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Identification Hydrochlorothiazide small molecule approved A thiazide diuretic often considered the prototypical member of this class. It reduces the reabsorption of electrolytes from the renal tubules. This results in increased excretion of water and electrolytes, including sodium, potassium, chloride, and magnesium. It has been used in the treatment of several disorders including edema, hypertension, diabetes insipidus, and hypoparathyroidism. [PubChem]

Description

Structure

Synonyms Categories CAS number Antihypertensive Agents Diuretics Sodium Chloride Symporter Inhibitors

58-93-5 Average: 297.739 Weight Monoisotopic: 296.964474846 Chemical Formula C7H8ClN3O4S2 IUPAC Name 6-chloro-1,1-dioxo-3,4-dihydro-2H-1$l^{6},2,4-benzothiadiazine-7-

sulfonamide Pharmacology Indication For the treatment of high blood pressure and management of edema. Thiazides such as hydrochlorothiazide promote water loss from the body (diuretics). They inhibit Na+/Cl- reabsorption from the distal convoluted tubules in the kidneys. Thiazides also cause loss of potassium and an increase in serum uric acid. Thiazides are often used to treat hypertension, but their hypotensive effects are not necessarily due to their Pharmacodynamics diuretic activity. Thiazides have been shown to prevent hypertensionrelated morbidity and mortality although the mechanism is not fully understood. Thiazides cause vasodilation by activating calcium-activated potassium channels (large conductance) in vascular smooth muscles and inhibiting various carbonic anhydrases in vascular tissue. Hydrochlorothiazide, a thiazide diuretic, inhibits water reabsorption in the nephron by inhibiting the sodium-chloride symporter (SLC12A3) in the distal convoluted tubule, which is responsible for 5% of total sodium reabsorption. Normally, the sodium-chloride symporter transports sodium and chloride from the lumen into the epithelial cell lining the distal convoluted tubule. The energy for this is provided by a sodium gradient established by sodium-potassium ATPases on the basolateral membrane. Once sodium has entered the cell, it is transported out into the basolateral interstitium via the sodium-potassium ATPase, causing an increase in the osmolarity of the interstitium, thereby establishing an osmotic gradient for water reabsorption. By blocking the sodium-chloride symporter, hydrochlorothiazide effectively reduces the osmotic gradient and water Mechanism of reabsorption throughout the nephron.Hydrochlorothiazide, a thiazide action diuretic, inhibits water reabsorption in the nephron by inhibiting the sodium-chloride symporter (SLC12A3) in the distal convoluted tubule, which is responsible for 5% of total sodium reabsorption. Normally, the sodium-chloride symporter transports sodium and chloride from the lumen into the epithelial cell lining the distal convoluted tubule. The energy for this is provided by a sodium gradient established by sodiumpotassium ATPases on the basolateral membrane. Once sodium has entered the cell, it is transported out into the basolateral interstitium via the sodium-potassium ATPase, causing an increase in the osmolarity of the interstitium, thereby establishing an osmotic gradient for water reabsorption. By blocking the sodium-chloride symporter, hydrochlorothiazide effectively reduces the osmotic gradient and water reabsorption throughout the nephron. Absorption 50-60% Volume of Not Available distribution Protein binding 67.9% Metabolism Route of elimination Half life Clearance Toxicity Hydrochlorothiazide is not metabolized. Hydrochlorothiazide is not metabolized but is eliminated rapidly by the kidney. Hydrochlorothiazide crosses the placental but not the blood-brain barrier and is excreted in breast milk. 5.6 and 14.8 hours Not Available The most common signs and symptoms observed are those caused by

Drug Interactions

electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis. If digitalis has also been administered, hypokalemia may accentuate cardiac arrhythmias. The oral LD50 of hydrochlorothiazide is greater than 10 g/kg in the mouse and rat. Interactions Not Available Avoid alcohol. Avoid excess salt/sodium unless otherwise instructed by your physician. Avoid natural licorice. Do not take calcium, aluminum, magnesium or Iron supplements within 2 hours of taking this medication. Increase potassium intake; add a banana or orange juice; unless instructed otherwise. Take with food.

Food Interactions

Mechanism of Action: The exact mechanism of the diuretic effect of hydrochlorothiazide is not fully understood. Bioelectric studies suggested a direct inhibition of sodium ion reabsorption in the toad bladder and studies of the effects of hydrochlorothiazide on ion movement in the isolated rabbit distal colon suggested specific inhibition of chloride absorption. In micropuncture studies, chloride transport in the medullary collecting duct of the rat kidney was almost completely inhibited by hydrochlorothiazide. To examine the effect of hydrochlorothiazide on Na+ -K+ ATPase activity in seven separate segments along the nephron of spontaneously hypertensive rats and the normotensive control rats. Hydrochlorothiazide was administered at 15 mg/kg for 7 days by an osmotic minipump. Individual nephron segments then were dissected from the kidney and ouabain-sensitive Na+ -K+ ATPase activity was determined. Activity in the normotensive strain was decreased by hydrochlorothiazide administration in the distal convoluted tubule and was increased in the cortical collecting duct.

Hydrochlorothiazide decreased Na+ -K+ ATPase activity in all but the proximal straight tubule and medullary collecting duct in the spontaneously hypertensive strain.
[DHHS/NTP; Toxicology and Carcinogenesis Studies of Hydrochlorothiazide in F344/N Rats and B6C3F1 Mice (Feed Studies) p.15 (1989) Technical Rpt Series No.357 NIH Pub No. 89-2812] **PEER REVIEWED**

Renal effects of hydrochlorothiazide include increased renin release and increased release of kallikrein. Renin is an enzyme released from the juxtaglomerular apparatus, which is active in the formation of angiotensin I in the blood stream. Angiotensin I is converted to angiotensin II by angiotensin I-converting enzyme in the vasculature in the lung. One of the actions of angiotensin II is to stimulate secretion of aldosterone from the adrenal cortex. Aldosterone acts on the distal convoluted tubule and collecting duct to promote sodium ion reabsorption and potassium ion secretion. This action acts to temper the diuresis induced by hydrochlorothiazide. Prostaglandin biosynthesis is thought to be involved in the increase in renin release in response to loop diuretics such as furosemide, but the renal effects of hydrochlorothiazide do not appear to be mediated by prostaglandins. ... Kallikrein is a protease purportedly released from the kidney and is involved in the formation of vasoactive kinins, including the vasodilator bradykinin. Urinary kallikrein activity was increased in hypertensive volunteers after 2 wk of daily dosing with 50 mg hydrochlorothiazide followed by 2 wk of daily dosing with 100 mg hydrochlorothiazide. This action may be important in the efficacy of hydrochlorothiazide therapy for hypertension
Methods of Manufacturing: ACYLATION OF 3-CHLOROANILINE WITH CHLOROSULFONIC ACID FOLLOWED BY TREATMENT WITH AMMONIA AND FORMALDEHYDE.