Hydrochlorothiazide

Hydrochlorothiazide is used for the treatment of hypertension, congestive heart failure, symptomatic edema, diabetes insipidus, renal tubular acidosis.[3] It is also used for the prevention of kidney stones in those who have high levels of calcium in their urine.[3]

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.[12][13][14] A review of randomised trials showed varying efficacy in cardiovascular outcomes on age, ethnicity and existing cardiovascular risks.[14][15] 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.[12]

Hydrochlorothiazide is less potent but not necessarily less effective than chlorthalidone in reducing blood pressure.[16][17]  More robust studies are required to confirm which drug is superior in reducing cardiovascular events.[18] Side effect profile for both drugs appear similar and are dose dependant.[16][17][18]

Hydrochlorothiazide is also sometimes used to prevent osteopenia and for treatment of hypoparathyroidism,[19] 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.

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.[20][21][22] Thiazides decrease mineral bone loss by promoting calcium retention in the kidney, and by directly stimulating osteoblast differentiation and bone mineral formation.[23]

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.[24][25]

• 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.[26][27][28]
• Hyperglycemia, high blood sugar
• Hyperlipidemia, high cholesterol and triglycerides
• Headache
• Nausea/vomiting
• Photosensitivity
• Weight gain
• Pancreatitis

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.[29] 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.[30] 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.[31]

There is an increased risk of non-melanoma skin cancer.[32] 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.[33] 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).[34]

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.[35] Additionally, by other mechanisms, hydrochlorothiazide is believed to lower peripheral vascular resistance.[6]

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.[36]

• "Hydrochlorothiazide". Drug Information Portal. U.S. National Library of Medicine.