COMMON TOXICANTS IN THE PHILIPPINES

PARACETAM
OL
TOXICITY
PHARMACY II - A
LEYLU D. REPATO INSTRUCTOR:
CLARK A. MENDOZA IAN KENNETH B. LAROCO RPh, MPH
JAYA LYN A. LUMAYNA
PARACETAMOL TOXICITY

NATURE OF
TOXICANT
MECHANISM OF 01
CLINICAL 02
TOXICITY AND ITS
TOPIC EFFECTS
OUTLINE TOXICITY 03
MANIFESTATION OF

TREATMENT
MODALITIES04
PARACETAMOL TOXICITY NATURE OF
TOXICANT
Name: Acetaminophen, N-acetyl-para-
aminophenol (APAP)

Began used as prescription drug (1947)

and became an OTC drugs (1960)

Most common used analgesic-antiypertic

PARACETAMOL

It has a weak anti-inflammatory effect.

Indication: relief of fever (antipyretic),

headaches (analgesics), and other minor
aches and pains.
PARACETAMOL TOXICITY NATURE OF
TOXICANT
MAXIMUM DAILY
DOSE
Children: Daily dose is 75mg/kg
Adults: Daily dose is 650 mg every 6 hours, as needed

PARACETAMOL
TOXIC DOSE
Adults: 7.5 – 10 g for adults
Children: 150 mg/kg
Healthy children aged 1-6 years threshold may be
increased to 200 mg/kg
 PARACETAMOL
TOXICITY

MISUSE AND MOST SERIOUS

OVERDOSE AND FATAL
CASES FOR
ADULTS

END ORGAN TOXICITY:

DELAYED 24-48 HOURS 56, 000 ER VISITS, 2,600
AFTER AN ACUTE HOSPITALIZATIONS,
INGESTION 500 DEATHS PER YEAR
(USA)

GASTROENTERITIS HEPATOTOXICITY IN 1
WITHIN HOURS TO 3 DAYS
 01
CONJUGATI
ON
Metabolism of 45-55 %
acetaminophen into
glucuronide(non-toxic
02
moiety)
CONJUGATI
ON
Metabolism of 35-45%
acetaminophen into
sulfate(non-toxic moiety)

03
Renal excretion of
5% acetaminophen
PATHWAY OF
PARACETAMOL
04
METABOLISM
CYP450
Metabolism of 5-10%
05 acetaminophen into NAPQI(N-
GLUTATHIONE VIA acetyl-p-benzoquinone imine
CONJUGATIOJN
Conversion of NAPQI into
cysteine and mercapturic
acid(non-toxic moiety)
MECHANISM OF TOXICITY TOXIC PATHWAY
Increase amount of acetaminophen also
01 means increase amount of NAPQI which
will become saturated
Saturated NAPQI could lead to depletion
02 of glutathione which may cause liver
necrosis/cell death
Sulfation and Glucuronidation pathways
03 will become saturated and can be further
induced by malnourished patient which
will now cause paracetamol-induced
liver injury.
CYP450 can be induced by the
04 following causes:
● Chronic alcohol ingestion
● Drugs
● Tobacco

Glutathione depletion can be induced

05 with alcoholism and may lead to liver
failure
 CLINICAL MANIFESTATION OF
TOXICITY

PHASE 1 PHASE 2 PHASE 3 PHASE 4

HEPATIC PHASE RECOVERY PHASE
24 HRS AFTER INGESTION 18-72 HRS AFTER 72-96 HRS AFTER 4 D TO 3 W AFTER
INGESTION INGESTION INGESTION

•NAUSEA AND VOMITING,

ANOREXIA, NAUSEA OR •RIGHT UPPER QUADRANT • SYMPTOMS AND
ABDOMINAL
VOMITING, AND ABDOMINAL PAIN, COMPLETE RESOLUTION OF
PAIN, AND A TENDER HEPATIC
MALAISE ANOREXIA, NAUSEA, AND ORGAN FAILURE
EDGE
VOMITING •HEPATIC NECROSIS AND
•RIGHT UPPER QUADRANT DYSFUNCTION ARE •IF THE TIME OF ACUTE
TENDERNESS MAY BE ASSOCIATED WITH JAUNDICE, INGESTION IS KNOWN, THE
PRESENT COAGULOPATHY, RUMACK-MATTHEW
PALLOR, DIAPHORESIS, • TACHYCARDIA AND HYPOGLYCEMIA, AND NOMOGRAM IS USED TO
HYPOTENSION INDICATE HEPATIC ENCEPHALOPATHY. ESTIMATE LIKELIHOOD OF
MALAISE, AND • DEATH FROM MULTIPLE HEPATOTOXICITY.
ONGOING VOLUME LOSSES
FATIGUE •OLIGURIA ORGAN FAILURE MAY OCCUR.
TREATMENT
MODALITIES
RECENT DRUG
HISTORY
SERUM
ACETAMINOPHEN
LEVELS
Drawn after 4 hours of ingestion
Note the amount of drug taken, the dosage form
ingested, the amount of time that has elapsed since the
last ingested dose, and if any other drugs
TREATMENT
MODALITIES
N-Acetylcysteine (NAC)
Mainstay for treatment for acetaminophen toxicity

• Nearly 100% hepatoprotective

• Given within 8 hours after an acute ingestion, may be beneficial up

to 48 hours of ingestion

• The Rumack-Matthew nomogram is used to interpret the

acetaminophen level
TREATMENT
MODALITIES
Rumack-Matthew Nomogram
● Used when time of ingestion is known

● Used to interpret plasma acetaminophen values to assess

hepatotoxicity risk after a single, acute ingestion

● Nomogram tracking begins 4 hours after and ends 24

hours after ingestion
TREATMENT
MODALITIES

Rumack-Matthew Nomogram
TREATMENT
MODALITIES
N-acetylcysteine (NAC)
Approved for both oral and IV administration

DOSING REGIMEN
Oral:
• Loading dose of 140 mg/kg
• 17 doses of 70 mg/kg given every four hours
• Total treatment duration of 72 hours
TREATMENT MODALITIES
DOSING REGIMEN

N-acetylcysteine (NAC)
The IV formulation of NAC (Acetadote) is commonly used in many
institutions for the treatment of acetaminophen ingestion.

Use of the IV formulation of NAC is preferred in the following situations:

• Altered mental status
• GI bleeding and/or obstruction
• A history of caustic ingestion
• Potential fetal acetaminophen toxicity in a pregnant woman
• Inability to tolerate oral NAC because of emesis refractory to proper
use of antiemetics
TREATMENT MODALITIES
DOSING REGIMEN
N-acetylcysteine (NAC)
FOR IV FORMULATION OF NAC:
• Loading dose: 150 mg/kg IV; mix in 200 mL of 5% dextrose in water (D5W) and infuse over 1 h
• Dose 2: 50 mg/kg IV in 500 mL D5W over 4 h
• Dose 3: 100 mg/kg IV in 1000 mL D5W over 16 h
In patients who weigh more than 100 kg
•limited data suggest a loading dose of 15,000 mg infused IV over 1 hours, then a first maintenance
dose of 5,000 mg IV over 4 hours and a second maintenance dose of 10,000 mg over 16 hours.
INTERMITTENT IV INFUSION MAY BE CONSIDERED FOR LATE-PRESENTING OR
CHRONIC INGESTION.
• A loading dose of 140 mg/kg IV (diluted in 500 mL D5W) is infused over 1 h.
•Maintenance doses of 70 mg/kg IV are given every 4 hours for at least 12 doses (dilute each dose in
250 mL of D5W and infuse over a minimum of 1 hour).
TREATMENT
MODALITIES
Activated Charcoal
● only GI decontamination

● patient is mentally alert with an intact airway. o

Large ingestion presenting ideally, within 1 hour post
ingestion

● Avoided in those with an increased risk of aspiration,

uncontrolled vomiting, or coingestion of a corrosive or
proconvulsant.
TREATMENT
MODALITIES
Liver Transplantation
Criteria for liver transplantation include the following:

● Metabolic acidosis, persistent after fluid resuscitation

● Renal failure
● Coagulopathy
● Encephalopathy
TREATMENT
MODALITIES
Chronic Acetaminophen
Poisoining
•Repeated Supratherapeutic Ingestion (RSTI)

•Evaluate the patients for the presence of persistent

acetaminophen serum concentration and laboratory indicators
of hepatotoxicity

•N-Acetylcysteine for 12 hours

PHARMACIST
ROLE
REFERENCES:
● https://emedicine.medscape.com/article/820200-overview
● https://www.medscape.com/answers/820200-27207/what-are-the-recommended-maximum-daily-dosages-of-
acetaminophen-in-adults-and-children
● https://www.mdlinx.com/article/common-otc-drugs-that-carry-serious-health-risks/
5G2nI0LWR2MlQ4W2j6BS0b
● https://www.msdmanuals.com/professional/injuries-poisoning/poisoning/acetaminophen-poisoning
● https://www.uspharmacist.com/article/acetaminophen-toxicity-what-pharmacists-need-to-know#: y
● https://www.tylenolprofessional.com/sites/tylenol_hcp_us/files/acetaminphen_overdose_treatment_info.pdf
● https://www.acep.org/tox/case-files/01_APAP%20Repeated%20Supratherapeutic%20Ingestion.pdf
● https://www.rch.org.au/clinicalguide/guideline_index/Paracetamol_poisoning/
● https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4498995/
METHODS

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LEYLU D. REPAO