Diuretics

Use of diuretics according to filling status

Mechanism of action

Diuretics have various effects on the nephrons in the kidneys and therefore increase sodium excretion via the urine. This also increases water excretion.

There are different types of diuretics, each with a different target at the nephrons:

Loop diuretics (furosemide, bumetanide, torasemide): inhibition of the Na-K-2Cl carrier (Na/K/2 Cl co-transporter) in the ascending part of the loop of Henle
Diuretics that target the proximal tubule
- Acetazolamide (Diamox): inhibition of carbonic anhydrase
- SGLT-2 inhibitors (dapagliflozin, empagliflozin)
Diuretics that target the distal nephron
- Thiazide diuretics (hydrochlorothiazide, chlorthalidone, indapamide,...): inhibition of NCC (Na-Cl cotransporter).
- MRA (mineralocorticoid receptor antagonists) (spironolactone, eplerenone): inhibition of aldosterone receptors.

Expected beneficial effects in heart failure

Decongestion: disappearance of the symptoms of fluid retention (edema, ascites, pleural effusion)
Decrease in intracardiac pressure
Improvement of dyspnea and exercise capacity.

Proven effects

Loop diuretics are old drugs. These came onto the market before today's randomized clinical trials became the standard in drug development. As a result, there are no large clinical trials of diuretics demonstrating their effects on hard clinical endpoints. Nevertheless, the pursuit of euvolemia with diuretics is given a class I indication in the European guidelines..

The appropriate dose of loop diuretics depends on many factors in the individual patient.

If the dose of diuretics is too low, there are persistent signs of congestion:

more dyspnea and a lower quality of life.
repeated hospital admissions.
increased mortality.

Too high a dose of diuretics can cause:

dehydration and hypotension.
prerenal renal insufficiency.
electrolyte disorders (hypokalemia, hyponatremia,...).
repeated hospital admissions.
probably also increased mortality.

Dose titration in chronic therapy with diuretics is therefore crucial: not too little, not too much.

The lowest effective dose should always be aimed to maintain euvolemia. With good heart failure therapy, the maintenance dose of loop diuretics can often be stopped and only taken as necessary. This often gives room to increase other guideline-directed medical therapies - which do have proven effects on outcome

Indications

Loop diuretics:
- Signs of fluid retention independent of LVEF.
SGLT-2 inhibitors :
- May have a synergistic effect with loop diuretics, but is one of the drug pillars in heart failure, independent of the LVEF.
MRA (mineralocorticoid receptor antagonists) :
- HFrEF, NYHA II-IV.
- In case of HFmrEF and HFpEF: to be considered, especially if hypokalemia is also present.
- As an antihypertensive.
Thiazide diuretics:

- In case of persistent fluid retention, despite an adequate dose of loop diuretic, SGLT-2 inhibitor and MRA (diuretic resistance).
- As an antihypertensive.

Acetazolamide:

- In case of persistent fluid retention, despite an adequate dose of loop diuretic, SGLT-2 inhibitor and MRA (diuretic resistance).
  
  Note: acetazolamide has only been studied in one clinical trial as intravenous adjunctive therapy to intravenous diuretic therapy in hospitalized patients with acute heart failure and fluid retention (ADVOR trial).

Practical use

The first important step in treating heart failure is to eliminate fluid retention or congestion, without underfilling or dehydration. This condition is also called euvolemia. The weight at which there is euvolemia is called the target weight for that patient for that specific period. The goal is to keep the patient's weight stable around this target weight. However, this target weight can change over time and must be regularly monitored and adjusted if necessary. The target weight can also increase or decrease due to weight changes, without fluid retention or dehydration, due to a changed diet and other comorbidities.

The optimal dose of diuretics is dynamic over time and should be adapted to clinical evolution.

The aim should always be to use the lowest possible effective dose, while maintaining stable weight and euvolemia.

In some patients, the loop diuretic can be stopped under optimal heart failure therapy. If necessary, these patients can occasionally take a diuretic for one or a few days to maintain their body weight at the target weight.
The dose of diuretics should be increased with rapidly increasing weight (> 2-3 kg in 2-3 days) with increasing dyspnea and/or signs of fluid retention

If there are signs of fluid retention, loop diuretics are first started or increased to achieve decongestion and euvolemia.

Diuretics are best taken in the morning, given the sometimes disturbing diuresis during the first hours after intake.

The dose should be high enough to produce a diuretic effect.

In renal insufficiency and heart failure, the dose required to achieve the same diuretic effect will be higher.

The following parameters must then be followed:

In the hospital: diuresis (monitoring micturition or via a bladder tube) and natriuresis (determination of sodium on a urine sample).
Weight: for effective decongestion, weight should drop.
Kidney function.
Ionogram

Practical use of the different types of diuretics:

Loop diuretics:
- Furosemide 40 mg (Lasix) = Bumetanide 1 mg (Burinex) = 20 mg Torasemide (Torrem).
- If a diuretic has insufficient effect, it is best to double the dose immediately. Maximum dose of burinex is 2 x 5 mg per day, maximum dose of furosemide is at home is 60mg ((1500 mg per day (dialysis patiënt, not oral therapy !)).
- If a higher maintenance dose is needed, Furosemide is best switched to Bumetanide. The oral bioavailability and efficacy of bumetanide is better and more predictable than furosemide. E.g. Furosemide 40 mg 1 or 2 times a day to Burinex 5 mg 0.5 tablet per day.
- If oral administration of diuretics at home does not have the desired effect, the patient can be hospitalized for intravenous administration (better efficiency).
- Short duration of action (2-4 hours). In case of persistent fluid retention, intake 2 or 3 times a day can be prescribed. For example, Bumetanide 5 mg 2x 0.5 tablets per day (first dose at 8 a.m., second dose around 2 p.m.). This reduces sodium rebound reabsorption by prolonging the diuretic effect and shortening the time between loop diuretic doses.
- Torasemide has a longer duration of action (6-8 hours) and also very good bioavailability.
SGLT-2 inhibitors
MRA (mineralocorticoid receptor antagonists)
Thiazide diuretics:
- Chlorthalidone (Hygroton) 25 mg or 50 mg once a day.
- Indapamide 2.5 mg 1x per day.
- Association with a thiazide diuretic can greatly increase the diuretic effect of loop diuretics (synergistic effect).
Acetazolamide (Diamox) 250 or 500 mg per day
- Association of acetazolamide can increase the diuretic effect of loop diuretics (synergistic effect), especially if there is also metabolic alkalosis (high HCO3).
- Acetazolamide has mainly been studied in combination with loop diuretics as additional intravenous therapy (500 mg once per day) in patients with acute heart failure and fluid retention ( ADVOR trial).
- This has not been investigated in an outpatient, chronic setting.

Diuretic resistance

This is an insufficient diuretic effect and failure to resolve signs of fluid retention despite loop diuretics at the correct dose.

It is then useful to combine the loop diuretic with diuretics that work on other parts of the nephron. Such a combination of diuretics is rarely used long-term due to the risk of ion disorders, underfilling and deterioration of renal function.

Therapeutic options:

Association of an MRA if the patient is not yet taking it.
Association of an SGLT2 inhibitor if the patient is not already taking it.
Association of a thiazide diuretic (e.g. Hygroton 25 or 50 mg per day) and/or acetazolamide.
- This can be temporary and intermittent. The patient then takes this occasionally for one or two days with increasing weight and signs of fluid retention until the body weight has dropped again to the predetermined target weight.
- Rarely is maintenance therapy necessary to maintain body weight at the target weight. For example, intake 3 times a week, or even daily.
- STRICT FOLLOW-UP IS THEN NECESSARY WITH A RE-EVALUATION AFTER 2-3 DAYS with a check:
  - clinical status, weight, parameters. Adjustment of the policy to achieve euvolemia. Avoid dehydration.
  - blood sample: renal function and ionogram (given the risk of significant hypokalemia and/or hyponatremia, especially after association with a thiazide-diuretic).
- In case of persistent fluid retention, insufficient response to oral therapy, no clinical improvement or deterioration, reduced renal function and/or electrolyte disturbances,... the patient is best hospitalized for monitoring, intravenous therapy, monitoring of diuresis and regular monitoring of renal function and the ionogram .
- In case of persistent therapy resistance and renal insufficiency , ultrafiltration via hemodialysis or peritoneal dialysis can be started on the advice of the cardiologist and/or nephrologist.

Contraindications

Known allergy
Dehydration

Points of attention

Monitoring of weight and signs of fluid retention. Dehydration to avoid.
Monitoring of renal function and ionogram (sodium, potassium, chlorine, bicarbonate and magnesium).
Dose to be adjusted according to clinical evolution.
Reduce or briefly interrupt (a few days) for:
- Underfilling, increasing renal insufficiency.
- Intercurrent illness with diarrhea, vomiting, anorexia, decreased fluid intake.
- Very hot weather (> 30 °C).

Possible specific side effects

Loop diuretics:
- Allergic reactions and skin rash (CAUTION in case of allergy to sulfonamides)
- Dehydration due to volume depletion with dry mouth, hypotension, renal insufficiency
- Hypokalemia, hypomagnesemia
- Metabolic alkalosis
- High dose of totoxicity
SGLT-2 inhibitors : mycotic infections (vaginal infections, balanitis)
MRA (mineralocorticoid receptor antagonists) :
Thiazide diuretics:
- Allergic reactions and skin rash (CAUTION in case of allergy to sulfonamides)
- Dehydration due to volume depletion with dry mouth, hypotension, renal insufficiency
- Hyponatremia (much more than loop diuretics)
- Hypokalemia, hypomagnesemia (much more than loop diuretics)
- Metabolic alkalosis
- Hyperuricemia and gout
- Hyperglycemia/diabetes mellitus
- Sexual dysfunction: impotence (in men)
Acetazolamide:
- Allergic reactions and skin rash
- Dehydration due to volume depletion with dry mouth, hypotension, renal insufficiency
- Hyponatremia
- Hypokalemia
- Metabolic acidosis
- Decreased hearing and tinnitus

BWGHF

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