Chlorothiazide

Chlorothiazide is an inhibitor of carbonic anhydrase and is slightly less potent than acetazolamide. This compound has been shown to block reabsorption of sodium and chloride ions.

Intravenous Chlorothiazide Versus Enteral Metolazone to Augment Loop Diuretic Therapy in the Intensive Care Unit.[Pubmed:28228057]

Ann Pharmacother. 2017 Apr;51(4):286-292.

BACKGROUND: In cases of loop diuretic resistance in the intensive care unit (ICU), recommendations for a specific second-line thiazide agent are lacking. OBJECTIVE: To compare the effects of intravenous Chlorothiazide (CTZ) and enteral metolazone (MET) on urine output (UOP) when added to furosemide monotherapy therapy in critically ill adults. METHODS: This was a retrospective cohort study conducted in the medical, surgical, and cardiothoracic ICUs of a quaternary medical center. The primary outcome was change in UOP induced by the study interventions compared with furosemide alone. Secondary outcomes included onset of diuresis, eventual need for hemodialysis, and incidence of adverse events. RESULTS: A total of 122 patients (58 in CTZ, 64 in MET) were included. When added to furosemide monotherapy, CTZ induced a greater change in UOP at 24 hours compared with MET (2405 vs 1646 mL, respectively; P = 0.01). CTZ also caused a more rapid dieresis: 1463 mL total UOP in the first 6 hours compared with 796 mL in the MET group ( P < 0.01). There were no differences found regarding ICU length of stay, need for renal replacement therapy, or survival to discharge. The CTZ arm required more potassium supplementation to maintain normokalemia (median 100 vs 57 mEq in MET; P = 0.02) and carried a higher cost (mean $97 vs $8, P < 0.01). CONCLUSION: Both CTZ and MET induced significant increases in UOP. CTZ induced a greater and more rapid change and was associated with higher cost and greater need for potassium replacement. Randomized controlled trials are needed to establish whether a preferable thiazide diuretic exists in this setting.

Efficacy of sequential nephron blockade with intravenous chlorothiazide to promote diuresis in cardiac intensive care infants.[Pubmed:27834164]

Cardiol Young. 2017 Aug;27(6):1104-1109.

BACKGROUND: Sequential nephron blockade using intravenous Chlorothiazide is often used to enhance urine output in patients with inadequate response to loop diuretics. A few data exist to support this practice in critically ill infants. METHODS: We included 100 consecutive patients <1 year of age who were administered intravenous Chlorothiazide while receiving furosemide therapy in the cardiac ICU in our study. The primary end point was change in urine output 24 hours after Chlorothiazide administration, and patients were considered to be responders if an increase in urine output of 0.5 ml/kg/hour was documented. Data on demographic, clinical, fluid intake/output, and furosemide and Chlorothiazide dosing were collected. Multivariable regression analyses were performed to determine variables significant for increase in urine output after Chlorothiazide administration. RESULTS: The study population was 48% male, with a mean weight of 4.9+/-1.8 kg, and 69% had undergone previous cardiovascular surgery. Intravenous Chlorothiazide was initiated at 89 days (interquartile range 20-127 days) of life at a dose of 4.6+/-2.7 mg/kg/day (maximum 12 mg/kg/day). Baseline estimated creatinine clearance was 83+/-42 ml/minute/1.73 m2. Furosemide dose before Chlorothiazide administration was 2.8+/-1.4 mg/kg/day and 3.3+/-1.5 mg/kg/day after administration. A total of 43% of patients were categorised as responders, and increase in furosemide dose was the only variable significant for increase in urine output on multivariable analysis (p<0.05). No graphical trends were noted for change in urine output and dose of Chlorothiazide. CONCLUSIONS: Sequential nephron blockade with intravenous Chlorothiazide was not consistently associated with improved urine output in critically ill infants.

Efficacy and Safety of Intravenous Chlorothiazide versus Oral Metolazone in Patients with Acute Decompensated Heart Failure and Loop Diuretic Resistance.[Pubmed:27393709]

Pharmacotherapy. 2016 Aug;36(8):852-60.

STUDY OBJECTIVE: To assess the efficacy and safety of intravenous (IV) Chlorothiazide versus oral metolazone when added to loop diuretics in patients with acute decompensated heart failure (ADHF) and loop diuretic resistance. DESIGN: Retrospective cohort study. SETTING: Large urban academic medical center. PATIENTS: Adults admitted with ADHF between 2005 and 2015 who had loop diuretic resistance, defined as administration of IV furosemide at a dose of 160 mg/day or higher (or an equivalent dose of IV bumetanide), during hospitalization, and who then received at least one dose of IV Chlorothiazide (88 patients) or oral metolazone (89 patients) to augment diuresis. MEASUREMENTS AND MAIN RESULTS: The primary efficacy end point was a change in 24-hour net urine output (UOP) from before to after thiazide-type diuretic administration, and the study was designed to test for the noninferiority of metolazone. Safety end points included changes in renal function and electrolyte concentrations. The mean dose of IV loop diuretic therapy (in IV furosemide equivalents) at baseline (before thiazide-type diuretic administration) was higher in the Chlorothiazide group (mean +/- SD 318.9 +/- 127.7 vs 268.4 +/- 97.6 mg/day in the metolazone group, p=0.004), but net UOP was similar (mean +/- SD 877.0 +/- 1189.0 ml in the Chlorothiazide group vs 710.6 +/- 1145.9 ml in the metolazone group, p=0.344). Mean doses of Chlorothiazide and metolazone were 491 +/- 282 mg and 5.8 +/- 3.5 mg, respectively. Following thiazide-type diuretic administration, net UOP improved to a similar degree (2274.6 +/- 1443.0 ml vs 2030.2 +/- 1725.0 ml in the Chlorothiazide and metolazone groups, respectively, p=0.308). For the primary efficacy end point, metolazone met the threshold for noninferiority by producing a net UOP of 1319.6 +/- 1517.4 ml versus 1397.6 +/- 1370.7 ml for Chlorothiazide (p=0.026 for noninferiority). No significant differences in renal function were observed between the groups. Although hypokalemia was more frequent in the Chlorothiazide group (75% with Chlorothiazide vs 60.7% with metolazone, p=0.045), no significant differences in the rates of severe hypokalemia or other electrolyte abnormalities were observed between the groups. CONCLUSION: Oral metolazone was noninferior to IV Chlorothiazide for enhancing net UOP in patients with ADHF and loop diuretic resistance and was similarly safe with regard to renal function and electrolyte abnormalities. Given the significant cost disparity between the two agents, these findings suggest that oral metolazone may be considered a first-line option in this patient population.