Hypertension and anti-hypertensive therapy

Hypertension – an overview

Hypertension (HT) is defined as a systolic blood pressure (BP) of ≥140 mmHg and/or a diastolic BP of ≥90 mmHg in young, middle-aged and elderly subjects (Williams et al., 2018). In 2004, HT was declared by the World Health Organization (WHO) as the lead risk factor for death worldwide, accounting for 7.5 million deaths (12.8% of total deaths). Hypertension is the leading risk factor for global disease burden (Lim et al., 2012) , particularly cardiovascular diseases, and an important risk factor for other diseases such as kidney failure. According to the Global Health Observatory data repository 2015, HT affects 1.13 billion people, with a global age-standardized prevalence of 22.1% (24.1% for males). In low-income countries, the high prevalence (28.4%) of hypertension is mainly attributed to flawed health systems, resulting in untreated and uncontrolled patients (Yeates et al., 2015). In high-income countries, hypertension prevalence levels are slightly decreased probably in response to public health actions (Lloyd-Jones and Levy, 2013; World Health Organization, 2013), however HT prevalence is expected to increase globally in coming years, due to the growth and ageing of world’s population, behavioral risk factors and lack of efficient therapies.
Hypertension is classified as primary or secondary according to its underlying cause. Most HT patients (~95%) have primary HT, which is defined as high BP without secondary causes. The remaining 5% have secondary HT, deriving from a known medical condition (‘secondary cause’) that is often reversible, (e.g. obstructive sleep apnea, renovascular disease, renal failure) (Carretero and Oparil, 2000; Oparil et al., 2003; Pullalarevu et al., 2014; Rimoldi et al., 2014). Conversely, primary HT has no single causative agent - it seems to be influenced by the presence of risk alleles and multiple other factors such as body mass index, gender, insulin resistance, high alcohol and salt intakes, low potassium and calcium intakes, stress, aging and sedentary lifestyle (Carretero and Oparil, 2000; Pullalarevu et al., 2014). Although still scarcely identified, genetic factors are thought to play a major role in primary HT, and primary HT tends to be associated with parental HT (Wang et al., 2008) - family studies estimated the heritability of BP from 30 to 50% (Ehret and Caulfield, 2013). However, this complex polygenic disorder seems to be influenced by the interaction of genomic and environmental factors, challenging the clear identification of susceptibility genes and epigenetically modulated mechanisms. The advent of high-throughput genotyping technologies provided some clues on the contribution of common genetic variation on BP traits and primary HT (Ehret et al., 2016; Burrello et al., 2017; Warren et al., 2017), although additional studies are needed to confirm associations. Further, epigenetic marks (e.g. DNA methylation, histone modifications and non-coding RNAs) might provide missing links in BP traits variability (Richard et al., 2017).

Antihypertensive therapy

The central role of HT in the pathophysiology of many age-related chronic diseases of high prevalence and socioeconomic burden, boosts research on effective antihypertensive therapies. Their main goal is to lower HT-associated complications, morbidity and mortality (Berryman, 2000; Kamath, 1990), related to target-organ damage such as cardiovascular events, heart failure and kidney disease (Berryman, 2000). Controlled BP is the most feasible clinical end point, but patients should be guided on both pharmacological therapy and lifestyle modifications (‘nonpharmacological therapy’), since BP reduction alone may not guarantee prevention of future target-organ damage ( Wells et al., 2009; Koda-Kimble and Alldredge, 2013;). There are many factors to consider when choosing the right antihypertensive therapy, such as: concomitant illnesses and medications, HT stage, age, compliance, genetics and special populations (Wells et al., 2009; Clark et al., 2011; Koda-Kimble and Alldredge, 2013). Nonpharmacological therapy can include a combination of weight loss, restricted sodium intake, increased aerobic exercise, moderation in alcohol consumption, and stress relief (Brunton et al., 2005; Kasper et al., 2015; Gouveia et al., 2017). Nonpharmacological therapy may suffice in cases of prehypertension and, when combined with pharmacological regimens, can increase the drug therapy efficacy, improving the quality of life and longevity (Gouveia et al., 2017).
A great variety of pharmacological antihypertensive agents can effectively lower BP. Current European Society of Cardiology and European Society of Hypertension (ESC/ESH) guidelines an initial therapy with a combination of ACEI or angiotensin receptor blockers (ARBs) with diuretics (including thiazides, chlorthalidone and indapamide) or calcium channel blockers (CCB). A triple combination could be prescribed but concomitant use of ACEi and ARB is discouraged (Williams et al., 2018). As add-on therapy, alternative potent antihypertensive drugs (e.g. spironolactone) can additionally lower BP in patients with resistant hypertension although they have an high incidence of adverse effects (Berryman, 2000). Supplementary Table S1 summarizes some of the first line antihypertensive agents according to their subclasses, action mechanism, produced effects and clinical applications. A list of antihypertensive drugs and common therapies is also provided.

Angiotensin I-Converting Enzyme Inhibitors

Angiotensin I- Converting Enzyme (ACE) is a main target in hypertension therapy given its key role in the Renin-Angiotensin system, the main metabolic pathway regulating human BP and fluid homeostasis. The action of ACE increases BP as a result of both increased vasoconstriction and diminished vasodilation.
In the past twenty years, synthetic ACEI have been one of the preferred first-line therapy for HT, especially in diabetic and chronic kidney disease patients (TH et al., 2003; Jimsheena and Gowda, 2010; Zisaki et al., 2015; Perico et al., 2017 ). ACEI act on both the Renin-Angiotensin and the Kallikrein-Kinin systems (Figure 1). By blocking ACE activity, ACEI prevent the conversion of angiotensin I into the potent vasoconstrictor angiotensin II (Berryman, 2000). ACEI also block the breakdown, by ACE, of the vasodilatory peptide bradykinin, responsible for increasing the production at the blood vessels of two potent vasodilators: prostacyclin and nitric oxide (Clark et al., 2011). By reducing angiotensin II levels, ACEI also decrease the secretion of aldosterone, and thus sodium and water retention (Berryman, 2000). Overall, ACE inhibition decreases BP as a result of both increased vasodilation (due to the action of bradykinin at blood vessels) and diminished vasoconstriction (resulting from the lack of angiotensin II and its target aldosterone) (Figure 1) (Clark et al., 2011).
ACE inhibitors have been divided in three categories: 1) captopril; 2) prodrugs, such as enalapril and fosinopril; and 3) lisinopril, a water-soluble and the only non-metabolized ACEI (Zisaki et al., 2014). Most of ACEI are prodrugs, requiring hepatic conversion to pharmacologically active metabolites. Captopril and lisinopril are exceptions to this rule and are prescribed to patients with severe hepatic impairment (Kelly and O’Malley, 1990; Zisaki et al., 2014). As the majority of ACEI are eliminated primarily by the kidney, they may require dose adjustments to varying degrees of renal impairment ( Weber, 1991; Piepho, 2000).
Although widely used for treating HT, congestive heart failure, and diabetic neuropathy (Jimsheena and Gowda, 2010; Zisaki et al., 2014) synthetic ACEI have been associated with various side effects including cough, skin rashes, hypotension, loss of taste, angioedema, reduced renal function and fetal abnormalities (Norris and FitzGerald, 2013). To minimize the risk of side effects, synthetic ACEI have been combined with other antihypertensive agents, such as calcium-channels blockers (Egan, 2007) (Supplementary Table S1). Moreover, naturally occurring ACEIp have gathered attention as potential antihypertensive agents to be used alone or in combination with other non-pharmacological therapies, for HT preventive measures and initial treatment of HT (Gouveia et al., 2017).