilizes |
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| Pediatric Dose | 0.1 mg/min IV infusion or 3 mg/m2 body surface area IM/SC q1-2h prn; decrease to 0.04-0.06 mg/min when pressure stabilizes |
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| Contraindications | Documented hypersensitivity; severe hypertension; ventricular tachycardia; uncorrected hypovolemia |
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| Interactions | Bretylium may potentiate action of vasopressors on adrenergic receptors, possibly resulting in arrhythmias; MAOIs may significantly enhance adrenergic effects, and pressor response may be increased 2- to 3-fold
Guanethidine may increase pressor response of direct-acting vasopressors, possibly resulting in severe hypertension| Pregnancy |
C - Safety for use during pregnancy has not been established.
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| Precautions | Caution in elderly patients, hyperthyroidism, myocardial disease, bradycardia, partial heart block, or severe arteriosclerosis; in hypovolemia, use is not a substitute for replacement of blood, fluids and electrolytes, and plasma (these should be restored promptly when loss has occurred) |
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Drug Name
| Lidocaine (Xylocaine) -- Class IB antiarrhythmic that increases electrical stimulation threshold of the ventricle, suppressing automaticity of conduction through the tissue. Second-line agent for treatment of ventricular dysrhythmias. |
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| Adult Dose | 1.5 mg/kg slow IV push over 2-3 min, loading dose; may repeat q5min up to 300 mg/h; if successful, begin infusion at 1-4 mg/min |
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| Pediatric Dose | 1 mg/kg slow IV push, drip at 10-50 mcg/kg/min |
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| Contraindications | Documented hypersensitivity to amide-type local anesthetics; avoid in Adams-Stokes syndrome and Wolff-Parkinson-White syndrome; avoid in severe sinoatrial, AV, or intraventricular block, if artificial pacemaker not in place |
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| Interactions | Coadministration with cimetidine or beta-blockers, increases toxicity; coadministration with procainamide and tocainide may result in additive cardiodepressant action; may increase effects of succinylcholine |
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| Pregnancy |
B - Usually safe but benefits must outweigh the risks.
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| Precautions | Use a solution without preservatives; caution in heart failure, hepatic disease, hypoxia, hypovolemia, shock, respiratory-depression, and bradycardia; may increase risk of CNS and cardiac adverse effects in elderly patients; high plasma concentrations can cause seizures, heart block, and AV conduction abnormalities |
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Drug Name
| Bretylium -- Class III anti-arrhythmic agent. Has catecholamine-releasing properties and adverse effects and should not be used as initial treatment. Second-line or third-line agent for treatment of ventricular dysrhythmias. Because of a manufacturer's discontinuation of bretylium tosylate production, availability has been extremely limited in recent years. |
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| Adult Dose | 5 mg/kg IV push; may increase to 10 mg/kg IV bolus and repeat q5min until maximum dose of 30-35 mg/kg |
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| Pediatric Dose | 5 mg/kg IV push; second dose 10 mg/kg IV push |
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| Contraindications | Documented hypersensitivity; systemic lupus erythematosus, digitalis-induced arrhythmias, complete heart block or second-degree or third-degree heart block if a pacemaker is not in place; avoid in torsade de pointes |
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| Interactions | Pressor catecholamines and digitalis may increase toxicity; coadministration with ofloxacin may increase risk of cardiotoxicity |
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| Pregnancy |
C - Safety for use during pregnancy has not been established.
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| Precautions | May cause hypotension especially in patients with fixed cardiac output (eg, aortic stenosis); caution in renal insufficiency, severe pulmonary hypertension, and aortic stenosis; half-life increases in elderly patients; administer 25-50% of dose with renal clearance of 10-50 mL/min; rapid IV injections may result in transient hypertension, nausea, and vomiting; limit injection to 5 mL (undiluted) at each injection site |
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Drug Category: Sedatives -- Most seizures are short, self-limited, and do not require treatment; however, if prolonged greater than several minutes or repetitive, treatment is indicated. Controversy exists about the indications for sodium bicarbonate with seizures. No definitive evidence of its efficacy exists. A trial is recommended if seizures continue after benzodiazepine treatment. If seizures are refractory to all treatment, paralysis is indicated to stop motor activity and resultant metabolic acidosis. Benzodiazepines may calm a patient presenting with agitation secondary to the anticholinergic effects.Drug Name
| Lorazepam (Ativan) -- Increasing the action of GABA, a major inhibitory neurotransmitter, may depress all levels of CNS, including limbic and reticular formation. DOC because of more prolonged anticonvulsant effects than diazepam or midazolam (4-6 h vs 1-3 h). Has an excellent safety profile. |
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| Adult Dose | 0.05-0.1 mg/kg (2-7 mg) IV/IM initial over 1-2 min |
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| Pediatric Dose | Children: 0.05 mg/kg IV (range 0.02-0.1 mg/kg)
Adolescents: Administer as in adults
Status epilepticus:
Adolescents: 0.07 mg/kg; not to exceed 4 mg, slowly over 2-5 min, with second dose in 10-15 min if needed
Infants and children: 0.1 mg/kg over 2-5 min, second dose of 0.05 mg/kg IV at 10-15 min if needed; not to exceed 4 mg/dose
Neonates: 0.05 mg/kg over 2-5 min; may repeat in 10-15 min if needed| Contraindications | Documented hypersensitivity; preexisting CNS depression; hypotension; narrow-angle glaucoma |
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| Interactions | Toxicity in CNS increases when used concurrently with alcohol, phenothiazines, barbiturates, and MAOIs |
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| Pregnancy |
D - Unsafe in pregnancy
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| Precautions | Monitor for respiratory depression with high or repeated doses; contains benzyl alcohol, which may be toxic to infants in high doses; caution in renal or hepatic impairment, myasthenia gravis, organic brain syndrome, Parkinson disease, or patients who may have inhibition of benzodiazepine metabolism and clearance (eg, using nicotine, taking cimetidine) |
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Drug Name
| Diazepam (Valium) -- Depresses all levels of CNS (eg, limbic and reticular formation), possibly by increasing activity of GABA. |
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| Adult Dose | 2-10 mg IV q10-15min until symptoms resolve; not to exceed 30 mg |
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| Pediatric Dose | 30 days to 5 years: 0.05-0.3 mg/kg/dose IV over 2-3 min (slowly) q15-30 min until symptoms resolve; not to exceed 5 mg
>5 years: 1 mg/dose IV over 2-3 min (slowly) q2-5min until symptoms resolve; not to exceed 10 mg| Contraindications | Documented hypersensitivity; hypotension; acute narrow-angle glaucoma |
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| Interactions | Increases toxicity in CNS with coadministration of phenothiazines, barbiturates, alcohols, and MAOIs |
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| Pregnancy |
D - Unsafe in pregnancy
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| Precautions | Caution with other CNS depressants, low albumin levels, or renal and hepatic disease (may increase toxicity); monitor for respiratory depression with high or repeated doses |
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Drug Name
| Phenobarbital (Barbita, Luminal) -- Not used often because of the improved safety profile of benzodiazepines. |
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| Adult Dose | 120 mg IV over 10 min, then 5 mg/min up to 500-600 mg/d total |
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| Pediatric Dose | 15-20 mg/kg IV load; 1-6 mg/kg/dose q15-30min prn maintenance |
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| Contraindications | Documented hypersensitivity; severe respiratory disease; marked impairment of liver function; nephritic patients |
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| Interactions | May decrease effects of chloramphenicol, digitoxin, corticosteroids, carbamazepine, theophylline, verapamil, metronidazole, and anticoagulants (patients stabilized on anticoagulants may require dosage adjustments if added to or withdrawn from their regimen); coadministration with alcohol may produce additive CNS effects and fatality; chloramphenicol, valproic acid, and MAOIs may increase phenobarbital toxicity; rifampin may decrease phenobarbital effects; induction of microsomal enzymes may result in decreased effects of oral contraceptives in women (must use additional contraceptive methods to prevent unwanted pregnancy; menstrual irregularities also may occur) |
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| Pregnancy |
D - Unsafe in pregnancy
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| Precautions | Monitor for respiratory depression with higher doses or prolonged dosing; 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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FOLLOW-UP
| Section 8 of 11 |
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Further Inpatient Care:
- Patient may need repeat boluses of bicarbonate or drip.
Complications:
Prognosis:
- Prognosis generally is favorable without long-term CNS or cardiovascular sequelae. Most fatalities occur within the first 24 hours; survival beyond this time suggests a favorable prognosis unless severe hypoxia was present before initial treatment.
- A small subset may have prolonged neurologic sequelae after status seizures or persistent hypotension.
- Patients who remain asymptomatic following 6 hours of emergency department observation are unlikely to develop toxicity.
Patient Education:
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MISCELLANEOUS
| Section 9 of 11 |
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Medical/Legal Pitfalls:
- Failure to appreciate the possibility of rapid deterioration
- Failure to provide sufficient cardiac monitoring, IV access, and observation
- Failure to administer sodium bicarbonate (indicated for QRS widening, dysrhythmia, block, shock)
- Failure to administer activated charcoal to the unstable patient
- Failure to aggressively manage the airway
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PICTURES
| Section 10 of 11 |
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| Caption: Picture 1. Toxicity, antidepressant. ECG shows the terminal R wave in aVR and the widened QRS complex associated with tricyclic antidepressant (TCA) toxicity.
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Picture Type: ECG |
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BIBLIOGRAPHY
| Section 11 of 11 |
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Boehnert MT, Lovejoy FH Jr: Value of the QRS duration versus the serum drug level in predicting seizures and ventricular arrhythmias after an acute overdose of tricyclic antidepressants. N Engl J Med 1985 Aug 22; 313(8): 474-9[Medline].
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Callaham M, Kassel D: Epidemiology of fatal tricyclic antidepressant ingestion: implications for management. Ann Emerg Med 1985 Jan; 14(1): 1-9[Medline].
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Toxicity, Antidepressant excerpt |
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