Acetazolamide and certain other drugs can cause metabolic acidosis, which may be classified as high anion gap (AG) or non-anion gap (non-AG) based on the underlying mechanism. Below, I’ll explain acetazolamide’s role, other drugs causing metabolic acidosis, and how to differentiate between high AG and non-AG acidosis, including relevant clinical context.

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Metabolic Acidosis Overview

• Definition: A decrease in blood pH due to reduced bicarbonate (HCO₃⁻) levels or accumulation of acid.
• Anion Gap (AG): Calculated as:AG=Na+−(Cl−+HCO3−)AG = \text{Na}^+ – (\text{Cl}^- + \text{HCO}_3^-)AG = \text{Na}^+ - (\text{Cl}^- + \text{HCO}_3^-)
  • Normal AG: ~8–12 mEq/L (varies by lab).
  • High AG acidosis: Caused by accumulation of unmeasured anions (e.g., lactate, ketones).
  • Non-AG acidosis: Caused by bicarbonate loss or chloride gain, maintaining a normal AG.

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Acetazolamide and Metabolic Acidosis

• Mechanism:
  • Acetazolamide is a carbonic anhydrase inhibitor used for glaucoma, altitude sickness, and edema.
  • It inhibits carbonic anhydrase in the proximal tubule of the kidney, reducing bicarbonate reabsorption.
  • This leads to bicarbonate loss in urine, causing a non-anion gap metabolic acidosis (hyperchloremic acidosis).
• Type: Non-AG acidosis.
  • The loss of HCO₃⁻ is balanced by increased chloride (Cl⁻) reabsorption to maintain electroneutrality, keeping the AG normal.
• Clinical Features:
  • Mild acidosis (HCO₃⁻ typically 15–20 mEq/L).
  • Hyperchloremia (elevated Cl⁻).
  • Compensatory respiratory alkalosis (hyperventilation, low PCO₂).
  • Common in prolonged use or high doses (e.g., >250 mg/day).
• Context:
  • Often seen in patients on acetazolamide for glaucoma, altitude sickness, or as a diuretic.
  • Acidosis is usually well-tolerated but may cause fatigue, confusion, or dyspnea in severe cases.

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Other Drugs Causing Metabolic Acidosis

1. Drugs Causing Non-Anion Gap Metabolic Acidosis

These drugs typically cause bicarbonate loss or chloride retention, leading to hyperchloremic acidosis.

• Other Carbonic Anhydrase Inhibitors:
  • Topiramate: An anticonvulsant with weak carbonic anhydrase inhibition, causing bicarbonate loss similar to acetazolamide.
  • Zonisamide: Another anticonvulsant with similar effects.
• Amphotericin B:
  • Causes distal renal tubular acidosis (RTA) by damaging renal tubules, impairing H⁺ secretion and HCO₃⁻ reabsorption.
  • Results in non-AG acidosis with hypokalemia.
• Cholestyramine:
  • A bile acid sequestrant that can bind HCO₃⁻ in the gut, leading to mild non-AG acidosis.
• Lithium:
  • Rarely causes distal RTA by impairing renal acid excretion, leading to non-AG acidosis.
• Saline Infusions (Large Volumes):
  • High chloride content in 0.9% saline can cause hyperchloremic acidosis by diluting HCO₃⁻ and increasing Cl⁻ relative to Na⁺.

2. Drugs Causing High Anion Gap Metabolic Acidosis

These drugs lead to accumulation of endogenous or exogenous acids, increasing the AG.

• Metformin:
  • Associated with lactic acidosis, especially in renal impairment or overdose.
  • Mechanism: Inhibits mitochondrial respiration, increasing lactate production.
  • High AG due to elevated lactate levels.
• Nucleoside Reverse Transcriptase Inhibitors (e.g., Zidovudine, Stavudine):
  • Cause mitochondrial dysfunction, leading to lactic acidosis.
  • High AG acidosis, often severe.
• Propylene Glycol (Solvent in IV Drugs, e.g., Lorazepam, Diazepam):
  • Metabolized to lactate and pyruvate, causing lactic acidosis.
  • Common in prolonged high-dose infusions (e.g., in ICU settings).
  • High AG due to lactate accumulation.
• Salicylates (Aspirin Overdose):
  • Cause lactic acidosis (by uncoupling oxidative phosphorylation) and ketoacidosis (in severe cases).
  • High AG acidosis, often mixed with respiratory alkalosis due to salicylate-induced hyperventilation.
• Methanol and Ethylene Glycol:
  • Toxic alcohols metabolized to formic acid (methanol) or glycolic/oxalic acid (ethylene glycol).
  • High AG acidosis due to these acidic metabolites.
  • Often accompanied by osmolar gap and severe toxicity.
• Isoniazid:
  • Can cause lactic acidosis by inhibiting lactate metabolism, especially in overdose.
  • High AG acidosis, often with seizures.
• Linezolid:
  • Rarely causes lactic acidosis due to mitochondrial toxicity with prolonged use.
  • High AG acidosis.

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Differentiating High AG vs. Non-AG Acidosis

To determine the type of acidosis caused by a drug, follow these steps:

1. Confirm Metabolic Acidosis:
   • Arterial blood gas (ABG): Low pH (<7.35) and low HCO₃⁻ (<22 mEq/L).
   • Check for compensatory respiratory response (low PCO₂).
2. Calculate Anion Gap:
   • Use: AG=Na+−(Cl−+HCO3−)AG = \text{Na}^+ – (\text{Cl}^- + \text{HCO}_3^-)AG = \text{Na}^+ - (\text{Cl}^- + \text{HCO}_3^-).
   • High AG (>12 mEq/L): Suggests accumulation of acids (e.g., lactate, ketones, toxic metabolites).
   • Normal AG (8–12 mEq/L): Suggests HCO₃⁻ loss or Cl⁻ gain.
3. Measure Additional Labs:
   • Lactate: Elevated in high AG acidosis (e.g., metformin, propylene glycol).
   • Ketones: Positive in ketoacidosis (e.g., salicylates).
   • Serum Osmolality: Elevated osmolar gap in methanol/ethylene glycol poisoning.
   • Urine pH and Electrolytes: Useful in non-AG acidosis (e.g., high urine pH in RTA from amphotericin B).
4. Clinical Context:
   • Review medications, dose, duration, and comorbidities (e.g., renal failure increases risk of metformin-induced lactic acidosis).
   • Consider mixed acid-base disorders (e.g., salicylates causing high AG acidosis + respiratory alkalosis).

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Key Examples

• Acetazolamide:
  • Non-AG acidosis (HCO₃⁻ loss, high Cl⁻, normal AG).
  • Example labs: pH 7.32, HCO₃⁻ 18 mEq/L, Cl⁻ 110 mEq/L, AG 10 mEq/L.
• Metformin Overdose:
  • High AG acidosis (lactate accumulation).
  • Example labs: pH 7.15, HCO₃⁻ 10 mEq/L, lactate 8 mmol/L, AG 20 mEq/L.
• Amphotericin B:
  • Non-AG acidosis (distal RTA, low K⁺, high urine pH).
  • Example labs: pH 7.30, HCO₃⁻ 16 mEq/L, Cl⁻ 108 mEq/L, AG 12 mEq/L, K⁺ 3.0 mEq/L.

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Management Principles

• Non-AG Acidosis (e.g., Acetazolamide):
  • Stop or reduce the offending drug if possible.
  • Administer oral or IV bicarbonate for severe acidosis (pH <7.2 or HCO₃⁻ <15 mEq/L).
  • Correct electrolyte imbalances (e.g., K⁺, Mg²⁺).
• High AG Acidosis (e.g., Metformin, Methanol):
  • Treat the underlying cause (e.g., hemodialysis for metformin or methanol poisoning).
  • Supportive care: IV fluids, bicarbonate if pH <7.1, and address lactate or toxin removal.
  • Specific antidotes (e.g., fomepizole for methanol/ethylene glycol).

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Summary

• Acetazolamide: Causes non-AG metabolic acidosis via bicarbonate loss in urine.
• Non-AG Acidosis Drugs: Topiramate, amphotericin B, lithium, cholestyramine, saline infusions.
• High AG Acidosis Drugs: Metformin, salicylates, methanol, ethylene glycol, propylene glycol, isoniazid, linezolid, nucleoside analogs.
• Diagnosis: Use AG calculation, lactate, ketones, and clinical context to differentiate.
• Management: Stop the drug, correct acidosis, and treat underlying causes.