New drugs for hypertension.
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Antihypertensive Agents↗
Biomedical subjects
D T Lowenthal
Publications and source records attributed to D T Lowenthal.
Controversies in the treatment of hypertension.
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Adolescent↗
Effects of antihypertensive drugs on cognitive function in adolescents.
The effects of clonidine and hydrochlorothiazide on cognitive function were studied in hypertensive adolescents requiring pharmacologic therapy for blood pressure control. Twenty-four adolescents with persistent blood pressure elevation (greater than 95th%) on placebo were randomized double blind to clonidine or hydrochlorothiazide treatment. A battery of cognitive tests were performed during the placebo phase and after 16 weeks of active therapy. Antihypertensive therapy resulted in significant blood pressure reduction (p less than .01). A slight interactive effect was observed in arithmetic performance (p less than .05). All other parameters of cognitive function were not affected by either treatment.
Adolescent↗
R-wave amplitude change during aerobic exercise in hypertensive adolescents after treatment.
This study attempts to determine whether the blunted reduction in R-wave amplitude during progressive aerobic exercise observed in adolescents with systemic hypertension could be altered by pharmacologic therapy to reduce blood pressure. Twenty-nine hypertensive adolescents were randomly assigned to treatment with either a diuretic, hydrochlorothiazide, or a centrally acting agent, clonidine. After 16 weeks of therapy, casual blood pressure was significantly reduced in both groups. Repeat exercise stress testing on therapy demonstrated a significant change in R-wave response. In both treatment groups the change in R-wave amplitude during exercise corresponded with the R-wave response pattern observed in normotensive control subjects. These observations indicate that the altered R-wave amplitude response to exercise observed in young hypertensive subjects is reversible and suggest that the altered R-wave response before treatment is related to a higher vascular resistance.
Adolescent↗
Influence of uremia, hemodialysis, and nonesterified fatty acids on zomepirac plasma protein binding.
Zomepirac binding to plasma of uremic patients before hemodialysis and to that of healthy subjects was compared. Unbound zomepirac in plasma of uremic patients averaged 3.7% to 4.0% of the 14C-zomepirac added (0.2, 2, and 20 micrograms/ml). This was more than the percentage of unbound zomepirac observed when the same 14C-zomepirac concentrations were dialyzed against plasma from healthy subjects (mean 1.3% to 1.4%). Plasma albumin from uremic patients appeared to have lower apparent binding affinity for zomepirac. Oleic, stearic, and palmitic acids, when added to plasma at concentrations of 2.0 mM, markedly reduced zomepirac free fraction, but, there were no significant differences between uremic and normal plasma in total nonesterified fatty acid (NEFA) concentrations after equilibrium dialysis. Thus, plasma NEFAs do not contribute to the differences in zomepirac plasma binding between normal and uremic plasma. Hemodialysis increased zomepirac binding to plasma of uremic patients, but NEFA concentrations were also increased in hemodialyzed plasma. Enhanced zomepirac binding by NEFAs could not be differentiated from other effects of hemodialysis, such as the removal of endogenous inhibitors of drug plasma protein binding. The binding of zomepirac was not affected by its three known metabolites: zomepirac glucuronide, hydroxyzomepirac, and 4-chlorobenzoic acid.
Adult↗
Pharmacokinetics and pharmacodynamics of clonidine in varying states of renal function.
Previous studies have reported a therapeutic window of 0.8 to 2.0 ng/ml within which clonidine exerts its antihypertensive effect. This study was designed to investigate whether there was any loss of blood pressure control when plasma clonidine concentrations exceeded this window owing to its accumulation in renal insufficiency. The results indicate that clonidine concentrations of up to 30 ng/ml in patients with end-stage renal disease (ESRD) can be associated with a maintenance of blood pressure control. It remains to be learned whether this phenomenon of high concentrations and control of blood pressure in our ESRD patient population may be related to altered (decreased) peripheral alpha-receptor sensitivity and inability to develop vasoconstriction. There is precedence for autonomic imbalance and altered tissue sensitivity in ESRD.
Adult↗
Overview of physiology in senescence.
As one ages, blood pressure and hemodynamic changes become apparent. This is reflected in a fall in cardiac output and a gradual increase in total peripheral-vascular resistance. Systolic hypertension is one of the fundamental abnormalities of the cardiovascular system in the elderly. Baroreceptor function and cerebral blood flow likewise may be compromised and result in altered drug sensitivity. Renal function decreases with age and is manifested by a decrease in renal blood plasma flow and in glomerular filtration rate. There is a gradual blunting of sympathetic nervous system responsiveness demonstrated by a decrease in the activity of the renin-angiotensin-aldosterone system. Finally, pathways of drug biotransformation may be altered, resulting in adverse drug reactions.
Aged↗
The use of clonidine monotherapy in adolescent hypertension.
The effect of a centrally acting agent (clonidine) vs a diuretic as a single agent was studied in a group of hypertensive adolescents. Following placebo therapy, adolescents with blood pressure greater than 95th percentile were randomized to clonidine 0.1 mg or hydrochlorothiazide 25 mg, each given twice daily. Following 12 weeks' active treatment, those who had not achieved blood pressure goals proceeded to clonidine 0.2 mg or hydrochlorothiazide 50 mg twice daily. Blood pressure and clinical assessment was performed at two-week intervals. Cardiovascular response to mental stress and pre-post stress catecholamines were obtained prior to active therapy and during therapy. Clonidine therapy significantly lowered systolic and diastolic pressure and heart rate (p less than .01). Hydrochlorothiazide significantly lowered systolic pressure only. Mental stress testing resulted in a lower diastolic pressure and heart rate response (p less than .01), with lower norepinephrine in the clonidine-treated group. The diuretic group had higher plasma norepinephrine and no significant reduction in stress response. Hypertensive juveniles may be more sensitive to central control of blood pressure and more resistant to diuretics.
Adolescent↗
The use of diuretics in varying degrees of renal impairment: an overview.
Administration of diuretics during acute renal failure in animals has been demonstrated to be of value with mannitol and/or loop-blocking diuretics, furosemide or ethacrynic acid. There is evidence that if these drugs are given very early in the controlled experimental environment that there will be some beneficial effect in maintaining renal function. However, in man the temporal relationship between the acute onset and the successful response to the administration of the drugs is, at best, coincidental and the use of diuretics in acute renal failure may not produce the same results as seen in the laboratory. One of the best guides to the underlying disease when there is acute decompensation in renal function is the utility of the renal failure index which utilizes urine and plasma sodium and urine and plasma creatinine ratios. Large doses of loop-blocking diuretics can be of benefit in patients with mild to moderate chronic renal insufficiency and fluid retention and/or hypertension. When renal insufficiency is severe in the pre-dialysis setting, furosemide, bumetanide or muzolimine may be of some benefit; however, as renal failure worsens the response of the kidney is sluggish and it is wise to begin to dialyze when glomerular filtration deteriorates below 5 ml per minute.
Acute Kidney Injury↗
Lack of effect of nonsteroidal anti-inflammatory drugs on exercise-induced hyperkalemia.
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Anti-Inflammatory Agents↗
Changes in R wave amplitude during aerobic exercise stress testing in hypertensive adolescents.
The change in R wave amplitude during progressive aerobic exercise was studied in hypertensive adolescent boys. A comparable control group consisted of normotensive adolescent boys matched for age, body size and race. Twenty-four normotensive and 22 hypertensive subjects exercised to exhaustion on a treadmill utilizing the Bruce protocol. Blood pressure and heart rate were monitored during exercise and recovery. The change in R wave amplitude in a lead V5 electrocardiogram was determined at each level of exercise. The normotensive group demonstrated a progressive increase in systolic pressure, heart rate and rate-pressure product (heart rate x systolic pressure) during exercise and a progressive decrease in R wave amplitude with a significant correlation of R wave change versus the cardiac response variable (p less than 0.001). Hypertensive subjects manifested a greater increase in systolic pressure, heart rate and rate-pressure product during exercise with no decrease in R wave amplitude until the exercise end point. The difference in R wave response to progressive exercise in the two groups was significant (p less than 0.01). A variation in myocardial function in hypertensive adolescents as demonstrated by a difference in R wave response to exercise may reflect a level of peripheral vascular resistance greater than that of normotensive control subjects.
Adolescent↗
Dynamic and biochemical responses to single and repeated doses of clonidine during dynamic physical activity.
Beta-adrenoceptor blockade increases serum K, which may be related to renin inhibition, hypoaldosteronism, and exercise-induced skeletal muscle release of serum K. We report on the dynamic and biochemical response to clonidine (C) after single (S) 0.2-mg and repeated (R) 0.1-mg bid doses of C to six normal subjects at rest, 2 hr after dosing and immediately before dynamic physical activity (DPA) on a treadmill, and at peak activity and 2 hr after DPA. Blood pressure (BP), heart rate (HR), plasma renin concentration (PRC), aldosterone (ALD), serum K, epinephrine (E), and norepinephrine (NE) were measured in standing subjects before and 2 hr after placebo or C (S or R), at peak DPA, and 2 hr after exercise. K, BP, and HR were also determined during all stages of DPA. Results show a parallel rise in K at peak over rest after C (S or R) and after placebo. NE, E, and PRC decreased after 1 wk of C (P less than 0.01), but the fall of ALD was only slight. The fall in NE at rest suggested a relationship to the decrease in systolic BP and rate pressure product after 1 wk on C. With DPA there is a normal yet smaller increase in systolic BP and also a smaller rise in HR with S- and R-dose C. There is no adverse rise in K in C-treated subjects during DPA.
Aldosterone↗
Effectiveness of centrally acting drugs and diuretics in adolescent hypertension.
The effectiveness and tolerance of a centrally acting antihypertensive agent (clonidine) was compared to that of a diuretic (hydrochlorothiazide) in treatment of adolescents with essential hypertension. After a phase on placebo 29 adolescents with fixed primary hypertension were randomly assigned, double blind, to one of two treatment groups. Active therapy was initiated at a low dose (0.1 mg clonidine b.i.d. or 24 mg hydrochlorothiazide b.i.d.) for 12 wk. In those in whom treatment goals for blood pressure control had not been reached, the dose was increased (clonidine to 0.2 mg and hydrochlorothiazide to 50 mg) for 12 wk. In the clonidine-treated group there was a reduction during low-dose therapy in systolic (P less than 0.05) and diastolic pressure (P less than 0.01) and heart rate (P less than 0.01). With low-dose diuretic therapy there was a reduction in systolic pressure only (P less than 0.05). Linear growth patterns were normal for both groups, but there was a reduction in serum potassium in the diuretic group (P less than 0.001). Of the two drugs investigated the centrally acting clonidine was more effective in blood pressure control (85%) than the diuretic (40%).
Adolescent↗
Biochemical and dynamic responses to single and repeated doses of methyldopa and propranolol during dynamic physical activity.
Our purpose was to describe changes in potassium disposition with antirenin antihypertensives during dynamic physical activity in normal subjects receiving methyldopa and propranolol. Before the study, 2 hr after dosing and coincident with immediate preexercise on treadmill (at graded increases of exercise), and 2 hr after exercise, blood was sampled for determination of potassium, renin, aldosterone, and catecholamine levels. Blood pressure and heart rate were measured. The results demonstrate no greater increase in potassium after single or multiple doses of methyldopa than after placebo. After the first dose of propranolol there was a greater rise in potassium over that with placebo, but it was not observed after multiple doses, which may be related to the low doses. There were minor, but significant, changes in norepinephrine, renin, and systolic pressure with multiple-dose methyldopa and in renin, heart rate, and systolic and diastolic pressure with propranolol. Overall, the adrenergic responses to exercise win methyldopa and propranolol were biochemically altered rather than functionally impaired. The latter is related to dose and the underlying age and state of health of our subjects. Methyldopa (or clonidine) may be useful in patients with hypertension who exercise and are predisposed to pertubations in potassium disposition.
Adult↗
Potassium disposition and neuroendocrine effects of propranolol, methyldopa and clonidine during dynamic exercise.
In order to determine the changes in potassium disposition with antirenin, antihypertensives during dynamic physical activity, a double-blind placebo controlled study was undertaken using normal volunteers receiving placebo or single and multiple dose clonidine, methyldopa and propranolol 0.2 mg. followed by 0.1 mg. bid x 7 days, 500 mg. followed by 250 mg. bid x 7 days or 80 mg. followed by 40 mg. bid x 7 days, respectively. Prior to study, 2 hours post dosing and coincident with immediate pre-exercise on treadmill, at graded increases of exercise and 2 hours post exercise (approximately 4 hours post dosing), blood was sampled for potassium, renin concentration, aldosterone and catecholamines. Blood pressure (BP) and heart rate (HR) were measured. The results demonstrate no greater increase in potassium over placebo with single or multiple dose clonidine or methyldopa. Following the initial dose of propranolol, 80 mg., there was a statistically greater rise in potassium over that seen with placebo but not observed with multiple dose. This may be related to the low multiple dose regimen. There were minor but significant changes in norepinephrine, renin and systolic pressure with multiple dose clonidine and methyldopa and in renin, heart rate and systolic and diastolic pressure with propranolol. Overall, the adrenergic responses, to exercise with methyldopa and propranolol are more biochemically altered than functionally impaired, yet the latter is related to dose and the underlying age and state of health of the group being studied.
Aldosterone↗
The pharmacodynamic effectiveness of metoprolol in adolescent hypertension.
The effectiveness of metoprolol in achieving blood pressure control was studied in 16 hypertensive adolescents. The hypertensive included two insulin dependent diabetics, four patients with renal disease, and ten adolescents with essential hypertension. Dose range was 100-200 mg/day for 3-12 months. Significant reductions on metoprolol therapy were achieved for systolic blood pressure (SBP) (P less than 0.001), diastolic blood pressure (DBP) (P less than 0.001), and heart rate (HR) (P less than 0.001). Side effects that had been present in previous therapy were absent. On metoprolol therapy the hyperkinetic cardiovascular response to mental stress was improved for SBP and HR. Exercise stress testing also resulted in a reduced SBP and HR, while endurance capacity was unimpaired. Metoprolol is effective in adolescent hypertension with negligible side effects.
Adolescent↗
Growth hormone release in hypertensive adolescents treated with clonidine.
The release of the growth hormone in the basal state and in response to strenuous exercise was studied in a group of 15 hypertensive adolescents receiving clonidine therapy and in a control group of 17 untreated adolescents of which ten were hypertensive volunteers and seven were health normotensive volunteers. Mean basal growth hormone in clonidine-treated adolescents was 2.8 +/- 0.50 S.E.M. ng/ml, compared to 2.7 +/- 0.48 ng/ml in untreated adolescents. Following exercise stimulation, mean growth hormone was 14.8 +/- 3..1 S.E.M. ng/ml in the treated group and 13.5 +/- 2.8 ng/ml in the untreated group. Growth hormone release is regulated by alpha-adrenergic receptor stimulation. Clonidine acts centrally by alpha-adrenergic stimulation. However, this study demonstrates no effect of chronic clonidine therapy on growth hormone release.
Adolescent↗
Failure of rifampin to induce the metabolism of clonidine in normal volunteers.
Patients receiving rifampin and methadone often incur withdrawal symptoms related to an increased rate of metabolism of methadone induced by rifampin. In order to test the hypothesis that clonidine metabolism is similarly altered by rifampin, six normal volunteers received clonidine 0.2 mg bid for four days and clonidine concentration was assayed by a RIA procedure. Beginning on day 5, rifampin 600 mg q12h was added to the clonidine regimen. Both drugs were taken for a total of seven days. On the last day of the study, blood was again sampled for clonidine. On days 4 and 12, urine was collected for d-glucaric acid. The results demonstrate that there is no change in the elimination kinetics of clonidine before and during rifampin administration. However, there was an increase in UDGA following the rifampin dosing. It is concluded that patients receiving rifampin can also receive clonidine for treatment of narcotic withdrawal.
Clonidine↗