Pharmacology and Toxicology of Loop Diuretics in Pediatrics
Sam Kacew in Drug Toxicity and Metabolism in Pediatrics, 1990
In certain conditions such as diuretic-resistant edema, the intentional use of several agents is a necessity. The current rationale is to employ drugs which exert a pharmacological action at different renal sites. Several investigators have thus administered furosemide in combination with metolazone, a diuretic which inhibits sodium reabsorption at the distal cortical and proximal convoluted tubule.106 Unlike furosemide, metolazone has the least tendency to produce kaliuresis.107 Epstein et al.108 found that in adult patients suffering from cardiac, hepatic, or renal edema who failed to respond to furosemide alone, the addition of metolazone produced a prompt and substantial diuresis. Various investigators reported similar findings in adult patients refractory to furosemide, but suggested a diminution in furosemide dosage due to a development in neurotoxicity.109,110 In children with a nephrotic syndrome resistant to furosemide, the addition of metolazone was found to achieve natriuresis.111 In a more extensive study, Arnold112 demonstrated that in furosemide-resistant edema in children, inclusion of metolazone produced an effective diuresis and natriuresis. However, combination furosemide and metolazone therapy was not effective in children with chronic renal insufficiency.111,112
Cardiovascular drug therapy in the elderly
Wilbert S. Aronow, Jerome L. Fleg, Michael W. Rich in Tresch and Aronow’s Cardiovascular Disease in the Elderly, 2019
A thiazide-like diuretic, such as hydrochlorothiazide, may be used in the occasional older patient with mild HF. However, thiazide-like diuretics have diminished effectiveness at conventional doses when the glomerular filtration rate falls below 30 mL/min; accordingly, older patients with moderate-to-severe HF should be treated with a loop diuretic, such as furosemide. Older patients with severe HF or concomitant significant renal insufficiency may need combination diuretic therapy employing a loop diuretic together with the thiazide-like diuretic metolazone (56). The slowly and erratically absorbed form of metolazone (Zaroxylyn®) is the preferred form when combination therapy is being considered. Nonsteroidal anti-inflammatory drugs (NSAIDs) may decrease both the antihypertensive and natriuretic effect of loop diuretics (56). This is a particular problem when loop diuretics are being employed to manage HF-related congestive symptomatology (58). A final consideration is the sometimes insidious manner by which NSAIDs can interact with diuretics in that several commonly used NSAIDs are now available over-the-counter.
The Advanced HEART FAILURE Patient
Andreas P. Kalogeropoulos, Hal A. Skopicki, Javed Butler in Heart Failure, 2023
Thiazide and thiazide-like diuretics act by blocking the sodium-chloride co-transporter in the distal convoluted tubule, thus increasing sodium secretion by the distal nephron. The addition of metolazone was an integral part of the stepped pharmacologic algorithm in the CARRESS-HF-trial, which resulted in the recommendation of thiazides as a second-line agent in both American and European guidelines.38 Observational studies support the effectiveness of thiazides in patients with reduced glomerular filtration rate (<30 mL/min/1.73 m2), which can be an advantage in patients with advanced HF.
Assessment of the genotoxic effects of antihypertensive drug active ingredient indapamide in human lymphocytes
Published in Drug and Chemical Toxicology, 2023
Ece Avuloglu-Yilmaz, Deniz Yuzbasioglu, Fatma Unal
On the other hand, some antihypertensive drug active ingredients are genotoxic in various organisms. The genotoxic effect of hydrochlorothiazide (5 and 40 µg/ml for 31 hours) was examined by MN and MN-FISH test in lymphocytes obtained from 32 healthy donors. Based on their results, authors have reported that the genotoxic effect of hydrochlorothiazide was stronger at high concentrations and the MN formation was generated mostly by the aneugenic effect (Andrianopoulos et al. 2006). Telez et al. (2000) reported that there was no significant change in SCE frequency in patients after chronic exposure to atenolol (50 mg/day), whereas a significant increase was determined in MN frequency and this increase occurred due to chromosome loss (aneugenicity) (Telez et al.2000). Genotoxic effects of metolazone (0.01, 0.02, and 0.04 mg/kg for 10 days) in male adult albino mice were examined by CA assay in bone marrow cells and spermatocytes. It was determined that metolazone caused a dose-dependent increase in abnormal sperm and CA frequency (germ and soma cells) (Fyiad and Roshdy 2012). In a different study, in vivo genotoxicity of furosemide (2.5, 5, 10, 20, 40, and 80 mg/kg for 7 days or a single dose) was investigated in bone marrow cells of Swiss albino mice using CA and comet assays, and in liver cells using the comet assay. Increased DNA fragmentation was found in hepatocytes and bone marrow as a result of the comet assay. However, furosemide did not induce structural CAs in bone marrow cells (Mondal et al. 2012).
Established and recent developments in the pharmacological management of urolithiasis: an overview of the current treatment armamentarium
Published in Expert Opinion on Pharmacotherapy, 2020
Mohamed Abou Chakra, Athanasios E. Dellis, Athanasios G. Papatsoris, Mohamad Moussa
There is a lack of data regarding adverse, long-term side effects of thiazides used for kidney stone prevention. However, the side effect profile of thiazide diuretics has been well studied in the setting of hypertension. Thiazide‐related side effects are more common with longer‐acting compounds, such as chlorthalidone and metolazone. Among the thiazide‐type diuretics, indapamide has the least significant metabolic derangements. Side effects may include hypokalemia, hypomagnesemia and hyperuricemia [54]. A large, prospective, cohort study (12,550 non diabetic adults [45‐ to 64‐ years old] who did not have diabetes concluded that subjects with hypertension who were taking thiazide diuretics were not at greater risk for the subsequent development of diabetes [55]. Adverse effects of thiazide and thiazide‐like diuretics on male sexual function are decreased libido, erectile dysfunction, and difficult ejaculation [56,57]. In addition, hydrochlorothiazide can cause photosensitivity [58]. There is a lack of data on the metabolic effects of thiazides used to prevent recurrent calcium nephrolithiasis. It remains unclear if metabolic effects occur and increase the risk of cardiovascular disease in otherwise healthy patients with recurrent nephrolithiasis on thiazide prophylaxis [59]. Thiazide prescription is associated with decreased urinary citrate, this is caused by thiazide‐induced hypokalemia, which would stimulate citrate reabsorption in the proximal tubules [60,61].
Usefulness of acetazolamide in the management of diuretic resistance
Published in Baylor University Medical Center Proceedings, 2021
Dalvir Gill, Naga Vaishnavi Gadela, Ayesha Azmeen, Abhishek Jaiswal
A 66-year-old obese (body mass index 34 kg/m2) woman with hypertension, diabetes mellitus type 2, and HF with preserved ejection fraction on bumetanide 2 mg daily at home presented for decompensated HF with fluid overload. In the outside hospital, her blood pressure was 145/75 mm Hg and her respiratory rate was 24 breaths/minute with an oxygen saturation of 96% on 2 L of nasal cannula. Examination revealed respiratory distress with accessory muscle use, inspiratory crackles, bilateral pitting lower-extremity edema, and elevated jugular venous pulse. Admission serum creatinine was 1.2 mg/dL; sodium, 138 mmol/L; potassium, 3.2 mmol/L; bicarbonate, 28 mg/dL; pro-brain natriuretic peptide, 3492 pg/mL; and troponin, <0.03 ng/mL. Chest radiograph showed pulmonary congestion, and an electrocardiogram showed sinus rhythm, with old Q waves in V1 to V4. On day 1, the patient received 40 mg of intravenous furosemide and a furosemide infusion at 10 mg/h to which she remained oliguric. On day 2, an intravenous bolus of 40 mg furosemide was given, and the infusion was increased to 20 mg/h with no response. On day 3, she was transitioned to bumetanide infusion at 1 mg/h without any improvement in urine output. On day 4, bumetanide infusion was increased to 1.5 mg/h in addition to 5 mg metolazone. Continued suboptimal urine output led to an increasing bumetanide infusion to 2 mg/h and another dose of 10 mg metolazone twice on day 5 with a somewhat improved urine output of 950 mL in 24 hours. During this period, her creatinine increased to 3.9 mg/dL.
Related Knowledge Centers
- Bumetanide
- Dehydration
- Edema
- Loop Diuretic
- Thiazide
- Hypertension
- Heart Failure
- Kidney
- Furosemide
- Electrolyte Imbalance