High blood pressure is a dangerous medical condition that eventually leads to cardiac disorders and stroke if not regulated on time, and around 75 million Americans (~one in every three adults) are afflicted with hypertension at present, according to the Centers for Disease Control and Prevention (CDC). The American College of Cardiology/American Heart Association (ACC/AHA) 2017 guidelines has categorized blood pressure (BP) into the following groups: <120/80 mm Hg as normal blood pressure, 120-129/80 mm Hg as elevated BP, 130-139 mm Hg systolic pressure or 80-89 mm Hg diastolic pressure as stage-I hypertension, and 140/90 mm Hg as stage-II hypertension. In addition to re-categorizing the BP subdivisions, greater emphasis rests on out-of-office BP measurement for accurate hypertension monitoring and for prescribing required medication.1-4
With myriad factors causing the incidence and progression of high blood pressure, including several lifestyle-related risks- obesity, inactivity, improper diet, stress and alcohol; pre-existing medical conditions- diabetes, pre-hypertension and chronic kidney disease (CKD); and othersfamily history, race and gender; hypertension is considered a silent killer. In terms of disease management, lifestyle modification is essential; patients are advised to maintain a healthy diet (heart-friendly, sodium restricted, and lipid- lowering), exercise regularly, and monitor BP constantly. High BP is generally associated with high sodium and subsequent fluid retention in the body, that can lead to swollen lower extremities and hardening of the heart arteries; advanced cases of hypertension can show signs of headache, dizziness, shortness of breath, and eye problems. Moreover, prolonged hypertension can cause more serious ailments that include retinopathy, cardiac failure, cerebral stroke, or renal dysfunction.5-7
Hypertension can be either primary, where no root cause is known, or secondary, caused by other medical conditions, like diabetes or chronic kidney disease (CKD). The combination and type of medications prescribed to the patients depend on patient medical history, background, comorbidities, age, and lifestyle.
The ACC/AHA, in the latest guidelines, has emphasized individualized cardiovascular risk measurement by ambulatory and home BP monitoring as crucial steps, in addition to clinic BP checking. Also, the ACC/AHA advices the physicians, the nursing staff or the nutritionist to provide a much-needed lifestyle modification education to the patients- BP of 130-139/80-89- with a <10% cardiovascular disease risk over the next 10 years and a more aggressive approach for those with a >10% risk of the onset of cardiovascular disease.3 Several types of drugs are prescribed to curb hypertension, such as diuretics; beta blockers; renin-angiotensin-aldosterone system blockers (RAASs)- angiotensin-converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARBs); and calcium channel blockers (CCBs).8,9 Diuretics, calcium channel blockers, and RAAS blockers form the first line of treatment.
RAAS inhibitors either reduce angiotensin II synthesis, thereby inhibiting aldosterone secretion (ACEIs), or may impair the angiotensin II receptors (AT I) (ARBs). The CCBs reduce blood pressure by relaxing vascular smooth muscle and dilates blood vessels, and therefore, reduce peripheral resistance. The diuretics, on the other hand, curbs sodium and water retention by the kidneys and hence, reduces extracellular fluid volume.
Hypertension lies at the crossroads of significant health complications- cardiac dysfunction, stroke, and renal disorder. The diuretics, a prominent class of medication prescribed to treat hypertensive patients, targets kidney function by tightly regulating sodium and water load; they affect the renal tubules of the kidney to expedite their release from the body. According to the ACC/AHA guidelines, the diuretics are incredibly favorable for patients with diabetes, >65 years of age, of African origin, with a history of stroke or low renin, and even people who have suffered from cardiac failure. The thiazide-type diuretics constitute the only category of diuretics that dilates blood vessels, in addition to regulating sodium and water retention in the body, thereby reducing blood pressure. Though the precise functional mechanism is unknown, these diuretics target the distal convoluted tubules in the kidney. Several meta-analyses and clinical studies (on patients with varied medical histories) have tested the efficacy of the thiazide-type diuretics. These diuretics have exhibited favorable outcomes in these studies; their effectiveness proved to be comparable with other classes of hypertension medications.
The thiazide-type diuretics are grouped into two separate sub-classes: thiazides (with a bi-cyclic benzothiadiazine backbone) and the thiazide-like diuretics (lacking the benzothiadiazine backbone), both target the first segment of the distal convoluted tubule. Studies performed on diabetic and elderly patients show promising outcomes with the thiazide-like diuretics in comparison to thiazides, the main differences lie in potency, dose, and side-effects. The thiazides are administered in high doses that are responsible for harmful side-effects such as hyperkalemia, dyslipidemia, and dysregulated glucose levels, to mention a few. Evident from independent clinical trials, the thiazide-like diuretics have an edge- their efficacy in low sustained doses have proved to control almost every adverse metabolic reaction in patients with primary hypertension. Specific thiazide-like drugs are preferred for their role in improving renal and cardiac markers too; independent trials show the positive impact of these diuretics on reviving endothelial and arterial functions of the heart.
Interestingly, the thiazide-like diuretics have greater half-lives, and therefore, have a prolonged duration of activity- reported in several clinical studies. These findings are consolidated by the latest guidelines from the ACC/AHA and the Latin American Society of Hypertension that propose the use of thiazide-like diuretics or calcium channel blockers (CCBs) as a preferred route for hypertension therapy for black patients in U.S. (tested with thiazide- like diuretic, chlorthalidone, in ALLHAT analysis).10, 11 Besides, meta-analyses reveal improved mortality risk only in hypertensive patients treated with thiazide-like diuretics.4, 10, 12, 13
Thus far, the thiazide-like diuretics fare considerably better than the thiazides- dose, half-life, potency, end-organ damage risk, and mortality. Therefore, the benefits with these diuretics place them at the forefront with other groups of antihypertensive treatments. The thiazide-like diuretics have the potential to be a primary candidate as a leading choice of medication to treat hypertension, although further detailed analyses are needed. Concludingly, every course of drugs has its upside and downside; we have to scrutinize each aspect of the drug (structure and functional mechanism) and the patient (medical history of self and family) before prescribing a particular combination of medicines to treat hypertension.
Progga Sen, Ph.D., is a Postdoctoral Research Fellow at the Stanford University School of Medicine and Veterans Affairs Health Care System in Palo Alto, CA.