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Why Can Furosemide Im...

Metadata

• Author: @AvrahamCooperMD on Twitter
• Full Title: 1/
  Why Can Furosemide Im...
• Category: #tweets
• URL: https://twitter.com/AvrahamCooperMD/status/1292134482812604418

Highlights

• 1/
  Why can furosemide improve dyspnea/pulmonary edema from acute congestive heart failure within minutes of administration?
  The answer does not involve diuresis.
  #medtwitter #tweetorial
  (View Tweet)
• 2/
  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.
  https://t.co/KdbMWjPbG4
  (View Tweet)
• 3/
  The first clue as to why came in a subsequent study in 1973.
  It was noted that left ventricular (LV) filling pressures ⬇️ within 5 minutes of administering furosemide to patients w/ heart failure.
  https://t.co/53MFjBtt7m
  (View Tweet)
• 4/
  In the same experiment, venous capacitance increased almost immediately after furosemide was given, while diuresis didn't start until 30 minutes later.
  🔑Venodilation seemed to be the cause of the rapid fall in LV filling pressure.
  https://t.co/53MFjBtt7m
  (View Tweet)
• 5/
  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://t.co/KuYXFiD5uh
  (View Tweet)
• 6/
  NSAIDs like indomethacin inhibit cyclooxygenase-1,2, blocking production of prostaglandins.
  Prostaglandins have many physiologic effects, including acting as potent vaso/venodilators.
  https://t.co/e4rGzs3rNt
  (View Tweet)
• 7/
  🔑Since indomethacin inhibited furosemide's non-diuretic effects on LV filling pressure, this implicated prostaglandins as the mediators of furosemide-induced venodilation. (View Tweet)
• 8/
  A subsequent study confirmed venodilation from furosemide, by way of prostaglandins.
  Arterial + venous blood flow was recorded after furosemide infusion. While arteries didn't react, veins dilated ~70%.
  💡This effect was blocked by indomethacin.
  https://t.co/kWW2SQXrfY
  (View Tweet)
• 9/
  A follow-up question: how does furosemide induce prostaglandin-mediated venodilation?
  The leading theory: furosemide⬆️endothelial cell production of prostaglandins (as occurred below in bovine endothelial cells), but isn't itself a direct venodilator.
  https://t.co/yNlIWKtN9i
  (View Tweet)
• 10/
  Before wrapping up, a couple of caveats:
  🔹The exact mechanism of how furosemide stimulates prostaglandin production isn't known
  🔹Furosemide also induces nitric oxide synthesis, but this doesn't seem to be the primary source of venodilation
  https://t.co/kWW2SQXrfY (View Tweet)
• 11/
  Let'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://t.co/qdSRIjW9VF
  (View Tweet)
• 12/
  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://t.co/EGcyco25hF
  (View Tweet)
• 13/
  Incubation with indomethacin blocked furosemide's effect on airway tone.
  🔑Amazingly, like venodilation, furosemide's apparent ability to bronchodilate seems to be mediated by prostaglandins.
  https://t.co/EGcyco25hF
  (View Tweet)
• 14/
  💡Furosemide rapidly⬇️LV filling pressures in acute heart failure, via venodilation and independent of diuresis
  💡Purported mechanism =⬆️endothelial cell prostaglandin production
  💡Furosemide also is a bronchodilator, likely via ⬆️prostaglandins in a similar fashion (View Tweet)