Metabolic acidosis is a physiological state where the body's acid-base balance is shifted towards acidity, often indicated by a low blood pH. While various diseases can cause this condition, a significant number of cases are related to pharmacological agents. Drug-induced metabolic acidosis is categorized primarily into two types based on the serum anion gap (AG): High Anion Gap Metabolic Acidosis (HAGMA) and Normal Anion Gap Metabolic Acidosis (NAGMA). Understanding the specific mechanisms by which different drug classes trigger this adverse effect is key for clinical management and patient safety.
High Anion Gap Metabolic Acidosis (HAGMA)
HAGMA occurs when there is an accumulation of unmeasured organic acids, such as lactate or ketoacids, causing an increase in the anion gap (AG), calculated as Na$^+ - (Cl^- + HCO_3^-)$. Several medications and toxic substances can lead to HAGMA by interfering with cellular metabolism or being metabolized into acidic compounds.
Biguanides (Metformin)
Metformin, used for type 2 diabetes, can cause lactic acidosis, particularly in patients with kidney or liver problems. It inhibits mitochondrial oxidative phosphorylation, increasing anaerobic glycolysis and lactic acid buildup. Serious metformin-associated lactic acidosis (MALA) is rare but risked in those with kidney dysfunction, advanced age, or conditions like sepsis.
Salicylates (Aspirin)
Salicylate overdose can induce HAGMA by disrupting oxidative phosphorylation and the Krebs cycle, accumulating lactic acid and ketoacids. Adult toxicity often includes a mixed metabolic acidosis with respiratory alkalosis.
Antiretroviral Therapy (NRTIs)
Some NRTIs in HIV treatment, like zidovudine and stavudine, are linked to lactic acidosis due to mitochondrial toxicity. This impairs oxidative phosphorylation. Risk is higher with certain drug combinations and patient factors.
Propylene Glycol
Propylene glycol, a solvent in IV drugs like lorazepam, can be metabolized into organic acids in large doses or with renal impairment, causing HAGMA and an elevated osmolar gap.
Other causes of HAGMA
- Linezolid: This antibiotic can cause lactic acidosis by inhibiting mitochondrial protein synthesis with prolonged use.
- Propofol: Propofol infusion syndrome (PRIS) is a rare, severe complication with high-dose propofol, causing severe lactic acidosis.
- Acetaminophen (Chronic Use): Long-term acetaminophen, especially with malnutrition or sepsis, can lead to 5-oxoproline accumulation by disrupting the gamma-glutamyl cycle.
- Toxic Alcohols: Methanol and ethylene glycol ingestion cause severe HAGMA as metabolites like formic and oxalic/glycolic acid accumulate.
Normal Anion Gap Metabolic Acidosis (NAGMA)
NAGMA, or hyperchloremic metabolic acidosis, results from bicarbonate loss with a compensatory chloride rise. Medications can cause NAGMA by affecting renal acid-base handling or causing GI bicarbonate loss.
Carbonic Anhydrase (CA) Inhibitors
Drugs like acetazolamide, topiramate, and zonisamide inhibit carbonic anhydrase, reducing renal bicarbonate reabsorption and causing hyperchloremic acidosis.
Mineralocorticoid-Related Acidosis (Type 4 RTA)
Type 4 RTA is hyperkalemic, hyperchloremic NAGMA from aldosterone deficiency or resistance. Drugs affecting the RAAS can cause this:
- ACE Inhibitors and ARBs: Block aldosterone production.
- Potassium-Sparing Diuretics: Block aldosterone receptors or sodium channels.
- Heparin: Can suppress aldosterone synthesis.
- NSAIDs: Can impair renin release.
Other causes of NAGMA
- Saline Infusion (Excessive): Large volumes of 0.9% saline can cause hyperchloremic acidosis due to high chloride load.
- Sevelamer Hydrochloride: This phosphate binder exchanges chloride, increasing chloride absorption and potentially causing hyperchloremic acidosis.
- Topical Mafenide: High doses of this burn cream can inhibit carbonic anhydrase and cause NAGMA.
Comparison of Drug-Induced Metabolic Acidosis
| Feature | High Anion Gap Metabolic Acidosis (HAGMA) | Normal Anion Gap Metabolic Acidosis (NAGMA) |
|---|---|---|
| Primary Mechanism | Accumulation of unmeasured organic acids. | Loss of bicarbonate or addition of chloride. |
| Anion Gap (AG) | Elevated (>12 mEq/L). | Normal (6-12 mEq/L), with increased chloride. |
| Key Drug Classes | Metformin, Salicylates, NRTIs, Linezolid, Propofol, Propylene Glycol, Acetaminophen (chronic). | Carbonic Anhydrase Inhibitors, ACEIs, ARBs, K-sparing diuretics, Sevelamer HCl. |
| Toxin Ingestions | Methanol, Ethylene Glycol, Isoniazid. | Toluene abuse can sometimes cause a mixed picture, but often presents with NAGMA. |
| Pathophysiology | Mitochondrial dysfunction, enzyme inhibition, or metabolism of toxic substances. | Impaired renal bicarbonate reabsorption or increased renal/GI bicarbonate loss. |
Conclusion
Drug-induced metabolic acidosis is a complex and potentially life-threatening condition from various medications and mechanisms. HAGMA often involves organic acid accumulation from mitochondrial toxicity or precursor metabolism (metformin, NRTIs, salicylates). NAGMA typically involves disturbed renal acid handling or intestinal bicarbonate loss (carbonic anhydrase inhibitors, RAAS drugs). Clinicians need a high index of suspicion, especially with risk factors like renal or hepatic impairment, and should review medication history when acid-base disturbances are found. Early identification, discontinuing the offending agent, and supportive care are crucial for better patient outcomes. Managing drug-induced acid-base disturbances is complex and requires understanding underlying causes, as reviewed in sources like Drug Safety from Springer Link.
Disclaimer: This information is for educational purposes and is not a substitute for professional medical advice. Always consult a healthcare provider for diagnosis and treatment.
