It is in the thiazide medication class and acts by decreasing the kidneys' ability to retain water.[3] This initially reduces blood volume, decreasing blood return to the heart and thus cardiac output.[7] It is believed to lower peripheral vascular resistance in the long run.[7]
Two companies, Merck and Ciba, state they discovered the medication which became commercially available in 1959.[8] It is on the World Health Organization's List of Essential Medicines.[9] It is available as a generic drug[3] and is relatively affordable.[10] In 2020, it was the eleventh most commonly prescribed medication in the United States, with more than 41million prescriptions.[11][12]
Multiple studies suggest hydrochlorothiazide could be used as initial monotherapy in people with primary hypertension; however, the decision should be weighed against the consequence of long-term adverse metabolic abnormalities.[13][14][15] A review of randomised trials showed varying efficacy in cardiovascular outcomes on age, ethnicity and existing cardiovascular risks.[15][16] A systematic, multinational, large-scale analysis by Suchard et al. supported equivalence between drug classes for initiating monotherapy in hypertension, however thiazide or thiazide-like diuretics showed better primary effectiveness and safety profiles than angiotensin-converting enzyme inhibitors and non-dihydropyridine calcium channel blockers.[13]
Hydrochlorothiazide is less potent but not necessarily less effective than chlorthalidone in reducing blood pressure.[17][18] More robust studies are required to confirm which drug is superior in reducing cardiovascular events.[19] Side effect profile for both drugs appear similar and are dose dependant.[17][18][19]
Hydrochlorothiazide is also sometimes used to prevent osteopenia and for treatment of hypoparathyroidism,[20]hypercalciuria, Dent's disease, and Ménière's disease. For diabetes insipidus, the effect of thiazide diuretics is presumably mediated by a hypovolemia-induced increase in proximal sodium and water reabsorption, thereby diminishing water delivery to the ADH-sensitive sites in the collecting tubules and increasing the urine osmolality.[medical citation needed]
A low level of evidence, predominantly from observational studies, suggests that thiazide diuretics have a modest beneficial effect on bone mineral density and are associated with a decreased fracture risk when compared with people not taking thiazides.[21][22][23] Thiazides decrease mineral bone loss by promoting calcium retention in the kidney, and by directly stimulating osteoblast differentiation and bone mineral formation.[24]
The combination of fixed-dose preparation such as losartan/hydrochlorothiazide has added advantages of a more potent antihypertensive effect with additional antihypertensive efficacy at the dose of 100 mg/25 mg when compared to monotherapy.[25][4]
Adverse effects
Hypokalemia, or low blood levels of potassium are an occasional side effect. It can be usually prevented by potassium supplements or by combining hydrochlorothiazide with a potassium-sparing diuretic
Other disturbances in the levels of serum electrolytes, including hypomagnesemia (low magnesium), hyponatremia (low sodium), and hypercalcemia (high calcium)
Hyperuricemia (high levels of uric acid in the blood). All thiazide diuretics including hydrochlorothiazide can inhibit excretion of uric acid by the kidneys, thereby increasing serum concentrations of uric acid. This may increase the incidence of gout in doses of ≥ 25 mg per day and in more susceptible patients such as male gender of <60 years old.[4][26][27]
Package inserts contain vague and inconsistent data surrounding the use of thiazide diuretics in patients with allergies to sulfa drugs, with little evidence to support these statements.[28] A retrospective cohort study conducted by Strom et al. concluded that there is an increased risk of an allergic reaction occurring in patients with a predisposition to allergic reactions in general rather than cross reactivity from structural components of the sulfonamide-based drug.[29] Prescribers should examine the evidence carefully and assess each patient individually, paying particular attention to their prior history of sulfonamide hypersensitivity rather than relying on drug monograph information.[30]
There is an increased risk of non-melanoma skin cancer.[31] In August 2020, the Australian Therapeutic Goods Administration required the Product Information (PI) and Consumer Medicine Information (CMI) for medicines containing hydrochlorothiazide to be updated to include details about an increased risk of non-melanoma skin cancer.[32] In August 2020, the U.S. Food and Drug Administration (FDA) updated the drug label about an increased risk of non-melanoma skin cancer (basal cell skin cancer or squamous cell skin cancer).[33]
Mechanism of action
Hydrochlorothiazide belongs to the thiazide class of diuretics. It reduces blood volume by acting on the kidneys to reduce sodium (Na+) reabsorption in the distal convoluted tubule. The major site of action in the nephron appears on an electroneutral NaCl co-transporter by competing for the chloride site on the transporter. By impairing Na+ transport in the distal convoluted tubule, hydrochlorothiazide induces a natriuresis and concomitant water loss. Thiazides increase the reabsorption of calcium in this segment in a manner unrelated to sodium transport.[34] Additionally, by other mechanisms, hydrochlorothiazide is believed to lower peripheral vascular resistance.[7]
Dosage
Hydrochlorothiazide has blood pressure lowering effect which depend on the dose.[4] In a double-blind, randomized study, the effects of 25 mg/day vs. 50 mg/day of hydrochlorothiazide were evaluated in geriatric patients (n = 51) with isolated systolic hypertension. Both dosages were associated with similar reductions in blood pressure; however, the higher dose (50 mg/day) caused a greater decline in serum potassium concentration.[35]
Two generic benazepril HCl 20 mg and hydrochlorothiazide 25 mg oral tablets
Brand names
Hydrochlorothiazide is available as a generic drug under a large number of brand names, including Apo-Hydro, Aquazide, BPZide, Dichlotride, Esidrex, Hydrochlorot, Hydrodiuril, HydroSaluric, Hypothiazid, Microzide, Oretic and many others.[medical citation needed]
To reduce pill burden and in order to reduce side effects, hydrochlorothiazide is often used in fixed-dose combinations with many other classes of antihypertensive drugs such as:
^ abcdMusini VM, Nazer M, Bassett K, Wright JM (May 2014). "Blood pressure-lowering efficacy of monotherapy with thiazide diuretics for primary hypertension". The Cochrane Database of Systematic Reviews (5): CD003824. doi:10.1002/14651858.cd003824.pub2. PMID24869750.
^Roush GC, Messerli FH (June 2021). "Chlorthalidone versus hydrochlorothiazide: major cardiovascular events, blood pressure, left ventricular mass, and adverse effects". Journal of Hypertension. 39 (6): 1254–1260. doi:10.1097/HJH.0000000000002771. PMID33470735. S2CID231649367.
^World Health Organization (2021). World Health Organization model list of essential medicines: 22nd list (2021). Geneva: World Health Organization. hdl:10665/345533. WHO/MHP/HPS/EML/2021.02.
^ abRahman M, Pressel S, Davis BR, Nwachuku C, Wright JT, Whelton PK, et al. (April 2005). "Renal outcomes in high-risk hypertensive patients treated with an angiotensin-converting enzyme inhibitor or a calcium channel blocker vs a diuretic: a report from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)". Archives of Internal Medicine. 165 (8): 936–946. doi:10.1001/archinte.165.8.936. PMID15851647. S2CID35719194.
^Wing LM, Reid CM, Ryan P, Beilin LJ, Brown MA, Jennings GL, et al. (February 2003). "A comparison of outcomes with angiotensin-converting--enzyme inhibitors and diuretics for hypertension in the elderly". The New England Journal of Medicine. 348 (7): 583–592. doi:10.1056/NEJMoa021716. PMID12584366.
^ abErnst ME, Carter BL, Goerdt CJ, Steffensmeier JJ, Phillips BB, Zimmerman MB, Bergus GR (March 2006). "Comparative antihypertensive effects of hydrochlorothiazide and chlorthalidone on ambulatory and office blood pressure". Hypertension. 47 (3): 352–358. doi:10.1161/01.HYP.0000203309.07140.d3. PMID16432050. S2CID739872.
^Aung K, Htay T, et al. (Cochrane Hypertension Group) (October 2011). "Thiazide diuretics and the risk of hip fracture". The Cochrane Database of Systematic Reviews (10): CD005185. doi:10.1002/14651858.CD005185.pub2. PMID21975748.
^Xiao X, Xu Y, Wu Q (July 2018). "Thiazide diuretic usage and risk of fracture: a meta-analysis of cohort studies". Osteoporosis International. 29 (7): 1515–1524. doi:10.1007/s00198-018-4486-9. PMID29574519. S2CID4322516.
^Lacourcière Y, Poirier L (December 2003). "Antihypertensive effects of two fixed-dose combinations of losartan and hydrochlorothiazide versus hydrochlorothiazide monotherapy in subjects with ambulatory systolic hypertension". American Journal of Hypertension. 16 (12): 1036–1042. doi:10.1016/j.amjhyper.2003.07.014. PMID14643578. S2CID26447230.
^Hueskes BA, Roovers EA, Mantel-Teeuwisse AK, Janssens HJ, van de Lisdonk EH, Janssen M (June 2012). "Use of diuretics and the risk of gouty arthritis: a systematic review". Seminars in Arthritis and Rheumatism. 41 (6): 879–889. doi:10.1016/j.semarthrit.2011.11.008. PMID22221907.
^Johnson KK, Green DL, Rife JP, Limon L (February 2005). "Sulfonamide cross-reactivity: fact or fiction?". The Annals of Pharmacotherapy. 39 (2): 290–301. doi:10.1345/aph.1E350. PMID15644481. S2CID10642527.
^Strom BL, Schinnar R, Apter AJ, Margolis DJ, Lautenbach E, Hennessy S, et al. (October 2003). "Absence of cross-reactivity between sulfonamide antibiotics and sulfonamide nonantibiotics". The New England Journal of Medicine. 349 (17): 1628–1635. doi:10.1056/NEJMoa022963. PMID14573734.
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