Drug Evaluation

Drugs 28: 189-235 (1984)

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Indapamide
A Review of its Pharmacodynamic Properties and Therapeutic
Efficacy in Hypertension

M. ChajJman, R.C. Heel, R.N. Brogden, T.M. Speight and

G.s. Avery
ADiS Drug Information Services, Auckland

Various sections of this manuscript reviewed by: R. Bloch, Faculte de Medecine, U niv-
ersite Louis Pasteur, Strasbourg, France; D.C. Brater, Department of Pharmacology, The
University of Texas Health Science Center at Dallas, Dallas, Texas, USA; N.M. Kaplan,
Department of Internal Medicine, The University of Texas Health Science Center at
Dallas, Dallas, Texas, U.S.A.; A. Lant, Department of Therapeutics, Westminster Medical
School, London, England; W.P. Leary, Department of Experimental and Clinical
Pharmacology, University of Natal, Durban, South Africa; M. Lebel, L'Hotel Dieu de
Quebec, Quebec, Canada; A. Mimran, Faculte de Medecine, Centre Hospitalier Univ-
ersitaire, Hopital Lapeyronie, Montpellier Cedex, France; R.I. Ogilvie, Division of Car-
diology and Clinical Pharmacology, Toronto Western Hospital, Toronto, Ontario, Can-
ada; G.E. Pl4nte, Department of Physiology, Pharmacology, and Family Medicine,
University of Sherbrooke; Sherbrooke, Quebec, Canada; F.O. Simpson, Department of
Medicine, University of Otago, Dunedin, New Zealand; P. Turner, Department of Clinical
Pharmacology, St Bartholomew's Hospital Medical College, London, England; H.I . WaaI-
Manning, Department of Medicine, Wellcome Medical Research Institute, University of
Otago, Dunedin, New Zealand; P. Weidmann, Medizinische Poliklinik, Bern, Switzer-
land; I.A. Whitworth, Department of Nephrology, The Royal Melbourne Hospital, Park-
ville, Victoria, Australia; N. Wright, St Joseph's Hospital, Hamilton, Ontario, Canada.

Contents
Summary ...................................................................................................................................... 190
I. Pharmacodynamic Effects ......................................................... ............................ ................. 194
1.1 Renal Effects ..................................................................................................................... 194
1.1.1 Effects on Renal Function ...................................................................................... 194
1.1.2 Diuretic Effects ........................................................................................................ 196
1.1.3 Effects on Urinary pH and Specific Gravity ........................................................ 197
1.2 Influence on Renin and Aldosterone ............................................................................. 197
1.3 Metabolic Effects ........................................................................'" ................................... 198
1.3.1 Effects on Sodium Balance ..................................................................................... 198
1.3.2 Effects on Potassium Balance................................................................................. 199
1.3.3 Other Electrolyte Effects ......................................................................................... 200
1.3.4 Effect on Uric Acid .................................................... ............................................. 202
1.3.5 Effects on Glucose Tolerance ................................................................................. 203
1.3.6 Influence on Lipid Metabolism ............................................................................. 204
Indapamide: A Review 190

1.4 Cardiovascular Effects ...................................................................................................... 205

1.4.1 In vitro Effects on Electromechanical Activity in Vascular Smooth Muscle
and Cardiac Muscle .......................................................................................................... 205
1.4.2 Effects of Vascular Reactivity and Peripheral Vascular Resistance ................... 205
1.4.3 Effects on the Heart ................................................................................................ 208
1.5 Effect on Prostaglandin Synthesis ................................................................................... 210
1.6 Mechanism of Antihypertensive Action ......................................................................... 210
1.7 Toxicology Studies ........................................................................................................... 212
1.7.1 Acute Toxicity ......................................................................................................... 212
1.7.2 Subacute and Chronic Toxicity .............................................................................. 212
1.7.3 Effects on Reproduction ......................................................................................... 212
2. Pharmacokinetic Studies ........................................................................................................ 212
2.1 Absorption and Plasma Concentrations ......................................................................... 212
2.2 Distribution ....................................................................................................................... 213
2.3 Metabolism and Elimination .......................................................................................... 213
2.3.1 Elimination Half-Life .............................................................................................. 214
2.4 Pharmacokinetics in Altered Renal Function ................................................................ 214
3. Therapeutic Trials ................................................................................................................... 215
3.1 Use in Hypertension ........................................................................................................ 215
3.1.1 Open Studies ............................................................................................................ 215
3.1.2 Comparisons with Placebo ..................................................................................... 217
3.1.3 Comparisons with Hydrochlorothiazide ................................................................ 218
3.1.4 Comparisons with Bendrofluazide ......................................................................... 220
3.1.5 Comparisons with Cyclopenthiazide ..................................................................... 221
3.1.6 Comparisons with Other Diuretic Agents ............................................................. 221
3.1.7 Comparisons with ~-Adrenergic Blocking Agents, and Their Use in
Combination ...................................................................................................................... 221
3.1.8 Comparison with Methyldopa, and Their Use in Combination ......................... 223
3.1.9 Use in Patients with Renal Insufficiency .............................................................. 224
3.2 Use in Oedematous States ............................................................................................... 226
4. Side Effects .............................................................................................................................. 227
4.1 Hypokalaemia ................................................................................................................... 227
4.2 Other Side Effects............................................................................................................. 227
5. Dosage and Administration ....................................................................................................228
6. Place of Indapamide in Therapy ........................................................................................... 228

Summary Synopsis: Indapamide J is an orally active sulphonamide diuretic agent. Although some
evidence appears to indicate that the antihypertensive action of indapamide is primarily
a result of its diuretic activity, only a limited diuresis occurs with the usual antihyperten-
sive doses of 2.5mg daily, and in vitro and in vivo data suggest that it may also reduce
blood pressure by decreasing vascular reactivity and peripheral vascular resistance. In mild
to moderate hypertension it is as effective as thiazide diuretics and (J-adrenergic blocking
agents in lowering blood pressure when used as the sole treatment. lndapamide has been
successfully combined with (J-adrenergic blocking agents, methyldopa, and other anti-
hypertensive agents. While such findings need confirmation, it appears that indapamide
shares the potential with other diuretic agents to induce electrolyte and other metabolic
abnormalities, although it may do so with less frequency or severity.
Thus, indapamide appears to offer a suitable alternative to more established drugs as
a 'first-line' treatment in patients with mild to moderate hypertension. Whether it differs
significantly from other diuretics when used as antihypertensive therapy, either in its mode
of action or its side effect profile, needs further clarification.

1 'Audex', 'Lozide', 'Natrilix' (Servier); 'Lozol' (USV).

Indapamide: A Review 191

Pharmacodynamic Studies: In dogs, indapamide 0.1 to 3.0 mg/kg did not alter effec-
tive renal plasma flow or glomerular filtration rate. Similar findings were reported in
healthy volunteers, where single doses ofindapamide 10mg and 2.5mg daily given long
term also failed to change these parameters significantly. In healthy volunteers and patients
with hypertension with or without renal insufficiency, single or multiple doses ofindap-
amide 2.5 to IOmg either increased endogenous creatinine clearance slightly (but sig-
nificantly) or had no effect. Alterations in mean serum creatinine have rarely occurred
during indapamide treatment, but increases in mean blood urea nitrogen have been noted
occasionally, the latter probably being a reflection of mild dehydration.
24-Hour urine volumes have not been significantly augmented by low doses « 2.5mg
daily) of indapamide, but moderate to large doses (5 to 30mg) have resulted in clinically
significant and dose-related water and electrolyte losses. Following oral administration,
the onset of diuresis occurs in 1 to 3 hours, and peak urinary flow at 6 hours. Increased
urinary volume from baseline may be noted up to 36 hours after a moderate (1 Omg)
dose of indapamide. In healthy volunteers or oedematous patients large doses (40 to
50mg) have induced a diuresis similar in volume to that of frusemide (furosemide) 40
or 80mg. In greater than half of the trials reported, indapamide 2.5 or 5mg daily has
resulted in mean bodyweight losses (an indirect measurement of diuresis) ranging from
approximately 0.5 to 2.4kg, which are similar to those noted with bendrofluazide 5mg,
hydrochlorothiazide loomg, or frusemide 4Omg, each administered daily. Similar to the
benzothiadiazine diuretics, the primary site of the diuretic action of indapamide is the
proximal segment of the distal renal tubule, with some activity also apparent in the
proximal tubule.
In a limited number of studies, indapamide 2.5 to 5mg daily has been shown to raise
plasma renin activity and plasma aldosterone concentrations to an extent similar to that
of other diuretic agents and vasodilator drugs (2- to 5-fold).
In healthy volunteers and patients with hypertension, single doses of indapamide
IOmg increased the percentage of filtered sodium excreted to 3.4% (p < 0.00 1), whereas
non-parallel studies have shown the percentage of filtered sodium excreted following
usual doses of thiazide compounds and frusemide to be 8 and 23%, respectively. Low
doses of indapamide « Img) have not resulted in statistically significant episodes of
natriuresis, but larger doses ranging from 2.5 to 30mg have increased urinary sodium
excretion by 72 to 127 "mol/min. In most studies, indapamide (usually 2.5mg daily) has
not altered total exchangeable sodium. Serum sodium concentrations following long term
administration of indapamide have generally not been altered.
Indapamide decreases estimated total body potassium, but these changes have been
statistically insignificant ("" 125 mmol). Single doses of indapamide 2.5 to 40mg have
consistently increased the rate and quantity of urinary potassium loss in healthy subjects
and statistically significant decreases in mean serum potassium concentrations have oc-
curred in approximately 75% of reported clinical trials of indapamide. Although these
decreases have usually not exceeded the normal lower physiological limit for serum po-
tassium concentration, some patients have required potassium supplements. In parallel
controlled studies, decreases in serum potassium concentrations following indapamide
2.5mg daily were equal in magnitude compared with those with hydrochlorothiazide 50
or lOOmg daily.
Urinary chloride excretion is significantly increased by indapamide in a dose-related
manner. A single dose of 40mg increased chloride excretion from 7.5 to 25 mmol/hour
(p < 0.01), and this increase in urinary excretion was prolonged (up to 72 hours). The
single-dose administration of indapamide 2.5mg increased 24-hour urinary chloride loss
up to 106.3%, whereas 40mg of the relatively short-acting ("" 6 hours) agent frusemide
increased excretion by 40%. However, serum chloride concentrations seen with indap-
amide have not resulted in concentrations below the normal range. Bicarbonate ion ex-
cretion and serum bicarbonate concentrations appear to be minimally affected by in-
dapamide.
Most studies have shown indapamide to have a hypocalciuric effect approximately
Indapamide: A Review 192

equal to that of hydrochlorothiazide in patients with hypertension with normal or ele-

vated serum calcium concentrations. Serum calcium concentrations have not been altered
during treatment with indapamide, and urinary phosphate excretion and serum phos-
phate concentrations have not been appreciably altered. Indapamide 40mg increased (0.05
> p > 0.02) urinary magnesium excretion and decreased serum magnesium concentra-
tions (p < 0.01), and serum concentrations remained decreased for 10 days following
this single dose.
The data regarding the effect of indapamide on serum uric acid concentrations is
divergent - probably due to varying patient selection criteria in clinical trials. However
uncommon, acute gouty arthritis has occurred during treatment with indapamide.
In isolated perfused rat pancreas, high concentrations of indapamide (10 or 100
mgjL) have reduced total insulin secretory response to glucose infusions. Although in-
dapamide 2.5 or 5mg daily for 12 weeks increased blood glucose concentrations similarly
to hydrochlorothiazide 50mg twice daily (8.3, 15.8 and 11.6%, respectively) in non-dia-
betic hypertensive patients, most studies in diabetic and non-diabetic patients with hyper-
tension have not revealed a significant decrease in glucose tolerance with indapamide.
Similarly, indapamide has not significantly altered blood glucose concentrations or in-
sulin secretion in hypertensive diabetics who have received it for up to 1 year. As de-
creased glucose tolerance with thiazide diuretics in non-diabetic patients with hyperten-
sion may take up to 2 years to develop, long term studies are required to determine the
exact potential indapamide has in inducing this metabolic abnormality. Although the
data are limited, indapamide I to 4mg daily for up to 24 months has not been reported
to increase total cholesterol or triglyceride concentrations, or lower high-density lipopro-
tein concentrations.
Although the ability of indapamide to relax vascular smooth muscle and decrease
peripheral vascular resistance has been demonstrated in various in vitro and in vivo in-
vestigations, further study is required to clarify the extent to which the antihypertensive
efficacy of indapamide can be attributed to actions oth~r than its diuretic effect.
Indapamide decreased inward calcium current, clonic phasic contractions, and out-
going potassium current in longitudinal muscle strips from isolated rabbit portal vein,
and inhibited increases in clonic contractions and calcium influx which could be elicited
by angiotensin II. However, the intensity of tonic contractions was not altered. In vitro,
cardiovascular smooth muscle preparations decreased action potential amplitude in the
presence of indapamide, although resting membrane potential remained unaffected. The
decrease in isometric contractions in normally polarised rat portal vein smooth muscle
was greater with indapamide than with hydrochlorothiazide or chlorthalidone, and only
indapamide decreased the action potential amplitude in this in vitro model when equal
concentrations of the 3 agents were used.
In vitro, various concentrations of indapamide have been shown to inhibit vascular
smooth muscle contractile responses to assorted vasopressor agents [angiotensin II, ad-
renaline (epinephrine), tyramine, prostaglandin F 2a , nicotine] and electrical stimulation,
while effects on noradrenaline-induced contractions have been inconsistent. Resting tone
in arterial and venous smooth muscle has usually not been affected.
The effects of indapamide on in vivo vascular reactivity have been studied both in
laboratory animals and in man. In rats, indapamide (usually 10 mg/kg daily) decreased
pressor response to oxotremorine, noradrenaline, and tyramine, whereas pretreatment
with hydrochlorothiazide 5 mg/kg intraperitoneally did not decrease pressor response to
the latter 2 agents. In patients with hypertension, vascular reactivity (i.e. pressor re-
sponsiveness) to phenylephrine, noradrenaline, and angiotensin II were decreased after
indapamide 2.5 to 5mg daily for 2 to 6 weeks. In small numbers of patients with hyper-
tension, indapamide 2.5mg daily for 6 to 12 weeks was shown to increase muscle blood
flow, and decrease limb vascular resistance, total peripheral resistance, and peripheral
resistance 'index'. However, the non-invasive techniques and indirect methods of as-
sessment used in the majority of these studies necessitate cautious interpretation of these
findings.
Indapamide: A Review 193

Heart rate, left ventricular end-diastolic or end-systolic volume, ejection fraction, and
stroke volume have generally been unaffected by indapamide administration. Similarly,
cardiac output has usually remained unchanged or increased. Regression of left ventric-
ular hypertrophy and cardiomegaly have also occurred after long term treatment. No
electrOcardiographic abnormalities have been reported during indapamide therapy in the
absence of metabolic disturbances.
In vitro. indapamide exhibited the greatest inhibitory effect on thromboxane synthesis,
and the most stimulatory effect on prostaglandin 12 (prostacyclin) synthesis when com-
pared with frusemide, hydrochlorothiazide and spironolactone. In patients with hyper-
tension, indapamide 2.Smg daily for 6 weeks increased urinary prostaglandin E2 excretion
(p < 0.02S). Some prostaglandins may play a role in the control of blood pressure in
man, but the clinical significance of these findings with indapamide is unknown.

Pharmacokinetic Studies: In healthy volunteers, bioavailability of indapamide after

a Smg dose was estimated to be 93%. Peak concentrations of indapamide occurred ap-
proximately O.S to 2 hours after oral administration and remained relatively constant
for up to 8 hours. Mean steady-state blood concentrations of 89 and IS8.S p.gJL occurred
after 4 daily doses of indapamide 2.S and Smg, respectively.
In vitro. indapamide accumulated in vascular smooth muscle and the red cell binding
of indapamide was found to be high. The red cell to plasma ratio of radioactivity after
in vitro incubation of whole blood with 14C-indapamide ranged up to 9: I, and in vivo
ratios obtained in man following treatment with indapamide were similar (S.7: I). In-
dapamide binds predominantly (98%) to the carbonic anhydrase fraction of the red cell,
but the activity of this enzyme remains intact. In man, indapamide is 76 to 79% protein
bound.
Human studies have shown indapamide to be excreted 60 to 70% renally, with about
7% as unchanged drug, and the remainder as metabolic products. Up to 19 metabolites
of indapamide have been detected in urine. The renal clearance of indapamide has been
estimated to be 1.71 ml/min; therefore, hepatic clearance is responsible for the greatest
portion ofthe total systemic clearance (20 to 23.4 ml/min). Faecal elimination accounts
for 16 to 23% of an orally administered dose. The elimination half-life of indapamide
has been estimated to range from 13.9 to 17.8 hours in healthy subjects.
Indapamide does not significantly accumulate in patients with renal insufficiency or
failure following long term treatment. Pharmacokinetic data in patients with hepatic dys-
function are lacking. Indapamide is not dialysable.

Therapeutic Trials: In open and placebo-controlled studies in patients with mild to

moderate hypertension, indapamide (usually 2.Smg daily) has been shown to be an ef-
fective antihypertensive agent, lowering resting systolic and diastolic blood pressures by
10 to 20%. Maximum blood pressure-lowering effect occurred most frequently at the
second or third month of therapy, and indapamide generally lowered blood pressure to
9Smm Hg or less in 60 to 80% of these patients.
In parallel group and crossover comparisons, indapamide 2.Smg daily was approxi-
mately equal in antihypertensive efficacy to other diuretic agents, including hydrochloro-
thiazide SOmg (alone or in combination with amiloride Smg), bendrofluazide Smg, chlor-
thalidone lOOmg, chlorothiazide sOOmg, or pindolol 10 or ISmg, atenolol lOOmg, or
metoprolol 200mg daily. In a few small studies, indapamide 2.Smg daily displayed a
superior blood pressure-lowering effect when compared with cyclopenthiazide O.Smg or
methyldopa SOOmg, each administered daily. Therapeutic regimens combining indapa-
mide with a ~-adrenoceptor blocking agent or methyldopa have exerted good antihyper-
tensive efficacy and have been well tolerated. Decreases in serum potassium concentra-
tions were generally of equal magnitude when indapamide was compared with other
diuretic agents. Indapamide has also been proven effective in reducing blood pressure
in a small number of patients with renal insufficiency or failure (on haemodialysis).
In patients with oedema due to unknown causes, congestive heart failure, or hepatic
Indapamide: A Review 194

disease, indapamide 2.5 to 20mg daily was an effective diuretic agent, with both lower
and moderately high doses (2.5, 5 and lOmg) being approximately equal in effectiveness
to hydrochlorothiazide l00mg daily. Hypokalaemia was a common complication of mod-
erate to high dose indapamide treatment in these patients, with reported incidences rang-
ing from 25 to 40%. Further studies are required before the efficacy of indapamide in
the treatment of oedema (and whether it offers any advantages over existing diuretics in
this setting) can be clearly stated.

Side Effects: The most common side effect reported during indapamide therapy is
hypokalaemia (serum potassium < 3.5 mmol/L); 1.2 to 3 and 7% of patients manifest
laboratory signs and/or clinical symptoms of hypokalaemia with indapamide 2.5 or 5mg
daily, respectively. Although central nervous system effects, fatigue, orthostatic hypoten-
sion, and gastrointestinal side effects have also occurred during indapamide therapy, they
have been infrequent and minor in severity. Sexual dysfunction said to be associated
with indapamide treatment has been reported only rarely.

Dosage and Administration: The recommended initial daily dose of indapamide for
the treatment of hypertension or oedema is 2.5mg daily, administered orally. The dose
may be increased to 5mg daily if an appropriate antihypertensive effect has not occurred
after 1 to 2 months of treatment. Likewise, an inadequate diuretic response after 1 week
of treatment with this dose in oedematous patients is indicative of a need for an increase
in dosage. Indapamide should probably be used with caution in patients with impaired
renal or hepatic function. Indapamide is capable of inducing hypokalaemia and possibly
other metabolic abnormalities and, as with other diuretics, laboratory and clinical moni-
toring of patients at appropriate intervals is advised.

1. Pharmacodynamic Effects diminished renal function (Frazier and Yager, 1973;

Indapamide [4-chloro - N - (2-methyl - l-indol-
inyl)-3-sulphamoyl benzamide] is an indoline de-
rivative of chlorsulphonamide and, like clopam-
ide, it differs chemically from benzothiadiazine
diuretics in that it contains only 1 sulphonamide
group and no 'thiazide ring system' (Campbell,
1983; Campbell et al., 1977; Choi et al., 1982; Gre-
bowet al., 1982) [fig. 1].
1.1 Renal Effects
1.1.1 Effects on Renal Function
Thiazide diuretics have been reported to de-
crease glomerular filtration rate, especially after
intravenous administration. This effect is probably
due to a direct vasoconstrictive action on the renal
vasculature. Although this increase in renal vas-
cular resistance usually has little clinical signifi-
cance, it may be of importance to patients with
Mudge, 1980).
In dogs, indapamide 0.1 mg/kg intravenously
did not influence effective renal plasma flow or
glomerular filtration rate, although a higher dose
(1.0 mgJkg) temporarily increased both para-
meters. Similar responses occurred when hydro-
chlorothiazide (1.0 mgjkg) or trichlormethazide (0.3
mgJkg) were administered intravenously to dogs
(Suzuki et aI., 1977). However, in other studies,
glomerular filtration rate in dogs was not altered
by the intravenous administration of indapamide
ImgJkg (Laubie and Schmitt, 1977) or 3 mgfkg
(Burke et aI., 1983); effective renal plasma flow was
increased (15%, p < 0.05) only at the higher dosage.
Similarly, effective renal plasma flow and glomer-
ular filtration rate were not altered in healthy
volunteers administered a single dose of indapa-
mide 10mg (Pitone et al., 1978), or in patients with
hypertension administered indapamide 2.5mg every
other day for 1 month (Waal-Manning and Does-
Indapamide: A Review 195

burg, 1982) or 2.Smg daily for 8 weeks, but was

decreased (approximately 10 ml/min, p < 0.01) fol-
lowing a single 20mg dose given to patients with
hypertension (Villarreal et aI., 1983).
In several studies, glomerular filtration rate fol-
lowing indapamide administration has been esti-
mated by measuring endogenous creatinine clear-
ance (Brennan et aI., 1982; Lemieux and L'Homme, Indapamide
1983; Waal-Manning and Doesburg, 1982). In
healthy volunteers receiving indapamide 10mg
daily for 4 days, creatinine clearance was decreased
(from 107 to 97 ml/min) [Goldberg and Furman,
1974]; however, creatinine clearance was un-
changed following long term administration of a
lower dose (2.Smg every other day) to the patients
ofWaal-Manning and Doesburg. After indapamide
Clopamide
2.5mg daily for 4 months, creatinine clearance was
increased (p < O.OS) compared with daily treat-
ment with placebo or hydrochlorothiazide SOmg
(Lemieux and L'Homme, 1983). Creatinine clear-
ance was also increased (SO.9 to 63.4 ml/min, p <
0.01) in 8 patients with hypertension and renal in-
sufficiency given indapamide 2.Smg daily for 6
weeks (Brennan et aI., 1982).
Although serum creatinine and blood urea ni-
trogen concentrations are less reliable indicators of Frusemide

glomerular filtration rate (Brooks and Mallick,

1982), they have nevertheless been used to monitor
renal function in many of the clinical studies of
indapamide. Alterations in serum creatinine attrib-
utable to indapamide treatment have been re-
ported only rarely, and have not been clinically sig-
nificant (Santoro et aI., 1982). Similarly, most
studies have not shown indapamide to affect blood Chlorthalidone
urea nitrogen concentrations (Bing et aI., 1981;
Brennan et aI., 1982; Capone et aI., 1983; Schle-
singer et aI., 1977), although there have been a few H
I

CI~ ~!H
exceptions where statistically significant elevations
were noted (Chalmers et aI., 1982; Hashida, 1977;
Lemieux and L'Homme, 1983; Santoro et aI., 1982).
Indapamide 1 to 2.Smg daily, alone or in combin- _ 0/ ' 0
ation with other hypertensive agents for 6 weeks S02NH2
to 4 months, increased blood urea nitrogen by a
Hydrochlorothiazide
mean of 0.46 to I.S4 mmol/L (p < O.OS) [Hashida,
1977; Lemieux and L'Homme, 1983], while indap- Fig. 1. Structural formulae of indapamide and other frequently
amide 2.Smg daily for 8 weeks resulted in a smaller used diuretiC agents.
Indapamide: A Review
but significant increase (0.33 to 0.40 mmol/L, p <
0.001) [Chalmers et aI., 1982]. In 18 patients with
hypertension and renal insufficiency (creatinine
clearance from 13 to 61 ml/min), serum concen-
trations of blood urea nitrogen and creatinine were
not elevated following indapamide 2.5mg daily for
6 weeks (Acchiardo and Skoutakis, 1983). The small
elevations seen in blood urea nitrogen concentra-
tions following indapamide therapy have been at-
tributed to mild dehydration (Lemieux and
L'Homme, 1983).
1.1.2 Diuretic Effects
Apparently, urinary volume per unit time in
man is not significantly or consistently increased
until dosages of indapamide exceed 2.5mg daily
(Goldberg and Furman, 1974; Schlesinger and
Benchimol, 1980; Schlesinger et aI., 1977). When
administered in moderate to large dosages (5 to
30mg) indapamide is a potent diuretic and results
in substantial water and electrolyte loss (Leary et
aI., 1973) [see sections 1.3.1 and 1.3.2].
Onset of diuresis occurs 1 to 3 hours after oral
administration (Goldberg and Furman, 1974). Al-
though the peak urinary excretion rate of indapa-
mide (section 2.3) occurs approximately 3 hours
following administration, maximum urinary flow
dpes not occur for 6 hours (Campbell and Phillips,
1974). The major diuretic response seen with mod-
erate (IOmg) dosages persists for up to 12 hours,
but a lesser effect may be noted up to 36 hours
following indapamide administration (Goldberg
and Furman, 1974). In healthy volunteers, urine
output following indapamide 0.5 to 30mg was
shown to be dose related (Caruso et aI., 1983; Onesti
et aI., 1977a) [fig. 2a].
In healthy subjects, indapamide 2.5 or IOmg re-
sulted in mean increases in 24-hour urinary vol-
ume of 0.78 and 0.6L, respectively (Goldberg and
Furman, 1974; Reyes et aI., 1983b) and a 40mg
dose more than doubled the rate of urine produc-
tion (from 1.8 to 4.3 ml/min) [Campbell and Phil-
lips, 1974). In patients with hypertension and as-
sociated congestive heart failure, indapamide 0.5
to 5.0mg daily for 21 days resulted in a mean daily
urine volume increase of 792ml (57%) [La Corte et
196
aI., 1980b]. Symptoms of intravascular volume de-
pletion were noted in healthy volunteers admini-
stered indapamide 20 or 30mg daily for 5 days
(Onesti et aI., 1977a). The diuresis resulting from
indapamide 40 or 50mg daily administered to
healthy subjects (Leary et aI., 1973) or oedematous
patients (Leary et aI., 1974) was comparable with
that with frusemide (furosemide) 40mg once or
twice daily, respectively. Urinary output in the 24
hours following the administration of indapamide
40mg was greater (p < 0.05) than that with cyclo-
penthiazide 5mg (Leary et aI., 1973).
The assessment of changes in bodyweight is a
useful, although indirect, method of gauging the
magnitude of urinary volume loss with a diuretic
agent. In at least one-half of the studies reported,
indapamide 2.5 or 5mg daily produced significant
bodyweight reductions both in healthy volunteers
and in patients with hypertension (Campbell, 1983).
At these dosages, mean individual weight losses
appear to range from 0.5 to 2.4kg (Bing et aI., 1981;
Grimm et aI., 1983; Leenen et aI., 1983; Noveck
et aI., 1983). In unblinded (Bing et aI., 1981) or
double-blind comparative studies (Slotkoff, 1983;
Witchitz et aI., 1975), weight loss with indapamide
2.5 or 5.0mg daily equalled that with bendroflu-
azide (bendrofluthiazide) 5mg (Bing et aI., 1981),
hydrochlorothiazide 100mg (Slotkoff, 1983) or fru-
semide 40mg (Witchitz et aI., 1975) daily.
In short term studies (4 to 6 weeks), indapamide
1.0, 2.5 or 5.0mg daily did not significantly de-
crease plasma volume in patients with hyperten-
sion (Brooks et aI., 1983; Grimm et aI., 1981a; Lee-
nen et aI., 1983). Neither indapamide 2.5ri1g nor
tienilic acid 250mg daily decreased plasma volume
in healthy volunteers or hypertensive patients when
administered for 6-week periods (Weidmann et aI.,
1981). In contrast, plasma volume was decreased
by 8% (360ml, p < 0.005) in patients with hyper-
tension treated with hydrochlorothiazide 50mg
twice daily, but returned to pretreatment values by
the eighth week of treatment (Shah et aI., 1978).
As 24-hour urine volume and bodyweight are most
often increased and decreased, respectively, during
indapamide administration, its lack of effect on
plasma volume suggests that redistribution of fluid
Indapamide: A Review 197

from interstitial to the intravascular spaces may

occur during treatment (Leenen et ai., 1983).
i In maximally hydrated healthy subjects or
i 1800 patients with hypertension, indapamide increased
~:::l 1600 osmolar clearance and decreased free water clear-
1400
~ ance, whereas it increased both osmolar clearance
1200
~
.c: and tubular reabsorption of free water under con-
:::l
1000
.!;; 800 ditions of maximal dehydration. These data sug-
~ 600
gest that the proximal segment of the distal renal
'~" 400
E" 200 tubule (cortical diluting segment) is the primary site
• of the diuretic action ofindapamide (Goldberg and
a P 0.5 1.0 2.5 5.0 10.0 20.0
Furman, 1974; Onesti et ai., 1977b; Pitone et ai.,
250 1978). Studies in animals (Burke et ai., 1983) and
humans (Villarreal et ai., 1983) have indicated that
200
• indapamide also exerts some diuretic activity in
E
:J
150 • the proximal tubule. Thus, the diuretic site of ac-
'6 tion of indapamide is identical to that of thiazide
o~

"'~ 100
diuretics (Wright and Robson, 1980).
~'O
c"'~ 0 •
.;:: E
::l E
50 •
c:- 1.1.3 Effects on Urinary pH and
'; 5 0 Specific Gravity
~~
~
" 0)x
E
" -50
• Urinary pH was unchanged 20 to 40 minutes
b P 0.5 1.0 2.5 5.0 10.0 20.0 following the intravenous administration ofindap-
E 50
amide 1 mg/kg to dogs (Laubie and Schmitt, 1977),
::l
'iii • and a single 40mg dose of indapamide given orally
'"'" 40 to 6 healthy volunteers only transiently increased
8.>: urinary pH (Campbell and Phillips, 1974).. In 13
~'O
"'~
c: 0
'" 30
'c: E patients with hypertension administered indapa-
:J E
c- 20 mide 2.5mg daily, urine specific gravity was in-
.~ 5
~ '(ii creased (average of 0.005, p < 0.05) after 4 to 6
~

"
0)
~ 10 weeks of treatment (Brennan et aI., 1982).
EO)
" X
•
C P 0.5 1.0 2.5 5.0 10.0 20.0 1.2 Influence on Renin and Aldosterone
250
Most diuretic agents can alter plasma renin ac-
0)

~
200 • tivity (Young and Riddiough, 1978), although the
52
.J::~
,,~
• mechanisms involved in this effect have not been
150
~'O completely clarified. Diuretics probably stimulate
"'~
c: 0
'c: E 100 renin release via alteration of sodium (or possibly
::l E
c:-
.- c chloride) concentrations in the tubular fluid at the
~.g 50 • •
~
0)
~
E" 0)
x " 0 Fig. 2. Dose response effect of indapamide on (8) urine vol-

-50
• ume, and 24-hour urinary, (b) sodium, (c) potassium, and
P 0.5 1.0 2.5 5.0 10.0 20.0 (d) chloride excretion in healthy volunteers on controlled fluid
d Indapamide (mg/day) and electrolyte intake (P = placebo) [adapted from Caruso et
al. (1983)].
Indapamide: A Review
macula densa (specialised tubular cells within the
juxtaglomerular apparatus, believed to act as
'chemoreceptors' controlling renin release), and/or
by reduction of blood pressure or plasma volume
(thereby altering renal perfusion pressure and stim-
ulating intrarenal baroreceptors controlling renin
release) [Gilmore, 1983; Nies, 1978; Young and
Riddiough, 1978].
Due to variations in laboratory technique, com-
parison of plasma renin activity values can be dif-
ficult. Indeed, accurate interpretation of plasma
renin activity data requires knowledge of a patient's
sodium balance, posture, and drug intake when
plasma samples were taken (Nies, 1978). Unfor-
tunately, this information was provided in only 3
reports of plasma renin activity following the
administration ofindapamide (Grimm et al., 1981a;
leBel et al., 1983; Noveck et al., 1983). Indapa-
mide 2.S or Smg daily for 2 to 6 weeks consistently
increased plasma renin activity 2- to 3-fold when
used as a single agent in healthy subjects (Grimm
et al., 1981a; Noveck et al., 1983) or patients with
hypertension (Grimm et al., 1981a; leBel et al.,
1983). In other studies, plasma renin activity was
increased 2- to S-fold following the administration
of indapamide 2.5mg daily alone (Anavekar et al.,
1979; Chalmers et al., 1982; de Ortiz et al., 1983;
Santoro et al., 1982) or in combination with ben-
drofluazide Smg (Bing et al., 1981) for up to 16
weeks. The increases which occur in plasma renin
activity with indapamide are similar to those with
other diuretics (Witchitz et al., 1974) and vasodi-
lator agents (Campbell and Moore, 1981). How-
ever, the rise in plasma renin activity was pre-
vented when indapamide 2.Smg was administered
with the p-adrenergic blocker pindolol 10 to 40mg
daily (Chalmers et al., 1982; leBel et al., 1983).
Renin reacts with an arglobulin substrate to
form angiotensin I. Converting-enzymes (predom-
inantly in the lung) convert angiotensin I to angio-
tensin II, the latter being not only a potent vaso-
constricting substance (section 1.4.2) but also
partially responsible for aldosterone release from
the adrenal cortex (Gilmore, 1983; Nies, 1978).
Circulating concentrations of potassium and sod-
ium also regulate the quantity of aldosterone re-
198
leased (Gilmore, 1983). Indapamide 2.Smg daily
for 6 to 8 weeks consistently elevated plasma al-
dosterone concentrations by 4S% or more (p < om,
or less) in healthy volunteers and patients with
hypertension (Chalmers et al., 1982; leBel et al.,
1983; Weidmann et al., 1980). Urinary aldosterone
excretion was increased from 3.7 to 8.4 1Jf)24 hours
(p < O.OS) in 6 healthy subjects administered in-
dapamide Smg daily for 14 days (Noveck et al.,
1983). There appears to be no correlation between
urinary prostaglandin excretion (reflecting in-
creased secretion of prostaglandins by the kidney)
and degree of increase in plasma renin activity and
plasma aldosterone during indapamide therapy'
(leBel et al., 1983) [see section I.S]. Pindolol 10
to 40mg daily did not influence the increased al-
dosterone secretion induced by indapamide (Chal-
mers et al., 1982; leBel et al., 1983).
1.3 Metabolic Effects
1.3.1 Effects on Sodium Balance
In healthy volunteers, the percentage of filtered
sodium excreted after a single 10mg dose of in-
dapamide was increased 3.4% (p < 0.001) 3.S to S
hours after administration (Onesti et al., 1977b; Pi-
tone et al., 1978). In patients with hypertension,
indapamide 1.0, 2.S, and Smg daily increased the
percentage of filtered sodium excreted from 0.6%
to 0.9, 0.83, and 1.0S%, respectively (Brooks et al.,
1983). In non-parallel studies, the percentage of fil-
tered sodium excreted following the administra-
tion of thiazide compounds or frusemide was es-
timated to be 8 and 23%, respectively (Brater and
Thier, 1978; Francisco and Ferris, 1982). Although
small decreases in total exchangeable sodium have
been noted occasionally (80 mmol, or 2.7S% de-
crease; Grimm et al., 1981a, 1983), most studies
have indicated that indapamide (2.5mg daily) does
not significantly alter this parameter (Grimm et al.,
1981a, 1983; Issac et al., 1977; Santoro et al., 1982;
Witchitz et al., 1974).
At a dose of Img or less, indapamide does not
appear to cause any significant natriuretic effect
(Onesti et al., 1977b), and no change in 24-hour
urinary sodium excretion was noted in healthy
Indapamide: A Review
volunteers or patients with hypertension after 6
weeks' treatment with indapamide 2.5mg daily
(Grimm et al., 1981a; 1983). However, a single dose
of indapamide 2.5mg administered to 7 healthy
subjects on controlled fluid and electrolyte intake
increased urinary sodium excretion by 140%, from
78 to 187 ~mol/min over 24 hours (p < 0.01; Reyes
et ai., 1983b), and a similar group administered
single doses of indapamide 2.5, 5.0, 10.0, 20.0 or
30.0mg had increases in urinary sodium excretion
of 72, 120, 141, 133 and 127 ~mol/min, respec-
tively (Onesti et ai., 1977a). Similar findings have
been reported by Caruso et ai. (1983) [fig. 2b]. In
maximally hydrated healthy volunteers and patients
with hypertension, urinary sodium excretion 3
hours after a single dose of indapamide 10 or 20mg
was increased from 202 to 406 ~mol/min (p <
0.001; Pitone et ai., 1978) and 150 to 525 ~mol/
min (Villarreal et ai., 1983), respectively. After a
single dose of indapamide 40mg, urinary sodium
excretion was increased (p < 0.01) for at least 14
hours, resulting in decreased serum sodium con-
centrations on the second and third days following
administration (Campbell and Phillips, 1974).
In hypertensive or healthy subjects, the natri-
uretic effects ofindapamide 2.5 and 40mg were sig-
nificantly greater than those of frusemide 40mg
during the initial 24 hours after administration [280
vs 189 mmol/24 hours (Witchitz et ai., 1974) and
429 vs 169 mmol/24 hours (Leary et ai., 1973), re-
spectively]. Indapamide 7.5 mg/day increased
urinary sodium excretion over 6 days to a similar
extent as did hydrochlorothiazide 25mg daily, and
greater than did chlorthalidone l00mg daily (Bloch
et aI., 1981) [fig. 3].
Serum sodium concentrations generally have not
been altered following long term administration of
indapamide, although a few studies have shown
statistically significant decreases (Andries et aI.,
1980; Brennan et aI., 1982; Charoenlarp and Ja-
roonvesama, 1981) or increases (Horgan et aI.,
1981; Kubik and Coote, 1981). Nevertheless, de-
spite their statistical significance, these alterations
have not resulted in values outside the normal con-
centration range (135 to 145 mmol/L) [Freitag and
Miller, 1980; Wallach, 1978a]. In parallel compar-
199
ative trials, indapamide 2.5mg daily did not affect
serum sodium concentrations significantly, and the
concentrations were not significantly different from
those obtained with hydrochlorothiazide 50mg
(Plante and Robillard, 1983), hydrochlorothiazide
50mg/amiloride 5mg (Anavekar et aI., 1979; De-
manet et aI., 1977), bendrofluazide 5mg (Bing et
ai., 1981), or metolazone 2.5mg (Vukovich et aI.,
1983), each administered daily for 10 weeks or more
to patients with hypertension. Similarly, serum
sodium concentrations were not significantly al-
tered following 3 months' daily administration of
indapamide 5mg or chlorothiazide 500mg (Milliez
and Tcherdakoff, 1975).
1.3.2 Effects on Potassium Balance
As indapamide increases the activity of the
renin-angiotensin-aldosterone system (section 1.2)
and increases sodium delivery to the renal distal
tubules (Pitone et aI., 1978), it is not surprising that
its administration should result in a dose-related
increase in urinary potassium excretion (fig. 2c) and
in decreased serum potassium concentrations.
In dogs, single-dose intravenous administration
of indapamide 0.3, 1.0 and 3.0 mg/kg resulted in
a dose-related increase in the fractional excretion
of potassium [from 26.1 to 39% (p < 0.05), 35.3 to
55.2% (p < 0.02) and 35.1 to 78.9% (p < 0.01),
respectively] (Burke et aI., 1983). The rate of po-
tassium excretion in dogs hydrated by intravenous
infusion of hypotonic (2.5%) mannitol was also in-
creased from 63 to 108 ~mol/min (p < 0.05) 30
minutes after a Img/kg intravenous dose (Laubie
and Schmitt, 1977).
Single-dose oral administration of indapamide
2.5 to 40.0mg consistently resulted in increases in
the rate and/or magnitude of kaliuresis in healthy
volunteers (Campbell and Phillips, 1974; Caruso et
aI., 1983; Leary et aI., 1973; Onesti et aI., 1977a;
Reyes et aI., 1983b; Villarreal et aI., 1983). Thus,
urinary excretion of potassium was elevated (p <
0.01) over a 14-hour period following indapamide
40mg, with the peak rate of potassium loss occur-
ring from 4 to 6 hours after administration (Camp-
bell and Phillips, 1974). The rate of kaliuresis 3
hours after the administration of indapamide 20mg
Indapamide: A Review 200

increased from 43 to 74 ~molfmin (p < 0.001) [Vil- was noted in healthy volunteers administered in-
larreal et al., 1983], and daily urinary potassium dapamide 5mg daily for 14 days while maintained
losses following a single dose of indapamide 40mg on a controlled potassium diet (80 mmol/day)
were consistently greater (p < 0.025 at 48 hours) [Noveck et aI., 1983]; but decreases in mean serum
than those with cyclopenthiazide 5mg or frusemide potassium concentrations following long term
40mg (Leary et aI., 1973). treatment with indapamide 2.5mg daily appeared
Although statistically significant decreases in to be oflesser degree, varying from 0.3 to 0.7 mmolf
mean serum potassium concentrations have oc- L (Grimm et aI., 1983; Hamilton and Kelly, 1977;
curred in the majority (~ 75%) of clinical trials Houde and Carriere, 1983; Noble et aI., 1983; San-
where indapamide 2.5 or 5.0mg daily was admin- toro et aI., 1982). In a non-parallel comparison, an
istered to patients with hypertension, they have analysis of publications on diuretic-induced hypo-
usually not lowered serum potassium concentra- kalaemia in patients with hypertension or conges-
tions to less than the normal physiological range tive heart failure indicated that mean decreases in
[3.5 to 5 mmolfL (Wallach, 1978a)]. However, 6 serum potassium concentrations of 0.62, 0.30 and
to 14% of patients administered indapamide with- 0.67 mmolfL occurred following long term treat-
out potassium supplementation have had serum ment with hydrochlorothiazide (mean dose 90mg),
potassium concentrations decreased to below 3.5 frusemide (mean dose 75mg) or chlorthalidone
mmolfL, whereas 1% have had concentrations less (mean dose loomg), respectively (Morgan and
than 3 mmolfL (Campbell, 1983). A mean decrease Davidson, 1980). In parallel controlled studies, de-
in serum potassium concentration of 1.1 mmolfL creases in serum potassium following indapamide
2.5mg daily have at least equalled those seen with
hydrochlorothiazide 50mg given once daily (Mor-
ledge, 1983; Noble et aI., 1983; Ogilvie et aI., 1983;
200 200 Plante and Robillard, 1983) or twice daily (Cou-
tinho et al., 1980) [section 3.1.3.].
190 190 In patients with hypertension, indapamide
180
2.5mg daily for up to 10 months decreased esti-
180
mated total body potassium insignificantly (mean
170 170 decrease 125 mmol, from 2785 to 2660 mmol), [Is-
~
"0 sac et aI., 1977]. Similar findings were made in the
~ 160 160
patients studied by Meyer-Sabellek et al. (1984) who
§. 150 150 had received indapamide 2.5mg daily for 6 months.
c:
.2 Antihypertensive treatment with thiazide diuretics
11 140 140 has been associated with total body potassium
~
5 130 130
losses approximating 200 mmol (Perez-Stable and
Caralis, 1983).
~
~ 120 120
c: 1.3.3 Other Electrolyte Effects
§ 110 110
0 2 3 4 5 6
Treatment time (days) Effects on Chloride
When sodium undergoes reabsorption and/or
Fig.3. Effects of indapamide 7.5mg (0-0). hydrochlorothiaz- passive efflux from the renal tubule, electroneu-
ide 25mg (.......). chlorthalidone 100mg (6---6). and tienilic acid
trality is maintained by the simultaneous reab-
(ticrynafin) 250mg (.........) on urinary sodium excretion in patients
with hypertension. Each agent was administered daily for 6 days. sorption of a cation or the tubular secretion of an
Change in urinary sodium excretion with hydrochlorothiazide was anion. As chloride is abundant in the glomerular
not significant. filtrate and readily penetrates the tubular mem-
Indapamide: A Review
brane, sodium diuresis is often accompanied by
concomitant chloride diuresis (Mangini and Young,
1978).
In healthy volunteers, a single dose of indapa-
mide 40mg increased urinary chloride excretion
from 7.S to 2S mmol/hour (p < 0.01), with excre-
tion significantly elevated for at least 14 hours
(Campbell and Phillips, 1974). Urinary chloride loss
following indapamide appears to be dose related
(Caruso et al., 1983) [fig. 2d]. The same dosage of
indapamide decreased serum chloride concentra-
tions in other healthy volunteers within 24 hours
(p < O.OS), and these concentrations continued to
fall for up to 72 hours (p < 0.02S). Serum concen-
trations of chloride were lower following 2 doses
of indapamide 40mg given 24 hours apart than after
2 doses of frusemide 40mg (p < O.ooS) or cyclo-
penthiazide Smg (p < O.OOS) [Leary et al., 1973].
Single-dose administration of lower doses of in-
dapamide (2.5mg daily) to healthy volunteers or
non-oedematous patients with hypertension in-
creased 24-hour urinary chloride excretion 86 to
95% and 106.3%, respectively (Mroczek, 1983;
Reyes et aI., 1983b; Witchitz et aI., 1974), whereas
frusemide 40mg only increased chloride excretion
by 40% (Witchitz et aI., 1974). However, natri-
uresis with frusemide is relatively brief(~ 6 hours)
[Lant, 1984].
Treatment with indapamide 1 to Smg for at least
4 weeks resulted in significant decreases in plasma
chloride concentrations in over half of the clinical
trials where this parameter was measured. The
mean decreases in serum chloride concentrations
generally ranged from 2 to 6.6 mmol/L (Capone et
al., 1983; Froment et al., 1975; Hamilton and Kelly,
1977; Noveck et al., 1983; O'Brien et al., 1984;
Royer, 1976), but did not result in serum chloride
concentrations below the normal physiological
range (9S to lOS mmol/L) [Freitag and Miller, 1980;
Wallach, 1978a]. The decreases in serum chloride
concentrations following indapamide 2.Smg daily
were not significantly different from those after
treatment with hydrochlorothiazide SOmg daily
alone (Lemieux and L'Homme, 1983; Plante and
Robillard, 1983) or in combination with amiloride
Smg (Anavekar et aI., 1979).
201
Effects on Bicarbonate
As with the benzothiadiazide diuretics (Fran-
cisco and Ferris, 1982), there appears to be little
change in bicarbonate excretion following treat-
ment with indapamide. Lemieux and L'Homme
(1983) reported a decrease in serum bicarbonate
(2.S ~mol/L; p < O.OS) following indapamide 2.Smg
daily for 4 months, but other investigators have
not found significant changes following long term
administration of indapamide 2.S or Smg daily
(Anavekar et al., 1979; Chalmers et al., 1982; Mil-
liez and Tcherdakoff, 1975; Turner et al., 1977;
Witchitz et aI., 1975).
Effects on Calcium and Phosphate
Although one short term study (Leary et aI.,
1973) indicated that urinary calcium losses follow-
ing indapamide were increased and approached
those seen with frusemide treatment, most reports
resulting from short or long term studies have
shown indapamide to have a hypocalciuric effect
(Andries et aI., 1980; Campbell and Phillips, 1974;
Reyes et aI., 1983b; Santoro et al., 1982; Waal-
Manning and Doesburg, 1982). The hypocalciuric
effects of indapamide 7.S or 2.Smg daily were ap-
proximately equal to those of hydrochlorothiazide
2S or SOmg daily, respectively (Bloch et aI., 1981;
Lemieux and L'Homme, 1983), and doses of 2.S
and 5mg daily have been shown to reduce urinary
calcium excretion in hypercalcaemic patients (Ca-
ruso et aI., 1983). As plasma calcium concentra-
tions are not necessarily dependent on urinary cal-
cium losses (Campbell and Phillips, 1974), plasma
calcium concentrations during short or long term
indapamide treatment have not been altered (De-
manet et aI., 1977; Kubik and Coote, 1981; lem-
ieux and L'Homme, 1983; Lenzi and Di Perri, 1977;
Plante and Robillard, 1983).
Campbell and Phillips (1974) reported in-
creased (p < 0.01) urinary phosphate excretion in
healthy volunteers following a single dose of in-
dapamide 4Omg, but indapamide 2.S or 7.Smg daily
for 1 or 6 days, respectively, did not result in sig-
nificant changes in urinary phosphate loss (Bloch
et al., 1981; Reyes et aI., 1983b). Long term admin-
istration of indapamide has not resulted in statis-
Indapamide: A Review
tically significant alterations in mean serum phos-
J)hate concentrations (Kubik and Coote, 1981 ;
Lemieux and L'Homme, 1983; Waal-Manning and
Doesburg, 1982).
Effects on Magnesium
As most of the magnesium in the glomerular
filtrate is reabsorbed at the proximal tubule and at
the thick ascending limb of the loop of Henle, the
kidney plays a large role in magnesium homeosta-
sis (Leary and Reyes, 1982). Renal magnesium ex-
cretion is enhanced by the benzothiadiazines, fru-
semide, and ethacrynic acid, although the mech-
anism by which this occurs is unclear (Leary and
Reyes, 1982; Porter, 1980).
Total body magnesium may be poorly reflected
by serum magnesium concentrations (Ogilvie,
1984); however, most studies of the effect of in-
dapamide on magnesium have also included urin-
ary magnesium excretion rate data. In 6 healthy
volunteers, a single dose of indapamide 40mg in-
creased the rate of urinary magnesium excretion
(0.05 > p > 0.02) and the concentration of mag-
nesium per volume of urine (p < 0.01), and de-
creased serum magnesium concentrations (p < 0.01)
[Campbell and Phillips, 1974J. Although urinary
concentrations and rate of excretion of magnesium
returned to pretreatment values 3 days after in-
dapamide administration, serum magnesium con-
centrations remained decreased for 10 days follow-
ing this single large dose (mean decrease from 1.2
to 0.8 mmol/L). The single-dose administration of
a smaller dose of indapamide (2.5mg) to 7 healthy
subjects did not alter 24-hour urinary magnesium
excretion, in spite of significant increases in urin-
ary volume and sodium, potassium, and chloride
loss (Reyes et aI., 1983b). The serum magnesium
concentrations of the patients of Acchiardo and
Skoutakis (1983) were not altered by indapamide
2.5mg daily; however, as these patients were anuric
or oliguric and undergoing long term haemodialy-
sis, these data are not representative of the effect
of indapamide on normal renal magnesium excre-
tion. As higher dosages of indapamide (>2.5mg
daily) appear to have the potential to increase both
urinary magnesium excretion and decrease serum
202
magnesium concentrations significantly, assess-
ment of magnesium balance during such treatment
may be indicated. Long term data regarding the use
of indapamide 2.5mg daily in patients with hyper-
tension are required before definitive statements
on the effect of usual doses of indapamide on mag-
nesium metabolism in this patient population can
be made.
1.3.4 Effect on Uric Acid
35 to 50% of patients with primary gout have
hypertension, and 26 to 33% of patients with mild
hypertension (untreated) are hyperuricaemic (Ogil-
vie, 1983). Since increases of 0.059 to 0.118 mmol/
L in. serum uric acid concentrations are common
during thiazide administration and 0.236 to 0.295
mmol/L elevations have been reported (Mangini
and Young, 1978), the incidence ofhyperuricaemia
may increase to 50 to 75% when diuretic therapy
is instituted (Ogilvie, 1983). Diuretic-induced
hyperuricaemia is mainly due to extracellular fluid
volume contraction (Mangini and Young, 1978;
Plante and Robillard, 1983), but decreased urate
excretion and/or postsecretory reabsorption may
also play roles (Lant, 1981; Mangini and Young,
1978). The incidence of diuretic-induced acute
gouty arthritis is relatively rare « 5%) [Ogilvie,
1983J, and it is not known whether these patients
are at increased risk for the development of gouty
nephropathy (Mangini and Young, 1978).
It is difficult to assess the exact potential of in-
dapamide to increase serum uric acid concentra-
tions. Several well-designed trials have shown that
indapamide (1 to 5mg daily; 3- to 108-week treat-
ment periods) could increase serum uric acid con-
centrations by 0.035 to 0.083 mmol/L (Houde and
Carriere, 1983; La Corte et al., 1980b; O'Brien et
al., 1984; Royer, 1976; Santoro et al., 1982; Weid-
mann et aI., 1981), while other similarly conducted
studies demonstrated no significant effect (Ana-
vekar et aI., 1979; Andries et al., 1980; Hatt and
Leblond, 1975; Witchitz et al., 1975). Some com-
parative studies (Coutinho et al., 1980; Lemieux
and L'Homme, 1983; table I) have shown in-
creased serum uric acid concentrations following
indapamide, but again there has been no consistent
Indapamide: A Review 203

Table I. Comparative effects of indapamlde (10) and other diuretic agents on serum uric acid concentrations in patients with hyper-
tension

Reference Number of patients Study Daily dose (mg) Effect on serum uric acid
[study duration] design
indapamide other agent indapamide other agent

Comparisons with hydrochlorothiazide

Coutinho et al. 120 Open 2 HCTZ 50 x 2 t 20% t 27.1%
(1980) [12 weeks] 2.5 t 16.8%
Lemieux and 26 pi 2.5 b HCTZ 50mgb t (p < 0.05; t (p < 0.05;
L'Homme (1983) [4 months (10), compared with compared with
> 6 months (HCTZ)] placebo and placebo)
HCTZ)

Plante and 24 db, pi 2.5mg HCTZ 50mg t (p < 0.05;

Robillard (1983) [12 weeks] compared with
placebo)

Comparisons with other agents

Anavekar et al. 20 r, db, co, pi 2.5b HCTZ 50 t (p < 0.01;
(1979) [8 weeks]" and AMR 5b compared with
placebo)

Hatt and Leblond 38 sb, co, pi 5.0 CHLR 100

(1975) [45 days]"

a Duration of treatment with each active agent.

b Administered alone or In combination with other non-diuretic antihypertensive agents.
Abbreviations: HCTZ = hydrochlorothiazide; AMR =
amilorlde; CHLR = chlorthalidone; r = randomised; db = double-blind;
=
sb single-blind; co = crossover; pi =
placebo-controlled; t= increased; - =no change.

agreement. The varying results may be due to the
exclusion of patients with histories of gout or
hyperuricaemia from many of the clinical trials
(Anavekar et al., 1979; Andries et al., 1980; Bren-
nan et al., 1982; Capone et al., 1983; Charoenlarp
and Jaroonvesama, 1981; Horgan et al., 1981;
Hashida, 1977) or the administration of allopuri-
nol or uricosuric agents during others (Beling et aI.,
1983; Demanet et al., 1977; Goto et al., 1982; Ro-
dat, 1975). As with other diuretic agents, the ele-
vations in serum uric acid concentrations seen with
indapamide usually do not progress beyond the up-
per limits of normal [0.443 and 0..502 mmol/L for
women and men, respectively (Wallach, 1978a)] or
result in symptoms, although the administration of
indapamide has been associated with the occur-
rence of acute gouty arthritis in a few patients (Bel-
ing et aI., 1983; Royer, 1976; Waal-Manning, 1984).
1.3.5 Effects on Glucose Tolerance
Up to 30% of patients with hypertension taking
thiazide diuretics may eventually develop abnor-
mal glucose tolerance (Amery et al., 1978). This
phenomenon may occur in non-diabetic patients,
but clinically significant hyperglycaemia usually
occurs only in 'pre-diabetic' patients or in diabetics
with poorly regulated blood glucose concentrations
(Perez-Stable and Caralis, 1983; Porter, 1980). The
mechanisms by which thiazide diuretics may upset
carbohydrate metabolism are not clear (Perry,
1983): decreased insulin secretion, decreased tissue
sensitivity to insulin, increased insulin output
(leading to depletion), and an enteropancreatic in-
sulin axis deficiency have all been proposed mech-
anisms. Hypokalaemia (which interferes with the
conversion of pro-insulin to insulin) may also con-
tribute to thiazide-induced glucose intolerance
Indapamide: A Review
(Perez-Stable and Caralis, 1983).
In isolated perfused rat pancreas, indapamide
10 or 100 mg/L produced dose-dependent reduc-
tions in total insulin secretory response to a high
concentration glucose infusion. A concentration of
500 mg/L completely suppressed insulin secretory
response to a glucose infusion, but increased (p <
0.05) the basal insulin secretion rate (Furman and
Razak, 1981).
In mice and rats, the oral administration of in-
dapamide 10 mg/kg/day for 24 days did not affect
fasting plasma glucose concentrations or those ob-
tained 60 to 120 minutes after the administration
of a glucose load (Furman and Razak, 1981). No
change in plasma immunoreactive insulin concen-
trations occurred in the rats up to 20 minutes after
glucose loading and only in the mice were plasma
glucose concentrations increased (p < 0.025) 30
minutes following the glucose load. However, as
glucose tolerance tests in rodents treated with.
hydrochlorothiazide have failed to demonstrate
impaired carbohydrate metabolism (Foy and Fur-
man, 1972), it is unclear whether diuretic agents
produce hyperglycaemic responses in animals sim-
ilar to .those seen in man (Furman, 1977).
Although abnormal glucose tolerance may oc-
cur following only a few months of treatment with
thiazide compounds (Hicks et aI., 1973), it usually
takes 1 to 2 years to develop in the elderly and up
to 5 years in younger populations (Amery et aI.,
1978; Lewis et aI., 1976). There have been rare in-
stances where patients have had elevated blood
glucose concentrations following indapamide (Bel-
ing et aI., 1983; Goto et aI., 1982; Slotkoff, 1983;
Wheeley et aI., 1982), but almost none of the stud-
ies of carbohydrate metabolism in non-diabetic
patients with hypertension have revealed altera-
tions in glucose tolerance (as assessed by mean glu-
cose concentrations) after treatment with this agent
(Andries et al., 1980; Beling et aI., 1983; Demanet
et aI., 1977; Goto et aI., 1982; Zorn, 1982). Basal
immunoreactive insulin secretion and oral glucose
tolerance test results were unchanged from control
values in 12 patients (non-obese, 30 to 50 years of
age) with mild to moderate hypertension and nor-
mal glucose tolerance treated with indapamide
204
2.5mg for up to 60 days (Greco et aI., 1983). In
non-diabetic patients with hypertension, only the
double-blind comparative study of Coutinho et aI.
(1980) indicated that indapamide 2.5 or 5.0mg daily
could increase (p < 0.05) blood glucose concentra-
tions after 8 weeks of treatment; and at 12 weeks,
indapamide 2 or 2.5mg daily increased blood glu-
cose concentrations similarly to hydrochlorothi-
azide 50mg twice daily (8.3, 15.8, and 11.6%, re-
spectively).
In diabetic patients with hypertension, indapa-
mide did not significantly modify mean blood glu-
cose concentrations or insulin secretion in studies
ranging in duration up to 1 year (although indi-
vidual patients have shown glucose intolerance)
[Baba et aI., 1982; Bam and Bouwer, 1983; Roux
and Courtois, 1981]. In a 6-month study of 20 dia-
betic patients with hypertension, glycosylated
haemoglobin measurements were not altered after
indapamide 2.5mg daily (Raggi et aI., 1982).
Most of the studies of insulin secretion and car-
bohydrate metabolism in diabetic or non-diabetic
patients have been relatively brief(::E; 1 year). Thus,
there are no data on the long term effects of in-
dapamide on glucose tolerance in either population
group. In view of this, and the comparatively low
number of reports detailing blood glucose concen-
trations and insulin release in man, a clear state-
ment on the effects of indapamide on glucose tol-
erance must await further long term controlled
trials.
1.3.6 Influence on Lipid Metabolism
Several sulphonamide diuretics in common use
(hydrochlorothiazide, chlorthalidone and frusem-
ide) are known to have a blood lipid-lipoprotein
elevating effect both in healthy and hypertensive
men (Grimm et aI., 1981b; Joos et aI., 1980) and
in postmenopausal women (Boehringer et aI., 1982).
The specific mechanism of diuretic-induced in-
creases in serum lipid concentrations is unknown
(Grimm et aI., 1981b; Perez-Stable and Caralis,
1983; Weidmann et al., 1983), but studies with
chlorthalidone have indicated that it occurs most
frequently in patients with low initial total chol-
esterol concentrations « 4.8 mmol/L) [Perry,
Indapamide: A Review
1983]. Although some investigators regard this
phenomenon as a 'biochemical' side effect of un-
certain clinical relevance (Boehringer et aI., 1982;
Ogilvie, 1982, 1983), it has been proposed that in-
creased serum low density lipoprotein, triglyceride,
and total cholesterol concentrations during anti-
hypertensive therapy with diuretics may favour an
increased risk of coronary artery disease (Grimm
et aI., 1981b) and counteract the benefits ofreduc-
tion of mild and moderate hypertension (Perez-
Stable and Caralis, 1983).
Long term data are limited, but the administra-
tion of indapamide 1 to 4mg daily to healthy and
hypertensive patients over 1 to 24 months has not
been associated with increases in total serum chol-
esterol (Baba et aI., 1982; Beling et aI., 1983; Goto
et aI., 1982; Hatt and Leblond, 1975; Scalabrino et
aI., 1984; Waal-Manning and Doesburg, 1982;
Witchitz et aI., 1975; Weidmann et aI., 1981), tri-
glycerides (Beling et aI., 1983; Scalabrino et aI.,
1984; Waal-Manning and Doesburg, 1982; Weid-
mann et aI., 1981), or low density lipoprotein con-
centrations (Baba et aI., 1982; Goto et aI., 1982;
Meyer-Sabellek et aI., 1984; Scalabrino et aI., 1984;
Waal-Manning and Doesburg, 1982), or decreases
in high density lipoprotein concentrations (Baba et
aI., 1982; Goto et aI., 1982; Scalabrino et aI., 1984;
Waal-Manning and Doesburg, 1982). The effects of
indapamide 2.5mg daily or tienilic acid 250mg daily
on serum lipid-lipoprotein concentrations in
healthy and hypertensive men have been studied
(Weidmann et aI., 1981). After 6 weeks of treat-
ment with tienilic acid, triglycerides and low den-
sity lipoprotein cholesterol were increased (12% and
17%, respectively; p < O.OS), while indapamide had
no effect on these substances. Neither agent sig-
nificantly affected high density lipoprotein chol-
esterol, total serum cholesterol, or apoprotein B
concentrations.
In a multicentre trial in progress, indapamide
Smg daily increased total serum cholesterol con-
centrations to a greater extent than did hydro-
chlorothiazide SOmg daily (0.49 mmol/L and 0.26
mmolfL increases, respectively) when each was ad-
ministered over a period of 40 weeks (Morledge,
1983).
205
1.4 Cardiovascular Effects
1.4.1 In Vitro Effects on Electromechanical
Activity in Vascular Smooth Muscle and
Cardiac Muscle
In vitro electrophysiological and mechanical ex-
periments on longitudinal muscle strips from iso-
lated rabbit portal vein have demonstrated that in-
dapamide (~ 0.1 giL) is capable of decreasing
inward calcium current and clonic (phasic) con-
tractions (Mironneau and Gargouil, 1979). Al-
though indapamide also decreases outgoing potas-
sium currents, it does not significantly change the
intensity of tonic contractions. Indapamide also
blocks the increases in clonic contractions and cal-
cium influx which can be elicited by angiotensin
II (0.1 mg/L) in the same in vitro model, but can-
not block the increas.es in tonic contraction and
outgoing potassium current induced by noradren-
aline 0.01 mg/L (table II) [Mironneau and Gar-
gouil, 1979]. The effects of indapamide noted in
this study were slowly reversible and dose related.
In other in vitro studies, indapamide was shown
to reduce the action potential amplitude of cardio-
vascular smooth muscle preparations, without al-
tering resting membrane potential (Gargouil, 1979;
Mironneau and Gargouil, 1976, 1977), to more po-
tently reduce the isometric contraction and action
potential amplitude of smooth muscle strips from
rat portal veins than hydrochlorothiazide or chlor-
thalidone (Mironneau et aI., 1981), and to reduce
transepithelial sodium transport resulting in de-
creased potential differences and short circuit cur-
rent across a frog skin membrane (Uhlich et aI.,
1977).
1.4.2 Effects on Vascular Reactivity and
Peripheral Vascular Resistance
In hypertension, increased blood pressure re-
sults from constriction of the small arteries and ar-
terioles, which leads to increased resistance to flow.
This increase in peripheral resistance may theo-
retically result either from the presence of in-
creased stimuli leading to excess vasoconstriction
or from intrinsic abnormalities within the resist-
ance vessels leading to an increased response to
Indapamide: A Review 206

Table II. Effect of indapamide on vascular reactivity in man. See text for further discussion

Reference Population Indapamide regimen Vasoconstrictor Effect on vasoconstrictor response"

stimulus

Boer et al. (1983) Hypertensive 1, 2.5mg or 5mg daily Noradrenaline IV 'Decrease' in pressor reactivity
x 28 days occurred in responding (8 of 10)
patients. Post-treatment pressor
reactivity appeared to be dose related

Carretta et al. Hypertensive 2.5mg daily x 90 days Noradrenaline IV ~(p < 0.05) pressor reactivity in 8 of
(1983) 10 patients

Grimm et al. Normotensive 2.5mg daily x 42 days Noradrenaline IV No significant change in pressor dose
(1981 a) Angiotensin II IV of either agent following indapamide
treatment
Hypertensive 2.5mg daily x 42 days Noradrenaline IV t (p < 0.001) in pressor dose required
Angiotensin II IV t (p < 0.05) in pressor dose required
Noveck et al. Normotensive 5mg daily x 14 days Phenylephrine IV t (p < 0.05) in pressor dose required
(1982) Angiotensin II IV

Weidmann et al. Normotensive and 2.5mg daily x 42 days Noradrenaline IV t (p < 0.02) in pressor dose required
(1980) hypertensive (15-30 mg/L) for borderline hypertensives (p <
0.02) and all subjects together but not
in normotensives
Angiotensin II Pressor dose in indapamide-treated
(1.5 to 3.0 I'g/L) patients approximately doubled, but
significant only when all patient
groups analysed together (p < 0.05)

a Pressor response measured indirectly using standard cuff and sphygmomanometer or automatic blood pressure recorder.

normal stimuli, or a combination of the two mech-
anisms. There is fairly general agreement that
hypertension is accompanied by evidence of in-
creased vascular reactivity to constrictor stimuli,
and this change may be responsible in part, if not
mainly, for the increased peripheral resistance
which characterises this disorder. The mechan-
ism(s) responsible for increased vascular activity
are unclear, although structural medial hypertro-
phy in resistance vessels, abnormalities in vascular
smooth muscle calcium-sodium exchange pro-
cesses, and local intravascular release of vasoactive
substances (particularly prostaglandins) have been
suggested as possible contributing events (Doyle,
1982).
In Vitro Effects on Vascular Reactivity
Indapamide has been shown to inhibit vascular
smooth muscle contractile response to various
agonist drugs and electrical stimulation in a wide
variety of in vitro preparations from rats (Bor-
kowski et aI., 1981; Finch et aI., 1977a,b; Kraetz
et aI., 1978; Kyncl et aI., 1975; Uhlich et aI., 1977)
and rabbits (Kyncl et aI., 1975; Usui et aI., 1978).
Angiotensin, adrenaline, tyramine, prostaglandin
F2a and nicotine resulted in decreased vasocon-
striction in the presence of indapamide, while its
effects on noradrenaline-induced smooth muscle
contraction have been inconsistent. Resting tone in
arterial and venous smooth muscle is usually not
affected by indapamide (Campbell and Moore,
1981 ).
Inhibition of noradrenaline-induced vasocon-
striction in the isolated perfused rat mesenteric ar-
tery was greater with indapamide than with hydro-
chlorothiazide, chlorthalidone or acetazolamide, but
not significantly greater than that with frusemide
(Kraetz et aI., 1978). The vascular activity of these
Indapamide: A Review
various agents does not correlate with their natri-
uretic potency.
Rat diaphragmatic twitch in response to con-
stant phrenic nerve stimulation was not antagon-
ised by indapamide, suggesting that it may have
little effect on skeletal muscle innervation [Bor-
kowski et aI., 1981].
Indapamide had a relaxing effect on contraction
in various rabbit arterial preparations which had
been stimulated by prostaglandin F2a ; this relaxa-
tion was not inhibited by atropine, propranolol or
aminophylline (Usui et aI., 1978). Hydrochloro-
thiazide produced a lower frequency of relaxation
than indapamide in these prostaglandin Fustim-
ulated vessels, although the statistical significance
of this difference was not stated. Interestingly, Usui
et ai. (1978) reported that indapamide potentiated
pulmonary arterial contractile response to trans-
mural electrical stimulation. Interference with neu-
ronal amine uptake was the apparent cause of the
inhibition of nicotine and tyramine-induced vaso-
constriction. Usui and co-workers indicated that
indapamide did not appear to relax vascular smooth
muscle through ganglionic blockade or decreased
noradrenaline from adrenergic nerve terminals, but
suggested [as have Burgess et ai. (1981) and Camp-
bell and Moore (1981)] that the effect of indapa-
mide on contraction may be due to a direct action
on vascular smooth muscle.
Decreased contractile response was not seen in
mesenteric arteries or portal veins removed from
indapamide-treated DOCA-hypertensive rats and
exposed in vitro to noradrenaline, serotonin (5-hy-
droxytryptamine) or adenosine-5' -triphosphate
(Finch et aI., I 977a,b).
In Vivo Effects on Vascular Reactivity
Several groups of investigators have studied the
changes in vascular reactivity (assessed as pressor
responsiveness) which occur in association with in-
dapamide administration in laboratory animals
(Finch et aI., 1977a,b; Hicks, 1979; Moore et aI.,
1977) and man (Boer et aI., 1983; Grimm et aI.,
1981a; Noveck et aI., 1982; Weidmann et aI., 1980).
Pressor response to oxotremorine following
blockade of peripheral muscarinic receptors with
207
atropine was decreased more than 50% from con-
trol values in normotensive rats administered in-
dapamide 10 mgjkgjday or reserpine 0.5 mgjkgj
day orally for 6 days (Moore et aI., 1977). The same
dose of indapamide administered to pithed DOCA/
saline-hypertensive rats for 10 days resulted in sig-
nificant decreases in vasoconstriction when the rats
were administered noradrenaline (norepinephrine)
[p < 0.03] or tyramine (p < 0.05) intravenously
(Finch et aI., 1977a,b). Pretreatment of other
DOCA/saline-hypertensive rats with hydrochloro-
thiazide 5 mg/kg intraperitoneally resulted in a
similar hypotensive response noted in the indap-
amide-treated rats, but pressor responses to
pharmacological or electrical stimuli were not al-
tered when compared with controls. However, in-
dapamide 10 mgjkg orally reduced (from approx-
imately 175 to 125mm Hg; p < 0.01) the pressor
response to an electrical stimulus (Hicks, 1979).
In studies in man (table II), Weidmann et ai.
(1980) administered indapamide 2.5mg daily to 12
patients for 6 weeks to evaluate response to va-
soconstrictive agents following long term therapy.
The pressor dose was defined as the quantity of
vasoconstrictor substance necessary to increase
mean (noradrenaline) or diastolic (angiotensin II)
blood pressure by 20mm Hg. Cardiovascular reac-
tivity to noradrenaline was significantly decreased
in patients with borderline hypertension only
(pressor dose was increased from 99 to 156 ng/kg/
min; p < 0.02). The pressor dose of angiotensin II
was also increased following indapamide treat-
ment, but only achieved statistical significance
when normo- and hypertensive patients were an-
alysed together (12 to 21 ng/kg/min; p < 0.05).
Similar findings were reported by Grimm et ai.
(1981a) in patients with mild to moderate hyper-
tension. Indapamide-induced changes in noradren-
aline pressor dose and mean blood pressure were
found to be inversely correlated (fig. 4).
Vascular reactivity was also assessed by Noveck
et ai. (1982), who administered indapamide 5mg
daily to healthy volunteers for 14 days prior to ad-
ministering increasing doses of phenylephrine or
angiotensin II. A pressor response was defined as
increases of 25 to 35mm Hg and 20 to 30mm Hg
Indapamide: A Review
in systolic and diastolic blood pressures, respec-
tively. Pressor doses of phenylephrine were in-
creased from S.03 to 10. 72 ~gJkg, and pressor doses
of angiotensin II increased from 16.7 to 31.7 ngJ
kg after indapamide treatment.
In these studies (Grimm et aI., 1981a; Noveck
et al., 1982; Weidmann et aI., 1980), significant
changes in plasma catecholamine concentrations
did not occur during indapamide treatment. How-
ever, plasma renin activity was increased (p < O.OS,
or less) in all 3 studies, and increases (p < O.OS) in
plasma (Weidmann et al., 1980) and urinary (No-
veck et aI., 1982) aldosterone concentrations were
also noted (see also section 1.2).
Effects on Peripheral Vascular Resistance
In patients with hypertension, indapamide
2.Smg daily for 6 to 12 weeks increased muscle or
limb blood flow (Burgess et al., 1981; Ogilvie et
aI., 1983; Velasco et aI., 1982), and decreased limb
vascular resistance, total peripheral resistance
(Gensini et aI., 1983; Velasco et aI., 1982; Villarreal
et al., 1983) and peripheral resistance 'index' (Can-
icave and Lesbre, 1977) [table III]. These findings
+10
, 1981), or hydrochlorothiazide SOmg alone (Ogilvie
~ 1979), each administered daily. The bradycardic
~ 0
a..
ID
c:
'"E
Q)
-10
.
.s
~ 2.S and Smg daily for 4 to 8 weeks had no effect
c:
'" -20~--~----~----,-----~
B on left ventricular end-diastolic or end-systolic vol-
-50 0 +100 +200 +300
Change in noradrenaline pressor dose (%)
Fig. 4. Inverse correlation between percentage change in mean
blood pressure and percentage change in noradrenaline (nor-
epinephrine) pressor dose in 14 patients with hypertension re-
ceiving indapamide (r = - 0.62, P < 0.05) [adapted from Grimm
et al. (1981 all.
208
were made in relatively small numbers of patients
with generally non-invasive assessment methods
which included a xenon 'washout' technique
(radiolabelled xenon is injected intramuscularly,
and tracer disappearance metered to determine
blood flow) [Burgess et aI., 1981], carotid pulse
wave recording (Canicave and Lesbre, 1977; Ve-
lasco et aI., 1982), and assorted plethysmographic
methods (Ogilvie et aI., 1983; Velasco et aI., 1982).
Only Villarreal et a1. (1983) utilised invasive tech-
niques to acquire data in a more direct manner.
Peripheral resistance was usually calculated as a
function of mean blood pressure and cardiac out-
put (Velasco et aI., 1982; Villarreal et aI., 1983),
but alternative resistance formulas were also used
(Canicave and Lesbre, 1977).
1.4.3 Effects on the Heart
Heart rate during long term treatment with in-
dapamide has generally remained unchanged, al-
though some clinical reports have revealed signifi-
cant decreases (Dean, 1981; Guidi et al., 1982;
Hamilton and Kelly, 1977; Turner et al., 1977) or
increases (Brennan et al., 1982; Houde and Car-
riere, 1983). Heart rate did not change from base-
line measurement or vary with treatment group in
parallel studies where indapamide 2.Smg daily was
compared with cyclopenthiazide O.Smg (Khan,
et aI., 1983; Plante and Robillard, 1983) or in com-
bination with amiloride Smg (Anavekar et al.,
response to the Valsalva manoeuvre was intact in
healthy volunteers administered indapamide Smg
daily for 14 days (Noveck et aI., 1983).
In patients with hypertension, indapamide 1.0,
umes (Dunn et aI., 1981; Gensini et al., 1983; Lee-
nen et al., 1983). Ejection fractions, as measured
by echocardiography, were unchanged following
long term treatment with indapamide in some
patients (Gensini et al., 1983; Leenen et al., 1983),
while those assessed by Dunn et al. (1981) had in-
creased ejection fractions (increased from 63 to
69%, p < O.OS). Stroke volumes were unchanged
Indapamide: A Review 209

Table III. Summary of the effects of indapamide (ID) 2.5mg daily on muscle blood flow and vascular resistance in patients with
essential hypertension (see section 1.4.2)

Reference Number of Study Variables measured, Results

patients design methods of assessmentb
blood flow vascular resistance
[duration of
treatment]

Burgess et al. 5 pi Resting and exercise MBF I. t (38%) resting

(1981) I. [1 week] measured by xenon washout MBF
II. [6 weeks] techniqueC ..... exercise MBF
II. t (52.6%) resting
MBF
t (18%) exercise
MBF

Canicave and 20 op PRI calculated from ~ (p < 0.001) PRI

Lesbre (1977) [2 months] carotidogram datad

Gensini et al. 9 pi CO measured by ~ TPR, from 1722-

(1983) [6 weeks] echocardiography. TPR 1426 dyne/sec/ems
calculated"

Ogilvie et al. 6 r, pi, db, co LBF (forearm) measured by LBF with:

(1983) [3 months]" plethysmographic technique pi = 3.53 ml/min/dl
ID = 4.01 ml/min/dl
HCTZ = 3.4 ml/min/dl

Velasco et al. 9 pi CO measured by impedance t (p < 0.05) LBF, 3.98 ~ (p < 0.01) LVR,
(1982) [6 weeks] cardiography' and LBF to 5.02 ml/100g • min from 47.3-31.8mm Hg
measured by • 100g • min/ml
plethysmographic technique. 9
TPR and LVR calculated"

Villarreal et al. 10 op CO measured with ~ TPR, from

(1983) [8 weeks] thermodilution catheter, CI approximately 1925-
and TPR calculated" 1550 dyne/sec/cm s

a Duration of treatment with each agent. LBF also measured following administration of hydrochlorothiazide (HCTZ) 50mg daily.
b BP measured in all studies.
c Method of Hirai (1974).
d A graphic recording of carotid pulse waves, allowing measurement of dicrotic and systolic wave amplitudes:
=
POW diastolic BP + (systolic BP - diastolic BP) ADW/ASW
=
PRI (systolic BP + PDW}/(systolic BP - POW).
e TPR = MBP (mm Hg}/CO (L/min); LVR = MBP (mm Hg}/LBF (ml/100g' min); CI = CO (L/min}/A (m 2).
f Method of O'Malley et al. (1976).
g Method of Greenfield et al. (1963).
Abbreviations: pi = placebo-controlled; op = open; r = randomised; db = double-blind; co = crossover; MBF = muscle blood flow;
PRI = peripheral resistance 'index'; CO = cardiac output; TPR = total peripheral resistance; LBF = limb blood flow; LVR = limb
vascular resistance; CI = cardiac index; POW = pressure of dicrotic wave; BP = blood pressure; ADW = amplitude of dicrotic wave;
ASW = amplitude of systolic wave; MBP = mean blood pressure; A = area (body surface); t = increase; ~ = decrease; ..... = no
change.
Indapamide: A Review
following indapamide 2.5mg daily for 6 to 8 weeks
(Dunn et al., 1981; Gensini et aI., 1983).
Cardiac output, as assessed by echocardio-
graphy, was increased in the patients of Gensini et
ai. (1983) [increased from 5.92 to 6.63 L/min, p <
0.05] and Dunn et ai. (1981) [4.4 to 5.3 L/min, p
< 0.01] after indapamide 2.5mg daily for 6 to 8
weeks; however, the same dosage administered for
6 weeks did not alter cardiac output in another
study (Velasco et aI., 1982). Cardiac index was un-
changed in patients administered indapamide 1 to
5mg daily for 4 to 8 weeks, whether assessed by
echocardiography (Leenen et aI., 1983) or via a
more precise technique utilising thermodilution
catheters (Villarreal et al., 1983).
Regression of left ventricular hypertrophy and
cardiomegaly (as assessed by unspecified methods)
occurred in 50 to 53% and 38 to 50%, respectively,
of the patients with these conditions treated with
indapamide 2.5mg daily for 1 to 18 months (Fro-
ment et aI., 1975; Naegel et aI., 1975; Rodat, 1975;
Royer, 1976). Reduction of heart and chamber size
was presumably due to improved blood pressure
control.
In healthy volunteers and patients with hyper-
tension, indapamide 2.5 or 5mg daily for 14 to 90
days did not induce electrocardiographic altera-
tions of the P-R or QRS intervals (Haiat et al., 1981;
Noveck et aI., 1983) or the QTc intervals and T
wave amplitude (Noveck et aI., 1983).
1.5 Effect on Prostaglandin Synthesis
Many studies have demonstrated the ability of
renal tissues to generate prostaglandins. Although
the exact interrelationships between prostaglandin
metabolism (primarily that of prostaglandins E2 and
12) and blood pressure have not been elucidated, it
is likely that some prostaglandins play some part
in the overall regulation of blood pressure (Camp-
bell, 1983; Lant, 1981).
The in vitro effects of indapamide, frusemide,
spironolactone and hydrochlorothiazide (all in
concentrations ranging from 0.1 to 5000 nmol/L)
on prostaglandin and thromboxane biosynthesis
were studied in sheep seminal vesicles and human
210
platelet microsomal fractions, respectively (Gbeas-
sor et aI., 1982). While indapamide was the most
potent inhibitor of thromboxane synthesis, hydro-
chlorothiazide showed no activity at all. Similarly,
indapamide was the most potent stimulator of the
vasodepressor prostaglandin 12 (prostacyclin), with
hydrochlorothiazide again showing little activity.
In 11 of 19 patients with essential hypertension,
indapamide 2.5mg daily for 6 weeks increased (p
< 0.025) urinary prostaglandin E2 excretion, prob-
ably via stimulation of renal production (LeBel et
aI., 1983). Urinary prostaglandin F 2a excretion was
not significantly altered, and there was no corre-
lation between the percentage difference in prosta-
glandin E2 excretion (43% increase) and the mean
changes in blood pressure, plasma renin activity or
plasma aldosterone concentrations (section 1.2).
Renal production of prostaglandin E2 is suppressed
in a certain percentage of patients with essential
hypertension, and alteration of concentrations dur-
ing treatment with indapamide could result in
intrarenal haemodynamic changes which might
contribute to a decrease in blood pressure (LeBel
et aI., 1983).
1.6 Mechanism of Antihypertensive
Action
It has been proposed that indapamide decreases
blood pressure via 2 major mechanisms: through
relaxation of vascular smooth muscle, and a di-
uretic effect (Campbell, 19"83; Caruso et al., 1983;
Issac et al., 1977; Rutsaert and Fernandes, 1983).
Evidence for a direct effect on vascular smooth
muscle consists of in vitro and in vivo data which
demonstrate the ability of indapamide to decrease
calcium inward currents, vascular reactivity and
peripheral arterial resistance.
Indeed, indapamide appears capable of decreas-
ing inward calcium currents and clonic (phasic)
contractions in in vitro smooth muscle prepara-
tions (section 1.4.1); it has therefore gained a pro-
visional classification as a calcium antagonist (Opie,
1980). However, the effect of indapamide on cal-
cium influx has not been shown to be dose-de-
pendent, as has been demonstrated with calcium
Indapamide: A Review
antagonists such as verapamil and nifedipine, and
it has not been possible to demonstrate any cal-
cium antagonist effect on the heart with indapa-
mide (Mironneau and Gargouil, 1979). Compari-
son of indapamide with calcium channel blocking
agents (e.g. papaverine, verapamil) did not dem-
onstrate any significant direct interference by in-
dapamide with transcellular or intracellular cal-
cium mobilisation (de Wildt and Hillen, 1983).
Also, the effects on calcium current are elicited only
when concentrations of indapamide are used which
exceed by a factor of 50 to 100 the concentration
in human serum required to induce a blood pres-
sure-lowering response. It is not clear whether in-
dapamide interferes directly with potential-de-
pendent or receptor-operated channels responsible
for smooth muscle contraction, or whether it alters
some other process such as the sodium/calcium ex-
change proposed to control smooth muscle relax-
ation (Murphy and Mras, 1983).
Similarly, the in vitro studies concerning the ef-
fect of indapamide on vascular reactivity involved
concentrations of indapamide in excess of what
would appear in human serum during treatment
with this agent (sections 1.4.2 and 2.1), and such
experiments have not been repeated with concen-
trations of indapamideresembling those achieved
clinically.
Studies in man have shown treatment with in-
dapamide to be associated with decreased vascular
reactivity (section 1.4.2) [table II]. In patients with
hypertension, limb vascular resistance, total peri-
pheral resistance and peripheral resistance index
were decreased and muscle blood flow was in-
creased following the administration of indapam-
ide. Although these changes were of statistical
significance, their clinical importance remains
uncertain, particularly since changes in calculated
resistance values are notoriously difficult to attrib-
ute solely to vasodilation or vasoconstriction (Sa-
far et al., 1983; Schlant et al., 1982).
Indapamide has demonstrated considerable ef-
ficacy as an antihypertensive agent in patients with
renal insufficiency and in a small group of patients
with renal failure of sufficient severity as to war-
rant frequent haemodialysis (section 3.1.9). This
211
has been suggested as being supportive of a pri-
marily vascular mechanism of action (Caruso et
aI., 1983; Santoro et aI., 1982) on the premise that
a diuretic antihypertensive agent would be ineffec-
tive in this patient population. Excepting the
patients requiring haemodialysis (a procedure cap-
able of lowering blood pressure through removal
of sodium), the mean creatinine clearance in the
patients with renal insufficiency receiving indap-
amide was approximately 50 ml/min. However,
thiazide diuretics may also lower blood pressure in
patients with creatinine clearances as low as 25 ml/
min (Acchiardo and Skoutakis, 1983); in other
studies, chlorothiazide significantly decreased blood
pressure in patients with a mean creatinine clear-
ance of 14 ml/min (Jones and Nanra, 1979); and
the quinazolinone diuretic metolazone was effec-
tive in the treatment of hypertensive patients with
creatinine clearance as low as 15 ml/min (Bennett
and Porter, 1973).
Although there are some notable differences, the
renal and metabolic effects exerted by indapamide
are similar to many available diuretic agents (sec-
tions 1.1.1 to 1.1.3 and sections 1.3.1 to 1.3.5), and
their blood pressure-lowering abilities are almost
identical (sections 3.1.3 to 3.1.6). Such biochemical
changes are generally not observed with vasodilat-
ing drugs which decrease blood pressure solely due
to their direct effect on vascular smooth muscle,
through inhibition of peripheral or central nervous
system activity, or through inhibition of inward
calcium current in vascular smooth muscle (Mim-
ran et aI., 1983). In addition, the reflexive increase
in sympathetic activity and heart rate usually seen
with direct-acting vasodilating agents (Gunnels,
1982) does not occur during indapamide treat-
ment. However, there is recent evidence (Carretta
et al., 1983) which shows that indapamide inter-
feres with the baroreceptor reflex, and this may ac-
count for the lack of tachycardia at rest seen fol-
lowing treatment with this agent. Thus, whether the
vascular effects of indapamide make an important
contribution to its clinical efficacy in hypertension,
or with usual therapeutic doses are only ancillary
properties, is not yet clear, and requires further
careful study.
Indapamide: A Review
1.7 Toxicology Studies
1. 7.1 Acute Toxicity
Indapamide has a low order of toxicity. Median
lethal doses (LD50) were: 410 to 557 mg/kg intra-
peritoneally and 577 to 635 mg/kg intravenously
in mice; 393 to 421 mg/kg intraperitoneally and
394 to 440 mg/kg intravenously in rats; and 347
to 416 mg/kg intraperitoneally and 272 to 358 mg/
kg intravenously in guinea-pigs. The oral LD50 for
all 3 species of rodent is > 3000 mg/kg, whereas
in dogs it was determined to be ~ 2000 mg/kg
(Kyncl et aI., 1975; Moore et aI., 1977; Pruss and
Wolf, 1983).
1.7.2 Subacute and Chronic Toxicity
Indapamide 25 to 150 mgjkg administered orally
to mice for 2 months and 100 to 300 mg/kg ad-
ministered orally to rats for 3 months was found
to be well-tolerated in these laboratory animals. Al-
though no abnormal organ histology occurred which
was attributable to indapamide, the higher dosage
levels did result in exacerbation of spontaneously
ocsurring renal and cardiac lesions (Moore et aI.,
1977; Pruss and Wolf, 1983).
Studies in mice and rats lasting 21 and 24
months, respectively, failed to demonstrate any
carcinogenic effects from the administration of in-
dapamide 10 to 100 mg/kg/daily (Pruss and Wolf,
1983).
1.7.3 Effects on Reproduction
Indapamide 0.5 to 18 mg/kg/daily neither af-
fected male or female reproductive capacity nor in-
duced teratogenic effects in mice, rats, or rabbits
(Moore et aI., 1977; Pruss and Wolf, 1983). Ma-
ternal treatment with indapamide during ges~tion
did not affect postnatal development in rat or
mouse offspring (Moore et aI., 1977).
2. Pharmacokinetic Studies
The pharmacokinetic properties of indapamide
are linear and independent of dose (Szabadi et aI.,
1982), and have been studied in healthy volunteers
and patients with hypertension following single- or
212
multidose administration, and in patients with renal
insufficiency or failure. There are no studies in
patients with hepatic dysfunction. Large species
differences exist regarding rate of absorption, mag-
nitude of peak plasma concentrations and clear-
ance (Campbell et aI., 1977; Grebow and Treit-
man, 1981). Consequently, caution should be ex-
ercised when pharmacokinetic information from
animal studies is used to supplement information
on the disposition of indapamide in man.
2.1 Absorption and Plasma Concentrations
In pharmacokinetic studies of indapamide,
blood, plasma, or urine concentrations have most
often been determined by use of an accurate and
specific spectrofluorometric assay (Grebow et aI.,
1977). In addition, a high-performance liquid chro-
matographic assay has recently been developed
(Choi et aI., 1982) which has the advantages over
the spectrofluorometric method of internal stan-
dardisation and easier handling. The correlation
coefficient between these two assay procedures has
been determined to be 0.97 (Choi et aI., 1982).
Absorption was rapid and complete following
single-dose administration of radio1abelled indap-
amide 5 or 10mg to healthy volunteers; mean peak
plasma indapamide concentrations of 43 and 140
ILg/L, respectively, occurred within 0.5 hour of
administration (Campbell et aI., 1977; Klunk et aI.,
1983). However, in another single-dose study (Sza-
bodi et aI., 1982), indapamide 2.5, 5.0 and IOmg
resulted in peak whole blood concentrations of 113,
236, and 536 ILg/L, respectively, which were sig-
nificantly (p < 0.001) dose-related and occurred 2.1
to 2.7 hours after administration. In the study by
Klunket aI. (1983), peak plasma indapamide con-
centrations remained relatively constant for 8 hours
following administration, and about 93% of the
radiolabelled drug was recovered, indicating high
bioavailability. The bioavailability of indapamide
was not significantly reduced when taken with food
or antacids (milk of magnesia or aluminium hy-
droxide gel) [Caruso et aI., 1983].
In healthy subjects, steady-state blood concen-
trations of 89.7 and 158.5 ILg/L were attained after
Indapamide: A Review 213

4 daily doses (88 hours) of2.5 or 5mg, respectively
(Szabadi et aI., 1982). Campbell et al. (1977) re-
ported proportionately lower steady-state plasma
concentrations which ranged from 20 to 50 p.gjL,
but these were measured 3 days after the com-
mencement of treatment (fig. 5). Steady-state blood
concentrations of indapamide appear to be inde-
pendent of bodyweight (Campbell et aI., 1977).
2.2 Distribution
A preliminary report of an in vitro study where
a rat hindquarter preparation was perfused with a
protein-free solution containing 14C-labelled in-
daparnide indicated that indapamide accumulates
in vascular smooth muscle in concentrations 10 and
2.5 times greater than in the protein-free perfusate
or skeletal muscle, respectively (Campbell et al.,
1977).
Within 5 minutes after the in vitro incubation
of washed human red blood cells with 14C-indap-
amide and over the first hour following the intra-
venous injection of 14C-indapamide in beagle dogs,
the red cell to plasma radioactivity ratios were as
high as 9: 1 (Campbell et aI., 1977). In human
volunteers, 14C-indaparnide 5mg resulted in a
blood/plasma radioactivity ratio of 5.7 : 1 at peak
concentrations (Klunk et al., 1983). These studies
indicate that indapamide preferentially binds to red
blood cells. The drug binds to the carbonic anhy-
drase fraction in a competitive and reversible man-
ner. This association with indapamide does not
significantly inhibit carbonic anhydrase activity,
although 98% of the total red blood cell indapa-
activity between the control rats and the rats with
reduced haematocrits. Apparently, when haema-
tocrit is altered, identical plasma indapamide con-
centration determinations may not reflect identical
amounts of drug in the body (Lettieri and Portelli,
1983).
Indaparnide is approximately 76 to 79% bound
to human plasma proteins (Campbell et aI., 1977;
Klunk et aI., 1983). The specific protein(s) in-
volved in binding have not been identified (Camp-
bell, 1980).
The indapamide volume of distribution is large,
and has been estimated from blood concentrations
to be 25 to 27L (Grebow et al., 1982; Klunk et aI.,
1983). The volume of distribution estimated from
plasma concentrations was llOL (Campbell et al.,
1976, 1977).
2.3 Metabolism and Elimination
In man, the major route of indapamide elim-
ination is the urine, where 60 to 70% of an orally
administered dose is excreted (Campbell et al.,
1976, 1977; Klunk et al., 1983). Up to 7.3% of the
administered dose is eliminated unchanged,
whereas the remainder of the dose is excreted as
CD
50
"C
'e
~:::J 40
"'-
"COl

mide is bound to this enzyme (Campbell et al.,

.5.5
"'e: 30-
5:8
.0. •
1977). In vitro, the red blood cell binding of in- '" I!! 20-
0.1:
dapamide was shown to be substantially decreased e: CD
CD c:
'" 0
by chlorthalidone or acetazolamide, each of which ~8 10-
have greater affinity for the binding site (Lettieri
and Portelli, 1983). In the same study, the effect
ef reduced haematocrit on red blood cell binding 6 8 10 12
2Time (days)
"
of indapamide in rats was found not to be as sig-
nificant as might be expected. Although whole
blood concentrations were lowered (p < 0.05) in Fig. 5. Mean concentrations of drug in plasma following the
the rats with reduced haematocrits, there were no administration of indapamide 2.5mg dally to 6 healthy volunteers
significant differences in plasma levels of radio- [adapted from Campbell et al. (1977)).
Indapamide: A Review
metabolic products (Campbell and Phillips, 1974;
Campbell et aI., 1977; Klunk et al., 1983). Klunk
et aI. (1983) detected at least 5 metabolites in ad-
dition to unchanged drug in the urine of volunteers
administered 5mg of 14C-labelled indapamide.
18.3% of the urinary radioactivity was due to the
presence of glucuronide and sulphate conjugates of
indapamide. In other studies, 14 to 19 metabolic
products have been detected in the urine of patients
treated with indapamide (Campbell et aI., 1977;
Taylor et aI., 1976). Most of these metabolites were
generated in small proportion to the others: only
5 were shown to individually account for greater
than 10% of the urine radioactivity (or 5% of the
total radioactivity of the administered dose) [Tay-
lor et aI., 1976]. The pharmacological activity of
the metabolites has not been reported.
The mean peak urinary excretion rate following
a single dose of indapamide 40mg was approxi-
mately 3 #£g/min (Campbell and Phillips, 1974).
Peak urinary excretion following oral administra-
tion has been reported as 3 hours for unchanged
indapamide (Campbell and Phillips, 1974), and as
6 to 8 hours for the total radioactivity, while max-
imum urinary flow occurs at a mean of 6 hours
after dosage (Klunk et al., 1983). Mean renal clear-
ance estimates (of total radioactivity following 14C_
indapamide) of 5 to 8.6 ml/min have been calcu-
lated (Campbell et al., 1977; Klunk et aI., 1983).
Since human glomerular filtration rates normally
range from 105 to 150 ml/min (Wallach, 1978b),
such a low clearance indicates extensive renal tu-
bular reabsorption (Campbell et al., 1977). The
reabsorption characteristics of indapamide are due
to its comparatively high lipid solubility [pKa =
8.3; octanol phosphate buffer partition coefficient
at pH 7.4 and 31" C is 31.7 (Campbell et al., 1977;
Caruso et aI., 1983)] conferred upon the molecule
by the side chain methylindoline substitution
(Campbell and Phillips, 1974). The renal clearance
estimate for unchanged indapamide is low (1.71
ml/min), reflecting the importance of hepatic clear-
ance (23.8 ml/min) in the determination of the es-
timated total systemic clearance (20 to 23.4 ml/
min) [Grebow et al., 1982; Klunk et aI., 1983].
Human faecal elimination of indapamide ac-
214
counts for 16 to 23% of an orally administered dose
(Campbell et aI., 1976, 1977; Klunk et aI., 1983).
The presence of metabolic products in the faeces
suggests that they are at least of molecular weight
500 or greater. Since the molecular weight of in-
dapamide is only 375, the metabolites are probably
glucuronide and sulphate conjugates (Campbell et
aI., 1977).
In rats, only a minor fraction of an admini-
stered dose of indapamide has been demonstrated
to undergo reabsorption via the enterohepatic cir-
culation (Klunk and Mangat, 1980), and no evi-
dence was found to indicate that indapamide is
capable of induction of mixed-function oxidases
(Klunk et al., 1981).
2.3.1 Elimination Half-Life
In healthy volunteers administered single doses
of indapamide 5 to 40mg, the plasma concentra-
tions of drug have undergone a biphasic pattern of
decline, with a terminal phase half-life of 13.9 to
17.8 hours (Campbell and Phillips, 1974; Campbell
et aI., 1976; Grebow et aI., 1982; Klunk et al., 1983).
Repeated-dose pharmacokinetics of indapamide
have also been studied in healthy volunteers
(Campbell et aI., 1977). Upon discontinuation of
administration of indapamide 2.5mg daily for 15
days, plasma concentrations of the drug declined
with an estimated elimination half-life of 17 hours.
2.4 Pharmacokinetics in Altered Renal
Function
Intravenous administration of 14C-labelled in-
dapamide to anephric dogs resulted in plasma
elimination of indapamide which was similar to
that of dogs with intact renal function. When the
renal route of excretion was eliminated, total body
clearance for indapamide and its metabolic prod-
ucts was not significantly changed; excretion of the
radioactivity was apparently shifted to the biliary
route (Klunk et aI., 1982).
Indapamide 2.5mg daily was administered to
patients with hypertension and varying degrees of
renal insufficiency in the 6-week study of Ac-
chiardo and Skoutakis (1983) [see also Berger et al.,
Indapamide: A Review
1982]. Patients with normal renal function were also
studied, and mean creatinine clearance for the nor-
mal, mildly impaired, moderately impaired, and
severely impaired patient groups were 100, 58, 44,
and 15 ml/min, respectively. In patients with nor-
mal renal function, whole serum indapamide con-
centrations ranged at the steady-state from 185 j.Lg/
L 2 hours after dosage to 76 j.Lg/L 24 hours after
dosage, whereas drug concentrations from patients
with renal insufficiency ranged from 234 j.Lg/L 2
hours after dosage to 127 j.Lg/L at 24 hours. No
correlations were found between whole blood in-
dapamide concentration or decrease in arterial
pressure and degree of renal impairment. Indapa-
mide did not accumulate significantly in these
patients or in functionally anephric patients with
hypertension undergoing frequent haemodialysis
who were administered 2.5mg daily for 4 weeks
(Acchiardo and Skoutakis, 1983). In the latter
patients, steady-state indapamide blood concentra-
tions ranged from approximately 50 to 100 j.Lg/L,
and indapamide was shown not to be removable
by haemodialysis (see sections 1.1.1 and 3.1.9).
3. Therapeutic Trials
The antihypertensive effectiveness of indapa-
mide has been assessed primarily in open and pla-
cebo-controlled trials in patients with mild to mod-
erate essential hypertension (sections 3.1.1 and
3.1.2). In addition, the diuretic efficacy of indap-
amide has been studied in a relatively small num-
ber of patients with oedema of cardiac or hepatic
origin (section 3.2).
The study design of the therapeutic trials often
included single- or double-blind techniques, treat-
ment crossover, random allocation of treatment,
and placebo 'run-in' phases - all included to min-
imise bias in the study results. However, the meth-
ods used to evaluate 'response' to indapamide have
been highly variable from study to study. Often,
the occurrence of symptomatic improvement was
combined with blood pressure response to for-
mulate a final 'efficacy rating'. Indeed, some symp-
toms (morning headache, depression, blurred vi-
sion and to a lesser extent faintness and nocturia)
215
have been identified as occurring with greater fre-
quency in untreated patients with hypertension than
in non-hypertensive subjects. However, there are
no specific symptoms of mild or moderate hyper-
tension (Bulpitt et aI., 1976). Therefore, the valid-
ity of many of these 'efficacy ratings' may be in
considerable doubt. Accordingly, the response rates
mentioned in this review are based solely upon
blood pressure responses.
The terms 'mild', 'moderate', and 'severe'
hypertension are widespread in this review, and re-
spectively refer to diastolic blood pressure ranges
of 90 to 104, 105 to 129 and ~ 130mm Hg, unless
otherwise specified.
3.1 Use in Hypertension
3.1.1 Open Studies
In hypertensive patients (usually with mild to
moderate hypertension) treated in published re-
ports of open studies, indapamide 2.5mg daily for
I to 12 months reduced resting systolic and dia-
stolic pressures by about 15 to 18% (table IV). In
2 studies (Naegel et aI., 1975; Rodat, 1975), effort
systolic and diastolic pressures were decreased by
approximately 10 to 16%.
In these uncontrolled studies, the patient groups
were predominantly (55 to 60%) female, and mean
patient age generally ranged from 52 to 61 years.
In several of the studies (Brun and Grunwald, 1976;
Naegel et aI., 1975; Reyes et aI., 1983a; Rodat,
1975), patient dietary sodium intake was restricted
at least to some degree, whereas the patients of Is-
sac et ai. (1977) were allowed ad lib sodium intake.
Several studies (Brun and Grunwald, 1976; Issac
et aI., 1977; Marais, 1981; Naegel et aI., 1975; Ro-
dat, 1975) permitted patients with severe or re-
sistant hypertension to continue previous anti-
hypertensive medications, including a-methyldopa,
guanethidine or dihydralazine. Following indapa-
mide 2.5mg daily for I month, Mimran et al. (1981,
1983) added a i3-adrenergic blocking agent to the
drug regimen of patients who had not achieved
blood pressure 'control' with indapamide alone
(approximately 10% of total patient group). When
combined treatment was administered to these
Indapamide: A Review 216

Table IV. Summary of open efficacy studies of indapamide 2.5mg daily in essential hypertension

Reference Severity of hypertension Study duration Blood pressure reduction (%)a

[total no. of pts]
erect supine otherb

Baba et al. (1982)C Mostly mild (49) or moderate 6 weeks-1 year 19/17
(27) (67 pt treated for 1
[79] year)

Brun and Grunwald Moderate (26) and severe 3 months 13/14 14/14
(1976) (15)
[41]

Caretta et al. (1983) All pts MAP> 105 3 months 17

[10]

Issac et al. (1977) MoStly moderate 4.5 months (mean) 13/9

[20]

Marais (1981) All pts BP ~ 150/90 12 weeks 23/20

[387]

Mimran et al. (1981, All pts DBP > 95 mean BP 3 months 17/17 17/17
1983) (erect) 186/105
[2184]

Naegel et al. (1975) Mostly moderate (15) or 5 weeks 12/15

severe (22) 15/16
[40]

Reyes et al. (1983a) All pts DBP (supine) 100-140 8 weeks 22/15 24/13
[10]

Rodat (1975) Mean BP (erect) 191/105 1-3 months (17 pts) 16/28 16/16
(supine) 187/104 6 months (21 pts)
[50l d 8-12 months (12 pts)

a Reduction expressed as percent decrease from pretreatment values; systolic/diastolic, or mean arterial pressure (MAP).
b Percentage reduction in systolic/diastolic pressures (seated) or in mean arterial pressure.
c Patients treated with indapamide 1 to 3mg daily.
d One patient believed to have hypertension secondary to renal causes.
Abbreviations: MAP = mean arterial pressure; BP = blood pressure; DBP = diastolic BP.

patients, mean diastolic blood pressure was de-
creased by 18mm Hg. In the study reported by
Marais (1981), 264 of the 387 patients achieved
'normalisation' of blood pressure on indapamide
alone: approximately 69% of the patients with mild
to moderate hypertension, and 40% of those with
severe hypertension.
In the trial with the largest patient population
(2184; Mimran et al., 1981, 1983), normalisation
of blood pressure occurred most frequently be-
tween the first and second month of indapamide
treatment. In this study, the antihypertensive ef-
ficacy and the tolerability of indapamide did not
appear to be influenced by the age or sex of the
patients, although the higher the untreated blood
pressure before the initiation of indapamide, the
greater the blood pressure reduction.
Overall effectiveness ratings were generally based
upon the ability of indapamide to reduce diastolic
blood pressure to 90 to 95mm Hg or less, although
ocular changes or functional symptoms were con-
sidered in some studies (Brun and Grunwald, 1976).
In the multicentre trial reported by Marais (1981),
indapamide was approximately 82% 'effective' in
Indapamide: A Review 217

the treatment of 189 patients with mild (diastolic
90 to 110mm Hg) hypertension: a single daily dose
of 2.5mg was the sole agent used in 154 of these
patients. This degree of effectiveness was similar
to that noted in other open studies (Baba et aI.,
1982; Mimran et aI., 1981, 1983; Naegel et al., 1975;
Rodat, 1975), where 'effective' ratings ranged from
approximately 70 to 80%. _ ation, although extremes of 7 days and 6 weeks did
Of the 60 patients of Baba et al. (1982) with
diabetes mellitus, only 4 exhibited decreased glucose
tolerance while taking indapamide, and none of the
467 patients of Mimran et ai. (1981, 1983) with
elevated (> 6.05 mmolfL) pretreatment fasting
blood sugars appeared to be affected when fasting
blood glucose concentrations were repeated at 3
months.
3.1.2 Comparisons with Placebo
Unblinded Comparisons
Indapamide has been compared with placebo
treatment in a large number of short to long term
(1- to 24-month) studies which have usually in-
volved small (10 to 30) numbers of patients with
mild or moderate essential hypertension. In such
studies, indapamide (usually 2.5mg daily) was
clearly more effective than placebo treatment, most
often lowering systolic and diastolic pressures or
mean blood pressure by 10 to 20% more than
placebo.
Generally, these comparisons involved patients
ranging in age from 40 to 60 years, and male and
female patients were equally represented. Placebo
treatment periods were usually 2 or 4 weeks in dur-
occur. In most studies, indapamide was used as the
sole antihypertensive agent; however, 4 of the 19
patients of Jorge and Perello (1980) were treated
with other agents [a-methyldopa, a is-adrenergic
blocker (atenolol or propranolol), or clonidine). In
another study, patients showing an inadequate re-
sponse (diastolic> 100mm Hg) to indapamide
2.5mg daily after 4 weeks were also treated with
nadolol (Houde and Carriere, 1983).
Of the 644 patients in the large multicentre trial
of Passeron et ai. (1981), the percentage of re-
sponders (in whom diastolic blood pressure nor-
malised or fell at least 30mm Hg) was 64% follow-
ing 3 months of treatment with indapamide 2.5mg
daily. This response rate was in general agreement
with those of other placebo comparisons, which
ranged from 70 to 90% (Charoenlarp and Jaroon-
vesama, 1981; Goto et aI., 1982; Guidi et aI., 1982;
de Ortiz et aI., 1983; Jorge and Perello, 1980; San-

n = 307 n = 282 220 n = 55

200 200
Cl 180 180 Cl 180
Cl
::c 160 ::c 160 ::c 160
E E 140
S 140 S 120 ~ 140
120 -; 120
~ ~
:::l
If)
100 en 100
:::l
~ 100
en en en 80
~ 80 80
~ 60
.<1)
a. 60 C. 60
'0 '0
0
0
40 0
0
40 "80 40
iIi 20 iIi 20 iIi 20
0 2 3 0 2 3 0 2 3
a Treatment time (months) b Treatment time (months) c Treatment time (months)

Fig.6. Mean systolic (D) and diastolic (II) blood pressure responses in patients with (8) mild [diastolic 90 to l09mm Hgj. (b) moderate
[diastolic 110 to 129mm Hgj. or (c) severe [diastolic ~ 130mm Hgj essential hypertension during treatment with indapamide 2.Smg
daily [data from Passeron et al. (1981)].
Indapamide: A Review 218

Table V. Summary of single- and double-blind placebo comparisons with indapamide in patients with essential hypertension

Reference Severity of hypertension" Study design b Daily Blood pressure Res- Criteria for response
[no. of pts/group] (duration of dose reduction (%)" ponse
active (mg) rate (%)
erect supine
treatment)

Andries et al. I. 176/97 (supine) [42] sb 2.5 17/16 76 Diastolic" 90mm Hg or

(1980) II. 201/116 (supine) [12] (10 months) 22/23 66 decrease in diastolic ~
III. 211/135 (supine) [5] 24/27 100 20mm Hg

Beling et al. 149/102 (erect) db. r, co 2.5 9/20 11/10 56 Diastolic < 90mm Hg or
(1983) 151/97 (supine) [260] (40 weeks) decrease in diastolic ~
10mm Hg (erect)

Capone et al. I. 157/103 (erect) db,co 1.0 9/6 9/5 33 As above

(1983) 157/100 (supine) (8 weeks)
II. 148/102 (erect) 2.5 10/8 9/6 43
150/98 (supine)
III. 152/102 (erect) 5.0 9/1 9/1 40
152/99 (supine) [87]

Casar (1977) 179/113 (erect) db, co 2.5 5/6 9/1

171/111 (supine) [10] (8 weeks)

Hamilton and I. 166/109 (erect) sb,co 2.5 Erect systolic and

Kelly (1977) 172/109 (supine) [14] (12 weeks) 12/14 16/20 50 diastolic pressures in
II. 158/104 (erect) ranges of 120-140 and
168/106 (supine) [10] 16/15 11/14 70 80-1oomm Hg

Horgan et al. 170/108 (erect) sb 2.5 15/13 13/17

(1981) 152/100 (supine) [17] (24 weeks)

Lenzi and Di 192/110 (erect) db,co 2.5 16/15 14/13

Perri (1977) 190/109 (supine) [47] (8 weeks)

O'Brien et al. 176/111 (erect) db,co 2.5d 11/8 10/9

(1984) 184/109 (supine) [24] (8 weeks)

Turner et al. 169/109 (erect) sb.co 2.5 22/15 18/18 60 As in Hamilton and Kelly
(1977) 175/105 (supine) [10] (12 weeks) (1977)

Van Hee et al. 197/112 (erect) sb 2.5 20/18 19/12

(1981) 198/110 (supine) [24] (2 months)

Velasco et al. 168/107 (erect) db, r 2.5 17/11 10/8

(1980) 167/109 (supine) [20] (8 weeks)

Whately and 180/104 (erect) sb,co 2.5 10/10 13/16 87.5° Very good response >
Heraty 184/103 (supine) [8] (12 weeks) 30mm Hg decrease in
(unpublished) diastolic pressure. Good
response 10-3Omm Hg
decrease

a Mean blood pressure (systolic/diastolic) following placebo treatment.

b = =
sb single-blind; db double-blind; r = randomised; pi = placebo-controlled; co =
crossover.
c Data shown are the additional blood pressure reductions over and above the placebo response; systolic/diastolic.
d All patients were administered oxprenolol160 to 480mg daily before and throughout the placebo comparison, and were consid-
ered oxprenolol 'failures' (diastolic pressure remaining > 95mm Hg).
e Very good response in 4 pts; good response in 3 pts.
Indapamide: A Review 219

toro et aI., 1982); a notable exception was the re-
sponse rate (2/13; 15%) of the patients studied by
Fernandes et ai. (1977), where the low (0.5 or
1.0mg) daily doses of indapamide probably pre-
vented optimum blood pressure responses.
The patients of Passeron et ai. (1981) were di-
vided into 3 groups according to pretreatment blood
pressures, and were monitored at monthly inter-
vals over the 3-month course of indapamide treat-
ment. In the 307 patients with mild hypertension
(fig. 6a), mean blood pressures normalised follow-
ing 1 month of therapy with indapamide 2.5mg
daily, while the patients with moderate (fig. 6b) and
severe (fig. 6c) hypertension showed their largest
declines in systolic and diastolic pressures after 2
and 3 months of treatment. Similarly, in the stud-
ies of Bam and Bouwer (1983) and Dunn et ai.
(1981), the antihypertensive effect of indapamide
appeared during the first month, increased during
the second, and stabilised during the third month
of treatment. In contrast to these findings, the
patients of Bhalla (1981) exhibited their maximum
antihypertensive response to indapamide during
their first month of treatment. The antihyperten-
sive effect of indapamide was sustained during up
to 24 months of continuous treatment in a recent
placebo comparison (Scalabrino et aI., 1984).
Single- and Double-Blind Comparisons
In blinded, parallel group and crossover com-
parisons of indapamide and placebo, the ami.-
hypertensive response to indapamide has been
consistently better than that with placebo (table V).
Systolic and diastolic blood pressures (erect and
supine) were generally reduced 10 to 20% from pla-
cebo levels, with 'response' rates usually falling
within the 50 to 75% range. The dose of indapa-
mide was most often 2.5mg daily, but Capone et

170

160

aJ:
E 150
S
~
:I
II) 140
II)

~
c-
"0
0 130
0
:0
]!
CD 120
t::
as
c:
as
Q)
n = 12
~ 110
n = 42

100
B P 2 3 4 5 6 7 8 9 10
Treatment time (months)

Fig. 7. Mel'!'l arterial pressure response in patients with mild [diastolic 90 to 109mm Hg (0-0)]. moderate [diastolic 110 to 129mm Hg
(~)]. or severe [diastolic;;' 130mm Hg (0--0)] hypertension administered indapamide 2.5mg daily (8 = baseline; P = placebo)
[data from Andries et al. (1980)].
Indapamide: A Review 220

Table VI. Summary of comparative studies between indapamide (ID) and selected benzothiadiazide diuretic agents in the treatment
of patients with essential hypertension

Reference Severity of hypertension" Study design b Daily doses Blood pressure response Relative
[no. of pts) (study duration) (mg) (% decrease)!l efficacyh

erect supine MAP

Comparisons with hydrochlorothiazide (HCTZ)

Coutinho et al. 'Mild to moderate' unb ID 2.0 -8.1 ID 2.0mg =
(1980) (120) (12 weeks) ID 2.5 -9.1 ID 2.5mg =
HeTZ 100 -6.2 HeTZ l00mg

Feldstein et al. BP - ID group (erect) 178/ db, r, pi ID 2.5 17/13 14/12 ID 2.5mg
(1981) 108, (supine) 177/103 (6 weeks) HeTZ 50 3/13 9/4 ,., HeTZ 50mg
BP - HeTZ group (erect)
173/98, (supine) 177/96
(36)

Lemieux and BP (supine) 208/128 pi ID 2.5 35/33 ID 2.5mg ~

L'Homme (1983) (26) (4 months)" HeTZ 50 29/27 HeTZ 50mg

Morledge (1983) BP (erect) 153/102 db, r, pi, co ID 2.5 26/16 ID 2.5mg,.,

BP (erect) 152/101 (40 weeks) ID 5.0 15/16 ID 5mg =
BP (erect) 151/101 HeTZ 50 15/17 HeTZ 50mg
(26)

Noble et al. (1983) BP - ID group (erect) db, pi ID 2.5 11/12 ID 2.5mg =

159/110 (8 weeks) HeTZ 50mg
BP - HeTZ group (erect) HeTZ 50 15/23
165/111
(29)

Ogilvie et al. BP (erect) 150/96 db, r, pi, co ID2.5 9/6 ID 2.5mg ..

(1983) (17) (3 months)d HeTZ 50 9/5 HeTZ 50mg

Plante and BP - ID group (erect) 139/ db, pi ID 2.5 9/14 8/11 ID 2.5mg,.,
Robillard (1983) 98, (supine) 138/93 (12 weeks) HeTZ 50mg
HeTZ group (erect) 150/98, HeTZ 50 7/8 5/4
(supine) 147/93
(24)

aI. (1983) also used I and 5mg daily doses and 18
of the 24 patients of Van Hee et aI. (1981) main-
tained excellent blood pressure control (decreases
in supine systolic and diastolic pressures of 19 and
15%, respectively) on indapamide 2.5mg every
other day following 2 months of daily administra-
tion.
Although the antihypertensive effect of indap-
amide was fully manifest in 4 to 6 weeks in several
of the blinded placebo comparisons (Capone et aI.,
1983; Lenzi and Di Perri, 1977; O'Brien et aI.,
1984), one group of patients had blood pressure
reductions which 'stabilised' only after 4 months
of treatment, regardless of the pretreatment sever-
ity of hypertension (Andries et aI., 1980) [fig. 7].
Most of these studies were relatively short term (8
to 12 weeks); however, the long term trials of An-
dries et aI. (1980) and Beling et al. (1983) [10
months] further demonstrate that indapamide is
capable of inducing a sustained blood pressure re-
duction in most patients treated.
3.1.3 Comparisons with Hydrochlorothiazide
In parallel group and crossover comparisons,
Indapamide: A Review 221

Table VI. (contd)

Reference Severity of hypertension" Study design b Daily dose" Blood pressure response Relative
[no. of pts) (study duration) (mg) (% decrease)9 efficacyh

erect supine MAP

Comparisons with bendrofluazide (BDR)

Bing et al. (1981) BP (erect) 164/100. (supine) r ID2.S 16/8 12/7 10 2.5mg =
160/92 (16 weeks) BDR S 14/8 8/4 BDR Smg
[15)

Zacharias (1981) BP (supine) 171/100. db. r. pl. co ID2.S 9/10 10 2.Smg =

181/102 (12 weeks) BDR S 13/9 BDR Smg
[16)

Comparisons with cyclopenthiazide (CYC)

James et al. (1981) BP (supine) 165/102. r. co ID2.S1 I. 8/6 10 2.Smg >
167/111 (2 weeks)d II. S/8 eye O.Smg
[44) eye O.SI I. 1/4
11.9/2

Khan (1981) BP - 10 group (erect) r. pi ID2.S 15/2 10 2.5mg ~

198/110 (6 months) eye O.Smg
BP - eye group (erect) eye O.S 3/7
194/107
[19)

a Mean systolic/diastolic pressures (mm Hg) [BP= blood pressure).

b pi = placebo-controlled; db = double-blinds r = randomised; co = crossover; unb = unblinded.
c Duration of indapamide treatment. Hydrochlorothiazide administered ~ 6 months.
d Duration of treatment with each agent.
e Hydrochlorothiazide was administered in a divided daily dose in the study of eoutinho et al. (1980).
f I signifies drug was the first agent administered in this crossover study; II signifies use of the drug as second agent.
9 Blood pressure response (systolic/diastolic) expressed as percentage decrease from pretreatment or placebo pressures. Data
of eoutinho et al. (1980) expressed as decrease from pretreatment mean arterial pressure (MAP) [mm Hg).
h Statement of relative efficacy based upon antihypertensive effect only.

indapamide 2.5mg daily demonstrated antihyper-
tensive efficacy essentially equal to that of hydro-
chlorothiazide 50mg daily (Morledge, 1983; Noble
et aI., 1983; Ogilvie et aI., 1983; Plante and Rob-
illard, 1983) or 100mg daily (Coutinho et aI., 1980)
[table VI]. In one partially retrospective study
(Lemieux and L'Homme, 1983), indapamide in-
duced a statistically greater decrease in blood pres-
sure although the difference was not necessarily
clinically important. Similarly, indapamide 2.5mg
daily showed statistically significant superiority
over hydrochlorothiazide 50mg daily in the study
of Feldstein et aI. (1981); however, randomisation
of patients (re: placebo blood pressures) [see table
VI] did not appear to be satisfactory. The patients
in these studies had mild to moderate hyperten-
sion, with the exception of the majority of those
studied by Lemieux and L'Homme (1983) and No-
ble et aI. (1983), where mean pretreatment dia-
stolic pressures were 129 and Illmm Hg, respec-
tively. Following the administration of indapamide
2.5mg or hydrochlorothiazide 50mg daily for 1
month, the patients of Noble et al. (1983) not re-
sponding (diastolic ~ 90mm Hg) were placed on
methyldopa as a 'second line' medication (starting
at 250mg twice daily, and titrated to a dose not
exceeding 3000mg daily). Amongst the patients who
required the addition of methyldopa to achieve ad-
Indapamide: A Review
equate blood pressure control (n = 10, both groups),
those receiving indapamide 2.smg daily required a
significantly smaller average dose than those re-
ceiving hydrochlorothiazide sOmg (1100 vs Is7smg,
p < 0.05). In the study of Lemieux and L'Homme
(1983), 11 patients also took reserpine and 9
patients took methyldopa, a ~-blocker or guaneth-
idine in addition to indapamide or hydrochloro-
thiazide. Antihypertensive agents other than the
study drugs were not used in the other trials.
In these comparisons, side effects which oc-
curred in any treatment group were not severe, and
those which did occur were similar in frequency in
both indapamide- and hydrochlorothiazide-treated
patients. Neither agent significantly reduced heart
rate (Feldstein et aI., 1981; Noble et aI., 1983; Ogil-
vie et aI., 1983; Plante and Robillard, 1983). The
decrease in serum potassium concentrations with
indapamide and hydrochlorothiazide were of equal
magnitude. The patients of Plante and Robillard
(1983) administered hydrochlorothiazide had a
mean serum potassium concentration (3.4 mmol/
L) in the hypokalaemic range; however, placebo
serum potassium concentrations were lower in these
patients than in the indapamide group (3.9 vs 4.2
mmol/L).
3.1.4 Comparisons with Bendrofluazide
(Bendroflumethiazide)
Single daily doses of indapamide 2.smg or ben-
drofluazide smg produced similar reductions in
blood pressure in 2 studies conducted in patients
with mild or moderate essential hypertension (Bing
et al., 1981; Zacharias, 1981) [table VI]. The two
diuretic agents were the sole antihypertensive agents
administered to the patients of Bing and co-work-
ers, whereas the patients of Zacharias were admin-
istered atenolol 100 or 200mg daily in addition to
the trial drugs. Indapamide and bendrofluazide in-
duced a mean decrease in bodyweight of approxi-
mately 2.skg, and significantly (p < 0.05) de-
creased serum potassium concentrations in the
patients of Bing et al. (1981), while these para-
meters were not changed in the patients of Za-
charias (1981).
In the study of Bing et al. (1981), 12 patients
222
were continued on a combination of indapamide
2.smg and bendrofluazide smg daily for an addi-
tional 16 weeks. This combination resulted in a
further fall in diastolic pressure [from approxi-
mately 92 to 87mm Hg (erect)], but not in systolic
or mean arterial pressure. Although further in-
creases in plasma renin activity and blood urea were
noted with the combination treatment, no further
decreases in bodyweight or serum potassium oc-
curred compared with either agent alone.
3.1.5 Comparisons with Cyc/openthiazide
In 2 randomised studies, the hypotensive effect
of indapamide 2.smg daily was generally superior
to that of cyclopenthiazide O.smg daily (James et
al., 1981; Khan, 1981) [table VI]. Blood pressures
increased when patients were 'crossed over' from
indapamide to cyclopenthiazide treatment, and de-
creased when indapamide followed cyclopenthia-
zide (James et aI., 1981). As has been noted in other
studies (section 3.1.1), blood pressure response to
indapamide (and cyclopenthiazide) was greatest in
patients with higher pressures on entering the study
(James et al., 1981). Although indapamide was
subjectively assessed as being much more effective
than cyclopenthiazide in the geriatric (mean age 77)
population studied by Khan (1981), blood pres-
sures (systolic only) were significantly lower with
indapamide only on the last patient visit of the 6-
month study.
The frequency of side effects was similar with
both drugs, and side effects were minor in nature.
Although both agents decreased serum potassium
concentrations, neither induced clinical or labora-
tory signs of hypokalaemia (James et al., 1981;
Khan, 1981).
3.1.6 Comparisons with Other Diuretic Agents
In controlled studies, generally of brief dura-
tion, indapamide 2.0 to s.Omg daily was shown to
have equal antihypertensive efficacy compared with
daily administration of a hydrochlorothiazide/ami-
loride combination (Anavekar et al., 1979), chlor-
thalidone loomg (Hatt and Leblond, 1975), meti-
crane 300mg (Ikeda et al., 1982), or chlorothiazide
soomg (Milliez and TcherdakotT, 1975) [table VII].
Indapamide: A Review 223

Pretreatment and placebo systolic and diastolic
pressures were usually decreased 10 to 20% by in-
dapamide and the other diuretics tested. Two of
the studies compared indapamide with other di-
uretics when each was used as the sole antihyper-
tensive agent, but patients in the other 2 studies
(Anavekar et aI., 1979; Hatt and Leblond, 1975)
continued previous non-diuretic therapy (includ-
ing methyldopa, fJ-blockers, guanethidine, cloni-
dine, prazosin and reserpine) throughout the com-
parisons.
In 2 studies (Anavekar et aI., 1979; Milliez and
Tcherdakoff, 1975) neither indapamide nor the
comparison diuretics (hydrochlorothiazide/amilor-
ide, chlorothiazide) significantly affected serum
electrolyte concentrations; however, this was not
the case in other trials. 25 of the 38 patients ofHatt
and Leblond (1975) administered chlorthalidone
required supplemental potassium due to 'severe'
decreases in serum potassium concentrations, while
only 1 of the 38 patients on indapamide needed
potassium supplementation. Of the 161 patients in
the multicentre trial of Ikeda et aI. (1982), 5 patients
administered indapamide became hypokalaemic
(mean decrease of 1.3 mmol/L), whereas only 1
patient treated with meticrane became hypokal-
aemic. Clinical signs or symptoms attributable to
hypokalaemia did not occur in any of these com-
parative studies.
3.1.7 Comparisons with /l-Adrenergic Blocking
Agents. and their Use in Combination
In double-blind, randomised, placebo-con-
trolled studies, the antihypertensive effectiveness

Table VII. Summary of placebo-controlled comparative studies of indapamide and various diuretic agents in the treatment of patients
with essential hypertension

Reference Severity of hypertension" Study design Daily doses Blood pressure response (% Relative
[no. of pts] (study duration) (mg) decrease)b efficacyd

erect supine MAP

Anavekar et al. ID group 172/105 db, r, co ID 2.5 9/12 ID 2.5mg =

(1979) HCTZ/AMRD group (8 weeks)" HCTZ 50/ 11/11 HCTZ 50mg/
173/101 c AMRD5 AMRD 5mg
[20]

Hatt and Leblond BP (supine) 190/102, sb, r, co 105 20/21 17.3 10 5.0mg =
(1975) MAP (supine) 127 (45 days)" CHLR 100 20/17 15.8 CHLR 100mg
[38]

Ikeda et al. (1982) ID group 175/102; db ID2f 14/12 10 2mg =

MTR group 172/103c (12 weeks) MTR 300f 13/13 MTR 300mg
[161]

Milliez and BP 166/103c db, r, co ID 5f.g 7/6 5.7 ID 5mg =

Tcherdakoff MAP 124 (1 month)" CTZ 500mg f.g 4/4 4.0 CTZ 500mg
(1975) [22]

a Mean systolic/diastolic blood pressures or mean arterial pressure (MAP) [mm Hg].
b Blood pressure response (systolic/diastolic) expressed as percentage decrease from placebo.
c Posture during blood pressure assessment not indicated.
d Statement of relative efficacy based upon antihypertensive effect only.
e Duration of treatment with each agent.
f Administered in divided daily dosages.
9 Administered 5 days per week only.
= = = = =
Abbreviations: db double-blind; r randomised; co crossover; sb single-blind; 10 indapamide; HCTZ/AMRD = hydrochloro-
=
thiazide/amiloride combination; CHLR chlorthalidone; MTR =
meticrane; CTZ =
chlorothiazide.
Indapamide: A Review 224

Table VIII. Summary of the relative antihypertensive efficacies of indapamide (10) and fj-adrenoceptor blocking agents when used
alone or in combination in patients with essential hypertension (HTN). All studies of double-blind, randomised, placebo-controlled
design

Reference Severity of Study Daily doses Blood pressure response Relative efficacyd
hypertension" durationb (mg) (% decrease)C
[no. of pts] (weeks) and
erect supine
design

Chalmers et al. BP (erect) 162/101; co 102.5 7/6 7/3 10 2.5mg '" POL
(1982) BP (supine) 164/94 (8 weeks) POL 10 11/8 10/9 10mg

102.5 + 16/10 15/11

POL 10

De Divitiis et al. BP (erect) 178/117; co 102.5 13/14 15/14 10 2.5mg =

(1983) BP (supine) 189/115 (4 weeks) ATN 100 14/16 18/16 ATN 100mg
[15]

102.5 + 24/21 25/22

ATN 100

Kubik and Coote BP (erect) 169/109; (8 weeks) 102.5 11/9 8/6 ID 2.5mg =
(1981) BP (supine) 168/105 MPL 200· 12/10 11/12 MPL 200mg
[27]

102.5 + 17/16 16/16

MPL 200·

Rumboldt et al. BP - 10 group:' co 102.5 13/17 11/12 10 2.5mg =

(1984) (erect) 158/108; (6 weeks) POL 15 11/14 12/14 POL 15mg
(supine) 161/105
BP - POL group:'
(erect) 160/108;
(supine) 163/106

a Mean systolic/diastolic blood pressure during placebo treatment (mm Hg).

b Duration of each treatment phase, excluding placebo.
c Expressed as percentage decrease from placebo blood pressure; systolic/diastolic.
d Statement of relative efficacy based upon antihypertensive effect only.
e Administered in a divided daily dose.
Placebo blood pressures listed were those recorded following the first placebo phase.
Abbreviations: co = crossover; ATN = atenolol; POL = pindolol; MPL = metoprolol; BP = blood pressure.

of indapamide 2.5mg daily was shown to equal that
of pindolo1 10 or 15mg daily (Chalmers et al., 1982;
Rumboldt et aI., 1984), atenolol 100mg daily (De
Divitiis et aI., 1983), or metoprolol 200mg daily
(Kubik and Coote, 1981) [table VIII]. In these 4
studies, indapamide generally decreased diastolic
pressures 6 to 14%, while ,B-adrenergic blockade re-
suited in diastolic pressures 7 to 16% below pla-
cebo values. The combination of indapamide with
a ,B-adrenergic blocker was always more effective
in decreasing diastolic pressures than either agent
used alone, with 10 to 20% decreases being most
common. A factorial analysis following the study
of Chalmers et al. (1982) revealed that the hypo-
Indapamide: A Review
tensive effects seen in the combination therapy
phase represented simple addition of the separate
effects of the two drugs. A 'response' rate of 67%
with combined therapy with indapamide and at-
enolol, compared with 47% with either drug alone,
was reported by De Divitiis et al. (1983) when re-
sponse was defined as a lowering of diastolic pres-
sure to ~ 95mm Hg.
As might be expected, each of the l3-antagonists
compared with indapamide induced a decrease in
heart rate (usually 5 to 10 beats/min) when used
alone or in combination. When indapamide was
used as the sole antihypertensive agent, significant
decreases in heart rate were not reported.
The biochemical parameters assessed by De
Divitiis et al. (1983) following indapamide and/or
atenolol treatment were not significantly altered;
however, this was not the case in the other com-
parisons. Increases in serum uric acid and blood
carbon dioxide content and decreases in serum po-
tassium and chloride were reported following the
use of indapamide as a single agent. In addition,
metoprolol was responsible for highly significant
increases in serum sodium and bilirubin, while
pindolol increased plasma urate concentrations.
Although all of these changes were of statistical sig-
nificance, no biochemical parameter in any of the
3 studies deviated from the normal range.
Indapamide 2.5mg daily for 8 weeks further de-
creased mean systolic and diastolic blood pressures
by approximately 10% in 24 patients who had an
inadequate antihypertensive response (diastolic
pressure remaining> 95mm Hg) to oxprenolol160
to 480mg daily (O'Brien et aI., 1984) [see section
3.1.2 and table V).
3.1.8 Comparison with Methyldopa, and Their
Use in Combination
In a single published report in 71 patients with
mild (diastolic pressure 95 to 109mm Hg, 52
patients) or moderate (diastolic pressure 110 to
120mm Hg, 19 patients) essential hypertension, in-
dapamide 2.5mg daily was essentially equal to
methyldopa 500mg daily in blood pressure-lower-
ing effect (Meine, 1981). After 8 weeks of active
treatment with either agent, indapamide decreased
225
systolic and diastolic pressures about 18% com-
pared with placebo levels, whereas methyldopa in-
duced an approximate 14% decrease. In addition,
the rate of blood pressure response was faster with
indapamide (2 vs 4 weeks for 'normalisation' of
blood pressure to 160/90 or less). Following 8 weeks
of treatment, 50% of the patients on indapamide
had 'normal' blood pressures, while only 22% of
the methyldopa patients had achieved this level of
antihypertensive control.
The antihypertensive efficacy of indapamide in
combination with methyldopa was studied by La
Corte et al. (1980a). 17 patients with hypertension
who had been 'stabilised' on methyldopa 500 to
1000mg daily were randomly placed on indapa-
mide 2.5mg daily or placebo for 6 weeks. The mean
decreases in systolic and diastolic blood pressure
following the addition of indapamide to methyl-
dopa treatment were 19/8mm Hg, indicating the
efficacy of the combination. The agents were well
tolerated during their coadministration.
3.1.9 Use in Patients with
Renal Insufficiency
Although the data are limited, indapamide ap-
pears to have antihypertensive activity in patients
who have renal insufficiency. Additional studies are
necessary to clarify further its efficacy in patients
with various degrees of renal function impairment.
In an open study by Brennan et al. (1982), in-
dapamide 2.5mg daily was substituted for the par-
ticular diuretic (frusemide, chlorthalidone, or a
thiazide) which had previously been administered
to 13 patients. The hypertension and renal insuf-
ficiency of the patient group were poth moderate
in severity (mean pressures, 161/103mm Hg; mean
creatinine clearance 50 ml/min, range 30 to 65 ml/
min). The antihypertensive regimen of each patient
included other agents (i.e. propranolol, methyl-
dopa, guanethidine, hydralazine, clonidine and
prazosin) which were continued throughout· the
trial. After 6 weeks' treatment with indapamide,
diastolic blood pressure measurements were un-
changed from those taken when the other diuretics
had been administered. Although the blood urea
nitrogen and serum creatinine values were un-
Indapamide: A Review
changed, mean creatinine clearance increased to 64
ml/min (p < 0.01), indicating that the blood pres-
sure control was not retained at the expense of renal
function impairment.
In 6 patients with moderate hypertension and
impaired renal function (creatinine clearance < 60
ml/min), indapamide 2.5mg daily for 8 weeks de-
creased systolic and diastolic blood pressures ap-
proximately 13.5% (p < 0.01), while mean serum
concentrations of uric acid and potassium were al-
tered from pretreatment values (from 0.42 to 0.45
mmol/L and from 4.7 to 4.4 mmol/L, respectively;
p < 0.05) [Santoro et al., 1982]. Indapamide 2.5mg
daily was also used as the sole antihypertensive
agent in 29 patients studied by Acchiardo and
Skoutakis (1983) [see also Berger et al., 1982]. While
11 of these patients had normal renal function (cre-
atinine clearance 91 to 110 ml/min), 13 others had
mild to moderate impairment (creatinine clearance
36 to 84 ml/min) and 4 had severely compromised
renal function (creatinine clearance 8 to 27 ml/min).
Regardless of the severity of the renal impairment,
systolic and diastolic blood pressures were de-
creased 5 to 10% after 6 weeks' administration.
Renal function (as measured by creatinine clear-
ance, blood urea nitrogen, and serum creatinine)
was unchanged after treatment with indapamide.
In a separate phase of this single-blind, placebo-
controlled study, Acchiardo and Skoutakis also ad-
ministered indapamide 2.5mg daily to 9 function-
ally anephric and hypertensive patients (mean pre-
dialysis pressures: systolic > 150mm Hg and
diastolic > 90mm Hg) who required frequent
haemodialysis. Over the 4-week treatment period,
pre- and post-dialysis blood pressures were re-
duced 4 to 8% (p < 0.05). However, since the blood
pressure of a dialysis patient may be influenced by
mUltiple factors and the patient groups were small,
it is difficult to conclusively attribute this hypo-
tensive effect solely to indapamide.
Heart rate and bodyweight were not signifi-
cantly changed by indapamide in either study (Ac-
chiardo and Skoutakis, 1983; Brennan et aI., 1982).
The pharmacodynamic and pharmacokinetic prop-
erties of indapamide in patients with renal insuf-
ficiency are discussed in sections 1.1.1 and 2.4.
226
3.2 Use in Oedematous States
In an open study, indapamide was administered
to 22 patients with oedema secondary to conges-
tive heart failure or cirrhosis (Goldberg and Fur-
man, 1974). 10 of the patients with congestive heart
failure responded well to indapamide 20mg daily,
with a mean weight loss of 4. 7kg over 5 days. Two
patients with cirrhosis and 6 patients with conges-
tive heart failure and severe chronic renal failure
(creatinine clearance ~ 16 ml/min) did not re-
spond to daily dosages of 20mg, and 40 to 300mg,
respectively.
A comparative study of indapamide 30 or 50mg
daily with frusemide 40mg twice daily in 15 patients
with oedema due to cirrhosis or congestive heart
failure was conducted by Leary et al. (1974).
Throughout the 72-hour study, daily urinary out-
put (approximately 2 to 3L) and mean total weight
loss (about 3 to 6kg) were not significantly different
between the two treatment groups.
In 214 patients with oedema due mainly to un-
known causes, congestive heart failure or liver dis-
ease, the diuretic efficacy of indapamide 2.5, 5.0
and lO.Omg daily was found to be similar to that
of hydrochlorothiazide 100mg daily (Slotkoff,
1983). In this double-blind trial, the usual diuretic
regimen of each patient was withdrawn and indap-
amide or hydrochlorothiazide was instituted when
pretibial oedema had increased by ~ 4mm and/or
when the patient had gained 1.8kg. Following up
to 12 weeks of study, no difference was found
among the 4 treatment groups regarding improve-
ment of pitting oedema scores (36 to 41% improve-
ment) or weight loss (average 2.6kg). Hypokalae-
mia was the most frequently noted adverse reaction,
being reported in 25 to 40% of patients in each
group. Eight of the 15 patients who withdrew from
the study due to side effects had been administered
indapamide 10mg daily and had withdrawn due to
symptoms associated with hypokalaemia (weak-
ness, leg cramps) and hypovolaemia (orthostatic
dizziness).
Thus, although the use of indapamide to reduce
sodium and water retention appears promising, de-
finitive statements regarding its place in the treat-
Indapamide: A Review
ment of oedematous states must await longer term
studies in larger patient groups.
4. Side Effects
Approximately 25% of the clinical trial reports
involving indapamide have stated that no side ef-
fects occurred during treatment, while an addi-
tional 25% have not addressed the subject of side
effects at all. The incidence and severity of indap-
amide-induced hypokalaemia has been reasonably
well documented, but little descriptive information
regarding other side effects of indapamide has been
reported. In comparative studies (sections 3.l.3 to
3.1.8), the frequency or severity of side effects
caused by indapamide was similar to or,
in some cases, less than those of several benzo-
thiadiazide diuretics, i3-adrenergic blockers and
methyldopa.
Most of the electrolyte and metabolic derange-
ments indapamide can induce occur only occa-
sionally and have been discussed in section l.3.
4.1 Hypokalaemia
As previously discussed (section l.3.1), the
administration of indapamide has resulted in sta-
tistically significant decreases in mean serum po-
tassium concentrations in approximately 75% of
published reports. Despite these decreases, most
patient groups have maintained mean potassium
concentrations within normal physiological limits.
The clinical significance of such mild diuretic-in-
duced changes in potassium balance is controver-
sial (Perez-Stable and Caralis, 1983), and beyond
the scope of this review. However, some patients
have had indapamide-induced decreases in serum
potassium concentrations large enough to warrant
supplemental potassium therapy (Beling et al., 1983;
Horgan et aI., 1981; Mimran et aI., 1983). Clinical
manifestations of hypoka1aemia have occurred in
1.2 or 3% and 7% of patients treated with indap-
amide 2.5 or 5.0mg, respectively (Canadian and
USA prescribing information).
In case reports involving 4 elderly patients (74
to 83 years of age) with essential hypertension, in-
227
dapamide 2.5mg daily induced clinically signifi-
cant hypokalaemia (Richard et al., 1978; Rodat and
Hamelin, 1978). Pretreatment serum potassium
concentrations of approximately 4 mmol/L fell to
2.7 to 2.9 mmol/L in 1 study (Richard et aI., 1978),
while the patient of Rodat and Hamelin had a post-
treatment serum potassium concentration of 0.9
mmol/L. Duration of treatment ranged from 2
months (Rodat and Hamelin, 1978) to only 3 to 7
days (Richard et aI., 1978). In most cases, the signs
and symptoms of hypokalaemia included electro-
cardiographic abnormalities [Q-T interval prolong-
ation, arrhythmia (bradycardia, atrial fibrillation)],
weakness and muscle cramping, and were accom-
panied by hypochloraemia and alkalosis. In both
studies, reversal of most abnormalities was accom-
plished by drug discontinuation and 2 to 6 days of
potassium supplementation.
Cosma and Pauly-Laubry (1978) reported sinus
bradycardia, Q-T prolongation, and intermittent
torsade de pointes in a patient treated with indap-
amide 2.5mg daily and disopyramide 100mg qid
for 6 weeks. On the first day of hospitalisation, the
patient's serum potassium concentration fell from
3.1 to 2.5 mmol/L in spite of potassium supple-
mentation. Discontinuation of both drugs and con-
tinuation of potassium administration resulted in
normokalaemia within 2 days and cessation of the
torsade de pointes. However, as both diuretic-in-
duced hypokalaemia and disopyramide are com-
mon causes of torsade de pointes (Fontaine et aI.,
1982; Schwertzer and Mark, 1982), indapamide
cannot be considered the sole causative agent.
4.2 Other Side Effects
Central nervous system side effects reported after
indapamide treatment have included headache
(Beling et al., 1983; Ikeda et al., 1982; Marais, 1981;
Seedat and Reddy, 1974), dizziness and similar
symptoms (Andries et aI., 1977; Bing et aI., 1981;
Bowker and Murphy, 1981; Brennan et aI., 1982;
Brun and Grunwald, 1976; de Ortiz et aI., 1983;
Slotkoff, 1983; Turner et al., 1977), and nervous-
ness and related complaints (Brennan et al., 1982;
Hashida, 1977).
Indapamide: A Review
Fatigue and similar symptoms have been fre-
quently reported (Bowker and Murphy, 1981; Goto
et aI., 1982; Hamilton and Kelly, 1977; Horgan et
aI., 1981). In one study, fatigue was experienced by
29 of the 644 patients (Passeron et aI., 1981) and
it was the most common side effect in the patients
of James et aI. (1981). Although fatigue with in-
dapamide is usually not a serious problem, 4 of the
437 patients of Royer (1977) withdrew from therapy
for this reason. Fatigue during indapamide treat-
ment has been associated with a marked increase
in sodium excretion (Milliez and Tcherdakoff,
1975). Muscular cramps or spasms (Anavekar et
aI., 1979; Astacio et aI., 1980; Passeron et aI., 1981)
have also occurred occasionally, most frequently
reported in the lower extremities (Noble et aI., 1983;
Vukovich et aI., 1983).
Although orthostatic hypotension (Andries et aI.,
1977; Bowker and Murphy, 1981; Goto et aI., 1982)
and palpitations (Brennan et aI., 1982; De Divitiis
et aI., 1983) have occasionally caused problems, the
cardiovascular tolerability of indapamide has been
good (see also section 1.4.3). A blood pressure 're-
bound' phenomenon does not occur following
withdrawal of indapamide (Reyes and Leary, 1983).
Mucocutaneous or gastrointestinal disturbances
(nausea, diarrhoea, indigestion, dry mouth, consti-
pation) have been infrequently reported (Bowker
and Murphy, 1981; Horgan et aI., 1981; Passeron
et aI., 1981; Van Hee et aI., 1981). Butaeye et aI.
(1979) reported a single case of indapamide-in-
duced hepatitis in a patient who had received 5mg
daily for 10 months. The diagnosis was confirmed
by histology and a positive lymphoblast transfor-
mation test. Withdrawal of indapamide resulted in
complete reversal of all abnormal laboratory and
clinical findings.
Although rare, impotence and decreased libido
have been reported in a few instances (Capone et
aI., 1983; Dunn et aI., 1981; de Ortiz et aI., 1983).
5. Dosage and Administration
The recommended initial daily dose of indap-
amide for the treatment of hypertension or oedema
is 2.5mg administered orally. If after 1 to 2 months
228
of therapy the antihypertensive response is found
to be inadequate, the dosage may be increased to
5mg daily or an additional antihypertensive agent
may be added. Similarly, in the treatment of oed-
ema, an inadequate diuretic response after 1 week
of treatment is an indication for the higher dosage.
Ifblood pressure is normalised within 1 to 2 months
with indapamide 2.5 to 5mg daily, the dose fre-
quency may be reduced to alternate days in some
patients without loss of control (Waal-Manning,
1984).
Indapamide is contraindicated in patients with
anuria or those who have demonstrated hypersen-
sitivity to the drug or other sulphonamide-derived
agents. It should be used with caution in patients
with renal insufficiency or impaired hepatic func-
tion, as alterations in fluid and/or electolyte bal-
ance induced by indapamide could exacerbate azo-
taemia or precipitate hepatic encephalopathy in
these patients.
As with other diuretics, patients receiving in-
dapamide should be observed for clinical signs of
fluid or electrolyte disorders, and periodic labora-
tory determinations of serum electrolytes and or-
ganic substances (uric acid, glucose, creatinine, etc.)
should be performed at appropriate intervals. Cau-
tion should be exercised when indapamide is ad-
ministered to patients also receiving digitalis gly-
cosides or lithium salts since hypokalaemia or
hyponatraemia, both potential problems with in-
dapamide therapy, may precipitate and/or worsen
toxic reactions to these agents. Studies in diabetic
patients with hypertension treated with indapam-
ide have revealed alterations in glucose tolerance
only rarely, but a clear statement on the effects of
indapamide on glucose tolerance must await fur-
ther long term well controlled trials.
6. Place of Indapamide in Therapy
Indapamide is an idoline derivative of chloro-
sulphonamide which shares many chemical, phar-
macodynamic, and therapeutic similarities with the
numerous sulphonamide diuretics currently avail-
able for therapeutic use. In addition to its diuretic
activity, indapamide has been shown to decrease
Indapamide: A Review
vascular smooth muscle reactivity and peripheral
resistance in various in vitro and in vivo models.
Whether these peripheral vascular effects make an
important contribution to the antihypertensive ac-
tivity of indapamide in man needs further clarifi-
cation. In usual dosages ("" 2.5mg daily), indapa-
mide has demonstrated similar efficacy to the
thiazide diuretics in lowering mild to moderately
elevated blood pressure. Higher dosages (~ 5mg
daily) have also been effective, but have been as-
sociated with significantly greater diuretic re-
sponses and tendencies toward biochemical aber-
rations.
The primary advantage of indapamide over cur-
rently available diuretic agents is its apparent low
side effect profile. Although more long term data
from larger patient groups are needed to confirm
the findings reported to date, some electrolyte and
other metabolic abnormalities appear to occur with
less frequency or severity with lower dosages of in-
dapamide (::;; 2.5mg) than with equipotent (re: blood
pressure effect) dosages of some other diuretic
agents. Indapamide also lacks significant effects
upon the central nervous system, and apparently
does not inhibit normal cardiac or pulmonary
function. Withdrawal of indapamide has not been
associated with a 'rebound' effect on blood pres-
sure.
Indapamide has also shown some efficacy in the
reduction of salt and fluid retention in relatively
small numbers of patients with oedema generally
due to unknown causes or congestive heart failure.
Thus, indapamide appears to be a suitable al-
ternative to more established drugs as a 'first-line'
treatment for patients with mild to moderate
hypertension. Further studies seem appropriate re-
garding its use in patients with salt and fluid re-
tention.
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