Understanding Drug-Induced Hyperlactatemia and Lactic Acidosis
Elevated lactate in the blood, known as hyperlactatemia, is a significant clinical concern. When this elevation is accompanied by a systemic decrease in pH (acidemia), it is termed lactic acidosis, a life-threatening condition. While often associated with tissue hypoxia (Type A lactic acidosis), a number of medications can induce this state without evidence of poor oxygen delivery (Type B lactic acidosis). Drug-induced lactic acidosis often results from mitochondrial dysfunction, where the cellular powerhouses are unable to process pyruvate, leading to its conversion into lactate. Unexplained elevations in lactate should always prompt clinicians to review a patient's medication list.
Key Medications That Increase Lactate Levels
A wide range of medications can lead to an increase in lactate. Commonly cited agents include metformin, linezolid, propofol, beta-2 agonists, and nucleoside reverse transcriptase inhibitors (NRTIs). A large analysis of adverse event reports identified metformin, linezolid, amlodipine, salbutamol (albuterol), and paracetamol (acetaminophen) among those with the most reported cases.
Metformin
Metformin, a first-line medication for type 2 diabetes, is strongly linked to lactic acidosis, a rare but serious side effect with a high mortality rate. It primarily works by inhibiting a mitochondrial complex, which reduces the liver's ability to clear lactate, causing it to build up. The risk of metformin-associated lactic acidosis (MALA) is higher in patients with impaired kidney function (eGFR below 30 ml/min/1.73 m²), liver disease, sepsis, or excessive alcohol intake.
Linezolid
Linezolid, an antibiotic used for resistant bacterial infections, can cause lactic acidosis, particularly with extended use. It inhibits mitochondrial protein synthesis, affecting the mitochondria's ability to produce energy aerobically and leading to increased lactate production. Risk factors include treatment longer than two weeks, older age, and kidney or liver problems.
Propofol
Propofol, an anesthetic, can lead to the rare but life-threatening Propofol Infusion Syndrome (PRIS). PRIS is characterized by severe metabolic acidosis, including lactic acidosis, and is often linked to high-dose (>4-5 mg/kg/hr) and prolonged (>48 hours) infusions. The mechanism involves propofol disrupting mitochondrial function and fatty acid metabolism, forcing cells into anaerobic metabolism and increasing lactate.
Beta-2 Adrenergic Agonists
Medications like albuterol and epinephrine, used for respiratory conditions, can cause hyperlactatemia. They stimulate beta-2 receptors, promoting glycolysis and lactate production, particularly in muscle. While often mild and temporary, lactate levels can be more significantly elevated with high or continuous doses.
Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
NRTIs, a class of HIV medications including drugs like zidovudine and stavudine, are associated with lactic acidosis. They cause mitochondrial toxicity by inhibiting an enzyme crucial for mitochondrial DNA, impairing energy production and causing lactate buildup. Risk factors include female gender, obesity, and longer treatment duration, with older NRTIs posing a higher risk.
Comparison of Common Culprits
| Medication Class | Common Drugs | Primary Mechanism | Onset / Risk Factors |
|---|---|---|---|
| Biguanides | Metformin | Inhibition of mitochondrial complex I; reduced hepatic lactate clearance | Renal impairment, liver disease, sepsis, alcohol use, overdose |
| Antibiotics | Linezolid | Inhibition of mitochondrial protein synthesis | Prolonged therapy (>2 weeks), renal/hepatic dysfunction, older age |
| Anesthetics | Propofol | Impaired mitochondrial fatty acid oxidation and electron transport chain | High-dose (>4 mg/kg/hr) and prolonged (>48 hr) infusions |
| Beta-2 Agonists | Albuterol, Terbutaline, Epinephrine | Increased glycolysis and pyruvate production via beta-2 receptor stimulation | High or continuous doses, especially in acute asthma treatment |
| Antiretrovirals | NRTIs (Stavudine, Zidovudine) | Inhibition of mitochondrial DNA polymerase gamma | Prolonged therapy, female gender, obesity; older-generation NRTIs |
| Miscellaneous | Acetaminophen, Valproic Acid, Theophylline | Varies; often involves hepatic injury or mitochondrial toxicity | Typically associated with overdose or toxicity |
Conclusion
An array of medications can cause elevated lactate levels, a condition ranging from mild hyperlactatemia to severe lactic acidosis. Many of these drugs disrupt mitochondrial function or increase lactate production. While individual drug risk may be low, the potential severity of lactic acidosis necessitates vigilance. Clinicians should consider medication-induced causes for unexplained hyperlactatemia, especially with known risk factors. Management typically involves stopping the offending drug and providing supportive care. For more authoritative information on drug-induced conditions, please visit {Link: MedlinePlus https://medlineplus.gov/ency/article/000391.htm}.
