This week’s episode makes use of knowledge and experience Avi has accumulated practicing his day job as a pulmonologist. He – and others! – have observed that patients with asthma may be improving (i.e., bronchospasm and tachypnea are decreasing) and they will develop an anion gap acidosis. More specifically, they develop lactic acidosis.
This phenomenon was first described in the early 1980s. The case report didn’t involve albuterol or asthma. Instead, another beta agonist called terbutaline was used as a tocolytic in 6 women with preterm labor. It was observed the patients’ serum lactate levels rose within hours of receiving the terbutaline. Given the proximity of the doses of drug to the emergence of a lactic acidosis it was presumed that terbutaline had caused it, though the authors incorrectly hypothesized that a drug-induced hyperglycemia and hyperinsulinemia was the cause.
In 1985 another case report was published, this time in The New England Journal of Medicine. Here, the authors report on one patient who presented with status asthmaticus. She was given huge doses of beta agonist and eventually improved in every way way except that her acidosis persisted (initially respiratory and then became metabolic). The lactate level increased to 7 mmol/L, which normalized when the beta agonist was stopped.
At the time the assumption was that muscular exertion from excessive work of breathing was the cause in these patients but it seemed tied to beta agonist therapy.
A reminder about lactate
In order to understand what’s really going on in these cases, a review of lactate generation is required. To start, the outcome of glycolysis is pyruvate, which normally is converted to ATP via the Krebs cycle. It also can be converted to lactate by lactate dehydrogenase. This typically occurs under two main circumstances: pyruvate over-production or impairment of cellular metabolism
Pyruvate over-production seems to be the main mechanism, but albuterol may have some indirect effects on cellular metabolism as well.
Beta adrenergic signaling increases pyruvate production, and when this occurs in tissues like muscle and liver, glycogen is converted to glucose. This increases intracellular glucose, fueling glycolysis. And, again, more glycolysis means more pyruvate production.
Of course most of that pyruvate will enter the Krebs cycle but some will be left over and get converted to lactate. So when albuterol gets absorbed systemically at high doses it stimulates those beta receptors and creates lactate.
This also explains why epinephrine can increase serum lactate. There are even cases of pheochromocytoma presenting with lactic acidosis. One might assume that this is part of a fight-or-flight response to help generate additional ATP during times of stress.
More than just pyruvate
Regarding impairment of cellular metabolism of pyruvate, pyruvate dehydrogenase can be seen as a gatekeeper, determining whether pyruvate will enter the Krebs cycle after it is converted into acetyl-CoA. Any pyruvate that undergoes this conversion won’t become lactate.
It turns out that pyruvate dehydrogenase is regulated by the presence of free fatty acids (an alternate oxidative fuel sources for mitochondria). Free fatty acids phosphorylate pyruvate dehydrogenase and inhibit its function. So, as free fatty acid levels increase, less pyruvate enters the Krebs cycle. Instead, they are converted to lactate.
Tying it back to albuterol, β₂ agonists increase plasma free fatty acid levels via inducing lipolysis. Increased free fatty acids from albuterol inhibits pyruvate dehydrogenase, increasing pyruvate availability in cells. This excess pyruvate is converted to lactate.
Interestingly, the corticosteroids we give during asthma exacerbations, including the most severe ones where albuterol-induced lactic acidosis will occur, may make this result more likely to occur.
Steroids increase the number of beta-receptors in tissues, including in the lung. This likely potentiates the effects of beta-agonists like albuterol as bronchodilators and while not proved, it may also make albuterol more likely to cause lactic acidosis based on the mechanisms that we learned about.
Take Home Points
- Albuterol and other short acting beta agonists can induce lactic acidosis by increasing glycolysis and thereby pyruvate availability. This excess pyruvate is converted to lactate
- Albuterol also increases serum free fatty acid levels. Free fatty acids block pyruvate dehydrogenase from breaking down pyruvate, further increasing pyruvate levels in cells
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Listen to the episode
Credits & Citation
◾️Episode written by Avi Cooper
◾️Show notes written by Avi Cooper and Tony Breu
◾️Audio edited by Clair Morgan of nodderly.com
Cooper AZ, Abrams HR, Breu AC. Why can albuterol cause a lactic acidosis when given in high doses? The Curious Clinicians Podcast. June 9, 2021
Image credit: https://abcnews.go.com/Health/critical-inhaler-medication-shortage-looms-coronavirus-cases-soar/story?id=69759965