APAP and SalicylatePoisoning

Corinne M. HohlR5, EM Training ProgramMcGill UniversitySeptember 2003

Acetaminophen

What is the therapeutic mechanism of action of APAP?

APAP – Question 1

Q1: mechanism of action

Central prostaglandin synthetase inhibitor

analgesic, antipyretic with weak anti-inflammatory properties.

APAP – Question 2 Name 4 metabolic pathways of APAP

and the proportion of APAP metabolized by each pathway in a normal adult host with a therapeutic ingestion.

Q2: met pathways of APAP Hepatic glucuronide conjugation(40-65%)

90% Hepatic sulfate conjugation(20-45%)

inactive metabolites excreted in the urine.

Excretion of unchanged APAP in the urine (5%).

Oxidation by P450 cytochromes (CYP 2E1, 1A2, and 3A4) to NAPQI (5-15%)

GSH combines with NAPQI

nontoxic cysteine/mercaptate conjugates

excreted in urine.

Q2: metabolic pathways of APAP The safety of acetaminophen depends on the

availability of electron donors such as reduced glutathione (GSH) and other thiol-containing substances required to detoxify NAPQI.

APAP – Question 3 What happens to APAP metabolism in

an OD situation?

Q3: APAP metabolism in OD Saturation of glucuronidation and sulfation pathways

Amount of APAP metabolized by p450 cytochromes to NAPQI increases.

Normally NAPQI is detoxified by reduced GSH (glutathione) and thiol-containing substances.

In OD: rate and quantity of NAPQI formation overwhelms GSH supply and regeneration:

elimination of NAPQI prolonged free NAPQI binds critical cell proteins with

sulfhydryl groups cellular dysfunction and cell death.

Animal models: hepatotoxicity when GSH stores fall <30% of baseline large margin of safety where therapeutic dose 10-15mg/kg to toxic dose of 150mg/kg for single acute ingestion.

APAP – Question 4 Name 3 factors which adversely affect

APAP metabolism.

Q4: APAP metabolism Upregulation (i.e. induction) of CYP 2E1 enzyme

activity: smoking, barbituates, rifampin, carbamazepine,

phenytoin, INH, + ethanol use of APAP by alcoholics has not been associated with

higher risk of liver injury in prospective trials Decreased glutathione stores. Frequent dosing interval of APAP. Prolonged duration of excessive dosing.

(Kuffner et al. 2001)

APAP – Question 5 Name 3 factors which decrease GSH

stores. Name 2 ways in which GSH stores can

be replaced.

Q5: GSH stores Glutathione stores are

determined by: age diet liver disease fasting prior ingestion chronic malnutrition

(anorexia) gastroenteritis chronic alcoholism HIV

Glutathione replacement by sulfhydryl compounds: eating NAC

Whitcomb DC, Block GD: Association of acetaminophen hepatotoxicity with fasting and ethanol use. JAMA 1994; 272:1845

Q5: toxicity in children Most APAP ODs in children occur in the

scenario of acute febrile illness. It is unclear whether short-term fasting in acute

febrile illness in children prediposes them to oxidant stress which depletes GSH leading to APAP toxicity, or whether this is simply the most common setting in which children most commonly receive multiple excessive dosing.

Given the large therapeutic index children are unlikely to become toxic from ingestion on one or two tablets.

Whitcomb DC, Block GD: Association of acetaminophen hepatotoxicity with fasting and ethanol use. JAMA 1994; 272:1845

Why is APAP toxic to the kidney as well? (Name 2 mechanisms).

APAP – Question 6

Organ dysfunction results everywhere where local oxidative metabolism (via p450) creates NAPQI that cannot be detoxified direct toxicity: cytochrome P-450 enzymes produce NAPQI in

the renal tubules NAPQI binds cellular macromolecules acute tubular necrosis.(25% of hepatotoxic cases).

Hepatorenal Syndrome Volume depletion

Q6: renal toxicity

How could one distinguish with a simple lab test between hepatorenal syndrome and ATN?

APAP – Question 7

Q7: HRS vs. direct toxicity Fractional excretion of sodium (FeNa) :

FeNa: >1 in primary renal injury

FeNa: <1 hepatorenal syndrome

What other 2 organs are most commonly (although overall rarely) damaged in an APAP overdose?

APAP – Question 8

Q8:other organs damaged Heart myocarditis Pancreas pancreatitis

It is controversial whether these entities are part of multisystem organ failure (MSOF) from fulminant hepatic failure (FHF) or from the local accumulation of toxic metabolites.

APAP – Question 9 What percent of pts whose APAP level

falls above the upper line of the Rumack-Matthew normogram will develop hepatotoxicity?

(defined as elevation of the plasma transaminases

above 1,000 U/L)

60%

Q9: % pts w/ hepatotoxicity

APAP – Question 10 By how many hrs after ingestion do

you expect the transaminases to rise if an APAP ingestion was hepatotoxic? In which clinical stage would this be?

Q10: time of AST/ALT rise I 0.5-24h n/v, anorexia, asymptomatic.

II 24-48 h resolution of stage I sxs RUQ pain, elevation of PTT, INR,

bili + enzymes (at the latest by 36h) III 48-96h coagulopathy, peaking of enzymes,

acidosis, hypoglycemia, bleeding diathesis, jaundice, anuria, cerebral edema, coma. ARF in 25% of pts with hepatotoxicity

IV 4-14d resolution

APAP – Question 11 Which lab test is the most sensitive for

early detection of hepatotoxicity.?

Q11: lab test AST

APAP – Question 12 Your resident saw a patient 90min post

APAP ingestion of unknown quantity: He tells you the APAP is <10 and AST 40. How would you dispo and manage this pt.

Q12: 1h level This patient needs a 4-hr APAP level – there is

no point in doing an APAP level in an acute single ingestion before 4h post ingestion unless it is a chronic ingestion or the history is unreliable.

There is no point in doing LFTs either unless the 4hr APAP is on or near the treatment line, the pt has symptoms suggestive of liver injury or pt looks unwell (i.e. prior liver disease).

APAP – Question 13 Another resident tells you another

patient has a 4 hr APAP of 70mg/mL with an AST of 50. As you pursue the story you find out that your patient is from Europe and may have ingested an extended release form of paracetamol. What is your management?

Q12: XR tablets Check 6h and 8h APAP levels. Tx with NAC if:

4, 6 or 8h level above the R-M tx line full course NAC. If all levels are below the tx line and the 8h APAP level is

less than 50% of tx line D/C home (NYPC). If the 8h APAP line is btw 50% of tx line and tx line NAC.

for 24-36h and D/C once APAP <10 or transaminases normal (NYPC).

If the 6-hour level is greater than the 4-hour level, begin NAC therapy.

* More prolonged monitoring of levels may be necessary if the patient has food in the stomach or co-ingestants that delay gastric emptying.

Q12: XR tablets Several studies show that elimination of extended

and immediate-release acetaminophen are nearly identical after 4 hours.

However, some case reports have documented APAP levels falling above the treatment normogram line as late as 11-14 hours post ingestion of the extended-release preparation.

Q12: XR tablets

Vasallo et al. Ann Intern Med. 1996; 125 (11) 940.

Healthy 17yo girl after ingestion of 13g of ER tylenol.

Both a 3 and 5hr level were below the treatment line.

NAC was started after the 11hr level was above the treatment line.

She did not develop hepatotoxicity.

APAP – Question 13 Name four indications (lab criteria) for

treating a patient for repeated excessive APAP dosing.

Q13: chronic OD If the APAP level is above the treatment

line (plot earliest possible dose to have high sensitivity).

Symptomatic pt with AST >normal. Any asymptomatic patient with a hx of

chronic excessive APAP ingestion and an AST > 2x normal.

AST >normal with APAP >10. If the APAP level is greater than expected

for the appropriate dose.

APAP – Question 14 A 3rd ingestion comes in:18 yr old pregnant girl

ingested 20g of Tylenol in a suicidal gesture 36h ago because she found out it is too late for her to have an abortion. Her APAP is <10 and her AST is 90.

How will you manage her medically? She asks you whether her baby will have any

defects.

Q14: APAP in pregnancy APAP crosses the placenta. She needs a full course of NAC. There is no point in giving her AC at

this point, although AC would probably be safe in an acute OD.

Birth defects: poorly studied in OD, some evidence for birth defects.

Q14: Pregnancy and APAP AC: Class C

Safety for use during pregnancy has not been established.

NAC: Class A Safe in pregnancy

APAP – Question 15 Name 4 mechanisms by which NAC

works.

Q15: 4 mech of action of NAC Early Prevents binding of NAPQI to hepatocytes.

GSH precursor increases GSH stores Increases sulfation metabolism of APAP less NAPQI formed Reduces NAPQI back to APAP (at least in animal models). Sulfur group of NAC binds and detoxifies NAPQI to cysteine and

mercaptate conjugate (= GSH substitute).

Late (12-24h) Modulates the inflammatory response. Antioxidant, free radical scavenger. Reservoir for thiol groups (i.e. GSH). Impairs WBC migration and function antiinflammatory. Positive inotropic and vasodilating effects (NO) improves

microcirculatory blood flow and O2 delivery to tissues. Decreases cerebral edema formation, prevents progression of

hepatic encephalopathy and improves survival.

APAP – Question 16 Name 4 indications for NAC therapy.

Q16: 4 indications for NAC APAP level above the treatment line. Hx of significant APAP ingestion presenting

close to 8h (give while waiting for level). All APAP ingestions who present late (>24h with

either detectable APAP or elevated transaminases.

Chronic lg ingestions (>4g/day in adult, >120mg/d in child) with elevated transaminases.

Hx of exposure and FHF.

IV NAC 3 situations in which IV NAC is undoubtedly

preferable to oral: Fulminant hepatic failure Pregnancy Inability to tolerate oral NAC.

APAP – Question 17 Name 4 poor prognostic indicators:

Q17: poor prognostic indicators pH <7.3 (2 days after OD, after fluids) Hepatic encephalopathy PT >1.8 times normal. Serum creatinine >300mmol/L Coagulation factor VIII/V ratio of >30

Note: Transaminase levels do NOT predict the clinical course. They can decline during hepatic recovery or with FHF.

Q17: other rules of thumb If PT in seconds > number of hours since

ingestion. If INR is abnormal and still increasing on 4th day

post ingestion.

Q17: indicators for need for transplant: Arterial pH <7.3 at any time after FHF develops

that fails to correct with colloid loading

OR In patients with a normal arterial pH all 3 of the

following:   PT >100 sec (without FFP or Vit K) Creatinine >300 μmol/L Grade III or grade IV hepatic encephalopathy

Makin AJ, Williams R: Acetaminophen-induced hepatotoxicity: Predisposing factors and treatments. Adv Intern Med 1997; 42:453

Lee WM: Acute liver failure. N Engl J Med 1993; 329:1862

Q17: indicators for transfer to transplant center INR > 5

OR

any of the following complications: ARF: creatinine >200 μmol/L metabolic acidosis: pH <7.35 or bicarb <18 mEq/L Hypotension Encephalopathy Hypoglycemia

A rising PT on the fourth day after overdose is the single best marker of a poor prognosis(39)

APAP – Question 18 Why is the coagulation factor VIII/V

ratio abnormal in APAP poisoning?

Q18: factor VIII/V ratio

Factor VIII is produced by endothelial cells and its production is not impaired by APAP

Factor V is produced by hepatocytes and its production diminishes with hepatocellular necrosis.

APAP – Question 19 Name 3 mechanisms by which you can

develop a metabolic acidosis in APAP poisoning?

Q19: metabolic acidosis Intravascular volume depletion and lactic

acidosis from dehydration/hypoperfusion. ARF Lactic acidosis without evidence of FHF from a

direct effect of acetaminophen inhibition of hepatic lactic acid uptake and metabolism.

FHF

Salicylates

ASA – Question 1

Name 3 factors which may delay salicylate absorption in an OD situation.

Q1: delayed absorption Enteric coating Bezoar formation Salicylate-induced pylorospasm Gastric outlet obstruction Concomitant ingestion of sustance which

decreases gastric motility

ASA – Question 2

What is the highest therapeutic dose of ASA that should be prescribed?

Q2: ASA dosing

Adult (usually for RA) acc. to the FDA: 650mg po q4h for 10d Initial dose can be 1000mg.

max: 3900mg/day for adults Child: no more than 15mg/kg q4

ASA – Question 3

Name 3 patient factors which enhance the toxicity of topical salicylates (i.e. oil of wintergreen)?

Q3: toxicity topical SA heat occlusive dressings young age (high BSA to weight ratio) inflammation psoriasis/break of the skin long application

** real danger is through oral ingestion of topical ingestion.

ASA – Question 4

What is the approximate daily dose of ASA beyond which we worry about toxicity in repeated daily ingestions?

Q4: chronic OD toxic dose

100mg/kg (vs. 200-300mg/kg in a single acute ingestion)

Especially predisposed are the elderly and infants.

ASA – Question 5

Contrast acute vs. chronic salicylism with respect to (4 out of 6): patient age Comorbidities serum concentration mental status hydration status mortality.

Q5: acute vs. chronic Characteristics:

Features Acute ChronicAge Young adult Older adult/infantsEtiology OD Therapeutic misuseCo-ingest. Frequent RarePast history OD or psych Comorbidities/pain/RFPresentation Early LateDehydration Moderate SevereMental status Normal(initially) AlteredSerum [conc] 40 - ≥120 mg/dL 30 to ≥80 mg/dLMortality Low w/ treatment High

MORE MORE DANGEROUS!DANGEROUS!

ASA – Question 6

Name 3 reasons why the serum concentration of SA rises dis-proportionately to the dose ingested in toxic doses.

Q6: metabolism in OD

Metabolizing enzymes get saturated: switch from first zero order kinetics.

Decrease in albumin binding at toxic levels. Urinary excretion is fixed. SA = weak acid:

at physiologic pH most SA is ionized does not penetrate tissues well.

acidosis more unionized SA greater tissue penetration.

methylsalicylate

Hydrolysis in GI tract, liver, RBC’s

2.5% excreted unchanged in urine (pH independent)

methylsalicylate

2.5% excreted unchanged in urine (pH independent)

90% of free SA binds albumin at conc < 10mg/dL

Free tissue SA

methylsalicylate

Hydrolysis in GI tract, liver, RBC’s

2.5% excreted unchanged in urine (pH independent)

zero order kinetics once saturated

zero order kinetics once saturated

% of free SA bound to albumin decreases as the [serum] increases: 75% bound @ 40mgdL 50% bound @ 75mg/dL

Free tissue SA increases

First order kinetics

ASA – Question 7:

Name 4 mechanisms by which ASA can cause a metabolic acidosis.

Q7: met acidosis in ASA Salicylate ion = weak acid which contributes to the acidosis.

Dehydration from hyperpnea, vomiting, diaphoresis and hyper-thermia contributes to lactic acidosis.

Uncoupling of mitochondrial oxidative phosphorylation anaerobic metabolism lactate and pyruvate production.

Increased fatty acid metabolism (as a consequence of uncoupling of oxydative phosphorylation) lipolysis ketone formation.

In compensation for the initial respiratory alkalosis the kidneys excrete bicarbonate which later contributes to the metabolic acidosis.

Increased sodium and potassium accompany the initial renal bicarbonate diuresis hypokalemia hydrogen ion shift out of cell to maintain electrical neutrality.

Inhibition of liver lactate elimination. Renal dysfunction accumulation of SA metabolites which are

acids: sulfuric and phosphoric acids.

ASA – Question 8

What is Reye’s syndrome?

Q8:

ASA associated hepatitis in children: Nausea, vomiting, hypoglycemia Elevated liver enzymes Fatty infiltration of liver Coma Following viral illness, usually influenza or

varicella 555 cases in US in 1980 steady decline since

with declining use of ASA.

ASA – Question 9

An adult presents with a respiratory acidosis post ASA ingestion. What 3 entities need to be ruled out quickly? (Trauma and prior lung disease have been ruled out.)

Q9: Respiratory decompensation from fatigue. Co-ingestants which blunt the respiratory

drive. SA induced acute lung injury.

ASA – Question 10 Name 2 risk factors for developing pulmonary

edema after ASA intoxication.

Q10: ALI Age > 30 Smoking Chronic salicylate ingestion Presence of neurologic symptoms on

presentation. Hypoxia (increase in pulmonary vasomotor

tone) Degree of acidosis independent of serum [SA]

is associated with ALI: it is unclear whether this is a causative factor or a consequence of ALI.

ASA – Question 11 List 15 clinical manifestations (signs or

symptoms) or laboratory abnormalities of SA poisoning excluding acid/base abnormalities.

Q11: clinical manifestations CNS: tinnitus, decreased hearing, vertigo, hallucinations,

agitation, hyperactivity, delirium, stupor, coma, lethargy, seizures, cerebral edema, SIADH

Hem: hypoprothrombinemia, platelet dysfunction and bleeding

GI: n/v, hemorrhagic gastritis, decreased GI motility, pylorospasm, abnormal LFTs

Met: fever, hypoglycemia, hyperglycemia, ketosis, ketonuria, rhabdomyolysis

Pulm: tachypnea, ALI Renal: proteinuria, Na and water retention

Volume: diaphoresis and dehydration.

Q11: temporal sequence Early: tinnitus, n/v, diaphoresis + hearing loss (a

bit later) Vertigo, hyperventilation, hyperactivity,

agitation, delirium, hallucinations, Sz, lethargy and stupor.

Late: coma (after massive ingestions levels >100mg/dL or co-ingestions)

Severe hyperthermia from uncoupling of oxidative phosphorylation is a preterminal event.

ASA – Question 12 Name 8 presenting manifestations of chronic

salicylism.

Q12: chronic clinical toxicity tinnitus, hearing loss, vertigo, n/v, dyspnea,

hyperventilation, tachycardia, hyperthermia, confusion, hallucinations, seizures, coma

Slower onset of symptoms than in acute OD and less severe manifestations.

nonspecific presentation maintain high index of suspicion in elderly on ASA.

Delayed diagnosis common mortality is higher when diagnosis is delayed.

ASA – Question 13 What 2 rapid pint-of-care bedside tests that we

have available in our EDs can confirm your suspicion for an ASA poisoning?

Q13: Urine dip: ketones CBGM: hypoglycemia

ASA – Question 14 The Done normogram was derived from

predominantly pediatric data for a level 6hrs post ingestion from a single, acute ingestion of non-enteric coated tablets. Also, it is only applicable for levels from a blood pH >7.4. It is notoriously unreliable.

What is a better way of following the severity of your pt’s acute or chronic ASA poisoning? Which lab tests, at what frequency?

Q14: lab monitoring ASA levels a 2-4 hourly intervals, looking for the

direction of change. Careful in interpreting a decreasing level: this can

indicate increased clearance with decreasing toxicity OR increased tissue distribution with lower pH and increased toxicity.

Even a lowering [ASA] with a decreasing pH may be ominous.

Serial ABG monitoring. Monitor the mental status.

ASA – Question 16 How would you decontaminate a 16yo boy who

ingested 100 tablets of 325mg ASA 2 hrs ago?

Q15: decontamination Aim for a 10:1 ration of AC: drug. So, 300g of AC

in multiple doses. Controversial:

Benefit of MDAC– may decrease GI absorption. WBI/PEG may diminish desorption of SA bound to AC

for enteric coated tablets, unknown whether this is superior to MDAC.

ASA – Question 16 Explain the concept of “ion trapping”.

Q16: ion trapping

the more acidotic the compartment the more SA will be NONionized because SA is a weak acid (the stronger acids will dissociate and give off their H+ first.)

the more basic a compartment the more IONIZED SA will be because there is a relative lack of H+ so because SA is an acid it will give off its H+ and be ionized, i.e. “trapped” in that milieu.

Q16: ion trappingTissue pH 6.8 Plasma pH 7.1 Urine pH 6.5

HA HA HA

H+ A- H+A- H+A-

Prior alkalinization.

Tissue pH 6.8 Plasma pH 7.5 Urine pH 8.0

HA HA HA

H+ A- H+A- H+A-

After alkalinization.

H+A- Pee it out….

Pee it out…

ASA – Question 17 Beyond what serum [SA] should you consider

urine alkalinization?

ASA – Question 17 >40mg/dL in an acute OD >30mg/dL in a chronic OD

ASA – Question 18 Name 5 indications for hemodialysis indications

in SA poisoned patients.

Q18 - HD Renal failure CHF Pulmonary edema or acute lung injury Refractory acidosis or electrolyte imbalance

despite maximal therapy Persistent CNS symptoms Progressive vital sign deterioration Acute OD with level >100mg/dL Liver failure with coagulopathy