Presentation is loading. Please wait.

Presentation is loading. Please wait.

Acetaminophen, salicylates & nsaid Toxicity

Similar presentations


Presentation on theme: "Acetaminophen, salicylates & nsaid Toxicity"— Presentation transcript:

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


Download ppt "Acetaminophen, salicylates & nsaid Toxicity"

Similar presentations


Ads by Google