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).