1. Acetaminophen, salicylates & nsaid Toxicity
Amy Gutman MD

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. Acetaminophen N–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 2% renally excreted
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:

14. management GI decontamination
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 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 Acetyl-salicylic acid
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 hours
Adult toxic ingestion mg/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 Death from:
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: Later: Late Pure respiratory alkalosis
7.50 – 7.60 /
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 Laboratory GI decontamination with multiple dose charcoal
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
Serum pH not to exceed 7.55
Must avoid hypokalemia

30. Urinary Alkalinization
Prior to Alkalinization
Tissue pH 6.8
Plasma pH 7.1
Urine pH 6.5 HA
H+ + A-

31. Urinary Alkalinization
After Alkalinization
Tissues pH 6.8
Plasma pH 7.4
Urine pH 8 HA
H+ + A-
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 High protein binding & rapid metabolism
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:
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:
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:
Defendi G. Consultant: Volume 12 - Issue 7 - July 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
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):
Temple AR. Acute and chronic effects of aspirin toxicity and their treatment. Arch Intern Med 1981;141:367