Present and future of drug therapy in hypertension: an overview

Abstract

Purpose: High blood pressure (HBP) is the leading cause of mortality and years of disability, and its prevalence is increasing. Therefore, diagnosis and effective treatment of HBP is one of the main goals to prevent and reduce its complications, and pharmacological treatment is the cornerstone of hypertension management.Materials and Methods: The gradual introduction of different drug families has led to the development of new molecules that have improved efficacy and reduced adverse effects. Results: Current drugs include a large number that target key mechanisms of blood pressure regulation as well as those that contribute to hypertension-induced organ damage. Recently, new antihypertensive drugs have been introduced that not only aim to lower blood pressure but also provide additional protection against organ damage and metabolic disorders. Some of them were introduced for specific indications other than hypertension and other are based in a pharmacogenomic approach. Other routes of administration, such subcutaneous injection, are also being explored to improve protection and compliance.Conclusions: The main characteristics of each class of antihypertensive drug are summarised.

Keywords:

• Hypertension
• blood pressure
• drugs lowering blood pressure
• pharmacogenomics
• oral
• parenteral drugs lowering blood pressure

Introduction

High blood pressure (HBP) is the leading cause of mortality and years lost to disability (DALYs) [1], and one of the most important risk factors for ischaemic heart disease, heart failure, peripheral arterial disease, stroke, chronic kidney disease [2–6], cognitive impairment and dementia [7–10].

The treatment of hypertension should start with lifestyle modifications that have to address overall cardiovascular risk factors. Recommendations include dietary salt reduction to less than 6 g of NaCl per day, and a diet rich in fruits and vegetables and low-fat dairy products, with reduced content of saturated fat and total fat. In addition, the diet should be rich in potassium, calcium and magnesium, with moderate alcohol consumption, smoking cessation and regular aerobic activity. These changes favourably affect blood pressure (BP) and should be an adjunct to drug therapy in hypertensive individuals.

Pharmacological treatment is the cornerstone of hypertension management. Its development since the 1950s has run parallel to advances in the pathophysiological mechanisms of BP elevation and its consequences. The pharmacologic treatment of hypertension began, at the middle of last century, with mercurial diuretics, reserpine, and acetolamide, which are seldom used nowadays. The progressive introduction of the different families of drugs have been developed with new molecules that have established improvements in efficiency and reduction of unwanted effects, pushing the older ones aside not only in terms of efficacy but also in terms of tolerance and safety. These drugs were soon followed by newer more potent agents that will be categorised, according to their main mechanism of action, as follows.

Recommendations to manage high blood pressure with available drugs

The classes of drugs used to control hypertension are shown in Figures 1 and 2. A summary of the most relevant characteristics of each class of antihypertensive agents is presented below.

Figure 1. Main class of antihypertensive drugs.

Figure 2. Parenteral antihypertensive drugs.

Central nervous system

Centrally acting alpha2-sympathetic agonist decrease peripheral resistance by inhibiting sympathetic outflow. They include clonidine and alpha-methyl-dopa. They are not considered first-line agents but clonidine is included as a drug potentially useful in resistant hypertension and alpha-methyl-dopa is a drug safe to be used in pregnancy.

Direct vasodilators

The direct vasodilators, Hydralazine and Minoxidil, today are out of the drugs used to treat hypertension due to side effects. Hydralazine is a direct vasodilator that has antioxidant and nitric oxide-enhancing actions and may induce a lupus-like syndrome. Minoxidil is a potent vasodilator that was used most frequently in patients with renal insufficiency that are refractory to other drugs. Although they are potentially effective antihypertensive agents, their usefulness is limited by orthostatic hypotension, sexual dysfunction and numerous side effects and drug-drug interactions.

Adrenergic blockers

Beta-adrenergic receptor blockers lower blood pressure by decreasing cardiac output owing to a reduction of heart rate and contractility. They are particularly effective in hypertensive patients with tachycardia, and though they are not considered a first-line drug its hypotensive potency is enhanced by co-administration of a diuretic or dihydropyridine calcium channel blocker and there are potential indications for its combination with other antihypertensive drugs [11]. There seems to be no difference in the antihypertensive potencies of cardio selective (bisoprolol, metoprolol) and non (propranolol, atenolol) [12,13] although the first are preferred for cardiovascular prevention. Development of beta-blockers with vasodilatory capacity due to dual blockade of beta 1 and 2, (carvedilol), blockade of beta-receptors and peripheral alpha-adrenergic receptors (labetalol) or increasing the nitric oxide production, (nebivolol), reduce some of the increment of peripheral resistance observed with the classic beta-blockers and derived side effects. Its potential advantage in treating hypertension remains to be determined. Beta-adrenergic receptor blockers reduce cardiovascular risk but they are less effective in to reduce the risk of stroke.

Postsynaptic, selective alfa-adrenergic blockers (prazosin, doxazosin, terazosin) lower blood pressure by decreasing peripheral vascular resistance [14]. They are effective antihypertensive drugs as monotherapy or in combination with other agents. However, in clinical trials of hypertensive patients, alpha blockade has not been shown to reduce cardiovascular morbidity and mortality. Non-selective alpha adrenoreceptor antagonists (phenoxybenzamine) bind to postsynaptic and presynaptic receptors and are used for the management of patients with pheochromocytoma.

Calcium channel blockers (CCB)

There are two main classes of drugs in this group: dihydropyridines (nifedipine, nimodipine, amlodipine, nicardipine etc.) and non-dihydropyridines (verapamil, diltiazem). Their common mechanism of action is to block the entrance of calcium in excitable cells (vascular, cardiac and renal). The group include drugs with different chemical structure and with different affinity for L (long-lasting), T (transitory) and N (Ca_v2.2), CCB receptors. CCB reduce vascular resistance by blunting vasoconstriction through L-channel blockade at vascular smooth vascular cells (VSMC), producing relaxation and decrease of peripheral vascular resistance [15,16]. Dihydropyridines binding depends on the resting membrane potential of the VSMC that is different in different vascular beds, providing vascular territorial selectivity, i.e. nimodipine is selective for the cerebral circulation. Dihydropyridines are a pivotal group for hypertension treatment and the highest used world-wide. Used alone or in combination with other agents, like angiotensin-converting-enzyme inhibitors (ACEI), angiotensin II-receptor blockers (ARB) and beta-blockers, effectively lower blood pressure; however, it is unclear if combination with a diuretic result in a further lowering of blood pressure. Side effects of dihydropyridines include flushing, and headaches due to their potency as arteriolar dilators, edoema due to an increased transcapillary pressure gradient and do not reduce even increase albuminuria. One new member of the drugs class, azelnidipine, induce blockade of the L and T channels in the vascular smooth vessel cells reducing albuminuria.

Verapamil and diltiazem blocking the L and T in the myocardiocyte and in the conduction system, decrease cardiac contractibility and heart rate, with an antiarrhythmic effect but are no recommended in hypertension treatment.

Diuretics

There are different classes of diuretic agents used in the treatment of hypertension. Thiazides (hydrochlorothiazide) and thiazide like (chlorthalidone, indapamide) inhibit the Na/Cl pump in the distal convoluted tube and increase sodium excretion and potassium loss [17]. Chlorthalidone and hydrochlorothiazide are structurally and pharmacokinetically very different, with chlorthalidone having both an extremely long half-life (approximately 40 to 60 h) and a large volume of distribution, with gradual elimination from the plasma compartment by tubular secretion. However, in a recent study [18], patients who received chlorthalidone did not have a lower occurrence of major cardiovascular outcome events or non–cancer-related deaths than patients who received hydrochlorothiazide. Reversible thiazide-induced hyperuricaemia occurs as a result of volume contraction and competition with uric acid for renal tubular secretion. Thiazides may be used alone or in combination with other antihypertensive drugs. When combined with beta-blockers, ACEI or ARAII receptor antagonists they provide additive blood pressure lowering. The addition of a diuretic to a calcium channel blocker is less effective.

Loop diuretics (furosemide, ethacrynic acid) act in the thick ascending limb of Henle, and are generally reserved for hypertensive patients with reduced glomerular filtration rates, congestive heart failure or sodium retention and edoema, where they can be combined with thiazide-type diuretics. Loop diuretics should not be used as first-line therapy in hypertension since there are no outcome data with them, although chlorthalidone proved efficacy for the treatment of HTN in advanced CKD [19]. Oral furosemide is the most widely used diuretic in the loop class; its oral usage can be complicated by extremely erratic absorption, with a bioavailability range of 12%–112% [18].

Potassium sparing diuretics (spironolactone, amiloride and triamterene) act by blocking sodium channels in the distal nephron, inhibiting potassium secretion (amiloride and triamterene) or blocking the aldosterone receptor in the distal convoluted tube (spironolactone). They are weak antihypertensive agents and may be used in combination with thiazide.

Renin-angiotensin system (RAAS) inhibitors

This group includes two classes of agents: angiotensin-converting-enzyme inhibitors (ACEI), angiotensin II-receptor blockers (ARB), and the recently introduced selective renin blocker. The ACEI group incorporates a broad number of agents (captopril, ramipril, lisinopril etc.) that decrease the production of angiotensin II and aldosterone, increase bradykinin levels, and reduce sympathetic nervous system activity. Drugs in the ARB group (losartan, candesartan, irbesartan, olmesartan, telmisartan, valsartan) act by selective blockade of the AT1 receptors; they provide vasodilation and lower catecholamine production. Both classes of drugs are effective antihypertensive agents and may be used as monotherapy or in combination with thiazides, calcium antagonists, and beta-blocking agents. They slow the decline in the estimated glomerular filtration rate, reduce proteinuria and delay progression to advanced chronic kidney disease [20–22]. In addition, they improve insulin action and ameliorate the adverse effects of diuretics on glucose metabolism. The ACEI/ARB combination is less effective in lowering blood pressure than is the case when either drug is used in combination with other classes of agents. In addition, in patients with vascular disease or high risk of diabetes such combination has been associated with more adverse events (cardiovascular death, myocardial infarction, stroke and heart failure) without increases in benefit [23]. Side effects of ACEIs and ARBs include functional renal insufficiency due to efferent arteriolar dilation in a kidney with a stenotic lesion in the renal artery. Persistent dry cough can be observed in 10% of patients receiving ACEIs due to the increase in bradykinin levels; this side effect does not occur with ARBs. Hyperkalemia due to hypoaldosteronism is an occasional side effect of both ACEIs and ARBs.

An alternative approach to blocking the renin-angiotensin system is the direct renin blockade, achieving a more complete block of the system [24]. Aliskiren is a first of class selective inhibitor of the enzymatic activity of renin interfering with the breakdown of angiotensinogen into angiotensin I. When given with an ARB aliskiren produces significant additional BP reduction indicative of complimentary pharmacology and more complete renin-angiotensin system blockade. In monotherapy, its antihypertensive effect is similar to that of ACEIs or ARBs for lowering blood pressure. Further blood pressure reductions can be obtained in combination with a diuretic or a calcium antagonist. At present, aliskiren is not considered a first-line antihypertensive agent.

The potential different protection in the heart and in the Central Nervous System of ACEi and ARBs was a matter of interest in the last years. While some evidence seems to point to ACEi being superior to ARBs in protecting against coronary heart disease [25], protection against cerebrovascular disease and cognitive impairment seems to be superior with ARBs [26]. The renin blocker share many of the properties of the other two groups with no additional advantages.

Drug combination

A combination of drugs concerning different pharmacologic agents is used to increase BP reduction due to an additive effect since each drug targets a different mechanism and are complementary. Likewise, the combination can reduce the drug-induced side effects. The most recommended combinations are a blocker of the RAAS plus a dihydropyridine CCB or diuretic thiazide or thiazide like. If needed the combination of the three drug classes are recommended. The use of a combination in the same pill, as opposed to the more usual practice of scaling the number of drugs according to the need to control BP values under the recommended objectives, is endorsed by the guidelines [27]. Information to date seems to support the advantages of this administration in the same pill in terms of elements such as faster BP reduction with lower cardiovascular risk and even a reduction in side effects [28]. Although all guidelines currently recommend initiating treatment with this strategy, monotherapy continues to have its place in patients with low CV risk or in elderly patients in whom therapeutic escalation is recommended with monitoring of potential side effects.

Parenteral antihypertensive medication

The need to rapidly reduce elevated BP in life-threatening situations, such as hypertensive encephalopathy, acute coronary events, cardiogenic acute pulmonary edoema, aortic dissection or malignant hypertension, requires intravenous drug administration. Some of the classes of antihypertensives mentioned above have formulations available for parenteral use: adrenergic blockers (esmolol, metoprolol, labetalol, phentolamine), calcium channel blockers (clevidipine, nicardipine), renin-angiotensin blockers (enalaprilat), centrally acting (clonidine). Others available are nitro-glycerine, nitroprusside and urapidil; the first two are direct vasodilators and the latter has a dual mechanism, selective antagonist of the postsynaptic α1-adrenoreceptor and an agonist of the 5-HT1A receptor at the central level [29].

Drugs with blood pressure lowering effect for other indications

The development of agents for the treatment of diseases other than hypertension has brought to the market drugs with targets that affect blood pressure regulation and thus are able to additionally produce a reduction in BP values. This is the case for drugs introduced for the treatment of diabetes mellitus, heart failure or chronic kidney disease. These drugs could come on the market for HTN, but the impact for other indications with greater economic investments.

Sacubitril/valsartan

Sacubitril is a pro-drug that, upon activation, acts as a neprilysin inhibitor. The combination with the ARB valsartan constitutes a first-in-class, novel-acting, angiotensin receptor neprilysin inhibitor (ARNI) that provides inhibition of the metalloprotease neprilysin-that breaks down natriuretic peptides- and the angiotensin (AT₁) receptor. Preventing the breakdown of natriuretic peptides leads to a prolonged duration of the favourable effects of these peptides [30]. The medication is approved to treat patients with chronic heart failure with reduced ejection fraction (HFrEF) with hypertension [31]. Compared with valsartan, dual-acting ARNI/valsartan provides complementary and fully additive reduction of blood pressure. Patients must be able to avoid ACEI at least for 48 h before being started on sacubitril/valsartan. The recent mechanistic study PARAMETER [32] demonstrated that sacubitril/valsartan is superior to angiotensin receptor blocker (ARB) monotherapy for reducing central aortic systolic pressure (primary endpoint) as well as for central aortic pulse pressure (secondary endpoint) and nocturnal BP preferentially. Sacubitril/valsartan has been included in clinical practice guidelines for the management of heart failure and for the management of hypertension, particularly in the prevention of heart failure in uncontrolled hypertensive elderly patients, and the related continuum from hypertension to heart failure. Sacubitril/Valsartan has not shown significant side effects so far but combination with ACEIs is contraindicated.

Diabetes driving agents

In 2008 the US Food and Drug Administration published a guideline for the pharmaceutical industry [33] and legislated that studies of diabetes drugs should include adjudicated CV events in a blinded fashion, such as cardiovascular mortality, myocardial infarction and stroke, hospitalisation for ACS, urgent revascularization procedures and other end points, including patients at increased risk of CV events. This guideline stimulated the development of drugs that could meet FDA's requirements.

Type 2 diabetes mellitus (DM2) and hypertension frequently coexist; they constitute a dual cardiovascular threat and should be adequately controlled. Advances in the treatment of DM2 have generated oral glucose-lowering agents that target different pathophysiological processes in DM2. Beyond their glucose-lowering effects, these drugs have also shown beneficial cardiovascular effects including BP lowering [34]. The two classes of agents relevant to BP control are glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose-cotransporter 2 (SGLT-2) inhibitors. The GLP-1, produced by the neuroendocrine intestinal L cells, is a natural insulin secretagogue and is also expressed in the atrium of the heart and within vascular smooth muscles. GLP-1 RA drugs are effective in reducing body weight. The actions of GLP-1 on the heart and blood vessels produce vasodilation [35]. To date, six GLP-1 RAs have been approved for the treatment of DM2: exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide and semaglutide. Different systematic reviews and meta-analysis including a large number of subjects in randomised control trials have shown than GLP-1 RAs induce a significant lowering of systolic blood pressure and minor changes in diastolic blood pressure, mainly dependent of weight reduction. The antihypertensive effects of GLP-1 RAs seem to be supplementary and independent of the effect of other antihypertensive agents given concomitantly [36].

The reabsorption of glucose from the glomerular filtrate is an active process linked to sodium and requires a carrier protein referred to as sodium glucose cotransporter (SGLT). Two isoforms of SGLT have been described: SGLT-1, located in the small intestine, and SGLT-2, found in the epithelial cells of the proximal renal tubule, where it is responsible for 90% of glucose reabsorption and 65% of sodium reabsorption [37]. The group of SGLT-2 inhibitors includes empagliflozin, dapagliflozin, canagliflozin, and ertugliflozin. Besides the glucose-lowering effects, robust data underline the cardiovascular benefits of these agents, favouring BP reductions of 2.5–5 mmHg for systolic and 1.5–3 mmHg for diastolic pressure [38–41] All related studies and their meta-analysis concluded that SGLT-2 have a beneficial effect on BP, and when compared with hydrochlorothiazide the efficacy was similar [42]. Any superiority among SGLT-2 inhibitors has not been established. The magnitude of the BP response is dependent on the chosen comparator and the baseline BP. Patients with elevated baseline BP achieve greater reductions than normotensive ones. A number of possible mechanisms, which may be interrelated, have been proposed for BP reduction with SGLT-2 inhibitors. The leading hypothesis include volume depletion, due to diuresis and natriuresis. Sotagliflozin inhibits both SGLT-1 and SGLT-2 and slows intestinal absorption of glucose; when compared with empagliflozin in a group of DM2 subjects, sotagliflozin changes from baseline in glycaemic and BP control were not different [43].

New drugs in development

Dual-Endothelin blockers

Endothelin-1 is a peptide produced by vascular endothelial cells which causes vasoconstriction, provokes endothelial dysfunction, stimulates aldosterone synthesis, and increases catecholamine release. Two types of endothelin (ET) receptors have been described: ETA and ETB. Both are found on vascular smooth muscle cells, where they mediate vasoconstriction, but only ETB receptors are present on endothelial cells and can mediate vasodilation [44]. Both selective and non-selective endothelin receptor antagonists (ERAs) have been studied to treat resistant hypertension. Aprocitentant is a dual antagonist of ETA and ETB receptors that when added to hypotensive therapy with three agents and a diuretic has shown significant lowering of BP in a phase 3 trial [45].

Aminopeptidase a inhibitors

In the brain, a metalloprotease, amino- peptidase A (APA), is involved in the renin-angiotensin system through its role in converting angiotensin II to angiotensin II [46]. Angiotensin III affects blood pressure by increasing central concentrations of vasopressin, stimulating the baroreflex function and lowering sympathetic tone [47]. Treatment with an APA inhibitor, EC33, has been shown to decrease blood pressure in salt-dependent hypertensive rat models by reducing the levels of brain angiotensin III without affecting systemic levels [48]. Firibastat, a novel orally active prodrug that is metabolised to EC33 has been shown to decrease blood pressure in overweight hypertensive subjects of different ethnic origin [49]. Systolic automated office blood pressure (AOBP) decreased by 9.5 mmHg (p < .0001), while diastolic AOBP decreased by 4.2 mm Hg (p < .0001); 85% of subjects did not receive hydrochlorothiazide and were treated with firibastat alone. However, two recent phase 3 open-label multicentre efficacy and safety studies (FRESH and REFRESH) of firibastat 500 mg BID in patients with difficult to treat hypertension have failed to reduce blood pressure in resistant hypertension [50].

Blockers of the mineralocorticoid receptors

The mineralocorticoid receptors (MR) are expressed in renal endothelial cells, vascular smooth muscle cells, podocytes, mesangial cells, and epithelial cells of the distal nephron [51]. In renal epithelial cells, aldosterone binds to the MR, causing water and sodium reabsorption, thereby elevating blood pressure.

Spironolactone, as described previously, is a steroidal mineralocorticoid receptor antagonist recommended as fourth-line therapy in the treatment of resistant hypertension, in addition to a renin-angiotensin blocker, CCB, and a thiazide diuretic [52]. Spironolactone decreases proteinuria and improves blood pressure; its use may not be appropriate in patients with advanced renal failure due to the increased risk of hyperkalemia.

The high incidence of spironolactone-associated hyperkalemia in clinical practice sparked efforts to identify potent, yet selective, non-steroidal MR antagonists (NS-MRA) with a favourable benefit-risk profile and a low risk of producing hyperkalemia [53,54]. Finerenone is a new agent in this class, showing to slow the decline of kidney function and reducing cardiovascular outcomes in patients with diabetic nephropathy [55]. Finerenone does have a significant blood pressure lowering ability at systolic pressures above 140 mmHg, but not in normotensive individuals, although exerts a much more potent hemodynamic effect that originally believed [56]. Several phase 3 studies are ongoing investigating the effects of finerenone on cardiovascular outcomes in diabetic patients with chronic renal disease. Other NSMRSs in development, esaxerenone and ocedurenone, are undergoing trials to manage resistant hypertension [57,58].

Selective aldosterone synthase inhibitors

Aldosterone synthase controls the synthesis of aldosterone. Selective inhibition of this enzyme supresses the hormone synthesis rather than by blocking the mineralocorticoid receptor. The suppression of aldosterone is essential but has proved difficult to achieve due to the combined interference of cortisol production [46]. Baxdrostat is a recent new agent that has high selectivity for inhibiting aldosterone synthase as compared with the enzyme required for cortisol synthesis. In a dose-dependent manner, baxdrostat increases natriuresis and reduces plasma and urine aldosterone levels but not cortisol levels. A phase 2 trial of baxdrostat for treatment-resistant hypertension has shown dose-related reductions in blood pressure [59]. Trials of aldosterone synthase inhibitors involving patients with primary aldosteronism are ongoing. These trials will probably determine the maximum reduction in blood pressure to be expected [60].

Pharmacogenomics contribution

Genomic and epigenetic research into the regulation of BP and hypertension has provided information on its complex genetic architecture. Advancing knowledge in the field of pharmacogenomics will allow to perform precision medicine and develop more effective drugs based on the identification of targets with high therapeutic impact. Increasing the therapeutic arsenal of therapies that effectively reduce BP with minimal side effects and additionally decrease the impact on cardiovascular and renal risk associated with HBP is important for future precision medicine. In addition to identifying new therapeutic targets, genetics can also provide insight into opportunities for drug development [61].

However, we are still a long way from the application of precision medicine in HBP. It is true that genetics contribute to individual differences with respect to drug exposure. A large number of SNPs influence the metabolism, pharmacokinetics, pharmacodynamics and therefore the efficacy of antihypertensive drugs and side effects. SNPs associated with different reductions in BP values have been described in thiazide diuretics, beta-blockers, calcium antagonists, and renin-angiotensin-aldosterone system blockers [62–66]. Likewise, not only the impact on BP has been studied, but also the association with greater or lesser protection of its impact on myocardial protection or renal function. The current status is that for most of the SNPs identified there is no level of evidence supporting their routine use in clinical practice.

On the other hand, progress is being made in the identification of therapeutic targets and in the development of drugs to access them by blocking or stimulating their function. Monoclonal antibodies, oligonucleotides and small or short interfering RNA (siRNA), targeting genes and/or blocking mRNA, envisage potential new treatment options. Drugs targeting the atrial natriuretic factor receptor gene [67] with monoclonal antibodies and blocking the mRNA hepatic angiotensinogen [68] by using oligonucleotides or siRNA are offering encouraging results in terms of their antihypertensive efficacy and the convenience of their administration, with monthly or even 6-monthly therapeutic regimens, which would favour one of the main current problems in the treatment of HT, the lack of therapeutic adherence.

Atrial natriuretic factor (ANP) receptor gene

NPR1 gene encodes the natriuretic peptide receptor; its binding to ANP results in the conversion of GTP to cGMP, activating other proteins (cGMP-dependent protein kinase I and II, PDEs and CNGs) and resulting in downstream effects of lowered BP and salt extraction. Allelic changes in SNPs rs35479618 and rs116245325 result in differences in the catalytic guanylate cyclase domain which are associated with increased BP as ligand binding results in decreased cGMP production. In contrast, changes at SNP rs61757359 increases the activity of cGMP [67,69].

An NPR1 agonist drug (REGN5381, monoclonal antibody) is in development as an antihypertensive drug. This is being evaluated in a Phase I and II clinical trial for its use as a hypertension treatment (NCT04506645). Phase III in hypertensives lack of control is starting with monthly subcutaneous injection.

Hepatic angiotensinogen inhibition

The degree of inhibition of the RAAS system with ACE inhibitors and ARBs is limited by dosing constraints, like hyperkalemia and renal dysfunction. Targeting the upstream enzyme angiotensinogen (AGT) blocks RAAS and confers additional advantages. Silencing AGT in the liver, as opposed to the kidney, results in a lower incidence of hyperkalemia and renal dysfunction, and a more potent inhibition of the RAAS.

Two different approaches are available for use in humans. First, an antisense oligonucleotide, IONIS-AGT-Lrx, reduces plasma AGT levels by AGT mRNA knockdown in the hepatocytes [70]. Results from phase 1 and phase 2 studies have shown significant reduction in AGT and a trend towards significant systolic and diastolic BP reductions, −12 mmHg and −6 mmHg respectively, in hypertensive patients treated with two antihypertensive medications and a weekly subcutaneous injection of this agent.

Another approach is the use of a small interference molecule (siRNA) that blocks mRNA synthesis of AGT that is presently under phase 1 studies [46]. Zilebesiran is the first drug using this way of action [71] in which the siRNA covalently linked to an N-acetylgalactosamine [GalNAc] ligand binds with high affinity to the hepatic asialoglycoprotein receptor, maintaining the blockade for periods up to six months. As has been shown in hypertensive rats, potential problems due to the long-term blockade of AGT synthesis can be overcome administering vasopressors or fludrocortisone [72].

In Table 1 a summary of the most recent studies with the new antihypertensive drugs in development are included.

Table 1. New antihypertensive drugs in development.

Drug and trial name	Phase trial	Inclusion criteria	Study design	Drug administration	Blood Pressure reduction mmHg	Comments
	Dual endothelin A and B receptor blocker
Aprocicentan [45] PRECISION	III	Resistant HTN	Placebo control over 3–4 drugs treatment^a	Oral oid 12.5 and 25 mg	Sist/Diast Office −3.8/−3.7 24h −4.2/−5.9	The most frequent adverse event was mild-to-moderate oedema or fluid retention (18% with 25 mg)
	Aminopeptidase A blocker
Firibastat [50] FRESH	III	Dificult BP control	Placebo control over 2–3 drugs treatment^a	Oral bid 500 mg	No superiority against placebo	No reported
	Mineralocorticoid receptor blocker
Eplerenone [56] ARTS-DN	IIb	Type 2 DM and CKD	Placebo control	Oral oid 10 and 15 mg	Sist 24h −8.3/−11.2	Serious AEs occurred in 3.3% of patients
	Aldosterone synthase blocker
Baxdrostat [59]	II	Resistant HTN	Placebo control over 3–4 drugs treatment^a	Oral oid 1 and 2 mg	Sist Office −8.1/−11.0	Adverse events that occurred in 5% or more patients in any of the trial groups were urinary tract infections, hyperkalemia, headache, and fatigue
	mRNA Angiotensinogen targeted
IONIS-AGT-Lrx^b [70]	II	Hypertensive	Placebo control over 2–3 drugs treatment^a	Weekly subcutaneous 80 mg	Despite large Sist (Diast reduction no significant differences with placebo
Zilebesiran^c [71]	I	Hypertensive	Placebo control and over irbesartan	One subcutaneous 800 mg	Sist/Diast 24 h −9.1/−2.4 + low salt diet −18.8/−8.4 + irbesartan plus −6.3/−3.0	Attenuation of the effect on blood pressure by a high-salt diet and with an augmented effect through coadministration with irbesartan
	Monoclonal antibody NPR1 gene activation
XXB750 [69]	II	Resistant HTN	Placebo control over 3–4 drugs treatment^a	Monthly subcutaneous Several dose 30 to 240 mg	24 h Sist/Diast	In development

^aMulticentre, blinded, randomised, parallel-group

^bAntisense oligonucleotide

^cSmall interfering molecule.

Conclusion

The therapeutic arsenal for the treatment of arterial hypertension has been developed over the last 70 years, with the introduction of drugs with the ability to influence the main mechanisms involved in the development and persistence of hypertension. The complexity of these mechanisms, as Irwing Page [73] saw so well, and the impact on different organs and systems, which are both cause and consequence of hypertension, has led to the combination of drugs. The development of these drugs seemed to stop at the end of the last century. However, disciplines such as pharmacogenetics offer new methods of intervention beyond the traditional galenic approach. The potential advantages should be tested and the possible disadvantages that may arise from their use should be addressed in the following years.

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