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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

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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/ ">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& #39;s acidemia persisted despite normalization of PCO₂, and a new anion gap emerged.

https://abs.twimg.com/emoji/v2/... draggable="false" alt="💥" title="Symbol für eine Kollision" aria-label="Emoji: Symbol für eine Kollision">Her lactate level was 7.

https://pubmed.ncbi.nlm.nih.gov/4033719/ ">https://pubmed.ncbi.nlm.nih.gov/4033719/&...

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Next let& #39;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/ ">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.

https://abs.twimg.com/emoji/v2/... draggable="false" alt="💡" title="Elektrische Glühbirne" aria-label="Emoji: Elektrische Glühbirne">This induces glycogen mobilization to glucose.

https://pubmed.ncbi.nlm.nih.gov/25394679/ ">https://pubmed.ncbi.nlm.nih.gov/25394679/...

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β₂ signalling thus increases intracellular glucose, fueling glycolysis.

More glycolysis means https://abs.twimg.com/emoji/v2/... draggable="false" alt="⬆️" title="Pfeil nach oben" aria-label="Emoji: Pfeil nach oben"> pyruvate production. Some of that pyruvate goes into the Krebs (aka TCA) cycle after conversion by pyruvate dehydrogenase.

https://abs.twimg.com/emoji/v2/... draggable="false" alt="🔑" title="Schlüssel" aria-label="Emoji: Schlüssel">The rest becomes lactate.

https://pubmed.ncbi.nlm.nih.gov/25394679/ ">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.

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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& #39;t become lactate.

http://www.bmrat.org/index.php/BMRAT/article/view/591">https://www.bmrat.org/index.php...

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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.

https://abs.twimg.com/emoji/v2/... draggable="false" alt="💡" title="Elektrische Glühbirne" aria-label="Emoji: Elektrische Glühbirne">In the presence of FFA, less pyruvate gets converted to acetyl-CoA.

https://pubmed.ncbi.nlm.nih.gov/24116221/ ">https://pubmed.ncbi.nlm.nih.gov/24116221/...

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Amazingly, β₂ agonists increase plasma free fatty acid levels (via lipolysis).

Sohttps://abs.twimg.com/emoji/v2/... draggable="false" alt="⬆️" title="Pfeil nach oben" aria-label="Emoji: Pfeil nach oben">free fatty acids from albuterol inhibit pyruvate dehydrogenase, increasing pyruvate availability in cells.

https://abs.twimg.com/emoji/v2/... draggable="false" alt="🔑" title="Schlüssel" aria-label="Emoji: Schlüssel">This excess pyruvate is then converted to lactate.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2495720/">https://www.ncbi.nlm.nih.gov/pmc/artic...

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Let& #39;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 https://abs.twimg.com/emoji/v2/... draggable="false" alt="⬆️" title="Pfeil nach oben" aria-label="Emoji: Pfeil nach oben"> the number of β receptors.

https://abs.twimg.com/emoji/v2/... draggable="false" alt="🔑" title="Schlüssel" aria-label="Emoji: Schlüssel">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/ ">https://pubmed.ncbi.nlm.nih.gov/6248064/&...

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https://abs.twimg.com/emoji/v2/... draggable="false" alt="🔑" title="Schlüssel" aria-label="Emoji: Schlüssel">Albuterol can induce lactic acidosis by:
https://abs.twimg.com/emoji/v2/... draggable="false" alt="⬆️" title="Pfeil nach oben" aria-label="Emoji: Pfeil nach oben"> glycolysis and pyruvate availability, which is converted to lactate
https://abs.twimg.com/emoji/v2/... draggable="false" alt="⬆️" title="Pfeil nach oben" aria-label="Emoji: Pfeil nach oben"> serum FFA, whichhttps://abs.twimg.com/emoji/v2/... draggable="false" alt="❌" title="Kreuzzeichen" aria-label="Emoji: Kreuzzeichen">pyruvate dehydrogenase, also increasing pyruvate availability

https://abs.twimg.com/emoji/v2/... draggable="false" alt="🔑" title="Schlüssel" aria-label="Emoji: Schlüssel">Steroidshttps://abs.twimg.com/emoji/v2/... draggable="false" alt="⬆️" title="Pfeil nach oben" aria-label="Emoji: Pfeil nach oben">β receptor number, potentiating albuterol& #39;s ability to https://abs.twimg.com/emoji/v2/... draggable="false" alt="⬆️" title="Pfeil nach oben" aria-label="Emoji: Pfeil nach oben">lactate