APAP Toxicity and Fulminant Liver failure

Question 1

What is the pediatric dose for APAP?

Answer 1

10-15 mg/kg/dose q4-6h (max 90 mg/kg/d)

Question 2

What is the adult dosing for APAP?

Answer 2

325-1,000 mg q4-6h (max 4,000 mg daily)

Question 3

What is the time to Cpeak for a normal therapeutic dose of APAP?

Answer 3

0.5-2 hours

Question 4

What is the time to Cpeak for an IR APAP product?

Answer 4

4 hours

Question 5

What is the time to Cpeak for an ER APAP product?

Answer 5

> 4 hours

Question 6

What is the half-life for APAP?

Answer 6

2-4 hours

Question 7

What is the therapeutic serum concentration for APAP?

Answer 7

10-20 mcg/ml

Question 8

How is APAP metabolized?

Answer 8

90% is metabolized to sulfate and glucuronide conjugates
5% is excreted in the urine unchanged
5% metabolized by 2E1 to NAPQI (hepatotoxic)

Question 9

What is the mechanism of APAP toxicity?

Answer 9

Sulfate and guluronide stores become saturated and a higher percentage of the ingested dose is metabolized by 2E1 to the toxic metabolite NAPQI
NAPQI interacts with hepatocellular sulfhydryl compounds on hepatocytes to cause hepatic necrosis
Renal toxicity ranging from oliguria to acute renal failure may also occur d/t direct effects of NAPQI on the renal system or hepatic injury leading to hepatorenal syndrome

Question 10

How many stages of APAP toxicity are there?

Answer 10

4

Question 11

What is stage I APAP toxicity?

Answer 11

First 24 hours
N/V, diaphoresis, pallor, lethargy, malaise; some pts asymptomatic
Labs typically normal

Question 12

What is stage II APAP toxicity?

Answer 12

24-72 hours
Stage I sx resolve and pr appears to improve
LFTs begin to increase
Increase PT, T bili, BUN, SCr
RUQ pain, liver enlargement, tenderness

Question 13

What is stage III APAP toxicity

Answer 13

72-96 hours
LFTs peak
Stage I sx reappear w/jaundice, hepatic encephalopathy, and potential bleeding
Continued/worsening renal function

Question 14

What is stage IV APAP toxicity?

Answer 14

4 days - 2 weeks
Recovery phase
Complete liver histological recovery w/in 3 months (no chronic liver dysfunction)
Renal function returns to normal (1-4 weeks)

Question 15

What is the dosing for an acute APAP OD?

Answer 15

>/= 7.5 g in adolescents/adult
>/= 150 mg/kg in children

Question 16

What is the dosing for chronic APAP overdose?

Answer 16

> 4 g/d in adults

> 75-90 mg/kg/d in children

Question 17

What are the RFs for hepatotoxicity from APAP OD?

Answer 17

Increased activity of CYP450
Depleted hepatic glutathione stores
Decreased capacity for glucuronidation

Question 18

What can cause increased activity of CYP450?

Answer 18

Chronic alcohol use (may decrease the risk of hepatotoxicity d/t competitive substrate for 2E1)
Genetic polymorphism of 2E1 gene (develop toxicity at lower APAP doses)
2E1 inducers (carbamazepine, phenobarb, phenytoin, rifampin, isoniazid)

Question 19

What can cause depleted glutathione stores?

Answer 19

Fasting

Chronic alcohol use

Question 20

What can cause decreased capacity for glucuronidation?

Answer 20

Bactrim

Zidovudine

Question 21

What is the treatment for chronic APAP OD?

Answer 21

Acetylcysteine

Question 22

What is acetylcysteine’s MOA?

Answer 22

Restoring

Question 23

What are acetylcysteine medications?

Answer 23

Oral: Mucomyst
IV: Acetdate

Question 24

How is mucomyst administered?

Answer 24

Dilute doses to a 5% concentrations with juice or water to improve palatability
Also cover the cup and drink through straw

Question 25

Which patient's are acetadote reserved for?

Answer 25

Refractory vomiting Intolerability to oral administration GI bleed or obstruction Encephalopathy

Question 26

What is the IV duration of NAC?

Answer 26

21

Question 27

What are the ADRs of IV NAC?

Answer 27

Anaphylactoid reactions | Acute flushing and erythema in the first hour of the infusion that typically resolves spontaneously

Question 28

What is the oral NAC duration?

Answer 28

72 hours

Question 29

What do we give with oral NAC?

Answer 29

Oral causes N/V | Antiemetics: metoclopramide, zofran, droperidol

Question 30

When do we give activated charcoal to patients?

Answer 30

50g to all adult pts presenting w/in 4 hours of ingestion, unless CI May be useful beyond 4 hours

Question 31

When do we treat with NAC?

Answer 31

Serum APAP concentration drawn at 4 hours or more after a single acute ingestion is above the treatment line of the nomogram Serum APAP concentration is unavailable or will not return w/in 8 hours of time of ingestion and APAP ingestion is suspected There is evidence of ANY hepatotoxicity w/a h/o APAP ingestion Patient reports or clinician suspects repeated excessive APAP ingestions, patient has RFs for APAP-induced hepatotoxicity, and the serum APAP concentration is greater than 10 mcg/mL

Question 32

Who do we treat with oral NAC?

Answer 32

Non-pregnant Intact GI tract No evidence of hepatotoxicity

Question 33

Who do we give IV NAC?

Answer 33

Pregnant Evidence of hepatotoxicity Unable to tolerate oral NAC Medical condition precluding oral administration

Question 34

What is the general presentation of fulminant liver failure?

Answer 34

Jaundice Encephalopathy leading to rapid onset of altered mental status (may progress quickly to coma) Prolonged PT Elevated aminotransferases

Question 35

What are the causes of fulminant liver failure?

Answer 35

``` Drug toxicity (APAP most common) Viral Hep (C>B) - second most common cause Other causes ```

Question 36

What are other causes of fulminant liver failure?

Answer 36

``` HSV (1&2) Budd-chiari syndrome Wilson disease Acute fatty liver of pregnancy Acute ischemic injury ("shock liver") Mushroom poisoning Toxins Reye's syndrome Automimmune hepatitis Lymphoma ```

Question 37

What is the management of fulminant liver failure?

Answer 37

Supportive! | Transport to transplant center

Question 38

What are the complications of fulminant liver failure?

Answer 38

``` Respiratory failure Cerebral edema Coagulation defects Hemodynamic instability Hepatorenal syndrome Nutrition and metabolic effects Infectious complications ```

Question 39

How do we treat respiratory failure?

Answer 39

Ventilator

Question 40

How do we treat cerebral edema?

Answer 40

Mannitol for increased ICP | Lactulose decreases ammonia levels

Question 41

How de we treat coagulation defects?

Answer 41

Vit K Fresh frozen plasma or platelets Factor VIIa

Question 42

How is nutrition and metabolism affected in FLF?

Answer 42

Electrolytes (hypo-ka/mg, phosphatemia, Na are common) Hypoglycemia Protein and calcoric maintenance

Question 43

How does FLF lead to infectious complications?

Answer 43

Impaired cell-mediated and humoral immunity