What medications can worsen metabolic acidosis?

Medications That Worsen Metabolic Acidosis

The most clinically significant medications that worsen metabolic acidosis are metformin (especially with renal impairment), carbonic anhydrase inhibitors like acetazolamide, and sodium bicarbonate itself when used inappropriately, along with several other drug classes that either increase acid production or impair acid excretion.

High-Risk Medications by Mechanism

Metformin and Biguanides

• Metformin is the most clinically significant drug cause of lactic acidosis, with an incidence of 2-9 per 100,000 patients/year, and risk dramatically increases with renal impairment 1, 2.
• The FDA mandates metformin should not be used when eGFR <30 mL/min/1.73 m², and it should be discontinued immediately in patients with sepsis, acute kidney injury, or hypoxic states 1.
• Metformin carries an FDA Black Box Warning for lactic acidosis, which though rare, can result in death, hypothermia, hypotension, and resistant bradyarrhythmias 3.
• Risk factors for metformin-associated lactic acidosis include renal impairment, age ≥65 years, concomitant use of carbonic anhydrase inhibitors, radiologic studies with contrast, surgery, hypoxic states (including acute heart failure), excessive alcohol intake, and hepatic impairment 3.

Carbonic Anhydrase Inhibitors (Acetazolamide, Methazolamide)

• Acetazolamide causes normal anion gap metabolic acidosis by inhibiting renal bicarbonate reabsorption, and can cause severe, life-threatening acidosis particularly in elderly patients, those with advanced renal failure, and diabetic patients 4, 2.
• Acetazolamide is contraindicated in patients undergoing dialysis and should be used with extreme caution in chronic kidney disease 5.
• When given during uncompensated COPD exacerbations, acetazolamide worsens acidosis and can cause clinical deterioration by reducing bicarbonate buffering capacity before the patient can adequately compensate respiratorily 6.
• The concomitant use of acetazolamide with aspirin in patients with even mild renal impairment can cause severe metabolic acidosis and hyperammonemia 5.

Sodium Bicarbonate (Paradoxical Worsening)

• Sodium bicarbonate can paradoxically worsen metabolic acidosis when given without effective ventilation, as it produces excess CO2 that cannot be eliminated, leading to respiratory acidosis 3.
• Routine initial use of sodium bicarbonate to treat cardiac arrest is not recommended, and it should only be used after effective ventilation has been established 3.

Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

• NRTIs, particularly stavudine and didanosine used in HIV treatment, cause mitochondrial toxicity leading to lactic acidosis with an incidence of approximately 1.3 cases per 1,000 person-years of exposure 1, 2.
• Risk factors include obesity, female sex, prolonged use (>6 months), and pregnancy 1.

Salicylates (Aspirin)

• Salicylates induce anion gap metabolic acidosis through multiple mechanisms including uncoupling oxidative phosphorylation and increasing organic acid production 2.
• Aspirin combined with acetazolamide in patients with chronic kidney disease creates particularly severe metabolic acidosis 5.

Toxic Alcohols and Related Substances

• Methanol and ethylene glycol produce toxic anions (formate and glycolate respectively) that cause severe anion gap metabolic acidosis 2.
• Toluene causes normal anion gap metabolic acidosis 2.

Other Medications

• Thiazolidinediones carry an FDA Black Box Warning and are not recommended in symptomatic heart failure, which can lead to tissue hypoperfusion and lactic acidosis 3.
• Hydrochloride salts of amino acids cause normal anion gap acidosis 2.
• Amphotericin produces normal anion gap metabolic acidosis through renal tubular dysfunction 2.
• Spironolactone can cause hyperchloremic metabolic acidosis 2.
• Non-steroidal anti-inflammatory drugs (NSAIDs) may cause normal anion gap acidosis through renal mechanisms 2.

Critical Clinical Scenarios to Avoid

Acetazolamide-Specific Pitfalls

• Never give acetazolamide in acute, uncompensated respiratory acidosis (pH <7.35 with elevated CO2 and no metabolic compensation), as it will worsen acidosis by removing bicarbonate buffer before respiratory compensation can occur 6.
• Acetazolamide should only be used in post-hypercapnic alkalosis or chronic compensated respiratory acidosis with metabolic alkalosis 7, 6.
• Avoid acetazolamide in patients with eGFR <30 mL/min/1.73 m² or in combination with aspirin in any patient with chronic kidney disease 5.

Metformin-Specific Pitfalls

• Discontinue metformin immediately in any patient presenting with sepsis, acute illness with hemodynamic instability, or acute kidney injury 1.
• Do not restart metformin until the patient is clinically stable and renal function has returned to baseline 1.

Bicarbonate Administration Pitfalls

• Do not administer sodium bicarbonate for metabolic acidosis from tissue hypoperfusion in sepsis, as it does not improve hemodynamics and may worsen outcomes 7.
• Never give bicarbonate by endotracheal route 3.
• Do not mix sodium bicarbonate with vasoactive amines or calcium 3.

Monitoring Requirements

For Patients on High-Risk Medications

• Monitor serum bicarbonate monthly in patients with chronic kidney disease taking metformin, maintaining levels ≥22 mmol/L 3, 7.
• Check renal function (eGFR) regularly in all patients on metformin, not just serum creatinine, as creatinine varies with age, ethnicity, and muscle mass 1.
• In patients on acetazolamide, monitor for subtle early symptoms including nonspecific gastrointestinal symptoms, dyspnea, generalized weakness, and myalgias, which often precede severe acidosis 1.

When Acidosis Develops

• Obtain arterial blood gas to determine pH and PaCO2 for complete acid-base assessment when bicarbonate <18 mmol/L or clinical deterioration occurs 7.
• Calculate anion gap (Na - [Cl + CO2]) to differentiate between anion gap and normal anion gap acidosis, with >16 indicating anion gap acidosis 1.
• Measure serum lactate if anion gap acidosis is present, with levels >2 mmol/L considered elevated and >5 mmol/L considered seriously abnormal 1.