NAPQI
Encyclopedia
NAPQI 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.
' 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.
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.
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.
liver failure
follows, often in combination with kidney failure, and death generally occurs within several days.
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.
Xenobiotic metabolism
Xenobiotic metabolism is the set of metabolic pathways that modify the chemical structure of xenobiotics, which are compounds foreign to an organism's normal biochemistry, such as drugs and poisons...
of the analgesic
Analgesic
An analgesic is any member of the group of drugs used to relieve pain . The word analgesic derives from Greek an- and algos ....
paracetamol
Paracetamol
Paracetamol INN , or acetaminophen USAN , is a widely used over-the-counter analgesic and antipyretic . It is commonly used for the relief of headaches and other minor aches and pains and is a major ingredient in numerous cold and flu remedies...
(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
Fulminant
Fulminant is any event or process that occurs suddenly and quickly, and is intense and severe to the point of lethality, i.e., it has an explosive character. The word comes from Latin fulmināre, to strike with lightning...
liver failure
Liver failure
Acute liver failure is the appearance of severe complications rapidly after the first signs of liver disease , and indicates that the liver has sustained severe damage . The complications are hepatic encephalopathy and impaired protein synthesis...
several days after the overdose.
General information
The names 'acetaminophen' and 'paracetamolParacetamol
Paracetamol INN , or acetaminophen USAN , is a widely used over-the-counter analgesic and antipyretic . It is commonly used for the relief of headaches and other minor aches and pains and is a major ingredient in numerous cold and flu remedies...
' are both correct. 'Acetaminophen' (USAN
United States Adopted Name
United States Adopted Names are unique nonproprietary names assigned to pharmaceuticals marketed in the United States. Each name is assigned by the USAN Council, which is co-sponsored by the American Medical Association , the United States Pharmacopeial Convention , and the American Pharmacists...
) is used primarily in the U.S. and 'paracetamol' (INN
International Nonproprietary Name
An International Nonproprietary Name is the official nonproprietary or generic name given to a pharmaceutical substance, as designated by the World Health Organization...
) 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
Tylenol
Tylenol is a North American brand of drugs advertised for reducing pain, reducing fever, and relieving the symptoms of allergies, cold, cough, and flu. The active ingredient of its original, flagship product, paracetamol , is marketed as an analgesic and antipyretic...
and Panadol
Panadol
Panadol is the GlaxoSmithKline trade name for paracetamol or acetaminophen , which is an over the counter pharmaceutical analgesic and antipyretic ....
. In this article, 'paracetamol' will be used to describe the compound.
Paracetamol has been sold as an over-the-counter
Over-the-counter drug
Over-the-counter drugs are medicines that may be sold directly to a consumer without a prescription from a healthcare professional, as compared to prescription drugs, which may be sold only to consumers possessing a valid prescription...
, non-aspirin analgesic
Analgesic
An analgesic is any member of the group of drugs used to relieve pain . The word analgesic derives from Greek an- and algos ....
since the mid-1950s. It is often given to children, as it has not been associated with Reye's syndrome
Reye's syndrome
Reye's syndrome is a potentially fatal disease that causes numerous detrimental effects to many organs, especially the brain and liver, as well as causing a lower than usual level of blood sugar . The classic features are liver damage, aspirin use and a viral infection...
, as aspirin has.
Metabolism
Glucuronidation
Glucuronidation is the addition of glucuronic acid to a substrate. Glucuronidation is often involved in xenobiotic metabolism of substances such as drugs, pollutants, bilirubin, androgens, estrogens, mineralocorticoids, glucocorticoids, fatty acid derivatives, retinoids, and bile acids...
. 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.
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, fulminantFulminant
Fulminant is any event or process that occurs suddenly and quickly, and is intense and severe to the point of lethality, i.e., it has an explosive character. The word comes from Latin fulmināre, to strike with lightning...
liver failure
Liver failure
Acute liver failure is the appearance of severe complications rapidly after the first signs of liver disease , and indicates that the liver has sustained severe damage . The complications are hepatic encephalopathy and impaired protein synthesis...
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 methionineMethionine
Methionine is an α-amino acid with the chemical formula HO2CCHCH2CH2SCH3. This essential amino acid is classified as nonpolar. This amino-acid is coded by the codon AUG, also known as the initiation codon, since it indicates mRNA's coding region where translation into protein...
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
- paracetamolParacetamolParacetamol INN , or acetaminophen USAN , is a widely used over-the-counter analgesic and antipyretic . It is commonly used for the relief of headaches and other minor aches and pains and is a major ingredient in numerous cold and flu remedies...
- glucuronidationGlucuronidationGlucuronidation is the addition of glucuronic acid to a substrate. Glucuronidation is often involved in xenobiotic metabolism of substances such as drugs, pollutants, bilirubin, androgens, estrogens, mineralocorticoids, glucocorticoids, fatty acid derivatives, retinoids, and bile acids...
- cytochrome P450 oxidaseCytochrome P450 oxidaseThe cytochrome P450 superfamily is a large and diverse group of enzymes. The function of most CYP enzymes is to catalyze the oxidation of organic substances. The substrates of CYP enzymes include metabolic intermediates such as lipids and steroidal hormones, as well as xenobiotic substances...
- glutathioneGlutathioneGlutathione is a tripeptide that contains an unusual peptide linkage between the amine group of cysteine and the carboxyl group of the glutamate side-chain...
- acetylcysteine
- methionineMethionineMethionine is an α-amino acid with the chemical formula HO2CCHCH2CH2SCH3. This essential amino acid is classified as nonpolar. This amino-acid is coded by the codon AUG, also known as the initiation codon, since it indicates mRNA's coding region where translation into protein...
- liver failureLiver failureAcute liver failure is the appearance of severe complications rapidly after the first signs of liver disease , and indicates that the liver has sustained severe damage . The complications are hepatic encephalopathy and impaired protein synthesis...
- MetabolismMetabolismMetabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...