Chlortalidone

Template:Short description Template:Cs1 config Template:Use dmy dates Template:Drugbox Chlortalidone, also known as chlorthalidone, is a thiazide-like diuretic drug<ref name=Ace2019/> used to treat high blood pressure, swelling (such as occurs in heart failure, liver failure, and nephrotic syndrome), diabetes insipidus, and renal tubular acidosis.<ref name=AHFS2019/><ref name=BNF76/> Because chlortalidone is effective in most patients with high blood pressure, it is considered a preferred initial treatment.<ref>Template:Cite journal</ref><ref name=AHFS2019/> It is also used to prevent calcium-based kidney stones.<ref name=AHFS2019/> It is taken by mouth.<ref name=AHFS2019>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Effects generally begin within three hours and last for up to three days.<ref name=AHFS2019/> Long-term treatment with chlortalidone is more effective than hydrochlorothiazide for prevention of heart attack or stroke.<ref>Template:Cite journal</ref>

Common adverse effects include low blood potassium, low blood sodium, high blood sugar, dizziness, and erectile dysfunction.<ref name=AHFS2019/><ref name=BNF76/><ref>Template:Cite journal</ref> Other adverse effects may include gout, low blood magnesium, high blood calcium, allergic reactions, and low blood pressure.<ref name=AHFS2019/><ref name=BNF76/><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Some reviews have found chlortalidone and hydrochlorothiazide to have a similar risk of adverse effects,<ref name=Din2019>Template:Cite journal</ref><ref name=Rou2018>Template:Cite journal</ref> while other reviews have found chlortalidone to have a higher risk.<ref name=Ace2019/><ref name=Spr2015>Template:Cite journal</ref> While it may be used in pregnancy it is a less preferred option.<ref name=AHFS2019/> How it works is not completely clear but is believed to involve increasing the amount of sodium and water lost by the kidneys.<ref name=AHFS2019/>

Chlortalidone was patented in 1957 and came into medical use in 1960.<ref>Template:Cite book</ref> It is on the World Health Organization's List of Essential Medicines.<ref name="WHO23rd">Template:Cite book</ref> It is available as a generic medication.<ref name=BNF76>Template:Cite book</ref> In 2022, it was the 108th most commonly prescribed medication in the United States, with more than 5Template:Nbspmillion prescriptions.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Medical use

High blood pressure

Chlortalidone is considered a first-line medication for treatment of high blood pressure.<ref name=AHFS2019/> Some recommend chlortalidone over hydrochlorothiazide.<ref name=Ace2019>Template:Cite journal</ref><ref>Template:Cite journal</ref> A meta-analysis of randomized controlled trials found that chlortalidone is more effective than hydrochlorothiazide for lowering blood pressure, while the two drugs have similar toxicity.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref name=Ace2019/><ref name=Spr2015/>

Trials of chlortalidone for high blood pressure found that lower doses of chlortalidone (e.g., 12.5 mg daily in ALLHAT study) had maximal blood pressure lowering effect and that higher doses did not lower it more. Chlortalidone and other thiazide diuretics are effective for lowering high blood pressure in persons with chronic kidney disease, although the risk of adverse effects is higher.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

Left ventricular hypertrophy

Chlortalidone is used to treat enlargement of the left ventricle of the heart; it works chiefly by lowering blood pressure, and thereby reducing systemic vascular resistance. There is evidence that chlortalidone is superior to hydrochlorothiazide for reducing the mass of the left ventricle of the heart in persons with enlargement of the left ventricle of the heart.<ref>Template:Cite journal</ref> Chlortalidone is superior to angiotensin converting enzyme Inhibitors or angiotensin II receptor blockers for inducing regression of enlargement of the left ventricle, which is the main pumping chamber of the heart.<ref>Template:Cite journal</ref>

Swelling

Chlortalidone reduces edema (swelling) by increasing urinary salt and water excretion, lowering intravascular hydrostatic pressure and thereby lowering transcapillary pressure (see Starling Equation). Edema may be caused by either increased hydrostatic pressure or reduced oncotic pressure in the blood vessels. Edema due to increased hydrostatic pressure may be a result of serious cardiopulmonary disease (which reduces glomerular perfusion in the kidney) or to kidney injury or disease (which may reduce glomerular excretion of salt and water by the kidney) or due to relatively benign conditions such as menstrual-related fluid retention, or as an adverse effect of dihydropyridine calcium channel blockers, which commonly cause swelling of the feet and lower legs. Edema due to decreased oncotic pressure may be a result of leaking of blood proteins through the glomeruli of an injured kidney<ref>Template:Cite journal</ref> or a result of diminished synthesis of blood proteins by a damaged liver. Regardless of cause, chlortalidone may reduce the severity of edema by reducing intravascular volume and thereby reducing intravascular hydrostatic pressure.<ref>Template:Cite journal</ref>

Bone fracture prevention

Chlortalidone decreases mineral bone loss by promoting calcium retention by the kidney, and by directly stimulating osteoblast differentiation and bone mineral formation.<ref name="pmid17656470">Template:Cite journal</ref> A Cochrane review found tentative evidence that thiazide exposure was associated with a reduced risk of hip fracture.<ref>Template:Cite journal</ref> A secondary analysis of data from the ALLHAT study found that chlortalidone reduced risk of hip and pelvis fracture.<ref>Template:Cite journal</ref>

Kidney stone prevention

Chlortalidone reduces the amount of calcium excreted in urine, reducing the risk of calcium oxalate kidney stones.<ref>Template:Cite journal</ref> In people who have had multiple episodes of calcium oxalate kidney stones, chlortalidone lowers the risk of having another episode of kidney stones.<ref>Template:Cite journal</ref> Chlortalidone is more effective than hydrochlorothiazide for lowering urine calcium levels and is therefore probably more effective.<ref>Template:Cite journal</ref>

Ménière's disease

Chlortalidone reduces the endolymph volume which reduces the hydrostatic pressure in the inner ear chambers; elevated endolymph pressure in the inner ear is thought to be the cause of Ménière's disease or ’Endolymphatic hydrops.’ Synthesis of evidence from multiple small, low-quality studies indicates that chlortalidone or other thiazide diuretics are effective for Ménière's Disease.<ref>Template:Cite journal</ref>

Diabetes insipidus

Chlortalidone (or other thiazide medication) is a key component of treatment of nephrogenic diabetes insipidus. Nephrogenic diabetes insipidus occurs when the kidney is unable to concentrate urine because it has an inadequate response to vasopressin-dependent removal of free water from the renal tubular filtrate. By blocking sodium ion resorption in the distal convoluted tubule, chlortalidone induces an increase in excretion of sodium ion in urine (natriuresis). Giving chlortalidone while simultaneously restricting dietary sodium intake causes mild hypovolemia (low intravascular volume), which induces isotonic reabsorption of solute from the proximal renal tubule, reducing solute delivery in the renal collecting tubule and renal medullary collecting duct. This reduced delivery of solute to the collecting tubule and medullary collecting duct allows increased water resorption and higher concentration of urine, which leads to reversal of nephrogenic diabetes insipidus by a means that is independent of vasopressin.<ref>Template:Cite journal</ref>

Adverse effects

Some reviews have found a similar risk as hydrochlorothiazide,<ref name=Din2019/><ref name=Rou2018/> while other reviews found a higher risk of side effects.<ref name=Ace2019/><ref name=Spr2015/>

• Hypokalemia (low blood potassium) occurs occasionally; the risk of hypokalemia is higher in persons who are magnesium deficient<ref>Template:Cite journal</ref>
• Hypomagnesemia (low blood magnesium) a review of four clinical trials found that low blood magnesium occurred in 20% of persons within a few weeks of beginning treatment with 50 mg of chlortalidone daily.<ref>Template:Cite journal</ref> The risk of chlortalidone-associated hypomagnesemia is higher in persons with diabetes mellitus who have low dietary magnesium intake.
• Hyponatremia (low blood sodium) occurred in 4.1% of subjects randomized to chlortalidone in the Systolic Hypertension in the Elderly Trial, compared to 1.3% of control subjects.<ref>Template:Cite journal</ref> The risk of hyponatremia varies from 5 per 100,000 person-years for those younger than 40 years of age to 730 per 100,000 person-years in those older than 80 years of age.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> Hyponatremia is more likely in persons with certain genetic variants of the prostaglandin transporter SLCO2A1 associated with elevated urinary PGE₂ and inappropriately low plasma ADH levels in the setting of low plasma osmolality.<ref>Template:Cite journal</ref> Thiazide-associated hyponatremia is often more severe than loop diuretic-associated hyponatremia because the predominant action of thiazides occurs late in the tubular flow, reducing opportunity to apply additional corrective action further along the tubule.<ref>Template:Cite book</ref>
• Hypercalcemia (high blood calcium level) can occur in normal persons exposed to chlortalidone but is more likely to occur when persons with sub-clinical hyperparathyroidism are exposed to chlortalidone.<ref>Template:Cite journal</ref>
• Hyperuricemia, high levels of uric acid in the blood
• Hyperlipidemia, high cholesterol and triglycerides
• Headache
• Nausea/vomiting
• Photosensitivity increased susceptibility to sunburn of skin with sun exposure
• Photoonycholysis detachment of nails from nailbed with sun exposure<ref>Template:Cite book</ref>
• Weight gain
• Gout; approximately doubles the risk<ref>Template:Cite journal</ref>
• Pancreatitis

Mechanism of action

Chlortalidone reduces reabsorption of sodium and chloride primarily through inhibition of the Na⁺/Cl⁻ symporter in the apical membrane of distal convoluted tubule cells in the kidney.<ref>Template:Cite journal</ref> Although chlortalidone is often referred to as a "thiazide-like" diuretic, it is unlike thiazide diuretics in that, in addition to its inhibition of the Na⁺/Cl⁻ symporter, it also strongly inhibits multiple isoforms of carbonic anhydrase.<ref>Template:Cite journal</ref> Some of chlortalidone's diuretic effect is also due to this inhibition of carbonic anhydrase in the proximal tubule.<ref>Template:Cite journal</ref> Chronic exposure to chlortalidone decreases the glomerular filtration rate. Chlortalidone's diuretic effect is diminished in persons with kidney impairment. By increasing the delivery of sodium to the distal renal tubule, chlortalidone indirectly increases potassium excretion via the sodium-potassium exchange mechanism (i.e. apical ROMK/Na channels coupled with basolateral Na+/K ATPases). This can result in a low blood concentration of potassium and chloride as well as a mild metabolic alkalosis; however, the diuretic effect of chlortalidone is not affected by the acid-base balance of the person being treated.

There is uncertainty about the mechanism of the blood pressure-lowering effect that occurs during chronic exposure to chlortalidone.<ref>Template:Cite journal</ref> Initially, diuretics lower blood pressure by decreasing cardiac output and reducing plasma and extracellular fluid volume. Eventually, cardiac output returns to normal, and plasma and extracellular fluid volume return to slightly less than normal, but a reduction in peripheral vascular resistance is maintained, thus resulting in an overall lower blood pressure. The reduction in intravascular volume induces an elevation in plasma renin activity and aldosterone secretion, further contributing to the potassium loss associated with thiazide diuretic therapy.

Pharmacokinetics

Chlortalidone is slowly absorbed from the gastrointestinal tract after oral ingestion. It has a long half-life and therefore a prolonged diuretic action, which results in continued diuretic effects despite a skipped dose. This prolonged action of chlortalidone despite missing doses may account for the higher efficacy of chlortalidone compared to the shorter half-life medication, hydrochlorothiazide. Chlortalidone is eliminated from the body mostly by the kidney, as unchanged drug. Thus, in persons with diminished kidney function, the clearance of chlortalidone is reduced and the elimination half-life is increased.<ref name = "Singer_1985" />

As with other thiazide diuretics, chlortalidone crosses the placenta and is excreted in breast milk.<ref>Template:Cite journal</ref> Chlortalidone may suppress lactation, and has been used for this indication. Due to its long half-life, chlortalidone may accumulate in newborns via breast milk, despite receiving only about 6% of the maternal weight-adjusted dose.<ref name="lactmed">Template:Cite journal</ref>

Chemistry

Chlortalidone is in the sulfamoylbenzamide class. As it lacks the benzothiadiazine structure of the thiazide-type diuretics, it is called a thiazide-like diuretic.<ref>National Center for Biotechnology Information. PubChem Compound Database; CID=2732, {{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Chlortalidone is freely soluble in dimethylacetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide (DMSO), and methanol; it is also soluble in warm ethanol.<ref name = "Singer_1985">Template:Cite book</ref>

Chlortalidone is the official name of the medication according to the (INN/BAN), which is the medication naming system coordinated by the World Health Organization. Chlorthalidone is the official name of the medication according to the (USAN), which is the medication naming system coordinated by the USAN Council, which is co-sponsored by the American Medical Association (AMA), the United States Pharmacopeial Convention (USP), and the American Pharmacists Association (APhA).

Society and culture

Chlortalidone is banned for some sports (including cricket) because it is a diuretic, and can be used to reduce body weight or to mask the concomitant use of performance-enhancing drugs.<ref>Template:Cite journal</ref> Sports such as wrestling or boxing categorize athletes according to body weight; taking a diuretic such as chlortalidone may lower body weight, and thereby permit an athlete to compete in a lighter weight class, which would provide an advantage. Diuretics such as chlortalidone also reduce the urine concentration of concomitantly-taken performance-enhancing drugs or of their metabolites, thus making it more difficult to detect these drugs using urine testing.<ref>Template:Cite news</ref>