From the Guidelines
Medications that can cause anion gap metabolic acidosis include salicylates, metformin, alcohols, certain anticonvulsants, nucleoside reverse transcriptase inhibitors, propylene glycol, isoniazid, linezolid, and iron. These medications can cause acidosis through various mechanisms, such as inhibiting the Krebs cycle, increasing lactic acid, or being metabolized to organic acids. When a patient presents with unexplained anion gap metabolic acidosis, a thorough medication review is essential to identify potential offending agents, as seen in a study published in 1. Treatment involves discontinuing the offending agent when possible, providing supportive care, and in some cases administering specific antidotes, as discussed in a review of ethylene glycol poisoning treatment in 1 and 1. Patients with renal impairment are at higher risk for drug-induced metabolic acidosis and may require dose adjustments of certain medications, as highlighted in guidelines for managing chronic kidney disease in HIV-infected patients 1. Key medications to consider in the context of anion gap metabolic acidosis include:
- Salicylates (aspirin)
- Metformin, particularly in patients with renal impairment 1
- Alcohols (ethanol, methanol, ethylene glycol)
- Certain anticonvulsants (valproic acid, topiramate)
- Nucleoside reverse transcriptase inhibitors (NRTIs) used in HIV treatment
- Propylene glycol (a vehicle in some IV medications like lorazepam and diazepam)
- Isoniazid
- Linezolid
- Iron It is crucial to prioritize the identification and management of these medications in patients presenting with anion gap metabolic acidosis to improve morbidity, mortality, and quality of life outcomes.
From the FDA Drug Label
Table 3: Clinically Significant Drug Interactions with Metformin Hydrochloride Tablets Carbonic Anhydrase Inhibitors Clinical Impact: Carbonic anhydrase inhibitors frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis Concomitant use of these drugs with metformin hydrochloride tablets may increase the risk for lactic acidosis.
The medications that can cause anion gap metabolic acidosis are not directly listed, but lactic acidosis, a type of anion gap metabolic acidosis, may be increased by concomitant use of metformin with certain drugs, including:
- Carbonic Anhydrase Inhibitors (e.g., topiramate, zonisamide, acetazolamide or dichlorphenamide)
- Drugs that Reduce metformin hydrochloride tablet Clearance (e.g., ranolazine, vandetanib, dolutegravir, and cimetidine)
- Alcohol 2
From the Research
Medications Causing Anion Gap Metabolic Acidosis
- Biguanides, such as metformin, can cause anion gap metabolic acidosis, particularly in patients with renal dysfunction 3, 4, 5, 6
- Salicylates can also induce anion gap metabolic acidosis 7
- Other medications that may contribute to anion gap metabolic acidosis include:
- Alcohols 7
- Polyhydric sugars 7
- Cyanide and carbon monoxide 7
- Histamine-2 receptor antagonists, which can reduce renal elimination of metformin 5
- Ribociclib, which can also reduce renal elimination of metformin 5
- Diclofenac sodium, which may have contributed to lactic acidosis in a patient with metformin-associated lactic acidosis 6
Key Factors Contributing to Anion Gap Metabolic Acidosis
- Renal impairment or dysfunction, which can reduce the clearance of metformin and increase the risk of lactic acidosis 3, 4, 5, 6
- Excessive alcohol consumption, which can consume nicotinamide adenine dinucleotides required for lactate metabolism 5
- Pre-existing chronic kidney disease, which can increase the risk of metformin-associated lactic acidosis 4, 5, 6