Paracetamol combination

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PARACETAMOL, active ingredient

PARACETAMOL - Latin name of the active substance PARACETAMOL

ATX codes for PARACETAMOL

N02BB72 (Metamizole sodium in combination with psycholeptics)

N02BA51 (Acetylsalicylic acid in combination with other drugs (excluding psycholeptics))

Table of contents:

N02BE51 (Paracetamol in combination with other drugs (excluding psycholeptics))

R05X (Other combination drugs used for colds)

R03DA54 (Theophylline in combination with other drugs (excluding psycholeptics))

N02AX52 (Tramadol in combination with other drugs)

R01BA53 (Phenylephrine in combination with other drugs)

M01AE51 (Ibuprofen in combination with other drugs)

N02BE71 (Paracetamol in combination with psycholeptics)

R01BA52 (Pseudoephedrine in combination with other drugs)

J05AX (Other antivirals)

M01AB55 (Diclofenac in combination with other drugs)

Analogs of the drug PARACETAMOL according to ATC codes:

Before using PARACETAMOL you should consult your doctor. These instructions for use are for informational purposes only. For more complete information, please refer to the manufacturer's instructions.

PARACETAMOL: Clinical and pharmacological groups

23.029 (Drug used for premenstrual syndrome)

03.007 (Combined drug with analgesic effect)

12.001 (Bronchodilator)

12.046 (Drug for symptomatic treatment of acute respiratory diseases)

10.003 (Drug for etiotropic and symptomatic treatment of respiratory viral infections)

05.006 (NSAIDs in combination with an analgesic-antipyretic)

03.010 (Analgesic-antipyretic combined composition)

PARACETAMOL: Pharmacological action

Analgesic-antipyretic. It has analgesic, antipyretic and weak anti-inflammatory effects. The mechanism of action is associated with inhibition of prostaglandin synthesis, with a predominant effect on the thermoregulation center in the hypothalamus.

PARACETAMOL: Pharmacokinetics

After oral administration, paracetamol is rapidly absorbed from the gastrointestinal tract, mainly in the small intestine, mainly by passive transport. After a single dose of 500 mg, Cmax in blood plasma is reached after a minute and is about 6 μg/ml, then gradually decreases and after 6 hours it is μg/ml.

Widely distributed in tissues and mainly in body fluids, with the exception of adipose tissue and cerebrospinal fluid.

Protein binding is less than 10% and increases slightly with overdose. Sulfate and glucuronide metabolites do not bind to plasma proteins even at relatively high concentrations.

Paracetamol is metabolized primarily in the liver by conjugation with glucuronide, conjugation with sulfate and oxidation with the participation of mixed liver oxidases and cytochrome P450.

The negatively active hydroxylated metabolite N-acetyl-p-benzoquinoneimine, which is formed in very small quantities in the liver and kidneys by mixed oxidases and is usually detoxified by binding to glutathione, can escalate with paracetamol overdose and cause tissue damage.

In adults, most paracetamol is bound to glucuronic acid and, to a lesser extent, to sulfuric acid. These conjugated metabolites do not have biological activity. In premature infants, newborns and in the first year of life, the sulfate metabolite predominates.

T1/2 is 1-3 hours. In patients with liver cirrhosis, T1/2 is slightly longer. The renal clearance of paracetamol is 5%.

It is excreted in the urine mainly in the form of glucuronide and sulfate conjugates. Less than 5% is excreted as unchanged paracetamol.

PARACETAMOL: Dosage

Orally or rectally in adults and adolescents weighing more than 60 kg, use a single dose of 500 mg, frequency of administration - up to 4 times a day. The maximum duration of treatment is 5-7 days.

Maximum doses: single - 1 g, daily - 4 g.

Single oral doses for children aged 6-12 years - mg, 1-5 years - mg, from 3 months to 1 year - mg, up to 3 months - 10 mg/kg. Single doses for rectal use in children aged 6-12 years - mg, 1-5 years - mg.

Frequency of use - 4 times a day with an interval of at least 4 hours. Maximum duration of treatment - 3 days.

Maximum dose: 4 single doses per day.

PARACETAMOL: Drug interactions

When used simultaneously with inducers of microsomal liver enzymes and drugs with hepatotoxic effects, there is a risk of increasing the hepatotoxic effect of paracetamol.

When used simultaneously with anticoagulants, a slight or moderate increase in prothrombin time is possible.

When used simultaneously with anticholinergic drugs, the absorption of paracetamol may be reduced.

When used simultaneously with oral contraceptives, the elimination of paracetamol from the body is accelerated and its analgesic effect may be reduced.

When used simultaneously with uricosuric drugs, their effectiveness decreases.

With simultaneous use of activated carbon, the bioavailability of paracetamol decreases.

When used simultaneously with diazepam, the excretion of diazepam may be reduced.

There are reports of the possibility of enhancing the myelosuppressive effect of zidovudine when used simultaneously with paracetamol. A case of severe toxic liver damage has been described.

Cases of toxic effects of paracetamol have been described when used simultaneously with isoniazid.

When used simultaneously with carbamazepine, phenytoin, phenobarbital, primidone, the effectiveness of paracetamol decreases, which is due to an increase in its metabolism (glucuronidation and oxidation processes) and excretion from the body. Cases of hepatotoxicity have been described with the simultaneous use of paracetamol and phenobarbital.

When using cholestyramine for a period of less than 1 hour after taking paracetamol, the absorption of the latter may be reduced.

When used simultaneously with lamotrigine, the excretion of lamotrigine from the body moderately increases.

When used simultaneously with metoclopramide, it is possible to increase the absorption of paracetamol and increase its concentration in the blood plasma.

When used simultaneously with probenecid, the clearance of paracetamol may be reduced; with rifampicin, sulfinpyrazone - it is possible to increase the clearance of paracetamol due to an increase in its metabolism in the liver.

When used simultaneously with ethinyl estradiol, the absorption of paracetamol from the intestine increases.

PARACETAMOL: Pregnancy and lactation

Paracetamol penetrates the placental barrier. To date, there have been no negative effects of paracetamol on the fetus in humans.

Paracetamol is excreted in breast milk: the content in milk is 0.04-0.23% of the dose taken by the mother.

If it is necessary to use paracetamol during pregnancy and lactation (breastfeeding), you should carefully weigh the expected benefits of therapy for the mother and the potential risk to the fetus or child.

Experimental studies have not established the embryotoxic, teratogenic and mutagenic effects of paracetamol.

PARACETAMOL: Side effects

From the digestive system: rarely - dyspeptic symptoms, with long-term use in high doses - hepatotoxic effect.

From the hematopoietic system: rarely - thrombocytopenia, leukopenia, pancytopenia, neutropenia, agranulocytosis.

Allergic reactions: rarely - skin rash, itching, urticaria.

PARACETAMOL: Indications

Pain syndrome of weak and moderate intensity of various origins (including headache, migraine, toothache, neuralgia, myalgia, algodismenorrhea; pain from injuries, burns). Fever in infectious and inflammatory diseases.

PARACETAMOL: Contraindications

Chronic active alcoholism, hypersensitivity to paracetamol.

PARACETAMOL: Special instructions

Use with caution in patients with impaired liver and kidney function, with benign hyperbilirubinemia, as well as in elderly patients.

With long-term use of paracetamol, monitoring of the peripheral blood picture and the functional state of the liver is necessary.

It is used to treat premenstrual tension syndrome in combination with pamabrom (a diuretic, a xanthine derivative) and mepiramine (a histamine H1 receptor blocker).

Experimental determination of drug analogues:

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ATX codes for PARACETAMOL

N02BA51 (Acetylsalicylic acid in combination with other drugs)

N02BE51 (Paracetamol in combination with other drugs)

R05X (Other combination drugs used for colds)

R03DA54 (Theophylline in combination with other drugs)

N02AX52 (Tramadol in combination with other drugs)

R01BA53 (Phenylephrine in combination with other drugs)

M01AE51 (Ibuprofen in combination with other drugs)

N02BE71 (Paracetamol in combination with psycholeptics)

R01BA52 (Pseudoephedrine in combination with other drugs)

J05AX (Other antivirals)

M01AB55 (Diclofenac in combination with other drugs)

Experimental determination of drug analogues:

  • Русский
  • METAMIZOL SODIUM Clinical and pharmacological groups 11.032 (Drug with m-anticholinergic, antacid and analgesic effects) 12.046 (Drug…
  • CAFFEINE Clinical and pharmacological groups 03.009 (Analgesic-antipyretic) 03.012 (Spasmoanalgesic) 02.011 (Anticonvulsant drug) 05.008 (Combined NSAID) 02.059 (Drug with…
  • PARACETAMOL 03.009 (Analgesic-antipyretic), Rectal suppositories for…
  • CALPOL 03.009 (Analgesic-antipyretic), Suspension for administration…
  • CAFFEINE + PARACETAMOL + CHLORPHENAMINE 12.046 (Drug for the symptomatic treatment of acute…
  • CODEINE + PARACETAMOL Clinical and pharmacological groups 03.012 (Spasmoanalgesic) 03.010 (Analgesic-antipyretic combined composition) Pharmacological…
  • PARACETAMOL-AKOS 03.009 (Analgesic-antipyretic), Syrup 2.4% in…
  • NAPROXEN Clinical and pharmacological groups 03.012 (Spasmoanalgesic) 05.008 (Combined NSAID) 03.010 (Combined analgesic-antipyretic) 05.001 (NSAID) Pharmacological…
  • CODEINE Clinical and pharmacological groups 12.034 (Drug with antitussive and expectorant effects) 03.012 (Spasmoanalgesic) 05.008 (combined NSAID…
  • CEFEKON D 03.009 (Analgesic-antipyretic), Suppositories…
  • UNISPAZ N 03.012 (Spasmoanalgesic), Tablets 1 tablet paracetamol 500…
  • GALANTAMINE Clinical and pharmacological groups 02.068 (Selective inhibitor of brain acetylcholinesterase. A drug for the treatment of disease…

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The information posted on the site is for reference purposes only and cannot be considered medical advice or replace it. For more detailed information, we recommend that you contact a specialist.

Source: http://drugfinder.ru/drugsubstance/paracetamol/

Paracetamol in combination with other drugs

The subject of this article is a group of combination drugs, the main active ingredient of which is paracetamol. The effect of drugs in this group is mainly due to the pharmacological properties of paracetamol. In the ATC classifier, these drugs are represented by codes N02BE71 (paracetamol in combination with psychotropic drugs) and N02BE51 (excluding the above combinations).

It should be taken into account that when using any paracetamol preparations together with substances that cause the induction of liver enzymes (in particular, alcohol and tricyclic antidepressants), the concentration of hydroxylated active metabolites of paracetamol increases, which significantly increases the risk of toxic liver damage, and therefore during treatment It is imperative to stop using ethanol and related drugs.

Content

According to the ATC classifier, this group includes all combination drugs containing paracetamol, with some exceptions:
  • Combinations with psycholeptics are counted in this group if their main use is as an analgesic. Otherwise, they are classified under codes reserved for psychotropic drugs. Similarly, combination drugs, the main function of which is not an analgesic effect, are recorded under the appropriate codes, for example: A03D, A03EA (antispasmodics in combination with analgesics), M02A (external agents for pain in muscles and joints), M03 (muscle relaxants), etc. P.
  • Combination medicines containing paracetamol and ibuprofen are classified under code M01AE51 (ibuprofen in combination with other medicines), even if they are intended for use as a pain reliever only.
  • Combinations with codeine containing 20 or more milligrams of codeine in one dose of the drug are classified according to group codes N02AA (codeine in combination with other drugs), if less are taken into account in this group.
  • Combinations with other opioid analgesics should be classified under the appropriate group codes N02A.
  • Preparations containing less than 50 mg of ascorbic acid in one dose are classified as single-dose paracetamol (for example, drugs such as Daleron S, Daleron S Junior, Paracetamol EXTRA for children), otherwise they are taken into account here. as a combination with paracetamol.
  • Cold remedies with small dosages of analgesics included in their composition are classified according to the appropriate codes, for example R05X (drugs for the treatment of colds), etc. Preparations with therapeutic dosages of analgesics are taken into account in this group.

As of 2012, many different drugs from this group are registered in Russia. [1]

Combinations with caffeine

This group includes combination preparations of paracetamol with caffeine (with a dosage of the latter from 40 to 65 mg), presented on the Russian market by such trademarks as “Askofen-P”, “Migrenol”, “Panadol extra”, “Paralen extra”, “ Pentalgin" and "Strimol Plus". Caffeine can also be included in more complex combinations (see the following sections) .

Drug developers assume that caffeine, being a psychoanaleptic, enhances the effect of analgesics, eliminates drowsiness and fatigue, and increases physical and mental performance. Research shows that this is in fact true, but with more than 100 mg of caffeine per tablet [2] .

However, independent experts believe that the inclusion of caffeine in painkillers does not increase their analgesic effect (possibly due to the fact that the amount of caffeine in combination products is not enough to exhibit the corresponding properties). It is also noted that no published studies have definitively established the role of caffeine as an analgesic adjuvant. In addition, long-term use of such combinations in large dosages increases their nephrotoxicity (leads to kidney disease). [3]

Combinations with codeine

Combinations of paracetamol and codeine with a dosage of the latter from 8 to 10 mg are used to relieve pain of mild and moderate severity of various origins (headache, dental and post-traumatic pain, migraine, algodismenorrhea, neuralgia (radicular syndrome, radiculitis, etc.), myalgia, arthralgia , ossalgia, sciatica, lumbodynia). It is assumed that codeine, even at subtherapeutic dosages, enhances the analgesic effect of paracetamol as a more powerful opioid analgesic. The duration of the analgesic effect is about 4-6 hours.

Also, similar combinations can be used for colds and flu, with paracetamol acting as an antipyretic and analgesic, and codeine as an antitussive (by suppressing the excitability of the cough center).

The main representatives of this group are the drug Codelmixt and its analogues with the addition of caffeine (Prohodol Forte and Solpadeine). In addition, such combinations may also include other drugs (other non-narcotic analgesics or antispasmodics): acetylsalicylic acid (Parcocet), propyphenazone (Caffetin), drotaverine (No-shpalgin, Unispaz).

It should be noted that the use of “strong” analgesics can mask the symptoms of serious diseases, which can make it difficult to establish an accurate and timely medical diagnosis, so such drugs are taken for no more than five days without consulting a doctor. Also, you should not exceed the recommended dosages, since long-term uncontrolled use of codeine-containing drugs in large doses may lead to the development of addiction (weakening of the analgesic effect) and drug dependence. During the period of use of such medications, it is necessary to refrain from driving vehicles and engaging in potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

It should be borne in mind that drugs containing aspirin (in this case, Parcocet) have a significant number of specific side effects (Reye's syndrome in children, decreased blood clotting, asthmatic reactions to salicylates, decreased excretion of uric acid, teratogenic effects, and others), which must be taken into account when using them.

According to available data, the Ministry of Health and Social Development of the Russian Federation plans to introduce mandatory prescription dispensing for all codeine-containing drugs from June 2012. [4]

Combinations with psychotropic drugs

This group of combination drugs in Russia is represented by combinations of paracetamol with phenobarbital and a number of other drugs. Thus, the trademarks “Quintalgin”, “Pentalgin-ICN”, “Pentalgin-Nova”, “Santoperalgin”, “Sedal-M” and “Sedalgin-Neo”, in addition to these two components, also contain codeine in a dosage of 7 to 10 mg, metamizole sodium and caffeine. There is also a drug on the market called Pentalgin Plus, which, in addition to paracetamol with phenobarbital, includes codeine (8 mg), propyphenazone and caffeine.

Drug developers assume that phenobarbital has additional sedative, hypnotic, antispasmodic and muscle relaxant effects.

However, independent experts note that the combination of phenobarbital with analgesics is completely unjustified due to the fact that barbiturates themselves currently have very limited medical use due to problems with addiction and possible serious, often fatal, withdrawal symptoms. [3] In addition, barbiturates, being inducers of microsomal oxidation, promote the formation of toxic paracetamol metabolites that affect liver function.

In this regard, in some countries, for example, in Turkey, combinations of analgesics with barbiturates are completely withdrawn from pharmaceutical circulation.

The use of codeine, as well as other non-narcotic analgesics, in these combinations leads to an increase in the number of corresponding side effects and restrictions on use (see section “Combinations with codeine”) . For example, metamizole, used in these drugs, is generally prohibited for use in most countries (excluding Russia) due to its dangerous properties.

Combinations with ascorbic acid

This group includes combination preparations of paracetamol with ascorbic acid (with a dosage of the latter from 150 to 600 mg), presented on the Russian market by such trademarks as “Apap S Plus”, “Paracetamol-S-Hemofarm”, “Paracetamol Extra”, “ FluZiOZ”, “Efferalgan with vitamin C”. Also, ascorbic acid can be part of more complex combinations (see the following sections) .

The developers of these drugs assume that ascorbic acid prolongs the effect of paracetamol, slowing its elimination.

At the same time, combinations of analgesics with vitamins are often viewed negatively as an irrational combination. In some countries (for example, India and Bangladesh), such drugs are prohibited. [3]

Source: http://ru-wiki.org/wiki/%D0%9F%D0%B0%D1%80%D0%B0%D1%86%D0%B5%D1%82%D0%B0%D0%BC %D0%BE%D0%BB_%D0%B2_%D0%BA%D0%BE%D0%BC%D0%B1%D0%B8%D0%BD%D0%B0%D1%86%D0%B8%D0 %B8_%D1%81_%D0%B4%D1%80%D1%83%D0%B3%D0%B8%D0%BC%D0%B8_%D0%BF%D1%80%D0%B5%D0%BF %D0%B0%D1%80%D0%B0%D1%82%D0%B0%D0%BC%D0%B8

Paracetamol

Systematic (IUPAC) name: N-(4-hydrophenyl)ethanamide

Trade names: Tylenol (USA), Panadol (Australia) and many others

Legal status: unregulated substance (Australia); allowed for free sale (Great Britain); available without a prescription (USA)

Directions for use: oral; rectal; intravenous

Protein binding: 10-25%

Metabolism: mainly in the liver

Half-life: 1-4 hours

Excretion: urinary (85-90%)

Paracetamol, also known as acetaminophen, is a drug with the chemical name N-acetyl-p-aminophenone that is widely used as an over-the-counter analgesic (pain reliever) and fever reducer. Paracetamol is the international nonproprietary name also approved in Australia and the UK, while acetaminophen is an adapted name common in the US and Japan. Paracetamol is classified as a mild analgesic. It is often used to relieve headaches and other minor pain and is the main ingredient in various cold and flu medications. In combination with opioid analgesics, paracetamol can also be used to relieve more severe pain, such as post-operative pain, and to alleviate pain in cancer patients. Although paracetamol is used to treat inflammatory pain, it is not always classified as an NSAID (non-steroidal anti-inflammatory drug) because paracetamol exhibits only weak anti-inflammatory activity. Paracetamol is safe to use at recommended doses, but even a small overdose of the drug can be fatal. Compared to other over-the-counter pain relievers, paracetamol is significantly more toxic in overdose, but may be less toxic when used chronically at recommended doses. Paracetamol is an active metabolite of phenacetin and acetanilide (formerly popular analgesics and antipyretics). However, unlike phenacetin, acetanilide and their combinations, paracetamol is not considered a carcinogen when taken in therapeutic doses. The words acetaminophen (used in the USA, Canada, Japan) and paracetamol (used everywhere) come from the chemical name of the compound - para-acetylaminophenol. In some cases, for example, when prescribing painkillers that contain this drug, it is abbreviated as APAF (acetyl-para-aminophenol). The drug is on the list of essential drugs of the World Health Organization.

Medical uses of paracetamol

Paracetamol and high fever

Paracetamol is a medicine approved as an antipyretic for people of all ages. The World Health Organization (WHO) recommends using paracetamol in children only for temperatures above 38.5°C (101.3°F). A meta-analysis shows that the drug is less effective than Ibuprofen.

Paracetamol and pain

Paracetamol is used to relieve pain of various origins. Its analgesic characteristics are similar to aspirin, but its anti-inflammatory effect is weaker. Compared with aspirin, paracetamol is better tolerated in patients at risk of excessive gastric acid secretion or prolonged bleeding time. Since 1959, the drug has been available without a prescription. Paracetamol has relatively weak anti-inflammatory activity, unlike other popular analgesics such as the NSAIDs aspirin and ibuprofen, but ibuprofen and paracetamol have similar effects in the treatment of headaches. Paracetamol can reduce arthritis pain, but does not affect inflammation, redness and swelling. Research shows that compared to NSAIDs, paracetamol shows conflicting results. A randomized controlled trial in adult patients experiencing chronic osteoarthritis pain found that paracetamol and ibuprofen were equally effective. In 1996 and 2009, studies were conducted on the effectiveness of drugs combining paracetamol and weak opioids such as codeine. Such drugs are 50% more effective than paracetamol alone, but have more side effects. Combining paracetamol and strong opioids such as morphine helps reduce the amount of opioid in the drug and increase the analgesic effect. A randomized controlled trial of children with musculoskeletal pain found that, at standard doses, ibuprofen was more effective in reducing pain than paracetamol.

Side effects of paracetamol

When taken in recommended doses and for a limited time, the side effects of paracetamol are usually silent or very mild.

Paracetamol and liver damage

Acute paracetamol overdose can cause potentially fatal liver damage. According to the US FDA, "Acetaminophen may cause serious liver damage when taken in doses higher than recommended." In 2011, the FDA required manufacturers to update labels on all products containing acetaminophen and warn users of the potential risks of serious liver damage. In addition, a public education program has begun in the United States to prevent overdose in patients. With chronic alcoholism, the risk of overdose increases. Paracetamol poisoning is a leading cause of liver injury in the Western world and is also a leading cause of drug poisoning in the United States, United Kingdom, Australia and New Zealand. According to the FDA, in the 1990s in the United States, “there were 458 emergency department visits, hospitalizations, and deaths per year associated with acetaminophen overdose. Unintentional acetaminophen overdose is associated with 25% of emergency department visits, 10% of hospitalizations, and 25% of deaths.” Paracetamol is metabolized in the liver and is a hepatotoxic substance; When taken in combination with alcohol, side effects increase and often occur in chronic alcoholics or patients with liver damage. Some studies show that chronic use of high doses of paracetamol increases the risk of upper gastrointestinal complications such as gastric bleeding. In rare cases, kidney damage has occurred, especially with overdose. The FDA does not recommend that physicians prescribe paracetamol in doses higher than 325 mg in combination with narcotic drugs due to the risks of hepatotoxicity outweighing the therapeutic benefits.

Skin reactions

On August 2, 2013, the US FDA issued a new warning for paracetamol, indicating that the drug may cause rare, and possibly fatal, skin reactions such as Steven-Johnson syndrome and toxic epidermal necrolysis. The FDA has required manufacturers to place information about possible skin reactions of drugs on their product labels.

Asthma

There is an association between the use of paracetamol and the development of asthma, but evidence from controlled studies suggests that this association may be influenced by other factors. As of 2014, the American Academy of Pediatrics and the National Institute of Health and Clinical Excellence continue to recommend acetaminophen for the management of pain and discomfort in children, however, some experts recommend avoiding the use of acetaminophen in children with or at risk of asthma.

Other factors

Unlike aspirin, paracetamol is not an antithrombotic agent, so it can be used in patients experiencing complications associated with blood clotting. In addition, the drug does not cause stomach problems. However, unlike aspirin, paracetamol does not help reduce inflammation. Compared to ibuprofen (whose side effects can include diarrhea, vomiting and abdominal pain), paracetamol does not have as much negative impact on the gastrointestinal tract. Unlike aspirin, paracetamol is considered generally safe for children because it does not pose a risk of Reye's syndrome in children with viral illnesses. When taken recreationally with opioids, paracetamol may cause hearing loss.

Paracetamol overdose

Paracetamol overdose if left untreated is associated with long-term, painful illness. Signs and symptoms of paracetamol overdose may not initially appear or may be nonspecific. Initial symptoms of overdose usually develop several hours after ingestion and include nausea, vomiting, sweating, and pain as acute renal toxicity begins to develop. Despite popular belief, paracetamol overdose is not associated with falling asleep or losing consciousness. In case of a fatal overdose of paracetamol, the dying process can take 3-5 days. By far the most common cause of acute liver toxicity in the United States and United Kingdom is acetaminophen hepatotoxicity. Paracetamol overdose is involved in the majority of calls to poison control centers in the United States. The toxicity of paracetamol is likely mediated by its quinone metabolite. If left untreated, an overdose can lead to liver failure and death within a few days. Treatment in this case is aimed at removing paracetamol from the body. Activated charcoal may be used to reduce the absorption of paracetamol if treatment is started immediately after an overdose. To help the body repair itself and prevent or reduce the risk of liver damage, the antidote acetylcysteine ​​(also called N-acetylcysteine ​​or NAC) may be used. For severe liver damage, liver transplants are often used. Acetylcysteine ​​is also useful in neutralizing the imidoquinone metabolite of paracetamol. Another possible side effect of paracetamol is kidney failure. Until 2004, tablets were available (under the trade name Paradot in the UK) that combined paracetamol with an antidote (methionine) to protect the liver in case of overdose. In June 2009, the FDA issued a recommendation for additional restrictions on the use of paracetamol in the United States in an effort to reduce the risk of possible toxic effects. The FDA insisted on reducing the maximum dose of the drug from 1000 mg to 650 mg and banning combinations of paracetamol and narcotic analgesics. FDA committee members were particularly concerned about the fact that the reported maximum doses of acetaminophen cause changes in liver function. In January 2011, the FDA asked manufacturers of drugs containing paracetamol to limit the amount of paracetamol to a maximum of 325 mg per tablet or capsule and required manufacturers to update labels on all products containing paracetamol and warn users of the possible risk of dangerous liver damage. Manufacturers were given 3 years to limit the amount of paracetamol in prescription drugs to 325 mg per dose. In November 2011, the Medicines Regulatory Agency revised dosing guidance for liquid paracetamol for children in the UK.

Paracetamol and pregnancy

Data from animal experiments and cohort studies in humans have shown no significant increase in the risk of congenital diseases with paracetamol use during pregnancy. In addition, paracetamol does not affect the closure of the ductus arteriosus, unlike NSAIDs. However, maternal use of paracetamol during pregnancy is associated with an increased risk of asthma in children.

Mechanism of action of paracetamol

The mechanism of action of paracetamol is currently poorly understood. The main proposed mechanism of action of the drug is inhibition of cyclooxygenase (COX). Recent results show that the substance is highly selective for COX-2. Due to its selectivity for COX-2, the substance does not significantly inhibit the production of thromboxanes. Although its analgesic and antifever activities are comparable to aspirin or other NSAIDs, its peripheral anti-inflammatory activity is usually limited by several factors, one of which is high levels of peroxides at inflammatory sites. In some cases, however, peripheral activity comparable to NSAIDs may be observed. A paper published in November 2011 by researchers from London, UK, and Lund, Sweden, in Nature Communications, describes a hypothesis regarding the analgesic mechanism of action of paracetamol. Metabolites of paracetamol, such as NAPQI, act on TRPA1 receptors in the spinal cord, inhibiting signal transduction from the outer layers of the dorsal horn, relieving pain. This assumption has been challenged in a new hypothetical paper about how paracetamol might work. The author acknowledges that NAPQI is an active metabolite, but states that this reactive compound must react not only with the thiol in TRPA1, but also with any other available nucleophiles. It is hypothesized that the analgesic effect may be provided by thiol groups in cysteine ​​proteases, for example, cysteases important for the formation of procytokines, such as the cysteases that create IL-1β and IL-6. The COX family of enzymes is responsible for metabolizing arachidonic acid into prostaglandin H2, an unstable molecule that can in turn be converted into countless other pro-inflammatory compounds. Classic anti-inflammatory compounds such as NSAIDs block this conversion. The COX enzyme is only highly active when sufficiently oxidized. Paracetamol reduces the oxidized form of the COX enzyme, preventing the formation of pro-inflammatory compounds. This leads to a decrease in the amount of prostaglandin E2 in the central nervous system. Aspirin is known to inhibit the cyclooxygenase family of enzymes and since the action of paracetamol is partly similar to that of aspirin, much of the research has focused on whether paracetamol inhibits COX like aspirin. It is now known that paracetamol acts through at least two mechanisms. The exact mechanism by which COX is inhibited under different circumstances is still a matter of scientific debate. Due to differences in activity between paracetamol, aspirin and other NSAIDs, it is believed that other COX variants may exist. One theory states that paracetamol works by inhibiting the COX-3 isoform, a variant of the COX-1 family of COX enzymes. In dogs, this enzyme is similar to other COX enzymes, produces pro-inflammatory substances and is selectively inhibited by paracetamol. Studies, however, indicate that in humans and mice the COX-3 enzyme does not exhibit inflammatory activity and its inhibition by paracetamol in humans is not significant. Another theory is that paracetamol (like aspirin) blocks cyclooxygenase, but when there is inflammation (and high peroxide concentrations), the high oxidation of paracetamol prevents this effect. This would mean that paracetamol does not have any direct effect on the site of inflammation, but instead acts in the central nervous system (in a non-oxidative environment), reducing temperature, etc. Paracetamol also modulates the endogenous cannabinoid system. Paracetamol is metabolized into AM404, a compound with multiple mechanisms of action; most importantly, it inhibits the reuptake of the endogenous cannabinoid/vanilloid anandamide into neurons. Anandamide reuptake reduces synaptic levels of anandamide and increases activation of the major pain receptor (nociceptor) TRPV1 in the body. By inhibiting anandamide reuptake, levels at the synapse remain high, which can lead to desensitization of the TRPV1 receptor. Moreover, AM404 inhibits sodium channels like the anesthetics lidocaine and procaine. Both of these actions in themselves reduce pain and are possible mechanisms of action of paracetamol. However, it has been demonstrated that when cannabinoid receptors are blocked by synthetic antagonists, the analgesic effect of paracetamol is reduced, suggesting that its analgesic effect involves the endogenous cannabinoid system. Dorsal TRPA1 receptors also mediate the antinociceptive effects of paracetamol and Δ9-tetrahydrocannabinol in mice. The increase in social behavior in mice given paracetamol (and the decrease in social behavior in humans) is not associated with cannabinoid receptor type 1 activity. It may be due to agonism of the serotonin receptor.

Pharmacokinetics of paracetamol

After oral administration, paracetamol is rapidly absorbed from the gastrointestinal tract; the volume of distribution is approximately 50 l. Paracetamol is metabolized mainly in the liver, into toxic and non-toxic products. There are three known mechanisms of paracetamol metabolism:

The hepatic cytochrome P450 enzyme system metabilizes paracetamol to form a small, but important, metabolite known as NAPQI (N-acetyl-p-benzoquinone imine) (also known as N-acetylimidoquinone). NAPQI then binds irreversibly to the sulfidryl groups of glutathione. All three mechanisms produce end products that are inactive, nontoxic, and ultimately excreted by the kidneys. In the third mechanism, however, the NAPQI intermediate is toxic. NAPQI is mainly responsible for the toxic effects of paracetamol. The production of NAPQI is mediated by two cytochrome P450 isoenzymes: CYP2E1 and CYP3A4. At normal doses, NAPQI is rapidly detoxified when bound to glutathione.

History of the discovery of paracetamol

Julius Axelrod and Bernard Brodie demonstrated that acetanilide and phenacetyl are metabolized to paracetamol, a better-tolerated analgesic. Acetanilide was the first known analine derivative with analgesic and antipyretic properties, and was quickly introduced into medical practice in 1886 by A. Kahn and P. Hepp under the trade name Antifebrin. However, unacceptable side effects (the most serious of which was cyanosis resulting from methemoglobinemia) led scientists to continue the search for less toxic aniline derivatives. Harmon Northrop Morse had already synthesized paracetamol in 1877 at Johns Hopkins University by reducing p-nitrophenol with tin in cold acetic acid, but paracetamol was tested in patients only in 1887 by clinical pharmacologist Joseph von Mehring. In 1893, von Mehring published a paper reporting the clinical results of using paracetamol with phenacetin, another aniline derivative. Von Mering stated that, unlike phenacetin, paracetamol tends to cause methemoglobinemia. Paracetamol was banned and phenacetin took its place. Sales of phenacetin have made Bayer the leading pharmaceutical company in the world. Phenacetin has been a popular drug for decades, most notably in well-advertised over-the-counter headache medications that typically contain phenacetin, an aminopyrine derivative of aspirin, caffeine, and sometimes some kind of barbiturate. Aspirin, introduced into medical practice by Heinrich Dreser in 1899, partially reduced the popularity of phenacetin. The data published by von Mehring were challenged only half a century later by two teams of researchers from the United States who were studying the metabolism of acetanilide and paracetamol. In 1947, David Lester and Leon Greenberg clearly demonstrated that paracetamol is the major metabolite of acetanilide in human blood and that large doses of paracetamol do not cause methemogrobinemia in albino rats. In three papers published in September 1948 in the Journal of Pharmacology and Experimental Therapeutics, Bernard Brodie, Julius Axelrod and Frederick Flynn confirmed, using more specific methods, that paracetamol is the main metabolite of acetanilide in the human bloodstream, and stated that paracetamol has an equal precursor analgesic effectiveness. They also suggested that methemoglobinemia in humans develops from exposure to another metabolite, phenylhydroxylamine. A subsequent paper published in 1949 by Brody and Axelrod indicated that phenacetin could also be metabolized into paracetamol. This led to the rediscovery of paracetamol. In 1950, paracetamol was first introduced to the US market under the brand name Triagesic. The drug was a mixture of paracetamol, aspirin and caffeine. After three cases of neuropenia (a blood disorder) were reported in 1951, the drug was withdrawn from the market for several years until it became clear that the condition was not related to the drug. Paracetamol was introduced to the market in 1953 by Sterling-Winthrop Co. under the brand name Panadol, available only by prescription. The drug was positioned as a more preferable drug than aspirin, safe for children and patients with stomach ulcers. In 1955, paracetamol was introduced to the market under the brand name Children's Tylenol Elixir from McNeil Laboratories. In 1956, paracetamol was marketed in 500 mg tablets in the UK under the brand name Panadol from Frederick Stearns & Co., a division of Sterling Drug Inc. Panadol was originally available only by prescription as a pain and fever reliever and was marketed as a “gentle on the stomach” because other analgesics of the time contained stomach-harming aspirin. In 1963, paracetamol was listed in the British Pharmacopoeia, and has since gained popularity as an analgesic with few side effects and interactions with other drugs. Concerns about the effectiveness of paracetamol delayed its widespread adoption until the 1970s, but in the 1980s paracetamol sales exceeded aspirin sales in many countries around the world, including the UK. This was accompanied by the commercial collapse of phenacetin, as the drug was shown to cause analgesic neuropathy and hematological toxicity. The US patent on paracetamol has long since expired, and many generic versions of the drug are now available, although some Tylenol products were protected as long ago as 2007.

Society and culture

Paracetamol is available as tablets, capsules, liquid suspension, suppositories, intravenous and intramuscular solutions, and effervescent tablets. The standard dose for adults is 500 to 1000 mg. The recommended maximum daily dose is 4000 mg for adults. When taken in recommended doses, paracetamol is considered safe for children and adults, but there are reports of cases of acute liver damage when taken in doses below 2500 mg per day. Some drugs combine paracetamol with the opioid codeine, sometimes called co-codamol. In the US, such combination drugs are available only by prescription, but in Canada, similar combinations with smaller amounts of the substance are sold freely from pharmacies. In other countries, such drugs may also be available without a prescription. Paracetamol is also combined with other opioids such as dihydrocodeine, also called co-dydramol, oxycodone or hydrocodone. Another common combination includes paracetamol and propoxyphene nasylate. A combination of paracetamol, codeine and the sedative doxylamine succinate is also found. New research disputes the effectiveness of paracetamol and codeine combinations. Paracetamol is often used in multi-ingredient formulas to treat headaches, which include butalbital and paracetamol with or without caffeine and sometimes codeine. Paracetamol is sometimes combined with phenylephrine hydrochloride. Sometimes a third active ingredient is added to this combination, such as ascorbic acid, caffeine, chlorpheniramine maleate or guaifenesin.

Veterinary use of paracetamol

Cats

Paracetamol is particularly toxic to cats because their bodies lack the enzyme glucoronyl transferase, which is necessary to safely break down paracetamol. Symptoms of poisoning include vomiting, increased drooling, and discoloration of the tongue and gums. Liver injury is a rare cause of death in cats from paracetamol poisoning. Instead, the formation of methemoglobin and the production of Heinz bodies in red blood cells are observed, inhibiting the transport of oxygen in the bloodstream and causing asphyxia (methemoglobinemia and hemolytic anemia). An effective treatment for poisoning when taking small doses of paracetamol is the use of N-acetylcysteine, methylene blue, or the simultaneous use of these drugs.

Dogs

Although paracetamol does not have significant anti-inflammatory activity, it is as effective as aspirin in treating musculoskeletal pain in dogs. Pardale-V, a product containing paracetamol and codeine, is available in the UK. It is used to treat dogs only with a doctor's prescription and in case of emergency. The main symptoms of paracetamol poisoning in dogs are liver damage and sometimes esophageal ulcers. Taking N-acetylcysteine ​​2 hours after taking paracetamol is an effective treatment for overdose.

Paracetamol is also lethal to snakes, and its use has been proposed as a population control measure for the invasive species Boiga irregularis on Guam. Doses of 80 mg are administered to dead mice, which are then dropped from a helicopter.

Controversy

In the September 2013 episode of This American Life, the "Only As Prescribed" episode highlighted the issue of acetaminophen overdose deaths. This was followed by two reports from ProPublica, which stated that “The FDA has long been aware of studies documenting the risks of acetaminophen. Tylenol's manufacturer, McNeil Consumer Healthcare, a division of Johnson & Johnson, was also aware of this" and "McNeil, the manufacturer of Tylenol, has repeatedly rejected the need for safety warnings, dose limits and other measures to protect users of the drug." The report, prepared by an internal FDA working group, describes the history of FDA initiatives aimed at educating users about the risks of acetaminophen overdose, noting that "one of the Agency's goals has been to communicate the safety of acetaminophen, especially when compared with other over-the-counter pain medications ( e.g. aspirin and other NSAIDs).” The report also states that “long-term use of NSAIDs is also associated with significant morbidity and mortality. NSAIDs have a negative effect on the gastrointestinal tract. One article reported the following data: 3,200 deaths and hospitalizations per year. In addition, the risks of cardiovascular toxicity have also recently been discussed. The purpose of the program is not to restrict the use of acetaminophen or to encourage the use of NSAIDs, but to educate users to avoid unnecessary and unnecessary health risks.”

Classification of paracetamol

Paracetamol is part of a group of drugs known as "analine analgesics"; and this drug is the only one of this group used today. It is not considered a NSAID because it does not have significant anti-inflammatory activity (and is a weak COX inhibitor), despite evidence of similar pharmacological activity between paracetamol and NSAIDs.

Availability

Paracetamol is used for pain syndromes of various origins (headache, dental, migraine, myalgia, menalgia, arthralgia); fever in infectious and inflammatory diseases; poor tolerance to salicylic acid derivatives.

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Paracetamol: indications, contraindications, side effects

Paracetamol is a widely used antipyretic and analgesic drug belonging to the anilide group. In some countries it is sold under the name Acetaminophen. The drug does not produce the side effects characteristic of most NSAIDs, but when taken in excessively large doses, it can negatively affect the functions of the liver, kidneys and circulatory system.

Important: the risk of developing side effects (hepato- and nephrotoxic) increases many times when taking Paracetamol and liquids containing ethanol (including pharmaceutical tinctures) in parallel. In this regard, it is recommended to refrain from drinking alcohol during treatment.

The undoubted advantage of Paracetamol over Acetylsalicylic acid (Aspirin) is the low risk of exacerbation of chronic gastritis and the development of gastric and duodenal ulcers.

This central non-narcotic analgesic is considered one of the most effective and safe. It is included in the list of “Life-Saving and Essential Medicines” adopted by the Government of the Russian Federation.

Active substance and release forms

The active ingredient is para-acetaminophenol (N-(4-Hydroxyphenyl) acetamide). Chemical formula – C8H9NO2. Paracetamol was synthesized in 1877 and clinical trials took place ten years later. Sales of the drug began in 1953 under the trade name Tylenol (USA). In 1956, Panadol appeared, based on the same chemical substance. Currently, a huge number of paracetamol-containing drugs are produced, which additionally include ingredients such as caffeine, acetylsalicylic acid, codeine, analgin, etc.

Domestic pharmaceutical companies produce Paracetamol in regular tablets (200, 325 and 500 mg), film-coated tablets (Panadol Extra 325 and 500 mg), capsules (325 and 500 mg), and also in the form of rectal suppositories (50 mg each). , 100, 125, 250 and 500 mg).

Pharmacy chains sell soluble tablets of 500 mg - Efferalgan, Panadol Extra, Flutabs and Paracetamol-Hemofarm.

Popular panadol-containing drugs include powders for preparing the solution Fervex and Theraflu.

An injection form is also available - Perfalgan solution (10 mg/ml). For children, you can purchase Panadol Baby and Efferalgan Children's syrups, as well as suspensions for oral administration of Paracetamol for Children, Calpol and Daleron.

Benefits of Paracetamol

Para-acetaminophenol acts on the thermoregulation center located in the hypothalamus, making its antipyretic effect as close as possible to the process of natural decrease in body temperature. The undoubted advantage of Paracetamol over NSAIDs is its selectivity of action, which makes it possible to use it for the treatment of children. In addition, drug metabolism products very quickly leave the body naturally, which eliminates cumulation (accumulation) in organs and tissues.

Paracetamol: indications for use

Paracetamol is a drug intended to relieve symptoms. It does not affect the dynamics of the pathological process in any way. The most common indications for starting to take this drug are increased body temperature (hyperthermia) due to colds and viral diseases, as well as pain (aches) in the bones and muscles during influenza and other acute respiratory viral infections.

Diseases and pathological conditions for which acetaminophen is recommended:

Directions for use and dosage of Paracetamol

Acetaminophen produces therapeutic effects when administered in doses of IMG per 1 kg of body weight.

Oral forms of Paracetamol (tablets or syrup) are recommended to be taken 1-2 hours after meals with plenty of liquid (preferably clean water). Taking on a full stomach slows down absorption and, therefore, the development of the expected therapeutic effect.

Paracetamol in the form of suppositories is administered rectally (1 suppository).

The recommended single dosage for adult patients and adolescents over 12 years of age (or weighing over 40 kg) is 1 g (2 tablets of 0.5 g each), and the daily dosage is 4 g.

For children under 12 years of age, the dose is determined individually based on mg per 1 kg of weight (60 mg/kg per day). Frequency – up to 4 times a day; It is advisable to maintain approximately equal time intervals between doses.

For babies from 3 months. up to 1 year of age, the dosage ranges from 24 to 120 mg (up to 4 times a day), and children from 1 to 6 years of age are given pomg per dose.

It is not advisable to take Paracetamol for more than 5 days in a row. If the fever persists for more than 3 days, and the pain persists for more than 5 days, you should consult your doctor. Usually in such cases it is recommended to replace the drug with another analgesic and antipyretic. To reduce the risk of undesirable consequences, it is advisable to limit yourself to the minimum effective doses and strictly adhere to the dosage regimen.

pharmachologic effect

The active substance is able to block the enzyme cyclooxygenase (COX1 and COX2), thereby reducing the level of production of pain mediators - prostaglandins. The drug has a direct effect on the thermoregulation and pain centers located in the brain. There is reason to believe that the pronounced antipyretic and analgesic effects are due, among other things, to the selective blockade of COX 3, an enzyme that accelerates the synthesis of prostaglandins and is involved in the formation of fever and pain.

This drug has relatively weak anti-inflammatory properties, since it is neutralized by peripheral tissue peroxidases. Paracetamol does not have a negative effect on water-electrolyte metabolism.

Pharmacodynamics

After oral administration, Paracetamol is rapidly absorbed from the digestive tract. The time to reach maximum serum concentration can vary from 30 minutes. up to 2 hours. About 15% of the active substance is conjugated with plasma proteins. The drug freely passes the blood-brain barrier. Most of the substance undergoes biotransformation in the liver. The half-life is from 1 to 4 hours (in elderly patients it is slightly longer). Metabolites (sulfates and glucoronides) and para-acetaminophenol unchanged (about 3%) are excreted in the urine.

Paracetamol: contraindications

Contraindications include:

  • individual hypersensitivity (increased sensitivity) to the active substance;
  • “aspirin triad” (a combination of intolerance to NSAIDs, bronchial asthma and recurrent polyposis of the nose and paranasal sinuses);
  • inflammatory diseases, erosions and ulcers of the gastrointestinal tract;
  • gastrointestinal bleeding;
  • severe functional renal failure;
  • diagnosed hyperkalemia;
  • condition after coronary artery bypass surgery.

Important: Paracetamol-containing drugs are contraindicated in newborns in the first month of life.

Particular caution should be exercised when taking this drug in case of the following diseases and pathological conditions:

Please note: if you have diabetes, it is not recommended to take Paracetamol in syrup form.

Side effects of Paracetamol

Taking Paracetamol by a woman during pregnancy greatly increases the risk of developing such an anomaly as an undescended testicle in newborn boys (treatment of cryptorchidism often requires surgical intervention). According to a number of researchers, the drug increases the likelihood of a child developing bronchial asthma (along with Aspirin).

It is also believed that taking Paracetamol can slightly reduce the patient's emotional response.

Excessively long-term use of this drug, even in therapeutic doses, can cause the development of analgesic nephropathy, which results in severe renal failure.

What is the danger of an overdose of Paracetamol?

Almost any pharmacological drug in a certain dosage can be deadly. The toxicity of Paracetamol is relatively low, but when taken simultaneously in a dose exceeding 140 mg/kg (for adults) or 140 mg/kg (for children), serious liver damage develops. This is due to the hepatotoxic effect of intermediate products of para-acetaminophenol metabolism.

Important: death is possible when taking 40 tablets per day. Following the instructions will prevent you from taking a dangerous amount of the drug.

Significant excess of recommended dosages is one of the causes of serious bleeding in the gastrointestinal tract, requiring urgent hospitalization. If medical assistance is not provided in a timely manner, death cannot be ruled out.

In case of overdose, hemodialysis is ineffective, and forced diuresis can even be dangerous. In case of intoxication with Paracetamol, the use of glucocorticoids and antihistamines is unacceptable, since they increase the level of synthesis of metabolic products that have a negative effect on the liver.

Interaction with other drugs

It is important to be careful when using Paracetamol in parallel with anticoagulants (Warfarin), antiplatelet agents (including Acetylsalicylic acid), glucocorticosteroid hormones (Prednisolone) and serotonin reuptake inhibitors (Fluoxetine, Sertraline, etc.).

Combination with drugs containing phenobarbital (Valocordin, Corvalol) is unacceptable.

Paracetamol during pregnancy and lactation

Paracetamol should not be taken by women in the third trimester of pregnancy. In the first and second trimesters, the medicine should be taken as prescribed by the doctor; in this case, the ratio of benefit to the mother and possible risk to the fetus is taken into account.

Less than 1% of the active substance passes into breast milk, so the lactation period is not a contraindication to taking the drug.

additional information

If, due to the disease, the patient's appetite is significantly reduced, it is recommended to halve the dosage of oral forms to avoid the risk of irritation on the mucous membranes of the digestive tract.

Some drugs contain para-acetaminophenol in combination with caffeine. It has been proven that caffeine enhances the effect of Paracetamol by increasing its bioavailability. This combination is very helpful in relieving headaches due to low blood pressure.

An enhanced effect of para-acetaminophenol is achieved with the parallel intake of ascorbic acid into the body. Vitamin C slows down the removal of the active substance from the body.

Plisov Vladimir, medical observer

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