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Furosemide (Lasix) PO to IV Dose Conversions Explained · This Is Why with Dr. Busti

• 0:00
  SPEAKER_00: Okay, we're on medical rounds in the hospital and have two patients admitted for two different reasons, but both are on the diuretic ferrosamide or LASIKs.
• 0:09
  SPEAKER_00: The attending physician on rounds asks you to convert ferrosamide or LASIKs from oral to IV for both patients as a teaching point.
• 0:20
  SPEAKER_00: Now both patients happen to be on ferrosamide 40 milligrams by mouth twice daily for their chronic heart failure.
• 0:29
  SPEAKER_00: One is stable but temporarily cannot take oral medication while in the hospital for an elective procedure.
• 0:36
  SPEAKER_00: The other has heart failure exacerbation due to fluid overload.
• 0:42
  SPEAKER_00: He reports compliance but says the ferozomiter LASIK is not working.
• 0:47
  SPEAKER_00: The real question is: should they receive the same IV dose regimen?
• 0:55
  SPEAKER_00: The familiar two to one conversion is a common teaching point, but is that the right mindset?
• 1:04
  SPEAKER_00: And conversion for both scenarios?
• 1:07
  SPEAKER_00: Understanding when to use it requires understanding what we're trying to accomplish.
• 1:14
  SPEAKER_00: Why?
• 1:15
  SPEAKER_00: Because that impacts the ultimate IV dose chosen and is going to be different for each of those scenarios.
• 1:26
  SPEAKER_00: On that note, I'm Dr.
• 1:27
  SPEAKER_00: Bustaye, your faculty and host on This Is Why, a show that helps healthcare professionals transform their medical knowledge from what to why, because when you know why you do what you do, it changes the how.
• 1:40
  SPEAKER_00: And that changes everything about the patient-oriented decisions that we make every day, including on rounds.
• 1:46
  SPEAKER_00: Again, our question is rather straightforward.
• 1:50
  SPEAKER_00: Is the IV dose the same for both scenarios?
• 1:55
  SPEAKER_00: Specifically, why can the appropriate IV dose be lower than the home oral dose in one patient, yet higher in another?
• 2:09
  SPEAKER_00: Let's start with the stable patient.
• 2:12
  SPEAKER_00: Now, assume the maintenance diuretic is still needed in this patient while they're in the hospital.
• 2:19
  SPEAKER_00: Volume status is at baseline, kidney function, blood pressure have not meaningfully changed while there.
• 2:26
  SPEAKER_00: The problem is simply that the patient cannot take the medication by mouth at the moment, but would continue to benefit from his daily dosage.
• 2:37
  SPEAKER_00: In that setting and scenario, 40 milligrams taken by mouth is approximately close to 20 milligrams IV.
• 2:49
  SPEAKER_00: For our twice-daily example, that would mean considering 20 milligrams IV twice daily as an initial substitute and then checking the response.
• 3:02
  SPEAKER_00: That is the classic two to one dose conversion.
• 3:06
  SPEAKER_00: That stable patient has known chronic or compensated heart failure with reduced EF.
• 3:13
  SPEAKER_00: That distinction depends on the current clinical state and the treatment goals that we are trying to use, not simply whether the heart failure appears on the problem list.
• 3:25
  SPEAKER_00: And being unable to take an oral medication doesn't automatically mean the diuretic even must continue.
• 3:33
  SPEAKER_00: If the patient has become volume depleted, hypotensive, or it could result in harm for some other reason while being in the hospital, well, then the treatment itself clearly needs reassessment.
• 3:47
  SPEAKER_00: But the question still remaining is why does the IV substitution often use fewer milligrams?
• 3:57
  SPEAKER_00: An IV dose completely obviously enters systemic central circulation directly.
• 4:03
  SPEAKER_00: So 100% of the dose makes it into the body when we give it IV.
• 4:09
  SPEAKER_00: That means the bioavailability is 100%.
• 4:14
  SPEAKER_00: That means 100% of the dose ordered and administered makes it into the body.
• 4:18
  SPEAKER_00: However, an oral dose must first dissolve and cross the intestinal wall within the gastrointestinal tract.
• 4:28
  SPEAKER_00: When given by mouth, ferrosamide's oral bioavailability is variable, commonly summarized as approximately 50 to 60%.
• 4:39
  SPEAKER_00: But commonly used resources will cite 64%.
• 4:43
  SPEAKER_00: But as we will see, that is a useful teaching average, not a measurement that applies to every patient.
• 4:52
  SPEAKER_00: It's for the otherwise normal, stable patient without gut edema, abnormal gut perfusion, food present, or impaired kidney functioning.
• 5:04
  SPEAKER_00: Therefore, if roughly half of the 40 milligram oral LASIKS dose is all that becomes systemically available, then 20 milligrams given IV provides a reasonable starting comparison or dose conversion.
• 5:21
  SPEAKER_00: And that is why the common or traditional teaching of PO to IV dosing of ferrosamide or LASIK conversion is two to one.
• 5:32
  SPEAKER_00: However, it is clinically relevant to know that comparable systemic availability does not, guys, guarantee the same level of diuresis.
• 5:44
  SPEAKER_00: The time course ferrosamide takes to get to the site of action also differs with the route of administration.
• 5:54
  SPEAKER_00: An IV bolus delivers drug promptly while oral absorption spreads delivery over time.
• 6:04
  SPEAKER_00: In addition, ferrosamide administered orally has limitations in both dissolution and intestinal permeability.
• 6:13
  SPEAKER_00: Ferrosamide is a known weak acid.
• 6:16
  SPEAKER_00: What does that mean?
• 6:17
  SPEAKER_00: Well, the drugs chemistry help explain why these are separate processes.
• 6:24
  SPEAKER_00: As the intestinal pH rises or becomes more basic, aqueous solubility can improve while increasing also ionization, which is charge on the drug molecule.
• 6:38
  SPEAKER_00: That makes passive passage through the lipid membranes less favorable.
• 6:44
  SPEAKER_00: Well, why is LASIKs or ferrosamide less favorable in that scenario?
• 6:49
  SPEAKER_00: Well, remember, guys, lipid membranes prefer lipophilic molecules.
• 6:55
  SPEAKER_00: Okay?
• 6:56
  SPEAKER_00: And when drug molecules have charges, they become more hydrophilic or water-loving and are less likely to travel through the lipid environment.
• 7:10
  SPEAKER_00: Therefore, dissolving a drug and getting it across the intestinal wall are, as we will see, separate steps.
• 7:19
  SPEAKER_00: For now, let's follow the drug after it reaches the blood and circulation.
• 7:25
  SPEAKER_00: Okay.
• 7:26
  SPEAKER_00: So ferrosamide circulates in the body largely bound to albumin, which limits its filtration at the level of the glomerulus in the nephron.
• 7:39
  SPEAKER_00: Much of ferosamide's access to tubular fluid depends on actual secretion into the proximal renal tubule.
• 7:50
  SPEAKER_00: Well, that's only with free or unbound drug.
• 7:53
  SPEAKER_00: So free or unbound drug moves from the blood side into the proximal renal tubular cells through organic anion transporters OAT1 and OAT3.
• 8:09
  SPEAKER_00: It then exits across those opposite membrane into the tubular lumen.
• 8:16
  SPEAKER_00: The drug then travels downstream to the thick ascending lumber where it inhibits the sodium potassium 2-chloride cotransporter from the luminal side.
• 8:32
  SPEAKER_00: So the proximal renal tubule delivers the drug, the thick ascending limb contains its principal naturitic target.
• 8:41
  SPEAKER_00: Blocking sodium chloride reabsorption there increases the sodium delivery farther along the nephron in the distal convoluted tubule all the way downstream, right?
• 8:56
  SPEAKER_00: So there's ability for the nephron to still reclaim and reabsorb some of that sodium that was blocked.
• 9:04
  SPEAKER_00: And that explains why.
• 9:07
  SPEAKER_00: An impressive plasma concentration alone doesn't necessarily produce, in all cases, an impressive response.
• 9:16
  SPEAKER_00: The drug must reach the nephron, get secreted into the nephron's lumen, where it is on the correct side for luminal transporter interaction.
• 9:29
  SPEAKER_00: Loop diuretics have a known steep threshold response relationship.
• 9:36
  SPEAKER_00: Below an effective level of delivery, the response may be small.
• 9:42
  SPEAKER_00: Once sufficient drug reaches the luminal target, though, sodium excretion increases substantially, eventually approaching a plateau.
• 9:55
  SPEAKER_00: So here is one of the main points, guys.
• 9:59
  SPEAKER_00: Both the amount delivered and the time above the effective threshold matter.
• 10:08
  SPEAKER_00: The plasma curve shown here illustrates the timing.
• 10:12
  SPEAKER_00: It doesn't directly measure drug concentration at that sodium potassium 2-chloride transporter.
• 10:20
  SPEAKER_00: And this all brings us to our second patient who now is here and has heart failure exacerbation due to fluid overload despite being compliant with his home regimen.
• 10:36
  SPEAKER_00: Now, during a heart failure exacerbation due to fluid overload, oral absorption may be reduced.
• 10:43
  SPEAKER_00: But the question is why?
• 10:46
  SPEAKER_00: Well, bowel wall edema altered perfusion or motility, food can interact and affect delivery, but their contributions vary between patients.
• 11:01
  SPEAKER_00: All of those things.
• 11:03
  SPEAKER_00: Slow absorption may produce a later, lower peak, and even despite total exposure being similar or sometimes lower.
• 11:15
  SPEAKER_00: Okay.
• 11:16
  SPEAKER_00: A small study comparing the same patients during heart failure exacerbation and after stabilization demonstrated that.
• 11:24
  SPEAKER_00: It did not establish that every patient with fluid overload preserves total absorption or ball edema explains poor response.
• 11:34
  SPEAKER_00: The clinical concern is that drug arriving too slowly inside of the body or in the central circulation may provide or fail to provide sufficient delivery above, guys, the effective threshold when sodium retention is more intense.
• 11:54
  SPEAKER_00: And the kidney baby contributing also independently to this.
• 11:59
  SPEAKER_00: Changes in renal perfusion, impaired tubular secretion, sodium retaining hormonal signals, and increased downstream reabsorption in the distal convoluted tubule can all influence the response of the ferrosamine.
• 12:17
  SPEAKER_00: Remember, a reduced ejection fraction from the heart alone doesn't tell us that cardiac output is low.
• 12:25
  SPEAKER_00: We have to assess the patient's actual hemodynamics and their kidney function since they are manifestation of the changes in cardiac output.
• 12:35
  SPEAKER_00: All of this matters because it impacts the pharmacokinetics and pharmacodynamics of ferosamide as well as the diuresis generating.
• 12:45
  SPEAKER_00: So let's go back to the PKPD curves and see that.
• 13:00
  SPEAKER_00: The maximum response may also be lower.
• 13:04
  SPEAKER_00: So while IV administration removes the gastrointestinal absorption step, the delivery to the kidney and response limitations remain.
• 13:14
  SPEAKER_00: So let's return to the prescription and separate and separate our two clinical goals for these two patients.
• 13:23
  SPEAKER_00: For the stable patient, we're trying to just maintain an established effect while changing the route.
• 13:30
  SPEAKER_00: Again, common resources that are out there that are reputable, report an exact 64%, but again, that's based on a lot of other confounders held stable or normal.
• 13:43
  SPEAKER_00: The approximate two to one conversion helps us to choose an initial substitute, and that aligns with knowing Frosamide's overall oral bioavailability of approximately 50 to 60 percent.
• 13:58
  SPEAKER_00: For the patient with heart failure exacerbation due to fluid overload, we need to remove the retained extra sodium and water.
• 14:10
  SPEAKER_00: Simply reducing an approximate maintenance exposure may not accomplish that new goal for that patient.
• 14:18
  SPEAKER_00: So we need a net loss of sodium and water, and that also means the intake and sodium retention between doses also matter.
• 14:28
  SPEAKER_00: So the home regimen of 40 milligrams by mouth twice daily totals to 80 milligrams a day.
• 14:38
  SPEAKER_00: So now what IV dose should we use?
• 14:43
  SPEAKER_00: In the dose trial, the lower dose strategy used an IV daily total numerically equal to the previous oral daily dose.
• 14:55
  SPEAKER_00: The higher dose strategy used 2.5 times the total daily oral amount.
• 15:03
  SPEAKER_00: Applied to our example, those strategies correspond to an 80 or 200 milligrams IV per day.
• 15:13
  SPEAKER_00: In the trials BOLUS ARMS, the daily amount was divided every 12 hours.
• 15:29
  SPEAKER_00: They don't establish, guys, a universal prescription for every single patient with edema or an abnormal creatinine.
• 15:39
  SPEAKER_00: Evidence on the best starting dose is actually surprisingly limited.
• 15:45
  SPEAKER_00: But let's dig a little deeper to consider the evidence and guidelines in context.
• 15:50
  SPEAKER_00: The dose trial that I was talking about enrolled 308 patients already taking oral loop diuretics.
• 16:07
  SPEAKER_00: Those strategies didn't differ significantly on co-primary outcomes.
• 16:13
  SPEAKER_00: Higher dosing improved secondary measures of decongestion, but caused more frequent transient rises in the creatinine, likely from volume contraction or prerenal azotemia.
• 16:27
  SPEAKER_00: More recent trials have focused on what happens after the first dose, such as measuring early naturian and escalating promptly when it's inadequate, or adding its second diuretic that acts at a different site.
• 16:45
  SPEAKER_00: What about current guidelines?
• 16:47
  SPEAKER_00: Well, they reflect both ideas.
• 16:50
  SPEAKER_00: The AHA, ACC, Heart Failure Society of America guidelines recommend prompt IV loop diuretics for hospitalized patients with significant fluid overload adjusted towards the resolution of that congestion.
• 17:06
  SPEAKER_00: The ESC guidelines add that urine sodium guided therapy may be considered in the first few days of treatment.
• 17:15
  SPEAKER_00: So, how do we individualize that treatment?
• 17:19
  SPEAKER_00: Well, you assess the prior diuretic exposure and response, the current degree of fluid overload, the current blood pressures, perfusion, kidney function, and current electrolytes.
• 17:34
  SPEAKER_00: Review the medications that the patients are receiving, looking for interactions, including the use of NSAIDs.
• 17:42
  SPEAKER_00: Older adults, they can have reduced drug clearance and still have weaker diuretic response.
• 17:49
  SPEAKER_00: Then reassess early urine output symptoms, exam findings, fluid balance, daily weight, serum creatinin, sodium, potassium, and magnesium.
• 18:00
  SPEAKER_00: Okay.
• 18:01
  SPEAKER_00: But a modest creatinine rise during effective fluid removal doesn't automatically require that you stop.
• 18:09
  SPEAKER_00: But worsening hypotension, oliguria, or perfusion needs prompt reassessment, obviously.
• 18:16
  SPEAKER_00: If response is inadequate, the regimen may need intensification after reassessing the patient.
• 18:24
  SPEAKER_00: Larger doses still require safe IV administration and attention to electrolyte losses and even autotoxicity, especially at high doses.
• 18:34
  SPEAKER_00: Now, the common mistake is allowing the conversion ratio to make the entire clinical decision.
• 18:41
  SPEAKER_00: It cannot tell us whether the patient needs maintenance, additional fluid removal, or less diuretic exposure.
• 18:51
  SPEAKER_00: So use the conversion to estimate a root change.
• 18:55
  SPEAKER_00: Use the patient's physiology treatment goal and measured response to determine the regimen.
• 19:02
  SPEAKER_00: I hope that you found that to be helpful.
• 19:05
  SPEAKER_00: And if you like those kind of clinically grounded explanations, check out the channel at This Is Why.
• 19:12
  SPEAKER_00: Also available on podcast channels, Spotify, Amazon, Apple, and also depending on the topic, Rumedi.
• 19:21
  SPEAKER_00: The website, thisiswhy.health, offers free memberships with downloads and things and tools.
• 19:26
  SPEAKER_00: But thank you guys so much for learning with me and bringing that understanding to the patients that we serve.
• 19:33
  SPEAKER_00: We'll see you next time.
• 19:35
  SPEAKER_00: Thanks again.