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Why does albuterol induce a lactic acidosis when given in high doses?
This can occur even as patients with severe asthma exacerbations are improving in every other way.
#medtwitter #tweetorial
Why does albuterol induce a lactic acidosis when given in high doses?
This can occur even as patients with severe asthma exacerbations are improving in every other way.
#medtwitter #tweetorial
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The first observation that β₂ agonists could produce lactic acidosis came in the early 1980s.
Terbutaline (a β₂ agonist like albuterol) was given as a tocolytic to 6 women in preterm labor. Their serum lactate levels rose within a few hours.
https://pubmed.ncbi.nlm.nih.gov/7315890/
The first observation that β₂ agonists could produce lactic acidosis came in the early 1980s.
Terbutaline (a β₂ agonist like albuterol) was given as a tocolytic to 6 women in preterm labor. Their serum lactate levels rose within a few hours.
https://pubmed.ncbi.nlm.nih.gov/7315890/
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By 1985, the first case report of lactic acidosis from inhaled β₂ agonist therapy for status asthmaticus was published.
The patient's acidemia persisted despite normalization of PCO₂, and a new anion gap emerged.
Her lactate level was 7.
https://pubmed.ncbi.nlm.nih.gov/4033719/
By 1985, the first case report of lactic acidosis from inhaled β₂ agonist therapy for status asthmaticus was published.
The patient's acidemia persisted despite normalization of PCO₂, and a new anion gap emerged.
Her lactate level was 7. https://pubmed.ncbi.nlm.nih.gov/4033719/
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Next let's review lactate production.
Lactate is formed from pyruvate (a product of glycolysis), as catalyzed by lactate dehydrogenase.
This occurs w/ either pyruvate over-production or impairment of cellular metabolism.
https://pubmed.ncbi.nlm.nih.gov/22613097/
Next let's review lactate production.
Lactate is formed from pyruvate (a product of glycolysis), as catalyzed by lactate dehydrogenase.
This occurs w/ either pyruvate over-production or impairment of cellular metabolism.
https://pubmed.ncbi.nlm.nih.gov/22613097/
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Adrenergic signaling is one source of increased pyruvate production.
Catecholamines, such as epinephrine, signal through β₂ receptors in tissues like muscle and liver.
This induces glycogen mobilization to glucose.
https://pubmed.ncbi.nlm.nih.gov/25394679/
Adrenergic signaling is one source of increased pyruvate production.
Catecholamines, such as epinephrine, signal through β₂ receptors in tissues like muscle and liver.
This induces glycogen mobilization to glucose.https://pubmed.ncbi.nlm.nih.gov/25394679/
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β₂ signalling thus increases intracellular glucose, fueling glycolysis.
More glycolysis means
pyruvate production. Some of that pyruvate goes into the Krebs (aka TCA) cycle after conversion by pyruvate dehydrogenase.
The rest becomes lactate.
https://pubmed.ncbi.nlm.nih.gov/25394679/
β₂ signalling thus increases intracellular glucose, fueling glycolysis.
More glycolysis means
pyruvate production. Some of that pyruvate goes into the Krebs (aka TCA) cycle after conversion by pyruvate dehydrogenase.The rest becomes lactate.https://pubmed.ncbi.nlm.nih.gov/25394679/
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It’s therefore not surprising that albuterol, as a β₂ agonist, can cause lactic acidosis.
But adrenergic signaling and increased glycolysis may not be the whole story.
It’s therefore not surprising that albuterol, as a β₂ agonist, can cause lactic acidosis.
But adrenergic signaling and increased glycolysis may not be the whole story.
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Recall from tweet #6 that pyruvate dehydrogenase allows pyruvate to enter the Krebs/TCA cycle (by converting it to acetyl-CoA).
As we learned, any pyruvate that enters the Krebs cycle won't become lactate.
http://www.bmrat.org/index.php/BMRAT/article/view/591
Recall from tweet #6 that pyruvate dehydrogenase allows pyruvate to enter the Krebs/TCA cycle (by converting it to acetyl-CoA).
As we learned, any pyruvate that enters the Krebs cycle won't become lactate.
http://www.bmrat.org/index.php/BMRAT/article/view/591
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It turns out that pyruvate dehydrogenase is a heavily regulated enzyme, including by free fatty acids (FFA), which phosphorylate and inhibit its function.
In the presence of FFA, less pyruvate gets converted to acetyl-CoA.
https://pubmed.ncbi.nlm.nih.gov/24116221/
It turns out that pyruvate dehydrogenase is a heavily regulated enzyme, including by free fatty acids (FFA), which phosphorylate and inhibit its function.
In the presence of FFA, less pyruvate gets converted to acetyl-CoA.https://pubmed.ncbi.nlm.nih.gov/24116221/
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Amazingly, β₂ agonists increase plasma free fatty acid levels (via lipolysis).
Sofree fatty acids from albuterol inhibit pyruvate dehydrogenase, increasing pyruvate availability in cells.
This excess pyruvate is then converted to lactate.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2495720/
Amazingly, β₂ agonists increase plasma free fatty acid levels (via lipolysis).
So
free fatty acids from albuterol inhibit pyruvate dehydrogenase, increasing pyruvate availability in cells.This excess pyruvate is then converted to lactate.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2495720/
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Let's conclude with a fascinating wrinkle to this story.
Any asthmatic who gets enough albuterol to induce lactic acidosis will also receive corticosteroids...
Let's conclude with a fascinating wrinkle to this story.
Any asthmatic who gets enough albuterol to induce lactic acidosis will also receive corticosteroids...
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Steroids actually potentiate the effects of β₂ agonists in various tissues, including lung, by the number of β receptors.
Thus they may make albuterol both more effective as a bronchodilator and more likely to induce lactic acidosis.
https://pubmed.ncbi.nlm.nih.gov/6248064/
Steroids actually potentiate the effects of β₂ agonists in various tissues, including lung, by
the number of β receptors. Thus they may make albuterol both more effective as a bronchodilator and more likely to induce lactic acidosis.https://pubmed.ncbi.nlm.nih.gov/6248064/
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Albuterol can induce lactic acidosis by:
glycolysis and pyruvate availability, which is converted to lactate
serum FFA, which
pyruvate dehydrogenase, also increasing pyruvate availability
Steroidsβ receptor number, potentiating albuterol's ability to lactate
Albuterol can induce lactic acidosis by: glycolysis and pyruvate availability, which is converted to lactate serum FFA, whichpyruvate dehydrogenase, also increasing pyruvate availabilitySteroidsβ receptor number, potentiating albuterol's ability to lactate
