Brian N. Swanson

Steady-state serum amiodarone concentrations: relationships with antiarrhythmic efficacy and toxicity.

The relationship of apparent steady-state serum concentrations of amiodarone and its metabolite, desethylamiodarone, to therapeutic and toxic effects was assessed in 127 patients who had treatment-resistant ventricular or supraventricular arrhythmias or were intolerant to other agents. After at least 2 months (mean, 9.8) of treatment with daily maintenance doses of 200 to 600 mg, arrhythmias were effectively suppressed in 78% of patients. Arrhythmias recurred in 47% of patients with serum amiodarone concentrations of less than 1.0 mg/L, whereas only 14% of patients with higher concentrations had recurrences (p less than 0.005). Side effects, most of them mild, occurred in 57%; only 9 patients required discontinuation of drug therapy. The risk of developing adverse reactions was related to serum amiodarone concentrations (p less than 0.0001). Adverse reactions were common in patients with serum values exceeding 2.5 mg/L, although pulmonary complications did occur at lower concentrations. Monitoring serum amiodarone concentrations may differentiate failure of drug therapy from suboptimal dosing and reduce the incidence of concentration-related side effects.

A Comparative Pilot Study of Enalapril, A New Converting Enzyme Inhibitor, and Hydrochlorothiazide in Essential Hypertension

Abstract: Eight patients with essential hypertension completed a double‐blind, randomly allocated crossover comparison of either 5 or 10 mg enalapril maleate, 50 mg hydrochlorothiazide, or their combination administered once daily during sequential two‐week periods. Blood pressure, pulse rate, plasma renin activity, angiotensin‐converting enzyme activity, plasma aldosterone concentration, and urinary electrolytes were monitored for 24 hours after placebo and on days 1 and 14 of each treatment period. After two weeks of each treatment, only the combination of enalapril and hydrochlorothiazide significantly lowered the mean seated diastolic blood pressure (SDBP). Likewise, SDBP control (≤ 90 mm Hg) was achieved only after combination therapy; six of the eight patients were controlled by the combination for up to 24 hours. The initial SDBP response to combination therapy differed with the sequence of drug addition; however, by day 14 the responses were comparable, regardless of whether hydrochlorothiazide or enalapril was first given. Mean converting enzyme activity was suppressed by enalapril in all patients, though it did not always correlate with changes in SDBP or plasma aldosterone. Mean plasma renin activity increased, but the increase was significant only on the combination. There were no serious adverse effects.

Sulindac disposition when given once and twice daily

To investigate whether sulindac once daily in the evening might be equivalent to the currently recommended twice‐daily dose schedule in sustaining plasma concentrations of bioactive sulfide metabolite, 12 healthy subjects received, in a randomized crossover study, sulindac, 200 mg b.i.d. (at 9:00 A.M. and 9:00 P.M.) and 400 mg once daily (at 9:00 P.M.), each for 7 days. At steady state the area under the plasma concentration‐time curve (AUC) over 24 hr for sulfide metabolite was greater after once‐daily dosing (112 and 84μg · hr · ml−1, P < 0.05), while mean trough concentrations did not differ. The greater AUC seemed to be related to diurnal variation in metabolite cumulation. A circadian rhythm was apparent at steady state during twice‐daily dosing; the mean AUC and peak plasma concentration (Cmax) were greater between 9 A.M. and 9 P.M. than between 9 P.M. and 9 A.M. (50 and 34 μg · hr · ml−1; 6.85 and 4.23 μg/ml). Although Cmax values of sulfide were higher after morning doses of sulindac, it was apparent that much of the plasma sulfide after morning doses was actually derived from the previous evening dose. This may be a consequence of circadian rhythm in gallbladder emptying. While renal clearance of sulindac was related to urinary pH, diurnal changes in urinary acidity did not cause the fluctuations in plasma sulfide. Since once‐daily sulindac in the evening is as, if not more, effective than twice‐daily drug in sustaining plasma sulfide levels, further studies on the therapeutic efficacy of once‐daily dosing are warranted.

Comparative Antihypertensive Effects of Enalapril Maleate and Hydrochlorothiazide, Alone and in Combination

Abstract: Enalapril maleate is an investigational oral prodrug whose hydrolyzed diacid metabolite is a potent angiotensin‐converting enzyme inhibitor. Fourteen patients with mild to moderate hypertension were evaluated after receiving placebo, and two weeks of treatment with each of the following: enalapril maleate (20 mg b.i.d.), hydrochlorothiazide (25 mg b.i.d.), and the two in combination. In comparison to placebo, the magnitudes of the blood pressure reduction after enalapril and hydrochlorothiazide alone were comparable. The reduction in blood pressure following enalapril was evident throughout the 12‐hour dosing interval. The combination of enalapril and hydrochlorothiazide resulted in a marked further reduction in blood pressure that was greater than that predicted from the responses to the individual drugs (P < 0.05). Biochemical parameters confirmed inhibition of angiotensin‐converting enzyme during enalapril treatment; serum angiotensin‐converting enzyme activity proved an excellent monitor of compliance. Enalapril was generally well tolerated. Adverse effects included symptomatic hypotension in three patients when enalapril was first added to hydrochlorothiazide and hyperesthesia of the oral mucosa without a loss of taste in one patient on enalapril. Enalapril maleate alone and especially in combination with hydrochlorothiazide appears to be an effective, well‐tolerated converting enzyme inhibitor with at least a 12‐hour duration of action.

Amiodarone: individualizing dosage with serum concentrations.

The purpose of the present report is to review the available pharmacokinetic informaation on amiodarone with an emphasis on our own experience in monitoring serum amiodarone concentrations. We have found that 400 mg should be the maximal maintenance dose; if that treatment fails, careful addition of other antiarrhythmic agents is preferable over an increase in amiodarone dosage. Serum concentrations below 2.5 mg/L will significantly improve amiodarones benefit‐to‐risk ratio.

Effect of captopril and hydrochlorothiazide on the response to pressor agents in hypertensives

SummaryThe effect on arterial pressure of incremental doses of norepinephrine (2 to 10 µg/min) and angiotensin II (50 to 800 ng/min) administered over 10 min periods was studied in sodium-replete hypertensive patients after crossover oral treatments with placebo, captopril 50 mg in a single dose, captopril 50 mg three times daily for one week and hydrochlorothiazide 50 mg daily for a week. Neither captopril nor hydrochlorothiazide affected the dose response to infusions of angiotensin II. In comparison to placebo responses, however, both single and multiple-dose captopril therapy, and hydrochlorothiazide attenuated the pressor responses to infusions of norepinephrine. Captopril significantly depressed angiotensin converting enzyme activity from predose levels and angiotensin II infusions significantly elevated plasma aldosterone concentrations. These results confirm findings reported for single dose captopril in normotensive volunteers and indicate that attenuation of the vascular responsiveness to sympathetic stimulation may contribute to the antihypertensive effects of captopril and hydrochlorothiazide therapy.

Bucindolol, a beta-adrenoceptor blocker with vasodilatory action: Its effect in systemic hypertension

Bucindolol is a newly developed, nonselective beta-adrenergic blocking agent with intrinsic sympathomimetic activity and direct vasodilator properties. In 14 patients with mild to moderate essential hypertension, the effects of bucindolol, hydrochlorothiazide and their combination on blood pressure (BP), heart rate (HR) and parameters of the renin-aldosterone system were compared with those after placebo. Bucindolols antihypertensive effect was evident within the first hour after drug administration, maximal at 2 to 3 hours, and lasted for as long as 12 hours. Compared with placebo values (108 +/- 5 mm Hg), both bucindolol (97 +/- 9 mm Hg) and hydrochlorothiazide (99 +/- 10 mm Hg) alone significantly and comparably reduced the 12-hour averaged standing diastolic BP, with the combination resulting in approximately additive effects (91 +/- 9 mm Hg). Although bucindolol alone did not affect HR, it attenuated the hydrochlorothiazide-induced increase in HR. There was a tendency for bucindolol to decrease plasma renin activity. Except for transient postural hypotension in 2 patients, bucindolol was well tolerated.

Measurement of sulindac and its metabolites in human plasma and urine by high-performance liquid chromatography

A sensitive high-performance liquid chromatography assay for simultaneous measurement of sulindac and its major metabolites was developed. The extraction methods provided greater than 89% recovery of sulindac and its sulfone and sulfide metabolites from both plasma and urine. Complete resolution and accurate detection of the three compounds was achieved with a reversed-phase column, UV detection at 254 nm and a methanol-acetate buffer mobile phase. Levels of sulindac and its metabolites were determined in plasma and urine from four volunteers after oral administration of 200 mg Clinoril. Glucuronide conjugates in urine were measured after alkaline hydrolysis.

Sulindac and Ibuprofen Inhibit Furosemide-Stimulated Renin Release but not Natriuresis in Men on a Normal Sodium Diet

We compared the effect of two commonly prescribed nonsteroidal anti-inflammatory drugs, ibuprofen and sulindac, and placebo on intravenous furosemide-induced natriuresis and renin stimulation in 11 healthy male volunteers, consuming a 100 mEq sodium, 80 mEq potassium diet. Chronic (6-day) therapy with each agent was followed by a 1-week washout period. There were no significant treatment-related differences in either urine volume or sodium excretion for any of the designated collection periods or for the cumulative value for the 4 h after furosemide administration. Similarly, differences among groups were not observed for creatinine clearance, urinary potassium and urinary chloride excretion. Mean basal plasma renin activity levels prior to furosemide administration on day 6 were significantly lower in the presence of ibuprofen (1.5 +/- 2.0 ng/ml/h;p less than 0.01) and sulindac (2,3 +/- 0.9 ng/ml/h; p less than 0.05), compared with placebo (3.3 +/- 1.1 ng/ml/h); the difference between the two NSAIDs was also significant (p less than 0.05). Mean plasma renin activity levels in the 4 h after furosemide increased significantly at all time points in comparison to basal values, but were significantly less for ibuprofen and sulindac groups in the first hour. Our data suggest that the natriuresis following intravenous furosemide in men consuming a normal sodium intake is not prostaglandin-dependent. Furthermore, the observation that sulindac suppressed basal and stimulated plasma renin activity levels, albeit to a lesser extent than ibuprofen, questions the claim that sulindac spares" the kidney and compels further evaluation of this issue.

Effect of phenobarbitone on the pharmacokinetics and tissue levels of amiodarone in the rat

Phenobarbitone pretreatment has been shown to increase amiodarone total clearance and decrease amiodarone elimination half‐life after a single intravenous amiodarone dose in the rat. Coadministration of phenobarbitone with amiodarone for 7 days resulted in decreased tissue amiodarone levels compared to controls. These results may have Implications for patients undergoing therapy with amiodarone and concomitant potent enzyme inducing drugs.