1. Toxicity, Cyclic Antidepressants
. 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.

2. uses
in pediatric :
treatment of enuresis, obsessive-compulsive disorder, attention-deficit hyperactivity disorder, school phobia, and separation anxiety
In adults :
depression, neuralgic pain, chronic pain, and migraine prophylaxis .

3. 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.

4. Toxic effects of tricyclics
toxic effects of tricyclics are results of their 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

5. Mechanism of toxicity
seizure :by increasing biogenic amines such as norepinephrine and serotonin at nerve terminals
Altered mental status :is mainly attributed to anticholinergic and antihistaminergic properties of CAs.
hypotension :mainly a result of the well-recognized anti–alpha-adrenergic effect of the CAs

6. The effects of CA overdose on the cvs
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 CA poisoned individuals.

7. Frequency:
In the US: Antidepressants are the third leading cause of toxic exposures in 2004 after analgesics and sedatives.
. The CA most frequently ingested in CA toxicity is amitriptyline, followed by doxepin and nortriptyline. Amitriptyline exposure is associated with the most number of deaths among the various CAs.

8. Mortality/Morbidity: Fatality before reaching a healthcare facility occurs in approximately 70% of patients attempting suicide with CAs.
Only 2-3% of CA overdoses that reach a healthcare facility result in death.
Sex: the incidence of CA exposure is greater in women than in men because women are at a higher risk for suicide attempts.

9. symptoms
Onset of symptoms typically occurs within 2 hours of ingestion, which corresponds to the peak cyclic antidepressant (CA) serum level, which may range from 2-12 hours.

10. sypmtoms Peripheral autonomic system Cardiovascular Dry mouth Dry skin
Palpitation
Chest pain
Hypotension
CNS
Convulsion
Decrease mental status
Respiratory depression
Drowsiness
Coma
Peripheral autonomic system
Dry mouth
Dry skin
Urinary retention
Blurred vision

11. 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

12. Lab Studies
Studies have shown that serum cyclic antidepressant (CA) level does not correlate well with severity of CA toxicity and is a poor predictor of clinical outcome.
Because multisubstance ingestion is common, routine screening for other potentially treatable toxins is recommended (eg, acetaminophen). Request for the other serum toxicologic levels should be guided based on the clinical picture (eg, acidosis: aspirin, ethylene glycol, methanol)
Check electrolytes, BUN, creatinine, and anion gap.
CBC
Alcohol level
ABG for evaluation of acidosis or hypoxia

13. Imaging Studies
A chest radiograph should be obtained in cases of suspected aspiration or when respiratory symptoms are noted, and it may be used to rule out other causes of fever, tachycardia, and altered mental status

14. Other Tests
ECG - Sinus tachycardia is the most common ECG finding in CA toxicity.
Measurement of limb-leads QRS duration can be used to assess severity of CA exposure. QRS interval of greater than 100 msec is the basis for treatment with bicarbonate (alkalinization).
Patients with QRS less than 100 msec are unlikely to develop seizures and arrhythmias. Those with QRS greater than 100 msec have up to a 34% chance of developing seizures and up to a 14% chance of developing a life-threatening cardiac arrhythmia. With QRS complex greater than 160 msec, chances for ventricular arrhythmias increase to 50%.

15. The greatest risk of seizures and arrhythmias occurs within the first 6-8 hours of CA ingestion.
For all patients with possible cyclic antidepressant toxicity,
airway protection,
ventilation and
oxygenation,
intravenous fluids,
cardiac monitoring, and
obtaining ECGs are all essential measures

16. Treatment
Airway: Endotracheal intubation may be necessary in patients who present with seizures or who are in a comatose state for airway protection.
Hypotension
Normal saline intravenous fluids are indicated for CA-induced hypotension.
For hypotension refractory to intravenous saline, vasopressors, such as Neo-Synephrine or norepinephrine, with alpha-agonist effect, may be used.

17. GI decontamination: Once the patient is stabilized, activated charcoal can be considered.
Intravenous sodium bicarbonate
Serum alkalinization with intravenous sodium bicarbonate has been the mainstay of therapy in CA-induced cardiovascular toxicity. Prolonged QRS is most often the indication for serum alkalinization in CA toxicity.

18. Benzodiazepines
The seizures in CA toxicity are usually self-limited. The treatment of choice for prolonged or recurrent seizures in cyclic antidepressant toxicity is a benzodiazepine. Most CA-induced seizures are usually brief and resolve prior to the administration of anticonvulsants. General anesthesia should be reserved for patients in status epilepticus who are unresponsive to the standard treatment regimen (eg, benzodiazepines, barbiturates, propofol). This may prevent hyperthermia and rhabdomyolysis

19. Further Inpatient Care:
Level of conscious and ECG changes at presentation are the most sensitive clinical predictors of serious complications.
CA toxicity typically lasts hours following a significant overdose. However, case reports exist demonstrating prolonged CA toxicity as long as 4-5 days. Amitriptyline is the drug most commonly implicated in these cases.
Consider ICU admission for any ECG changes.
Admission to a monitored bed is appropriate for patients exhibiting only anticholinergic symptoms and no cardiac manifestations

20. Medical/Legal Pitfalls:
Use of physostigmine in CA poisoning has been associated with complete heart block, asystole, and hypotension.
Ipecac syrup is not recommended as the procedure in GI decontamination because of the possibility that patients experience sudden neurologic deterioration (eg, lethargy, seizures) and aspirate.
Use of type IA and IC antidysrhythmics or other sodium channel blockade agents may exacerbate toxic effects of CAs on the myocardium.
Use of flumazenil for reversal of benzodiazepines overdose with concomitant CAs exposure can precipitate seizures

21. Special Concerns:
ECG is a highly sensitive tool and can be used to rule out CA toxicity. However, it is not specific enough to be used alone to diagnose CA overdose. Widening of QRS complex can be used as a rough guide in determining the prognosis of TCA poisoning (eg, seizures, dysrhythmias). However, characteristic ECG changes in addition to clinical presentation (anticholinergic toxidrome, seizures, hypotension, tachycardia) seen with CAs can be an adjunction in diagnosing CA toxicity.
Lidocaine, when used to treat ventricular arrhythmia, should be administered with caution to avoid precipitating seizures.
Ventricular bradyarrhythmias, due to depressed AV conduction and automaticity, can be treated by placement of a temporary pacemaker, or consider the use of a chronotropic agent.
CA exposure in children is common. The potentially lethal dose (with desipramine, imipramine, or amitriptyline) is as low as 15 mg/kg. Toddlers can exceed this threshold with only 1 or 2 pills, and they should be evaluated in the emergency department .

22. The End
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