APAP Toxicity and Fulminant Liver failure Flashcards
What is the pediatric dose for APAP?
10-15 mg/kg/dose q4-6h (max 90 mg/kg/d)
What is the adult dosing for APAP?
325-1,000 mg q4-6h (max 4,000 mg daily)
What is the time to Cpeak for a normal therapeutic dose of APAP?
0.5-2 hours
What is the time to Cpeak for an IR APAP product?
4 hours
What is the time to Cpeak for an ER APAP product?
> 4 hours
What is the half-life for APAP?
2-4 hours
What is the therapeutic serum concentration for APAP?
10-20 mcg/ml
How is APAP metabolized?
90% is metabolized to sulfate and glucuronide conjugates
5% is excreted in the urine unchanged
5% metabolized by 2E1 to NAPQI (hepatotoxic)
What is the mechanism of APAP toxicity?
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
How many stages of APAP toxicity are there?
4
What is stage I APAP toxicity?
First 24 hours
N/V, diaphoresis, pallor, lethargy, malaise; some pts asymptomatic
Labs typically normal
What is stage II APAP toxicity?
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
What is stage III APAP toxicity
72-96 hours
LFTs peak
Stage I sx reappear w/jaundice, hepatic encephalopathy, and potential bleeding
Continued/worsening renal function
What is stage IV APAP toxicity?
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)
What is the dosing for an acute APAP OD?
>/= 7.5 g in adolescents/adult >/= 150 mg/kg in children
What is the dosing for chronic APAP overdose?
> 4 g/d in adults
> 75-90 mg/kg/d in children
What are the RFs for hepatotoxicity from APAP OD?
Increased activity of CYP450
Depleted hepatic glutathione stores
Decreased capacity for glucuronidation
What can cause increased activity of CYP450?
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)
What can cause depleted glutathione stores?
Fasting
Chronic alcohol use
What can cause decreased capacity for glucuronidation?
Bactrim
Zidovudine
What is the treatment for chronic APAP OD?
Acetylcysteine
What is acetylcysteine’s MOA?
Restoring
What are acetylcysteine medications?
Oral: Mucomyst
IV: Acetdate
How is mucomyst administered?
Dilute doses to a 5% concentrations with juice or water to improve palatability
Also cover the cup and drink through straw
Which patient’s are acetadote reserved for?
Refractory vomiting
Intolerability to oral administration
GI bleed or obstruction
Encephalopathy
What is the IV duration of NAC?
21
What are the ADRs of IV NAC?
Anaphylactoid reactions
Acute flushing and erythema in the first hour of the infusion that typically resolves spontaneously
What is the oral NAC duration?
72 hours
What do we give with oral NAC?
Oral causes N/V
Antiemetics: metoclopramide, zofran, droperidol
When do we give activated charcoal to patients?
50g to all adult pts presenting w/in 4 hours of ingestion, unless CI
May be useful beyond 4 hours
When do we treat with NAC?
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
Who do we treat with oral NAC?
Non-pregnant
Intact GI tract
No evidence of hepatotoxicity
Who do we give IV NAC?
Pregnant
Evidence of hepatotoxicity
Unable to tolerate oral NAC
Medical condition precluding oral administration
What is the general presentation of fulminant liver failure?
Jaundice
Encephalopathy leading to rapid onset of altered mental status (may progress quickly to coma)
Prolonged PT
Elevated aminotransferases
What are the causes of fulminant liver failure?
Drug toxicity (APAP most common) Viral Hep (C>B) - second most common cause Other causes
What are other causes of fulminant liver failure?
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
LymphomaWhat is the management of fulminant liver failure?
Supportive!
Transport to transplant center
What are the complications of fulminant liver failure?
Respiratory failure Cerebral edema Coagulation defects Hemodynamic instability Hepatorenal syndrome Nutrition and metabolic effects Infectious complications
How do we treat respiratory failure?
Ventilator
How do we treat cerebral edema?
Mannitol for increased ICP
Lactulose decreases ammonia levels
How de we treat coagulation defects?
Vit K
Fresh frozen plasma or platelets
Factor VIIa
How is nutrition and metabolism affected in FLF?
Electrolytes (hypo-ka/mg, phosphatemia, Na are common)
Hypoglycemia
Protein and calcoric maintenance
How does FLF lead to infectious complications?
Impaired cell-mediated and humoral immunity
