Paracetamol

Paracetamol, also known as acetaminophen, is a widely used non-opioid analgesic and antipyretic. It is commonly utilized for alleviating mild to moderate pain and reducing fever. The World Health Organization (WHO) recommends paracetamol as a first-line treatment for pain conditions.

Chemical Structure

Paracetamol, chemically known as N-(4-hydroxyphenyl)ethanamide, has the molecular formula C8H9NO2 and a molar mass of 151.165 g/mol. Structurally, it is an aromatic compound featuring an OH (hydroxyl) functional group and an HN-CO-R (amide) functional group. It possesses a density of 1.263 g/cm³ and a melting point of 169 °C (336 °F). Paracetamol’s solubility in water ranges from 7.21 g/kg at 0 °C to 12.78 g/kg at 20 °C.

Mechanism of Action

The precise mechanism of action of acetaminophen remains incompletely understood. It is believed to act by inhibiting chemical messengers in the brain that signal pain and by modulating those that regulate body temperature. Paracetamol’s effects are thought to involve several central mechanisms, including inhibition of prostaglandin synthesis and interactions with serotonergic, opioid, nitric oxide (NO), and cannabinoid pathways.

Pharmacokinetics

Absorption

Paracetamol is well absorbed in the gastrointestinal tract, with oral bioavailability increasing with larger doses due to a reduced hepatic first-pass effect. Rectal administration is possible but results in inconsistent and generally lower bioavailability due to incomplete suppository dissolution.

Distribution

Paracetamol distributes homogeneously throughout body fluids and penetrates the brain in small amounts, which is critical for its analgesic effects. It has a volume of distribution of approximately 0.9 L/kg, with 10-20% bound to red blood cells and less than 20% bound to plasma proteins under therapeutic conditions. In cases of overdose, protein binding can increase up to 50%.

Metabolism

Primarily metabolized in the liver, paracetamol undergoes conjugation with glucuronic acid (55%) and sulfuric acid (35%). Small amounts of hepatotoxic metabolites are produced via cytochrome P450 isoenzyme CYP2E1, which are detoxified by conjugation with glutathione within the therapeutic plasma concentration range.

Excretion

Paracetamol metabolites are excreted through the kidneys, with only 2-5% excreted unchanged. Due to its short elimination half-life (1-3 hours), 98% of a single dose is eliminated within 24 hours.

Clinical Implications

Given its hepatic metabolism, acetaminophen must be used cautiously in patients with severe hepatic failure, who exhibit a prolonged elimination half-life. Paracetamol intoxication, a significant clinical issue due to its widespread availability, can result in life-threatening hepatic and renal failure.

Therapeutic Uses

Paracetamol is widely used to manage mild to moderate pain and fever. Its therapeutic applications include:

• Pain Relief: Effective for headaches, muscle aches, minor arthritis pain, toothaches, and pain from sprains.
• Fever Reduction: An effective antipyretic.
• Cold and Flu Symptoms: Commonly included in medications for cold and flu to alleviate sore throat and sinus pain.
• Menstrual Pain: Used to relieve dysmenorrhea.
• Post-operative Pain: Utilized to manage pain after surgeries.

It is crucial to understand that while paracetamol alleviates symptoms, it does not address the underlying causes of pain or fever.

Side Effects

Common Side Effects

• Itchy skin
• Constipation
• Nausea
• Vomiting
• Headache
• Insomnia
• Agitation

Rare Side Effects

• Bloody or black, tarry stools
• Bloody or cloudy urine
• Fever with or without chills
• Severe pain in the lower back or side
• Pinpoint red spots on the skin
• Skin rash, hives, or itching
• Sore throat
• Sores, ulcers, or white spots on lips or in the mouth
• Sudden decrease in urine output
• Unusual bleeding or bruising
• Unusual tiredness or weakness
• Yellow eyes or skin

Symptoms of Overdose

Overdose requires immediate medical attention and may present with:

• Diarrhea
• Increased sweating
• Loss of appetite
• Nausea or vomiting
• Stomach cramps or pain
• Swelling, pain, or tenderness in the upper abdomen

Drug Interactions

Paracetamol can interact with 124 drugs, 3 disease states, and 1 food/alcohol interaction. Significant drug interactions include those with amobarbital, butalbital, pentobarbital, phenobarbital, diflunisal, and isoniazid.

Safety Considerations

Paracetamol has a favorable safety profile when used within therapeutic ranges, especially compared to NSAIDs or opioids. However, even recommended doses can lead to toxicity in certain patients due to altered metabolism. Acute overdose can result in severe hepatotoxicity.

Regulatory Status

Paracetamol is one of the most commonly used drugs worldwide, available over-the-counter, and used across all age groups. The Medicines and Healthcare products Regulatory Agency (MHRA) authorizes a dose of 1 g up to four times daily for adults over 50 kg, with a minimum 4-hour interval between doses.

Contraindications

Allergy

Paracetamol should not be taken by individuals with a history of allergic reactions to it or similar medications.

Liver or Kidney Problems

It may not be suitable for individuals with liver or kidney impairments and should be used cautiously in patients with G6PD deficiency.

Alcohol Consumption

Chronic alcohol consumption increases the risk of paracetamol toxicity.

Malnutrition and Chronic Alcoholism

Patients with malnutrition or chronic alcoholism should use paracetamol with caution.

Dehydration and Severe Hypovolemia

Patients with these conditions should be cautious, particularly with intravenous administration.

Body Weight

Individuals weighing less than 50 kg may require lower doses.

Pregnancy and Breastfeeding

While paracetamol can be used during pregnancy and breastfeeding, consultation with a healthcare provider is advised.

Drug Interactions

Number of Interactions

Paracetamol interacts with 124 drugs, including 8 major, 80 moderate, and 36 minor interactions.

Types of Interactions

Significant interactions include those with amitriptyline, amlodipine, aspirin, atorvastatin, and others. Paracetamol should not be taken with other paracetamol-containing medications to avoid overdose but can be taken with other painkillers like ibuprofen or codeine.

Symptoms of Paracetamol Overdose

Early Symptoms

Within the first 24 hours, symptoms may include:

• Paleness
• Nausea and vomiting
• Loss of appetite
• Sweating

Later Symptoms

After 24 hours, symptoms may include:

• Pain under the ribs on the right side
• Yellowing of the eyes and skin
• Loss of coordination
• Low blood sugar

Untreated overdose can lead to liver injury and, in severe cases, fulminant hepatic failure. Immediate medical attention is essential if overdose is suspected.

Summary Table

Always consult your healthcare provider for personalized medical advice and before starting or stopping any medication.