Kinetics of salicylate elimination by anephric patients.

The objectives of this research were to determine the kinetics of salicylate elimination in anephric patients and particularly to establish if these patients form the major metabolite of salicylic acid, salicyluric acid, at a normal rate. This investigation was initiated because of conflicting reports concerning the contribution of the kidneys to the formation of salicyluric acid in man. Six patients, 20-44 yr old, three of whom were anatomically anephric while the other three were physiologically anephric, received an intravenous injection of 500 mg salicylic acid (as sodium salicylate)/1.73 m(2) body surface area on an interdialysis day. Serial blood samples were obtained for 12 or 16 h after injection and the plasma was assayed for salicylic acid, salicyluric acid, total protein, albumin, and creatinine. Detailed pharmacokinetic analysis based on an open, two-compartment linear model revealed no significant differences in apparent volume of distribution and apparent first-order distribution and elimination rate constants between the anephric patients and normal adult subjects. An estimate of salicyluric acid formation rate by the anephric patients, based on the initial rate of increase of salicylurate concentrations in plasma, indicates that the metabolite is formed at a normal rate. These results suggest that the kidneys do not contribute significantly to the formation of salicyluric acid from salicylic acid in man.

Plasma norepinephrine in exercise-induced ventricular tachycardia.

The relation between plasma norepinephrine levels and the occurrence of ventricular tachycardia during exercise testing was prospectively evaluated in 17 patients. Ten patients had reproducible ventricular tachycardia exclusively during exercise or recovery, or both; 7 patients had ventricular tachycardia only during ambulatory electrocardiographic monitoring. The two groups did not differ in age, exercise duration, left ventricular ejection fraction at rest, heart rate throughout the exercise protocol, rest QTc interval, change in QTc interval during exercise, the presence of coronary artery disease or exercise-related myocardial ischemia. Furthermore, there was no difference between groups in plasma norepinephrine levels at rest, peak exercise or in the recovery period. Myocardial ischemia was detectable by thallium perfusion scan in only 2 of the 10 patients with exercise-induced ventricular tachycardia. The 10 patients with exercise-induced ventricular tachycardia underwent repeat exercise testing immediately after maximal intravenous beta-adrenergic blockade with propranolol. Although they had no change in exercise duration, ventricular tachycardia did not occur in 9 of these 10 patients. Plasma norepinephrine levels were significantly decreased compared with levels before beta-adrenergic blockade (p less than 0.0002). Thus, plasma norepinephrine levels do not distinguish patients with reproducible exercise-induced ventricular tachycardia from otherwise comparable patients. Propranolol is highly effective in abolishing this arrhythmia and this effect is associated with decreased norepinephrine levels.

Effect of hemodialysis on kinetics of acetaminophen elimination by anephric patients.

The pharmacokinetics of acetaminophen elimination were determined in 4 anephric patients during hemodialysis and on an interdialysis day. The biologic half-life of acetaminophen ranged from 119 to 147 min on an interdialysis day and was decreased by 42% to 53% during hemodialysis. Individual mean dialyzer extraction ratios, based on assay of plasma samples from blood flowing into and out of the dialysis unit, were 0.46 to 0.78 for acetaminophen, 0.53 to 0.57 for acetaminophen glucuronide, 0.13 to 0.60 for acetaminophen sulfate, and 0.70 to 0.87 for urea nitrogen. There was a strong correlation between the extraction ratios of acetaminophen and urea nitrogen. Hemodialysis was the major or sole routine of elimination of acetaminophen glucuronide and sulfate in the anephric patients.

Pentobarbital elimination in patients with poor renal function.

Drug oxidation is slowed in experimental uremia in animals but has been reported to be normal or accelerated in uremic patients. Eleven normal subjects and 9 uremic patients were each given 100 mg pantobarbital orally. Several blood samples were drawn over a 36-hr period starting on the morning after the dose. Plasma pentobarbital concentration was measured by GLC. The log concentration values were graphed against time elapsed after dose for each patient, and the plasma T/2 and extrapolated value of concentration at the time of drug administration (Co) were determined. The T/2 values in normals ranged from 18 to 48 hr; mean, 26.5 +/- 9.2 (SD). In uremic patients, T/2 values are 10 to 38 hr, mean, 21.3 +/- 8.7. Four of the uremic patients had T/2 values below 18 hr (which was the lowest in the normals). The apparent volumes of distribution of pentobarbital (aVD = dose divided by Co) were 62 +/- 25 L in the normal subjects and 58 +/- 24 L in the uremic patients. The four uremic patients with the short T/2 values tended to have small apparent volumes of distribution so that the metabolic clearnce rates (aVd X 0.693 divided by half-life) were normal in 3 of them. We conclude that pentobarbital elimination is normal in renal failure. Some uremic patients have short plasma T/2 values for pentobarbital, and these more likely result from low apparent volumes of distribution with normal metabolic clearance rates than from accelerated metabolism of pentobarbital.

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%).

Effects of amiloride on oral glucose loading, serum potassium, renin, and aldosterone in diet-controlled diabetes.

The effects of amiloride on oral glucose loading, serum potassium, renin, and aldosterone were evaluated in 10 patients with diet-controlled diabetes. Eight had mild hypertension, and 2 had normal blood pressure. Prior to receiving amiloride all were studied for renin and aldosterone responses while supine and after 2 hr ambulation. All had a normal response to change in position in the renin and aldosterone systems. Before administration of amiloride glucose tolerance tests were carried out, with simultaneous determinations for potassium and insulin. Amiloride 5 to 10 mg was given orally for 6 wk. Blood glucose and serum potassium levels were monitored weekly. After 6 wk renin and aldosterone responses were again determined, as were oral glucose tolerance and serum potassium and serum insulin levels. Amiloride did not induce hyperkalemia in these diabetic patients and did not alter the postamiloride relationship. It is concluded that amiloride is safe for patients with an intact renin aldosterone system, more especially those with normal renal function and diet-controlled diabetes mellitus.

Elimination of procainamide in end stage renal failure.

To investigate the effect of end stage renal insufficiency and hemodialysis on the serum half-life of procainamide, 500 mg of procainamide was given orally to control subjects and dialysis patients on interdialysis days. Procainamide was assayed by spectrophotometry and spectrophotofluorometry. Mean half-life in normal subjects was 3.2 hr by spectrophotometry and 3.5 hr by spectrophotofluorometry. Mean half-life in patients was 11.3 hr by spectrophotometry and 16.0 hr by spectrophotofluorometry (p less than 0.001 compared to control subjects). Half-life of procainamide during dialysis in patients given 500 mg of procainamide 1 hr before dialysis was 4.3 hr and 9.6 hr on a nondialysis day (p less than 0.001). Both methods of assay gave higher levels of procainamide when the metabolite, N-acetylprocainamide, was present in serum and the extract allowed to stand in 1 N HCl, but spectrophotometry was less affected. Thus, end stage renal insufficiency greatly prolongs the half-life of procainamide, procainamide is readily dialyzable, and N-acetylprocainamide is hydrolyzed in 1 N HCl to procainamide during routine serum determinations.

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.

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.

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.

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.

Cumulation of N-acetylprocainamide, an active metabolite of procainamide, in patients with impaired renal function.

N-Acetylprocainamide (NAPA) accumulated in the plasma of 6 cardiac patients with renal failure taking procainamide chronically for therapy (4 were undergoing hemodialysis) and contributed to the therapeutic and toxic effects of the procainamide. NAPA plasma levels ranged from 14.0 to 28.0 microgram/ml 3 hr after a dose of procainamide which is well above the 3-hr NAPA plasma levels of nonazotemic cardiac patients (range 1.9 to 6.3 microgram/ml; p = 0.002) on larger doses of procainamide. There was almost no decline in NAPA plasma levels on interdialysis days. In one of the patients with renal failure NAPA was still present 15 days (13.8 microgram/ml) and 38 days (0.9 microgram/ml) after procainamide was stopped, indicating a half-life of several days. Measurement of procainamide plasma concentrations by the usual fluorometric or colorimetric methods does not detect NAPA. Since NAPA accumulates in patients with impaired renal function, the concentrations of both this active metabolite and procainamide should be determined in these patients if drug level monitoring is to be helpful.

Propranolol in hypertensive dialysis patients: efficacy and compliance.

The effect of propranolol therapy on plasma renin activity and blood pressure control was evaluated in 35 uremic patients receiving intermittent center-based outpatient hemodialysis. Patients were determined to be either compliant or noncompliant with therapy based on the steady-state predialysis plasma propranolol concentration. Noncompliance occurred with remarkable frequency and was associated with persistent hyperreninemia and poorly controlled hypertension. Blood pressure control was significantly better in compliant patients, in whom plasma renin activity was generally, but not universally, suppressed. Propranolol can be effectively used in the management of hypertensive dialysis patients, but steady-state plasma propranolol levels should be measured to assess compliance in patients apparently refractory to treatment.

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 less than 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 greater than 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.

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; C cr, 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 (C max) 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. N and 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 N and 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 of timolol 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.

Steady-state serum levels of quinidine and active metabolites in cardiac patients with varying degrees of renal function.

The concentrations of quinidine, (3S)-3-hydroxyquinidine (3-OH), and 2'-oxoquinidinone (2'-OXO) in serum samples from 25 patients on long-term quinidine therapy were determined by a high-pressure liquid chromatography assay. Large individual variation in the levels of each of the compounds measured was observed. After correcting for differences in protein binding, the ratio of 3-OH/quinidine in serum water is 0.61 +/- 0.31 (SD) and the ratio of 2'-OXO/quinidine is 0.39 +/- 0.44. Seven of the 25 patients had serum water levels of one of these metabolites similar to or greater than that of quinidine. The quinidine levels, after normalizing for dose, are significantly higher in hemodialysis patients (about twice) than in nonazotemic patients; azotemic patients have mean values intermediate between them. Quinidine, 3-OH, and 2'-OXO are equally potent antiarrhythmic drugs (ED50 = 0.18, 0.17, and 0.21 mmoles/kg, respectively) when tested against chloroform- and hypoxia-induced ventricular fibrillation in mice. O-Desmethylquinidine, a new metabolite detected in urine of quinidine-treated patients, is less active. Quinidine and 2'-OXO are equally potent (ED50 = 0.010 mmoles/kg), while 3-OH seems less potent and more toxic when tested against BaCl2-induced ventricular arrhythmias in rabbits. Thus, these metabolites appear to contribute to the effects of quinidine and may make a significant contribution in some cases.

Conversion from intravenous to oral mexiletine in the acute management of repetitive ventricular arrhythmia.

We evaluated the safety and efficacy of intravenous mexiletine and a method for converting from intravenous to oral mexiletine therapy. Fifteen patients with repetitive ventricular ectopy (13 had ventricular tachycardia) received intravenous mexiletine at a rate of 10 mg/min for 30 to 60 minutes. Ventricular ectopy was suppressed with minimal side effects in 10 of 15 subjects. Oral mexiletine was begun immediately after completion of the intravenous infusion at a dose of 10 mg/kg/24 hr in the 10 responders to intravenous therapy. In eight, the oral dose was effective in suppressing the arrhythmia, but it induced side effects in three of them. In one of these three, dose reduction resulted in adequate arrhythmia control with acceptable toxicity. In the two who did not respond to the original dose, a larger dose (15 mg/kg/24 hr) induced arrhythmia control with acceptable side effects in one subject. Thus rapid control of nonsustained repetitive ventricular arrhythmia can be achieved with intravenous mexiletine in about two thirds of patients, and conversion to oral therapy can often be achieved smoothly without significant arrhythmia recurrence.

Proton magnetic resonance spectroscopy can differentiate Alzheimer's disease from normal aging.

In order to evaluate the pattern of proton magnetic resonance spectroscopy (1H-MRS) in the gray and white matter of patients with Alzheimer's disease (AD) and healthy controls, a cross-sectional study was carried out on 13 consecutive AD patients and 7 healthy older subjects who were referred to the Day-Hospital for diagnostic assessment. All examinations were performed on a 1.5 Tesla whole-body scanner. Volumes of interest were selected in both the gray (temporal region) and the white (frontal region) matter. N-acetyl group, total creatine, total choline and myo-inositol were quantified referring the metabolite peak area to the unsuppressed water peak area acquired under the same conditions, and the ratio was expressed in arbitrary units. A significant decrease in N-acetyl-aspartate (NAA) in both gray and white matter and an increase in myo-inositol (mI) in gray matter of AD patients were observed. The gray matter NAA/mI ratio clearly separated the two groups. White matter mI was significantly associated with severity and duration of dementia. No association with age was documented. It can be concluded that in vivo 1H-MRS can contribute to the knowledge of pathophysiology of AD, giving neurochemical details of both gray and white matter. In particular, the gray matter NAA/ml ratio seems to be able to differentiate normal cerebral aging from Alzheimer's disease.

Mechanisms of action and the clinical pharmacology of beta-adrenergic blocking drugs.

At present more than 20 beta-adrenergic blocking drugs are commercially available in Western Europe, and six are available in the United States. The clinical indications for their usage include hypertension, arrhythmias, ischemic heart disease, thyrotoxicosis, migraine headaches, glaucoma, and anxiety states. We will review the mechanisms suggested for the antihypertensive action of beta-adrenergic blocking drugs as well as these agents' clinical pharmacologic aspects. In general, the pharmacodynamic effects of the beta blocking drugs are quite similar, yet the properties of biotransformation, including pharmacokinetics, tend to be distinguishing features.