How does paracetamol (acetaminophen) cause a decrease in bicarbonate levels?

Mechanism of Paracetamol-Induced Bicarbonate Reduction

Paracetamol (acetaminophen) causes decreased bicarbonate levels primarily through inhibition of mitochondrial respiration leading to lactic acidosis, which occurs either in massive overdose scenarios or as a consequence of established liver failure.

Primary Mechanisms

Mitochondrial Respiratory Chain Inhibition

• In massive overdose, paracetamol's toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI) directly inhibits electron transfer in the mitochondrial respiratory chain, impairing aerobic respiration and leading to lactic acid accumulation 1
• This inhibition of aerobic metabolism occurs at very high concentrations of paracetamol, preceding cellular injury by several hours 1
• The resulting lactic acidosis consumes bicarbonate as it acts as a buffer, leading to decreased bicarbonate levels

Hepatotoxicity-Induced Metabolic Acidosis

• Paracetamol is extensively metabolized in the liver, with a small fraction converted to the reactive metabolite NAPQI 2
• In overdose situations, glutathione stores become depleted, allowing NAPQI to bind to vital cell constituents, causing hepatic necrosis 2, 3
• Liver damage impairs lactate clearance, contributing to lactic acid accumulation and bicarbonate consumption 1

Clinical Scenarios of Bicarbonate Reduction

Early-Phase Lactic Acidosis

• Occurs early in massive paracetamol poisoning before hepatotoxicity develops 1
• Often associated with coma in severe overdose cases 1
• Results from direct inhibition of mitochondrial respiration by high concentrations of paracetamol metabolites

Late-Phase Lactic Acidosis

• Develops as a consequence of established liver failure in paracetamol poisoning 1
• Bicarbonate levels decrease as it's consumed in buffering the accumulating lactic acid
• Post-resuscitation arterial lactate concentration is a strong predictor of mortality in patients with paracetamol hepatotoxicity 1

Pathophysiological Sequence

1. Paracetamol overdose leads to excessive NAPQI formation 2, 3
2. NAPQI depletes glutathione stores and inhibits mitochondrial respiration 1
3. Impaired aerobic metabolism results in lactic acid production 1
4. Bicarbonate is consumed as it buffers the accumulating acid
5. Hepatic damage further impairs lactate clearance, worsening acidosis 1

Clinical Implications

• Post-resuscitation lactate measurement is recommended in all patients with severe paracetamol overdose resulting in either reduced consciousness or hepatic failure 1
• Elevated lactate levels with corresponding decreased bicarbonate are included in the modified King's College criteria for consideration of liver transplantation 1
• Early administration of N-acetylcysteine can prevent hepatic damage by replenishing glutathione stores and limiting NAPQI toxicity 2

Monitoring Considerations

• Serial monitoring of bicarbonate levels can help track the severity of metabolic acidosis in paracetamol overdose 1
• The half-life of paracetamol changes during treatment, decreasing from an initial prolonged state during N-acetylcysteine administration 4
• Repeated measurements of paracetamol concentrations and calculation of half-lives are important when using paracetamol half-life as a marker of hepatotoxicity 4

Renal Effects

• While less common than hepatotoxicity, paracetamol can also cause nephrotoxicity, which may contribute to acid-base disturbances 5
• Renal damage can occur with or without concurrent liver damage, potentially affecting bicarbonate regulation 5