Current and Emerging Classes of Pharmacological Agents for the Management of Hypertension

Utkarsh Ojha; Sanjay Ruddaraju; Navukkarasu Sabapathy; Varun Ravindran; Pitchaya Worapongsatitaya; Jeesanul Haq; Raihan Mohammed; Vinod Patel


Am J Cardiovasc Drugs. 2022;22(3):271-285. 

In This Article

Abstract and Introduction


Cardiovascular disease accounts for more than 17 million deaths globally every year, of which complications of hypertension account for 9.4 million deaths worldwide. Early detection and management of hypertension can prevent costly interventions, including dialysis and cardiac surgery. Non-pharmacological approaches for managing hypertension commonly involve lifestyle modification, including exercise and dietary regulations such as reducing salt and fluid intake; however, a majority of patients will eventually require antihypertensive medications. In 2020, the International Society of Hypertension published worldwide guidelines in its efforts to reduce the global prevalence of raised blood pressure (BP) in adults aged 18 years or over. Currently, several classes of medications are used to control hypertension, either as mono- or combination therapy depending on the disease severity. These drug classes include those that target the renin-angiotensin-aldosterone system (RAAS) and adrenergic receptors, calcium channel blockers, diuretics and vasodilators. While some of these classes of medications have shown significant benefits in controlling BP and reducing cardiovascular mortality, the prevalence of hypertension remains high. Significant efforts have been made in developing new classes of drugs that lower BP; these medications exert their therapeutic benefits through different pathways and mechanism of actions. With several of these emerging classes in phase III clinical trials, it is hoped that the discovery of these novel therapeutic avenues will aid in reducing the global burden of hypertension.


Hypertension is a multifactorial, complex disorder estimated to affect one in three adults in the United States (US).[1] Globally, the prevalence of hypertension is expected to reach 1.6 billion by 2025.[2] Several factors influencing elevated blood pressure (BP) have been identified. Modifiable risk factors affecting BP include diet, obesity, smoking and physical exercise, while non-modifiable factors include increasing age, sex and genetics. Adequately controlling high BP reduces the risk of stroke, coronary artery disease, peripheral vascular disease, congestive heart failure and end-stage renal failure. The risk of developing these complications can start at a BP level as low as 115/75 mmHg.[3] In 2017, the American College of Cardiology (ACC) and American Heart Association (AHA) released updated guidelines in which they lowered the traditional BP cut-off value for diagnosing hypertension (Table 1).[4] Accurately diagnosing hypertension can still pose significant challenges for physicians, as BP readings can fluctuate unexpectedly, a phenomenon referred to as labile hypertension. In 2020, the International Society of Hypertension produced global guidelines to enable physicians to diagnose and manage hypertension as accurately as possible.[5] These guidelines classified hypertension based on systolic and diastolic cut-offs, taking into account the manner and environment in which the BP measurements were taken.

The exact pathophysiology of hypertension remains largely unknown. It is thought that up to 5% of patients with hypertension have either renal or adrenal system impairment. In the remainder of patients, the cause is not entirely clear and these patients are labelled as having 'essential hypertension'. The regulation of BP relies on cardiac output and systemic vascular resistance. Most patients with essential hypertension have normal cardiac output but raised peripheral resistance. Peripheral resistance is determined by the small arterioles which contain smooth muscle. A rise in intracellular calcium leads to contraction of these smooth muscles, which in turn raises peripheral resistance. The autonomic nervous system is also thought to play an important role in increasing BP. Sympathetic nervous system (SNS) stimulation can lead to an increase in cardiac output and both arteriolar constriction and dilation. The SNS has an important function in short-term changes in BP that occur in response to physical exercise, however there is a lack of evidence suggesting its involvement in the development of chronic hypertension. It has also been suggested that endothelial dysfunction can lead to essential hypertension. Currently available antihypertensive agents exert their therapeutic effect by altering these underlying pathologic processes. These drug classes include those that target the renin-angiotensin-aldosterone system (RAAS), adrenergic receptors, and calcium channel blockers (CCBs), and induce diuresis and vasodilation. The increasing global incidence and burden of hypertension and its associated complications has necessitated the development of novel drugs with greater safety and efficacy than existing treatments.