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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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
bmrat.org/index.php/BMRA…
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.
bmrat.org/index.php/BMRA…
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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.
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.
pubmed.ncbi.nlm.nih.gov/24116221/
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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.
ncbi.nlm.nih.gov/pmc/articles/P…
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.
ncbi.nlm.nih.gov/pmc/articles/P…
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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.
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.
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
🔑Steroids⬆️β 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, which❌pyruvate dehydrogenase, also increasing pyruvate availability
🔑Steroids⬆️β receptor number, potentiating albuterol's ability to ⬆️lactate
