1. Toxicology Program Case presentation Dr. KK Lam TMH 23 rd March 2005

2. F / 53 Hypertension DO 4 hrs ago Drowsy

3. GCS 356 P 40 BP 54/36 RR 18 34.8 0 C H’stix 14 DDx?

4. Exact amount of drugs uncertain Adalat retard Metoprolol (Betaloc) Natrilix

5. 08454056/43 NS 300 ml 08504065/42Atropine 1.8 mg 08544472/45CaCl 2 2 g 09054086/43Glucagon 6 mg 09186192/55Dopamine 500 mcg/min 092473103/71AC 50 g 09496391/48Dopamine 630 mcg/min Progress & Treatment

6. AED I-stat results Na 142 mmol/L K 3.3 mmol/L I-Ca 1.91 mmol/L Hb 12.9 g/dL pH 7.141 pCO 2 5.54 kPa pO 2 20.4 kPa HCO 3 14 mmol/L BE –15 mmol/L SO 2 99%

7. ICU D1 GCS 356 P 59 83 BP 67/40 109/67 CVP 23 15 34.8 0 C 38.2 0 C CaCl 2 160 mg/h Glucagon 1 mg Isoprenaline 40 mcg/h Transvenous pacing AC 2 doses

8. ICU D2 GCS 356 P 80 BP 145/70 CVP 6 Stop CaCl 2, Isoprenaline, pacing Phenylephrine 2 ml/h –Alpha agonist AC 3 doses To Medical

9. Toxicology result Metoprolol

10. Myocardial cell contraction Ca ++ flow through voltage sensitive channel Trigger opening of Ca ++ releasing channel at sacroplasmic reticulum Ca ++ induce Ca ++ release phenomenon Ca ++ bind to troponin, actin-myosin sliding

11. Myocardial cell relaxation Ca ++ actively pump into sacroplasmic reticulum Ca-Na antiporter: passive transport– 3Na in, 1Ca out Ca ++ ATPase Fall intracellular Ca ++ conc Ca ++ release from troponin

12. Beta adrenergic agonist Activation of beta adrenergic receptor Activate G-protein Increase cAMP Activate protein kinase Phosphorylation of phospholamban  increase Ca ++ store in SR Increase Ca ++ influx from voltage sensitive Ca ++ channel Phosphorylation of troponin  facilitating unbinding of Ca ++

13. Characteristic of beta blocker Membrane stabilizing –Inhibit fast Na channel –Propanolol, acebutolol Lipid solubility –Cross BBB –Propanolol, metoprolol, labetalol Instrinic sympathomimetic activity –acebutolol

14. Characteristic of beta blocker Beta 1 selectivity –Acebutolol, metoprolol –Loss cardioselectivity in overdose K + channel blockage –Sotalol (anti-arrhythmic property) Vasodilation (alpha antagonist activity) –labetalol

15. Clinical features Cardiogenic shock –hypotension, bradyarthymia, heart block Hypoglycemia –common in child, uncommon in adult Depressed mental state Respiratory depression Prolong QRS, QTc Coma, confusion, convulsion Slightly hyperkalemia Bronchospasm (uncommon)

16. Clinical features All major symptoms develop within 6 hours Except controlled release preparation Except sotalol

17. DDX of Bradyarrthymia Overdose of: –Beta-adrenergic antagonist –Calcium channel blocker –Digoxin –Na channel blocker –Anticholinerstase –Alpha 1 agonist –Alpha 2 agonist (e.g. clonidine) –Opioids –Sedative hypnotics –GHB (gamma hydroxybutyrate) –Coingestion P Propranolol and other Beta-blockers, Poppies A Anitcholinesterase C Calcium channel blockers, clonidine E Ethanol and other sedatives. D Digoxin

18. Treatments General –ABC –Decontamination –IVF –Atropine

19. Specific treatments Glucagon Calcium Insulin Inotropes Phosphodiesterase inhibitor Pacing Extracorporeal removal Mechanical pump

20. Glucagon– glucagon receptor  increase cAMP Calcium – increase Ca ++ influx during depolarization Phosphodiesterase inhibitor  increase cAMP Inotropes – beta adrenergic agnoist  increase cAMP

21. Glucagon First line after IVF and atropine Adult:Initial 3-5mg IVI, up to 10mg Child:50-150ug/kg Followed by infusion –“response dose” per hour or –2-5mg/hr –Up to 10mg/hr even glucagon is not responsive –Pedi: 50ug/kg/hr on to max adult dose HA preparation NS as diluent (does not contain phenol

22. Calcium Adult –CaCl 3 1-3g IVI, up to 5gm in adult Children –Ca gluconate 10-20mg/kg IVI

23. Insulin Combined with glucose, maintain euglycemia (monitor glucose during and several hr after discontinuing insulin) Effective in beta adrenergic antagonist and CCB overdose May increase glucose utilization or Ca ++ handling in myocardial cell Delayed onset of response (15-30 minutes) 0.5-1unit/kg/hr with glucose 1g/kg/hr Frequent glucose monitoring

24. Catecholamines (inotropes) Isoproterenol Epineprine Unopposed alpha effect Invasive monitor

25. Phosphodiesterase inhibitor Amrinone Long half life Vasodilatation Invasive monitor

26. Other treatments Ventricular pacing Extracorporeal removal –Water soluble drugs only e.g. atenolol –Difficult in bradycardia and hypotension Intra-aortic balloon pump/ extracorporeal circulation

27. Special conditions Membrane stabilizing effect –NaHCO 3 Peripheral vasodilation effect –alpha adrenergic agonist Sotalol –Correct electrolyte disturbance –Mg/ overdrive pacing for ventricular dysrrthymia

28. Observation ICU for all symptomatic For regular-release preparation –Medically fit for discharge if adequate GI decontamination, asymptomatic, normal vital sign and ECG for 6-8 hours, Sotalol overdose or extended release preparation -- 24 hours observation

29. Summary Beta adrenergic antagonist is one of commonest drugs cause hypotension and bradyarrthymia Aggressive treatment should be initiated at AED Glucogan is an antidote All symptomatic cases should be managed amd monitored in ICU Prolong observation for extended release preparation and sotalol

30. Thank you