David T. Lowenthal

The effect of renal function on enalapril kinetics

Enalapril maleate (MK‐421), a nonmercapto‐containing angiotensin converting enzyme (ACE) inhibitor, is converted in vivo to enalaprilat (MK‐422), the active diacid. We evaluated serum profiles and urinary excretion of oral enalapril maleate in patients with renal disease (group I, creatinine clearance <3 ml/ min, patients undergoing dialysis, n = 10; group II, creatinine clearance 10 to 79 ml/min, n = 9) compared with healthy subjects (group III, creatinine clearance >80 ml/min, n = 10). Group I received a 10 mg dose during a day while not receiving dialysis and a 10 mg dose 1 hour before dialysis 2 weeks later. Groups II and III received a single 10 mg dose. Blood samples and urine were collected for 48 hours. Impaired renal function resulted in elevated serum and plasma concentrations of enalapril maleate and decreased excretion rates and urinary recovery of enalapril maleate and enalaprilat. The data suggest an apparent increase in the extent of metabolism of enalapril maleate to enalaprilat or an increase in nonrenal elimination of unchanged enalapril maleate in renal disease compared with normal health. Enalaprilat was dialyzable.

Dynamics and kinetics of ophthalmic timolol

Timolol is a beta adrenergic antagonist in 0.25% or 0.5% eyedrop solution for glaucoma. In a double‐blind crossover study in healthy males we measured systemic beta blockade, intraocular pressure, and timolol kinetics after the first and ninth 12‐hourly dose of a 0.5% ophthalmic solution. Timolol ophthalmic and placebo were each given as 2 drops to each eye with precautions to prevent the normal loss of drug in tears and overflow (high dose) and as 1 drop to each eye with no special precautions (standard therapeutic dose). Exercise tachycardia, measured at 70 and 255 min after administration of drug, was lower at both levels. Postexercise 1‐sec forced expiratory volume (FEV1) was not affected. Intraocular pressure measured at 3 and 8 hr after drug was lower at both dose levels. Timolol was consistently present in urine but was not detectable in most plasma samples. Dynamic effects were not greater after the ninth than after the first dose, and the urinary excretion data provided no evidence of drug cumulation.

Prazosin kinetics and effectiveness in renal failure

Single and repeated doses of prazosin were given to 17 hypertensive patients, 5 with normal renal function and 12 with impaired renal function. Blood for prazosin assay was drawn after a 1‐mg single dose and after patients reached steady‐state levels with their long‐term maintenance dose. As blood was drawn blood pressure was recorded. Prazosin absorption was not altered in patients with impaired renal function, and there is no cumulation of the drug when given repeatedly to patients with impaired renal function. Elimination kinetics were virtually identical regardless of degree of renal function. Effect on blood pressure was significantly better at the dosage range of 3 to 8 mg/day than at higher doses of 9 to 20 mg/day. There does not appear to be a direct relationship between the peak plasma prazosin level and the nadir of antihypertensive response. This would seem to indicate that the drug leaves the plasma and goes to the vascular smooth muscle receptor site of action. There appears to be no impairment in prazosin elimination in patients with impaired renal function, and its effectiveness (with diuretic or dialysis) is optimum at 3 to 8 mg/day.

Timolol kinetics in chronic renal insufficiency

A single‐dose kinetic study of oral timolol, 20 mg, was undertaken in 3 groups of volunteers with varying degrees of renal function—(1) 10 normal subjects (N); (2) 9 patients with moderate chronic renal insufficiency (MCRI; Ccn 20 to 50 ml/min); (3) 4 patients with end‐stage renal disease (ESRD)—to assess the need for dosage modification as renal function diminishes. There were borderline statistical differences in absorption between groups. The mean peak concentration (Cmax) was 84.3 ± 44.8 ng/ml at 0.8 ± 0.4 hr for N and 87.1 ± 22.8 ng/ml at 1.7 ± 1.2 hr (p, NS) for MCRI. Nand MCRI mean half‐lives (5.2 ± 2.6 hr and 4.0 ± 1.2 hr) were not statistically different. Salivary levels correlated with plasma levels in 3 Nand 1 MCRI patient. Group differences in blood pressure and pulse response to timolol seems to reflect differences present at baseline with percent change from baseline identical for the two groups except at 12 to 24 hr. Administration oftimolol on an interdialysis day revealed similar kinetic and physiologic response in the normal and the MCRI group. During dialysis, timolol, 20 mg, induced significant hypotension and bradycardia.

Long-Term Clinical Effects, Bioavailability, and Kinetics of Minoxidil in Relation to Renal Function

Minoxidil was used to treat 26 patients (17 to 67 years old) with severe hypertension and varying degrees of renal function. Our object was to assess long-term clinical efficacy, kinetics (acute and chronic), and bioavailability of minoxidil in chronic renal insufficiency. Minoxidil, 27 to 30 mg per day, decreased systolic and diastolic blood pressure during the first three months of therapy. Between the third and 24th months (30 months in one patient) there was no further change. Propranolol or clonidine was needed to control heart rate, and furosemide or dialysis was needed to control edema induced by minoxidil. Renal function improved in some of the mildy azotemic patients. Minoxidil kinetics after the customary dose did not differ whether the drug was taken as tablet or solution. Kinetic parameters during chronic administration of minoxidil did not differ from those after acute administration. The kinetics in chronic renal insufficiency do not differ from these in subjects with normal renal function.

The antihypertensive effect of indapamide in low doses

SummaryA dose-titration study was performed to assess the minimal antihypertensive dose of indapamide and the dose-response curve in ambulatory patients with mild essential hypertension (diastolic blood pressure 90 to 114 mmHg). After a 30-day placebo period, patients received 0.5 mg indapamide daily for 6 weeks and this was increased to 1.0 mg daily for a further 6 weeks in those not responding, i.e. with a standing diastolic pressure greater than 90 mmHg. Although indapamide demonstrated an antihypertensive effect at these dose levels, normalization of blood pressure was achieved in only 2 of the 13 patients on 0.5 mg per day and in none of the 11 patients receiving 1.0 mg per day. No clinical side-effects or abnormalities in serum potassium and uric acid were noted.

Glucose, insulin and lipid parameters in 10,000 m running

SummaryThirteen conditioned athletes were studied before and 5 min after running 10,000 m. This distance was run in an average of 41±4 min. All runners lost weight and accompanying this weight loss was an increase in the serum osmolality in the six runners in which it was measured. There was a significant increase in serum glucose (96±11 mg-% before run; 170±48 mg-% after run) and this increase was inversely correlated with running time. There was also a small, but significant, increase in serum insulin (15±2 ΜU/ml before run; 19±4 ΜU/ml after run). There was no consistent effect of running 10,000 m on serum cholesterol and triglyceride levels and on plasma lipoprotein electrophoresis patterns.

Pharmacodynamics and Pharmacokinetics of Oral and Transdermal Clonidine in Chronic Renal Insufficiency

Use of the skin as a means for drug delivery, especially transdermal application of nitroglycerine, has been receiving increasing attention in the area of cardiovascular medicine (Adkinson 1977; Karsh et al. 1978; Hansen et al. 1979; Muller et al. 1982; Colfer et al. 1982; Olivari and Cohn 1983). Although some controversy exists now about bioavailability and effectiveness, it still remains a viable alternative to sublingual and oral administration. Two antihypertensive drugs have been studied by means of application to the skin. Preliminary data on the transdermal application of timolol has shown that it is effective in blunting the exercise response in normals (Lowenthal et al. unpublished). Further studies on its effectiveness as an antihypertensive when applied transdermally are being initiated.

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.

Growth Hormone Release in Hypertensive Adolescents Treated with Clonidine

Abstract: 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 healthy 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 α‐adrenergic receptor stimulation. Clonidine acts centrally by α‐adrenergic stimulation. However, this study demonstrates no effect of chronic clonidine therapy on growth hormone release.