1/17
[Why] is furosemide susceptible to malabsorption from "gut edema"?
When a patient with heart failure is hospitalized with congestion I often hear "let's use IV furosemide; they're probably not absorbing the PO."
It's a comment unique to furosemide.
But is it accurate?
[Why] is furosemide susceptible to malabsorption from "gut edema"?
When a patient with heart failure is hospitalized with congestion I often hear "let's use IV furosemide; they're probably not absorbing the PO."
It's a comment unique to furosemide.
But is it accurate?
2/
In order to understand what happens in heart failure, we must first understand what happens under normal conditions.
🔑Furosemide absorption is in the small intestine and stomach
🔑Some data suggest greater absorption in the duodenum than stomach
t.ly/JjdK
In order to understand what happens in heart failure, we must first understand what happens under normal conditions.
🔑Furosemide absorption is in the small intestine and stomach
🔑Some data suggest greater absorption in the duodenum than stomach
t.ly/JjdK
3/
Regarding oral bioavailability:
🔑 It is highly variable (ranging from 11-100%) even in those without heart failure
🔑 This variability is both between patients and within the same patient
t.ly/a0CU
Regarding oral bioavailability:
🔑 It is highly variable (ranging from 11-100%) even in those without heart failure
🔑 This variability is both between patients and within the same patient
t.ly/a0CU
4/
Let's turn to heart failure (HF).
In 1985, Vasko et al. gave 11 patients with HF oral furosemide during decompensation and again when they were compensated.
When compensated,
➤ Absorption was faster
➤ Peak plasma concentrations were higher
BUT...
t.ly/6GWl
Let's turn to heart failure (HF).
In 1985, Vasko et al. gave 11 patients with HF oral furosemide during decompensation and again when they were compensated.
When compensated,
➤ Absorption was faster
➤ Peak plasma concentrations were higher
BUT...
t.ly/6GWl
5/
...this study also found no significant difference in the area under the curve for plasma concentration when decompensated.
🔑Conclusion: there is no difference in the total amount of drug that reaches the blood for a given oral dose of furosemide, even when decompensated.
...this study also found no significant difference in the area under the curve for plasma concentration when decompensated.
🔑Conclusion: there is no difference in the total amount of drug that reaches the blood for a given oral dose of furosemide, even when decompensated.
6/
A later study confirmed that there is little difference in total absorption of furosemide between compensated and decompensated states.
In fact, this study found no difference in speed of absorption (Tmax) or peak plasma either.
t.ly/J9Pt
A later study confirmed that there is little difference in total absorption of furosemide between compensated and decompensated states.
In fact, this study found no difference in speed of absorption (Tmax) or peak plasma either.
t.ly/J9Pt
7/
Assuming that decompensation leads to delayed absorption of furosemide and NOT decreased total absorption, what explains this?
I found little data for this being due to "gut edema".
Instead, many propose delayed gastric emptying as the culprit
t.ly/49ko
Assuming that decompensation leads to delayed absorption of furosemide and NOT decreased total absorption, what explains this?
I found little data for this being due to "gut edema".
Instead, many propose delayed gastric emptying as the culprit
t.ly/49ko
8/
Supporting this are experiments in mice demonstrating that:
➤ Injection of BNP &
➤ Left ventricular dysfunction induced by myocardial infarction
Both lead to delayed gastric emptying and decreased furosemide absorption.
t.ly/FtZG
t.ly/lSTM
Supporting this are experiments in mice demonstrating that:
➤ Injection of BNP &
➤ Left ventricular dysfunction induced by myocardial infarction
Both lead to delayed gastric emptying and decreased furosemide absorption.
t.ly/FtZG
t.ly/lSTM
9/
Patients with decompensation also have ↑ sympathetic and ↓ parasympathetic tone. This may lead to delayed gastric emptying.
If the small bowel is the preferred site of furosemide absorption, delayed delivery could be the cause of delayed absorption.
t.ly/Qcrx
Patients with decompensation also have ↑ sympathetic and ↓ parasympathetic tone. This may lead to delayed gastric emptying.
If the small bowel is the preferred site of furosemide absorption, delayed delivery could be the cause of delayed absorption.
t.ly/Qcrx
10/
This explanation is supported by data in Roux-en-Y gastric bypass recipients. These patients have RAPID gastric emptying. This results in:
➤ Faster time to maximum plasma furosemide concentration
➤ Earlier natriuresis
t.ly/xCqW
This explanation is supported by data in Roux-en-Y gastric bypass recipients. These patients have RAPID gastric emptying. This results in:
➤ Faster time to maximum plasma furosemide concentration
➤ Earlier natriuresis
t.ly/xCqW
11/
Other explanations have been offered for the observed differences. These include:
➤ Decreased renal blood flow and delivery to the nephron
➤ Altered blood flow
➤ Concomitant medications
And, of course, "gut edema".
t.ly/vGQb
Other explanations have been offered for the observed differences. These include:
➤ Decreased renal blood flow and delivery to the nephron
➤ Altered blood flow
➤ Concomitant medications
And, of course, "gut edema".
t.ly/vGQb
12/
Given that there is little diuretic or natriuretic effect below a given plasma concentration (the “threshold”), it could be that reduced peak absorption results in less reliable natriuresis.
BUT...
t.ly/xnKq
Given that there is little diuretic or natriuretic effect below a given plasma concentration (the “threshold”), it could be that reduced peak absorption results in less reliable natriuresis.
BUT...
t.ly/xnKq
13/
... furosemide pharmacodynamics seem unaffected by decompensation.
In fact, the study in tweet 4 found INCREASED urinary sodium excretion during decompensation.
t.ly/6GWl
... furosemide pharmacodynamics seem unaffected by decompensation.
In fact, the study in tweet 4 found INCREASED urinary sodium excretion during decompensation.
t.ly/6GWl
14/
Before closing, let me offer a natural experiment supporting the idea that oral furosemide can be absorbed during decompensation.
In 2012 Ontario faced a shortage of IV furosemide. More oral furosemide was used, even in decompensated heart failure.
t.ly/kM8B
Before closing, let me offer a natural experiment supporting the idea that oral furosemide can be absorbed during decompensation.
In 2012 Ontario faced a shortage of IV furosemide. More oral furosemide was used, even in decompensated heart failure.
t.ly/kM8B
15/
Despite the shift from IV to PO furosemide, hospitals saw NO DIFFERENCE in:
➤ 30-day mortality
➤ ICU admission
➤ Length of stay <6 days
➤ 30-day readmission
The oral furosemide seemed to work just fine, even in decompensated heart failure.
t.ly/kM8B
Despite the shift from IV to PO furosemide, hospitals saw NO DIFFERENCE in:
➤ 30-day mortality
➤ ICU admission
➤ Length of stay <6 days
➤ 30-day readmission
The oral furosemide seemed to work just fine, even in decompensated heart failure.
t.ly/kM8B
16/
Clearly, many patients can achieve natriuresis with oral furosemide, even when decompensated.
But others have absorption issues, whether from delayed gastric emptying, "gut edema", or something else.
Here, as with much in medicine, the exceptions drive our practice.
Clearly, many patients can achieve natriuresis with oral furosemide, even when decompensated.
But others have absorption issues, whether from delayed gastric emptying, "gut edema", or something else.
Here, as with much in medicine, the exceptions drive our practice.
17/17 CONCLUSIONS
⚡️Though furosemide absorption may be delayed during decompensated heart failure
⚡️Total absorption appears less affected
⚡️Delayed absorption may be related to delayed gastric emptying
⚡️Though furosemide absorption may be delayed during decompensated heart failure
⚡️Total absorption appears less affected
⚡️Delayed absorption may be related to delayed gastric emptying
I want to extend a HUGE thank you to...
🎗️Brooke Barlow (@theABofPharmaC)
🎗️Alex Pipilas (@apipilasMD)
...for their peer review of this tweetorial.
If you want to get smarter, give them a follow.
🎗️Brooke Barlow (@theABofPharmaC)
🎗️Alex Pipilas (@apipilasMD)
...for their peer review of this tweetorial.
If you want to get smarter, give them a follow.
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