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Why can furosemide improve dyspnea/pulmonary edema from acute congestive heart failure within minutes of administration?

The answer does not involve diuresis.

#medtwitter #tweetorial

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Furosemide (aka Lasix) was introduced as a loop diuretic in 1964.

It was soon observed that treatment of pulmonary edema w/ furosemide led to rapid improvement in dyspnea, sometimes before diuresis.

The mechanism of this effect was unknown.

#b1">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2014966/ #b1">https://www.ncbi.nlm.nih.gov/pmc/artic...

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The first clue as to why came in a subsequent study in 1973.

It was noted that left ventricular (LV) filling pressures https://abs.twimg.com/emoji/v2/... draggable="false" alt="⬇️" title="Pfeil nach unten" aria-label="Emoji: Pfeil nach unten"> within 5 minutes of administering furosemide to patients w/ heart failure.

https://pubmed.ncbi.nlm.nih.gov/4697939/ ">https://pubmed.ncbi.nlm.nih.gov/4697939/&...

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In the same experiment, venous capacitance increased almost immediately after furosemide was given, while diuresis didn& #39;t start until 30 minutes later.

https://abs.twimg.com/emoji/v2/... draggable="false" alt="🔑" title="Schlüssel" aria-label="Emoji: Schlüssel">Venodilation seemed to be the cause of the rapid fall in LV filling pressure.

https://pubmed.ncbi.nlm.nih.gov/4697939/ ">https://pubmed.ncbi.nlm.nih.gov/4697939/&...

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What, then, is the mechanism by which furosemide induces venodilation?

In a study in anuric dogs, pre-treatment w/ the NSAID indomethacin before furosemide prevented reduction in pulmonary capillary wedge pressure.

https://pubmed.ncbi.nlm.nih.gov/874816/ ">https://pubmed.ncbi.nlm.nih.gov/874816/&q...

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NSAIDs like indomethacin inhibit cyclooxygenase-1,2, blocking production of prostaglandins.

Prostaglandins have many physiologic effects, including acting as potent vaso/venodilators.

https://pubmed.ncbi.nlm.nih.gov/24900965/ ">https://pubmed.ncbi.nlm.nih.gov/24900965/...

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https://abs.twimg.com/emoji/v2/... draggable="false" alt="🔑" title="Schlüssel" aria-label="Emoji: Schlüssel">Since indomethacin inhibited furosemide& #39;s non-diuretic effects on LV filling pressure, this implicated prostaglandins as the mediators of furosemide-induced venodilation.

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A subsequent study confirmed venodilation from furosemide, by way of prostaglandins.

Arterial + venous blood flow was recorded after furosemide infusion. While arteries didn& #39;t react, veins dilated ~70%.

https://abs.twimg.com/emoji/v2/... draggable="false" alt="💡" title="Elektrische Glühbirne" aria-label="Emoji: Elektrische Glühbirne">This effect was blocked by indomethacin.

https://pubmed.ncbi.nlm.nih.gov/9323071/ ">https://pubmed.ncbi.nlm.nih.gov/9323071/&...

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A follow-up question: how does furosemide induce prostaglandin-mediated venodilation?

The leading theory: furosemidehttps://abs.twimg.com/emoji/v2/... draggable="false" alt="⬆️" title="Pfeil nach oben" aria-label="Emoji: Pfeil nach oben">endothelial cell production of prostaglandins (as occurred below in bovine endothelial cells), but isn& #39;t itself a direct venodilator.

https://pubmed.ncbi.nlm.nih.gov/7996475/ ">https://pubmed.ncbi.nlm.nih.gov/7996475/&...

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Before wrapping up, a couple of caveats:

https://abs.twimg.com/emoji/v2/... draggable="false" alt="🔹" title="Kleine blaue Raute" aria-label="Emoji: Kleine blaue Raute">The exact mechanism of how furosemide stimulates prostaglandin production isn& #39;t known

https://abs.twimg.com/emoji/v2/... draggable="false" alt="🔹" title="Kleine blaue Raute" aria-label="Emoji: Kleine blaue Raute">Furosemide also induces nitric oxide synthesis, but this doesn& #39;t seem to be the primary source of venodilation https://pubmed.ncbi.nlm.nih.gov/9323071/ ">https://pubmed.ncbi.nlm.nih.gov/9323071/&...

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Let& #39;s close with a fascinating clinical correlate.

Inhaled furosemide has been studied as treatment for air hunger in lung cancer, as well as dyspnea that was induced in healthy subjects.

This may involve modulation of pulmonary J-receptor output.

https://pubmed.ncbi.nlm.nih.gov/16935035/ ">https://pubmed.ncbi.nlm.nih.gov/16935035/...

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But even more incredibly, furosemide appears to be a bronchodilator.

When rat airways were pre-constricted w/ methacholine or serotonin, treatment w/ furosemide significantly decreased bronchoconstriction.

https://pubmed.ncbi.nlm.nih.gov/9087943/ ">https://pubmed.ncbi.nlm.nih.gov/9087943/&...

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Incubation with indomethacin blocked furosemide& #39;s effect on airway tone.

https://abs.twimg.com/emoji/v2/... draggable="false" alt="🔑" title="Schlüssel" aria-label="Emoji: Schlüssel">Amazingly, like venodilation, furosemide& #39;s apparent ability to bronchodilate seems to be mediated by prostaglandins.

https://pubmed.ncbi.nlm.nih.gov/9087943/ ">https://pubmed.ncbi.nlm.nih.gov/9087943/&...

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https://abs.twimg.com/emoji/v2/... draggable="false" alt="💡" title="Elektrische Glühbirne" aria-label="Emoji: Elektrische Glühbirne">Furosemide rapidlyhttps://abs.twimg.com/emoji/v2/... draggable="false" alt="⬇️" title="Pfeil nach unten" aria-label="Emoji: Pfeil nach unten">LV filling pressures in acute heart failure, via venodilation and independent of diuresis
https://abs.twimg.com/emoji/v2/... draggable="false" alt="💡" title="Elektrische Glühbirne" aria-label="Emoji: Elektrische Glühbirne">Purported mechanism =https://abs.twimg.com/emoji/v2/... draggable="false" alt="⬆️" title="Pfeil nach oben" aria-label="Emoji: Pfeil nach oben">endothelial cell prostaglandin production
https://abs.twimg.com/emoji/v2/... draggable="false" alt="💡" title="Elektrische Glühbirne" aria-label="Emoji: Elektrische Glühbirne">Furosemide also is a bronchodilator, likely via https://abs.twimg.com/emoji/v2/... draggable="false" alt="⬆️" title="Pfeil nach oben" aria-label="Emoji: Pfeil nach oben">prostaglandins in a similar fashion