Indapamide: Clinical Pharmacology,Therapeutic Efficacy in Hypertension,and Adverse Effects

Indapamide will soon be marketed in the United States as an oral antihypertensive agent and diuretic. Its molecular structure includes both a polar sulfamoyl chlorobenzamide moiety and a lipid-soluble methylindoline molety. It differs chemically from the thiazides in that it does not possess the thiazide ring system and it contains only one sulfonamide group. Indapamide is rapidly and well absorbed after oral Ingestion, and it has a long terminal half-life in whole blood which permits once daily administration. Indapamide is extensively metabolized by the liver with excretion of unchanged drug accounting for approximately 5% of the total dose. Although indapamide is thought to exert its antihypertensive effect by its diuretic action, several investigations employing laboratory animal preparations have documented a direct vascular action. It has been categorized as a calcium channel blocking agent and this may account for a portion of its antihypertensive effectiveness. In both the treatment of edema and as an antihypertensive agent, indapamide appears to be comparable to hydrochlorothiazide, chlorthalidone and furosemide and seems to have no clinically important advantage over these agents. Side effects associated with indapamide are minimal and appear to be comparable to those observed with other antihypertensive diuretics. Based on few published studies, indapamide appears to be a useful long acting antihypertensive and diuretic agent that is well tolerated and associated with minimal biochemical abnormalities or side effects.     

Position of indapamide, a diuretic with vasorelaxant activities, in antihypertensive therapy

INTRODUCTION: Diuretics play a pivotal role in the management of hypertension. A large experience has been accumulated with indapamide , a long-acting thiazide-like diuretic that lowers blood pressure (BP) primarily through its natriuretic diuretic effect. Some of its long-term antihypertensive efficacy may be due to calcium antagonist-like vasorelaxant activities. Indapamide has protecting effects in a variety of conditions associated with high cardiovascular risk, such as diabetes, left ventricular hypertrophy, nephropathy and stroke. It is highly effective in lowering BP, whether given alone or in combination. Indapamide is well tolerated and has the advantage of having no adverse impact on glucose and lipid metabolism. Today, thiazide-like diuretics are regarded more and more as preferred drugs, when diuretic therapy is required to lower BP. AREAS COVERED: The aim of this paper is to review the experience accumulated with indapamide. It is limited to clinical studies that are relevant for the everyday management of hypertensive patients, whether or not they exhibit cardiovascular or renal disease. EXPERT OPINION: Indapamide, because of its well-documented beneficial effects on cardiovascular and renal outcomes, represents a safe and valuable option for treating patients with high BP. There is, however, still room for new trials evaluating the combination of this diuretic with other types of antihypertensive drugs, in particular a calcium antagonist such as amlodipine. There is also the need to compare the indapamide-perindopril and indapamide-amlodipine combinations, in terms of antihypertensive efficacy, tolerability and effects on target organ damage and, ideally, on cardiovascular mortality.     

Pinacidil. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in the treatment of hypertension

Pinacidil is an orally administered antihypertensive drug that acts via direct relaxation of vascular smooth muscle to produce peripheral vasodilatation and a reduction in blood pressure without significant direct effects on cardiac electrophysiology. Pinacidil is unrelated to other antihypertensive drugs in clinical use, either in structure or mechanism of action. It belongs to a new class of agents called 'potassium channel openers' which act via potassium efflux to hyperpolarize cell membranes, indirectly causing a net reduction in intracellular calcium that leads to relaxation of vascular smooth muscle. Pinacidil is indicated in the management of essential hypertension. In clinical trials of up to 1 year duration, pinacidil administered twice daily in a controlled release capsule formulation has been shown to achieve adequate blood pressure control both in previously untreated patients and in those with blood pressure inadequately controlled by beta-adrenoceptor blocking drugs or thiazide diuretics. In long term (up to 1 year) comparative studies pinacidil was at least as effective as hydralazine, prazosin or nifedipine in maintaining blood pressure control. Pinacidil may also have a potential use in the treatment of patients with secondary renal hypertension. Clinical trials to date have usually allowed the addition of a thiazide diuretic and/or beta-adrenoceptor blocking drug to enhance the efficacy of pinacidil and/or to reduce the incidence of adverse effects. The main adverse effects of pinacidil treatment, which result from its peripheral vasodilator activity, are headache, oedema, palpitations and tachycardia. Although the overall incidence of adverse effects is quite high, they are usually mild, transient in nature and respond to a reduction in dose. Nevertheless, these effects may occasionally be severe, necessitating withdrawal from therapy. Thus, pinacidil is an effective antihypertensive drug for the treatment of mild to moderate essential hypertension. Despite its novel mechanism of action pinacidil causes adverse effects typical of peripheral vasodilators; during long term use with twice daily administration of the controlled release capsule formulation, the addition of a diuretic is often necessary to attenuate peripheral oedema and maintain adequate control of blood pressure. Further long term controlled trials are needed to determine the precise role of pinacidil relative to that of the angiotensin converting enzyme (ACE) inhibitors and calcium channel blocking drugs.     

Guanfacine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in the treatment of hypertension

Guanfacine, a phenylacetyl-guanidine derivative, is a centrally acting alpha-adrenoceptor agonist, with a mechanism of antihypertensive action similar to that of clonidine. It reduces blood pressure in patients with essential hypertension at least as effectively as clonidine or methyldopa. Like lower doses of clonidine, guanfacine can be given once daily due to its relatively long elimination half-life. Although dry mouth and sedation occur frequently with higher doses of guanfacine, their incidence is lower than with other centrally acting antihypertensives; in addition, other troublesome side effects such as orthostatic hypotension or sexual dysfunction also occur much less with guanfacine than with other centrally acting antihypertensive agents. While a withdrawal syndrome may occur on abruptly discontinuing guanfacine administration, the symptoms are generally mild, and the incidence of withdrawal symptoms appears lower than occurs with abrupt withdrawal of clonidine. Thus, guanfacine is an effective and well tolerated alternative to other centrally acting antihypertensive drugs. Whether its final place in therapy will be as an alternative 'second-line' drug, or as initial monotherapy in patients with mild to moderate hypertension, remains to be clarified in comparative studies with diuretics, calcium antagonists, and beta-adrenoceptor blocking drugs.     

Felodipine. A review of the pharmacology and therapeutic use of the extended release formulation in cardiovascular disorders.

Felodipine is a vascular-selective, dihydropyridine calcium antagonist previously investigated as a conventional tablet formulation administered twice daily. More recently considerable experience has been gained with an extended release (ER) formulation which has the convenience of once daily administration. Felodipine ER has been well studied in patients with essential hypertension. As monotherapy in mild to moderate essential hypertension, felodipine ER is at least as effective in reducing blood pressure as other calcium antagonists, beta-blockers, diuretics and ACE inhibitors, with some results favouring felodipine ER at a statistically significant level at the dosages used. It is also effective combined with controlled release metoprolol or enalapril in patients with mild to moderate essential hypertension. In patients with more severe forms of essential hypertension uncontrolled by beta-blocker and/or diuretic therapy, felodipine ER was effective as an 'add-on' therapy in placebo-controlled trials, and, at the dosages used, more effective than either sustained release nifedipine or nitrendipine. Felodipine produces effective control of blood pressure without negative effects on cardiac performance. In addition to its antihypertensive action, results suggest that felodipine therapy is associated with significant regression of left ventricular hypertrophy. Furthermore, it appears suitable for use in patients with concomitant diabetes, renal dysfunction or asthma, and is also being investigated for use in patients with congestive heart failure or angina pectoris. Felodipine ER is an effective drug for the treatment of all grades of essential hypertension, and can be used both as monotherapy and in combination with other antihypertensive agents. Further clinical experience should fully establish the long term tolerability of felodipine ER and consequently its place in therapy relative to other accepted antihypertensive drugs. However, with the convenience of once daily administration, felodipine ER is a worthwhile innovation in the treatment of hypertension.     

Indapamide sustained release: a review of its use in the treatment of hypertension

A low-dose sustained-release (SR) formulation of the thiazide-type diuretic indapamide, indapamide SR (Natrilix SR), retains the antihypertensive activity of the immediate-release (IR) formulation, with a smoother pharmacokinetic profile. In well controlled 12- to 52-week clinical trials, indapamide SR 1.5 mg/day was well tolerated and reduced blood pressure as effectively as therapeutic dosages of amlodipine, candesartan, enalapril, hydrochlorothiazide or indapamide IR. Indapamide SR was also more effective than enalapril in reducing left ventricular hypertrophy (LVH), and similar reductions in renal end-organ damage, assessed by microalbuminuria, were seen with indapamide SR- and enalapril-based antihypertensive strategies. Indapamide SR provides an effective option for initial antihypertensive monotherapy and a basis for multidrug antihypertensive strategies.     

Acute effect of indapamide on urine calcium excretion in nephrolithiasis and human essential hypertension

The effects of indapamide (2.5 mg once a day) on urinary composition are reported in 20 patients (10 with recurrent calcium nephrolithiasis and 10 with essential hypertension) compared with 20 controls. Indapamide was well absorbed in every patient (mean plasma level at the steady state was 111 +/- 41 ng/ml) and its antihypertensive action was more pronounced in hypertensive than in normotensive patients. It lowered calcium excretion in 18/20 patients (mean fall on the 7th day of treatment: 53%) and raised the Mg/Ca ratio in 20/20 patients (mean increase on the 7th day: 167%). The effect on Ca2+ and Mg2+ excretion was not associated with a strong diuretic effect. During intravenous calcium loading (0.375 mmol/kg body weight) 6 normal subjects after a single oral dose of indapamide excreted less calcium, suggesting a direct renal hypocalciuric action by the drug. Indapamide could represent an alternative drug to thiazide diuretics in diseases with dangerous renal calcium losses, but long-term studies are needed.     

Delapril plus indapamide: a review of the combination in the treatment of hypertension

Although many data indicate that the management of hypertension has improved over the last two decades, there is still a large proportion of hypertensive individuals who do not receive adequate management of their blood pressure (BP). Combination therapy with two or more antihypertensive agents from different drug classes is increasingly being recognised as the most effective means of achieving target BP values by pharmacological means, particularly in the large number of patients in whom monotherapy proves to be ineffective. Use of an angiotensin-converting enzyme (ACE) inhibitor combined with a diuretic is a well established antihypertensive combination that is very effective because of the different, yet synergistic, mechanisms of actions of agents from these two drug classes. Delapril is a potent antihypertensive ACE inhibitor, and indapamide is a thiazide-like diuretic with additional antihypertensive properties. The combination of delapril and indapamide provides renoprotective effects, and indapamide is also cardioprotective. Use of these two drugs together is therefore a rational selection for combination therapy, and one that has consistently demonstrated lowering of BP to target values with a level of efficacy that is at least as good as other combinations of ACE inhibitors and diuretics. This combination has also been found to provide favourable effects on haemodynamic parameters, including left ventricular mass index and ejection fraction. Furthermore, combining an ACE inhibitor and a thiazide-type diuretic has been associated with a decreased risk of stroke and is recommended for patients with cerebrovascular disease, a setting in which the combination of delapril and indapamide has therapeutic potential. Because of the additive mechanisms of delapril and indapamide, the dose required for an effective antihypertensive effect is relatively low, and the combination is well tolerated at such doses. In particular, metabolic effects normally associated with diuretics are rare at the therapeutic dose of indapamide used in combination with delapril, making the combination suitable for patients with metabolic disorders in whom diuretic therapy would otherwise not be recommended. Delapril 30 mg and indapamide 2.5mg have been combined in a fixed combination, offering the convenience of a one-tablet-per-day antihypertensive drug regimen for most patients, which, along with good tolerability, helps to address the issue of noncompliance.     

Antihypertensive action of indapamide. Comparative studies in several experimental models.

1-(4-Chloro-3-sulfamylbenzamido)-2-methyl-indoline (indapamide), after single oral dose administration, showed antihypertensive activity in genetically hypertensive rats, DOCA/saline hypertensive rats, unilaterally-nephrectomised DOCA/saline hypertensive rats and dogs made hypertensive by renal encapsulation. The activity was observed at doses as low as 1-3 mg/kg and lasted at least 48 h. Increasing the dose level considerably prolonged the duration of action but did not substantially enhance the maximum antihypertensive effect. In genetically hypertensive rats indapamide was 30-300 times more potent than furosemide, spironolactone and chlorthalidone. Indapamide had no effect on blood pressure in normotensive rats. In concentrations of 1 X 10(-5) to 1 X 10(-3) g/ml, indapamide antagonised contractions of arterial and venous strips to angiotensin, epinephrine and norepinephrine revealing a direct vascular action. Indapamide has a prolonged saluretic action which in combination with the direct vascular effects may well account for its antihypertensive activity.     

Modification of the antihypertensive effect of indapamide by indomethacin

Oral treatment with indapamide was found to reduce blood pressure of hypertensive rats but not of normotensive rats. Chronic indomethacin treatment had no effect on blood pressure of untreated normotensive and hypertensive rats. Also indomethacin did not modify the antihypertensive effect of indapamide excluding the direct involvement of PGs in the antihypertensive effect of indapamide. Vascular reactivity to pressor agents NA, ADR and ANG was significantly increased after indomethacin treatment. This may be due to the blockade of the actions of PG in modifying vascular reactivity to vasoconstrictor agents or may be a direct effect of indomethacin on calcium fluxes. Indapamide reduced the reactivity to NA and ANG in the presence of indomethacin suggesting that the antihypertensive effect of indapamide may be through a decrease in reactivity to pressor agents which is independent of increase in the synthesis of vasodilator PGs.     

Torasemide. A review of its pharmacological properties and therapeutic potential.

Torasemide (torsemide) is a high-ceiling loop diuretic which acts on the thick ascending limb of the loop of Henle to promote rapid and marked excretion of water, sodium and chloride. Like furosemide (frusemide), its major site of action is from the luminal side of the cell. Torasemide is at least twice as potent as furosemide on a weight-for-weight basis, produces equivalent diuresis and natriuresis at lower urinary concentrations and has a longer duration of action, allowing once-daily administration without the paradoxical antidiuresis seen with furosemide. Torasemide also appears to promote excretion of potassium and calcium to a lesser extent than furosemide. In trials of up to 48 weeks' duration in patients with mild to moderate essential hypertension, torasemide, administered as a single daily dose, has been shown to achieve adequate blood pressure control reaching steady-state within 8 to 12 weeks. Those patients not responding initially have generally responded to a doubling of the dose. Comparative trials of up to 6 months show torasemide is as effective as indapamide, hydrochlorothiazide or a combination of triamterene/hydrochlorothiazide in maintaining control of blood pressure. Torasemide has also been used successfully to treat oedematous states associated with chronic congestive heart failure, renal disease and hepatic cirrhosis. In short term trials control of blood pressure, bodyweight and residual oedema has been sustained. Torasemide appears to be a useful alternative to furosemide in these patients, providing potent and long-lasting diuresis while being relatively potassium and calcium sparing. In clinical trials to date torasemide has been well tolerated with adverse effects of a mild, transient nature reported by only small numbers of patients. Changes in biochemical parameters have been common, including decreases in plasma sodium and potassium levels and increases in plasma creatinine and uric acid levels. These changes are typical of loop diuretics. No changes were clinically significant nor were clinically relevant changes noted in glucose metabolism, cholesterol or triglyceride levels or in haematological values. Thus, torasemide is an interesting new loop diuretic with potential use in the treatment of mild to moderate essential hypertension and of oedematous states in which diuretic therapy is warranted. Preliminary studies suggest it to be as efficacious as other diuretics in common use and to have some advantage over furosemide in duration of action and in effects on potassium and calcium. However, further long term trials in larger groups of patients are needed to delineate the place of torasemide in therapy fully, both as a single agent and in combination with other currently accepted drug regimens.     

Verapamil. An updated review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in hypertension

Although verapamil is a well-established treatment for angina, cardiac arrhythmias and cardiomyopathies, this review reflects current interest in calcium antagonists as anti-hypertensive agents by focusing on the role of verapamil in hypertension. Verapamil is a phenylalkylamine derivative which antagonises calcium influx through the slow channels of vascular smooth muscle and cardiac cell membranes. By reducing intracellular free calcium concentrations, verapamil causes coronary and peripheral vasodilation and depresses myocardial contractility and electrical activity in the atrioventricular and sinoatrial nodes. Verapamil is well suited for the management of essential hypertension since it produces generalised systemic vasodilation resulting in a marked reduction in systemic vascular resistance and, consequently, blood pressure. Evidence from clinical studies supports the role of oral verapamil as an effective and well-tolerated first-line treatment for the management of patients with mild to moderate essential hypertension. Clinical studies have shown that verapamil is more effective the higher the pretreatment blood pressure and some authors have found a more pronounced antihypertensive effect in older patients or in patients with low plasma renin activity. Sustained release verapamil formulations are available for oral administration which, as a single daily dose, are as effective in lowering blood pressure over 24 hours as equivalent doses of conventional verapamil formulations given 3 times daily. As a first-line antihypertensive agent, oral verapamil is equivalent to several other calcium antagonists, beta-blockers, diuretics, angiotensin-converting enzyme (ACE) inhibitors and other vasodilators, and is not associated with many of the common adverse effects of these treatments. Verapamil may be preferred as an alternative first-line antihypertensive treatment to diuretics in elderly patients because it has similar efficacy in these patients without causing the adverse effects commonly linked with diuretic treatment. Furthermore, because verapamil does not cause bronchoconstriction, it may be used in preference to beta-blockers in patients with asthma or chronic obstructive airway disease. Reflex tachycardia, orthostatic hypotension or development of tolerance is not evident following verapamil administration. As a second- or third-line treatment for patients refractory to established antihypertensive regimens, verapamil produces marked blood pressure reductions when combined with diuretics and/or ACE inhibitors, beta-blockers and vasodilators such as prazosin.(ABSTRACT TRUNCATED AT 400 WORDS)     

Terazosin: a new alpha adrenoceptor blocking drug.

Terazosin (Hytrin; Abbott Laboratories, North Chicago, IL) is a new, selective alpha 1-adrenoceptor blocking agent used on once-a-day basis for therapy of mild-to-moderate hypertension. Its pharmacologic properties are similar to those of prazosin. Terazosin however, differs from prazosin in that its water solubility is 25 times greater than that of prazosin and its elimination half-life is about three times that of prazosin. Greater water solubility facilitates intravenous formulation, and longer half-life allows once-daily administration of terazosin. Terazosin is effective in lowering blood pressure and has a beneficial effect on plasma lipid profile. The major advantage of terazosin compared with prazosin, however, is its long duration of action. Terazosin is safe and effective when used in combination with diuretics and other antihypertensive agents, and in the long-term treatment of patients with mild to moderate essential hypertension.     

Antihypertensive effect of indapamide given in conjunction with captopril in severe hypertension

The efficacy of captopril alone or in combination with indapamide was evaluated in 17 patients with severe hypertension (diastolic greater than 120 mmHg) previously treated with triple antihypertensive therapy, i.e. diuretic, beta-blocker and a vasodilator. After a wash-out period of 1 week, captopril was given initially as 75 mg/day for 2 weeks; at the end of this period, the dosage was doubled to 150 mg/day and continued at this level for a further 2 weeks. Indapamide (2.5 mg/day) was then added to the regimen and administered for 1 month. The results showed that captopril alone lowered, but did not normalize the blood pressure. The mean diastolic pressure was reduced to 117 and 103.8 mmHg after dosages of captopril of 75 mg and 150 mg, respectively. On the addition of indapamide, the blood pressure was normalized to 93.82 mmHg mean diastolic pressure. Systolic readings were similarly reduced. Two patients developed skin rashes while on captopril alone: no other treatment-related side-effects were reported once indapamide therapy had commenced.     

Nitrendipine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in the treatment of hypertension

Nitrendipine is a calcium entry blocker shown to inhibit the movement of calcium through the 'slow channel' of cardiac and vascular smooth muscle, thus inducing peripheral vasodilation with consequent reductions in elevated blood pressure. As evidenced by clinical trials, nitrendipine promptly lowers blood pressure in patients with mild to moderate hypertension, and sustains this effect during long term administration. Combining nitrendipine with other antihypertensive agents such as diuretics or beta-blockers often results in successful treatment in patients unresponsive to nitrendipine monotherapy. Headache, oedema, flushing and palpitations commonly occurring during treatment with nitrendipine are generally mild, usually subsiding with continued therapy. Thus, although additional long term studies are required to properly assess the relative merits of the drug compared with other antihypertensives, by providing the clinician with an effective and safe alternative to traditional therapies, nitrendipine represents a step forward in the treatment of mild to moderate hypertension.     

吲达帕胺对高血压病人血浆内皮素-1的影响

目的　研究轻、中度原发性高血压病人的血浆内皮素 1(ET 1)的变化及其在原发性高血压发生及发展中的作用 ,评价吲达帕胺对轻、中度原发性高血压的降压疗效及对这类病人血浆ET 1水平的影响 ,探讨吲达帕胺对高血压的影响机制。方法　将 30例轻、中度原发高血压病人和 30例正常人的血浆采用放射免疫法测定血浆ET 1水平 ,对高血压病人给予吲达帕胺治疗 2周 ,并进行治疗前后对照研究。结果　高血压组治疗后血压明显下降 ,平均舒张压降低 9 8mmHg ,P <0 0 1,降压有效率为 6 0 %。高血压组治疗前血浆ET 1较正常组显着升高 ,平均升高 34 5 5 3pg/L ,P <0 0 0 1,治疗后ET 1水平显着下降 ,平均降低 35 5 5 0pg/L ,P <0 0 0 1。结论　原发性高血压病人血浆ET 1较正常人高 ,这类人群存在内皮细胞分泌活动的紊乱 ,是原发性高血压疾病发展的重要环节。吲达帕胺 (2 5mg/d)对轻、中度原发高血压病人降压疗效显著 ,同时可降低血浆ET 1水平 ,从而可抑制内素促进高血压进展的作用。     

Antihypertensive effect of metoprolol in diuretic-treated,mild primary hypertension

Metoprolol tartrate was administered to 41 patients with mild essential hypertension already treated with a diuretic for a period of 2 weeks. In the majority of those patients, other step 2 antihypertensive agents either failed to control high blood pressure or caused adverse reactions. All other antihypertensive agents except diuretics were discontinued during the 2-week wash-out period. Patients with a diastolic blood pressure of 95 to 104 mmHg (inclusive) received oral metoprolol at a dose of 50mg twice daily for 2 weeks. Subsequently, metoprolol titration was individualized on a bi-weekly basis until either the diastolic blood pressure was = 90 mmHg and/or a maximal daily dose of 300mg of metroprolol was reached. The analysis of efficacy and safety was done for a total period of 14 weeks. Diastolic blood pressure and heart rates were significantly reduced (P≤0.05) in all treatment groups. Minor adverse reactions such as mild fatigue in 11 patients, nervousness in 2, and leg cramps in 2 patients were reported. Transient skin rash, dizziness, headache, chest pain, insomnia, and cold extremities were also reported in one patient each. It is concluded from the present study that metropolol (in twice daily dose) in combination with a diuretic is safe, effective, and well tolerated in the treatment of mild hypertension.     

Treating hypertension by rational use of diuretics: results of the Russian ARGUS-2 study

ABSTRACT

Objective: Insufficient use of diuretics in combination antihypertensive therapy is a main cause of poor blood pressure (BP) control in Russia. The objective of the ARGUS-2 study was to demonstrate that a rational use of a thiazide-like diuretic, indapamide sustained release (SR), alone or in combination, improves BP control in patients with arterial hypertension difficult to control due to isolated systolic hypertension (ISH), diabetes mellitus (DM), chronic nephropathy, or metabolic syndrome.

Methods: The open-label, non-comparative, 3-month study without preliminary washout included 1438 hypertensive patients (mean age: 57.3?±?10.7 years, mean BP: 158.8?±?14.2/93.4?±?10.0?mmHg), with difficult-to-control arterial hypertension and who had never been treated with diuretics previously. Throughout the study, patients received indapamide SR 1.5?mg OD. BP control was defined as <140/90?mmHg for all patients and <130/80?mmHg for those with diabetes mellitus or chronic nephropathy.

Results: Indapamide SR was given as initiation monotherapy to 13.7% of the patients, as substitutive monotherapy to 6.8% of the patients uncontrolled by a previous monotherapy, as additive therapy to 31.9% of the patients uncontrolled by previous monotherapy, and as additive therapy to 47.6% uncontrolled by previous combination therapy without a diuretic. Among included patients 75.7% received also an ACE inhibitor or an angiotensin II receptors blocker, 43.9% a calcium channel blocker, and 32.8% a beta-blocker. In 3 months after indapamide SR administration, average BP level decreased to 131.8?±?9.7/80.5?±?6.9?mmHg and 84.5% of the study population achieved BP control. BP was controlled in 91.9% of patients with ISH (n?=?477), 74.8% of those with diabetes (n?=?214), 75.6% of those with chronic nephropathy (n?=?82), and 85.1% of patients with metabolic syndrome (n?=?745). No case of hypokalemia was reported.

Conclusion: The study demonstrates the value of including the thiazide-like diuretic indapamide SR in a combined antihypertensive regimen to control BP in hypertensive patients with added cardiovascular risk factors whose hypertension is difficult to treat. Methodological limitations of this study are its open-label design and the possibility of a change in concomitant antihypertensive treatment during the study.     

Systemic and pulmonary hemodynamic effects of indapamide in patients with mild arterial hypertension

We studied the hemodynamic mechanism responsible for the antihypertensive effect of indapamide in eight patients with mild essential hypertension. Systemic and pulmonary hemodynamics were measured using direct techniques (right heart catheterization and thermodilution method), before and 7-10 days after oral treatment with indapamide (2.5 mg/day). Indapamide reduced mean arterial blood pressure from 120 +/- 1.6 (mean +/- SE) to 101 +/- 1.4 mm Hg (p less than 0.01), and mean pulmonary artery pressure from 21 +/- 0.59 to 17 +/- 1.05 mm Hg (p less than 0.01). Total peripheral vascular resistance (TPR) and pulmonary vascular resistance were reduced from 36 +/- 0.85 to 29 +/- 0.72 U/m2 (p less than 0.01) and from 4.3 +/- 0.17 to 3.8 +/- 0.18 U/m2 (p less than 0.01), respectively. Indapamide did not change cardiac index (CI) (3,311 +/- 61.6 vs. 3,325 +/- 72.1 ml/min/m2), heart rate (HR) (75 +/- 1.7 vs. 75 +/- 9 beats/min), mean rate of left ventricular ejection index 140 +/- 2.04 vs. 139 +/- 1.99 ml/s/m2, and stroke index (44 +/- 5.6 vs. 43 +/- 5.8 ml/m2). Mean pulmonary wedge pressure decreased from 7 +/- 0.6 to 5 +/- 0.5 mm Hg (p less than 0.05). Body weight, 24-h urinary volume, and hematocrit were unchanged after treatment. We conclude that the hemodynamic mechanism responsible for the antihypertensive action of indapamide is a reduction in TPR without changes in CI and HR.     

Comparison of cicletanine with other antihypertensive drugs in SHR-SP models

The effects of cicletanine were compared with those of four other antihypertensive drugs (prazosin, a highly selective alpha 1 antagonist; captopril, an angiotensin-converting enzyme inhibitor; indapamide, an antihypertensive diuretic; and hydrochlorothiazide, a purely diuretic agent) on young stroke-prone SHR rats with high-salt diet. All the drugs except hydrochlorothiazide prevented the onset of hypertension. The minimal effective dose on blood pressure was 1 mg/kg for both cicletanine and captopril, and 3 mg/kg for indapamide. The action on cardiac hypertrophy and diuresis occurs at a dose of cicletanine 10 to 30 times higher than that required to produce the antihypertensive effect. Renal hypertrophy was also decreased significantly by cicletanine at a dose of 100 mg/kg.