Acetaminophen, salicylates & nsaid Toxicity

1. Acetaminophen, salicylates & nsaid Toxicity Amy Gutman MD prehospitalmd@gmail.com

2. Common prescribed medications & overdoses* • Opioids • Sedatives-Hypnotics-Antipsychotics • Cardiovascular drugs • Antidepressants • Stimulants • Acetaminophen *Intentional & unintentional

3. What a difference a decade makes… • American Association of Poison Control Centers 2006 • Among analgesics, acetaminophen & salicylate are 40% of overdose cases • American Association of Poison Control Centers 2016 • Among analgesics, opiates are 70% of overdose cases

4. Prevalence & Utilization • Acetaminophen, ibuprofen & aspirin are the most commonly used analgesic medications among US adults • In any given week, 23% adults (48 million) use acetaminophen-containing products, 17% use aspirin, 17% use ibuprofen, & 4% use naproxen One-Week Prevalence of Most Commonly Used Analgesic Products in the US Adult Population (n= 209 million); Slone Survey of Medication Use

5. AcetaminophenN–acetyl–p–aminophenol (APAP) • 1st synthesized in 1800’s • Synthetic non-opiate analgesic • MOI: • CNS prostaglandin inhibition • Blocks generation of peripheral pain impulses • Antipyresis via inhibiting hypothalamic heat regulation

6. Ubiquitous! Arthritis Foundation Pain Reliever Aspirin Free Aspirin Free Pain Relief Aspirin Free Anacid Maximum Strength Atasol Atasol Forte Genapap Extra Strength Genebs Extra Strength Caplets Panadol Panadol Junior Strength Tapanol Extra Strength Tylenol Arthritis Extended Relief Tylenol Caplets Capsules: Dapacin Meda Cap Aceta Genapap Children's Mapap Children's Oraphen-PD Ridenol Silapap Children's Tylenol Children's Aspirin Free Anacid Maximum Strength Tapanol Extra Strength Tylenol Extra Strength Atasol Children's Acetaminophen Elixir Drops Halenol Children's Panadol Children's Pediatrix Tempra Tempra 2 Syrup Tempra Children's Syrup Tylenol Extra Strength Oral Solution: Acetaminophen Drops Apacet Atasol Children's Acetaminophen Oral Solution Genapap Infants' Drops Mapap Infant Drops Panadol Infants' Drops Pediatrix PMS-Acetaminophen Silapap Infants Tempra 1 Tylenol Infants' Drops Uni-Ace Tylenol Children's Suspension Tylenol Infants' Suspension Sprinkle Capsules: Feverall Children's Feverall Junior Strength Suppositories: Abenol 120, 325, 650 mg Acephen Acetaminophen Uniserts Children's Feverall Infant's Feverall Junior Strength Feverall Neopap Aceta A.F. Anacin A.F. Anacin Extra Strength Apo-Acetaminophen Aspirin Free Pain Relief Aspirin Free Anacin Maximum Strength Atasol Atasol Forte Extra Strength Acetaminophen Fem-Etts Genapap Genapap Extra Strength Genebs Genebs Extra Strength Mapap Regular Strength Mapap Extra Strength Maranox Meda Tab Panadol Redutemp Regular Strength Acetaminophen Tapanol Regular Strength Tapanol Extra Strength Tempra Tylenol Regular Strength Tylenol Extra Strength Tylenol Junior Strength Tylenol Tablets 325 mg, 500 mg Tablets, Chewable: Apacet Children's Chewable Acetaminophen Children's Genapap Children's Panadol Children's Tylenol Tempra Tempra 3 Tylenol Chewable Tablets Fruit Tylenol Junior Strength Chewable Tablets Fruit Acetaminophen, buffered (Bromo Seltzer)

7. APAP Metabolism • Rapidly absorbed from GIT • Primarily small intestine • Peak serum concentrations 2 hours post-ingestion • With acute OD, peak serum concentration at 4 hours • Coingestants delaying gastric emptying, or extended-release APAP increases time to peak serum concentrations

8. Apap METABOLISM • 90-95% in liver • Primary metabolic pathways are sulfation (children) & glucuronidation • 2% renally excreted • Water-soluble by-products of hepatic metabolism • 4% biotransformed by CYP-450 system • Creates reactive toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI)

9. Apap METABOLISM • Hepatic glutathione binds NAPQI producing non-toxic renally excreted byproduct • Acute APAP OD depletes liver glutathione stores by 70-80% limiting NAPQI metabolism • NAPQI buildup causes hepatic injury by binding to hepatocyte lipid bilayer, causing centrilobular necrosis (zone 3) • N-Acetylcysteine (NAC) limits liver injury by replenishing glutathione to metabolize excess NAPQI

10. Clinical evidence of toxicity

11. Toxicicity • Fatalities uncommon • Chronic ingestion has low mortality, moderate morbidity • High risk: APAP > 10mcg/ml, AST 2X normal • Low risk: APAP <10mcg/ml, AST <2X normal • Severe toxicity related to acuity of OD, co-ingestants & PMH • Pediatric: single dose >250 mg/kg • Adult: single dose >150 mg/kg or >12 g

12. Rumack-Matthew nomogram Only useful for 24 hours post ingestion

13. Laboratory prognosis predictors • King’s College Criteria • pH < 7.30, or • PT >100sec • Creatinine > 3.4 mg/dL • Grade III+ encephalopathy • PPV= 98%, NPV=82% Chung PY, Sitrin MD, Te HS. Serum phosphorus level predict clinical outcome in fulminant hepatic failure. Liver Transplantation. 2003;9:248-253

14. management • Limit GI absorption, provide supportive care, control symptoms • GI decontamination • Rapid GI absorption limits effective gastric lavage • Activated charcoal • Very early presentation • Co-ingestants • Adsorbs to NAC

15. Nac treatment • Reduces hepatotoxic metabolite NAPQI via bio-transformation • NAC becomes cysteine & mercapturic acid, replenishing glutathione stores, serving as sulfation substrate • Dosing: 140mg/kg bolus followed by 17 doses of 70mg/kg Q4º • Pregnancy: • APAP crosses placenta • 2nd trimester fetal cytochrome P450 enzymes present • IV NAC achieves higher maternal-fetal NAC gradient than oral

16. Late NAC Therapy • Decreased hepatotoxicity when treatment begins 16-24 hours post ingestion • IV NAC post onset of fulminant hepatic failure decreases vasopressor requirements, & lowers incidence of cerebral edema & death • Improved extra-hepatic oxygen delivery & utilization including cerebral blood flow due to preservation of microvascular tone

17. Salicylates Apo-Asa   Asaphen   Aspergum Aspirin Aspirin Regimen Bayer 81 mg with Calcium Bayer Children's Aspirin Easprin Ecotrin Caplets and Tablets Ecotrin Maximum Strength Caplets and Tablets Empirin Entrophen   Excedrin Geltabs Genprin Genuine Bayer Aspirin Caplets and Tablets Halfprin 8-Hour Bayer Timed-Release Caplets Maximum Bayer Aspirin Caplets and Tablets MSD Enteric Coated ASA   Norwich Extra Strength Novasen   St. Joseph Adult Chewable Aspirin Therapy Bayer Caplets ZOR-prin (Easprin and ZOR-prin are Rx) Acetylsalicylic acid, buffered (Ascriptin Regular Strength, Bufferin) Acetylsalicylic acid, buffered Alka-Seltzer with Aspirin Alka-Seltzer with Aspirin (flavored) Alka-Seltzer Extra Strength with Aspirin Arthritis Pain Formula Ascriptin Regular Strength Ascriptin A/D Bayer Buffered Buffered Aspirin Bufferin Buffex Cama Arthritis Pain Reliever Magnaprin Magnaprin Arthritis Strength Captabs Tri-Buffered Bufferin Caplets and Tablets Acetyl-salicylic acid

18. Pharmacokinetics • Decreased prostaglandins & thromboxane TXA2 production • Irreversible inactivation of cyclooxygenase (COX) enzyme • Acetylating agent uncouples mitochondiral oxidative phosphorylation • At toxic levels (>30mg/dL), elimination routes saturated, with decreased fraction protein bound

19. Salicylate Uncoupling Krebs cycle inhibition causes increased amounts of lactic & pyruvic acid ATP Pyruvate decarboxylase Kreb’s Cycle Glycolysis Glucose Pyruvate CO2 • Methanol • Uremia • DKA, SKA, AKA • Paraldehyde • INH, Iron, Infection • Lactate • Ethylene glycol • Salicylates Lactate Oxidative Phosphorylation NADH2 H2O SALICYLATES ATP

20. Mechanism of Toxicity • High ASA levels depress medullary respiratory center • Uncoupling ETC • High metabolism & temperature • Increased CO2 production & O2 use • Increased glycolysis with hypoglycemia • Hypokalemia from inhibition of active transport • Renal losses: • Urinary ASA excretion pH-sensitive • Hypokalemia from vomiting • Increased renal losses of Na+ & HCO3 • Increased renal tubercle permeability with intracellular H2O, Na+ retention • Decreased renal blood flow, causes ARI & SIADH from negative feedback loop

21. Serum Levels & Acute Toxicity • Absorbed well in small intestine • Slow absorption in stomach • Peak serum levels 30 minutes • Toxic dose ½ life 15-30 hours • Adult toxic ingestion 200-300mg/kg • 500mg/kg often lethal • Serum levels = tissue levels • Follow levels with arterial pH, clinical condition Done nomogram (1960)

22. Toxicity • Tinnitus • N/V • Pylorospasm • Diaphoresis • AMS • Bleeding risk • Decreased Factor VI & platelet aggregation • Death from: • Metabolic acidosis • Hypoglycemia • Seizure • Hyperthermia • Pulmonary edema • Cerebral edema • Renal failure *Increased CNS glucose utilization

23. Chronic Salicylism • Common in elderly • SSX consistent with acute toxicity • May also present as: • Delirium • Encephalopathy • CHF • Mortality of chronic toxicity 25% vs 1% for acute

24. ASA Chronic toxicity • Any decreased blood flow to liver decreases ASA biotransformation • Any decreased kidney function decreases salicylate clearance • Decreased albumin binding leads to free salicylate • Free salicylate enters cells causing symptoms with lower serum concentration • Chronic toxicity at 40mg/dL may be more ill than in an acute ingestion at 80mg/dL

25. ABG = Toxicity • Early: • Pure respiratory alkalosis • 7.50 – 7.60 / 20 - 30 • Later: • Respiratory alkalosis with compensated anion gap metabolic acidosis • 7.47 / 25 • Late • Severe toxicity • 7.40 / 15

26. Typical ABG* • High anion gap metabolic acidosis • Concomitant normal anion gap metabolic acidosis • Respiratory alkalosis • Decreased delta ratio • Mixed acid-base order exists in elevated AG acidosis *Lifeinthefastlane.com

27. ASA Toxicity ~ pulmonary Edema • MOA unknown • At risk adults • Smoking • 30+ y/o • Chronic use • Metabolic acidosis • CNS symptoms • Salicylate > 40mg/dL • Hypokalemia • Hypocapnea

28. Management Limit absorption, increase excretion, correct fluid & acid-base abnormalities • Laboratory • ABG • CBC / CMP • ASA level (mg/dL) 6 & 8 hours post ingestion • GI decontamination with multiple dose charcoal • ASA is slow release, clumping in GIT where it is poorly souable with delayed absorbtion • Fluid resuscitation & electrolyte repletion • Forced alkaline diuresis • Hemodialysis

29. Urinary Alkalinization • Acidemia facilitates transfer of ASA into tissue • Alkalinizing urine from pH 5 to 8 increases renal ASA elimination from 1.3 mL/min to 100 mL/min (10-20 times) • Serum half-life decreases from 48 hours to 6 hours • Acetazolamide creates alkyluria & metabolic acidosis while avoiding systemic alkalosis • NaHCO3 increases urinary elimination 10-20x • Bolus 1-2 mEq/kg followed by 3 amps • Goal: urine pH 7.5-8.0 • Serum pH not to exceed 7.55 • Must avoid hypokalemia

30. Urinary Alkalinization Prior to Alkalinization

31. Urinary Alkalinization After Alkalinization Temple AR. Acute and chronic effects of aspirin toxicity and their treatment. Arch Intern Med 1981;141:367

32. Extracorporeal Removal • ASA primarily protein-bound with small VOD • Binding site saturation leads to large levels of free drug, which is easily dialyzable • Indications • Critically ill / • Severe fluid / electrolyte disturbance • High serum levels / unable to eliminate salicylates • Hemoperfusion • Better clearance than hemodialysis for protein-bound & lipid-soluble drugs • Hemodialysis • Better clearance for water-soluble & small molecules • Fluid, electrolyte, acid-base correction

33. Nonsteroidal Anti-inflammatory Drugs (NSAIDs) • Common indications & adverse effects based upon common mechanism of action • Cyclooxygenase inhibition • Different selectivity to COX I & II = different pharmacokinetics & potency • Same toxicity management

34. Pharmacologic Effects • Analgesic • CNS & peripheral • Antipyretic • CNS • Anti-inflammatory • Prostaglandin inhibition • Inhibit activation, aggregation, adhesion of neutrophils & release of lysosomal enzymes

35. Common Adverse Effects • Platelet dysfunction • Gastritis & peptic ulceration • Nephropathy • Na+ & H2O retention with edema • Inhibition of labor • Hypersenstivity (PG inhibition)

36. NSAID Toxicity • Toxicity based on COX selectivity • COX-1: concentrated in platelets, gastric mucosa, renal collecting tubules, vascular endothelium • COX-2: anti-inflammatory with fewer GI side effects, primarily kidney & platelet toxicity with increased risk of thrombotic events • Most OD have only minor CNS or GI disturbances • N/V, abdominal pain, drowsiness • Severe* • Renal dysfunction • Bleeding dyscrasias • Acidosis • AMS / Coma • Seizure • Fever • Respiratory / cardiac arrest • Arrhythmias *Does not correlate with serum level

37. Management • Laboratory • CBC, LFTS, CMP, Magnesium, Phosphorus • PTT / PT / INR • ABG • Lactate • NSAID concentrations NOT useful • Salicylates, APAP, drug screen, alcohol • High protein binding & rapid metabolism • There is no role for urinary alkalinization or forced diuresis • Multidose charcoal decreases elimination half-life by 30% • Hemodialysis against an alkaline bath facilitates correction of acid-base & electrolyte abnormalities & management of volume status

38. management • NSAIDs acidic (i.e. carboxylic acid) or metabolized to acidic compounds • Anion gap acidosis from accumulation of parent compound & metabolites, inhibition of mitochondrial respiration & distributive shock in the setting of progressive acidosis • Sodium bicarbonate • Not a specific antidote for NSAID toxicity • Consider with other supportive cares in an acidotic patient • Transient acidosis moderate toxicity typically self-limiting • Lactic secondary to tissue hypoperfusion refractory to bicarbonate • Supportive cares aimed at restoring normal tissue oxygenation & perfusion are key

39. Nitroaspirins decrease nsaid toxicity

40. Summary • Management of acute APAP, ASA, NSAID poisoning is supportive & symptom-specific • Initial stabilization always consists of ABCs • No evidence exists that empiric administration of activated charcoal in drug OD improves clinical outcome • Be wary of chronic toxicity & co-ingestants

41. References • Acetaminophen and Salicylates Toxicity and Management. Joseph Rella, MD. NJMS • Morgan AG, Polak A. The excretion of salicylate in salicylate poisoning. Clin Sci 1971;41:475-484 • Smilkstein, Knapp, Kulig, Rumack. Efficacy of oral N-Acetylcysteine in the treatment of acetaminophen overdose: Analysis of the national multicenter study. N Engl J Med 1988;319:1557-1562 • Smilkstein, Knapp, Kulig, Rumack. N-Acetylcysteine in the treatment of acetaminophen overdose. N Engl J Med 1989;320:1418 • Keays, Harrison, Wendon, et al. Intravenous acetylcysteine in paracetamol induced fulminant hepatic failure: A prospective trial. Br Med J 1991;303:1026-1029 • Defendi G. Consultant: Volume 12 - Issue 7 - July 2013. Acetaminophen toxicity in children: diagnosis, clinical assessment, and treatment of acute overingestion. July 24, 2013    • Mottram AR, Kumar AM. Focus on: acetaminophen toxicity and treatment. ACEP News. May 200712 • Temple AR, Baggish JS. Guidelines for the Management of Acetaminophen Overdose. Fort Washington, PA: McNeil Consumer & Specialty Pharmaceuticals. 2005 • Blackford MG, Felter T, Gothard MD, Reed MD. Assessment of the clinical use of intravenous and oral N-acetylcysteine in the treatment of acute acetaminophen poisoning in children: a retrospective review. Clin Ther. 2011;33(9):1322-1330. • Temple AR. Acute and chronic effects of aspirin toxicity and their treatment. Arch Intern Med 1981;141:367