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.     

Periprocedural bridging therapy in patients receiving chronic oral anticoagulation therapy

ABSTRACT

Background: In patients receiving chronic oral anticoagulation with vitamin K antagonists (VKAs) it may be necessary to temporarily discontinue VKA therapy to allow surgery or other invasive procedures to be performed, as maintaining treatment may increase the risk of bleeding during the procedure. This, however, creates a clinical dilemma, since discontinuing VKAs may place the patient at risk of thromboembolism.

Scope: We undertook a systematic narrative review of patients on chronic oral anticoagulation, requiring a periprocedural bridging therapy with heparin during invasive procedures.

Findings and recommendations: For patients requiring temporary discontinuation of VKA, current guidelines recommend the use of ‘bridging’ therapy with unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) in patients considered to be at intermediate-to-high risk of thromboembolism, such as those with prosthetic heart valves or atrial fibrillation. Recent studies show that LMWHs are associated with low rates of thromboembolism and, when compared with UFH, are as effective and safe as UFH when used as periprocedural bridging therapy in such patients. LMWHs also offer advantages such as ease of administration and predictable anticoagulant effects. Moreover, outpatient-based periprocedural bridging therapy with LMWH has been shown to result in significant cost savings compared with in-hospital UFH.

Conclusions: The decision to provide bridging therapy requires careful consideration of the relative risks of thromboembolism and bleeding in each patient. Based upon the studies reviewed we recommend a therapeutic dose of UFH or LMWH for patients at intermediate-to-high thromboembolic risk requiring interruption of VKA, especially for low bleeding risk procedures. We would like to propose upgrading the American College of Chest Physicians (ACCP) guideline recommendations from 2C to 1C. However, there is still a need for a randomized controlled trial on the efficacy and safety of the available bridging strategies, including heparin and placebo comparators, in preventing thromboembolism for specific patients and procedures.     

Periprocedural bridging therapy in patients receiving chronic oral anticoagulation therapy

BACKGROUND: In patients receiving chronic oral anticoagulation with vitamin K antagonists (VKAs) it may be necessary to temporarily discontinue VKA therapy to allow surgery or other invasive procedures to be performed, as maintaining treatment may increase the risk of bleeding during the procedure. This, however, creates a clinical dilemma, since discontinuing VKAs may place the patient at risk of thromboembolism. SCOPE: We undertook a systematic narrative review of patients on chronic oral anticoagulation, requiring a periprocedural bridging therapy with heparin during invasive procedures. FINDINGS AND RECOMMENDATIONS: For patients requiring temporary discontinuation of VKA, current guidelines recommend the use of 'bridging' therapy with unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) in patients considered to be at intermediate-to-high risk of thromboembolism, such as those with prosthetic heart valves or atrial fibrillation. Recent studies show that LMWHs are associated with low rates of thromboembolism and, when compared with UFH, are as effective and safe as UFH when used as periprocedural bridging therapy in such patients. LMWHs also offer advantages such as ease of administration and predictable anticoagulant effects. Moreover, outpatient-based periprocedural bridging therapy with LMWH has been shown to result in significant cost savings compared with in-hospital UFH. CONCLUSIONS: The decision to provide bridging therapy requires careful consideration of the relative risks of thromboembolism and bleeding in each patient. Based upon the studies reviewed we recommend a therapeutic dose of UFH or LMWH for patients at intermediate-to-high thromboembolic risk requiring interruption of VKA, especially for low bleeding risk procedures. We would like to propose upgrading the American College of Chest Physicians (ACCP) guideline recommendations from 2C to 1C. However, there is still a need for a randomized controlled trial on the efficacy and safety of the available bridging strategies, including heparin and placebo comparators, in preventing thromboembolism for specific patients and procedures.     

Acute renal effects of oral felodipine in normal man

Summary The acute renal effects of a single oral dose of felodipine 0.15 mg/kg were studied in 8 healthy males. Thirty minutes after administration the mean plasma concentration was 25.7 nmol/l. There was a significant reduction in diastolic blood pressure (24%) and a concomitant rise in heart rate (38%), leaving the systolic pressure unchanged. Glomerular filtration rate (GFR) and renal plasma flow (RPF) were measured by the constant infusion technique using the clearance of¹²⁵I-iothalamate and¹³¹I-hippuran respectively. GFR was unchanged and the filtration fraction (FF) was reduced, whilst there was a decrease in renal vascular resistance (RVR). The glomerular filter characteristics were unchanged, as estimated by the unchanged excretion rate of albumin. There was a significant rise in the clearance of sodium (176%) but only a small and insignificant increase in urine volume. Clearance of potassium was decreased. An increase in the clearance of uric acid and a rise in the beta-2-microglobulin excretion rate were found, both suggesting a proximal tubular effect of felodipine. The excretion rate of calcium was increased.     

Comparison of long-term renal hemodynamic effects of methyldopa and propranolol in patients with hypertension and renal insufficiency

Studies were carried out in 15 patients with renal insufficiency and hypertension to compare the long-term effects of methyldopa and propranolol on renal hemodynamics. Inulin and PAH clearance measurements were made under baseline conditions and four to six months of antihypertensive therapy with each of the two drugs. Eight of the 15 patients (group I) were started on methyldopa and then switched to propranolol; and in the other seven (group II), the sequence was reversed. There were no statistical differences in blood pressure or inulin or PAH clearances under baseline conditions between the two groups of patients. Blood pressure was controlled equally with the two drugs in combination with furosemide. In group I, there was no significant effect of either antihypertensive drug on inulin clearance, but PAH clearance was significantly higher during methyldopa than propranolol therapy. In group II, the same higher PAH clearance was found with methyldopa, even though the sequence of drug administration was opposite to that of group I. Challenge with iv furosemide resulted in a greater 3-hour natriuresis during methyldopa than propranolol treatment. The observations indicate that glomerular filtration rate (GFR) is not significantly affected by long-term treatment with methyldopa or propranolol but that renal plasma flow (RPF) is higher during treatment with methyldopa in patients with renal insufficiency and hypertension. The higher RPF apparently enhances the acute natriuretic effect of iv furosemide.     

Onset of cardiovascular action after oral ibopamine. Early hemodynamic effects of single and repeated doses in patients with idiopathic dilated myocardiopathy

The acute effects of ibopamine (active ingredient of Inopamil), an orally active dopaminergic agent, were invasively evaluated in 16 consecutive patients with idiopathic dilated cardiomyopathy (New York Heart Association Functional Class II and III) Single doses of 100 and 200 mg were administered to 7 and 9 patients, respectively, and two repeated doses of 100 mg were studied in 6 patients. In order to assess the onset of cardiovascular effect, control hemodynamic measurements were repeated 5, 10, 15, 20, 30, 60, 120, and 180 min after ibopamine 200 mg. Both the tested doses of ibopamine increased the mean pulmonary arterial pressure and the mean pulmonary wedge pressure, with a maximal effect 15 min after drug ingestion (+ 47.0 and + 65.4% in the 200 mg group, p less than 0.002). Pulmonary pressures returned to baseline or lower values beyond 60 min. Systemic arterial pressure showed a small transient increase (+ 7.9% in the 200 mg group at 15 min), but fell significantly below baseline after 120 min, a larger decrease occurring in the 100 mg group (p less than 0.05). Ibopamine had a slower but more prolonged effect on cardiac output (increase of up to 32.1% at 60 min) and systemic vascular resistances. Repeated doses (100 mg after an 8-h interval) elicited comparable cardiovascular effects. Oral ibopamine caused a significant increase in mean pulmonary arterial and capillary pressures as early as 5 min after drug ingestion, before cardiac output and peripheral vascular resistances were affected. A biphasic hemodynamic response was also observed after single and repeated low (100 mg) doses of ibopamine.     

Antihypertensive and hormonal effects of single oral doses of Captopril and Nifedipine in essential hypertension

Summary In a single-dose crossover study Captopril (SQ 14225), 1 mg/kg body weight, and Nifedipine (Bay a 1040) 20 mg were administered orally to 12 hospitalized patients with essential hypertension (Stage 1 or 2, W. H. O.). Both drugs significantly reduced blood pressure, but each dose acted differently: the mean maximum arterial pressure reduction was faster and greater with Nifedipine than with Captopril: –23±2% at 37±15 min and –17±1% at 86±25 min, respectively. Captopril inhibited angiotensin II and aldosterone production, but did not accelerate heart rate or stimulate vasopressin release. Nifedipine stimulated vasopressin release and increased heart rate, but the renin angiotensin aldosterone system was not significantly affected. The blood pressure reduction was related to the initial level of activation of the renin angiotensin system only for Captopril. The blood pressure reduction induced by one drug was not related to that produced by the other in the same patient.     

Natriuretic and diuretic effects of felodipine and hydrochlorothiazide after single and repeated doses

The effects of the calcium antagonist, felodipine, and hydrochlorothiazide (HCTZ) on natriuresis/diuresis and blood pressure were evaluated in 12 healthy subjects. The investigation was designed as a double-blind, three-way, randomised, crossover study, and all comparisons were performed against placebo. Urine volume, urine sodium excretion, heart rate and blood pressure were measured after a single dose of felodipine 10 mg, HCTZ 12.5 mg or placebo as well as during steady-state conditions (6 days of treatment with felodipine 10 mg b.i.d., HCTZ 12.5 mg b.i.d. or placebo).A significant increase in natriuresis was seen in the first 4 h after a single dose of felodipine and HCTZ, and the effect of felodipine was approximately 40% that of HCTZ. When the entire 24-h period after a single dose was studied, there was a significant increase in natriuresis after HCTZ, but not after felodipine, compared with placebo.A significant increase in diuresis was found in the first 4 h after a single dose of HCTZ, but not after felodipine, compared with placebo.Under steady-state conditions, there were no statistically significant differences between felodipine and placebo or HCTZ and placebo when the 24-h period, as a whole was considered.Potassium excretion was not affected by any of the drugs. Felodipine caused a significant decrease in diastolic blood pressure in this study. This was not the case for HCTZ or placebo.     

Pharmacokinetic and pharmacodynamic studies of felodipine in healthy subjects after various single, oral and intravenous doses

The objective of this single-dose study was to evaluate the pharmacokinetics and haemodynamic changes in healthy male subjects following the administration of three oral (5, 15, and 40 mg) and two intravenous (1 and 3 mg) doses of felodipine, a new calcium antagonist with a selective effect on the peripheral resistance vessels. Felodipine was rapidly absorbed within 1 h when administered as an oral solution, but underwent extensive presystemic elimination. The systemic availability varied between 10 and 23 per cent. The disposition was adequately described by a two-compartment model: the disposition was essentially dose-independent up to 40 mg orally and 3 mg intravenously. Felodipine produced significant dose-dependent reduction of diastolic blood pressure and a significant reflexogenic increase in heart rate, without having any major effect on systolic blood pressure. These changes indicate that felodipine acts predominantly as an arteriodilator. The decrease in diastolic blood pressure and increase in heart rate were closely correlated with the plasma concentrations of unchanged felodipine, being maximal at 0.5 h and lasting for at least 4 h after the highest dose.     

Pharmacokinetics of meropenem in patients with renal failure and patients receiving renal replacement therapy

Meropenem is a well established carbapenem antibacterial with a wide spectrum of activity against Gram-positive and Gram-negative bacteria, including beta-lactamase producers and Pseudomonas aeruginosa. Because of its clinical and bacteriological efficacy, meropenem is an important antimicrobial drug in the treatment of serious infections in adults and in children. Meropenem is predominately excreted unchanged in the urine, and thus dosage adjustments are necessary in patients with renal insufficiency and those undergoing intermittent haemodialysis (IHD) or various forms of continuous renal replacement therapy (CRRT), such as continuous venovenous haemodialysis, continuous venovenous haemodiafiltration (CVVHDF), continuous venovenous haemofiltration (CVVHF) or continuous ambulatory peritoneal dialysis (CAPD). The half-life of meropenem (approximately 1 hour in healthy volunteers) is prolonged up to 13.7 hours in anuric patients with end-stage renal disease. In patients receiving renal replacement therapy, half-life is influenced by drug-specific factors as well by membrane and treatment modalities (IHD, CRRT or CAPD). Plasma meropenem concentrations reach a peak of between 53 and 62 mg/L after the administration of meropenem 1g intravenously to healthy volunteers, up to 53 mg/L after meropenem 0.5g in haemodialysis patients, and between 18 and 45 mg/L after meropenem 1g during CRRT in critically ill patients. Approximately 50% of meropenem is eliminated by IHD, 25 to 50% by CVVHF and 13 to 53% by CVVHDF. Such differences are not negligible and demonstrate the great influence of the treatment modality on the elimination of the drug during renal replacement therapy. Thus, physicians run the risk of underdosing with this antimicrobial drug because of the quite different recommendations in the literature. Because of the excellent tolerability profile of meropenem, such underadministration should be avoided.     

Pharmacokinetics and clinical effects of alprazolam following single and multiple oral doses in patients with panic disorder

The anxiolytic triazolobenzodiazepine alprazolam was administered to six male patients, aged 26 to 46 years, with panic disorder or agoraphobia (with panic attacks) to assess clinical effects and steady-state pharmacokinetics following multiple dosing at three levels: 3.0 mg/d, 6.0 mg/d, and 9.0 mg/d. Multiple-dose kinetics of alprazolam were compared with alprazolam disposition after a 1.0-mg oral dose in the same patients. Kinetic variables after the single dose were very similar to those reported previously for healthy young male volunteers. Mean values were peak plasma concentration, 19 ng/mL; time of peak, 1.33 hours after dosage; elimination half-life, 10.0 hours; total oral clearance, 1.11 mL/min/kg. During multiple dosage, mean steady-state plasma concentrations (Css) was proportional to dosing rate, and steady-state clearance was independent of dosage. Clinical improvement was rapid, with the greatest decrement in symptoms at the 3-mg/d dosage, at a mean Css of 30 ng/mL. Further improvement was not seen at 6 mg/d (Css, 62 ng/mL), or at 9 mg/d (Css, 103 ng/mL). Side effects, however, were directly related to dosage and plasma level, and increased progressively in number at the 3-, 6-, and 9-mg/d dosage levels. Thus, the disposition of alprazolam in young male patients with panic disorder is essentially identical to that in healthy male volunteers of similar age. Alprazolam clearance is independent of dose and plasma concentration up to daily doses of at least 9 mg/d, with steady-state plasma level proportional to dosing rate.     

Comparison of the initial hemodynamic effects of immediate-release versus sustained-release isosorbide-5-mononitrate following single oral doses

In this double-blind, randomized, placebo-controlled cross-over study, the authors investigated the initial time course of effects of isosorbide-5-mononitrate (IS-5-MN) on hemodynamic parameters in 15 healthy male volunteers after administering a single oral dose of either an immediate-release formulation (IS-5-MN 20 mg) or of a sustained-release formulation (IS-5-MN 50 mg). The latter formulation released 15 mg IS-5-MN immediately, while 35 mg of the dose was sustained release. The onset of effect on the a/b-ratio of the finger pulse curve (20 minutes after administration) and on heart rate following orthostatic challenge (30 minutes) was not different following ingestion of either the immediate-release or the sustained-release formulation. Only the systolic blood pressure following orthostatic challenge was affected earlier after ingestion of the immediate-release form of IS-5-MN (10 vs. 30 minutes). There was no statistically significant difference in the maximum effect on the measured hemodynamic parameters between the two formulations. There was no significant difference with respect to the effect per dose between both of the active treatments (i.e., IS-5-MN 20 mg immediate release and IS-5-MN 50 mg sustained release) within 6 hours after administration. The hemodynamic findings were consistent with the observed rates of the increase of plasma concentrations of IS-5-MN following both formulations. Thus, the administration of the sustained-release formulation of IS-5-MN 50 mg caused similar maximum effects when compared with an immediate-release formulation (20 mg). While the onset of effect of IS-5-MN on the a/b-ratio of the finger pulse curve and on heart rate following orthostasis was similar after administration of either the immediate- or the sustained-release formulation, the onset of effect of the sustained-release formulation on systolic blood pressure orthostasis was determined slightly later. However, the latter difference seems to be of minor clinical relevance.     

Pharmacokinetics of baclofen in spastic patients receiving multiple oral doses

The pharmacokinetics of racemic baclofen as determined from plasma and urine data in six spastic patients treated with individualized oral doses, 30–80 mg daily, are presented. Peak plasma concentrations were achieved 1.9 h (±0.7) after a dose. The fluctuation in the plasma concentration was great, ranging from 188 to 439%. The total body clearance averaged 175 ml·min^–1 (±44), plasma protein binding 35% (±6). Baclofen was for the greater part excreted unchanged by the kidney, 65% (±16). Its apparent renal clearance equalled the creatinine clearance. The contribution of the renal clearance to the total body clearance can explain the previously described toxicity when renal impairment is present. The results agree with earlier reports on single doses in healthy subjects.     

Sustained haemodynamic effects of felodipine in patients with chronic cardiac failure.

1. The efficacy of felodipine a new calcium channel blocker with selective vasodilator activity in the management of severe low output cardiac failure, secondary to coronary heart disease, was determined in 10 patients. 2. Haemodynamic measurements were made at rest and during dynamic exercise and left ventricular function was assessed by radionuclide ventriculography. 3. Significant increases in cardiac index, stroke volume index and ejection fraction were found particularly during exercise, both acutely and following 4 weeks administration of felodipine therapy. 4. Felodipine could well have a significant role in the long term management of the patient with chronic cardiac failure.     

The acute haemodynamic and renal effects of oral felodipine and ramipril in healthy subjects

Summary The aim of the present investigation was to compare the acute haemodynamic and renal effects of the calcium antagonist felodipine with the ACE inhibitor ramipril and with placebo.Single oral doses of felodipine 5 and 20 mg, ramipril 2.5 and 10 mg, and placebo were given to ten healthy subjects in a double-blind cross-over study. Blood pressure, heart rate, forearm blood flow (FBF), forearm vascular resistance (FVR), renal blood flow (RBF), renal vascular resistance (RVR), glomerular filtration rate (GFR), filtration fraction (FF), diuresis, and sodium excretion were recorded for 4.75 h after administration.Felodipine 20 mg caused a significant fall in diastolic blood pressure, maximal 12 % compared with placebo, while there were no significant effects of felodipine 5 mg or the two doses of ramipril. Heart rate increased significantly after both doses of felodipine, maximal 28% after the 20 mg dose. There was also a small but significant increase in heart rate of 12% after ramipril 2.5 mg. FVR fell significantly after both doses of felodipine, maximal 38 % after the 20 mg dose. There were no significant changes in FVR after any of the ramipril doses. Both doses of felodipine and both doses of ramipril caused significant reductions in RVR. Maximal reduction, 33 %, was found after felodipine 20 mg. There were no significant changes in GFR or FF with either drug. Felodipine caused a significant increase in natriuresis, maximal 129% while ramipril did not.     

Tolerability of beta-blockers in outpatients with refractory heart failure who were receiving continuous milrinone

STUDY OBJECTIVE: To investigate the dosing, tolerability, and outcomes associated with the use of concomitant beta-blockers and inotropic therapy in patients with refractory heart failure during the first 6 months of their therapy. DESIGN: Retrospective review. SETTING: University-based, tertiary care heart failure and transplant center. PATIENTS: Sixteen inotrope-dependent outpatients with end-stage refractory heart failure who were receiving continuous intravenous milrinone. Of these patients, 12 also received an oral beta-blocker; the remaining four patients who did not receive beta-blockers served as the comparator group. MEASUREMENTS AND MAIN RESULTS: For each patient, the initial and final study drug doses of continuous intravenous milrinone and oral beta-blocker treatment, when applicable, were recorded over the 6-month period. Mean heart rate, blood pressure, ejection fraction, and oxygen consumption were measured, and 95% confidence intervals were calculated. Serum sodium and creatinine concentrations, as well as the creatinine clearance, were measured. In the 12 patients who received concomitant milrinone and beta-blockers, the mean baseline ejection fraction was approximately 18%, and they received milrinone for 18.6 weeks. Seven patients received carvedilol for 16.1 weeks, and five received metoprolol tartrate for 17.6 weeks. Dosages of the beta-blockers were titrated. Final daily doses were carvedilol 42.8 mg (95% confidence interval 20.3-65.4) and metoprolol 42.5 mg (95% confidence interval 28.0-57.2). Patients continued to receive other standard oral drug therapy for heart failure. One patient discontinued metoprolol and one discontinued carvedilol because of hypotension and/or worsening heart failure. Cardiac adverse events in the concomitant milrinone plus beta-blocker group were heart failure requiring hospitalization in 10 patients and ventricular arrhythmias in one. CONCLUSION: Inotrope-dependent patients with refractory end-stage heart failure tolerated continuous intravenous milrinone plus beta-blockers in addition to diuretics and vasodilators for the 6-month observation period. Beta-blocker dosages were titrated, and three patients achieved the target beta-blocker dosage established for stage A-C heart failure. Additional studies are needed to determine the optimal selection and dosing of drug combinations in this population.     

Antiarrhythmic and electrocardiographic effects of single oral doses of disopyramide

Summary Ten patients with various heart diseases and ventricular arrhythmia received a single oral dose of disopyramide (DE) 200 mg. The ECG was recorded continuously for about 50 h from 2–4 h before drug administration. A statistically significant reduction in the number of ventricular ectopic beats (VEBs) was seen 1.0–3.5 h after drug intake; the average number of VEBs per 30 min decreased from 317 during the control period to 92 by 1.0–3.5 h after treatment and if one patient who did not respond is excluded, the corresponding figures were 272 and 14, respectively. Consecutive VEBs were seen in seven patients before DE was given and decreased significantly (p<0.05) 1.5–5.5 h after drug administration. There was no change in the PQ interval, the QRS interval showed a slight increase, whereas the QT interval was prolonged 0.5–4 h after administration of DE. A specific gas chromatographic method was used for DE assay in plasma and urine. Absorption was rapid in all patients. Urinary excretion during the first 48 h after drug intake varied between 35 and 75%. The lowest effective antiarrhythmic concentration estimated in six patients ranged from 1.4 to 7.0 µg/ml. -Phase half-life in five patients was between 10.3 and 22.1 h.     

噻嗪类利尿药在高血压患者中的应用

利尿药是治疗高血压的重要药物,临床使用已经>50年,但目前临床使用中仍存在许多争议与问题。本文对噻嗪类利尿药治疗高血压的作用机制、药物分型与药代动力学、治疗高血压的循证证据、噻嗪类利尿药治疗高血压的临床地位和指南与共识推荐等进行综述。