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Recommendations on dosage of  paracetamol administration

Introduction

Paracetamol, also known as acetaminophen, is one of the most commonly used medications across the world to relieve pain and reduce fever. It belongs to the class of analgesics and antipyretics, widely taken for self-medication and prescribed in various medical contexts.

Paracetamol is widely available without a prescription in many countries, making it a popular choice for the treatment of various ailments, including headaches, muscle pain, joint pain, and fever associated with various conditions.

The objective of this article is to explore the pharmacological, medical and social aspects of paracetamol. We will examine how this drug works pharmacologically, its common medical uses, as well as its social impact and widespread use in modern society. This exploration will also include an analysis of the risks associated with excessive or inappropriate use of paracetamol, as well as the recommended safety measures for its administration.

History and development

Origin and history of paracetamol as a medicine.

Paracetamol was first synthesized in 1878 by German chemist Harmon Northrop Morse, although at the time its precise chemical structure was not fully understood. It was only later, in the 1940s, that its structure was precisely determined.

Development as a drug

• 1940s-1950s: Paracetamol began to be marketed as a medicine in the 1940s, mainly in Europe and the United States. It was initially used as an alternative to aspirin due to its less severe side effects on the stomach.
• 1960s: Its popularity continued to grow, largely due to its relative safety compared to nonsteroidal anti-inflammatory drugs (NSAIDs) like ibuprofen and naproxen, which can cause gastrointestinal irritation in some patients .
• 1980s-1990s: Paracetamol became a commonly used medicine worldwide to treat pain and fever in adults and children. Its formulation has been adapted for various uses, including in the form of tablets, capsules, syrups and suppositories.

Action mechanism

Paracetamol works primarily by inhibiting the enzyme cyclooxygenase (COX) in the brain, which decreases the production of prostaglandins, chemicals involved in the transmission of pain and the regulation of body temperature.

Current use

Today, acetaminophen is widely recommended as a first-line treatment for fever and mild to moderate pain in many common medical conditions.

Evolution of uses and formulations of paracetamol over time.

Evolution of uses

 Analgesic and antipyretic

Since its beginnings, paracetamol has been mainly used for its analgesic (painkiller) and antipyretic (anti-fever) properties. It is effective in reducing mild to moderate pain and lowering fever.

 Treatment of chronic pain

Over time, paracetamol has been incorporated into the treatment of mild to moderate chronic pain, particularly for conditions such as osteoarthritis and recurrent headaches.

 Pediatric use

It is widely recommended for the treatment of fever and pain in children, with suitable formulations such as syrups and suppositories in appropriate doses.

 Combination with other drugs

Acetaminophen is often combined with other medications, such as opioids (in some prescription products) or antihistamines (in cold and flu medications), to improve its effectiveness in treating specific conditions.

Evolution of formulations

 Tablets and capsules

Initial formulations were primarily in tablet and capsule form, providing convenient oral administration.

 Syrups

The syrups were developed to facilitate administration in children and adults who have difficulty swallowing tablets.

 Suppositories

Suppositories are used in cases where oral administration is not possible, such as in patients with severe nausea or difficulty swallowing.

 Sustained release formulations

Sustained-release formulations have been developed to maintain more constant drug levels in the blood, reducing the need for frequent dosing.

Recent innovations

 Gluten-free and lactose-free formulations

To meet the needs of patients with food allergies or intolerances, gluten-free and lactose-free formulations are available.

 Improved safety and efficiency

Formulations have been adjusted to improve safety, limiting the risk of overdose and minimizing gastrointestinal side effects.

Composition and mechanism of action

Chemical composition and molecular structure of paracetamol

Paracetamol, also known as acetaminophen, is chemically referred to as 4-hydroxyacetanilide. Its chemical formula is C8H9NO2, which indicates its composition of carbon, hydrogen, nitrogen and oxygen atoms.

Structurally, paracetamol is a small organic molecule consisting of a benzene nucleus to which is linked an acetamide function (-CONH2) and a hydroxyl group (-OH) in the para position on the benzene nucleus. This structure is essential to understand how paracetamol interacts with receptors in the human body, particularly for its analgesic (against pain) and antipyretic (against fever) effect.

Detailed explanation of the mechanism of action of paracetamol in the human body

The mechanism of action of paracetamol in the human body mainly centers on its effectiveness as an analgesic (against pain) and antipyretic (against fever). Here is a detailed explanation of how it works:

 Inhibition of cyclooxygenase (COX)

Paracetamol works primarily by inhibiting the enzyme cyclooxygenase (COX), specifically COX-3 in the brain and potentially COX-1. Unlike nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen or aspirin, it does not significantly block COX in peripheral tissues, where prostaglandin production is important for inflammation.

 Formation of active metabolites

Paracetamol is metabolized in the liver into several metabolites, the main one being N-acetyl-p-benzoquinone imine (NAPQI). This metabolite is normally neutralized by glutathione, a cellular antioxidant, to prevent oxidative damage.

 Effect on the central nervous system

By inhibiting COX-3 in the brain, paracetamol decreases the production of prostaglandins which are involved in pain transmission and the regulation of body temperature.

 Antipyretic

Paracetamol acts on the temperature regulation center in the hypothalamus, thereby reducing fever by decreasing the production of prostaglandins which influence body temperature.

 Analgesic

By blocking COX-3 in the brain, paracetamol helps reduce the sensation of pain by acting directly on the neural mechanisms involved in pain perception.

Paracetamol works primarily by inhibiting COX in the brain to reduce prostaglandin production, leading to reduced pain and fever. Its analgesic and antipyretic effectiveness makes it one of the most used drugs in the world for these specific indications.

Medical uses

Main medical indications for paracetamol: pain management and fever reduction

Paracetamol is widely used for its analgesic (pain management) and antipyretic (fever reduction) properties. Here are some key points on its main medical indications:

 Pain management

• Paracetamol is effective in relieving different types of mild to moderate pain, such as headaches, muscle pain, joint pain, and pain associated with colds and infections.
• It works primarily by inhibiting cyclooxygenase (COX), an enzyme involved in the synthesis of prostaglandins, which are mediators of pain in the body.

 Reduction of fever

Paracetamol is widely used to lower high body temperature associated with fever, often in cases of influenza, viral or bacterial infections, or other illnesses.

 Relief from menstrual pain

It is also used to ease menstrual pain in women, helping to improve comfort during menstrual periods.

 Pediatric use

Paracetamol is commonly prescribed for children for the relief of pain and fever. Specific formulations adapted to their weight and age are available.

 Combined with other drugs

In some cases, paracetamol is combined with other painkillers such as codeine to enhance its analgesic effect, especially in the treatment of moderate to severe pain.

These medical indications make paracetamol one of the most used and recommended analgesics worldwide for its safe and effective effects on pain management and fever reduction.

Specific applications in the treatment of certain medical conditions

Paracetamol also finds specific applications in the treatment of certain medical conditions other than general pain management and fever reduction. Here are some examples of specific applications:

 Osteoarthritis

Acetaminophen is often used as a treatment option to relieve pain associated with osteoarthritis, a degenerative joint disease. It can help improve quality of life by reducing pain and making joint movement easier.

 Migraines

Although less common than other migraine-specific pain relievers, acetaminophen is sometimes used to ease the symptoms of mild to moderate migraine. However, it is often combined with other medications in complex migraine treatments.

 Postoperative pain

After minor surgical procedures, paracetamol is often given to help manage post-operative pain, reducing the need for stronger painkillers.

 Flu syndrome and viral infections

As well as reducing fever, paracetamol can help relieve symptoms of flu-like illness, including body aches, headaches and general malaise associated with viral infections.

 Dental pain

For mild to moderate dental pain, paracetamol can be used as an effective pain reliever before resorting to more specific dental treatments.

 Musculoskeletal pain

Paracetamol is also prescribed to relieve muscle pain and chronic pain associated with musculoskeletal conditions like sprains, strains and other injuries.

These specific applications show the versatility of acetaminophen in treating various medical conditions that require effective pain and fever management. However, it is essential to always follow specific medical recommendations and respect prescribed doses to avoid any risk of adverse effects.

Dosage and administration

Recommendations for the dosage and frequency of administration of paracetamol

General recommendations for the dosage and frequency of administration of paracetamol may vary depending on age, weight, individual health status and the medical condition being treated. However, here are some general guidelines that can be followed when using paracetamol:

 Adults (18 years and over)

• Usual dosage: 500 mg to 1000 mg every 4 to 6 hours as needed, with a maximum dose of 4000 mg per day.
• For fever: Start with a dose of 1000 mg, then 500 mg every 4 to 6 hours if necessary.
• For pain: Start with a dose of 500 mg to 1000 mg, then adjust as needed.

 Children (depending on age and weight)

• Doses vary depending on the age and weight of the child. It is crucial to follow the specific recommendations of the doctor or pediatrician.
• General dosage: Calculated based on the child's body weight. For example, 10 to 15 mg per kg every 4 to 6 hours.

 Elderly people and fragile patients

Dosage may be adjusted based on kidney function and other health factors. It is recommended to consult a healthcare professional for appropriate advice.

 Duration of use

• Do not exceed the recommended dose per day.
• Limit use to the minimum duration necessary to control symptoms.
• Avoid prolonged use without medical advice, especially in cases of chronic pain.

It is essential to carefully follow the doctor's or pharmacist's instructions regarding the use of paracetamol, especially when combined with other medications or in the presence of specific medical conditions.

Special considerations for different populations (children, elderly, patients with specific conditions)

For different populations, it is important to take specific considerations into account when using paracetamol, including:

 Children

• The dosage is often calculated based on the child's body weight.
• Use child-friendly formulations (e.g., syrups) with age-appropriate dosages.
• Avoid self-administration and consult a pediatrician for specific advice on dosage and frequency.

 Elderly people

• Increased risk of kidney and liver problems, requiring increased caution in the use of paracetamol.
• Avoid maximum recommended doses and prefer lower doses if possible.
• Monitor side effects closely and consult a doctor if unusual symptoms occur.

 Patients with specific conditions

• Hepatic insufficiency: Reduce the dosage and space out the doses.
• Renal insufficiency: Adapt the dosage according to creatinine clearance.
• Patients taking other medications: Avoid potential drug interactions and consult a healthcare professional.

 Pregnancy and breastfeeding

• Use paracetamol only under the supervision of a healthcare professional during pregnancy.
• Favor the lowest doses and the shortest possible treatments.
• While breastfeeding, use minimal doses and avoid prolonged use.

 Pre-existing medical conditions

• Consult a doctor before using paracetamol in case of chronic illnesses such as heart disease, gastrointestinal disorders, etc.
• Adapt the dosage and frequency according to the patient's general health.

In summary, the use of paracetamol should be tailored to each specific population taking into account potential risks and pre-existing medical conditions. A medical consultation is always recommended for personalized and safe advice.

Side effects and precautions

List of common side effects associated with the use of paracetamol

Common side effects associated with paracetamol use may include:

 Gastrointestinal effects

• Nausea
• Vomiting
• Abdominal pain
• Loss of appetite

 Skin reactions

• Rashes
• Itching
• Urticaria

 Hepatic effects

• Increased liver enzymes in blood tests
• Serious liver damage in case of overdose

 Allergic reactions

• Serious allergic reactions (very rare), such as swelling of the face, lips, tongue or throat, difficulty breathing

 Hematological disorders

• Anemia (rare)

It is important to note that these side effects are generally rare when using paracetamol correctly at recommended doses. However, any adverse reactions should be reported to a healthcare professional for evaluation and appropriate management.

Precautions to take when using paracetamol, including drug interactions and contraindications

To use paracetamol safely, here are some precautions to take, particularly regarding drug interactions and contraindications:

 Drug interactions

• Avoid taking other medicines containing paracetamol simultaneously to avoid overdose.
• Tell your healthcare professional about all the medications you take, including prescription drugs, nonprescription drugs, supplements, and herbal products.
• Some medicines may interact with paracetamol, including medicines that affect the liver such as anticonvulsants, antibiotics and HIV medicines.

 Contraindications

• Do not use paracetamol if you have a known hypersensitivity to it.
• Avoid taking paracetamol if you have severe liver problems, such as liver failure.
• Avoid long-term use or in high doses without medical supervision, especially if you have pre-existing health conditions.

 General precautions

• Strictly adhere to the recommended doses and frequency of administration.
• Do not exceed the maximum recommended daily dose (usually 4 g per day for adults).
• Follow specific recommendations for children and the elderly, as doses may vary depending on age and medical condition.

 Medical consultation

• Consult a healthcare professional before starting any treatment with paracetamol if you have any concerns about your health or if you are taking other medications.

These precautions help to minimize the risk of side effects and ensure safe and effective use of paracetamol.

Regulations and availability

Regulatory framework and sales status of paracetamol in different countries

 Nordics

Total sales of paracetamol increased in the Nordic countries from 2000 to 2015, with highest sales in Denmark. A significant proportion of paracetamol is sold by prescription, particularly in Denmark (78%), compared to Iceland (38%) (Wastesson et al., 2018).

 Europe

A survey found that 67% of European countries had restrictions on the size of packages sold in pharmacies (ranging from 8 to 30 g). Sales at non-pharmaceutical outlets were associated with a higher frequency of reported poisonings (Morthorst et al., 2018).

 United Kingdom

Since 1998, the UK has introduced restrictions on packaging sizes to reduce poisonings. Studies show mixed results on the effectiveness of these measures, with initial reductions in hospitalizations and deaths, but less clear long-term trends (Morgan & Majeed, 2005), (Hawkins et al., 2007).

 Denmark

The over-the-counter sale of paracetamol led to a dramatic increase in overdose sales and admissions, but without an epidemic of deaths as observed in the United Kingdom (Ott et al., 1990).

 Norway

The lifting of the outlet restriction in 2003 did not lead to a significant increase in hospitalizations for poisoning, although the number of consultations at poison centers increased (Haga et al., 2011).

Accessibility and availability of paracetamol on the market

 Europe

In a European survey, it was observed that 67% of countries had implemented restrictions on the size of paracetamol packages sold in pharmacies, ranging from 8 to 30 g. Sales at non-pharmaceutical outlets were also common in some countries, although this was associated with a higher frequency of claims related to paracetamol poisoning (Morthorst et al., 2018).

 United Kingdom and France

One study found that the increased availability of acetaminophen correlated with an increase in acetaminophen-related overdoses and suicides. Restrictions on the amount of paracetamol available in a single transaction appear to reduce associated morbidity and mortality (Gunnell et al., 1997).

 Ireland

A study carried out in Dublin showed that it was possible to buy quantities of paracetamol above the legal limits in 50% of pharmacies and 81.8% of non-pharmaceutical outlets. A year later, compliance had improved in non-pharmaceutical outlets, but not in pharmacies (Ní Mhaoláin et al., 2009).

 Bangladesh

A quality analysis of seven paracetamol brands available in the Bangladeshi market found that almost all of them met the USP quality specifications for quality controls, except for two local products which did not meet the quality standards. hardness (Kar et al., 2015).

Social and economic impacts of paracetamol

Impact on society and the economy

 Health costs and productivity

o Paracetamol is widely used to treat pain and fever, reducing work absences and improving productivity. However, the costs of treating paracetamol overdoses can be high, particularly due to prolonged hospitalizations and treatments for acute liver injury (Gunnell et al., 2000).

 Mortality and morbidity

o A UK study showed that changes in guidelines for managing paracetamol poisoning led to increased hospital admissions and treatment, without reducing adverse reactions, increasing healthcare costs (Bateman et al. , 2014).

Recreational use and social implications

 Recreational use and intoxication

Paracetamol is frequently used in suicide attempts due to its availability and toxic potential in overdose. Restrictions on package size can reduce overdose-related morbidity and mortality rates (Gunnell et al., 2000), (Hawton et al., 1996).

 Long-term effects and public health

Chronic use of acetaminophen is associated with long-term adverse effects, such as hypertension, gastrointestinal bleeding and kidney damage, which can affect quality of life and increase healthcare costs (McCrae et al ., 2018).

 Risks during pregnancy

Paracetamol consumption during pregnancy may have negative effects on children's neurocognitive development, leading to additional costs in terms of healthcare and special education (Golding et al., 2019).

Recent innovations and ongoing research on paracetamol

Recent innovations

 Sustained release formulations

The development of new formulations of paracetamol aimed at sustained release and rapid absorption for faster and prolonged action is underway. For example, a new sustained release (SR) formulation of paracetamol showed better absorption and improved pharmacokinetic characteristics, making the treatment more effective for chronic pain (Liu et al., 2015).

 Intravenous formulations

Intravenous paracetamol, already used for the management of postoperative pain and fever in intensive care, is likely to see its use expand. These formulations provide an effective option for patients unable to take oral medications (Prescott, 2003).

 Advanced formulation technologies

o The use of 3D printing technology to personalize doses and release mechanisms of paracetamol shows promising potential. This technology makes it possible to create formulations tailored to the specific needs of patients, thereby reducing side effects (Guo & Zhang, 2022).

Current research

 Mechanisms of action

Studies on the mechanisms of action of paracetamol continue to develop, in particular its interaction with cyclooxygenase enzymes and endocannabinoid pathways. This research could lead to wider clinical use of paracetamol (Przybyła et al., 2020).

 Hepatotoxicity and liver protection

Significant efforts are devoted to the study of the molecular mechanisms of paracetamol hepatotoxicity. The objective is to prevent liver failure, even in the event of late treatment after overdose (Prescott, 2003).

Prospects for the future

 New formulations

Formulations aimed at better rectal administration and controlled release mechanisms to prolong the duration of action of paracetamol are being developed (Prescott, 2003).

 Potential therapeutic applications

Paracetamol could be used as an antioxidant to prevent atherosclerosis and cardiovascular disease by inhibiting the oxidation of low-density lipoproteins, as well as to prevent the formation of cataracts (Prescott, 2003).

Continued importance of research and monitoring

Safety and efficiency

Continuous monitoring of the safety and effectiveness of paracetamol is essential to prevent serious adverse effects and optimize its therapeutic use. Continuing research into mechanisms of action and new formulations helps improve the drug's safety profile and expand its therapeutic indications (Prescott, 2003).

Responses to overdoses

The development of new strategies to treat acetaminophen overdoses, including molecular approaches to prevent liver damage, is crucial to reduce the morbidity and mortality associated with acetaminophen poisoning (Kozer & Koren, 2001).

Expanded clinical application

Continuing research into new clinical applications of paracetamol, such as its potential use as an antioxidant, could offer new therapeutic options for various medical conditions, thereby increasing the therapeutic value of this well-established drug (Przybyła et al., 2020).

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