1. Acetaminophen, NSAID and Salicylate poisoning Presented by Dr. Hellman Slides prepared by Brian A Romito, DO IM/EM PGY-5 Feb 8 th 2007

2. Acetaminophen (APAP) Overdose Most absorption 2 º, even after OD Peak concentration 4 º then hepatic metabolism 90% elimination 3 routes; conjugation w/ gluconroide (40-67%) or sulphate (20-46%), or oxidation via CP450 or similar enzyme then conjugation Oxidation by CP450 or subfamily CYP2E1--> very reactive electrophile; NAPQI (aka N-acetyl-p- benzoquinoeimine)

3. Glutathione oxidation

4. Glutathione; it’s about moving electrons via Sulfur

5. Most common cause of liver failure

6. APAP Toxicity MOA NAPQI normally combines w/ glutathione & other thio- compounds forming non-toxic conjugates in urine NAPQI exceeds glutathione supply, Free NAPI binds hepatocyte intracellular proteins--> toxicity CYP450 inducers (EtOH, Isoniazid, anticonvulsants), & Inhibitors (cimetidine) affect NAPQI formation Renal injury may occur w/ or w/o Hepatic Injury!!! Activation Prostaglandin syntheses in Kidneys

7. Liver Failure- how much Tylenol has he taken in the past 40 years???

8. Liver Pathology Most oxidative metabolism in Liver Zone III, affected most by acetaminophen toxicity! Sever toxicity also affects Liver Zones I & II & can destroy the entire Liver! Fulminate Liver Failure 2 º to toxicity rather than direct APAP effects

9. hepatocytes closest to the arterioles (zone 1 below) are the best oxygenated, are the first to "see" and potentially absorb blood- borne toxins absorbed into portal blood from the small intestine while those farthest from the arterioles have the poorest supply of oxygen.

10. Tx for Acetaminophen Toxicity N-acetylcysteine (NAC) serves as both glutathione precursor & substitute NAC may ↓ NAPQI formation & ↑ non-toxic sulfation NAC improves survival in pts w/ acetaminophen-induced fulminant liver failure, even long after initial metabolism Possible MOA for survival benefit; ↑ oxygen delivery/uptake by tissues, change in microcirculation, scavenging ROS & ↓ cerebral edema

11. NAC as a Liver Damage Snack

12. 4 stages APAP-induced Hepatic Injury post ingestion Stage 1: pre-injury; 1 st 24 º, no specific Sx; N/V, anorexia, diaphoresis, malaise... common in 1 st 8º Stage 2: onset Liver injury 24º (12 to 36º after OD). If sever may be 8º; N/V, RUQ/mid-epigastric pain Stage 3; Max liver injury; 3-4 days. Sx vary; fulminant hepatic failure; encephalopathy, coma, coagulopathy, hypoglycemia, metab acidosis, haemorrhage, ARDS Risk renal injury ↑ 25% w/ severe toxicity vs. 2% w/o hepatotoxicity

13. 4 stages APAP-induced Hepatic Injury post ingestion Stage 4; Recovery Liver Enzymes to baseline 5-7 days, longer w/ severe injury. Histologicly- months Regeneration of liver is complete w/o chronic dys-fxn

14. Diagnostic strategies ID risk for Hepatotoxicity & initiate timely Tx w/ NAC! H&P establish risk, but early Sx are unreliable, and late Sx occur long after ideal NAC start time... Lab evaluation is essential Once APAP toxicity risk determined, START NAC Acute OD is a single ingestion w/in a 4 º period Liver failure/death can be completely prevented if NAC is started early after ingestion

15. Diagnostic Consideration Factors that complicate eval & Management; inability to est time of ingestion, presents > 24 hours post ingestion, age < 5yrs, pregnancy Management of Chronic excessive APAP dosing controversial

16. Assess/Tx Acute APAP Ingestion Lab eval; serum APAP level 4 º & ASAP AST; Pt has Sx of hepatic injury, APAP on or above nomogram line, time of ingestion unknown PT, Lytes, Glu, BUN, creatine kinase if AST greatly ↑ NAC Tx if; APAP is on or above nomogram tx line, AST ↑, APAP > 10ug/mL, or unknown ingestion time

17. Assess/Tx Chronic APAP ingestion Sx hepatic injury Children; ingest > 75mg/kg in 24 º w/ febrile illness, malnutrition, chronic use CYP450 inducers, or > 150/kg in 24 º Adults; Ingest >4g in 24º assoc w/ chronic EtOH, malnutrition, or CYP450 inducers (anticonvulsants), or ingest > 7.5g in 24º

18. Assess/Tx Chronic APAP ingestion HIGH Risk APAP <10; 1) AST 2X Norm 2) AST> Normal; pt ASX HIGH Risk APAP>10 & as expected for normal dose 1) AST>10 HIGH Risk APAP concentration > expected for dose LOW Risk; APAP <10, AST Normal to 2X, pt ASX, or APAP as expected for normal dose & AST Normal Minimal risk; APAP <10; AST normal

19. Tx based on Risk Higher risk; admit, Tx w/ NAC Low Risk; Give return instructions for Sign or SX of hepatic injury, F/U in 24 º... otherwise admit, Tx NAC Minimal Risk; DC from hospital, provide return instructions

20. APAP potential for toxicity Assume the pt has ingest the greatest amount & LAB Ingestions > 7.5g in adult or > 150mg/kg child indicate risk and Lab eval Establish Risk, then Get APAP concentration at 4 º or ASAP if after 4º If PE is consistent w/ hepatic injury or timing of ingestion can Not be established, AST should be measured, then Treat

21. Nomogram

23. APAP potential for toxicity Plot APAP concentration on Tx Nomogram APAP concentration measured b/t 4 º & 24 º US tx line is 25% lower than original line Rumack- matthew adaptation nomogram (inc sensitivity) Concentration on or above Tx line should be treated! Pts who present after 8º post ingestion, start NAC & adjust according to Nomogram results NAC not recommended; pts unknown ingestion time, w/ APAP level below detectable limit, Norm AST

24. APAP potential Hepatic toxicity Pt w/ RUQ or epigastric pain or tenderness w/ Hx of APAP ingestion suggests hepatic injury AST as screening test If ↑ AST but APAP plots below the Tx line, consider other source of hepatic injury, but still tx w/ NAC Extended release APAP; immediate releases ½ of APAP dose, then sustained 2 nd ½ over several hours Extend release; get 4 º & 8-10 º APAP levels to r/o delayed elevations... Peak plasma levels usually at 4º

25. APAP toxicity eval Acute exposure < 5yrs; severe hepatotoxicity, death Lab eval on (febrile or on CP450 inducers) > 90mg/kg concentration in a child or > 4g in adult in 24 º Pts w/o predisposing risk (ie not febrile, or no CP450 meds); ingestion >150mg/kg in child or >7.5g in adult After normal dosing peak APAP level should be < 30ug/mL, 30 to 90 min post dose & < 10 by 4-6º

26. APAP management Goals; limit GI absorption, start NAC w/in 8 º of ingestion, control Sx, provide supportive & F/U care Gastric Lavage, limited use b/c rapid GI absorption Activated charcoal may bind NAC, no benefit outcome. Do NOT give charcoal for at least 2º post NAC, unless directed otherwise NAC PO; dilute solution (3-5%)... loading dose 140mg/kg, followed by maintenance 70mg/kg Q4º N/V common w/ NAC, re-give dose vomited w/in 1º

27. APAP toxicity management IV NAC if pts can not tolerate PO... not widely available... Can give PO NAC IV w/ dilution…consult pharmacy Risks of IV NAC...anaphylactoid RXN's, flushing urticaria, angioedema, bronchospasm, hypotension 4-14% pts develop transient rash with IV NAC Dose adjustment to slower rate, antihistamine, fluid boluses in place of discontinuation

28. APAP toxicity management IV NAC (3% soln); 30g NAC in D5W total 1L Bolus 140/150mg/Kg for 1 º, then 4º 15mg/kg/hr, then 16º 7.5mg/kg/hr For chronic ingestion or continuous infusion 15mg/kg/hr for 44 º IV NAC fulminant Hepatic failure.. British study; less vasopressor use, less Death/cerebral edema Use IV in Oral intolerance, N/V resolved switch to PO

29. APAP toxicity management APAP crosses placenta, can cause fetal death 2 nd Trimester fetal CYP450 enzymes present Maternal NAC safe/effective, fetal outcome usually good Oral NAC may reach fetus, but IV NAC may achieve higher maternal-fetal NAC gradient! NAC Treatment course; PO loading followed by 17 doses, 4 º intervals. 20 º IV NAC in UK & 48º IV in US All durations NAC effective when started w/in 8 º, longer treatment duration when liver injury

30. Disposition Contact poison control center Fulminant Hepatic failure, need ICU, frequent Neuro checks, glucose measurements, VS monitoring Early contact Liver transplant center if Liver failure Serum PH < 7.3 after resuscitation likely to die w/o transplant.

31. Aspirin & NSAID toxicity Less Deaths; FDA limits 36 tabs baby ASA per bottle, child resistant containers Poisoning underestimated; leads to metabolic acidosis, seizure, hyperthermia, pulmonary edema, cerebral edema, renal failure & Death

32. ASA Absorption & Elimination Salicylic Acid salts absorbed rapidly GI tract; serum concentrations ½ º, 2/3 of dose in 1º & peak 2-4º Absorption to 12º post large ingestion or coated tabs ASA hydrolyzed to free Salicylic acid via RBC, Liver, Intestinal wall & reversibly binds albumin Free Salicylate & conjugates excretion is Renal

33. ASA Absorption, Elimination cont… Therapeutic dose is 1 st order kinetics, but > 30mg/dL has Zero order Kinetics w/ constant Metabolic Rate Ph-sensitive urinary excretion of ASA det half- life…toxic doses may be 15-30º Salicylate stim medullary respiratory center to PH and CO2 partial pressure.  amts ASA depress respiratory center. Loss bicarb, metabolic acidosis; 2º buffering respiratory alkalosis.

34. Aspirin

35. ASA Toxicity; Metabolic, Renal Inhibition of Krebs cycle   amts lactic & pyruvic acid. Uncoupling ETC;  metabolism &Temp, thus  CO 2 production & O 2 use,  glycolysis  risk  BS. Less common  BS due to adrenaline  K + ; Vomiting,  Renal Na + K + HCO3 loss,  Renal Tubercle permeability, Intracellular H 2 O, Na + retention Uncoupling ETC also  K + by inhibiting active transport  Renal Blood flow; ARF & secretion inappropriate ADH ETC= electron transport chain, arrows; increase or dec, 3 dots; therefore

36. ASA Toxicity; pulmonary Edema MOA unknown  Risk Adults; smoking, 30+ y/o, chronic use, metabolic acidosis, Neuro Sx, Salicylate > 40mg/dL  Risk Peds; High salicylate level, large anion gap,  K + level,  CO 2 concentration

37. ASA Toxicity; Chronic Ingestion Aged;  blood flow to Liver   biotransofmation of salicylate. Kidneys;  function   clearance  albumin binding w/ chronic use   free salicylate Free salicylate enters cells causing signif illness w/ lower serum concentration Chronic toxicity w/ serum 40mg/dL may be more ill than pt w/ acute ingestion w/ 80mg/dL

38. Clinic ASA Toxicity Peds aggressive dosing ? more serious than acute ingestion. Sweating, F, tachycardia may be an underlying infection Breast milk, teething gels, skin ointments; all have higher concentrations Toxic 200-300mg/kg; 500mg/kg potentially Lethal

39. Clinic ASA Toxicity Sx; Tinnitus, impaired hearing, vomiting, hyperpnea (may be  respiratory depth w/o  rate), dehydration Vomiting may be w/in 8º of ingestion, CNS Sx; associated w/ Acidemia SOB & altered sensorium; pulmonary & cerebral edema; fail to recognize pulmonary edema  M&M Bleeding risk;  hepatic Factor VI & platelet aggregation

40. Diagnostic Approach; serum salicylates Measure level 6º post ingestion, then 2 nd sample in 2º If 2 nd sample > 1 st sample; do serial; caution w/ coated preps, or chronic ingestion Frequently monitor PH Death by CNS depression & Cardiovascular collapse

41. Sx of Salicylate Toxicity ASX; occasionally none Mild; Mild-mod hyperpnea, Tinnitus, may get lethargy Moderate; Severe Hypernea, marked lethargy or excitable, NO COMA, NO Convulsions Severe; Severe Hypernea, COMA, Semi-coma, may get convulsions

42. Tx Goals prevent > absorption, correct fluid acid-base deficit &  excretion Urine output 2-3mL/kg/hr w/ D5NS or D5LR, but No Forced diuresis. D5 w/ 100mEq bicarb/L Fix  K + & Monitor pH, avoid systemic alkalosis Alkalize Urine; ABG; 1-2meq/kg Bicarb, then as needed (50ml Bicarb  pH by 0.1) DIALYSIS IF; Coma/Seizure, Hepatic failure, Pulm edema, Severe acid-base imbalance, Deteriorating Status, level > 100mg/dl & 40mg/dL if chronic

43. ASA Tox management VS; especially respiratory rate, assess minute Volume, skin temp, ABG Activated Charcoal reduces absorption; consider if ingestion w/in 1º NO Evidence of benefit of outcome IVF; dehydration occurs early, correct K + use dextrose, accu check frequently. CNS glu maybe low even if serum euglycemic Alkalize urine especially if salicylates > 35mg/dL, urine pH 7.5-8 necessary to  excretion Consider exchange transfusion in young or dialysis

44. Salicylate toxicity Pregnancy; greater concentration on fetal side of placenta, fetal distress, associated w/ fetal demise Deliver distressed fetus if possible If acute intoxication; pulmonary edema, acidosis, electrolyte abnormality, renal insufficiency, CNS Sx other than Tinnitus; ADMIT Mortality Rate of chronic toxicity 25% vs 1% for acute DO a Psych EVAL

45. NSAIDS Toxicity Based on COX selectivity, various activities, analgesia. 13 million Americans use Daily. COX-1; concentrated in platelets, gastric mucosa, renal collecting tubules, vascular endothieal cells COX-2; usually expressed in inflammatory stimuli. Weak organic acids readily cross and high concentration in gastric mucosa Most OD even w/ large amounts are ASX or only minor CNS or GI disturbances. Elimination half-life in OD not significantly prolonged!

46. NSAID Toxicity OD w/ mefenamic acid, a fenamate, high risk seizure 2-7º Post Ingestion– Tx IV Benzo, rapid recovery Reversible Renal dys-fxn only after massive OD, supportive, do not correlate w/ serum level Phenylbutazone (pyrazolone) rarely used risk aplastic anemia, more toxic than other NSAIDS - mild poisoning; N/V, abdominal pain, drowsiness - Severe; hematemesis, coma, convulsion, fever, respiratory arrest, acidosis, EKG abnormalities, cardiac arrest. Long clinical course vs other NSAID

47. Phenylbutazone-NSAID Phenylbutazone (pyrazolone) rarely used risk aplastic anemia, more toxic than other NSAIDS - mild poisoning; N/V, abdominal pain, drowsiness - Severe; hematemesis, coma, convulsion, fever, respiratory arrest, acidosis, EKG abnormalities, cardiac arrest. Long clinical course vs other NSAID

48. Management; mostly supportive Screen for APAP, NSAID concentrations NOT useful Lytes, RFP, Hepatic Fxn Panel, ASA, UA, CXR only help w/ significant Sx or ASA or APAP toxicity Peds 300mg/kg need eval. 100-300, eval if Sx Adults; 6º obs & psych eval Pyrazolone & Fenamate ingestions NEED EVAL Activated charcoal use after massive ingestion

49. Management Observe 4º High protein binding & rapid metabolism  urine alkalinization, hemodialysis, hemoperfusion not clinically useful. Multi-dose activated charcoal  elimination half-life phenylbutazone by 30% & some benefit in severe intoxication.

50. Works cited Paediatrics 55: 871, 1975 Rosen's Emergency Medicine Chapters 146, 147 Annals of Emergency Medicine; Vol 45, Num 5 5-05 Google Images