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Toxicity, Cyclic Antidepressants
Updated: Jun 10, 2008
Introduction
Background
Most of the cyclic antidepressants (CAs) contain a 3-ring molecular structure. CAs were first used in the 1950s to treat clinical depression. The first report of the adverse effects of tricyclic overdose came within 2 years of their clinical use.
Despite the increasing popularity of the selective serotonin reuptake inhibitors (SSRIs) in the treatment of depression, CAs continue to play an important role in the treatment of enuresis, obsessive-compulsive disorder, attention deficit hyperactivity disorder, school phobia, and separation anxiety in the pediatric population. In adults, indications for CAs include depression, neuralgic pain, chronic pain, and migraine prophylaxis. Some of the more commonly prescribed CAs include amitriptyline, desipramine, imipramine, nortriptyline, doxepin, clomipramine, and protriptyline. Maprotiline, a tetracyclic compound, and amoxapine, a dibenzoxapine, are newer compounds that have a slightly different structure and toxicologic profile.
Pathophysiology
The CAs are well absorbed orally and undergo significant first-pass metabolism in the liver. They have a large volume of distribution and have long half-lives that generally exceed 24 hours. After the CAs are metabolized in the liver via glucuronic acid conjugation, they are then excreted through the kidneys.
The toxic effects of tricyclics are results of the following 4 main pharmacologic properties:
- Inhibition of norepinephrine and serotonin reuptake at nerve terminals
- Anticholinergic action
- Direct alpha-adrenergic blockade
- Membrane stabilizing effect on the myocardium by blocking the cardiac myocyte fast sodium channels
Tricyclic antidepressants (TCAs) may also penetrate into the CNS. Given the appropriate dosage, a particular CA exerts its therapeutic antidepressant effects by increasing biogenic amines such as norepinephrine and serotonin at nerve terminals. The same mechanism is thought to be responsible for seizure occurrence in CA overdose. Altered mental status is also frequently seen in CA overdose and is mainly attributed to anticholinergic and antihistaminergic properties of CAs.
The effects of CA overdose on the cardiovascular system result mainly from the impediment of the cardiac conduction system. CAs, like the class IA antiarrhythmics, decrease the sodium influx through the fast sodium channels and consequently decrease the slope of phase 0, leading to the widened QRS complex that is typically seen on ECGs of individuals with CA poisoning. An in vitro study reported that CAs also directly decrease myocardial contractility in a dose-dependent manner.1 Profound hypotension is sometimes seen in CA overdose and is mainly due to the well-recognized anti–alpha-adrenergic effect of the CAs; however, these direct myocardial depressive effects may also contribute to the severe hypotension seen in CA toxicity.
Frequency
United States
Antidepressants are the third leading cause of toxic exposures in 2004 after analgesics and sedatives. In the 2004 Toxic Exposure Surveillance System (TESS) national report, 12,270 cases of CA exposures and 86 CA-related deaths were reported.2 The CA most frequently ingested is amitriptyline, followed by doxepin and nortriptyline. Amitriptyline exposure is associated with the most number of deaths among the various CAs.
Mortality/Morbidity
Fatality before reaching a healthcare facility occurs in approximately 70% of patients attempting suicide with CAs. CA were the number one cause of fatality from drug ingestion until the last decade when they were surpassed by analgesics. Only 2-3% of CA overdose cases that reach a healthcare facility result in death.
Sex
CA toxicity occurs in both men and women. However, the incidence of CA exposure is greater in women than in men because women are at a higher risk for suicide attempts.
Age
CA toxicity occurs at all ages. Incidence of CA toxicity is most prevalent in persons aged 20-29 years. This again reflects the demographics of suicidal attempts.
Clinical
History
History of suicidal ideation, prior suicide attempts, circumstances around ingestion, intended CA (CA) usage, co-ingestants, time of ingestion, and dose ingested should be obtained from the patient directly and also from the patient's family.
Onset of symptoms typically occurs within 2 hours of ingestion, which corresponds to the peak CA serum level, which may range from 2-12 hours.
Determining which specific CA is involved may be helpful. Although amoxapine is associated with higher incidence of seizures, maprotiline exhibits more severe cardiac toxicity. Determine status in the following systems:
- Cardiovascular
- Palpitation
- Chest pain
- Hypotension
- CNS
- Convulsion
- Decrease mental status
- Respiratory depression
- Drowsiness
- Coma
- Peripheral autonomic system
- Dry mouth
- Dry skin
- Urinary retention
- Blurred vision
Physical
Physical findings are usually consistent with the anticholinergic toxidrome and quinidinelike cardiotoxicity.
- Tachycardia
- Hypotension and orthostasis
- Fever
- Altered mental status
- Ileus
- Absent bowel sounds
- Rigidity
- Dry skin and mucous membranes
- Mydriasis
Causes
- Unintentional ingestion (most common cause in pediatric population)
- Intentional ingestion; suicidal ideation
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References
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Further Reading
Keywords
tricyclic antidepressants, TCAs, CAs, cyclic antidepressant toxicity, cyclic antidepressant overdose, Brugada syndrome, cyclic antidepressants, cyclic antidepressant poisoning, tricyclic antidepressant poisoning, tricyclic antidepressant overdose, cyclic antidepressant overdose, TCA overdose, CA overdose, amitriptyline, doxepin, nortriptyline, TCA poisoning, CA poisoning, enuresis, obsessive-compulsive disorder, attention-deficit hyperactivity disorder, school phobia, separation anxiety, suicide attempts, hypotension
