Actual Place of Diuretics in Hypertension Treatment-Juniper Publishers
JUNIPER PUBLISHERS-OPEN ACCESS JOURNAL OF CARDIOLOGY & CARDIOVASCULAR THERAPY
Diuretics represent a large and heterogeneous class
of drugs, differing from each other by structure, site and mechanism of
action. Diuretics are widely used, and have several indications in
different cardiovascular disorders, particularly in hypertension and
heart failure.
Despite the large number of available
anti-hypertensive drugs, diuretics remained a cornerstone of
hypertension treatment. In the current editorial, we assessed the actual
place of different diuretics in the hypertension guidelines focusing on
the concept of tailored approach in prescribing them for hypertensive
patients.
Introduction
Diuretics represent a large and heterogeneous class
of drugs, differing from each other by structure, site and mechanism of
action. Diuretics are widely used, and have several indications in
different cardiovascular disorders, particularly in hypertension and
heart failure.
Despite the large number of available
anti-hypertensive drugs, diuretics remained a cornerstone of
hypertension treatment [1]. Indeed, they are the second most commonly
prescribed class of antihypertensive medication. For instance, 12% of US
adults were prescribed a diuretic, and the relative increase in
prescriptions from 1999 through 2012 was 1.4 [2]. However, a question
remains looking for an answer: which diuretic for which hypertensive
patient?
The overall action of diuretics (except osmotic
diuretics) can be summarized as the blockage of sodium reabsorption at
the nephron major sites leading to an increase in water excretion.
Figure 1 illustrates the sites of action of different diuretic agents;
Table 1 describes their mechanisms of action.
a: Osmotic diuretics; b: Carbonic anhydrase inhibitors; c: Loop
diuretics: d: Indapamide & Chlorthalidone; e: Hydrochlorothiazide; f:
Amiloride & Triamterene; i: Spironolactone.
ALoH: Ascending Loop of Henle; BC: Bowman Capsule; CD:
Collecting Duct; DCT: Distal Convoluted Tubule; DLoH: Descending
Loop of Henle; PCT: Proximal Convoluted Tubule
*Carbonic anhydrase inhibitors and osmotic diuretics are not included.
In addition to their nephrogenic effects, some diuretics
according to their structural proprieties can lower blood
pressure via other pathways. For instance, indapamide has
calcium antagonist-like vasorelaxant effects that strengthen
its lowering blood pressure action [3]. Spironolactone likewise
has another site of action on arterioles receptors, where it
antagonizes aldosterone-induced vasoconstriction, resulting in
diastolic and mean pressure reduction [4].
Nonetheless, the most worrying adverse effects of this class
of agents is electrolytes derangement. Serum potassium level
may be lowered by thiazides and loop diuretics and elevated by
aldosterone antagonists. Hyponatremia is more common with
chlorthaliadone than hydrochlorthiazide but not at equipotent
doses and the incidence of hyponatremia for both medications is
very strongly age related [5].
Formerly, diuretics were considered to be one of the most
effective antihypertensive treatments. Nowadays, after the onset
of new potent anti-hypertensive drugs, diuretics may be no
longer considered the most privileged first-line strategy [6,7].
Indeed, most of the current guidelines downgraded the place
of thiazide diuretics in the management of hypertension from
the preferential initial therapy to one of the possible first-line
alternatives among a large armamentarium of anti-hypertensive
drugs [8-12].
The recent Australian guidelines emphasize that the choice
of a drug to initiate or to maintain an anti-hypertensive therapy
should consider several parameters: patient’s age, race, comorbidities,
potential interaction with other drugs, cost,
patient’s choice and implication for adherence [12]. Hence,
these guidelines suggest to the practitioner 4 or 5 different class
drugs, giving him the freedom to choose the most suitable drug
for each patient as a personalized treatment approach.
Among the diuretics, thiazide and thiazide like diuretics
are those recommended as first-line strategy for primary
hypertensive treatment in different guidelines [8-12]. Table
2 summarized the evolution of the place given to diuretics in
hypertension treatment in different guidelines.
CHEP: Canadian Hypertension Education Program; ESC: European
Society of Cardiology; JNC8: The Eighth Joint National Committee;
NHFA: National Heart Foundation of Australia, NICE: National Institute
for Health and Clinical Excellence; WHO: World Health Organization.
Thiazide diuretics are privileged as the appropriate option in
a variety of circumstances like for salt sensitive patients (such as
black patients) and for those elderly with systolic hypertension
[13]. In other clinical scenarios, they can be prescribed as one of
5 first-line antihypertensive alternatives [8-12].
However, other types of diuretics are barely mentioned
in different guidelines and thereby are underutilized in daily
practice [1]. Table 3 summarized the ideal clinical indications of
each diuretic.
Thiazide and thiazide like diuretics do not have the same
structure neither the same site of action, and that would explain
the huge disparities concerning their efficiency and side effects.
Despite their differences, the recommendations generally
do not favor any agent on the other [8-11]. Indeed, although
recommendations encouraged a treatment approach based on
considering patient’s characteristics, the majority of guidelines
are based on evidence for drug classes rather than individual
drugs. Only Australian guidelines encourage when initiating or
changing treatment, to prescribe a thiazide-like diuretic, such
as chlorthalidone or indapamide in preference to a conventional
thiazide diuretics [12].
Hydrochlorothiazide: Much evidence support the inferiority
of hydrochlorothiazide compared to other thiazide like agents
[1]. In fact, hydrochlorothiazide duration of antihypertensive
action is less than 24hour, while indapamide has even in the
immediate release form, at least 24-hour duration of action for
blood pressure reduction [14]. Duration of action is important
in view of the fact that targeting nighttime blood pressure may
reduce cardiovascular events [1]. Hydrochlorothiazide is also
less potent than converting enzyme inhibitors, angiotensin
receptor blockers, beta-blockers, and calcium channel blockers.
In a network analysis, hydrochlorothiazide alone was
shown to be less effective in preventing cardiovascular events
in comparison with chlorthalidone and the association
hydrochlorothiazide-amiloride [15]. Furthermore, it is
inferior to indapamide in improving endothelial function and
longitudinal strain in patients with hypertension and diabetes [16]. Hydrochlorothiazide is also inferior to spironolactone in
improving coronary flow reserve [17].
The only advantage of hydrochlorothiazide over both
chlorthalidone and indapamide seems to be it extensive
availability in formulations with other classes of antihypertensive
drugs and his low price.
Indapamide: Many authors suggest that indapamide is by far
the most efficient and tolerable diuretic for hypertensive patients
[8]. Compared to hydrochlorothiazide, it was demonstrated to
be more efficient in improving micro-albuminuria (in diabetics),
reducing left ventricular mass index, inhibiting platelet
aggregation, and reducing oxidative stress. Indapamide also
proved its capacity to reduce left ventricular hypertrophy more
than enalapril [18].
Another important feature, is that indapamide do not share
with thiazide diuretics their adverse effects on lipid and glucide
metabolism, thereby it can safely prescribed in diabetics patient
[1].
Indapamide or chlorthalidone: The choice between
indapamide and chlorthalidone is quite a relevant question. But
the main obstacle that is faced to answer to this question is that
there is no trial through literature that compares chlorthalidone
and indapamide in the literature.
Kaplan [19] suggests that the choice between these 2
efficient drugs should be based on the 3 following criteria: (i)
the ease of use; (ii) the cost; and (iii) hypokalemia which is a
considerable drawback of chlorthalidone [8]. Indeed, the fall in
serum potassium with 12.5mg doses of chlorthalidone is nearby
0.1mmol/L greater than that seen with equivalent doses of
hydrochlorothiazide [1].
The huge disparities of thiazides prescription may be due
to that chlorthalidone is only commercialized with atenolol
and azilsartan. Likewise, Indapamide is only combined with
perindopril.
Both observational and randomized trials have shown that
thiazide and thiazide-like diuretics (generally at higher doses)
can cause ventricular ectopy and sudden death [1]; the addition
of potassium-sparing diuretics might prevent it [20].
Furthermore, in elderly hypertensive patients, both amiloride
and triamterene were showed to be efficient when combined to
hydrochlorothiazide to reduce cardiovascular events compared
to placebo [21]. While spironolactone did not show appropriate
evidence for reducing cardiovascular events in hypertensive
patients, its place in reducing total mortality in advanced heart
failure is well known [22]. Moreover, its efficiency in resistant
hypertension is well established [23].
Spironalctone has several others non blood pressure
benefits like reducing proteinuria by 61% in proteinuric kidney disease, albuminuria by 60% in type 1 diabetes, and normalizing
left ventricular hypertrophy in primary aldosteronism and low
renin hypertension [1].
Both spironalactone and eplerenone are indicated in patients
affected by heart failure. Although resulting in similar rates of
hyperkalemia, eplerenone was shown to have greater impact on
systolic blood pressure and to improve endothelial function in
hypertensive patients [24,25].
Loop diuretics are mostly indicated as an alternative to
thiazide diuretics in case of chronic kidney disease with serum
creatinine is >1.5mg/dL or eGFR is <30mL/min/1.73m² [1].
The antihypertensive effect of low-dose loop diuretics could be
improved with nighttime administration.
Diuretics are a popular, heterogenous class of antihypertensive
drugs with several decades of clinical application. The concept to
replace “one size fits all” paradigm to a more tailored approach
in prescribing diuretics to hypertensive patients seems to be
rational and appropriate for a better clinical benefit.
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