975893

research-article20202020
JRA0010.1177/1470320320975893Journal of the Renin-Angiotensin-Aldosterone SystemSun and Sever

Original Article

Journal of the Renin-Angiotensin-

Amiloride: A review Aldosterone System

October-December 2020: 1­–9
© The Author(s) 2020
Article reuse guidelines:
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DOI: 10.1177/1470320320975893
https://doi.org/10.1177/1470320320975893
journals.sagepub.com/home/jra
Qianhui Sun1 and Peter Sever2

Abstract
Amiloride is a potassium retaining diuretic and natriuretic which acts by reversibly blocking luminal epithelial sodium
channels (ENaCs) in the late distal tubule and collecting duct. Amiloride is indicated in oedematous states, and for
potassium conservation adjunctive to thiazide or loop diuretics for hypertension, congestive heart failure and hepatic
cirrhosis with ascites. Historical studies on its use in hypertension were poorly controlled and there is insufficient data
on dose-response. It is clearly highly effective in combination with thiazide diuretics where it counteracts the adverse
metabolic effects of the thiazides and its use in the Medical Research Council Trial of Older Hypertensive Patients,
demonstrated convincing outcome benefits on stroke and coronary events. Recently it has been shown to be as effective
as spironolactone in resistant hypertension but there is a real need to establish its potential role in the much larger
number of patients with mild to moderate hypertension in whom there is a paucity of information with amiloride
particularly across an extended dose range.

Keywords
Amiloride, hypertension, natriuretic, diuretic, review

Date received: 2 November 2020; accepted: 4 November 2020

Introduction an acylguanidine group attached to ring position 2, amino

groups attached at ring positions 3 and 5, and a Cl group
In 1965, Bickling and colleagues observed that certain non- attached at position 6 (Figure 1). Due to the guanidium
steroidal acylguanidine derivatives displayed both natriuretic moiety, amiloride is a weak base with a pKa of 8.7 in aque-
and antikaliuretic properties. This led to the synthesis of ami- ous solution. Protonation of amiloride occurs in the guani-
loride.1 Amiloride hydrochloride (3,5-diamino-N-carba- dine group and not in the amino groups. Due to these
mimidoyl-6-chloropyrazine-2-carboxamide) is a synthetic acid-base properties, amiloride can effectively penetrate
pyrazine derivative. It is a potassium-sparing diuretic. It biological and artificial membranes.4 Amiloride is rarely
inhibits sodium reabsorption through epithelial sodium chan- soluble in water.1
nels in the distal convoluted tubules and collecting ducts of
the kidney. Currently, amiloride is indicated in oedematous
states, and for potassium conservation adjunctive to thiazide Clinical pharmacology
or loop diuretics for hypertension, congestive heart failure Amiloride reaches the nephron largely by glomerular fil-
and hepatic cirrhosis with ascites.2 Amiloride is currently tration and acts on the luminal membrane of the distal con-
being used increasingly in hypertension management yet it is voluted tubule and collecting ducts3 (Figure 2). In the late
an old drug and there is a paucity of information on its blood distal tubules and collecting ducts, particularly in the
pressure effects across an extended dose range and in various cortical collecting tubules, there are principal cells which
subgroups of patients with hypertension. This review sum-
marises a number of clinical trials investigating the effects of
1
amiloride for its natriuretic and diuretic effects and for its Imperial College London, Faculty of Medicine, Faculty Building, Level 2,
London, UK
effects on blood pressure (BP). 2
Imperial College London, National Heart and Lung Institute, ICTEM
Building, Level 3, London, UK
Basic pharmacology Corresponding author:
Professor Peter Sever, Imperial College London, National Heart and
Amiloride is a pyrazine-carbonyl-guanidine derivative and Lung Institute, ICTEM Building, Level 3, Du Cane Road, London, W12
it is chemically unrelated to other diuretics or antikaliu- 0NN, UK.
retic agents.3 It consists of a substituted pyrazine ring with Email: [email protected]

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2 Journal of the Renin-Angiotensin-Aldosterone System

A trial by Sabanathan et al.9 examined the effects of

ageing and hypertension on the pharmacokinetics and
pharmacodynamics of a combination capsule of atenolol
(50 mg), hydrochlorothiazide (25 mg) and amiloride
(2.5 mg). Three patient groups with a total of 18 volunteers
participated – a group of young healthy subjects, a group
of elderly healthy subjects, and a group of elderly hyper-
tensive patients. Hypertension did not affect the pharma-
cokinetics of any drugs. However, a significant fall in BP
was observed in the hypertensive group. Ageing signifi-
cantly increased the bioavailability and the 24-h plasma
Figure 1. Structure of amiloride. concentration in all three drugs. The half-life of amiloride
was also significantly longer in the elderly. Chronic dosing
have epithelial sodium channels (ENaCs) in their luminal of amiloride increased the 24-h plasma concentration in all
membranes. ENaC is a heterotrimer consisting of three patient groups. There were no significant differences in the
subunits – alpha, beta and gamma. ‘Maximal sodium per- urinary recovery of amiloride between the young and
meability is induced when all three subunits are coex- elderly on acute or chronic dosing.
pressed in the same cell’.5,6 In Liddle’s syndrome, Current knowledge indicates that amiloride is absorbed
mutations in the ENaC result in hyperactivity leading to from the gastrointestinal tract and has an oral bioavailabil-
severe hypertension. ENaCs are a highly regulated site for ity of around 50%. Co-administration with food can
sodium reabsorption and sodium enters the cell by passive decrease absorption to 30%, but the absorption rate is
diffusion down the electrochemical gradient created by the unchanged. After administration, the onset of diuretic
basolateral Na+/K+ pump.5,7 The high sodium permeabil- activity usually occurs within 2 h. Peak diuresis occurs
ity depolarises the luminal but not the basolateral mem- within 6–10 h. The diuretic effects persist for about 24 h
brane. This creates a lumen-negative transepithelial post administration. Amiloride is not metabolised by the
potential difference. The transepithelial potential differ- liver. Approximately 50% is excreted unchanged by the
ence provides a driving force for potassium secretion into kidneys in the urine, around 40% is excreted in the faeces.
the lumen through the apical potassium channels.5 In patients with normal renal function, amiloride has a
Amiloride can reversibly block luminal ENaCs of the prin- serum half-life of 6–9 h.10–13
cipal cells by binding to the channel pore. There is a lim-
ited capacity for the late distal tubule and collecting duct to Dose-response to diuretic and
reabsorb solutes, therefore inhibition of the sodium chan-
nel at this site only mildly increases Na+and Cl- excretion
natriuretic effects
rates.5 The inhibition of ENaC hyperpolarises the luminal The dose-response of amiloride was investigated in six
membrane, reducing the lumen-negative transepithelial healthy male subjects aged between 21 and 30.14 Each sub-
voltage. Normally, the lumen-negative potential difference ject received oral amiloride in doses of 5, 10, 20, 30, 40
facilitates cation secretion, its attenuation then decreases and 60 mg. In addition, to determine the period of maxi-
K+, H+, Ca2+ and Mg2+ excretion rates.3,5,6 mum amiloride activity, a single oral dose of 40 mg of ami-
loride was given to six more healthy males. Control and
experimental urine samples were collected hourly through-
Pharmacokinetics
out the day. The results demonstrated that by increasing
A 1973 trial8 studying the kinetics and bioavailability of the dose from 5 to 40 mg, the effects produced also
amiloride (single dose of 20 mg) found that peak serum con- increased. This includes increases in urinary volume,
centrations were reached at 4 h post amiloride administra- sodium and chloride excretion, and reduced potassium
tion, with an average of 47.5 ng/mL (±13.8). Approximately loss. However, above 40 mg, the responses reached a pla-
half of an oral dose of amiloride can be recovered in the teau. Some of these effects persisted for more than 10 h
urine as unmetabolised drug.3 The remainder of the unme- after drug administration. However, this effect was more
tabolised drug can be recovered in the stool. In this study prominent in doses above 30 mg. For a single dose of
peak serum levels were reached at 3 h with a half-life of 6 h. 40 mg, the response began in the second hour, reaching a
Amiloride had extensive extravascular distribution as dem- maximum between 4 and 6 h and declined thereafter. At
onstrated by its volume of distribution. around 9 h post amiloride administration, the reduction in
A further study1 suggested that a single oral dose of potassium secretion decreased to control values. Both
20 mg amiloride had a biological half-life of 9.6 ± 1.8 h in sodium and chloride excretion effects persisted beyond
humans. Its effects began approximately 2 h post drug 10 h. Urinary bicarbonate excretion was also increased by
administration and peak activity was reached within 4–8 h. the 40 mg oral dose.
Sun and Sever 3

Figure 2. Reproduced TMed Web diuretic_pharm [TUSOM I Pharmwiki].

In a second study,15 the dose-response was investigated or more daily was maintained for 3–5 months in a hyper-
in 14 subjects. Amiloride was given orally, once or twice tensive patient with idiopathic oedema, clinical effective-
daily, in dosages ranging from 1 mg/day to 30 mg/twice ness was maintained with no adverse effects.
daily. For single-day administration of doses varying from In a 1981 review, Vidt3 concluded that by increasing the
1 mg to 20 mg, 1 mg was able to produce a slight natriure- dose from 5 to 40 mg, a greater diuretic and natriuretic
sis. Between 4 and 20 mg, natriuresis and potassium reten- response was observed. However, a plateau occurred
tion took place but with little diuresis. A more prolonged above 40 mg. The onset of action occurred within 2 h and
administration of amiloride was also examined in two nor- the maximal effect occurred between 4 and 6 h. At lower
mal subjects and a cirrhotic patient. A total of 20 mg/day of doses, these effects were present for the first 10 h after
amiloride was administered for 2–4 days and similar administration. At doses above 40 mg, these effects may be
changes were seen. The magnitude of the daily effects prolonged up to 24 h.
declined by the fourth day. Withdrawal of therapy caused a There are no clear records of studies of a dose-effect
rebound in sodium retention and potassium secretion. In relation between increasing doses of amiloride and pla-
another six patients, 20 mg/day of amiloride was adminis- cebo-controlled BP responses.
tered for 5–12 days. There were more pronounced potas-
sium retention and mild hyperchloremic acidosis. In one
Adverse effects
hypertensive patient in whom the dose was maintained for
a further 2 weeks, there was a slow return of potassium and The most dangerous adverse effect of amiloride is hyper-
bicarbonate to control values. An amiloride dose of 20 mg kalaemia due to its potassium-sparing effects.3 Therefore,
4 Journal of the Renin-Angiotensin-Aldosterone System

amiloride is contraindicated in patients with hyperkalae- study clearly shows the complementarity of combining
mia, and those at increased risk of developing hyperkalae- amiloride with a thiazide, but the monotherapy compari-
mia. This includes patients with renal failure, and those sons reflect low doses of amiloride compared with high
receiving other K+-sparing diuretics or potassium supple- doses of hydrochlorothiazide.
ments. Care should be exercised in patients taking Thomas and Thomson19 investigated the biochemical dis-
angiotensin-converting-enzyme inhibitors or angiotensin- turbance produced by thiazide diuretics and its potential
receptor blockers. NSAIDs can also increase the likelihood reversal by amiloride in patients with moderate hyperten-
of hyperkalaemia in patients receiving sodium channel sion. In previously untreated patients, the thiazide produced
blockers. Amiloride has also been associated with side a significant fall in plasma potassium and hyperuricaemia
effects on the central nervous, gastrointestinal, endocrine, that did not occur with amiloride. Patients receiving long
musculoskeletal, dermatological and haematological sys- term treatment for their hypertension who continued to take
tems. The most common adverse effects include nausea, thiazides had persistent hypokalaemia and hyperuricaemia,
vomiting, diarrhoea and headache.5,11 Chronic amiloride whereas substitution with amiloride corrected the hypoka-
treatment may also increase serum uric acid concentrations laemia and serum uric acid returned towards normal ranges.
due to increased reabsorption in the proximal tubule.3,5 Patients receiving long term treatment also had impaired glu-
cose tolerance, which was corrected in those receiving ami-
loride. Control of hypertension was equally effective with
Clinical trials in hypertension both preparations (metoprolol and thiazide 45/31 mmHg;
metoprolol and amiloride 44/32 mmHg; continued thiazide
Early trials (pre-2000)
7/8 mmHg; substituted amiloride 11/10 mmHg), but the dose
Paterson et al.16 in 1968 conducted a clinical trial to com- of amiloride was only 5–10 mg daily.
pare the effect of amiloride hydrochloride with hydrochlo- Svendsen et al.20 investigated the effects of amiloride in
rothiazide in 12 previously untreated mild hypertensives. thiazide-treated hypertensive patients. A total of 28 patients
Each patient was treated with amiloride 5 mg three times with essential hypertension, 12 men and 16 women aged
daily, hydrochlorothiazide 50 mg daily or a combination of between 26 and 71, were initially treated with hydrochlo-
both for three 6-week periods. All three treatments low- rothiazide (1 mg/kg body weight, median 75 mg/day) for
ered BP by approximately 24/12 mmHg, although there 8 weeks. Patients were then randomly assigned to continue
was no placebo control. Hypotensive effects were not sig- hydrochlorothiazide therapy (12 patients, same dosage) or
nificantly increased with the two treatments combined, to receive adjunctive amiloride treatment (16 patients,
however, two patients withdrew on the combination due to 5 mg/25 mg hydrochlorothiazide, median 15 mg/day) for
excessive diuresis. When the two agents were combined, the following 3 months. In the adjunctive amiloride treat-
serum potassium was maintained near pre-treatment levels ment group, both plasma potassium and total body potas-
whereas thiazide alone led to hypokalaemia and amiloride sium increased by 15% and 4% respectively. The addition
alone caused a slight increase in plasma potassium. The of amiloride induced an activation of the renin-angioten-
study included too few patients, however, to determine dif- sin-aldosterone (RAAS) system, a significant rise was
ferential BP responses in the three groups of patients. seen in the plasma concentrations of renin, angiotensin II
In a study by Kremer et al.,17 amiloride (40 mg/day) was and aldosterone. There was a significant decrease in stand-
given to 19 patients with primary hyperaldosteronism. ing SBP in the hydrochlorothiazide and amiloride group,
Systolic blood pressure (SBP) and diastolic blood pressure however, standing DBP and supine BP did not change. The
(DBP) fell by 29/15 mmHg but again there was no placebo antihypertensive effect of amiloride could be antagonised
control. There were reductions in total exchangeable sodium, by this stimulation of the RAAS. The increase in aldoster-
and in serum sodium and bicarbonate; while total exchange- one secretion could also limit the potassium-retaining abil-
able potassium, total body potassium, serum potassium, ity of amiloride.
chloride and urea, and plasma renin, angiotensin II and Backhouse et al.21 compared the efficacy and tolerabil-
aldosterone all increased significantly. Falls of a smaller ity of frusemide plus amiloride and hydrochlorothiazide
magnitude (12/9 mmHg) were observed in five patients with plus amiloride in patients with mild to moderate hyperten-
essential hypertension; hyperkalaemia was not observed. sion. Thirty six patients were included in the study, age
A multicentre study conducted in 198118 compared ranging between 40 and 68 years. Eighteen patients were
amiloride 5–10 mg, amiloride 5–10 mg and hydrochloro- treated with frusemide 40 mg and amiloride 5 mg, the other
thiazide 50–100 mg and hydrochlorothiazide 50–100 mg in 18 were given hydrochlorothiazide 50 mg and amiloride
179 patients (aged between 21 and 69 years) with mild to 5 mg, both groups took one tablet daily for 2 weeks. Both
moderate essential hypertension for 12 weeks. Significant treatments were found to reduce BP effectively in the
BP reduction (amiloride 14/8 mmHg; amiloride plus majority of patients, 13/18 patients in the furosemide/ami-
hydrochlorothiazide 23/11 mmHg; hydrochlorothiazide loride group and 14/18 patients in the hydrochlorothiazide/
20/10 mmHg) was seen in all three treatment groups. This amiloride group showed a ‘good response’ (mean supine
Sun and Sever 5

DBP <90 mmHg or decreased by 10 mmHg). There was a A study conducted by Pratt et al.25 used amiloride to
significant decrease in the mean potassium and sodium investigate the racial difference in the activity of ENaC
levels in the hydrochlorothiazide/amiloride group, this since it is known that people with black ethnic origin
was not seen in the frusemide/amiloride group. appear to retain more sodium which suppresses the secre-
One of the most important studies with amiloride and tion of renin and aldosterone, compared to those of white
the only one in which longer term follow up was designed ethnic origin. Therefore, ENaC activity could either be
to obtain morbidity and mortality data was the Medical higher in black ethnic groups leading to sodium retention
Research Council Trial of Hypertension in Older Patients.22 or lower due to reduced stimulation by aldosterone. To
The trial was designed to establish whether lowering examine differences in ENaC activity between the two eth-
BP in elderly hypertensive patients reduced cardiovascular nic groups, 5 mg/day amiloride for 1 week was used to
outcomes, notably stroke and myocardial infarction. In inhibit ENaC in 20 black and 25 white normotensive
this trial of around 4000 patients, BP was lowered with a young subjects. BP and measurements of potassium were
combination of hydrochlorothiazide and amiloride or aten- used for comparison. The study found that amiloride
olol and compared with placebo. reduced BP in the white ethnic group but not in those with
Follow up was for an average of 5.8 years. BP was low- black ethnic origin. This is consistent with less ENaC
ered more effectively by the diuretic combination, although activity to inhibit in the blacks. Serum potassium concen-
in some patients the beta-blocker was added to control BP tration was higher in blacks than whites, also consistent
(15/6 mmHg compared with placebo). Both stroke and with lower ENaC activity in blacks. The authors suggested
coronary events were reduced significantly by thiazide/ that in those with black ethnic origin, there was an increase
amiloride (31% and 44%, respectively). In this trial, only in sodium retention at other sites that suppressed aldoster-
relatively low doses of amiloride (2.5 mg) were used in one levels, resulting in fewer ENaCs at the cell surface.
combination with hydrochlorothiazide (25 mg). In 2008, Guerrero et al.26 published a study which
investigated the efficacy of amiloride and enalapril as sec-
ond option antihypertensive drugs in patients with uncon-
Later trials (2000–2010) trolled BP receiving hydrochlorothiazide (HCT) treatment.
Pratt et al.23 investigated the BP responses to amiloride and Eighty two patients (18–75 years of age) treated with
spironolactone in normotensive subjects. The authors hydrochlorothiazide 25 mg/day for at least 4 weeks, with
hypothesised that secondary hyperaldosteronism as a uncontrolled BP, participated in this randomised, double-
response to the decreased sodium reabsorption caused by blind clinical trial. Patients were randomised to receive
amiloride may reduce its usefulness to lower BP. Therefore, enalapril (10 mg/day) or amiloride (2.5 mg/day) during a
they tested the BP response in 40 normotensive subjects follow-up period of 12 weeks. If in the fourth week, office
using amiloride 5 mg/day, spironolactone 25 mg/day, the BP was not controlled, the doses were doubled (enalapril
combination of amiloride 5 mg/day and spironolactone to 20 mg and amiloride to 5 mg). If office BP was still
25 mg/day or placebo. Over 4 weeks, the combination of uncontrolled in the eighth week, propranolol 40 mg BID
amiloride and spironolactone lowered SBP by 4.6 ± 1.6 was added. Both ABPM and office BP were used for the
(mean ± SEM) mmHg and DBP by 2.2 ± 1.2 mmHg. analysis. Overall 43.2% of the patients in the amiloride
However, either drug alone had no significant effect on BP. group had controlled office BP compared to 75% of the
Thus, the authors speculated that the combination of drugs patients in the enalapril group at the end of the follow-up
was complimentary, resulting in overall greater inhibition of period. HCT-amiloride reduced office BP by 16.4 ±
ENaC function than either drug used alone. It was also sug- 12.3/5.8 ± 12.7 mmHg and HCT-enalapril by 22.2 ±
gested that the significant decline in BP provides additional 15.8/9.7 ± 9.4 mmHg. In addition, more patients in the
support for the importance of ENaC in regulating BP. HCT-amiloride group doubled the amiloride dose or
Baker et al.24 conducted a trial to investigate the effec- needed to use propranolol. ABPM in both groups had a
tiveness of amiloride in the treatment of hypertension in similar circadian pattern. There was a significant increase
people of African origin with T594M polymorphism. The in serum potassium levels in both groups and a significant
T594M polymorphism of ENaC is found in ~5% of people increase in triglycerides in the HCT-amiloride group.
of African origin and is significantly associated with high Cough was more frequent in participants treated with enal-
BP. The T594M polymorphism leads to high BP by dis- april. The authors concluded that enalapril was more effec-
rupting negative regulation of ENaC and increasing tive than amiloride as an add-on drug in patients taking
sodium channel activity similar to that seen in Liddle’s hydrochlorothiazide with uncontrolled BP.
syndrome. Since amiloride can control BP in Liddle’s syn-
drome, the authors investigated whether amiloride would
Recent trials (2010–2020)
also control BP in subjects of African origin with T594M
polymorphism. The study showed that amiloride 20 mg In 2012, Matthesen et al.27 tested the effect of amiloride
was able to control the BP of these subjects as effectively and spironolactone on renal tubular function, ambulatory
as taking two or more other antihypertensive agents. blood pressure (ABP) and pulse wave velocity (PWV)
6 Journal of the Renin-Angiotensin-Aldosterone System

during baseline conditions and after furosemide bolus in (120–129/80–84 mmHg, n = 11). Improvements in
healthy participants in a double-blinded, randomised, pla- CF-PWV and AI%HR75 were also greater. The major
cebo-controlled, crossover trial. Eleven Caucasian males findings in this study include amiloride decreased periph-
and 13 Caucasian females participated in the trial with a eral and central BPs; amiloride improved endothelial
mean age of 22 years and BMI of 23 ± 3 kg/m2. Mean BP function and lowered peripheral arterial stiffness; ami-
was 119/73 ± 9/10 mmHg. Participants were given ami- loride mediated improvements in FMD and PWV may be
loride 5 mg twice daily, spironolactone 25 mg twice daily, independent of its BP-lowering effects, and amiloride
or placebo twice daily for three periods of 28 days. monotherapy increased serum aldosterone. The differ-
Examinations were done both at baseline conditions and ences in observations between stage 2 and stage 1 prehy-
after furosemide 40 mg intravenous bolus. There were no pertension led the authors to propose that amiloride might
differences in 24-h ABP, PWV, renal tubular function or be more efficacious when BP is higher in drug naïve
plasma concentration of vasoactive hormones in baseline young adults. The improvements in endothelial function
conditions in the treatment groups. Urinary output (UO) led to the proposition that amiloride improves FMD and
and CH2O (tubular function) were not significantly different PWV by blocking vascular ENaC. The authors concluded
after 4 weeks of placebo, amiloride and spironolactone that amiloride could be used as an early intervention to
treatment. Urinary sodium and potassium excretion were halt the progression to hypertension and cardiovascular
the same at the end of all three treatments. Thus, amiloride disease in young adults with prehypertension.
and spironolactone did not change the cardiovascular and The PATHWAY-3 trial conducted by Brown et al.29 was
renal effect variables. However, furosemide increased UO, a parallel-group, randomised, double-blind trial which
CH2O, and urinary sodium and potassium output. Water compared the effects of hydrochlorothiazide and amiloride,
absorption via AQP2 and sodium absorption via ENaC either alone or in combinations, on glucose tolerance and
were also increased simultaneously. Furosemide induced a BP. The trial included patients aged 18–80 years, with clinic
more pronounced increase in PWV, CSBP, plasma concen- SBP 140 mmHg or higher, home SBP 130 mmHg or higher,
trations of angiotensin II and aldosterone after amiloride an indication for diuretic treatment, and at least one compo-
and spironolactone treatment compared to placebo. nent of the metabolic syndrome in addition to hypertension.
In 2014, Bhagatwala et al.28 evaluated the effects of Patients were randomly assigned to 24 weeks of daily oral
amiloride monotherapy on BP and cardiovascular risk in treatment with starting doses of 10 mg amiloride, 25 mg
young (18–35 years), drug naïve adults with prehyperten- hydrochlorothiazide or 5 mg amiloride plus 12.5 mg hydro-
sion (120–139/80–89 mmHg). The participants took chlorothiazide. All doses were doubled after 12 weeks. An
10 mg daily amiloride in the morning with breakfast for OGTT (oral glucose tolerance test) was done at baseline,
4 weeks, in a non placebo-controlled, open-label study. 12 weeks and 24 weeks. Seated home and clinic BP were
After 4 weeks of amiloride monotherapy, there were sig- measured for each patient for the duration of the trial. The
nificant reductions in peripheral SBP (7.06 ± 2.25 primary outcome, assessed on a modified intention-to-treat
mmHg), peripheral DBP (4.35 ± 1.67 mmHg), central basis, was the change in plasma glucose concentration 2 h
SBP (7.68 ± 2.56 mmHg) and central DBP (4.49 ± 1.78 after oral administration of 75 g glucose drink from base-
mmHg). No changes in heart rate and weight were line at 12 and 24 weeks. The main secondary outcome was
observed. The reductions in peripheral and central BPs the change in home SBP from baseline at 12 and 24 weeks.
did not differ between Caucasians and African Americans. The modified intention-to-treat analysis included 132
There was a significant increase in FMD (brachial artery patients in the amiloride group, 134 patients in the hydro-
flow-mediated dilation, a biomarker of nitric oxide chlorothiazide group and 133 patients in the amiloride plus
dependent vasodilation and endothelial function) and a hydrochlorothiazide group. 2 h glucose concentrations
significant reduction in CR-PWV (carotid radial pulse after OGTT, averaged at 12 and 24 weeks, were signifi-
wave velocity, a surrogate marker of arterial stiffness). cantly lower in the amiloride group than in the hydrochlo-
There were no significant changes in CF-PWV (carotid rothiazide group (difference from hydrochlorothiazide:
femoral pulse wave velocity) and AI%HR75 (augmenta- −0.55 mmol/L, p = 0.0093) and in the combination group
tion index adjusted for heart rate at 75). There was an compared to the hydrochlorothiazide group (difference
increase in serum aldosterone concentration. The rise in from hydrochlorothiazide: −0.42 mmol/L, p = 0.048). The
the plasma renin activity (PRA) was insignificant. mean reduction in home SBP during 24 weeks between the
Aldosterone-renin ratio, serum potassium concentration amiloride and hydrochlorothiazide groups did not differ
and serum creatinine concentration were all significantly significantly (12.9 mmHg and 12.2 mmHg, respectively).
elevated. Participants with stage 2 prehypertension (130– However, the reduction in BP in the combination group was
139/85–89 mmHg, n = 6) had significantly greater mean significantly greater than that in the hydrochlorothiazide
reductions in peripheral SBP (14.5 ± 4.60 mmHg, p < group. The mean rise in renin concentration at 12 and
0.01) and central SBP (16.15 ± 5.44 mmHg, p < 0.01), 24 weeks in the combination group was 1.69 times higher
compared with participants with stage 1 prehypertension than in the hydrochlorothiazide group. Plasma potassium
Sun and Sever 7

Figure 3. Schematic for PATHWAY 2 trial.30

was unchanged in the combination group, but a significant doxazosin 4–8 mg and the change in home SBP was
dose-dependent rise in concentration was seen in the ami- assessed as the primary outcome. In a substudy of this
loride group (by 0.63 mmol/L at 24 weeks) and a significant trial, the effect of amiloride 10–20 mg once daily on clinic
fall was seen in the hydrochlorothiazide group (by SBP was assessed during an optional 6–12 week open-
0.27 mmol/L at 24 weeks). Seven patients (4.8%) in the label runout phase (Figure 3).
amiloride group and three patients (2.3%) in the combina- Amiloride (10 mg once daily) reduced clinic SBP by
tion group reported hyperkalaemia. Thirteen serious 20.4 mmHg (95% CI 18.3–22.5), compared with a reduc-
adverse events occurred but the frequency did not differ tion of 18.3 mmHg (16.2–20.5) with spironolactone (25 mg
significantly between the groups. The trial demonstrated once daily). No serious adverse events were recorded.
that after 24 weeks of treatment, a potassium-sparing diu- Mean plasma potassium concentrations increased from
retic reduced BP as efficaciously as high-dose thiazide 4.02 mmol/L (95% CI 3.95–4.08) on placebo to 4.50
without inducing adverse effects on blood glucose concen- (4.44–4.57) on amiloride (p < 0.0001).
trations. A combination of half the conventional doses of Ydegaard et al.31 investigated the relationship between
amiloride and hydrochlorothiazide was not associated with the BP-lowering effect of amiloride and endothelial ENaC
increased 2 h glucose concentrations compared with hydro- and eNOS (endothelial nitric oxide synthase). Nitric oxide
chlorothiazide treatment alone, instead, significantly larger (NO) products and cGMP (cyclic guanosine monophos-
reductions in BP was observed compared to full doses of phate) were measured in the urine and plasma samples of
either diuretic given alone. Amiloride monotherapy did not diabetic patients before and after amiloride treatment (20–
cause clinically significant hyperkalaemia, amiloride com- 40 mg for 2 days: plasma n = 22, urine n = 12; 5–10 mg for
bined with hydrochlorothiazide did not affect potassium 8 weeks: plasma n = 52, urine n = 55). Treatment with
concentrations significantly either. Based on these results, high dose oral amiloride (20–40 mg/day) for 2 days in type
the authors recommended that the combination of ami- 1 diabetes patients with or without nephropathy lowered
loride and hydrochlorothiazide in doses equipotent for BP systolic and diastolic arterial pressure significantly (7.5 ±
reduction becomes the first-choice diuretic in patients in 2.4/4.3 ± 1.8 mmHg). Plasma and urine NO-products
whom adequate diuretic has not yet been prescribed. increased significantly. The decrease in BP was not signifi-
PATHWAY-230 was a randomised, double-blind crosso- cantly related to the increase in plasma or urine NO-products.
ver trial done at 14 UK primary and secondary care sites in Plasma cGMP decreased in response to amiloride while
314 patients with resistant hypertension. Patients were urine cGMP was unchanged. Plasma NO-product concen-
given 12 weeks of once daily treatment with each of pla- tration directly correlated with urinary NO-product concen-
cebo, spironolactone 25–50 mg, bisoprolol 5–10 mg and tration significantly after amiloride treatment. This
8 Journal of the Renin-Angiotensin-Aldosterone System

correlation was not observed before treatment. There were but avoid the steroidogenic side effects are promising. To
no significant relations between NO-products and cGMP in date, however, their use has been confined to heart failure
urine and plasma. Eight weeks of treatment with low dose (finerenone)33 or of restricted geographical distribution
amiloride (5–10 mg/day) in type 2 diabetes patients with (esaxerenone).34
treatment-resistant hypertension significantly lowered Further trials in hypertension are to be encouraged.
average daytime arterial BP by 6.3/3.0 mmHg, night-time
BP by 7.1/2.8 mmHg and 24-h BP by 6.1/3.6 mmHg. There Acknowledgements
were no changes in plasma or urine NO-products and PS is supported by the Biomedical Research Centre Award to
cGMP. The authors found that the BP decline in patients did Imperial College Healthcare NHS Trust.
not relate to NO-products or cGMP. The researchers con-
cluded that the antihypertensive effect of ENaC blockers is Declaration of conflicting interests
primarily due to an effect on renal epithelial but not The author(s) declared no potential conflicts of interest with
endothelial ENaC-eNOS interaction. respect to the research, authorship, and/or publication of this
article.
Summary
Funding
Amiloride has been studied in a number of trials since its
The author(s) received no financial support for the research,
discovery, often as an adjunctive treatment for hydrochloro- authorship, and/or publication of this article.
thiazide or furosemide. Where amiloride monotherapy was
administered, the trials generally consisted of a small num-
ORCID iD
ber of subjects, of normotensives or prehypertensives, or of
patients of African origin with specific polymorphisms. Peter Sever https://orcid.org/0000-0003-0421-2409
Amiloride has dose-dependent diuretic effects up to
40 mg, although there is little data following higher doses. References
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