Chlortalidone

Chlortalidone, also known as chlorthalidone, is a diuretic medication used to treat high blood pressure, swelling including that due to heart failure, liver failure, and nephrotic syndrome, diabetes insipidus, and renal tubular acidosis.[1][2] In high blood pressure it is a preferred initial treatment; in resistant high blood pressure chlortalidone is preferred over hydrochlorothiazide.[1][3] It is also used to prevent calcium-based kidney stones.[1] It is taken by mouth.[1] Effects generally begin within three hours and last for up to 3 days.[1]

Chlortalidone
Clinical data
Trade namesHygroton, Thalitone, others
AHFS/Drugs.comMonograph
MedlinePlusa682342
Pregnancy
category
  • C (Au), B (U.S.)
Routes of
administration		By mouth
Drug classThiazide diuretic
ATC code
Legal status
Legal status
  • UK: POM (Prescription only)
Pharmacokinetic data
Protein binding75%
Elimination half-life40 hours
ExcretionKidney
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.000.930
Chemical and physical data
FormulaC14H11ClN2O4S
Molar mass338.766 g/mol g·mol−1
3D model (JSmol)
ChiralityRacemic mixture
  (verify)

Common side effects include low blood potassium, high blood sugar, dizziness, and erectile dysfunction.[1][2] Other serious side effects may include gout, allergic reactions, and low blood pressure.[1][2] Some reviews have found chlortalidone to have a higher risk of side effects than hydrochlorothiazide,[3][4] while other reviews have found a similar risk.[5][6] While it may be used in pregnancy it is a less preferred option.[1] It is specifically a thiazide-like diuretic.[3] How it works is not completely clear but is believed to involve increasing the amount of sodium and water lost by the kidneys.[1]

Chlortalidone was patented in 1957 and came into medical use in 1960.[7] It is available as a generic medication.[2] In the United States the wholesale cost is about US$13.50 a month.[8] In 2016 it was the 174th most prescribed medication in the United States with more than 3 million prescriptions.[9]

Medical use

High blood pressure

Chlortalidone is considered a first-line medication for treatment high blood pressure, and is preferred over hydrochlorothiazide[10] because of its greater efficacy and because of the greater body of evidence supporting its use.[11] A meta-analysis of 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.[12]

Chlortalidone has a modestly greater effect on blood pressure than hydrochlorothiazide[13] but the two medications have similar effects on lowering potassium.[14][15] The thiazide-like diuretics (chlortalidone and indapamide) are more effective than the thiazide-type diuretics (including hydrochlorothiazide) for reducing the risk of heart attack, stroke, and heart failure in persons with high blood pressure and the thiazide-like and thiazide-type diuretics have similar rates of adverse effects.[16]

Chlortalidone is more effective than hydrochlorothiazide for prevention of heart failure in persons with high blood pressure.[17]

Chlortalidone, like other thiazides, appears effective in people with kidney disease.[18]

Swelling

Chlortalidone may improve 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[19] or a result of decreased synthesis of blood proteins by the liver. Regardless of cause, chlortalidone may sometimes improve the severity of edema by reducing intravascular volume and thereby reducing intravascular hydrostatic pressure.[20]

Left ventricular hypertrophy

Chlortalidone is used to treat left ventricular hypertrophy in 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.[21] 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.[22]

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.[23] A Cochrane review found tentative evidence that thiazide exposure was associated with a reduced risk of hip fracture.[24] A secondary analysis of data from the ALLHAT study found that chlortalidone reduced risk of hip and pelvis fracture.[25]

Kidney stone prevention

Chlortalidone reduces the amount of calcium excreted in urine, reducing the risk of calcium oxalate kidney stones.[26] In people who have had multiple episodes of calcium oxalate kidney stones, chlortalidone lowers the risk of having another episode of kidney stones.[27] Chlortalidone is more effective than hydrochlorothiazide for lowering urine calcium levels and is therefore probably more effective.[28]

Ménière's disease

Chlortalidone reduces the volume and thereby reduces the 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.[29]

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 produce concentrated 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.[30]

Adverse effects

Adverse effects are similar to those of thiazides:

  • Hypokalemia, or low blood level of potassium occurs occasionally; the risk of hypokalemia is higher in persons who are magnesium deficient[31]
  • Hypomagnesemia, or low blood level of magnesium occurs occasionally, particularly in persons with diabetes mellitus who have low dietary magnesium intake
  • Hyponatremia (low sodium) 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.[32][33] 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.[34] 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.[35]
  • 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.[36]
  • Hyperuricemia, high levels of uric acid in the blood
  • Hyperglycemia, high blood sugar is more common in persons who are magnesium deficient
  • 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[37]
  • Weight gain
  • Gout; approximately doubles the risk[38]
  • Pancreatitis

The frequency and severity of these adverse effects is much reduced when chlortalidone is used at lower doses (e.g., 12.5 mg per day).

Mechanism of action

Although chlortalidone is often referred to as a "thiazide-like" diuretic, it is unlike thiazide diuretics in that chlortalidone strongly inhibits multiple isoforms of carbonic anhydrase.[39]

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.[40] Some of chlortalidone's diuretic effect is also due to inhibition of carbonic anhydrase in the proximal tubule.[41] 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.[42] 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.[43]

As with other thiazide diuretics, chlortalidone crosses the placenta and is excreted in breast milk.[44] 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.[45]

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.[46] Chlortalidone is freely soluble in dimethylacetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide (DMSO), and methanol; it is also soluble in warm ethanol.[47]

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.[48] 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.[49]

See also

References
  1. "Chlorthalidone Monograph for Professionals". Drugs.com. American Society of Health-System Pharmacists. Retrieved 18 April 2019.
  2. British national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. pp. 229–230. ISBN 9780857113382.
  3. Acelajado MC, Hughes ZH, Oparil S, Calhoun DA (March 2019). "Treatment of Resistant and Refractory Hypertension". Circ. Res. 124 (7): 1061–1070. doi:10.1161/CIRCRESAHA.118.312156. PMC 6469348. PMID 30920924. A long-acting thiazide-like diuretic, specifically chlorthalidone, if available, is recommended over hydrochlorothiazide (HCTZ) given its superior efficacy and clear benefit demonstrated in multiple outcome studies of hypertension.
  4. Springer, K (1 December 2015). "Chlorthalidone vs. Hydrochlorothiazide for Treatment of Hypertension". American Family Physician. 92 (11): 1015–6. PMID 26760416.
  5. Dineva S, Uzunova K, Pavlova V, Filipova E, Kalinov K, Vekov T (October 2019). "Comparative efficacy and safety of chlorthalidone and hydrochlorothiazide-meta-analysis". J Hum Hypertens. 33 (11): 766–774. doi:10.1038/s41371-019-0255-2. PMC 6892412. PMID 31595024.
  6. Roush GC, Abdelfattah R, Song S, Ernst ME, Sica DA, Kostis JB (October 2018). "Hydrochlorothiazide vs chlorthalidone, indapamide, and potassium-sparing/hydrochlorothiazide diuretics for reducing left ventricular hypertrophy: A systematic review and meta-analysis". J Clin Hypertens (Greenwich). 20 (10): 1507–1515. doi:10.1111/jch.13386. PMID 30251403.
  7. Fischer, Jnos; Ganellin, C. Robin (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 457. ISBN 9783527607495.
  8. "NADAC as of 2019-02-27". Centers for Medicare and Medicaid Services. Retrieved 3 March 2019.
  9. "The Top 300 of 2019". clincalc.com. Retrieved 22 December 2018.
  10. Vongpatanasin W (July 2015). "Hydrochlorothiazide is not the most useful nor versatile thiazide diuretic". Curr. Opin. Cardiol. 30 (4): 361–5. doi:10.1097/HCO.0000000000000178. PMC 4460599. PMID 26049382.
  11. Carey RM, Whelton PK (March 2018). "Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: Synopsis of the 2017 American College of Cardiology/American Heart Association Hypertension Guideline". Ann. Intern. Med. 168 (5): 351–358. doi:10.7326/M17-3203. PMID 29357392.
  12. Musini VM, Nazer M, Bassett K, Wright JM (May 2014). "Blood pressure-lowering efficacy of monotherapy with thiazide diuretics for primary hypertension". Cochrane Database Syst Rev (5): CD003824. doi:10.1002/14651858.CD003824.pub2. PMID 24869750.
  13. Roush GC, Buddharaju V, Ernst ME (July 2013). "Is chlorthalidone better than hydrochlorothiazide in reducing cardiovascular events in hypertensives?". Curr. Opin. Cardiol. 28 (4): 426–32. doi:10.1097/HCO.0b013e3283622075. PMID 23736816.
  14. Dineva S, Uzunova K, Pavlova V, Filipova E, Kalinov K, Vekov T (October 2019). "Comparative efficacy and safety of chlorthalidone and hydrochlorothiazide-meta-analysis". J Hum Hypertens. 33 (11): 766–774. doi:10.1038/s41371-019-0255-2. PMC 6892412. PMID 31595024.
  15. Ernst ME, Carter BL, Zheng S, Grimm RH (April 2010). "Meta-analysis of dose-response characteristics of hydrochlorothiazide and chlorthalidone: effects on systolic blood pressure and potassium". Am. J. Hypertens. 23 (4): 440–6. doi:10.1038/ajh.2010.1. PMID 20111008.
  16. Olde Engberink RH, Frenkel WJ, van den Bogaard B, Brewster LM, Vogt L, van den Born BJ (May 2015). "Effects of thiazide-type and thiazide-like diuretics on cardiovascular events and mortality: systematic review and meta-analysis". Hypertension. 65 (5): 1033–40. doi:10.1161/HYPERTENSIONAHA.114.05122. PMID 25733241.
  17. Roush GC, Holford TR, Guddati AK (June 2012). "Chlorthalidone compared with hydrochlorothiazide in reducing cardiovascular events: systematic review and network meta-analyses". Hypertension. 59 (6): 1110–7. doi:10.1161/HYPERTENSIONAHA.112.191106. PMID 22526259.
  18. Sinha AD, Agarwal R (May 2019). "Clinical Pharmacology of Antihypertensive Therapy for the Treatment of Hypertension in CKD". Clin J Am Soc Nephrol. 14 (5): 757–764. doi:10.2215/CJN.04330418. PMC 6500954. PMID 30425103. thiazides either alone or in combination with a loop diuretic in advanced CKD, and all show some degree of efficacy, whether for hypertension or diuresis
  19. Khan S, Floris M, Pani A, Rosner MH (July 2016). "Sodium and Volume Disorders in Advanced Chronic Kidney Disease". Adv Chronic Kidney Dis. 23 (4): 240–6. doi:10.1053/j.ackd.2015.12.003. PMID 27324677.
  20. O'Brien JG, Chennubhotla SA, Chennubhotla RV (June 2005). "Treatment of edema". Am Fam Physician. 71 (11): 2111–7. PMID 15952439.
  21. Roush GC, Abdelfattah R, Song S, Ernst ME, Sica DA, Kostis JB (October 2018). "Hydrochlorothiazide vs chlorthalidone, indapamide, and potassium-sparing/hydrochlorothiazide diuretics for reducing left ventricular hypertrophy: A systematic review and meta-analysis". J Clin Hypertens (Greenwich). 20 (10): 1507–1515. doi:10.1111/jch.13386. PMID 30251403.
  22. Roush GC, Abdelfattah R, Song S, Kostis JB, Ernst ME, Sica DA (June 2018). "Hydrochlorothiazide and alternative diuretics versus renin-angiotensin system inhibitors for the regression of left ventricular hypertrophy: a head-to-head meta-analysis". J. Hypertens. 36 (6): 1247–1255. doi:10.1097/HJH.0000000000001691. PMID 29465713.
  23. Dvorak MM, De Joussineau C, Carter DH, et al. (2007). "Thiazide diuretics directly induce osteoblast differentiation and mineralized nodule formation by targeting a NaCl cotransporter in bone". J. Am. Soc. Nephrol. 18 (9): 2509–16. doi:10.1681/ASN.2007030348. PMC 2216427. PMID 17656470.
  24. Aung K, Htay T (October 2011). "Thiazide diuretics and the risk of hip fracture". Cochrane Database Syst Rev (10): CD005185. doi:10.1002/14651858.CD005185.pub2. PMID 21975748.
  25. Puttnam R, Davis BR, Pressel SL, Whelton PK, Cushman WC, Louis GT, Margolis KL, Oparil S, Williamson J, Ghosh A, Einhorn PT, Barzilay JI (January 2017). "Association of 3 Different Antihypertensive Medications With Hip and Pelvic Fracture Risk in Older Adults: Secondary Analysis of a Randomized Clinical Trial". JAMA Intern Med. 177 (1): 67–76. doi:10.1001/jamainternmed.2016.6821. PMID 27893045.
  26. Pearle MS, Roehrborn CG, Pak CY (November 1999). "Meta-analysis of randomized trials for medical prevention of calcium oxalate nephrolithiasis". J. Endourol. 13 (9): 679–85. doi:10.1089/end.1999.13.679. PMID 10608521.
  27. Fink HA, Wilt TJ, Eidman KE, Garimella PS, MacDonald R, Rutks IR, Brasure M, Kane RL, Ouellette J, Monga M (April 2013). "Medical management to prevent recurrent nephrolithiasis in adults: a systematic review for an American College of Physicians Clinical Guideline". Ann. Intern. Med. 158 (7): 535–43. doi:10.7326/0003-4819-158-7-201304020-00005. PMID 23546565.
  28. Wolfgram DF, Gundu V, Astor BC, Jhagroo RA (August 2013). "Hydrochlorothiazide compared to chlorthalidone in reduction of urinary calcium in patients with kidney stones". Urolithiasis. 41 (4): 315–22. doi:10.1007/s00240-013-0568-5. PMID 23660825.
  29. Crowson MG, Patki A, Tucci DL (May 2016). "A Systematic Review of Diuretics in the Medical Management of Ménière's Disease". Otolaryngol Head Neck Surg. 154 (5): 824–34. doi:10.1177/0194599816630733. PMID 26932948.
  30. Verbalis JG (May 2003). "Diabetes insipidus". Rev Endocr Metab Disord. 4 (2): 177–85. doi:10.1023/a:1022946220908. PMID 12766546.
  31. DiNicolantonio JJ, O'Keefe JH, Wilson W (2018). "Subclinical magnesium deficiency: a principal driver of cardiovascular disease and a public health crisis". Open Heart. 5 (1): e000668. doi:10.1136/openhrt-2017-000668. PMC 5786912. PMID 29387426.
  32. Barber J, McKeever TM, McDowell SE, Clayton JA, Ferner RE, Gordon RD, Stowasser M, O'Shaughnessy KM, Hall IP, Glover M (April 2015). "A systematic review and meta-analysis of thiazide-induced hyponatraemia: time to reconsider electrolyte monitoring regimens after thiazide initiation?". Br J Clin Pharmacol. 79 (4): 566–77. doi:10.1111/bcp.12499. PMC 4386942. PMID 25139696.
  33. van Blijderveen JC, Straus SM, Rodenburg EM, Zietse R, Stricker BH, Sturkenboom MC, Verhamme KM (August 2014). "Risk of hyponatremia with diuretics: chlorthalidone versus hydrochlorothiazide". Am. J. Med. 127 (8): 763–71. doi:10.1016/j.amjmed.2014.04.014. PMID 24811554.
  34. Ware JS, Wain LV, Channavajjhala SK, Jackson VE, Edwards E, Lu R, Siew K, Jia W, Shrine N, Kinnear S, Jalland M, Henry AP, Clayton J, O'Shaughnessy KM, Tobin MD, Schuster VL, Cook S, Hall IP, Glover M (September 2017). "Phenotypic and pharmacogenetic evaluation of patients with thiazide-induced hyponatremia". J. Clin. Invest. 127 (9): 3367–3374. doi:10.1172/JCI89812. PMC 5669583. PMID 28783044.
  35. Peri, Alessandro (2019). Disorders of fluid and electrolyte metabolism : focus on hyponatremia. Basel New York: Karger. ISBN 978-3-318-06383-7.
  36. Griebeler ML, Kearns AE, Ryu E, Thapa P, Hathcock MA, Melton LJ, Wermers RA (March 2016). "Thiazide-Associated Hypercalcemia: Incidence and Association With Primary Hyperparathyroidism Over Two Decades". J. Clin. Endocrinol. Metab. 101 (3): 1166–73. doi:10.1210/jc.2015-3964. PMC 4803175. PMID 26751196.
  37. Rubin, Adam (2018). Scher and Daniel's nails : diagnosis, surgery, therapy. Cham: Springer. pp. 453–489. ISBN 978-3319656472.
  38. Evans PL, Prior JA, Belcher J, Mallen CD, Hay CA, Roddy E (July 2018). "Obesity, hypertension and diuretic use as risk factors for incident gout: a systematic review and meta-analysis of cohort studies". Arthritis Res. Ther. 20 (1): 136. doi:10.1186/s13075-018-1612-1. PMC 6034249. PMID 29976236.
  39. Kurtz TW (September 2010). "Chlorthalidone: don't call it "thiazide-like" anymore". Hypertension. 56 (3): 335–7. doi:10.1161/HYPERTENSIONAHA.110.156166. PMID 20625074.
  40. Gamba G (October 2009). "The thiazide-sensitive Na+-Cl- cotransporter: molecular biology, functional properties, and regulation by WNKs". Am. J. Physiol. Renal Physiol. 297 (4): F838–48. doi:10.1152/ajprenal.00159.2009. PMC 3350128. PMID 19474192.
  41. Johnston MM, Li H, Mufson D (December 1977). "Chlorthalidone analysis using carbonic anhydrase inhibition". J Pharm Sci. 66 (12): 1735–8. doi:10.1002/jps.2600661220. PMID 411910.
  42. Shahin MH, Johnson JA (April 2016). "Mechanisms and pharmacogenetic signals underlying thiazide diuretics blood pressure response". Curr Opin Pharmacol. 27: 31–7. doi:10.1016/j.coph.2016.01.005. PMC 4915478. PMID 26874237.
  43. Singer, Jeff M., Michael J. O'Hare, Carl R. Rehm, and John E. Zarembo. "Chlorthalidone." In Analytical Profiles of Drug Substances, vol. 14, pp. 1-36. Academic Press, 1985.
  44. Mulley BA, Parr GD, Pau WK, Rye RM, Mould JJ, Siddle NC (May 1978). "Placental transfer of chlorthalidone and its elimination in maternal milk". Eur. J. Clin. Pharmacol. 13 (2): 129–31. doi:10.1007/bf00609757. PMID 658109.
  45. "LACTMED: CHLORTHALIDONE". toxnet.nlm.nih.gov. U.S. National Library of Medicine. Retrieved 13 December 2018.
  46. National Center for Biotechnology Information. PubChem Compound Database; CID=2732, https://pubchem.ncbi.nlm.nih.gov/compound/2732 (accessed July 29, 2018).
  47. Singer, Jeff M., Michael J. O'Hare, Carl R. Rehm, and John E. Zarembo. "Chlorthalidone." In Analytical Profiles of Drug Substances, vol. 14, pp. 1-36. Academic Press, 1985. https://doi.org/10.1016/S0099-5428(08)60575-4
  48. Cadwallader AB, de la Torre X, Tieri A, Botrè F (September 2010). "The abuse of diuretics as performance-enhancing drugs and masking agents in sport doping: pharmacology, toxicology and analysis". Br. J. Pharmacol. 161 (1): 1–16. doi:10.1111/j.1476-5381.2010.00789.x. PMC 2962812. PMID 20718736.
  49. "Yasir Shah provisionally suspended after failed drugs test". BBC News. December 27, 2015.
This article is issued from Wikipedia. The text is licensed under Creative Commons - Attribution - Sharealike. Additional terms may apply for the media files.