Pharmacology of Paracetamol

PHARMACOLOGY OF PARACETAMOL

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Introduction to Paracetamol

• Also known as acetaminophen or N-acetyl-p-aminophenol.

• Classification: Paracetamol is an anilide analgesic.

• Active Metabolite: It is the active metabolite of phenacetin.

• Historical Use of Phenacetin:

  • Introduced in 1887 as an analgesic and antipyretic.

  • Used extensively in analgesic mixtures but withdrawn due to nephropathy caused by analgesic abuse.

• Effects of Paracetamol:

  • Analgesic effect (pain relief).

  • Antipyretic effect (fever reduction).

  • No Anti-inflammatory Effects: Ineffective in inflammatory conditions.

Mechanism of Action (MoA)

• Understanding:

  • The exact mechanism of action remains debated and not fully elucidated despite its long history of use.

  • Postulated to exert analgesic effects mainly through central rather than peripheral mechanisms.

• Metabolism in the Liver:

  • Paracetamol is hepatically deacetylated to produce p-aminophenol.

  • In the brain, p-aminophenol is metabolized by the enzyme FAAH (fatty acid hydrolase) to form AM404, which is primarily found in the brain.

Further Details on Mechanism of Action

• Hydrolysis in the Liver:

  • Paracetamol undergoes hydrolysis, producing:

  • p-aminophenol

  • AM404 (N-arachidonoylphenolamine)

• Actions of AM404:

  1. Acts as an inhibitor of COX (cyclooxygenases).

  2. Increases levels of the endogenous cannabinoid compound anandamide, which involves the CB1 receptor.

  3. Influences the TRPV (transient receptor potential vanilloid) system.

  4. Increases serotonin levels (5-HT).

The COX Pathway

• Eicosanoids:

  • Key mediators and modulators of inflammation, examples include PGE2, PGI2, and TXA2.

  • Generated in cells as needed; they are not stored.

• Arachidonic Acid Metabolism:

  • Metabolized in a two-step process to prostanoids by prostaglandin H2 synthetase (PGHS), commonly referred to as COX.

  • Key Enzyme Functions:

  • PGH2 has an active COX site and an active POX (peroxidase) site.

  • For COX to be active, it must be in oxidized form.

  • Paracetamol acts as a reducing co-substrate at the POX site, preventing oxidation.

• Cellular Context:

  • In intact cells (low arachidonic acid levels, CNS), paracetamol inhibits prostaglandin synthesis by preventing regeneration of the POX site.

  • In broken cells (higher levels of arachidonic acid, PNS), prostaglandin synthesis is only weakly inhibited.

Serotonin Pathway Activation

• Role of Serotonin:

  • Part of the descending pain modulation system stemming from various regions of the brain.

  • Interaction with pain afferents in the dorsal horn contributes to pain perception.

• Impact of Paracetamol:

  • Studies indicate that paracetamol elevates levels of 5-HT in several CNS areas, modulating and reducing pain perception.

TRPV1 Receptor

• AM404 Effects:

  • It is identified as a potent activator of the capsaicin receptor TRPV1 (Transient Receptor Potential Vanilloid 1).

  • Experimental studies blocking the TRPV1 receptor demonstrated the prevention of paracetamol's analgesic effects, indicating its significance in the mechanism of action.

Pharmacology of Paracetamol

Absorption and Distribution

• Absorption Characteristics:

  • Paracetamol exhibits good oral bioavailability (though it can be variable).

  • The absorption process occurs predominantly in the small intestine; gastric emptying is the rate-limiting step and may be influenced by food intake, drugs, pregnancy, or co-morbidities (such as migraine).

  • Peak plasma concentrations are typically reached within 2 hours.

  • Half-life (T1/2) is approximately 2 hours.

  • Plasma protein binding is variable but usually not a clinical concern regarding drug interactions.

• Distribution:

  • Paracetamol rapidly and uniformly distributes throughout body tissues.

  • Volume of distribution (Vd) is around $0.9 ext{ L/kg}$.

Metabolism

• Metabolism Process:

  • Hepatically metabolized through three primary pathways:

  1. Glucuronidation (50%)

  2. Sulphation

  3. Oxidative reduction and hydrolysis to generate non-toxic metabolites.

• Formation of Toxic Metabolite:

  • A small percentage is metabolized via CYP450 enzymes to form N-acetyl-p-benzo-quinone imine (NAPQI), which is the toxic metabolite.

  • NAPQI is detoxified by conjugating with glutathione, resulting in cysteine and mercapturatic acid conjugates, which are primarily eliminated renally.

  • In conditions of glutathione insufficiency, NAPQI can cause acute hepatic necrosis by interacting with hepatic cell membrane molecules.

Glutathione Insufficiency

• Possible causes of glutathione insufficiency include:

  • Paracetamol overdose

  • Genetic glutathione deficiency

  • Theoretical insufficiency in the elderly and infants

  • Starvation and malnutrition

Elimination

• Post-metabolism, paracetamol is mainly eliminated renally as inactive glucuronide and sulphate conjugates, with less than 5% excreted unchanged.

Side Effects at Therapeutic Doses

• Rarely seen at normal therapeutic doses.

• Possible adverse effects include:

  • Hypersensitivity reactions

  • Neutropenia

  • Thrombocytopenia

  • Renal effects (more likely with chronic use, especially with multiple analgesic utilization).

  • Abdominal pain (particularly associated with long-term use).

Cautions and Contraindications

• Contraindications:

  • Severe hepatic dysfunction

  • Severe renal failure

• Cautions:

  • Patients with a history of alcoholism

  • Hepatic dysfunction

  • Renal dysfunction

  • G6PD deficiency

Clinical Uses of Paracetamol

• Primarily used as an analgesic and antipyretic.

• Particularly advantageous when aspirin is contraindicated.

• Dosages (Adults):

  • Pain and fever (oral): $500 ext{ mg} - 1 ext{ g}$ every 4-6 hours as needed, maximum of $4 ext{ g/day}$.

  • Post-operative pain (patients over 50 kg): $1 ext{ g}$ up to 4 times a day intravenously or orally during the first 24 hours.

  • Post-operative pain (patients under 50 kg): administer pediatric doses of $15 ext{ mg/kg}$.

• Adjustments for Renal Impairment:

  • For patients with a GFR of $10-50 ext{ mL/min}$: administer every 6 hours.

  • For patients with a GFR of less than $10 ext{ mL/min}$: administer every 8 hours.

• Overdose Considerations:

  • Ingesting $10-15 ext{ g}$ can lead to hepatotoxicity.

  • Ingesting $20-25 ext{ g}$ can be potentially fatal.

Drug Interactions and Formulations

• Drug Interactions (D/Is):

  • Paracetamol may potentiate the effects of warfarin; monitoring of INR is advised, reducing the paracetamol dose to a maximum of $2 ext{ g/day}$.

• Formulations Available:

  • Tablets

  • Capsules

  • Caplets

  • Effervescent tablets

  • Syrup

  • Infant drops

  • Injection

  • Suspension

  • Combination products

Paracetamol Overdose Management

Introduction to Overdose

• Causes of Paracetamol Toxicity:

  • Acute ingestion of paracetamol:

  • For adults: ingestion of $10 ext{ g}$ or more, or $200 ext{ mg/kg}$ (whichever is less).

  • For children under 6 years: ingestion of $ext{≥} 200 ext{ mg/kg}$.

  • Hepatic and renal damage may manifest 2 to 5 days post-ingestion.

  • Repeated supra-therapeutic ingestion of paracetamol (RSTI):

  • Multiple ingestions, often at prescribed doses, or uses of numerous paracetamol-containing products over a period of 24 hours or longer:

    1. $10 ext{ g}$ or $200 ext{ mg/kg}$ (lesser amount) ingested in 24 hours.

    2. $12 ext{ g}$ or $300 ext{ mg/kg}$ (lesser amount) ingested in 48 hours.

    3. A daily therapeutic dose of $60 ext{ mg/kg/day}$ for over 48 hours in patients exhibiting symptoms (e.g., abdominal pain, nausea, vomiting).

Symptom Progression

• Initial Symptoms (within 0.5 to 24 hours after acute overdose):

  • Patients may be asymptomatic or exhibit:

  • Gastrointestinal irritability

  • Anorexia

  • Nausea and Vomiting (N&V)

  • Abdominal pain

• Subsequent Symptoms (during the next 24-48 hours):

  • Symptoms may decrease, but blood chemistry shows abnormalities:

  • INR should be $≤ 1.3$.

  • Elevated ALT levels.

• Severe Poisoning Outcomes:

  • Progressive hepatic failure can occur within 2 to 5 days, leading to:

  • Severe metabolic issues like hypoglycaemia and hyperammonaemia.

  • Coagulopathy

  • Renal failure.

Treatment Options

• Gastric Lavage and Activated Charcoal:

  • Used within the first 1 to 2 hours post-ingestion if a large amount was consumed.

  • Avoid activated charcoal if an oral antidote is being administered.

• Acetylcysteine:

  • Antidote of choice for paracetamol overdose.

  • Administration is ideally within 8 hours of ingestion; it is emphasized that it is never too late to begin acetylcysteine treatment.

  • Preferred Route: Intravenous infusion.

• Alternatives if acetylcysteine is unavailable:

  • Oral carbocysteine

  • Methionine.

When to Start Acetylcysteine

• Plasma Concentrations:

  • Obtain plasma concentrations of paracetamol 4 hours after ingestion, as earlier levels do not reflect peak concentrations.

  • If sustained-release formulations were used, recheck levels 4 hours post-first test.

  • If patients present more than 24 hours after overdose with detectable plasma concentrations or biochemical evidence of hepatotoxicity, acetylcysteine should be administered.

  • If initial paracetamol concentration is in the toxic range, proceed with administration of acetylcysteine.

• Indications for Immediate Administration:

  • If unsure about the timing of paracetamol ingestion, administer acetylcysteine and monitor kidney and liver function.

  • If the quantity consumed is potentially toxic.

Monitoring During Treatment

• Key Parameters:

  • Monitor plasma potassium levels as hypokalaemia can occur irrespective of treatment.

  • If paracetamol concentrations are in the toxic range, monitor daily:

  • Hepatic function

  • Renal function

  • Glucose levels (lactic acidosis and hyperglycaemia may appear hours before liver injury).

  • INR levels.

• Considerations:

  • Hemodialysis may be indicated for patients presenting with altered mental status, metabolic acidosis, and elevated lactate levels.

  • Treatment should continue until paracetamol concentrations are below $10 ext{ mcg/mL}$ and hepatic function shows improvement.

N-acetylcysteine, Carbocysteine, Methionine

N-acetylcysteine - Mechanism of Action

• Recall: NAPQI is detoxified via conjugation with glutathione, forming cysteine and mercapturatic acid conferring renally eliminated properties.

• Acetylcysteine converts to cysteine, necessary for glutathione production, stimulating hepatic glutathione synthesis.

• It may also form a direct adduct with NAPQI (N-acetyl-p-benzoquinone imine).

N-acetylcysteine - Cautions

• Use cautiously in patients with asthma history.

• Monitor for hypersensitivity reactions, which can range from skin rash to anaphylaxis caused by histamine release.

  • In mild cases, cease acetylcysteine temporarily, administer an antihistamine, and then continue infusion.

• Considered safe in pregnancy, lactation, and in patients with porphyria.

Dosage for N-acetylcysteine

• Adult Dosage: 200 mg/kg in 500 mL of 5% dextrose infused over 4 hours, followed by:

  • 100 mg/kg in 1 L of dextrose over 4 to 16 hours.

  • 150 mg/kg in 1 L of dextrose over 24 hours.

• Guidance for Second 24 Hours:

  • Extended therapy may be necessary in severe poisoning or where treatment was initiated late.

Carbocysteine

• Animal Studies: Indicate it does not provide adequate protection against liver damage.

• Contraindications: Active peptic ulceration.

• Cautions:

  • History of peptic ulcer disease.

  • Patients with porphyria.

• Potential Side Effects include:

  • Headaches.

  • Gastrointestinal disturbances (nausea, diarrhea, bleeding).

  • Skin rashes.

• Dosage Recommendation: 150 mg/kg every 4 hours for 24 hours (oral).

Methionine

• Effective in paracetamol overdose; however, safety and efficacy beyond 15 hours post-ingestion are not established.

• Dosage:

  • Oral = 2.5 g every 4 hours for a total of 4 doses, taken within 10 to 12 hours post-ingestion.

  • Can be mixed with orange juice or soft drink.

• Considered relatively safe during pregnancy and lactation.

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