Intravenous captopril in congestive heart failure

Hemodynamic and neurohumoral effects of intravenous captopril were studied in ten patients with severe chronic congestive heart failure (NYHA Functional Class III and IV). Incremental bolus doses of captopril, titrated to a maximum cumulative dose of 15 mg, were given at 10-minute intervals. Systemic arterial pressure, mean pulmonary capillary wedge pressure, systemic vascular resistance, mean pulmonary artery pressure, and heart rate decreased (P less than .05). Cardiac index and stroke volume index increased (P less than .05). Maximum hemodynamic effects occurred after cumulative doses of 7 mg and were seen within 30 minutes after initiation of therapy; responses persisted for 30-90 minutes after the last dose. Plasma renin activity increased, and plasma atrial natriuretic factor concentration decreased. No adverse effects were observed with the use of intravenous captopril. Thus, intravenous captopril produces rapid and favorable hemodynamic improvement in advanced heart failure patients.     

Acute and chronic effects of flosequinan on resting and exercise haemodynamics in congestive heart failure

1 The acute and chronic (8 weeks) haemodynamic responses to oral flosequinan have been investigated in 12 male patients of mean age 58.9 years with congestive heart failure of N.Y.H.A. classes II and III. 2 Flosequinan 125 mg orally significantly reduced right atrial pressure, pulmonary artery pressure and pulmonary wedge pressure prior to and following 8 weeks chronic treatment (125 mg daily). A significant decrease in systemic pressure and an increase in heart rate were also observed with acute flosequinan prior to chronic treatment. A reduction in systemic vascular resistance and an increase in cardiac index reached significance in response to flosequinan 125 mg orally following 8 weeks of therapy. 3 In the erect position, flosequinan reduced pulmonary wedge pressure and tended to reduce systemic vascular resistance, without decreasing mean arterial pressure. 4 Following chronic treatment, there was a trend towards a reduction in pulmonary wedge pressure and an increase in cardiac index, otherwise resting and exercise haemodynamics were unchanged. 5 The response to flosequinan was similar at week 1 and after 8 weeks of treatment for all of the haemodynamic parameters. 6 Flosequinan increased bicycle exercise times and attenuated exercise-induced increases in pulmonary arterial and systemic pressures. There was a trend towards an increase in treadmill exercise time. 7 Sublingual glyceryl trinitrate (0.5 mg) and oral flosequinan (125 mg) had similar effects on right atrial pressure, pulmonary arterial and pulmonary wedge pressures at 5 min and 2 h respectively post-dosing. A small additive effect on pulmonary arterial and wedge pressures was observed.     

Lack of correlation between the acute haemodynamic response to intravenous captopril and plasma concentrations of angiotensin II in patients with chronic cardiac failure

Summary We have given a series of incremental intravenous injections of captopril to ten patients with chronic cardiac failure.Small doses of captopril produced significant changes in pulmonary artery end-diastolic pressure and right atrial pressure, up to a total cumulative dose of captopril of 2.5 mg, after which further injections had no significant effect. There were large changes in systemic vascular resistance and blood pressure up to a cumulative dose of captopril of 5.0 mg, after which the injection of larger doses caused no further significant changes.Small doses of intravenous captopril produced large increases in plasma renin activity and plasma angiotensin I concentrations up to a total cumulative dose of captopril of 1.25 mg, after which there were no significant further changes in either plasma renin activity or plasma angiotensin I concentration. However the plasma concentration of angiotensin II fell more slowly, no further change being recorded after a total cumulative dose of captopril of 10 mg.These results suggest that plasma renin activity is not the only determinant of plasma angiotensin II concentrations.     

The acute haemodynamic effects of quinapril,a new non-sulfhydryl angiotensin converting enzyme inhibitor,in patients with severe congestive cardiac failure

Summary This study investigates the acute haemodynamic effects of Quinapril (CI-906) a new non-sulphydryl angiotensin converting enzyme inhibitor in 15 patients with refractory congestive cardiac failure. There were 14 males and 1 female mean age 59.5 years.After administration of Quinapril there was a significant reduction in mean arterial pressure (MAP) from 93.1 to 79 mmHg, systemic vascular resistance (SVR) from 1887 to 1349 dyn s cm^–5 and PCW from 27.3 to 15.3 mmHg. This was accompanied by an increase in CO from 3.7 to 4.7 l/min, cardiac index (CI) from 1.97 to 2.5 l/min/m² and Stroke volume index from 21.1 to 28.7 ml/m². There was no significant change in heart rate (HR), right atrial pressure (RAP), or pulmonary vascular resistance.The peak effect on pulmonary capillary wedge pressure (PCW) and cardiac output (CO) occurred at 75–120 min after Quinapril administration. The maximum effect on mean arterial pressure (MAP) occurred slightly later at 120–150 min. SVR and CI exhibited 2 periods of peak effects, at 90 and 180 min. This time course is very similar to that observed in studies on the acute effects of Captopril.The significant improvement in haemodynamic measurements acutely, following administration of Quinapril 5 mg orally, suggests that this drug is worthy of further study in the management of patients with refractory congestive cardiac failure, in particular its long term effects.     

Acute haemodynamic effects of urapidil in patients with chronic left ventricular failure

Summary Urapidil, a new alpha₁-adrenoceptor blocking drug, has been shown to be effective in the treatment of hypertension. Ten normotensive patients with severe congestive heart failure were given Urapidil 25 mg i.v. twice in 15 min and the haemodynamic effects were measured.There was a significant fall in systolic blood pressure (–16%), mean blood pressure (–13%), left ventricular end-diastolic pressure (–38%), mean pulmonary artery pressure (–31%) and wedge pressure (–40%). Total peripheral resistance fell by 25%, whereas pulmonary arteriolar resistance did not change significantly. Cardiac output increased by 22%.The increase in cardiac output with decreasing peripheral resistance and LV pressures suggests that urapidil may be useful in the therapy of congestive heart failure.     

Haemodynamic profile of captopril treatment in various forms of hypertension

Summary The effects of captopril 450 mg/day for 4 weeks on blood pressure, heart rate, cardiac output and extracellular fluid volume were compared in severe, often drug-resistant hypertension (n=23), mild to moderate hypertension associated with renal artery stenosis (n=10) and mild to moderate essential hypertension (n=20). Plasma renin in the three groups was 52±19, 58±17 and 20±4 µU/ml (mean ± SEM), respectively. Blood pressure fell by 18±4%, 21±2% and 18±1%. The pressure drop was mainly due to a fall in peripheral vascular resistance. Addition of the diuretic hydrochlorothiazide (25–100 mg/day) caused a further fall in resistance. Despite the vasodilator effect of captopril, reflex cardiostimulation and reactive fluid retention were not observed. In severe hypertension, captopril alone was more effective in lowering blood pressure than combined diuretic-betablocker-vasodilator therapy. Moreover, cardiac output in these patients was higher and resistance was lower after captopril than during combined treatment. Thus, captopril was capable of normalising the abnormal haemodynamic state in patients with essential hypertension, and in hypertension associated with renal artery stenosis. Despite marked differences in pre-treatment plasma renin, the effects of captopril on systemic haemodynamics were similar in all the patients.     

A randomized cross-over study of enalapril in congestive heart failure: Haemodynamic and hormonal effects during rest and exercise

Summary We performed a randomized double-blind placebo controlled cross-over study of enalapril in 16 patients with chronic congestive heart failure, to assess haemodynamic and hormonal effects at rest and on exercise. Acute effects were measured 4 h after enalapril 10 mg, and chronic effects after 6 weeks treatment with enalapril 10–20 mg per day.Exercise tolerance, assessed by the duration of a maximal bicycle ergometer test, was not altered by enalapril. Mean blood pressure was reduced after enalapril, at rest and on exercise, acutely by 7% and 8% respectively, and chronically by 14% and 16%. Systemic vascular resistance was reduced by 16% at rest both acutely (NS) and chronically (p<0.05). The resting pulmonary capillary wedge pressure was reduced by 28% with chronic treatment. In the acute study, total body oxygen consumption on exercise was 26% higher after enalapril. Chronically, resting oxygen consumption was reduced by 13% after enalapril, with mixed venous oxygen saturation increasing by 16%.In the acute study enalapril increased plasma renin activity at rest and on exercise by 181% and by 189%, and reduced aldosterone by 49% (NS) and 39% (p<0.05), and these effects were sustained after 6 weeks. Enalapril increased antidiuretic hormone concentrations at rest acutely by 73% (NS) and chronically by 34% (p<0.05) but not on exercise; the increase in the acute study correlated with plasma enalaprilat levels (r=0.66, p<0.05). Enalapril did not alter plasma catecholamine concentrations.Patients preferred enalapril to placebo, and radiographic heart size was reduced during chronic treatment. There were no serious adverse effects.We conclude that enalapril is an effective angiotensin converting enzyme inhibitor of clinical value in chronic heart failure, but study design and methods of assessment of benefit can have a major influence on the results of pharmacological studies in such patients.     

Hemodynamic and neurohumoral responses to intravenous nicorandil in congestive heart failure in humans.

Nicorandil is a vasodilator drug that combines potassium channel opening properties with nitrate effects. The resulting potent and unique vasodilating properties suggest a potential therapeutic role in congestive heart failure. We therefore studied the acute hemodynamic and neurohumoral responses to nicorandil, given as single intravenous bolus doses of 158, 251, 398, or 630 micrograms/kg, to 22 patients with chronic congestive heart failure (ejection fraction less than 40%). Hemodynamic responses occurred within 5 min of dosing and terminated within 240 min. The heart rate was significantly increased only at 5 min after the 158 micrograms/kg dose, and was unchanged after all other doses. The mean arterial pressure was reduced only by the 398 and 630 micrograms/kg doses. The pulmonary capillary wedge pressure and right atrial pressure were significantly reduced by all doses within the initial 30 min; this reduction in pulmonary capillary wedge pressure was better sustained over time by the two larger doses, whereas the reduction in right atrial pressure was sustained only by the 158 micrograms/kg dose. The cardiac index was reduced by the 158 micrograms/kg dose, but increased after 251, 398, and 630 micrograms/kg of nicorandil. Plasma nicorandil concentrations were positively correlated with changes in cardiac index, systemic arterial pressure, pulmonary capillary wedge pressure, heart rate, and systemic vascular resistance. When measured 1 h after dosing, plasma immunoreactive ANF decreased, norepinephrine concentrations did not change, and plasma renin activity increased, but only at the 630 micrograms/kg dose level.(ABSTRACT TRUNCATED AT 250 WORDS)     

Acute haemodynamic and neurohumoral effects of intravenous nisoldipine in patients with severe congestive heart failure

Summary Twenty patients (5 females, 15 males) with severe heart failure (NYHA IV), due to coronary artery disease in 14, and congestive cardiomyopathy in 6, received an intravenous bolus of the calcium blocker nisoldipine 0.2 mg followed by a continous infusion of 0.2 g · kg^–1 · min^–1. Haemodynamic measurements were performed at baseline and after 30 min.The mean arterial pressure fell from 91 to 73 mm Hg, pulmonary capillary wedge pressure from 31 to 26 mm Hg and systemic vascular resistance from 1695 to 1040 dyn · s · cm^–5.The cardiac index (2.2 to 2.71 · min^–1 · m^–2, and stroke volume index (25 to 33 ml · m^–2) were markedly increased. There was no reflex tachycardia as the heart rate dropped from 92 to 85 beats · min^–1. Plasma renin activity and norepinephrine concentration did not change significantly.The findings indicate that nisoldipine acts as a strong vasodilator and that it has a beneficial acute haemodynamic effect in patients with severe left heart failure irrespective of its aetiology.     

EFFECTS OF 1-SAR-8-ALA-ANGIOTENSIN II ON SYSTEMIC AND PULMONARY HAEMODYNAMICS IN HYPERTENSIVE PATIENTS

1.The angiotensin II antagonist, 1-Sar-8-Ala-angiotensin II (saralasin), was infused intravenously at a rate of 10 μg/kg per min in thirty-three hypertensive patients, on a normal sodium diet (130 mmol per day) and/or during sodium depletion by low sodium diet (20 mmol per day) and chlorthalidone. 2. In both series, saralasin induced a transient rise in intra-arterial pressure (P < 0.01), accompanied by a slight decrease in heart rate (P < 0.01). The elevation of systolic arterial pressure reached its maximum after 4 min and was more pronounced in sodium-replete patients. Plasma noradrenaline was significantly elevated by 29.7% (P<0.01), but the rise in pressure was not related to concomitant changes in plasma noradrenaline. 3. After the initial pressor effect, arterial pressure, heart rate, cardiac output and total peripheral resistance remained unchanged in the sodium-replete patients, while in the sodium-depleted conditions mean arterial pressure and peripheral resistance were reduced, by 17.8% and 18.6% (P< 0.001) respectively, within 60min. Reflex increases in heart rate (+3.8%) and cardiac output (+ 11.1%) occurred after 10 min (P<0.05), but were not sustained thereafter. 4. Pulmonary vascular resistance was not affected by saralasin. In sodium-depleted patients, pulmonary capillary wedge pressure decreased by 1.2mmHg (P<0.01), with parallel changes of pulmonary artery pressure (P< 0.01).     

Controlled,eight-hour haemodynamic study of a sustained-release formulation of isosorbide dinitrate in moderate left ventricular failure

Summary The aim of the study was to assess the duration of the haemodynamic effects of a new sustained-release oral formulation of isosorbide dinitrate (ISDN). Twenty patients (17 men and 3 women; mean age 60 years) with acute myocardial infarction (10 anterior, 10 inferior) complicated by moderate left ventricular failure took part in a randomized controlled trial. Ten patients were randomly assigned to the placebo group and 10 to the ISDN group, who received 40 mg sustained release isosorbide dinitrate. Haemodynamic variables were measured before treatment, after 0.5 and 1 h and then every 2 hours up to the 8th hour after treatment. There was no significant change in any haemodynamic parameter in the placebo group, during the study period. In the ISDN group there was a significant fall in pulmonary artery diastolic pressure at 4 and 8 h, from 19.0±1.0 mmHg to 16.5±1.2 mmHg and 15.5±0.8 mmHg, respectively. The mean pulmonary capillary wedge pressure fell progressively from 17.9±1.0 to 12.5±1.2 mmHg at 2 h (p<0.001 in comparison with the placebo group. The fall remained significant up to 8 h. There was no statistically significant change in heart rate, cardiac index, systemic blood pressure or systemic and pulmonary vascular resistances. On the whole the cardiac index remained unchanged. There were numerous individual variations of cardiac index in relation to the initial mean pulmonary capillary wedge pressure and the magnitude of its fall following administration of ISDN. The change in cardiac index was inversely correlated with the control cardiac index (r=–0.69, p<0.02).     

Comparative hemodynamic effects of intravenous dobutamine and dibutyryl cyclic AMP, a new inotropic agent, in severe congestive heart failure.

In nine patients with chronic congestive heart failure, the acute hemodynamic response to intravenous (i.v.) dibutyryl cyclic AMP (DBcyclicAMP) administration was compared with i.v. dobutamine administration. Both agents led to a significant and similar increase in cardiac index. Dobutamine caused a significant increase in mean arterial pressure but did not produce a significant change in pulmonary capillary wedge, mean pulmonary artery, or mean right atrial pressures. In contrast, DBcyclicAMP caused a significant decrease in mean arterial, mean pulmonary capillary wedge, mean pulmonary artery, and mean right atrial pressures, reflecting vasodilator activity. The fall in systemic vascular resistance was larger after DBcyclicAMP than after dobutamine. DBcyclicAMP achieves an optimal improvement in cardiovascular hemodynamics in concert with substantial vasodilating effect. This pharmacologic action constitutes the mainstay of i.v. therapy for severe congestive heart failure (CHF).     

贝前列素钠对慢性左心衰竭合并肺动脉高压患者的影响

目的 探讨贝前列素钠对慢性左心衰竭合并肺动脉高压患者的疗效和安全性.方法 选择慢性左心衰竭合并肺动脉高压患者50例,采用随机数字表法分成两组,分别给予常规治疗(常规组)和常规治疗基础上加贝前列素钠治疗(贝前列素钠,口服,每次40μg,每日3次),疗程12周.对所有患者进行基线评估,包括美国纽约心脏病学会(NYHA)分级、6 min步行距离(6MWT)、Borg呼吸困难评分、心肺血流动力学参数及脑钠肽(BNP)等,治疗随访12周后重复上述检查.结果 与常规组比较,贝前列素钠组治疗12周后NYHA功能分级、6MWT[(350±106)m比(320±101)m]、Borg呼吸困难评分[(3.0±2.4)分比(3.8±2.6)分]、肺动脉收缩压[(56±13)mmHg比(67±15)mmHg]、平均肺动脉压[(33±6)mmHg比(40±8)mm-Hg]和肺循环阻力[(3.5±1.5)WU比(4.6±1.6)WU]及肺毛细血管楔压均明显改善,差异有统计学意义(P<0.05).药物相关不良反应:贝前列素钠组用药初期1例患者有头痛伴面部潮红,1例患者出现恶心、呕吐,均可耐受,1周后症状消失.结论 贝前列素钠可改善慢性左心衰竭合并肺动脉高压患者的运动耐力、心肺血流动力学参数和临床症状且安全.     

硝苯地平与卡托普利单用及联合应用对低氧性肺动脉高压的作用

目的 :探讨硝苯地平与卡托普利单用及联用对低氧性肺动脉高压 (PAH)的作用。方法 :30例慢性阻塞性肺疾病 (COPD)合并肺心病病人 ,通过Swan_Ganz导管分别观察了硝苯地平 2 0mg舌下含服与卡托普利 2 0mg静脉注射 ,单用或 2药联用 3组各 10例对平均肺动脉压 (MPAP)等血流动力学参数的影响。结果 :硝苯地平无明显降低MPAP、肺血管阻力 (PVR)的作用 (P >0 .0 5) ,但却显著降低体循环平均压 (MAP )、动脉血氧分压Pao2 (P <0 .0 1,P <0 .0 5)。卡托普利可显著降低MPAP和PVR(P <0 .0 5) ,对MAP和Pao2 无明显的影响。 2药联用可更显著地降低MPAP、PVR (P <0 .0 1)。结论 :卡托普利是治疗低氧性PAH的一个有效药物 ,与硝苯地平联用有协同作用     

Comparison of the effects of dilevalol and propranolol on systemic and regional haemodynamics in healthy volunteers at rest and during exercise

The effects of single oral doses of dilevalol 400 mg and propranolol 80 mg on systemic and regional haemodynamics at rest and after sub-maximal exercise, were compared, in a placebo-controlled, randomised, double-blind, crossover study in 6 healthy male volunteers.At rest, as compared to placebo, neither dilevalol nor propranolol significantly affected arterial pressure and heart rate but, whereas propranolol decreased cardiac output (–27% at 2 h) and tended to increase total peripheral resistance, dilevalol tended to increase cardiac output and decreased total peripheral resistance (–7% at 2 h). Neither dilevalol nor propranolol affected brachial artery diameter. Propranolol tended to decrease brachial artery flow (–20% at 2 h) and to increase brachial vascular resistance (+25% at 2 h), but dilevalol did not and the brachial irrigation ratios did not change. Neither of the drugs affected carotid haemodynamics or plasma atrial natriuretic factor. Both drugs tended to decrease plasma renin activity, and dilevalol (+82% at 2 h) increased norepinephrine more than propranolol (+19% at 2 h).After exercise, dilevalol and propranolol produced similar falls in the induced increases in arterial pressure, heart rate and cardiac output, and had the same effects on regional haemodynamics, plasma renin activity and atrial natriuretic factor. Finally, dilevalol greatly increased plasma norepinephrine.We conclude that the ₂-adrenoceptor agonist activity of dilevalol was clearly expressed at rest, thus inducing vasodilation and counteracting the -adrenoceptor blockade-induced negative chronotropic and inotropic effects. However, during sub-maximal exercise, only the -adrenoceptor antagonist activity of dilevalol was apparent.     

Isosorbide-5-mononitrate in the treatment of acute left ventricular failure following acute myocardial infarction

Summary Eleven patients with acute left ventricular failure following acute myocardial infarction (mean pulmonary capillary wedge pressure [PCW]>20 20 mmHg) were entered into an open, haemodynamic study of oral isosorbide-5-mononitrate (ISMN). Left ventricular failure was resistant to intravenous diuretic therapy. No patient received concurrent cardioactive drugs nor further diuretic therapy during the study period. Haemodynamic data were acquired via a flow-directed thermodilution catheter placed in the pulmonary artery. Baseline data were acquired prior to the intravenous administration of an ISMN challenge. Thereafter, oral ISMN (20 mg, 8 hourly) was administered over 48 h.Following intravenous ISMN challenge, mean PCW fell from 26.2 to 17.5 mmHg. Cardiac index fell from 2.4 to 2.3 l/min/m² due to a fall in heart rate (103 to 96.8 beats/min) as stroke volume and blood pressure were unchanged. At 8 h following ISMN, two patients were withdrawn due to hypotension (systolic pressure <85 mmHg). In the remainder, PCW remained acceptable throughout 48 h (13.1 mmHg at 48 h), cardiac output, systemic blood pressure and heart rate showed no further significant change.These data suggest that ISMN is effective in the treatment of acute left ventricular failure following acute myocardial infarction.     

Effects of a new angiotensin-converting enzyme inhibitor, alacepril, on changes in neurohormonal factors and arterial baroreflex sensitivity in patients with congestive heart failure

Objective: Patients with heart failure have abnormal neurohormonal regulation during orthostatic stress, and abnormal arterial baroreflex function. This study investigated the effects of alacepril, a new angiotensin-converting enzyme inhibitor with sulfhydryls, on changes in neurohormonal factors during tilt and on the arterial baroreflex control of heart rate. Methods: Plasma concentrations of noradrenaline, adrenaline, renin activity, angiotensin II, and atrial natriuretic peptide were measured at supine rest and after 30° head-up tilt with measurements of central venous pressure and cardiac dimensions in seven patients with congestive heart failure (65 years, ejection fraction = 34%). Arterial baroreflex control of heart rate was assessed by phenylephrine bolus. The arterial baroreflex test was re-examined 3 h after oral alacepril (37.5 mg). The tilt and arterial baroreflex tests were repeated 12 weeks after alacepril treatment (50 mg␣·␣day⁻¹). Results: Heart rate, blood pressure, and neurohormonal factors did not differ before and after chronic alacepril, except for a trend toward an increase in renin activity (2.0 vs 4.9 ng · ml⁻¹· h⁻¹). Head-up tilt decreased central venous pressure (−2.5 mmHg) with a decrease in cardiac dimensions in the pre-alacepril phase. These changes were accompanied by increases in noradrenaline, adrenaline, and angiotensin II and a decrease in atrial natriuretic peptide. After chronic alacepril, the increase in noradrenaline during head-up tilt tended to be smaller (84 vs 30 pg · ml⁻¹), with similar changes in central venous pressure (−3.4 mmHg) and cardiac dimensions. Both acute (3.6 vs 4.8 ms · mmHg⁻¹) and chronic (3.6 vs 6.7 ms · mmHg⁻¹) alacepril treatment was associated with a trend towards an increase in the arterial baroreflex control of heart rate. Conclusion: These results suggest that treatment with alacepril may cause a reduction of sympathetic activation during orthostatic stress and may enhance arterial baroreflex function in patients with mild to moderate heart failure. Received: 25 June 1997 / Accepted in revised form: 20 January 1998     

雾化吸入硝酸甘油对慢性肺心病血流动力学的影响

目的 观察雾化吸入硝酸甘油对慢性肺心病血流动力学的影响.方法 将60例符合条件的慢性肺心病住院患者随机分为治疗组和对照组.对照组给予常规治疗,治疗组在常规治疗的基础上加用雾化吸入硝酸甘油,3d后观察二组的临床疗效.结果 治疗组显效率73.3%,总有效率为90.0%;对照组显效率为46.7%,总有效率为67.2%,治疗后二组疗效对比,显效率和总有效率差异均有统计学意义(P＜.05).雾化吸入硝酸甘油10 min、60 mim、1 d、2 d和3 d右室射血前期(RPEP)/加速时间(AT)、肺动脉平均压(PAMP)均较吸入前基础值明显下降(P＜.05).而HR、平均动脉压(MAP)、肺动脉峰值血流速度(PA)及雾化吸入硝酸甘油后与吸入前基础值相比均无明显变化(P＜0..05).结论 雾化吸入硝酸甘油可以降低慢性肺心病肺动脉高压,改善肺动脉高压患者肺循环的血流动力学,而对体循环无明显影响.     

A pharmacokinetic and pharmacodynamic evaluation of buffered sublingual captopril in patients with congestive heart failure

Objective: The pharmacokinetics and pharmacodynamics of buffered sublingual captopril were assessed in patients with congestive heart failure (CHF). Methods: The study was carried out in a randomised single-blind cross-over fashion (n=6, 4 males and 2 females) and involved two study days, at least 7 days apart. Baseline measurements were carried out for plasma renin activity (PRA), blood pressure (B.P.) and heart rate (H.R.). Captopril (12.5 mg) was administered sublingually with dibasic potassium phosphate which maintained salivary pH at 7, or perorally with 100 ml of water. Further B.P., H.R. measurements and venous blood samples were taken over a 3 hour period post-drug administration. Blood samples were analysed for captopril and PRA levels. Results: t_max after buffered sublingual administration of captopril, which ranged from 40–60 min (median=40 min), was significantly shorter than after peroral administration (range 60–120 min, median=90 min). C_max was slightly greater after buffered sublingual than after peroral administration with mean values of 108.2 vs. 94.0 ng·ml^–1. AUC values were similar after both routes of administration. Systolic and diastolic B.P. vs. time profiles for each administration method were significantly different i.e. sublingual administration produced an earlier reduction in B.P., however, HR did not differ significantly between the two routes. Conclusion: The data indicate that this novel administration method of captopril leads to an increased rate, but an unchanged extent of captopril absorption, suggesting a modest therapeutic advantage with the use of buffered sublingual captopril if a rapid reduction in blood pressure is required.     

Comparative Haemodynamic Responses to the First Dose of Short- and Long-acting ACE Inhibitors in Patients with Congestive Heart Failure

Summary

Background: Angiotensin Converting Enzyme inhibitors (ACEi's) confer significant mortality and morbidity benefits in all functional grades of chronic heart failure (CHF). However, physicians' concerns regarding the possible occurrence of first-dose hypotension appear to be a contributing factor to their under-utilisation in both hospital and primary care settings. We investigated whether long-acting and short-acting ACEi's differ in their haemodynamic responses to the first-dose in patients with CHF.

Method: This was a multicentre, randomised, open, two-parallel-group study of captopril 6.25?mg and perindopril 2mg. 240 patients with CHF, age 68.9?±?8.9 years, of whom 66% were male, NYHAII—IV, with average blood pressure baseline values of 132.2?±?16.2/78.5?±?10.5mmHg for systolic and diastolic blood pressure, and left ventricular ejection fraction (LVEF) of 31.3?±?7.4% received either captopril (n?=?124) or perindopril (n?=?116). Blood pressure was continuously monitored during the 8?h following drug intake. Minimum levels and maximum decreases in systolic, diastolic and mean arterial pressures were measured, along with the incidence of hypotensive episodes defined as mean blood pressure (MBP) fall?>?20mmHg, whether symptomatic or not. Subgroups of patients distributed according to age, baseline blood pressure (BP) and LVEF were subsequently analysed.

Results: Overall, a statistically significant treatment effect in favour of perindopril was observed. First-dose hypotension was observed more frequently following captopril than perindopril administration, with lower MAP minimal levels (78.0?±?8.9 vs. 84.5?±?10.1?mmHg, p?<?0.0001), greater maximum falls (17.6?±?8.3 vs. 12.8?±?7.3mmHg, p?<?0.0001) and more frequent hypotensive episodes (42% vs. 15%, p?<?0.0001). The incidence of at least one symptomatic episode was also significantly higher with captopril (10 patients vs. one patient, p?=?0.029). Subgroup analyses according to age (< 70 years or > 70 years) or LVEF (< 30% or > 30%) reflected the main result.

Conclusion: Initiation of treatment with ACE inhibitors is associated with different haemodynamic and clinical tolerances in CHF patients, regardless of their risk for hypotension, with possible clinical implications.