Which drug increases metabolic acidosis?: A Guide to Pharmacological Causes

According to the National Institutes of Health, drug-induced metabolic acidosis is a significant clinical concern, with numerous medications implicated in altering the body's acid-base balance. This guide explains which drug increases metabolic acidosis and the distinct mechanisms behind these adverse effects, from common prescriptions to accidental ingestions.

Quick Summary

Several medications can disrupt the body's acid-base balance, leading to metabolic acidosis. This article details drugs like metformin, salicylates, and carbonic anhydrase inhibitors that cause high or normal anion gap metabolic acidosis and outlines the different mechanisms and necessary management strategies.

Key Points

• Metformin and Lactic Acidosis: Metformin can cause high anion gap metabolic acidosis (HAGMA) by inhibiting mitochondrial respiration, especially in patients with impaired renal function.

• Salicylates and Mixed Disorder: Overdose of salicylates leads to HAGMA by uncoupling oxidative phosphorylation and a simultaneous respiratory alkalosis from direct respiratory center stimulation.

• Carbonic Anhydrase Inhibitors and NAGMA: Drugs like acetazolamide and topiramate cause normal anion gap metabolic acidosis (NAGMA) by inhibiting carbonic anhydrase, leading to renal bicarbonate wasting.

• Toluene Abuse and Hyperchloremic Acidosis: Chronic toluene sniffing can induce NAGMA by increasing hippuric acid production, which promotes bicarbonate excretion.

• Management Depends on the Cause: Treatment for drug-induced acidosis involves stopping the offending medication, supportive care, and potentially alkali therapy or hemodialysis for severe cases.

• Monitoring is Key for Prevention: Patients on high-risk medications, such as topiramate, should have their serum bicarbonate levels regularly monitored to detect and manage acidosis early.

Understanding Metabolic Acidosis

Metabolic acidosis is an acid-base disorder characterized by a low blood pH ($<7.35$) and a low serum bicarbonate concentration ($<22$ mEq/L). It is often classified by the anion gap (AG), which represents unmeasured anions. There are two main types: high anion gap metabolic acidosis (HAGMA) caused by accumulated organic acids like lactate, and normal anion gap metabolic acidosis (NAGMA) resulting from bicarbonate loss or hydrogen ion retention balanced by increased chloride. Distinguishing between HAGMA and NAGMA is key to diagnosis and management.

Medications Causing High Anion Gap Metabolic Acidosis

Metformin

Metformin can lead to lactic acidosis, a rare HAGMA, especially with overdose or kidney/liver issues. It increases lactate production by affecting mitochondrial respiration.

Salicylates (Aspirin)

Salicylate overdose causes acid-base imbalance. Salicylates disrupt energy production, leading to lactic acid buildup (HAGMA), and stimulate breathing, causing respiratory alkalosis. This often results in a combined disorder.

Other Agents Inducing Lactic Acidosis

Some medications cause HAGMA via increased lactic acid production. These include the antibiotic Linezolid, certain HIV medications (NRTIs) that harm mitochondria, and Propylene Glycol found in some IV drugs, which is converted to lactic acid.

Medications Causing Normal Anion Gap Metabolic Acidosis

Carbonic Anhydrase Inhibitors

Drugs such as acetazolamide and the epilepsy drug topiramate block carbonic anhydrase, leading to bicarbonate loss in urine and NAGMA. This can lower bicarbonate levels and cause issues like kidney stones.

Medications Affecting Aldosterone and Potassium

Drugs impacting the renin-angiotensin-aldosterone system can cause NAGMA with high potassium. This includes potassium-sparing diuretics (like spironolactone) and blood pressure medications (ACE inhibitors, ARBs).

Other Causes of Normal Anion Gap Acidosis

Other causes of NAGMA include toluene exposure (due to hippuric acid production) and sevelamer hydrochloride, which increases bicarbonate loss.

Drug-Induced Metabolic Acidosis Comparison

Drug Class / Agent	Acidosis Type	Mechanism of Action	Common Clinical Context
Metformin	High Anion Gap	Inhibits mitochondrial respiration, increasing lactate production.	Diabetes; often involves overdose or renal impairment.
Salicylates	High Anion Gap (Mixed)	Uncouples oxidative phosphorylation, stimulating anaerobic metabolism.	Acute or chronic overdose.
Acetazolamide	Normal Anion Gap	Inhibits carbonic anhydrase, leading to bicarbonate loss in urine.	Glaucoma, altitude sickness, heart failure.
Topiramate	Normal Anion Gap	Inhibits carbonic anhydrase, causing renal tubular acidosis.	Epilepsy, migraine prophylaxis.
Toluene	Normal Anion Gap	Metabolism to hippuric acid, resulting in hyperchloremic acidosis.	Chronic solvent abuse.
Potassium-Sparing Diuretics	Normal Anion Gap	Blocks aldosterone, reducing renal hydrogen and potassium excretion.	Hypertension, heart failure; especially with hyperkalemia.

Management and Reversal

Treating drug-induced metabolic acidosis primarily involves stopping the causative drug. Severe cases (pH <7.2) may require IV sodium bicarbonate, while ongoing issues might use oral citrate. Hemodialysis can remove substances like salicylates or toxic alcohols in poisoning cases. Supportive care addresses underlying conditions and electrolyte imbalances. For methanol or ethylene glycol poisoning, fomepizole can prevent acid buildup. Regular bicarbonate monitoring is recommended for patients on drugs like topiramate. Dosage adjustments or medication changes may be necessary if acidosis persists.

Conclusion

Drug-induced metabolic acidosis should be considered in patients with acid-base disturbances. The type of acidosis and the drug's mechanism guide treatment, typically involving stopping the drug, supportive care, and sometimes interventions like hemodialysis. Identifying which drug increases metabolic acidosis is crucial for patient safety. Further information on drug mechanisms is available from resources like the National Institutes of Health (NIH).

Frequently Asked Questions

What is the most common drug to cause metabolic acidosis?

Metformin is a commonly prescribed drug associated with metabolic acidosis, specifically lactic acidosis, though this is a rare complication and typically occurs in cases of overdose or pre-existing renal impairment.

Can over-the-counter medications cause metabolic acidosis?

Yes, an overdose of salicylates, such as aspirin, can cause a severe mixed acid-base disturbance that includes high anion gap metabolic acidosis.

What is the difference between high and normal anion gap acidosis?

High anion gap metabolic acidosis (HAGMA) results from the accumulation of unmeasured acids (like lactate), while normal anion gap metabolic acidosis (NAGMA) occurs from the loss of bicarbonate, typically balanced by increased chloride.

How do carbonic anhydrase inhibitors cause metabolic acidosis?

By inhibiting the enzyme carbonic anhydrase, these medications reduce the kidney's ability to reabsorb bicarbonate, causing it to be lost in the urine and leading to normal anion gap metabolic acidosis.

Which drugs can cause metabolic acidosis through kidney problems?

Several drugs, including carbonic anhydrase inhibitors like topiramate and acetazolamide, can cause metabolic acidosis by inducing renal tubular acidosis, which impairs the kidney's ability to handle acid-base balance.

Is metabolic acidosis a side effect of epilepsy medication?

Yes, some anticonvulsants, most notably topiramate, are known to cause metabolic acidosis by inhibiting carbonic anhydrase in the kidneys. Another anticonvulsant, valproic acid, can also contribute to acidosis.

What is the first step in treating drug-induced metabolic acidosis?

The initial and most critical step is to identify and discontinue the drug that is causing the metabolic acidosis. After that, supportive care and other specific interventions can be implemented.