Paracetamol: Drug Effects, Side Effects, Dosage and Uses

Products

Paracetamol is commercially available in the form of tablets, film-coated tablets, melting tablets, effervescent tablets, as granules, drops, syrups, suppositories, soft capsules, and infusion solution, among others (e.g., Acetalgin, Dafalgan, Panadol, and Tylenol). Paracetamol was not approved until the 1950s (Panadol, Tylenol), although it was developed in the 19th century. It has been registered in many countries since 1959 (Panadol). Paracetamol is fixedly combined with other active ingredients, for example, codeine, caffeine, vitamin C, agents for the common cold, and tramadol. In Anglo-Saxon countries, the active ingredient has a different name – it is usually called acetaminophen.

Structure and properties

Paracetamol (C8H9NO2, Mr = 151.2 g/mol) exists as a white crystalline powder that is sparingly soluble in water. It has a slightly bitter taste and is odorless. The taste may be noticed after ingestion. Paracetamol is an acetamide. It is a derivative of acetanilide, which was launched in the 1880s as one of the first synthetic antifebrile agents (antifebrine). Acetanilide is no longer commercially available due to its side effects. Paracetamol is also a metabolite of phenacetin, which is also no longer marketed.

Effects

Paracetamol (ATC N02BE01) has analgesic and antipyretic properties. Unlike NSAIDs, it has little anti-inflammatory activity and does not inhibit platelet aggregation. The mechanism of action has not yet been conclusively elucidated. A central inhibition of prostaglandin synthesis is involved. The half-life is short, 2 to 3 hours. The duration of action is only about 4 to 6 hours.

Biotransformation

Paracetamol is extensively metabolized in the liver. It is conjugated mainly with glucuronic acid and with sulfuric acid and excreted mainly in the urine. Especially at high doses, the toxic metabolite -acetyl–benzoquinoneimine (NAPQI) is formed by CYP2E1 because the conjugation is saturated. However, when therapeutic doses are administered, NAPQI can be detoxified with endogenous glutathione. If concentrations increase too much, acetaminophen is liver toxic because of NAPQI formation (see below).

Indications

For symptomatic treatment of fever and mild to moderate pain. Possible indications include, for example (selection):

  • Headache, migraine
  • Toothache
  • Muscle and joint pain, arthritis pain
  • Pain after injury or surgery
  • Fever and pain associated with flu or colds

Dosage

According to the drug label. Adults take 500 mg to 1000 mg orally up to a maximum of four times daily. An interval of 4 to 8 hours should be allowed between individual doses (usually 6 hours). This information refers to adults. For children, dosing is based on body weight. The dosing interval is longer at 6 to 8 hours. Taking after meals may delay the onset of action. On the other hand, onset of action may be earlier after administration of prokinetics such as domperidone or metoclopramide. The effect also occurs more quickly with effervescent tablets. The 1 g tablets are large and may be difficult to swallow. They can be divided into two halves and taken shortly after each other. Other dosage forms are also available.

Abuse

Paracetamol is abused in high doses for suicide because of its liver-toxic properties. This is strongly discouraged not only because the dying is excruciating and lasts for days. The active ingredient is also contained in fixed combinations together with opioids, which are used as intoxicants. Overdosing on such preparations poses a risk.

Contraindications

  • Hypersensitivity
  • Severe liver dysfunction, acute hepatitis, decompensated active liver disease.
  • Meulengracht’s disease

Full precautions can be found in the drug label.

Interactions

Other medicines containing acetaminophen should not be given at the same time to reduce the risk for overdose. Cold medicines in particular contain “hidden” acetaminophen. Several drug interactions are known. These include (selection):

  • Liver toxic drugs, enzyme inducers, and alcohol may increase liver toxicity.
  • Paracetamol may potentiate the effects of anticoagulants.

Adverse effects

Adverse effects are generally rare. They include an increase in liver enzymes, blood count changes, hypersensitivity reactions, skin reactions, and gastrointestinal disturbances. Skin reactions can be severe and life-threatening. Paracetamol is usually better tolerated than the nonsteroidal anti-inflammatory drugs (NSAIDs).

Overdose and liver toxicity

Taking 5 to 10 g of acetaminophen as a single dose can cause severe liver and kidney damage and death. In children, the dose is lower. Risk factors are:

  • Age: children, elderly
  • Liver disease
  • Chronic alcohol abuse
  • Chronic malnutrition, eating disorders (empty glutathione stores).
  • Enzyme-inducing drugs

Poisoning is regularly reported. Activated charcoal and N-acetylcysteine are used as antidotes.