NAPQI

NAPQI

Systematic (IUPAC) name
N-(4-Oxo-1-cyclohexa-2,5-dienylidene)acetamide
Clinical data
Pregnancy cat.	?
Legal status	?
Identifiers
CAS number	50700-49-7 Y
ATC code	?
PubChem	CID 39763
ChemSpider	36356 Y
UNII	G6S9BN13TI N
ChEBI	CHEBI:29132 N
ChEMBL	CHEMBL33232 Y
Chemical data
Formula	C8H7NO2
Mol. mass	149.147 g/mol
SMILES	eMolecules & PubChem
InChI InChI=1S/C8H7NO2/c1-6(10)9-7-2-4-8(11)5-3-7/h2-5H,1H3 Y Key:URNSECGXFRDEDC-UHFFFAOYSA-N Y
N(what is this?)  (verify)

NAPQI (N-acetyl-p-benzoquinone imine) is a toxic byproduct produced during the xenobiotic metabolism of the analgesic paracetamol (acetaminophen). It is normally produced only in small amounts, and then almost immediately detoxified in the liver.

However, under some conditions in which NAPQI is not effectively detoxified (usually in case of paracetamol overdose), it causes severe damage to the liver. This becomes apparent after 3–4 days after ingestion and may result in death from fulminant liver failure several days after the overdose.

General information

The names 'acetaminophen' and 'paracetamol' are both correct. 'Acetaminophen' (USAN) is used primarily in the U.S. and 'paracetamol' (INN) is used in the UK and elsewhere, but they both describe the same chemical compound. It may also be abbreviated APAP, especially in the medical profession. There are also numerous brand names associated with the drug; some of the more common ones are Tylenol and Panadol. In this article, 'paracetamol' will be used to describe the compound.

Paracetamol has been sold as an over-the-counter, non-aspirin analgesic since the mid-1950s. It is often given to children, as it has not been associated with Reye's syndrome, as aspirin has.

Metabolism

The reactions involved in paracetamol metabolism.

The primary metabolic pathway for paracetamol is glucuronidation. This yields a relatively non-toxic metabolite, which is excreted into bile and passed out of the body. A small amount of the drug is metabolized via the cytochrome P-450 pathway (to be specific, CYP1A2 and CYP2E1) into NAPQI, which is extremely toxic to liver tissue, as well as being a strong biochemical oxidizer.

In a normal person, the majority of the paracetamol is metabolized by glucuronidation, and the small amount (approximately 10% of paracetamol dose) of NAPQI that is produced is immediately inactivated by conjugation with glutathione. This differs among special populations.^{[citation needed]}

Chronic alcoholics may not have enough glutathione to inactivate all of the NAPQI produced, and other populations may create more NAPQI than normal due to differences in P-450 enzyme activity. The primary concern, however, is ingestion of large amounts of paracetamol due to accidental or intentional overdose. Since the drug is available over the counter almost everywhere in the world, it is a common choice for suicide attempts, especially among those unfamiliar with the manner of death it causes.

A toxic dose of paracetamol usually varies between 4 g in special populations and 6 g in the average person. The lethal dose is usually between 10 g and 15 g, however concurrent alcohol intake will lower that figure significantly. When a toxic dose is ingested, the sheer quantity of the drug saturates the normal glucuronide pathway, causing large amounts of NAPQI to be produced. Some of this is conjugated with glutathione, but eventually the glutathione reserves in the liver are depleted. This leaves only NAPQI, which in these large quantities kills liver cells very effectively.

Toxicity

The prognosis is good for paracetamol overdoses if treatment is initiated up to 8 hours after the drug has been taken. Most hospitals stock the antidote (acetylcysteine), which replenishes the liver's supply of glutathione, allowing the NAPQI to be metabolized safely. However, what often happens is that suicidal individuals, recognizing they are still alive hours later, assume that the suicide attempt was a failure and give it little thought. After the initial overdose, there may be a period where they feel relatively normal, but have no knowledge that their liver is in the process of being destroyed. Symptoms of liver failure typically appear 16–36 hours after the initial overdose, and, by this time, nothing short of a liver transplant can be done to save their life. Without early administration of the antidote, fulminant liver failure follows, often in combination with kidney failure, and death generally occurs within several days.

Antidote

The preferred antidote for NAPQI poisoning (usually secondary to paracetamol poisoning) is acetylcysteine. It can be given in large amounts without side-effects. The amino acid methionine can also be used effectively as an antidote for NAPQI toxicity. These antidotes must be given within hours of the initial overdose to be useful. The antidote should be given as soon as possible, up to 8 hours post-ingestion. The sooner the antidote is administered the better the prognosis. If given within two hours of overdose, the prognosis is excellent.

See also

• paracetamol poisoning
• paracetamol
• glucuronidation
• cytochrome P450 oxidase
• glutathione
• acetylcysteine
• methionine
• liver failure
• Metabolism

External links

• Alsalim W, Fadel M (July 2003). "Towards evidence based emergency medicine: best BETs from the Manchester Royal Infirmary. Oral methionine compared with intravenous N-acetyl cysteine for paracetamol overdose". Emerg Med J 20 (4): 366–7. doi:10.1136/emj.20.4.366. PMC 1726135. PMID 12835357. http://emj.bmj.com/content/20/4/366.full. 
• van de Straat R, de Vries J, Debets AJ, Vermeulen NP (July 1987). "The mechanism of prevention of paracetamol-induced hepatotoxicity by 3,5-dialkyl substitution. The roles of glutathione depletion and oxidative stress". Biochem. Pharmacol. 36 (13): 2065–70. doi:10.1016/0006-2952(87)90132-8. PMID 3606627. 
• Cytochrome P-450 Inducers, Inhibitors, and Substrates