Pulmonary Arterial Hypertension (PAH)

Diuretics are commonly prescribed to patients who have pulmonary arterial hypertension (PAH) with fluid retention.¹ In PAH, vasoconstriction caused by endothelial and smooth muscle cell dysfunction, remodeling of the pulmonary arterial wall, and thrombosis results in right ventricular (RV) afterload.² The increase in pulmonary vascular resistance leads to RV dilatation as well as RV diastolic and systolic dysfunction. These events ultimately result in reduced cardiac output, the release of antidiuretic hormone, and activation of the renin-angiotensin-aldosterone system, and increased fluid retention.² 

Fluid overload is a characteristic of right heart failure (RHF), a medical condition associated with increased mortality in PAH. Diuretics can be used to control pressure and RV overload to prevent RHF in patients with PAH. It promotes LV filing by reducing pressure, decompresses the RV, reduces tricuspid regurgitation, and right ventricular wall stress.² No randomized controlled trials of diuretic treatment in PAH have been published,^1-3 and little information on the use of these drugs in managing fluid overload (volume) is available. However, many studies have reported on the use of diuretics in left-sided heart failure, and the benefits of diuretic treatment in patients with PAH and fluid overload are supported by clinical experience.^2,3

Main Classes of Diuretics Used to Treat PAH

Each of the 3 main classes of diuretics^1,2 acts at a different level of the nephron to prevent the renal reabsorption of sodium.² Diuretics can be used to treat patients with PAH and RV failure; the specific dose should be determined according to the individual patient’s salt and fluid balance. Over time, the dose typically will need to be increased, and combined therapy may be prescribed.¹

Loop diuretics act at the loop of Henle. The drugs of this class, which include furosemide, bumetanide, and torsemide, are the most effective in decreasing sodium reabsorption.^1,4-7 Volume management is typically started on an outpatient basis with furosemide; the dose may be adjusted or the diuretic changed when diuresis no longer occurs.²

Thiazide diuretics, including metolazone, act at the distal tubule to inhibit sodium reabsorption and can be used to prevent or manage the progressive accumulation of excessive fluid.² Thiazide diuretics can be combined with loop diuretics for diuretic synergy.^2,7 Sodium excretion may increase, but this therapeutic strategy entails risks, including hypotension, decreased kidney function, and decreased levels of both sodium and potassium.⁸

Aldosterone antagonists are also used to manage fluid overload in PAH; however, these drugs block the effects of aldosterone on mineralocorticoid receptors.¹ Aldosterone activation is linked to cardiac fibrosis and pulmonary vascular changes; therefore, treatment with aldosterone antagonists may be an important therapeutic approach to PAH.² Potassium-sparing aldosterone antagonists include spironolactone, which is typically prescribed together with a loop diuretic to increase diuresis; acting in the collecting duct of the kidney, the drug prevents potassium elimination.² The serum potassium levels of patients taking spironolactone must be closely monitored to detect hyperkalemia.² An ongoing randomized controlled trial (NCT01712620), which is currently recruiting, is evaluating the effectiveness of spironolactone in reducing inflammation and improving blood vessel function in patients with PAH.^9,10

Managing the Side Effects of Diuretics

Diuretics have several side effects, including dizziness, headache, muscle cramps, skin rashes, thirst, and electrolyte imbalance (eg, hypokalemia, hyperkalemia, hypomagnesemia, hyponatremia, and hyperuricemia).^1,2 Most often, patients are not symptomatic, and the imbalances can be resolved with electrolyte replacement or therapeutic adjustment. Monitoring fluid retention that occurs due to calcium channel blockers and endothelin receptor antagonists are critical. Managing diuretic use and educating patients on incorporating dietary restrictions, daily weight monitoring, and recognising symptoms associated with volume overload are important as well.² Renal function and blood biochemistry must be monitored to detect hypokalemia and prevent renal dysfunction.³ The frequency of monitoring should be determined according to the prescribed diuretic and dose and the patient’s renal function.²

Patients can take additional measures to manage their side effects. Drinking iced water, for example, can help control dry mouth or thirst, and muscle cramps may be controlled with oral magnesium supplements.¹ 

References

1. Stickel S, Gin-Sing W, Wagenaar M, Gibbs JSR. The practical management of fluid retention in adults with right heart failure due to pulmonary arterial hypertension. Eur Heart J Suppl. 2019;21(Suppl K):K46-K53. doi:10.1093/eurheartj/suz207

2. Hansen L, Burks M, Kingman M, Stewart T. Volume management in pulmonary arterial hypertension patients: an expert pulmonary hypertension clinician perspective. Pulm Ther. 2018;4(1):13-27. doi:10.1007/s41030-018-0052-z

3. Galiè N, Humbert M, Vachiery JL, at al. 2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension: the Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J. 2016;37(1):67-119. doi:10.1093/eurheartj/ehv317

4. Furosemide. MedlinePlus. Revised September 15, 2017. Accessed May 26, 2022

5. Bumetanide. MedlinePlus. Revised October 15, 2017. Accessed May 26, 2022

6. Torsemide. MedlinePlus. Revised January 15, 2018. Accessed May 26, 2022

7. Brater DC. Diuretic therapy. N Engl J Med. 1998;339(6):387-395. doi:10.1056/NEJM199808063390607

8. Jentzer JC, DeWald TA, Hernandez AF. Combination of loop diuretics with thiazide-type diuretics in heart failure. J Am Coll Cardiol. 2010;56(19):1527-1534. doi:10.1016/j.jacc.2010.06.034

9. Spironolactone for pulmonary arterial hypertension. ClinicalTrials.gov. October 23, 2012. Updated May 25, 2022. Accessed May 26, 2022.

10. Elinoff JM, Rame JE, Forfia PR, et al. A pilot study of the effect of spironolactone therapy on exercise capacity and endothelial dysfunction in pulmonary arterial hypertension: study protocol for a randomized controlled trial. Trials. 2013;14:91. doi:10.1186/1745-6215-14-91

Reviewed by Debjyoti Talukdar, MD, on 5/30/2022.

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Diana Diez Gaspar, PharmD, PhD

Diana earned her PhD and PharmD with distinction in the field of Medicinal and Pharmaceutical Chemistry at the Universidade do Porto. She is an accomplished oncology scientist with 10+ years of experience in developing and managing R&D projects and research staff directed to the development of small proteins fit for medical use.