Are all diuretics equal for the treatment of hypertensive patients?

Thiazide (hydrochlorothiazide, etc.) and thiazide-like (chlortalidone, indapamide,etc.) diuretics are widely used to treat hypertensive patients. There is growing evidence that these diuretics are not interchangeable and that it might be preferable to choose a thiazide-likediuretic whenever the use of a diuretic is considered. This is in order to prevent optimally the development of cardiovascular complications and the occurrence of metabolic side effects, in particular diabetes (AU)

Las tiazidas (hidroclorotiazida, etc.) y los diuréticos de tipo tiazídico (clortalidona,indapamida, etc.) son fármacos ampliamente utilizados para tratar la hipertensión. Existe pruebas crecientes de que estos diuréticos no son intercambiables y sería preferible elegir un diurético de tipo tiazídico siempre que se considere el uso de los mismos. La razón para ello es evitar de manera óptima el desarrollo de complicaciones cardiovasculares y la aparición de efectos secundarios metabólicos, en particular la diabetes (AU)

Clinical pharmacology of the angiotensin II receptor antagonist losartan potassium in healthy subjects.

INTRODUCTION: The evaluation of a new drug in normotensive volunteers provides important pharmacodynamic and pharmacokinetic information as long as the compound has a specific mechanism of action which can be evaluated in healthy subjects as well as in patients. The purpose of the present paper is to discuss the results that have been obtained in normal volunteers with the specific angiotensin II receptor antagonist, losartan potassium. DOSE-FINDING: Over the last few years, studies in normotensive subjects have demonstrated that the minimal dose of losartan that produces maximal efficacy is 40-80 mg. Losartan has a long duration of action and its ability to produce a sustained blockade of the renin-angiotensin system is due almost exclusively to the active metabolite E3174. HORMONAL EFFECTS: Angiotensin II receptor blockade with losartan induces an expected increase in plasma renin activity and plasma angiotensin II levels. A decrease in plasma aldosterone levels has been found only with a high dose of losartan (120 mg). RENAL AND BLOOD PRESSURE EFFECTS: In normotensive subjects, losartan has little or no effect on blood pressure unless the subjects are markedly salt-depleted. Losartan causes no change in the glomerular filtration rate and either no modification or only a slight increase in renal blood flow. Losartan significantly increases urinary sodium excretion, however, and surprisingly produces a transient rise in urinary potassium excretion. Finally, losartan increases uric acid excretion and lowers plasma uric acid levels. CONCLUSIONS: These results suggest that losartan is an effective angiotensin II receptor antagonist in normal subjects. Its safety and clinical efficacy in hypertensive patients will be addressed in large clinical trials.

Amlodipine compared to nitrendipine in hypertensive patients: the effects on toleration in relationship to the onset of action.

Amlodipine and nitrendipine are calcium antagonists of the 1,4-dihydropyridine group which differ in their pharmacokinetic and pharmacodynamic properties. The clinical relevance of these differences was investigated in a study designed to compare the efficacy and safety of once-daily amlodipine (5 mg) and nitrendipine (20 mg) in patients with mild-to-moderate essential hypertension. Ambulatory blood pressure monitoring and conventional measurements showed that amlodipine and nitrendipine produced comparable reductions in blood pressure after 4 weeks of treatment. However, the onset of the antihypertensive effect was gradual for amlodipine, while most of the reduction achieved at the end of treatment with nitrendipine was seen after the first dose. There were no significant changes in heart rate with amlodipine, but significant increases occurred during the first 6 h of nitrendipine treatment. Amlodipine was associated with a significantly lower incidence of vasodilator-related adverse effects at initiation of therapy (headache, flushing, tachycardia) compared with nitrendipine, which may reflect its slower onset of action. The different pharmacodynamic and toleration profiles of amlodipine and nitrendipine at therapeutically equivalent doses suggest that amlodipine may have advantages in the treatment of hypertension, especially in terms of the low incidence of acute side effects, which may ultimately translate into improved patient compliance.

Individual responses to converting enzyme inhibitors and calcium antagonists.

This study was designed to assess whether the acute blood pressure response of an individual hypertensive patient to a calcium antagonist or an angiotensin converting enzyme (ACE) inhibitor is a good predictor of the long-term efficacy of these drug classes in this particular patient. The concept that good responses to ACE inhibitors and calcium antagonists may be mutually exclusive was also tested. Sixteen patients were included in a randomized crossover trial of enalapril, 20 mg daily, and diltiazem, 120 mg daily, for 6 weeks each. Blood pressure was measured by ambulatory blood pressure recording. During the washout phase, the acute effect of nifedipine, 10 mg p.o., and enalaprilat, 5 mg i.v., was evaluated. Nifedipine and enalaprilat reduced blood pressure equally well. The long-term blood pressure reduction induced by enalapril and diltiazem was similar. The acute blood pressure response to a given drug was not a good predictor of the result obtained with long-term therapy. No age dependency of the antihypertensive effect of either drug class was apparent. There was no evidence that a good response to one drug excluded a similarly good response to the other.

Neuropeptide Y prevents the blood pressure fall induced by endotoxin in conscious rats with adrenal medullectomy.

Neuropeptide Y (NPY) is a vasoconstrictor peptide known to be present in the adrenal medulla, the terminal nerve endings, and in plasma. This study was designed to test whether NPY could prevent the acute blood pressure fall induced by endotoxin administration. Normotensive rats were subjected to adrenal demedullation on the right side and were either adrenalectomized or sham-operated on the left side. Eight to ten days later, NPY (0.07 microgram/min i.v.) or its vehicle were infused for 95 minutes into these conscious, semirestrained rats. The same experiments were performed with rats that received an infusion of epinephrine (0.1 microgram/min). These doses of NPY and epinephrine when given alone had no blood pressure effect. During the last 75 minutes of the 95-minute infusion, endotoxin (lipopolysaccharide Escherichia coli 0.111:B4, 10 micrograms/min i.v.) or its vehicle were administered. In rats with an intact adrenal gland, endotoxin failed to induce hypotension. In rats lacking a functioning adrenal medulla, however, endotoxin induced a pronounced mean blood pressure fall of 55 +/- 11.6 mm Hg (mean +/- SEM). This blood pressure drop could be prevented equally well with NPY and with epinephrine infusion and averaged 11 +/- 2.3 and 16 +/- 2.4 mm Hg, respectively, at the end of the experiment. Additional rats were biadrenalectomized and supplemented with an excess of glucocorticoids and mineralocorticoids. In these rats also, NPY markedly attenuated the blood pressure fall resulting from endotoxemia. These data taken together indicate that in conscious rats with no adrenal medulla, the acute blood pressure fall induced by endotoxin administration is greatly enhanced.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute antihypertensive effect of angiotensin converting enzyme inhibition and calcium entry blockade.

The acute blood pressure response to an angiotensin converting enzyme inhibitor (enalaprilat) was compared in patients with uncomplicated essential hypertension with that obtained under similar conditions with a calcium entry blocker (nifedipine). The patients were studied after a 3 week washout period. At a 48 h interval, each patient received in randomized order either enalaprilat (5 mg i.v.) or nifedipine (10 mg p.o.). Enalaprilat and nifedipine were equally effective in acutely lowering blood pressure. However, good responders to one agent were not necessarily good responders to the other.

Clinical pharmacology of atrial natriuretic (3-28) eicosahexapeptide.

The clinical pharmacology of a synthetic rat atrial natriuretic peptide (rANP) was evaluated in normal volunteers. During a dose-ranging study at 1-40 micrograms/min we observed a dose-dependent decrease in mean intra-arterial blood pressure, an acceleration of the heart rate and a transient increase in blood flow to the skin. During a 4-h constant-dose infusion at 0.5 and 5.0 micrograms/min, inulin clearance remained unchanged but there was a dose-related fall in paraaminohippurate (PAH) clearance and an increase in the filtration fraction. Urinary excretion of sodium, chloride and calcium increased in a dose-related fashion, but with the high dose the excretion curve had a bell-shape. No change in plasma renin activity, angiotensin II and aldosterone was observed during the rANP infusion despite the excretion of large amounts of sodium and a blood pressure reduction with the high dose. Indocyanine green clearance, a measure of hepatic blood flow, was significantly decreased by a 2-h rANP infusion at 1.0 microgram/min. In normal volunteers, therefore, rANP induced vasodilation and blood pressure reduction, a decrease in renal and hepatic blood flow and a natriuretic and transient diuretic effect without activation of the renin-angiotensin-aldosterone system.

Four-hour infusions of synthetic atrial natriuretic peptide in normal volunteers.

Two doses of synthetic atrial natriuretic peptide (0.5 and 5.0 micrograms/min) and its vehicle were infused intravenously for 4 hours in eight salt-loaded normal volunteers, and the effect on blood pressure, heart rate, renal hemodynamics, solute excretion, and secretion of vasoactive hormones was studied. The 0.5 micrograms/min infusion did not alter blood pressure or heart rate, whereas the 5.0 micrograms/min infusion significantly reduced the mean pressure by 20/9 mm Hg after 2.5 to 3 hours and increased the heart rate slightly. Inulin clearance was not significantly changed, but the mean p-aminohippurate clearance fell by 13 and 32% with the lower and higher doses, respectively. Urinary excretion of sodium and chloride increased slightly with the lower dose. With the higher dose, a marked increase in urinary excretion of sodium, chloride, and calcium was observed, reaching a peak during the second hour of the infusion. Potassium and phosphate excretion did not change significantly. A brisk increase in urine flow rate and fractional water excretion was seen only during the first hour of the high-dose infusion. Signs and symptoms of hypotension were observed in two subjects. No change in plasma renin activity, angiotensin II, or aldosterone was observed during either infusion, but a marked increase occurred after discontinuation of the high-dose infusion. In conclusion, the 5 micrograms/min infusion induced a transient diuretic effect, delayed maximal natriuretic activity, and a late fall in blood pressure, with no change in inulin clearance but a dose-related decrease in p-aminohippurate clearance. Despite large amounts of sodium excreted and blood pressure reduction, no counterregulatory changes were observed in the renin-angiotensin-aldosterone system or plasma vasopressin levels during the infusion.

Haemodynamic role of vasopressin released during Finnish sauna.

The effect of vasopressin released during Finnish sauna on blood pressure, heart rate and skin blood flow was investigated in 12 healthy volunteers. Exposure to the hot air decrease body weight by 0.6 to 1.25 kg (mean = 0.8 kg, P less than 0.001). One hour after the end of the sauna sessions, plasma vasopressin was higher (1.7 +/- 0.2 pg/ml, P less than 0.01 mean +/- SEM) than before the sauna (1.0 +/- 0.1 pg/ml). No simultaneous change in plasma osmolality, plasma renin activity, plasma norepinephrine, epinephrine, cortisol, aldosterone, beta-endorphin and metenkephalin levels was observed. Despite the slight sauna-induced elevation in circulating vasopressin, intravenous injection of the specific vascular vasopressin antagonist d(CH2)5Tyr(Me)AVP (5 micrograms/kg) 1 h after the sauna had no effect on blood pressure, heart rate or skin blood flow. These data suggest that vasopressin released into the circulation during a sauna session reaches concentrations which are not high enough to interfere directly with vascular tone.

Clinical studies with a vascular vasopressin antagonist.

The effect of circulating arginine vasopressin (AVP) on blood pressure, heart rate, and skin blood flow was assessed in normotensive subjects, mild hypertensive patients, and patients with congestive heart failure, utilizing the specific antagonist of AVP at the vascular receptor level, d(CH2)5Tyr(Me)AVP (5 micrograms/kg i.v.). The renin system of the normal volunteers treated with the AVP antagonist was either intact or acutely blocked with the angiotensin converting-enzyme inhibitor captopril (25 mg p.o.). In some volunteers, the cardiovascular effect of AVP released by Finnish sauna or cigarette smoking was studied. In patients with congestive heart failure, hemodynamic measurements (pressures and cardiac output) were obtained invasively. Acute blockade of AVP vascular receptors produced no cardiovascular effect unless plasma AVP levels were markedly elevated. In our experience, abnormally high circulating AVP appears to be responsible for the decrease in skin blood flow induced by cigarette smoking and to some extent for the maintenance of vascular tone in the rare patients with particularly severe congestive heart failure.

[New therapeutic approaches to arterial hypertension]. / Nouvelles approches thérapeutiques de l'hypertension artérielle.

Today two largely new approaches are available for the treatment of clinical hypertension. First, captopril, an orally active angiotensin converting enzyme inhibitor, makes possible chronic blockade of the renin-angiotensin system. This compound, given alone or in combination with a diuretic, normalizes the blood pressure of most hypertensive patients. Unfortunately, because captopril may induce serious adverse effects the use of this inhibitor must be restricted to patients with high blood pressure refractory to conventional antihypertensive drugs. Second, compounds such as verapamil and nifedipine are capable of producing a marked vasodilating effect by inhibiting the entry of calcium into the vascular smooth muscle cells. However, the role of calcium channel blockers in the treatment of hypertensive disease awaits more precise definition.