1. Antidotes Dr. F.L. Lau COS (AED) UCH

2. Effective antidotes are limited Effective antidotes are limited  Availability / stocking level variable  Some very expensive (expire before use) Appropriate use can : Appropriate use can :  reduce M&M  avoid unnecessary investigation Not without risk—poison itself Not without risk—poison itself

3. UCH Antidotes Use (1999-2004)AntidoteFrequencyNaloxone 136 (7%) N-acetylcysteine 57 (3%) Flumazenil 29 (2%) NaHCO 3 11 (1%) Calcium 8 (0%) Physostigmine 3 (0%) Glucagon 1 (0%) Atropine Antivenom No Antidotes 1648 (87%)

4. Use of Antidote Consider risk benefit ratio Consider risk benefit ratio Patients clinical status (e.g. Benzodiazepine) Patients clinical status (e.g. Benzodiazepine) Appropriate laboratory result (Panadol) Appropriate laboratory result (Panadol) Expected pharmaceutical action of toxin Expected pharmaceutical action of toxin Possible adverse reactions of antidote Possible adverse reactions of antidote

5. Case1 F/30 mental patient F/30 mental patient Found unconscious in bed with suicidal note Found unconscious in bed with suicidal note RR 10/min, BP 100/80, pulse 60/min RR 10/min, BP 100/80, pulse 60/min Pupil small (E&R) SaO 2 : 98% Pupil small (E&R) SaO 2 : 98% After initial stabilization After initial stabilization What antidote will you use? What antidote will you use?

6. Drug induced coma A alcohols & anticonvulsants B barbiturate & benzodiazepine & other sedatives C carbon monoxide & cyanide N neuroleptics O opiates & oral hypoglycemic T TCA & other tranquilizers

7. Relative produce empty bags of Doloxene, Mogadon & Sinequan Relative produce empty bags of Doloxene, Mogadon & Sinequan When would you give When would you give  Narcan?  Anexate?  NaHCO 3 ?

8. Naloxone (Narcan) Indications Reversal of CNS & respiratory depression in opioid poisoning Also effective for clonidine +/- ethanol/benzo/valproic acid Diagnostic use for coma patient

9. Naloxone (Narcan) Dosage: 0.4-2mg I.V. bolus, can be repeated up to 10 mg For chronic user, titrate with low dose (0.1mg) upward Infusion usually indicated (T ½ ~ 1 hour) -2/3 initial effective close hourly Caution: Rapid reversion cause withdrawal seizure Pulmonary edema & vent. fibrillation

10. Flumazenil (Anexate) Pure competitive benzodiazepine receptor antagonist Indications Post op or post procedure reversal of benzodiazepine sedation Post op or post procedure reversal of benzodiazepine sedation Rapid reversal of benzodiazepine – induced coma & resp. depression as a diagnostic aid or avoid intubation Rapid reversal of benzodiazepine – induced coma & resp. depression as a diagnostic aid or avoid intubation

11. Flumazenil (Anexate) Cautions Oral benzodiazepine overdose never life-threatening Oral benzodiazepine overdose never life-threatening In chronic user cause withdrawal & convulsion In chronic user cause withdrawal & convulsion In polydrug overdose, removal of protective effective of benzodiazepine unmask convulsion or arrhythmia of TCA or cocaine In polydrug overdose, removal of protective effective of benzodiazepine unmask convulsion or arrhythmia of TCA or cocaineDosage: Titrate with response starting 0.2mg I.V. over 30 sec Titrate with response starting 0.2mg I.V. over 30 sec Up to 3mg Up to 3mg

12. Case1 F/30 mental patient F/30 mental patient Found unconscious in bed with suicidal note Found unconscious in bed with suicidal note RR 10/min, BP 100/80, pulse 60/min RR 10/min, BP 100/80, pulse 60/min Pupil small (E&R) SaO 2 : 98% Pupil small (E&R) SaO 2 : 98% Compatible with TCA poisoning?

13. NaHCO 3 Indications 1.Reverse sodium channel blockers overdose TCA TCA Antiarrhythmic Antiarrhythmic 1a: Quindine, procainamide & disopyramide 1a: Quindine, procainamide & disopyramide 1c: Encainide & flecaimide 1c: Encainide & flecaimide Propanolol Propanolol Propoxyphene (Doloxene) Propoxyphene (Doloxene) Phenothiazines (melleril) Phenothiazines (melleril) Diphenhydramine (benadryl) Diphenhydramine (benadryl) Cocaine Cocaine

14. Quinidine-like effect Quinidine-like effect  Myocardial depression – hypotension  Reduce excitability – heart block  Reduce conduction velocity – wide QRS  Delay repolarization – prolong QTc Sodium ion load & alkalaemia reverse membrane depressant effects Sodium ion load & alkalaemia reverse membrane depressant effects Indicated if QRS > 0.1 sec, hypotension & bradycardia Indicated if QRS > 0.1 sec, hypotension & bradycardiaDosage: 1-2mEq/Kg bolus repeated q 5-10 min till pH: 7.45-7.5 or QRS shorten to normal

15. NaHCO 3 2. Urinary alkalinazation  Enhance elimination of salicylate & phenobarbital  Prevent renal deposition of myoglobin after rhadomyolysis  100 ml NaHCO3 in 1 litre of D5 in 0.25% saline at 150ml/hour  Adjust rate to maintain urine pH7-8  Add 20 mEq/L of potassium

16. NaHCO 3 3.Correction of Acidaemia For poisoning of methanol ethylene glycol salicylate

17. What if the patient taken a bottle of industrial alcohol ? What antidote to use?

18. Ethanol Compete with methanol/ethylene glycol Compete with methanol/ethylene glycol Higher affinity for alcohol dehydrogenase Higher affinity for alcohol dehydrogenase Allow toxic alcohol excreted avoiding toxic metabolite production Allow toxic alcohol excreted avoiding toxic metabolite productionIndication Symptoms of toxicity/anion gap metabolic acidosis with history of ingestion Symptoms of toxicity/anion gap metabolic acidosis with history of ingestion

19. Ethanol Dosage: Dosage: Loading: 750 mg/kg Loading: 750 mg/kg Maintenance: 100-150 mg/kg/hr to keep serum level 100mg/dL Maintenance: 100-150 mg/kg/hr to keep serum level 100mg/dL Increase rate with dialysis Increase rate with dialysis (Fomepizole : not A/V in HK)

20. Case II M/30 M/30 Well all along Well all along Recent depression after diagnosis of T.B. Recent depression after diagnosis of T.B. Status epilepticus 1 hour after dinner Status epilepticus 1 hour after dinner Poor response to all anticonvulsants Poor response to all anticonvulsants What is your DDX?

21. Drug induced convulsion Status epilepticuts O rganophosphate T ricyclic antidepressantAmoxopine I soniazidINAH S ympathomimetic Camphor, cocainecocaine A mphetaminesAmphetamines M ethylxanthinestheophylline P hencyclidine B enzodiazepine withdrawal E thenol withdrawalethanol withdrawal L ithium, lidocaine L eadLead Tetramine

22. Pyridoxine (vit B6) INAH inhibit brain pyridoxal phosphate INAH inhibit brain pyridoxal phosphate decrease GABA levels causing repeated seizure decrease GABA levels causing repeated seizure block liver metabolism causing lactate acidosis block liver metabolism causing lactate acidosis High dose Pyridoxine control the convulsion High dose Pyridoxine control the convulsion Also correct the lactic acidosis Also correct the lactic acidosis Adjunct therapy for ethylene glycol poisoning Adjunct therapy for ethylene glycol poisoning (Glyoxylic acid to glycine) (Glyoxylic acid to glycine)Dosage: 1 gm pyridoxine per gram of INAH or empirically 5g I.V.I. 1 gm pyridoxine per gram of INAH or empirically 5g I.V.I.

23. If no response, think of tetramine Especially if no evidence of suicidal drug ingestion no evidence of suicidal drug ingestion

24. DMPS Sodium dimercaptopropane sulfonate is related to BAL (dimercaprol) & succimer (dimercaptosuccinic acid) Sodium dimercaptopropane sulfonate is related to BAL (dimercaprol) & succimer (dimercaptosuccinic acid) All are chelating agents All are chelating agents DMPS & succimer also useful for non- metalic pesticide -Tetramine DMPS & succimer also useful for non- metalic pesticide -Tetramine

25. HH SS R1CCR2 HH R2R1Compound HCH2OHBAL COOHCOOHSuccimer CH2SO2NaHDMPS

26. Mechanism of action unknown (? Dithiol group) Mechanism of action unknown (? Dithiol group) Proven in animal study control convulsion & Proven in animal study control convulsion & mortality mortality Many studies in China show effectiveness Many studies in China show effectiveness Study not vigorous Study not vigorous

27. Journal of China Clin Med 2002 Cheng KidsRxDeath Disable 20DMPS + Valium0 0 4Luminal + Valium3 1 Henan Journ Pract Neuro Diseae: Yee 10 DMPs0 deaths 11 control2 deaths

28. Action within 30 min. reduce convulsion Action within 30 min. reduce convulsion Side effect mild: allergic reactions, vertigo & weakness Side effect mild: allergic reactions, vertigo & weakness

29. Dosage No standard protocol No standard protocol Na-DMPS 0.25 mg IMI (0.5 mg/kg for child), response within 30 mins Na-DMPS 0.25 mg IMI (0.5 mg/kg for child), response within 30 mins Can be repeated 30-60 min. to max. 1gm/day Can be repeated 30-60 min. to max. 1gm/day Then 2 doses on D2 Then 2 doses on D2 Then 1 dose daily for 2-3 weeks Then 1 dose daily for 2-3 weeks

30. Adjunct therapy Vit B6 0.5-1.5/D I.V. Vit B6 0.5-1.5/D I.V. plasmaphoresis plasmaphoresis

31. If taken huge dose of organophosphate, what is the antidote? what is the antidote?

32. Atropine For organophosphate or carbamate poisoning For organophosphate or carbamate poisoning Anti-muscarinic effect & central effect Anti-muscarinic effect & central effect Will not reverse nicotinic effects Will not reverse nicotinic effects Dosage: 1mg I.V. titrated as needed Dosage: 1mg I.V. titrated as needed May need huge doses May need huge doses Endpoint: drying of secretions and lung clear Endpoint: drying of secretions and lung clear

33. Pralidoxime Reverse cholinesterase inhibition Reverse cholinesterase inhibition Reactivate phosphorylated cholinesterase Reactivate phosphorylated cholinesterase enzyme (before it aged) enzyme (before it aged) Most pronounced with organophosphate Most pronounced with organophosphate Also in carbamate with nicotinic toxicity Also in carbamate with nicotinic toxicity May precipitate myasthenic crisis May precipitate myasthenic crisis Rapid infusion : tachycardia, laryngospasm, Rapid infusion : tachycardia, laryngospasm, muscle rigidity muscle rigidity

34. Pralidoxime Dosage: 1-2 gm IV over 30 min 1-2 gm IV over 30 min Repeat the dose if muscle weakness not improved Repeat the dose if muscle weakness not improved Followed by infusion 200-500 mg/hr Followed by infusion 200-500 mg/hr May need several days (for fat soluble one, avoid intermediate syndrome) May need several days (for fat soluble one, avoid intermediate syndrome)

35. Patient was on TCA, which is known to have anticholinergic property What is the antidote for anticholingergic poisoning? Should we use it?

36. Physostigmine Reversible inhibitor of acetyl cholinesterase Reversible inhibitor of acetyl cholinesterase Tertiary amine cross BBB exerting central cholinergic effects Tertiary amine cross BBB exerting central cholinergic effects Onset of action a few minute & half life ~ 30 min Onset of action a few minute & half life ~ 30 min Non-specific arousal reticular activating system Non-specific arousal reticular activating system

37. Physostigmine Indication Severe anticholinergic poisoning – agitated delirium, seizure + (coma, severe hypertension, arrhythmia and hypothermia). Severe anticholinergic poisoning – agitated delirium, seizure + (coma, severe hypertension, arrhythmia and hypothermia). Sometimes diagnostic test for delirium (functional/anticholinergic) Sometimes diagnostic test for delirium (functional/anticholinergic)

38. Physostigmine Contraindications Not for TCA poisoning Not for TCA poisoning  Aggravate arrhythmia & induce convulsion Not for non-specific coma Not for non-specific coma  Unless pure anticholinergic toxidrome Not with depolarizing NM blockers (scoline) Not with depolarizing NM blockers (scoline)

39. Dosage Diagnostic trial 1mg IV slowly over 5 min Diagnostic trial 1mg IV slowly over 5 min Therapeutic 0.5mg I.V. repeated every 5 min till 2mg or desired effect Therapeutic 0.5mg I.V. repeated every 5 min till 2mg or desired effect Atropine standby to reverse excessive muscarinic stimulation Atropine standby to reverse excessive muscarinic stimulation

40. Case III M/30 M/30 Worker caught in factory fire Worker caught in factory fire No burn nor smoke inhalation, SaO 2 90% No burn nor smoke inhalation, SaO 2 90% Persistent hypotension, acidosis Persistent hypotension, acidosis What antidote to use?

41. Oxygen 100% or hyperbaric 100% or hyperbaric For possible carbon monoxide poisoning For possible carbon monoxide poisoning Also for : Also for :  hypoxaemia from toxic lung injury  Cellular respiration inhibitor (cyanide & H2S) Use with care in paraquat poisoning aggravate lipid peroxidation in lung resulting in fibrosis) Use with care in paraquat poisoning aggravate lipid peroxidation in lung resulting in fibrosis)

42. Co-oximetry: COHb level: 10% What antidote to use?

43. Cyanide Kit Sodium nitrite (Amyl nitrite) Sodium nitrite (Amyl nitrite) Produce cyanide – scavenging methemoglobin Produce cyanide – scavenging methemoglobin 1 dose produce 20-30% met Hb 1 dose produce 20-30% met Hb C/1 pre-existing methemoglobinaemia > 40% hypotension & concurrent CO poisoning C/1 pre-existing methemoglobinaemia > 40% hypotension & concurrent CO poisoningDosage: NaNO2 300mg I.V. over 3-5min NaNO2 300mg I.V. over 3-5min Half dose can be repeated if no response within 30 min Half dose can be repeated if no response within 30 min

44. Sodium thiosulphate Sulfur donor that promote convertion of cyanide to thiocyanate Sulfur donor that promote convertion of cyanide to thiocyanate Non-toxic can be used empirically Non-toxic can be used empirically Also for prophylaxis during Nitroprusside infusion Also for prophylaxis during Nitroprusside infusion Cause burning sensation, muscle clamping & twitching Cause burning sensation, muscle clamping & twitchingDosage: 12.5g IV at 5ml/min Half dose can be repeated after 30-60 min

45. Hydroxocohalamin Synthetic form of Vit B12 Synthetic form of Vit B12 Exchange with plasma cyanide to give non-toxic cyanocobalamin Exchange with plasma cyanide to give non-toxic cyanocobalamin Minimal adverse effect Minimal adverse effect Brown coloration of body fluid (interfere lab test) Brown coloration of body fluid (interfere lab test) Nausea/vomiting Nausea/vomiting Muscle twitching & spasm Muscle twitching & spasmDosage: Give 50 times of cyanide exposed or empirically 4gm Give 50 times of cyanide exposed or empirically 4gm

46. Other antidotes MethanolEthanol Ethylene glycolFomepizole* PanadolAcetylcysteine Calcium channel blockerCa cl Hydrogen florideCa gluconate Oral hypoglycaemicD50 InsulinOctreotide Arseric, Hg, LeadDimercaprol, Succimer* Beta blockersGlucagon MethaemoglobinaemiaMethylene blue WarfarinVit K1 IronDeferoxamine

47. Other antidotes HeparinProtamine sulphate Methotrexate, MethanolFolinic acid* Valproic acidcarnitine* DigoxinDigoxin-specific antibodies (digibind) Stone fish stingStone fish antivenom Bamboo snakespecific antivenin Russell riper Chinese Cobra King Cobra Banded Krait BotulismBotulinum antitoxin*

48. Minimal Stocking Level AED AED Hospital Hospital Know where to get at odd hour Know where to get at odd hour Need a central station (PCC?) Need a central station (PCC?) Stock taking in all AEDs/Hospital Pharmacies Stock taking in all AEDs/Hospital Pharmacies

49. Thank you