1. CPC Conclusion Michael D. Schwartz, MD Centers for Disease Control/ ATSDR/Georgia Poison Center (Fellowship Sponsor: Oak Ridge Institute for Science & Education, Department of Energy)

2. The ingestion was 100 x 100 mg (10 gm) Amantadine hydrochloride tablets Prescribed for Parkinsonian Sxs along with DPH Stockpiled two months’ supply 10 DPH tablets were missing Subsequent comprehensive toxicology testing revealed no co-ingestants

3. Amantadine hydrochloride Dopamine agonist –Parkinsonism/EPS/Movement disorders –Inhibits Influenza virus uncoating 90% absorbed from GI tract 75 - 90% protein bound Vd = 6 to 8 L/kg Peak plasma levels in 4 hours 15% acetylated in liver; 85% unchanged (renal) T 1/2 = 15 hours (even in moderate overdose)

4. Amantadine Toxicity Five reports detailing 1 gm to 3.5 gm ingestions –All ingestions (n=3) over 2.5 gm died CNS Toxicity –Levels 1000 – 3400 ng/ml (Reference 100 – 1000) –Hallucinations, Psychosis, Delerium, Tremors Cardiotoxicity (Levels >3000 ng/ml) –Ventricular arrhythmias, bradycardia, QT prolongation –Case reports (1 PVCs, 3 V-Tach/TdP) –Worsened by anticholinergic co-ingestion

5. Amantadine is a tricyclic amine AmantadineAmitriptyline

6. Amantadine Cardiotoxicity Fast Sodium Channel blockade –QRS widening Block of Outward Repolarizing K + Channels –Prolonged QT; Risk of Torsades –Intracellular shift K + /channel blockade

7. Amantadine Cardiotoxicity: Treatment Sodium bicarbonate or Hypertonic NaCl Magnesium for Torsades –Chemical overdrive pacing is risky/fatal outcomes Ventricular ectopy (PVCs) – Lidocaine Hypotension: Direct-acting vasopressors (NE) –Epinephrine may worsen hypokalemia –Dopamine/isoproterenol worsen cardiotoxicity Associated with all 3 fatalities in Case Reports

8. Serum Quantitative Amantadine and DPH Levels Hours Post- ingestion +6+16+24 Amantadine (#100) 29,000 ng/ml (100-1000) 7,000 ng/ml920 ng/ml Diphen- hydramine (#10) 5,900 ng/ml (100-1000) 1,200 ng/ml99 ng/ml

9. Clinical course Remained normotensive/NSR in ICU Prolonged intubation Developed ICU pneumonia Progressed to ARDS; protracted recovery Discharged on hospital day 30 to psych