1. Tricyclic Toxicity Joshua Rocker, MD Pediatric Emergency Medicine Schneider Children’s Hospital

2. Tricyclics 3 aromatic rings Mechanism of action: Blocks re-uptake of Norepinephrine and Serotonin- primary therapeutic effect Blocks re-uptake of Norepinephrine and Serotonin- primary therapeutic effect Anticholinergic- considered to be side effect Anticholinergic- considered to be side effect Used in treatment of: Depression, Chronic pain, Enuresis, ADHD, OCD, School phobia, Separation Anxiety Depression, Chronic pain, Enuresis, ADHD, OCD, School phobia, Separation Anxiety

3. TCAs and trade names Amitriptyline (Elavil) Nortriptyline (Aventyl or Pamelor) Imipramine (Tofranil) Desipramine (Norpramin) Clomipramine (Anafranil) Doxepin (Prudoxin, Sinequan, Zonalon)

4. Epidemiology Bimodal frequency Accidental toddler/child Accidental toddler/child Intentional adolescent Intentional adolescent

5. Epidemiology 1998 Poison Control Center study 68k antidepressant exposure, 16k TCAs 68k antidepressant exposure, 16k TCAs 4k <19yrs, 2k <6 y/o 1-2% Mortality 1-2% Mortality Cardiac in nature usually presented within first hour of ingestion 2004 Poison Control Center 3 rd leading cause of toxic exposures (1 st - analgesics, 2 nd - sedatives) 3 rd leading cause of toxic exposures (1 st - analgesics, 2 nd - sedatives) 12k cases, similar number of deaths 12k cases, similar number of deaths

6. As you can see… Decrease usage (↓16k to 12k, in 6 yrs) Secondary to adverse events and increased popularity with SSRIs

7. Toxicity Low toxicity threshold Therapeutic Dose 2-4 mg/kg/d Toxic Dose seen at 10-20 mg/kg Example: Pincer grasp- 8-12 months, 8-11 kgs. 1 tablet 50 mg, 2 tablets 100mg

8. Pharmokinetics Rapidly absorbed by GI tract The anticholinergic effects may impair gastric emptying and delay peak serum levels up to 12 hours Tissue levels of TCAs far exceed those found in plasma Therefore, dialysis clinically ineffective at enhancing elimination

9. Toxicology Anticholinergic Reuptake Inhibitor Initially hyperadrenergic and then catecholamine deplete Initially hyperadrenergic and then catecholamine deplete Alpha adrenergic blockade Vasodilation then subsequent hypotension Vasodilation then subsequent hypotension Blocks cardiac myocyte fast sodium channels Direct myocardial toxicity + catecholamine depletion + alpha-adrenergic blockade can produce profound cardiovascular dysfunction.

10. Presentation Usually within 2 hours Consistent with presumed peak concentration

11. Presentation Anticholinergic Dry mouth Flushed/dry skin Blurred vision Urinary retention ConstipationDizzinessEmesis Altered Mental Status Sinus Tachycardia Mydriasis Fever

12. Presentation Cardiac Palpitation, chest pain, hypotension, arrhythmia Palpitation, chest pain, hypotension, arrhythmiaCNS AMS to coma, Sz, respiratory depression AMS to coma, Sz, respiratory depression Peripheral Autonomic Dry mouth/skin, urinary retention, blurry vision, mydriasis, ileus Dry mouth/skin, urinary retention, blurry vision, mydriasis, ileus

13. Arrhythmia TCAs inhibit the fast sodium channel, thereby slowing phase O depolarization in His-Purkinje and ventricular myocytes Slows conduction (↑ QRS) Slows conduction (↑ QRS) Impairs contractility (impaired calcium entry) Impairs contractility (impaired calcium entry) The sodium channel blockade is mitigated by larger concentrations of extracellular sodium (overcome competitive blockade) and alkalemia

14. Work up Toxic labs, alcohol level, anion gap (co- ingestions) CBC, Lytes with LFTs, D-stick If ↓Ca, Mg or Phos - may exacerbate cardiac and CNS disturbances If ↓Ca, Mg or Phos - may exacerbate cardiac and CNS disturbancespHEKG

15. EKG Sinus tachycardia most common finding Anti-muscarinic effect Anti-muscarinic effect Measure QRS interval- if >100msec, treat If > 100 msec- If > 100 msec- Chance of seizures 34% Chance of life-threatening cardiac arrhythmia 14% If > 160 msec If > 160 msec Chance of ventricular arrythmia 50%

16. EKG The amplitude of the R wave in lead aVR and the ratio of the R/S waves in aVR are greater in patients who developed seizures or dysrhythmias When the R wave in aVR > 3 mm, the sensitivity of subsequent development of seizures or arrhythmias are 81% and 73%, respectively

17. Treatment The greatest risk of seizures and arrhythmias occurs within the first 6-8 hours If asymptomatic - supportive therapy. For all patients with possible cyclic antidepressant toxicity: airway protection, ventilation and oxygenation, intravenous fluids, cardiac monitoring, and obtaining ECGs are all essential measures

18. Treatment ABCs Gastric decontamination- charcoal vs lavage charcoal vs lavage Benzodiazepines (seizures- which are often self-limited) Lidocaine, to treat ventricular arrhythmia, should be administered with caution to avoid precipitating seizures Lidocaine, to treat ventricular arrhythmia, should be administered with caution to avoid precipitating seizures Foley catheterization

19. IV Sodium Bicarbonate Dose 1-2 meq/kg Prolonged QRS is most often the indication for serum alkalinization Evidence exists demonstrating the reversal of toxic effects of CA such as QRS prolongation and myocardial depression following serum alkalization and sodium loading with sodium bicarbonate. (hyperventilation for alkalination has also been proposed but not universally accepted)

20. Physostigmine Cholinesterase inhibitor Has been used in past for anti-muscarinic effects but is no longer used secondary to cases of asystole

21. OKAY

23. What is Ciguatera Fish Poisoning and where does it occur?

24. Ciguatera A common foodborne disease related to the consumption of subtropical and tropical marine finfish which have accumulated naturally occurring toxins. The concerned –ciguatoxic -fish are either feeding on small algae species known as dinoflagellates or feeding on toxic herbivore fish.

25. Ciguatera Symptoms within 10 minutes GI- N/V, salivation CNS- tingling and numbness in the mouth and the extremities, muscle cramping and sensation of temperature reversal tingling and numbness in the mouth and the extremities, muscle cramping and sensation of temperature reversal headache, vertigo, hallucinations, headache, vertigo, hallucinations,

26. Ciguatera Treatment Supportive Supportive GI decontamination GI decontamination Anti-emetic Anti-emetic Antihistamine if pruritis Antihistamine if pruritis Some studies have shown mannitol works well Some studies have shown mannitol works well

27. Case I just had some Mahi-mahi and I feel like hell. V/D, flushed, dysphagia, perioral tingling. What do I got? How do you treat it?

28. Scombroid After eating spoiled mahi-mahi, amber jack (both non-scombroid fish) or fish in the scombroidea family- tuna, albacore, bonito, mackerel and skipjack. After spoiling histamnie levels on the fish increase by a factor of 100 within 12 hours.

29. Scombroid The histamine is converted to saurine by bacteria and the saurine is what casues the symptoms.

30. Scombroid Tx- anti-histamines