Combining two swords to get rid of "frustration" - acetazolamide combined with loop diuretics significantly increases the efficacy!

"The Synopsis of the Golden Chamber" calls cardiogenic edema "heart water", but it is not necessary to use "heart medicine" to get rid of "heart water". In the treatment of cardiogenic edema, the combination of diuretics and acetazolamide bears the brunt! So, what is acetazolamide? What about efficacy and price? Let’s take a look!

"Favorite"——cardiogenic edema

"The Fahrenheit Sutra" says: "There is nothing more difficult to treat than water." Cardiogenic edema is body edema caused by cardiac dysfunction. Cardiogenic edema occurs in heart failure. At the same time, cardiogenic edema is also the main reason for hospitalization of patients with acute heart failure.

Cardiogenic edema is generally related to poor blood circulation caused by heart failure. It usually appears in the early morning, worsens after activities during the day, and is relieved after resting at night. Diuretics are indispensable drugs in the treatment of cardiogenic edema. They are highly efficient and have a better effect in successfully relieving edema, and loop diuretics are by far the most commonly used diuretics.

The heart picture comes from Google, any infringement will be deleted

"The First of Two Swords" - Acetazolamide

Who is acetazolamide, the “first sword of the two swords”?

Acetazolamide is mainly used as a diuretic and carbonic anhydrase inhibitor. It can inhibit carbonic anhydrase in renal tubular epithelial cells, reducing the formation of carbonic acid and the production of hydrogen ions. Therefore, the exchange of hydrogen ions and sodium ions is greatly slowed down, resulting in increased excretion of bicarbonate ions, sodium ions and potassium ions, and increased urine output, achieving the effects of diuresis and edema removal. It mainly treats cardiogenic edema, but is ineffective in renal and hepatic edema.

At present, acetazolamide is rarely used alone as a diuretic. Because its diuretic effect is not strong and long-term use may lead to drug resistance, it is often used in combination with loop diuretics. Combined use can correct the acid-base balance imbalance caused by each other, so combined use has better efficacy. At the same time, it can also inhibit the secretion process of aqueous humor, reduce intraocular pressure, and treat glaucoma.

"Two swords combined" - what is the effect?

In May 2019, "Eur J Heart Fail" published a pilot study to explore whether adding acetazolamide can increase the diuretic effect of loop diuretics in the treatment of patients with acute heart failure (AHF) compared with loop diuretics alone.

The study included 34 patients with acute heart failure who were taking loop diuretics and randomly divided them into an experimental group and a control group. 18 patients in the experimental group received combined treatment with acetazolamide and low-dose loop diuretics; 16 patients in the control group received high-dose loop diuretic monotherapy. The primary efficacy endpoint is the comparison of cyclic diuretic response between the experimental group and the control group after 24 hours. The secondary efficacy endpoint was the comparison of N-terminal pro-brain natriuretic peptide (NT-proBNP) levels between the experimental group and the control group after 72 hours.

Six of 16 patients (38%) in the control group received high-dose loop diuretic monotherapy, and 4 of 18 patients (22%) in the experimental group received a combination of acetazolamide and a low-dose loop diuretic. Within the first 24 hours of the combination treatment group, the cyclic diuretic response of patients in the experimental group who received combined treatment with acetazolamide and a low-dose loop diuretic was significantly higher than that in the control group. Details are shown in Figure 1:

Figure 1: Comparison of cyclic diuretic response between the test group and the control group after 24 hours

Within 72 hours of the combined treatment group, the change rate of N-terminal pro-brain natriuretic peptide (NT-proBNP) in the experimental group, that is, the patients who received acetazolamide and low-dose loop diuretics, was significantly higher than that in the control group. Details are shown in Figure 2:

Figure 2: Comparison of the change rate of N-terminal brain natriuretic peptide precursor (NT-proBNP) between the test group and the control group after 72 hours

The cyclic diuretic response and the change rate of N-terminal pro-brain natriuretic peptide (NT-proBNP) in the experimental group were higher than those in the control group. Therefore, combined treatment with acetazolamide and a low-dose loop diuretic is more effective than treatment with a high-dose loop diuretic alone.

In summary, the efficacy of combination therapy with the addition of acetazolamide significantly increases compared with loop diuretics alone!

Acetazolamide – how much does it cost?

Acetazolamide Japanese version (DIAMOX), 280mg*100 capsules, about 260$ per box.

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Global research and development of cardiogenic edema drugs

Currently, there are 8 drugs for cardiogenic edema, in addition to the marketed acetazolamide. There are 3 drugs currently in the non-development stage, 1 drug in the preclinical stage, 1 drug in clinical phase 1, 1 drug in clinical phase 2, and 1 drug in clinical phase 3. In addition, there are 4 drugs that have appeared in front of you. Today I will briefly introduce two of them:

Tolvaptan

Tolvaptan (Sumac) was developed by Otsuka Corporation of Japan and approved by the US FDA in 2009 for the treatment of patients with heart failure and other diseases.

This drug binds to the V2 receptor on the collecting duct and blocks its activity, causing AQP2 to fall off the intima, reducing its expression, preventing V2 receptor-mediated renal water reabsorption, and can also increase the excretion of free water in urine, reduce retention, reduce volume load, without affecting electrolytes, and restore sodium ion levels. In addition, it can also inhibit the production and accumulation of cAMP, increase the concentration of sodium ions in plasma, and help excess water be excreted from the urine.

Triamterene

Triamterene is a potassium-sparing diuretic. It was first launched in France in 1964. It is available in tablets and capsules in the United States. In 1982, Mudanjiang Lingtai Pharmaceutical first launched this drug in China. The current domestic approved specification is 50mg.

This drug can directly inhibit the entry of Na+ from the distal convoluted tubule and collecting duct of the kidney into epithelial cells, thereby changing the transmembrane potential and reducing the secretion of K+; the reabsorption of Na+ is reduced, thereby increasing the excretion of Na+, Cl- and water, while reducing the excretion of K+, thereby achieving a diuretic effect. Mainly used to treat various types of edema, such as cardiogenic edema. It is often used in combination with potassium-depleting diuretics and can also be used in cases that are ineffective against hydrochlorothiazide or spironolactone.

Zhou Jingmin, deputy director of the Department of Cardiology at Zhongshan Hospital of Fudan University and executive chairman of the China Heart Failure Center, said: "In the ADVOR study, acetazolamide was not used alone, but as an auxiliary diuretic measure with high-dose intravenous loop diuretics, and was only used for 3 days during hospitalization. This is helpful for us to understand the design of this study and the future clinical use scenarios of acetazolamide."

Zhou Jingmin, deputy director of the Department of Cardiology, Zhongshan Hospital Affiliated to Fudan University and executive chairman of the China Heart Failure Center, pictures from Google, deleted if infringement