Download Paracetamol toxicity

Paracetamol toxicity
PHARMACOKINETICS
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PARA is rapidly and completely absorbed from the gastrointestinal tract.
Peak serum concentrations are reached within four hours following overdose of immediate-release preparations,
but may be delayed beyond four hours when drugs that delay gastric emptying (eg, opiates, anticholinergic
agents) are coingested or following overdose of extended releases preparations
Elimination half-lives range from two to four hours for all PARA preparations, but the Half-lives greater than four
hours have been noted in patients with hepatotoxicity.
Biochemical toxicity
NAPQI arylates and binds covalently to the cysteine groups on hepatic macromolecules, forming NAPQI-protein
adducts. This process is irreversible and leads to oxidative injury and hepatocellular centrilobular necrosis. Cytokine
release from hepatocytes may initiate a secondary inflammatory response from Kupffer cells and other inflammatory
cells, extending the zone of hepatic injury. This secondary injury occurs during stage II of clinical toxicity.
CLINICAL FACTORS INFLUENCING TOXICITY
 Acute alcohol ingestion is NOT a risk factor for hepatotoxicity and may even be protective by competing with
PARA for CYP2E1 and, thereby, decreasing the amount of NAPQI produced.
 Chronic alcohol ingestion increases CYP2E1 activity two-fold and depletes glutathione level. The chronic alcoholic
is more often malnourished, more likely to have a period of recent fasting, and more likely to have depleted
hepatic glutathione stores than the nonalcoholic, all of which predispose to hepatic injury.
 Single overdose — Chronic alcoholics do NOT appear to be at increased risk compared with non-alcoholics for
developing hepatotoxicity following a SINGLE overdose of PARA and management need not be altered for this
patient group.
 Multiple overdoses — In contrast to chronic alcoholics with an isolated ingestion, chronic alcoholics appear to be
at increased risk for hepatotoxicity following ingestion of multiple supratherapeutic doses of PARA.
 Chronic liver disease who do not regularly ingest alcohol do NOT appear to be at increased risk for PARAinduced hepatic injury. Although the PARA elimination half-life in this patient population may be prolonged,
accumulation of the drug does not occur with repeated administration. More importantly, cytochrome P450
enzyme activity is low and cannot be induced in this patient population, which confers hepatoprotection following
overdose [67].
 Medications — inducors of CYP2E1 enzymes can cause hepatotoxicity in the absence of overt PARA overdose,
and may worsen the outcome of an intentional overdose. Examples - anticonvulsants (eg, carbamazepine,
phenobarbital, and phenytoin) and antituberculosis drugs (eg, isoniazid and rifampin). Drugs such as
trimethoprim-sulfamethoxazole and zidovudine may potentiate PARA hepatotoxicity by competing for
glucuronidation pathways, resulting in increased CYP2E1-dependent metabolism of PARA.
 Malnutrition and a period of fasting may predispose to PARA hepatotoxicity due to reduced hepatic
glucuronidation and depleted glutahione stores. Patients at greatest risk appear to be those that consume
repeated excessive doses, not a single overdose.
 Genetics — Polymorphisms exist in the cytochrome isoenzymes that contribute to diminished or excessive
oxidative metabolism of PARA The clinical relevance of these polymorphisms is unknown. Impaired
glucuronidation secondary to Gilbert's syndrome appears to enhance toxicity.
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Age — Older patients appear more likely to develop hepatotoxicity following acute overdose whereas children
less than five years old appear less susceptible to toxicity
Tobacco — Tobacco smoke contains CYP1A2 inducers and increases oxidative metabolism [85,86]. One review
found tobacco use to be an independent risk factor for mortality following PARA overdose independent of the
amount of tobacco consumed [87]. Mortality was greatest in smokers who also drink alcohol.
Pattern of use — Patients who accidentally poison themselves with repeated excessive doses in an attempt to
relieve pain or treat fever are more likely to have established risk factors for hepatotoxicity (eg, fasting, chronic
ethanol use) and are more likely to present late, when the toxic effects of PARA are already established.
Kings colledge criteria
In acetaminophen-induced ALF, there are two broad criteria for referral for orthotopic liver transplantation: an arterial
pH of less than 7.3, irrespective of grade of encephalopathy; or a prothrombin time (PT) greater than 100 seconds and
a serum creatinine concentration greater than 3.4 mg/dL (301 µmol/L) in patients who have grade III or IV
encephalopathy.