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Optimization of the therapeutic index by adjustment of the rate of drug administration or use of drug combinations: exploratory studies of diuretics.

Zhi J, Levy G.

Department of Pharmaceutics, School of Pharmacy, State University of New York, Buffalo, Amherst 14260.

The purpose of this investigation was to explore theoretically certain strategies for optimizing the therapeutic index of drugs and to assess these strategies experimentally with two diuretics. Diuretic agents allow dosing rate flexibilities because the temporal profile of diuretic action can vary considerably as long as the total diuretic effect per day is the same. They can also be used in combination. Experiments were designed to determine if the therapeutic index of furosemide and hydrochlorothiazide can be optimized by administering one or the other at a certain rate or by administering the two drugs together in a certain ratio and at a certain rate. Male Lewis rats received one or the other drug, or combinations of the two, by i.v. infusion at different rates. Several timed urine collections were made under steady-state conditions, with excreted urine replaced volume for volume by i.v. lactated Ringer's solution. The urine flow rates and the urinary excretion rates of the diuretics and of Na+ and K+ were determined. The relationship between the diuretic effect of either of the two drugs given alone and the respective drug excretion rate could be described by the Hill equation. The ratio of urine flow rate to K+ excretion rate exhibited a marked dependence on hydrochlorothiazide excretion rate (highest ratio at high excretion rates), whereas the K+/Na+ excretion rate ratio was constant over a wide range of hydrochlorothiazide excretion rates. There was no significant change of these ratios with changing excretion rate of furosemide.(ABSTRACT TRUNCATED AT 250 WORDS)

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2395796&dopt=Abstract hydrochlorothiazide Microzide



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The influence of hydrochlorothiazide and tripamide on serum and urinary amylase.

Conrad KA, Fagan TC, Simons JA.

University of Arizona College of Medicine, Tucson.

Pancreatitis and asymptomatic elevations of serum amylase have been reported after therapy with thiazide diuretics. In the current study, the effects of hydrochlorothiazide and tripamide treatment on serum and urinary amylase excretion were investigated in 12 hypertensive volunteers. Two patients developed modest elevations of the serum amylase above the normal range after 12 weeks of treatment with hydrochlorothiazide 50 mg daily, but the mean serum amylase did not change. Hydrochlorothiazide did not produce a statistically significant increase in urinary amylase excretion but did reduce the ratio of salivary amylase/creatinine clearance in a two-hour urine collection. Tripamide 10 mg daily had no effect on serum or urinary amylase.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2455741&dopt=Abstract hydrochlorothiazide Microzide



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Monitoring the effect of triamterene and hydrochlorothiazide on dihydrofolate reductase activity using a new spectrophotometric method.

Sidhom MB, Velez MR.

College of Pharmacy, University of Puerto Rico, San Juan 00936.

A new spectrophotometric method is developed and applied for the study of the inhibitory effect of triamterene, hydrochlorothiazide and their combinations on the in vitro activity of dihydrofolate reductase enzyme. The method is based on incubating the drug (0.1-1.0 microM) or a buffer control with a solution containing reduced nicotinamide adenine dinucleotide phosphate (0.5 mM), magnesium chloride (1.29 mM), and folic acid as a substrate (0.01-0.1 mM) with the dihydrofolate reductase (0.25 unit). The resulting tetrahydrofolic acid is determined by first hydrolysing it by a methanol-hydrochloric acid mixture to produce p-aminobenzoyl glutamic acid, then adding p-dimethylaminocinnamic aldehyde reagent to form a stable pink coloured product. The colour is found to develop within 5 min and is stable over 12 h, with a maximum absorption at 545 nm. A linear calibration curve is formed by using standard solutions of tetrahydrofolic acid. The presence of the studied drugs did not interfere with the determination. Lineweaver-Burk plots of the reaction kinetics, in the presence of triamterene and/or hydrochlorothiazide showed a competitive inhibition of the dihydrofolate reductase in the presence of triamterene with or without hydrochlorothiazide. A 100% inhibition is obtained by 1 microM solution of triamterene at a folic acid concentration of 0.01 mM. No measurable effect of hydrochlorothiazide at the studied concentration range is demonstrated.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2490542&dopt=Abstract hydrochlorothiazide Microzide



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Predictors of left ventricular hypertrophy in patients with essential hypertension.

Glasser SP, Koehn DK.

Division of Cardiology, University of South Florida College of Medicine, Tampa 33612.

The purpose of this study was to assess clinical variables which might be predictive of echocardiographic left ventricular hypertrophy in mildly hypertensive patients. Eighteen patients (mean age 51) were studied following four weeks of hydrochlorothiazide monotherapy. Variables assessed included age, duration of hypertension, body surface area, serum cholesterol, alcohol consumption, smoking, maximum systolic and mean blood pressures, and variability of blood pressure determined from hourly measurements taken 12 hours after hydrochlorothiazide dosing. Using stepwise multiple linear regression (with left ventricular mass index analyzed as a continuous variable), the variability of blood pressure was predictive of an elevated left ventricular mass index (p less than 0.0003, r2 = 0.61). The duration of hypertension added significantly to the variability in predicting an elevated left ventricular mass index (p less than 0.004, multiple r = 0.74). In conclusion, echocardiographic left ventricular hypertrophy was significantly related to the variability of blood pressure recorded hourly for 12 h after subjects received 50 mg of hydrochlorothiazide.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2522362&dopt=Abstract hydrochlorothiazide Microzide



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Hypertension and sudden death. Disparate effects of calcium entry blocker and diuretic therapy on cardiac dysrhythmias.

Messerli FH, Nunez BD, Nunez MM, Garavaglia GE, Schmieder RE, Ventura HO.

Department of Internal Medicine, Ochsner Clinic, New Orleans, LA 70121.

This study was designed to evaluate the impact of antihypertensive therapy on cardiac dysrhythmias in 13 hypertensive patients who received calcium entry blockers and in 10 hypertensive patients who received hydrochlorothiazide. Mean arterial pressure fell to a similar extent in both treatment groups; however, left ventricular mass index decreased (from 102 +/- 4 to 95 +/- 2 g/m2) only in patients receiving calcium entry blockers, but not in those taking hydrochlorothiazide. The prevalence of premature ventricular contractions decreased 74% from 21 +/- 14/h to 5.7 +/- 6/h in the calcium entry blocker group, but did not change in the hydrochlorothiazide group (15 +/- 17/h to 16 +/- 13/h). Couplets, multiform contractions, ventricular tachycardia, and supraventricular tachycardia were completely abolished after calcium entry blocker therapy, whereas the prevalence of these arrhythmias remained unchanged during treatment with hydrochlorothiazide. We conclude that antihypertensive therapy with calcium entry blockers (but not with thiazide diuretics) reduces left ventricular mass and the prevalence and severity of ventricular dysrhythmias. Whether this reduction will improve the ominous prognosis of left ventricular hypertrophy and diminish the risk of sudden death remains unknown.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2525012&dopt=Abstract hydrochlorothiazide Microzide