Trefor Morgan

Brachial Blood Pressure But Not Carotid Arterial Waveforms Predict Cardiovascular Events in Elderly Female Hypertensives

Central arterial waveforms and related indices of large artery properties can be determined with relative ease. This would make them an attractive adjunct in the risk stratification for cardiovascular disease. Although they have been associated with some classical risk factors and the presence of coronary disease, their prospective value in predicting cardiovascular outcomes is unknown. The present study determined the relative predictive value for cardiovascular disease–free survival of large artery properties as compared with noninvasive brachial blood pressure alone in a population of elderly female hypertensive subjects. We measured systemic arterial compliance, central systolic pressure, and carotid augmentation index in a subset of female participants in the Second Australian National Blood Pressure Study (untreated blood pressure 169/88±12/8 mm Hg). There were a total of 53 defined events during a median of 4.1 years of follow-up in 484 women with complete measurements. Although baseline blood pressures at the brachial artery predicted cardiovascular disease–free survival (hazard ratio [HR], 2.3; 95% CI, 1.3 to 4.1 for pulse pressure ≥81 versus <81 mm Hg; P=0.01), no such relation was found for carotid augmentation index (HR, 0.80; 95% CI, 0.44 to 1.44; P value not significant) or systemic arterial compliance (HR, 1.25; 95% CI, 0.72 to 2.16; P value not significant). Blood pressure, but not noninvasively measured central arterial waveforms, predict outcome in the older female hypertensive patient. Thus, blood pressure measurement alone is superior to measurement of arterial waveforms in predicting outcome in this group.

Clinical Pharmacokinetics and Pharmacodynamics of Carvedilol

SummaryCarvedilol is an arylethanolamine that is a racemic mixture of 2 enantiomers. The S-(−)-enantiomer has β-adrenoceptor blocking activity, while the racemate also has α1-receptor blocking activity due to the activity of the R- (+)-enantiomer. The drug is rapidly absorbed and undergoes extensive first-pass metabolism in the liver. It reaches a peak concentration 1 to 2 hours postdose and has an elimination half-life of about 4 to 7 hours. Absorption is delayed by food.The drug is highly lipophilic and is highly protein bound. The drug is metabolised by the liver, with some metabolites having biological activity. The pharmacokinetic profile is not altered in the elderly or in patients with renal disease. However, bioavailability of the oral medication is greatly increased in patients with liver disease.Carvedilol lowers blood pressure as a result of its β-blocking and vasodilatory activity. The reduction in blood pressure is similar to that achieved with other antihypertensive drugs, and there are no adverse effects on renal or cerebral blood flow. Carvedilol has been used in small numbers of patients with cardiac failure. It reduces left ventricular hypertrophy and has no significant adverse metabolic effects.

Ace inhibitors, beta-blockers, calcium blockers, and diuretics for the control of systolic hypertension*

The objective of this study was to determine which of the common groups of antihypertensive drugs is most effective at lowering systolic blood pressure (SBP) in elderly patients with previously untreated hypertension and the percentage of patients controlled with single or sequential monotherapy. Subjects were recruited from patients attending other outpatient clinics and entered into the study if their SBP was more than 150 mm Hg after three visits. Patients were given a low and high dose of each of the main classes of drugs or placebo for 1 month each. The study was a balanced, randomized crossover design with five periods: placebo; angiotensin converting enzyme inhibitors; beta-blocking drugs; calcium-blocking drugs; and thiazide diuretics. Blood pressure (BP) was measured 24 to 26 h after the previous dose. A questionnaire for side effects was administered at each visit. Seventy-four patients entered the study. beta-Blockers could not be used in 15 patients because of asthma or bronchospasm and these had two placebo periods. There were 9 of 66 patients on P, 9 of 46 on beta-blockers, 4 of 65 on calcium-blocking drugs, 4 of 65 on diuretic, and 1 of 62 patients on ACE inhibitors who did not progress to the higher dose because of side effects. Decreases in SBP compared to randomized placebo were calcium-blocking drugs 15 mm Hg = diuretic 13 mm Hg > ACE inhibitors 8 mm Hg = beta-blockers 5 mm Hg. Blood pressure decrease correlated with placebo BP (P < .0005, r = 0.53 to 0.70). When corrected for placebo, target SBP (<140 mm Hg) was reached in between 6% to 15% of patients on monotherapy. Sequential monotherapy achieved target in 29%. Angiotensin converting enzyme inhibitors, calcium-blocking drugs, and diuretics had no more side effects than placebo. Patients on beta-blockers had more side effects and the well-being score was reduced. Diuretics and calcium-blocking drugs are more effective in elderly patients at lowering SBP pressure. beta-Blockers were relatively ineffective, were frequently contraindicated, and had more side effects. Monotherapy achieved control in only a small number of patients. In elderly people with essential hypertension, therapy should be instituted with diuretics or calcium-blocking drugs, but combination therapy will usually be required to achieve goal.

The effect of nonsteroidal anti-inflammatory drugs on blood pressure in patients treated with different antihypertensive drugs

Hypertension and arthritis are both common diseases in the older age group and require pharmacologic treatment. Nonsteroidal anti‐inflammatory drugs (NSAIDs) alter renal function if given in high enough doses, reducing renal blood flow and the glomerular filtration rate and causing sodium retention. In salt sensitive subjects, this retention of sodium will cause blood pressure to rise. Salt sensitivity is more common in elderly patients, in diabetics, and in people with renal failure. When most antihypertensive drugs are used, people become salt sensitive, as shown by the additive effect of salt restriction or diuretics on blood pressure response. The responses to dihydropyridine and possibly other calcium channel blocking drugs are not affected to any major extent by sodium intake or by diuretics. Studies are described which indicate that indomethacin elevates blood pressure in elderly people treated with enalapril, but not in people whose blood pressure is controlled with amlodipine or felodipine. It is unclear whether the various NSAIDs have different effects on blood pressure. It is proposed that if the same analgesic effect is achieved with the same amount of cyclooxygenase inhibition, the response will be similar. Aspirin, used in a prophylactic dose, does not inhibit to this extent and does not elevate blood pressure. If elderly people require NSAIDs, it would appear that dihydropyridine calcium channel blocking drugs are more effective at lowering and maintaining blood pressure control and should be one of the drugs used. If patients are on other antihypertensive agents, it is important to monitor blood pressure when a NSAID is added to therapy.

The relationship of plasma levels of pindolol in hypertensive patients to effects on blood pressure, plasma renin and plasma noradrenaline levels

1 Fifteen, previously untreated, hypertensive patients were given 20 mg of pindolol, orally. The systolic and diastolic blood pressures fell significantly in 1 h; the effect was maximal 4 h after pindolol, and persisted for at least 8 h. 2 After oral administration of 20 mg of pindolol, its concentration in the plasma reached a peak in 2–3 h. At the end of 8 h, pindolol was not detectable in the plasma. 3 There was a significant relationship between the peak concentration of pindolol in plasma and the maximal change in blood pressure in fifteen previously untreated hypertensive patients. In a separate study of ninety‐nine hypertensive outpatients taking 15–80 mg of pindolol daily, the blood pressure responses corresponded generally to the concentration of pindolol in plasma 2–3 h after the morning dose. 4 There were no significant changes in plasma renin activity, plasma renin concentration or plasma noradrenaline concentration in the previously untreated patients taking 20 mg of pindolol. There was no relationship between initial plasma renin or noradrenaline levels and blood pressure responses to pindolol. Nor was there any significant relationship between the changes in plasma renin or noradrenaline levels and the changes in blood pressure.

Long-term efficacy of a new, fixed, very-low-dose angiotensin-converting enzyme-inhibitor/diuretic combination as first-line therapy in elderly hypertensive patients

Objective To determine the long-term efficacy and safety of a fixed, very-low-dose tablet combining one-half the standard dose of perindopril with one-quarter the standard dose of indapamide as first-line treatment in elderly patients. Design Double-blind, randomized, placebo-controlled study in an outpatient setting. Patients and interventions Following a single-blind, placebo run-in period of 4 weeks, patients [65–85 years, with mild-to-moderate essential hypertension or isolated systolic hypertension (ISH)] were randomized to receive one tablet of perindopril 2 mg/indapamide 0.625 mg (Per/ Ind) (n = 193) or placebo (n = 190), daily for 12 weeks. After this first 12-week period, all patients on Per/Ind (n = 138) and patients responding to placebo (n = 61) were maintained on their previous regimen for a further 48 weeks. Patients in the placebo group whose blood pressure was not normalized, were switched to Per/Ind (n = 60). Main outcome measure The primary endpoint was the proportion of patients with blood pressure that normalized between weeks 0 and 60. Results After 1 year of treatment (intention-to-treat) supine systolic and diastolic blood pressure decreased by 23.0 ± 15.3 mmHg and 13.3 ± 9.4 mmHg with Per/Ind (n = 253: 193 from randomized Per/Ind group and 60 from the placebo group switched at week 12). The mean decreases in systolic blood pressure were similar in essential hypertension and ISH (systolic blood pressure 23.2 versus 22.7 mmHg, respectively). Per/Ind treatment (n = 253) achieved an initial normalization of blood pressure in 96.2% [95% confidence interval (CI) 93.6–98.9%; Kaplan-Meier estimate] of Per/Ind-treated patients; 79.8% (95% CI 74.1–85.5%) of these maintained a normalized blood pressure throughout the 1-year follow-up. The incidence of adverse events was similarly low in the placebo and active therapy groups. Efficacy and safety results for the over 75 years subgroup were similar to those for the younger elderly subjects Conclusions The fixed, very low-dose combination of perindopril 2 mg/indapamide 0.625 mg results in sustained blood pressure control when used as first line treatment of elderly hypertensive patients over 1-year, and is well-tolerated.

Similar Effects of Treatment on Central and Brachial Blood Pressures in Older Hypertensive Subjects in the Second Australian National Blood Pressure Trial

The Second Australian National Blood Pressure Trial reported better prognosis for hypertensive subjects randomly assigned to an angiotensin-converting enzyme inhibitor (ACE-I) compared with a diuretic-based regimen despite no difference in brachial blood pressure control. A possible explanation is that there was a difference in central aortic pressures despite similar brachial pressure reductions. We examined this hypothesis in a subset of the Second Australian National Blood Pressure Trial cohort evaluated both before and after 4 years of treatment. The average age of the 479 subjects was 71.6±4.7 years (mean±SD), and 56% were women. Brachial systolic and pulse pressures after treatment were 145±1 (mean±SEM), 143±1, 72±1, and 70±1 mm Hg for diuretic and ACE-I groups, respectively. The respective changes from pretreatment values were −17±2, −16±2, −9±1, and −7±1 mm Hg. None of the differences between diuretic and ACE-I groups were significant. Central arterial pressure waveforms were acquired from carotid tonometry and calibrated from brachial pressures. Central systolic and pulse pressures posttreatment were 144±2, 144±2, 71±2, and 72±2 mm Hg for diuretic and ACE-I groups, respectively. The respective changes from pretreatment values were −15±2, −17±2, −6±2, and −8±2 mm Hg. None of the differences between diuretic and ACE-I groups were significant. The similarity of central and brachial pressures in this cohort of older hypertensive subjects is most likely because of the influences of age and hypertension in increasing arterial stiffness. There is no evidence that the better prognosis for patients randomly assigned to ACE-I in Second Australian National Blood Pressure Trial resulted from a disproportionate lowering of central blood pressure.

Interaction between sodium intake, angiotensin II, and blood pressure as a cause of cardiac hypertrophy ☆

Cardiac hypertrophy is common in hypertension but its development is influenced by angiotensin II, sodium intake aldosterone, and the time of day blood pressure (BP) is elevated. This study examined and compared cardiac hypertrophy in the 2 kidney-1 clip (2K-1C) and 1 kidney-clip (1K-1C) Goldblatt models of hypertension. Blood pressure was measured by telemetry in a selected group of rats. Rats were placed on a high (4%) or reduced (0.2%) salt intake and were given captopril (75 mg/kg per day) or losartan (10 mg/kg per day). Appropriate sham-operated and untreated controls were used. Cardiac hypertrophy was greater in the IK-1C than in the 2K-1C model. Day and sleep BP were also higher. In the 2K-1C model BP was lower on the reduced salt intake and BP decreased with captopril in both reduced and high salt groups. Cardiac weight and index decreased significantly only in the reduced salt and captopril group and was less than the size before treatment. In the 1K-1C model captopril caused all BP measures to decrease in the reduced salt group but had no significant effect in the high salt group. Cardiac weight and index were reduced only in the reduced salt + captopril group and cardiac weight was less than the pretreatment control. Losartan had a similar effect in the lK-1C model to that achieved with captopril. The responses achieved correlated in part with renin status and dependency level. There is no prime determinant of cardiac hypertrophy. Blood pressure, sodium intake, and hormonal status are all important. It is postulated that the common pathway may be alterations in cell composition that signal the nucleus to increase cell growth.

Renin secretion at the individual nephron level.

SummaryBlood was collected from the descending aorta, from a renal efferent arteriole and from the renal vein of a rat. The renin concentrations of the blood samples were measured. The renal vein renin concentration was 673±81 (SE) ng ml−1 h−1 which was significantly higher than the concentration in the aorta of 456±50 (SE) ng ml−1 h−1. The concentration of renin in the renal efferent arteriole was significantly lower than that in the aorta. These observations imply that net renin secretion is a combination of two processes; removal between artery and efferent arteriole and entry between efferent arteriole and renal vein. It appears that renin is released into the interstitium and enters the circulation at the capillary level rather than being released into the afferent or efferent arterioles. This mode of secretion supports the suggestion that the renin angiotensin system may primarily work intra-renally rather than through the systemic circulation.

Effects of combined administration of ACE inhibitor and angiotensin II receptor antagonist are prevented by a high NaCl intake.

Background To prevent the action of angiotensin II by blockade with either an angiotensin converting enzyme inhibitor (ACE I) or an angiotensin receptor antagonist (ARA) is difficult due to the physiological compensations. Combined therapy with both drugs may enable complete blockade, and in rats in high doses this has produced a syndrome that results in death. Objective To determine the effect of combined blockade using losartan (10 mg/kg per day) and perindopril (6 mg/kg per day) on blood pressure, cardiac growth, renal function and behaviour, and to determine how this is influenced by different salt intakes in normotensive Sprague Dawley rats. Methods Rats were fed an 0.2 or 4% NaCl diet and received the above drugs intraperitoneally. Blood pressure was measured by telemetry. Cardiac weight was measured after 10 days of therapy. Renal function was assessed by plasma creatinine and electrolytes, plasma renin and angiotensinogen concentrations were measured. Results On 0.2% NaCl intake, combined blockade lowered blood pressure progressively; at day 7, rats on 0.2% NaCl developed a syndrome of listlessness and failure to eat which led to loss of weight and death. Cardiac size was dramatically reduced. Plasma creatinine was elevated to 50% above normal. There was a polyuria. The syndrome was reversed by adding NaCl to the drinking water or prevented in rats on a 4% NaCl intake. In rats on 0.2% NaCl plasma renin rose dramatically with medication and angiotensinogen became depleted. Haematocrit in all groups of rats did not differ. Conclusion Combined blockade of the renin–angiotensin system can cause death in rats on a reduced NaCl intake. This was prevented by a high salt intake. The syndrome may result from depletion of angiotensinogen and the failure to synthesize sufficient angiotensin II that may be critical for normal cardiac growth and function and critical for survival.