Diuretic Therapy in Hypertension and Heart Failure: Classes, Uses, and Resistance

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• Thiazide Diuretics for Hypertension
• Loop Diuretics for Heart Failure
• Potassium-Sparing Diuretics and MRAs
• SGLT2 Inhibitors and Proximal Tubule Diuretics
• Managing Diuretic Resistance
• Clinical Goals of Diuretic Treatment
• Full Transcript

Thiazide Diuretics for Hypertension

Thiazide-type diuretics are the most commonly used class for hypertension treatment. Dr. David Ellison, MD, explains that these drugs work in the distal convoluted tubule by blocking a sodium and chloride co-transport pathway. Their widespread use is strongly supported by clinical evidence, particularly the famous ALLHAT trial. This major study compared various antihypertensive classes and demonstrated that thiazide diuretics were highly effective at lowering blood pressure.

Dr. David Ellison, MD, emphasizes that thiazides were shown to be as effective as other drug classes. Importantly, they offered additional benefits, including a superior ability to prevent the development of heart failure. Consequently, thiazide diuretics remain a cornerstone of hypertension management, recommended as either first-line or second-line therapy.

Loop Diuretics for Heart Failure

Loop diuretics are the first-line therapy for heart failure, chosen for their potent fluid-removing capabilities. Dr. David Ellison, MD, notes that these drugs, including furosemide, bumetanide, and torasemide, act in the thick ascending limb of the loop of Henle. This segment of the kidney absorbs approximately 25% of the body's filtered salt load, making drugs that target it the most effective diuretics available.

They are often termed "high ceiling diuretics" due to their strength. Dr. Ellison clarifies the different treatment goals: in heart failure, the primary aim is to remove salt and fluid from the body to relieve congestion. This is distinct from hypertension, where the goal is simply to reduce blood pressure. Therefore, loop diuretics are titrated based on the patient's clinical status to achieve effective decongestion.

Potassium-Sparing Diuretics and MRAs

Drugs acting in the aldosterone-sensitive distal nephron, or collecting duct, form another critical class. Dr. David Ellison, MD, describes two types: mineralocorticoid receptor antagonists (MRAs) like spironolactone and sodium channel blockers like amiloride. While both can cause a mild diuretic effect, MRAs hold a special place in heart failure therapy.

Dr. David Ellison, MD, highlights that MRAs have been proven to prolong life in patients with heart failure with reduced ejection fraction. This mortality benefit is a primary reason for their use, making them a key component of guideline-directed medical therapy. They are used not just for diuresis but fundamentally to help patients live longer and healthier lives.

SGLT2 Inhibitors and Proximal Tubule Diuretics

Although diuretics that work in the proximal tubule are rarely used, a new class has emerged with significant importance. Dr. David Ellison, MD, points to sodium-glucose co-transporter 2 (SGLT2) inhibitors. These drugs were developed for diabetes but inhibit sodium transport in the proximal tubule, giving them diuretic capabilities.

Dr. Ellison calls this a "fascinating class of drugs" due to their ability to improve mortality from a variety of diseases. Their unique mechanism of action and proven benefits have generated excitement, leading to their increased use in both heart failure and diabetes care, even though they were not originally developed as diuretics.

Managing Diuretic Resistance

Diuretic resistance is a major challenge in advanced heart failure, predicting high mortality and frequent re-hospitalization. Dr. David Ellison, MD, explains that patients often become resistant to loop diuretics, developing edema that doesn't respond to high doses. To combat this, a common and effective strategy is to add a thiazide-type diuretic.

This combination therapy, studied in the lab and translated to the clinic, is remarkably effective at increasing salt and fluid removal. Dr. David Ellison, MD, gives a real-world example, noting that he added metolazone (a thiazide diuretic) for a volume-overloaded patient just the day before the interview. This approach is a standard part of managing tough, diuretic-resistant cases.

Clinical Goals of Diuretic Treatment

The ultimate goal of diuretic therapy in heart failure is to achieve deep decongestion and improve patient outcomes. Dr. David Ellison, MD, describes patients with diuretic resistance as a very difficult-to-treat subgroup. They face a high risk of repeated hospitalizations due to fluid overload, leading to breathing difficulties and extreme discomfort.

Dr. David Ellison, MD, states that a major current focus in heart failure treatment is finding better ways to decongest these patients thoroughly. The aim is to break the cycle of recurrent hospitalizations and provide lasting relief, significantly improving their quality of life and prognosis. This makes effective diuretic management a critical component of comprehensive heart failure care.

Full Transcript

Dr. Anton Titov, MD: You are a world-renowned expert on the use of diuretics in hypertension and heart failure. Could you please give a bird's-eye overview of different classes of diuretics used in heart failure and in hypertension? Perhaps you could highlight some principal differences between the different classes of diuretics.

Dr. David Ellison, MD: I'm happy to do that. We have diuretics that work in all segments of the kidney tubule. These drugs have been around for many, many years, so none of the classes is really new. We know pretty much how to use them.

We have drugs that block transport in the proximal tubule, in the loop of Henle, in the distal convoluted tubule, and in the distal nephron or the collecting duct. Diuretic drugs that work in the proximal tubule are rarely used.

I say that, although there is another drug that has become very popular recently and has amazing qualities. It wasn't developed as a diuretic but has diuretic capabilities. That's the sodium-glucose co-transporter inhibiting drugs, SGLT2 inhibitors.

In addition to inhibiting glucose transport in the proximal tubule, they inhibit sodium transport in the proximal tubule. I'm not going to spend most of my time talking about those drugs, but that's a fascinating class that improves mortality from a whole variety of diseases. We are very excited about using them.

For hypertension, the most commonly used class of diuretic is the thiazide-type diuretics that work in the distal convoluted tubule and block a sodium and chloride co-transport pathway. Thiazide diuretics are used very commonly.

I think that is based on the results of the famous ALLHAT clinical trial some decades ago. It compared treatment with different classes of drugs and showed that treatment with thiazide diuretics was very effective. It was as effective as other classes in lowering blood pressure and had some additional benefits, including preventing the development of heart failure much more effectively than other classes of drugs.

So those are still recommended as either first-line or second-line hypertensive drugs, and people use them all the time. They are used less commonly to treat heart failure.

In heart failure, we typically start with drugs that act in the loop of Henle, or in the thick ascending limb of the loop of Henle. We call these loop diuretic drugs because of their site of action. These drugs are furosemide, bumetanide, and torasemide.

All these drugs have been around for many years, so we have lots of experience using them. They are also called high-ceiling diuretics because the loop of Henle absorbs about 25% of your salt load. They are the most effective, the strongest diuretics we have.

So they're chosen as first-line therapy for heart failure. In heart failure, what you want to achieve is removing salt and fluid from the body. In hypertension, what you want to achieve is reducing blood pressure, and they're not strictly connected.

In heart failure, the first-line drug is loop diuretics, and we usually titrate that up based on the patient's clinical syndrome. The other class of diuretics that I mentioned already are the drugs that act in the so-called aldosterone-sensitive distal nephron, or the collecting duct.

Those drugs are of two types. They are drugs that either antagonize aldosterone actions—we call them mineralocorticoid receptor antagonists—and also drugs that block sodium channels, for example, amiloride. Really, those classes of drugs have similar effects.

But the most important thing about the mineralocorticoid receptor antagonists, like spironolactone, is that those drugs have also been shown in patients with heart failure with reduced ejection fraction to prolong life. We use those partly because they can cause a little bit of diuretic effect, but mostly because they can prolong life and make people feel better and live longer.

So in heart failure, the main two classes of drugs we start with are the loop diuretics to reduce the extracellular fluid volume, and the mineralocorticoid receptor antagonists to help people live longer and healthier. But that doesn't mean we don't use other classes of diuretics as well.

Many times, we need to turn to another class of diuretics because people often become resistant to loop diuretics. They begin to develop an edema that doesn't respond even to high doses of loop diuretics.

One of the other things that we've studied in the laboratory and translated to the clinic is the fact that in those situations, adding a thiazide-type diuretic, like we typically use in hypertension, is remarkably effective at increasing fluid and salt removal from the body and helping people return to normal salt balance.

We use that every day of the week, every day of the year. In fact, in clinic yesterday, we just added metolazone, which is a thiazide diuretic, for a patient who kept getting volume overloaded because of his heart failure. That's a common approach.

Additionally, we now consider using proximal tubule diuretics to treat patients who are resistant as well. The patients who become resistant to diuretics, the heart failure patients, are a very tough-to-treat subgroup. It also predicts a very high mortality rate and frequent re-hospitalization.

I think there's a lot of focus these days on trying to find ways to better deeply decongest these patients. So they don't keep coming back into the hospital again and again, filled up with fluid and unable to breathe and very uncomfortable. That's one of the major goals right now of heart failure treatment.