Ralph E. Cutler

Effect of antihypertensive agents on lipid metabolism

Diuretics and adrenergic blocking agents have been used extensively in the treatment of hypertension. Recent studies have indicated that the thiazides and chlorthalidone have an adverse effect on lipid metabolism, by increasing plasma triglycerides, total cholesterol, and low density lipoprotein cholesterol in mildly hypertensive patients. These same agents produced little change in high density lipoprotein cholesterol. On the other hand, the loop diuretic furosemide adversely affected the cholesterol ratio by lowering high density lipoproteins (HDL) instead of increasing very low density lipoproteins (VLDL) or low density lipoproteins (LDL). The centrally acting drug methyldopa has also been reported to lower HDL, while another centrally acting drug, reserpine, appears to be lipid-neutral. Practically all the beta blocking agents increase triglycerides or decrease HDL, thus yielding an adverse cholesterol ratio. The alpha 1-adrenergic blocking agent prazosin has been shown in several studies to have no adverse effect on the lipid profile.

The Pharmacokinetics and Colonic Tissue Concentrations of Cyclosporine After IV, Oral, and Enema Administration

This study compares pharmacokinetic parameters and colonic tissue concentrations of cyclosporine administered by olive‐oil or water‐retention enemas with conventional intravenous (IV) and oral dosing. Five medical students were enrolled in a prospective crossover study. All subjects received a single dose of cyclosporine on four separate occasions, once orally, once as an olive‐oil enema, once as a water enema, and once IV. Cyclosporine concentration was measured in blood and in colonic tissue obtained by flexible sigmoidoscopy. Bioavailability was 18 ± 7% (mean ± SDJ for the oral dose and was unmeasurable for the oil and water enemas. The concentration of cyclosporine in colon tissue was 32,443 ± 17,251 ng/g (mean ± SDJ for the IV dose, 2797 ± 1812 ng/g for the oral dose, 21,727 ± 14,090 ng/g for the oil enema, and 25,318 ± 30,408 ng/g for the water enema. The authors conclude that the bioavailability of cyclosporine, and thus the systemic absorption after administration by a retention enema, is negligible. The colonic tissue concentration of cyclosporine after IV or rectal administration via an enema is tenfold higher than that for oral dosing. These findings suggest that cyclosporine‐retention enemas produce high distal colonic tissue concentrations with negligible systemic absorption after a single dose in healthy subjects and should be evaluated as treatment for patients with left‐sided colitis. Because cyclosporine administered by the IV route provided sharply higher colonic tissue concentrations than those seen with oral therapy, pulse IV cyclosporine should be tried for patients with severe ileitis and colitis.

Oral Flecainide Pharmacokinetics in Patients with Impaired Renal Function

The pharmacokinetics of flecainide acetate were studied in 20 patients with varying degrees of renal impairment following a single oral dose. The patients were divided into two groups, on the basis of renal creatinine clearance (CLCR), for statistical and kinetic analysis. Patients with a CLCR between 4 and 41 mL/min/m2 were designated group 1 and those below 4 mL/min/m2 or unmeasurable because of lack of urine output were designated group 2. In both groups peak plasma flecainide concentrations, time to peak concentrations, and apparent volume of distribution (Vd) were similar to those reported in healthy subjects with normal renal function. The mean flecainide plasma elimination half‐lives from both groups 1 and 2 were longer than those previously reported by several investigators in normal subjects. Nine patients in group 1 and seven patients in group 2 had half‐lives within the range reported in healthy subjects. Therefore, CLCR alone is not a good predictor of plasma elimination half‐life following a single oral dose of flecainide. Although renal clearance of flecainide is significantly reduced in end‐stage renal disease (ESRD), total plasma clearance of flecainide (CLflec) was not reduced to the same degree, although there was a significant, modest correlation with CLCR. Less than 1% of the administered oral dose of flecainide was removed during hemodialysis. The relationship between dosage and plasma elimination half‐life in patients with ESRD needs further study to evaluate possible dose‐dependent kinetics.

Apparent reduced absorption of gemfibrozil when given with colestipol.

Colestipol and gemfibrozil may be used in combination to lower serum cholesterol and triglycerides. Since colestipol is known to bind certain anionic drugs, we studied the effect of colestipol on the pharmacokinetics of gemfibrozil in 10 patients with elevated serum cholesterol and triglycerides. Each patient received 600 mg of gemfibrozil by mouth during four different studies. Gemfibrozil was given randomly either alone, with, 2 hours before, or 2 hours after 5 grams of colestipol. The serum gemfibrozil concentration time curves were similar when gemfibrozil was given alone or two hours before or after colestipol. There was also no statistical difference in peak gemfibrozil concentration (Cmax), time to Cmax (tmax), area under the curve (AUC), or serum elimination half‐life (t1/2) between any of these three treatments. However, when colestipol was given with gemfibrozil, there was a decrease in AUC (43.6 ± 21.9 mg*hr/L) compared with gemfibrozil given alone (62.6 ± 10.3 mg*hr/L) which was statistically different by both ANOVA and paired t‐test. This finding suggests a decrease in gemfibrozil bioavailability. Cmax when colestipol was given with gemfibrozil (14.7 ± 6.6 mg/L) was not statistically different from gemfibrozil alone (20.1 ± 4.9 mg/L). However, the mean serum concentrations when gemfibrozil was given with colestipol were significantly lower at the 0.5, 1.0 and 1.5 hour sampling times when compared to the other regimens. Gemfibrozil serum elimination half‐life was not significantly altered by combination with colestipol. The data suggest a reduction of gemfibrozil bioavailability when colestipol is administered concomitantly. Separating the administration of these two drugs by at least two hours will avoid this drug interaction.

Antihypertensive therapy in the elderly: Effects on blood pressure and cerebral blood flow

Antihypertensive therapy significantly reduces cardiovascular morbidity and mortality in the rapidly growing population of elderly patients. However, the desire to treat more of these patients is dampened by the concern that a reduction in blood pressure may compromise cerebral blood flow, causing untoward consequences. This study evaluated the therapeutic effect of titrated doses of prazosin, an alpha-adrenergic blocking agent, on systemic blood pressure and cerebral blood flow in elderly patients with chronic stable hypertension. Prazosin alone or co-administered with hydrochlorothiazide significantly lowered mean systolic and diastolic blood pressures in 31 elderly hypertensive patients. At the same time, however, there was no significant change in cerebral blood flow, which was measured in eight patients. Neither harmful biochemical changes nor treatment-related adverse effects were observed in any patients. Prazosin therapy alone or in combination with low-dose diuretic therapy was effective in the treatment of hypertension in this elderly population. Furthermore, blood pressure reduction with prazosin therapy was accomplished without compromising cerebral blood flow and without unfavorably altering lipid profiles.

Flecainide Pharmacokinetics After Multiple Dosing in Patients with Impaired Renal Function

Study objective: To determine the pharmacokinetics of oral flecainide acetate after single and multiple doses in patients with impaired renal function. Design: Paired study of single followed by multiple oral doses. Setting: Patients enrolled in a Veterans Administration Hospital renal subspecialty clinic and dialysis unit. Patients: Twenty men and one woman between the ages of 33 and 74 years with impaired renal function including ten patients with end‐stage renal disease receiving maintenance hemodialysis. Interventions: All patients received a single, oral, 200‐mg dose of flecainide acetate followed by sequential venous blood sampling. Seven to 14 days after the single‐dose study, each patient received 100 mg of flecainide acetate by mouth every 12 hours or every 24 hours for 10 days. Venous blood samples were drawn periodically during multiple dosing and sequentially after the last dose. Measurements and primary results: Peak flecainide acetate concentrations (μgA*) were 330 ±104 μg/L (mean ± SD) after the single dose and 687 ± 505 μg/L after multiple doses. Time to peak occurred at 3.3 ± 2.3 hours and 2.7 ± 1.2 hours after single and multiple doses, respectively. The apparent volume of distribution was 8.2 ± 2.9 L/kg and 9.2 ± 5 L/kg after single and multiple dose studies, respectively. Plasma elimination half‐life after the single dose (20.4 ± 9.0 hours) was significantly shorter (P <.001) than after multiple doses (37.8 ± 39.7 hours), as was total body clearance: 391 ±154 mL/min versus 302 ±194 mL/min. There were no statistically significant differences between pharmacokinetic measurements determined for patients on chronic hemodialysis when compared with nondialysis patients during the multiple‐dose study. No meaningful correlation was found between either plasma elimination half‐life or total body clearance and creatinine clearance. Renal clearance of flecainide correlated reasonably well (r2 = .785) with creatinine clearance after multiple doses. Conclusion: The pharmacokinetics of orally administered flecainide acetate are significantly different after multiple doses compared with single doses in patients with impaired renal junction. Single‐dose studies should not be used to determine dose requirements for patients with renal impairment. Creatinine clearance is not an accurate guide for flecainide acetate dosing. For patients with normal renal function or those with impairment but not requiring hemodialysis, a dose of 100 mg every 12 hours should be safe and effective. Patients requiring chronic hemodialysis should be started on a lower dose, for example 100 mg daily (or 50 mg bid). Plasma flecainide concentrations should be carefully monitored in patients with impaired renal function during dose optimization and until steady‐state concentrations are reached. Dosage increases should be made very cautiously when plasma concentrations have plateaued because it may take longer than 7 days before a new steady state is achieved after a dosage change.

Pharmacokinetics of Iothalamate in Endstage Renal Disease

Some nephrologists make alterations in routine peritoneal and hemodialysis schedules after diagnostic studies that use radiographic contrast agents. A study to determine the pharmacokinetics of one contrast agent, iothalamate, is reported. The plasma (total body) clearance of iothalamate was measured in seven patients who had endstage renal disease (ESRD) and who received maintenance hemodialysis. During an interdialytic period, plasma clearance of iothalamate varied from 0.7 to 5.2 mL/min (3.1 ± 1.8 mL/min, mean ± SD) with an elimination rate constant (beta) of 0.0164 ± 0.01 hr−1, a terminal half‐life of 61 ± 42 hours, and an estimated distribution volume of 11 ± 3.9 L. Hemodialysis clearance of iothalamate was 104 ± 54 mL/min. With the assumption that iothalamate is mainly distributed in the extracellular fluid (ECF) compartment, the theoretical fluid shift from the intracellular fluid (ICF) compartment to the ECF compartment was 323 mL after administration of the largest dose (2.1 mL/kg or 1.6 mmol/kg of body weight) of 60% meglumine iothalamate solution. The average maximum serum osmolarity change was less than expected, suggesting some type of internal buffering of meglumine iothalamate. In the first few hours after radiocontrast administration in four patients, the average change in serum osmolarity was 5 mmol/L; the average change in serum sodium concentration during this same time was a decrease of 0.5 mmol/L. The minor increase in ECF volume induced by hyperosmolar contrast agents does not require immediate dialysis in most patients. When needed, however, for contrast‐related adverse effects, hemodialysis is efficient in rapidly removing iothalamate.

Comparison of blood pressure, plasma lipid and cardiac performance responses to prazosin versus propranolol in thiazide-treated hypertensive patients

Twenty-seven patients with uncontrolled hypertension (diastolic blood pressure greater than or equal to 95 mm Hg) receiving thiazide diuretics were treated with the addition of either propranolol (n = 10) or prazosin (n = 17). Nine patients were successfully controlled with propranolol and 12 with prazosin. Six patients required both study drugs for optimal blood pressure control, 5 of whom had received prazosin as the initial study drug. Changes in serum lipid components and cardiac performances with the addition of the study drugs were monitored. A decrease in total cholesterol and an increase in high-density lipoprotein (HDL) cholesterol were seen when prazosin was added, and an increase in total cholesterol and a decrease in HDL cholesterol occurred after the addition of propranolol. Although in this small group of patients these changes did not reach statistical significance, they were similar to changes described in other studies in which these drugs were used as monotherapy for hypertension. The only lipid change of statistical significance was a small increase in the serum triglyceride concentration in patients receiving propranolol. The findings for total cholesterol and its fractions suggest that the effects of the study drugs may not be additive to those of thiazides and that thiazides had already effected a maximal lipid response. Both agents in combination with a thiazide diuretic were equally effective in decreasing diastolic blood pressure to the goal of less than or equal to 85 mm Hg.(ABSTRACT TRUNCATED AT 250 WORDS)

Human Plasma Concentrations of R, S, and Racemic Flurbiprofen Given as a Toothpaste

Flurbiprofen, an arylpropionic acid (APA) class nonsteroidal antiinflammatory drug (NSAID), is commercially available only as the racemic mixture, although its pharmacologic effect has been credited primarily to the S isomer. In humans, the bioavailability of racemic flurbiprofen absorbed from the oral cavity has been studied measuring the total concentration of S‐ and R‐flurbiprofen, and the pharmacokinetics of S‐ and R‐flurbiprofen have been studied after oral administration of racemic flurbiprofen. In this study, the plasma concentrations of S‐flurbiprofen and to some extent R‐flurbiprofen were studied after brushing with a toothpaste containing different mixtures of S‐ and R‐flurbiprofen. The toothpaste formulations contained 1% racemic (50:50), eutectic (14:86), 1%, 0.5%, and 0.25% (5:95) R‐ to S‐flurbiprofen. Both S‐ and R‐flurbiprofen were rapidly absorbed, with a time to reach maximum concentration (tmax) of 1.2 to 1.4 hours. Based on the AUC, the amount of S‐flurbiprofen absorbed increased proportionally when given as the 0.25% (5:95) preparation to the 0.5% (5:95) mixture but did not increase significantly above the 0.5% (5:95) mixture when given as 1% (5:95) R‐ to S‐flurbiprofen. This suggests that dose‐proportional absorption of S‐flurbiprofen is not maintained at higher concentrations. The elimination of S‐flurbiprofen appears to be variable and prolonged after this mode of administration, as observed from plasma concentrations. Further controlled and more prolonged studies of S‐ and R‐flurbiprofen are needed to confirm these observations.

Pharmacokinetics and Pharmacodynamics of Oral and Intravenous Cimetidine in Seriously III Patients

This study was done to determine if the pharmacokinetics and gastric pH response of intravenous cimetidine are superior to oral dosing in seriously ill patients. A paired study of intravenous followed by oral liquid cimetidine was given to eight men and two women who were inpatients in a VA Hospital. Treatment was prescribed for either upper gastrointestinal (GI) bleeding or prophylaxis against GI bleeding. All patients received cimetidine 300 mg every 6 hours intravenously on day 1 and orally on day 2. After the fourth dose each day, venous blood samples and gastric pH measurements were taken serially for 6 hours. Peak serum cimetidine concentration was 2.0 ± 0.5 mg/L for the intravenous dose and 1.5 ± 0.3 mg/L for the oral dose (P = .001). Area under the curve (AUC) of cimetidine concentration was 3.81 ± 1.1 mg/hr/L for the intravenous dose and 4.19 ± 1.22 mg/hr/L for the oral dose (P > .30). Bioavailability (AUCpo/AUCiv) was 1.13 ± 0.25, demonstrating complete oral absorption. The time during a 6‐hour dosing interval that the gastric pH remained above 3.0 was 3.3 ± 2.1 hours for the intravenous dose and 2.5 ± 2.3 hours for the oral dose, P = .171). The time that the serum cimetidine concentration remained above 0.5 mg/L was 2.0 ± 0.9 hours for the intravenous dose and 2.7 ± 1.0 hours for the oral dose (P = .055).